Lecture 4:�

Biomaterials Surfaces: Chemistry�

Hydrolysis�Supporting notes�

3.051J/20.340J Materials for Biomedical Applications, Spring 2006

1

Hydrolysis�

• Hydrolysis is a kind of “Solvolysis”, solvent + lysis: cleavage by the solvent.

Br

H2O

3

OH

OCH3

OCOH

l

CH OH

HCOOH

2-Bromo-2-methy propane

+ HBr Hydoloysis

+ HBr Methanolysis

+ HBr Formic acidolysis

2

Polymer Hydrolysis�

•�Polymers prepared by polycondensation can be susceptible to hydrolysis.

n 1,4-Butanediol

+ HO

OH

O

O

n O

O

H

H

Succinic acid

O

O*

*

O

O

n 2O l Δ

H+ -,

+ nHAs, Zn cata ysts,

, OH or enzyme

Poly(butylene succinate), PBS 3

Hydrolysable is “degradable”.�Synthetic polymers�· Polyesters · Polyamides · Polyanhydrides · Polyethers · Polyurethanes · Polycarbonates · Polyureas

Material properties can be tuned readily. Cheaper!

Naturally-occurring polymers · Proteins and polyamides

Collagen Fibrinogen and fibrin Gelatin Casein

· Polysaccharides Cellulose Starch and amylose Chitin and chitosan Dextran

· Polynucleotides DNA and RNA

4

Biodegradation:�An event which takes place through the action of enzymes and/or chemical decomposition associated with living organisms (bacteria, fungi, etc.) or their secretion products.

Albertsson and Karlsson, in Chemistry and Technology of Biodegradable Polymers 1994

O R C

O

N R C

OH

O R O C

O

Polyester Polyamide Polycarbonate

C R O C

OO

N P

R

R'O

O

O

O

R"

R'R

O

Polyanhydride Polyphosphazene Poly(ortho ester)

Typical examples of synthetic biodegradable polymers 5

Key factors in hydrolysis�

1. Bond stability

Example: Hydrolysis of polyester C Oδ+ δ-

Base-catalyzed polyester hydrolysis

δ-

δ+

O

CR O R'

- O

C-R O R'

OH

O-

CR O R'

OH

H+ O

CR OH + R’

OH

OH

6

Acid-catalyzed polyester hydrolysis

δ-

H+

δ +

O

CR O R'

O+

CR O R'

H O

C+R O R'

H O

CR O+ R'

H

H

O

H

O

CR O R'

H

O+H

H

-H+H2O + R’OH

O

CR OH

Polyamide hydrolysis

H2O O

CR N R'

H

O

CR OH + H2N-R’

7

Key factors in hydrolysis�

2. Hydrophobicity

3. Molecular weight & architecture

4. Morphology Crystallinity, porosity

5. Tg Mobility of polymer chain

Chance to contact with H2O

8

0 80

90

� a (

degr

ees)

100

120

12 24 36 48 0 12 24 36 48

Amorphous PLLA Crystalline PLLA

108 110

Alkaline Treatment Time (h) Alkaline Treatment Time (h)

113

Orthorhombic crystal structure of α-PLLA�

Figures removed for copyright reasons.

6.1

28.8

ddcrystal: 1.290 g/cm3

amorphous: 1.248 g/cm3

10.5 Å 10

Hydrolysable polymers�Polyanhydride O

CR O C R'

O

O

CR O R'

O

CR N R'

H

H2O O

CR OH

O

CR OH

O

CR OH

+

Polyester H2O +

Polyamide H2O +

Polyether OR R' OHR

H2O +

Polyether urethane O

CO N R'

H

R

R N

H

C

O

N R'

H

R O C

O

O R'

H2O OHR +

O

CHO R'

HO R'

H2N R'

HO R'

O

CHO N R'

H

Polyurea H2O R N

H

C

O

OH

R O C

O

OH

+ H2N R'

Polycarbonate H2O + HO R' 11

Poly(sebacic anhydride)�Properties: rapid degradation, Tg: 50 °C, Tm : 80 °C Uses: drug delivery matrices

O

O O

Table. Half-lives of hydrolyzable polymers

Incorporation ofPolymer class Half-life hydrophobic segment

Polyanhydrides 0.1 h

PLLA 3.3 years

83,000 years Poly(bis-(p-carboxyphenoxy)propane-co-sebacic anhydride)

C

O

O C3H6 O O

O O

C8H16

O

O

Polyamides

Tabata et al., Pharm. Res., 10, 391, 1993 Göpferich, Biomater., 17, 103, 1996 12

Poly(glycolide-co-lactide) (polyglactide)

Properties: rapid degradation, amorphous*, Tg: 45-55 °C Uses: bioresorbable sutures, controlled release matrices,

tissue engineering scaffolds *Depending on composition

O

O

O

O

Glycolate Lactate (GA) (DL-LA)

Dexon®: the first synthetic bioresorbable suture in 1960s. (PGA)�Histological response can be predictable in comparison to non-

synthetic materials. High-crystalline nature limits processability.

13

Poly(L-lactide), poly(L-lactic acid) (PLLA) Properties: rapid degradation, semicrystalline, Tg: 60 °C, Tm: 180 °C Uses: fracture fixation, ligament augmentation

O

O

*

PLLA

O

H

HO

H

HO

H

OH

OHHH

OH

HO

O

O

H* O

O

*

Fermentation -H2O

microorganisms e.g. Lactobacilli L-lactic acid

O

O O

O

*

*

PLLAD-glucose from agricultural product; -H2Ocorn, potato, rice

L-lactide 14

Physical properties of various plastics�

PLLA PET PS PP�

Density/g/cm3 1.27 1.34 1.04 0.90

Tensile strength/MPa 66.7 55.9 43.1 37.3

Yong’s modulus/MPa 3300 2600 3300 2100

Elongation@break/% 4 300 2 700

Cost/$/lb 1-5 0.75 0.55 -

*Polymeric materials were non-oriented (as prepared).

Tsuji, Polylactic acid, JPS press, Kyoto, 1997, Ikada, Macromol. Rapid Commun., 21, 117, 2000 15

O

Polyethylene oxide (PEO) Properties: water soluble, semicrystalline, Tg: -60 °C, Tm: 60 °C Uses: hydrogel, protein-resistant coatings

Two photos removed for copyright reasons.

PEO Figure 6 in Irvine, D., et al. "Nanoscale Clustering of RGD Peptides at

Surfaces Using Comb Polymers. 1. Synthesis and Characterization of

Comb Thin Films." Biomacromolecules 2, no. 1 (2001): 85 -94.

Rate of hydrolysis:

anhydride > ester >> amide >>>> ether etc.

Matrices for drug delivery 16

Hydrolysis of polymeric materials�

Acid- or base-catalyzed hydrolysis

Time

MW

Enzymatic hydrolysis -surface erosion-

Time

MW

17

Hydrolysis of Bionole® (PBS)�O

O*

*

O

O

Photos removed for copyright reasons.

Alkaline treated Lipase PS treatedTaniguchi I., unp ub lished results

18

Application of biodegradable polymers and minimal requirements of biomaterials

PAA: PBS: PCA: PCL: PEA: PGA:

PGALA:

PDLLA:

PDLLA

PGALA PGA

PCA

POE PAA Starch

PLLA PHA (PHB)

PCL PEC

PBS PES

PEA

Chitin PPZ

Fibrin

Application of Biodegradable Polymers

Poly(acid anhydride) Poly(butylene succinate) Poly(�-cyanoacrylate) Poly(�-caprolactone) Poly(ester amide) Poly(glycolide), Poly(glycolic acid) Poly(glycolide-co-lactide), Poly(glycolic acid-co-lactic acid) Poly(DL-lactide), Poly(DL-lactic acid)

PHA: PHB:

PLLA:

POE: PEC: PES:

Poly(hydroxyalkanoate Poly(3-hydroxybutyrate) Poly(L-lactide), Poly(L-lactic acid) Poly(orthoester) Poly(ester carbonate) Poly(ethylene succinate)

Oxidized cellulose

CelluloseHyaluronate

Collagen

Medical Application Ecological Application

Minimal Requirements of Biomaterials

B) Effective Functionality, Performance, Durability, etc.

C) Sterilizable Ethylene oxide, Θ-Irradiation, Electron beams, Autoclave, Dry heating, etc.

D) Biocompatible Interfacially, Mechanically, and Biologically

A) Non-toxic (biosafe) Non-pyrogenic, Non-hemolytic, Chronically non-inflammative, Non-allergenic, Non-carcinogenic, Non-teratogenic, etc.

Figure by MIT OCW.

19 Figure by MIT OCW.

Control

With S. waywayandensis JCM 9114

With A. orientalis subsp. Orientalis IFO 12362

Microbial degradation of PLLA (rare case)�

Photos removed for copyright reasons.

O

O

*Hydrolysable polymer Esterases do not degrade except proteinase K.

PLLA�

Figure. SEM images of PLLA film treated with microbe Jarerat et al., Macromol. Biosci., 2, 420, 2002

20�

21

Enzymatic degradation -Lipase-

Brzozowski, et al., Nature 1991, 351, 491

Lipase: an esterase (EC3.1.1.3)

O

CR O R'

O

CR OH HO R'+H2O+lipase

In toluene at 90 °C

stable in organic solvents @ high temp.

MW of the polyester is usually low (< 10 k).Poor mechanical properties.

Two figures removed for copyright reasons.