Michel Vert

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.

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).

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.

Optically active poly (\-malic-acid)

SummaryA simple and reproducible method of synthesizing enantiomers of benzyl malolactonate is described starting from optically active aspartic acid. Chiral benzyl malolactonate is a β-substituted β-lactone monomer which can be readily polymerized anionically using triethylamine as the initiator to yield poly(benzyl β-malate) which is an optically active, semicrystalline polymer. Cleavage of protecting benzyl ester groups yields optically active poly(β-malic acid). The properties of the racemic and optically active monomers and polymers are compared. Optically active (−)poly(β-malic acid) shows one accessible positive CD band in the far UV.

Poly(β-malic acid) : a new polymeric drug-carrier

SummaryPoly(β-malic acid) is a new synthetic functional polyester of the poly(β-hydroxy-acid)-type whose properties are investigated in regard to possible uses as bioresorbable polyvalent drug-carrier. Degradation of polymer chains in 0.15 N phosphate buffer at pH=7.5 is monitored by aqueous GPC on SEPHADEX gels and by enzymatic titration of ultimate degradation products. It is shown that the rate of degradation obeys first order kinetics at the begining and that poly(β-malic acid) degrades to malic acid at last.

Totally Bioresorbable Composites Systems for Internal Fixation of Bone Fractures

Metals have been used extensively for internal fixation of bone fractures. However, shortcomings of metallic plating or nailing are now well identified and the interest for internal fixation devices made of more flexible materials is growing fast. In this respect, plastic-based systems appear attractive, particularly carbon fiber reinforced composites. However, the most suitable solution remains the use of bioresorbable plastic systems due to their combining various potential advantages: — better bone remodeling because of better matching of mechanical properties with respect to bone, — no need for reoperation to remove the appliance after bone-healing, and — possibility for incorporating antibiotics in view of preventing infection through sustained delivery of the entrapped drug.

Partially quaternized poly(tertiary amine) as pH-dependent drug carrier for solubilization and temporary trapping of lipophilic drugs in aqueous media

Abstract Deprotonated macro molecules of partially quaternized poly(tertiary amine) of the poly-[thio-1-(N,N-diethyl aminomethyl) ethylene] type with less than 20% quaternized repeating units take globular conformations which form a molecularly dispersed organic microphase in water. It is shown that drugs reputedly insoluble in water can be dissolved and temporarily trapped in this lipophilic microphase. Because of pH-dependent destabilization, occurring through an all-or-none cooperative mechanism, instantaneous release can be obtained in a very narrow pH range. Factors affecting trapping and release are considered in regard to characteristics of body fluids and use of these polymers as drug carriers.

In vivo Fate of Repeat-Unit-Radiolabelled Poly(β-malic acid), a Potential Drug Carrier

In order to compare the fates of end-chain-radiolabelled and repeat-unit-radiolabelled poly(β-malic acid)s after intravenous injection in mice, repeat-unit 14C-radiolabelling of this biodegradable water-soluble poly carboxylic acid polymer was achieved starting from 14C-aspartic acid. The ac tivity of the resulting radioactive poly(β-malic acid) (sodium salt) (Mw ∼ 20,000 as determined by aqueous SEC) was 4.5 μCi·g -1. Aliquots of a neutral 0.3 monoM (4.14% w/v) solution of poly(β-malic acid) (sodium salt) were given intravenously to mice through a lateral tail vein. Intravenous and intra peritoneal toxicity was checked in order to show whether injection of this polymer can affect significantly the normal behavior of experimental animals. Radioactivity was counted in liver, kidney, intestine, lung, brain, spleen, heart, muscle, urine and blood for various post-injection times up to 24 h. Data con firmed the occurrence of predominant and fast urinary excretion (70% after 1 h) already observed with the end-chain-radiolabelled homologue. Although the polymer is basically metabolizable, the fast elimination of radioactivity via urinary tract is most likely to be due to the excretion of polymeric molecules and not of metabolic by-products because end-chain- and repeat-unit-labellings led to similar excretion patterns.