evaluation of novosorb™ biodegradable …...faculty of science, engineering and technology...

Evaluation of Novosorb™ Biodegradable

Polyurethanes: Understanding

Degradation Characteristics

A thesis submitted in fulfilment of the requirements for the degree of

Doctor of Philosophy

by

Lisa Tatai

BSc (Honours) Biotechnology

Faculty of Science, Engineering and Technology

Swinburne University of Technology 2014

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Abstract

This study aims to investigate the in-vitro degradation of novel synthetic biodegradable

polyurethanes primarily developed for biomedical applications. A series of

thermoplastic polyurethanes were synthesised with varying hard and soft segment ratios

and using novel chain extenders, namely ethyl lysine diisocyanate or hexamethylene

diisocyanate. On the other hand, thermoset polyurethanes were also prepared using

ethyl lysine diisocyanate in varying ratios and using different polyols. These

polyurethanes were subsequently characterised by gel permeation chromatography

(thermoplastics only), tensile strengths and differential scanning calorimetry. The main

results evidenced the existence of several categories of materials differing vastly in

molecular weights, mechanical strengths and thermal properties.

The different series of polyurethanes were then subjected to in vitro degradations, using

phosphate buffered saline solutions to mimic biological conditions, for a period of one

year and then analysed for mass loss, molecular weight loss and changes in mechanical

and thermal properties. For the thermoplastics, it was shown that the extent of

degradation was very much dependent on the types of chain extender and diisocyanate.

Polyurethanes incorporating degradable chain extenders into the hard segments were

found to degrade faster than those with non-degradable chain extenders.

The extent of degradation of the thermosets appeared to depend largely on the type of

polyol used during the synthesis of the materials. Polymers containing higher

proportions of polyglycolic acid exhibited the fastest degradation, most probably due to

being significantly more hydrophilic and, hence, possess a higher susceptibility to

undergo hydrolysis. On the other hand, polymers with higher proportions of mandelic

acid were shown to degrade the slowest.

For both thermoplastic and thermoset polyurethanes, degradation was evidenced by

variations in mass number, weight losses and changes in mechanical strengths and

thermal properties.

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Finally, in an attempt to determine the nature of the by-products generated by the

degradation process, samples of the recirculated physiological fluids were analysed by

using amine concentration analysis (ninhydrin assay), high performance liquid

chromatography, nuclear magnetic resonance and mass spectrometry.

Both thermoplastic and thermoset polyurethanes were shown to liberate amines during

the in vitro degradation experiments. Polyurethanes incorporating degradable chain

extenders into the hard segments were found to liberate a considerably higher

concentration of amines than those with non-degradable chain extenders. Thermoset

polymers with higher proportions of polyglycolic acid also liberated a higher

concentration of amines that polymers with lower proportions of polyglycolic acid.

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Acknowledgments

I would like to thank PolyNovo Biomaterials Pty Ltd and the Division of Molecular

Science, CSIRO (Commonwealth Scientific and Industrial Research Organisation)

where all the polymer work was carried out, for allowing me to work as a student in

their laboratories under the supervision of Dr Thilak Gunatillake. I especially thank Drs

Thilak Gunatillake, Tim Moore, Raju Adhikari and Ian Griffiths for their supervision,

guidance and support.

A would also like to thank late Professor Greg Lonergan (1957-2006) from Swinburne

University of Technology for allowing me to take on this project and Dr Ranjith

Jayasekara for his role as an associate supervisor. Thank you also to Chris Key for his

help in the Swinburne Laboratories. I especially thank Dr François Malherbe for his

enduring commitment and support over the many years.

I would also like to acknowledge the work done by Jason Dang and Iain Cooke from

Chemical Analysis on the HPLC-NMR analysis of degradation products.

Finally, I’d like to thank my husband and family for making this post-graduate degree

possible by way of their support and understanding throughout my studies.

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Declaration

This thesis contains no material which has been accepted for the award of any other

degree or diploma, except where due reference is made in the text of the thesis. To the

best of my knowledge, this thesis contains no material previously published or written

by another person except where due reference is made in the text of the thesis.

Signature of Candidate:

Date: 28th November 2014

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Research Publications and Awards

Journal Articles

Tatai L, Moore T.G, Adhikari R, Malherbe F, Jayasekara R, Griffiths I, Gunatillake

P.A, Thermoplastic biodegradable polyurethanes: The effect of chain extender structure

on properties and in-vitro degradation. Biomaterials 2007; 28: 5407-5417

Adhikari R, Gunatillake P.A, Griffiths I, Tatai L, Wickramaratna M, Houshyar S,

Moore T.G, Mayadunne R.T.M, Field J, McGee M, Carbone T, Biodegradable

injectable polyurethanes: synthesis and evaluation for orthopaedic applications.

Biomaterials 2008; 29:3762-3770

Conference Proceedings

Tatai L, Moore T.G, Adhikari R, Jayasekara R, Malherbe F, Gunatillake PA, Effect of

chain extender structure on in-vitro degradation of NovoSorbTM polyurethane. 17th

Annual Conference, Australasian Society for Biomaterials. 2007. p. 37 – Oral

Presentation

Tatai L, Moore T.G, Adhikari R, Malherbe F, Jayasekara R, Griffiths I, Gunatillake P.A

Effect of Chain Extender Structure on In-vitro Degradation of Thermoplastic

Polyurethanes, 8th World Biomaterials Congress, Amsterdam, Netherlands, May 28th –

June 1st , 2008 – Poster Presentation

Awards

Commendation for Student Presentation - Annual Conference, Australasian Society for

Biomaterials, 2007

Table of Contents

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TABLE OF CONTENTS

1 INTRODUCTION ............................................................................................................ 1

Overview ........................................................................................................................................1 1.1

Aims of the Thesis ...........................................................................................................................2 1.2

Outline of the Study and Thesis Organisation ................................................................................4 1.3

2 LITERATURE REVIEW ................................................................................................. 6

Overview ........................................................................................................................................6 2.1

Polyurethanes .................................................................................................................................7 2.2

Thermoplastic Polyurethanes – Chemistry and Properties .............................................................9 2.3

2.3.1 Structure ................................................................................................................................9

2.3.2 Synthesis ..............................................................................................................................10

2.3.3 Morphology .........................................................................................................................10

2.3.4 Polyols/Macrodiols – Soft Segments ....................................................................................11

Poly(ε-caprolactone) (PCL) ............................................................................................................12

Poly(glycolic acid) (PGA) ................................................................................................................12

Poly(lactic acid) (PLA) ....................................................................................................................13

2.3.5 Chain Extenders and Diisocyanates – Hard Segments ...........................................................13

Chain Extenders ............................................................................................................................13

Diisocyanates ................................................................................................................................14

Hexamethylene diisocyanate (HDI) ...........................................................................................14

Ethyl lysine diisocyanate (ELDI) .................................................................................................15

Thermoset Polyurethanes – Chemistry and Properties ................................................................15 2.4

2.4.1 Structure ..............................................................................................................................15

2.4.2 Synthesis ..............................................................................................................................16

2.4.3 Morphology .........................................................................................................................17

2.4.4 NovoSorbTM Thermoset Polyurethanes ................................................................................17

Biodegradable Polyurethanes .......................................................................................................20 2.5

2.5.1 PCL-based Biodegradable Polyurethanes .............................................................................21

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2.5.2 PCL with Degradable Chain Extender Structures ...................................................................23

2.5.3 PLA-based Biodegradable Polyurethane ...............................................................................24

2.5.4 PGA and PLGA-based Biodegradable Polyurethane ..............................................................26

2.5.5 PEG/PEO-based Biodegradable Polyurethanes .....................................................................27

In vitro vs. in vivo Degradation .....................................................................................................28 2.6

By-products of Degradation and Their Toxicity ............................................................................31 2.7

Summary of Current Literature .....................................................................................................33 2.8

3 MATERIALS AND METHODS ................................................................................... 35

Preparation of Polyurethane Starting Materials ...........................................................................35 3.1

Synthesis of the Degradable Chain Extenders ..............................................................................35 3.2

Polyol Synthesis ............................................................................................................................36 3.3

3.3.1 PE-GA Synthesis (MW 399) ...................................................................................................36

3.3.2 PE-DLLA Synthesis (MW 434) ...............................................................................................36

3.3.3 PE-LLA:MA (1:1) Synthesis (MW 320) ...................................................................................37

3.3.4 Fundamental Physico-chemical Properties ...........................................................................37

Acid number ..................................................................................................................................37

Hydroxyl number ...........................................................................................................................37

Molecular weight ..........................................................................................................................38

Water content ...............................................................................................................................38

Polyurethane Nomenclature ........................................................................................................38 3.4

3.4.1 Thermoplastic Polyurethane Series ......................................................................................38

3.4.2 Thermoset Polyurethane Series ...........................................................................................40

Polyurethane Synthesis ................................................................................................................42 3.5

3.5.1 General Procedure for Thermoplastic Polyurethane .............................................................42

3.5.2 General Procedure for Thermoset Polyurethane ..................................................................42

Polyurethane Processing and Sample Preparation .......................................................................43 3.6

3.6.1 Thermoplastic Polyurethane Processing ...............................................................................43

3.6.2 Thermoset Polyurethane Processing ....................................................................................43

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Gel Permeation Chromatography (GPC) .......................................................................................44 3.7

Differential Scanning Calorimetry (DSC) .......................................................................................44 3.8

Fourier Transform Infrared (FTIR) .................................................................................................45 3.9

Tensile Testing – Instron ..........................................................................................................45 3.10

Proton Nuclear Magnetic Resonance (1H-NMR) .......................................................................46 3.11

High Performance Liquid Chromatography (HPLC) ..................................................................46 3.12

3.12.1 Analytical HPLC ................................................................................................................46

3.12.2 Preparative HPLC .............................................................................................................47

Gas Chromatography Mass Spectrometry (GC-MS) .................................................................47 3.13

LC-NMR ....................................................................................................................................48 3.14

Ion Chromatography (IC) ..........................................................................................................48 3.15

Ninhydrin Assay .......................................................................................................................49 3.16

Accelerated Solvent Extraction (ASE) .......................................................................................49 3.17

Rotary Evaporation ..................................................................................................................49 3.18

Polyurethane Water Absorption Tests .....................................................................................50 3.19

In vitro Degradation Procedures ..............................................................................................50 3.20

3.20.1 Real-Time in vitro Degradation ........................................................................................50

3.20.2 Accelerated in vitro Degradation .....................................................................................51

Accelerated degradation at 100C .................................................................................................51

Accelerated degradation at 70C ...................................................................................................51

Accelerated degradation under acidic and alkaline conditions ......................................................52

4 CHARACTERISATION OF THE SYNTHETIC POLYURETHANES ..................... 53

Introduction ..................................................................................................................................53 4.1

Characterisation of the Thermoplastic Polyurethanes .................................................................57 4.2

4.2.1 Average Number Molecular Weights....................................................................................57

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4.2.2 Mechanical Properties .........................................................................................................62

4.2.3 Thermal Properties ..............................................................................................................64

4.2.4 Water Absorption ................................................................................................................68

Characterisation of Thermoset Polyurethanes .............................................................................71 4.3

4.3.1 Mechanical Properties .........................................................................................................72

4.3.2 Thermal Properties ..............................................................................................................76

4.3.3 Water Absorption ................................................................................................................79

Summary ......................................................................................................................................81 4.4

4.4.1 Thermoplastic Polyurethanes (series 1 and 2) ......................................................................81

4.4.2 Thermoset Polyurethanes (series 4 and 5) ...........................................................................83

5 IN VITRO DEGRADATION OF THERMOPLASTIC POLYURETHANES:

EFFECTS ON PHYSICO-CHEMICAL PROPERTIES ....................................................... 84

Introduction ..................................................................................................................................84 5.1

Materials and Methods ................................................................................................................87 5.2

Results and Discussion ..................................................................................................................89 5.3

5.3.1 Mass Loss and Decrease in Molecular Weight ......................................................................89

5.3.2 Mass loss..............................................................................................................................95

5.3.3 Changes in Mechanical Properties ........................................................................................99

5.3.4 Changes in Thermal Properties ........................................................................................... 101

5.3.5 Accelerated Solvent Extraction ........................................................................................... 104

Summary .................................................................................................................................... 107 5.4

6 IN VITRO DEGRADATION OF THERMOSET POLYURETHANES .................. 110

Physico-chemical Properties of Degraded Polymers................................................................... 110 6.1

6.1.1 Materials and Methods ...................................................................................................... 112

6.1.2 Mass Loss ........................................................................................................................... 114

6.1.3 Changes in Mechanical Properties ...................................................................................... 120

Mechanical properties for Series 4 polyurethanes ....................................................................... 121

Mechanical properties for Series 5 polyurethanes ....................................................................... 125

6.1.4 Changes in Thermal Properties ........................................................................................... 128

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Thermal traces for Series 4 .......................................................................................................... 129

Glass transition for Series 5 polyurethanes .................................................................................. 132

6.1.5 Accelerated Degradation at 70°C........................................................................................ 134

6.1.6 Summary ............................................................................................................................ 135

‘THE EFFECT OF CHANGING RATIOS OF TWO DIFFERENT POLYOLS ON

PROPERTIES AND DEGRADATION’ ............................................................................... 135

The Effects of Crosslink Density .................................................................................................. 136 6.2

6.2.1 Methods ............................................................................................................................ 137

6.2.2 Real Time Degradation ....................................................................................................... 138

6.2.3 Accelerated Degradation .................................................................................................... 140

The effect of increased temperature ........................................................................................... 140

The effect of pH on polyurethane degradation ............................................................................ 141

6.2.4 Summary ............................................................................................................................ 143

7 IN VITRO DEGRADATION OF THERMOPLASTIC AND THERMOSET

POLYURETHANES: PRELIMINARY ANALYSIS OF THE DEGRADATION

PRODUCTS ......................................................................................................................... 144

Introduction ................................................................................................................................ 144 7.1

Materials and Methods .............................................................................................................. 147 7.2

Results and Discussion ................................................................................................................ 147 7.3

7.3.1 Ninhydrin Assay ................................................................................................................. 147

Thermoplastic polyurethane series 1-3 ........................................................................................ 147

Thermoset polyurethane series 4 and 5....................................................................................... 154

7.3.2 Identification of Polyurethane Degradation Products ......................................................... 157

Analytical HPLC of the Degradation Products .............................................................................. 158

Preparative HPCL analysis of degradation products ..................................................................... 160

LC-MS Analysis of degradation products ...................................................................................... 160 1H-NMR of isolated degradation products ................................................................................... 161

7.3.3 Conclusion ......................................................................................................................... 163

8 CONCLUSION .............................................................................................................. 164

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Overview .................................................................................................................................... 164 8.1

Main properties of synthesised polymers .................................................................................. 165 8.2

In vitro degradation of Series 1-3 ............................................................................................... 166 8.3

In vitro degradation of Series 4 and 5 ......................................................................................... 168 8.4

Future Work................................................................................................................................ 169 8.5

REFERENCES...................................................................................................................... 170

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LIST OF FIGURES Figure 1.1 Flowchart outlining the structure of the thesis. .........................................................................5

Figure 2.1 Formation of a urethane linkage (circled). ................................................................................7

Figure 2.2 The main areas of application of modern polyurethanes. ..........................................................7

Figure 2.3. (a) Reaction of diisocyanate with a chain extender to form hard segment – hard segment (red)

and polyol (blue) reacted to form TPU exhibiting two-phase morphology, (b) two-phase

morphology with hard (red) and soft segment (blue) domains. .........................................................9

Figure 2.4 TPU two-phase morphology with hard and soft segment domains – Soft segment domain

magnified and highlighted in red. .................................................................................................. 10

Figure 2.5 Chemical structure of Poly(glycolic acid) (PGA), Poly(ε-caprolactone) (PCL) and Poly(lactid

acid) (PLA) ................................................................................................................................... 12

Figure 2.6 Chemical structure of ethylene glycol (EG), lactic acid-ethylene glycol (LA-EG) and 1,4-

butanediol (BDO) chain extenders. ................................................................................................ 13

Figure 2.7 Structure of aliphatic diisocyanates (a) ethyl lysine diisocyanate (ELDI) (b) hexamethylene

diisocyanate (HDI) and (c) NCO functional group. ........................................................................ 14

Figure 2.8 Basic morphology of (a) amorphous thermoset polyurethane, and (b) of thermoplastic

polyurethane with semicrystalline and amorphous domains. .......................................................... 16

Figure 2.9 Formation of thermoset (cross-linked) polyurethane NovoSorbTM. Starting with the formation

of prepolymer A with pentaerythritol functionalised with ELDI. Prepolymer A is reacted with

prepolymer B (a polyol) and a cross-linked network is formed. ..................................................... 18

Figure 2.10 Formation of pentaerythritol-L-lactic acid (PE-LLA) (1:4). .................................................. 19

Figure 4.1 Graph summarising the trends observed in weight average molecular weights for series 1 and 2

polyurethanes. ............................................................................................................................... 58

Figure 4.2 Tensile strength (---) and modulus ( ) for series 1 and 2 polymers with 30, 50 and 70% HS. 62

Figure 4.3 DSC traces for Series 1 polyurethanes. The dotted line ellipse indicates the Tg and the full line

one the Tm. .................................................................................................................................... 64

Figure 4.4 DSC traces for Series 2 polyurethanes. The dotted line ellipse indicates the Tg and the full line

one the Tm. .................................................................................................................................... 65

Figure 4.5 Evolution of Tg with increasing hard segment in series 1 and 2.............................................. 66

Figure 4.6 DSC traces for Series 3 polyurethanes. Note: All polymers in this series have 30% hard

segment. ........................................................................................................................................ 67

Figure 4.7 Water absorption for series 1 and 2 after 24 h incubation at 37°C in PBS. .............................. 68

Figure 4.8 Water absorption data for Series 3 after 24h incubation at 37°C in PBS. ................................ 70

Figure 4.9 Polyols used in Series 4 & 5 polyurethanes. ........................................................................... 71

Figure 4.10 Modulus and tensile strength for series 4 and 5 polyurethanes. ............................................. 72

Figure 4.11 Percentage Elongation for series 4 and 5 polyurethanes........................................................ 74

Figure 4.12 Effect of polyol structure on mechanical properties. ............................................................. 75

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Figure 4.13 Plot of glass transition temperature against the percentage of GA in Series 4 & 5

polyurethanes. ............................................................................................................................... 76

Figure 4.14 Structures of the linear PCL and the branched PCL4 polyols used in Series 6. ..................... 77

Figure 4.15 Evolution of Tg with increasing percentage of PCL. ............................................................. 78

Figure 4.16 Water absorption data for series 4 and 5 after 24 h incubation in PBS at 37°C. ..................... 79

Figure 4.17 Water absorption data for Series 6 after 24 h incubation in PBS at 37°C. ............................. 80

Figure 5.1 Flowchart indicating the techniques used to analyse the degraded polymers. .......................... 85

Figure 5.2 (a) Formation of a urethane bond, (b) an ester bond, and (c) ELDI & LAEG with ester and

urethane bonds. ............................................................................................................................. 86

Figure 5.3 Percentage molecular weight (number average) loss at times t = 0, 90, 180 and 365 days post-

degradation at 37°C in PBS buffer (pH 7.4) for Series 1. ............................................................... 89

Figure 5.4 Percentage molecular weight (number average) loss at times t = 0, 90, 180, 365 days post-


Figure 5.5 Percentage molecular weight (number average) loss at times t = 0, 90, 180, 365 days post-


Figure 5.6 Correlation between change in molecular weight and overall mass loss.................................. 93

Figure 5.7 Percentage residual mass after in vitro degradation for Series 1. ............................................ 95

Figure 5.8 Percentage residual mass for Series 2 after 365 days in vitro degradation. .............................. 96

Figure 5.9 Percentage residual mass for Series 3 after 365 days in vitro degradation. .............................. 98

Figure 5.10 Modulus for series 1-3 at ambient temperature and at 37C after soaking 24h in PBS. ......... 99

Figure 5.11 Tensile strength for series 1-3 at ambient temperature and at 37°C after soaking 24h in PBS.

.................................................................................................................................................... 100

Figure 5.12 Thermograms for series 1 and 2 polymers pre and post-degradation. .................................. 101

Figure 5.13 Thermograms for ELDI-LAEG-30 and ELDI-LAEG-70 pre- and post-degradation. .......... 102

Figure 5.14 Thermogram for ELDI-0 after 365 days in vitro degradation compared to neat PCL1000. .. 103

Figure 5.15 (a) IC traces of HDI-EG-30 extracts, and (b) concentrations of chloride and phosphate ions

pre- and post-degradation. ........................................................................................................... 105

Figure 5.16 Ester bond hydrolysis resulting in the addition of one water molecule. ............................... 106

Figure 6.1 Schematic diagram for the study of series 4-6 ...................................................................... 110

Figure 6.2 Star polyols prepared from pentaeythritol (PE). ................................................................... 111

Figure 6.3 Degradation behaviours of polyurethanes with different polyols. ......................................... 114

Figure 6.4 Series 4 - Percentage mass remaining after 365 days in vitro degradation............................. 115

Figure 6.5 Series 5 - Percentage mass remaining after 365 days in vitro degradation............................. 116

Figure 6.6 Degradation rates for series 4 and 5 polyurethanes. .............................................................. 117

Figure 6.7 Calculated degradation rates fro series 4 and 5 polyurethanes vs. percentage of GA. ............ 118

Figure 6.8 Schematic representation of the mixed polymer. .................................................................. 119

Figure 6.9. Overall degradation rate and degradation rate from the onset point for series 4 and 5

polyurethanes. ............................................................................................................................. 120

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Figure 6.10 Modulus for thermoset polyurethane Series 4 over a period of 90 days in vitro degradation.

.................................................................................................................................................... 121

Figure 6.11 Tensile strength for thermoset polyurethane Series 4 over a period of 90 days in vitro

degradation.................................................................................................................................. 123

Figure 6.12 Elongation for thermoset polyurethane Series 4 over a period of 90 days in vitro degradation.

.................................................................................................................................................... 124


(Note: Zero values indicate that the materials were not testable) .................................................. 125

Figure 6.14 Tensile strength for thermoset polyurethane Series 5 after 90 days in vitro incubation (Note:

Zero values indicate that the materials were not testable). ............................................................ 127


.................................................................................................................................................... 128

Figure 6.16 DSC thermograms for Series 4 polyurethane materials pre-degradation and at 42 and 90 days

post-degradation. ......................................................................................................................... 129





Figure 6.19 Mass loss for selected samples of series 4 and 5 under accelerated conditions. ................... 134

Figure 6.20 Schematic diagram for Series 6 polyurethane ..................................................................... 136

Figure 6.21 Series 6 polyurethanes degradation over 365 days. ............................................................. 138

Figure 6.22 Series 6 polyurethane degradation – mass remaining after 365 days of in vitro degradation.

.................................................................................................................................................... 139

Figure 6.23 Mass loss for Series 6 polyurethane materials at 70ºC. ....................................................... 140

Figure 6.24 Mass loss for selected Series 6 polyurethanes under acid in vitro conditions (pH 2). .......... 141

Figure 6.25 Mass loss for selected series 6 polyurethanes under alkaline in vitro conditions (pH 11). ... 142

Figure 6.26 Mass loss for selected series 6 polyurethane materials under acidic and alkaline conditions at

42 days in vitro. ........................................................................................................................... 143

Figure 7.1 Schematic representation of the analysis of degradation by-products. ................................... 145

Figure 7.2 A trimer (ELDI-LAEG-ELDI) joined by urethane and ester bonds with flanking secondary

amine groups (circled). ................................................................................................................ 146

Figure 7.3 Amine detection for (A) Series 1 and (B) Series 2 polyurethanes over 365 days in vitro

degradation.................................................................................................................................. 148

Figure 7.4 Predicted against actual amine concentration for Series 1 ..................................................... 149

Figure 7.5 EG-ELDI-EG illustrating the formation of terminal amino groups by hydrolytic degradation

.................................................................................................................................................... 150

Figure 7.6 Amine detection for Series 3 polyurethanes during in vitro degradation ............................... 151

Figure 7.7 Comparing mass loss with amine concentration for series 1-3 polyurethanes ....................... 152

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Figure 7.8 Amine concentrations for Series 4 (top) and Series 5 (bottom) polyurethanes over 365 days in

vitro degradation. ........................................................................................................................ 154

Figure 7.9 Comparing mass loss with amine concentration for series 4 and 5 polyurethanes ................. 156

Figure 7.10 Experimental approach to separate and identify by-products of in vitro degradation. .......... 157

Figure 7.11 HPLC profile for ELDI-LAEG-100 polymer after complete degradation ........................... 158

Figure 7.12 1H NMR of Fraction 12 (top) and Fraction 5 (bottom). ....................................................... 161

Figure 7.13 Simulated 1H NMR of lactic acid. ...................................................................................... 162

Figure 7.14 1H NMR simulated spectrum of EG-ELDI-EG .................................................................. 163

List of Tables

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LIST OF TABLES

Table 2.1 Biomedical applications of polyurethanes. ................................................................................8

Table 3.1 Nomenclature and abbreviations of Series 1 thermoplastic polyurethanes. ............................... 39



Table 3.4 Nomenclature and abbreviations of Series 4 thermoset polyurethanes. .................................... 40



Table 3.7 Glossary of abbreviations ........................................................................................................ 41

Table 3.8 Real-time and accelerated degradation sampling times, temperature and pH. ........................... 52

Table 4.1 Analytical techniques used for the characterisation of selected polymers. ................................ 53

Table 4.2 Nomenclature and abbreviations for series 1-3 thermoplastic polyurethanes. ........................... 54

Table 4.3 Nomenclature & abbreviations for series 4-6 thermoset polyurethanes. ................................... 56

Table 4.4. Number and weight average molecular weights, dispersity, mechanical properties and thermal

characteristics of series 1- 3 thermoplastic polyurethanes. ............................................................. 59

Table 4.5 Mechanical and thermal properties of Series 4 & 5 thermoset polyurethanes. .......................... 71

Table 4.6 Thermal properties of thermoset polyurethane Series 6............................................................ 78

Table 5.1 Nomenclature and abbreviations of series 1-3 thermoplastic polyurethanes. ............................ 88

Table 5.2 Number average molecular weight change and Mn percentage loss for Series 1-3 polyurethanes

over 365 days in vitro degradation. ................................................................................................ 92

Table 5.3 Percentage molar ratio of urethane and ester bonds for Series 3 polymers. .............................. 94

Table 6.1 Series 4 - Thermoset polyurethanes ....................................................................................... 113

Table 6.2 Series 5 - Thermoset polyurethanes ....................................................................................... 113

Table 6.3 Glass transition temperature for Series 4 polyurethanes pre-degradation (t = 0) and at 42 and 90

days exposed to in vitro conditions. ............................................................................................. 131

Table 6.4 Glass transition temperature (midpoint) for Series 5 polyurethane materials pre-degradation (t =

0) and at 42 and 90 days exposed to in vitro conditions. .............................................................. 133

Table 6.5Polyurethane formulations for Series 6. .................................................................................. 137

Table 7.1 List of predicted by-products of the polymer ELDI-LAEG-100. ............................................ 159

Table 7.2 Possible structures of some degradation by-products. ............................................................ 160

List of Tables

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ABBREVIATIONS [ ] Concentration

ASE Accelerated Solvent Extraction

ASTM American Standard Testing Method

BDI 1,4-butanediol diisocyanate

BDO 1,4-butane diol

DCE Degradable Chain Extenders

DMF Dimethyl formamide

DMSO Dimethyl sulfoxide

DSC Differential Scanning Calorimetry

EG Ethylene glycol

ELDI Lysine ethyl ester diisocyanate

FDA Food and Drug Administration

GA Glycolic acid

GC-MS Gas Chromatography – Mass Spectroscopy

GPC Gel Permeation Chromatography

HDI Hexamethylene diisocyanate

HNMR 1Hydrogen Nuclear Magnetic Resonance

HPLC High Performance Liquid Chromatography

IC Ion Chromatography

IPDI Isophorone diisocyanate

IR Infrared spectroscopy

LA Lactic acid

LA-EG 2-Hydroxy-propionic acid 2-hydroxy-ethyl ester

LLA L-Lactic Acid

LC-NMR Liquid Chromatography – Nuclear Magnetic Resonance

MA Mandelic Acid

Mn Number average molecular weight

MP Peak Molecular Weight Average (GPC)

MS-MS Tandem mass spectrometer

Mw Weight average molecular weight

PCL Poly-ε-caprolactone

PE Pentaerythritol

PEG Polyethylene glycol

PE-LLA Pentaerythritol – L-Lactic Acid

PGA Poly(glycolic acid)

List of Tables

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PEO Polyethylene Oxide

PLA Poly(lactic acid)

PLLA Poly-L-lactide

PDLLA Poly-DL-lactide

PLGA Poly Lactic Acid- Glycolic Acid

PPO Polypropylene

PTMO Poly(tetramethylene oxide)

PU Polyurethane

Tg Glass Transition Temperature

TS Tensile Strength

THF Tetrahydrofuran

TMDI Methylene diphenyl diisocyanate

TPU Thermoplastic Polyurethane

Chapter One

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1 INTRODUCTION

OVERVIEW 1.1

For a long time, one of the main objectives of polymer scientists working in the area of

biomaterials has been to design products that would not be extremely resistant to

degradation in a physiological environment and, thus, remain unaltered when placed

within the human body. However, due to their intrinsic properties, which are often a

direct consequence of the requirements for them to be biocompatible, most of these

polymers are prone to oxidation, hydrolysis or enzymatic degradations, and, thus, they

generally have limited longevity in physiological media. These problems have

galvanised the development of even tougher materials that would have a longer lifetime

when used in vivo.

However, in many other areas of medical technology, there are increased demands for

materials with antagonistic properties: nowadays, with significant advances in

technologies, more and more applications require polymers that have the propensity to

slowly degrade inside the body. In this regard, we have seen in recent years the

development of research focusing on designing novel polymers that are programmed to

degrade following strict patterns, depending on the purpose of the new devices

(controlled drug release, scaffold for tissue engineering, sutures, etc.) With these new

applications, there comes a need to control the kinetics of the degradation process, as

well as to ensure that the by-products of in vivo degradation are non-toxic. Aside from

being biocompatible and not eliciting an immune response, the ideal materials must also

be biodegradable and bioresorbable, which means that the products resulting from their

degradation can be assimilated back in the body and metabolised without causing harm.

Chapter One

2 | P a g e

The general strategy in developing this new generation of polymers is as follows: the

degradation can take place through a variety of mechanisms but the final objective is

that the long polymeric chains would be broken down into much smaller moieties. On

the other hand, in order to allow a particular device to perform a certain function on a

temporary basis, the polymer should be able to maintain most of its mechanical

properties, despite the fact that it is undergoing gradual degradation. In this respect, one

of the major aims is to conceive synthetic pathways that will afford polymers with

tuneable properties and degradation rates by controlling critical parameters such as;

crystallinity, molecular weight and hydrophobicity (Suggs and Mikos, 1996).

There are numerous hurdles to overcome for these goals to be achieved due to the fact

that degradation rates are generally dependent on the location in the body: the

physiological environment surrounding the polymer will vary accordingly. The

mechanisms involved in the degradation processes are also crucial in determining the

mechanical integrity of the resorbable polymers: i.e., whether degradation occurs

mainly through surface or bulk erosion. A thorough understanding of the major

parameters that regulate erosion, such as bond cleavage or the solubilisation and

dispersion of the by-products, is primordial to the development of novel materials

(Azevedo & Reis, 2004).

AIMS OF THE THESIS 1.2

This study aims to investigate the in vitro degradation of a series of novel biodegradable

polyurethanes developed primarily for biomedical applications. The polyurethanes have

been formulated to represent the main chemical and structural features of NovoSorb ™,

a class of proprietary polymers specifically designed to meet the strictest regulatory

requirements for new and emerging technologies, and to bridge technology gaps not

achievable with commonly available biodegradable materials.

The main objectives are to

synthesise and characterise a series of novel thermoplastic and thermoset

polyurethanes with formulae based on NovoSorbTM,

study the effects of in vitro degradation on these polymers,

analyse and identify the degradation products liberated during degradation.

Chapter One

3 | P a g e

Since NovoSorb™ polyurethanes are predominantly polyester based, poly(ester

urethanes) will be the primary focus of this study. Within each series, systematic

changes in the chemistry of the materials are envisaged in the view of imparting

significant differences to individual polymers and generating meaningful data in the

degradation profiles. The investigations focussed on changes in thermal and mechanical

properties, and variations in polymer masses and molecular weights, which would occur

as a result of prolonged exposure to simulated biological environments.

In the work described, Series 1-3 polyurethanes are thermoplastics and Series 4-6 are

thermosets. The rationale behind the synthesis of Series 1 and 2 was essentially to

compare the properties and degradation rates of polyurethanes with a degradable chain

extender (DCE) versus those containing a non-degradable chain extender (non-DCE),

with variable contents in hard segment. As such, two effects could be measured: the

importance of using DCE vs. non-DCE and, with the non-DCE polymers, how the

relative contents in hard segment could affect the physico-chemical properties of the

polymers. Polycaprolactone (PCL) was chosen as the soft segment because of its high

hydrophobicity and known slow degradation rate. By minimising the contribution of the

soft segment to overall degradation, mass losses observed during the studies can be

attributed solely to the hard segment.

Series 3 polyurethanes were designed to investigate the effects of the nature of the

diisocyanate on the properties and degradation rate of the polyurethanes. Two different

components, namely hexamethylene diisocyanate (HDI) and ethyl lysine ester

diisocyanate (ELDI) with either non-DCE or DCE were used. As it will be discussed in

the next chapter, there is a substantial difference between the structures of these two

diisocyanates, with HDI being linear and highly symmetrical while ELDI bears a side

branch, which decreases the symmetry and introduces a steric factor.

The main idea behind the synthesis of Series 4 and 5 polyurethanes was to determine

how the ratio of two different polyols would affect the physico-chemical properties and

degradation rates of the resulting polymers. The data thus obtained can then be

compared within each series and against each other. Since both series contain increasing

quantities of the relatively fast degrading glycolic acid-based polyol, the effect of

increasing its content can be investigated.

Chapter One

4 | P a g e

OUTLINE OF THE STUDY AND THESIS ORGANISATION 1.3

The next chapter will provide an overview of the literature on polyurethanes and their

applications, followed by Chapter 3: Materials and Methods, which will describe the

synthesis and characterisation of the various polymer series. This section will also

provide a brief description of the analytical techniques employed to analyse the

degradation products liberated during in vitro degradation.

Chapter 4 reports on the physico-chemical characteristics of polyurethanes prior to the

in vitro degradation tests. Six series of polyurethanes were synthesised and,

subsequently, chatacterised using a variety of analytical techniques to determine their

properties at time zero. Since the main objective of this study is to examine the

degradation properties of polyurethanes, these results are reported and discussed in

separate sections.

Chapters 5-7 are structured as follows:

1. Introduction

2. Overview of methods and materials with reference to Chapter 2

3. Results and discussions

4. Summary of findings

The study of polyurethane degradation will be subdivided into two parts. Firstly, the

full characterisation of the residual polyurethane after in vitro degradation tests, and,

secondly, the isolation and analysis of by-products formed during in vitro degradation.

Figure 1.11 (next page) illustrates how this is dealt with.

Chapter 5 reports on series 1-3 thermoplastics, while Chapter 6 details the investigations

on series 4-6 thermoset polyurethanes. Chapter 7 examines the degradation products

liberated during in vitro degradation of selected materials. In this section, the soluble

by-products accumulated are analysed using a number of established techniques.

Finally, Chapter 8 provides a summary of the main conclusions and potential future

work in this area.

Chapter One

5 | P a g e

Figure 1.1 Flowchart outlining the structure of the thesis.

Chapter Two

6 | P a g e

2 LITERATURE REVIEW

OVERVIEW 2.1

The increased interest in polyurethanes for biomedical applications is related to their

proven mechanical properties, excellent biocompatibility, and structural versatility. The

variety of chemical functionalities that can be built into the polymer chain offers

potentials for the design of polyurethanes that are degradable in a biological

environment. In designing these biodegradable polyurethanes, the chemical structures of

their two major constituents, the ‘diisocyanate’ and the ‘polyol’, play an essential role.

Through the judicious choice of these components, as well as their relative proportions,

polyurethanes can be tailored to possess a range of mechanical properties and

biodegradation characteristics that would suit different physiological environments, and,

hence, considered as potential candidates for diverse biomedical applications.

The in vitro degradation of common polymers such as polyesters, for example

poly(lactic acid) and poly(glycolic acid) and their copolymers, has been extensively

explored and a relatively clear understanding of the mode and kinetics of degradation,

and the nature of their resulting products has been reported (Liebmann-Vinson &

Timmins 2003; Timmins & Liebmann-Vinson 2003). On the other hand, the in vitro

degradation of biocompatible polyurethanes has been explored to a lesser extent, due to

their more complex structure, and their modes of degradation have been rather difficult

to elucidate. As a result, there is a need for more detailed studies in this area to better

understand the mechanism of the degradation process and to determine the exact nature

of the degradation products in order to assess the adequacy and safety of these novel

materials for biomedical applications.

Chapter Two

7 | P a g e

POLYURETHANES 2.2

In essence, polyurethanes are polymeric materials consisting of a chain of organic sub-

units joined by urethane (carbamate) linkages. They are formed by the reaction between

a monomer containing at least two isocyanate functional groups (diisocyanate) with

another monomer/oligomer containing at least two hydroxyl groups (diols or polyols),

as illustrated in Figure 2.1.

Figure 2.1 Formation of a urethane linkage (circled).

Polyurethanes have an extremely wide range of physical properties from soft

thermoplastic elastomers to hard, brittle and highly cross-linked thermosets. Figure 2.2

illustrates the main fields where polyurethanes are used.

Figure 2.2 The main areas of application of modern polyurethanes.

HO-R-OH

+

OCN-R'-NCO

OCNR'

N OR

OH

O

H

Chapter Two

8 | P a g e

NovoSorbTM polyurethanes generally fall under the umbrella of ‘other uses’ as they are

designed and formulated primarily for use as biomedical implants and devices. Table

2.1 lists some biomedical applications of conventional polyurethanes (Gunatillake &

Adhikari 2003).

Table 2.1 Biomedical applications of polyurethanes.

Cardiovascular Reconstructive Surgery Surgical Aids

-Vascular grafts and patches -Cardiac valves -Vascular prostheses -Cardiac-assist pump bladder

-Skin dressings and tapes -Suture materials -Breasts implants -Orthopaedic splints

-Bloodbags, closures -Blood oxygenating tubing -Endotracheal tubes -Haemodyalysis-tubing

The use of polyurethanes for medical implants started around late 1950’s and the

original interest in them was mostly due to their outstanding properties. Most of the

initial research on biomedical polyurethanes was focused on improving their

biocompatibility and stability as they were mostly designed for use as biostable

materials in vivo. Since then, many polyurethane materials have been investigated for

their stability in the biological environment. However, it is now well understood that

many conventional polyurethanes are not stable in vivo as they are susceptible to

hydrolytic, oxidative and enzymatic degradations (Liebmann-Vinson & Timmins 2003).

In general, polyurethanes can be divided into two major sub-categories:

(i) thermoplastic polyurethanes (TPU), and

(ii) thermoset polyurethanes (TS).

The distinguishing features are that; a thermoplastic (TPU) behaves like a fluid above a

certain temperature, while a thermoset (TS) subjected to an increase in temperature

generally leads to its degradation without going through a fluid state (Mark 2007).

More specifically, TPUs are capable of being repeatedly softened by heating and

hardened by cooling, and in the softened state can be shaped by flow, whereas TS

polyurethanes undergo a chemical reaction following mild thermal treatment which

cures the polymer and leads to a ‘cross-linked’ state (Cheremisinoff & Dekker 1989).

Thermoset polyurethanes, unlike TPU, are not altered by elevated temperatures until

reaching a limit where decomposition starts.

Chapter Two

9 | P a g e

THERMOPLASTIC POLYURETHANES – CHEMISTRY AND PROPERTIES 2.3

Thermoplastic polyurethanes (TPU) are a widely used class of polymer with excellent

mechanical properties and good biocompatibility (Gorna & Gogolewski 2002;

Gunatillake, Mayadunne & Adhikari 2006; Hiltunen, Tuominen & Seppälä 1998;

Liebmann-Vinson & Timmins 2003; Tang, Labow & Santerre 2003). They represent a

major class of polymers extensively studied for a variety of biomedical applications.

2.3.1 Structure

As illustrated in Figure 2.3, TPUs are generally prepared from three starting

materials:(i) a diisocyanate, (ii) a chain extender, and, (iii) a macrodiol (or polyol).

(a)

(b)

Figure 2.3. (a) Reaction of diisocyanate with a chain extender to form hard segment – hard segment (red) and polyol (blue) reacted to form TPU exhibiting two-phase morphology, (b) two-phase morphology with hard (red) and soft segment (blue) domains.

These monomers and macrodiols react to form linear, segmented copolymers consisting

of alternating hard and soft segments, which are the characteristic structural features of

conventional TPUs. The soft segment is often made of polyol derivatives such as

OCN

NCOOH

OH+

Diisocyanate Chain Extender Hard Segment

*O *

O

n

Polyol Soft Segment

+

Chapter Two

10 | P a g e

polyesters or polyethers with varying molecular weights and copolymer ratios, while the

hard segment is composed of the diisocyanate unit and the chain extender (Gorna &

Gogolewski 2002; Hiltunen, Tuominen & Seppälä 1998; Liebmann-Vinson & Timmins

2003; Tang, Labow & Santerre 2003)

2.3.2 Synthesis

Thermoplastic polyurethanes are generally prepared through a one or two-step batch

processes or by semi-continuous processes such as reactive extrusion (Gunatillake &

Adhikari 2003; Gunatillake,, Mayadunne & Adhikari 2006). The one-step batch

synthesis for TPUs involves reacting a mixture of pre-dried macrodiols, the chain

extender, and the diisocyanate in presence of a catalyst such as dibutyltin dilurate. The

mixing of the reagents is typically carried out between 70 and 80°C but the

exothermicity of the reaction can cause an increase in temperature to 200°C and above.

The two-step procedure can be carried out in bulk or in solvents (Gunatillake &

Adhikari 2003; Gunatillake, Mayadunne & Adhikari 2006). The procedure involves

end-capping the macrodiols with diisocyanate and subsequently chain ending the

resulting prepolymer with a low molecular weight diol. The two-step method provides

better control of the polyurethane structure compared to the one-step method.

2.3.3 Morphology

Due to the co-existence of hard and soft segment domains, TPUs exhibit a two-phase

morphology. The hard segments aggregate to form micro domains resulting in structure

consisting of glassy or semicrystalline domains while the rubbery soft segments

aggregate to form soft domains that are mostly amorphous (Figure 2.4).

Figure 2.4 TPU two-phase morphology with hard and soft segment domains – Soft segment domain magnified and highlighted in red.

Chapter Two

11 | P a g e

The soft segment of TPUs, often has a glass transition temperature below usage

temperature, and gives the material its elastic properties, while the hard segment works

as a physical cross-link through either crystalline domains and/or hydrogen bonding.

The degree of microphase separation and overall microphase texture can be tailored

through many parameters. These include the hard-soft segment composition ratio, the

average length, solubility parameter and crystallinity of each segment, and the thermal

history.

2.3.4 Polyols/Macrodiols – Soft Segments

Thermoplastic polyurethanes properties and morphology are highly dependent on the

nature of their constituents, in particular the polyol properties. The nature of the polyol

soft segment has a significant influence on the mechanical and thermal properties, the

biocompatibility, and most importantly the biostability and/or biodegradability of the

TPU in vivo. Soft segment polyols for TPUs are predominantly polyester or polyether

based. For long-term medical implant applications, polyurethanes based on

poly(tetramethylene oxide) (PTMO) have been used until recently. Although PTMO-

based polyurethanes show good stability in hydrolytic environments, their oxidative

stability is very poor; the ether linkages are susceptible to oxidative degradation in vivo.

A family of polyurethanes (Elast-Eon™), recently introduced for clinical applications,

exhibit superior biostability over PTMO-base materials primarily due to the

replacement of PTMO with siloxane macrodiols.

Since all TPUs in this work are polyester based and designed to degrade, only polyester

polyols will be explored in this review. Frequently used and described TPU polyester

soft segments are generally based on poly(ε-caprolactone) (PCL), poly(lactic acid)

(PLA) and poly(glycolic acid) (PGA) and their respective copolymer (Bravo-Grimaldo

& Sheth 1997, Guelcher et al. 2005, Gunatillake, Mayadunne & Adhikari 2006, Hassan

et al. 2006, Loh et al. 2005, Santerre et al. 2005, Timmins & Liebmann-Vinson 2003,

Younes, Bravo-Grimaldo & Amsden 2004). These polymers are all thermoplastic

aliphatic polyesters and can be synthesised to a variety of molecular weights either

through polycondensation reactions or ring opening polymerisation.

Chapter Two

12 | P a g e

Poly(ε-caprolactone) (PCL)

PCL-diols used in TPUs typically have a molecular weight around 530 to 3000 kDa and

are relatively hydrophobic (Figure 2.5). The main advantages of using PCL as soft

segments are the low glass transition that it imparts to the TPU and the high strength

and elasticity. In a biological environment polycaprolactone degrades through the

hydrolysis of its ester linkages and is often utilised in biomedical implant polymer

formulations. It can also be used in the preparation of implants designed to degrade over

2 to 3 years due to its hydrophobic nature that causes slower degradation rates. In

addition, PCL is a Food and Drug Administration (FDA) approved material that can

safely be used in the human body (Vandamme & Legras 1995; Wang & Bo,1992).

Figure 2.5 Chemical structure of Poly(glycolic acid) (PGA), Poly(ε-caprolactone) (PCL) and Poly(lactid acid) (PLA)

Poly(glycolic acid) (PGA)

Poly(glycolic acid) (PGA) (Figure 2.5) is a rigid thermoplastic with relatively high

crystallinity (46-50%). The glass transition and melting temperatures of PGA are 36 and

225ºC, respectively. PGA is susceptible to hydrolytic degradation and the appeal of

PGA as a polymer in biomedical applications is that its degradation product, glycolic

acid, is a natural metabolite. PGA polyols will impart greater hydrophilicity and

degradability when used as a polyol for TPUs. PGA also has Food and Drug

Administration (FDA) approval for human clinical use (Lee & Gardella 2001; Shawe et

al. 2006).

Chapter Two

13 | P a g e

Poly(lactic acid) (PLA)

Poly(lactic acid) (Figure 2.5) is present in three forms: the isomeric d(-) and l(+) and

the racemic mixture (d,l). The polymers are usually abbreviated to indicate the chirality.

Poly(l)LA and poly(d)LA are semi-crystalline solids, with similar rates of hydrolytic

degradation as PGA. PLA is more hydrophobic than PGA, and is more resistant to

hydrolytic attack than PGA. For most applications the (l) isomer of lactic acid (LA) is

chosen because it is preferentially metabolised in the body. PLA has Food and Drug

Administration (FDA) approval for human clinical use.

2.3.5 Chain Extenders and Diisocyanates – Hard Segments

Chain Extenders

The direct reaction of polyols with diisocyanates produces polymers with mediocre

mechanical strength. However, their properties can be significantly improved by the

addition of a chain extender. The role of the chain extender is to produce an “extended”

sequence in the copolymer consisting of alternating chain extenders and diisocyanates.

These extended sequences, or hard segments, form crystalline domains through inter

molecular hydrogen bonding and contribute to enhance mechanical strengths. These

hard domains are dispersed in the amorphous soft segment domains exhibiting high

strength elastomeric properties.

Chain extenders in TPUs are typically low molecular weight bifunctional monomers

such as ethylene glycol (EG) or 1,4-butane diol (BDO), and their structures may also be

rendered degradable by the addition of hydrolysable ester linkages or other types of

hydrolytically unstable bonds. The hydroxy terminated chain extenders are typically

reacted with the terminal -NCO of the diisocyanate to form urethane linkages.

Figure 2.6 Chemical structure of ethylene glycol (EG), lactic acid-ethylene glycol (LA-EG) and 1,4-butanediol (BDO) chain extenders.

OH

OH OHOH

OHO

O

OH

EG LA-EG BDO

Chapter Two

14 | P a g e

Diisocyanates

A diisocyanate has two terminal –N=C=O functional groups (Figure 2.7). In general, the

high reactivity of the NCO groups makes them harmful to living tissues. However, once

the NCO has reacted with a hydroxyl group, leading to the formation of a urethane

bond, the resulting compound no longer presents any harm. One major limitation in the

type of diisocyanate that can be used in thermoplastic polyurethanes for biomedical

applications is mainly related to the toxicity of their degradation products. Given that,

diisocyanates such as methylene diphenyl diisocyanate (MDI) are unsuitable for

biodegradable polymers use in medical devises due to the toxic nature of the aromatic

products formed upon degradation, most research has been focussing primarily on

aliphatic diisocyanates. Two aliphatic diisocyanates are used in the current study.

Figure 2.7 Structure of aliphatic diisocyanates (a) ethyl lysine diisocyanate (ELDI) (b) hexamethylene diisocyanate (HDI) and (c) NCO functional group.

Hexamethylene diisocyanate (HDI)

HDI is the most commonly used aliphatic diisocyanate in TPU formulations. It is

relatively inexpensive compared to other diisocyanates and degrades to give 1,6-

hexanediamine (1,6-hexamethylenediamine). HDI-based TPUs are characteristically

very strong and tough.

R N C O O C N R ' + + H 2 O

- C O 2 ( g )

R N H

O

N H

R '

R ' ' N C O

R N H

O

N R '

O H N

R ' '

OCNNCO

O O

OCN NCO

N C O

NCO Functional group ELDI HDI

OCNNCO

O O

OCN NCO

N C O

NCO Functional group ELDI HDI

(a)

(b)

(c)

Chapter Two

15 | P a g e

Ethyl lysine diisocyanate (ELDI)

ELDI-based TPUs are more amorphous than TPUs made from a linear diisocyanate due

to the effect of the methyl/ethyl ester side chain that prevents neatly aligned inter-chain

hydrogen bonding. The resulting polyurethanes are not as strong as their HDI

counterparts and are rubbery rather than plastic. However, ELDI yields lysine as a by-

product, which has low toxicity and can be safely reabsorbed by the body.

THERMOSET POLYURETHANES – CHEMISTRY AND PROPERTIES 2.4

Thermoset polyurethanes are usually liquid or malleable prior to curing and are often

designed to be moulded into their final form. The curing process transforms the liquid

material or ‘prepolymer’ into a set or cured polyurethane by a cross-linking process.

The system is further activated by heat or with a catalyst causing the molecular chains

to react at chemically active sites and turning the resulting material into a rigid, three

dimensional structure. The cross-linked process produces a material where polymer

chains/segments are covalently linked to each other. As a result of this extensive

network of crosslinks, and contrarily to thermoplastics, which are capable of being

repeatedly softened by heat and hardened by cooling, thermoset materials cannot be

melted and re-shaped after they have been cured, and are generally stronger than

thermoplastic materials due to the three dimensional network of bonds. Because the

polymer network is produced in an irreversible way, the synthesis of a thermosetting

polymer is carried out to produce the final product with the desired shape. Therefore,

polymerisation and final shaping are performed in a single process.

2.4.1 Structure

Thermosetting polyurethanes may be defined as polymer networks formed by the

chemical reaction of monomers, at least one of which has three or more reactive groups

per molecule (a functionality of 3 or higher), and that are present in specific amounts

such that a gel/network is formed at a particular conversion during the synthesis.

Chapter Two

16 | P a g e

2.4.2 Synthesis

The synthesis of thermosetting polyurethanes occurs in a classic two-step method

starting with a sol phase, the monomers. After partial conversion of the functional

groups, a gelation process takes place giving the gel phase. This critical sol–gel

transition is a distinctive feature of thermosetting polymers, and subsequent to gelation,

an insoluble fraction (the gel fraction) remains present in the system. Finally, at full

conversion of the functional groups in stoichiometric quantities, the sol fraction

disappears and the final polymer is composed of one giant molecule of a gel.

As schematised in Figure 2.8, thermosetting polyurethanes may be formed in two ways:

by polymerisation reactions, step or chain mechanisms, where at least one of the

monomers has a functionality higher than 2,

by chemically creating cross-links between previously formed linear or branched

macromolecules (cross-linking of primary chains).

Figure 2.8 Basic morphology of (a) amorphous thermoset polyurethane, and (b) of thermoplastic polyurethane with semicrystalline and amorphous domains.

(a) (b)

Chapter Two

17 | P a g e

2.4.3 Morphology

Thermosetting polyurethanes are usually amorphous because there is the lack of

possibilities to induce an ordering of the network structure due to steric restrictions

imposed by the presence of cross-links. Since these materials are essentially comprised

of one giant molecule, once the mass has set there is no movement between molecules.

Thermosetting polymers are thus extremely rigid and generally have much higher

strengths than their thermoplastic counterparts.

Also, since there is no opportunity for motion between molecules in a thermosetting

polymer, they will not become plastic when heated, meaning that there will not be a

glass transition temperature.

2.4.4 NovoSorbTM Thermoset Polyurethanes

Gunatillake & Adhikari (2003) have developed polyurethane pre-polymers that can be

cross-linked to form both rigid and elastomeric materials (NovoSorb™). The

differential reactivity of the isocyanate functional groups in diisocyanates such as ELDI,

is used to prepare pre-polymers that are liquids at ambient temperatures, by reacting it

with polyhydroxy-functional core molecules such as pentaerythritol.

Under controlled reaction conditions, star/hyperbranched pre-polymers with isocyanate

end-functional groups can be prepared. The reaction of a diisocyanate with a core

molecule such as pentaerythritol produces isocyanate end-functional pre-polymers. A

typical example of such pre-polymer (Pre-polymer A) structure is shown in Figure 2.9.

The second component (Pre-polymer B) is usually a polyester polyol, and suitable

polyols include poly(caprolactone), poly(glycolic acid), poly(lactic acid) and their

copolymers . The polyol component may be modified by adding a second polyol to alter

the hydrophilic/hydrophobic characteristics. Reaction of pre-polymer A with pre-

polymer B in appropriate proportions, along with other additives if needed, produces a

cross-linked polymer network.

Chapter Two

18 | P a g e

Figure 2.9 Formation of thermoset (cross-linked) polyurethane NovoSorbTM. Starting with the formation of prepolymer A with pentaerythritol functionalised with ELDI. Prepolymer A is reacted with prepolymer B (a polyol) and a cross-linked network is formed.

Thermoset polyurethanes are synthesised with similar starting materials as TPUs.

However, as previously discussed, there is a slight difference in the synthetic pathway,

as is the morphology of the resulting polyurethane. The diisocyanates and polyols or

hydroxyl-terminated monomers used to synthesise TS polyurethane in this study are the

Prepolymer A Prepolymer B

HO

HO

OH

OH

OCN

NCOOCN

NCO

HO

HO

OH

HO

HO OH

HO OH

OH

HO

OH

OH

NHCOO

NHCOO

OOCHN

OOCHN

+

Pentaerythritol ELDI

OCN (CH2)4 NCO

COOC2H5

CHCH2OHHOCH2

HOCH2 CH2OH

+

CH2OOCNHHOCH2

HOCH2 CH2OOCNH

(CH2)4 NCO

COOC2H5

CH

(CH2)4 NCO

COOC2H5

CH

OCN (CH2)4 NCO

COOC2H5

CH

OCN (CH2)4 NCO

COOC2H5

CH

Chapter Two

19 | P a g e

same as mentioned earlier, with the addition of mandelic acid (an aromatic hydroxy acid

from almond extracts) and pentaerythritol.

Pentaerythritol is a tetra-functional alcohol with primary hydroxyl groups (Figure 2.10).

The hydroxyl groups of pentaerythritol can also react with carboxylic acid ends of

organic acids such as lactic acid and glycolic acid, forming a ‘star’ shaped polyol with

ester linkages.

Figure 2.10 Formation of pentaerythritol-L-lactic acid (PE-LLA) (1:4).

These ‘star’ polyols can then react with pentaerythritol functionalised with terminating

–N=C=O groups to form a tight cross-linking polyurethane network with the

incorporation of ester bonds.

OOH

OO

O

O

O

O

O

OH

OH

OH

OH

OH

OH OH

+

OH

O

OH

Pentaerythritol Lactic Acid

PE-LLA

Chapter Two

20 | P a g e

BIODEGRADABLE POLYURETHANES 2.5

In the context of biomedical polymers, biodegradation can be defined as structural or

chemical changes occurring in a in a material that are initiated and/or accelerated by the

vital activity of the biological environment.

Over the last 20 years, research foci for biomedical applications have shifted from

designing and synthesising biostable polymers to tailoring polymers that are

biodegradable, albeit with limited stability. The driving force has been the need for

novel materials with specific properties and tailored to meet the biochemical and

biomechanical requirements in emerging technologies such as tissue engineering,

regenerative medicine, innovative drug delivery systems, and implantable devices

(Gunatillake Mayadunne & Adhikari 2006). The novel materials must be able to favour

the process of tissue regeneration and provide mechanical support while eventually

degrading to non-toxic products with no harm to the body. Also, in the development of

advanced tissue engineered products and therapies, the polymers may be used as a cell

delivery system using minimally invasive procedures.

At present, biodegradable polymers are mostly used as materials for reconstructive

surgery if the body has the potential to heal itself, as the polymers can be absorbed in

the body after healing. If there is no potential for healing, biodegradable polymers are

inserted into affected regions as scaffolds for tissue regeneration, with the expectation

that the polymer will disappear after regeneration. For example, one of the first

biodegradable polymer products was poly(glycolic acid), which has been utilised as a

surgical suturing material (DexonTM & MedifitTM) (Reis & San Román 2004) and with

the development of tissue engineering in the 1990s, there have been numerous studies

on biodegradable polymers as scaffolds for tissue regeneration.

All polyurethanes are degradable to a certain extent and will degrade through several

pathways in vivo. The polymer chain, containing primarily ester, ether and urethane

linkages, is susceptible to hydrolysis, oxidation, and enzymatic attack in vivo. Both soft

and hard segments play an important role in the biodegradability of polyurethanes. The

incorporation of polyester during the synthesis of polyurethanes increases

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biodegradability due to the high susceptibility of ester bonds to undergo hydrolytic

degradation. Polyesters can also be more or less susceptible to degrade depending on

their overall crystallinity and hydrophilicity. The incorporation of polyether lowers the

degradability of the polyurethane, as these bonds are generally stable in a hydrolytic

environment. However, polyether bonds are more susceptible to oxidation and are

highly hydrophilic. In general, polymers containing a higher number of hydrolytically

stable urethane bonds exhibit lower degradation rates, but there can be exceptions to this

rule depending on the entire composition of the polyurethane. This relative molecular

instability of polyurethanes is deliberately exploited in the design biodegradable

materials.

In the following sections, the properties of biodegradable polyurethanes are discussed

with respect to the type of soft segment used for their synthesis.

2.5.1 PCL-based Biodegradable Polyurethanes

As mentioned earlier, polycaprolactone (PCL) is a highly hydrophobic and crystalline

polyester that degrades relatively slowly (Wang & Bo 1992). It has the ability to impart

high strength and elongation, as well as slow degradation rates when added as a

polyester soft segment to polyurethane. It can be used in polyurethanes as a copolymer

with polyesters such as PLA & PGA when attempting to increase degradation rates, and

it can also be co-polymerised with polyethers such as polethyleneglycol (PEG) or

polyethylene oxide (PEO) to increase polyurethane hydrophilicity.

PCL is typically used as a degradable polyester and co-polyester soft segment with a

variety of diisocyanates, which include isophorone diisocyanate, methylene diphenyl

diisocyanate, hexamethylene diisocyanate, lysine ethyl ester diisocyanate and 1,4-

butanediol diisocyanate (Brown, Lowry & Smith 1980; Fromstein & Woodhouse 2002;

Gorna & Gogolewski 2002a, 2002b; Guan et al. 2002, Lendlein et al. 2001; Lendlein,

Neuenschwander & Suter 1998; Nair & Laurencin 2007; Sarkar & Lopina 2007; Skarja

& Woodhouse 2002), and various chain extender structures to make up the hard

segment.

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Gorna & Gogolewski (2002a, 2002b) reported on the synthesis and in vitro degradation

of HDI-based and IPDI-based polyurethanes with PCL and PCL-PEO-PPO-PEG

(poly(ethylene-propylene-ethylene oxide)) soft segments. These polyurethanes showed

high tensile strengths and moduli and high elongations and were found to be good

candidates in applications such as biodegradable scaffolds for tissue engineering. In

vitro degradation data revealed that PCL-based polyurethanes absorb less water than

PCL-PEO-PPO-PEG based polyurethanes, and when polyether was added to the

polyurethanes, there was a significant variation in the overall mass loss from ~3% (for

PCL based PUs) to 96%, after 76 weeks. These authors also demonstrated that

increasing the overall hydrophilicity of the material could enhance the extent of

polyurethane degradation.

Lendlein, Neuenschwander & Suter (1998) and Lendlein et al. (2001) provided further

evidence on the role of PCL contents in determining the rates at which some

polyurethanes undergo degradation. They synthesised and hydrolytically degraded

methylene diphenyl diisocyanate trimethyl hexamethylene diisocyanate (TMDI)-based

co-poly(ester urethanes) with soft segment of polycaprolactone-diglycolide and ethylene

glycol at 37°C and 70°C. Interestingly, they observed that the mass loss by hydrolysis

after one day at 70°C corresponded to the loss observed after 2 weeks at 37°C.

Degradation occurred mostly at the glycolyl-glycolate ester bonds in the soft segments,

and polyurethanes with high PCL content showed less mass loss than polyurethanes

with higher molar ratios of glycolide segments.

Jiang et al. (2007) demonstrated that PCL is also susceptible to enzymatic degradation

by lipases. They synthesised polyurethanes with isophorone diisocyanate (IPDI) and

butane diol (BDO) based hard segments with copolymer PCL-PEG soft segments. The

polyurethanes showed good tensile strengths (Ts) and very high elongation. In vitro

degradations were carried out at 37°C with lipase in PBS for 30 hours, and it was shown

that the degree of degradation was directly proportional to the content of PCL in the

polyurethane while there was an inverse relationship with respect to the content in PEG.

No mass loss was reported for degradation tests in PBS, most probably due to the

incubation time being only 30 hours

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2.5.2 PCL with Degradable Chain Extender Structures

Guan et al. (2002a, 2002b) synthesised biodegradable poly(ester-urethane)ureas based

on PCL as a soft segment, with 1,4-butanediol diisocyanate (BDI) and either a novel

degradable chain extender ‘Lys-ethyl ester’ or putrescine, made up the hard segment.

The polyurethanes with DCEs showed increased mass loss compared to little mass loss

for putrescine based PUs over 8 weeks in vitro degradation. On the other hand, an

increase in PCL soft segment was apparent in polyurethane with DCE indicating that

degradation had occurred mostly in the hard segment with negligible effects in the soft

segment.

Overall DCE-based polyurethanes exhibited around 50% mass loss and putrescine-

based PUs only ~10% mass loss after 8 weeks in vitro degradation. These studies also

demonstrated that replacing a non-DCE with a DCE had the potential to increase hard

segment degradation and thus the overall degradation rate. Traditionally, the soft

segment is the part of the structure that would preferentially undergo degradation due to

the hydrolytically unstable ester bonds, and by introducing these bonds into the hard

segment one can control degradation in both the hard and soft segment of the

polyurethane.

Similarly, Sarkar & Lopina (2007) synthesised PCL-based and PEG-based

polyurethanes with HDI and either degradable (tyrosol hexyl ester (DTH)) or non-

degradable chain extenders (CDM) as hard segments. The in vitro degradation was

performed under oxidative and enzymatic conditions, and DCE-based polyurethane

showed higher mass loss than non-DCE-based polyurethane. Interestingly, PEG-based

polyurethanes degraded at the soft segment ether bonds under oxidative conditions

while under the same conditions PCL-based ones degraded at the hard segment.

Overall, the results indicated that PCL-based polyurethanes degraded slower than the

PEG based, most probably due to the increased hydrophobicity of PCL soft segments.

Skarja & Woodhouse (2001), and Fromstein & Woodhouse (2002) reported on enzyme

mediated and hydrolytic in vitro degradation of a series of polyurethanes containing a

novel amino acid-based degradable chain extender with additional ester linkages

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(phenylalanine diester chain extender). The polyurethane was LDI-based with either a

degradable chain extender or a non-DCE (CDM) and PEO-PCL soft segments. DCE-

based polyurethane exhibited higher susceptibility to enzymatic degradation but not to

buffer-mediated hydrolysis. It was also reported that the use of poly(ethylene oxide) as

a soft segment led to increased erosion in both buffered and enzymatic solutions, in

comparison to PCL-based polyurethane. A decrease in PCL molecular weight led to

increased enzyme-mediated mass loss indicating that the degradation process was also

dependent on the relative molecular weight of the soft segment.

Zhang, Zhang & Wen (2005) examined the effect of chain extender structure on

polyurethane degradation, mechanical properties and cytophilicity. The soft segment of

both polyurethane series was PCL with hard segments of either MDI and BDO, or MDI

and MIDE (2,2’-(methylimino) diethanol). Polyurethanes containing the chain extender

MIDE showed a higher degradation rate and hydrophilicity compared to polyurethanes

with a BDO chain extender.

On the other hand, polyurethanes with a BDO chain extender showed superior tensile

strengths in both wet and dry conditions. Interestingly, the authors reported that, in

terms of mass loss, 32 days in vitro degradation at 77°C is approximately equivalent to

9-10 months in vitro degradation at 37°C.

2.5.3 PLA-based Biodegradable Polyurethane

Poly(lactic acid) exists in three forms D(-), L(+) and racemic (DL). Poly(L)LA and

poly(D)LA are semi-crystalline solids (~37% crystallinity) and are more hydrophobic

than PGA, and, hence, are more resistant to hydrolysis.

PLLA is relatively slow degrading compared to PGA, and has good tensile strength, low

elongation and high modulus. Poly(lactic acid)-based polymers have been extensively

studied for use as biodegradable polymers for biomedical applications (Cam, Hyon &

Ikada 1995; Chaubal et al. 2003; Henn et al. 2001; Shih 1995; van Nostrum et al. 2004)

and as copolymers, particularly with glycolic acid. Some examples of PLLA based

commercial products include; Phantom Soft Thread Tissue Fixation Screw®,

Bioscrew®, Bio-Anchor®, Sculptra® (Nair LS & Laurencin 2007).

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It has been reported that high molecular weight PLLA polymers can take between 2 and

6 years for complete degradation and resorption in vivo (Nair & Laurencin 2007). The

rate of degradation is also dependent on the degree of crystallinity and the porosity of

the matrix. Poly-L-lactide (PLLA) is less degradable and stronger than poly-DL-lactide

(PDLLA) and therefore these two isomeric forms of PLA are often copolymerised to

increase degradation rates without significantly compromising the integrity and strength

of the polymer. PDLLA polymers are amorphous and, in general, will have lower

strengths that PLLA.

Polylactides undergo hydrolytic degradation via a bulk erosion mechanism by random

scissions of the ester backbone. They degrade into innocuous lactic acid, which is

further broken down via a simple metabolic citric acid cycle (Krebs Cycle). It has been

reported that selected polymers were well tolerated by the tissue, with no observed

localised inflammation or necrosis (Gogolewski et al, 1993).

PLLA and PDLLA have been used as a degradable polyester and copolyester soft

segments with a variety of diisocyanates which include TMDI/MDI, HDI and BDI

(Cordewener et al. 2000; De Groot 1998; Feng & Li 2006; Hiltunen, Tuominen &

Seppälä 1998; Zhan et al. 2002).

Hiltunen, Tuominen & Seppälä (1998) demonstrated that PLLA-based polyurethanes

undergo degradation at a slower rate than PDLLA-based polymers. Polyurethanes with

HDI-BDO based hard segments and either PLLA or PDLLA soft segments were

degraded at pH 7 in PBS at 37°C and 55°C over a period of 56 days. Polyurethanes

with increased amounts of PDLLA showed faster mass loss than polyurethanes with

higher PLLA contents. The onset of mass loss was at 40 days for all polyurethanes

incubated at 37°C and at 3 days for polyurethanes incubated at 55°C. After 50 days at

37°C, PLLA based polyurethanes exhibited a mass loss of 60% compared to the 100%

loss observed for PDLLA based materials.

PLA-based polyurethanes have also been shown to degrade under oxidative conditions.

Feng and Li (2006) observed that PLA-co-GA based polyurethanes showed accelerated

degradation under oxidative (H2O2/CoCl2) conditions.

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2.5.4 PGA and PLGA-based Biodegradable Polyurethane

As previously mentioned poly(glycolic acid) (PGA) is a rigid thermoplastic material

with high crystallinity and therefore high tensile modulus. PGA-based polymers are

susceptible to hydrolytic degradation and they impart greater hydrophilicity and

degradability when used as a polyol soft segment for polyurethane. Polyglycolide was

one of the first biodegradable synthetic polymers investigated for biomedical

applications and has been used as a synthetic biodegradable suture (called DEXON®)

since the 1960’s. It has also been investigated for use as scaffold for tissue

regeneration, glue composite matrices and bone internal fixation devises.

Polyglycolide degrades by bulk degradation and non-specific scissions of the ester

backbone. PGA polymers are broken down to glycine, which can be excreted in the

urine or converted to carbon dioxide and water through the metabolic citric acid cycle

(Lee & Gardella 2001; Nair & Laurencin 2007; Shawe et al. 2006).

While PGA polyester polymers are common and have been synthesised for many years,

there is no literature that reports on polyurethanes that include PGA as a soft segment

on its own. PGA polyesters have a high crystallinity (up to 55%) and high glass

transitions and melting temperatures, and as a result are extremely difficult to work with

when used as a soft segment with polyurethane. Although there are polyurethanes that

include PGA, it is most often copolymerised with other diols and polyols such as PLA

(Agrawal et al. 2000; Andriano et al. 1999; Jiang et al. 2007; Tienen et al. 2002; von

Burkersroda, Schedl & Gopferich 2002; Wu & Ding 2004; You et al. 2006), PCL

Lendlein et al. 2001 & Lendlein, Neuenschwander & Suter 1998) and PEO/PEG prior to

reacting with the diisocyanate to form a poly(ester urethane).

One of the most frequently examined co-polyesters is PLGA (Agrawal et al. 2000;

Andriano et al. 1999; Jiang et al. 2007; Tienen et al. 2002; von Burkersroda, Schedl &

Gopferich 2002; Wu & Ding 2004; You et al. 2006). A ratio of 50/50 poly(L-lactide-co-

glycolide) is very unstable in a hydrolytic medium and degrades in approximately 1-2

months. For PLGA 75/25, degradation takes roughly 4-5 months and for PLGA 85/15

degradation occurs within 5-6 months (Nair & Laurencin 2007). PLGA polymers have

a range of different mechanical, thermal and degradation properties, which are simply

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27 | P a g e

determined by the ratios of PLA (either PLLA or PDLLA) and PGA added to the

polymer and the molecular weight of each of these polymers. Some commercially

available PLGA polymers include, PuraSorb®PLG, Vicryl®, PANACRYL®,

LUPRON DEPOT®, and CYTOPLAST Resorb®.

Feng and Li (2006), and Alteheld et al. (2005) used the H2O2/CoCl2 oxidative system to

investigate in vitro behaviours of TMDI-based cross-linked (thermoset) poly(ester

urethane) with a four armed PE polymerised oligo(D,L-lactide-co-glycolide). In vitro

degradation was carried out under oxidative (Feng and Li 2006) and hydrolytic

conditions at 37°C, at pH 7 in PBS (Alteheld et al. 2005). In PBS, polyurethane

degrades completely (100% mass loss) after approximately 180 days with an induction

period of 60 to 125 days. Under oxidative conditions the induction period was reduced

to 50 days and full polymer degradation was achieved after 85 days. In general,

polyurethanes showed accelerated degradation under oxidative conditions, which is

believed to more accurately reflect in vivo conditions. There have been reports on

strategies to limit the degradation by oxidative environment through the attachment of

antiodxidant on the surface to the polyurethane (Stachelek et al., 2006).

Lendlein et al. (2001) and Lendlein, Neuenschwander & Suter (1998) synthesised

DegraPolTM/btgc with soft segments of poly(glycolide-co(ε-caprolactone))-diol and

ethylene glycol, and hard segments of TMDI and Poly3-(R)-hydroxybutyrate and 3-(R)-

hydroxyvalarate and EG. Mass loss was evidenced at both 37°C and 70°C and found to

occur as a result of the breakage of ester bonds of the soft segment poly(glycolide-co(ε-

caprolactone))-diol. The Poly3-(R)-hydroxybutyrate and 3-(R)-hydroxyvalarate

component (the hard segment) of the polyurethane remained post degradation,

concluding that there was primarily degradation of the soft segments.

2.5.5 PEG/PEO-based Biodegradable Polyurethanes

PEG and PEO are synthesised by polymerisation of ethylene glycol and ethylene oxide

respectively, but are chemically equivalent linear polyethers of repeating –CH2-CH2O-

units (Liebmann-Vinson & Timmins 2003). PEG by itself is highly soluble in water,

absorbed in vivo within 6 weeks, and excreted through the kidneys. The mechanism

involved in the degradation of PEG and PEO is mainly through in vivo oxidation and,

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alternatively, enzymatic degradation can also be a contributor, albeit minimally. There

are a number of commercially available PEG & PEO-based polyurethanes, for example,

Biomer, Pellethane, Corethane and Tecothane (Liebmann-Vinson & Timmins 2003).

These polyurethanes are generally considered as non-biodegradable even though they

are susceptible to oxidative degradation.

PEG & PEO are predominantly copolymerised with PCL as a soft segment (Fromstein

& Woodhouse 2002; Gorna & Gogolewski 2002a, 2002b; Gorna & Gogolewski 2003;

Guan et al. 2002, Jia et al; 2006, Jiang et al. 2007; Sarkar & Lopina 2007; Skarja &

Woodhouse 2000; Skarja & Woodhouse 2001) and with HDI, LDI, BDI, TDI, MDI and

ISDI, and mostly the chain extender BDO as a hard segment (Christenson et al. 2003;

Christenson et al. 2006; Dahiyat et al. 1995; Fromstein & Woodhouse 2002; Gorna &

Gogolewski 2002a, 2002b; Gorna & Gogolewski 2003; Guan et al. 2002; Jia et al. 2006;

Jiang et al. 2007; Korley et al. 2006; Loh et al. 2005; Sarkar & Lopina 2007; Skarja &

Woodhouse 2000; Skarja & Woodhouse 2001). PEG and PEO are most commonly

copolymerised with PCL to impart increased strength and hydrophilicity. The latter

property is considered critical to induce degradability into the polyurethane. Cometa et

al (2010) have reported the synthesis of polyurethanes with varying ratios of PEG/PCL

to fine-tune their hyydrophilicity.

IN VITRO VS. IN VIVO DEGRADATION 2.6

In order to help predicting polymer degradation mechanisms and kinetics, in vitro and

in vivo correlation studies are carried out to determine their relative degradation rates. A

number of studies have examined the correlation between in vitro and in vivo

degradation of polyester and polyether polymers and copolymers (Andriano et al. 1999;

Chaubal et al. 2003; Deschamps et al. 2004; Henn et al. 2001; van Dijkhuizen-

Radersma et al. 2001). What is generally understood from these studies is that the mode

of degradation differs for different polymer compositions and the rate of degradation is

generally faster in vivo than under biologically simulated in vitro conditions. However,

there are a few known exceptions to the latter. For example, Henn et al. (2001)

synthesised PDLLA polymers for the manufacture of intra-medullary plugs, to be used

in total hip arthroplasty. The plugs were subjected to both in vivo (implanted in dogs)

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29 | P a g e

and in vitro conditions (PBS pH 7.3, 37°C) for up to 2 years. The in vitro samples

degraded faster than the in vivo samples with changes of Mw at a constant rate of 1.47 x

10-2 Da day-1and 2.86 x 10-3 Da day-1 for in vivo respectively. The authors concluded

that the difference between the two results relates to the availability of water that

diffuses into the polymer to hydrolyse the lactide linkage, suggesting that in vivo

degradation of PDLLA will be influenced by the availability of moisture at the site of

implantation as well as by the geometry of the implant.

On the other hand, Chaubal et al. (2003) synthesised microspheres of poly(lactide-co-

ethylphosphate), a class of linear phosphorus-containing copolymers made by chain

extending low molecular weight polylactide prepolymers with ethyl dichlorophosphate.

Degradation under in vivo, subcutaneous rat injections, and in vitro (PBS pH 7.4, 37°C)

conditions were investigated, and the studies demonstrated good correlations in terms of

the pattern of mass and molecular weight losses.

However, the rate of degradation was faster in vivo than in vitro, with approximately

70% mass loss for the in vivo samples compared to about 40% in vitro after 12 weeks.

Interestingly, the in vitro and in vivo molecular weight losses showed the same pattern

as well as similar molecular weight loss percentages at each sampling time point, even

though the mass loss between the two samples differed vastly. It would appear that

both polymer samples were undergoing bulk erosion as indicated by the significant

rapid decrease in molecular weight losses. However, according to mass loss data, the

samples appeared to be undergoing surface erosion, given the high mass loss seen very

early in the experiment. Chaubal et al. (2003) suggested that the presence of

solubilising lipids, and enzymes and mass transport of degradation products might

enhance in vivo degradation.

Few studies are available on the correlation between in vitro and in vivo polyurethane

degradation, in particular poly(ester urethane). Often attempts were made to closely

mimic a biological environment in vitro by subjecting polyurethanes to oxidative and

enzymatic conditions. However, even under these conditions, it is difficult to correlate

in vitro and in vivo data since there are many additional factors that need to be

considered when polyurethanes undergo in vivo degradation.

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Van Minnen et al. (2005) and van Minnen et al. (2006) investigated PDLLA/PCL-based

polyurethane foams based on BDI/BDO hard segments. Polyurethane foams lost 3.7%

their mass under in vitro conditions at 37°C after 12 weeks, with an induction period

before any significant mass loss is observed between 6-8 weeks. The same

polyurethane foam was implanted subcutaneously into rats and examined after 1, 4 and

12 weeks. Although the mass losses for the polyurethane foams were not recorded, the

results suggested that degradation in vivo had begun after one week and by Week 12,

nearly the whole mass of the foams was penetrated by tissue and cells, and exhibited

signs of degradation. These results indicate that in vivo degradation for the poly(ester

urethane) foams occurs at a greater rate than simulated hydrolytic in vitro degradation.

Tienen et al. (2002) and De Groot et al. (1998) synthesised porous polyurethane

scaffolds, for meniscal lesion repair, based on BDI-BDO hard segments with PLA-co-

PCL (1:1) soft segments. Although these polyurethanes showed excellent

biocompatibility, only minimal degradation was observed in vivo over 6 months In

similar studies involving tissue engineering, Jovanovic et al (2010) suggested the use of

hydrolysable soft segment to decrease the surface hydrophobicity and induce

degradation.

Pellethane®, a polyether-based polyurethane, has been the subject of in vitro and in vivo

degradation comparison studies (Martin et al. 2001, Frautschi et al. 1993). Since under

in vivo conditions polyether based polyurethanes degrade primarily at the ether bonds

through oxidation (Martin et al. 2001, Frautschi et al. 1993), the in vitro studies

investigated degradation using an oxidative medium such as the H2O2/CoCl2 system,

rather than a simple buffer system. Frautschi et al. (1993) observed that polyether based

polyurethanes, such as Pellethane® and Biomer®, most likely undergo oxidative in

vitro and in vivo degradation catalysed by metal ions (Frautschi et al. 1993). On the

other hand, Martin et al. (2001) investigated two types of Pellethane® (Pellethane 2363

55D and Pellethane 2363 80A) and observed that P80A underwent similar degradation

both in vivo and in vitro, while P55D exhibited different behaviours. These

polyurethanes performed badly under in vitro conditions, cautioning that care must be

taken when interpreting in vitro results in the absence of in vivo data.

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BY-PRODUCTS OF DEGRADATION AND THEIR TOXICITY 2.7

Traditionally, studies on biodegradable polymers are carried out in vitro, with a focus

on the hydrolytic degradation of polyester-based polymers and the oxidative

degradation of polyether-based polymers. Typically, these studies investigate polymer

mass loss, molecular weight loss (GPC), and changes in both thermal (DSC) and

mechanical properties to create a degradation model for each type of polymer. These

data provide useful information regarding degradation modes and kinetics for polymers

with simple chemistry. However, for more complex materials, such as polyurethanes,

these data may not generate enough information to fully explain the nature and routes of

degradation.

A more systematic approach for the investigation of polymer degradation is to examine

the by-products formed. By collecting and analysing products formed during in vitro

degradation, one may also determine the major species produced at various stages of

degradation and the dynamics of their formation. The resulting mixtures may contain

oligomers at intermediate stages and, possibly, monomers in the later phases. Once

accumulated and collected, the degradation mixtures can be subjected to a variety of

tests in order to identify the exact nature of the constituents and determine their

potential cytotoxicity.

Chaubal et al. (2003) carried out accelerated in vitro degradation at 70°C on

poly(lactide-co-ethylphosohate) microspheres and used NMR to identify the by-

products and determine the major species produced. The main results indicated that the

final degradation products of the copolymers included starting monomers such as lactic

acid, phosphoric acid, propylene and ethanol, and that phosphoester-lactide bonds

degraded before the lactide-lactide bonds, due to the order of the formation of

intermediate and final degradation products. These authors also demonstrated that

NMR analysis was an excellent tool for examining polymer degradation products as

well as changes in residual polymer.

Wang et al. (1997) investigated the by-products liberated during the in vitro enzymatic

degradation of biomedical polyurethanes based on TDI and ethylene diamine (ED), and

polyester PCL soft segments. The biodegradation products were isolated from the

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system using a combination of techniques such as ultrafiltration, freeze-drying and

solid-liquid extraction. The authors managed to separate and detect more than 20

different degradation products using gradient reverse-phased high performance liquid

chromatography (HPLC), and the products were further analysed using a tandem mass

spectrometer (MS-MS). Through this approach, the molecular structure of two

dominant isolates could be identified and it was found that they contained a single TDI

unit covalently coupled to terminal polyester segments. It was also found that

intermolecular cleavages were mainly associated with the ester linkages rather than the

urethane.

Using a similar approach to Wang, Santerre & Labow (1997) and Tang, Labow &

Santerre (2003) applied enzymatic degradation, and isolated products from

polycarbonate-polyurethanes based on HDI, HMDI and MDI, BD hard segments with

different ratios of polycarbonate. For each polymer sample, around 10 degradation

products were isolated and identified based on their molecular weight, and their

structures were predicted on the basis of their molecular weight, acquired through MS,

and the components of the starting polymer.

Van Minnnen et al. (2006) accumulated degradation products of polyurethane with

BDI-BD hard segment and DLLA/PCL soft segments under accelerated conditions at

60°C in distilled water for up to 52 weeks. The degradation products, collected at

different time points, were subjected to further examination to determine their effects on

mouse fibroblast viability. The fist signs of cytotoxicity were detected after 3 weeks of

degradation when the polyurethane had lost approximately 20-60% of its mass. Beyond

this point, cell viability was relatively low until the termination of the experiment at 52

weeks. The accumulated degradation products of the soft segment alone were also

examined and showed much lower cytotoxicity on fibroblast than the polyurethanes.

The metabolic activity of the fibroblasts, incubated with these degradation products

accumulated over 52 weeks, was still relatively high when compared to the negative

control. The greater effect of the polyurethane degradation products, as opposed to the

soft segment degradation products, on cell viability may be attributed to the

accumulation of urethane segments and urethane based intermediate degradation

products.

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SUMMARY OF CURRENT LITERATURE 2.8

Based on current literature, it is understood that, to a certain extent, polyurethanes are

indeed biodegradable both in vivo and in vitro. The rates and modes of the degradation

are fundamentally governed by the molecular make up of its constituents and how they

interact with one another.

For slow degrading polyurethane, a soft segment of PCL, either alone or copolymerised

with other polyesters or polyethers, is generally used as it provides polyurethane with

increased hydrophobicity and thus slower hydrolytic degradation. To increase the

degradation rate of polyurethanes, faster degrading polyols such as PLLA, PDLLA and

PGA can be added to a polyurethane formulation in different ratios, depending on the

mechanical strength and degradation time required for specific applications.

Diisocyanate may also influence polyurethane degradation both in vitro and in vivo.

HDI and BDI have a molecular symmetry that leads to strong intermolecular attractions

through hydrogen bonding. As a result, HDI and BDI-based polyurethane may show

lower degradation rates due to the fact that tight bonding makes it difficult for water

molecules to access urethane bonds. Alternatively, ELDI, with an asymmetrical

structure, does not produce the same hydrogen bonding patterns as symmetrical

diisocyanates like HDI and BDI. Based on the same rationale, it can be anticipated that

ELDI-based polyurethanes would show higher degradation rates, as in this case an

increased space between the bonds will facilitate diffusion of water in the bulk of the

polymer.

A survey of the literature reveals that the structure of the chain extender also plays a

critical role in the degradation of polyurethanes (Guan et al. 2002a, 2002b; Skarja and

Woodhouse; 2001 Fromstein & Woodhouse 2002; Zhang, Zhang & Wen 2005).

Traditionally, the soft segment of polyurethanes is altered to control degradation rates.

With the advent of degradable chain extenders, polyurethane hard segments may also be

designed to degrade and, thus, promote the overall degradation process of polyurethane.

Adding a hydrolytically unstable ester link into the chain extender structure has the

potential to increase the ability of the hard segment to undergo degradation.

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The ratios of soft and hard segment in the polyurethane (for TPU) are also important

factors; in general, polyurethanes with a high soft-to-hard segment ratio tend to degrade

faster. The degradation rates of polyurethanes with higher hard segment contents are

generally slower due to the larger number of stable urethane bonds. However, since the

introduction of degradable chain extender structures, this general principle may no

longer apply.

In general, the other key factors that will have an influence on the susceptibility of

polymers to undergo hydrolytic, oxidative and enzymatic biodegradations are their

molecular properties, i.e. molecular weight, chirality and stereochemistry, morphology,

and degree of crystallinity (Timmins & Liebmann-Vinson 2003). Other important

factors that may significantly influence degradation kinetics and mechanisms are the

location of polymer implants, availability of water, and cellular and enzyme contacts.

As the literature suggests, due to the complex structure of polyurethanes, it is difficult

for one to elucidate and compare the discrepancy between in vitro and in vivo

degradation given the occasional conflicting results. However, it is reasonably safe to

conclude that, in most cases, polyurethanes will degrade at a faster rate in vivo than

under in vitro conditions, but the extent of degradation can be highly influenced by the

location of the device. For in vivo studies, it is difficult to determine how and what the

polyurethane degrades to, due to the difficulty to retrieve the degradation products.

The analysis of in vitro degradation products proves to be a useful approach when

attempting to achieve a better understanding of polyurethanes behaviours. Predicting

the key degradation products based on the polyurethane structure, assuming the material

degrades completely to monomer species, can be a very useful tool. However, this may

not be the case under actual situations as the degradation process may release other

intermediate products that go into solution at different stages of degradation.

What is not clearly understood is what effects these intermediate degradation products

may have on the surrounding tissues and cells, and whether they will continue to

degrade once released from the polyurethane. These questions are difficult to answer

with the limited literature currently available in this area of study.

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35 | P a g e

3 MATERIALS AND METHODS

PREPARATION OF POLYURETHANE STARTING MATERIALS 3.1

Ethylene glycol (EG) (Sigma 99%), DL-lactic acid (LA) (Fluka 90%), poly(ε-

caprolactone)-1000 diol (PCL) (Era Polymers), glycolic acid (Sigma 90%), mandelic

acid (Fluka) and CAPA™ 4101 (Solvay) were degassed at 80C for 2 hours under

vacuum (0.1 Torr) prior to use.

Prior to use, ethyl lysine diisocyanate (ELDI) (Kyowa Hakko Kogyo Co Ltd.) and

hexamethylene diisocyanate (HDI) (Fluka) were distilled under vacuum (3 x 10-2 Torr)

at 135ºC and 120ºC respectively. Dibutyl tin dilaurate (Aldrich 95%) was used as

received.

SYNTHESIS OF THE DEGRADABLE CHAIN EXTENDERS 3.2

Two hundred grams of 90% DL-lactic acid were heated under nitrogen atmosphere for 6

hours to 160˚C in a round-bottom flask equipped with a magnetic stirrer, a still-head

sidearm and condenser. A five to one molar ratio of ethylene glycol (650 g) was added

to the polylactic acid and heated at 180˚C for 21 hours. The ethylene glycol was then

distilled from the round-bottomed flask at 70˚C under vacuum (0.01 Torr) and collected

in a liquid nitrogen trap. After the trap was cleaned, the temperature was raised to

130˚C to distil the 2-hydroxyethyl 2-hydroxypropanoate (LA-EG) dimer. The yield was

130 g (48.5%).

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POLYOL SYNTHESIS 3.3

Three different polyols were synthesised for the thermoset polyurethane series 4 & 5.

These polyols were mixed with the diisocyanate, ELDI, to form a thermoset

polyurethane.

3.3.1 PE-GA Synthesis (MW 399)

To prepare 250 g of PE-GA, 80.248 g of PE and 317.761 g of GA (70%) were added to

a three-necked round-bottom flask. The reaction mixture was dissolved at 80C in an

oil bath for 12 hours under a nitrogen flow (20 mL/min). When the reaction mixture

appeared to be clear and colourless, a distillation head was attached to the flask and the

temperature was increased to 155C and the reaction maintained for 24 hours.

The resulting polyol was cooled to 70C and transferred to a single-neck round bottom

flask. The flask was then attached to a Kugelrohr oven connected to a vacuum tap (0.1

Torr) and heated to 120C for 2 hours to reduce the acid number.

3.3.2 PE-DLLA Synthesis (MW 434)

To prepare 250 g of PE-DL-LA polyol, 80.25 g of PE and 235.77 g of DL-LA (90%)

were added to a three-neck round bottom flask. The reaction mixture was dissolved at

80C in an oil bath for 12 hours and kept under nitrogen flow (20 mL/min). When the

mixture appeared to be clear and colourless, a distillation head was attached to the flask.

The temperature was then increased to 155C and the reaction maintained for 24 hours.

The resulting polyol was cooled to 70C and transferred to a single neck round bottom

flask. The flask was attached to a Kugelrohr oven connected to a vacuum pump (0.1

mm Hg) and heated to 120C for 2 hours to reduce the acid number.

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37 | P a g e

3.3.3 PE-LLA:MA (1:1) Synthesis (MW 320)

To prepare 1300 g of PE-LLA:MA (1:1) polyol, 442.48 g of PE, 425.67 g of L-LA

(88%) and 632.70 g of DL-MA were added to a three-necked round bottom flask. The

reaction mixture was dissolved at 80 C in an oil bath for 12 hours under nitrogen flow

(20 mL/min).

When the mixture appeared to be clear and colourless, a distillation head was attached

to the flask, the temperature was increased to 200C and the reaction maintained for 21

hours. The resulting polyol was cooled to 70C and transferred to a round bottom flask.

The flask was then attached to a Kugelrohr oven connected to a vacuum pump (0.1 mm

Hg) and heated to 120C for 2 hours to reduce the acid number.

3.3.4 Fundamental Physico-chemical Properties

Acid number

The acid number is the amount of KOH (in mg) required to neutralise the carboxylic

end groups, in 1 gram of oligomer. The acid number is given by Eq. (3.1).

Acid Number = (V × N × 56.1)/W (3.1)

Where V = volume of KOH titre, N = normality of the KOH solution, 56.1 = molecular

weight of KOH, W = mass of the sample in grams.

Hydroxyl number

The hydroxyl number represents the amount of KOH (in mg) required to react with the

hydroxyl end groups in 1 gram of oligomer. The hydroxyl number is given by Eq. (3.2)

Hydroxyl Number = (V × N × 56.1)/W (3.2)

Where V = volume of KOH titre, N = normality of the KOH solution, 56.1 = molecular

weight of KOH, W = mass of the sample in grams.

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Molecular weight

Equation 3.3 was used to calculate the molecular weight of the oligomer based on the

hydroxyl number (OH#) and acid number (Acid#):

Molecular Weight = (56.1 x 2 x 1000)/(OH# + Acid#) (3.3)

Water content

The water contents of chain extenders and polyols were measured after degassing the

samples at 50ºC under vacuum (0.1 Torr), with a Mettler DL37 KF Coulometer.

Polyols with water content less than 200 ppm were deemed acceptable for use, while

polyols that yielded more than 200 ppm were subjected to further degassing.

POLYURETHANE NOMENCLATURE 3.4

All thermoplastic polyurethanes, except those synthesised with 100% hard segment,

contained the polyol PCL1000. Since this polyol was present in most samples, it is not

referred to in the nomenclature of the polymer series.

3.4.1 Thermoplastic Polyurethane Series

Polyurethanes are named accordingly: diisocyanate--chain extender--% hard segment.

For example, ELDI-LAEG-30 indicates that the polyurethane was synthesised with the

diisocyanate ELDI and LAEG as a degradable chain extender and 30% of the

polyurethane was hard segment (ELDI including chain extender), with the remaining

70% being PCL1000.

For simplicity, polyurethanes with 18% ELDI, with no chain extender, and PCL (1:1

ratio) were named as 0% hard segment or ELDI-0. Tables 3.1-3.3 summarise the

systematic used in the nomenclature of the polymers synthesised in this study.

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Table 3.1 Nomenclature and abbreviations of Series 1 thermoplastic polyurethanes.

Polyurethane

Name

Diisocyanate Chain

Extender

Polyol Hard

Segment %

ELDI-0 ELDI - PCL1000 0

ELDI-LAEG-30 ELDI LAEG PCL1000 30



ELDI-LAEG-100 ELDI LAEG - 100


Polyurethane

Name

Diisocyanate Chain

Extender

Polyol Hard

Segment %


ELDI-EG-30 ELDI EG PCL1000 30



ELDI-EG-100 ELDI EG - 100


Polyurethane

Name

Diisocyanate Chain

Extender

Polyol Hard

Segment %


HDI-LAEG-30 HDI LAEG PCL1000 30


HDI-EG-30 HDI EG PCL1000 30

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3.4.2 Thermoset Polyurethane Series

Given that all thermoset polyurethanes (series 4-6) were ELDI-based, ELDI is not

included in the names of the polymers. Accordingly, the polymers were named:

Polyol/s—percentage ratio of polyol/s. For example, DLLA:GA-75:25, refers to a

polymer that contains ELDI as a diisocyanate and the polyols PE-DLLA and PE-GA in

a percentage ratio of 75:25. Tables 3.4-3.6 list the various polymers series and Table 3.7

summarises the abbreviations used.

Table 3.4 Nomenclature and abbreviations of Series 4 thermoset polyurethanes.

Polyurethane

Name

Diisocyanate Polyol 1 (P1) Polyol 2 (P2) P1 to P2 ratio

(weight)

DLLA-100 ELDI PE-DLLA - 100:0

DLLA:GA-75:25 ELDI PE-DLLA PE-GA 75:25



GA-100 ELDI - PE-GA 0:100


Polyurethane

Name

Diisocyanate Polyol 1 (P1) Polyol 2 (P2) P1 to P2

ratio

(weight)

LLA/MA-100 ELDI PE-LLA:MA-1:1 - 100:0

LLA/MA:GA-75:25 ELDI PE-LLA:MA-1:1 PE-GA 75:25




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Polyurethane

Name

Diisocyanate Polyol 1 (P1) Polyol 2 (P2) P1 to P2

ratio

(weight)

PCL4-100 ELDI PCL4 - 100:0

PCL4:PCL-75:25 ELDI PCL4 PCL1000 75:25






PCL-100 ELDI - PCL1000 0:100

Table 3.7 Glossary of abbreviations

Abbreviation Name Mw Chemical Name

DLLA DL-Lactic Acid 90 2-hydroxypropanoic acid

LLA L-Lactic Acid 90 2-hydroxypropanoic acid

MA Mandelic Acid 152 2-Phenyl-2-hydroxyacetic acid

GA Glycolic Acid 76 2-Hydroxyethanoic acid

EG Ethylene Glycol 62 1,2-ethanediol

PCL1000 Poly(ε-caprolactone) 1000

Mw

1000 (Mn) Poly(ε-caprolactone) Diol

PCL4 CAPA 4101 1000 (Mn) Poly(ε-caprolactone) Tetrol

ELDI Ethyl Lysine Diisocyanate 226 Ethyl 2,6-diisocyanatohexanoate

HDI Hexamethylene

Diisocyanate

168 1,6-hexamethylene diisocyanate

PE Pentaerythritol 136 2,2-Bis(hydroxymethyl)1,3-

propanediol

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POLYURETHANE SYNTHESIS 3.5

The following section describes the general procedure for the synthesis of both

thermoset and thermoplastic polyurethane series. Only one example is detailed for

each.

3.5.1 General Procedure for Thermoplastic Polyurethane

The following process illustrates the general procedure used to make 50 g of

polyurethane ELDI-LAEG-30 (30% hard segment, 70% soft segment (PCL)). 35 g of

PCL and 2.63 g of LAEG, plus 0.05 g of the catalyst dibutyl tin dilaurate were added to

a pre-dried glass beaker heated to 70C. 12.36 g of ELDI was also heated to 70C and

added to the mixture of diols and stirred vigorously with a spatula for about 2-5 minutes

until uniformly mixed. Once the mixture was viscous and hot, it was poured into a

Teflon® coated metal tray and left to cure under nitrogen atmosphere at 100C for 18

hours.

3.5.2 General Procedure for Thermoset Polyurethane

The following describes the general procedure used to make 15 g of thermoset

polyurethane. For example, for polyurethane DLLA-100 (100% PE-DLLA with ELDI

(1:2)), 7.34 g of the polyol PE-DLLA and 7.65 g of ELDI were added to a 25 mL round

bottom flask and heated to 100°C with a stirrer bead, until the mixture became clear and

colourless. The mixture was then cooled to approximately 50°C and 0.015 g of the

catalyst dibutyl tin dilaurate was added to the mixture. The mixture was then stirred and

degassed for 3 minutes. The degassed mixture was then subjected to the processing

method described in Section 3.6.2

The temperature chosen for this particular example, 100°C, was based on the thermal

properties of the polyol. Some of the polyols were not miscible with the diisocyanate at

lower temperatures and had to be heated for the mixture to react. Not all reactions were

performed at high temperatures.

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POLYURETHANE PROCESSING AND SAMPLE PREPARATION 3.6

The resulting films, both thermoplastics and thermosets, were cut into 45 mm x 5 mm

strips with a scalpel. Prior to tensile testing and in vitro degradations, the polymer was

weighed on a Mettler Toledo AB204-S Classic balance and the thickness of the sheets

was measured with digital callipers (Fowler Value-Cal).

To avoid uptake of ambient moisture, the samples were placed in plastic bags and

stored in a desiccator prior to degradation experiments.

3.6.1 Thermoplastic Polyurethane Processing

Compression moulding was performed on the newly synthesised thermoplastic

polyurethanes using a hydraulic press with a thermostat and water-cooling capability.

The polyurethane was cut into small pieces using clean tin snips and pressed into a 1

mm thick plaque at a temperature above the melting point of the polymer, typically

around 175ºC. The temperature was maintained for 5 minutes before cooling under a

flow of cold water.

The standard mould used consisted of a rectangular cavity, 100 mm x 60 mm x 1 mm

deep, cut into a metal plate. Teflon fabric sheet was used on both sides of the mould to

prevent adhesion of the polymer to the metal. The thermoplastic polyurethanes were

compression moulded into 500 m thick sheets.

3.6.2 Thermoset Polyurethane Processing

The following describes the procedure to prepare 500 µm thick thermoset polyurethane

films. After degassing of the uncured polyurethane (Section 2.5.2), approximately 3.7 g

were poured on a non-stick glass plate (Diamond Fusion Australia), into a 500 µm thick

metallic template while another non-stick glass plate was placed on top and tightly

clamped together. The polyurethane was then cured for 24 hours at 100C under

nitrogen.

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GEL PERMEATION CHROMATOGRAPHY (GPC) 3.7

GPC was performed on all raw and processed thermoplastic polyurethane samples pre-

and post-degradation and at predetermined sampling time points. The GPC set-up used

to determine molecular weight was composed of a Waters 515 HPLC pump attached to

a Waters 2414 Refractive Index Detector. Tetrahydrofuran (THF) was used as the

mobile phase, with a flow rate of 1.0 mL/min.

The polyurethanes were dissolved in THF then filtered using a 0.5 µm (MFS Advantec)

syringe-filter and injected (50 µL) using a Waters 717 plus auto-sampler. A calibration

of the GPC was performed with polystyrene standards with molecular weights ranging

from 500 to 250,000 Da.

The data were analysed using Empower Pro software. For each material, the number

average molecular weight (Mn), the weight average molecular weight (Mw) and the

polydispersity (Mw/Mn) were determined.

DIFFERENTIAL SCANNING CALORIMETRY (DSC) 3.8

Differential Scanning Calorimetry (DSC) analyses were performed using a Mettler

Toledo DSC821e with a TSO 801RO Sample Robot to determine the thermal properties

of the materials, both pre- and post-degradation. The heat rate employed was 10C/min

under nitrogen flow, and the sample weight was between 5-15 mg. Each DSC analysis

was performed twice to ensure a consistent thermal history.

The first DSC run was within a temperature range of -60°C to just below the melting

temperature followed by -60°C to 250°C on the second run. The DSC data were

analysed using Mettler: STARe V.9.00 software to determine the glass transition

temperature (Tg) and the melting point (Tm) of the materials. The midpoints of the glass

transition temperatures were used for all data.

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FOURIER TRANSFORM INFRARED (FTIR) 3.9

For thermoplastic polyurethanes, approximately 10 mg of polymer sample was

dissolved in chloroform (Merck) and placed between two sodium chloride discs and

exposed to air to allow evaporation of the chloroform. For pre- and post-degradation

materials, the FTIR spectra were recorded at room temperature using a Perkin Elmer

Instrument Spectra One FTIR Spectrometer in the range of 400-4000 cm-1.

Infrared measurements for thermoset polyurethanes were performed with a Perkin

Elmer FTIR spectrometer, Spectrum 2000, and the samples were analysed in the range

of 400-4000 cm-1. All FTIR data were processed with Spectrum software.

TENSILE TESTING – INSTRON 3.10

The method used to test the materials was based on ASTM D 882-01(American Society

for Testing and Materials 2002). Tensile testing was performed using an Instron Model

4468 at ambient temperatures and in an environmental chamber at 37C. For all

thermoplastic polyurethanes a 100 N load cell was used with a crosshead speed in the

range of 2.5-120 mm/min (depending on the elasticity of the material). For the

thermoset polyurethanes (excluding Series 6), a 1 kN load cell was used with a

crosshead speed of 2.5 mm/min. The data were processed using BlueHill Version 2.5

software. The polyurethanes were tested under various conditions; dry at ambient

temperatures, wet, after immersion in PBS, at 37 C, and at a number of sampling time

points post-degradation.

Three parameters were measured:

- Tensile Strength (Ts), which represents the maximum amount of tensile stress

that the material can take before failure,

- Young’s Modulus (E), also known as the tensile modulus, is a measure of the

stiffness of an elastic material, i.e the ratio of stress, which has units of pressure,

to strain, and

- Elongation (, the percentage increase in length that occurs before it breaks

under tension.

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PROTON NUCLEAR MAGNETIC RESONANCE (1H-NMR) 3.11

General 1H NMR spectra were recorded on a Bruker AV-400 NMR spectrometer at

400.13 MHz at room temperature. The 1H NMR measurements were carried out with

an acquisition time of 2.7 s, a relaxation delay of 1 s and 30° pulse width, 5995 Hz

spectral width and 32 K data points. The chemical shift was referred to the solvent peak

DMSO (δ = 2.49 ppm). The samples for 1H NMR were made up as a dilute solution in

~0.7 mL deuterated DMSO in a NMR tube.

HIGH PERFORMANCE LIQUID CHROMATOGRAPHY (HPLC) 3.12

Since the analysis of the degradation products was at developmental stage, several

protocols were used to achieve a variety of results.

3.12.1 Analytical HPLC

A Waters HPLC system was used for chromatographic analysis of the degradation

products. The system components included a Waters 600 controller pump. An aliquot

of the dried degradation product dissolved in either distilled water, 0.1M PBS (Gibco)

or acetonitrile (Merck) was placed in a Waters 717 Plus auto-sampler and automatically

injected on a Prevail C18 5 m Hydro column (150 mm x 4.6 mm). The mobile phase

solvents included acetonitrile (Merck), PBS, Trifluroacetic acid (TFA) (Sigma),

distilled and deionised water and a phosphate buffer at pH 2.9 (20 mM KPO4). Prior to

use, all solvents were filtered through 0.45 µm fluorocarbon filter (Millipore). The

degradation products were analysed with a Waters 2996 Photodiode Array Detector,

Waters 2414 Refractive Index detector and a Waters 2487 Dual Absorbance Detector.

Acquisition and processing of the HPLC experimental data were performed using

Millennium.

Prior to each HPLC run, the column was stripped using 100% ACN/TFA (0.7%). The

mobile phase was changed according to the desired outcome. For example, a mobile

phase of 10-25% ACN/Water was used to separate degradation products. To elute more

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47 | P a g e

hydrophobic and high molecular weight degradation products the ratio of ACN/water

was increased to minimise their elution. A mobile phase of phosphate buffer was used

to separate and study the elution times of hydrophilic, low molecular weight

degradation products, polyurethane starting materials and theoretically predicted

degradation products.

3.12.2 Preparative HPLC

A Waters 590 Programmable HPLC pump was used to perform preparative HPLC to

separate, isolate and collect degradation products. The mixtures were separated using a

preparative column (Phenomenex PREPLC, 4m Hydro-RP 80A, 250 mm x 21.20

mm) and fractions were detected with a Hitachi Mode 100-40 UV Spectrophotometer.

As peaks were detected, the fractions were collected in glass vials and their purity

determined by analytical HPLC.

The isolated fractions were further analysed by gas chromatography mass spectrometry,

LC-MS and 1H-NMR to determine the molecular mass and structure of the isolated

compound.

GAS CHROMATOGRAPHY MASS SPECTROMETRY (GC-MS) 3.13

GC-mass spectra were obtained with a ThermoQuest TRACE DSQ GC mass

spectrometer in the positive ion mode with an ionisation energy of 70 eV. The gas

chromatography was performed with a SGE BPX5 (15 mm x 0.1 mm ID, 0.1 m film

thickness), with a temperature program of 40°C for 2 minutes, then heating to 300°C at

25°C/min and the temperature was held for 17.6 minutes. The injections were either

splitless or with a split ratio of 10, the injector temperature was set at 280°C and the

transfer line was also kept at 280°C. High-purity helium was used as carrier gas with a

flow rate of 1 mL/min.

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LC-NMR 3.14

The HPLC system was Hewlett Packard Series 1100 with UV detector G1314A, Binary

Pump G1312A, Autoinjection Module G1313A and Column Heater G1316A. 20 µL of

the sample (mobile phase of water: actetonitrile (80:20)) were injected onto the column

(Prevail C18 5u Hydro column (150 mm x 4.6 mm)) via the auto injector, after

equilibrium of the column with mobile phase. The column temperature was set at 25°C

with a flow rate of 1 mL/min. The progress of the UV trace from the LC chromatogram

was monitored using the Bruker Hystar 3.1 software set on the ON-Flow mode. When

the desired peak was observed in the UV trace, the LC system was stopped using the

Bruker Stop Flow Unit (BSFU), which allows for measured delay, so the sample can be

moved from the UV cell to the NMR probe. The NMR experiment was then set up and

monitored using the Bruker TOPSPIN 2.1 software and finally processed using the

NMR Utility Transform Software for Windows (NUTS) software. On completion of the

NMR experiment the LC system was restarted and monitored until the next peak of

interest was observed. This process is repeated until all peaks of interest have been

analysed. The spectrum processing software was NMR Utility Transform Software for

Windows, 1D version 20050105. The pulse program was LC1pncwps, multiple pre-

saturation 1D NOESY sequence.

ION CHROMATOGRAPHY (IC) 3.15

Ion chromatography (IC) was performed on a Metrohm Modular System. The system

consisted of 5 modules: an 818 IC Pump, an 819 IC Detector which measures the

conductivity of the particles moving through the mobile phase, an 820 IC separation

centre, an 830 IC interface and an 833 Liquid Handling Unit. A Metrosep (6.1005.200

Organic Acids) column was used to separate degradation products with a mobile phase

of 0.5 mmol/L of sulphuric acid flowing at a rate of 0.5 mL/min. All samples were

filtered through a 0.45 m filter before injection of 20 L into the unit. The data were

processed using ICNet Version 2.3.

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NINHYDRIN ASSAY 3.16

Determination of the amine concentration of degradation products was performed using

a ThermoSpectronic spectrophotometer using a commercially available ninhydrin

reagent solution (Sigma). A calibration curve was prepared using the method provided

by the vendor.

The concentrations of amines in the degradation products were determined by acquiring

the absorbance at 570 nm (A570) and quantified against a calibration curve. The

experiments were performed in triplicates and the results are reported as the average of

three measurements.

ACCELERATED SOLVENT EXTRACTION (ASE) 3.17

An accelerated solvent extraction unit, ASE 100 Accelerated Solvent Extractor (Dionex

Co.), was used for the extraction experiments. A stainless steel extraction cell with a

maximum volume of 47 mL was used to hold the samples.

The mobile phase was warm distilled water (30C) and the system subjected to a

maximum pressure of 1700 psi. Polymer samples were approximately 200 mg and

sample extracts 250 mL.

ROTARY EVAPORATION 3.18

Rotary evaporation was performed with a Rotavapor (Büchi RE111) attached to a

Vacuubrand CVC 2000II (PC 2001 Vario). Samples were placed in 5-15 mL round

bottom flasks and subjected to vacuum at ambient temperature until the solvent had

completed evaporated.

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POLYURETHANE WATER ABSORPTION TESTS 3.19

Water absorption/uptake was carried out in line with (American Society for Testing and

Materials 2010). Polymer samples, in triplicates, were first dried and weighed using a

Mettler Toledo AB204-S Classic balance. They were then placed into 0.1M Phosphate

Buffered Saline solutions at pH 7.4 (PBS: Na2HPO4 0.07 M, KH2PO4 0.008 M, NaCl

0.15 M, NaN3 1%) and kept at 37C for 24 hours. The samples were then reweighed

whilst wet to determine the water uptake of the polymer, using Equation 3.4.

Water Absorption (%) = %100)(

0

0

mmmw (3.4)

Where wm is the wet mass and 0m is the dry mass of the sample.

IN VITRO DEGRADATION PROCEDURES 3.20

Polymers were subjected to different degradation procedures. Real time degradation

experiments were carried out to simulate biological conditions and study the changes

that occur in the polymer during the degradation process.

Accelerated degradation experiments were carried out to speed up the process of

degradation to only study the degradation products.

3.20.1 Real-Time in vitro Degradation

In vitro degradations were carried out in line with ASTM F 1635 (American Society for

Testing Materials 2004), in 65 mL glass vials containing 0.1 M PBS pH 7.4 0.2 at

37C in a shaking incubator set at 50 rpm, for up to one year with sampling time points

at t = 24 hours, 14 days, 42 days, 90 days, 180 days, 365 days. Six samples of each

polymer were immersed and the pH was measured with a Cyberscan 100 pH meter at

each sampling time point and recorded. After removal from degradation at each

sampling time point, the polymers were placed in water for 7 days to remove any salts

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that may have become trapped within the polymer, then dried under nitrogen and

subsequently under vacuum for 7 days or until a constant weight was reached.

Post-degradation masses were determined with a Mettler Toledo AB204-S Classic

balance and mass losses of the polymers were calculated using Equation 3.5:

Mass Loss (%) = %100)(

0

0

mmm t (3.5)

Where 0m is the original dry weight of the polymer, prior to degradation, and tm is the

dry weight of the material post-degradation, t indicates the number of days the polymer

was subjected to the degradation process in PBS.

The PBS was further analysed for the presence of primary and secondary amines, and

other predicted degradation products.

3.20.2 Accelerated in vitro Degradation

Polymers were also subjected to an accelerated degradation to identify the degradation

by-products liberated from the polymer.

Accelerated degradation at 100C

Polymer samples were added to a 250 mL round bottom flask with distilled water and

attached to a condenser and heated to 100C for up to 72 hours (depending on the

degradability of the polymer) or until the polymer had appeared to have undergone

some degradation.

Accelerated degradation at 70C

Polymer samples in closed glass vials were incubated in distilled water at 70C for up to

2 weeks.

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Accelerated degradation under acidic and alkaline conditions

Polyurethanes were exposed to acidic and alkaline conditions to accelerate in vitro

degradation. A buffer solution of pH 1 (0.13 M HCL, 0.05 M KCl) and a buffer solution

of pH 11.5 (0.05 M Na2HPO4, 0.022 M NaOH) were used for in vitro degradation

studies on thermoset polyurethane Series 6 to determine the effects of pH on

polyurethane degradation.

Table 3.8 Real-time and accelerated degradation sampling times, temperature and pH.

Series Real Time Degradation Accelerated Degradation

Sampling Time Points Temperature pH

24 h 14 d 42 d 90 d 180 d 365 d 100°C 70°C pH 1 pH 11.5

1 - - -

2 - - - -

3 - - - -

4 - - -

5 - - -

6 - -

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4 CHARACTERISATION OF THE

SYNTHETIC POLYURETHANES

INTRODUCTION 4.1

This chapter deals with the determination of the most important physical characteristics

of thermoplastic and thermoset polyurethanes before undergoing in vitro degradation.

These data are used as reference, i.e. time t = 0, which will be subsequently compared to

data acquired after degradation, to measure the impact of exposure to a physiological

environment.

The analytical techniques used to build a profile of the polyurethanes prior to

degradation are summarised in Table 4.1.

Table 4.1 Analytical techniques used for the characterisation of selected polymers.

PU

Series

GPC (Molecular

Weight)

DSC (Thermal

Properties)

Tensile Testing (Mechanical

Properties) FTIR

Water

Absorption

1 (Tm & Tg) (E, Ts & ) 2 (Tm & Tg) (E, Ts & ) 3 (Tm & Tg) (E, Ts & ) 4 - (Tg) (E, Ts & ) 5 - (Tg) (E, Ts & ) 6 - (Tg) -

Tm = melting temperature, Tg = glass transition temperature, E = modulus Ts= tensile strength, = elongation

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A total of six series of thermoplastic and thermoset biodegradable polyurethanes were

synthesised for the purpose of this study, with series 1-3 being thermoplastic

polyurethanes and the remaining series 4-6 being thermoset polyurethanes. Table 4.2

lists the compounds used to synthesise series 1-3 thermoplastic biodegradable

polyurethane and describe briefly the nomenclature of these polyurethanes.

Table 4.2 Nomenclature and abbreviations for series 1-3 thermoplastic polyurethanes.

Polyurethane Name

Diisocyanate Chain Extender Polyol % Hard Segment

Series 1






Series 2






Series 3





Chapter Four

55 | P a g e

The rationale behind synthesising polyurethane series 1 and 2 was essentially to

compare the properties and degradation rates of polyurethanes following modifications

in the formulations of the polymers.

The primary goals were to investigate whether (a) the percentage content in hard

segment, and, (b) the incorporation of a degradable chain extender (DCE), would have

an effect on the main properties and the degradation rates. PCL1000 was utilised as a

soft segment because of its high hydrophobicity and low tendency to undergo hydrolytic

degradation. The presence of a slow degrading soft segment should make it easier to

determine the impact of alterations imparted into the hard segment.

Series 3 polyurethanes were designed to investigate the effect of the nature of the

diisocyanate on the properties of the polyurethanes and their degradation rates by using

two types, HDI and ELDI, with either DCE or non-DCE. There is a substantial

difference between the structures of these two diisocyanates: with HDI being a straight

chain molecule with a greater symmetry than ELDI, the latter bearing a side branch on

the main carbon chain. The geometry of the molecules will influence the way the

polymer is finally formed and somehow affect its basic properties. In the case of the

linear HDI, there is an expectation that the material form will be more tightly packed

and thus be denser. On the other hand, the presence of a side branch on the ELDI

monomer will result in the final polymer being more porous and not as dense.

Table 4.3 lists the compounds used to synthesise series 4-6 thermoset biodegradable

polyurethanes. Series 4 and 5 were synthesised to measure the effects of changing ratios

of two different polyols. The results for series 4 and 5 can be compared within each

series, by determining the effects of varying ratios of the fast degrading polyol PE-GA

(P2), and against each other, by measuring the effects of the nature of the

complementary polyol used, (P1).

For Series 6 thermoset polyurethanes the main objective was to assess the effects of

increasing cross-linking density. By increasing the volume of PCL4 (a star polymer) in

a formulation, the resulting polyurethane crosslink density would also be expected to

increase.

Chapter Four

56 | P a g e

Table 4.3 Nomenclature & abbreviations for series 4-6 thermoset polyurethanes.

Polyurethane

Name

Diisocyanate Polyol 1

(P1)

Polyol 2

(P2)

% of P1 to

P2

Series 4






Series 5






Series 6

PCL4-100 ELDI PCL4 - 100:0







PCL-100 ELDI - PCL1000 0:100

Chapter Four

57 | P a g e

CHARACTERISATION OF THE THERMOPLASTIC POLYURETHANES 4.2

Table 4.4 (next page) reports all data relative to molecular weights, mechanical

properties and thermal properties of polyurethane in series 1-3 prior to in vitro

degradation. Essentially, the molecular weights were determined by chromatography,

the thermal properties by differential scanning calorimetry and the tensile strengths and

moduli using an Instron.

4.2.1 Average Number Molecular Weights

The average number molecular weights (Mn) and weight average molecular weight

(Mw) of the polyurethanes are shown to be in the range 2.3 x 104 to 16.3 x 104 Da and

3.7 x 104 to 24.4 x 104 Da respectively. Within series 1 and 2, the general trend

observed is a decrease in Mn & (Mw) with increasing hard segment (Figure 4.1). One

trivial reason would be that it follows a reduction in the formulations of the proportion

of PCL, which is the highest molecular weight component in the PU. For example,

ELDI-0 shows the highest Mn & (Mw) for both series.

Chapter Four

58 | P a g e

Figure 4.1 Graph summarising the trends observed in weight average molecular weights for series 1 and 2 polyurethanes.

2030405060708090100

0

20000

40000

60000

80000

100000

120000

140000

160000

180000

200000

0 10 20 30 40 50 60 70 80Weg

ht A

vera

ge M

olec

ular

Wei

ght,

Mw

(Da)

Percentage PCL (wt/wt %)

ELDI-LAEG

ELDI-EG

Percentage Hard Segment (wt/wt %)

Chapter Four

59 | P a g e

Table 4.4. Number and weight average molecular weights, dispersity, mechanical properties and thermal characteristics of series 1- 3 thermoplastic polyurethanes.

Series 1 Mn Mw ĐM E (MPa) Ts (MPa) (%) Tm (°C)(SS) Tg (°C) ELDI-0 163, 010 244,515 1.5 7.90 1.71 4.62 0.81 1172 126 38.9 -46.2

ELDI-LAEG-30 61,629 123,258 2.0 4.03 1.06 2.94 0.19 983 167 40.0 -35.9

ELDI-LAEG-50 68,244 116,015 1.7 3.99 0.69 1.05 0.85 1165 118 38.9 -10.2

ELDI-LAEG-70 40,454 60,681 1.5 2.09 0.77 3.55 0.41 979 46 40.6 13.6

ELDI-LAEG-100 23,658 37,853 1.6 1159 114 33.0 4.6 5.0 0.4 - 36.1

Series 2 Mn Mw ĐM E (MPa) Ts(MPa) (%) Tm (°C)(SS) Tg (°C) ELDI-0 163, 010 244,515 1.5 7.90 1.71 4.62 0.81 1172 126 38.8 -46.2

ELDI-EG-30 117,991 176,987 1.5 11.20 1.78 1.15 0.08 263 21 38.1 -35.1

ELDI-EG-50 113,552 170,328 1.5 8.54 0.82 1.02 0.1 1519 152 40.6 -3.1

ELDI-EG-70 80,876 137,489 1.7 4.20 0.93 4.74 0.6 889 79 41.4 16.0

ELDI-EG-100 51,185 61,422 1.2 1109 64 35.0 4.1 5.2 0.9 - 36.7

Series 3 Mn Mw ĐM E (MPa) Ts(MPa) (%) Tm (°C)(SS) Tg (°C) ELDI-LAEG-30 61,629 123,258 2.0 4.11 1.06 2.94 0.19 983 167 40.3 -35.9

HDI-LAEG-30 102,704 143,786 1.4 17.04 4.22 6.20 0.50 923 71 55.1, 70.2* -44.9

ELDI-EG-30 117,991 176,987 1.5 11.20 1.78 1.15 0.08 263 21 38.1 -35.1

HDI-EG-30 140,479 238,814 1.7 21.12 4.60 29.0 3.7 1084 67 50.2, 120.4* -45.2

Mn= number average molecular weight, Mw= weight average molecular weight, E= Young’s modulus, ĐM = molecular weight dispersity

Ts= Tensile strength, = elongation, Tm= melting temperature, Tg= glass transition temperature

Chapter Four

60 | P a g e

Reasoning only on the basis of the molecular weight of the individual component, and

assuming that all other parameters are strictly identical (reactivity of the mixture, degree

of polymerisation, completeness of the reaction), the ascending order of the weight

average molecular weights of Series 3 would be:

ELDI-LAEG > HDI-LAEG > ELDI-EG > HDI-EG

However, the results show exactly the opposite trend, with HDI-EG having the highest

molecular weight and ELDI-LAEG the lowest. This is an indication that there are either

other factors governing the polymerisation process or that one or more of the reaction

parameters would differ significantly, being influenced by the chemical properties of the

individual components.

The decrease in Mn with the polymers containing degradable chain extenders could be

partly due to two effects:

(a) Compared to ethylene glycol, which has two primary hydroxyl groups, the

degradable chain extender LA-EG has one primary and one secondary hydroxyl

groups. Also, LA-EG is a dihydroxy ester, compared to EG, which is a diol, and as

such the terminal OH groups are expected to differ in reactivity due to the inductive

effect of the ester group.

(b) The starting molecules of the degradable chain extender being structurally more

complex than ethylene glycol, the non-DCE, will have an influence on its chemical

reactivity, and may affect the way the monomers interact to each other.

For Series 3, a similar trend is seen, with HDI-based polyurethanes showing a higher Mn

than their counterparts with ELDI. This difference may be partly attributed to the

difference in reactivity of the isocyanate groups in HDI and ELDI, with the ester group

in ELDI having an effect similar to that observed with the polyol.

In the linear HDI, both terminal isocyanate groups have equal reactivity due to the

symmetry of the molecule. On the other hand, in ELDI one isocyanate group is attached

to a secondary carbon itself connected to an ester group. Ester groups are known to have

Chapter Four

61 | P a g e

an electron withdrawing effect, which can result in a decrease in the reactivity of the

end –NCO. The pulling effect of the ester group will limit delocalisation of the electrons

on the carbonyl of the NCO. The reaction between the diisocyanate and the alcohol is

dependent on the polarisability of the carbonyl group of the –NCO, with a migration of

the charge on the oxygen. The presence of an ester group in the proximity may induce a

slight deactivation, rendering the terminal –NCO less electrophile.

Besides the reactivity factor, steric hindrance can also influence impose limitations on

reactivity by restricting access to the active sites or affecting the way the components

interlink to generate the polymer network. Linear molecules like EG and HDI, will pack

more tightly and thus in the same volume more molecules can be accommodated,

compared to the branched analogues, yielding a denser and heavier material.

The molecular weight dispersity (ĐM = Mw/Mn) of the materials ranged from 1.2 and

2.0, which is a fairly narrow range, with no evident correlation between dispersity and

molecular weight. The molecular weight dispersity indicates the distribution of

individual molecular masses in a batch of polymers and it can be affected by a variety of

reaction conditions: ratio of reactants, duration, degree of completion, etc. By contrast a

monodisperse polymer is composed of molecules of the similar molecular weight,

within a very close range. The low values for dispersity observed in general in the

synthesised polymers imply that the degree of heterogeneity in molecular weights is

rather small.

One interesting observation with the molecular weight dispersity data is the variance

induced upon the introduction of the degradable chain extender LAEG, a branched

molecule. When compared to the initial material without a chain extender, ELDI-0,

which has a dispersity of 1.5, there is a non-negligible increase to 2.0. On the other

hand, considering a value of 1.6 obtained for the 100% hard segment polymer, ELDI-

LAEG-100, it would seem that LAEG has very little impact on dispersity. However, a

trend can be noted in the change in dispersity with increasing load of hard segment.

This may be due to the fact that these materials are heteropolymers with three

components (ternary system), which tend to have less heterogeneity when the

proportion of one of the ingredients is decreased, behaving more like a binary system.

Chapter Four

62 | P a g e

The effect of branching on dispersity becomes more apparent when comparing Series 1

to Series 2. In the ELDI-EG polymers, the dispersity remains almost constant within the

series. Comparing ELDI-LAEG-100 (ĐM =1.6) to that ELDI-EG-100 (ĐM =1.2) we can

quite confidently suggest that for these polymer series, the use of a branched chain

extender bearing distinctive functional groups, will have an influence on the reactivity

of the monomers as well as on the way they interconnect.

4.2.2 Mechanical Properties

Figure 4.2 illustrates the trends observed in the both tensile strength and modulus of

series 1 & 2 polymers with increasing percentages of hard segment. The tensile

strengths and moduli for polyurethanes were generally low with the exception of

polyurethanes containing 100% hard segment. As anticipated, polyurethanes without

PCL, i.e. no soft segment, showed the highest modulus (E) and tensile strength (Ts), and

the lowest percentage elongation (), making them the stiffest samples in the two series.

Figure 4.2 Tensile strength (---) and modulus ( ) for series 1 and 2 polymers with 30, 50 and 70% HS.

Polyurethanes with a degradable chain extender exhibited slightly lower E but similar Ts

compared to Series 2 with non-DCE. The introduction of a branched component tends

to decrease the molecular weight, making the material less dense, and, thus, affecting its

0

2

4

6

8

10

12

0

1

2

3

4

5

0 10 20 30 40 50 60 70 80

You

ng's

Mod

ulus

, E (M

Pa)

Ten

sile

Stre

ngth

, Ts (

MPa

)

Percentage of PCL (wt/wt %)

(Ts) ELDI-LAEG

(Ts) ELDI-EG

(E) ELDI-LAEG

(E) ELDI-EG

Chapter Four

63 | P a g e

mechanical properties. However, within each series there was a relatively weak

correlation between molecular weight and tensile strength. The general observation with

both DCE and non-DCE-based polyurethanes is that the as the Mn decrease, the tensile

strength decreased slightly. The difference in tensile strength between the two series is

not significant.

The modulus showed an opposite trend, which may be attributed to decreasing

molecular weight rather than to any other structural effects resulting from the difference

in composition. However, the difference in modulus is more substantial with non-DCE

(EG) based polyurethanes showing higher modulus compared to Series 1 containing

DCE. In non-DCE based polyurethanes, the modulus appears to be proportional to the

percentage of hard segment.

In Series 3, HDI-based polymers showed slightly higher moduli and tensile strengths

than ELDI-based ones. Most particularly HDI-EG-30 exhibits exceptionally high tensile

strength, although the polymer is made up of 70% soft segment. Its Ts is of the same

order of magnitude as the 100% hard segment polyurethane ELDI-EG -100 and ELDI-

LAEG-100, but has a much higher molecular weight.

However, although the moduli of HDI-polyurethanes are significantly increased, as

compared to all the other polymers in series 1 and 2, they are still much lower than the

values observed for 100% hard segments. Polyurethanes with 100% hard segment

showed very high modulus (and tensile strength) due to urethane bond interactions and

the polymer behaves more like a glass. Whereas in the HDI-polymers the presence of

significant proportion of the soft segment PCL (70%) allows the material to maintain its

elasticity. In general, the elongation for all polyurethanes with the exception of 100%

HS Polyurethane and ELDI-EG-30 was in the range of ~900 to 1500%.

Within both series, when comparing the 100% hard segment to the rest, all containing

the soft segment PCL, the overall the mechanical properties seems to be governed by

the soft segment: drastic loss in modulus and tensile strength but significant gain in

elasticity. The general trend in Series 3 gives an insight into the role of the hard

segment: it can be seen as a ‘fine tuning’, where the nature of the diisocyanate-polyol

pair provides a means to adjust both the modulus and tensile strength.

Chapter Four

64 | P a g e

4.2.3 Thermal Properties

In series 1 and 2, all polyurethanes except those with 100% hard segment, exhibited

both a melting endotherm due to the mostly crystalline domains of the soft segment and

a glass transition. This is mainly due to the presence of PCL which gives the materials

most of their plasticity. The DSC thermal traces of Series 1 polymers are reported in

Figure 4.3. All polyurethanes, except the 100% hard segment ELDI-LAEG-100 showed

considerable soft segment phase separation indicated by the presence of melting

endotherms and typical of thermoplastics.

Figure 4.3 DSC traces for Series 1 polyurethanes. The dotted line ellipse indicates the Tg and the full line one the Tm.

The two zones are identified on the graph: Tg, where the polymers undergo a transition

from a viscous amorphous structure to a brittle glassy amorphous solid and, Tm, which

characterises a transition from a crystalline or semi-crystalline phase to a solid

amorphous phase. The absence of any thermal transitions at higher temperature is

indicative of a lack of crystallinity in the hard segment. This can be largely attributed to

the asymmetrical nature of ELDI, which due to its branched structure will not favour

close and tight packing.

The general trend observed with the Tm is that the temperature range tends to broaden

with increasing loading of hard segment. A sharp feature of the endotherm associated

Hea

t Flo

w (a

.u)

Temperature (ºC)

Tg

ELDI-0

ELDI-LAEG-30

ELDI-LAEG-50

ELDI-LAEG-70

ELDI-LAEG-100

X

Tm

Chapter Four

65 | P a g e

with Tm is a general characteristic of highly crystalline substances. This correlates quite

well with the data for molecular weights: decreasing Mw with increasing hard segment.

The polymer is made up of smaller blocks which increase the number of

interconnections and generates a broader distribution of energies. This heterogeneity at

macromolecular level contributes to induce significant disturbances to inhibit

crystallisation and form a more amorphous material. The changes in mechanical

properties discussed previously are also in agreement with this trend, with a loss of

modulus (less crystalline) and gain in elasticity (more amorphous).

The intensity of the endotherm related to Tm is proportional to the relative percentage of

PCL, which corroborates with the observation made in the mechanical properties of the

polymers, i.e. governed by the soft segment. In ELDI-0, which actually contains 18%

hard segment but with no chain extender, the thermal event occurring at around -60°C

and noted ‘X’ on the graph, most probably represents the glass transition of PCL. This

would then imply that at high loading of PCL in the formulation, there could be partial

phase segregation. On the other hand, at lower loading of PCL there appears to be a

better miscibility of the hard and soft segments as only one Tg and one Tm are observed

(Mohamed et al 2008). With 100% hard segment only a glass transition is observed as

this material is completely amorphous. A similar trend is observed with Series 2

polymers (Figure 4.4).

Figure 4.4 DSC traces for Series 2 polyurethanes. The dotted line ellipse indicates the Tg and the full line one the Tm.

Hea

t Flo

w (a

.u)

Tg

ELDI-0

ELDI-EG-30

ELDI-EG-50

ELDI-EG-70

ELDI-EG-100

X

Tm

Temperature (ºC)

Chapter Four

66 | P a g e

Figure 4.5 shows the trend observed in the glass transition temperatures with increasing

hard segment content in series 1 and 2. In both series there appears to be a linear

relationship between the percentage of hard segment and the glass transition

temperature.

Figure 4.5 Evolution of Tg with increasing hard segment in series 1 and 2.

y = 1.0393x - 64.229 R² = 0.9889

-60

-50

-40

-30

-20

-10

0

10

20

30

40

50

0 10 20 30 40 50 60 70 80 90 100

Tem

pera

ture

(ºC

)

% Hard segment (wt/wt)

Series1

y = 1.0447x - 62.335 R² = 0.9729

-60

-50

-40

-30

-20

-10

0

10

20

30

40

50

0 10 20 30 40 50 60 70 80 90 100

Tem

pera

ture

(ºC

)

% Hard segment (wt/wt)

Series 2

Chapter Four

67 | P a g e

By dosing the amount of hard segment the two series exhibit the gradual transformation

from a thermoplastic to a glassy material. The data also fit well with the experimental

value of Tg obtained for pure PCL, which is around 60ºC. An extrapolation of the two

curves above would give 64ºC and 62ºC. The presence of DCE does not appear to have

major effects on the morphological properties of the polyurethanes. As anticipated the

melting endotherm peak temperature varied within a very narrow temperature range in

both series.

The thermal traces of the polyurethanes determined by DSC are shown in Figure 3.6.

HDI-based polyurethanes showed lower Tg and higher Tm than ELDI-based

polyurethanes. The structure of the diisocyanate appeared to have more effect on

thermal transitions. The incorporation of HDI produced polyurethanes with ordered

hard segments, resulting in hard segment melting endotherms at 70ºC and 120ºC,

respectively for DCE and EG chain extended polyurethanes.

Figure 4.6 DSC traces for Series 3 polyurethanes. Note: All polymers in this series have 30% hard segment.

Chapter Four

68 | P a g e

The glass transition for HDI-based polyurethanes shifted to lower temperatures,

indicating better phase separation compared to ELDI-based materials. The presence of a

more linear molecule facilitates the movement of the polymer chains inside the

materials, thus decreases the Tg. The presence of branching tends to produce some

interference with the flow of the molecular chains thereby causing the glass transition

temperature to increase.

4.2.4 Water Absorption

Water absorption measurements were carried out after 24 hours incubation in PBS at

37C and the samples were pre-treated according to strict protocol to minimise errors. It

has been reported elsewhere that the initial amount of water absorbed may have an

influence on the subsequent degradation of the polyurethanes, given that degradation

takes place via hydrolysis of the urethane bonds (Timmins & Liebmann-Vinson 2003;

Penco 1996). The rate of degradation will be affected if water molecules can infiltrate

the bulk of the polymer, as opposed to being restricted to surface erosion. Water

absorption for Series 1 (Figure 4.7) was in the range of 2-10%.

Figure 4.7 Water absorption for series 1 and 2 after 24 h incubation at 37°C in PBS.

020406080100

0

2

4

6

8

10

12

0 20 40 60 80 100

Mas

s Inc

reas

e (%

)

Hard Segment (wt/wt %)

Series 1 ELDI-LAEGSeries 2 ELDI-EG

PCL (wt/wt %)

Chapter Four

69 | P a g e

The general observation is that polyurethanes containing non-DCE absorbed more water

than those with DCE. While within Series 1 the trend is a continuous absorption with

increasing hard segment percentage, with Series 2, the polymer reaches saturation at

70% hard segment. Beyond this composition the polymer does not seem to be able to

absorb more water within the prescribed equilibration time. For polyurethanes without

PCL (100% HS), the water absorption pattern was reversed, with the polyurethanes

containing DCE showing a higher water uptake than those containing EG.

It is obvious that an increase in the content of PCL causes the materials to become more

hydrophobic as they consequently restrict water absorption. This is reflected in the

graph as a decrease in water uptake as the percentage of PCL increases in the polymers

(from right to left on the upper axis in Figure 4.7). As the results also suggest, the hard

segment would then be more hydrophilic as more water is absorbed in those

polyurethanes with higher hard segment content. Other factors, such as an increase in

porosity in the bulk of the polymer can also affect the intake of water.

In the presence of PCL, there seems to be very little difference in the capacity of the

polyurethane to absorb water whether hard segment is degradable or not. Water

absorption in the mixed materials, although increases, appears to be governed by the

nature of PCL. Polyurethanes with lactic acid as DCE appear to be slightly more

hydrophobic than those with ethylene glycol. Based on solubility data, which gives an

indication of their affinity to water, ethylene glycol is highly soluble with 100% wt/wt

while lactic acid, with a maximum of only 10g/L is comparatively rather insoluble.

However, in the presence of PCL, this significant difference does not seem to affect the

capacity of the mixed polymers to withhold water.

On the other hand, the materials without soft segments (PCL) i.e. ELDI-LAEG-100 and

ELDI-EG-100, exhibited a different pattern to those with soft segments. This is possibly

a result of the ethylene glycol chain extender-based polyurethanes’ ability to pack

tightly and subsequently allowing less water to infiltrate into the bulk of the

polyurethane. Moreover, in the absence of PCL, intrinsic properties of the component

will take over, and in the case of ELDI-LAEG, part of the lactic acid may have

undergone hydrolysis making the material more avid of water.

Chapter Four

70 | P a g e

In Series 3 polyurethanes (Figure 4.8), water absorption ranged from ~0.7% to 3% with

ELDI-based polyurethanes showing a higher water uptake than HDI-based ones.

Figure 4.8 Water absorption data for Series 3 after 24h incubation at 37°C in PBS.

For ELDI-based polyurethanes, there was a trend towards higher water absorption for

polyurethanes with non-DCE as opposed to those with a degradable chain extender.

However, for HDI-based polyurethanes, the opposite trend was observed, presumably

due to more ordered hard segment in HDI-EG polyurethane. The combination of two

linear components seems to have an enhanced effect of their ability to not absorb water.

However, the differences are very small and is an indication that most water adsorbed

will be limited to superficial intake, rather than in the bulk of the material. At the same

time there could be variations in the hydrophobicity of the polymer as a result of the

changes in chemical composition.

0.00

0.50

1.00

1.50

2.00

2.50

3.00

3.50

4.00

4.50

ELDI-LAEG-30 HDI-LAEG-30 ELDI-EG-30 HDI-EG-30

Sample

Mas

s Inc

reas

e (%

)

Chapter Four

71 | P a g e

CHARACTERISATION OF THERMOSET POLYURETHANES 4.3

The purpose of synthesising series 4 and 5 thermoset polyurethanes is to determine the

effects of changing the ratio of the two different polyols on properties and degradation.

The polyols differ significantly in their structure: a linear chain for glycolic acid, a

branched chain for lactic acid and an aromatic ring with mandelic acid. The structures

of the various additives are shown in Figure 4.9.

Figure 4.9 Polyols used in Series 4 & 5 polyurethanes.

Table 4.5 summarises the mechanical and thermal properties of polyurethane in series 4

and 5, prior to in vitro degradation.

Table 4.5 Mechanical and thermal properties of Series 4 & 5 thermoset polyurethanes.

Series 4 E (MPa) Ts (MPa) E (%) Tg (ºC)

DLLA-100 1404±90 22.0±4.5 42±9 64.19

DLLA:GA-75:25 1249±200 20.0±2.6 68±15 64.29

DLLA:GA-50:50 1141±113 18.0±3.1 65±6 63.67

DLLA:GA-25:75 530±146 12.0±2.2 64±5 64.66

GA-100 482±39 14.0±0.4 70.0±1.6 61.78

Series 5 E (MPa) Ts (MPa) E (%) Tg (ºC)

LLA/MA-100 1826±185 38.0±4.3 5.2±0.7 83.86

LLA/MA:GA-75:25 1772±138 33.0±2.3 6.0±2.0 88.22

LLA/MA:GA-50:50 1592±207 29.0±4.9 6.6±2.3 63.97

LLA/MA:GA-25:75 1400±347 44.0±2.1 40.0±2.6 64.01

GA-100 482±39 14.0±0.4 70.0±1.6 61.78

Poly(lactic acid)) Poly(glycolic acid)) Mandelic acid

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72 | P a g e

4.3.1 Mechanical Properties

The modulus (E) and tensile strength (Ts) data for series 4 and 5 reported in Figure 4.10

are indicative of the very good mechanical strength they possess. The general trend

observed in both series is a decrease in modulus with increasing proportions of glycolic

acid. The first observation is that both E and Ts are generally lower for Series 4

polyurethanes. For these polymers E ranges from 500 to 1400 MPa; with GA-100

showing the lowest value and DLLA-100 the highest.

Figure 4.10 Modulus and tensile strength for series 4 and 5 polyurethanes.

The trend observed tends to suggest that it is PE-DLLA that imparts the materials their

high modulus: as the PE-DLLA content decreases, so too does the modulus. This

pattern is also seen with the Ts results. Series 5 polyurethanes show similar patterns for

E and Ts, compared to Series 4, although the E and Ts are noticeably higher for the

latter. Specifically, the modulus ranges from 500 to 1800 MPa with 100% PE-LLA/MA

polyol based polyurethanes showing the highest E and 100% GA polyol based

polyurethanes showing the lowest E. As with Series 4 the pattern appears to be relative

to the percentage of PE-LLA/MA in the material with the E decreasing as this polyol

decreases. This pattern is also seen with the tensile strength results. However,

polyurethane LLA/MA-25:75 appears to be an outlier, with the Ts being superior to all

polyurethanes tested. This result does not fit into the pattern and is possibly due to the

05101520253035404550

0

500

1000

1500

2000

0 20 40 60 80 100

Tensile Strength (MPa)

Mod

ulus

(MPa

)

Percentage GA (wt/wt)

Modulus Series 4Modulus Series 5Tensile Series 4Tensile Series 5

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73 | P a g e

chemical morphology of this polyurethane. The mandelic acid has pendant phenyl

moieties which results in steric hindrance and pi-pi interactions between MA’s in close

proximity which can result in low elongation and a stiff material. This is normal for

polymers with a high content of mandelic acid. It looks like this is causing premature

breakage (values of 5 and 6% elongation are quite low) in the high-MA polymers which

results in lower tensile strength. The reduced content of MA in LLA/MA:GA-25:75 has

resulted in a slightly reduced modulus compared with the LLA/MA-100, ’75:25, and

’50:50. The modulus is expected to drop off rapidly due to a thermal transition we are

crossing there (due to change in the madelic acid content) and it appears to occur

somewhere between the ’25:75 and ‘100 since it drops rapidly from 1400 MPa to

482MPa with the change of composition. There is also an increased elongation (40% is

a significant increase compared with 5% and 6 – it is a combination of these two

(elongation and modulus) which explains the tensile strength.

Elongation data for series 4 and 5 are summarised Figure 4.11. Series 4 polyurethanes

show a considerably higher percentage elongation compared to the Series 5

homologues. The percentage elongation for most polymers in Series 4 is between 65%

and 70%, with the 100% PE-DLLA-based polyurethane showing a slightly lower value.

Within this series a significant increase is observed upon addition of 25% GA but not

much variation is noted at higher loading. Beyond a certain composition, there appears

to be no particular pattern or relationship between the percentage of polyol present in

the PU and the elongation properties. For Series 5, polyurethanes with more PE-

LLA/MA polyol tend to be more rigid but show a drastic increase in elongation at 75%

loading in PE-GA. This is related to the softening of the material with the increased GA

content as evidenced by the corresponding moduli. High modulus thermosets typically

do not have good elongation, whereas low modulus thermosets typically do.

Chapter Four

74 | P a g e

Figure 4.11 Percentage Elongation for series 4 and 5 polyurethanes.

In summary, Series 4 Polyurethane showed lower E and Ts with considerably higher

elongation compared to Series 5 polyurethanes, which are tougher, more brittle

materials with high E and Ts, and very low elongation. Within each series the same

pattern was observed: increasing proportions of the PE-GA polyol caused a decrease in

E and Ts. The plasticising effect of PE-GA making the materials softer and more

flexible.

These results suggest that the chemistry of the polyurethanes has a non-negligible effect

on their mechanical properties, with polyurethanes containing the PE-LLA/MA-base

polymers being the strongest and most brittle, and GA-based materials proving to be the

weakest and most elastic materials. PE-LLA/MA based materials have almost twice the

Ts than PE-DLLA based materials, and when comparing the first member of each series,

DLLA-100 and LLA/MA-100, it can be confidently suggested that the main differences

observed in mechanical are due to the introduction of mandelic acid. Figure 4.12

illustrates how the polyols affect the mechanical properties.

0

10

20

30

40

50

60

70

80

0 20 40 60 80 100

Elo

ngat

ion

(%)

Perecentage GA (wt/wt %)

Series 4

Series5

Chapter Four

75 | P a g e

Figure 4.12 Effect of polyol structure on mechanical properties.

The superior elastic property of the PE-GA polymer stands out, being over twelve times

more elastic than PE-LLA/MA. As expected, an opposite trend is observed in modulus

and tensile strength; both DLLA and LLA/MA have higher moduli and tensile

strengths, and are thus not as deformable. These two polyols will give the resulting

polyurethanes their rigidity in their respective series. There could be a structural origin

for these divergences in mechanical properties. If we consider elasticity, apart from the

requirement for long polymer chains, there is also a need for the chains to have some

degree of conformational mobility. This is generally achieved by the existence of voids

in the bulk of the material (amorphous regions) and free rotation around the linking

bonds.

With the linear GA, free rotation in a confined environment can still be envisaged. In

the case of DLLA, with a branched methyl group, and the aromatic ring of mandelic

acid there will be some restrictions on the movement of the molecules which will have

repercussions on the behaviour of the macromolecule.

0

2

4

6

8

10

12

14

Modulus Tensile Elongation

Rel

ativ

e M

agni

tude

(a.u

.)

Mechanical Property

GA-100

DLLA-100

LLA/MA-100

Chapter Four

76 | P a g e

4.3.2 Thermal Properties

The effect of the percentage of glycolic acid on the glass transition temperatures of

Series 4 & 5 polymers is reported in Figure 4.13. All polyurethanes exhibited glass

transitions between ~60 and 90°C.

Figure 4.13 Plot of glass transition temperature against the percentage of GA in Series 4 & 5 polyurethanes.

At low percentages of PE-GA, the glass transition temperatures for Series 5

polyurethanes were higher than those of Series 4 polyurethanes. But as the amount of

PE-GA increases the Tg shows a sharp decrease to stabilise around 65°C. On the other

hand, the Tg temperatures for Series 4 varied in a narrow range oscillating around ~62 to

64°C. Interestingly, although the E and Ts for Series 4 were negatively affected by

increasing proportions of PE-GA, this does not seem to have any effects on the glass

transition temperatures.

50

55

60

65

70

75

80

85

90

95

0 20 40 60 80 100

Gta

ss T

ran

siti

on

Tem

per

atu

re (

°C)

Percentage GA (wt/wt %)

Series 4

Series 5

Chapter Four

77 | P a g e

For Series 5 polyurethanes, the glass transition temperature appeared to be influenced

by the presence of the PE-LLA/MA polyol. Polyurethanes with high proportions of this

polyol had considerably higher glass transition temperatures. Again, this may be a direct

result of the presence of mandelic acid that has a much higher melting point than both

lactic acid and glycolic acid. However, at higher proportions of PE-GA, the effect is

annihilated by a better miscibility of the two components.

None of the polyurethanes in Series 4 and 5 exhibited melting endotherms at higher

temperatures. This is typical of thermoset polyurethanes that lack any ordered segments

unlike their counterpart thermoplastic polyurethanes, which often possess ordered hard

and/or soft segments depending on the diisocyanate and polyol used to synthesis the

PU.

Series 6 polyurethanes were prepared to study the effect of crosslinking. The polyols

used in this series are shown in Figure 4.14.

Figure 4.14 Structures of the linear PCL and the branched PCL4 polyols used in Series 6.

The thermal transitions for Series 6 polyurethanes determined by DSC are summarised

in Table 3.6. Series 6 polyurethanes exhibited low glass transition temperatures and

only two compositions exhibited a melting endotherm, due to their high proportions of

PCL1000 which has a melting endotherm at ~40°C.

PCL PCL4

Chapter Four

78 | P a g e

Table 4.6 Thermal properties of thermoset polyurethane Series 6

Series 6 Tm (ºC) (SS) Tg (ºC)

PCL4-100 - -11.18

PCL4:PCL-75:25 - -19.36

PCL4:PCL-50:50 - -30.98

PCL4:PCL-25:75 - -34.25

PCL4:PCL-15:85 - -41.23

PCL4:PCL-10:90 - -41.27

PCL4:PCL-5:95 40 -45.52

PCL-100 41 -45.36

Figure 4.15 shows change in glass transition temperatures accompanied by variations in

composition of polyols. There is a clear relationship between the Tg and the ratios of

PCL4 to PLC1000, with the polyurethane having high proportions of PCL4 showing

higher Tg. The glass transition temperatures are shown to decline steadily with

increasing proportions of PCL1000 in the blend.

Figure 4.15 Evolution of Tg with increasing percentage of PCL.

y = -0.3426x - 11.374 R² = 0.9833

-50

-45

-40

-35

-30

-25

-20

-15

-10

-5

00 20 40 60 80 100

Gla

ss T

rans

ition

Tem

pera

ture

(ºC

)

Percentage PCL (wt/wt)

Chapter Four

79 | P a g e

These results indicate that polyurethanes with higher cross-linked density exhibit higher

glass transitions temperatures. The absence of melting endotherms also indicates a lack

of structural ordering, which is a characteristic of thermoset type polyurethanes. It is

only until a loading of 95% in linear PCL1000 polyol is reached that the polyurethane

exhibits a melting endotherm. This endotherm indicates that part of the structure now

contains a crystalline domain much like that of thermoplastic polyurethanes. PCL4,

even at very low concentrations, seems to have an inhibitive effect on crystallisation.

With regard to the trend observed with glass transition temperatures, at high loading of

PCL4 the extensive branching does not leave enough free volume for the polymer chain

to move and this stiffness will cause Tg to be higher.

The overall trend suggests that there is a very good miscibility of the two components

allowing the materials to move gradually from one extreme to the other.

4.3.3 Water Absorption

Figure 4.16 reports the water uptake for series 4 and 5.

Figure 4.16 Water absorption data for series 4 and 5 after 24 h incubation in PBS at 37°C.

The amount of water absorbed by the polymers of series 4 and 5 was quite low and the

average increase in mass was about 3%. The only variants to this were the DLLA-100

and DLLA:GA-25:75 polyurethane, which showed ~1% and ~5% mass increase

0

1

2

3

4

5

6

0 20 40 60 80 100

Mas

s in

crea

se (%

)

Percentage of GA (wt/wt)

Series 4

Series 5

Chapter Four

80 | P a g e

respectively. There appeared to be no difference in water uptake data between the two

series indicating that the variation in chemistry of the polyurethane had no influence on

their ability to absorb water. Figure 4.17 illustrates the water adsorption data obtained

for Series 6 polyurethanes.

Figure 4.17 Water absorption data for Series 6 after 24 h incubation in PBS at 37°C.

The variations in mass observed for all Series 6 polyurethanes were within a very

narrow range, between 1% and 2%. There appeared to be no relationship between the

cross-linked density of the polyurethanes and water uptake as no particular pattern was

seen with increasing proportions of the linear diol PCL1000. As expected, Series 6

polyurethanes showed little water absorption due to hydrophobic nature of both the PCL

diol and PCL tetrol.

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

Mas

s Inc

reas

e (%

)

Sample

Chapter Four

81 | P a g e

SUMMARY 4.4

4.4.1 Thermoplastic Polyurethanes (series 1 and 2)

‘The effects of different ratios of hard and soft segment domains on molecular weight,

mechanical properties, thermal properties and water absorption’.

Polyurethanes with a higher percentage of soft segments tend to have higher

molecular weights. A considerable difference in weight average molecular

weights was observed between the polyurethanes with 100% soft segment and

0% soft segment.

With the exception of polyurethanes containing 100% hard segment, the

modulus and tensile strength of all polyurethanes were very similar. The ratio of

hard to soft segment seemed to have little effect on mechanical properties of

these materials. Polyurethanes with 100% hard segment were found to have

significantly higher modulus and low tensile strength..

With the exception of 100% hard segment polyurethanes, the melting points (Tm)

for all polyurethanes studied were approximately the same (~38-40ºC).

However, the glass transition temperature increased with increasing hard

segment.

There was also an increase in water absorption with increasing hard segment.

In general, different ratios of hard and soft segment had a considerable effect on

the molecular weight, thermal properties and water absorption. On the other

hand, the mechanical properties were found to be least affected by changing

ratios of hard and soft segment.

Chapter Four

82 | P a g e

‘The effect of incorporating degradable chain extender structures (into thermoplastic

hard segments) on molecular weight, mechanical properties, thermal properties and

water absorption’

In general, the incorporation of DCE into the hard segment of polyurethane was

shown to have a considerable effect the molecular weights, but very little effect

on mechanical and thermal properties and water absorption capacity.

‘The effects of diisocyanate on molecular weight, mechanical properties, thermal

properties and water absorption’.

Polyurethanes with HDI yielded material with a higher molecular weight

compared to polyurethane with ELDI

Polyurethanes with HDI generally show higher modulus and tensile strength

than those with ELDI.

HDI-based polyurethanes showed two melting endotherms, one for soft segment

domains and the other for hard segment domains. This was not seen for ELDI-

based polyurethanes. HDI-based polyurethanes yielded lower glass transition

temperature. Diisocyanate appears to have an effect on polyurethane thermal

properties.

HDI-based polyurethane absorbed less water than ELDI-polyurethane.

In general, diisocyanate appeared to have a considerable effect on the molecular

weight, mechanical and thermal properties and water absorption of

polyurethane.

Chapter Four

83 | P a g e

4.4.2 Thermoset Polyurethanes (series 4 and 5)

‘The effects of changing ratios of two different polyols the mechanical properties,

thermal properties and water absorption’.

Increasing ratio of glycolic acid to lactic acid, caused polyurethanes to lose in

tensile strength and modulus and gain in elongation. Polyurethane with mandelic

acid showed higher tensile strengths and modulus compared with polyurethane

without.

Glass transition temperature for polyurethane was slightly lowered in the

presence of greater ratio of glycolic acid to lactic acid. Polyurethane with high

ratios of mandelic acid showed higher glass transition temperatures.

Water absorption was similar for all polyurethane.

In general, changing ratios of two different polyols on polyurethane mechanical

properties was considerable; however, polyurethane thermal properties and

water absorption percentage were affected minimally.

‘The effect of increasing cross-linking density of thermal properties and water

absorption’.

The glass transition of polyurethane increased with increasing cross-link density.

Increasing cross-link density had little or no effect on the percentage of water

absorbed in polyurethane.

In general, increasing cross-link density had a considerable effect on the thermal

properties of polyurethane.

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84| P a g e

5 IN VITRO DEGRADATION OF

THERMOPLASTIC

POLYURETHANES: EFFECTS ON

PHYSICO-CHEMICAL PROPERTIES

INTRODUCTION 5.1

Chapter 5 reports on the in vitro degradation of thermoplastic polyurethane series 1-3.

Figure 5.1 (next page) outlines the techniques used to characterise the changes in the

physicochemical properties of the polyurethanes post in vitro degradation. The blue

boxes indicate data that are reported and discussed in this chapter.

In biodegradable thermoplastic polyurethanes, the linkages that are most susceptible to

hydrolytic degradation are esters (-COO-) and urethanes (-NHCOO-). As reported by

Timmins & Liebmann-Vinson (2003), under identical conditions, ester linkages are

known to degrade at a much faster rate than urethanes . In designing biodegradable

polyurethanes, the relative amounts of these two types of linkages are expected to have

significant influences on the degradation rates. In this respect a strategy was developed,

as detailed in Chapter 3, whereby a variety of materials would be synthesised with this

main objective in mind.

Chapter Five

85| P a g e

The two series of polyurethanes were designed to address two main structural variations

in polyurethanes:

1. the relative amounts of urethane and ester linkages, and,

2. the introduction of ester linkages to the hard segment of polyurethanes via the

incorporation of a chain extender with ester groups in the backbone (DCE).

Figure 5.1 Flowchart indicating the techniques used to analyse the degraded polymers.

PCL was the soft segment of choice, as it is known to be a very slow degrading polymer

as a result of its highly hydrophobic nature. It is also commercially available and safe to

use as a biomedical implant. Synthesising polyurethane with a particularly slow

degrading soft segment made it possible to examine hard segment degradation without

too much influence of soft segment degradation.

PU Series 1-3

PU Characterisation

Water Absorption FTIR Tensile Testing

(Mechanical Properties)

DSC (Thermal

Properties)

GPC (Mn)

In-Vitro Degradation

(365 d)

Mn Change

Change in Thermal

Properties

Change in Mechanical Properties

PU Mass Loss

Pre-degradation

Post-degradation

Chapter Five

86| P a g e

One of the major aims of this particular study was to examine the effect of introducing a

chain extender with a hydrolysable ester linkage (DCE) into the hard segment of the

polyurethanes (Figure 5.2).

Figure 5.2 (a) Formation of a urethane bond, (b) an ester bond, and (c) ELDI & LAEG with ester and urethane bonds.

HO-R-OH

+

OCN-R'-NCO

OCNR'

N OR

OH

O

H

O O

N2H N

O

O

H

O

O

O N

H

OO O

NH2

ELDI ELDI LAEG

(a)

(b)

OHO

O

OH

(c)

Chapter Five

87| P a g e

The study investigated the effect of chain extender structures on the properties of three

series of poly(ester urethanes) (reported in Chapter 3) and their in vitro degradation. The

rationale was to generate a material containing degradable chain extender structures that

would have similar physicochemical properties to their equivalent non-degradable chain

extender-based polyurethanes but would exhibit a faster degradation. This study also

examined the effect of different ratios of hard segment and soft segment on in vitro

degradation and the effects of diisocyanate on the properties and in vitro degradation of

polyurethanes.

MATERIALS AND METHODS 5.2

The nomenclature and chemical compositions of series 1-3 polyurethane (see Table 5.1

on next page) are discussed in more details in Chapter 3, Section 3.4. Essentially, the

soft segments of series 1 and 2 were made of a commercially available polycaprolactone

polyol (1000 Mw) at ratios of 100, 70, 50, 30 and 0% relative to the hard segment. This

polyol was specifically chosen because of its hydrophobicity and very slow degradation

rate, hence, facilitating the study of the effects of the other component, namely the chain

extender, on the hard segment.

The polyurethanes in both series were ethyl lysine diisocyanate (ELDI)-based.

However, Series 1 polyurethanes contained degradable chain extenders incorporating

ester linkages developed by PolyNovo Laboratories (Moore et al., 2005,2006, Tatai et

al, 2007), while Series 2 polyurethanes contained non-degradable chain extenders in the

hard segment.

Series 3 polyurethanes were composed of 70% PCL as a soft segment with 30% hard

segment of either ELDI or hexamethylene diisocyanate (HDI), and degradable or non-

degradable chain extenders. The effects of the incorporation of chain extenders on the

molecular weight, and the mechanical and thermal properties were investigated by GPC,

tensile testing, and DSC-thermal analysis.

Chapter Five

88| P a g e

Table 5.1 Nomenclature and abbreviations of series 1-3 thermoplastic polyurethanes.

Polyurethane Name

Diisocyanate Chain Extender

Polyol Hard Segment %

Series 1

ELDI-0 ELDI PCL1000 0





Series 2






Series 3





The polyurethanes were then subjected to water absorption analysis, as reported in

Chapter 3, and in vitro degradation with regular monitoring of changes in mass,

molecular weight, and mechanical and thermal properties over a period of 365 days.

Chapter Five

89| P a g e

RESULTS AND DISCUSSION 5.3

5.3.1 Mass Loss and Decrease in Molecular Weight

The variations in number average molecular weight (Mn) for polyurethanes as a function

of degradation time are shown in figures 5.3, 5.4 & 5.5 and the comparative numeric

data are reported in Table 5.2 (with the exception ELDI-LAEG-100 and ELDI-EG-100).

The molecular weight data provided are for the residual insoluble polymer left at

different degradation time points. As expected, the longer the degradation time the

higher the decrease in molecular weight for all polymers. In Series 1 (Figure 5.3) the

variability at the 90 days time point was significant but became less important at longer

time points; the general trend observed was an increase in loss with increase in hard

segment content.

Figure 5.3 Percentage molecular weight (number average) loss at times t = 0, 90, 180 and 365 days post-degradation at 37°C in PBS buffer (pH 7.4) for Series 1.

0

10

20

30

40

50

60

70

80

90

100

90 180 365

Mol

ecul

ar W

iegh

t (M

n) L

oss (

%)

Duration of in vitro degradation (days)

ELDI-0 ELDI-LAEG-30ELDI-LAEG-50 ELDI-LAEG-70

Chapter Five

90| P a g e

In Series 2, the variations in Mn loss were more consistent between the different

polymers at 90 days (Figure 5.4) and did not appear to follow the same pattern as the

one observed for Series 1 polymers. In fact, for the same exposure time to degradation,

the results show a decrease in Mn loss with increasing hard segment. This may be

attributed to the decreasing number of ester bonds available in polymers with shorter

soft segments.

Figure 5.4 Percentage molecular weight (number average) loss at times t = 0, 90, 180, 365 days post-degradation at 37°C in PBS buffer (pH 7.4) for Series 2.

0

10

20

30

40

50

60

70

80

90

100

90 180 365

Mol

ecul

ar W

iegh

t (M

w) L

oss (

%)


ELDI-0 ELDI-EG-30ELDI-EG-50 ELDI-EG-70

Chapter Five

91| P a g e

Molecular weight loss percentage for Series 3 (Figure 5.5) polymers showed

considerable variation at the 90 days time point with ELDI-LAEG-30 showing a

comparably low Mn loss compared to other polymers in the series.

Figure 5.5 Percentage molecular weight (number average) loss at times t = 0, 90, 180, 365 days post-degradation at 37°C in PBS buffer (pH 7.4) for Series 3.

ELDI-LAEG-30 appears to ‘catch up’ in Mn loss percentage in the remaining testing

time points, with the degradation rate being slower during the first 90 days but

increasing rapidly after to exhibit similar loss to the other polymers. At 365 days, there

is no substantial difference in Mn between the four polymers in the series with all

polymers exhibiting around 90% mass loss. However, polymers with non-DCE show a

slightly lower molecular weight loss (~ 2-3%) than polymers with DCE.

0

10

20

30

40

50

60

70

80

90

100

90 180 365

Mol

ecul

ar W

iegh

t (M

n) L

oss

(%)


ELDI-LAEG-30 HDI-LAEG-30ELDI-EG-30 HDI-EG-30

Chapter Five

92| P a g e

Table 5.2 below summarises the data related to number average molecular weight

changes observed within the various series.

Table 5.2 Number average molecular weight change and Mn percentage loss for Series 1-3 polyurethanes over 365 days in vitro degradation.

Series 1 Days ELDI-0 ELDI-LAEG-30 ELDI-LAEG-50 ELDI-LAEG-70 0 163,010 61,629 68,244 40,454 90 52,457 30,677 18,056 18,347 180 32,122 11,614 6,466 4,792 365 19,932 5,228 3,009 2,622

Total % Mn Loss 88 92 96 94

Total % Mass Loss 0.28 18 40 74

Series 2 Days ELDI-0 ELDI-EG-30 ELDI-EG-50 ELDI-EG-70 0 163,010 117,991 113,552 80,876 90 52,457 35,899 38,181 30,414 180 32,122 25,893 27,449 27,576 365 19,932 12,275 18,347 16,340


Total % Mass Loss 0.28 0.69 1.8 2.3

Series 3 Days ELDI-LAEG-30 HDI-LAEG-30 ELDI-EG-30 HDI-EG-30 0 61,629 102,704 117,991 140,479 90 30,677 20,652 35,899 37,315 180 11,614 14,154 25,893 29,872 365 5,228 6,632 12,275 15,255


Total % Mass Loss 18 4 0.69 0

For Series 2, the mass loss percentage was negligible despite a substantial decrease in

Mn (over 80%) at 365 days. The Mn loss is most probably a result of the hydrolysis of

esters and urethane groups, but the molecular weights of the resulting break down

products are still too high to be solubilised in PBS. Polymers with higher mass loss also

had lower molecular weight (Mn <6000 Da) residues.

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93| P a g e

For all polymers, it is interesting to correlate the global trend in the decrease in

molecular weight number Mn to mass loss, irrespective of the series. Figure 5.6 is a plot

of the residual molecular weights versus the corresponding mass loss for the three

series. The data reported on the graph relates to the 365-days samples. The major

observation is that the polyurethanes show a more substantial mass loss when the Mn

has fallen below ~5000 Da. This trend has been reported by Lendlein et al (2001) and

correlates well with the results across all series.

Figure 5.6 Correlation between change in molecular weight and overall mass loss.

The molecular weight data reported in Table 5.2 clearly indicate that all polyurethanes

degrade to some extent under the testing conditions, but only those with a degradable

chain extender showed a more substantial mass loss percentage over the study period.

The expectation was that the other polymers would have continued to degrade had the

experiments been extended beyond the one year test period. Although the initial

molecular weight seem to have an effect on degradation, the observation that DCE-

-5

5

15

25

35

45

55

65

75

0 5000 10000 15000 20000 25000

Mas

s Lo

ss (

%)

Residual Molecular Weight (Da)

Chapter Five

94| P a g e

based TPUs show greater mass loss at shorter time points supports the claim that the

degradable chain extender influences the degradation behaviour of these polyurethanes.

The molar percentages of ester and urethane functional groups for Series 3

polyurethanes are reported in Table 5.3. The effect of HDI on decrease of Mn appears to

be almost negligible, but the observed mass loss was considerable. The mass loss at 365

days was 18% and 4%, respectively for ELDI-LAEG-30 and HDI-LAEG-30. For the

four materials in Series 3, Mn varied in a very narrow range typically between 89% and

94%, consistent with the content in ester and urethane functional groups present. The

initial molecular weight also seems to play an important role in the level of mass loss

exhibited at different time points.

Table 5.3 Percentage molar ratio of urethane and ester bonds for Series 3 polymers.

Polyurethane Total Urethane (%)

Total Ester (%)

PCL-Ester (%)

LA-EG-Ester (%)

Mn Loss (%)

ELDI-LAEG-30 27 73 68 4.8 92

HDI-LAEG-30 29 70 63 6.8 94

ELDI-EG-30 29 70 70 0 90

HDI-EG-30- 34 65 65 0 89

Despite the fact that DCE-based polyurethanes showed greater mass loss than non-

DCE-based polyurethanes, the Mn loss between these series of polyurethanes was not as

considerable. For example, polyurethane ‘ELDI-LAEG-70’ (Series 1) showed a mass

loss of 74% and a decrease in Mn loss of 94% while polyurethane ‘ELDI-EG-30’ (Series

2) showed a mass loss of 0.69% and a loss in Mn of 90%. While there is only 4%

difference in the loss of Mn between the polyurethanes, there is ~74% difference in mass

loss.

All polyurethanes in series 1-3 showed a relatively narrow range of 84-96% molecular

weight (Mw) loss over a period of 365 days with the molecular weight (Mw) decreasing

at each consecutive testing time point. While these data seems to indicate that

polyurethane degradation occurs at a molecular level, whether the loss of molecular

weight (Mw) is a result of both ester and urethane bond degradation is yet to be

Chapter Five

95| P a g e

elucidated. It appears that polyurethane with DCE tend to show a slightly higher

percentage molecular weight loss than those with non-DCE which is consistent with

mass loss data reported in Section 5.3.2 in detail and in figures 5.7, 5.8 and 5.9.

5.3.2 Mass loss

Figure 5.7 shows the percentage mass remaining at several time-points following in

vitro degradation for Series 1 polyurethanes.

Figure 5.7 Percentage residual mass after in vitro degradation for Series 1.

Depending on the composition, after 365 days incubation, the mass losses were between

0% to 100% with greater losses observed in polyurethanes with a higher percentage of

hard segments. Polyurethanes with PCL-ELDI (ELDI-0) did not degrade and showed

virtually no mass loss after 365 days (0.28%) while polyurethanes with 100% hard

segment were completely degraded after 180 days. The mass loss pattern appears to be

congruent with the percentage of hard segment and degradable chain extender present in

the polyurethane. For these materials, as it was shown earlier (see Figure 4.7) that there

-55

152535455565758595

105

0 50 100 150 200 250 300 350 400

Res

idua

l Mas

s (%

)

Time (days)

ELDI-0 ELDI-LAEG-30 ELDI-LAEG-50ELDI-LAEG-70 ELDI-LAEG-100

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96| P a g e

was also a strong relationship between mass loss and water absorption, the polymers

absorbing the highest percentage of water are also the ones that undergo the greatest

mass loss. Urethane and ester bonds are generally very susceptible to degradation

through hydrolysis, thus the more water molecules available around these bonds the

greater would be the degree of degradation.

For Series 2 polyurethanes (Figure 5.8), the observed mass losses after 365 days

incubation were between ~0% to 6.6%, again with the greater mass losses seen in

polyurethanes with higher hard segment percentages, although this trend was not as

pronounced as in Series 1.

Figure 5.8 Percentage residual mass for Series 2 after 365 days in vitro degradation.

90

92

94

96

98

100

102

104

0 50 100 150 200 250 300 350 400

Res

idua

l Mas

s (%

)

Time (days)

ELDI-0 ELDI-EG-30 ELDI-EG-50ELDI-EG-70 ELDI-EG-100

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97| P a g e

The pattern of mass loss observed for Series 2 polyurethanes is rather unusual, as for

polyurethanes with 30% and 50% HS, the mass loss observed at 180 days was greater

than that at 365 days. The mass loss at early time points may involve lower molecular

weight polymer fragments hydrolysing down to low enough molecular weights to be

soluble in PBS.

At longer time points higher molecular weight fragments may start to degrade but not to

fragments with low enough molecular weight to be soluble in PBS. As discussed

previously, and as evidenced from the data reported in Table 5.2, the average molecular

number has not reached the threshold value of around 5,000 Da to yield enough

fractions that can be easily solubilised and eliminated from the bulk of the materials to

engender a mass loss.

The slight gain in mass with some samples may be the result of an uptake in water

molecules following the hydrolysis of an ester bond. This is further detailed in Section

5.3.5.

The overall observation is that polyurethanes of Series 2 exhibited considerably less

mass loss than those of Series 1. Since the only difference between these two series is

the chemical nature of the chain extender, non-degradable versus degradable (non-DCE

vs. DCE), it can be suggested with confidence that the ester bonds in the degradable

component are the major contributors to the faster degradation of these polyurethanes.

The propensity of the materials to absorb water is also a significant as it increases the

extent of hydrolysis of the internal ester bonds and hence increase the mass loss.

For Series 3 polyurethanes (Figure 5.9), after 365 days in vitro degradation the decrease

in mass loss observed was in the range of 0% to 18%. The materials containing a

degradable chain extender, in this case LA-EG, exhibited greater mass loss. A higher

mass loss was observed in ELDI-based polyurethanes compared to the HDI-based ones.

Chapter Five

98| P a g e

Figure 5.9 Percentage residual mass for Series 3 after 365 days in vitro degradation.

Based on the mass loss data of series 1-3, the order of degradation rate of the

polyurethanes can be expressed as a function of the percentage of hard segment,

Hard Segment % 0% HS > 30% HS > 50%HS > 70% HS > 100% HS

or the composition of the hard segment,

HDI-EG < ELDI-EG < HDI-LAEG < ELDI-LAEG

The degradation rates of polyurethanes are shown to be very dependent on the nature of

the chain extender and its relative percentage within the materials, followed by the type

of diisocyanate used. The asymmetrical structure of ELDI does not allow the

polyurethanes to pack as tightly and regularly as HDI-based polyurethanes.

Polyurethanes that are more loosely packed and hydrophilic (i.e. polyurethanes with less

PCL in this case) enable more water to be absorbed in the bulk of the polymer and,

hence, allowing more water molecules to reach the inner ester and urethane bonds.

These bonds are subsequently hydrolysed, forming smaller fragments that are more

readily solubilised and released from the polymer. On the other hand, HDI-based

polymers are more tightly packed making it difficult for water molecules to access the

urethane and ester bonds in the bulk of the materials, resulting in a much lower mass

loss. With the addition of PCL-1000, a highly hydrophobic component, to the

80

85

90

95

100

105

0 100 200 300 400

Res

idua

l Mas

s (%

)

Time (days)

HDI-LAEG-EG-30 ELDI-EG-30HDI-EG-30 ELDI-LAEG-30

Chapter Five

99| P a g e

polyurethane mixture, the water molecules are essentially repelled from the

polyurethane making it more difficult for the inner urethane and ester bonds to be

hydrolysed.

5.3.3 Changes in Mechanical Properties

Figure 5.10 reports modulus data obtained for polyurethanes at ambient temperature and

at 37°C after 24 h soaking in PBS.

Figure 5.10 Modulus for series 1-3 at ambient temperature and at 37C after soaking 24h in PBS.

The mechanical properties of series 1-3 polyurethanes prior to degradation (original

samples at ambient temperature) have been reported in the previous chapter. To

measure the effect of prolonged exposure to a biological environment on these

properties, the polyurethanes were soaked in a physiological buffer (PBS) at 37C for

24 hours to saturate the samples with water. The materials, post PBS immersion, were

then tested at 37C in an environmental chamber to emulate the temperature of a

biological environment.

0

2

4

6

8

10

12

14

16

18

Mod

ulus

(MPa

)

Polyurethane

Original Soaked

Chapter Five

100| P a g e

Figure 5.11 shows the trend observed in the tensile strength for the same materials. In

both graphs the data for 100% HS polyurethane and HDI-EG-30 are not reported on the

graph due to the fact that the values are much higher and would mask the trends

observed in the other materials.

Figure 5.11 Tensile strength for series 1-3 at ambient temperature and at 37°C after soaking 24h in PBS. As evidenced by the significant decrease in modulus and tensile strength, the

mechanical integrity of the materials are negatively affected. With a loss ranging from

80-100% of the original mechanical property. With the exclusion of 100% hard segment

and HDI-based TPUs, polyurethanes with soft segment exhibit melting points of around

37C, which explains these dramatic decrease in strength. Polyurethanes with 100% HS

also exhibited a considerable drop in modulus and tensile strength at this temperature

due to fact that their glass transition temperatures are approximately 37C.

HDI-based TPUs showed the least decrease in modulus and tensile strength, with the

most likely reason being that their soft segments exhibit a melting point above 37C, at

around ~50C. This may also be assumed, as HDI-based TPUs did not show mechanical

properties that were considerably superior or different to that of ELDI-based polymers

at ambient temperatures.

01234567

Tens

ile S

tren

gth

(MPa

)

Polyurethane

Original Soaked

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101| P a g e

5.3.4 Changes in Thermal Properties

Figure 5.12 shows the change in thermal behaviour of the polyurethanes after 365 days

in vitro degradation.

Figure 5.12 Thermograms for series 1 and 2 polymers pre and post-degradation.

After the degradation period and prior to the DSC analyses, the residual polyurethane

samples were vacuum dried and purged under nitrogen flow for 7 days at ambient

temperature to remove residual water. The results obtained were compared to thermal

traces of the original polyurethanes and analysed for variations in melting points and

glass transition temperatures. For Series 1 polyurethanes, a slight shift of the glass

temperatures, Tg, to lower temperatures was observed compared to that of non-degraded

Series 1

(a)

(b)

(c)

(a)

(b)

(c)

(a)

(b)

(c)

(a)

(b)

(c)

Series 2

T

T

t = 365 days

t= 0

t= 0

t = 365 days

New Peak

(a) 30% Hard segment (b) 50% Hard segment (c) 70% Hard segment

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102| P a g e

polyurethane, which is an indication of significant structural changes in the bulk of the

material. The melting point, Tm, peaks for ELDI-LAEG increased in amplitude with

decreasing content of the hard segment, accompanied by the appearance of an additional

peak in the composite polymers. For ELDI-LAEG-30, the thermogram shows a small

peak appearing around 15C as well as a shoulder on the left of the main peak.

Figure 5.13 highlights the most significant changes observed in ELDI-LAEG-30 and

ELDI-LAEG-70 following degradation.

Figure 5.13 Thermograms for ELDI-LAEG-30 and ELDI-LAEG-70 pre- and post-degradation.

Prior to degradation (i.e. at t = 0) the thermal properties of the polymers seem to be

governed by the hard segment part, as evidenced by the shape of the thermograms for

both series 1 and 2. With increasing percentage of hard segment, from (a) to (c) the

thermograms are shown to gradually lose the main thermal event at around 40C.

Figure 5.14 compares the DSC traces of post-degradation ELDI-0 to that of pure

PCL1000. Overall, the thermograms evidenced that following the degradation

procedure the thermal responses of Series 1 polyurethanes looks more and more similar

mW

10

min

°C-60 -50 -40 -30 -20 -10 0 10 20 30 40 50 60 70 80 90 100

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

exo

STARe SW 9.00Lab: METTLER

mW

10

min

°C-60 -50 -40 -30 -20 -10 0 10 20 30 40 50 60 70 80 90 100

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

^exo


mW

5

min

°C-60 -50 -40 -30 -20 -10 -0 10 20 30 40 50 60 70 80 90

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

^exo


ELDI-LAEG-70

ELDI-LAEG-30

Exo

ther

m

t = 0

t = 365

t = 0

Tm

t = 365 days

New Peak

Tg

Temperature

Chapter Five

103| P a g e

to that of pure PCL1000 as the percentage of hard segment decreases. The explanation

for this observation is rather trivial when the mass loss data are taken into consideration:

the less hard segment the more the PCL1000 content, and the closer the thermogram of

the degraded sample will be to that of PCL1000. The sharp melting endotherm at

around 40C is attributed to the crystalline portions of PCL. While in Series 1

significant mass losses are observed with LAEG materials, the resulting thermograms of

the residual materials will also exhibit important variations.

Figure 5.14 Thermogram for ELDI-0 after 365 days in vitro degradation compared to neat PCL1000.

The other transition observed at around 15C is attributed to glass transition temperature

of the amorphous segments of PCL, which is a semi-crystalline material. These results

suggest that PCL segment of the polyurethanes does not undergo considerable

degradation over 365 days.

On the other hand, it is clearly shown that in EG containing polyurethane (Series 2)

only minor changes were observed in the thermal behaviours after 365 days in PBS.

This can be related to the lower mass losses observed, indicating that the polymers are

Chapter Five

104| P a g e

not much different to the initial ones. The decrease in molecular weight over that period

of time appeared to have little or no contribution to change DSC thermal transitions.

The DSC traces for HDI-based polyurethanes post degradation are not reported here, as,

much like Series 2 polyurethanes, the thermal traces did not change over time, which is

also consistent with the low mass losses and resulting in minor change in the polymer

chain structures.

5.3.5 Accelerated Solvent Extraction

On the assumption that these polyurethanes may contain traces of PBS components

such as phosphate, chloride and sodium after in vitro degradation, selected

polyurethanes (HDI-EG-30, HDI-LAEG-30) were further examined. Using an

Accelerated Solvent Extractor (ASE), the residual polymer samples were subjected to

high-pressure solvent extraction followed bi ion chromatography to identify and

quantify possible contaminants. These polyurethanes showed little mass loss or even

some gain in mass over 365 days despite the fact that their average molecular number,

Mn , had significantly decreased, up to 89% and above. Although it is theoretically

possible that a polymer can exhibit a significant drop in Mn and yet shows no mass loss,

it is rather unusual for a material to exhibit a gain in mass. Given that these gains in

mass are very low, typically less than 1%, three hypotheses are proposed to bring some

insight into this observation:

i) Retention of water, even after vacuum drying

ii) Retention of PBS components within the PU

iii) Ester bonds hydrolysis, i.e. the addition of a water molecule

Since post-degradation polyurethanes are thoroughly vacuum dried and weighed until

constant weight is achieved, it had been assumed that water retention could not be the

major contributing factor to the mass gain. With this factor being discarded, it was

proposed that the retention of PBS components could possibly contribute to the mass

gain of the polyurethanes.

Chapter Five

105| P a g e

A summary of the results from analysis of the samples obtained by accelerated solvent

extractions (ASE) is presented in Figure 5.15.

Figure 5.15 (a) IC traces of HDI-EG-30 extracts, and (b) concentrations of chloride and phosphate ions pre- and post-degradation.

Chloride – t = 365 d

Chloride – t = 0 d

Phosphate – t = 365 d

(a)

HDI-EG-30Sample Chloride (ppm) Phosphate (ppm)dH20 0.176 0.016t=0d 0.216 0.028t=365d 0.434 0.3

HDI-LAEG-30Sample Chloride (ppm) Phosphate (ppm)dH20 0.176 0.016t=0d 0.173 0.009t=365d 0.614 0.77

(b)

Chapter Five

106| P a g e

The polyurethanes (HDI-EG-30, HDI-LAEG) were subjected to ASE to extract any

loose particles trapped within the bulk of the materials. The collected aliquots, diluted in

distilled water, were then passed through an Ion Chromatograph (IC) to determine

whether they contained traces of chlorides and/or phosphates. The ion chromatography

trace for the HDI-EG-30 extract (Figure 4.15 (a)) clearly evidences a difference in

relative content between the samples pre- and post-degradation and the quantification of

the species present (Figure 4.15 (b)) shows the values in ppm of chloride and phosphate

extracted from the selected PU’s compared to that of distilled water (used as a

reference). The results showed that the polymers do retain substantial amounts of

chloride and phosphate ions after a 365-day incubation period in PBS. The retention of

these components in the case of HDI-LAEG-30 could increase the polymer weight up to

0.02%. Although this is not a significant amount, it could still cause a polymer showing

minute or no degradation to weigh more after in vitro degradation.

Ester bonds hydrolysis may also cause a slight increase in mass after in vitro

degradation, as one water molecule adds to the polymer every time a bond is broken

(Figure 5.16).

Figure 5.16 Ester bond hydrolysis resulting in the addition of one water molecule.

The effect of ester bonds hydrolysis can be calculated by the change in over time on

the assumption that the bonds that have broken are mostly ester bonds (as opposed to

urethane bonds). For example, in the case of HDI-LAEG-30, it could cause up to

0.253% increase in mass based on the loss of this polyurethane. Together, both

ester hydrolysis and PBS component retention could cause up to 0.275% increase in

total polyurethane mass post in vitro degradation.

nM

nM

R OR'

O

R OH

O

R'OHH2O +

Chapter Five

107| P a g e

SUMMARY 5.4

The following summarises the main experimental results related to the original aims of

the project.

‘The effects of different ratios of hard and soft segment domains on in vitro degradation

of polyurethane (changes in molecular weight, mechanical properties (after 24h

soaking), thermal properties and mass loss)’.

There was an increase in molecular weight loss in Series 1 materials with

increasing hard segment. However, an opposite trend was observed for Series 2

polyurethanes. Overall, the decrease in molecular weight was substantial for all

polyurethanes.

All polyurethane materials showed considerable loss of tensile strength and

modulus with no particular pattern observed.

The melting endotherms and glass transition temperatures for Series 1

polyurethanes were significantly affected, with a shift of the glass transition

temperatures to lower temperatures, and the melting endotherms sharpening with

the appearance of an additional peak, attributed to the resulting larger proportion of

PCL. Polyurethane with increased hard segment domains showed greater glass

transition shifts than polyurethane with lower hard segment. Series 2 polyurethanes

did not exhibit these trends, most probably due to limited mass loss.

The mass loses observed for Series 1 increased considerably with increasing

percentage of hard segment. However, this pattern was observed for Series 2

polyurethanes to a much lesser extent.

Chapter Five

108| P a g e

‘The effects of incorporating degradable chain extender structures (into thermoplastic

hard segments) on in vitro degradation of polyurethane (changes in molecular weight,

mechanical properties, thermal properties and mass loss)’

Polyurethanes with a degradable chain extender (DCE) showed a slightly higher

molecular weight loss than polyurethane with non-DCE. Molecular weight loss

was substantial for all polyurethane.

The mechanical properties for all polyurethanes decreased considerably after in

vitro degradation with no particular pattern seen.

The melting endotherms and glass transition temperatures for Series 1

polyurethanes changed, with glass transition temperatures shifting to a lower

temperature and melting endotherms being dictated by the residual PCL.

Polyurethane with DCE showed greater glass transition shifts compared to

polyurethane with non-DCE, which showed no substantial changes post

degradation.

Polyurethane with DCE showed considerable mass loss over a 365-day period

compared to little or no mass loss for polyurethanes with non-DCE.

In general, the incorporation of DCE into the hard segment of polyurethane is

shown to have a considerable effect on polyurethane molecular weight loss, thermal

properties and polyurethane mass loss. This is an indication that the desired effects

were achieved.

Chapter Five

109| P a g e

‘The effects of diisocyanate on the in vitro degradation of polyurethanes (changes in

molecular weight, mechanical properties, thermal properties and mass loss)’.

Post in vitro degradation analyses revealed that there was no substantial difference

in molecular weight loss for polyurethane with HDI and ELDI. Molecular weight

loss was substantial for all polyurethane.

Polyurethane with HDI and ELDI showed considerable modulus and tensile

strength decrease. HDI-based polyurethane seemed to have better resistance to

degradation and retained their modulus, more so than ELDI-based polyurethane.

There were no noticeable changes in the thermal traces of HDI-based polyurethane

post in vitro degradation.

A greater mass loss was observed for HDI-based polyurethane compared to ELDI-

based polyurethane.

In general, HDI-based polyurethanes were less affected, showing less mass loss and

change in thermal properties. Molecular weight loss and mechanical properties for

HDI and ELDI-based polyurethane were affected.

All polyurethanes investigated in this study showed degradation as evidenced by the

decrease in molecular weight. The DCE-based polyurethanes yielded the highest mass

loss in the three series of polyurethanes. The presence of the DCE and the initial

molecular weight of the polyurethane are the key factors responsible for high mass

losses. The changes in thermal properties and the observation that mass loss was

directly proportional to the percentage of hard segment weight strongly suggested that

the hard segment is the most susceptible to degradation in these polyurethanes. The

hydrophobic PCL-based soft segment appears to undergo little or no degradation under

these test conditions.

This study further demonstrated that polyurethanes with different degradation rates can

be prepared by judiciously modifying the composition, e.g. by incorporating a

degradable chain extender and by varying the ratio of hard and soft segment

Chapter Six

110 | P a g e


THERMOSET POLYURETHANES

PHYSICO-CHEMICAL PROPERTIES OF DEGRADED POLYMERS 6.1This chapter reports on the effects of in vitro degradation of thermoset polyurethanes

series 4-5 on their physico-chemical properties. An outline of the techniques used to

determine physicochemical changes in polyurethane properties post in vitro degradation

is summarised in Figure 6.1, with the blue boxes indicating data reported in this chapter.

Figure 6.1 Schematic diagram for the study of series 4-6

PU Series 4 & 5

PU Characterisation

Water Absorption

FTIR Tensile Testing (Mechanical Properties)

DSC (Thermal Properties)

In-Vitro Degradation

(365 d)

Change in Thermal

Properties

Change in Mechanical Properties

PU Mass Loss

Pre-degradation

Post-degradation

Chapter Six

111 | P a g e

One of the objectives of this study was to examine the effect of the chemical structure of

the polyol on the main properties and the degradability of a series of novel thermoset

polyurethanes. Figure 6.2 shows the main star polyols prepared from the original

pentaerythritol.

Figure 6.2 Star polyols prepared from pentaeythritol (PE).

Series 4 was prepared using ELDI as the diisocyanate and a mixture of the star polyols

PE-DLLA (D,L-lactic acid) and PE-GA (glycolic acid) in different proportions to

produce thermoset polyurethanes with high degrees of cross linking. In Series 5, the

polyol PE-LLA:MA (L-lactic acid and D,L- mandelic acid) was added in place of the

OH

O O-O

OH

O

O-O

O-O OH

O

O-O

O

H O

OH

O O-O

OH

O

O-O

O-O OH

O

O-O

O

H O

OH

O O-O

OH

O

O-O

O-O OH

O

O-O

O

H O

OH O

O-O

OH

O

O-O

O-O HO O

O-O

H

O

O

OH

OH

OH HO

D,L-Lactic Acid L-Lactic Acid

Glycolic Acid Mandelic Acid

Pentaerythritol

Chapter Six

112 | P a g e

PE-DLLA, with the same diisocyanate and changing ratios of each star polyol. The

degradation rates and changes in mechanical and thermal properties were compared

within series 4 and 5 to determine the effects of decreasing concentrations of DLLA and

LLA:MA respectively. Between the two series, the effects of different polyols i.e. PE-

DLLA versus PE-LLA:MA, on in vitro degradation and properties were investigated.

These polyols were selected to represent slow, medium and fast degradation rates based

on studies reported in the literature (Gunatillake et al, 2006).

Since poly(glycolic acid) is known to be a more hydrophilic and faster degrading

polymer, the expectations were that polyurethanes with higher concentrations of GA

would exhibit faster degradation rates and show lower tensile strength post in vitro

degradation. On the other hand, given that poly(L-lactic acid) is a slower degrading

polymer than poly(D,L-lactic acid) and mandelic acid contains an aromatic ring, it was

also proposed that polyurethane with PE-LLA:MA as a polyol would show slower in

vitro degradation rates and higher tensile strengths than polyurethane with PE-DLLA.

The focus is on the changes in thermal and mechanical properties, and mass loss for

thermoset polyurethanes over a period of 365 days. The sampling time points were at

14, 42, 90, 180 and 365 days, and at each time point the polyurethane samples were

weighed for mass changes and subjected to tensile testing and DSC analysis. The

polyurethane degradation products accumulated during in vitro degradation were

collected at each sampling time point and subjected to further analysis, the latter data

are reported in Chapter 6.

6.1.1 Materials and Methods

The nomenclature and chemical compositions of series 4 and 5 polyurethanes are

described in details in Chapter 2, and these are summarised in tables 6.1 and 6.2.

Briefly, the diisocyanate and polyol were mixed in a round bottom flask and heated

until the uncured polyurethane mixture became clear and colourless. Upon cooling, a

catalyst was added after a 3-minute degassing period. Prior to curing, the mixture was

poured between two non-stick glass plates and cured for 24 hours at 100°C under a

nitrogen flow. The resulting thermoset polyurethanes were analysed by FTIR to verify

Chapter Six

113 | P a g e

for unreacted isocyanates and to assess the extent of curing. Prior to the degradation

tests, the cured polyurethane sheets were cut into strips. The major results related to the

physico-chemical properties of the initial thermoset polyurethanes, i.e. thermal

properties, mechanical properties and water absorption data, are reported in Chapter 4.

Table 6.1 Series 4 - Thermoset polyurethanes

Polyurethane Diisocyanate Polyol 1 (P1) (Mw 434)

Polyol 2 (P2) (Mw 399) % of P1 to P2






Table 6.2 Series 5 - Thermoset polyurethanes

Polyurethane Diisocyanate Polyol 1 (P1) (Mw 320)

Polyol 2 (P2) (Mw 399)

% of P1 to P2






Chapter Six

114 | P a g e

6.1.2 Mass Loss

The graph in Figure 6.3 illustrates the data for the three polyurethanes containing 100%

of one polyol i.e. PE-DLLA, PE-GA or PE-LLA/MA. The three polyols are rather close

in molecular mass, PE-GA (MW 399) to either PE-DLLA (MW 434) or PE-LL/MA

(MW 320), but they differ substantially in their chemistry.

Figure 6.3 Degradation behaviours of polyurethanes with different polyols.

These data illustrate how each polyol present in the polyurethane influences the

degradation rates. Clearly, the polyurethane with 100% GA (GA-100) loses mass at a

much faster rate than the other two polymers. Series 4 DLLA-100 shows an induction

time of 180 days and undergoes further degradation to gradually lose mass over the

following 180 days. LLA/MA-100 shows negligible mass loss over 365 days. Mass loss

rate for these polyurethanes was in the order of:

GA-100 > DLLA-100 > LLA/MA-100

This demonstrates that the nature of the polyol is crucial in designing polymers with

varying degrees of degradability.

GA-100

DLLA-100

LLA/MA-1000

20

40

60

80

100

014

4290

180365

Res

idua

l Mas

s (%

)

Time (days)

Chapter Six

115 | P a g e

Figure 6.4 Series 4 - Percentage mass remaining after 365 days in vitro degradation.

All Series 4 polyurethanes were completely degraded (100% mass loss) after 365 days

of in vitro. The material containing only glycolic acid, GA-100, showed the fastest mass

loss, achieving complete degradation within 90 days. DLLA:GA-25:75 and DLLA:GA-

50:50 were fully degraded after 180 days while DLLA:GA-75:25 and DLLA-100

showed complete degradation only at the termination of the experiment at 365 days.

The reference material, Series 1 ELDI-0, containing the linear polyol PCL did not

undergo any degradation as evidenced by the lack of mass loss.

The polyurethanes showed little mass loss at the 42-day sampling time point with only

2% mass loss recorded for all samples. Following the 42-day sampling point, both

GA-100 and DLLA:GA-25:75 show a substantial decrease in mass with the former

being totally degraded after 90 days and DLLA:GA-25:75 showing ~50% mass loss

after the same period of time. For DLLA:GA-50:50 and DLLA:GA-75:25, the

observed mass loss was minimal at the 90-day time point, and thereafter, the mass loss

increased considerably with 100% degradation at 180 days for DLLA:GA-50:50 and

~50% for DLLA:GA-75:25. Polyurethane DLLA-100 showed minimal mass loss at

180 days and 100% mass loss seen at 365 days.

GA-100

DLLA:GA-25:75

DLLA:GA-50:50DLLA:GA-75:25

DLLA-100

0

20

40

60

80

100

014

4290

180365

Res

idua

l Mas

s (%

)

Time (days)

Chapter Six

116 | P a g e

The pattern of mass loss for Series 4 polyurethanes appears to correlate well with the

ratio of DLLA:GA, increasing with increasing amount of GA in the polyol.

Polyurethanes with no GA proved to be the least degradable.

Unlike Series 4 polyurethanes, not all polymers in Series 5 showed 100% mass loss

after 365 days (Figure 6.5). However, the same overall pattern is observed: a period of

latency whereby no mass loss is observed followed by a gradual mass loss until

complete degradation.

Figure 6.5 Series 5 - Percentage mass remaining after 365 days in vitro degradation.

Polyurethanes LLA/MA:GA-25:75 and LLA/MA:GA-50:50 have a relatively similar

behaviour, with both materials exhibiting minor weight losses within the first 90 days,

followed by a rapid degradation, with the polymers being completely degraded at the

180-day time point. On the other hand, polyurethanes LLA/MA:GA-75:25 and

LLA/MA-100 exhibited minimal degradation after 365 days with a mass loss of only

between 4-6% observed. Again, the pattern of mass loss appears to be correlated to the

content of glycolic acid such that polyurethane with higher GA to LLA/MA ratios lost

more mass at a faster rate.

Overall, the main observations are that DLLA polyurethanes showed an induction

period of 42 days prior to degradation while for LLA/MA polyurethanes the induction

time is around 90 days. Also, the steepness (gradient) of the slope of the degradation

GA-100

LLA/MA:GA-25:75LLA/MA:GA-50:50

LLA/MA:GA-75:25LLA/MA-100

0

20

40

60

80

100

014

4290

180365

Res

idua

l Mas

s (%

)

Time (days)

Chapter Six

117 | P a g e

graphs indicates that the degradation rate for DLLA polyurethanes is slower than

LLA/MA, which showed a more rapid decline in mass from the 90-day time point to the

next sampling time point at 180 days where completed degradation was observed. There

seems to be a close relationship between the percentage of PE-GA polyol present in the

polyurethane and the induction time for both series 4 and 5. Series 4 polyurethanes have

a shorter induction period when compared to Series 5 polyurethanes, most probably due

to the slow degrading nature of the polyol segments holding the network structure.

Figure 6.6 shows the relative degradation rate for all polyurethanes in series 4 and 5 in

order from fastest to slowest degradation rate. Degradation rates were estimated using

the gradient of the line of best fit measured from day zero to the time point where the

polyurethane had degraded completely.

Figure 6.6 Degradation rates for series 4 and 5 polyurethanes.

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Deg

rada

tion

Rat

e (%

/day

)

Polyurethane

Chapter Six

118 | P a g e

The degradation rates reported here are only empirical as it is not always calculated over

a period of 365 days, and the main purpose is to observe general trends in the behaviour

of the two series. Polyurethane GA-100 is seen to degrade almost twice as fast the other

materials. Series 4 polyurethanes in general have faster degradation rates than Series 5

polyurethanes. The polyurethanes with the highest concentrations of LLA/MA and

polyurethane without GA appear to have the slowest degradation rates.

Glycolic acid is known to generate polymers with high degradability and Figure 6.7

illustrates the degradation rates versus the percentage of GA.

Figure 6.7 Calculated degradation rates fro series 4 and 5 polyurethanes vs. percentage of GA. At higher contents in glycolic acid (>50%), there is not much difference between DLLA

and LLA/MA, which indicates that beyond certain content the degradation is dictated by

the degradability of GA. This observation can be correlated to earlier conclusive

comments about the changes in molecular weight and the apparent existence of a

threshold at ~5000 Da. The introduction of glycolic acid in the materials does not have

much effect at lower content, which is very obvious with Series 5 polymers. In the

latter, no mass loss is observed until the percentage of GA polymer has reached 50%.

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 10 20 30 40 50 60 70 80 90 100

Deg

rad

atio

n R

ate

(%/d

ay)

Percentage of GA Polyol (%)

DLLA LLA/MA

Chapter Six

119 | P a g e

On the assumption that there is a homogeneous dispersion of the various constituents in

the bulk of the polymer, the mixed polymer can be represented graphically as per the

drawing shown in Figure 6.8.

Figure 6.8 Schematic representation of the mixed polymer.

There is a general understanding that these materials will undergo degradation by both

surface and bulk erosions. In a material where a secondary component is gradually

added in a matrix, it is most likely that at low concentrations the component will be

dispersed in the bulk. As higher concentrations, the dispersion in the bulk will be less

efficient, leading to clusters and migration to the surface, exposing partly the GA. At

low contents, following degradation of the GA, the residual particles are not small

enough to be solubilised and engender a mass loss in the polymer. The red dots

represents GA and, following exposure to the degradation conditions, their degradation

will cause holes to form in the bulk of the polymer.

Figure 6.9 compares the total degradation rate (from day zero to complete degradation)

to the rate of degradation from the onset of degradation to complete degradation. As

the data show, for most of the polyurethanes studied, the degradation rate from mass

loss onset is significantly higher than the total degradation rate. The exceptions are the

polyurethanes composed majorly of LLA/MA, with little or no GA.

25% 50% 75% Increase in GA

Increase in degradability

DLLA or LLA/MA GA

Chapter Six

120 | P a g e

Figure 6.9. Overall degradation rate and degradation rate from the onset point for series 4 and 5 polyurethanes.

The trends observed are a strong indication that the polyurethanes may undergo initial

bulk erosion whereby the ester and urethane bonds are hydrolysed. However, this partial

degradation may not be extensive enough to generate sub-particle that are small enough

to be released from the bulk. The rate of mass loss from the onset of degradation is

significantly enhanced, which suggest that once the polymer reaches a certain extent of

degradation it undergoes both surface and bulk-like erosion.

6.1.3 Changes in Mechanical Properties

The mechanical properties of polyurethane series 4 and 5 prior to degradation (wet,

37°C) are reported in Chapter 3, Section 4.3. The samples were tested at 37C in an

environmental chamber to mimic a biological environment. The following data report

on the effect of degradation time upon the mechanical properties of thermoset

polyurethane series 4 and 5. The polyurethanes were immersed in PBS at pH 7.2±0.2

and 37ºC for up to 90 days. The sampling time points for mechanical tests were at 1,

14, 42 and 90 days.

0.0

0.5

1.0

1.5

2.0

2.5

Deg

rada

tion

Rat

e (%

/day

)

Polyurethane

Overall Rate

Rate from Onset

Chapter Six

121 | P a g e

Mechanical properties for Series 4 polyurethanes

As shown in Figure 6.10, the modulus for Series 4 polyurethanes decreased gradually

over a period of 90 days of incubation.


Only slight variations in the modulus were observed within the first 2 weeks of

degradation but after 42 days most polymers were shown to be significantly affected,

particularly for polyurethanes containing higher proportions of the PE-GA polyol

component. Polyurethanes with 50-75% PE-GA polyol exhibited very low modulus at

90 days. It is interesting to note that DLLA:GA-50:50 (50% PE-GA polyol) showed low

modulus at 90 days despite only showing ~5% mass loss at this particular time point.

This strongly suggests that the material has undergone significant degradation in the

bulk leading to mediocre mechanical properties, but not to the extent of engendering a

substantial mass loss. Polymer DLLA:GA-50:50 (50% PE-GA polyol) also showed an

increased modulus and tensile strength (figure 6.11) at data point 42 days compared to

0

200

400

600

800

1000

1200

1400

1600

0 14 28 42 56 70 84 98

Mod

ulus

(MPa

)

Time (days)

DLLA-100DLLA:GA-75:25DLLA:GA-50:50DLLA:GA-25:75GA-100

Chapter Six

122 | P a g e

14 days. This effect is seen with the other polymers in this series from T=0 until T=14

days however a decline in modulus and tensile strength is seen beyond these time

points. Polymer DLLA:GA-50:50 shows an initial decrease from T=0 until T=14 days

then an increase from T=14 until T=42 days. This may be due to a delayed

crystallisation Polyurethanes with only PE-DLLA as a polyol, maintained the highest

modulus over the 90-day testing period losing about 45% of its initial strength. When

compared to the other materials this seems to indicate that the incorporation of glycolic

acid in the formulation induces a faster degradation kinetic.

As it can be seen on the graphs of Figure 6.11, the data obtained for tensile strengths

show similar trends to that of the modulus. DLLA-100, the polyurethane devoid of PE-

GA polyol, shows the highest tensile strength throughout the testing period and

decreases only minimally (~10%) at the 90-day sampling point. Again, polyurethanes

with higher proportions of PE-GA polyol show very low tensile strength after 90 days.

Similar to modulus, only polyurethanes with > 50% PE-DLLA retained reasonable

mechanical strength over the 90-day test period. Again, the loss of tensile strength is

obviously associated with the degradability of glycolic acid and the results correlate

well with the trends observed with the modulus.

Chapter Six

123 | P a g e

Figure 6.11 Tensile strength for thermoset polyurethane Series 4 over a period of 90 days in vitro degradation.

0

5

10

15

20

25

30

0 14 28 42 56 70 84 98

Tens

ile S

tren

gth

(MPa

)

Time (days)

DLLA-100DLLA:GA-75:25DLLA:GA-50:50DLLA:GA-25:75GA-100

Chapter Six

124 | P a g e

For polyurethanes containing 75% PE-DLLA polyol component or more, elongation did

not change considerably over 90 days (Figure 6.12).


For polyurethanes with <50% PE-DLLA polyol component i.e. high PE-GA polyol

component, the elongation decreased to zero at 90 days in vitro degradation. These data

correspond well to the modulus and tensile strength data such that the polyurethanes

with higher PE-GA polyol component tend to lose their mechanical properties relatively

quickly when exposed to in vitro biologically simulated conditions.

Another point to consider is that these polymers tend to show inferior starting

mechanical properties when compared to the polyurethanes with higher PE-DLLA

polyol components. The polyurethanes with higher content of PE-GA may be affected

to a similar extent by the in vitro conditions. However, the modulus and tensile strength

values only need to decrease moderately for the materials to fail mechanically. This will

be discussed in the following section.

0

10

20

30

40

50

60

70

80

90

0 14 28 42 56 70 84 98

Elo

ngat

ion

(%)

Time (days)

DLLA-100 DLLA:GA-75:25DLLA:GA-50:50 DLLA:GA-25:75GA-100

Chapter Six

125 | P a g e

Mechanical properties for Series 5 polyurethanes

The modulus data for Series 5 polyurethanes showed interesting patterns over the 90-

day degradation period (Figure 6.13).

Figure 6.13 Modulus for thermoset polyurethane Series 5 over a period of 90 days in vitro degradation. (Note: Zero values indicate that the materials were not testable)

The modulus for two polyurethane materials was shown to increase over the testing

period. More interestingly, one of the polymers contained 75% of the PE-GA polyol

component. The modulus for this polymer, LLA/MA:GA-25:75, increased by

approximately 15% reaching the same value as the strongest Series 5 original material.

It is difficult to determine why this occurred particularly when its counterpart in Series

4 (DLLA/GA-25:75) has lost its mechanical properties at day 90 of the experiment. It

is not uncommon for the mechanical properties i.e. tensile strength and modulus, to

increase slightly under in vitro degradation conditions after several weeks; this

uncommon behaviour has been reported elsewhere (Vernengo et al., 2008).

0

500

1000

1500

2000

2500

0 14 28 42 56 70 84 98

Mod

ulus

(MPa

)

Time (days)

LLA/MA-100 LLA/MA:GA-75:25LLA/MA:GA-50:50 LLA/MA:GA-25:75GA-100

Chapter Six

126 | P a g e

The mass loss for all Series 5 polyurethanes (excluding GA-100) at day 90 was

negligible. However, two of the polyurethane materials (the 50:50 and LLA/MA-100

formulas) lost approximately half of their modulus indicating that in vitro conditions did

have some effects on the polymers despite showing no mass loss. This may be

indicative of partial hydrolysis whereby the mechanical integrity is compromised but

the extent of hydrolysis was not significant enough for the polymers to release low

molecular weight components from the network, thus exhibiting no significant weight

loss.

Similar patterns in the values of the modulus are not obvious when comparing Series 5

to Series 4 polyurethanes. Unlike Series 4 polyurethanes, there appears to be no clear

relationship between the percentage of PE-GA polyol in the polyurethane and loss of

mechanical properties. Since the initial modulus of Series 5 polyurethanes were

considerably higher than that of Series 4, it can be assumed that a period of 90 days in

vitro do not represent harsh enough conditions to significantly affect materials with

such strong mechanical properties. Given the mass loss induction time for these

materials was beyond 90 days, the expectation was that the mechanical properties for

Series 5 would not show much variations in the modulus prior to this time limit. The

results are consistent with mass loss data observed for this series.

The pattern with tensile strength for Series 5 polyurethane materials was similar to that

of the modulus data (Figure 6.14). The tensile strength exhibited an increase over time

for polyurethane 75:25 and 25:75 and a decrease between 40-60% for the LLA/MA-100

and 50:50 formulas. The latter two polyurethane materials maintained relatively high

tensile strength after a 90-day in vitro degradation period. Polyurethane materials 75:25

and 25:75 showed superior tensile strength at this sampling time point.

Chapter Six

127 | P a g e

Figure 6.14 Tensile strength for thermoset polyurethane Series 5 after 90 days in vitro incubation (Note: Zero values indicate that the materials were not testable).

As mentioned previously, these polymers showed no mass loss at this stage of the

experiment. Perhaps if there were sampling time points beyond 90 days, more

meaningful data may have been observed.

Elongation for 25:75 (75% PE-GA polyol) showed interesting results (Figure 6.15).

The tensile strength and modulus for this particular polymer increased over time, yet the

elongation decreased considerably. This implies that the materials were becoming

stronger and less elastic as a result of being exposed to in vitro conditions. The

elongation for LLA/MA-100 increased substantially at the 90-day sampling time point,

the results suggest that this particular material weakened and became more elastic under

in vitro conditions.

0

10

20

30

40

50

60

0 14 28 42 56 70 84 98

Tens

ile S

tren

gth

(MPa

)

Time (days)

LLA/MA-100 LLA/MA:GA-75:25LLA/MA:GA-50:50 LLA/MA:GA-25:75GA-100

Chapter Six

128 | P a g e


Elongation for the other materials (excluding GA-100), remained the same throughout

the 90 day duration.

6.1.4 Changes in Thermal Properties

The DSC thermograms for series 4 and 5 prior to in vitro degradation are reported in

Chapter 4, Section 4.3.2. Prior to testing the thermal properties, residual polyurethanes

at sampling time points were vacuum dried at room temperature for 3 days and purged

with nitrogen to remove residual water. These data were compared to the thermal traces

of their equivalent pre-degraded polyurethanes and analysed for shifts in glass transition

temperatures as a result of exposure to in vitro conditions. The following figures

display sampling time points are at day zero (pre-degradation), 42 days and 90 days of

in vitro degradation.

0

10

20

30

40

50

60

70

80

0 20 40 60 80 100

Elo

ngat

ion

(%)

Time (days)

LLA/MA-100

LLA/MA:GA-75:25

LLA/MA:GA-50:50

LLA/MA:GA-25:75

GA-100

Chapter Six

129 | P a g e

Thermal traces for Series 4

Figure 6.16 shows the DSC thermograms for three of Series 4 polyurethanes. The glass

transitions areas are marked for each material showing the changes in thermal shifts

over a period of 90 days under in vitro conditions.

Figure 6.16 DSC thermograms for Series 4 polyurethane materials pre-degradation and at 42 and 90 days post-degradation.

At this stage of degradation the materials show considerable decrease in mechanical

properties but very little mass loss (< 5%). The thermal traces illustrate that the glass

transition temperature for DLLA-100 and DLLA:GA:75:25 does not shift over a period

of 90 days, however, the transition peak becomes more pronounced with time. This

may be indicative of an annealing effect on the polyurethane. Although the materials

have lost considerable mechanical properties at this point, this does not appear to have

significant effect on the glass transition temperature. For DLLA:GA-50:50 the glass

Exot

herm

Temperature °C

!^LT8-2 T=0 (b)LT8-2 T=0 (b), 11.5800 mg

!LT8-5 T=0 (b)LT8-5 T=0 (b), 10.3500 mg !LT8-4 T=0 (b)

LT8-4 T=0 (b), 9.2900 mg

!LT8-3 T=0 (b)LT8-3 T=0 (b), 10.0800 mg

!LT8-1 T=0 (b)LT8-1 T=0 (b), 8.9000 mg

!LT8-5 T=6W (b)LT8-5 T=6W (b), 7.5000 mg

!LT8-4 T=6W (b)LT8-4 T=6W (b), 7.3500 mg

!LT8-1 T=6W (b)LT8-1 T=6W (b), 12.1200 mg!LT8-2 T=6W (b)

LT8-2 T=6W (b), 12.6100 mg!LT8-3 T=6W (b)LT8-3 T=6W (b), 13.7500 mg

!LT8-1 T=3M (b)LT8-1 T=3M (b), 10.2700 mg

!LT8-2 T=3M (b)LT8-2 T=3M (b), 10.4700 mg

!LT8-3 T=3M (b)LT8-3 T=3M (b), 6.0400 mg

!LT8-4 T=3M (b)LT8-4 T=3M (b), 9.2400 mg

Wg -1

2

min

°C-60 -40 -20 0 20 40 60 80 100 120 140 160 180 200 220 240

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

êxo


!^LT8-2 T=0 (b)LT8-2 T=0 (b), 11.5800 mg

!LT8-5 T=0 (b)LT8-5 T=0 (b), 10.3500 mg !LT8-4 T=0 (b)

LT8-4 T=0 (b), 9.2900 mg

!LT8-3 T=0 (b)LT8-3 T=0 (b), 10.0800 mg

!LT8-1 T=0 (b)LT8-1 T=0 (b), 8.9000 mg

!LT8-5 T=6W (b)LT8-5 T=6W (b), 7.5000 mg

!LT8-4 T=6W (b)LT8-4 T=6W (b), 7.3500 mg



!LT8-1 T=3M (b)LT8-1 T=3M (b), 10.2700 mg

!LT8-2 T=3M (b)LT8-2 T=3M (b), 10.4700 mg

!LT8-3 T=3M (b)LT8-3 T=3M (b), 6.0400 mg

!LT8-4 T=3M (b)LT8-4 T=3M (b), 9.2400 mg

Wg -1

2

min

°C-60 -40 -20 0 20 40 60 80 100 120 140 160 180 200 220 240

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

êxo


!^LT8-2 T=0 (b)LT8-2 T=0 (b), 11.5800 mg

!LT8-5 T=0 (b)LT8-5 T=0 (b), 10.3500 mg !LT8-4 T=0 (b)

LT8-4 T=0 (b), 9.2900 mg

!LT8-3 T=0 (b)LT8-3 T=0 (b), 10.0800 mg

!LT8-1 T=0 (b)LT8-1 T=0 (b), 8.9000 mg

!LT8-5 T=6W (b)LT8-5 T=6W (b), 7.5000 mg

!LT8-4 T=6W (b)LT8-4 T=6W (b), 7.3500 mg



!LT8-1 T=3M (b)LT8-1 T=3M (b), 10.2700 mg

!LT8-2 T=3M (b)LT8-2 T=3M (b), 10.4700 mg

!LT8-3 T=3M (b)LT8-3 T=3M (b), 6.0400 mg

!LT8-4 T=3M (b)LT8-4 T=3M (b), 9.2400 mg

Wg -1

2

min

°C-60 -40 -20 0 20 40 60 80 100 120 140 160 180 200 220 240

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

êxo


!^LT8-2 T=0 (b)LT8-2 T=0 (b), 11.5800 mg

!LT8-5 T=0 (b)LT8-5 T=0 (b), 10.3500 mg !LT8-4 T=0 (b)

LT8-4 T=0 (b), 9.2900 mg

!LT8-3 T=0 (b)LT8-3 T=0 (b), 10.0800 mg

!LT8-1 T=0 (b)LT8-1 T=0 (b), 8.9000 mg

!LT8-5 T=6W (b)LT8-5 T=6W (b), 7.5000 mg

!LT8-4 T=6W (b)LT8-4 T=6W (b), 7.3500 mg



!LT8-1 T=3M (b)LT8-1 T=3M (b), 10.2700 mg

!LT8-2 T=3M (b)LT8-2 T=3M (b), 10.4700 mg

!LT8-3 T=3M (b)LT8-3 T=3M (b), 6.0400 mg

!LT8-4 T=3M (b)LT8-4 T=3M (b), 9.2400 mg

Wg -1

2

min

°C-60 -40 -20 0 20 40 60 80 100 120 140 160 180 200 220 240

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

êxo


!^LT8-2 T=0 (b)LT8-2 T=0 (b), 11.5800 mg

!LT8-5 T=0 (b)LT8-5 T=0 (b), 10.3500 mg !LT8-4 T=0 (b)

LT8-4 T=0 (b), 9.2900 mg

!LT8-3 T=0 (b)LT8-3 T=0 (b), 10.0800 mg

!LT8-1 T=0 (b)LT8-1 T=0 (b), 8.9000 mg

!LT8-5 T=6W (b)LT8-5 T=6W (b), 7.5000 mg

!LT8-4 T=6W (b)LT8-4 T=6W (b), 7.3500 mg



!LT8-1 T=3M (b)LT8-1 T=3M (b), 10.2700 mg

!LT8-2 T=3M (b)LT8-2 T=3M (b), 10.4700 mg

!LT8-3 T=3M (b)LT8-3 T=3M (b), 6.0400 mg

!LT8-4 T=3M (b)LT8-4 T=3M (b), 9.2400 mg

Wg -1

2

min

°C-60 -40 -20 0 20 40 60 80 100 120 140 160 180 200 220 240

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

êxo


!^LT8-2 T=0 (b)LT8-2 T=0 (b), 11.5800 mg

!LT8-5 T=0 (b)LT8-5 T=0 (b), 10.3500 mg !LT8-4 T=0 (b)

LT8-4 T=0 (b), 9.2900 mg

!LT8-3 T=0 (b)LT8-3 T=0 (b), 10.0800 mg

!LT8-1 T=0 (b)LT8-1 T=0 (b), 8.9000 mg

!LT8-5 T=6W (b)LT8-5 T=6W (b), 7.5000 mg

!LT8-4 T=6W (b)LT8-4 T=6W (b), 7.3500 mg



!LT8-1 T=3M (b)LT8-1 T=3M (b), 10.2700 mg

!LT8-2 T=3M (b)LT8-2 T=3M (b), 10.4700 mg

!LT8-3 T=3M (b)LT8-3 T=3M (b), 6.0400 mg

!LT8-4 T=3M (b)LT8-4 T=3M (b), 9.2400 mg

Wg -1

2

min

°C-60 -40 -20 0 20 40 60 80 100 120 140 160 180 200 220 240

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

êxo


DLLA-100

DLLA:GA-75:25

DLLA:GA-50:50

Tg

Tg

Tg

t=0

t=90 d

Chapter Six

130 | P a g e

transition at 90 days showed a slight shift to lower temperatures (~8ºC shift) relative to

that of the original material and the sample incubated for 42 days, which is an indication

of significant structural changes. After 90 days of exposure to in vitro conditions

DLLA:GA-50:50 showed about 5% mass loss and very low modulus and tensile

strength. The evident structural change demonstrated by the thermal trace, may

contribute to the loss of mechanical properties for these materials.

Figure 6.17 shows the DSC thermograms for two of Series 4 polyurethane materials.

For polyurethane DLLA:GA-25:75 the glass transition shows a shift to lower

temperature relative to that of the pre-degraded at day 42 and a further shift at day 90

signifying considerable structural change.


Exo

ther

m

Temperature °C

!^LT8-2 T=0 (b)LT8-2 T=0 (b), 11.5800 mg

!LT8-5 T=0 (b)LT8-5 T=0 (b), 10.3500 mg !LT8-4 T=0 (b)

LT8-4 T=0 (b), 9.2900 mg

!LT8-3 T=0 (b)LT8-3 T=0 (b), 10.0800 mg

!LT8-1 T=0 (b)LT8-1 T=0 (b), 8.9000 mg

!LT8-5 T=6W (b)LT8-5 T=6W (b), 7.5000 mg

!LT8-4 T=6W (b)LT8-4 T=6W (b), 7.3500 mg



!LT8-1 T=3M (b)LT8-1 T=3M (b), 10.2700 mg

!LT8-2 T=3M (b)LT8-2 T=3M (b), 10.4700 mg

!LT8-3 T=3M (b)LT8-3 T=3M (b), 6.0400 mg

!LT8-4 T=3M (b)LT8-4 T=3M (b), 9.2400 mg

Wg -1

2

min

°C-60 -40 -20 0 20 40 60 80 100 120 140 160 180 200 220 240

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

êxo


!^LT8-2 T=0 (b)LT8-2 T=0 (b), 11.5800 mg

!LT8-5 T=0 (b)LT8-5 T=0 (b), 10.3500 mg !LT8-4 T=0 (b)

LT8-4 T=0 (b), 9.2900 mg

!LT8-3 T=0 (b)LT8-3 T=0 (b), 10.0800 mg

!LT8-1 T=0 (b)LT8-1 T=0 (b), 8.9000 mg

!LT8-5 T=6W (b)LT8-5 T=6W (b), 7.5000 mg

!LT8-4 T=6W (b)LT8-4 T=6W (b), 7.3500 mg



!LT8-1 T=3M (b)LT8-1 T=3M (b), 10.2700 mg

!LT8-2 T=3M (b)LT8-2 T=3M (b), 10.4700 mg

!LT8-3 T=3M (b)LT8-3 T=3M (b), 6.0400 mg

!LT8-4 T=3M (b)LT8-4 T=3M (b), 9.2400 mg

Wg -1

2

min

°C-60 -40 -20 0 20 40 60 80 100 120 140 160 180 200 220 240

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

êxo


!^LT8-2 T=0 (b)LT8-2 T=0 (b), 11.5800 mg

!LT8-5 T=0 (b)LT8-5 T=0 (b), 10.3500 mg !LT8-4 T=0 (b)

LT8-4 T=0 (b), 9.2900 mg

!LT8-3 T=0 (b)LT8-3 T=0 (b), 10.0800 mg

!LT8-1 T=0 (b)LT8-1 T=0 (b), 8.9000 mg

!LT8-5 T=6W (b)LT8-5 T=6W (b), 7.5000 mg

!LT8-4 T=6W (b)LT8-4 T=6W (b), 7.3500 mg



!LT8-1 T=3M (b)LT8-1 T=3M (b), 10.2700 mg

!LT8-2 T=3M (b)LT8-2 T=3M (b), 10.4700 mg

!LT8-3 T=3M (b)LT8-3 T=3M (b), 6.0400 mg

!LT8-4 T=3M (b)LT8-4 T=3M (b), 9.2400 mg

Wg -1

2

min

°C-60 -40 -20 0 20 40 60 80 100 120 140 160 180 200 220 240

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

êxo


!^LT8-2 T=0 (b)LT8-2 T=0 (b), 11.5800 mg

!LT8-5 T=0 (b)LT8-5 T=0 (b), 10.3500 mg !LT8-4 T=0 (b)

LT8-4 T=0 (b), 9.2900 mg

!LT8-3 T=0 (b)LT8-3 T=0 (b), 10.0800 mg

!LT8-1 T=0 (b)LT8-1 T=0 (b), 8.9000 mg

!LT8-5 T=6W (b)LT8-5 T=6W (b), 7.5000 mg

!LT8-4 T=6W (b)LT8-4 T=6W (b), 7.3500 mg



!LT8-1 T=3M (b)LT8-1 T=3M (b), 10.2700 mg

!LT8-2 T=3M (b)LT8-2 T=3M (b), 10.4700 mg

!LT8-3 T=3M (b)LT8-3 T=3M (b), 6.0400 mg

!LT8-4 T=3M (b)LT8-4 T=3M (b), 9.2400 mg

Wg -1

2

min

°C-60 -40 -20 0 20 40 60 80 100 120 140 160 180 200 220 240

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

êxo


DLLA:GA-25:75

GA-100 Tg

Tg

Tg

Tg

Tg

Chapter Six

131 | P a g e

While at Day 42 the mass loss was minimal for DLLA:GA-25:75, the mechanical

properties showed a substantial decrease and at day 90 it was not possible to measure

the modulus and tensile strength as the materials were too weak. These data show that a

decrease in mechanical strength corresponds to a decrease in glass transition

temperatures.

For GA-100, the data show pre-degraded materials (time zero) and day 42 sampling

time point as these materials had undergone 100% mass loss by day 90. At day 42 the

glass transition for GA-100 polyurethane materials had shifted substantially left to a

lower temperature indicating major structural change. Despite showing minimal mass

loss, these materials exhibited zero modulus and tensile strength after 42 days exposed

to in vitro conditions.

Table 6.3 summarises the glass transition pre- and post-degradation (42 & 90 days) for

Series 4 polyurethanes. Prior to degradation all Series 4 polymers exhibit very similar

glass transition temperatures.

Table 6.3 Glass transition temperature for Series 4 polyurethanes pre-degradation (t = 0) and at 42 and 90 days exposed to in vitro conditions.

Series 4 Tg (°C) t= 0 t= 42 days t= 90 days

DLLA-100 64.1 64.0 63.0

DLLA:GA-75:25 64.2 64.0 62.1

DLLA:GA-50:50 63.6 61.1 55.3

DLLA:GA-25:75 64.6 55.5 25.0

GA-100 61.7 32.2 -

As the percentage of PE-GA polyol component increases in the polyurethane formula,

the glass transition at the 90-day sampling time point shows a constant decrease. The

structural changes in these polyurethane materials caused by the exposure to in vitro

conditions is reflected in the loss of mechanical properties and a decrease in the glass

transition for these materials. Interestingly, the changes in both thermal and mechanical

properties can be observed prior to the actual mass loss of the materials. Since the

Chapter Six

132 | P a g e

materials in these two series are cross-linked networks, hydrolysis of some linkages will

not lead to any mass loss. However, such changes can be reflected in mechanical and

thermal properties as have been observed demonstrated by these data.

For Series 4, the addition of PE-GA polyol in higher proportions to the polyurethane

causes mechanical and thermal properties to decrease at a faster rate according to the

data presented.

Glass transition for Series 5 polyurethanes

Figure 6.18 shows the thermal traces for Series 5 polyurethanes (excluding GA-100)

prior to degradation and at days 42 and 90 under in vitro conditions.


!LT9-1 T=6W (b)LT9-1 T=6W (b), 7.6300 mg

!LT9-2 T=6W (b)LT9-2 T=6W (b), 9.2400 mg !LT9-3 T=6W (b)

LT9-3 T=6W (b), 10.5900 mg

!LT9-4 T=6W (b)LT9-4 T=6W (b), 10.7100 mg

!LT9-1 T=3M (b)LT9-1 T=3M (b), 12.4700 mg !LT9-2 T=3M (b)

LT9-2 T=3M (b), 11.4800 mg !LT9-4 T=3M (b)LT9-4 T=3M (b), 11.4300 mg

!LT9-1 T=0 (b)LT9-1 T=0 (b), 9.5500 mg

!LT9-2 T=0 (b)LT9-2 T=0 (b), 12.1800 mg

!LT9-3 T=0 (b)LT9-3 T=0 (b), 12.6700 mg

!LT9-4 T=0 (b)LT9-4 T=0 (b), 10.5000 mg

!LT9-3 T=3M (b)LT9-3 T=3M (b), 8.8500 mg

Wg -1

2

min

°C-60 -40 -20 0 20 40 60 80 100 120 140 160 180 200 220

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

êxo


!LT9-1 T=6W (b)LT9-1 T=6W (b), 7.6300 mg


LT9-3 T=6W (b), 10.5900 mg

!LT9-4 T=6W (b)LT9-4 T=6W (b), 10.7100 mg



!LT9-1 T=0 (b)LT9-1 T=0 (b), 9.5500 mg

!LT9-2 T=0 (b)LT9-2 T=0 (b), 12.1800 mg

!LT9-3 T=0 (b)LT9-3 T=0 (b), 12.6700 mg

!LT9-4 T=0 (b)LT9-4 T=0 (b), 10.5000 mg

!LT9-3 T=3M (b)LT9-3 T=3M (b), 8.8500 mg

Wg -1

2

min

°C-60 -40 -20 0 20 40 60 80 100 120 140 160 180 200 220

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

êxo


!LT9-1 T=6W (b)LT9-1 T=6W (b), 7.6300 mg


LT9-3 T=6W (b), 10.5900 mg

!LT9-4 T=6W (b)LT9-4 T=6W (b), 10.7100 mg



!LT9-1 T=0 (b)LT9-1 T=0 (b), 9.5500 mg

!LT9-2 T=0 (b)LT9-2 T=0 (b), 12.1800 mg

!LT9-3 T=0 (b)LT9-3 T=0 (b), 12.6700 mg

!LT9-4 T=0 (b)LT9-4 T=0 (b), 10.5000 mg

!LT9-3 T=3M (b)LT9-3 T=3M (b), 8.8500 mg

Wg -1

2

min

°C-60 -40 -20 0 20 40 60 80 100 120 140 160 180 200 220

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

êxo


!LT9-1 T=6W (b)LT9-1 T=6W (b), 7.6300 mg


LT9-3 T=6W (b), 10.5900 mg

!LT9-4 T=6W (b)LT9-4 T=6W (b), 10.7100 mg



!LT9-1 T=0 (b)LT9-1 T=0 (b), 9.5500 mg

!LT9-2 T=0 (b)LT9-2 T=0 (b), 12.1800 mg

!LT9-3 T=0 (b)LT9-3 T=0 (b), 12.6700 mg

!LT9-4 T=0 (b)LT9-4 T=0 (b), 10.5000 mg

!LT9-3 T=3M (b)LT9-3 T=3M (b), 8.8500 mg

Wg -1

2

min

°C-60 -40 -20 0 20 40 60 80 100 120 140 160 180 200 220

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

êxo


!LT9-1 T=6W (b)LT9-1 T=6W (b), 7.6300 mg


LT9-3 T=6W (b), 10.5900 mg

!LT9-4 T=6W (b)LT9-4 T=6W (b), 10.7100 mg



!LT9-1 T=0 (b)LT9-1 T=0 (b), 9.5500 mg

!LT9-2 T=0 (b)LT9-2 T=0 (b), 12.1800 mg

!LT9-3 T=0 (b)LT9-3 T=0 (b), 12.6700 mg

!LT9-4 T=0 (b)LT9-4 T=0 (b), 10.5000 mg

!LT9-3 T=3M (b)LT9-3 T=3M (b), 8.8500 mg

Wg -1

2

min

°C-60 -40 -20 0 20 40 60 80 100 120 140 160 180 200 220

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

êxo


!LT9-1 T=6W (b)LT9-1 T=6W (b), 7.6300 mg


LT9-3 T=6W (b), 10.5900 mg

!LT9-4 T=6W (b)LT9-4 T=6W (b), 10.7100 mg



!LT9-1 T=0 (b)LT9-1 T=0 (b), 9.5500 mg

!LT9-2 T=0 (b)LT9-2 T=0 (b), 12.1800 mg

!LT9-3 T=0 (b)LT9-3 T=0 (b), 12.6700 mg

!LT9-4 T=0 (b)LT9-4 T=0 (b), 10.5000 mg

!LT9-3 T=3M (b)LT9-3 T=3M (b), 8.8500 mg

Wg -1

2

min

°C-60 -40 -20 0 20 40 60 80 100 120 140 160 180 200 220

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

êxo


!LT9-1 T=6W (b)LT9-1 T=6W (b), 7.6300 mg


LT9-3 T=6W (b), 10.5900 mg

!LT9-4 T=6W (b)LT9-4 T=6W (b), 10.7100 mg



!LT9-1 T=0 (b)LT9-1 T=0 (b), 9.5500 mg

!LT9-2 T=0 (b)LT9-2 T=0 (b), 12.1800 mg

!LT9-3 T=0 (b)LT9-3 T=0 (b), 12.6700 mg

!LT9-4 T=0 (b)LT9-4 T=0 (b), 10.5000 mg

!LT9-3 T=3M (b)LT9-3 T=3M (b), 8.8500 mg

Wg -1

2

min

°C-60 -40 -20 0 20 40 60 80 100 120 140 160 180 200 220

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

êxo


!LT9-1 T=6W (b)LT9-1 T=6W (b), 7.6300 mg


LT9-3 T=6W (b), 10.5900 mg

!LT9-4 T=6W (b)LT9-4 T=6W (b), 10.7100 mg



!LT9-1 T=0 (b)LT9-1 T=0 (b), 9.5500 mg

!LT9-2 T=0 (b)LT9-2 T=0 (b), 12.1800 mg

!LT9-3 T=0 (b)LT9-3 T=0 (b), 12.6700 mg

!LT9-4 T=0 (b)LT9-4 T=0 (b), 10.5000 mg

!LT9-3 T=3M (b)LT9-3 T=3M (b), 8.8500 mg

Wg -1

2

min

°C-60 -40 -20 0 20 40 60 80 100 120 140 160 180 200 220

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

êxo


!LT9-1 T=6W (b)LT9-1 T=6W (b), 7.6300 mg


LT9-3 T=6W (b), 10.5900 mg

!LT9-4 T=6W (b)LT9-4 T=6W (b), 10.7100 mg



!LT9-1 T=0 (b)LT9-1 T=0 (b), 9.5500 mg

!LT9-2 T=0 (b)LT9-2 T=0 (b), 12.1800 mg

!LT9-3 T=0 (b)LT9-3 T=0 (b), 12.6700 mg

!LT9-4 T=0 (b)LT9-4 T=0 (b), 10.5000 mg

!LT9-3 T=3M (b)LT9-3 T=3M (b), 8.8500 mg

Wg -1

2

min

°C-60 -40 -20 0 20 40 60 80 100 120 140 160 180 200 220

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

êxo


!LT9-1 T=6W (b)LT9-1 T=6W (b), 7.6300 mg


LT9-3 T=6W (b), 10.5900 mg

!LT9-4 T=6W (b)LT9-4 T=6W (b), 10.7100 mg



!LT9-1 T=0 (b)LT9-1 T=0 (b), 9.5500 mg

!LT9-2 T=0 (b)LT9-2 T=0 (b), 12.1800 mg

!LT9-3 T=0 (b)LT9-3 T=0 (b), 12.6700 mg

!LT9-4 T=0 (b)LT9-4 T=0 (b), 10.5000 mg

!LT9-3 T=3M (b)LT9-3 T=3M (b), 8.8500 mg

Wg -1

2

min

°C-60 -40 -20 0 20 40 60 80 100 120 140 160 180 200 220

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

êxo


Temperature °C

Exot

herm

!LT9-1 T=6W (b)LT9-1 T=6W (b), 7.6300 mg


LT9-3 T=6W (b), 10.5900 mg

!LT9-4 T=6W (b)LT9-4 T=6W (b), 10.7100 mg



!LT9-1 T=0 (b)LT9-1 T=0 (b), 9.5500 mg

!LT9-2 T=0 (b)LT9-2 T=0 (b), 12.1800 mg

!LT9-3 T=0 (b)LT9-3 T=0 (b), 12.6700 mg

!LT9-4 T=0 (b)LT9-4 T=0 (b), 10.5000 mg

!LT9-3 T=3M (b)LT9-3 T=3M (b), 8.8500 mg

Wg -1

2

min

°C-60 -40 -20 0 20 40 60 80 100 120 140 160 180 200 220

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

êxo


!LT9-1 T=6W (b)LT9-1 T=6W (b), 7.6300 mg


LT9-3 T=6W (b), 10.5900 mg

!LT9-4 T=6W (b)LT9-4 T=6W (b), 10.7100 mg



!LT9-1 T=0 (b)LT9-1 T=0 (b), 9.5500 mg

!LT9-2 T=0 (b)LT9-2 T=0 (b), 12.1800 mg

!LT9-3 T=0 (b)LT9-3 T=0 (b), 12.6700 mg

!LT9-4 T=0 (b)LT9-4 T=0 (b), 10.5000 mg

!LT9-3 T=3M (b)LT9-3 T=3M (b), 8.8500 mg

Wg -1

2

min

°C-60 -40 -20 0 20 40 60 80 100 120 140 160 180 200 220

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

êxo


!LT9-1 T=6W (b)LT9-1 T=6W (b), 7.6300 mg


LT9-3 T=6W (b), 10.5900 mg

!LT9-4 T=6W (b)LT9-4 T=6W (b), 10.7100 mg



!LT9-1 T=0 (b)LT9-1 T=0 (b), 9.5500 mg

!LT9-2 T=0 (b)LT9-2 T=0 (b), 12.1800 mg

!LT9-3 T=0 (b)LT9-3 T=0 (b), 12.6700 mg

!LT9-4 T=0 (b)LT9-4 T=0 (b), 10.5000 mg

!LT9-3 T=3M (b)LT9-3 T=3M (b), 8.8500 mg

Wg -1

2

min

°C-60 -40 -20 0 20 40 60 80 100 120 140 160 180 200 220

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

êxo


!LT9-1 T=6W (b)LT9-1 T=6W (b), 7.6300 mg


LT9-3 T=6W (b), 10.5900 mg

!LT9-4 T=6W (b)LT9-4 T=6W (b), 10.7100 mg



!LT9-1 T=0 (b)LT9-1 T=0 (b), 9.5500 mg

!LT9-2 T=0 (b)LT9-2 T=0 (b), 12.1800 mg

!LT9-3 T=0 (b)LT9-3 T=0 (b), 12.6700 mg

!LT9-4 T=0 (b)LT9-4 T=0 (b), 10.5000 mg

!LT9-3 T=3M (b)LT9-3 T=3M (b), 8.8500 mg

Wg -1

2

min

°C-60 -40 -20 0 20 40 60 80 100 120 140 160 180 200 220

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

êxo


!LT9-1 T=6W (b)LT9-1 T=6W (b), 7.6300 mg


LT9-3 T=6W (b), 10.5900 mg

!LT9-4 T=6W (b)LT9-4 T=6W (b), 10.7100 mg



!LT9-1 T=0 (b)LT9-1 T=0 (b), 9.5500 mg

!LT9-2 T=0 (b)LT9-2 T=0 (b), 12.1800 mg

!LT9-3 T=0 (b)LT9-3 T=0 (b), 12.6700 mg

!LT9-4 T=0 (b)LT9-4 T=0 (b), 10.5000 mg

!LT9-3 T=3M (b)LT9-3 T=3M (b), 8.8500 mg

Wg -1

2

min

°C-60 -40 -20 0 20 40 60 80 100 120 140 160 180 200 220

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

êxo


!LT9-1 T=6W (b)LT9-1 T=6W (b), 7.6300 mg


LT9-3 T=6W (b), 10.5900 mg

!LT9-4 T=6W (b)LT9-4 T=6W (b), 10.7100 mg



!LT9-1 T=0 (b)LT9-1 T=0 (b), 9.5500 mg

!LT9-2 T=0 (b)LT9-2 T=0 (b), 12.1800 mg

!LT9-3 T=0 (b)LT9-3 T=0 (b), 12.6700 mg

!LT9-4 T=0 (b)LT9-4 T=0 (b), 10.5000 mg

!LT9-3 T=3M (b)LT9-3 T=3M (b), 8.8500 mg

Wg -1

2

min

°C-60 -40 -20 0 20 40 60 80 100 120 140 160 180 200 220

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

êxo


!LT9-1 T=6W (b)LT9-1 T=6W (b), 7.6300 mg


LT9-3 T=6W (b), 10.5900 mg

!LT9-4 T=6W (b)LT9-4 T=6W (b), 10.7100 mg



!LT9-1 T=0 (b)LT9-1 T=0 (b), 9.5500 mg

!LT9-2 T=0 (b)LT9-2 T=0 (b), 12.1800 mg

!LT9-3 T=0 (b)LT9-3 T=0 (b), 12.6700 mg

!LT9-4 T=0 (b)LT9-4 T=0 (b), 10.5000 mg

!LT9-3 T=3M (b)LT9-3 T=3M (b), 8.8500 mg

Wg -1

2

min

°C-60 -40 -20 0 20 40 60 80 100 120 140 160 180 200 220

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

êxo


!LT9-1 T=6W (b)LT9-1 T=6W (b), 7.6300 mg


LT9-3 T=6W (b), 10.5900 mg

!LT9-4 T=6W (b)LT9-4 T=6W (b), 10.7100 mg



!LT9-1 T=0 (b)LT9-1 T=0 (b), 9.5500 mg

!LT9-2 T=0 (b)LT9-2 T=0 (b), 12.1800 mg

!LT9-3 T=0 (b)LT9-3 T=0 (b), 12.6700 mg

!LT9-4 T=0 (b)LT9-4 T=0 (b), 10.5000 mg

!LT9-3 T=3M (b)LT9-3 T=3M (b), 8.8500 mg

Wg -1

2

min

°C-60 -40 -20 0 20 40 60 80 100 120 140 160 180 200 220

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

êxo


Tg

Tg

Tg

Tg t=0

t=90

LLA/MA-100

LLA/MA:GA-75:25

LLA/MA:GA-50:50

LLA/MA:GA-25:75

Temperature °C

Exot

herm

!LT9-1 T=6W (b)LT9-1 T=6W (b), 7.6300 mg


LT9-3 T=6W (b), 10.5900 mg

!LT9-4 T=6W (b)LT9-4 T=6W (b), 10.7100 mg



!LT9-1 T=0 (b)LT9-1 T=0 (b), 9.5500 mg

!LT9-2 T=0 (b)LT9-2 T=0 (b), 12.1800 mg

!LT9-3 T=0 (b)LT9-3 T=0 (b), 12.6700 mg

!LT9-4 T=0 (b)LT9-4 T=0 (b), 10.5000 mg

!LT9-3 T=3M (b)LT9-3 T=3M (b), 8.8500 mg

Wg -1

2

min

°C-60 -40 -20 0 20 40 60 80 100 120 140 160 180 200 220

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

êxo


!LT9-1 T=6W (b)LT9-1 T=6W (b), 7.6300 mg


LT9-3 T=6W (b), 10.5900 mg

!LT9-4 T=6W (b)LT9-4 T=6W (b), 10.7100 mg



!LT9-1 T=0 (b)LT9-1 T=0 (b), 9.5500 mg

!LT9-2 T=0 (b)LT9-2 T=0 (b), 12.1800 mg

!LT9-3 T=0 (b)LT9-3 T=0 (b), 12.6700 mg

!LT9-4 T=0 (b)LT9-4 T=0 (b), 10.5000 mg

!LT9-3 T=3M (b)LT9-3 T=3M (b), 8.8500 mg

Wg -1

2

min

°C-60 -40 -20 0 20 40 60 80 100 120 140 160 180 200 220

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

êxo


!LT9-1 T=6W (b)LT9-1 T=6W (b), 7.6300 mg


LT9-3 T=6W (b), 10.5900 mg

!LT9-4 T=6W (b)LT9-4 T=6W (b), 10.7100 mg



!LT9-1 T=0 (b)LT9-1 T=0 (b), 9.5500 mg

!LT9-2 T=0 (b)LT9-2 T=0 (b), 12.1800 mg

!LT9-3 T=0 (b)LT9-3 T=0 (b), 12.6700 mg

!LT9-4 T=0 (b)LT9-4 T=0 (b), 10.5000 mg

!LT9-3 T=3M (b)LT9-3 T=3M (b), 8.8500 mg

Wg -1

2

min

°C-60 -40 -20 0 20 40 60 80 100 120 140 160 180 200 220

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

êxo


!LT9-1 T=6W (b)LT9-1 T=6W (b), 7.6300 mg


LT9-3 T=6W (b), 10.5900 mg

!LT9-4 T=6W (b)LT9-4 T=6W (b), 10.7100 mg



!LT9-1 T=0 (b)LT9-1 T=0 (b), 9.5500 mg

!LT9-2 T=0 (b)LT9-2 T=0 (b), 12.1800 mg

!LT9-3 T=0 (b)LT9-3 T=0 (b), 12.6700 mg

!LT9-4 T=0 (b)LT9-4 T=0 (b), 10.5000 mg

!LT9-3 T=3M (b)LT9-3 T=3M (b), 8.8500 mg

Wg -1

2

min

°C-60 -40 -20 0 20 40 60 80 100 120 140 160 180 200 220

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

êxo


!LT9-1 T=6W (b)LT9-1 T=6W (b), 7.6300 mg


LT9-3 T=6W (b), 10.5900 mg

!LT9-4 T=6W (b)LT9-4 T=6W (b), 10.7100 mg



!LT9-1 T=0 (b)LT9-1 T=0 (b), 9.5500 mg

!LT9-2 T=0 (b)LT9-2 T=0 (b), 12.1800 mg

!LT9-3 T=0 (b)LT9-3 T=0 (b), 12.6700 mg

!LT9-4 T=0 (b)LT9-4 T=0 (b), 10.5000 mg

!LT9-3 T=3M (b)LT9-3 T=3M (b), 8.8500 mg

Wg -1

2

min

°C-60 -40 -20 0 20 40 60 80 100 120 140 160 180 200 220

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

êxo


!LT9-1 T=6W (b)LT9-1 T=6W (b), 7.6300 mg


LT9-3 T=6W (b), 10.5900 mg

!LT9-4 T=6W (b)LT9-4 T=6W (b), 10.7100 mg



!LT9-1 T=0 (b)LT9-1 T=0 (b), 9.5500 mg

!LT9-2 T=0 (b)LT9-2 T=0 (b), 12.1800 mg

!LT9-3 T=0 (b)LT9-3 T=0 (b), 12.6700 mg

!LT9-4 T=0 (b)LT9-4 T=0 (b), 10.5000 mg

!LT9-3 T=3M (b)LT9-3 T=3M (b), 8.8500 mg

Wg -1

2

min

°C-60 -40 -20 0 20 40 60 80 100 120 140 160 180 200 220

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

êxo


!LT9-1 T=6W (b)LT9-1 T=6W (b), 7.6300 mg


LT9-3 T=6W (b), 10.5900 mg

!LT9-4 T=6W (b)LT9-4 T=6W (b), 10.7100 mg



!LT9-1 T=0 (b)LT9-1 T=0 (b), 9.5500 mg

!LT9-2 T=0 (b)LT9-2 T=0 (b), 12.1800 mg

!LT9-3 T=0 (b)LT9-3 T=0 (b), 12.6700 mg

!LT9-4 T=0 (b)LT9-4 T=0 (b), 10.5000 mg

!LT9-3 T=3M (b)LT9-3 T=3M (b), 8.8500 mg

Wg -1

2

min

°C-60 -40 -20 0 20 40 60 80 100 120 140 160 180 200 220

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

êxo


!LT9-1 T=6W (b)LT9-1 T=6W (b), 7.6300 mg


LT9-3 T=6W (b), 10.5900 mg

!LT9-4 T=6W (b)LT9-4 T=6W (b), 10.7100 mg



!LT9-1 T=0 (b)LT9-1 T=0 (b), 9.5500 mg

!LT9-2 T=0 (b)LT9-2 T=0 (b), 12.1800 mg

!LT9-3 T=0 (b)LT9-3 T=0 (b), 12.6700 mg

!LT9-4 T=0 (b)LT9-4 T=0 (b), 10.5000 mg

!LT9-3 T=3M (b)LT9-3 T=3M (b), 8.8500 mg

Wg -1

2

min

°C-60 -40 -20 0 20 40 60 80 100 120 140 160 180 200 220

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

êxo


Tg

Tg

Tg

Tg t=0

t=90

LLA/MA-100

LLA/MA:GA-75:25

LLA/MA:GA-50:50

LLA/MA:GA-25:75

LLA/MA-100

LLA/MA:GA-75:25

LLA/MA:GA-50:50

LLA/MA:GA-25:75

t = 0

t = 90 d

Chapter Six

133 | P a g e

For all Series 5 polyurethanes there were no significant variations in the glass

transitions after the 90-day degradation period. As it can be seen, in most cases, it is

difficult to distinguish the glass transition point without the aid of DSC thermal analysis

software due to the low intensity of the thermal event, reflected by an almost flat curve.

Table 6.4 reports the values determined for Series 5 polyurethane glass transitions prior

to the degradation test and after an incubation period of 42 and 90 days where, with the

exception of GA-100, there is no major change in the temperature of glass transition

over this period of time.

Table 6.4 Glass transition temperature (midpoint) for Series 5 polyurethane materials pre-degradation (t = 0) and at 42 and 90 days exposed to in vitro conditions.

Series 5 Tg (°C)

t= 0 t= 42 days t= 90 days

LLA/MA-100 83.8 84.0 90.6

LLA/MA:GA-75:25 88.2 72.8 80.2

LLA/MA:GA-50:50 63.9 77.3 64.2

LLA/MA:GA-25:75 64.0 64.0 60

GA-100 61.7 32.2 -

These data indicate that there were no major structural changes in the polymers over this

period of time: no mass loss was evident and the modulus and tensile strength had

shown minimal change for Series 5 polyurethanes.

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134 | P a g e

6.1.5 Accelerated Degradation at 70°C

The methods for accelerated degradations are described in Chapter 3, Section 3.19.2.

Selected samples from series 4 and 5 were degraded in distilled water at 70ºC for up to

2 weeks to determine their behaviour under these conditions. The main results are

summarised in Figure 6.19.

Figure 6.19 Mass loss for selected samples of series 4 and 5 under accelerated conditions.

With the exception of LLA/MA-100, all materials were rapidly degraded over the 2

weeks incubation at 70ºC, exhibiting a mass loss in excess of 90% (Figure 6.19) A

mass loss of >90% was seen for these polymers over a 2 week period. Polymer

LLA/MA-100 showed only about 40% mass.

0

10

20

30

40

50

60

70

80

90

100

Mas

s Los

s (%

)

Selected Polyurethanes

t=7 t=14 d

Chapter Six

135 | P a g e

Mass loss data reveal that DLLA-100 materials are faster degrading than that of

LLA/MA-100 polyurethane materials, which is supported by the real-time mass loss

data. Since all of the other materials degraded so rapidly i.e. >90% mass loss within the

first 7 days, it is impossible to determine exactly when they began to lose mass and in

which order.

All that can be determined from this data is that the LLA/MA-100 polyurethane

materials is the slowest degrading material in series 4 and 5, and that the materials with

PE-GA polyol tend to show faster degradation than polyurethanes without PE-GA

polyol in the formula.

6.1.6 Summary

This section provides an overview of the main findings and how they relate to the

original aims of the project.

‘The effect of changing ratios of two different polyols on properties and degradation’

The incorporation of GA-based polyol to either the LA-based or MA-based polymers

has been shown to accelerate their degradation. This can be observed through the loss

of mechanical properties for polyurethane with higher proportions of GA-based polyol,

together with higher mass losses.

Increasing proportions of MA-based polyol was shown to improve the mechanical

properties, evidenced by higher tensile strength and modulus. The effect on mass loss

was also noticeable, as these materials exhibited higher stability.

DSC traces indicate that glass transition temperature decreases over time for

polyurethane with higher proportions of GA-based polyol compared to little change in

polyurethanes with higher proportions of MA-based polyol.

In general, the results data indicate that polyurethane containing higher

proportions of GA-based polyol accelerates degradation and polyurethane

containing higher proportions of MA-based polyol retards degradation.

Chapter Six

136 | P a g e

THE EFFECTS OF CROSSLINK DENSITY 6.2

Figure 6.20 outlines the techniques used to analyse the physicochemical changes in

polyurethane properties post in vitro degradation. Blue boxes indicate data reported in

this chapter.

Figure 6.20 Schematic diagram for Series 6 polyurethane

One of the major aims of this study was to examine the effect of cross-link density on

the in vitro degradation of PCL-based polyurethanes. The polyurethane formulations

are shown in the methods section 3.4 and in Table 6.5 below. PCL4, otherwise known

as Capa® 4101, is a commercially available tetra-functional polyol terminated with

primary hydroxyl groups with the polyol having a molecular weight of 1000 Da.

For the purpose of this study, PCL4 was used to synthesise a series of polyurethanes

with varying cross-link densities. A linear PCL (PCL1000) with a molecular weight of

PU Series 6

PU Characterisation

Water Absorption

FTIR DSC (Thermal Properties)

Real Time Degradation

(365 d)

PU Mass Loss

Pre-degradation

Post-degradation

The effects of Temperature and pH on

PU Mass Loss

Accelerated Degradation (temp and pH)

Chapter Six

137 | P a g e

1000 Da was added in different ratios to PCL4 to gradually reduce the crosslink density

such that polymers with higher ratios of PCL4 had greater crosslink density. The

objective was to determine whether the crosslink density would affect the degradation

rate of the resulting polyurethanes.

Table 6.5Polyurethane formulations for Series 6.

6.2.1 Methods

The detailed methods of synthesis and degradation can be found in chapter 3, with the

properties of these materials reported in chapter 4. The study examined the degradation

or mass loss of these materials for both real time degradation and accelerated

degradation using elevated temperatures and acid or alkaline in vitro conditions.

For the real time studies, the polymers were added to PBS buffer (pH 7.4±0.2) and

incubated at 37ºC for up to 365 days with sampling time points at 14, 42, 90, 180 and

Polyurethane

Diisocyanate Polyol 1 (P1) Polyol 2 (P2) % P1 to

P2

PCL4-100 ELDI PCL4 - 100:0







PCL-100 ELDI - PCL1000 0:100

Chapter Six

138 | P a g e

365 days. For the accelerated degradation temperature studies, the polymers were

added to PBS at 70ºC for up to 70 days with sampling time points at 42 and 70 days.

For the accelerated degradation studies under acid or alkaline conditions, the polymers

were incubated at 37ºC at either pH 2 or pH 11 for up to 42 days with a 21-day

sampling time point. Only mass loss data are reported for these materials.

6.2.2 Real Time Degradation

Figure 6.21 shows mass remaining for Series 6 polyurethane materials over a period of

365 days under in vitro conditions. From day zero until 180 days, no mass change was

evident for all materials. From 180 days until 365 days, minimal mass loss was

observed for 4 of the 8 polyurethane materials tested and one polyurethane material

showed a gain in mass.

Figure 6.21 Series 6 polyurethanes degradation over 365 days. The mass loss data for Series 6 polyurethanes after 365 days in vitro are reported in

Figure 6.22. Due to the very low mass losses observed, it is difficult to determine

whether a pattern exist in the degradation. It appears as though the polyurethanes with

greater crosslink density showed a higher mass loss than polyurethane with a lower

98.0

98.5

99.0

99.5

100.0

100.5

0 50 100 150 200 250 300 350 400

Res

idua

l Mas

s (%

)

Time (days)

PCL4-100 PCL4:PCL-75:25 PCL4:PCL-50:50 PCL4:PCL-25:75

PCL4:PCL-15:85 PCL4:PCL-10:90 PCL4:PCL-5:95 PCL-100

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139 | P a g e

crosslink density. PCL4-100, the polyurethane with the highest crosslink density

showed the greatest mass loss with the PCL4:PCL-75:25 and PCL4:PCL-50:50 showing

the next greatest mass loss. However, PCL4-100 showed large error. The remaining

polymers which all contained >75% of PCL1000, showed roughly the same mass loss

over this time. It is difficult to draw a meaningful conclusion from these results

without further investigation. Since poly(ε-caprolactone) is a slow degrading polymer,

the 1 year time frame may not be long enough to see the effect of cross link density on

degradation.

Figure 6.22 Series 6 polyurethane degradation – mass remaining after 365 days of in vitro degradation.

97.0

97.5

98.0

98.5

99.0

99.5

100.0

100.5

Res

idua

l Mas

s (%

)

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140 | P a g e

6.2.3 Accelerated Degradation

The effect of increased temperature

Figure 6.23 shows the mass loss for selected Series 6 polyurethanes over a period of 70

days at 70ºC under in vitro conditions.

Figure 6.23 Mass loss for Series 6 polyurethane materials at 70ºC.

Minimal mass loss is seen under these conditions with less than 0.05% mass loss seen at

42 days and between 0.15 and 0.3% mass loss at 70 days. Therefore, the materials

appear to be losing mass over time at a slow rate. There appears to be no pattern of

mass loss seen in these data. It may be concluded that the crosslink density has no

effect of the mass loss of these materials after 70 days in vitro at 70ºC. Although we are

referring to “mass loss” it must be pointed out that the percentages involved here are

very small and are not comparable to the mass losses observed with the other

polyurethane series.

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

PCL4-100 PCL4:PCL-75:25 PCL4:PCL-50:50 PCL4:PCL-25:75 PCL-100

Mas

s Los

s (%

)

t=42 d t=70 d

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141 | P a g e

The effect of pH on polyurethane degradation

Figure 6.24 shows the mass loss data for Series 6 polyurethane materials incubated in

vitro under acidic conditions (pH 2) at 37ºC.

Figure 6.24 Mass loss for selected Series 6 polyurethanes under acid in vitro conditions (pH 2).

Mass loss increases over time with polyurethanes showing higher mass loss at 42 days

when compared with mass loss at 21 days. However, the mass loss over this period of

time is minimal, if not negligible. There appears to be no mass loss pattern seen

regarding percentage mass loss and crosslink density. The acidic environment does not

appear to affect the ability of these materials to degrade, and overall they remain almost

inert.

0.000

0.001

0.002

0.003

0.004

0.005

0.006

0.007

0.008

0.009

0.010


Mas

s Los

s (%

)

t=21 d t=42 d

Chapter Six

142 | P a g e

Figure 6.25 shows the mass loss data for Series 6 polyurethane materials incubated in

vitro under alkaline conditions (pH 11) at 37ºC. Mass loss increases over time with

polyurethanes showing higher mass loss at 42 days when compared with mass loss at 21

days. However, similar to that of these materials under acidic conditions, the mass loss

over this period of time is minimal, if not negligible. There also appears to be no

particular mass loss pattern seen regarding percentage mass loss and crosslink density.

Figure 6.25 Mass loss for selected series 6 polyurethanes under alkaline in vitro conditions (pH 11).

Figure 6.26 compares the mass losses at 42 days for Series 6 polyurethane materials

incubated under alkaline and acidic conditions. The materials showed similar but

minimal mass loss under both types of conditions. There appears to be no correlation

between crosslink density and mass loss under both conditions. It would be reasonable

to say that the alkaline and acidic conditions that Series 6 polyurethane materials were

exposed to did not have a vast affect on the polymer mass changes. This may be due to

the number of days the materials were exposed to the materials or very hydrophobic

nature of the PCL that the materials were synthesised with.

0.000

0.001

0.002

0.003

0.004

0.005

0.006

0.007

0.008

0.009

0.010


Mas

s Los

s (%

)

t=21 d t=42 d

Chapter Six

143 | P a g e

Figure 6.26 Mass loss for selected series 6 polyurethane materials under acidic and alkaline conditions at 42 days in vitro.

6.2.4 Summary

The following includes a summary of conclusions related to the original aims of the

project.

‘Examine the effects of increasing cross-linking density on polyurethane properties and

degradation’

Due to the choice of PCL as a polyol, the results of this study did not provide

any conclusive evidence to indicate the effect of the degree of cross-linking on

degradation. These results are more a reflection of the slow degradation of PCL.

0.000

0.001

0.002

0.003

0.004

0.005

0.006

0.007

0.008

0.009

0.010


Mas

s Los

s (%

) Acid Basic

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144 | P a g e


THERMOPLASTIC AND

THERMOSET POLYURETHANES:

PRELIMINARY ANALYSIS OF THE

DEGRADATION PRODUCTS

INTRODUCTION 7.1

The traditional approach to studying biodegradable polymers is to carry out an in-vitro

degradation focussing on hydrolytic degradation when dealing with polyesters and on

oxidative degradation when working with polyethers. Typically, these studies

investigate polymer mass and molecular weight losses (GPC), changes in thermal

properties (DSC), and mechanical properties, to derive a degradation model for each

type of polymers. For chemically simple polymers, these data would generally provide

useful information about degradation modes as well as some clues about the kinetics

involved. However, when it comes to more complex materials, such as polyurethanes,

these data may not provide enough information to comprehend the full extent of the

degradation processes.

A more comprehensive alternative is to consider a thorough analysis by systematically

collecting and analysing by-products resulting from in-vitro degradations. It may then

be able to determine the most probable mechanisms behind their formation. It is

Chapter Seven

145 | P a g e

anticipated that these by-products would be mostly intermediate oligomers as well as

compounds derived from basic building blocks of the complex polymers. Once

collected, the degradation products are subjected to a variety of tests to identify their

chemical structure and to some extent determine their potential cytotoxicity.

This chapter reports on the sampling and analysis of the degradation by-products

obtained as a result of both real-time and accelerated degradations. Figure 6.1 below

describes schematically how the chapter is organised.

Figure 7.1 Schematic representation of the analysis of degradation by-products.

Declaration: The results discussed in this chapter have been published as (Tatai et al.

2007b):

Tatai, L, Moore, TG, Adhikari, R, Malherbe, F, Jayasekara, R, Griffiths, I, & Gunatillake, PA, 2007 Thermoplastic biodegradable polyurethanes: The effect of chain extender structure on properties and in-vitro degradation. Biomaterials, 28(36), 5407-5417

PU Series 1-5

PU Characterisation

PU Mass Loss

Pre-degradation

Post-degradation In-Vitro Degradation

(365 d)

Analysis of Degradation

Products

Ninhydrin Assay Preparative and Analytical HPLC

Analysis

NMR Analysis MS/ESI Analysis

Accelerated Degradation

Chapter Seven

146 | P a g e

Due to the high number of different polymers that were synthesised, the results reported

here on the analysis of degradation products by no means represent a complete study of

all samples. The purpose of this chapter is to introduce a very important step in the

development of materials for medical application; their safety validation, before any

trial is performed in vivo, by confirming that they are at least non-cytotoxic.

For real time degradation studies, the amine concentrations in the degradation medium

of polyurethane series 1-5 were monitored over a period of 365 days. It is generally

recognised that the presence of amines in a degradation medium is indicative of the

hydrolysis of urethane bonds. These tests were performed using a commercially

available assay with the ability to detect primary and secondary amines at low

concentrations in a liquid media. The assays were only performed on the polyurethane

materials that were subjected to real time degradation studies. Figure 7.2 shows an

example of a trimer that may be formed by the hydrolytic degradation of the

polyurethanes.

Figure 7.2 A trimer (ELDI-LAEG-ELDI) joined by urethane and ester bonds with flanking secondary amine groups (circled).

In order to have a better insight into the nature of the degradation products formed

during in-vitro degradation, a range of approaches were considered. Firstly, selected

materials were subjected to an accelerated degradation at 100ºC for up to 5 days. The

materials were selected on the basis of their behaviour under real-time in-vitro

conditions, favouring those samples with a simple chemical composition and exhibiting

a fast degradation rate.

In view of identifying the major species, upon completion of the accelerated

degradation process, samples of the media were analysed using a variety of techniques.

These techniques included analytical HPLC to separate the products and derive a

degradation profile for the polymers under investigation. When an appropriate profile

O O

N2H N

O

O

H

O

O

O N

H

OO O

NH2

Chapter Seven

147 | P a g e

was obtained, preparative HPLC was then used to separate and isolate the main

constituents. The isolated products were then subjected to further chemical analyses to

determine their molecular weight by ESI/MS and their structure by NMR.

Concurrently, the molecular weights were also determined using LC-MS. This method

has the advantage of being relatively fast but being a destructive technique, due to the

spectrometry component, the products could not be collected for subsequent structural

determination by NMR.

MATERIALS AND METHODS 7.2

The methods for the various analyses are described in details in Chapter 3 – Materials

and Methods. Samples from the PBS degradation medium were taken at time 0, 42, 90,

180 and 365 days for further chemical analysis.

RESULTS AND DISCUSSION 7.3

7.3.1 Ninhydrin Assay

Thermoplastic polyurethane series 1-3

The amine analysis data for polyurethane series 1 and 2 polyurethanes are shown in

Figure 7.3. The data report the concentration of amine detected at the various time

points over the 365 days of in vitro degradation, with a normal trend of a gradual

increase with time, as the polymers degrade. The overall observation is that as the

percentage of degradable hard segment (% of LAEG) in the polymer increases more

amines are liberated. The data correlates well with the mass losses (figure 5.7 and 5.8)

indicating that the increase in the concentration of amines in the degradation mixtures is

a direct result of the degradation of the polyurethanes. While the trend follows that of

the mass losses, the quantitative changes in concentrations do not correlate well with the

actual mass losses. For example, the 100%-HS material was completely degraded after

365 days, while the 0%-HS polyurethane only lost around 3% of its mass but the

amount of amine detected is not in the same ratio. On the other hand, Figure 7.3 (B)

shows an almost uniform behaviour for all polyurethanes of the series, irrespective of

the content in HS, except for the 50%-EG, which can be considered as an outlier.

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148 | P a g e

Figure 7.3 Amine detection for (A) Series 1 and (B) Series 2 polyurethanes over 365 days in vitro degradation.

0

50

100

150

200

250

300

350

0 50 100 150 200 250 300 350 400

Am

ine

Con

cent

ratio

n (

mol

es)

Time (days)

(A) ELDI-0 ELDI-LAEG-30 ELDI-LAEG-50

ELDI-LAEG-70 ELDI-LAEG-100

0

20

40

60

80

100

120

140

160

0 50 100 150 200 250 300 350 400

Am

ine

Con

cent

ratio

n (

mol

es)

Time (days)

(B) ELDI-0 ELDI-EG-30 ELDI-EG-50

ELDI-EG-70 ELDI-EG-100

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149 | P a g e

For example, 0% hard segment polyurethanes liberated less than half the amount of

amine when compared to the 100% hard segment material. The overall observation was

that the polyurethanes that exhibited the greater mass losses also liberated a higher

amine concentration. This trend is not what would be expected if it is assumed that: (a)

polyurethanes with higher percentages of hard segment contain more urethane linkages,

and (b) polyurethanes exhibiting higher mass losses have undergone a greater extent of

degradation by hydrolysis, thereby liberating by-products. Although the trend observed

in the amounts of liberated amines are consistent with predictions, the actual amounts

detected are about three orders of magnitude lower than theoretical values based on the

mass losses (Figure 7.4).

Figure 7.4 Predicted against actual amine concentration for Series 1

0

5000

10000

15000

20000

0 20 40 60 80 100Am

ine

conc

entr

atio

n (

mol

es)

LAEG (%)

Predicted

0

50

100

150

200

250

300

350

0 20 40 60 80 100Am

ine

conc

entr

atio

n (

mol

es)

LAEG (%)

Actual

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150 | P a g e

This may be a result of the degradation process whereby the degradation products are

oligomer units rather than monomers, indicating that the hydrolysis process is not

uniform within the materials and will proceed at different rates, depending on whether it

occurs at the surface of in the bulk. For the amine groups to be detected by the

technique involved, the polymer must undergo hydrolysis at the urethane linkage as

illustrated in Figure 7.5. As the process is slower than the hydrolysis of ester bonds, and

in view of the quantification results obtained, it appears that the degradation process

forms oligomers that may still contain significant proportion of urethane linkages. In

fact, as it has been demonstrated in a previous section, solubilisation, hence mass loss,

starts with sub-particles of around 5,000 Daltons, which would definitely contain a

significant amount of urethane linkages.

Figure 7.5 EG-ELDI-EG illustrating the formation of terminal amino groups by hydrolytic degradation

The data for Series 2 polyurethanes show that the all materials liberated roughly the

same amount of amine, irrespective of the content in hard segment. The mass losses

determined for these materials (Section 5.3.2, Figure 5.8) were relatively small, in the

range of 0-6.6%. This is yet another indication of the influence of the chemical nature of

the hard segment on the degradation process. The fact that there is no distinction

between materials with different EG contents suggest that the release of amine

associated with these may be the result of surface erosion or may be due to diisocyanate

adsorbed on the surface or even trapped in the bulk.

For Series 3 (Figure 7.6), the data show similar trend to that observed with Series 2,

with all materials liberating similar amount of amines over 365 days, and that the

cumulative amine concentrations steadily increased with time. There does not seem to

be a correlation between the type of diisocyanate or chain extender within the structure

and the detectable concentration of liberated amine.

HO

HCO2

NH2

O O

NH2O N N OOHOH

O

H

O O

H

O

OHOH+2

2 + 2

Chapter Seven

151 | P a g e

Figure 7.6 Amine detection for Series 3 polyurethanes during in vitro degradation

The fact that no amine is detected within the first 50 days or so may be related to the

detection limit of the analytical technique, or as previously pointed out in the

monitoring of mass losses, there is first the formation of larger subunits, that would not

necessarily involve the breakage of numerous bonds.

Figure 7.7 compares the mass loss to the amount of amine detected. Series 1 shows a

positive correlation between the two parameters, which is an indication of a

straightforward mechanism connecting degradation of the polymers with the release of

amines. Referring back to the chemical structure of ELDI (Figure 2.7), it can be

hypothesised that the presence of a branching on the ELDI molecule may have some

steric hindrance and affect the geometry of the bonding involving the terminal cyanate

group. As a result the bonds may be less stable and more accessible to water molecules,

thus facilitating hydrolysis.

-20

0

20

40

60

80

100

120

140

160

180

0 50 100 150 200 250 300 350 400

Am

ine

Con

cent

ratio

n (

mol

es)

Time (days)

ELDI-LAEG-30 HDI-LAEG-30 ELDI-EG-30 HDI-EG-30

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152 | P a g e

Figure 7.7 Comparing mass loss with amine concentration for series 1-3 polyurethanes

0

40

80

120

160

200

240

280

320

360

400

0

10

20

30

40

50

60

70

80

90

100

Am

ine

Co

nce

ntratio

n (

mo

le)

Mas

s Los

s (%

)

Polymer

% Mass Loss Amine Concentration

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153 | P a g e

There is also extra evidence in the graph, through the detection of non-negligible

amounts of amines, that although no significant mass loss is observed in the ELDI-0,

the material is still undergoing degradation. This observation is crucial in order to be in

a position to validate the safety of these types of materials in human applications: the

absence of mass loss does not mean that the material is safe.

On the other hand, no such trend is observed with Series 2. Although most polymers of

the series lost very little mass, the cumulative amount of amine detected over the 365

days test period was found to be of the same order irrespective of the composition. This

is an indication that there could be enough surface erosion to generate detectable

amounts of amine but not enough to be quantified by mass. By comparing ELDI-0,

ELDI-LAEG-30 and ELDI-EG-30, it is clear that mass losses are related to the nature of

the degradable chain extender, but across the series there is no direct correlation

between mass loss and the amount of amine liberated.

The nature of the diisocyanate used in the synthesis does not seem to have much impact

on the detectable quantities of amine, as there are no significant variations within the

materials of Series 3: ELDI-LAEG-30, HDI-LAEG-30, ELDI-EG-30 and HDI-EG-30.

This phenomenon may occur due to the fact that all polyurethanes prepared in this study

were formulated to have isocyanate end-groups. Once exposed to an aqueous medium,

these chains will be converted to amines. It is also reasonable to assume that through the

process of polymerisation, low molecular weight amine-terminated chains could be

formed and leach out into the medium. Also, as indicated earlier in Chapter 5 (Section

5.3.1) investigating polymers that either showed little or no mass loss, and occasionally

a mass gain over a period of 365 days, these materials exhibited high molecular weight

losses. The breaking down of large chains into smaller units provide free space in the

bulk to allow infiltration of the medium, and can lead to a gain in mass through the

accumulation of salts and other particles following immersion in PBS over the test

periods. The polyurethanes may be hydrolysed at the urethane linkages and eventually

leach out sub-units into the medium, but shown little or no mass loss due to the

accumulation of other substances that would compensate for the overall mass loss.

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154 | P a g e

Thermoset polyurethane series 4 and 5

The amine analysis data for series 4 and 5 are reported in Figure 7.8.

Figure 7.8 Amine concentrations for Series 4 (top) and Series 5 (bottom) polyurethanes over 365 days in vitro degradation.

-100

0

100

200

300

400

500

600

700

800

0 100 200 300 400

Am

ine

Co

nce

ntr

atio

n (

mo

les)

Time (days)

DLLA-100 DLLA:GA-75:25 DLLA:GA-50:50

DLLA:GA-25:75 GA-100

0

100

200

300

400

500

600

700

800

0 100 200 300 400

Am

ine

Con

cent

ratio

n (

mol

es)

Time (days)

LLA/MA-100 LLA/MA:GA-75:25 LLA/MA:GA-50:50LLA/MA:GA-25:75 GA-100

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155 | P a g e

For all polyurethanes in Series 4, the amount of amine liberated into the medium

increased gradually over a period of 365 days. It is noteworthy that amount liberated up

until 180 days was relatively low for all samples. However, the sampling point at 365

days evidences a significant increase for GA-100 and DLLA:GA-25:75. In this series,

the overall concentration of amine does not appear to be correlated to the complete

degradation, given that all samples under investigation in this part were fully degraded.

The trend appears to be consistent with the overall mass loss.

For Series 5 the amine concentration is also seen to increase over a period of 365 days.

Much like the previous series, the amine concentration liberated is relatively low during

the first 180 days, and increases more significantly for the polymers with higher PE-GA

contents. Within this series, the results are consistent with the mass loss data for the

same material such that amine concentration liberated increases with the mass loss of

the material, which also corresponds to the increased percentage of in the formulation.

However, it is unclear why the trend is not as obvious as with Series 4. The fact that

Series 5 involved the introduction of an extra component, mandelic acid, does not allow

a direct comparison, and the overall chemical properties of the polymer would have

been affected.

Figure 7.9 compares the total mass loss and amine concentration at the 365-day

sampling time point for series 4 and 5. Since all materials, excluding LLA/MA-100 and

LLA/MA:GA-75:25, lost 100% mass, no conclusive trend was discernable between

mass loss and amine concentration. These data indicate that although a material has

undergone complete degradation, as evidenced by 100% mass loss, i.e. no intact residue

is present in the solution; the solubilised degradation products may not have undergone

complete decomposition to smaller oligomers or monomers. The polymers are initially

fragmented into sub units that are small enough to be eliminated from the bulk into the

medium, although not visible. Once the fragments end up in the degradation medium,

they will undergo further degradation. The rate of degradation of these fragments will

be much faster than that of similar-sized particles that may still be connected to the bulk

of the polymer, due to a greater accessibility of water molecules.

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156 | P a g e

Figure 7.9 Comparing mass loss with amine concentration for series 4 and 5 polyurethanes

0

80

160

240

320

400

480

560

640

720

800

0

10

20

30

40

50

60

70

80

90

100A

min

e Co

ncen

tration

(m

ole)

Mas

s Los

s (%

)

Polymer

% Mass loss

Amine concentration

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157 | P a g e

The major observation when comparing Series 4 to Series 5 is the role that glycolic acid

seems to play in the formation of detectable amine compounds. It seems that materials

with increased PE-GA content undergo the initial fragmentation at a faster rate, and the

further degradation of these fragments, present is significant amount in the medium is

the main cause of the increase in concentration of detectable amines.

7.3.2 Identification of Polyurethane Degradation Products

In order to determine the safety of biodegradable polymer that have an intended use in

human applications it is primordial to positively identify all intermediate and final by-

products of their degradation. In this study, the solutions were not changed during the

incubation intervals, providing a worst-case model of the effects of accumulation of

degradation products. Figure 7.10 illustrates the basic initial investigations undertaken

to look into the nature of these compounds.

Figure 7.10 Experimental approach to separate and identify by-products of in vitro degradation.

NMR Analysis of Collected Fractions

Accelerated Degradation - 100°C, 72 h in dH20

Real Time Degradation - 37ºC, 365 d in PBS

Analytical HPLC – To obtain degradation

product profile

Preparative HPLC – Isolation & Collection of Degradation Products

LC-MS of Degradation Products

Chapter Seven

158 | P a g e

Analytical HPLC of the Degradation Products

Figure 7.11 illustrates a typical degradation profile for ELDI-LAEG-100 using as

determined by analytical HPLC, used as a tool to examine degradation products

liberated from the PU during in vitro degradation.

Figure 7.11 HPLC profile for ELDI-LAEG-100 polymer after complete degradation

In this example, an accelerated degradation of Series 1 ELDI-LAEG-100 was

performed in distilled water, as this sample has been shown earlier to degrade quite

quickly, and that it would liberate only few easily predicted degradation by-products,

rendering the analysis and identification a much simpler process. After the accelerated

degradation process, an aliquot of the degradation product was subjected to analytical

HPLC to determine the degradation products profile that would assist in the

development of methods to optimise the elution and detection of the individual

components. The chromatogram indicates that most of the by-products are eluted within

20 minutes; with some minor components in the mid-range at around 25 and 35 mins

further evidence of other components at around 90 and 95 mins. The profile provides

extra clues on the nature of the biodegradation products as it is obvious that the

Chapter Seven

159 | P a g e

components that are eluted later are higher molecular weights sub-units, which have not

been exposed long enough to the degradation medium to undergo further break downs.

Table 7.1 below lists the predicted degradation products for ELDI-LAEG-100 based on

the polymerisation mechanisms presented in Chapter 4, with the assumption that

depolymerisation of the macromolecules will be initiated at the respective linkages.

Table 7.1 List of predicted by-products of the polymer ELDI-LAEG-100.

Compound* Molecular Weight Compound Molecular Weight

EG-LDI

Lysine

EG-LA-LDI

LDI-EG

LDI-LA-EG

LA-EG-LDI

LA-LDI

LDI-EG-LA

LDI-LA

LA-ELDI

ELDI-LA

EG

EG-LDI-EG

LA-EG

Lactic Acid

234

147

306

234

306

306

262

306

262

290

290

62

322

134

90

EG-LDI-LA

LA-LDI-EG

EG-ELDI

EG-LDI-EG

Ethanol

Ethyl Lysine

ELDI-EG

LA-ELDI-EG

EG-LA-ELDI

ELDI-LA-EG

LA-EG-ELDI

ELDI-EG-LA

LA-EG-ELDI

LA-LDI-LA

LA-ELDI-LA

350

350

262

350

46

174

262

378

334

334

334

334

334

378

406

*Refer to the abbreviations page for description of the acronyms

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160 | P a g e

Preparative HPCL analysis of degradation products

After the profile of the degradation products was recorded and analysed, an aliquot was

injected into a preparative HPLC column to collect detected components with the goal

of isolating degradation products for further analysis and identification. Approximately

27 fractions were collected during each preparative HPLC experiment, and each one

was injected back into the HPLC to determine its purity and relative position against the

total degradation profile. Pure fractions were analysed further to determine their

molecular weight and structure using MS/ESI and NMR.

LC-MS Analysis of degradation products

Table 7.2 reports the molecular weights of selected fractions collected through

preparative HPLC and analysed directly by LC-MS, together with suggestions for the

structure of the products.

Table 7.2 Possible structures of some degradation by-products.

Mw Possible Structure

90

234

262

322

350

OHOH

O

O N NH2

OH

O

H

O OH

O N NH2

OH

O

H

O OH

O

O N N OOHOH

O

H

O OH

H

O

O N N OOHOH

O

H

O O

H

O

Chapter Seven

161 | P a g e

The MS/ESI analyses of the fractions showed the molecular weights of isolated

degradation products to be ranging from 90–406. The degradation products eluting

earliest are generally of the lowest molecular weights while those eluting later at ~90

minutes are of higher molecular weights. Most degradation products eluted between 1

and 20 minutes, with molecular weights of 360, and under with no products were seen

to elute after 100 mins.

1H-NMR of isolated degradation products

Proton NMR (1H NMR) was performed on pure fractions collected through preparative

HPLC. After the molecular weight of each pure fraction was determined, the sample

was subjected to rotary evaporation to evaporate the solvent and collect the solid

degradation product. The sample was then redissolved in DMSO for 1H NMR analysis.

Figure 7.12 shows the 1H NMR spectra of two separate fractions, noted 5 and 12. An

ESI analysis on these fractions revealed molecular weights of 350 and 90 respectively.

Figure 7.12 1H NMR of Fraction 12 (top) and Fraction 5 (bottom).

Based on the molecular weight of these fractions, it was relatively easy to suggest a

structure for the degradation products. For Fraction 5, molecular weight 90, there was

only one possible structure, lactic acid, based on the known composition of the starting

polymer.

a d b c

c b a

c j k+l c f+g i k d g k I h h f e l h j d e i b a a b

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162 | P a g e

Figure 7.13 shows the simulated 1H NMR spectrum for lactic acid using ChemNMR

(ChemDraw). The calculated spectrum is very similar to the experimental one, with the

exception of the peaks at chemical shift 2.8 ppm and 12.86 ppm.

Figure 7.13 Simulated 1H NMR of lactic acid.

Since the actual sample was most probably slightly contaminated with residual amounts

of water, evidenced by the broad peak at around 3.3 ppm in Figure 7.12, it is thought

that the large water peak may mask the peak at 2.8 ppm, which represents the hydroxyl

end of lactic acid. The peak at ~12 ppm observed in the spectrum of the degradation

product (Figure 7.12) is also relatively small; however, on comparison to the simulated

spectrum, the relative size of this peak appears to almost be in agreement with the

predicted NMR peak integration.

As far as the predicted NMR spectrum is concerned, the peaks corresponding to the

methyl and methine groups (at 1.3 and 4.3 ppm respectively) were shown to have

similar integrals to that of the 1H NMR spectrum for Fractions 5.

For Fraction 12, with a molecular weight of 350, Table 7.1 lists all the possible

degradation intermediates with this mass: EG-LDI-LA and LA-LDI-EG (in various

sequences), and EG-ELDI-EG. Since the 1H NMR spectrum does not show peaks at

chemical shifts that would indicate the presence of lactic acid, it was decided that

predicted structures incorporating LA would be discounted, leaving only one possible

product: EG-ELDI-EG. The predicted 1H NMR spectrum is relatively similar to that of

the actual 1H NMR of Fractions 12. Both spectra show 10 peaks at different chemical

shifts, and although difficult to see in figures x and x, the peaks contain the same

02468101214PPM

12.864.33

2.80

1.30

HOOH

O

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163 | P a g e

splitting patterns. For the actual 1H NMR spectra of Fractions 12, the peaks integrate at

the appropriate ratios relative to one another for this degradation product to be identified

as EG-ELDI-EG.

Figure 7.14 1H NMR simulated spectrum of EG-ELDI-EG

7.3.3 Conclusion

This part represents an attempt to develop a methodology in order to identify the by-

products of the biodegradation of selected polyurethanes. In this study, in order to

obtain adequate amounts of degradation mixtures in a reasonable amount of time, an

accelerated degradation method. The samples were heated in water at 100°C for 72

hours, with most samples being completely degraded at the end of this test period.

While this approach is not an accurate representation of what would normally occur in a

physiological environment, it does however provide a good insight in the potential

intermediate and end–products, as these polymers generally degrade through a simple

hydrolytic mechanism. Further works need to completed in this area, as in vivo other

mechanisms can be involved such as oxidations and enzymatic attacks, that may yield

different by-products.

012345678PPM

4.90

3.55

4.22 3.18

1.55

1.25

1.90

6.76

4.51 4.22

3.55

7.39

4.21 1.29

HOO N

O

H

N OOH

H

OO O

4.90

Chapter Eight

164 | P a g e

8 CONCLUSION

OVERVIEW 8.1

The main conclusions and future work outlined in this chapter refer to the original aims

and outline of the study detailed in Chapter 1 Section 1.2.

The primary goals were to:

Synthesise and characterise a series of novel thermoplastic and thermoset

polyurethanes with formulas based on NovoSorbTM to capture key structural

features

Study the effects of in-vitro degradation on synthesised biodegradable

polyurethanes

Analyse and identify degradation products liberated during in-vitro degradation.

The secondary goals were to:

1. Examine the effect of different ratios of hard segment and soft segment on the

properties and in vitro degradation of thermoplastic polyurethane

2. Examine the influence of incorporating degradable chain extenders in

thermoplastic polyurethane hard segments

3. Determine the effect of diisocyanate on polyurethane properties and polyurethane

in-vitro degradation

4. Determine the effect of changing ratios of two different polyols on polyurethane

properties and polyurethane in-vitro degradation

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165 | P a g e

5. Examine the effects of increasing cross-linking density on polyurethane

properties and polyurethane in-vitro degradation

6. Determine whether polyurethane degrades to molecular species corresponding to

each monomer unit in-vitro

MAIN PROPERTIES OF SYNTHESISED POLYMERS 8.2

Chapter 4 describes thermoplastic and thermoset polyurethane series physical

characteristics prior to in-vitro degradation. Six series of thermoplastic and thermoset

biodegradable polyurethanes were synthesised for the purpose of this study with

polyurethane series 1-3 being thermoplastic polyurethane and the remaining

polyurethane series 4-6 being thermoset polyurethane.

For thermoplastic polyurethane (series 1-3), changing the ratios of hard and soft

segment had a considerable effect polyurethane molecular weight with molecular

weight increasing with increasing volume of soft segment PCL-1000. Polyurethane

glass transitions were also affected considerably by changing ratios of hard and soft

segments showing thermal shifts to a higher temperature with increased proportions of

hard segment. Water uptake percentage also increased with increasing proportions of

hard segment. Mechanical properties i.e. tensile strength and modulus were found to be

least affected by changing ratios of hard and soft segment.

The incorporation of degradable chain extenders (DCE) into the hard segment of

polyurethane appeared to have a considerable effect on polyurethane molecular weight

showing polyurethane with DCE having lower molecular weights than their non-DCE

counterparts. However the incorporation of DCE into hard segments showed little effect

on polyurethane mechanical properties i.e. tensile strength and modulus, and thermal

properties i.e. glass transitions and melting points. Water absorption percentage was

similar for both series of polyurethane.

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166 | P a g e

The incorporation of ELDI or HDI into the polyurethane hard segment appeared to have

a minor effect on the molecular weight of the polyurethane, with ELDI-based

polyurethane showing slightly lower molecular weights than HDI-based polyurethane.

The modulus and tensile strength for ELDI-based polyurethane was slightly lower than

their HDI-based polyurethane counterparts.

For thermoset polyurethane series 4 & 5, the effect of changing the ratios of two

different polyols, PE-GA & PE-DLLA, on the mechanical properties of the materials

was considerable: polyurethanes with increasing amounts of PE-GA polyol resulted

having lower tensile strength and modulus. However, the thermal properties, i.e. glass

transitions, and water absorption capacities were only minimally affected by increasing

relative proportions of PE-GA polyol. Altering the polyol composition from PE-DLLA

to PE-LLA:MA (with changing ratios of PE-GA) caused the tensile strength and

modulus of the polyurethane to increase considerably. Polyurethane with higher

proportions of PE-LLA:MA showed superior tensile strength and modulus. Water

uptake percentages for both PE-DLLA and PE-LLA:MA based polyurethanes were

similar. Increasing cross-link density for Series 6 polyurethane had an effect on the

thermal properties showing that as the cross-link density increased so too did the glass

transition temperature. These polymers showed minimal water uptake and there

appeared to be no link between cross-link density and water uptake.

IN VITRO DEGRADATION OF SERIES 1-3 8.3

Chapter 5 reported on the in vitro degradation of thermoplastic polyurethane series 1-3.

One of the major aims of this study was to examine the effect of introducing a chain

extender with a hydrolysable ester linkage (DCE) into the hard segment of

polyurethane. The study investigated the effect of chain extender structures on the

properties and in vitro degradation of three series of poly(ester urethanes). It was

proposed that polyurethanes with incorporated degradable chain extender structures

would have similar properties to their equivalent non-degradable chain extender-based

polyurethanes but exhibit fast degradation. This study also examined the effect of

different ratios of hard segment and soft segment on in-vitro degradation and the effect

of diisocyanate on properties and in-vitro degradation of polyurethanes.

Chapter Eight

167 | P a g e

In general, varying ratios of polyurethane hard and soft segment appeared to have an

effect on molecular weight loss, thermal properties and mass loss in particular for Series

1 polyurethanes. The molecular weight data clearly indicate that all polyurethanes

degrade to some extent under the testing conditions, but only those with a degradable

chain extender incorporated into hard segments showed a more substantial mass loss

percentage over the study period. Results showed that after 365 days incubation under

simulated biological conditions the mass loss was between 0 to100% with the greater

mass loss observed in polyurethanes with a higher percentage of hard segment.

Polyurethanes with PCL-ELDI (ELDI-0) were not degraded and showed virtually no

mass loss after 365 days (0.28%) while polyurethanes with 100% hard segment were

completely degraded after 180 d. The percentage mass loss of the remaining Series 1

polyurethanes showed a pattern of showing a correlation with the percentage of hard

segment. The mass loss pattern appears to be congruent with the percentage of hard

segment and degradable chain extender present in the polyurethane.

For Series 2 polyurethanes, molecular weight loss, thermal properties i.e. tensile

strength and modulus, and mass loss were affected minimally by varying ratios of hard

and soft segment. Molecular weight loss was similar for each polymer in series 2 for a

given time point as was mass loss. Mechanical properties were not significantly affected

by changing ratios of hard and soft segment, probably due to the fact that little

degradation was apparent over time.

The incorporation of DCE into the hard segment of polyurethane appeared to have the

greatest effect on polyurethane molecular weight loss, thermal properties i.e. tensile

strength and modulus, and polyurethane mass loss. HDI-based polyurethanes were less

affected by in-vitro degradation conditions showing less mass loss and change in

thermal properties compared to ELDI-based polymers. Molecular weight loss and

mechanical properties for HDI and ELDI-based polyurethane were affected equally

under in-vitro degradation conditions.

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168 | P a g e

All polyurethanes investigated in this study showed degradation as illustrated by the

decrease in molecular weight. However, substantial mass losses were observed for those

polymers only when the molecular weight was decreased to below 6000 during the

degradation process. The DCE-based polyurethanes yielded the highest mass loss in the

three series of polyurethanes. The presence of the DCE and the initial molecular weight

of the polyurethane are the key factors responsible for high mass losses. The change in

thermal properties and the observation that mass loss was directly proportional to hard

segment weight percentage strongly supported that the polyurethane hard segment is the

most susceptible segment to degradation in these polyurethanes. The hydrophobic

PCL-based soft segment appears to undergo little or no degradation under these test

conditions.

This study further demonstrates that polyurethanes with different degradation rates can

be prepared by incorporating a degradable chain extender and by varying the ratio of

hard and soft segments.

IN VITRO DEGRADATION OF SERIES 4 AND 5 8.4

Chapter 6-Part 1 reported on the in vitro degradation of thermoset polyurethanes series

4 and 5. One of the major aims of this study was to investigate the effects of the

chemical structure of the polyol on the properties of a series of novel thermoset

polyurethanes and their in vitro degradation. Part 2 reported on in vitro degradation of

thermoset Series 6, with the major objective being to examine the effect of cross-link

density on the in vitro degradation of PCL-based polyurethanes.

The main results indicate that polyurethanes containing higher proportions of PE-GA-

based polyol exhibit a faster degradation rate while the introduction of higher

proportions of MA-based polyol seems to delay degradation. All series 4 polyurethanes

exhibited 100% mass loss after 365 days of in-vitro degradation with degradation

occurring the fastest for polymers with 100 % PE-GA polyol and the slowest for

polymers with 100 % PE-LLA. All polyurethanes showed little mass loss at the early

42-day sampling time point but between the 42 day and 365 day sampling point, all

polyurethane in this series lost 100 % mass. The pattern of mass loss for Series 4

Chapter Eight

169 | P a g e

polyurethanes appears to correlate with the ratio of DLLA:GA. The degradation rate

increased with the increasing amount of PE-GA in the polyol. Poly glycolic acid (PGA)

is known to be hydrophilic and fast degrading polymer due to the polymers

susceptibility to hydrolytic attack (ref).

The mechanical properties i.e. modulus and tensile strength, for series 4 polyurethanes

decreased gradually over a period of 90 days for all polymers tested. Polymers with

higher proportions of PE-GA polyol lost most of their strength by the 90 day test point.

Only polyurethanes with more than 50% PE-DLLA retained reasonable mechanical

strength over a 90 day test period. These results correlated well with the mass loss data

such that polyurethane with high proportions of PE-GA showed greater decrease in

mechanical strength i.e. tensile strength and modulus, over time.

DSC traces indicated that polyurethane with higher proportions of GA-based polyol

degraded faster than polyurethane with higher proportions of LA and MA-based polyol.

Polyurethane glass transition temperature decreases over time for polyurethane with

higher proportions of GA-based polyol compared to little change in glass transition

temperature for polyurethane with higher proportions of MA-based polyol.

In Part 2, due to the choice of PCL as a polyol, the results of this study did not provide

any conclusive evidence to indicate the effect of degree of cross-linking on degradation.

This result is more a reflection of the slow degradation of PCL.

FUTURE WORK 8.5

Following various synthetic approaches, two types of materials have been identified on

the basis of their biodegradability: one that would degrade relatively fast and another

that is rather recalcitrant. The fast degrading ones may find useful applications in drug

delivery systems, implants that would eventually be resorbed by the body. On the other

hand the resilient materials could be used in long-term implants or applications where

superior mechanical properties are required. In order to validate the use of these

polymers for use in humans two major steps would need to be completed: a full analysis

of the degradation products followed by cytotoxicity studies and thorough in vivo

animal studies.

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