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The present study investigated the in vitro mechanism and degradation rate of polyhydroxyoctanoate (PHO). Solution-cast PHO films were incubated in either water or isoosmotic phosphate-buffered saline (PBS) for periods ranging from 1 to 24 months. Physical characterization included weight loss, water absorption, pH change, tensile strength, and scanning electron microscopy (SEM) studies. Analytical investigations including electron spectroscopy for chemical analysis, Fourier transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), wide-angle X-ray diffraction, and size exclusion chromatography were also performed to assess chemical and morphological changes to the structure of the PHO. The results show that the PHO-cast films incubated in either water or isoosmotic PBS underwent a simple hydrolytic degradation process characterized by water absorption, gradual molecular weight decrease, and negligible mass loss after 24 months of incubation. DSC results suggest that degradation occurred in the amorphous zone, followed by an attack in the crystalline domain. An increase in the vibration stretching of OH after 24 months of incubation, as revealed by FTIR, may indicate that the degradation process began internally, moving outwardly toward the surface of the PHO films. This process was more rapid in the films incubated in PBS than in those incubated in water. However, no significant changes in the morphology of the films were detected by SEM. This study demonstrated that the in vitro degradation of PHO in water or in PBS is a very slow hydrolytic process, exceeding 2 years. Our findings also suggest that the internal degradation mechanism is faster in PBS because of the ionic strength of the medium and that this internal process surface moves gradually toward the surface., (Copyright 2000 John Wiley & Sons, Inc.)

In the literature, many papers deal with the behavior of proteins in aqueous media in the presence of poly(ethylene glycol) (PEG) molecules or poly(ethylene oxide) (PEO) segments, physically adsorbed onto, or covalently attached to, macromolecules or to solid surfaces. In particular, it is well known that PEO segments make foreign materials stealthy, i.e. they are much less detected by the immune system either through humoral reactions or, at the cell level, through opsonins. Revisiting the literature led us to challenge the largely accepted opinion that the decreased recognition of PEO segment-bearing foreign macromolecules and particles by the mononuclear phagocyte system is primarily the consequence of the repulsion of all blood proteins by PEG segments through the excluded volume effect. This challenge is based on the finding that albumin and PEG are compatible in phosphate-buffered saline at room temperature and at concentrations comparable to those measured by others on the surface of PEO segment-bearing species, whereas fibrinogen and PEG phase-separated and were incompatible despite the much lower concentration of the latter protein. According to literature and to these observations, it is proposed that the stealth effect induced by PEO segments is primarily due to the compatibility between PEO segments of intermediate molar mass and albumin, thus rendering PEO-bearing macromolecules or surfaces to look like native albumin. Under such conditions, the hospitality offered by PEG macromolecules or PEO segments to albumin, the dominant plasma protein, results in a 'chameleon' effect that prevents the activation of other PEG-compatible or -incompatible plasma proteins or cells involved in foreign body recognition and elimination. PEG with molar masses > or = 8000 did not accommodate albumin in agreement with the excluded volume phenomenon.

With the aim of promoting the targeting of macrophage mannose receptors and the internalisation of the norfloxacin antibiotic, which is active against some intracellular bacteria, a macromolecular prodrug was synthesised where the antibiotic and mannosyl moieties were coupled to a polymeric carrier, namely poly(L-lysine citramide imide). This carrier, which derived from two metabolites, citric acid and L-lysine, is known to be biocompatible and slowly degradable under slight acidic conditions. Norfloxacin was coupled onto the acid groups present along the polymer chains, and conjugates were characterised by UV, TLC and SEC. The mannosyl groups selected to promote the targeting of the mannose-specific lectin present on the outer membrane of macrophages were incorporated through a biodegradable glycolic spacer arm. Two different strategies were considered to synthesise the full conjugates, namely coupling norfloxacin onto mannosylated conjugates, and coupling mannose onto PLCAI/Nflx conjugates. The second pathway led to better results regarding mannosylation. The presence of norfloxacin and mannose caused chain aggregation, especially for conjugates with a high content of mannosyl residues. The targeting ability of the prodrug was investigated using a method based on the competition between the mannosylated macromolecules and glucose oxidase, a mannosyl-bearing non-human protein. This method showed that prodrug macromolecules competed effectively with glucose oxidase and thus should be able to bring the drug up to the mannosyl receptor-bearing membranes of macrophages infected by intracellular bacteria.

The present study examined the biocompatibility and degradation properties of poly (beta-hydroxy octanoate) (PHO) as an impregnation substrate on arterial prostheses. PHO-impregnated polyester grafts sterilized by ethylene oxide (EO) or gamma (gamma) radiation, and polyester Dacron(R) prostheses impregnated with fluoropolymer, gelatin, or albumin were implanted subcutaneously in rats for periods ranging from 2 to 180 days. The biocompatibility was assessed by quantifying the alkaline and acid phosphatase secretion while performing histological studies at the tissue/prosthesis interface. The degradation was determined by chemical analysis of the EO and gamma-sterilized PHO after implantation using differential scanning calorimetry (DSC), wide angle x-ray diffraction (WAXD), and size exclusion chromatography (SEC). Alkaline phosphatase activity by the sterilized PHO and by the gelatin and albumin grafts was significantly elevated early after implantation in contrast to that of the Dacron and fluoropolymer grafts that occurred later, at 7 and 5 days, respectively The peak of acid phosphatase activity for all of the grafts occurred between 5 and 10 days postimplantation, with the gamma-sterilized PHO grafts recording the greatest activity. Histological study revealed that the tissue incorporation into the graft wall was earlier and more complete for the Dacron and fluoropolymer grafts after 6 months than for the gelatin and albumin grafts, because the latter induced important inflammatory reactions during the resorption of the cross-linked protein substrates. The EO and gamma-sterilized PHO grafts exhibited a similar healing sequence characterized by the development of a collagenous tissue surrounding the prostheses. However, no infiltration of tissue into the graft wall was observed after 6 months, mainly because of the presence of the PHO. Degradation of the EO and gamma-sterilized PHO occurred preferentially by a hydrolytic mechanism as shown by a 30% molecular weight decrease after 6 months. In conclusion, PHO showed good biocompatibility in terms of enzyme activity and tissue reaction. Degradation was a slow, in vivo process controlled primarily by a random hydrolytic reaction and by a local enzymatic attack by macrophages and giant cells.

The surface chemical characterisation of sub-200 nm poly(DL-lactide co-glycolide) nanospheres has been carried out using the complementary analytical techniques of static secondary ion mass spectrometry (SSIMS) and X-ray photoelectron spectroscopy (XPS). The nanospheres, which are of interest for site-specific drug delivery, were prepared using an emulsification-solvent evaporation technique with poly(vinyl alcohol), Poloxamer 407 and Poloxamine 908 respectively as stabilisers. The presence of surfactant molecules on the surface of cleaned biodegradable colloids was confirmed and identified on a qualitative molecular level (SSIMS) and from a quantitative elemental and functional group analysis (XPS) perspective. SSIMS and XPS data were also used in combination with electron microscopy to monitor the effectiveness of cleaning procedures in removing poorly bound surfactant molecules from the surface of nanospheres. The findings are discussed with respect to the development of nanoparticle delivery systems, particularly the composition of the surface for extending blood circulation times and achieving site-specific deposition.

Nowadays, many degradable polymers are being used under the form of interference screws to fix the bone-tendon-bone autograft in anterior cruciate ligament reconstruction. However, little is known about the post-implantation fate of these screws, especially about the formation of crystalline residues which seems to be a critical factor for the success of surgery with temporary implants based on lactic and glycolic acid derived polymers (PLAGA). In an attempt to bring in some new insights, various high molecular weight stereoregular poly(lactide)s (PLAX with X = percentage of L-lactyl units) obtained by ring-opening polymerization of lactides in the presence of zinc-metal (PLA98-Zn), zinc lactate (PLA98-Znlac) or stannous octoate (PLA100-Sn), were processed by injection-molding to make interference screws to be compared. In vivo data were collected from screws implanted in sheep knees with follow ups ranging from 6 months to 5 years. Histology confirmed the heterogeneous degradation mechanism introduced nearly 10 years ago from in vitro investigations of homemade implants having simpler geometry. The effects of the initiator system (zinc- or tin derivatives) used to polymerize the lactide monomer on the properties of injection molded interference screws was also investigated in vitro in a phosphate buffer solution at 37 degrees C. Major differences in terms of hydrophilicity, hydrolysis rate and loss of mechanical properties were observed between PLA-Zinc and PLA-Tin. Discussion of the behavior of interference screws of different compositions was made on the basis of the present understanding of PLAGA morphology and degradation characteristics.

Degradable polyelectrolyte complexes were made by mixing a degradable carboxyl-bearing polyacid, namely poly(beta-malic acid), with a degradable primary amine group-bearing polybase, namely poly(amino serinate), derived from serine. Both oppositely charged polyelectrolytes are functional polymers which belong to the family of poly(beta-hydroxy acid)-type aliphatic polyesters. Poly(amino serinate) polymers were synthesized by a new route starting from the N-carbobenzoxy derivative (N-Z) of DL- or L-serine. These derivatives were allowed to react with mesyl chloride to yield in one step corresponding N-protected derivatives of poly(N-Z-amino serinate) with molar masses in the 20000-40000 range after fractionation. Progressive deprotection of pendent primary amino groups was carried out using a HBr/acetic acid mixture and led to PAS with up to 95% deprotected amine repeat units for less than 15% decrease of the initial molar mass, as shown by N-reprotection with Z groups. Poly(beta-malic acid) and poly(amino serinate) were complexed by mixing aqueous solutions of the two polyelectrolytes: 1-1 neutral precipitates were formed regardless of the respective compositions, provided the molecular weights of both components were high enough. When allowed to age in aqueous media, the solid complexes went rapidly back into solution because of the hydrolytic degradation of at least one of the components. Whether the degradation of one component is affected by that of the other is still unknown.

The present study examined the potential applicability of poly(beta-hydroxy octanoate) (PHO), a bacterial polyester, as a candidate for biomaterial applications, by investigating the effect of sterilization on the physical and structural characteristics of PHO. PHO-cast films were sterilized by either ethylene oxide (EO) gas at 38 degrees C or gamma radiation (2.5 Mrad) in air at room temperature. The physical characteristics of the EO and gamma-sterilized PHO were determined by scanning electron microscopy (SEM) and tensile strength analyses. In addition, various analytical methods were used to detect modifications in the chemical and morphological structure of PHO, namely, electron spectroscopy for chemical analysis (ESCA), Fourier transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), wide angle X-ray diffraction (WAXD), and size exclusion chromatography (SEC). The results show that EO sterilization did not modify the chemical and physical characteristics of PHO, however, significant modifications in both the structural and tensile properties were observed with gamma-sterilized PHO. These changes accounted for decreases in both the weight average, number average and melting temperature, and increases in the heat of fusion and tensile strength. No residual EO was detected following sterilization as revealed by head-space chromatography. The physical and structural properties of PHO were shown to be well preserved following EO sterilization, whereas gamma radiation caused random chain scission and physical cross-linking, a frequent phenomenon observed with organic polymers.

The present study examined the degradation behaviour of poly(beta-hydroxy octanoate) (PHO), a bacterial poly(beta-hydroxy alkanoate), following incubation under hydrolytic or enzymatic conditions in vitro. Solution-cast PHO films were incubated in a citrate buffer solution with and without acid phosphatase and in an acetate buffer with and without beta-glucuronidase for periods ranging from 7 to 60 days. The physical characterization of the PHO films was analyzed by SEM and tensile strength studies. In addition, various analytical methods were used to detect modifications in the chemical and morphological structure of the PHO, namely, ESCA, FTIR, DSC, X-ray diffraction, and SEC. The results indicate that the enzymatic conditions selected in the present study induced no significant surface morphological or chemical modifications, and no significant weight loss was observed after 60 days of incubation. However, as revealed by weight average molecular weight Mw and number average molecular weight Mn decreases, changes in the bulk structure of the PHO were observed with acid phosphatase at 28 and 60 days, in contrast to smaller Mw and Mn decreases recorded in both the buffers and the beta-glucuronidase. The tensile properties had decreased following incubation, yet showed no difference under all of the selected conditions. With no weight loss or surface changes, the PHO films incubated in acid phosphatase showed only a chemical hydrolytic process characterized by Mw and Mn decreases with time of incubation. The present study demonstrated that the degradation of PHO films is one of slow, chemical hydrolysis only, perhaps requiring several months of incubation. The hydrophobic nature of the long alkyl pendent chain in PHO may be responsible for this slow process. The inability of enzymes to degrade PHO may be attributed to the latter's poor adsorption capacity, due to its hydrophobic nature, and to a lack of specificity in the catalytic activity of these enzymes.

Polymers issued from glycolic acid and lactic acids (PLAGA) are now used worldwide as bioresorbable devices in surgery and in pharmacology. Their abiotic hydrolytic degradation has been shown to depend on diffusion-reaction phenomena and to proceed homogeneously or heterogeneously, depending on many factors. Two initiators are presently used industrially to make PLAGA polymers by ring opening polymerisation of lactide and/or glycolide in the bulk, namely Sn octanoate and zinc metal. In this contribution, attention is paid to the differences generated by the use of these two initiator systems in the case of the polymerisation of DL-lactide. Various poly(DL-lactide)s were prepared and characterised by size-exclusion chromatography (SEC), differential scanning calorimetry (DSC) and nuclear magnetic resonance spectroscopy (NMR). These polymers were allowed to age in pH=7.4 isoosmolar phosphate buffer at 37 degrees C. Under these conditions, polymers prepared by the two initiator systems showed dramatic differences when the fates of parallel sided specimens of rather large dimensions were considered. These differences were related to the esterification of some of the OH chain ends by octanoic acid and to the presence of rather hydrophobic low molecular weight by-products which were insoluble in the solvent generally used to purify the crude PLAGA polymers. These new findings should be of great interest in the case of PLAGA based matrices aimed at drug delivery.

Capillary zone electrophoresis (CZE) with neutral phosphate buffer as the background electrolyte was used to analyse water-soluble oligomers obtained by polycondensation of racemic lactic acid. Two CZE separation modes were tested. The first mode was based on normal separation (injection at the anodic side) using a fused-silica capillary. Eight peaks were observed within a 60-min migration time range. They were ascribed to dimer and higher water-soluble oligomers. Peaks from dimer to tetramer were split due to sensitivity for the fine structures at the level of the distribution of chiral lactic acid moieties in oligomer chains. The second mode was based on reverse separation (injection at the cathodic side) using a fused-silica capillary modified by adsorption of a polycation on its inner wall. Under these conditions, oligomers were rapidly separated without peak splitting. Considering the forces which are involved in CZE, data were plotted as a function of 1/t scale, according to the equation [signal]=f((-1)(k)/t) where k=0 and k=1 for normal and reverse separation modes, respectively. Such a plot allowed direct comparison between the various runs after a simple translation along the 1/t axis, regardless of the separation mode and the variation of electroosmotic flow. The second separation mode allowed separation of 3-hydroxybutyric acid and 6-hydroxyhexanoic acid oligomers. For the former series of oligomers, a side reaction generating crotyl bonds was observed due to the high sensitivity of CZE. It was shown that separation was governed by the ratio charge/mass of the oligoesters whatever their structure.

4-Aminofluorescein (F1-NH2) was conjugated with various macromolecular carriers of the poly(L-lysine citramide)-type which were hydrophobised by ethyl (C2), heptyl (C7), and dodecyl (C12) alkyl groups attached to the pendent carboxyl of the lysine moieties present in repeating units. The dye was used to label the carriers and monitor their intracellular fate after introduction within the incubation medium of K562 cells. The labelled hydrophobised carriers formed multimolecular compacted aggregates stabilised by the balance of attractive hydrophobic interactions and repulsive electrostatic forces in the aqueous culture medium. The apparent molecular weights and the sizes of these aggregates were determined by Size Exclusion Chromatography (SEC) and by light scattering respectively. Comparison was made of the cell distribution of free and conjugated F1-NH2 in the cell cytoplasm and nucleus by using fluorescence microscopy and laser microspectrofluorometry. It was shown that cell uptakes resulted from adsorptive pinocytosis and depended on hydrophobicity and aggregation of the conjugates. The influence of physical entrapment of free-F1-NH2 within the hydrophobic microdomains formed by aggregates F1-NH2 conjugates was also discussed.

In order to analyze the alginate components of alginate dressings and the fractions which are released when the dressing is in contact with model biological fluids, the use of various analytical methods was considered. The first step was the conversion of a calcium alginate batch to pure sodium alginate. The recovery of the latter from either insoluble or soluble mixed sodium/calcium alginates was performed by complexation of calcium ions with sodium citrate followed by ultrafiltration. Comparisons were made between sugar analysis, 1H NMR and circular dichroism (CD) data to determinate the contents in guluronic and mannuronic acids of sodium alginate chains. It was shown that CD measurements afford a rapid and nondestructive method for determination of %G when one takes the ratio theta200/theta220 into account. Fractionation of crude alginate (generally ranging from 30 to 70% G) was achieved by the triangle dissolution/precipitation method in order to increase the range of alginate in sugar composition. The various validated procedures were applied to investigate the effects of irradiation sterilization on alginate dressings. It was shown that sugar composition is retained whereas molecular weight decreased dramatically due to chain scission.

The use of poly(beta-malic acid) and poly(l-lysine citramide) carriers to transport doxorubicin (Dox) within K562 myeloblastic cells was studied by taking advantage of laser microspectrofluorometry (L-MSF). This technique provided a means to monitor and to quantify the penetration of Dox molecules in the cytoplasm and in the nucleus of Dox-sensitive and Dox-resistant cells. Comparison was made between polymer-drug conjugates more or less hydrophobised by C2, C7 and C12 aliphatic substituents and by the Dox attached to the polymer backbone as pendent chains. Furthermore, a method was proposed to introduce a cleavable non-peptidic spacer of the lactyllactyl-type between the poly(L-lysine citramide) backbone and the drug. It is shown that: Dox was released from the conjugates by a non-enzymatic route in the absence of cells, the Dox-uptake by cells was slower for the conjugates than for the free drug, and the hydrophobisation promoted the penetration of the released drug within the nucleus, even in the case of Dox-resistant cells. However, no reversion of the resistance was observed.

The ability of some microorganisms to use lactic acid stereocopolymers and copolymers with glycolic acid as sole carbon and energy sources was studied under controlled or natural conditions. First, 14 filamentous fungal strains were tested in liquid cultures, adopting total lactic acid consumption, nitrogen source exhaustion, and maximal biomass production as selection criteria. Two strains of Fusarium moniliforme and one strain of Penicillium roqueforti were able to totally assimilate DL-lactic acid, partially soluble racemic oligomers (MW = 1,000), and the nitrogen source. Only one strain of F. moniliforme was able to grow on a poly(lactic acid)-glycolic acid copolymer (MW = 150,000) after 2 months of incubation at 28 degrees C on synthetic agar medium. Mycelium development was examined by scanning electron microscopy. F. moniliforme filaments were observed to grow not only at the copolymer surface but also through the bulk of the copolymer. In a second approach, plates made of a racemic poly(lactic acid) were buried in the soil before being incubated in petri dishes containing mineral agar medium under controlled conditions. Five strains of different filamentous fungi were isolated, and their ability to assimilate racemic poly(lactic acid) oligomers was tested in liquid cultures.

Biodegradable films were prepared by casting acetone solutions of mixtures of a high molecular weight poly(DL-lactic acid) (HMW-PLA50) with 0, 10, and 30% w/w poly(DL-lactic acid) oligomers (LMW-PLA50), before drying. From size exclusion chromatography (SEC) it was shown that degradation occurred during film processing, in agreement with the acid-catalyzed degradation of polyesters. The higher the content of LMW-PLA50, the larger the decrease of the molar masses. The three selected film formulations were then allowed to age in isoosmolar 0.13M, pH 7.4 sodium phosphate buffer at 37 degrees C. The hydrolytic degradation was monitored by using various techniques, namely weighing to quantify water absorption and weight loss, SEC to evaluate molar mass changes, head space gas chromatography to assess the desorption of residual acetone, and enzymatic assay of the L-lactic acid released in the aging media. The presence of LMW-PLA50 clearly accelerated film degradation. Moreover, it was shown that the mechanism of degradation greatly depended on the content in the oligomers.

A bioresorbable aliphatic polyester was synthesized by bulk copolymerization of a 1/1 M/M L,L-lactide/epsilon-caprolactone mixture using zinc metal as initiator. The actual composition of the copolymer was found to be 1.5/1 as deduced from 1H NMR spectra obtained in DMSO-d6 solutions where higher resolution was obtained as compared with chlorinated solvents. Resonances due to L-lactyl units (L) exhibited triads stereosensitivity, epsilon-oxycaproyl units (C) being sensitive to dyads. Average lengths of both poly(lactic acid) and polycaprolactone sequences were evaluated and showed the presence of rather long PLA blocks. Furthermore, no CLC triad signal was found, suggesting the absence of transesterification rearrangements. 10 x 10 x 2 mm specimens made of the copolymer were allowed to age in isoosmolar pH = 7.4 phosphate buffer at 37 degrees C. Degradation was monitored by various analytical techniques such as SEC, X-ray diffractometry, DSC, and 1H NMR. Data were compared with the behaviour of PCL and PLA homopolymers allowed to age under similar conditions. Crystallinity and composition changes are discussed in terms of preferential degradation in L- and C-containing amorphous domains, crystallized long PLA blocks being much more resistant.

A bioresorbable composite material composed of a high molecular weight poly(DL-lactic acid) and granules of natural coral (40/60 w/w) was made by blending in acetone with further evaporation of the solvent. The blend and the unfilled polymer matrix were compression moulded and machined to yield 12 x 12 mm plates of different thicknesses (1.4 mm for the blend vs 2.1 mm for the polymer). The resulting plates were allowed to age at 37 degrees C in a pH 7.4 isoosmolar phosphate buffer solution taken as a model of body fluids. Hydrolytic degradation of the blend was investigated comparatively with the unfilled polymer matrix. The fate of the specimens was monitored by weighing, enzymatic assay, size-exclusion chromatolography and differential scanning calorimetry. Data on water absorption, weight loss, release of L-lactic acid, molecular weight and morphology changes conclusively showed that the presence of coral dramatically modified the degradation characteristics of poly(DL-lactic acid). In particular, the faster internal degradation observed for the unfilled polymer matrix was not detected for the blend. This finding was assigned to the buffering effect of calcium carbonate which neutralized the carboxyl end groups of the degradation products and to the presence of coral/polymer interfaces which facilitated ion exchanges with the external solution, both contributing to eliminate autocatalysis.

In order to investigate the effects of sample size, sample shape, and polymer composition on the hydrolytic degradation of water-insoluble benzylated poly(beta-malic acid) derivatives, three polymers were synthesized, namely PMLABe100, PMLABe90H10 and PMLABe80H20, containing 100, 90, and 80% of benzyl units respectively. For each polymer, 4-mm-thick compression molded pellets, 0.3-mm-thick casted films and 250-500 microns ground particles were made and allowed to age in 0.13 M, pH 7.4 sodium phosphate buffer at 37 degrees C. Degradation was monitored by measuring weight changes, variations of polymer composition, formation of benzyl alcohol, and molecular weight decreases. It was shown that degradation of particles and films depended initially on polymer composition due primarily to fast degradation of acid-rich segments present or formed by benzyl ester cleavages which led more or less rapidly to similar compositions for the three polymers. The higher the content in acid groups, the faster the degradation rate and the characteristic changes. It was also found that pellets made of PMLABe90H10 or PMLABe80H20 degraded heterogeneously and much faster than corresponding films and particles.

In the present paper, the authors call in mind the definitions of biocompatibility and the essential qualities required for biomaterials. The materials mostly used in implantology and maxillofacial surgery are numerous alloys, bioceramics, resorbable and non-resorbable polymers, and finally osseous substitutes of human or animal origin. As to synthetic and non-living materials, the risks in patients are generated by the degradation products. These may induce tissular reactions of inflammatory or immune origin owing to toxic effects. Concerning osseous substitutes, rejections are mostly of immune origin, for allografts and in particular for xenografts. Infections may be another major risk and in spite of all precautionary measures viral infections by hepatitis B, HIV and transmissible spongiform encephalopathy are not yet got under total control. It is just in these domains that one can state juristic lacks which national and european organisation of standardisation and homologation have to cover during the next few years.

In order to study the tissue distribution of biodegradable nanoparticles after oral administration in animals, end-chain-radiolabeled poly(D,L-lactides) were prepared. Two groups of polymers (Mn = 7500, I = 2.4 and Mn = 28000, I = 1.4 as determined by organic size-exclusion chromatography) were chemically modified by reaction of [14C]acetic anhydride with hydroxyl end-chain groups. The activities of both resulting radioactive poly(D,L-lactides) varied from 57 to 1140 microCi/g. Poly(D,L-lactide) or poly(D,L-lactide-co-glycolide) nanoparticles containing various amounts of radioactive polymer were prepared according to the solvent evaporation process with acetone as cosolvent with methylene chloride in the organic phase. Their mean diameter was 133 +/- 25 nm, measured by photon correlation spectroscopy. The radiolabeled-end-group stability of these particles in buffer solutions was found to be greater when the matrix was made from the radiolabeled poly(D,L-lactide) having the highest molecular weight and the lowest polydispersity index. The polymer-chain stability was totally retained for at least 1 week in a phosphate buffer, pH 7.4, i.e. for the selected experiment time.

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.

The biocompatibility and degradation processes of biomembranes made of a mixture of a high molecular weight racemic polylactic acid (PLA50P) with 0, 10, 20 and 30% w/w racemic polylactic acid oligomers (PLA50p) were assessed for morphological changes in subcutaneous abdominal membrane implantations after 15, 21, 30 and 60 d in 45 Wistar rats. These membranes, prepared for periodontal guided tissue regeneration, showed excellent tissue tolerance without an inflammatory reaction. The higher the content in low molecular weight polylactic acid, the higher the degradation rate. At 60 d, the resorption process was almost complete. This process was initiated by outgrowths of short vascular septa, which developed into lobular networks infiltrating the membranes, which were progressively replaced by normal fibrous connective tissue.

The fate was examined of poly(lactic acid) microbeads implanted in large artificial defects created in cortical bone of dog mandibles. Two poly(lactic acid) polymers--poly(L-lactic acid) (PLA 100) and poly(DL-lactic acid) (PLA 50)--were used to make microbeads by solvent evaporation with poly(vinyl alcohol) as surfactant. Histological observation of non-decalcified mandibular bone showed that no real bone regeneration existed in the experimental bone defects 18 months after PLA 100 microbeads implantation. The same observation was made 6 months after implantation of PLA 50 microbeads. PLA 100 and PLA 50 microbeads appeared unable to induce regeneration of cortical bone defects of dog mandible, in contrast to previous observations in man for PLA 50 large implants. The failure is tentatively assigned to the presence of poly(vinyl alcohol) at the surface of microbeads.

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.

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.

Vinorelbine is a new 5' nor Vinca alkaloid, active by i.v. route, in various types of cancer disease such as non-small cell lung cancer and advanced breast cancer. In order to evaluate the possibility of using this drug for local treatment of cancer, Vinorelbine-loaded bioresorbable polymeric implants were prepared using a copolymer of D,L-lactic and glycolic acids (PLA 37.5 GA 25). According to the manufacturing process, the 1.2-mm-diameter cylindrical rods obtained had a drug content of 1, 5, or 20% (w/w) and released half of their content within about 6 days in vitro. In vivo release in rats was slower, half of the drug being released after about 14 days. A dose-dependent antitumoral effect was observed in mice (solid P388 leukemia model) when implants were administered into or in contact with the tumor. At highest drug loads and when administered soon after tumor implantation, Vinorelbine implants were more effective than i.v. administration (median survival time of treated animals related to untreated controls, greater than 360 versus 188). In dogs, results of toxicity experiments revealed that administration of implants in vital organs must be avoided. On the contrary, s.c. administration was well tolerated. A transient local necrosis was observed in the days following implantation, but normal skin was recovered after about 10 weeks. Thus, a clinical trial was conducted on patients with head and neck cancer; implantation of 20% loaded polymeric implants into the tumor sites succeeded in 8 of 9 patients. The sole failure was attributed to the unusual hardness of the tumor tissue. Except for a local transient inflammatory reaction (easily treated with nonsteroidal antiinflammatory agents), no other sign of toxicity was detected, and patients tolerated the device well. Fourteen days after implantation, patients underwent their planned surgery, and the implants were recovered. Residual drug content varied from 24 to 55%. In all cases, there was a clearly delimited necrotic area around the implant, ranging from 0.5 to 3.5 cm in diameter. In the smallest tumors, necrosis was also observed in the normal tissue inside this area. These results invite further studies to evaluate such drug-loaded polymeric implants.

A number of drug-carrier systems have been considered, so far, for time-controlled delivery, targeting, and decrease of toxicity of biologically active compounds. Many of these drug carriers are based on synthetic polymers. Prerequisites for polymeric drug carriers and the need for polyvalent systems capable of carrying different drugs are examined from the viewpoint of effective pharmaceutical uses. The cases of microcapsules, microspheres, nanoparticles, and emulsions based on polymers are recalled. Of particular interest are copolymers, such as amphiphilic block-copolymers and partially quaternized polytertiary amines, that can form hydrophobic microdomains in aqueous media. Discussions are focused on the capability of the corresponding microphases to solubilize, carry, and release lipophilic drugs. The present state of the art is illustrated by recent examples.

Two kinds of cisplatin-containing implants were prepared from polylactic acid (type I) and from lactic acid-glycolic acid copolymer (type II). Type I implants were almost unaffected when inserted in the renal parenchyma of mice. In contrast, type II implants evolved clearly after in vivo implantation. X-ray pictures and platinum concentration measurements showed a continuous release of platinum over at least three weeks. The release resulted in high platinum concentrations in the kidney tissues and low plasma concentrations, compared to systemic injection. Type II implants seem adequate for further clinical trials of local treatment by cisplatin.