phd presentation, april 2003 v2
TRANSCRIPT
N. Weir
School of Mechanical & Manufacturing Engineering
Accelerated Degradation of Accelerated Degradation of Bioabsorbable Polymers Used in Bioabsorbable Polymers Used in
Surgical ApplicationsSurgical Applications
David Farrar Visit – Smith + Nephew15th April 2003
Overview of the Project
• Accelerated In Vitro Studies at Increased Temperatures• Accelerated In Vitro Studies Using Chemical Methods
• Two Polymers Investigated Poly--caprolactonePoly-L-lactide
Characterised Through Processing and Sterilisation
• In Vitro Degradation Studies Conducted at 37°C and In VivoStudies Using Rat as the Animal Model
Processing of PCL
Characterising PCL
In vitro & in vivo PCL Degradation Studies
Processing of PLLA
Characterising PLLA
In vitro & in vivo PLLA Degradation Studies
Chemical Degradation Studies on Both PCL & PLLA
October 2000 PresentTimeline
Poly--caprolactone• Member of the Aliphatic Polyester Family
• Developed as a Copolymer in SutureMaterials & also in Drug Delivery Devices
In vitro & in vivo PLLA Degradation Studies
Processing of PCL
Characterising PCL
In vitro & in vivo PCL Degradation Studies
Processing of PLLA
Characterising PLLA
Chemical Degradation Studies on Both PCL & PLLA
October 2000 Present
CAPA 6400 – Solvay Caprolactones
Melting Point 58-60°C Glass Transition -60°C Molecular Weight 37,000 % Crystallinity 50% PCL Pellets
Extruded
2mm Diameter Rod
Injection Moulded
Tensile
Flexural
Impact
Processing of PCL
Characterising PCL
In vitro & in vivo PCL Degradation Studies
Processing of PLLA
Characterising PLLA
In vitro & in vivo PLLA Degradation Studies
Chemical Degradation Studies on Both PCL & PLLA
October 2000 Present
Poly--caprolactone - Processing
• Effects of Processing and Sterilisation on Properties
CrystallinityMolecular WeightMechanical Strength
EtO Sterilisation Conditions
Conditions Temperature Time, (Hours)
Relative Humidity
Preconditioning 38-48°C 20-40 60-80% Gas Dwell 36-46°C 7-7.5 NA Degassing 38-48°C 16 NA
PCL Characterisation Tests and Degradation Studies Conducted on ASTM D 638-99 Tensile Samples and 30mm Lenghts of 2mm Diameter Extruded Rod
Characterising PCL
Processing of PCL
Characterising PCL
In vitro & in vivo PCL Degradation Studies
Processing of PLLA
Characterising PLLA
In vitro & in vivo PLLA Degradation Studies
Chemical Degradation Studies on Both PCL & PLLA
October 2000 Present
0
50
100
150
200
0 25 50 75 100 125
Extension, (mm)
Load
, (N)
0
40
80
120
160
0.0 0.5 1.0 1.5 2.0
Extension, mm
Load
, N
Characterising PCL
Processing of PCL
Characterising PCL
In vitro & in vivo PCL Degradation Studies
Processing of PLLA
Characterising PLLA
In vitro & in vivo PLLA Degradation Studies
Chemical Degradation Studies on Both PCL & PLLA
October 2000 Present
40 50 60 70
Temperature, °C
Heat
Flo
w
40 50 60 70
Temperature, °C40 50 60 70
Temperature, °C
Before Sterilisation After Sterilisation
Pellets Extruded Injected
Sterilisation may have caused some annealing of the polymer.
0
5
10
15
-80 -30 20 70
Temperature, oC
Heat
Flo
w, m
W
Thermal Analysis - DSCNo Significant Change in Thermal Properties After Processing
Characterising PCL
Processing of PCL
Characterising PCL
In vitro & in vivo PCL Degradation Studies
Processing of PLLA
Characterising PLLA
In vitro & in vivo PLLA Degradation Studies
Chemical Degradation Studies on Both PCL & PLLA
October 2000 Present
Conditions Temperature Time, (Hours)
Relative Humidity
Preconditioning 38-48°C 20-40 60-80% Gas Dwell 36-46°C 7-7.5 NA Degassing 38-48°C 16 NA
SurgicalAdhesive
Forceps
Scalpel with No. 11 Blade
Material Feeder
10 Gauge HypodermicNeedle
• In Vivo Degradation using Rat as the Animal Model30mm lengths of 2mm diameter rod implanted subdermally
PCL Degradation
Processing of PCL
Characterising PCL
In vitro & in vivo PCL Degradation Studies
Processing of PLLA
Characterising PLLA
In vitro & in vivo PLLA Degradation Studies
Chemical Degradation Studies on Both PCL & PLLA
October 2000 Present
• In Vitro Degradation at 37°C in pH 7.4 Phosphate BufferedSolution
• In Vitro Degradation at 50°C in pH 7.4 Phosphate BufferedSolution
• No Change in Molecular Weight Detected After 82 Weeks
Mechanical Properties
Tensile Samples
14
16
18
20
22
24
0 20 40 60 80 100
Weeks
Tens
ile S
treng
th, M
Pa
37°C 50°C
10
14
18
22
26
30
0 20 40 60 80 100
Weeks
Shea
r St
reng
th, M
Pa
37°C 50°C In vivo
Extruded Rod Samples
PCL Degradation - Results
Processing of PCL
Characterising PCL
In vitro & in vivo PCL Degradation Studies
Processing of PLLA
Characterising PLLA
In vitro & in vivo PLLA Degradation Studies
Chemical Degradation Studies on Both PCL & PLLA
October 2000 Present
Crystallinity of Extruded Rod
30
35
40
45
50
55
60
0 20 40 60 80 100
Weeks
% C
ryst
allin
ity
37°C 50°C
40 50 60 70 80Temperature °C
Heat
Flo
w
Pellets Control Rod 82 Weeks at 50°C
Conclusions• CAPA 6400 Degrades very Slowly• Increased Temperature Does Not Accelerate Degradation Rate
PCL Degradation - Results
Processing of PCL
Characterising PCL
In vitro & in vivo PCL Degradation Studies
Processing of PLLA
Characterising PLLA
In vitro & in vivo PLLA Degradation Studies
Chemical Degradation Studies on Both PCL & PLLA
October 2000 Present
Melting point 192°C Glass Transition Onset 67°C Molecular Weight, Mv 133,131 % Crystallinity 61% Properties of Supplied PLLA Pellets
Melting point 192°C Glass Transition Onset 67°C Molecular Weight, Mv 133,131 % Crystallinity 61% Properties of Supplied PLLA Pellets
Poly-L-lactide
Processing of PCL
Characterising PCL
In vitro & in vivo PCL Degradation Studies
Processing of PLLA
Characterising PLLA
In vitro & in vivo PLLA Degradation Studies
Chemical Degradation Studies on Both PCL & PLLA
October 2000 Present
• Also a Member of Aliphatic Polyester Family
• Significant Research Focussed on DevelopingPLLA for Orthopaedic Applications
Extruded PLLA
Extruded Annealed PLLA
Extruded PLLA
Poly-L-lactide - Processing
PLLA Pellets
Compression Moulded PLLA
Compression Moulded Annealed PLLA
Compression Moulded PLLA
• PLLA Annealed at 120°C for 4 Hours
In vitro & in vivo PLLA Degradation Studies
Processing of PCL
Characterising PCL
In vitro & in vivo PCL Degradation Studies
Processing of PLLA
Characterising PLLA
Chemical Degradation Studies on Both PCL & PLLA
October 2000 Present
Thermal Properties
40 90 140 190 240
Temperature, °C
Heat
Flo
w
Before Annealing
40 90 140 190 240
Temperature, °C
Heat
Flo
w
After Annealing
Pellets Compressed Extruded
61%12%20%
61%43%40%
• Sterilisation by EtO Gas Further Increased Crystallinity by Approximately 5%
Characterising PLLA
Processing of PCL
Characterising PCL
In vitro & in vivo PCL Degradation Studies
Processing of PLLA
Characterising PLLA
In vitro & in vivo PLLA Degradation Studies
Chemical Degradation Studies on Both PCL & PLLA
October 2000 Present
• Study Conducted to Determine the Effects of ProcessingAnnealing and Sterilisation on PLLA’s Properties
Molecular Weight
320
360
400
440
480
520
PLLA Pellets CompressedPLLA
AnnealedPLLA
AnnealedSterile PLLA
Equi
vale
nt M
wt x
103
Mechanical Properties
0
20
40
60
80
0 5 10 15 20
Percentage Strain
Stre
ss, M
Pa
Compressed Compressed Annealed
Compressed Annealed Sterile
• Similar Pattern Evident for the Extruded PLLA Tested in Shear
Characterising PLLA
Processing of PCL
Characterising PCL
In vitro & in vivo PCL Degradation Studies
Processing of PLLA
Characterising PLLA
In vitro & in vivo PLLA Degradation Studies
Chemical Degradation Studies on Both PCL & PLLA
October 2000 Present
3004756508251000
Wavenumber, cm-1
3004756508251000
Wavenumber,cm-1
3004756508251000
Wavenumber, cm-1
10 15 20 25 30 35
2 Theta
Inte
nsity
15 20 25 30 35
2 Theta
10 15 20 25 30 35
2 Theta
Pellets Compressed Compressed Annealed
Characterising PLLA• PLLA Was Further Characterised Using the Techniques of XRD and Raman
Spectroscopy
Processing of PCL
Characterising PCL
In vitro & in vivo PCL Degradation Studies
Processing of PLLA
Characterising PLLA
In vitro & in vivo PLLA Degradation Studies
Chemical Degradation Studies on Both PCL & PLLA
October 2000 Present
• Accelerated In Vitro Studies50°C in pH 7.4 Phosphate Buffered Solution70°C in pH 7.4 Phosphate Buffered SolutionIn Accordance With Annex A of ISO 15814
At 37oC in pH 7.4 Phosphate Buffered SolutionIn Accordance With ISO 15814
• Control In Vitro Study
Mass loss, Mechanical Strength, Molecular Weight and Thermal Properties
Degradation of PLLA
Processing of PCL
Characterising PCL
In vitro & in vivo PCL Degradation Studies
Processing of PLLA
Characterising PLLA
In vitro & in vivo PLLA Degradation Studies
Chemical Degradation Studies on Both PCL & PLLA
October 2000 Present
• In Vivo Study Using Rat as the Animal Model
37°C Mass Change
-6
-4
-2
0
2
0 20 40 60 80 100 120
Days
% M
ass
Cha
nge
Before Drying After Drying
50°C Mass Change
14 Days
18 Days
21 Days
23 Days
Mass Change
-0.4
0
0.4
0.8
1.2
1.6
0 10 20 30 40 50
Weeks
% M
ass
Cha
nge
Before Drying After Drying
Processing of PCL
Characterising PCL
In vitro & in vivo PCL Degradation Studies
Processing of PLLA
Characterising PLLA
In vitro & in vivo PLLA Degradation Studies
Chemical Degradation Studies on Both PCL & PLLA
October 2000 Present
-12
-8
-4
0
4
0 5 10 15 20 25
Days
% M
ass
Cha
nge
After Drying Before Drying
70°C Mass Change
-10
0
10
20
30
40
50
60
70
80
0 50 100 150 200 250
Days
Tens
ile S
treng
th, M
Pa
37°C 50°C 70°C
Zero Order Linear Model
Cktt
70°C
256.652214.037
tC
t82.02 R
37°C
375.61261.150
tC
t96.02 R
50°C
202.61999.870
tC
t94.02 R
Mechanical Properties
Processing of PCL
Characterising PCL
In vitro & in vivo PCL Degradation Studies
Processing of PLLA
Characterising PLLA
In vitro & in vivo PLLA Degradation Studies
Chemical Degradation Studies on Both PCL & PLLA
October 2000 Present
• Applying the Arrhenius Relationship
RTEa
AeK
ATREaK ln)1)((ln
TvK 1)(ln
-2.0
-1.0
0.0
1.0
2.0
3.0
0.0029 0.003 0.0031 0.0032 0.0033
1/T °K
ln K
75.36ln)1(11799ln TK
or;
TexK11799151013.9
Activation Energy for PLLA of 98 KJ mol-1
Mechanical Properties
Processing of PCL
Characterising PCL
In vitro & in vivo PCL Degradation Studies
Processing of PLLA
Characterising PLLA
In vitro & in vivo PLLA Degradation Studies
Chemical Degradation Studies on Both PCL & PLLA
October 2000 Present
0
40,000
80,000
120,000
160,000
200,000
0 50 100 150 200 250 300 350
Days
Num
ber A
vera
ge M
olec
ular
W
eigh
t, Mn
37°C 50°C 70°C
0
40,000
80,000
120,000
160,000
200,000
0 10 20 30 40 50
Weeks
Mol
ecul
ar W
eigh
t, M
n
In Vitro 37°C In Vivo
OHRRCOOHOHRCOOR '2
'
Kinetics of the hydrolytic reaction can be expressed by the rate equation;
]][2][[][][ EOHCOOHkdtCOOHddtEd
Where, E = Ester concentration COOH = Acid Concentration OH2 = Water Concentration
Molecular Weight
Processing of PCL
Characterising PCL
In vitro & in vivo PCL Degradation Studies
Processing of PLLA
Characterising PLLA
In vitro & in vivo PLLA Degradation Studies
Chemical Degradation Studies on Both PCL & PLLA
October 2000 Present
Molecular WeightTimevMn )(ln
y = -0.1101x + 11.569R2 = 0.9076
8
9
10
11
12
13
0 5 10 15 20 25
Days
ln M
n
70°C
y = -0.0364x + 12.064R2 = 0.8533
9.00
10.00
11.00
12.00
13.00
0 10 20 30 40 50
Weeks
ln M
n
37°C
y = -0.0219x + 11.942R2 = 0.9828
8
9
10
11
12
13
0 50 100 150
Days
ln M
n
50°C
Processing of PCL
Characterising PCL
In vitro & in vivo PCL Degradation Studies
Processing of PLLA
Characterising PLLA
In vitro & in vivo PLLA Degradation Studies
Chemical Degradation Studies on Both PCL & PLLA
October 2000 Present
40
4550
55
606570
75
0 30 60 90 120 150
Days
% C
ryst
allin
ity
50°C Crystallinity
50
60
70
80
90
100
0 5 10 15 20 25
Days
% C
ryst
allin
ity
70°C Crystallinity
40 90 140 190
Temperature, °C
Heat
Flo
w, m
W
40 90 140 190
Temperature, °C
Control 23 Days at 70°C
Crystallinity
Processing of PCL
Characterising PCL
In vitro & in vivo PCL Degradation Studies
Processing of PLLA
Characterising PLLA
In vitro & in vivo PLLA Degradation Studies
Chemical Degradation Studies on Both PCL & PLLA
October 2000 Present
Similar Pattern Evident at 37°C
• Study Focussed on the Secondary Amine Diethylamine
• Initial Objective to Accelerate the Degradation of PCL
Chemical Studies• Amine Based Drugs Accelerated the Degradation of
Bioabsorbable Drug Delivery Systems
• Study Suggesting Secondary and Tertiary Amines SimplyCatalysed the Hydrolysis Reaction Without Taking Part in It
Processing of PCL
Characterising PCL
In vitro & in vivo PCL Degradation Studies
Processing of PLLA
Characterising PLLA
In vitro & in vivo PLLA Degradation Studies
Chemical Degradation Studies on Both PCL & PLLA
October 2000 Present
• PCL Pellets Degraded in 0.5M DEA & Methanol Solution
y = -1.6915x + 3.9108R2 = 0.9822
y = -0.9553x + 7.354R2 = 0.9903
-120
-100
-80
-60
-40
-20
0
20
0 20 40 60 80
Days
% M
ass
Chan
ge
Before Drying After Drying
0
20,000
40,000
60,000
80,000
0 10 20 30 40 50
DaysM
oleu
lar W
eigh
t, M
n
Chemical Degradation of PCL
Processing of PCL
Characterising PCL
In vitro & in vivo PCL Degradation Studies
Processing of PLLA
Characterising PLLA
In vitro & in vivo PLLA Degradation Studies
Chemical Degradation Studies on Both PCL & PLLA
October 2000 Present
• Crystallinity Also Increased Significantly • Study of PCL in Methanol Only Showed Limited Changes
to PCL’s Properties
Results Revealed PLLA Degraded by Surface Erosion
y = -3.0952x + 0.1011R2 = 0.994
-40
-30
-20
-10
0
0 2 4 6 8 10 12
Weeks
% C
hang
e in
Are
a
% Change in Area in DEA & H2O
Differentiation Between the Materials Interior and Surface Molecular Weight
Processing of PCL
Characterising PCL
In vitro & in vivo PCL Degradation Studies
Processing of PLLA
Characterising PLLA
In vitro & in vivo PLLA Degradation Studies
Chemical Degradation Studies on Both PCL & PLLA
October 2000 Present
Chemical Degradation of PLLA• PLLA Degraded in 0.5M DEA & Methanol and 0.5M
DEA & Water
Conclusions
• Increased Temperature Appears to be a Powerful Means ofAccelerating Degradation of PLLA
• While Chemical Methods Appear to be More AppropriateFor Accelerating the Degradation of PCL
• PCL is Insensitive to Processing Although AnnealsSlightly Upon Sterilisation by EtO Gas
• PLLA is Sensitive to Processing and Sterilisation
Future Work• Further Analysis of Experimental Results
• Writing Up of papers;
Processing, Annealing and Sterilisation of Poly-L-lactide
The Influence of Processing and Sterilisation on the Properties of Poly--caprolactone
Accelerated Degradation of PLLA at Increased Temperatures
In vitro and In Vivo Degradation of PCL
Accelerated Degradation of PCL and PLLA by the Secondary Amine Diethylamine
• Thesis Write Up