Chapter 2 Lactide Polymerization with Iron Alkoxide Complexes
Degradation of poly-L-lactide. Part 2, IMechE, 2004
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Transcript of Degradation of poly-L-lactide. Part 2, IMechE, 2004
321
Degradation of poly-L-lactide Part 2 increasedtemperature accelerated degradation
N A Weir1 F J Buchanan1 J F Orr1 D F Farrar2 and G R Dickson31School of Mechanical and Manufacturing Engineering Queenrsquos University Belfast Belfast UK2Smith and Nephew Group Research Centre Heslington York UK3Department of Trauma and Orthopaedic Surgery Queenrsquos University Belfast Musgrave Park Hospital Belfast UK
Abstract Poly-L-lactide (PLLA) is one of the most significant members of a group of polymersregarded as bioresorbable The degradation of PLLA proceeds through hydrolysis of the ester linkagesin the polymerrsquos backbone however the time for the complete resorption of orthopaedic devicesmanufactured from PLLA is known to be in excess of five years in a normal physiological environ-ment To evaluate the degradation of PLLA in an accelerated time period PLLA pellets were pro-cessed by compression moulding into tensile test specimens prior to being sterilized by ethylene oxidegas (EtO) and degraded in a phosphate-buffered solution (PBS) at both 50 degC and 70 degC On retrievalat predetermined time intervals procedures were used to evaluate the materialrsquos molecular weightcrystallinity mechanical strength and thermal properties The results from this study suggest that atboth 50 degC and 70 degC degradation proceeds by a very similar mechanism to that observed at 37 degCin vitro and in vivo The degradation models developed also confirmed the dependence of massloss melting temperature and glass transition temperature (Tg) on the polymerrsquos molecular weightthroughout degradation Although increased temperature appears to be a suitable method foraccelerating the degradation of PLLA relative to its physiological degradation rate concerns stillremain over the validity of testing above the polymerrsquos Tg and the significance of autocatalysis atincreased temperatures
Keywords poly-L-lactide degradation accelerated molecular weight crystallinity
Tg glass transition temperatureNOTATIONTm melting temperature
DSC differential-scanning calorimetryEa activation energy DHmelt enthalpy of fusionEtO ethylene oxide gasGPC gel-permeation chromatographym0 initial mass 1 INTRODUCTIONmt
mass at time tMn number average molecular weight Poly-L-lactide (PLLA) is a member of the aliphatic
polyester family of bioresorbable polymers the mostMnt
number average molecular weight at time tPBS phosphate-buffered solution attractive group of polymers that currently meet the
various medical and physical demands for safe clinicalPCL poly-e-caprolactonePGA polyglycolide applications [1] Other significant members of this family
include polyglycolide (PGA) and poly-e-caprolactonePLLA poly-L-lactide(PCL) PLLA is a semicrystalline polymer and the mostcommon bioresorbable polymer used for orthopaedicapplications [2] due to its relatively high tensile strengthThe MS was received on 4 February 2004 and was accepted after revision
for publication on 17 June 2004 and low elongation [3] Like all the members of the Corresponding author School of Mechanical and Manufacturing
aliphatic polyester family PLLA degrades in vivo throughEngineering Queenrsquos University Belfast Ashby Building StranmillisRoad Belfast BT9 5AH UK email fbuchananqubacuk simple hydrolysis of the hydrolytically unstable ester
H01204 copy IMechE 2004 Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
322 N A WEIR F J BUCHANAN J F ORR D F FARRAR AND G R DICKSON
linkage in the polymerrsquos backbone with the degradation 2 MATERIALS AND METHODSproducts ultimately metabolized to carbon dioxide andwater and eliminated from the body [4] 21 Materials
The evaluation of PLLA and other bioresorbableThe polymer studied in this investigation poly-L-lactide
polymersrsquo properties throughout resorption is commonly(PLLA) ResomerA L (batch number 26033) was supplied
determined through in vitro and in vivo experiments within a sealed moisture-proof container by Boehringer
samples retrieved at predetermined time intervals andIngelheim (Ingelheim Germany) in pellet form
properties of mechanical strength molecular weightcrystallinity and mass change monitored Typically thein vitro test techniques developed to evaluate perform-ance are conducted with the polymer fully submerged
22 Methodsin a pH 74 phosphate-buffered solution (PBS) andincubated at 37 degC mimicking the physiological environ- 221 Processingment [5] Many studies have been conducted investi-
The PLLA was processed by compression moulding intogating the degradation of PLLA by this method [6ndash8]
plates 08 mm thick ASTM D638-99 type-V tensile speci-However considering that the times for the complete
mens were then cut from the plates The tensile specimensresorption of PLLA orthopaedic devices in a physio-
were annealed at 120 degC for a period of four hours in alogical environment have been reported to be in excess
preheated air-circulating oven prior to being sterilizedof five years [9] the impact this can have on product
using ethylene oxide gas (EtO) by Griffith Microsciencedevelopment periods is substantial Accelerating this
(Derbyshire UK ) on their standard EtO cycle forinitial evaluation process would obviously benefit the
medical polymers ie lsquoCycle 33rsquo [19]development of this promising group of biomaterials Todate a number of techniques with varying success have
222 Increased temperature degradationbeen investigated for accelerating the in vitro degradationof bioresorbable polymers These have included the The initial mass m0 of each of the tensile specimensintroduction of applied strain [10] increasing the tem- was recorded Individual specimens were then placed inperature of the degradation medium [11ndash13] or varying 28 ml screw-top glass bottles and fully immersed in aits pH [14] and [15] introducing organic compounds to pH 74 PBS in accordance with ISO 158141999 [5] Thethe polymer matrix [16 ] the application of ultrasound samples were divided into two separate groups and[17] and introducing enzymes to the degradation medium placed in separate air-circulating ovens maintaining their[18] However currently limited practical insight has been temperatures at 50 degC and 70 degC The pH of the solutionsgained from these accelerated test methods with extra- was monitored at regular intervalspolation of results back to service conditions proving Six PLLA tensile specimens were removed at eachvery difficult follow-up time (three mechanical test specimens and
This study investigates the potential of increasing the three mass-change specimens) Follow-up times for eachtemperature of the degradation medium for accelerating of the 50 degC and 70 degC studies are given in Table 1the in vitro degradation of PLLA relative to its physio-logical degradation rate at 37 degC and is a continuation
223 Characterization of retrieved materialof previous studies conducted by this research groupthat investigated the processing annealing sterilization Mechanical properties The mechanical properties of
the PLLA tensile specimens were determined using a[19] and physiological degradation of PLLA in vitroand in vivo [20] The present study aims to model the JJ Lloyd EZ 50 tensile testing machine (Hampshire
UK) equipped with a 1 kN load cell and tested at adegradation of PLLA at 50 degC and 70 degC and comparethe degradation mechanisms at these increased tempera- constant strain rate of 10 mmmin Youngrsquos modulus
tensile strength and extension at break were calculatedtures to those at 37 degC Additionally consideration isgiven to the influence of testing at increased temperatures from each of the load versus extension curves
In accordance with ISO 158141999 [5] the retrievedon the autocatalytic heterogeneous degradation mech-anism reported for PLLA [21] and the effect of testing material underwent mechanical testing while lsquowetrsquo with
testing conducted within three hours of retrieval fromabove the polymerrsquos glass transition temperature (Tg)on its degradation kinetics the in vitro buffered solution
Table 1 Accelerated degradation follow-up times
Follow-up Days
50 degC 1 3 5 11 21 32 50 72 88 11570 degC 1 3 5 7 9 11 14 16 18 21 23
H01204 copy IMechE 2004Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
323DEGRADATION OF POLY-L-LACTIDE PART 2
Mass change On retrieval the tensile specimens were rate of the unstable ester linkages Anderson [23] reporteda statistical method for relating molecular weight todried immediately with a paper towel to remove any
surface moisture before being weighed using an electronic hydrolysis rate assuming that the extent of degradationwas not large the following kinetic relationship basedbalance (Mettler Toledo Fisher Scientific UK) to deter-
mine the percentage swelling of the polymer and water on the polymers Mn was reporteduptake The specimens were then dried in a vacuum oven
1Mnt=1Mn0+k1t (3)(Townson+Mercer Altrincham UK) at approximately
30 degC for 48 hours at a vacuum of 068 bar (20 in Hg)where Mn
t=Mn at time t Mn0=Mn at t=0 k1=rateand reweighed to obtain their mass at time t (m
t) The
constant and t=time If this theory holds true a linearoverall percentage mass change after drying was thenrelationship should exist between 1Mn versus time upcalculated from equation (1)until the point of mass loss
However a disadvantage of this statistical approachpercentage mass change=
mtminusm0m0
times100 per cent is that it does not account for the possibility of auto-catalysis accelerating the polymerrsquos degradation rate(1)Pitt and Gu [24] derived a relationship based on thekinetics of the ester hydrolysis reaction accounting forMolecular weight and thermal properties Followingautocatalysis by the generated carboxylic acid endmass change measurements the dried PLLA specimensgroups described by the rate equationwere reused for gel-permeation chromatography (GPC)
analysis to determine their weight and number averaged(E)dt=minusd(COOH)dt=minusk(COOH)(H2O)(E)
molecular weights (Mn) throughout degradation andalso for differential-scanning calorimetry (DSC) to deter- (4)mine their thermal properties and percentage crystallinity
where (COOH) (H2O) and (E) represent the con-centrations of carboxyl end groups water and estersMolecular weight The GPC analysis was conducted byrespectivelyRapra Technology Ltd (Shropshire UK) Samples were
On further analysis of equation (4) and assuming thatprepared by adding 10 ml of choloform solvent to 20 mgthe ester and water concentrations remain constant andof sample taken through a cross-section of the materialthe concentration of acid end groups is equal to 1MnA Plgel-mixed bed column with refractive index responseit can be shown thatdetector was used The GPC system was calibrated
with polystyrene and all results were expressed as theMnt=Mn
0eminusk2t (5)lsquopolystyrene equivalentrsquo molecular weights
If this relationship holds true a linear relationshipThermal properties The thermal properties of the driedshould exist between the ln Mn versus time up until theretrieved PLLA tensile specimens were analysed using apoint of mass lossPerkin Elmer DSC 6 (Beaconsfield Buckinghamshire
UK) testing machine over a temperature range of 40 degC ln Mnt=minusk
2t+ ln Mn
0(6)
to 200 degC at a heating rate of 10 degCmin providingmeasurements of glass transition temperature Tg melt- Furthermore the mechanical properties of polymersing point Tm and enthalpy of fusion DHmelt Jg The have also been shown to be related to their Mn throughDSC results were derived from this single heating cycle the Flory relationship [25] and [26 ]to provide a true indication of changes in the polymerrsquosthermal properties and morphology as a direct result of
s=s2minus
B
Mnt
(7)degradation The enthalpy of fusion DHmelt was thenused to calculate the polymerrsquos percentage crystallinities
where s=fracture strength s2=fracture strength atrelative to the enthalpy of fusion of a 100 per cent
infinite molecular weight and B=constant This relation-crystalline sample of PLLA reported to be 93 Jg [22]ship implies that a significant loss of molecular weight
percentage crystallinity=(DHmelt 93)times100 per cent can occur before any significant loss in mechanical(2) properties is observed
232 The Arrhenius relationship23 TheoryThe Arrhenius relationship (equation (8)) represents a231 Modelling bioresorbable polymer degradationcommon method used for extrapolating results from
Since Mn is directly related to the scission of the polymer higher temperatures back to service temperatures [27]chains a number of relationships have been derivedrelating the changes in Mn with time to the hydrolysis k=AeminusEaRT (8)
H01204 copy IMechE 2004 Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
324 N A WEIR F J BUCHANAN J F ORR D F FARRAR AND G R DICKSON
where k=rate constant A=constant Ea=activation were so brittle they simply disintegrated on handling Asimilar pattern was also observed at 50 degC with the whiteenergy Jmol R=universal gas constant 8314 J molminus1
Kminus1 and T=temperature in Kelvins K If the relation- areas developing at 50 days and increasing with timeship holds true a linear relationship should exist betweenthe ln k versus 1T
32 Molecular weight versus time
ln k=minusAEa
R BA 1TB+ ln A (9) As expected the molecular weight of the PLLAtensile specimens at 50 degC and 70 degC decreased with time(Table 2) After 115 days at 50 degC the tensile specimensrsquoMn had decreased by approximately 93 per cent At70 degC a decrease of approximately 95 per cent in 23 days
3 RESULTS was observed in comparison to an 82 per cent decreaseafter 44 weeks at 37 degC the final time point analysed
31 Visual examination Additionally the profiles of the molecular weight-losscurves (Fig 2) most notably at 70 degC are characterizedInitially at 0 weeks the annealed PLLA tensile specimensby initial rapid loss in molecular weight up untilwere opaque and off-white in colour (Fig 1) After fiveapproximately five days at 70 degC followed by a perioddays at 70 degC small areas of the specimens became morewhere the molecular weight loss slowed considerablyintensely white and as degradation time increased more
white areas became visible At 23 days the specimens
Fig 2 Comparison between Mw and Mn at 50 degC and 70 degCFig 1 PLLA specimens degraded at 70 degC
Table 2 Molecular weight versus time summary at 37 degC 50 degC and 70 degC
Temperature Molecular weight
Days at 37 degC 0 28 70 140 182 224 266 308
37 degC Mw 424 000 339 000 309 000 199 000 199 000 159 000 133 500 74 900Mn 158 500 143 000 120 000 72 500 93 850 65 800 53 050 22 500
Days at 50 degC 0 1 5 11 21 32 50 72 88 115
50 degC Mw 409 500 327 500 332 500 238 500 248 500 175 500 128 600 73 250 47 500 18 650Mn 166 000 132 000 129 000 104 500 113 000 77 650 62 650 33 150 20 600 11 700
Days at 70 degC 0 1 3 5 9 14 18 21 23
70 degC Mw 409 500 276 500 127 500 86 200 52 550 56 950 25 000 19 350 11 350Mn 166 000 119 000 64 450 39 300 24 900 29 200 13 750 11 700 9 090
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325DEGRADATION OF POLY-L-LACTIDE PART 2
Table 3 Thermal properties and crystallinity of PLLA33 Mass change versus timesamples degraded at 50 degC
Before drying a similar pattern was observed at bothDegradation50 degC and 70 degC (Fig 3) Initially after one day increasestime days crystallinity Tm degC Tg onset degCof approximately 05 per cent and 07 per cent were
observed at 50 degC and 70 degC respectively Swelling then 0 470 1817 6741 457 1818 663gradually increased to approximately 1 per cent after 72
11 471 1818 651days at 50 degC and 14 days at 70 degC This 1 per cent swell-21 434 1815 656
ing appeared to coincide with the onset of polymer mass 32 453 1817 66050 564 1816 643loss after drying with specimens at both 50 degC and 70 degC72 617 1792 663losing mass from this point onwards A maximum mass88 659 1746 610
loss of 4 per cent was observed at 50 degC after 115 days 115 665 1717 ndashand 76 per cent after 23 days at 70 degC The resultsof the mass-change analysis are in agreement with thegeneral sequence of aliphatic polyester degradation which
Table 4 Thermal properties and crystallinity of PLLAsuggests a time-lag before any mass loss is observed [3]samples degraded at 70 degCand have a very similar profile to the previous control
study that investigated the in vitro degradation of PLLADegradation
tensile specimens at 37 degC [20] time days crystallinity Tm degC Tg onset degC
0 575 1805 6581 599 1809 639
34 DSC analysis versus time 3 575 1805 6405 771 1788 637
At both 50 degC and 70 degC a general trend of increasing 9 857 1745 59714 762 1767 603crystallinity and decreasing Tg onset temperature was18 889 1723 578observed with increasing degradation time (Tables 321 851 1719 577
and 4) reflecting the findings of a similar study conducted 23 922 1718 ndashat 37 degC in vitro [20] Additionally a significant decreasein the specimensrsquo melting point Tm was observed after72 days at 50 degC and five days at 70 degC
The DSC thermograms for the specimens degraded at At 0 weeks (Fig 4(a)) a sharp peak commencingat approximately 66 degC was observed related to theboth 50 degC and 70 degC are shown in Fig 4 along with a
control specimen at 0 days degradation Again the pro- polymerrsquos Tg and indicating unfreezing of main chainsegmental motion as weak secondary bonds in thefiles of the DSC thermograms reflect those observed at
37 degC [20] albeit in an accelerated time frame amorphous regions are broken As the temperatureincreased further a small endothermic dip was observedjust before melting commenced followed by the mainmelting peak It is suggested that the dip before meltingwas caused by some crystallization of the polymerAlthough the polymer was annealed prior to degradationwith the aim of limiting crystallization throughout thestudy close to the polymerrsquos melting point the chainmobility would have increased allowing some of theamorphous segments to order themselves into a morecrystalline structure
At 50 days at 50 degC and five days at 70 degC (Figs 4(b)and (e)) as degradation increased presumably in theamorphous regions the initial dip before melting observedat 0 weeks had disappeared with less amorphous regionsremaining capable of crystallization with a new peakforming in its place after 50 days at 50 degC (Fig 4(b))It is suggested that this new peak represents the melt-ing of new crystallites formed by the crystallization ofthe internal degradation by-products As degradationproceeds further it is speculated that the newly formedcrystallitersquos size also increases moving it to higher tem-peratures while the main melting peak is shifting to lower
Fig 3 Percentage mass change at 50 degC and 70 degC temperatures This results in the two peaks eventually
H01204 copy IMechE 2004 Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
326 N A WEIR F J BUCHANAN J F ORR D F FARRAR AND G R DICKSON
Fig 4 Comparison between DSC thermograms for samples degraded at 50 degC and 70 degC
Table 6 Change in the tensile properties of PLLA throughoutmerging with the smaller newly formed peak appearingdegradation at 70 degCas a shoulder on the larger peak before finally only one
sharp melting peak becomes visible (Figs 4(c) and (f))Degradation Youngrsquos Tensile Extension attime days modulus (MPa) strength (MPa) break (mm)
0 6684 643 16235 Mechanical strength versus time1 6056 473 1173 5362 403 108The tensile strength of the specimens reduced to zero5 3167 78 102
after approximately 50 days at 50 degC and 7 days at 70 degC 7 1029 23 056(Tables 5 and 6) A gradual decrease in Youngrsquos moduluswas also observed with the load versus extension curves
displaying a transition from a more ductile to brittleTable 5 Change in the tensile properties of PLLA throughout failure mode after five days at 50 degC and one day at
degradation at 50 degC 70 degC
Degradation Youngrsquos Tensile Extension attime days modulus (MPa) strength (MPa) break (mm)
4 MODELLING DEGRADATION0 6684 643 1621 6250 614 181
41 Molecular weight models3 6244 613 1595 6081 494 129
Molecular weight loss Analysing the data presented in11 5809 511 13521 4783 278 083 Table 2 in conjunction with equations (3) and (6) the32 3571 179 156 rate constants k1 for the uncatalysed model and k2 50 ndash 29 109
for the autocatalysed model were determined by linear
H01204 copy IMechE 2004Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
327DEGRADATION OF POLY-L-LACTIDE PART 2
regression from plots of (1Mntminus1Mn0) versus time for Dependence of mass loss Tm and Tg on molecular
weight Analysing the percentage mass loss results afterthe uncatalysed model and ln(MntMn0) versus time
for the autocatalysed model (Fig 5) at 37 degC 50 degC and drying in conjunction with the molecular-weight-lossresults it is apparent that a relationship exists between70 degC The analysis was conducted up until the point of
mass loss at each of the temperatures investigated It is the polymerrsquos Mn and percentage mass loss (Fig 7)with mass loss only observed after the polymerrsquos Mn hadapparent from Table 7 that as the degradation tem-
perature increased the correlation coefficient (R2 value) reduced to less than approximately 20 000 A similartrend was also observed when considering the reductionalso generally increased
Considering the rate constants k2 for the auto- in Tm with Mn (Fig 8) Only once the polymerrsquos Mnhad decreased to approximately 50 000 were significantcatalysed model further it is apparent that as the tem-
perature increased the rate of molecular weight loss decreases in the polymerrsquos melting temperature observedThis suggests that once the polymerrsquos molecular weightappeared to increase exponentially with an approximate
four-fold increase observed at 50 degC compared to a forty- had diminished sufficiently and presumably with theamorphous regions exhausted the crystalline regionsfold increase at 70 degC relative to the degradation rate at
37 degC Applying the Arrhenius relationship (equation (9)) were then predominantly attacked A similar dependenceof Tg on Mn was also observed (Fig 9)it is obvious that a linear relationship does exist (Fig 6)
with a high linear regression correlation coefficient of0995 The activation energy (Ea) for the loss of Mn wascalculated from Fig 6 as 1005 kJmol over the 37 degC to50 degC to 70 degC temperature range For the uncatalysedmodel an Ea of 1027 kJmol was calculated
Fig 7 Percentage change after drying versus Mn
Fig 5 Autocatalysed degradation model
Table 7 Uncatalysed and autocatalysed hydrolysisrates
Model Uncatalysed Autocatalysed
Temperature k1 R2 k2 R2
37 degC 9times10minus8 063 00052 08550 degC 3times10minus7 090 00196 096 Fig 8 Relationship between melting temperature and70 degC 4times10minus6 099 02155 095 molecular weight
Fig 9 Relationship between glass transition temperature andFig 6 Arrhenius plot of ln k2 versus 1T molecular weight
H01204 copy IMechE 2004 Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
328 N A WEIR F J BUCHANAN J F ORR D F FARRAR AND G R DICKSON
Mechanical strength and molecular weight An effort the results of previous researchers [28ndash30] investigatingsimilarly semicrystalline PLLA at 37 degC in vitro andwas also made to model the mechanical properties
of the tensile specimens investigated in this study in vivo They observed that as degradation increased thedistributions of the GPC curves became bimodal andagainst molecular weight using the Flory relationship
(equation (7)) However it is obvious from Fig 10 that even multimodal in nature as a result of the selectivedegradation of the amorphous regionsa relationship similar to the one predicted by Flory is not
derived from the results of the present study However The molecular weight models (Figs 7ndash9) also showthe dependence of the degradation of PLLA on itson further analysis it became apparent that an almost
linear relationship existed for the loss of tensile strength molecular weight with mass loss melting temperatureand glass transition displaying a strong dependence onwith time most notably at 50 degC and 70 degCmolecular weight An obvious benefit of these models isthe possibility of being able to predict the initial molecularweight of PLLA required to produce devices with vary-5 DISCUSSIONing resorption times However the failure of the Florymodel to predict mechanical strength is perhaps not51 Degradation mechanismssurprising considering it only accounts for molecular
The results presented for the accelerated degradationweight loss and not changes in morphology such as
of PLLA at increased temperatures suggest that atthe increases in crystallinity observed for the PLLA
50 degC and 70 degC degradation proceeded by the sameinvestigated in this study
mechanism and followed the general sequence of bulkdegradation reported previously for semicrystalline
Significance of autocatalysis at increased temperaturesaliphatic polyesters This suggests degradation occurs inThe degradation of aliphatic polyesters has been showntwo distinct stages [21] and is characterized by molecularto occur more rapidly at the centre than at the surfaceweight loss being observed first before loss of mechanical[21] due to the hydrolytic cleavage of the ester bondsstrength and before any physical mass loss is observedforming new acidic carboxyl end groups resulting in[3] Evidence from the results of the present study sup-a higher internal acidity and a differentiation betweenporting this two-stage bulk degradation mechanism arethe surface and interior degradation rates The resultsdiscussed belowof the present study modelling the loss of Mn to boththe uncatalysed and autocatalysed degradation modelsRelationship between molecular weight loss and degradationshowed no significant difference between activationThe general concensus that the degradation of semi-energies calculated for the two models Pohjonen andcrystalline aliphatic polyesters like the PLLA investi-Tormala [11] found a similar value for activation energygated in this study proceeds via random bulk hydrolysisof self-reinforced PLLA of 1014 kJmol using the auto-in two distinct stages is supported by considering thecatalytic model Previous research conducted by Li andprofile of the molecular-weight-loss curves of Fig 2McCarthy [32] on the in vitro degradation of poly-The curves show a faster initial loss of molecular weight(DL-lactide) at 60 degC showed that a hollow structureup until approximately five days at 70 degC before thewas not obtained during degradation in contrast torate of molecular weight loss slows considerably Thisdegradation at 37 degC in vitro where a hollow structuredegradation behaviour is typical where the rate of chainwas observed after 12 weeks due to autocatalysis [33]scission events is relatively constant with time TheLi and McCarthy [32] attributed this to the rapidmolecular weight is therefore inversely proportional todegradation at 60 degC and increase in the diffusiontime However interestingly the GPC curves for both thecoefficient of water and water-soluble oligomers abovetensile specimens at 50 degC and 70 degC remained essentiallythe polymerrsquos Tg They concluded that although hetero-monomodal throughout degradation contradictory togeneous degradation was still detected at 60 degC it wasmuch less significant and the relative importance ofinternal autocatalysis diminished as temperature increasedThis does not appear to be the case in the current studywith no observable difference between surface and coredegradation rate
52 Suitability of increased temperature for acceleratingthe degradation of PLLA
The results presented for the accelerated degradation ofPLLA at 50 degC and 70 degC indicate that the degradationFig 10 Relationship between tensile strength and molecular
weight mechanisms were very similar to the in vitro and
H01204 copy IMechE 2004Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
329DEGRADATION OF POLY-L-LACTIDE PART 2
in vivo degradation mechanism reported at 37 degC [20] However further work is needed to assess the validityof this hypothesis with only semicrystalline PLLA withThis suggests that increasing the temperature of the
degradation medium is a suitable method for accelerating identical initial crystallinities investigated in this presentstudythe degradation of PLLA relative to its physiological
degradation rate However in previous increased-temperature studies caution has often been noted whenusing test results performed at temperatures greater than 6 CONCLUSIONSthe polymerrsquos Tg for predicting degradation behaviourbelow the polymerrsquos Tg [11] and [12] Above the poly- This study suggests that increasing the temperature ofmerrsquos Tg it would be expected that with main chain the degradation medium represents a powerful methodsegmental motion unfrozen and the weak van der Waals for accelerating the degradation of PLLA with theforces holding the amorphous regions in place broken degradation mechanisms at 37 degC 50 degC and 70 degCwater molecules would be able to access the amorphous proving to be very similar However concerns stillregions more easily initiating hydrolytic chain scission remain over the validity of testing above the Tg of PLLAresulting in a further increased degradation rate The when predicting results at service temperatures below itscompression-moulded PLLA tensile specimens investi- Tg and the significance of the autocatalytic phenomenongated in this study had a Tg (dry) of approximately 66 degC as the temperature is increased relative to that at 37 degC(Tables 3 and 4) two temperatures were investigatedbelow the polymerrsquos Tg (37 degC and 50 degC) and one abovethe polymerrsquos Tg (70 degC) The high linear correlation
ACKNOWLEDGEMENTScoefficient (R2=0995) achieved for the Arrhenius plotmodelling the loss of molecular weight (Fig 6) suggests
The authors would like to thank Boehringer Ingelheimthat the degradation kinetics were not greatly affected(Ingelheim Germany) for supplying the PLLA Smithabove Tg Ideally to fully assess the implications testingamp Nephew Group Research Centre (York UK) forabove the polymerrsquos Tg has on the degradation rate atheir assistance with processing Griffith Microsciencerange of temperatures would need to be investigated(Derbyshire UK) for the ethylene oxide sterilizationabove and below Tg However this is not as straight-and Rapra Technology Limited (Shropshire UK) for theforward as it might appear When determining themolecular-weight characterization Finally the EPSRCpolymerrsquos Tg it must be realized that a small amount of(Swindon UK) for financial assistancewater can have a marked plasticizing effect causing a
reduction in the polymerrsquos Tg [34] Combine this withthe reduction in Tg due to the loss of molecular weight(Fig 9) and it is evident that defining the polymerrsquos Tg REFERENCESand determining the test temperatures that remain aboveand below the polymerrsquos Tg is an ever changing scenario 1 Li S and Vert M Biodegradation of aliphatic polyesters
In Degradable Polymers Principles amp Applications (EdsTraditionally as in this study and previous studiesG Scott and D Gilead) 1995 pp 43ndash87 (Chapman amp Hallinvestigating the degradation of bioresorbable polymersLondon)for convenience Tg is commonly determined by DSC on
2 Barber F A Resorbable materials for arthroscopicretrieved dried specimens however ideally for accuratefixation a product guide Orthopedic Special Edn 2002Tg measurements representative of the polymers con-8 29ndash37
dition in service test regimes need to be developed that 3 Middleton J C and Tipton A J Synthetic biodegradablecan accurately monitor the polymers Tg while the polymers as orthopedic devices Biomaterials 2000 21specimens remain lsquowetrsquo 2335ndash2346
Although concerns still remain about the validity of 4 Hayashi T Biodegradable polymers for biomedical usestesting above the Tg of PLLA when predicting behaviour Prog Polym Sci 1994 19 663ndash702
5 Implants for surgerymdashcopolymers and blends based onbelow its Tg it is hypothesized from the results of thepolylactidemdashIn vitro degradation testing ISO 158141999present study and from those of Pohjonen and Tormala
6 Duek E A R Zavaglia C A C and Belangero W D[11 ] and Agrawal et al [12 ] that the polymerrsquosIn vitro of poly( lactic acid) pin degradation Polymer 1999morphology may also have a significant role to play in40 6456ndash6473determining the validity of any relationships derived It is
7 Matsusue Y Yamamuro T Oka M Shikinami Y et alspeculated that for semicrystalline polymers results fromIn vitro and in vivo studies on bioabsorbable ultra-high-
tests performed above their Tg may be more valid for strength poly(L-lactide) rods J Biomed Mater Res 1992predicting degradation below their Tg due to their greater 26 1553ndash1567volume constrained in tightly packed less-accessible 8 Kellomaki M Paasimaa S and Tormala P Pliable poly-crystalline domains in comparison to polymers that are lactide plates for guided bone regeneration manufacturingintrinsically amorphous or likely to crystallize through and in vitro Proc Instn Mech Engrs Part H J Engineering
in Medicine 2000 214 615ndash629annealing as a direct result of the increased temperature
H01204 copy IMechE 2004 Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
330 N A WEIR F J BUCHANAN J F ORR D F FARRAR AND G R DICKSON
9 Bergsma J E de Bruijn W C Rozema F R 22 Fischer E W Sterzel H J and Wegner G Investigationof the structure of solution grown crystals of lactideBos R R M and Boering G Late degradation tissue
response to poly(L-lactide) bone plates and screws copolymers by means of chemical reactions Kolloid-Z uZ Polymere 1973 251 980ndash990Biomaterials 1995 16 25ndash31
10 Miller N D and Williams D F The in vivo and in vitro 23 Anderson J M Perspectives on the in vivo responsesof biodegradable polymers In Biomedical Applications ofdegradation of poly(glycolic acid) suture material as a
function of applied strain Biomaterials 1984 5 365ndash368 Synthetic Biodegradable Polymers (Ed J O Hollinger)1995 pp 223ndash233 (CRC Press Boca Raton FL USA)11 Pohjonen T and Tormala P Hydrolytic degradation of
ultra-high-strength self-reinforced poly-L-lactide A tem- 24 Pitt C G and Gu Z-W Modification of the rates of chaincleavage of poly(e-caprolactone) and related polyesters inperature dependence study In Biodegradable Implants in
Fracture Fixation (Eds L K Hung and P C Leung) 1994 the solid state J Control Release 1987 4 283ndash29225 Ward I M Mechanical Properties of Solid Polymerspp 75ndash88 (Department of Orthopaedics and Traumatology
Chinese University of Hong Kong and World Scientific) 1st edn 1971 p 335 ( Wiley-Interscience Chichester)26 Farrar D F and Gillson R K Hydrolytic degradation of12 Agrawal C M Huang D Schmitz J P and
Athanasiou K A Elevated temperature degradation of a polyglyconate B the relationship between degradationtime strength and molecular weight Biomaterials 20025050 copolymer of PLA-PGA Tissue Eng 1997 3(4)
345ndash352 23 3905ndash391227 Wise J Gillen K T and Clough R L An ultrasensitive13 Bucholz B Accelerated degradation test on resorbable
polymers In Degradation Phenomena on Polymeric Bio- technique for testing the Arrhenius extrapolation assump-tion for thermally aged elastomers Polym Degrad Stabmaterials (Eds H Planck M Dauner and M Renardy)
1992 pp 67ndash76 (Springer-Verlag Berlin) 1995 49 403ndash41828 Vert M Li S and Garreau H New insights on the14 Chu C C The in-vitro degradation of poly(glycolic acid)-
suturesmdasheffect of pH J Biomed Mater Res 1981 15 degradation of bioresorbable polymeric devices based onlactic and glycolic acids Clin Mater 1992 10 3ndash8795ndash804
15 Cam D Hyon S-H and Ikada Y Degradation of high 29 Li S Garreau H and Vert M Structure-propertyrelationships in the case of the degradation of massivemolecular weight poly(L-lactide) in alkaline medium
Biomaterials 1995 16 833ndash843 poly(a-hydroxy acids) in aqueous media Part 3 influenceof the morphology of poly(L-lactic acid) J Mater Sci16 Cha Y and Pitt C G The acceleration of degradation-
controlled drug delivery from polyester microspheres Mater Med 1990 1 198ndash20630 Pistner H Bendix D R Muhling J and Reuther JJ Control Release 1989 8 259ndash265
17 Agrawal C M Kennedy M E and Micallef D M Poly(L-lactide) a long-term degradation study in vivoPart III Analytical characterization Biomaterials 1993The effects of ultrasound irradiation on a biodegradable
50ndash50 per cent copolymer of polylactic and polyglycolic 14 291ndash29831 Von Recum H A Cleek R L Eskin S G andacids J Biomed Mater Res 1994 28 851ndash859
18 Gan Z Liang Q Zhang J and Jing X Enzymatic Mikos A G Degradation of polydispersed poly(L-lacticacid) to modulate lactic acid release Biomaterials 1995degradation of poly(e-caprolactone) film in phosphate
buffer solution containing lipases Polym Degrad Stab 16 441ndash44732 Li S and McCarthy S Further investigations on the1997 56 209ndash213
19 Weir N A Buchanan F J Orr J F Farrar D F and hydrolytic degradation of poly (DL-lactide) Biomaterials1999 20 35ndash44Boyd A Processing annealing and sterilisation of poly-L-
lactide Biomaterials 2004 25 3939ndash3949 33 Li S M Garreau H and Vert M Structure-propertyrelationships in the case of the degradation of massive20 Weir N A Buchanan F J Orr J F and Dickson G R
Degradation of poly-L-lactide Part 1mdashin vitro and in vivo aliphatic poly-(a-hydroxy acids) in aqueous media Part 1poly(DL-lactic acid) J Mater Sci Mater Med 1990physiological temperature degradation Proc Instn Mech
Engrs Part H J Engineering in Medicine (article in press) 1 123ndash13034 Siemann U The influence of water on the glass transition21 Li S Hydrolytic degradation characteristics of aliphatic
polyesters derived from lactic and glycolic acids J Biomed of poly(dl-lactic acid) Thermochimica Acta 1985 85513ndash516Mater Res (Appl Biomater) 1999 48 342ndash353
H01204 copy IMechE 2004Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
322 N A WEIR F J BUCHANAN J F ORR D F FARRAR AND G R DICKSON
linkage in the polymerrsquos backbone with the degradation 2 MATERIALS AND METHODSproducts ultimately metabolized to carbon dioxide andwater and eliminated from the body [4] 21 Materials
The evaluation of PLLA and other bioresorbableThe polymer studied in this investigation poly-L-lactide
polymersrsquo properties throughout resorption is commonly(PLLA) ResomerA L (batch number 26033) was supplied
determined through in vitro and in vivo experiments within a sealed moisture-proof container by Boehringer
samples retrieved at predetermined time intervals andIngelheim (Ingelheim Germany) in pellet form
properties of mechanical strength molecular weightcrystallinity and mass change monitored Typically thein vitro test techniques developed to evaluate perform-ance are conducted with the polymer fully submerged
22 Methodsin a pH 74 phosphate-buffered solution (PBS) andincubated at 37 degC mimicking the physiological environ- 221 Processingment [5] Many studies have been conducted investi-
The PLLA was processed by compression moulding intogating the degradation of PLLA by this method [6ndash8]
plates 08 mm thick ASTM D638-99 type-V tensile speci-However considering that the times for the complete
mens were then cut from the plates The tensile specimensresorption of PLLA orthopaedic devices in a physio-
were annealed at 120 degC for a period of four hours in alogical environment have been reported to be in excess
preheated air-circulating oven prior to being sterilizedof five years [9] the impact this can have on product
using ethylene oxide gas (EtO) by Griffith Microsciencedevelopment periods is substantial Accelerating this
(Derbyshire UK ) on their standard EtO cycle forinitial evaluation process would obviously benefit the
medical polymers ie lsquoCycle 33rsquo [19]development of this promising group of biomaterials Todate a number of techniques with varying success have
222 Increased temperature degradationbeen investigated for accelerating the in vitro degradationof bioresorbable polymers These have included the The initial mass m0 of each of the tensile specimensintroduction of applied strain [10] increasing the tem- was recorded Individual specimens were then placed inperature of the degradation medium [11ndash13] or varying 28 ml screw-top glass bottles and fully immersed in aits pH [14] and [15] introducing organic compounds to pH 74 PBS in accordance with ISO 158141999 [5] Thethe polymer matrix [16 ] the application of ultrasound samples were divided into two separate groups and[17] and introducing enzymes to the degradation medium placed in separate air-circulating ovens maintaining their[18] However currently limited practical insight has been temperatures at 50 degC and 70 degC The pH of the solutionsgained from these accelerated test methods with extra- was monitored at regular intervalspolation of results back to service conditions proving Six PLLA tensile specimens were removed at eachvery difficult follow-up time (three mechanical test specimens and
This study investigates the potential of increasing the three mass-change specimens) Follow-up times for eachtemperature of the degradation medium for accelerating of the 50 degC and 70 degC studies are given in Table 1the in vitro degradation of PLLA relative to its physio-logical degradation rate at 37 degC and is a continuation
223 Characterization of retrieved materialof previous studies conducted by this research groupthat investigated the processing annealing sterilization Mechanical properties The mechanical properties of
the PLLA tensile specimens were determined using a[19] and physiological degradation of PLLA in vitroand in vivo [20] The present study aims to model the JJ Lloyd EZ 50 tensile testing machine (Hampshire
UK) equipped with a 1 kN load cell and tested at adegradation of PLLA at 50 degC and 70 degC and comparethe degradation mechanisms at these increased tempera- constant strain rate of 10 mmmin Youngrsquos modulus
tensile strength and extension at break were calculatedtures to those at 37 degC Additionally consideration isgiven to the influence of testing at increased temperatures from each of the load versus extension curves
In accordance with ISO 158141999 [5] the retrievedon the autocatalytic heterogeneous degradation mech-anism reported for PLLA [21] and the effect of testing material underwent mechanical testing while lsquowetrsquo with
testing conducted within three hours of retrieval fromabove the polymerrsquos glass transition temperature (Tg)on its degradation kinetics the in vitro buffered solution
Table 1 Accelerated degradation follow-up times
Follow-up Days
50 degC 1 3 5 11 21 32 50 72 88 11570 degC 1 3 5 7 9 11 14 16 18 21 23
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323DEGRADATION OF POLY-L-LACTIDE PART 2
Mass change On retrieval the tensile specimens were rate of the unstable ester linkages Anderson [23] reporteda statistical method for relating molecular weight todried immediately with a paper towel to remove any
surface moisture before being weighed using an electronic hydrolysis rate assuming that the extent of degradationwas not large the following kinetic relationship basedbalance (Mettler Toledo Fisher Scientific UK) to deter-
mine the percentage swelling of the polymer and water on the polymers Mn was reporteduptake The specimens were then dried in a vacuum oven
1Mnt=1Mn0+k1t (3)(Townson+Mercer Altrincham UK) at approximately
30 degC for 48 hours at a vacuum of 068 bar (20 in Hg)where Mn
t=Mn at time t Mn0=Mn at t=0 k1=rateand reweighed to obtain their mass at time t (m
t) The
constant and t=time If this theory holds true a linearoverall percentage mass change after drying was thenrelationship should exist between 1Mn versus time upcalculated from equation (1)until the point of mass loss
However a disadvantage of this statistical approachpercentage mass change=
mtminusm0m0
times100 per cent is that it does not account for the possibility of auto-catalysis accelerating the polymerrsquos degradation rate(1)Pitt and Gu [24] derived a relationship based on thekinetics of the ester hydrolysis reaction accounting forMolecular weight and thermal properties Followingautocatalysis by the generated carboxylic acid endmass change measurements the dried PLLA specimensgroups described by the rate equationwere reused for gel-permeation chromatography (GPC)
analysis to determine their weight and number averaged(E)dt=minusd(COOH)dt=minusk(COOH)(H2O)(E)
molecular weights (Mn) throughout degradation andalso for differential-scanning calorimetry (DSC) to deter- (4)mine their thermal properties and percentage crystallinity
where (COOH) (H2O) and (E) represent the con-centrations of carboxyl end groups water and estersMolecular weight The GPC analysis was conducted byrespectivelyRapra Technology Ltd (Shropshire UK) Samples were
On further analysis of equation (4) and assuming thatprepared by adding 10 ml of choloform solvent to 20 mgthe ester and water concentrations remain constant andof sample taken through a cross-section of the materialthe concentration of acid end groups is equal to 1MnA Plgel-mixed bed column with refractive index responseit can be shown thatdetector was used The GPC system was calibrated
with polystyrene and all results were expressed as theMnt=Mn
0eminusk2t (5)lsquopolystyrene equivalentrsquo molecular weights
If this relationship holds true a linear relationshipThermal properties The thermal properties of the driedshould exist between the ln Mn versus time up until theretrieved PLLA tensile specimens were analysed using apoint of mass lossPerkin Elmer DSC 6 (Beaconsfield Buckinghamshire
UK) testing machine over a temperature range of 40 degC ln Mnt=minusk
2t+ ln Mn
0(6)
to 200 degC at a heating rate of 10 degCmin providingmeasurements of glass transition temperature Tg melt- Furthermore the mechanical properties of polymersing point Tm and enthalpy of fusion DHmelt Jg The have also been shown to be related to their Mn throughDSC results were derived from this single heating cycle the Flory relationship [25] and [26 ]to provide a true indication of changes in the polymerrsquosthermal properties and morphology as a direct result of
s=s2minus
B
Mnt
(7)degradation The enthalpy of fusion DHmelt was thenused to calculate the polymerrsquos percentage crystallinities
where s=fracture strength s2=fracture strength atrelative to the enthalpy of fusion of a 100 per cent
infinite molecular weight and B=constant This relation-crystalline sample of PLLA reported to be 93 Jg [22]ship implies that a significant loss of molecular weight
percentage crystallinity=(DHmelt 93)times100 per cent can occur before any significant loss in mechanical(2) properties is observed
232 The Arrhenius relationship23 TheoryThe Arrhenius relationship (equation (8)) represents a231 Modelling bioresorbable polymer degradationcommon method used for extrapolating results from
Since Mn is directly related to the scission of the polymer higher temperatures back to service temperatures [27]chains a number of relationships have been derivedrelating the changes in Mn with time to the hydrolysis k=AeminusEaRT (8)
H01204 copy IMechE 2004 Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
324 N A WEIR F J BUCHANAN J F ORR D F FARRAR AND G R DICKSON
where k=rate constant A=constant Ea=activation were so brittle they simply disintegrated on handling Asimilar pattern was also observed at 50 degC with the whiteenergy Jmol R=universal gas constant 8314 J molminus1
Kminus1 and T=temperature in Kelvins K If the relation- areas developing at 50 days and increasing with timeship holds true a linear relationship should exist betweenthe ln k versus 1T
32 Molecular weight versus time
ln k=minusAEa
R BA 1TB+ ln A (9) As expected the molecular weight of the PLLAtensile specimens at 50 degC and 70 degC decreased with time(Table 2) After 115 days at 50 degC the tensile specimensrsquoMn had decreased by approximately 93 per cent At70 degC a decrease of approximately 95 per cent in 23 days
3 RESULTS was observed in comparison to an 82 per cent decreaseafter 44 weeks at 37 degC the final time point analysed
31 Visual examination Additionally the profiles of the molecular weight-losscurves (Fig 2) most notably at 70 degC are characterizedInitially at 0 weeks the annealed PLLA tensile specimensby initial rapid loss in molecular weight up untilwere opaque and off-white in colour (Fig 1) After fiveapproximately five days at 70 degC followed by a perioddays at 70 degC small areas of the specimens became morewhere the molecular weight loss slowed considerablyintensely white and as degradation time increased more
white areas became visible At 23 days the specimens
Fig 2 Comparison between Mw and Mn at 50 degC and 70 degCFig 1 PLLA specimens degraded at 70 degC
Table 2 Molecular weight versus time summary at 37 degC 50 degC and 70 degC
Temperature Molecular weight
Days at 37 degC 0 28 70 140 182 224 266 308
37 degC Mw 424 000 339 000 309 000 199 000 199 000 159 000 133 500 74 900Mn 158 500 143 000 120 000 72 500 93 850 65 800 53 050 22 500
Days at 50 degC 0 1 5 11 21 32 50 72 88 115
50 degC Mw 409 500 327 500 332 500 238 500 248 500 175 500 128 600 73 250 47 500 18 650Mn 166 000 132 000 129 000 104 500 113 000 77 650 62 650 33 150 20 600 11 700
Days at 70 degC 0 1 3 5 9 14 18 21 23
70 degC Mw 409 500 276 500 127 500 86 200 52 550 56 950 25 000 19 350 11 350Mn 166 000 119 000 64 450 39 300 24 900 29 200 13 750 11 700 9 090
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325DEGRADATION OF POLY-L-LACTIDE PART 2
Table 3 Thermal properties and crystallinity of PLLA33 Mass change versus timesamples degraded at 50 degC
Before drying a similar pattern was observed at bothDegradation50 degC and 70 degC (Fig 3) Initially after one day increasestime days crystallinity Tm degC Tg onset degCof approximately 05 per cent and 07 per cent were
observed at 50 degC and 70 degC respectively Swelling then 0 470 1817 6741 457 1818 663gradually increased to approximately 1 per cent after 72
11 471 1818 651days at 50 degC and 14 days at 70 degC This 1 per cent swell-21 434 1815 656
ing appeared to coincide with the onset of polymer mass 32 453 1817 66050 564 1816 643loss after drying with specimens at both 50 degC and 70 degC72 617 1792 663losing mass from this point onwards A maximum mass88 659 1746 610
loss of 4 per cent was observed at 50 degC after 115 days 115 665 1717 ndashand 76 per cent after 23 days at 70 degC The resultsof the mass-change analysis are in agreement with thegeneral sequence of aliphatic polyester degradation which
Table 4 Thermal properties and crystallinity of PLLAsuggests a time-lag before any mass loss is observed [3]samples degraded at 70 degCand have a very similar profile to the previous control
study that investigated the in vitro degradation of PLLADegradation
tensile specimens at 37 degC [20] time days crystallinity Tm degC Tg onset degC
0 575 1805 6581 599 1809 639
34 DSC analysis versus time 3 575 1805 6405 771 1788 637
At both 50 degC and 70 degC a general trend of increasing 9 857 1745 59714 762 1767 603crystallinity and decreasing Tg onset temperature was18 889 1723 578observed with increasing degradation time (Tables 321 851 1719 577
and 4) reflecting the findings of a similar study conducted 23 922 1718 ndashat 37 degC in vitro [20] Additionally a significant decreasein the specimensrsquo melting point Tm was observed after72 days at 50 degC and five days at 70 degC
The DSC thermograms for the specimens degraded at At 0 weeks (Fig 4(a)) a sharp peak commencingat approximately 66 degC was observed related to theboth 50 degC and 70 degC are shown in Fig 4 along with a
control specimen at 0 days degradation Again the pro- polymerrsquos Tg and indicating unfreezing of main chainsegmental motion as weak secondary bonds in thefiles of the DSC thermograms reflect those observed at
37 degC [20] albeit in an accelerated time frame amorphous regions are broken As the temperatureincreased further a small endothermic dip was observedjust before melting commenced followed by the mainmelting peak It is suggested that the dip before meltingwas caused by some crystallization of the polymerAlthough the polymer was annealed prior to degradationwith the aim of limiting crystallization throughout thestudy close to the polymerrsquos melting point the chainmobility would have increased allowing some of theamorphous segments to order themselves into a morecrystalline structure
At 50 days at 50 degC and five days at 70 degC (Figs 4(b)and (e)) as degradation increased presumably in theamorphous regions the initial dip before melting observedat 0 weeks had disappeared with less amorphous regionsremaining capable of crystallization with a new peakforming in its place after 50 days at 50 degC (Fig 4(b))It is suggested that this new peak represents the melt-ing of new crystallites formed by the crystallization ofthe internal degradation by-products As degradationproceeds further it is speculated that the newly formedcrystallitersquos size also increases moving it to higher tem-peratures while the main melting peak is shifting to lower
Fig 3 Percentage mass change at 50 degC and 70 degC temperatures This results in the two peaks eventually
H01204 copy IMechE 2004 Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
326 N A WEIR F J BUCHANAN J F ORR D F FARRAR AND G R DICKSON
Fig 4 Comparison between DSC thermograms for samples degraded at 50 degC and 70 degC
Table 6 Change in the tensile properties of PLLA throughoutmerging with the smaller newly formed peak appearingdegradation at 70 degCas a shoulder on the larger peak before finally only one
sharp melting peak becomes visible (Figs 4(c) and (f))Degradation Youngrsquos Tensile Extension attime days modulus (MPa) strength (MPa) break (mm)
0 6684 643 16235 Mechanical strength versus time1 6056 473 1173 5362 403 108The tensile strength of the specimens reduced to zero5 3167 78 102
after approximately 50 days at 50 degC and 7 days at 70 degC 7 1029 23 056(Tables 5 and 6) A gradual decrease in Youngrsquos moduluswas also observed with the load versus extension curves
displaying a transition from a more ductile to brittleTable 5 Change in the tensile properties of PLLA throughout failure mode after five days at 50 degC and one day at
degradation at 50 degC 70 degC
Degradation Youngrsquos Tensile Extension attime days modulus (MPa) strength (MPa) break (mm)
4 MODELLING DEGRADATION0 6684 643 1621 6250 614 181
41 Molecular weight models3 6244 613 1595 6081 494 129
Molecular weight loss Analysing the data presented in11 5809 511 13521 4783 278 083 Table 2 in conjunction with equations (3) and (6) the32 3571 179 156 rate constants k1 for the uncatalysed model and k2 50 ndash 29 109
for the autocatalysed model were determined by linear
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327DEGRADATION OF POLY-L-LACTIDE PART 2
regression from plots of (1Mntminus1Mn0) versus time for Dependence of mass loss Tm and Tg on molecular
weight Analysing the percentage mass loss results afterthe uncatalysed model and ln(MntMn0) versus time
for the autocatalysed model (Fig 5) at 37 degC 50 degC and drying in conjunction with the molecular-weight-lossresults it is apparent that a relationship exists between70 degC The analysis was conducted up until the point of
mass loss at each of the temperatures investigated It is the polymerrsquos Mn and percentage mass loss (Fig 7)with mass loss only observed after the polymerrsquos Mn hadapparent from Table 7 that as the degradation tem-
perature increased the correlation coefficient (R2 value) reduced to less than approximately 20 000 A similartrend was also observed when considering the reductionalso generally increased
Considering the rate constants k2 for the auto- in Tm with Mn (Fig 8) Only once the polymerrsquos Mnhad decreased to approximately 50 000 were significantcatalysed model further it is apparent that as the tem-
perature increased the rate of molecular weight loss decreases in the polymerrsquos melting temperature observedThis suggests that once the polymerrsquos molecular weightappeared to increase exponentially with an approximate
four-fold increase observed at 50 degC compared to a forty- had diminished sufficiently and presumably with theamorphous regions exhausted the crystalline regionsfold increase at 70 degC relative to the degradation rate at
37 degC Applying the Arrhenius relationship (equation (9)) were then predominantly attacked A similar dependenceof Tg on Mn was also observed (Fig 9)it is obvious that a linear relationship does exist (Fig 6)
with a high linear regression correlation coefficient of0995 The activation energy (Ea) for the loss of Mn wascalculated from Fig 6 as 1005 kJmol over the 37 degC to50 degC to 70 degC temperature range For the uncatalysedmodel an Ea of 1027 kJmol was calculated
Fig 7 Percentage change after drying versus Mn
Fig 5 Autocatalysed degradation model
Table 7 Uncatalysed and autocatalysed hydrolysisrates
Model Uncatalysed Autocatalysed
Temperature k1 R2 k2 R2
37 degC 9times10minus8 063 00052 08550 degC 3times10minus7 090 00196 096 Fig 8 Relationship between melting temperature and70 degC 4times10minus6 099 02155 095 molecular weight
Fig 9 Relationship between glass transition temperature andFig 6 Arrhenius plot of ln k2 versus 1T molecular weight
H01204 copy IMechE 2004 Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
328 N A WEIR F J BUCHANAN J F ORR D F FARRAR AND G R DICKSON
Mechanical strength and molecular weight An effort the results of previous researchers [28ndash30] investigatingsimilarly semicrystalline PLLA at 37 degC in vitro andwas also made to model the mechanical properties
of the tensile specimens investigated in this study in vivo They observed that as degradation increased thedistributions of the GPC curves became bimodal andagainst molecular weight using the Flory relationship
(equation (7)) However it is obvious from Fig 10 that even multimodal in nature as a result of the selectivedegradation of the amorphous regionsa relationship similar to the one predicted by Flory is not
derived from the results of the present study However The molecular weight models (Figs 7ndash9) also showthe dependence of the degradation of PLLA on itson further analysis it became apparent that an almost
linear relationship existed for the loss of tensile strength molecular weight with mass loss melting temperatureand glass transition displaying a strong dependence onwith time most notably at 50 degC and 70 degCmolecular weight An obvious benefit of these models isthe possibility of being able to predict the initial molecularweight of PLLA required to produce devices with vary-5 DISCUSSIONing resorption times However the failure of the Florymodel to predict mechanical strength is perhaps not51 Degradation mechanismssurprising considering it only accounts for molecular
The results presented for the accelerated degradationweight loss and not changes in morphology such as
of PLLA at increased temperatures suggest that atthe increases in crystallinity observed for the PLLA
50 degC and 70 degC degradation proceeded by the sameinvestigated in this study
mechanism and followed the general sequence of bulkdegradation reported previously for semicrystalline
Significance of autocatalysis at increased temperaturesaliphatic polyesters This suggests degradation occurs inThe degradation of aliphatic polyesters has been showntwo distinct stages [21] and is characterized by molecularto occur more rapidly at the centre than at the surfaceweight loss being observed first before loss of mechanical[21] due to the hydrolytic cleavage of the ester bondsstrength and before any physical mass loss is observedforming new acidic carboxyl end groups resulting in[3] Evidence from the results of the present study sup-a higher internal acidity and a differentiation betweenporting this two-stage bulk degradation mechanism arethe surface and interior degradation rates The resultsdiscussed belowof the present study modelling the loss of Mn to boththe uncatalysed and autocatalysed degradation modelsRelationship between molecular weight loss and degradationshowed no significant difference between activationThe general concensus that the degradation of semi-energies calculated for the two models Pohjonen andcrystalline aliphatic polyesters like the PLLA investi-Tormala [11] found a similar value for activation energygated in this study proceeds via random bulk hydrolysisof self-reinforced PLLA of 1014 kJmol using the auto-in two distinct stages is supported by considering thecatalytic model Previous research conducted by Li andprofile of the molecular-weight-loss curves of Fig 2McCarthy [32] on the in vitro degradation of poly-The curves show a faster initial loss of molecular weight(DL-lactide) at 60 degC showed that a hollow structureup until approximately five days at 70 degC before thewas not obtained during degradation in contrast torate of molecular weight loss slows considerably Thisdegradation at 37 degC in vitro where a hollow structuredegradation behaviour is typical where the rate of chainwas observed after 12 weeks due to autocatalysis [33]scission events is relatively constant with time TheLi and McCarthy [32] attributed this to the rapidmolecular weight is therefore inversely proportional todegradation at 60 degC and increase in the diffusiontime However interestingly the GPC curves for both thecoefficient of water and water-soluble oligomers abovetensile specimens at 50 degC and 70 degC remained essentiallythe polymerrsquos Tg They concluded that although hetero-monomodal throughout degradation contradictory togeneous degradation was still detected at 60 degC it wasmuch less significant and the relative importance ofinternal autocatalysis diminished as temperature increasedThis does not appear to be the case in the current studywith no observable difference between surface and coredegradation rate
52 Suitability of increased temperature for acceleratingthe degradation of PLLA
The results presented for the accelerated degradation ofPLLA at 50 degC and 70 degC indicate that the degradationFig 10 Relationship between tensile strength and molecular
weight mechanisms were very similar to the in vitro and
H01204 copy IMechE 2004Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
329DEGRADATION OF POLY-L-LACTIDE PART 2
in vivo degradation mechanism reported at 37 degC [20] However further work is needed to assess the validityof this hypothesis with only semicrystalline PLLA withThis suggests that increasing the temperature of the
degradation medium is a suitable method for accelerating identical initial crystallinities investigated in this presentstudythe degradation of PLLA relative to its physiological
degradation rate However in previous increased-temperature studies caution has often been noted whenusing test results performed at temperatures greater than 6 CONCLUSIONSthe polymerrsquos Tg for predicting degradation behaviourbelow the polymerrsquos Tg [11] and [12] Above the poly- This study suggests that increasing the temperature ofmerrsquos Tg it would be expected that with main chain the degradation medium represents a powerful methodsegmental motion unfrozen and the weak van der Waals for accelerating the degradation of PLLA with theforces holding the amorphous regions in place broken degradation mechanisms at 37 degC 50 degC and 70 degCwater molecules would be able to access the amorphous proving to be very similar However concerns stillregions more easily initiating hydrolytic chain scission remain over the validity of testing above the Tg of PLLAresulting in a further increased degradation rate The when predicting results at service temperatures below itscompression-moulded PLLA tensile specimens investi- Tg and the significance of the autocatalytic phenomenongated in this study had a Tg (dry) of approximately 66 degC as the temperature is increased relative to that at 37 degC(Tables 3 and 4) two temperatures were investigatedbelow the polymerrsquos Tg (37 degC and 50 degC) and one abovethe polymerrsquos Tg (70 degC) The high linear correlation
ACKNOWLEDGEMENTScoefficient (R2=0995) achieved for the Arrhenius plotmodelling the loss of molecular weight (Fig 6) suggests
The authors would like to thank Boehringer Ingelheimthat the degradation kinetics were not greatly affected(Ingelheim Germany) for supplying the PLLA Smithabove Tg Ideally to fully assess the implications testingamp Nephew Group Research Centre (York UK) forabove the polymerrsquos Tg has on the degradation rate atheir assistance with processing Griffith Microsciencerange of temperatures would need to be investigated(Derbyshire UK) for the ethylene oxide sterilizationabove and below Tg However this is not as straight-and Rapra Technology Limited (Shropshire UK) for theforward as it might appear When determining themolecular-weight characterization Finally the EPSRCpolymerrsquos Tg it must be realized that a small amount of(Swindon UK) for financial assistancewater can have a marked plasticizing effect causing a
reduction in the polymerrsquos Tg [34] Combine this withthe reduction in Tg due to the loss of molecular weight(Fig 9) and it is evident that defining the polymerrsquos Tg REFERENCESand determining the test temperatures that remain aboveand below the polymerrsquos Tg is an ever changing scenario 1 Li S and Vert M Biodegradation of aliphatic polyesters
In Degradable Polymers Principles amp Applications (EdsTraditionally as in this study and previous studiesG Scott and D Gilead) 1995 pp 43ndash87 (Chapman amp Hallinvestigating the degradation of bioresorbable polymersLondon)for convenience Tg is commonly determined by DSC on
2 Barber F A Resorbable materials for arthroscopicretrieved dried specimens however ideally for accuratefixation a product guide Orthopedic Special Edn 2002Tg measurements representative of the polymers con-8 29ndash37
dition in service test regimes need to be developed that 3 Middleton J C and Tipton A J Synthetic biodegradablecan accurately monitor the polymers Tg while the polymers as orthopedic devices Biomaterials 2000 21specimens remain lsquowetrsquo 2335ndash2346
Although concerns still remain about the validity of 4 Hayashi T Biodegradable polymers for biomedical usestesting above the Tg of PLLA when predicting behaviour Prog Polym Sci 1994 19 663ndash702
5 Implants for surgerymdashcopolymers and blends based onbelow its Tg it is hypothesized from the results of thepolylactidemdashIn vitro degradation testing ISO 158141999present study and from those of Pohjonen and Tormala
6 Duek E A R Zavaglia C A C and Belangero W D[11 ] and Agrawal et al [12 ] that the polymerrsquosIn vitro of poly( lactic acid) pin degradation Polymer 1999morphology may also have a significant role to play in40 6456ndash6473determining the validity of any relationships derived It is
7 Matsusue Y Yamamuro T Oka M Shikinami Y et alspeculated that for semicrystalline polymers results fromIn vitro and in vivo studies on bioabsorbable ultra-high-
tests performed above their Tg may be more valid for strength poly(L-lactide) rods J Biomed Mater Res 1992predicting degradation below their Tg due to their greater 26 1553ndash1567volume constrained in tightly packed less-accessible 8 Kellomaki M Paasimaa S and Tormala P Pliable poly-crystalline domains in comparison to polymers that are lactide plates for guided bone regeneration manufacturingintrinsically amorphous or likely to crystallize through and in vitro Proc Instn Mech Engrs Part H J Engineering
in Medicine 2000 214 615ndash629annealing as a direct result of the increased temperature
H01204 copy IMechE 2004 Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
330 N A WEIR F J BUCHANAN J F ORR D F FARRAR AND G R DICKSON
9 Bergsma J E de Bruijn W C Rozema F R 22 Fischer E W Sterzel H J and Wegner G Investigationof the structure of solution grown crystals of lactideBos R R M and Boering G Late degradation tissue
response to poly(L-lactide) bone plates and screws copolymers by means of chemical reactions Kolloid-Z uZ Polymere 1973 251 980ndash990Biomaterials 1995 16 25ndash31
10 Miller N D and Williams D F The in vivo and in vitro 23 Anderson J M Perspectives on the in vivo responsesof biodegradable polymers In Biomedical Applications ofdegradation of poly(glycolic acid) suture material as a
function of applied strain Biomaterials 1984 5 365ndash368 Synthetic Biodegradable Polymers (Ed J O Hollinger)1995 pp 223ndash233 (CRC Press Boca Raton FL USA)11 Pohjonen T and Tormala P Hydrolytic degradation of
ultra-high-strength self-reinforced poly-L-lactide A tem- 24 Pitt C G and Gu Z-W Modification of the rates of chaincleavage of poly(e-caprolactone) and related polyesters inperature dependence study In Biodegradable Implants in
Fracture Fixation (Eds L K Hung and P C Leung) 1994 the solid state J Control Release 1987 4 283ndash29225 Ward I M Mechanical Properties of Solid Polymerspp 75ndash88 (Department of Orthopaedics and Traumatology
Chinese University of Hong Kong and World Scientific) 1st edn 1971 p 335 ( Wiley-Interscience Chichester)26 Farrar D F and Gillson R K Hydrolytic degradation of12 Agrawal C M Huang D Schmitz J P and
Athanasiou K A Elevated temperature degradation of a polyglyconate B the relationship between degradationtime strength and molecular weight Biomaterials 20025050 copolymer of PLA-PGA Tissue Eng 1997 3(4)
345ndash352 23 3905ndash391227 Wise J Gillen K T and Clough R L An ultrasensitive13 Bucholz B Accelerated degradation test on resorbable
polymers In Degradation Phenomena on Polymeric Bio- technique for testing the Arrhenius extrapolation assump-tion for thermally aged elastomers Polym Degrad Stabmaterials (Eds H Planck M Dauner and M Renardy)
1992 pp 67ndash76 (Springer-Verlag Berlin) 1995 49 403ndash41828 Vert M Li S and Garreau H New insights on the14 Chu C C The in-vitro degradation of poly(glycolic acid)-
suturesmdasheffect of pH J Biomed Mater Res 1981 15 degradation of bioresorbable polymeric devices based onlactic and glycolic acids Clin Mater 1992 10 3ndash8795ndash804
15 Cam D Hyon S-H and Ikada Y Degradation of high 29 Li S Garreau H and Vert M Structure-propertyrelationships in the case of the degradation of massivemolecular weight poly(L-lactide) in alkaline medium
Biomaterials 1995 16 833ndash843 poly(a-hydroxy acids) in aqueous media Part 3 influenceof the morphology of poly(L-lactic acid) J Mater Sci16 Cha Y and Pitt C G The acceleration of degradation-
controlled drug delivery from polyester microspheres Mater Med 1990 1 198ndash20630 Pistner H Bendix D R Muhling J and Reuther JJ Control Release 1989 8 259ndash265
17 Agrawal C M Kennedy M E and Micallef D M Poly(L-lactide) a long-term degradation study in vivoPart III Analytical characterization Biomaterials 1993The effects of ultrasound irradiation on a biodegradable
50ndash50 per cent copolymer of polylactic and polyglycolic 14 291ndash29831 Von Recum H A Cleek R L Eskin S G andacids J Biomed Mater Res 1994 28 851ndash859
18 Gan Z Liang Q Zhang J and Jing X Enzymatic Mikos A G Degradation of polydispersed poly(L-lacticacid) to modulate lactic acid release Biomaterials 1995degradation of poly(e-caprolactone) film in phosphate
buffer solution containing lipases Polym Degrad Stab 16 441ndash44732 Li S and McCarthy S Further investigations on the1997 56 209ndash213
19 Weir N A Buchanan F J Orr J F Farrar D F and hydrolytic degradation of poly (DL-lactide) Biomaterials1999 20 35ndash44Boyd A Processing annealing and sterilisation of poly-L-
lactide Biomaterials 2004 25 3939ndash3949 33 Li S M Garreau H and Vert M Structure-propertyrelationships in the case of the degradation of massive20 Weir N A Buchanan F J Orr J F and Dickson G R
Degradation of poly-L-lactide Part 1mdashin vitro and in vivo aliphatic poly-(a-hydroxy acids) in aqueous media Part 1poly(DL-lactic acid) J Mater Sci Mater Med 1990physiological temperature degradation Proc Instn Mech
Engrs Part H J Engineering in Medicine (article in press) 1 123ndash13034 Siemann U The influence of water on the glass transition21 Li S Hydrolytic degradation characteristics of aliphatic
polyesters derived from lactic and glycolic acids J Biomed of poly(dl-lactic acid) Thermochimica Acta 1985 85513ndash516Mater Res (Appl Biomater) 1999 48 342ndash353
H01204 copy IMechE 2004Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
323DEGRADATION OF POLY-L-LACTIDE PART 2
Mass change On retrieval the tensile specimens were rate of the unstable ester linkages Anderson [23] reporteda statistical method for relating molecular weight todried immediately with a paper towel to remove any
surface moisture before being weighed using an electronic hydrolysis rate assuming that the extent of degradationwas not large the following kinetic relationship basedbalance (Mettler Toledo Fisher Scientific UK) to deter-
mine the percentage swelling of the polymer and water on the polymers Mn was reporteduptake The specimens were then dried in a vacuum oven
1Mnt=1Mn0+k1t (3)(Townson+Mercer Altrincham UK) at approximately
30 degC for 48 hours at a vacuum of 068 bar (20 in Hg)where Mn
t=Mn at time t Mn0=Mn at t=0 k1=rateand reweighed to obtain their mass at time t (m
t) The
constant and t=time If this theory holds true a linearoverall percentage mass change after drying was thenrelationship should exist between 1Mn versus time upcalculated from equation (1)until the point of mass loss
However a disadvantage of this statistical approachpercentage mass change=
mtminusm0m0
times100 per cent is that it does not account for the possibility of auto-catalysis accelerating the polymerrsquos degradation rate(1)Pitt and Gu [24] derived a relationship based on thekinetics of the ester hydrolysis reaction accounting forMolecular weight and thermal properties Followingautocatalysis by the generated carboxylic acid endmass change measurements the dried PLLA specimensgroups described by the rate equationwere reused for gel-permeation chromatography (GPC)
analysis to determine their weight and number averaged(E)dt=minusd(COOH)dt=minusk(COOH)(H2O)(E)
molecular weights (Mn) throughout degradation andalso for differential-scanning calorimetry (DSC) to deter- (4)mine their thermal properties and percentage crystallinity
where (COOH) (H2O) and (E) represent the con-centrations of carboxyl end groups water and estersMolecular weight The GPC analysis was conducted byrespectivelyRapra Technology Ltd (Shropshire UK) Samples were
On further analysis of equation (4) and assuming thatprepared by adding 10 ml of choloform solvent to 20 mgthe ester and water concentrations remain constant andof sample taken through a cross-section of the materialthe concentration of acid end groups is equal to 1MnA Plgel-mixed bed column with refractive index responseit can be shown thatdetector was used The GPC system was calibrated
with polystyrene and all results were expressed as theMnt=Mn
0eminusk2t (5)lsquopolystyrene equivalentrsquo molecular weights
If this relationship holds true a linear relationshipThermal properties The thermal properties of the driedshould exist between the ln Mn versus time up until theretrieved PLLA tensile specimens were analysed using apoint of mass lossPerkin Elmer DSC 6 (Beaconsfield Buckinghamshire
UK) testing machine over a temperature range of 40 degC ln Mnt=minusk
2t+ ln Mn
0(6)
to 200 degC at a heating rate of 10 degCmin providingmeasurements of glass transition temperature Tg melt- Furthermore the mechanical properties of polymersing point Tm and enthalpy of fusion DHmelt Jg The have also been shown to be related to their Mn throughDSC results were derived from this single heating cycle the Flory relationship [25] and [26 ]to provide a true indication of changes in the polymerrsquosthermal properties and morphology as a direct result of
s=s2minus
B
Mnt
(7)degradation The enthalpy of fusion DHmelt was thenused to calculate the polymerrsquos percentage crystallinities
where s=fracture strength s2=fracture strength atrelative to the enthalpy of fusion of a 100 per cent
infinite molecular weight and B=constant This relation-crystalline sample of PLLA reported to be 93 Jg [22]ship implies that a significant loss of molecular weight
percentage crystallinity=(DHmelt 93)times100 per cent can occur before any significant loss in mechanical(2) properties is observed
232 The Arrhenius relationship23 TheoryThe Arrhenius relationship (equation (8)) represents a231 Modelling bioresorbable polymer degradationcommon method used for extrapolating results from
Since Mn is directly related to the scission of the polymer higher temperatures back to service temperatures [27]chains a number of relationships have been derivedrelating the changes in Mn with time to the hydrolysis k=AeminusEaRT (8)
H01204 copy IMechE 2004 Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
324 N A WEIR F J BUCHANAN J F ORR D F FARRAR AND G R DICKSON
where k=rate constant A=constant Ea=activation were so brittle they simply disintegrated on handling Asimilar pattern was also observed at 50 degC with the whiteenergy Jmol R=universal gas constant 8314 J molminus1
Kminus1 and T=temperature in Kelvins K If the relation- areas developing at 50 days and increasing with timeship holds true a linear relationship should exist betweenthe ln k versus 1T
32 Molecular weight versus time
ln k=minusAEa
R BA 1TB+ ln A (9) As expected the molecular weight of the PLLAtensile specimens at 50 degC and 70 degC decreased with time(Table 2) After 115 days at 50 degC the tensile specimensrsquoMn had decreased by approximately 93 per cent At70 degC a decrease of approximately 95 per cent in 23 days
3 RESULTS was observed in comparison to an 82 per cent decreaseafter 44 weeks at 37 degC the final time point analysed
31 Visual examination Additionally the profiles of the molecular weight-losscurves (Fig 2) most notably at 70 degC are characterizedInitially at 0 weeks the annealed PLLA tensile specimensby initial rapid loss in molecular weight up untilwere opaque and off-white in colour (Fig 1) After fiveapproximately five days at 70 degC followed by a perioddays at 70 degC small areas of the specimens became morewhere the molecular weight loss slowed considerablyintensely white and as degradation time increased more
white areas became visible At 23 days the specimens
Fig 2 Comparison between Mw and Mn at 50 degC and 70 degCFig 1 PLLA specimens degraded at 70 degC
Table 2 Molecular weight versus time summary at 37 degC 50 degC and 70 degC
Temperature Molecular weight
Days at 37 degC 0 28 70 140 182 224 266 308
37 degC Mw 424 000 339 000 309 000 199 000 199 000 159 000 133 500 74 900Mn 158 500 143 000 120 000 72 500 93 850 65 800 53 050 22 500
Days at 50 degC 0 1 5 11 21 32 50 72 88 115
50 degC Mw 409 500 327 500 332 500 238 500 248 500 175 500 128 600 73 250 47 500 18 650Mn 166 000 132 000 129 000 104 500 113 000 77 650 62 650 33 150 20 600 11 700
Days at 70 degC 0 1 3 5 9 14 18 21 23
70 degC Mw 409 500 276 500 127 500 86 200 52 550 56 950 25 000 19 350 11 350Mn 166 000 119 000 64 450 39 300 24 900 29 200 13 750 11 700 9 090
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325DEGRADATION OF POLY-L-LACTIDE PART 2
Table 3 Thermal properties and crystallinity of PLLA33 Mass change versus timesamples degraded at 50 degC
Before drying a similar pattern was observed at bothDegradation50 degC and 70 degC (Fig 3) Initially after one day increasestime days crystallinity Tm degC Tg onset degCof approximately 05 per cent and 07 per cent were
observed at 50 degC and 70 degC respectively Swelling then 0 470 1817 6741 457 1818 663gradually increased to approximately 1 per cent after 72
11 471 1818 651days at 50 degC and 14 days at 70 degC This 1 per cent swell-21 434 1815 656
ing appeared to coincide with the onset of polymer mass 32 453 1817 66050 564 1816 643loss after drying with specimens at both 50 degC and 70 degC72 617 1792 663losing mass from this point onwards A maximum mass88 659 1746 610
loss of 4 per cent was observed at 50 degC after 115 days 115 665 1717 ndashand 76 per cent after 23 days at 70 degC The resultsof the mass-change analysis are in agreement with thegeneral sequence of aliphatic polyester degradation which
Table 4 Thermal properties and crystallinity of PLLAsuggests a time-lag before any mass loss is observed [3]samples degraded at 70 degCand have a very similar profile to the previous control
study that investigated the in vitro degradation of PLLADegradation
tensile specimens at 37 degC [20] time days crystallinity Tm degC Tg onset degC
0 575 1805 6581 599 1809 639
34 DSC analysis versus time 3 575 1805 6405 771 1788 637
At both 50 degC and 70 degC a general trend of increasing 9 857 1745 59714 762 1767 603crystallinity and decreasing Tg onset temperature was18 889 1723 578observed with increasing degradation time (Tables 321 851 1719 577
and 4) reflecting the findings of a similar study conducted 23 922 1718 ndashat 37 degC in vitro [20] Additionally a significant decreasein the specimensrsquo melting point Tm was observed after72 days at 50 degC and five days at 70 degC
The DSC thermograms for the specimens degraded at At 0 weeks (Fig 4(a)) a sharp peak commencingat approximately 66 degC was observed related to theboth 50 degC and 70 degC are shown in Fig 4 along with a
control specimen at 0 days degradation Again the pro- polymerrsquos Tg and indicating unfreezing of main chainsegmental motion as weak secondary bonds in thefiles of the DSC thermograms reflect those observed at
37 degC [20] albeit in an accelerated time frame amorphous regions are broken As the temperatureincreased further a small endothermic dip was observedjust before melting commenced followed by the mainmelting peak It is suggested that the dip before meltingwas caused by some crystallization of the polymerAlthough the polymer was annealed prior to degradationwith the aim of limiting crystallization throughout thestudy close to the polymerrsquos melting point the chainmobility would have increased allowing some of theamorphous segments to order themselves into a morecrystalline structure
At 50 days at 50 degC and five days at 70 degC (Figs 4(b)and (e)) as degradation increased presumably in theamorphous regions the initial dip before melting observedat 0 weeks had disappeared with less amorphous regionsremaining capable of crystallization with a new peakforming in its place after 50 days at 50 degC (Fig 4(b))It is suggested that this new peak represents the melt-ing of new crystallites formed by the crystallization ofthe internal degradation by-products As degradationproceeds further it is speculated that the newly formedcrystallitersquos size also increases moving it to higher tem-peratures while the main melting peak is shifting to lower
Fig 3 Percentage mass change at 50 degC and 70 degC temperatures This results in the two peaks eventually
H01204 copy IMechE 2004 Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
326 N A WEIR F J BUCHANAN J F ORR D F FARRAR AND G R DICKSON
Fig 4 Comparison between DSC thermograms for samples degraded at 50 degC and 70 degC
Table 6 Change in the tensile properties of PLLA throughoutmerging with the smaller newly formed peak appearingdegradation at 70 degCas a shoulder on the larger peak before finally only one
sharp melting peak becomes visible (Figs 4(c) and (f))Degradation Youngrsquos Tensile Extension attime days modulus (MPa) strength (MPa) break (mm)
0 6684 643 16235 Mechanical strength versus time1 6056 473 1173 5362 403 108The tensile strength of the specimens reduced to zero5 3167 78 102
after approximately 50 days at 50 degC and 7 days at 70 degC 7 1029 23 056(Tables 5 and 6) A gradual decrease in Youngrsquos moduluswas also observed with the load versus extension curves
displaying a transition from a more ductile to brittleTable 5 Change in the tensile properties of PLLA throughout failure mode after five days at 50 degC and one day at
degradation at 50 degC 70 degC
Degradation Youngrsquos Tensile Extension attime days modulus (MPa) strength (MPa) break (mm)
4 MODELLING DEGRADATION0 6684 643 1621 6250 614 181
41 Molecular weight models3 6244 613 1595 6081 494 129
Molecular weight loss Analysing the data presented in11 5809 511 13521 4783 278 083 Table 2 in conjunction with equations (3) and (6) the32 3571 179 156 rate constants k1 for the uncatalysed model and k2 50 ndash 29 109
for the autocatalysed model were determined by linear
H01204 copy IMechE 2004Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
327DEGRADATION OF POLY-L-LACTIDE PART 2
regression from plots of (1Mntminus1Mn0) versus time for Dependence of mass loss Tm and Tg on molecular
weight Analysing the percentage mass loss results afterthe uncatalysed model and ln(MntMn0) versus time
for the autocatalysed model (Fig 5) at 37 degC 50 degC and drying in conjunction with the molecular-weight-lossresults it is apparent that a relationship exists between70 degC The analysis was conducted up until the point of
mass loss at each of the temperatures investigated It is the polymerrsquos Mn and percentage mass loss (Fig 7)with mass loss only observed after the polymerrsquos Mn hadapparent from Table 7 that as the degradation tem-
perature increased the correlation coefficient (R2 value) reduced to less than approximately 20 000 A similartrend was also observed when considering the reductionalso generally increased
Considering the rate constants k2 for the auto- in Tm with Mn (Fig 8) Only once the polymerrsquos Mnhad decreased to approximately 50 000 were significantcatalysed model further it is apparent that as the tem-
perature increased the rate of molecular weight loss decreases in the polymerrsquos melting temperature observedThis suggests that once the polymerrsquos molecular weightappeared to increase exponentially with an approximate
four-fold increase observed at 50 degC compared to a forty- had diminished sufficiently and presumably with theamorphous regions exhausted the crystalline regionsfold increase at 70 degC relative to the degradation rate at
37 degC Applying the Arrhenius relationship (equation (9)) were then predominantly attacked A similar dependenceof Tg on Mn was also observed (Fig 9)it is obvious that a linear relationship does exist (Fig 6)
with a high linear regression correlation coefficient of0995 The activation energy (Ea) for the loss of Mn wascalculated from Fig 6 as 1005 kJmol over the 37 degC to50 degC to 70 degC temperature range For the uncatalysedmodel an Ea of 1027 kJmol was calculated
Fig 7 Percentage change after drying versus Mn
Fig 5 Autocatalysed degradation model
Table 7 Uncatalysed and autocatalysed hydrolysisrates
Model Uncatalysed Autocatalysed
Temperature k1 R2 k2 R2
37 degC 9times10minus8 063 00052 08550 degC 3times10minus7 090 00196 096 Fig 8 Relationship between melting temperature and70 degC 4times10minus6 099 02155 095 molecular weight
Fig 9 Relationship between glass transition temperature andFig 6 Arrhenius plot of ln k2 versus 1T molecular weight
H01204 copy IMechE 2004 Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
328 N A WEIR F J BUCHANAN J F ORR D F FARRAR AND G R DICKSON
Mechanical strength and molecular weight An effort the results of previous researchers [28ndash30] investigatingsimilarly semicrystalline PLLA at 37 degC in vitro andwas also made to model the mechanical properties
of the tensile specimens investigated in this study in vivo They observed that as degradation increased thedistributions of the GPC curves became bimodal andagainst molecular weight using the Flory relationship
(equation (7)) However it is obvious from Fig 10 that even multimodal in nature as a result of the selectivedegradation of the amorphous regionsa relationship similar to the one predicted by Flory is not
derived from the results of the present study However The molecular weight models (Figs 7ndash9) also showthe dependence of the degradation of PLLA on itson further analysis it became apparent that an almost
linear relationship existed for the loss of tensile strength molecular weight with mass loss melting temperatureand glass transition displaying a strong dependence onwith time most notably at 50 degC and 70 degCmolecular weight An obvious benefit of these models isthe possibility of being able to predict the initial molecularweight of PLLA required to produce devices with vary-5 DISCUSSIONing resorption times However the failure of the Florymodel to predict mechanical strength is perhaps not51 Degradation mechanismssurprising considering it only accounts for molecular
The results presented for the accelerated degradationweight loss and not changes in morphology such as
of PLLA at increased temperatures suggest that atthe increases in crystallinity observed for the PLLA
50 degC and 70 degC degradation proceeded by the sameinvestigated in this study
mechanism and followed the general sequence of bulkdegradation reported previously for semicrystalline
Significance of autocatalysis at increased temperaturesaliphatic polyesters This suggests degradation occurs inThe degradation of aliphatic polyesters has been showntwo distinct stages [21] and is characterized by molecularto occur more rapidly at the centre than at the surfaceweight loss being observed first before loss of mechanical[21] due to the hydrolytic cleavage of the ester bondsstrength and before any physical mass loss is observedforming new acidic carboxyl end groups resulting in[3] Evidence from the results of the present study sup-a higher internal acidity and a differentiation betweenporting this two-stage bulk degradation mechanism arethe surface and interior degradation rates The resultsdiscussed belowof the present study modelling the loss of Mn to boththe uncatalysed and autocatalysed degradation modelsRelationship between molecular weight loss and degradationshowed no significant difference between activationThe general concensus that the degradation of semi-energies calculated for the two models Pohjonen andcrystalline aliphatic polyesters like the PLLA investi-Tormala [11] found a similar value for activation energygated in this study proceeds via random bulk hydrolysisof self-reinforced PLLA of 1014 kJmol using the auto-in two distinct stages is supported by considering thecatalytic model Previous research conducted by Li andprofile of the molecular-weight-loss curves of Fig 2McCarthy [32] on the in vitro degradation of poly-The curves show a faster initial loss of molecular weight(DL-lactide) at 60 degC showed that a hollow structureup until approximately five days at 70 degC before thewas not obtained during degradation in contrast torate of molecular weight loss slows considerably Thisdegradation at 37 degC in vitro where a hollow structuredegradation behaviour is typical where the rate of chainwas observed after 12 weeks due to autocatalysis [33]scission events is relatively constant with time TheLi and McCarthy [32] attributed this to the rapidmolecular weight is therefore inversely proportional todegradation at 60 degC and increase in the diffusiontime However interestingly the GPC curves for both thecoefficient of water and water-soluble oligomers abovetensile specimens at 50 degC and 70 degC remained essentiallythe polymerrsquos Tg They concluded that although hetero-monomodal throughout degradation contradictory togeneous degradation was still detected at 60 degC it wasmuch less significant and the relative importance ofinternal autocatalysis diminished as temperature increasedThis does not appear to be the case in the current studywith no observable difference between surface and coredegradation rate
52 Suitability of increased temperature for acceleratingthe degradation of PLLA
The results presented for the accelerated degradation ofPLLA at 50 degC and 70 degC indicate that the degradationFig 10 Relationship between tensile strength and molecular
weight mechanisms were very similar to the in vitro and
H01204 copy IMechE 2004Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
329DEGRADATION OF POLY-L-LACTIDE PART 2
in vivo degradation mechanism reported at 37 degC [20] However further work is needed to assess the validityof this hypothesis with only semicrystalline PLLA withThis suggests that increasing the temperature of the
degradation medium is a suitable method for accelerating identical initial crystallinities investigated in this presentstudythe degradation of PLLA relative to its physiological
degradation rate However in previous increased-temperature studies caution has often been noted whenusing test results performed at temperatures greater than 6 CONCLUSIONSthe polymerrsquos Tg for predicting degradation behaviourbelow the polymerrsquos Tg [11] and [12] Above the poly- This study suggests that increasing the temperature ofmerrsquos Tg it would be expected that with main chain the degradation medium represents a powerful methodsegmental motion unfrozen and the weak van der Waals for accelerating the degradation of PLLA with theforces holding the amorphous regions in place broken degradation mechanisms at 37 degC 50 degC and 70 degCwater molecules would be able to access the amorphous proving to be very similar However concerns stillregions more easily initiating hydrolytic chain scission remain over the validity of testing above the Tg of PLLAresulting in a further increased degradation rate The when predicting results at service temperatures below itscompression-moulded PLLA tensile specimens investi- Tg and the significance of the autocatalytic phenomenongated in this study had a Tg (dry) of approximately 66 degC as the temperature is increased relative to that at 37 degC(Tables 3 and 4) two temperatures were investigatedbelow the polymerrsquos Tg (37 degC and 50 degC) and one abovethe polymerrsquos Tg (70 degC) The high linear correlation
ACKNOWLEDGEMENTScoefficient (R2=0995) achieved for the Arrhenius plotmodelling the loss of molecular weight (Fig 6) suggests
The authors would like to thank Boehringer Ingelheimthat the degradation kinetics were not greatly affected(Ingelheim Germany) for supplying the PLLA Smithabove Tg Ideally to fully assess the implications testingamp Nephew Group Research Centre (York UK) forabove the polymerrsquos Tg has on the degradation rate atheir assistance with processing Griffith Microsciencerange of temperatures would need to be investigated(Derbyshire UK) for the ethylene oxide sterilizationabove and below Tg However this is not as straight-and Rapra Technology Limited (Shropshire UK) for theforward as it might appear When determining themolecular-weight characterization Finally the EPSRCpolymerrsquos Tg it must be realized that a small amount of(Swindon UK) for financial assistancewater can have a marked plasticizing effect causing a
reduction in the polymerrsquos Tg [34] Combine this withthe reduction in Tg due to the loss of molecular weight(Fig 9) and it is evident that defining the polymerrsquos Tg REFERENCESand determining the test temperatures that remain aboveand below the polymerrsquos Tg is an ever changing scenario 1 Li S and Vert M Biodegradation of aliphatic polyesters
In Degradable Polymers Principles amp Applications (EdsTraditionally as in this study and previous studiesG Scott and D Gilead) 1995 pp 43ndash87 (Chapman amp Hallinvestigating the degradation of bioresorbable polymersLondon)for convenience Tg is commonly determined by DSC on
2 Barber F A Resorbable materials for arthroscopicretrieved dried specimens however ideally for accuratefixation a product guide Orthopedic Special Edn 2002Tg measurements representative of the polymers con-8 29ndash37
dition in service test regimes need to be developed that 3 Middleton J C and Tipton A J Synthetic biodegradablecan accurately monitor the polymers Tg while the polymers as orthopedic devices Biomaterials 2000 21specimens remain lsquowetrsquo 2335ndash2346
Although concerns still remain about the validity of 4 Hayashi T Biodegradable polymers for biomedical usestesting above the Tg of PLLA when predicting behaviour Prog Polym Sci 1994 19 663ndash702
5 Implants for surgerymdashcopolymers and blends based onbelow its Tg it is hypothesized from the results of thepolylactidemdashIn vitro degradation testing ISO 158141999present study and from those of Pohjonen and Tormala
6 Duek E A R Zavaglia C A C and Belangero W D[11 ] and Agrawal et al [12 ] that the polymerrsquosIn vitro of poly( lactic acid) pin degradation Polymer 1999morphology may also have a significant role to play in40 6456ndash6473determining the validity of any relationships derived It is
7 Matsusue Y Yamamuro T Oka M Shikinami Y et alspeculated that for semicrystalline polymers results fromIn vitro and in vivo studies on bioabsorbable ultra-high-
tests performed above their Tg may be more valid for strength poly(L-lactide) rods J Biomed Mater Res 1992predicting degradation below their Tg due to their greater 26 1553ndash1567volume constrained in tightly packed less-accessible 8 Kellomaki M Paasimaa S and Tormala P Pliable poly-crystalline domains in comparison to polymers that are lactide plates for guided bone regeneration manufacturingintrinsically amorphous or likely to crystallize through and in vitro Proc Instn Mech Engrs Part H J Engineering
in Medicine 2000 214 615ndash629annealing as a direct result of the increased temperature
H01204 copy IMechE 2004 Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
330 N A WEIR F J BUCHANAN J F ORR D F FARRAR AND G R DICKSON
9 Bergsma J E de Bruijn W C Rozema F R 22 Fischer E W Sterzel H J and Wegner G Investigationof the structure of solution grown crystals of lactideBos R R M and Boering G Late degradation tissue
response to poly(L-lactide) bone plates and screws copolymers by means of chemical reactions Kolloid-Z uZ Polymere 1973 251 980ndash990Biomaterials 1995 16 25ndash31
10 Miller N D and Williams D F The in vivo and in vitro 23 Anderson J M Perspectives on the in vivo responsesof biodegradable polymers In Biomedical Applications ofdegradation of poly(glycolic acid) suture material as a
function of applied strain Biomaterials 1984 5 365ndash368 Synthetic Biodegradable Polymers (Ed J O Hollinger)1995 pp 223ndash233 (CRC Press Boca Raton FL USA)11 Pohjonen T and Tormala P Hydrolytic degradation of
ultra-high-strength self-reinforced poly-L-lactide A tem- 24 Pitt C G and Gu Z-W Modification of the rates of chaincleavage of poly(e-caprolactone) and related polyesters inperature dependence study In Biodegradable Implants in
Fracture Fixation (Eds L K Hung and P C Leung) 1994 the solid state J Control Release 1987 4 283ndash29225 Ward I M Mechanical Properties of Solid Polymerspp 75ndash88 (Department of Orthopaedics and Traumatology
Chinese University of Hong Kong and World Scientific) 1st edn 1971 p 335 ( Wiley-Interscience Chichester)26 Farrar D F and Gillson R K Hydrolytic degradation of12 Agrawal C M Huang D Schmitz J P and
Athanasiou K A Elevated temperature degradation of a polyglyconate B the relationship between degradationtime strength and molecular weight Biomaterials 20025050 copolymer of PLA-PGA Tissue Eng 1997 3(4)
345ndash352 23 3905ndash391227 Wise J Gillen K T and Clough R L An ultrasensitive13 Bucholz B Accelerated degradation test on resorbable
polymers In Degradation Phenomena on Polymeric Bio- technique for testing the Arrhenius extrapolation assump-tion for thermally aged elastomers Polym Degrad Stabmaterials (Eds H Planck M Dauner and M Renardy)
1992 pp 67ndash76 (Springer-Verlag Berlin) 1995 49 403ndash41828 Vert M Li S and Garreau H New insights on the14 Chu C C The in-vitro degradation of poly(glycolic acid)-
suturesmdasheffect of pH J Biomed Mater Res 1981 15 degradation of bioresorbable polymeric devices based onlactic and glycolic acids Clin Mater 1992 10 3ndash8795ndash804
15 Cam D Hyon S-H and Ikada Y Degradation of high 29 Li S Garreau H and Vert M Structure-propertyrelationships in the case of the degradation of massivemolecular weight poly(L-lactide) in alkaline medium
Biomaterials 1995 16 833ndash843 poly(a-hydroxy acids) in aqueous media Part 3 influenceof the morphology of poly(L-lactic acid) J Mater Sci16 Cha Y and Pitt C G The acceleration of degradation-
controlled drug delivery from polyester microspheres Mater Med 1990 1 198ndash20630 Pistner H Bendix D R Muhling J and Reuther JJ Control Release 1989 8 259ndash265
17 Agrawal C M Kennedy M E and Micallef D M Poly(L-lactide) a long-term degradation study in vivoPart III Analytical characterization Biomaterials 1993The effects of ultrasound irradiation on a biodegradable
50ndash50 per cent copolymer of polylactic and polyglycolic 14 291ndash29831 Von Recum H A Cleek R L Eskin S G andacids J Biomed Mater Res 1994 28 851ndash859
18 Gan Z Liang Q Zhang J and Jing X Enzymatic Mikos A G Degradation of polydispersed poly(L-lacticacid) to modulate lactic acid release Biomaterials 1995degradation of poly(e-caprolactone) film in phosphate
buffer solution containing lipases Polym Degrad Stab 16 441ndash44732 Li S and McCarthy S Further investigations on the1997 56 209ndash213
19 Weir N A Buchanan F J Orr J F Farrar D F and hydrolytic degradation of poly (DL-lactide) Biomaterials1999 20 35ndash44Boyd A Processing annealing and sterilisation of poly-L-
lactide Biomaterials 2004 25 3939ndash3949 33 Li S M Garreau H and Vert M Structure-propertyrelationships in the case of the degradation of massive20 Weir N A Buchanan F J Orr J F and Dickson G R
Degradation of poly-L-lactide Part 1mdashin vitro and in vivo aliphatic poly-(a-hydroxy acids) in aqueous media Part 1poly(DL-lactic acid) J Mater Sci Mater Med 1990physiological temperature degradation Proc Instn Mech
Engrs Part H J Engineering in Medicine (article in press) 1 123ndash13034 Siemann U The influence of water on the glass transition21 Li S Hydrolytic degradation characteristics of aliphatic
polyesters derived from lactic and glycolic acids J Biomed of poly(dl-lactic acid) Thermochimica Acta 1985 85513ndash516Mater Res (Appl Biomater) 1999 48 342ndash353
H01204 copy IMechE 2004Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
324 N A WEIR F J BUCHANAN J F ORR D F FARRAR AND G R DICKSON
where k=rate constant A=constant Ea=activation were so brittle they simply disintegrated on handling Asimilar pattern was also observed at 50 degC with the whiteenergy Jmol R=universal gas constant 8314 J molminus1
Kminus1 and T=temperature in Kelvins K If the relation- areas developing at 50 days and increasing with timeship holds true a linear relationship should exist betweenthe ln k versus 1T
32 Molecular weight versus time
ln k=minusAEa
R BA 1TB+ ln A (9) As expected the molecular weight of the PLLAtensile specimens at 50 degC and 70 degC decreased with time(Table 2) After 115 days at 50 degC the tensile specimensrsquoMn had decreased by approximately 93 per cent At70 degC a decrease of approximately 95 per cent in 23 days
3 RESULTS was observed in comparison to an 82 per cent decreaseafter 44 weeks at 37 degC the final time point analysed
31 Visual examination Additionally the profiles of the molecular weight-losscurves (Fig 2) most notably at 70 degC are characterizedInitially at 0 weeks the annealed PLLA tensile specimensby initial rapid loss in molecular weight up untilwere opaque and off-white in colour (Fig 1) After fiveapproximately five days at 70 degC followed by a perioddays at 70 degC small areas of the specimens became morewhere the molecular weight loss slowed considerablyintensely white and as degradation time increased more
white areas became visible At 23 days the specimens
Fig 2 Comparison between Mw and Mn at 50 degC and 70 degCFig 1 PLLA specimens degraded at 70 degC
Table 2 Molecular weight versus time summary at 37 degC 50 degC and 70 degC
Temperature Molecular weight
Days at 37 degC 0 28 70 140 182 224 266 308
37 degC Mw 424 000 339 000 309 000 199 000 199 000 159 000 133 500 74 900Mn 158 500 143 000 120 000 72 500 93 850 65 800 53 050 22 500
Days at 50 degC 0 1 5 11 21 32 50 72 88 115
50 degC Mw 409 500 327 500 332 500 238 500 248 500 175 500 128 600 73 250 47 500 18 650Mn 166 000 132 000 129 000 104 500 113 000 77 650 62 650 33 150 20 600 11 700
Days at 70 degC 0 1 3 5 9 14 18 21 23
70 degC Mw 409 500 276 500 127 500 86 200 52 550 56 950 25 000 19 350 11 350Mn 166 000 119 000 64 450 39 300 24 900 29 200 13 750 11 700 9 090
H01204 copy IMechE 2004Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
325DEGRADATION OF POLY-L-LACTIDE PART 2
Table 3 Thermal properties and crystallinity of PLLA33 Mass change versus timesamples degraded at 50 degC
Before drying a similar pattern was observed at bothDegradation50 degC and 70 degC (Fig 3) Initially after one day increasestime days crystallinity Tm degC Tg onset degCof approximately 05 per cent and 07 per cent were
observed at 50 degC and 70 degC respectively Swelling then 0 470 1817 6741 457 1818 663gradually increased to approximately 1 per cent after 72
11 471 1818 651days at 50 degC and 14 days at 70 degC This 1 per cent swell-21 434 1815 656
ing appeared to coincide with the onset of polymer mass 32 453 1817 66050 564 1816 643loss after drying with specimens at both 50 degC and 70 degC72 617 1792 663losing mass from this point onwards A maximum mass88 659 1746 610
loss of 4 per cent was observed at 50 degC after 115 days 115 665 1717 ndashand 76 per cent after 23 days at 70 degC The resultsof the mass-change analysis are in agreement with thegeneral sequence of aliphatic polyester degradation which
Table 4 Thermal properties and crystallinity of PLLAsuggests a time-lag before any mass loss is observed [3]samples degraded at 70 degCand have a very similar profile to the previous control
study that investigated the in vitro degradation of PLLADegradation
tensile specimens at 37 degC [20] time days crystallinity Tm degC Tg onset degC
0 575 1805 6581 599 1809 639
34 DSC analysis versus time 3 575 1805 6405 771 1788 637
At both 50 degC and 70 degC a general trend of increasing 9 857 1745 59714 762 1767 603crystallinity and decreasing Tg onset temperature was18 889 1723 578observed with increasing degradation time (Tables 321 851 1719 577
and 4) reflecting the findings of a similar study conducted 23 922 1718 ndashat 37 degC in vitro [20] Additionally a significant decreasein the specimensrsquo melting point Tm was observed after72 days at 50 degC and five days at 70 degC
The DSC thermograms for the specimens degraded at At 0 weeks (Fig 4(a)) a sharp peak commencingat approximately 66 degC was observed related to theboth 50 degC and 70 degC are shown in Fig 4 along with a
control specimen at 0 days degradation Again the pro- polymerrsquos Tg and indicating unfreezing of main chainsegmental motion as weak secondary bonds in thefiles of the DSC thermograms reflect those observed at
37 degC [20] albeit in an accelerated time frame amorphous regions are broken As the temperatureincreased further a small endothermic dip was observedjust before melting commenced followed by the mainmelting peak It is suggested that the dip before meltingwas caused by some crystallization of the polymerAlthough the polymer was annealed prior to degradationwith the aim of limiting crystallization throughout thestudy close to the polymerrsquos melting point the chainmobility would have increased allowing some of theamorphous segments to order themselves into a morecrystalline structure
At 50 days at 50 degC and five days at 70 degC (Figs 4(b)and (e)) as degradation increased presumably in theamorphous regions the initial dip before melting observedat 0 weeks had disappeared with less amorphous regionsremaining capable of crystallization with a new peakforming in its place after 50 days at 50 degC (Fig 4(b))It is suggested that this new peak represents the melt-ing of new crystallites formed by the crystallization ofthe internal degradation by-products As degradationproceeds further it is speculated that the newly formedcrystallitersquos size also increases moving it to higher tem-peratures while the main melting peak is shifting to lower
Fig 3 Percentage mass change at 50 degC and 70 degC temperatures This results in the two peaks eventually
H01204 copy IMechE 2004 Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
326 N A WEIR F J BUCHANAN J F ORR D F FARRAR AND G R DICKSON
Fig 4 Comparison between DSC thermograms for samples degraded at 50 degC and 70 degC
Table 6 Change in the tensile properties of PLLA throughoutmerging with the smaller newly formed peak appearingdegradation at 70 degCas a shoulder on the larger peak before finally only one
sharp melting peak becomes visible (Figs 4(c) and (f))Degradation Youngrsquos Tensile Extension attime days modulus (MPa) strength (MPa) break (mm)
0 6684 643 16235 Mechanical strength versus time1 6056 473 1173 5362 403 108The tensile strength of the specimens reduced to zero5 3167 78 102
after approximately 50 days at 50 degC and 7 days at 70 degC 7 1029 23 056(Tables 5 and 6) A gradual decrease in Youngrsquos moduluswas also observed with the load versus extension curves
displaying a transition from a more ductile to brittleTable 5 Change in the tensile properties of PLLA throughout failure mode after five days at 50 degC and one day at
degradation at 50 degC 70 degC
Degradation Youngrsquos Tensile Extension attime days modulus (MPa) strength (MPa) break (mm)
4 MODELLING DEGRADATION0 6684 643 1621 6250 614 181
41 Molecular weight models3 6244 613 1595 6081 494 129
Molecular weight loss Analysing the data presented in11 5809 511 13521 4783 278 083 Table 2 in conjunction with equations (3) and (6) the32 3571 179 156 rate constants k1 for the uncatalysed model and k2 50 ndash 29 109
for the autocatalysed model were determined by linear
H01204 copy IMechE 2004Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
327DEGRADATION OF POLY-L-LACTIDE PART 2
regression from plots of (1Mntminus1Mn0) versus time for Dependence of mass loss Tm and Tg on molecular
weight Analysing the percentage mass loss results afterthe uncatalysed model and ln(MntMn0) versus time
for the autocatalysed model (Fig 5) at 37 degC 50 degC and drying in conjunction with the molecular-weight-lossresults it is apparent that a relationship exists between70 degC The analysis was conducted up until the point of
mass loss at each of the temperatures investigated It is the polymerrsquos Mn and percentage mass loss (Fig 7)with mass loss only observed after the polymerrsquos Mn hadapparent from Table 7 that as the degradation tem-
perature increased the correlation coefficient (R2 value) reduced to less than approximately 20 000 A similartrend was also observed when considering the reductionalso generally increased
Considering the rate constants k2 for the auto- in Tm with Mn (Fig 8) Only once the polymerrsquos Mnhad decreased to approximately 50 000 were significantcatalysed model further it is apparent that as the tem-
perature increased the rate of molecular weight loss decreases in the polymerrsquos melting temperature observedThis suggests that once the polymerrsquos molecular weightappeared to increase exponentially with an approximate
four-fold increase observed at 50 degC compared to a forty- had diminished sufficiently and presumably with theamorphous regions exhausted the crystalline regionsfold increase at 70 degC relative to the degradation rate at
37 degC Applying the Arrhenius relationship (equation (9)) were then predominantly attacked A similar dependenceof Tg on Mn was also observed (Fig 9)it is obvious that a linear relationship does exist (Fig 6)
with a high linear regression correlation coefficient of0995 The activation energy (Ea) for the loss of Mn wascalculated from Fig 6 as 1005 kJmol over the 37 degC to50 degC to 70 degC temperature range For the uncatalysedmodel an Ea of 1027 kJmol was calculated
Fig 7 Percentage change after drying versus Mn
Fig 5 Autocatalysed degradation model
Table 7 Uncatalysed and autocatalysed hydrolysisrates
Model Uncatalysed Autocatalysed
Temperature k1 R2 k2 R2
37 degC 9times10minus8 063 00052 08550 degC 3times10minus7 090 00196 096 Fig 8 Relationship between melting temperature and70 degC 4times10minus6 099 02155 095 molecular weight
Fig 9 Relationship between glass transition temperature andFig 6 Arrhenius plot of ln k2 versus 1T molecular weight
H01204 copy IMechE 2004 Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
328 N A WEIR F J BUCHANAN J F ORR D F FARRAR AND G R DICKSON
Mechanical strength and molecular weight An effort the results of previous researchers [28ndash30] investigatingsimilarly semicrystalline PLLA at 37 degC in vitro andwas also made to model the mechanical properties
of the tensile specimens investigated in this study in vivo They observed that as degradation increased thedistributions of the GPC curves became bimodal andagainst molecular weight using the Flory relationship
(equation (7)) However it is obvious from Fig 10 that even multimodal in nature as a result of the selectivedegradation of the amorphous regionsa relationship similar to the one predicted by Flory is not
derived from the results of the present study However The molecular weight models (Figs 7ndash9) also showthe dependence of the degradation of PLLA on itson further analysis it became apparent that an almost
linear relationship existed for the loss of tensile strength molecular weight with mass loss melting temperatureand glass transition displaying a strong dependence onwith time most notably at 50 degC and 70 degCmolecular weight An obvious benefit of these models isthe possibility of being able to predict the initial molecularweight of PLLA required to produce devices with vary-5 DISCUSSIONing resorption times However the failure of the Florymodel to predict mechanical strength is perhaps not51 Degradation mechanismssurprising considering it only accounts for molecular
The results presented for the accelerated degradationweight loss and not changes in morphology such as
of PLLA at increased temperatures suggest that atthe increases in crystallinity observed for the PLLA
50 degC and 70 degC degradation proceeded by the sameinvestigated in this study
mechanism and followed the general sequence of bulkdegradation reported previously for semicrystalline
Significance of autocatalysis at increased temperaturesaliphatic polyesters This suggests degradation occurs inThe degradation of aliphatic polyesters has been showntwo distinct stages [21] and is characterized by molecularto occur more rapidly at the centre than at the surfaceweight loss being observed first before loss of mechanical[21] due to the hydrolytic cleavage of the ester bondsstrength and before any physical mass loss is observedforming new acidic carboxyl end groups resulting in[3] Evidence from the results of the present study sup-a higher internal acidity and a differentiation betweenporting this two-stage bulk degradation mechanism arethe surface and interior degradation rates The resultsdiscussed belowof the present study modelling the loss of Mn to boththe uncatalysed and autocatalysed degradation modelsRelationship between molecular weight loss and degradationshowed no significant difference between activationThe general concensus that the degradation of semi-energies calculated for the two models Pohjonen andcrystalline aliphatic polyesters like the PLLA investi-Tormala [11] found a similar value for activation energygated in this study proceeds via random bulk hydrolysisof self-reinforced PLLA of 1014 kJmol using the auto-in two distinct stages is supported by considering thecatalytic model Previous research conducted by Li andprofile of the molecular-weight-loss curves of Fig 2McCarthy [32] on the in vitro degradation of poly-The curves show a faster initial loss of molecular weight(DL-lactide) at 60 degC showed that a hollow structureup until approximately five days at 70 degC before thewas not obtained during degradation in contrast torate of molecular weight loss slows considerably Thisdegradation at 37 degC in vitro where a hollow structuredegradation behaviour is typical where the rate of chainwas observed after 12 weeks due to autocatalysis [33]scission events is relatively constant with time TheLi and McCarthy [32] attributed this to the rapidmolecular weight is therefore inversely proportional todegradation at 60 degC and increase in the diffusiontime However interestingly the GPC curves for both thecoefficient of water and water-soluble oligomers abovetensile specimens at 50 degC and 70 degC remained essentiallythe polymerrsquos Tg They concluded that although hetero-monomodal throughout degradation contradictory togeneous degradation was still detected at 60 degC it wasmuch less significant and the relative importance ofinternal autocatalysis diminished as temperature increasedThis does not appear to be the case in the current studywith no observable difference between surface and coredegradation rate
52 Suitability of increased temperature for acceleratingthe degradation of PLLA
The results presented for the accelerated degradation ofPLLA at 50 degC and 70 degC indicate that the degradationFig 10 Relationship between tensile strength and molecular
weight mechanisms were very similar to the in vitro and
H01204 copy IMechE 2004Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
329DEGRADATION OF POLY-L-LACTIDE PART 2
in vivo degradation mechanism reported at 37 degC [20] However further work is needed to assess the validityof this hypothesis with only semicrystalline PLLA withThis suggests that increasing the temperature of the
degradation medium is a suitable method for accelerating identical initial crystallinities investigated in this presentstudythe degradation of PLLA relative to its physiological
degradation rate However in previous increased-temperature studies caution has often been noted whenusing test results performed at temperatures greater than 6 CONCLUSIONSthe polymerrsquos Tg for predicting degradation behaviourbelow the polymerrsquos Tg [11] and [12] Above the poly- This study suggests that increasing the temperature ofmerrsquos Tg it would be expected that with main chain the degradation medium represents a powerful methodsegmental motion unfrozen and the weak van der Waals for accelerating the degradation of PLLA with theforces holding the amorphous regions in place broken degradation mechanisms at 37 degC 50 degC and 70 degCwater molecules would be able to access the amorphous proving to be very similar However concerns stillregions more easily initiating hydrolytic chain scission remain over the validity of testing above the Tg of PLLAresulting in a further increased degradation rate The when predicting results at service temperatures below itscompression-moulded PLLA tensile specimens investi- Tg and the significance of the autocatalytic phenomenongated in this study had a Tg (dry) of approximately 66 degC as the temperature is increased relative to that at 37 degC(Tables 3 and 4) two temperatures were investigatedbelow the polymerrsquos Tg (37 degC and 50 degC) and one abovethe polymerrsquos Tg (70 degC) The high linear correlation
ACKNOWLEDGEMENTScoefficient (R2=0995) achieved for the Arrhenius plotmodelling the loss of molecular weight (Fig 6) suggests
The authors would like to thank Boehringer Ingelheimthat the degradation kinetics were not greatly affected(Ingelheim Germany) for supplying the PLLA Smithabove Tg Ideally to fully assess the implications testingamp Nephew Group Research Centre (York UK) forabove the polymerrsquos Tg has on the degradation rate atheir assistance with processing Griffith Microsciencerange of temperatures would need to be investigated(Derbyshire UK) for the ethylene oxide sterilizationabove and below Tg However this is not as straight-and Rapra Technology Limited (Shropshire UK) for theforward as it might appear When determining themolecular-weight characterization Finally the EPSRCpolymerrsquos Tg it must be realized that a small amount of(Swindon UK) for financial assistancewater can have a marked plasticizing effect causing a
reduction in the polymerrsquos Tg [34] Combine this withthe reduction in Tg due to the loss of molecular weight(Fig 9) and it is evident that defining the polymerrsquos Tg REFERENCESand determining the test temperatures that remain aboveand below the polymerrsquos Tg is an ever changing scenario 1 Li S and Vert M Biodegradation of aliphatic polyesters
In Degradable Polymers Principles amp Applications (EdsTraditionally as in this study and previous studiesG Scott and D Gilead) 1995 pp 43ndash87 (Chapman amp Hallinvestigating the degradation of bioresorbable polymersLondon)for convenience Tg is commonly determined by DSC on
2 Barber F A Resorbable materials for arthroscopicretrieved dried specimens however ideally for accuratefixation a product guide Orthopedic Special Edn 2002Tg measurements representative of the polymers con-8 29ndash37
dition in service test regimes need to be developed that 3 Middleton J C and Tipton A J Synthetic biodegradablecan accurately monitor the polymers Tg while the polymers as orthopedic devices Biomaterials 2000 21specimens remain lsquowetrsquo 2335ndash2346
Although concerns still remain about the validity of 4 Hayashi T Biodegradable polymers for biomedical usestesting above the Tg of PLLA when predicting behaviour Prog Polym Sci 1994 19 663ndash702
5 Implants for surgerymdashcopolymers and blends based onbelow its Tg it is hypothesized from the results of thepolylactidemdashIn vitro degradation testing ISO 158141999present study and from those of Pohjonen and Tormala
6 Duek E A R Zavaglia C A C and Belangero W D[11 ] and Agrawal et al [12 ] that the polymerrsquosIn vitro of poly( lactic acid) pin degradation Polymer 1999morphology may also have a significant role to play in40 6456ndash6473determining the validity of any relationships derived It is
7 Matsusue Y Yamamuro T Oka M Shikinami Y et alspeculated that for semicrystalline polymers results fromIn vitro and in vivo studies on bioabsorbable ultra-high-
tests performed above their Tg may be more valid for strength poly(L-lactide) rods J Biomed Mater Res 1992predicting degradation below their Tg due to their greater 26 1553ndash1567volume constrained in tightly packed less-accessible 8 Kellomaki M Paasimaa S and Tormala P Pliable poly-crystalline domains in comparison to polymers that are lactide plates for guided bone regeneration manufacturingintrinsically amorphous or likely to crystallize through and in vitro Proc Instn Mech Engrs Part H J Engineering
in Medicine 2000 214 615ndash629annealing as a direct result of the increased temperature
H01204 copy IMechE 2004 Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
330 N A WEIR F J BUCHANAN J F ORR D F FARRAR AND G R DICKSON
9 Bergsma J E de Bruijn W C Rozema F R 22 Fischer E W Sterzel H J and Wegner G Investigationof the structure of solution grown crystals of lactideBos R R M and Boering G Late degradation tissue
response to poly(L-lactide) bone plates and screws copolymers by means of chemical reactions Kolloid-Z uZ Polymere 1973 251 980ndash990Biomaterials 1995 16 25ndash31
10 Miller N D and Williams D F The in vivo and in vitro 23 Anderson J M Perspectives on the in vivo responsesof biodegradable polymers In Biomedical Applications ofdegradation of poly(glycolic acid) suture material as a
function of applied strain Biomaterials 1984 5 365ndash368 Synthetic Biodegradable Polymers (Ed J O Hollinger)1995 pp 223ndash233 (CRC Press Boca Raton FL USA)11 Pohjonen T and Tormala P Hydrolytic degradation of
ultra-high-strength self-reinforced poly-L-lactide A tem- 24 Pitt C G and Gu Z-W Modification of the rates of chaincleavage of poly(e-caprolactone) and related polyesters inperature dependence study In Biodegradable Implants in
Fracture Fixation (Eds L K Hung and P C Leung) 1994 the solid state J Control Release 1987 4 283ndash29225 Ward I M Mechanical Properties of Solid Polymerspp 75ndash88 (Department of Orthopaedics and Traumatology
Chinese University of Hong Kong and World Scientific) 1st edn 1971 p 335 ( Wiley-Interscience Chichester)26 Farrar D F and Gillson R K Hydrolytic degradation of12 Agrawal C M Huang D Schmitz J P and
Athanasiou K A Elevated temperature degradation of a polyglyconate B the relationship between degradationtime strength and molecular weight Biomaterials 20025050 copolymer of PLA-PGA Tissue Eng 1997 3(4)
345ndash352 23 3905ndash391227 Wise J Gillen K T and Clough R L An ultrasensitive13 Bucholz B Accelerated degradation test on resorbable
polymers In Degradation Phenomena on Polymeric Bio- technique for testing the Arrhenius extrapolation assump-tion for thermally aged elastomers Polym Degrad Stabmaterials (Eds H Planck M Dauner and M Renardy)
1992 pp 67ndash76 (Springer-Verlag Berlin) 1995 49 403ndash41828 Vert M Li S and Garreau H New insights on the14 Chu C C The in-vitro degradation of poly(glycolic acid)-
suturesmdasheffect of pH J Biomed Mater Res 1981 15 degradation of bioresorbable polymeric devices based onlactic and glycolic acids Clin Mater 1992 10 3ndash8795ndash804
15 Cam D Hyon S-H and Ikada Y Degradation of high 29 Li S Garreau H and Vert M Structure-propertyrelationships in the case of the degradation of massivemolecular weight poly(L-lactide) in alkaline medium
Biomaterials 1995 16 833ndash843 poly(a-hydroxy acids) in aqueous media Part 3 influenceof the morphology of poly(L-lactic acid) J Mater Sci16 Cha Y and Pitt C G The acceleration of degradation-
controlled drug delivery from polyester microspheres Mater Med 1990 1 198ndash20630 Pistner H Bendix D R Muhling J and Reuther JJ Control Release 1989 8 259ndash265
17 Agrawal C M Kennedy M E and Micallef D M Poly(L-lactide) a long-term degradation study in vivoPart III Analytical characterization Biomaterials 1993The effects of ultrasound irradiation on a biodegradable
50ndash50 per cent copolymer of polylactic and polyglycolic 14 291ndash29831 Von Recum H A Cleek R L Eskin S G andacids J Biomed Mater Res 1994 28 851ndash859
18 Gan Z Liang Q Zhang J and Jing X Enzymatic Mikos A G Degradation of polydispersed poly(L-lacticacid) to modulate lactic acid release Biomaterials 1995degradation of poly(e-caprolactone) film in phosphate
buffer solution containing lipases Polym Degrad Stab 16 441ndash44732 Li S and McCarthy S Further investigations on the1997 56 209ndash213
19 Weir N A Buchanan F J Orr J F Farrar D F and hydrolytic degradation of poly (DL-lactide) Biomaterials1999 20 35ndash44Boyd A Processing annealing and sterilisation of poly-L-
lactide Biomaterials 2004 25 3939ndash3949 33 Li S M Garreau H and Vert M Structure-propertyrelationships in the case of the degradation of massive20 Weir N A Buchanan F J Orr J F and Dickson G R
Degradation of poly-L-lactide Part 1mdashin vitro and in vivo aliphatic poly-(a-hydroxy acids) in aqueous media Part 1poly(DL-lactic acid) J Mater Sci Mater Med 1990physiological temperature degradation Proc Instn Mech
Engrs Part H J Engineering in Medicine (article in press) 1 123ndash13034 Siemann U The influence of water on the glass transition21 Li S Hydrolytic degradation characteristics of aliphatic
polyesters derived from lactic and glycolic acids J Biomed of poly(dl-lactic acid) Thermochimica Acta 1985 85513ndash516Mater Res (Appl Biomater) 1999 48 342ndash353
H01204 copy IMechE 2004Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
325DEGRADATION OF POLY-L-LACTIDE PART 2
Table 3 Thermal properties and crystallinity of PLLA33 Mass change versus timesamples degraded at 50 degC
Before drying a similar pattern was observed at bothDegradation50 degC and 70 degC (Fig 3) Initially after one day increasestime days crystallinity Tm degC Tg onset degCof approximately 05 per cent and 07 per cent were
observed at 50 degC and 70 degC respectively Swelling then 0 470 1817 6741 457 1818 663gradually increased to approximately 1 per cent after 72
11 471 1818 651days at 50 degC and 14 days at 70 degC This 1 per cent swell-21 434 1815 656
ing appeared to coincide with the onset of polymer mass 32 453 1817 66050 564 1816 643loss after drying with specimens at both 50 degC and 70 degC72 617 1792 663losing mass from this point onwards A maximum mass88 659 1746 610
loss of 4 per cent was observed at 50 degC after 115 days 115 665 1717 ndashand 76 per cent after 23 days at 70 degC The resultsof the mass-change analysis are in agreement with thegeneral sequence of aliphatic polyester degradation which
Table 4 Thermal properties and crystallinity of PLLAsuggests a time-lag before any mass loss is observed [3]samples degraded at 70 degCand have a very similar profile to the previous control
study that investigated the in vitro degradation of PLLADegradation
tensile specimens at 37 degC [20] time days crystallinity Tm degC Tg onset degC
0 575 1805 6581 599 1809 639
34 DSC analysis versus time 3 575 1805 6405 771 1788 637
At both 50 degC and 70 degC a general trend of increasing 9 857 1745 59714 762 1767 603crystallinity and decreasing Tg onset temperature was18 889 1723 578observed with increasing degradation time (Tables 321 851 1719 577
and 4) reflecting the findings of a similar study conducted 23 922 1718 ndashat 37 degC in vitro [20] Additionally a significant decreasein the specimensrsquo melting point Tm was observed after72 days at 50 degC and five days at 70 degC
The DSC thermograms for the specimens degraded at At 0 weeks (Fig 4(a)) a sharp peak commencingat approximately 66 degC was observed related to theboth 50 degC and 70 degC are shown in Fig 4 along with a
control specimen at 0 days degradation Again the pro- polymerrsquos Tg and indicating unfreezing of main chainsegmental motion as weak secondary bonds in thefiles of the DSC thermograms reflect those observed at
37 degC [20] albeit in an accelerated time frame amorphous regions are broken As the temperatureincreased further a small endothermic dip was observedjust before melting commenced followed by the mainmelting peak It is suggested that the dip before meltingwas caused by some crystallization of the polymerAlthough the polymer was annealed prior to degradationwith the aim of limiting crystallization throughout thestudy close to the polymerrsquos melting point the chainmobility would have increased allowing some of theamorphous segments to order themselves into a morecrystalline structure
At 50 days at 50 degC and five days at 70 degC (Figs 4(b)and (e)) as degradation increased presumably in theamorphous regions the initial dip before melting observedat 0 weeks had disappeared with less amorphous regionsremaining capable of crystallization with a new peakforming in its place after 50 days at 50 degC (Fig 4(b))It is suggested that this new peak represents the melt-ing of new crystallites formed by the crystallization ofthe internal degradation by-products As degradationproceeds further it is speculated that the newly formedcrystallitersquos size also increases moving it to higher tem-peratures while the main melting peak is shifting to lower
Fig 3 Percentage mass change at 50 degC and 70 degC temperatures This results in the two peaks eventually
H01204 copy IMechE 2004 Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
326 N A WEIR F J BUCHANAN J F ORR D F FARRAR AND G R DICKSON
Fig 4 Comparison between DSC thermograms for samples degraded at 50 degC and 70 degC
Table 6 Change in the tensile properties of PLLA throughoutmerging with the smaller newly formed peak appearingdegradation at 70 degCas a shoulder on the larger peak before finally only one
sharp melting peak becomes visible (Figs 4(c) and (f))Degradation Youngrsquos Tensile Extension attime days modulus (MPa) strength (MPa) break (mm)
0 6684 643 16235 Mechanical strength versus time1 6056 473 1173 5362 403 108The tensile strength of the specimens reduced to zero5 3167 78 102
after approximately 50 days at 50 degC and 7 days at 70 degC 7 1029 23 056(Tables 5 and 6) A gradual decrease in Youngrsquos moduluswas also observed with the load versus extension curves
displaying a transition from a more ductile to brittleTable 5 Change in the tensile properties of PLLA throughout failure mode after five days at 50 degC and one day at
degradation at 50 degC 70 degC
Degradation Youngrsquos Tensile Extension attime days modulus (MPa) strength (MPa) break (mm)
4 MODELLING DEGRADATION0 6684 643 1621 6250 614 181
41 Molecular weight models3 6244 613 1595 6081 494 129
Molecular weight loss Analysing the data presented in11 5809 511 13521 4783 278 083 Table 2 in conjunction with equations (3) and (6) the32 3571 179 156 rate constants k1 for the uncatalysed model and k2 50 ndash 29 109
for the autocatalysed model were determined by linear
H01204 copy IMechE 2004Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
327DEGRADATION OF POLY-L-LACTIDE PART 2
regression from plots of (1Mntminus1Mn0) versus time for Dependence of mass loss Tm and Tg on molecular
weight Analysing the percentage mass loss results afterthe uncatalysed model and ln(MntMn0) versus time
for the autocatalysed model (Fig 5) at 37 degC 50 degC and drying in conjunction with the molecular-weight-lossresults it is apparent that a relationship exists between70 degC The analysis was conducted up until the point of
mass loss at each of the temperatures investigated It is the polymerrsquos Mn and percentage mass loss (Fig 7)with mass loss only observed after the polymerrsquos Mn hadapparent from Table 7 that as the degradation tem-
perature increased the correlation coefficient (R2 value) reduced to less than approximately 20 000 A similartrend was also observed when considering the reductionalso generally increased
Considering the rate constants k2 for the auto- in Tm with Mn (Fig 8) Only once the polymerrsquos Mnhad decreased to approximately 50 000 were significantcatalysed model further it is apparent that as the tem-
perature increased the rate of molecular weight loss decreases in the polymerrsquos melting temperature observedThis suggests that once the polymerrsquos molecular weightappeared to increase exponentially with an approximate
four-fold increase observed at 50 degC compared to a forty- had diminished sufficiently and presumably with theamorphous regions exhausted the crystalline regionsfold increase at 70 degC relative to the degradation rate at
37 degC Applying the Arrhenius relationship (equation (9)) were then predominantly attacked A similar dependenceof Tg on Mn was also observed (Fig 9)it is obvious that a linear relationship does exist (Fig 6)
with a high linear regression correlation coefficient of0995 The activation energy (Ea) for the loss of Mn wascalculated from Fig 6 as 1005 kJmol over the 37 degC to50 degC to 70 degC temperature range For the uncatalysedmodel an Ea of 1027 kJmol was calculated
Fig 7 Percentage change after drying versus Mn
Fig 5 Autocatalysed degradation model
Table 7 Uncatalysed and autocatalysed hydrolysisrates
Model Uncatalysed Autocatalysed
Temperature k1 R2 k2 R2
37 degC 9times10minus8 063 00052 08550 degC 3times10minus7 090 00196 096 Fig 8 Relationship between melting temperature and70 degC 4times10minus6 099 02155 095 molecular weight
Fig 9 Relationship between glass transition temperature andFig 6 Arrhenius plot of ln k2 versus 1T molecular weight
H01204 copy IMechE 2004 Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
328 N A WEIR F J BUCHANAN J F ORR D F FARRAR AND G R DICKSON
Mechanical strength and molecular weight An effort the results of previous researchers [28ndash30] investigatingsimilarly semicrystalline PLLA at 37 degC in vitro andwas also made to model the mechanical properties
of the tensile specimens investigated in this study in vivo They observed that as degradation increased thedistributions of the GPC curves became bimodal andagainst molecular weight using the Flory relationship
(equation (7)) However it is obvious from Fig 10 that even multimodal in nature as a result of the selectivedegradation of the amorphous regionsa relationship similar to the one predicted by Flory is not
derived from the results of the present study However The molecular weight models (Figs 7ndash9) also showthe dependence of the degradation of PLLA on itson further analysis it became apparent that an almost
linear relationship existed for the loss of tensile strength molecular weight with mass loss melting temperatureand glass transition displaying a strong dependence onwith time most notably at 50 degC and 70 degCmolecular weight An obvious benefit of these models isthe possibility of being able to predict the initial molecularweight of PLLA required to produce devices with vary-5 DISCUSSIONing resorption times However the failure of the Florymodel to predict mechanical strength is perhaps not51 Degradation mechanismssurprising considering it only accounts for molecular
The results presented for the accelerated degradationweight loss and not changes in morphology such as
of PLLA at increased temperatures suggest that atthe increases in crystallinity observed for the PLLA
50 degC and 70 degC degradation proceeded by the sameinvestigated in this study
mechanism and followed the general sequence of bulkdegradation reported previously for semicrystalline
Significance of autocatalysis at increased temperaturesaliphatic polyesters This suggests degradation occurs inThe degradation of aliphatic polyesters has been showntwo distinct stages [21] and is characterized by molecularto occur more rapidly at the centre than at the surfaceweight loss being observed first before loss of mechanical[21] due to the hydrolytic cleavage of the ester bondsstrength and before any physical mass loss is observedforming new acidic carboxyl end groups resulting in[3] Evidence from the results of the present study sup-a higher internal acidity and a differentiation betweenporting this two-stage bulk degradation mechanism arethe surface and interior degradation rates The resultsdiscussed belowof the present study modelling the loss of Mn to boththe uncatalysed and autocatalysed degradation modelsRelationship between molecular weight loss and degradationshowed no significant difference between activationThe general concensus that the degradation of semi-energies calculated for the two models Pohjonen andcrystalline aliphatic polyesters like the PLLA investi-Tormala [11] found a similar value for activation energygated in this study proceeds via random bulk hydrolysisof self-reinforced PLLA of 1014 kJmol using the auto-in two distinct stages is supported by considering thecatalytic model Previous research conducted by Li andprofile of the molecular-weight-loss curves of Fig 2McCarthy [32] on the in vitro degradation of poly-The curves show a faster initial loss of molecular weight(DL-lactide) at 60 degC showed that a hollow structureup until approximately five days at 70 degC before thewas not obtained during degradation in contrast torate of molecular weight loss slows considerably Thisdegradation at 37 degC in vitro where a hollow structuredegradation behaviour is typical where the rate of chainwas observed after 12 weeks due to autocatalysis [33]scission events is relatively constant with time TheLi and McCarthy [32] attributed this to the rapidmolecular weight is therefore inversely proportional todegradation at 60 degC and increase in the diffusiontime However interestingly the GPC curves for both thecoefficient of water and water-soluble oligomers abovetensile specimens at 50 degC and 70 degC remained essentiallythe polymerrsquos Tg They concluded that although hetero-monomodal throughout degradation contradictory togeneous degradation was still detected at 60 degC it wasmuch less significant and the relative importance ofinternal autocatalysis diminished as temperature increasedThis does not appear to be the case in the current studywith no observable difference between surface and coredegradation rate
52 Suitability of increased temperature for acceleratingthe degradation of PLLA
The results presented for the accelerated degradation ofPLLA at 50 degC and 70 degC indicate that the degradationFig 10 Relationship between tensile strength and molecular
weight mechanisms were very similar to the in vitro and
H01204 copy IMechE 2004Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
329DEGRADATION OF POLY-L-LACTIDE PART 2
in vivo degradation mechanism reported at 37 degC [20] However further work is needed to assess the validityof this hypothesis with only semicrystalline PLLA withThis suggests that increasing the temperature of the
degradation medium is a suitable method for accelerating identical initial crystallinities investigated in this presentstudythe degradation of PLLA relative to its physiological
degradation rate However in previous increased-temperature studies caution has often been noted whenusing test results performed at temperatures greater than 6 CONCLUSIONSthe polymerrsquos Tg for predicting degradation behaviourbelow the polymerrsquos Tg [11] and [12] Above the poly- This study suggests that increasing the temperature ofmerrsquos Tg it would be expected that with main chain the degradation medium represents a powerful methodsegmental motion unfrozen and the weak van der Waals for accelerating the degradation of PLLA with theforces holding the amorphous regions in place broken degradation mechanisms at 37 degC 50 degC and 70 degCwater molecules would be able to access the amorphous proving to be very similar However concerns stillregions more easily initiating hydrolytic chain scission remain over the validity of testing above the Tg of PLLAresulting in a further increased degradation rate The when predicting results at service temperatures below itscompression-moulded PLLA tensile specimens investi- Tg and the significance of the autocatalytic phenomenongated in this study had a Tg (dry) of approximately 66 degC as the temperature is increased relative to that at 37 degC(Tables 3 and 4) two temperatures were investigatedbelow the polymerrsquos Tg (37 degC and 50 degC) and one abovethe polymerrsquos Tg (70 degC) The high linear correlation
ACKNOWLEDGEMENTScoefficient (R2=0995) achieved for the Arrhenius plotmodelling the loss of molecular weight (Fig 6) suggests
The authors would like to thank Boehringer Ingelheimthat the degradation kinetics were not greatly affected(Ingelheim Germany) for supplying the PLLA Smithabove Tg Ideally to fully assess the implications testingamp Nephew Group Research Centre (York UK) forabove the polymerrsquos Tg has on the degradation rate atheir assistance with processing Griffith Microsciencerange of temperatures would need to be investigated(Derbyshire UK) for the ethylene oxide sterilizationabove and below Tg However this is not as straight-and Rapra Technology Limited (Shropshire UK) for theforward as it might appear When determining themolecular-weight characterization Finally the EPSRCpolymerrsquos Tg it must be realized that a small amount of(Swindon UK) for financial assistancewater can have a marked plasticizing effect causing a
reduction in the polymerrsquos Tg [34] Combine this withthe reduction in Tg due to the loss of molecular weight(Fig 9) and it is evident that defining the polymerrsquos Tg REFERENCESand determining the test temperatures that remain aboveand below the polymerrsquos Tg is an ever changing scenario 1 Li S and Vert M Biodegradation of aliphatic polyesters
In Degradable Polymers Principles amp Applications (EdsTraditionally as in this study and previous studiesG Scott and D Gilead) 1995 pp 43ndash87 (Chapman amp Hallinvestigating the degradation of bioresorbable polymersLondon)for convenience Tg is commonly determined by DSC on
2 Barber F A Resorbable materials for arthroscopicretrieved dried specimens however ideally for accuratefixation a product guide Orthopedic Special Edn 2002Tg measurements representative of the polymers con-8 29ndash37
dition in service test regimes need to be developed that 3 Middleton J C and Tipton A J Synthetic biodegradablecan accurately monitor the polymers Tg while the polymers as orthopedic devices Biomaterials 2000 21specimens remain lsquowetrsquo 2335ndash2346
Although concerns still remain about the validity of 4 Hayashi T Biodegradable polymers for biomedical usestesting above the Tg of PLLA when predicting behaviour Prog Polym Sci 1994 19 663ndash702
5 Implants for surgerymdashcopolymers and blends based onbelow its Tg it is hypothesized from the results of thepolylactidemdashIn vitro degradation testing ISO 158141999present study and from those of Pohjonen and Tormala
6 Duek E A R Zavaglia C A C and Belangero W D[11 ] and Agrawal et al [12 ] that the polymerrsquosIn vitro of poly( lactic acid) pin degradation Polymer 1999morphology may also have a significant role to play in40 6456ndash6473determining the validity of any relationships derived It is
7 Matsusue Y Yamamuro T Oka M Shikinami Y et alspeculated that for semicrystalline polymers results fromIn vitro and in vivo studies on bioabsorbable ultra-high-
tests performed above their Tg may be more valid for strength poly(L-lactide) rods J Biomed Mater Res 1992predicting degradation below their Tg due to their greater 26 1553ndash1567volume constrained in tightly packed less-accessible 8 Kellomaki M Paasimaa S and Tormala P Pliable poly-crystalline domains in comparison to polymers that are lactide plates for guided bone regeneration manufacturingintrinsically amorphous or likely to crystallize through and in vitro Proc Instn Mech Engrs Part H J Engineering
in Medicine 2000 214 615ndash629annealing as a direct result of the increased temperature
H01204 copy IMechE 2004 Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
330 N A WEIR F J BUCHANAN J F ORR D F FARRAR AND G R DICKSON
9 Bergsma J E de Bruijn W C Rozema F R 22 Fischer E W Sterzel H J and Wegner G Investigationof the structure of solution grown crystals of lactideBos R R M and Boering G Late degradation tissue
response to poly(L-lactide) bone plates and screws copolymers by means of chemical reactions Kolloid-Z uZ Polymere 1973 251 980ndash990Biomaterials 1995 16 25ndash31
10 Miller N D and Williams D F The in vivo and in vitro 23 Anderson J M Perspectives on the in vivo responsesof biodegradable polymers In Biomedical Applications ofdegradation of poly(glycolic acid) suture material as a
function of applied strain Biomaterials 1984 5 365ndash368 Synthetic Biodegradable Polymers (Ed J O Hollinger)1995 pp 223ndash233 (CRC Press Boca Raton FL USA)11 Pohjonen T and Tormala P Hydrolytic degradation of
ultra-high-strength self-reinforced poly-L-lactide A tem- 24 Pitt C G and Gu Z-W Modification of the rates of chaincleavage of poly(e-caprolactone) and related polyesters inperature dependence study In Biodegradable Implants in
Fracture Fixation (Eds L K Hung and P C Leung) 1994 the solid state J Control Release 1987 4 283ndash29225 Ward I M Mechanical Properties of Solid Polymerspp 75ndash88 (Department of Orthopaedics and Traumatology
Chinese University of Hong Kong and World Scientific) 1st edn 1971 p 335 ( Wiley-Interscience Chichester)26 Farrar D F and Gillson R K Hydrolytic degradation of12 Agrawal C M Huang D Schmitz J P and
Athanasiou K A Elevated temperature degradation of a polyglyconate B the relationship between degradationtime strength and molecular weight Biomaterials 20025050 copolymer of PLA-PGA Tissue Eng 1997 3(4)
345ndash352 23 3905ndash391227 Wise J Gillen K T and Clough R L An ultrasensitive13 Bucholz B Accelerated degradation test on resorbable
polymers In Degradation Phenomena on Polymeric Bio- technique for testing the Arrhenius extrapolation assump-tion for thermally aged elastomers Polym Degrad Stabmaterials (Eds H Planck M Dauner and M Renardy)
1992 pp 67ndash76 (Springer-Verlag Berlin) 1995 49 403ndash41828 Vert M Li S and Garreau H New insights on the14 Chu C C The in-vitro degradation of poly(glycolic acid)-
suturesmdasheffect of pH J Biomed Mater Res 1981 15 degradation of bioresorbable polymeric devices based onlactic and glycolic acids Clin Mater 1992 10 3ndash8795ndash804
15 Cam D Hyon S-H and Ikada Y Degradation of high 29 Li S Garreau H and Vert M Structure-propertyrelationships in the case of the degradation of massivemolecular weight poly(L-lactide) in alkaline medium
Biomaterials 1995 16 833ndash843 poly(a-hydroxy acids) in aqueous media Part 3 influenceof the morphology of poly(L-lactic acid) J Mater Sci16 Cha Y and Pitt C G The acceleration of degradation-
controlled drug delivery from polyester microspheres Mater Med 1990 1 198ndash20630 Pistner H Bendix D R Muhling J and Reuther JJ Control Release 1989 8 259ndash265
17 Agrawal C M Kennedy M E and Micallef D M Poly(L-lactide) a long-term degradation study in vivoPart III Analytical characterization Biomaterials 1993The effects of ultrasound irradiation on a biodegradable
50ndash50 per cent copolymer of polylactic and polyglycolic 14 291ndash29831 Von Recum H A Cleek R L Eskin S G andacids J Biomed Mater Res 1994 28 851ndash859
18 Gan Z Liang Q Zhang J and Jing X Enzymatic Mikos A G Degradation of polydispersed poly(L-lacticacid) to modulate lactic acid release Biomaterials 1995degradation of poly(e-caprolactone) film in phosphate
buffer solution containing lipases Polym Degrad Stab 16 441ndash44732 Li S and McCarthy S Further investigations on the1997 56 209ndash213
19 Weir N A Buchanan F J Orr J F Farrar D F and hydrolytic degradation of poly (DL-lactide) Biomaterials1999 20 35ndash44Boyd A Processing annealing and sterilisation of poly-L-
lactide Biomaterials 2004 25 3939ndash3949 33 Li S M Garreau H and Vert M Structure-propertyrelationships in the case of the degradation of massive20 Weir N A Buchanan F J Orr J F and Dickson G R
Degradation of poly-L-lactide Part 1mdashin vitro and in vivo aliphatic poly-(a-hydroxy acids) in aqueous media Part 1poly(DL-lactic acid) J Mater Sci Mater Med 1990physiological temperature degradation Proc Instn Mech
Engrs Part H J Engineering in Medicine (article in press) 1 123ndash13034 Siemann U The influence of water on the glass transition21 Li S Hydrolytic degradation characteristics of aliphatic
polyesters derived from lactic and glycolic acids J Biomed of poly(dl-lactic acid) Thermochimica Acta 1985 85513ndash516Mater Res (Appl Biomater) 1999 48 342ndash353
H01204 copy IMechE 2004Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
326 N A WEIR F J BUCHANAN J F ORR D F FARRAR AND G R DICKSON
Fig 4 Comparison between DSC thermograms for samples degraded at 50 degC and 70 degC
Table 6 Change in the tensile properties of PLLA throughoutmerging with the smaller newly formed peak appearingdegradation at 70 degCas a shoulder on the larger peak before finally only one
sharp melting peak becomes visible (Figs 4(c) and (f))Degradation Youngrsquos Tensile Extension attime days modulus (MPa) strength (MPa) break (mm)
0 6684 643 16235 Mechanical strength versus time1 6056 473 1173 5362 403 108The tensile strength of the specimens reduced to zero5 3167 78 102
after approximately 50 days at 50 degC and 7 days at 70 degC 7 1029 23 056(Tables 5 and 6) A gradual decrease in Youngrsquos moduluswas also observed with the load versus extension curves
displaying a transition from a more ductile to brittleTable 5 Change in the tensile properties of PLLA throughout failure mode after five days at 50 degC and one day at
degradation at 50 degC 70 degC
Degradation Youngrsquos Tensile Extension attime days modulus (MPa) strength (MPa) break (mm)
4 MODELLING DEGRADATION0 6684 643 1621 6250 614 181
41 Molecular weight models3 6244 613 1595 6081 494 129
Molecular weight loss Analysing the data presented in11 5809 511 13521 4783 278 083 Table 2 in conjunction with equations (3) and (6) the32 3571 179 156 rate constants k1 for the uncatalysed model and k2 50 ndash 29 109
for the autocatalysed model were determined by linear
H01204 copy IMechE 2004Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
327DEGRADATION OF POLY-L-LACTIDE PART 2
regression from plots of (1Mntminus1Mn0) versus time for Dependence of mass loss Tm and Tg on molecular
weight Analysing the percentage mass loss results afterthe uncatalysed model and ln(MntMn0) versus time
for the autocatalysed model (Fig 5) at 37 degC 50 degC and drying in conjunction with the molecular-weight-lossresults it is apparent that a relationship exists between70 degC The analysis was conducted up until the point of
mass loss at each of the temperatures investigated It is the polymerrsquos Mn and percentage mass loss (Fig 7)with mass loss only observed after the polymerrsquos Mn hadapparent from Table 7 that as the degradation tem-
perature increased the correlation coefficient (R2 value) reduced to less than approximately 20 000 A similartrend was also observed when considering the reductionalso generally increased
Considering the rate constants k2 for the auto- in Tm with Mn (Fig 8) Only once the polymerrsquos Mnhad decreased to approximately 50 000 were significantcatalysed model further it is apparent that as the tem-
perature increased the rate of molecular weight loss decreases in the polymerrsquos melting temperature observedThis suggests that once the polymerrsquos molecular weightappeared to increase exponentially with an approximate
four-fold increase observed at 50 degC compared to a forty- had diminished sufficiently and presumably with theamorphous regions exhausted the crystalline regionsfold increase at 70 degC relative to the degradation rate at
37 degC Applying the Arrhenius relationship (equation (9)) were then predominantly attacked A similar dependenceof Tg on Mn was also observed (Fig 9)it is obvious that a linear relationship does exist (Fig 6)
with a high linear regression correlation coefficient of0995 The activation energy (Ea) for the loss of Mn wascalculated from Fig 6 as 1005 kJmol over the 37 degC to50 degC to 70 degC temperature range For the uncatalysedmodel an Ea of 1027 kJmol was calculated
Fig 7 Percentage change after drying versus Mn
Fig 5 Autocatalysed degradation model
Table 7 Uncatalysed and autocatalysed hydrolysisrates
Model Uncatalysed Autocatalysed
Temperature k1 R2 k2 R2
37 degC 9times10minus8 063 00052 08550 degC 3times10minus7 090 00196 096 Fig 8 Relationship between melting temperature and70 degC 4times10minus6 099 02155 095 molecular weight
Fig 9 Relationship between glass transition temperature andFig 6 Arrhenius plot of ln k2 versus 1T molecular weight
H01204 copy IMechE 2004 Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
328 N A WEIR F J BUCHANAN J F ORR D F FARRAR AND G R DICKSON
Mechanical strength and molecular weight An effort the results of previous researchers [28ndash30] investigatingsimilarly semicrystalline PLLA at 37 degC in vitro andwas also made to model the mechanical properties
of the tensile specimens investigated in this study in vivo They observed that as degradation increased thedistributions of the GPC curves became bimodal andagainst molecular weight using the Flory relationship
(equation (7)) However it is obvious from Fig 10 that even multimodal in nature as a result of the selectivedegradation of the amorphous regionsa relationship similar to the one predicted by Flory is not
derived from the results of the present study However The molecular weight models (Figs 7ndash9) also showthe dependence of the degradation of PLLA on itson further analysis it became apparent that an almost
linear relationship existed for the loss of tensile strength molecular weight with mass loss melting temperatureand glass transition displaying a strong dependence onwith time most notably at 50 degC and 70 degCmolecular weight An obvious benefit of these models isthe possibility of being able to predict the initial molecularweight of PLLA required to produce devices with vary-5 DISCUSSIONing resorption times However the failure of the Florymodel to predict mechanical strength is perhaps not51 Degradation mechanismssurprising considering it only accounts for molecular
The results presented for the accelerated degradationweight loss and not changes in morphology such as
of PLLA at increased temperatures suggest that atthe increases in crystallinity observed for the PLLA
50 degC and 70 degC degradation proceeded by the sameinvestigated in this study
mechanism and followed the general sequence of bulkdegradation reported previously for semicrystalline
Significance of autocatalysis at increased temperaturesaliphatic polyesters This suggests degradation occurs inThe degradation of aliphatic polyesters has been showntwo distinct stages [21] and is characterized by molecularto occur more rapidly at the centre than at the surfaceweight loss being observed first before loss of mechanical[21] due to the hydrolytic cleavage of the ester bondsstrength and before any physical mass loss is observedforming new acidic carboxyl end groups resulting in[3] Evidence from the results of the present study sup-a higher internal acidity and a differentiation betweenporting this two-stage bulk degradation mechanism arethe surface and interior degradation rates The resultsdiscussed belowof the present study modelling the loss of Mn to boththe uncatalysed and autocatalysed degradation modelsRelationship between molecular weight loss and degradationshowed no significant difference between activationThe general concensus that the degradation of semi-energies calculated for the two models Pohjonen andcrystalline aliphatic polyesters like the PLLA investi-Tormala [11] found a similar value for activation energygated in this study proceeds via random bulk hydrolysisof self-reinforced PLLA of 1014 kJmol using the auto-in two distinct stages is supported by considering thecatalytic model Previous research conducted by Li andprofile of the molecular-weight-loss curves of Fig 2McCarthy [32] on the in vitro degradation of poly-The curves show a faster initial loss of molecular weight(DL-lactide) at 60 degC showed that a hollow structureup until approximately five days at 70 degC before thewas not obtained during degradation in contrast torate of molecular weight loss slows considerably Thisdegradation at 37 degC in vitro where a hollow structuredegradation behaviour is typical where the rate of chainwas observed after 12 weeks due to autocatalysis [33]scission events is relatively constant with time TheLi and McCarthy [32] attributed this to the rapidmolecular weight is therefore inversely proportional todegradation at 60 degC and increase in the diffusiontime However interestingly the GPC curves for both thecoefficient of water and water-soluble oligomers abovetensile specimens at 50 degC and 70 degC remained essentiallythe polymerrsquos Tg They concluded that although hetero-monomodal throughout degradation contradictory togeneous degradation was still detected at 60 degC it wasmuch less significant and the relative importance ofinternal autocatalysis diminished as temperature increasedThis does not appear to be the case in the current studywith no observable difference between surface and coredegradation rate
52 Suitability of increased temperature for acceleratingthe degradation of PLLA
The results presented for the accelerated degradation ofPLLA at 50 degC and 70 degC indicate that the degradationFig 10 Relationship between tensile strength and molecular
weight mechanisms were very similar to the in vitro and
H01204 copy IMechE 2004Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
329DEGRADATION OF POLY-L-LACTIDE PART 2
in vivo degradation mechanism reported at 37 degC [20] However further work is needed to assess the validityof this hypothesis with only semicrystalline PLLA withThis suggests that increasing the temperature of the
degradation medium is a suitable method for accelerating identical initial crystallinities investigated in this presentstudythe degradation of PLLA relative to its physiological
degradation rate However in previous increased-temperature studies caution has often been noted whenusing test results performed at temperatures greater than 6 CONCLUSIONSthe polymerrsquos Tg for predicting degradation behaviourbelow the polymerrsquos Tg [11] and [12] Above the poly- This study suggests that increasing the temperature ofmerrsquos Tg it would be expected that with main chain the degradation medium represents a powerful methodsegmental motion unfrozen and the weak van der Waals for accelerating the degradation of PLLA with theforces holding the amorphous regions in place broken degradation mechanisms at 37 degC 50 degC and 70 degCwater molecules would be able to access the amorphous proving to be very similar However concerns stillregions more easily initiating hydrolytic chain scission remain over the validity of testing above the Tg of PLLAresulting in a further increased degradation rate The when predicting results at service temperatures below itscompression-moulded PLLA tensile specimens investi- Tg and the significance of the autocatalytic phenomenongated in this study had a Tg (dry) of approximately 66 degC as the temperature is increased relative to that at 37 degC(Tables 3 and 4) two temperatures were investigatedbelow the polymerrsquos Tg (37 degC and 50 degC) and one abovethe polymerrsquos Tg (70 degC) The high linear correlation
ACKNOWLEDGEMENTScoefficient (R2=0995) achieved for the Arrhenius plotmodelling the loss of molecular weight (Fig 6) suggests
The authors would like to thank Boehringer Ingelheimthat the degradation kinetics were not greatly affected(Ingelheim Germany) for supplying the PLLA Smithabove Tg Ideally to fully assess the implications testingamp Nephew Group Research Centre (York UK) forabove the polymerrsquos Tg has on the degradation rate atheir assistance with processing Griffith Microsciencerange of temperatures would need to be investigated(Derbyshire UK) for the ethylene oxide sterilizationabove and below Tg However this is not as straight-and Rapra Technology Limited (Shropshire UK) for theforward as it might appear When determining themolecular-weight characterization Finally the EPSRCpolymerrsquos Tg it must be realized that a small amount of(Swindon UK) for financial assistancewater can have a marked plasticizing effect causing a
reduction in the polymerrsquos Tg [34] Combine this withthe reduction in Tg due to the loss of molecular weight(Fig 9) and it is evident that defining the polymerrsquos Tg REFERENCESand determining the test temperatures that remain aboveand below the polymerrsquos Tg is an ever changing scenario 1 Li S and Vert M Biodegradation of aliphatic polyesters
In Degradable Polymers Principles amp Applications (EdsTraditionally as in this study and previous studiesG Scott and D Gilead) 1995 pp 43ndash87 (Chapman amp Hallinvestigating the degradation of bioresorbable polymersLondon)for convenience Tg is commonly determined by DSC on
2 Barber F A Resorbable materials for arthroscopicretrieved dried specimens however ideally for accuratefixation a product guide Orthopedic Special Edn 2002Tg measurements representative of the polymers con-8 29ndash37
dition in service test regimes need to be developed that 3 Middleton J C and Tipton A J Synthetic biodegradablecan accurately monitor the polymers Tg while the polymers as orthopedic devices Biomaterials 2000 21specimens remain lsquowetrsquo 2335ndash2346
Although concerns still remain about the validity of 4 Hayashi T Biodegradable polymers for biomedical usestesting above the Tg of PLLA when predicting behaviour Prog Polym Sci 1994 19 663ndash702
5 Implants for surgerymdashcopolymers and blends based onbelow its Tg it is hypothesized from the results of thepolylactidemdashIn vitro degradation testing ISO 158141999present study and from those of Pohjonen and Tormala
6 Duek E A R Zavaglia C A C and Belangero W D[11 ] and Agrawal et al [12 ] that the polymerrsquosIn vitro of poly( lactic acid) pin degradation Polymer 1999morphology may also have a significant role to play in40 6456ndash6473determining the validity of any relationships derived It is
7 Matsusue Y Yamamuro T Oka M Shikinami Y et alspeculated that for semicrystalline polymers results fromIn vitro and in vivo studies on bioabsorbable ultra-high-
tests performed above their Tg may be more valid for strength poly(L-lactide) rods J Biomed Mater Res 1992predicting degradation below their Tg due to their greater 26 1553ndash1567volume constrained in tightly packed less-accessible 8 Kellomaki M Paasimaa S and Tormala P Pliable poly-crystalline domains in comparison to polymers that are lactide plates for guided bone regeneration manufacturingintrinsically amorphous or likely to crystallize through and in vitro Proc Instn Mech Engrs Part H J Engineering
in Medicine 2000 214 615ndash629annealing as a direct result of the increased temperature
H01204 copy IMechE 2004 Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
330 N A WEIR F J BUCHANAN J F ORR D F FARRAR AND G R DICKSON
9 Bergsma J E de Bruijn W C Rozema F R 22 Fischer E W Sterzel H J and Wegner G Investigationof the structure of solution grown crystals of lactideBos R R M and Boering G Late degradation tissue
response to poly(L-lactide) bone plates and screws copolymers by means of chemical reactions Kolloid-Z uZ Polymere 1973 251 980ndash990Biomaterials 1995 16 25ndash31
10 Miller N D and Williams D F The in vivo and in vitro 23 Anderson J M Perspectives on the in vivo responsesof biodegradable polymers In Biomedical Applications ofdegradation of poly(glycolic acid) suture material as a
function of applied strain Biomaterials 1984 5 365ndash368 Synthetic Biodegradable Polymers (Ed J O Hollinger)1995 pp 223ndash233 (CRC Press Boca Raton FL USA)11 Pohjonen T and Tormala P Hydrolytic degradation of
ultra-high-strength self-reinforced poly-L-lactide A tem- 24 Pitt C G and Gu Z-W Modification of the rates of chaincleavage of poly(e-caprolactone) and related polyesters inperature dependence study In Biodegradable Implants in
Fracture Fixation (Eds L K Hung and P C Leung) 1994 the solid state J Control Release 1987 4 283ndash29225 Ward I M Mechanical Properties of Solid Polymerspp 75ndash88 (Department of Orthopaedics and Traumatology
Chinese University of Hong Kong and World Scientific) 1st edn 1971 p 335 ( Wiley-Interscience Chichester)26 Farrar D F and Gillson R K Hydrolytic degradation of12 Agrawal C M Huang D Schmitz J P and
Athanasiou K A Elevated temperature degradation of a polyglyconate B the relationship between degradationtime strength and molecular weight Biomaterials 20025050 copolymer of PLA-PGA Tissue Eng 1997 3(4)
345ndash352 23 3905ndash391227 Wise J Gillen K T and Clough R L An ultrasensitive13 Bucholz B Accelerated degradation test on resorbable
polymers In Degradation Phenomena on Polymeric Bio- technique for testing the Arrhenius extrapolation assump-tion for thermally aged elastomers Polym Degrad Stabmaterials (Eds H Planck M Dauner and M Renardy)
1992 pp 67ndash76 (Springer-Verlag Berlin) 1995 49 403ndash41828 Vert M Li S and Garreau H New insights on the14 Chu C C The in-vitro degradation of poly(glycolic acid)-
suturesmdasheffect of pH J Biomed Mater Res 1981 15 degradation of bioresorbable polymeric devices based onlactic and glycolic acids Clin Mater 1992 10 3ndash8795ndash804
15 Cam D Hyon S-H and Ikada Y Degradation of high 29 Li S Garreau H and Vert M Structure-propertyrelationships in the case of the degradation of massivemolecular weight poly(L-lactide) in alkaline medium
Biomaterials 1995 16 833ndash843 poly(a-hydroxy acids) in aqueous media Part 3 influenceof the morphology of poly(L-lactic acid) J Mater Sci16 Cha Y and Pitt C G The acceleration of degradation-
controlled drug delivery from polyester microspheres Mater Med 1990 1 198ndash20630 Pistner H Bendix D R Muhling J and Reuther JJ Control Release 1989 8 259ndash265
17 Agrawal C M Kennedy M E and Micallef D M Poly(L-lactide) a long-term degradation study in vivoPart III Analytical characterization Biomaterials 1993The effects of ultrasound irradiation on a biodegradable
50ndash50 per cent copolymer of polylactic and polyglycolic 14 291ndash29831 Von Recum H A Cleek R L Eskin S G andacids J Biomed Mater Res 1994 28 851ndash859
18 Gan Z Liang Q Zhang J and Jing X Enzymatic Mikos A G Degradation of polydispersed poly(L-lacticacid) to modulate lactic acid release Biomaterials 1995degradation of poly(e-caprolactone) film in phosphate
buffer solution containing lipases Polym Degrad Stab 16 441ndash44732 Li S and McCarthy S Further investigations on the1997 56 209ndash213
19 Weir N A Buchanan F J Orr J F Farrar D F and hydrolytic degradation of poly (DL-lactide) Biomaterials1999 20 35ndash44Boyd A Processing annealing and sterilisation of poly-L-
lactide Biomaterials 2004 25 3939ndash3949 33 Li S M Garreau H and Vert M Structure-propertyrelationships in the case of the degradation of massive20 Weir N A Buchanan F J Orr J F and Dickson G R
Degradation of poly-L-lactide Part 1mdashin vitro and in vivo aliphatic poly-(a-hydroxy acids) in aqueous media Part 1poly(DL-lactic acid) J Mater Sci Mater Med 1990physiological temperature degradation Proc Instn Mech
Engrs Part H J Engineering in Medicine (article in press) 1 123ndash13034 Siemann U The influence of water on the glass transition21 Li S Hydrolytic degradation characteristics of aliphatic
polyesters derived from lactic and glycolic acids J Biomed of poly(dl-lactic acid) Thermochimica Acta 1985 85513ndash516Mater Res (Appl Biomater) 1999 48 342ndash353
H01204 copy IMechE 2004Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
327DEGRADATION OF POLY-L-LACTIDE PART 2
regression from plots of (1Mntminus1Mn0) versus time for Dependence of mass loss Tm and Tg on molecular
weight Analysing the percentage mass loss results afterthe uncatalysed model and ln(MntMn0) versus time
for the autocatalysed model (Fig 5) at 37 degC 50 degC and drying in conjunction with the molecular-weight-lossresults it is apparent that a relationship exists between70 degC The analysis was conducted up until the point of
mass loss at each of the temperatures investigated It is the polymerrsquos Mn and percentage mass loss (Fig 7)with mass loss only observed after the polymerrsquos Mn hadapparent from Table 7 that as the degradation tem-
perature increased the correlation coefficient (R2 value) reduced to less than approximately 20 000 A similartrend was also observed when considering the reductionalso generally increased
Considering the rate constants k2 for the auto- in Tm with Mn (Fig 8) Only once the polymerrsquos Mnhad decreased to approximately 50 000 were significantcatalysed model further it is apparent that as the tem-
perature increased the rate of molecular weight loss decreases in the polymerrsquos melting temperature observedThis suggests that once the polymerrsquos molecular weightappeared to increase exponentially with an approximate
four-fold increase observed at 50 degC compared to a forty- had diminished sufficiently and presumably with theamorphous regions exhausted the crystalline regionsfold increase at 70 degC relative to the degradation rate at
37 degC Applying the Arrhenius relationship (equation (9)) were then predominantly attacked A similar dependenceof Tg on Mn was also observed (Fig 9)it is obvious that a linear relationship does exist (Fig 6)
with a high linear regression correlation coefficient of0995 The activation energy (Ea) for the loss of Mn wascalculated from Fig 6 as 1005 kJmol over the 37 degC to50 degC to 70 degC temperature range For the uncatalysedmodel an Ea of 1027 kJmol was calculated
Fig 7 Percentage change after drying versus Mn
Fig 5 Autocatalysed degradation model
Table 7 Uncatalysed and autocatalysed hydrolysisrates
Model Uncatalysed Autocatalysed
Temperature k1 R2 k2 R2
37 degC 9times10minus8 063 00052 08550 degC 3times10minus7 090 00196 096 Fig 8 Relationship between melting temperature and70 degC 4times10minus6 099 02155 095 molecular weight
Fig 9 Relationship between glass transition temperature andFig 6 Arrhenius plot of ln k2 versus 1T molecular weight
H01204 copy IMechE 2004 Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
328 N A WEIR F J BUCHANAN J F ORR D F FARRAR AND G R DICKSON
Mechanical strength and molecular weight An effort the results of previous researchers [28ndash30] investigatingsimilarly semicrystalline PLLA at 37 degC in vitro andwas also made to model the mechanical properties
of the tensile specimens investigated in this study in vivo They observed that as degradation increased thedistributions of the GPC curves became bimodal andagainst molecular weight using the Flory relationship
(equation (7)) However it is obvious from Fig 10 that even multimodal in nature as a result of the selectivedegradation of the amorphous regionsa relationship similar to the one predicted by Flory is not
derived from the results of the present study However The molecular weight models (Figs 7ndash9) also showthe dependence of the degradation of PLLA on itson further analysis it became apparent that an almost
linear relationship existed for the loss of tensile strength molecular weight with mass loss melting temperatureand glass transition displaying a strong dependence onwith time most notably at 50 degC and 70 degCmolecular weight An obvious benefit of these models isthe possibility of being able to predict the initial molecularweight of PLLA required to produce devices with vary-5 DISCUSSIONing resorption times However the failure of the Florymodel to predict mechanical strength is perhaps not51 Degradation mechanismssurprising considering it only accounts for molecular
The results presented for the accelerated degradationweight loss and not changes in morphology such as
of PLLA at increased temperatures suggest that atthe increases in crystallinity observed for the PLLA
50 degC and 70 degC degradation proceeded by the sameinvestigated in this study
mechanism and followed the general sequence of bulkdegradation reported previously for semicrystalline
Significance of autocatalysis at increased temperaturesaliphatic polyesters This suggests degradation occurs inThe degradation of aliphatic polyesters has been showntwo distinct stages [21] and is characterized by molecularto occur more rapidly at the centre than at the surfaceweight loss being observed first before loss of mechanical[21] due to the hydrolytic cleavage of the ester bondsstrength and before any physical mass loss is observedforming new acidic carboxyl end groups resulting in[3] Evidence from the results of the present study sup-a higher internal acidity and a differentiation betweenporting this two-stage bulk degradation mechanism arethe surface and interior degradation rates The resultsdiscussed belowof the present study modelling the loss of Mn to boththe uncatalysed and autocatalysed degradation modelsRelationship between molecular weight loss and degradationshowed no significant difference between activationThe general concensus that the degradation of semi-energies calculated for the two models Pohjonen andcrystalline aliphatic polyesters like the PLLA investi-Tormala [11] found a similar value for activation energygated in this study proceeds via random bulk hydrolysisof self-reinforced PLLA of 1014 kJmol using the auto-in two distinct stages is supported by considering thecatalytic model Previous research conducted by Li andprofile of the molecular-weight-loss curves of Fig 2McCarthy [32] on the in vitro degradation of poly-The curves show a faster initial loss of molecular weight(DL-lactide) at 60 degC showed that a hollow structureup until approximately five days at 70 degC before thewas not obtained during degradation in contrast torate of molecular weight loss slows considerably Thisdegradation at 37 degC in vitro where a hollow structuredegradation behaviour is typical where the rate of chainwas observed after 12 weeks due to autocatalysis [33]scission events is relatively constant with time TheLi and McCarthy [32] attributed this to the rapidmolecular weight is therefore inversely proportional todegradation at 60 degC and increase in the diffusiontime However interestingly the GPC curves for both thecoefficient of water and water-soluble oligomers abovetensile specimens at 50 degC and 70 degC remained essentiallythe polymerrsquos Tg They concluded that although hetero-monomodal throughout degradation contradictory togeneous degradation was still detected at 60 degC it wasmuch less significant and the relative importance ofinternal autocatalysis diminished as temperature increasedThis does not appear to be the case in the current studywith no observable difference between surface and coredegradation rate
52 Suitability of increased temperature for acceleratingthe degradation of PLLA
The results presented for the accelerated degradation ofPLLA at 50 degC and 70 degC indicate that the degradationFig 10 Relationship between tensile strength and molecular
weight mechanisms were very similar to the in vitro and
H01204 copy IMechE 2004Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
329DEGRADATION OF POLY-L-LACTIDE PART 2
in vivo degradation mechanism reported at 37 degC [20] However further work is needed to assess the validityof this hypothesis with only semicrystalline PLLA withThis suggests that increasing the temperature of the
degradation medium is a suitable method for accelerating identical initial crystallinities investigated in this presentstudythe degradation of PLLA relative to its physiological
degradation rate However in previous increased-temperature studies caution has often been noted whenusing test results performed at temperatures greater than 6 CONCLUSIONSthe polymerrsquos Tg for predicting degradation behaviourbelow the polymerrsquos Tg [11] and [12] Above the poly- This study suggests that increasing the temperature ofmerrsquos Tg it would be expected that with main chain the degradation medium represents a powerful methodsegmental motion unfrozen and the weak van der Waals for accelerating the degradation of PLLA with theforces holding the amorphous regions in place broken degradation mechanisms at 37 degC 50 degC and 70 degCwater molecules would be able to access the amorphous proving to be very similar However concerns stillregions more easily initiating hydrolytic chain scission remain over the validity of testing above the Tg of PLLAresulting in a further increased degradation rate The when predicting results at service temperatures below itscompression-moulded PLLA tensile specimens investi- Tg and the significance of the autocatalytic phenomenongated in this study had a Tg (dry) of approximately 66 degC as the temperature is increased relative to that at 37 degC(Tables 3 and 4) two temperatures were investigatedbelow the polymerrsquos Tg (37 degC and 50 degC) and one abovethe polymerrsquos Tg (70 degC) The high linear correlation
ACKNOWLEDGEMENTScoefficient (R2=0995) achieved for the Arrhenius plotmodelling the loss of molecular weight (Fig 6) suggests
The authors would like to thank Boehringer Ingelheimthat the degradation kinetics were not greatly affected(Ingelheim Germany) for supplying the PLLA Smithabove Tg Ideally to fully assess the implications testingamp Nephew Group Research Centre (York UK) forabove the polymerrsquos Tg has on the degradation rate atheir assistance with processing Griffith Microsciencerange of temperatures would need to be investigated(Derbyshire UK) for the ethylene oxide sterilizationabove and below Tg However this is not as straight-and Rapra Technology Limited (Shropshire UK) for theforward as it might appear When determining themolecular-weight characterization Finally the EPSRCpolymerrsquos Tg it must be realized that a small amount of(Swindon UK) for financial assistancewater can have a marked plasticizing effect causing a
reduction in the polymerrsquos Tg [34] Combine this withthe reduction in Tg due to the loss of molecular weight(Fig 9) and it is evident that defining the polymerrsquos Tg REFERENCESand determining the test temperatures that remain aboveand below the polymerrsquos Tg is an ever changing scenario 1 Li S and Vert M Biodegradation of aliphatic polyesters
In Degradable Polymers Principles amp Applications (EdsTraditionally as in this study and previous studiesG Scott and D Gilead) 1995 pp 43ndash87 (Chapman amp Hallinvestigating the degradation of bioresorbable polymersLondon)for convenience Tg is commonly determined by DSC on
2 Barber F A Resorbable materials for arthroscopicretrieved dried specimens however ideally for accuratefixation a product guide Orthopedic Special Edn 2002Tg measurements representative of the polymers con-8 29ndash37
dition in service test regimes need to be developed that 3 Middleton J C and Tipton A J Synthetic biodegradablecan accurately monitor the polymers Tg while the polymers as orthopedic devices Biomaterials 2000 21specimens remain lsquowetrsquo 2335ndash2346
Although concerns still remain about the validity of 4 Hayashi T Biodegradable polymers for biomedical usestesting above the Tg of PLLA when predicting behaviour Prog Polym Sci 1994 19 663ndash702
5 Implants for surgerymdashcopolymers and blends based onbelow its Tg it is hypothesized from the results of thepolylactidemdashIn vitro degradation testing ISO 158141999present study and from those of Pohjonen and Tormala
6 Duek E A R Zavaglia C A C and Belangero W D[11 ] and Agrawal et al [12 ] that the polymerrsquosIn vitro of poly( lactic acid) pin degradation Polymer 1999morphology may also have a significant role to play in40 6456ndash6473determining the validity of any relationships derived It is
7 Matsusue Y Yamamuro T Oka M Shikinami Y et alspeculated that for semicrystalline polymers results fromIn vitro and in vivo studies on bioabsorbable ultra-high-
tests performed above their Tg may be more valid for strength poly(L-lactide) rods J Biomed Mater Res 1992predicting degradation below their Tg due to their greater 26 1553ndash1567volume constrained in tightly packed less-accessible 8 Kellomaki M Paasimaa S and Tormala P Pliable poly-crystalline domains in comparison to polymers that are lactide plates for guided bone regeneration manufacturingintrinsically amorphous or likely to crystallize through and in vitro Proc Instn Mech Engrs Part H J Engineering
in Medicine 2000 214 615ndash629annealing as a direct result of the increased temperature
H01204 copy IMechE 2004 Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
330 N A WEIR F J BUCHANAN J F ORR D F FARRAR AND G R DICKSON
9 Bergsma J E de Bruijn W C Rozema F R 22 Fischer E W Sterzel H J and Wegner G Investigationof the structure of solution grown crystals of lactideBos R R M and Boering G Late degradation tissue
response to poly(L-lactide) bone plates and screws copolymers by means of chemical reactions Kolloid-Z uZ Polymere 1973 251 980ndash990Biomaterials 1995 16 25ndash31
10 Miller N D and Williams D F The in vivo and in vitro 23 Anderson J M Perspectives on the in vivo responsesof biodegradable polymers In Biomedical Applications ofdegradation of poly(glycolic acid) suture material as a
function of applied strain Biomaterials 1984 5 365ndash368 Synthetic Biodegradable Polymers (Ed J O Hollinger)1995 pp 223ndash233 (CRC Press Boca Raton FL USA)11 Pohjonen T and Tormala P Hydrolytic degradation of
ultra-high-strength self-reinforced poly-L-lactide A tem- 24 Pitt C G and Gu Z-W Modification of the rates of chaincleavage of poly(e-caprolactone) and related polyesters inperature dependence study In Biodegradable Implants in
Fracture Fixation (Eds L K Hung and P C Leung) 1994 the solid state J Control Release 1987 4 283ndash29225 Ward I M Mechanical Properties of Solid Polymerspp 75ndash88 (Department of Orthopaedics and Traumatology
Chinese University of Hong Kong and World Scientific) 1st edn 1971 p 335 ( Wiley-Interscience Chichester)26 Farrar D F and Gillson R K Hydrolytic degradation of12 Agrawal C M Huang D Schmitz J P and
Athanasiou K A Elevated temperature degradation of a polyglyconate B the relationship between degradationtime strength and molecular weight Biomaterials 20025050 copolymer of PLA-PGA Tissue Eng 1997 3(4)
345ndash352 23 3905ndash391227 Wise J Gillen K T and Clough R L An ultrasensitive13 Bucholz B Accelerated degradation test on resorbable
polymers In Degradation Phenomena on Polymeric Bio- technique for testing the Arrhenius extrapolation assump-tion for thermally aged elastomers Polym Degrad Stabmaterials (Eds H Planck M Dauner and M Renardy)
1992 pp 67ndash76 (Springer-Verlag Berlin) 1995 49 403ndash41828 Vert M Li S and Garreau H New insights on the14 Chu C C The in-vitro degradation of poly(glycolic acid)-
suturesmdasheffect of pH J Biomed Mater Res 1981 15 degradation of bioresorbable polymeric devices based onlactic and glycolic acids Clin Mater 1992 10 3ndash8795ndash804
15 Cam D Hyon S-H and Ikada Y Degradation of high 29 Li S Garreau H and Vert M Structure-propertyrelationships in the case of the degradation of massivemolecular weight poly(L-lactide) in alkaline medium
Biomaterials 1995 16 833ndash843 poly(a-hydroxy acids) in aqueous media Part 3 influenceof the morphology of poly(L-lactic acid) J Mater Sci16 Cha Y and Pitt C G The acceleration of degradation-
controlled drug delivery from polyester microspheres Mater Med 1990 1 198ndash20630 Pistner H Bendix D R Muhling J and Reuther JJ Control Release 1989 8 259ndash265
17 Agrawal C M Kennedy M E and Micallef D M Poly(L-lactide) a long-term degradation study in vivoPart III Analytical characterization Biomaterials 1993The effects of ultrasound irradiation on a biodegradable
50ndash50 per cent copolymer of polylactic and polyglycolic 14 291ndash29831 Von Recum H A Cleek R L Eskin S G andacids J Biomed Mater Res 1994 28 851ndash859
18 Gan Z Liang Q Zhang J and Jing X Enzymatic Mikos A G Degradation of polydispersed poly(L-lacticacid) to modulate lactic acid release Biomaterials 1995degradation of poly(e-caprolactone) film in phosphate
buffer solution containing lipases Polym Degrad Stab 16 441ndash44732 Li S and McCarthy S Further investigations on the1997 56 209ndash213
19 Weir N A Buchanan F J Orr J F Farrar D F and hydrolytic degradation of poly (DL-lactide) Biomaterials1999 20 35ndash44Boyd A Processing annealing and sterilisation of poly-L-
lactide Biomaterials 2004 25 3939ndash3949 33 Li S M Garreau H and Vert M Structure-propertyrelationships in the case of the degradation of massive20 Weir N A Buchanan F J Orr J F and Dickson G R
Degradation of poly-L-lactide Part 1mdashin vitro and in vivo aliphatic poly-(a-hydroxy acids) in aqueous media Part 1poly(DL-lactic acid) J Mater Sci Mater Med 1990physiological temperature degradation Proc Instn Mech
Engrs Part H J Engineering in Medicine (article in press) 1 123ndash13034 Siemann U The influence of water on the glass transition21 Li S Hydrolytic degradation characteristics of aliphatic
polyesters derived from lactic and glycolic acids J Biomed of poly(dl-lactic acid) Thermochimica Acta 1985 85513ndash516Mater Res (Appl Biomater) 1999 48 342ndash353
H01204 copy IMechE 2004Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
328 N A WEIR F J BUCHANAN J F ORR D F FARRAR AND G R DICKSON
Mechanical strength and molecular weight An effort the results of previous researchers [28ndash30] investigatingsimilarly semicrystalline PLLA at 37 degC in vitro andwas also made to model the mechanical properties
of the tensile specimens investigated in this study in vivo They observed that as degradation increased thedistributions of the GPC curves became bimodal andagainst molecular weight using the Flory relationship
(equation (7)) However it is obvious from Fig 10 that even multimodal in nature as a result of the selectivedegradation of the amorphous regionsa relationship similar to the one predicted by Flory is not
derived from the results of the present study However The molecular weight models (Figs 7ndash9) also showthe dependence of the degradation of PLLA on itson further analysis it became apparent that an almost
linear relationship existed for the loss of tensile strength molecular weight with mass loss melting temperatureand glass transition displaying a strong dependence onwith time most notably at 50 degC and 70 degCmolecular weight An obvious benefit of these models isthe possibility of being able to predict the initial molecularweight of PLLA required to produce devices with vary-5 DISCUSSIONing resorption times However the failure of the Florymodel to predict mechanical strength is perhaps not51 Degradation mechanismssurprising considering it only accounts for molecular
The results presented for the accelerated degradationweight loss and not changes in morphology such as
of PLLA at increased temperatures suggest that atthe increases in crystallinity observed for the PLLA
50 degC and 70 degC degradation proceeded by the sameinvestigated in this study
mechanism and followed the general sequence of bulkdegradation reported previously for semicrystalline
Significance of autocatalysis at increased temperaturesaliphatic polyesters This suggests degradation occurs inThe degradation of aliphatic polyesters has been showntwo distinct stages [21] and is characterized by molecularto occur more rapidly at the centre than at the surfaceweight loss being observed first before loss of mechanical[21] due to the hydrolytic cleavage of the ester bondsstrength and before any physical mass loss is observedforming new acidic carboxyl end groups resulting in[3] Evidence from the results of the present study sup-a higher internal acidity and a differentiation betweenporting this two-stage bulk degradation mechanism arethe surface and interior degradation rates The resultsdiscussed belowof the present study modelling the loss of Mn to boththe uncatalysed and autocatalysed degradation modelsRelationship between molecular weight loss and degradationshowed no significant difference between activationThe general concensus that the degradation of semi-energies calculated for the two models Pohjonen andcrystalline aliphatic polyesters like the PLLA investi-Tormala [11] found a similar value for activation energygated in this study proceeds via random bulk hydrolysisof self-reinforced PLLA of 1014 kJmol using the auto-in two distinct stages is supported by considering thecatalytic model Previous research conducted by Li andprofile of the molecular-weight-loss curves of Fig 2McCarthy [32] on the in vitro degradation of poly-The curves show a faster initial loss of molecular weight(DL-lactide) at 60 degC showed that a hollow structureup until approximately five days at 70 degC before thewas not obtained during degradation in contrast torate of molecular weight loss slows considerably Thisdegradation at 37 degC in vitro where a hollow structuredegradation behaviour is typical where the rate of chainwas observed after 12 weeks due to autocatalysis [33]scission events is relatively constant with time TheLi and McCarthy [32] attributed this to the rapidmolecular weight is therefore inversely proportional todegradation at 60 degC and increase in the diffusiontime However interestingly the GPC curves for both thecoefficient of water and water-soluble oligomers abovetensile specimens at 50 degC and 70 degC remained essentiallythe polymerrsquos Tg They concluded that although hetero-monomodal throughout degradation contradictory togeneous degradation was still detected at 60 degC it wasmuch less significant and the relative importance ofinternal autocatalysis diminished as temperature increasedThis does not appear to be the case in the current studywith no observable difference between surface and coredegradation rate
52 Suitability of increased temperature for acceleratingthe degradation of PLLA
The results presented for the accelerated degradation ofPLLA at 50 degC and 70 degC indicate that the degradationFig 10 Relationship between tensile strength and molecular
weight mechanisms were very similar to the in vitro and
H01204 copy IMechE 2004Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
329DEGRADATION OF POLY-L-LACTIDE PART 2
in vivo degradation mechanism reported at 37 degC [20] However further work is needed to assess the validityof this hypothesis with only semicrystalline PLLA withThis suggests that increasing the temperature of the
degradation medium is a suitable method for accelerating identical initial crystallinities investigated in this presentstudythe degradation of PLLA relative to its physiological
degradation rate However in previous increased-temperature studies caution has often been noted whenusing test results performed at temperatures greater than 6 CONCLUSIONSthe polymerrsquos Tg for predicting degradation behaviourbelow the polymerrsquos Tg [11] and [12] Above the poly- This study suggests that increasing the temperature ofmerrsquos Tg it would be expected that with main chain the degradation medium represents a powerful methodsegmental motion unfrozen and the weak van der Waals for accelerating the degradation of PLLA with theforces holding the amorphous regions in place broken degradation mechanisms at 37 degC 50 degC and 70 degCwater molecules would be able to access the amorphous proving to be very similar However concerns stillregions more easily initiating hydrolytic chain scission remain over the validity of testing above the Tg of PLLAresulting in a further increased degradation rate The when predicting results at service temperatures below itscompression-moulded PLLA tensile specimens investi- Tg and the significance of the autocatalytic phenomenongated in this study had a Tg (dry) of approximately 66 degC as the temperature is increased relative to that at 37 degC(Tables 3 and 4) two temperatures were investigatedbelow the polymerrsquos Tg (37 degC and 50 degC) and one abovethe polymerrsquos Tg (70 degC) The high linear correlation
ACKNOWLEDGEMENTScoefficient (R2=0995) achieved for the Arrhenius plotmodelling the loss of molecular weight (Fig 6) suggests
The authors would like to thank Boehringer Ingelheimthat the degradation kinetics were not greatly affected(Ingelheim Germany) for supplying the PLLA Smithabove Tg Ideally to fully assess the implications testingamp Nephew Group Research Centre (York UK) forabove the polymerrsquos Tg has on the degradation rate atheir assistance with processing Griffith Microsciencerange of temperatures would need to be investigated(Derbyshire UK) for the ethylene oxide sterilizationabove and below Tg However this is not as straight-and Rapra Technology Limited (Shropshire UK) for theforward as it might appear When determining themolecular-weight characterization Finally the EPSRCpolymerrsquos Tg it must be realized that a small amount of(Swindon UK) for financial assistancewater can have a marked plasticizing effect causing a
reduction in the polymerrsquos Tg [34] Combine this withthe reduction in Tg due to the loss of molecular weight(Fig 9) and it is evident that defining the polymerrsquos Tg REFERENCESand determining the test temperatures that remain aboveand below the polymerrsquos Tg is an ever changing scenario 1 Li S and Vert M Biodegradation of aliphatic polyesters
In Degradable Polymers Principles amp Applications (EdsTraditionally as in this study and previous studiesG Scott and D Gilead) 1995 pp 43ndash87 (Chapman amp Hallinvestigating the degradation of bioresorbable polymersLondon)for convenience Tg is commonly determined by DSC on
2 Barber F A Resorbable materials for arthroscopicretrieved dried specimens however ideally for accuratefixation a product guide Orthopedic Special Edn 2002Tg measurements representative of the polymers con-8 29ndash37
dition in service test regimes need to be developed that 3 Middleton J C and Tipton A J Synthetic biodegradablecan accurately monitor the polymers Tg while the polymers as orthopedic devices Biomaterials 2000 21specimens remain lsquowetrsquo 2335ndash2346
Although concerns still remain about the validity of 4 Hayashi T Biodegradable polymers for biomedical usestesting above the Tg of PLLA when predicting behaviour Prog Polym Sci 1994 19 663ndash702
5 Implants for surgerymdashcopolymers and blends based onbelow its Tg it is hypothesized from the results of thepolylactidemdashIn vitro degradation testing ISO 158141999present study and from those of Pohjonen and Tormala
6 Duek E A R Zavaglia C A C and Belangero W D[11 ] and Agrawal et al [12 ] that the polymerrsquosIn vitro of poly( lactic acid) pin degradation Polymer 1999morphology may also have a significant role to play in40 6456ndash6473determining the validity of any relationships derived It is
7 Matsusue Y Yamamuro T Oka M Shikinami Y et alspeculated that for semicrystalline polymers results fromIn vitro and in vivo studies on bioabsorbable ultra-high-
tests performed above their Tg may be more valid for strength poly(L-lactide) rods J Biomed Mater Res 1992predicting degradation below their Tg due to their greater 26 1553ndash1567volume constrained in tightly packed less-accessible 8 Kellomaki M Paasimaa S and Tormala P Pliable poly-crystalline domains in comparison to polymers that are lactide plates for guided bone regeneration manufacturingintrinsically amorphous or likely to crystallize through and in vitro Proc Instn Mech Engrs Part H J Engineering
in Medicine 2000 214 615ndash629annealing as a direct result of the increased temperature
H01204 copy IMechE 2004 Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
330 N A WEIR F J BUCHANAN J F ORR D F FARRAR AND G R DICKSON
9 Bergsma J E de Bruijn W C Rozema F R 22 Fischer E W Sterzel H J and Wegner G Investigationof the structure of solution grown crystals of lactideBos R R M and Boering G Late degradation tissue
response to poly(L-lactide) bone plates and screws copolymers by means of chemical reactions Kolloid-Z uZ Polymere 1973 251 980ndash990Biomaterials 1995 16 25ndash31
10 Miller N D and Williams D F The in vivo and in vitro 23 Anderson J M Perspectives on the in vivo responsesof biodegradable polymers In Biomedical Applications ofdegradation of poly(glycolic acid) suture material as a
function of applied strain Biomaterials 1984 5 365ndash368 Synthetic Biodegradable Polymers (Ed J O Hollinger)1995 pp 223ndash233 (CRC Press Boca Raton FL USA)11 Pohjonen T and Tormala P Hydrolytic degradation of
ultra-high-strength self-reinforced poly-L-lactide A tem- 24 Pitt C G and Gu Z-W Modification of the rates of chaincleavage of poly(e-caprolactone) and related polyesters inperature dependence study In Biodegradable Implants in
Fracture Fixation (Eds L K Hung and P C Leung) 1994 the solid state J Control Release 1987 4 283ndash29225 Ward I M Mechanical Properties of Solid Polymerspp 75ndash88 (Department of Orthopaedics and Traumatology
Chinese University of Hong Kong and World Scientific) 1st edn 1971 p 335 ( Wiley-Interscience Chichester)26 Farrar D F and Gillson R K Hydrolytic degradation of12 Agrawal C M Huang D Schmitz J P and
Athanasiou K A Elevated temperature degradation of a polyglyconate B the relationship between degradationtime strength and molecular weight Biomaterials 20025050 copolymer of PLA-PGA Tissue Eng 1997 3(4)
345ndash352 23 3905ndash391227 Wise J Gillen K T and Clough R L An ultrasensitive13 Bucholz B Accelerated degradation test on resorbable
polymers In Degradation Phenomena on Polymeric Bio- technique for testing the Arrhenius extrapolation assump-tion for thermally aged elastomers Polym Degrad Stabmaterials (Eds H Planck M Dauner and M Renardy)
1992 pp 67ndash76 (Springer-Verlag Berlin) 1995 49 403ndash41828 Vert M Li S and Garreau H New insights on the14 Chu C C The in-vitro degradation of poly(glycolic acid)-
suturesmdasheffect of pH J Biomed Mater Res 1981 15 degradation of bioresorbable polymeric devices based onlactic and glycolic acids Clin Mater 1992 10 3ndash8795ndash804
15 Cam D Hyon S-H and Ikada Y Degradation of high 29 Li S Garreau H and Vert M Structure-propertyrelationships in the case of the degradation of massivemolecular weight poly(L-lactide) in alkaline medium
Biomaterials 1995 16 833ndash843 poly(a-hydroxy acids) in aqueous media Part 3 influenceof the morphology of poly(L-lactic acid) J Mater Sci16 Cha Y and Pitt C G The acceleration of degradation-
controlled drug delivery from polyester microspheres Mater Med 1990 1 198ndash20630 Pistner H Bendix D R Muhling J and Reuther JJ Control Release 1989 8 259ndash265
17 Agrawal C M Kennedy M E and Micallef D M Poly(L-lactide) a long-term degradation study in vivoPart III Analytical characterization Biomaterials 1993The effects of ultrasound irradiation on a biodegradable
50ndash50 per cent copolymer of polylactic and polyglycolic 14 291ndash29831 Von Recum H A Cleek R L Eskin S G andacids J Biomed Mater Res 1994 28 851ndash859
18 Gan Z Liang Q Zhang J and Jing X Enzymatic Mikos A G Degradation of polydispersed poly(L-lacticacid) to modulate lactic acid release Biomaterials 1995degradation of poly(e-caprolactone) film in phosphate
buffer solution containing lipases Polym Degrad Stab 16 441ndash44732 Li S and McCarthy S Further investigations on the1997 56 209ndash213
19 Weir N A Buchanan F J Orr J F Farrar D F and hydrolytic degradation of poly (DL-lactide) Biomaterials1999 20 35ndash44Boyd A Processing annealing and sterilisation of poly-L-
lactide Biomaterials 2004 25 3939ndash3949 33 Li S M Garreau H and Vert M Structure-propertyrelationships in the case of the degradation of massive20 Weir N A Buchanan F J Orr J F and Dickson G R
Degradation of poly-L-lactide Part 1mdashin vitro and in vivo aliphatic poly-(a-hydroxy acids) in aqueous media Part 1poly(DL-lactic acid) J Mater Sci Mater Med 1990physiological temperature degradation Proc Instn Mech
Engrs Part H J Engineering in Medicine (article in press) 1 123ndash13034 Siemann U The influence of water on the glass transition21 Li S Hydrolytic degradation characteristics of aliphatic
polyesters derived from lactic and glycolic acids J Biomed of poly(dl-lactic acid) Thermochimica Acta 1985 85513ndash516Mater Res (Appl Biomater) 1999 48 342ndash353
H01204 copy IMechE 2004Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
329DEGRADATION OF POLY-L-LACTIDE PART 2
in vivo degradation mechanism reported at 37 degC [20] However further work is needed to assess the validityof this hypothesis with only semicrystalline PLLA withThis suggests that increasing the temperature of the
degradation medium is a suitable method for accelerating identical initial crystallinities investigated in this presentstudythe degradation of PLLA relative to its physiological
degradation rate However in previous increased-temperature studies caution has often been noted whenusing test results performed at temperatures greater than 6 CONCLUSIONSthe polymerrsquos Tg for predicting degradation behaviourbelow the polymerrsquos Tg [11] and [12] Above the poly- This study suggests that increasing the temperature ofmerrsquos Tg it would be expected that with main chain the degradation medium represents a powerful methodsegmental motion unfrozen and the weak van der Waals for accelerating the degradation of PLLA with theforces holding the amorphous regions in place broken degradation mechanisms at 37 degC 50 degC and 70 degCwater molecules would be able to access the amorphous proving to be very similar However concerns stillregions more easily initiating hydrolytic chain scission remain over the validity of testing above the Tg of PLLAresulting in a further increased degradation rate The when predicting results at service temperatures below itscompression-moulded PLLA tensile specimens investi- Tg and the significance of the autocatalytic phenomenongated in this study had a Tg (dry) of approximately 66 degC as the temperature is increased relative to that at 37 degC(Tables 3 and 4) two temperatures were investigatedbelow the polymerrsquos Tg (37 degC and 50 degC) and one abovethe polymerrsquos Tg (70 degC) The high linear correlation
ACKNOWLEDGEMENTScoefficient (R2=0995) achieved for the Arrhenius plotmodelling the loss of molecular weight (Fig 6) suggests
The authors would like to thank Boehringer Ingelheimthat the degradation kinetics were not greatly affected(Ingelheim Germany) for supplying the PLLA Smithabove Tg Ideally to fully assess the implications testingamp Nephew Group Research Centre (York UK) forabove the polymerrsquos Tg has on the degradation rate atheir assistance with processing Griffith Microsciencerange of temperatures would need to be investigated(Derbyshire UK) for the ethylene oxide sterilizationabove and below Tg However this is not as straight-and Rapra Technology Limited (Shropshire UK) for theforward as it might appear When determining themolecular-weight characterization Finally the EPSRCpolymerrsquos Tg it must be realized that a small amount of(Swindon UK) for financial assistancewater can have a marked plasticizing effect causing a
reduction in the polymerrsquos Tg [34] Combine this withthe reduction in Tg due to the loss of molecular weight(Fig 9) and it is evident that defining the polymerrsquos Tg REFERENCESand determining the test temperatures that remain aboveand below the polymerrsquos Tg is an ever changing scenario 1 Li S and Vert M Biodegradation of aliphatic polyesters
In Degradable Polymers Principles amp Applications (EdsTraditionally as in this study and previous studiesG Scott and D Gilead) 1995 pp 43ndash87 (Chapman amp Hallinvestigating the degradation of bioresorbable polymersLondon)for convenience Tg is commonly determined by DSC on
2 Barber F A Resorbable materials for arthroscopicretrieved dried specimens however ideally for accuratefixation a product guide Orthopedic Special Edn 2002Tg measurements representative of the polymers con-8 29ndash37
dition in service test regimes need to be developed that 3 Middleton J C and Tipton A J Synthetic biodegradablecan accurately monitor the polymers Tg while the polymers as orthopedic devices Biomaterials 2000 21specimens remain lsquowetrsquo 2335ndash2346
Although concerns still remain about the validity of 4 Hayashi T Biodegradable polymers for biomedical usestesting above the Tg of PLLA when predicting behaviour Prog Polym Sci 1994 19 663ndash702
5 Implants for surgerymdashcopolymers and blends based onbelow its Tg it is hypothesized from the results of thepolylactidemdashIn vitro degradation testing ISO 158141999present study and from those of Pohjonen and Tormala
6 Duek E A R Zavaglia C A C and Belangero W D[11 ] and Agrawal et al [12 ] that the polymerrsquosIn vitro of poly( lactic acid) pin degradation Polymer 1999morphology may also have a significant role to play in40 6456ndash6473determining the validity of any relationships derived It is
7 Matsusue Y Yamamuro T Oka M Shikinami Y et alspeculated that for semicrystalline polymers results fromIn vitro and in vivo studies on bioabsorbable ultra-high-
tests performed above their Tg may be more valid for strength poly(L-lactide) rods J Biomed Mater Res 1992predicting degradation below their Tg due to their greater 26 1553ndash1567volume constrained in tightly packed less-accessible 8 Kellomaki M Paasimaa S and Tormala P Pliable poly-crystalline domains in comparison to polymers that are lactide plates for guided bone regeneration manufacturingintrinsically amorphous or likely to crystallize through and in vitro Proc Instn Mech Engrs Part H J Engineering
in Medicine 2000 214 615ndash629annealing as a direct result of the increased temperature
H01204 copy IMechE 2004 Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
330 N A WEIR F J BUCHANAN J F ORR D F FARRAR AND G R DICKSON
9 Bergsma J E de Bruijn W C Rozema F R 22 Fischer E W Sterzel H J and Wegner G Investigationof the structure of solution grown crystals of lactideBos R R M and Boering G Late degradation tissue
response to poly(L-lactide) bone plates and screws copolymers by means of chemical reactions Kolloid-Z uZ Polymere 1973 251 980ndash990Biomaterials 1995 16 25ndash31
10 Miller N D and Williams D F The in vivo and in vitro 23 Anderson J M Perspectives on the in vivo responsesof biodegradable polymers In Biomedical Applications ofdegradation of poly(glycolic acid) suture material as a
function of applied strain Biomaterials 1984 5 365ndash368 Synthetic Biodegradable Polymers (Ed J O Hollinger)1995 pp 223ndash233 (CRC Press Boca Raton FL USA)11 Pohjonen T and Tormala P Hydrolytic degradation of
ultra-high-strength self-reinforced poly-L-lactide A tem- 24 Pitt C G and Gu Z-W Modification of the rates of chaincleavage of poly(e-caprolactone) and related polyesters inperature dependence study In Biodegradable Implants in
Fracture Fixation (Eds L K Hung and P C Leung) 1994 the solid state J Control Release 1987 4 283ndash29225 Ward I M Mechanical Properties of Solid Polymerspp 75ndash88 (Department of Orthopaedics and Traumatology
Chinese University of Hong Kong and World Scientific) 1st edn 1971 p 335 ( Wiley-Interscience Chichester)26 Farrar D F and Gillson R K Hydrolytic degradation of12 Agrawal C M Huang D Schmitz J P and
Athanasiou K A Elevated temperature degradation of a polyglyconate B the relationship between degradationtime strength and molecular weight Biomaterials 20025050 copolymer of PLA-PGA Tissue Eng 1997 3(4)
345ndash352 23 3905ndash391227 Wise J Gillen K T and Clough R L An ultrasensitive13 Bucholz B Accelerated degradation test on resorbable
polymers In Degradation Phenomena on Polymeric Bio- technique for testing the Arrhenius extrapolation assump-tion for thermally aged elastomers Polym Degrad Stabmaterials (Eds H Planck M Dauner and M Renardy)
1992 pp 67ndash76 (Springer-Verlag Berlin) 1995 49 403ndash41828 Vert M Li S and Garreau H New insights on the14 Chu C C The in-vitro degradation of poly(glycolic acid)-
suturesmdasheffect of pH J Biomed Mater Res 1981 15 degradation of bioresorbable polymeric devices based onlactic and glycolic acids Clin Mater 1992 10 3ndash8795ndash804
15 Cam D Hyon S-H and Ikada Y Degradation of high 29 Li S Garreau H and Vert M Structure-propertyrelationships in the case of the degradation of massivemolecular weight poly(L-lactide) in alkaline medium
Biomaterials 1995 16 833ndash843 poly(a-hydroxy acids) in aqueous media Part 3 influenceof the morphology of poly(L-lactic acid) J Mater Sci16 Cha Y and Pitt C G The acceleration of degradation-
controlled drug delivery from polyester microspheres Mater Med 1990 1 198ndash20630 Pistner H Bendix D R Muhling J and Reuther JJ Control Release 1989 8 259ndash265
17 Agrawal C M Kennedy M E and Micallef D M Poly(L-lactide) a long-term degradation study in vivoPart III Analytical characterization Biomaterials 1993The effects of ultrasound irradiation on a biodegradable
50ndash50 per cent copolymer of polylactic and polyglycolic 14 291ndash29831 Von Recum H A Cleek R L Eskin S G andacids J Biomed Mater Res 1994 28 851ndash859
18 Gan Z Liang Q Zhang J and Jing X Enzymatic Mikos A G Degradation of polydispersed poly(L-lacticacid) to modulate lactic acid release Biomaterials 1995degradation of poly(e-caprolactone) film in phosphate
buffer solution containing lipases Polym Degrad Stab 16 441ndash44732 Li S and McCarthy S Further investigations on the1997 56 209ndash213
19 Weir N A Buchanan F J Orr J F Farrar D F and hydrolytic degradation of poly (DL-lactide) Biomaterials1999 20 35ndash44Boyd A Processing annealing and sterilisation of poly-L-
lactide Biomaterials 2004 25 3939ndash3949 33 Li S M Garreau H and Vert M Structure-propertyrelationships in the case of the degradation of massive20 Weir N A Buchanan F J Orr J F and Dickson G R
Degradation of poly-L-lactide Part 1mdashin vitro and in vivo aliphatic poly-(a-hydroxy acids) in aqueous media Part 1poly(DL-lactic acid) J Mater Sci Mater Med 1990physiological temperature degradation Proc Instn Mech
Engrs Part H J Engineering in Medicine (article in press) 1 123ndash13034 Siemann U The influence of water on the glass transition21 Li S Hydrolytic degradation characteristics of aliphatic
polyesters derived from lactic and glycolic acids J Biomed of poly(dl-lactic acid) Thermochimica Acta 1985 85513ndash516Mater Res (Appl Biomater) 1999 48 342ndash353
H01204 copy IMechE 2004Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine
330 N A WEIR F J BUCHANAN J F ORR D F FARRAR AND G R DICKSON
9 Bergsma J E de Bruijn W C Rozema F R 22 Fischer E W Sterzel H J and Wegner G Investigationof the structure of solution grown crystals of lactideBos R R M and Boering G Late degradation tissue
response to poly(L-lactide) bone plates and screws copolymers by means of chemical reactions Kolloid-Z uZ Polymere 1973 251 980ndash990Biomaterials 1995 16 25ndash31
10 Miller N D and Williams D F The in vivo and in vitro 23 Anderson J M Perspectives on the in vivo responsesof biodegradable polymers In Biomedical Applications ofdegradation of poly(glycolic acid) suture material as a
function of applied strain Biomaterials 1984 5 365ndash368 Synthetic Biodegradable Polymers (Ed J O Hollinger)1995 pp 223ndash233 (CRC Press Boca Raton FL USA)11 Pohjonen T and Tormala P Hydrolytic degradation of
ultra-high-strength self-reinforced poly-L-lactide A tem- 24 Pitt C G and Gu Z-W Modification of the rates of chaincleavage of poly(e-caprolactone) and related polyesters inperature dependence study In Biodegradable Implants in
Fracture Fixation (Eds L K Hung and P C Leung) 1994 the solid state J Control Release 1987 4 283ndash29225 Ward I M Mechanical Properties of Solid Polymerspp 75ndash88 (Department of Orthopaedics and Traumatology
Chinese University of Hong Kong and World Scientific) 1st edn 1971 p 335 ( Wiley-Interscience Chichester)26 Farrar D F and Gillson R K Hydrolytic degradation of12 Agrawal C M Huang D Schmitz J P and
Athanasiou K A Elevated temperature degradation of a polyglyconate B the relationship between degradationtime strength and molecular weight Biomaterials 20025050 copolymer of PLA-PGA Tissue Eng 1997 3(4)
345ndash352 23 3905ndash391227 Wise J Gillen K T and Clough R L An ultrasensitive13 Bucholz B Accelerated degradation test on resorbable
polymers In Degradation Phenomena on Polymeric Bio- technique for testing the Arrhenius extrapolation assump-tion for thermally aged elastomers Polym Degrad Stabmaterials (Eds H Planck M Dauner and M Renardy)
1992 pp 67ndash76 (Springer-Verlag Berlin) 1995 49 403ndash41828 Vert M Li S and Garreau H New insights on the14 Chu C C The in-vitro degradation of poly(glycolic acid)-
suturesmdasheffect of pH J Biomed Mater Res 1981 15 degradation of bioresorbable polymeric devices based onlactic and glycolic acids Clin Mater 1992 10 3ndash8795ndash804
15 Cam D Hyon S-H and Ikada Y Degradation of high 29 Li S Garreau H and Vert M Structure-propertyrelationships in the case of the degradation of massivemolecular weight poly(L-lactide) in alkaline medium
Biomaterials 1995 16 833ndash843 poly(a-hydroxy acids) in aqueous media Part 3 influenceof the morphology of poly(L-lactic acid) J Mater Sci16 Cha Y and Pitt C G The acceleration of degradation-
controlled drug delivery from polyester microspheres Mater Med 1990 1 198ndash20630 Pistner H Bendix D R Muhling J and Reuther JJ Control Release 1989 8 259ndash265
17 Agrawal C M Kennedy M E and Micallef D M Poly(L-lactide) a long-term degradation study in vivoPart III Analytical characterization Biomaterials 1993The effects of ultrasound irradiation on a biodegradable
50ndash50 per cent copolymer of polylactic and polyglycolic 14 291ndash29831 Von Recum H A Cleek R L Eskin S G andacids J Biomed Mater Res 1994 28 851ndash859
18 Gan Z Liang Q Zhang J and Jing X Enzymatic Mikos A G Degradation of polydispersed poly(L-lacticacid) to modulate lactic acid release Biomaterials 1995degradation of poly(e-caprolactone) film in phosphate
buffer solution containing lipases Polym Degrad Stab 16 441ndash44732 Li S and McCarthy S Further investigations on the1997 56 209ndash213
19 Weir N A Buchanan F J Orr J F Farrar D F and hydrolytic degradation of poly (DL-lactide) Biomaterials1999 20 35ndash44Boyd A Processing annealing and sterilisation of poly-L-
lactide Biomaterials 2004 25 3939ndash3949 33 Li S M Garreau H and Vert M Structure-propertyrelationships in the case of the degradation of massive20 Weir N A Buchanan F J Orr J F and Dickson G R
Degradation of poly-L-lactide Part 1mdashin vitro and in vivo aliphatic poly-(a-hydroxy acids) in aqueous media Part 1poly(DL-lactic acid) J Mater Sci Mater Med 1990physiological temperature degradation Proc Instn Mech
Engrs Part H J Engineering in Medicine (article in press) 1 123ndash13034 Siemann U The influence of water on the glass transition21 Li S Hydrolytic degradation characteristics of aliphatic
polyesters derived from lactic and glycolic acids J Biomed of poly(dl-lactic acid) Thermochimica Acta 1985 85513ndash516Mater Res (Appl Biomater) 1999 48 342ndash353
H01204 copy IMechE 2004Proc Instn Mech Engrs Vol 218 Part H J Engineering in Medicine