Tuning the Polylactide Hydrolysis Rate by Plasticizer Architecture and

Biomacromolecules 2010, 11, 3617–3623

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Tuning the Polylactide Hydrolysis Rate by Plasticizer Architecture and Hydrophilicity without Introducing New Migrants Sofia Regnell Andersson, Minna Hakkarainen, and Ann-Christine Albertsson* Department of Fibre and Polymer Technology, School of Chemical Science and Engineering, Royal Institute of Technology (KTH), S-100 44, Stockholm, Sweden Received September 10, 2010; Revised Manuscript Received October 18, 2010

The possibility to tune the hydrolytic degradation rate of polylactide by plasticizer architecture and hydrophilicity without introduction of new degradation products was investigated by subjecting polylactide with cyclic oligolactide and linear oligolactic acid additives to hydrolytic degradation at 37 and 60 °C for up to 39 weeks. The more hydrophilic oligolactic acid plasticizer led to larger water uptake and rapid migration of plasticizer from the films into the aging water. This resulted in a porous material more susceptible to further hydrolysis. During hydrolysis at 37 °C the mass loss was generally 10-20% higher for the material containing linear oligolactic acid plasticizers. The hydrolysis accelerating effect of the linear oligolactic acid is probably counteracted by the higher degree of crystallinity in the films containing oligolactic acid additives. The degradation process was monitored by measurements of mass loss, water uptake, molar mass changes, material composition changes, surface changes, and thermal properties. The water-soluble degradation products were analyzed by following pH changes and identified by electrospray ionization-mass spectrometry (ESI-MS). The time frame for formation of water-soluble products was influenced by the architecture and hydrophilicity of the plasticizer. Furthermore, the advantage with oligolactide and oligolactic acid plasticizers was clearly demonstrated as they do not introduce any new migrants into the degradation product patterns.

Introduction Degradation rate together with the possible release of degradation products and additives are important parameters to control for the safe use of degradable polymers in different applications. Several approaches have been made to tune the properties and degradation rate of aliphatic polyesters including copolymerization,1–4 cross-linking,5,6 surface modification,7 and stereocomplexation.8 However, all of these modifications also influence the degradation product patterns.5 Poly(L-lactide) (PLLA), one of the most promising degradable polymers, is a hard and rigid material that results in a certain brittleness. The approaches for improving the impact strength or tensile toughness of polylactide include control of stereochemistry, copolymerization, blending with degradable or nondegradable polymers, and plasticization.9 An improved autocatalytic equation was recently developed to predict the evolution of number average molecular weight of aliphatic polyesters on hydrolytic degradation.10 The most promising polylactide plasticizers include the cyclic lactide monomer,11 oligolactic acid additives,12 citrate esters,13 as well as polymeric additives such as poly(butylene adipate)14 and poly(ethylene glycol).15 The migration of plasticizers from the material is a potential problem due to the fast deterioration of material properties. When dealing with degradable materials, other key concerns are the environmental degradability and adaptability of the additives and their effect on the degradation rate. As an example, lactide is an environmentally degradable, nontoxic additive that is well-known as a good plasticizing agent for PLA, however, its rather fast migration rate results in a stiff * To whom correspondence should be addressed. Phone: +46-8-790 82 74. Fax: +46-8-20 84 77. E-mail: [email protected].

material with time and it can easily contaminate the process equipment.16 Previous studies mainly concentrated on the effect of plasticizers on the mechanical and thermal properties of PLLA.14,17 However, depending on the nature of the plasticizer, it could also either increase or decrease the degradation rate by influencing material properties such as the degree of crystallinity, glass transition temperature, and hydrophilicity. In a recent paper we showed that the hydrophobic citrate plasticizer prohibited the hydrolysis of the polylactide matrix.18 At the same time, the plasticizer and its degradation products dominated the water-soluble product patterns. Cyclic lactide, cyclic oligolactides, and linear oligolactic acid have been shown to function as polylactide plasticizers.11,12 These plasticizers should be ideal in comparison to traditional plasticizers as they have a structure similar to the polylactide chain and they are, thus, not expected to cause any new migrants. Because the linear plasticizer is more hydrophilic, it could hypothetically be used as a hydrolysis accelerating additive. At the same time, however, the linear oligolactic acid can function as a nucleation agent, which could lead to a higher degree of crystallinity and higher hydrolytic stability.19 In addition to plasticizing PLLA, we aimed to tune the hydrolytic degradation rate by the plasticizer architecture and hydrophilicity. The hypothesis was tested by subjecting polylactide with cyclic oligolactide or linear oligolactic acid additives to hydrolytic degradation. The degradation process was followed by determining the mass loss, molar mass changes, pH, thermal properties, and surface morphology as a function of hydrolysis time. The water-soluble product patterns were monitored by electrospray ionization mass spectrometry (ESI-MS).

10.1021/bm101075p  2010 American Chemical Society Published on Web 11/16/2010

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Experimental Section Samples/Materials. Two different polylactide materials were obtained from Hycail Finland, poly(L-lactide) (HM1011) with cyclic oligolactide additives, denoted PLLA-C and poly(L-lactide) (HM1011) modified with linear oligolactic acid additives, denoted PLLA-L. Films were prepared by dissolving approximately 8 g of material in 40 mL of chloroform (HPLC grade, Fisher scientific) and solution casting on 18.5 cm diameter glass molds. The solvent was allowed to evaporate and the resulting films were dried under vacuum for one week at room temperature. Circular plates weighing approximately 20 mg and with a diameter of 10 mm were cut from the films. Hydrolysis. The polylactide films were exposed to hydrolytic degradation at 37 and 60 °C in LC-MS grade water (Merck). Samples were placed in 20 mL glass vials with 5 mL of water. The vials were sealed with butyl/PTFE septa and aluminum lids and placed in thermostatically controlled ovens. After predetermined periods of time, ranging from 24 h to 39 weeks, triplicate samples of each material were withdrawn from the incubator and subsequently withdrawn from the test medium, dried under vacuum, and subjected to the various analyses. Remaining Mass and Water Absorption. The course of degradation was followed by determining the remaining mass and water absorption of the samples after different periods of time. After withdrawing the samples from the degradation medium, the samples were, if possible, gently wiped with a tissue and the wet weight was determined. The percentage of remaining mass of the solid polymer was determined after drying the samples to constant weight for 2 weeks under vacuum and comparing the dry weight (md) with the initial weight (m0) according to eq 1.

remaining mass )

md × 100 m0

(1)

The percentage of water in the samples was determined by comparing the wet weight (mw) to the dry weight according to eq 2.

water absorption )

mw - md × 100 md

Results and Discussion (2)

pH. The pH measurements in the degradation medium were carried out using a pH meter equipped with an Ag/AgCl electrode. Differential Scanning Calorimetry (DSC). The thermal properties of the samples were investigated using a DSC (Mettler Toledo DSC 820 module) under a nitrogen atmosphere. A total of 2-6 mg of the sample was placed in a 40 µL aluminum cap and sealed with a lid. Samples were heated under a nitrogen gas flow of 50 mL/min from -30 to 240 °C at a rate of 10 °C/min, held at 240 °C for 2 min, and thereafter cooled to -30 °C at a rate of 10 °C/min and held at the lowest temperature for 2 min. Finally the samples were heated from -30 to 240 °C at a rate of 10 °C/min. Duplicate samples were analyzed at each temperature and time. The melting temperatures and crystallization temperatures were noted as the maximum value and the minimum value of the peaks, respectively, and the glass transition temperatures were taken as the midpoint of the glass transition. Determination of Tg, Tm, and Tc was made from both the first and the second heating scan. The approximate degree of crystallinity of the samples was calculated according to eq 3, where wc is the degree of crystallinity, ∆Hf is the heat of fusion of the sample and ∆Hf0 is the heat of fusion for a 100% crystalline polymer. The value used for ∆H 20 0 f was 93 J/g for all materials.

wc )

∆Hf ∆Hf0

× 100

Electrospray Ionization-Mass Spectrometry (ESI-MS). The water fractions after each hydrolysis temperature and time were analyzed with a Finnigan LCQ ion trap mass spectrometer (Finnigan, San Jose, CA). Methanol (LC-MS grade, Fluka) was added to the water fractions (water/MeOH ) 2:1 v/v), and the solutions were continuously infused by the instrument syringe pump at a rate of 5 µL/min. For the analysis of the low molecular weight fractions in the samples before hydrolysis, a 5 mg piece of the film was placed in 1 mL of methanol or methanol/ water for 10 min after which the solvent was removed and analyzed by ESI-MS. Positive ion mode was used for all analyzes. The LCQ ion source was operating at 5 kV and the capillary heater was set to 175 °C. Nitrogen was used as nebulizing gas, and helium was used as damping gas and collision gas in the mass analyzer. No cationizing agents were needed. Scanning Electron Microscopy (SEM). The surfaces of the samples after different degradation times were studied using a Hitachi S-4800 SEM with an acceleration voltage of 0.6-2.0 kV. The samples were mounted on metal studs and sputter-coated with gold-palladium using a Cressington 208HR sputter coater. Size Exclusion Chromatography (SEC). The molar masses of the polymers were determined by SEC. The polymers were analyzed with a Verotech PL-GPC 50 Plus system equipped with a PL-RI Detector and two PolarGel-M Organic (300 × 7.5 mm) columns from Varian. The samples were injected with a PL-AS RT Autosampler for PLGPC 50 Plus and THF was used as mobile phase (1 mL/min, 35 °C). The calibration was made using polystyrene standards with a narrow molecular weight distribution. Corrections for the flow rate fluctuations were made using toluene, with a retention time of 19.5 min, as an internal standard. CirrusTM GPC Software was used to process data. Nuclear Magnetic Resonance (NMR). The changes in the composition of the solid polymer matrix over time were followed by 1H NMR spectroscopy. Spectra were recorded using a Bruker Advance Nuclear Magnetic Resonance spectrometer operating at 400 MHz. Approximately 5 mg of sample was dissolved in 1 mL CDCl3 in a 5 mm sample tube. Nondeuterated chloroform was used as an internal standard (δ ) 7.26 ppm).

(3)

The effect of plasticizer architecture and hydrophilicity on the degradation rate and release of water-soluble compounds were evaluated by subjecting PLLA with cyclic oligolactide or linear oligolactic acid additives to hydrolytic degradation. Degradation Products. The ESI-MS analysis of methanol and/or methanol/water extracts from unhydrolyzed materials confirmed that PLLA-C originally contained homologous series of cyclic lactide oligomers, while PLLA-L contained linear lactic acid oligomers. For PLLA-C the ESI-MS analysis of the water used in the degradation study did not show any water-soluble products until after 2 weeks at 60 °C, Figure 1. The watersoluble migrants were identified as linear hydrolysis products from cyclic oligomers and from polylactide matrix. When aging PLLA-C at 37 °C, the first oligomeric degradation products were observed first after 13 weeks. However, in the case of PLLA-L containing linear oligomers, linear lactic acid oligomers were detected immediately after immersion in water, Figure 2. The initial rapid migration is explained by the migration of the linear oligolactic acid additives. On prolonged aging, however, the migrants also included hydrolysis products formed due to the hydrolysis of polylactide matrix. The peak intensity increased during hydrolysis until 2 weeks at 60 °C after which no visible differences between spectra with longer degradation time could be observed. Changes in Material Composition. 1H NMR spectroscopy was applied to follow the changes in composition of the solid polymer matrix over time. Figure 3 shows the NMR spectra of

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Figure 1. Positive ESI-MS spectra showing the water-soluble migrants from PLLA-C after hydrolysis in water at 60 °C for (a) 1 and (b) 2 weeks.

Figure 2. Positive ESI-MS spectra showing the water-soluble migrants from PLLA-L after hydrolysis in water at 60 °C for (a) 1 and (b) 2 weeks.

Figure 3. NMR spectra of solid samples dissolved in chloroform: (a) unaged PLLA-C, (b) PLLA-C subjected to hydrolytic degradation for 2 weeks at 60 °C, (c) unaged PLLA-L, and (d) PLLA-L subjected to hydrolytic degradation for 2 weeks at 60 °C.

PLLA-C and PLLA-L matrices before (a, c) and after degradation for 2 weeks at 60 °C (b, d). In the spectra of PLLA-C additional peaks, marked with arrows in Figure 3b, corresponding to the end groups became visible and more intense with degradation time, as the polymer chains were degraded into shorter chains. In the case of PLLA-L, peaks originating from the low molecular weight oligolactic acid additives were clearly

visible for example at 4.2 ppm, in the NMR spectra of the unhydrolyzed materials, Figure 3c. Analogous peaks for low molecular weight PLLA was also observed by Espartero et al.21 These peaks were not seen in the spectrum for unhydrolyzed PLLA with cyclic additives. After two weeks at 60 °C, there were only small signs of the additives left, Figure 3d, indicating rather rapid migration of the low molecular weight additives

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Figure 4. Average residual mass for PLLA-C and PLLA-L after different hydrolysis times and temperatures. Standard deviation indicated with bars. ([) PLLA-C 37 °C, (]) PLLA-L 37 °C, (b) PLLA-C 60 °C, (O) PLLA-L 60 °C.

from the material. Also the PLLA-L peaks corresponding to the end groups became visible with time and are marked with arrows in Figure 3d. Comparison of Figure 3b and d shows that, after 2 weeks of aging in water, the NMR spectrum of PLLA-L is basically analogous to the spectrum of PLLA-C. This correlates well with the ESI-MS analysis that showed rapid migration of the linear low molecular weight lactic acid additives into the water phase and no major changes in the degradation product patterns after the first two weeks. Mass Loss. Figure 4 shows the remaining mass for PLLA-C and PLLA-L as a function of hydrolysis time. The weight decreased continuously from the start of the experiment both during aging at 37 °C and at 60 °C. At 37 °C the weight decreased at a rather constant rate until 26 weeks after which the degradation rate slowed down. At 37 °C the mass loss for PLLA-L was generally 10-20% higher compared to the mass loss for PLLA-C. This is mainly explained by the migration of the linear oligolactic acid additives from the material. At 60 °C the hydrolysis of both materials proceeded quite rapidly and it was difficult to observe any significant differences between the materials based on the mass loss. After 13 weeks at 60 °C the mass loss was close to 100% for both of the materials, while only 30-50% mass loss was observed for the materials aged at 37 °C. After 26 weeks at 60 °C the samples had either completely degraded to water-soluble products or the remaining amount of material could not be reliably measured due to extensive fragmentation of the samples. Water Uptake. The observed mass loss followed the same pattern as the water uptake, Figure 5. Consequently, at 37 °C the water uptake for PLLA-C was about 10-20% lower compared to PLLA-L. The difference in water uptake between the two temperatures was about 40% after 7 weeks of aging. The migration of oligolactic acid additive led to a more porous structure that in turn could increase the water uptake and accelerate the hydrolysis of the PLLA matrix. However, a higher water uptake could also lead to faster transport of hydrolysis products from the sample matrix, which could slow down the degradation. The water contents shown in Figure 5 may for the extensively degraded samples be slightly overestimated compared to the actual value due to the difficulty of removing water from the surface of those samples. pH Variations. The pH change was followed for the aging solutions as it gives an indication of the amount of hydroxyacids released from the samples during hydrolysis. At 60 °C a rapid change in pH was observed for both aging solutions, and at prolonged aging, only a slight further pH decrease took place, Figure 6. At this temperature, the PLLA-L aging solutions

Andersson et al.

Figure 5. Average water uptake for PLLA-C and PLLA-L after different hydrolysis times and temperatures. Standard deviation indicated with bars. ([) PLLA-C 37 °C, (]) PLLA-L 37 °C, (b) PLLA-C 60 °C, (O) PLLA-L 60 °C.

Figure 6. pH of PLLA-C and PLLA-L after different hydrolysis times at 37 and 60 °C. Standard deviation indicated with bars. ([) PLLA-C 37 °C, (]) PLLA-L 37 °C, (b) PLLA-C 60 °C, (O) PLLA-L 60 °C. Table 1. Number Average Molecular Mass (Mn), Weight Average Molecular Mass (Mw), and Polydispersity Index of the Studied Materials before Hydrolysis material

Mn (g/mol)

Mw (g/mol)

PDI (%)

PLLA-C PLLA-L

97300 ( 9.5% 36700 ( 12.4%

230300 ( 1.5% 76400 ( 7.4%

2.4 ( 7.6% 2.1 ( 4.7%

reached their final pH value of 2.9 already after 2 weeks, which is consistent with the results from ESI-MS and NMR analysis. After 24 h at 60 °C some low molecular weight oligolactic acid had already migrated from PLLA-L, and thus, already a significant change in pH was observed in contrast to PLLA-C. This was confirmed by ESI-MS analysis, which clearly showed the fast release of oligomeric products from PLLA-L. During aging at 37 °C the difference in rate of the pH change followed the same pattern but proceeded at a slower rate. Also in this case the pH of the PLLA-L aging solutions initially decreased rapidly as the oligolactic acid was released from the matrix. For PLLA-C, the initial pH values measured after aging times shorter than 13 weeks at 37 °C are not shown in Figure 6 because they were not considered reliable due to the initial lack of ions in the deionized water. The major pH change for PLLA-C was measured first after 13 weeks, which corresponds to a mass loss of approximately 25%. This is approximately the same value as for PLLA-L after 4 weeks where the major drop in pH was measured. Molar Mass Changes. The molar masses and polydispersities of the unhydrolyzed materials are given in Table 1. For PLLA-L only the high molar mass peak was integrated. The linear



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Figure 7. Percentage of molar mass: (a) number average molecular mass (Mn) and (b) weight average molecular mass (Mw) remaining for PLLA-C and PLLA-L after hydrolysis as a function of different hydrolysis times at 37 and 60 °C. Standard deviation indicated with bars. ([) PLLA-C 37 °C, (]) PLLA-L 37 °C, (b) PLLA-C 60 °C, (O) PLLA-L 60 °C.

Figure 8. SEC chromatogram for PLLA-C hydrolyzed at (a) 37 °C. From top to bottom: unhydrolyzed, hydrolyzed for 24 h, 1, 4, 7, and 13 weeks. (b) At 60 °C. From top to bottom: unhydrolyzed, hydrolyzed for 24 h, 1, 2, and 7 weeks.

Figure 9. SEC chromatogram for PLLA-L hydrolyzed at (a) 37 °C. From top to bottom: unhydrolyzed, hydrolyzed for 24 h, 1, 4, 7, and 13 weeks. (b) At 60 °C. From top to bottom: unhydrolyzed, hydrolyzed for 24 h, 1, 2, 4, and 7 weeks.

oligolactic acid fraction was seen as a broad bump after the main peak, Figure 9. The lower initial molar mass of PLLA-L could be a result of transesterification reactions during manufacturing of the material. The change in molar mass with degradation time was more rapid for PLLA-L. The hydrolysis had a similar effect on both Mn and Mw, Figure 7, indicating that the distribution of chains with high and low molecular weight is rather constant. During aging at 37 °C the SEC curve of PLLA-C was monomodal, irrespective of aging time, Figure 8. However, after two weeks at 60 °C a bimodal SEC curve was observed. In the case of PLLA-L, a bimodal SEC curve was observed after 13 weeks at 37 °C and after 1 week at 60 °C, Figure 9. This behavior is probably due to the faster hydrolysis of the amorphous regions leading to faster molar mass decrease for the amorphous chains. The higher original degree of crystallinity for the PLLA-L film could explain the earlier formation of bimodal SEC curves. The ESI-MS analysis shows that the largest water-soluble degradation products have a molar mass around 1300 g/mol. The main peak in the SEC chromato-

grams for the materials hydrolyzed for 2 weeks at 60 °C is below this value, which indicates substantial degradation. Visual Examination. Before hydrolysis all the films were transparent and had a smooth and even surface structure. Examination of the aged samples revealed whitening of the surface of both materials already after 24 h at 37 °C. The observed whitening during hydrolysis is assumed to be an effect of molecular reorganization during degradation and has previously been concluded to be a result from accelerated spherulite formation.22,23 Already after 4 weeks at 60 °C the materials were fragile and the following drying of the samples caused breakage and fragmentation. With time, PLLA-L fell apart into smaller pieces, fragmenting to fine powder. Changes in Surface Morphology. SEM examination revealed holes on the surface of the PLLA-L film after aging for 7 weeks at 37 °C, Figure 10, while for PLLA-C no signs of degradation were visible. The large holes could be a result of migration of oligolactic acid additives not evenly distributed throughout the material as it has been shown in several previous

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Figure 10. SEM micrographs showing the surface of PLLA-L: (a) unaged, (b) hydrolyzed for 7 weeks at 37 °C, (c) hydrolyzed for 13 weeks at 37 °C, (d) hydrolyzed for 7 weeks at 60 °C, and (e) hydrolyzed for 13 weeks at 60 °C. Table 2. Initial Tg, Tc, wc, and Tm Values for the Materials from the Second DSC Heating Scan material

Tg (°C)

Tc (°C)

wc (%)

Tm (°C)

PLLA-C PLLA-L

57.1 ( 0.7 23.6 ( 3.1

96.8 ( 10.8

19.3 ( 4.3

133.6 ( 4.8

studies that increase in crystallinity with time can lead to formation of phase-separated microdomains.24 During the crystallization, plasticizers concentrate on the amorphous regions leading to holes during the subsequent hydrolysis. After hydrolysis at 60 °C for 7 weeks both the materials showed surface erosion throughout the whole surface. In addition, small holes, similar to those observed after aging at 37 °C, were observed for PLLA-L. Thermal Analysis. The changes in thermal properties and crystallinity during hydrolysis were monitored by differential scanning calorimetry, DSC. The initial Tm, Tg, Tc, and degree of crystallinity were taken from the second heating scan to compare the pure material properties and are given in Table 2. With hydrolysis time the glass transition temperatures for PLLA-L increased as the plasticizers migrated from the polymer matrix into the water phase. At the same time, the Tg for PLLA-C decreased due to the formation of shorter chains. As

Figure 11. The degree of crystallinity, wc, from the first heating scan after the films were aged for different times at 37 and 60 °C. ([) PLLA-C 37 °C, (]) PLLA-L 37 °C, (b) PLLA-C 60 °C, (O) PLLA-L 60 °C.

a result, the Tg values for the two materials taken from the second heating approached the same temperature with time. The addition of oligolactic acid gave a lower Tg, which can initially favor degradation, however, at the same time oligolactic acid facilitated crystallization, probably by functioning as a nucleation agent. This explains the behavior displayed in Figure 11, where


the PLLA-L film initially had a higher degree of crystallinity. This difference, however, decreased as the hydrolysis proceeded. It can also be seen that the degree of crystallinity increased as the degradation time increased. This is related to the decreasing amount of amorphous material and to the increased mobility of the chains and the possibility for the polymer chains to reorganize and crystallize.3,22,25 The ability to reorganize is both due to the shortening of the chains as well as the increased chain flexibility, which is a result of the swelling of the amorphous phase. The degree of crystallinity obtained from the second heating was somewhat lower because of the shorter crystallization time. This was again more apparent for PLLAC. After aging at 37 °C, PLLA-C had a lower degree of crystallinity compared to PLLA-L, this correlates with the lower initial degree of crystallinity. When the samples were heated for the second time, clear peaks for crystallization and melting were observed for PLLA-L, even for the samples that had not been subjected to hydrolytic degradation. This is a result of the larger free space promoting crystal formation. In addition, the oligolactic acids could function as nucleation agents. The DSC measurements showed that the melting temperatures, taken from the first heating scan to evaluate the effects of the aging, decreased with hydrolysis time. The reasons for this behavior are the formation of smaller crystals and the decreasing molecular weight.25 The melting peak for all the materials was around 140 °C. Tm taken from the second heating was lower compared to the one recorded in the first heating because the shorter chains, formed in the degradation process, can be included in new crystals.25 The majority of the melting endotherms, especially from the second heating show bimodality. A reason for this could be lamellar rearrangement, which can occur during crystallization and this could be an indication of the formation of crystals of different thicknesses.

Conclusions The possibility to tune the hydrolytic degradation rate of polylactide by plasticizer architecture and hydrophilicity was shown. The water uptake by the materials was increased by introduction of the more hydrophilic oligolactic acid. The linear oligolactic acid rapidly migrated from the films as shown by mass loss, pH changes, and ESI-MS analysis of aging water. The migration of oligolactic acid led to porous materials with increased susceptibility to further hydrolysis. This was probably counteracted by the somewhat higher degree of crystallinity in the film containing linear lactic acid oligomers. During hydrolysis at 60 °C, that is, above the glass transition temperature, the weight loss, molar mass loss, and release of low molecular weight products were drastically larger and the differences between PLLA-C and PLLA-L films were not as obvious as at 37 °C. The time frame for formation of water-soluble products was influenced by the architecture and hydrophilicity of the plasticizer. The advantage with oligolactide and oligolactic acid plasticizers was clearly demonstrated as they did not introduce


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any new migrants into the degradation product patterns. A crucial point especially for materials to be used in biomedical applications.26 Acknowledgment. The authors gratefully acknowledge the European Community Sixth Framework Programme Sustainable Microbial and Biocatalytic Production of Advanced Functional Materials (BIOPRODUCTION) under the Contract Number NMP2-CT-2007-026515 for financial support of this work. Hycail Finland is thanked for providing the PLA materials.

References and Notes (1) Hakkarainen, M.; Ho¨glund, A.; Odelius, K.; Albertsson, A.-C. J. Am. Chem. Soc. 2007, 129, 6308–6312. (2) Hakkarainen, M.; Adamus, G.; Ho¨glund, A.; Kowalczuk, M.; Albertsson, A.-C. Macromolecules 2008, 41, 3547–3554. (3) Hakkarainen, M.; Albertsson, A.-C.; Karlsson, S. Polym. Degrad. Stab. 1996, 52, 283–291. (4) Wanamaker, C. L.; Tolman, W. B.; Hillmyer, M. A. Biomacromolecules 2009, 10, 443–448. (5) Hakkarainen, M.; Albertsson, A.-C. AdV. Polym. Sci. 2008, 211, 85– 116. (6) Ho¨glund, A.; Hakkarainen, M.; Kowalczuk, M.; Adamus, G.; Albertsson, A.-C. J. Polym. Sci., Part A: Polym. Chem. 2008, 46, 4617– 4629. (7) Ho¨glund, A.; Hakkarainen, M.; Edlund, U.; Albertsson, A.-C. Langmuir 2009, 26, 378–383. (8) Andersson, S. R.; Hakkarainen, M.; Inkinen, S.; So¨dergård, A.; Albertsson, A.-C. Biomacromolecules 2010, 11, 1067–1073. (9) Anderson, K. S.; Schreck, K. M.; Hillmyer, M. A. Polym. ReV. 2008, 48, 85–108. (10) Antheunis, H.; van der Meer, J.-C.; de Geus, M.; Heise, A.; Koning, C. E. Biomacromolecules , 11, 1118–1124. (11) Sinclair, R. G. J. Macromol. Sci., Part A: Pure Appl. Chem. 1996, 33, 585–597. (12) Martin, O.; Ave´rous, L. Polymer 2001, 42, 6209–6219. (13) Labrecque, L. V.; Kumar, R. A.; Dave´, V.; Gross, R. A.; McCarthy, S. P. J. Appl. Polym. Sci. 1997, 66, 1507–1513. (14) Ren, Z.; Dong, L.; Yang, Y. J. Appl. Polym. Sci. 2006, 101, 1583– 1590. (15) Baiardo, M.; Frisoni, G.; Scandola, M.; Rimelen, M.; Lips, D.; Ruffieux, K.; Wintermantel, E. J. Appl. Polym. Sci. 2003, 90, 1731– 1738. (16) Jacobsen, S.; Fritz, H. G. Polym. Eng. Sci. 1999, 39, 1303–1310. (17) Ljungberg, N.; Wesslen, B. Biomacromolecules 2005, 6, 1789–1796. (18) Ho¨glund, A.; Hakkarainen, M.; Albertsson, A.-C. Biomacromolecules 2009, 11, 277–283. (19) Kulinski, Z.; Piorkowska, E.; Gadzinowska, K.; Stasiak, M. Biomacromolecules 2006, 7, 2128–2135. (20) Fischer, E. W.; Sterzel, H. J.; Wegner, G. Colloid Polym. Sci. 1973, 251, 980–990. (21) Espartero, J. L.; Rashkov, I.; Li, S. M.; Manolova, N.; Vert, M. Macromolecules 1996, 29, 3535–3539. (22) So¨dergård, A.; Stolt, M. Prog. Polym. Sci. 2002, 27, 1123–1163. (23) Cam, D.; Hyon, S.-h.; Ikada, Y. Biomaterials 1995, 16, 833–843. (24) Murariu, M.; Da Silva Ferreira, A.; Alexandre, M.; Dubois, P. Polym. AdV. Technol. 2008, 19, 636–646. (25) Li, S.; Garreau, H.; Vert, M. J. Mater. Sci.: Mater. Med. 1990, 1, 198–206. (26) van Sliedregt, A.; van Loon, J. A.; van der Brink, J.; de Groot, K.; van Blitterswijk, C. A. Biomaterials 1994, 15, 251–256.

BM101075P

Tuning the Polylactide Hydrolysis Rate by Plasticizer Architecture and

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