Next Article in Journal
Deacetylation of Chitosan: Material Characterization and in vitro Evaluation via Albumin Adsorption and Pre-Osteoblastic Cell Cultures
Next Article in Special Issue
The Effect of Synovial Fluid Enzymes on the Biodegradability of Collagen and Fibrin Clots
Previous Article in Journal
Large-Scale Growth of Tubular Aragonite Whiskers through a MgCl2-Assisted Hydrothermal Process
Previous Article in Special Issue
Controlled Delivery of Gentamicin Using Poly(3-hydroxybutyrate) Microspheres
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Synthesis and Hydrolytic Degradation of Substituted Poly(DL-Lactic Acid)s

Department of Environmental and Life Sciences, Graduate School of Technology, Toyohashi University of Technology, Tempaku-cho, Toyohashi, Aichi 441-8580, Japan
*
Author to whom correspondence should be addressed.
Materials 2011, 4(8), 1384-1398; https://doi.org/10.3390/ma4081384
Submission received: 25 May 2011 / Revised: 27 July 2011 / Accepted: 29 July 2011 / Published: 10 August 2011
(This article belongs to the Special Issue Biodegradability of Materials in Biomedical Applications 2011)

Abstract

:
Non-substituted racemic poly(DL-lactic acid) (PLA) and substituted racemic poly(DL-lactic acid)s or poly(DL-2-hydroxyalkanoic acid)s with different side-chain lengths, i.e., poly(DL-2-hydroxybutanoic acid) (PBA), poly(DL-2-hydroxyhexanoic acid) (PHA), and poly(DL-2-hydroxydecanoic acid) (PDA) were synthesized by acid-catalyzed polycondensation of DL-lactic acid (LA), DL-2-hydroxybutanoic acid (BA), DL-2-hydroxyhexanoic acid (HA), and DL-2-hydroxydecanoic acid (DA), respectively. The hydrolytic degradation behavior was investigated in phosphate-buffered solution at 80 and 37 °C by gravimetry and gel permeation chromatography. It was found that the reactivity of monomers during polycondensation as monitored by the degree of polymerization (DP) decreased in the following order: LA > DA > BA > HA. The hydrolytic degradation rate traced by DP and weight loss at 80 °C decreased in the following order: PLA > PDA > PHA > PBA and that monitored by DP at 37 °C decreased in the following order: PLA > PDA > PBA > PHA. LA and PLA had the highest reactivity during polymerization and hydrolytic degradation rate, respectively, and were followed by DA and PDA. BA, HA, PBA, and PHA had the lowest reactivity during polymerization and hydrolytic degradation rate. The findings of the present study strongly suggest that inter-chain interactions play a major role in the reactivity of non-substituted and substituted LA monomers and degradation rate of the non-substituted and substituted PLA, along with steric hindrance of the side chains as can be expected.

1. Introduction

Poly(hydroxyalkanoate)s [i.e., poly(hydroxyalkanoic acid)s or PHAs] such as polylactide [i.e., poly(lactic acid)], poly(glycolide) [i.e., poly(glycolic acid)], poly(3-hydroxybutyrate) [i.e., poly(3-hydroxybutanoic acid)], poly(ε-caprolactone) [i.e., poly(6-hydroxyhexanoic acid)], and their copolymers have been used as scaffolds and pharmaceutical materials whose hydrolytic degradation behavior in vivo should be accurately manipulated [1,2,3,4,5,6,7]. Polylactide and polyglycolide are kinds of poly(2-hydroxyalkanoic acid); poly(3-hydroxybutyrate) is a kind of poly(3-hydroxyalkanoic acid); and poly(ε-caprolactone) is a kind of poly(6-hydroxyalkanoic acid). The degradation in vivo and enzymatic and non-enzymatic hydrolytic degradation in vitro of poly(lactic acid)—a PHA—have been intensively researched [7]; poly(lactic acid) has also been investigated in terms of its molecular weight [8,9,10,11,12], tacticity [8,11,12,13,14], comonomer type [13,15,16,17,18,19], additives such as polymers [20,21,22,23,24,25,26,27,28,29,30,31], crystallinity [32,33,34], crystalline size [35,36,37,38,39], orientation [40,41,42,43,44], and material morphology [45,46,47]. The molecular weight and comonomer type are crucial parameters for determining the hydrolytic degradation rate and mechanism of poly(lactic acid) [7]. The hydrolytic degradation rate has been found to increase by decreasing the molecular weight and to decrease by incorporating a hydrophilic comonomer.
Poly(2-hydroxybutyrate) also known as poly(2-hydroxybutyric acid) or poly(2-hydroxybutanoic acid [P(2HB)] can be synthesized from 2-hydroxybutanoic acid with a chiral α-carbon. The structure of P(2HB) (Figure 1) is similar to that of PLA, the methyl group of the latter being substituted with an ethyl group. Baker et al. intensively synthesized a wide variety of substituted PLAs, including P(2HB), and investigated their physical properties and thermal degradation [48,49,50]. In their study, most of the synthesized polymers were racemic and noncrystallizable. Tsuji et al. synthesized optically active phenyl-substituted PLA (Figure 1) and its copolymers with lactic acid and investigated their crystallization behavior and thermal properties [51]. They also synthesized optically active and crystallizable poly(L-2-hydroxybutyrate) [P(L-2HB)] and poly(D-2-hydroxybutyrate) [P(D-2HB)] and found that stereocomplexation occurs in the blends of P(L-2HB) and P(D-2HB), which enhances the crystallization and hydrolytic/thermal degradation resistance compared to intact P(L-2HB) or P(D-2HB) [52,53]. Very recently, they found that hetero-stereocomplexation occurs between poly(D-lactic acid) (PDLA) and P(L-2HB) or between poly(L-lactic acid) (PLLA) and P(D-2HB) [54]. Interestingly, PDLA is reported to have a stronger interaction with the L-form of phenyl-substituted PLA than with the D-form [55].
Figure 1. Molecular structures of substituted and non-substituted poly(DL-lactic acid)s (PLAs).
Figure 1. Molecular structures of substituted and non-substituted poly(DL-lactic acid)s (PLAs).
Materials 04 01384 g001
However, in spite of numerous studies on the hydrolytic degradation behavior of PLA and PGA and their copolymers [7], few reports can be found for other P(2HB)s. Reported examples for P(2HB) are those of enzymatic and nonenzymatic degradation of poly(lactic acid-co-mandelic acid or phenyllactic acid), which are copolymers with lactic acid units, methyl groups of which are substituted with aromatic groups [56,57,58]. To the best of our knowledge, no report on hydrolytic degradation of PLA homopolymers, methyl groups of which are substituted with other aliphatic groups, has been published so far. In the present study, we synthesized PLA homopolymers, the methyl groups of which are substituted with other aliphatic groups, such as ethyl, butyl, or octyl groups, as well as non-substituted PLA homopolymer (Figure 1) by a conventional polycondensation method and investigated the hydrolytic degradation behavior of the substituted and non-substituted PLA homopolymers. Here, we used racemic DL-monomers to obtain noncrystallizable substituted and non-substituted PLA homopolymers to exclude the effects of highly ordered structures formed by crystallization during specimen preparation and hydrolytic degradation on hydrolytic degradation behavior.

2. Experimental Section

2.1. Materials

Substituted and non-substituted PLA polymers were synthesized by polycondensation or step-growth polymerization of DL-lactic acid (abbreviated as LA, Wako Pure Chemical Industries, Ltd., Tokyo, Japan), DL-2-hydroxybutanoic acid (butyric acid or BA) (Tokyo Chemical Industry Co., Ltd., Tokyo, Japan), DL-2-hydroxyhexanoic acid or HA (Sigma-Aldrich Co., St. Louis, MO), and DL-2-hydroxydecanoic acid or DA (Wako Pure Chemical Industries, Ltd., Tokyo, Japan) at 130 °C with 2.5 wt% of p-toluenesulfonic acid monohydrate (Nacalai Tesque, Inc., Kyoto, Japan) under a constant nitrogen gas flow. For monitoring synthesis, the polymerization of monomers was performed at atmospheric pressure for 5 h (first polymerization step) and then under reduced pressure of 2.7 kPa (20 mmHg) for up to 24 h (second polymerization step) [51,52]. For the synthesis of polymers having number-average molecular weight (Mn) of several thousands for hydrolytic degradation experiments, the second polymerization step was carried out for 24 h. The synthesized polymers from BA, HA, and DA (PBA, PHA, and PDA, respectively) were purified with precipitation with chloroform and methanol/water (v/v = 1/1) as a solvent and non-solvent. The synthesized polymer from LA (PLA) was purified by the same procedure, although acetone was used as the solvent instead of chloroform. The precipitated polymers were dried under reduced pressure for at least 7 days. The purified PLA was a fragile solid, whereas PBA, PHA, and PDA were highly viscous liquids.

2.2. Hydrolytic Degradation

Hydrolytic degradation of each sample (20 mg) was performed using the purified polymers in 100 mL of phosphate-buffered solution (pH 7.4) at 80 °C or 37 °C. After hydrolytic degradation, the samples were rinsed with fresh distilled water, soaked in fresh distilled water for 1 h, soaked for another 3 h in a new batch of fresh distilled water, and then dried under reduced pressure for at least 7 days. Although the polymerization and hydrolytic degradation were performed once in the present study, the subsequent investigations indicated similar dependences of the rates of polymerization [at fixed catalyst concentrations (mol%) and under atmospheric pressure] and hydrolytic degradation on the monomer type.

2.3. Measurements

The respective weight and number-average molecular weights (Mw and Mn, respectively) of polymers were evaluated in chloroform at 40 °C by a Tosoh (Tokyo, Japan) GPC system with two TSK gel columns (GMHXL) using polystyrene standards. Therefore, the molecular weights are relative to polystyrene.

3. Results

3.1. Synthesis

In the first polymerization step, each monomer was polymerized by polycondensation to yield its oligomers at 130 °C at atmospheric pressure for 5 h to have a sufficiently high molecular weight not to be removed under reduced pressure in the second polymerization step. In the second polymerization step, thus formed oligomers were further polymerized by polycondensation under reduced pressure at 130 °C for 24 h [50,51]. Figure 2 shows the changes in molecular weight distribution curves of PLA, PBA, PHA, and PDA during the second polymerization under reduced pressure. As seen, whole curves shifted to a higher molecular weight with the second polymerization. Table 1 and Figure 3 show Mn, molecular weight distribution (Mw/Mn), the degree of polymerization estimated from Mn, (DP), and DPaDPb of PLA, PBA, PHA, and PDA during the first polymerization step of the monomers at atmospheric pressure and the second polymerization step under reduced pressure. Here, DPa and DPb are DP before and after polymerization, respectively, and DPb for the first polymerization step is one. As seen in Table 1 and Figure 3, the DP and DPaDPb of polymers after the first polymerization step for 5 h and the second polymerization step for 24 h decreased in the following orders: PLA > PDA > PHA ≅ PBA and PLA > PDA > PBA > PHA, respectively. The catalytic p-toluenesulfonic acid concentrations for LA, BA, HA, and DA during polymerization per mol monomer were 1.18, 1.37, 1.74, and 2.61 × 10−2 (mol/mol). The catalytic concentration and, therefore, its effect should decrease in the following order: DA > HA > BA > LA. However, the highest DPaDPb value of PLA despite the lowest catalytic concentration for LA and the lowest DPaDPb value of PHA despite the second highest catalytic value for HA should be due to the highest and lowest reactivities of LA and HA, respectively. For reference, we calculated the DPaDPb relative to the catalytic concentrations (mol/mol). The calculated values were 277, 42, 34, and 112 (mol/mol) for PLA, PBA, PHA, and PDA after the first polymerization step for 5 h and 2273, 503, 285, and 376 (mol/mol) after the second polymerization step for 24 h. These values and, therefore, the actual reactivity values of the monomers in the presence of p-toluenesulfonic acid decreased in the following order: LA > DA > BA > HA for the first step and LA > BA > DA > HA for the second step. The former trend is consistent with the aforementioned non-normalized DP and DPaDPb values after the second polymerization step.
Figure 2. Molecular weight distribution curves of PLA (a); poly(DL-2-hydroxybutanoic acid) (PBA) (b); poly(DL-2-hydroxyhexanoic acid) (PHA) (c); and poly(DL-2-hydroxydecanoic acid) (PDA) (d) before the second polymerization step (0 h) and after polymerization under reduced pressure for 24 h.
Figure 2. Molecular weight distribution curves of PLA (a); poly(DL-2-hydroxybutanoic acid) (PBA) (b); poly(DL-2-hydroxyhexanoic acid) (PHA) (c); and poly(DL-2-hydroxydecanoic acid) (PDA) (d) before the second polymerization step (0 h) and after polymerization under reduced pressure for 24 h.
Materials 04 01384 g002
Table 1. Number-average molecular weight (Mn), molecular weight distribution (Mw/Mn), and degree of polymerization (DP) of 2-hydroxyalkanoic acid homopolymers after the first polymerization step at atmospheric pressure for 5 h and subsequent second polymerization for 24 h under reduced pressure.
Table 1. Number-average molecular weight (Mn), molecular weight distribution (Mw/Mn), and degree of polymerization (DP) of 2-hydroxyalkanoic acid homopolymers after the first polymerization step at atmospheric pressure for 5 h and subsequent second polymerization for 24 h under reduced pressure.
CodeAfter first polymerization step at atmospheric pressure for 5 hours After second polymerization step under reduced pressure for 24 hours
Mn a)Mw/Mn a)DPDPaDPb b) Mn a)Mw/Mn a)DPDPaDPb b)
PLA3091.404.293.29 (4.29–1) 22504.2331.226.9 (31.2–4.3)
PBA1352.131.560.56 (1.56–1) 7283.248.466.90 (8.46–1.56)
PHA1822.181.590.59 (1.59–1) 7483.506.554.96 (6.55–1.59)
PDA6682.953.922.92 (2.92–1) 23403.0513.79.8 (13.7–3.9)
a) Mn and Mw are the number- and weight-average molecular weights, respectively.
b) DPb and DPa are DP before and after polymerization, respectively. The actual calculation is shown in the parentheses.
Figure 3. Mn (a), DP estimated from Mn (b), and molecular weight distribution (Mw/Mn) (c) of PLA, PBA, PHA, and PDA during the second polymerization step under reduced pressure at different times, as a function of reaction time.
Figure 3. Mn (a), DP estimated from Mn (b), and molecular weight distribution (Mw/Mn) (c) of PLA, PBA, PHA, and PDA during the second polymerization step under reduced pressure at different times, as a function of reaction time.
Materials 04 01384 g003

3.2. Hydrolytic Degradation at 80 °C

Figure 4 shows the weight loss values of PLA, PBA, PHA, and PDA during hydrolytic degradation at 80 °C as a function of degradation time. The weight loss is an indicator of the fraction of water-soluble oligomers and monomers that are formed by hydrolytic degradation and diffused out of the mother material. The weight loss of all polymers increased monotonically with degradation time, without any induction period. The rate of weight loss, with the exception of PDA at 3 days, decreased in the following order: PLA > PDA > PHA > PBA. This trend is consistent with that for the reactivity of the monomers, with the exception of PHA. The higher values of PHA compared to those of PBA may be ascribed to the lowest starting DP value of 8.7 (Table 2).
Figure 4. Weight loss of PLA, PBA, PHA, and PDA during hydrolytic degradation at 80 °C, as a function of degradation time.
Figure 4. Weight loss of PLA, PBA, PHA, and PDA during hydrolytic degradation at 80 °C, as a function of degradation time.
Materials 04 01384 g004
Table 2. Mn, Mw/Mn, and DP of PLA, PBA, PHA, and PDA after hydrolytic degradation at 80 °C for 4 days and at 37 °C for 28 days.
Table 2. Mn, Mw/Mn, and DP of PLA, PBA, PHA, and PDA after hydrolytic degradation at 80 °C for 4 days and at 37 °C for 28 days.
CodeAfter Purification (Before hydrolytic degradation) After hydrolytic degradation at 80 °C for 4 days After hydrolytic degradation at 37 °C for 28 days
Mn a)Mw/Mn a)DP Mn a)Mw/Mn a)DP Mn a)Mw/Mn a)DP
PLA38502.4653.5 3501.924.85 8566.0211.9
PBA8613.0510.0 4502.285.23 5733.226.66
PHA9912.778.68 3862.173.38 6573.305.75
PDA29103.6617.1 7992.394.69 14363.548.43
a) Mn and Mw are the number- and weight-average molecular weights, respectively.
Figure 5 shows the molecular weight distribution curves of PLA, PBA, PHA, and PDA before hydrolytic degradation and after hydrolytic degradation at 80 °C for 4 days. Table 2 and Figure 6 show Mn, DP estimated from Mn, and molecular weight distribution (Mw/Mn) of PLA, PBA, PHA, and PDA during hydrolytic degradation. The degradation rate was calculated according to the following equation [59]:
ln D P ( t 2 ) = ln D P ( t 1 ) k ( t 2 t 1 ) ,
where DP(t2) and DP(t1) are DP values at degradation times of t2 and t1, respectively. The k values thus obtained 0.506, 0.091, 0.230, and 0.337 day−1 for PLA, PBA, PHA, and PDA, respectively. The k values of the polymers decreased in the following order: PLA > PDA > PHA > PBA. Owing to the difficulty of synthesis of substituted PLA homopolymers including poly(mandelic acid), the hydrolytic or enzymatic degradation rates or k values have been reported only for the copolymers of LA with BA, DL-2-hydroxy-3-methylbutanoic acid, DL-2-hydroxy-4-methylpentanoic acid, phenyllactic acid, or mandelic acid [56,57,58]. Most Mw/Mn values were in the range of 2 to 3. This is in marked contrast with crystalline PLLA, which showed Mw/Mn values over 4 [34].
Figure 5. Molecular weight distribution curves of PLA (a), PBA (b), PHA (c), and PDA (d) before hydrolytic degradation (0 days) and after hydrolytic degradation at 80 °C for 4 days.
Figure 5. Molecular weight distribution curves of PLA (a), PBA (b), PHA (c), and PDA (d) before hydrolytic degradation (0 days) and after hydrolytic degradation at 80 °C for 4 days.
Materials 04 01384 g005
Figure 6. Mn (a), DP estimated from Mn (b), and molecular weight distribution (Mw/Mn) (c) of PLA, PBA, PHA, and PDA, during hydrolytic degradation at 80 °C, as a function of degradation time.
Figure 6. Mn (a), DP estimated from Mn (b), and molecular weight distribution (Mw/Mn) (c) of PLA, PBA, PHA, and PDA, during hydrolytic degradation at 80 °C, as a function of degradation time.
Materials 04 01384 g006

3.3. Hydrolytic degradation at 37 °C

Figure 7 shows the weight loss values of PLA, PBA, PHA, and PDA during hydrolytic degradation at 37 °C as a function of degradation time. Similar to the weight loss at 80 °C, the weight loss of all polymers at 37 °C increased monotonically with degradation time, without any induction period. For the degradation period of 7–21 days, PBA showed the highest weight loss, whereas PLA, PHA, and PDA showed similar weight losses that were lower. The weight loss of PLA was highest at a degradation period of 28 days. Due to the low and dispersed weight loss values at 37 °C, the hydrolytic degradation rate at that temperature is not discussed here.
Figure 7. Weight loss of PLA, PBA, PHA, and PDA during hydrolytic degradation at 37 °C, as a function of degradation time.
Figure 7. Weight loss of PLA, PBA, PHA, and PDA during hydrolytic degradation at 37 °C, as a function of degradation time.
Materials 04 01384 g007
Figure 8 shows the molecular weight distribution curves of PLA, PBA, PHA, and PDA before hydrolytic degradation (0 day) and after hydrolytic degradation at 37 °C for 28 days. Figure 9(a)–(c) shows Mn, DP estimated from Mn, and Mw/Mn of PLA, PBA, PHA, and PDA during hydrolytic degradation. The k values calculated according to equation (1) were 5.08, 1.76, 1.44, 2.02 × 10−2 day−1, for PLA, PBA, PHA, and PDA, respectively. The k values decreased in the following order: PLA > PDA > PBA > PHA. This trend is consistent with the reactivity of the monomers.
Figure 8. Molecular weight distribution curves of PLA (a), PBA (b), PHA (c), and PDA (d) before hydrolytic degradation (0 days) and after hydrolytic degradation at 37 °C for 28 days.
Figure 8. Molecular weight distribution curves of PLA (a), PBA (b), PHA (c), and PDA (d) before hydrolytic degradation (0 days) and after hydrolytic degradation at 37 °C for 28 days.
Materials 04 01384 g008
Figure 9. Mn (a), DP estimated from Mn (b), and molecular weight distribution (Mw/Mn) (c) of PLA, PBA, PHA, and PDA during hydrolytic degradation at 37 °C, as a function of degradation time.
Figure 9. Mn (a), DP estimated from Mn (b), and molecular weight distribution (Mw/Mn) (c) of PLA, PBA, PHA, and PDA during hydrolytic degradation at 37 °C, as a function of degradation time.
Materials 04 01384 g009

4. Discussion

The hydrolytic degradation rate is known to vary with molecular and highly ordered structures and material shapes [1,2,3,4,5,6,7,60]. In the present study, amorphous poly(DL-2-hydroxyalkanoic acid)s were used to eliminate the effects of highly ordered structures such as crystallinity. The molecular weight, the structures of terminal groups, and material shape are crucial for the hydrolytic degradation [60]. All the poly(DL-2-hydroxyalkanoic acid)s were synthesized by the same method and, therefore, the structures of terminal groups should be identical. For precise comparisons of the hydrolytic degradation rates of poly(DL-2-hydroxyalkanoic acid)s with different side chain lengths, the polymers with the similar DP values should be used. However, due to the differences in the reactivities of DL-2-hydroxyalkanoic acids with different side chain lengths, the poly(DL-2-hydroxyalkanoic acid)s had different DP values. Nevertheless, since polymerization and hydrolytic degradation are inverse reactions, the poly(DL-2-hydroxyalkanoic acid) synthesized from higher reactive monomers will have higher hydrolytic degradation rates. In other words, poly(DL-2-hydroxyalkanoic acid) with higher DP values after polymerization or before hydrolytic degradation will have higher hydrolytic degradation rates. The hydrolytic degradation rate decreased in the following order: PLA > PDA > PBA > PHA, which is consistent with that of monomer reactivity traced by DP: LA > DA > BA > HA (or HA > BA). This result suggests that the effects of monomer unit structure dominate those of DP.
If the rates of polymerization and hydrolytic degradation solely depend on the steric hindrance of side groups of the monomers and polymers, i.e., methyl, ethyl, butyl, and octyl groups for LA and PLA, BA and PBA, HA and PHA, and DA and PDA, respectively, the reaction rate should decrease in the following order: PLA (LA) > PBA (BA) > PHA (HA) > PDA (DA). This trend is based on the assumption that steric hindrance disturbs the formation and hydrolytic degradation of ester groups. However, the relative reaction rate when monitored by DP or weight loss in the present study was found to be PLA (LA) > PDA (DA) > PBA (BA) > PHA (HA) [or PHA (HA) > PBA (BA)]. This indicates that there must be an additional factor enhancing the polymerization and hydrolytic degradation of DA and PDA. It is probable that the weakest inter-chain interaction of PDA due to its largest side chains may have assisted in the removal of water molecules from the formed mixtures of oligomers and the diffusion of water molecules to the ester groups during hydrolytic degradation, although the highest hydrophobicity of PDA with the longest octyl side groups may help in the removal of water molecules during polymerization but disturbs the approach of water molecules during hydrolytic degradation. As stated in a review article [60], hydrophilicity and inter-chain interactions, which can be monitored by water absorption and glass transition temperature, will affect the rates of polymerization and hydrolytic degradation. However, these two indicators could not be measured in the present study due to the low molecular weights of the synthesized polymers. Further detailed studies using the polymers with high and similar molecular weights are required to investigate exact causes for the different reactivities of polymers.

5. Conclusions

The reactivity of monomers during polycondensation monitored by DP decreased in the following order: LA > DA > BA > HA, whereas the hydrolytic degradation rate traced by DP and weight loss at 80 °C decreased in the following order: PLA > PDA > PHA > PBA and that monitored by DP at 37 °C decreased in the following order: PLA > PDA > PBA > PHA. LA and PLA had the highest reactivity during polymerization and degradation rate, respectively, followed by DA and PDA; BA, HA, PBA, and PHA had the lowest reactivity and degradation rates. The findings of the present study strongly suggest that not only the steric hindrance of the side chains but also the inter-chain interaction determine the reactivity of the non-substituted and substituted LA monomers and the hydrolytic degradation rate of the non-substituted and substituted PLA.

Acknowledgement

We are grateful to Hiroaki Sugiyama for the supplementary experiments of the present study.

References

  1. Biodegradable Polymers and Plastics; Vert, M.; Feijen, J.; Albertsson, A.-C.; Scott, G.; Chiellini, E. (Eds.) Royal Society of Chemistry: Cambridge, UK, 1992.
  2. Plastics from Microbes; Mobley, D.P. (Ed.) Hanser Publishers: New York, NY, USA, 1994.
  3. Handbook of Biodegradable Polymers (Drug Targeting and Delivery); Domb, A.J.; Kost, J.; Wieseman, D.M. (Eds.) Harwood Academic Publishers: Amsterdam, The Netherlands, 1997; Volume 7.
  4. Biopolymers from Renewable Resources; Kaplan, D.L. (Ed.) Springer: Berlin, Germany, 1998.
  5. Degradable Aliphatic Polyesters (Advances in Polymer Science); Albertsson, A.-C. (Ed.) Springer: Berlin, Germany, 2002; Volume 157.
  6. Polyesters I, II, III (Biopolymers); Doi, Y.; Steinbüchel, A. (Eds.) Wiley-VCH: Weinheim, Germany, 2002; Volume 3a, 3b, 4.
  7. Tsuji, H. Hydrolytic Degradation, in Poly(lactic acid): Synthesis, Structures, Properties, Processing, and Applications (Wiley Series on Polymer Engineering and Technology); Auras, R., Lin, L.-T., Selke, S.E.M., Tsuji, H., Eds.; John Wiley & Sons, Inc.: Hoboken, NJ, USA, 2010; pp. 345–381. [Google Scholar]
  8. Fukuzaki, H.; Yoshida, M.; Asano, M.; Kumakura, M. Synthesis of Copoly(D,L-lactic acid) with relatively low molecular weight and in vitro degradation. Eur. Polym. J. 1989, 25, 1019–1026. [Google Scholar] [CrossRef]
  9. Hyon, S.H.; Jamshidi, K.; Ikada, Y. Effects of residual monomer on the degradation of DL-lactide polymer. Polym. Int. 1998, 46, 196–202. [Google Scholar] [CrossRef]
  10. Cam, D.; Hyon, S.H.; Ikada, Y. Degradation of high molecular weight poly(-lactide) in alkaline medium. Biomaterials 1995, 16, 833–843. [Google Scholar] [PubMed]
  11. Tsuji, H.; Miyauchi, S. Enzymatic hydrolysis of poly(lactide)s: Effects of molecular weight, L-lactide content, and enantiomeric and diastereoisomeric polymer blending. Biomacromolecules 2001, 2, 597–604. [Google Scholar] [CrossRef] [PubMed]
  12. Saha, S.K.; Tsuji, H. Effects of molecular weight and small amounts of D-lactide units on hydrolytic degradation of poly(L-lactic acid)s. Polym. Degrad. Stab. 2006, 91, 1665–1673. [Google Scholar] [CrossRef]
  13. Tsuji, H.; Tezuka, Y. Alkaline and enzymatic degradation of L-lactide copolymers, 1: Amorphous-made Films of L-lactide copolymers with D-lactide, glycolide, and ε-caprolactone. Macromol Biosci. 2005, 5, 135–148. [Google Scholar] [PubMed]
  14. Tsuji, H. Autocatalytic Hydrolysis of amorphous-made polylactides: Effects of L-lactide content, tacticity, and enantiomeric polymer blending. Polymer 2002, 43, 1789–1796. [Google Scholar] [CrossRef]
  15. Reed, A.M.; Gilding, D.K. Biodegradable polymers for use in surgery-poly(glycolic)/poly(lactic acid) homo and copolymers: 2. In vitro degradation. Polymer 1981, 22, 494–498. [Google Scholar]
  16. Vert, M.; Li, S.M.; Garreau, H. More about the degradation of LA/GA-derived matrices in aqueous media. J. Control. Release 1991, 16, 15–26. [Google Scholar] [CrossRef]
  17. Vert, M.; Li, S.M.; Garreau, H. New insights on the degradation of bioresorbable polymeric devices based on lactic and glycolic acids. Clin. Mater. 1992, 10, 3–8. [Google Scholar] [CrossRef] [PubMed]
  18. Vert, M.; Mauduit, J.; Li, S.M. Biodegradation of PLA/GA polymers: Increasing complexity. Biomaterials 1994, 15, 1209–1213. [Google Scholar] [PubMed]
  19. Li, S.M. Hydrolytic degradation characteristics of aliphatic polyesters derived from lactic and glycolic acids. J. Biomed. Mater. Res. (Appl. Mater.) 1999, 48, 342–353. [Google Scholar] [CrossRef]
  20. Kishida, A.; Yoshioka, S.; Takeda, Y.; Uchiyama, M. Base-induced polymer hydrolysis in poly(β-hydroxybutyrate/β-hydroxyvalerate) matrices. Chem. Pharm. Bull. 1989, 37, 1954–1956. [Google Scholar] [CrossRef]
  21. Nakamura, T.; Hitomi, S.; Watanabe, S.; Shimizu, Y.; Jamshidi, K.; Hyon, S.H.; Ikada, Y. Bioabsorption of polylactide with different molecular properties. J. Biome. Mater. Res. 1989, 23, 1115–1130. [Google Scholar]
  22. Pitt, C.G.; Cha, Y.; Shah, S.S.; Zhu, K.J. Blends of PVA and PLGA: Control of permeability and degradability of hydrogels by blending. J. Control. Release 1992, 19, 189–200. [Google Scholar] [CrossRef]
  23. Mauduit, J.; Pérouse, E.; Vert, M. Hydrolytic degradation of films prepared from blends of high and low molecular weight poly(DL-lactic acid)s. J. Biomed. Mater. Res. 1996, 30, 201–207. [Google Scholar] [CrossRef] [PubMed]
  24. Nijenhuis, A.J.; Colstee, E.; Grijpma, D.W.; Pennings, A.J. High molecular weight poly(L-lactide) and poly(ethylene oxide) blends: Thermal characterization and physical properties. Polymer 1996, 37, 5849–5857. [Google Scholar] [CrossRef]
  25. Shikinami, Y.; Okuno, M. Bioresorbable devices made of forged composites of hydroxyapatite (HA) particles and poly-L-lactide (PLLA): Part II. Practical properties of miniscrews and miniplates. Biomaterials 2001, 22, 3197–3211. [Google Scholar] [CrossRef] [PubMed]
  26. Ignatius, A.A.; Augat, P.; Claes, L.E. Degradation behavior of composite pins made of tricalcium phosphate and poly(L,DL-lactide). J. Biomater. Sci. Polym. Ed. 2001, 12, 185–194. [Google Scholar] [CrossRef] [PubMed]
  27. Tsuji, H.; Muramatsu, H. Blends of aliphatic polyesters: V. Non-enzymatic and enzymatic hydrolysis of blends from hydrophobic poly(L-lactide) and hydrophilic poly(vinyl alcohol). Polym. Degrad. Stab. 2001, 71, 403–415. [Google Scholar] [CrossRef]
  28. Renouf-Glauser, A.C.; Rose, J.; Farrar, D.F.; Cameron, R.E. A degradation study of PLLA containing lauric acid. Biomaterials 2005, 26, 2415–2422. [Google Scholar] [PubMed]
  29. Renouf-Glauser, A.C.; Rose, J.; Farrar, D.F.; Cameron, R.E. Comparison of the hydrolytic degradation and deformation properties of a PLLLA-lauric acid based family of biomaterials. Biomacromolecules 2006, 7, 612–617. [Google Scholar] [CrossRef] [PubMed]
  30. You, Y.; Lee, S.W.; Youk, J.H.; Min, B. M.; Lee, S.J.; Park, W.H. In vitro degradation behaviour of non-porous ultra-fine poly(glycolic acid)/poly(L-lactic acid) fibres and porous ultra-fine poly(glycolic acid) fibres. Polym. Degrad. Stab. 2005, 90, 441–448. [Google Scholar] [CrossRef]
  31. Shirahase, T.; Komatsu, Y.; Tominaga, Y.; Asai, S.; Sumita, M. Miscibility and hydrolytic degradation in alkaline solution of poly(L-lactide) and poly(methyl methacrylate) blends. Polymer 2006, 47, 4839–4844. [Google Scholar]
  32. Li, S. M.; Garreau, H.; Vert, M. Structure-property relationships in the case of the degradation of massive poly(α-hydroxy acids) in aqueous media. Part 3. Influence of the morphology of poly(L-lactic acid). J. Mater. Sci. Mater. Med. 1990, 1, 198–206. [Google Scholar] [CrossRef]
  33. Tsuji, H.; Miyauchi, S. Poly(L-lactide). VI. Effects of crys-tallinity on enzymatic hydrolysis of poly(L-lactide) without free amorphous region. Polym. Degrad. Stab. 2001, 71, 415–424. [Google Scholar] [CrossRef]
  34. Tsuji, H.; Mizuno, A.; Ikada, Y. Properties and morphology of poly(L-lactide). 3. Effects of crystallinity on long-term in vitro hydrolysis of poly(L-lactide) film in phosphate-buffered solution. J. Appl. Polym. Sci. 2000, 77, 1452–1464. [Google Scholar] [CrossRef]
  35. Tsuji, H.; Ikada, Y. Properties and Morphology of Poly(L-lactide). II. Hydrolysis in Alkaline Solution. Polym. Sci. Part A Polym. Chem. 1998, 36, 59–66. [Google Scholar] [CrossRef]
  36. Tsuji, H.; Miyauchi, S. Poly(L-lactide): 7. Enzymatic hydrolysis of free and restricted amorphous regions in poly(L-lactide) Films with different crystallinities and a fixed crystalline thickness. Polymer 2001, 42, 4463–4467. [Google Scholar]
  37. Tsuji, H.; Ikada, Y. Properties and morphology of poly(L-lactide). 4. Effects of structural parameters on long-term in vitro hydrolysis of poly(L-lactide) in phosphate-buffered solution. Polym. Degrad. Stab. 2000, 67, 179–189. [Google Scholar]
  38. Tsuji, H.; Nakahara, K. Poly(L-lactide): 8. high-temperature hydrolysis of poly(L-lactide) films with different crystallinities and crystalline thicknesses in phosphate-buffered solution. Macromol. Mater. Eng. 2001, 286, 398–406. [Google Scholar] [CrossRef]
  39. Tsuji, H.; Ikarash, K.; Fukuda, N. Poly(L-lactide): XII. Formation, growth, and morphology of crystalline residues as extended-chain crystallites through hydrolysis of poly(L-lactide) films in phosphate-buffered solution. Polym. Degrad. Stab. 2004, 84, 515–523. [Google Scholar] [CrossRef]
  40. Hyon, S. H.; Jamshidi, K.; Ikada, Y. Melt spinning of poly-L-lactide and hydrolysis of the fiber in vitro. In Polymers as Biomaterials; Shalaby, S.W., Hoffman, A.S., Ratner, B.D., Horbett, T.A., Eds.; Plenum Press: New York, NY, USA, 1984; pp. 51–65. [Google Scholar]
  41. Jamshidi, K.; Hyon, S.H.; Nakamura, T.; Ikada, Y.; Shimidu, Y.; Teramatsu, T. In vitro and in vivo degradation of poly-L-lactide fibers. In Biological and Biomechanical Performance of Biomaterials; Christel, P., Meunier, A., Lee, A.J.C., Eds.; Elsevier Science Publisher B.V.: Amsterdam, The Netherlands, 1985; pp. 227–232. [Google Scholar]
  42. Hyon, S.H.; Jin, F.; Jamshidi, K.; Tsutsumi, S.; Kanamoto, T. Biodegradable ultra high strength poly(L-lactide) rods for bone fixation. Macromol. Symp. 2003, 197, 355–368. [Google Scholar] [CrossRef]
  43. Tsuji, H.; Kidokoro, Y.; Mochizuki, M. Enzymatic degradation of poly(L-lactic acid) fibers: effects of small drawing. J. Appl. Polym. Sci. 2007, 103, 2064–2071. [Google Scholar] [CrossRef]
  44. Tsuji, H.; Ogiwara, M.; Saha, S.K.; Sakaki, T. Enzymatic, alkaline, and autocatalytic degradation of poly(L-lactic acid): Effects of biaxial orientation. Biomacromolecules 2006, 7, 380–387. [Google Scholar] [CrossRef] [PubMed]
  45. Grizzi, I.; Garreau, H.; Li, S.; Vert, M. Hydrolytic degradation of devices based on poly(L-lactic acid) size-dependence. Biomaterials 1995, 16, 305–311. [Google Scholar]
  46. Cai, Q.; Shi, G.; Bei, J.; Wang, S. Enzymatic degradation behavior and mechanism of Poly(lactide-co-glycolide) foams by trypsin. Biomaterials 2003, 24, 629–638. [Google Scholar] [CrossRef] [PubMed]
  47. Lu, L.; Garcia, C. A.; Mikos, A.K. In vitro degradation of thin poly(DL-lactic-co-glycolic acid) films. J. Biomed. Mater. Res. 1999, 46, 236–244. [Google Scholar] [CrossRef] [PubMed]
  48. Yin, M.; Baker, G.L. Preparation and characterization of substituted polylactides. Macromolecules 1999, 32, 7711–7718. [Google Scholar] [CrossRef]
  49. Jing, F.; Smith, M.R., III; Baker, G.L. Cyclohexyl-substituted polyglycolides with high glass transition temperatures. Macromolecules 2007, 40, 9304–9312. [Google Scholar] [CrossRef]
  50. Liu, T.; Simmons, T.L.; Bohnsack, D.A.; Mackay, M.E.; Smith, M.R., III; Baker, G.L. Synthesis of polymandelide: A degradable polylactide derivative with polystyrene-like properties. Macromolecules 2007, 40, 6040–6047. [Google Scholar] [CrossRef]
  51. Tsuji, H.; Matsuoka, H.; Itsuno, S. Synthesis, physical properties, and crystallization of optically active poly(L-phenyllactic acid) and poly(L-phenyllactic acid-co-L-lactic acid). J. Appl. Polym. Sci. 2008, 110, 3954–3962. [Google Scholar]
  52. Tsuji, H.; Okumura, A. Stereocomplex formation between enantiomeric substituted poly(lactide)s: blends of poly[(S)-2-hydroxybutyrate] and poly[(R)-2-hydroxybutyrate]. Macromolecules 2009, 42, 7263–7266. [Google Scholar] [CrossRef]
  53. Tsuji, H.; Okumura, A. Crystallization and hydrolytic/thermal degradation of a novel stereocomplexationable blend of poly(L-2-hydroxybutyrate) and poly(D-2-hydroxybutyrate). Polym. J. 2011, 43, 317–324. [Google Scholar]
  54. Tsuji, H.; Yamamoto, S.; Okumura, A.; Sugiura, Y. Hetero-stereocomplexation between biodegradable and optically active polyesters as a versatile preparation method for biodegradable materials. Biomacromolecules 2010, 11, 252–258. [Google Scholar] [CrossRef] [PubMed]
  55. Tsuji, H.; Matsuoka, H. Stereoselective interaction between isotactic and optically active poly(lactic acid) and phenyl-substituted poly(lactic acid). Macromol. Rapid Commun. 2008, 29, 1372–1377. [Google Scholar] [CrossRef]
  56. Fukuzaki, H.; Yoshida, M.; Asano, M.; Kumakura, M.; Imasaka, K.; Nagai, T.; Mashimo, T.; Yuasa, H.; Imai, K.; Yamanaka, H. Synthesis of biodegradable copoly(L-lactic acid/aromatic hydroxy acids) with relatively low molecular weight. Eur. Polym. J. 1990, 26, 1273–1277. [Google Scholar] [CrossRef]
  57. Fukuzaki, H.; Yoshida, M.; Asano, M.; Kumakura, M.; Mashimo, T.; Yuasa, H.; Imai, K.; Yamanaka, H. In vivo characteristics of low molecular weight copolymers composed of L-lactic acid and various DL-hydroxy acids as biodegradablec arriers for drug delivery systems. Biomaterials 1990, 11, 441–446. [Google Scholar]
  58. Moon, S.-I.; Urayama, H.; Kimura, Y. Structural characterization and degradability of poly(L-lactic acid)s incorporating phenyl-substituted α-hydroxy acids as comonomers. Macromol. Biosci. 2003, 3, 301–309. [Google Scholar] [CrossRef]
  59. Pitt, C.G.; Zhong-wei, G. Modification of the rates of chain cleavage of poly(ε-caprolactone) and related polyesters in the solid state. J. Control. Release 1987, 4, 283–292. [Google Scholar] [CrossRef]
  60. Vert, M. Glycolide and Copolyesters with Lactide, in Polyesters III (Biopolymers); Doi, Y., Steinbüchel, A., Eds.; Wiley-VCH: Weinheim, Germany, 2002; Volume 4, pp. 179–202. [Google Scholar]

Share and Cite

MDPI and ACS Style

Tsuji, H.; Eto, T.; Sakamoto, Y. Synthesis and Hydrolytic Degradation of Substituted Poly(DL-Lactic Acid)s. Materials 2011, 4, 1384-1398. https://doi.org/10.3390/ma4081384

AMA Style

Tsuji H, Eto T, Sakamoto Y. Synthesis and Hydrolytic Degradation of Substituted Poly(DL-Lactic Acid)s. Materials. 2011; 4(8):1384-1398. https://doi.org/10.3390/ma4081384

Chicago/Turabian Style

Tsuji, Hideto, Takehiko Eto, and Yuzuru Sakamoto. 2011. "Synthesis and Hydrolytic Degradation of Substituted Poly(DL-Lactic Acid)s" Materials 4, no. 8: 1384-1398. https://doi.org/10.3390/ma4081384

Article Metrics

Back to TopTop