Henri Garreau

Structure-property relationships in the case of the degradation of massive poly(α-hydroxy acids) in aqueous media

A standard protocol is proposed which has been used to study comparatively the degradation mechanism of bioresorbable poly(α-hydroxy acids) with respect to macromolecular structural characteristics and solid-state morphologies. As a first approach, the hydrolytic degradation of poly(dl-lactic acid) (PLA50) parallelepipedic specimens (15 mm×10 mm×2 mm), processed by compression moulding and machining, was investigated in two aqueous media: iso-osmolar saline and pH 7.4 phosphate buffer. Various techniques (namely weighing, size-exclusion chromatography (SEC), potentiometry, cryometry and enzymatic assay) have been applied to these specimens in order to monitor the degradation. Data show conclusively that the degradation of massive PLA50 specimens proceeds more rapidly in the centre than at the surface. This feature has been related to the formation of an outer layer of slowly degrading polymer, which is caused by surface phenomena and entraps degrading macromolecules. Only oligomers can diffuse and dissolve in the surrounding media. Accordingly, the number of carboxylic groups present in the inner part of the degrading specimens becomes larger than at the surface and accelerates ester bond cleavage. The resultant autocatalytic mechanism explains well the fact that partially degraded PLA50 exhibits bimodal SEC chromatograms although this polymer is amorphous.

More about the degradation of LA/GA-derived matrices in aqueous media

Abstract Aliphatic polyesters are the source of the most attractive polymeric matrices currently investigated to make devices aimed at controlled drug delivery. In spite of the large number of investigations dealing with LA/GA-polymers which have been reported in the literature, only little is known about the degradation mechanism of these polyesters in solid state. Recent data collected from in vitro ageing under experimental conditions mimicking the physiological medium show that initial morphology and morphology changes are very important factors determining the degradation behaviors of LA/GA-polymer matrices. In particular, it is shown that intrinsically amorphous members of the family and quenched semi-crystalline ones can crystallize while degrading. The possible effects of drug loads on such phenomena are discussed.

In vivo degradation of massive poly(α-hydroxy acids): Validation of In vitro findings

The degradation of various high-molecular-weight aliphatic polyesters derived from glycolic acid and/or lactic acid enantiomers was previously investigated in vitro. It was demonstrated that the bulk degradation mechanism proposed in the literature actually proceeds heterogeneously and proceeds faster in the centre than at the surface of large specimens. In order to compare them, similar compression-moulded specimens were implanted intramuscularly in the backs of rabbits, namely PLA50 (poly(DL-lactic acid)), PLA37.5GA25 (75% DL-lactide and 25% glycolide in the feed) and PLA75GA25 (75% L-lactide and 25% glycolide). These three intrinsically amorphous compounds exhibited faster central degradation. Furthermore, preferential degradation of glycolic acid units and induced crystallization of L-lactic acid enriched fragments were observed in the case of PLA75GA25. These findings are comparable to phenomena observed in vitro and are conclusively supported by the re-examination of some old in vivo results. Accordingly, data reported in this paper validate both the in vitro modelling and new understanding of the degradation of lactic acid/glycolic acid-based aliphatic polyesters reported previously.

New insights on the degradation of bioresorbable polymeric devices based on lactic and glycolic acids.

This contribution recalls some recent advances in the understanding of the mechanisms of degradation of bioresorbable polymers of the poly(beta-hydroxy acid) type derived from lactic and glycolic acids, which are receiving increasing interest for their potential for osteosynthesis. First, the various polymers are introduced and the field of applications is delimited. It is confirmed that degradation proceeds faster in amorphous domains than in crystallites. It is also shown that degradation proceeds faster in the center than at the surface, although this feature is not predominant in the case of semicrystalline lactic acid stereocopolymers. Of special interest are the findings that quenched compounds can crystallize at body temperature during degradation and that highly crystalline degradation residues can remain in situ for several years. Data show that osteosynthesis with bioresorbable plastics might become a reality for reasonably loaded bones, provided the peculiarities of polymers are taken into account by surgeons.

Enzymatic degradation of stereocopolymers derived from l-, dl- and meso-lactides

Three stereocopolymers, namely PLA50-rac, PLA50-mes, and PLA62.5, were synthesized by ring opening polymerization of racemic-lactide (or dl-lactide), meso-lactide, and a mixture of 25/75 l/dl-lactides, respectively. The enzymatic degradation of these PLA polymers was investigated at 37°C in a pH=8.6 Tris–HCl buffer solution in the presence of proteinase K. Degradation of PLA50-mes was found to be much faster than that of PLA50-rac, PLA62.5 degrading at an intermediate rate. It was assumed that proteinase K preferentially degrades l–l, l–d and d–l bonds as opposed to d–d ones. On the other hand, the much higher water uptake ratio of PLA50-mes as compared to those of PLA50-rac and PLA62.5 could have facilitated the enzymatic attack in the former case.

Attempts to map the structure and degradation characteristics of aliphatic polyesters derived from lactic and glycolic acids.

During the past 5 years, important advances have been accomplished in the understanding of the fate of aliphatic polyesters derived from lactic acid (LA) and glycolic acid (GA) in aqueous media. Hydrolysis of solid LA/GA polymers is now regarded as dependent upon a diffusion-reaction mechanism. Faster central degradation, degradation-induced composition, and morphology changes are three of the most important findings which appeared to be composition-dependent as deduced from the behavior of different LA/GA polymers. An attempt is made to generalize these findings to the whole family and to elaborate a map which could be used to predict degradation characteristics of LA/GA polymers from their initial composition and morphology.

Hydrolytic degradation of poly(oxyethylene)–poly-(ε-caprolactone) multiblock copolymers

The degradation of poly(oxyethylene)–poly(e-caprolactone) (POE–PCL) multiblock copolymers was investigated at 37°C in a 0.13M, pH 7.4 phosphate buffer selected to mimic in vivo conditions. The copolymers were obtained by coupling polycaprolactone diols and poly(ethylene glycol) diacids using dicyclohexylcarbodiimide as coupling agent. Various techniques, such as weighing, size exclusion chromatography, infrared, 1H nuclear magnetic resonance, differential scanning calorimetry, and X-ray diffractometry, were used to monitor changes in total mass, water absorption, molar mass, thermal properties, degree of crystallinity, and composition. The results showed that introduction of POE sequences considerably increased the hydrophilicity of the copolymers as compared with PCL homopolymers. Nevertheless, the degradability of PCL sequences was not enhanced due to the phase separation between the two components. Significant morphological changes were also observed during the degradation.

Monitoring of the poly(d,l-lactic acid) degradation by-products by capillary zone electrophoresis

Abstract Capillary zone electrophoresis (CZE) is presented as a new tool to resolve and analyze the ultimate degradation products of poly( d,l -lactic acid) aliphatic polyesters, namely water-soluble oligomers with a degree of polymerization lower than 8. The investigated oligomers were those present in a concentrated commercial d,l -lactic acid solution and those obtained by concentration of the same solution under vacuum. The repeatability of peak migration time was increased by introducing a relative migration factor aimed at minimizing the run-to-run peak shifts which depend on the experimental conditions, especially on the capillary and even on the instrument. Ring-opening of d,l -lactide was used to assign CZE peaks due to lactoyllactate and lactate. The rate constant and the activation energy of lactoyllactate hydrolysis were determined by monitoring the formation of lactate by CZE.

Growth of various cell types in the presence of lactic and glycolic acids: the adverse effect of glycolic acid released from PLAGA copolymer on keratinocyte proliferation

Poly(α-hydroxy-acid)s derived from lactic acid (LA) and glycolic acid (GA) are bioresorbable polymers that are currently used in human surgery and in pharmacology to make temporary therapeutic devices. Nowadays, increasing attention is paid to these polymers in the field of tissue engineering. However, the literature shows that a large number of factors can affect many of their properties and the responses of biological systems. As part of our investigation of the biocompatibility of degradable aliphatic polyesters, the effects of LA and GA on the proliferation of various cells under in vitro cell culture conditions were studied. The release of LA and GA from films made of a copolymer synthesized by the zinc lactate method and composed of 37.5% L-lactyl, 37.5% D-lactyl, and 25% glycolyl repeating units was first investigated over a period of 30 days under abiotic conditions in a cell culture medium in order to identify a range of acid concentrations consistent with releases to be expected in real cell cultures. Four cell lines, namely 3T3-J2, C3H101/2, A431, and HaCat, and three primary cell cultures, namely rat endothelial cells, rat smooth muscle cells, and human dermal fibroblasts, were then allowed to grow in the presence of LA and GA at various concentrations taken within the selected 10–1000 mg/cm3 range. Little or no effect was observed on the proliferation of all cells except human keratinocytes, whose growth was dramatically inhibited by GA at concentrations as low as 10 mg/cm3. The inhibiting effect of GA was confirmed by considering the growth of keratinocytes on films made of the same copolymer, in comparison with poly(DL-lactic acid) and polystyrene taken as references. This work shows that GA-releasing degradable matrices are not adapted to the culture of keratinocytes with the aim of making skin grafts.

Tissue Healing during Degradation of a Long-Lasting Bioresorbable γ-Ray-Sterilised Poly(Lactic Acid) Mesh in the Rat: A 12-Month Study

Aim: The purpose was to evaluate soft-tissue healing after poly(lactic acid) (PLA94) mesh implantation in a rat model. Methods: Full-thickness abdominal wall defects were created in 108 Wistar rats, and reconstructed with 83 PLA94 and 25 lightweight polypropylene (PPL) meshes. The meshes were previously γ-ray sterilised with 25, 75 or 125 kGy to accelerate PLA94 degradation. Results: The inflammatory response in PLA94 was significantly less pronounced and collagen organisation significantly better than in PPL. The higher the level of γ-radiation, the higher the incidence of abdominal wall herniation (22.2, 31.3 and 52.6% with 25, 75 and 125 kGy, respectively). No herniation occurred in the PPL group. Tensile strength was dramatically reduced after γ-ray-sterilised PLA94 mesh implantation. Conclusion: The γ-ray-sterilised PLA94 mesh was poor in preventing abdominal wall hernia recurrences in a rat model.