Suming Li

Hydrolytic degradation of devices based on poly(dl-lactic acid) size-dependence

The hydrolytic degradation of aliphatic polyesters derived from lactic and glycolic acids (PLA/GA polymers) has been previously shown to proceed heterogeneously in the case of large size devices, the rate of degradation being greater inside than at the surface. A qualitative model based on diffusion-reaction phenomena was proposed which accounts for the formation of the more stable outer layer. However, this model also suggested that devices with dimensions smaller than the thickness of the outer layer should degrade less rapidly than larger ones. In an attempt to check this hypothesis, 15 x 10 x 2 mm compression moulded plates, millimetric beads and submillimetric microspheres and cast films, derived from the same batch of poly (DL-lactic acid) polymer were allowed to age comparatively in isoosmolar 0.13 M phosphate buffer, pH 7.4, at 37 degrees C. Ageing of the various devices was monitored by measuring water absorption, weight loss, L-lactic acid formation, pH and molar mass changes. As expected, large size plates and millimetric beads degraded heterogeneously and much faster than homogeneously degraded submillimetric films and particles.

Bioresorbability and biocompatibility of aliphatic polyesters

The field of biodegradable polymers is a fast growing area of polymer science because of the interest of such compounds for temporary surgical and pharmacological applications. Aliphatic polyesters constitute the most attractive family among which poly(α-hydroxy acids) have been extensively studied. In the past two decades, several excellent reviews have been published to present the general properties of aliphatic polyesters. The aim of this paper is to complete the information collected so far with a special attention to the complex phenomena of biodegradability and biocompatibility. Indeed, the degradation of a polymer leads to the delivery of low molecular weight degradation by-products whose effects on the host body have to be considered. The consequences of the absence of standard terminology are first discussed with respect to words such as biodegradable and bioresorbable. Poly(α-hydroxy acids) derived from lactic and glycolic acids are then introduced in order to make easier the critical discussions of the following problems from literature data: biocompatibility, biodegradability, bioresorbability, mechanism of hydrolysis (enzymaticvs simple chemistry), polymodality of molecular weight distributions during degradation and the effects of the presence of oligomers. Finally, some specific comments are made on other aliphatic polyesters such as poly(hydroxy butyrate) and poly(β-malic acid).

Biodegradation of PLA/GA polymers: increasing complexity

The degradation of aliphatic polyesters derived from lactic and glycolic acids (PLA/GA) depends on many factors. It has been found recently that the interior of large size devices degrades faster than the outer zone. A qualitative model has been proposed to account for this heterogeneous degradation. It is based on diffusion-reaction phenomena combined with the well-known autocatalytic effect of carboxylic chain ends. This contribution recalls the present understanding of the hydrolytic degradation of PLA/GA polymers and emphasizes its complexity on the basis of the influence of secondary factors such as the presence of a basic load, namely, gentamycin, in poly(lactic acid) matrices, and the presence of long stereoregular sequences in poly(DL-lactic acid) macromolecules.

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.

Further investigations on the hydrolytic degradation of poly (DL-lactide)

The hydrolytic degradation of poly(DL-lactide) (PLA50) material was investigated in order to elucidate the effects of temperature and acidity of the external medium on the degradation characteristics. It was observed that at 60 degrees C and at pH = 7.4, degradation was extremely rapid as compared with degradation at 37 degrees C. After only 2 days, heterogeneous degradation was observed due to larger internal autocatalysis. On the other hand, in the case of degradation at 37 degrees C in an acidic medium with pH = 3.7, the heterogeneous degradation was preceded by a much longer lag time. Water absorption was found to be pH dependent. At pH = 7.4, water absorption was increased due to the osmotic pressure driving the buffer solution into the polymer matrix to neutralize acidic endgroups, which was not the case for degradation at pH = 3.7. In both cases, the oligomeric stereocomplex was obtained as degradation residue at the end of the degradation period.

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.

Protein release from physically crosslinked hydrogels of the PLA/PEO/PLA triblock copolymer-type

A series of PLA/PEO/PLA triblock copolymers was prepared by ring opening polymerization of rac-lactide in the presence of various di-hydroxyl poly (ethylene glycol)s, using CaH2 as a biocompatible initiator. Hydrogels were prepared by a phase separation method consisting of introducing small amounts of water over solutions of the copolymers in a biocompatible organic solvent, namely tetraglycol [poly(ethylene glycol monotetrahydrofurfuryl ether)]. The resulting hydrogels appeared much more hydrophilic than the rather tough hydrogels formed by swelling of dry tablets or films processed from the same copolymers. The phase separation-derived hydrogels were soft enough to be injected through a trochar. Two proteins, namely bovine serum albumine (BSA) and fibrinogen, were physically entrapped in these hydrogels by mixing with the polymer solutions before gel formation. This procedure appeared to be protein-respecting according to circular dichroism analysis on the released BSA. Dramatically different release profiles were obtained for the two proteins. In the case of BSA, the release depended on the quantity of protein incorporated in the hydrogel and presented a parabolic-type profile, in agreement with the behaviors of diffusion-controlled monolitic drug delivery devices. In contrast, almost linear release profiles were observed in the case of fibrinogen, the hydrogels behaving like a reservoir drug delivery system. These findings are tentatively interpreted in terms of gel-protein compatibility in the case of BSA and gel-protein incompatibility in the case of fibrinogen.

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.

Enzyme-catalyzed polymerization and degradation of copolymers prepared from ϵ-caprolactone and poly(ethylene glycol)

Abstract Copolymerizations of ϵ-caprolactone (CL) with monohydroxyl or dihydroxyl poly(ethylene glycol) (PEG) were successfully performed using Novozyme-435 (immobilized lipase B from Candida antartica ) as catalyst. Diblock and triblock copolymers with different compositions were characterized by 1 H NMR, GPC, DSC and X-ray diffraction. The enzymatic copolymerization carried out in toluene presented higher reaction rate and yield than that in bulk. Increasing the [CL]/[EO] feed ratio resulted in increases of molecular weight ( M n ) of copolymers. Moreover, the compositions of triblock copolymers were closer to the monomer feed ratios than those of diblock copolymers. The resulting copolymers were all semicrystalline, the crystalline structure being of the PCL type. Solution cast films were allowed to degrade in a pH 7.0 phosphate buffer solution containing Pseudomonas lipase. Weight loss data showed that the introduction of PEG segments to the PCL main chain did not alter the enzymatic degradation of PCL significantly.