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Racemic α,α,β-trisubstituted β-lactones are the monomer units of poly((R,S)-3,3-dimethylmalic acid) (PDMMLA) derivatives, new biopolyesters showing great potential for biomedical applications. Using different groups during the synthesis of these β-lactones allows a tailored synthesis of PDMMLA copolymers with adjustable hydrophilic/phobic ratio. The degradation kinetics of the employed material is one of the most important criteria in the development of bioresorbable implants. The degradation time of PDMMLA derivatives can be controlled using different β-lactones of different hydrophilicity levels during the polymerization stage. Furthermore, PDMMLA has chemically available groups on its side chain allowing to graft functional groups on the polymer via covalent bonds. In this work, following a Steglich esterification protocol, the chemical grafting of cholesterol was carried out on a PDMMLA monomer derived β-lactone as well as on homopolymer PDMMLA–H, and copolymer PDMMLAH40-co-Hex60 (PDMMLA 40/60). Nuclear magnetic resonance (NMR) analyses of the products confirm and quantify the grafting ratio. 100% of cholesterol grafting has been realized on the homopolymer PDMMLA–H giving PDMMLA–Chol, and 10% on the copolymer PDMMLA 40/60, giving PDMMLAH30-ter-Chol10-ter-Hex60 (PDMMLA–Chol 30/10/60) as wished. Fourier-transform infrared (FT-IR) spectra, elemental analysis on the β-lactones and thermogravimetric analyses on the polymers also confirm the chemical modification of the products.

International audience; Cardiovascular diseases are the leading cause of death around the world according to the World Health Organization. In-stent restenosis is an inflammatory response of the immune system to endovascular stent implantation in atherosclerotic patients. Biocompatible and biodegradable polymers are of great interest in this field in order to limit the side effects of stent treatments. Poly([R,S]-3,3-dimethylmalic acid) (PDMMLA) is a new biodegradable statistical polyester which presents promising properties as a stent coating. In this work, we studied by dynamic tensiometry, the adhesion of extracellular matrix proteins (bovine serum albumin, fibronectin, fibrinogen, and vitronectin) and plasma membrane proteoglycan (syndecan-4) on three PDMMLA derivatives with different hydrophilicity levels. The results show that proteins have different adhesion profiles and affinity on these surfaces. They show similar behavior on the most hydrophilic surface, making hydrophilic, ionic and hydrogen type bonds. Then we compared each protein's individual profile to that of a mixture of all studied proteins. The comparison shows that vitronectin and syndecan-4 are the quantitatively dominating proteins adsorbed by specific interactions. Based on the results from previous studies, this work allowed us to identify the most important PDMMLA surface as a promising biomaterial for bioactive stent-coating.

A number of works have been focused on the study of polymers microtacticity and the probability of iso-, syndio-, and atactic arrangement of monomers such as polypropylene and poly(methacrylic esters) before the 1980s. This type of study was fewer in the last four decades despite the importance of stereochemical knowledge of macromolecules in the biomedical field. NMR analysis was the invaluable tool for the study of stereochemistry. This work detailed the synthesis and the physicochemical and microtacticity characterizations of new semicrystalline and amorphous polyesters, poly(3-allyl-3-methylmalic acid) (PAlMMLA) derivatives which are part of the poly(malic acid) family. This polymer is biodegradable and biocompatible. It can also be chemically modified for a possible combination with bioactive molecules. It can be synthesized from chiral product leading a stereoregular and semicrystalline structure. In the case of a racemic starting product, the obtained macromolecular structure is amorphous. Semi-crystalline polyester presented a highly diisotactic structure. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017

Poly((R,S)-3,3-dimethylmalic acid) (PDMMLA) copolymers were synthesized by anionic ring opening polymerization of benzylic and hexylic lactones. The PDMMLA copolymer family has biodegradable and biocompatible properties of interest as nanoparticles (NPs) can be formed from PDMMLA derivatives. For this purpose, three statistical copolymers (PDMMLAH30-co-Hex70, PDMMLAH50-co-Hex50 and PDMMLAH70-co-Hex30) and three block copolymers (PDMMLAH30-b-Hex70, PDMMLAH50-b-Hex50 and PDMMLAH70-co-Hex30) were synthesized and characterized. The main objective of the present study was to formulate new PDMMLA derivative NPs with defined size and shape that can efficiently be used as a novel controlled delivery system for a hydrophobic antithrombotic drug: warfarin. Polymeric NPs were prepared by nanoprecipitation method, optimized and characterized by Transmission Electronic Microscopy (TEM) for morphology investigation and Dynamic Light Scattering (DLS) for size and surface charge analysis. Controlled release of the drug is followed by reverse phase High Performance Liquid Chromatography (HPLC) for four weeks in phosphate buffer at pH = 7.4.

International audience; a r t i c l e i n f o Biodegradable and bioassimilable poly((R,S)-3,3 dimethylmalic acid) (PDMMLA) derivatives were synthesized and characterized in order to develop a new coating for coronary endoprosthesis enabling the reduction of reste-nosis. The PDMMLA was chemically modified to form different custom groups in its side chain. Three side groups were chosen: the hexyl group for its hydrophobic nature, the carboxylic acid and alcohol groups for their acid and neutral hydrophilic character, respectively. The sessile drop method was applied to characterize the wettability of biodegradable polymer film coatings. Surface energy and components were calculated. The van Oss approach helped reach not only the dispersive and polar acid–base components of surface energy but also acid and basic components. Surface topography was quantified by atomic force microscopy (AFM) and subnanometer average values of roughness (Ra) were obtained for all the analyzed surfaces. Thus, roughness was considered to have a negligible effect on wettability measurements. In contrast, heterogeneous surfaces had to be corrected by the Cassie–Baxter equation for copolymers (10/90, 20/80 and 30/70). The impact of this correction was quantified for all the wettability parameters. Very high relative corrections (%) were found, reaching 100% for energies and 30% for contact angles.

This article presents the synthesis of a new family of synthetic isotactic polyesters derived from poly((S)-3,3-dimethylmalic acid) (PDMMLA). These polyesters are prepared via the lactone route bearing functionalized groups in its main or side chain. The aim of this work is twofold: metabolism and stereochemistry. First, the synthesis of these new polyesters is chosen to provide biodegradable polyesters biocompatible and bioassimilable by the human body. Next, the molecular chain of this family contains a stereogenic center in the aim to provide 100% isotactic homopolymers and copolymers (statistical and block). Finally, these polymers have been characterized by several analytical techniques: FTIR, 1H and 13C NMR, SEC, DSC, and TGA. The greatest importance will be given to the 13C NMR and DSC to principally confirm the stereoregularity and crystallinity of these stereopolyesters. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016, 54, 1495–1507

Various optically active (4R)-alkyloxycarbonyl-3,3-dialkyl-2-oxetanones as monomers were synthesized from L-(S)-malic acid in six steps to prepare a new family of stereopolyesters for biomedical applications. The synthesis began with an esterification followed of a dialkylation in the aim to introduce hydrophobic groups as methyl or reactive group as allyl. Then, a saponification has permitted to obtain the corresponding diacids that reacted with appropriate alcohols to furnish different monoesters. The last and most important step was activation of hydroxyl group of monoesters with the asymmetric carbon configuration inversion according to the Mitsunobu reaction. Thus, this reaction has provided lactones from monoesters with 100% enantiomeric excess which was confirmed by 1H NMR and by the synthesis of corresponding isotactic and semicrystalline homopolyesters. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015, 53, 2586–2597

All individuals in social insect colonies benefit from being informed about the presence and fertility state of reproducers. This allows the established reproductive individuals to maintain their reproductive monopoly without the need for physical control, and the non-reproductive individuals to make appropriate reproductive choices. Here, we studied whether fertility signaling is responsible for the partitioning of reproduction in the ant Neoponera apicalis. This species forms small colonies from one single-mated queen, with workers establishing reproductive hierarchies when hopelessly queenless. Previous studies identified putative fertility signals, particularly the hydrocarbon 13-methylpentacosane (13-MeC25), and have shown that precise status discrimination based on these signals could be involved in the regulation of reproductive activities. Here, we extend these findings and reveal that all individuals, be they queens or workers, differ in their cuticular hydrocarbon profile according to fertility state. Proportions of 13-MeC25 were a strong predictor of an individual's ovarian activity, and could, thus, advertise the established reproducer(s) in both queenright and queenless conditions. Furthermore, this compound might play a key role in the establishment of the reproductive hierarchy, since workers with low fertility at the onset of hierarchy formation already have relatively high amounts of 13-MeC25. Dyadic encounters showed that individuals with experimentally increased amounts of 13-MeC25 triggered less agonistic interactions from top rankers, in accord with them "advertising" higher status. Thus, these bioassays supported the use of 13-MeC25 by competing ants. This simple recognition system potentially allows permanent regulation of partitioning of reproduction in this species.

International audience; a r t i c l e i n f o In order to reduce restenosis, the necessity to develop the appropriate coating material of metallic stent is a challenge for biomedicine and scientific research over the past decade. Therefore, biodegradable copolymers of poly((R,S)-3,3 dimethylmalic acid) (PDMMLA) were prepared in order to develop a new coating exhibiting different custom groups in its side chain and being able to carry a drug. This material will be in direct contact with cells and blood. It consists of carboxylic acid and hexylic groups used for hydrophilic and hydrophobic character , respectively. The study of this material wettability and dynamic surface properties is of importance due to the influence of the chemistry and the potential motility of these chemical groups on cell adhesion and polymer kinetic hydrolysis. Cassie theory was used for the theoretical correction of contact angles of these chemical heterogeneous surfaces coatings. Dynamic Surface Analysis was used as practical homogenizer of chemical heterogeneous surfaces by cycling during many cycles in water. In this work, we confirmed that, unlike receding contact angle, advancing contact angle is influenced by the difference of only 10% of acidic groups (%A) in side-chain of polymers. It linearly decreases with increasing acidity percentage. Hysteresis (H) is also a sensitive parameter which is discussed in this paper. Finally, we conclude that cycling provides real information, thus avoiding theoretical Cassie correction. H 10 is the most sensible parameter to %A.

Amphiphilic and biodegradable micelles and nanoparticles designed as potential drug carriers were prepared from biodegradable statistical and block copolyesters obtained by a living anionic ring-opening process. These novel materials display amphiphilic properties arising from the joint presence of hydrophilic poly((RS)-3,3-dimethylmalic acid) and hydrophobic poly(hexyl (RS)-3,3-dimethylmalate) segments. Micelles obtained from a well-defined block copolymer have been characterized by their critical aggregation concentration, and nanoparticles derived from statistical copolymer have been analyzed by transmission electron microscopy (TEM).

The synthesis of novel amphiphilic graft copolyesters based on hydrophobic poly(e-caprolactone) (PCL) segments grafted all along a hydrophilic poly((R,S)-β-malic acid) (PMLA) backbone is proposed. ...

The preparation of α,α,β-trisubstituted β-lactones has opened the route to living anionic ring-opening polymerization of these monomers. Therefore, transfer reactions due to hydrogen abstraction were limited and it is now possible to strickly control sample molecular weight. Moreover, living end-groups lead to the preparation of block co-polymers with block controlled lenghts. In the same way, high-molecular-weight statistical co-polymers have been synthesized. Hydrolyzable micelles and nanoparticles will be prepared from these co-polymers after chemical modifications to adjust the hydrophilic/hydrophobic balance.

Novel polyester and copolyesters have been prepared by anionic ring-opening polymerization of racemic 4-alkyloxycarbonyl-3,3-dimethyl-2-oxetanones that had been synthesized in five steps from diethyl oxalpropionate used as chemical precursor. The anionic polymerizations, realized in bulk or in solution with tetraethylammonium benzoate as initiator, led to a homopolymer and copolymers with high molecular weights and polydispersity indices close to unity. These features can be explained by the presence of two methyl groups on the same carbon atom in the lactone, preventing transfer reactions to the monomer. Preparation of seeds and re-initiation by addition of fresh monomer confirmed a living process. The hydrolysis of poly[(R,S)-3,3-dimethylmalic acid] under physiological conditions yielded (R,S)-3,3-dimethylmalic acid. A terpolymer was also prepared for biological studies related to its use as biodegradable materials for tissue regeneration.

Novel α, α′, β-trisubstituted β-lactones have been prepared by a concise and efficient synthesis in five steps from commercial racemic diethyl oxalpropionate. These lactones with different lateral groups can be polymerized or co-polymerized for obtaining polyesters with high molecular weight. Chemical modification of these functionalized hydrolyzable polymers will be used to adjust their properties to the selected temporary applications.

Radiation-induced intestinal fibrosis is characterized by collagen accumulation, a process in which TGF-beta1 plays a key role. We analyzed the effects of gamma radiation on collagen expression and TGF-beta1 distribution in human intestinal smooth muscle cells (HISM). We investigated the activity of a carboxymethylated and sulfated dextran (RG-1503), exhibiting antifibrotic properties and promoting in vivo intestinal tissue repair, on irradiated HISM. After (60)Co irradiation (10 Gy), HISM were labeled with [(3)H] proline (+/-RG-1503). Radiolabeled collagen I, III, and V were quantified by SDS-PAGE. TGF-beta1 was quantified by ELISA in culture medium, pericellular and intracellular compartments. Irradiation induced a specific 2.85-fold increase in collagen III production by HISM. Collagen V decreased by 80% 72 h after irradiation. Pericellular TGF-beta1 was increased (up to twofold) in irradiated HISM. RG-1503 added before or after irradiation reversed both mRNA and protein levels of collagen III and V to control values. RG-1503 decreased the amount of TGF-beta1 in the cell layer below the control values. Irradiation of HISM induced the development of a fibrotic phenotype in terms of collagen production and TGF-beta1 distribution. The antifibrotic RG-1503 restored HISM physiological characteristics and may represent a promising therapeutic approach for radiation-induced intestinal fibrosis.

Poly((3-hydroxypropyl β malate) has been synthesized starting from aspartic acid and benzyloxy-1-propanol as precursors. This new polymer was characterized by 1H and 13C NMR, size exclusion chromatography and differential scanning calorimetry. Homopolymer is soluble in water. Two kinds of amphiphilic copolymers were also prepared and characterized. Such polymers have been synthesized with a view to preparing non-charged degradable associating networks or drug carriers.

A water soluble and hydrolysable polyester derived from malic acid has been synthesized by copolymerization of three different malolactonic acid esters. Functional pendant groups have been selected to interact with and protect heparin binding growth factors (HBGF). Three β-substituted β-lactones have been synthesized by using aspartic acid as a chiral precursor and benzyl, allyl and butyl alcohols in the formation of the ester pendant groups. The terpolymer has been subjected to three consecutive different chemical modifications. This modified terpolymer, able to induce new bone formation in an in vivo model, has the same property as carboxymethyl benzylamide sulfonate dextrans (CMDBS). Consequently, the distribution of the lateral functional groups is more essential than the glucidic nature of the backbone to acquire biological efficiency.

Ischemia and denervation of EDL muscle of adult rat induce a large central zone of degeneration surrounded by a thin zone of peripheral surviving muscle fibers. Muscle regeneration is a complex phenomenon in which many agents interact, such as growth factors and heparan sulfate components of the extracellular matrix. We have shown that synthetic polymers, called RGTA (as regenerating agents), which imitate the heparan sulfates, are able to stimulate tissue repair when applied at the site of injury. In crushed muscles, RGTA were found to accelerate both regeneration and reinnervation. In vitro, RGTA act as protectors and potentiators of various heparin binding growth factors (HBGF). It was postulated that in vivo their tissue repair properties were due in part to an increase of bioavailability of endogenously released HBGF. In the present work, we show that ischemic and denervated EDL muscle treated by a unique injection of RGTA differs from the control after 1 wk in several aspects: 1) the epimysial postinflammatory reaction is inhibited and the area of fibrotic tissue among fibers is reduced; 2) the peripheral zone, as measured by the number of intact muscle fibers, was increased by more than twofold; and 3) In the central zone, RGTA enhances the regeneration of the muscle fibers as well as muscle revascularization. These results suggest that RGTA both protects muscle fibers from degeneration and preserves the differentiated state of the surviving fibers. For the first time it is demonstrated that a functionalized polymeric compound can prevent some of the damage resulting from muscle ischemia. RGTA may therefore open a new therapeutic approach for muscle fibrosis and other postischemic muscle pathologies.

We developed regenerating agents (RGTAs) corresponding to polysaccharides derived from dextran and containing defined amounts of carboxymethyl (CM), carboxymethyl sulfate (CMS), carboxymethyl benzylamide (CMB), or carboxymethyl benzylamide sulfate (CMBS) groups with varying degrees of substitution. These compounds mimicked some effects of heparin on smooth muscle cell (SMC) proliferation and promoted in vivo tissue remodeling. We demonstrated that only RGTAs containing both CM and sulfate groups decreased SMC proliferation, in correlation with increased sulfation level. This effect was amplified by the presence of benzylamide. Independent of this activity on cell proliferation (i.e., with postconfluent cells), RGTAs modulated collagen biosynthesis by SMCs. On the one hand, CMBS more than CMS RGTAs induced a decrease of collagen III synthesis at the level of mRNA steady state and protein production. On the other hand, CMS to a greater extent than CMBS RGTAs increased both collagen V mRNA and protein production. In addition, only benzylamide-containing RGTAs increased accumulation of collagen I and III in the cell layer. In conclusion, RGTA bioactivities required the presence of CM functions, increased with the sulfation level, and varied with benzylamide substitution. RGTAs that modulate cell proliferation and collagen biosynthesis by differential mechanisms may represent potential antifibrotic agents. © 1998 John Wiley & Sons, Inc. J Biomed Mater Res, 42, 286–294, 1998.

International audience; Amphotericin B (AmB) and clofazimine are potent drugs hindered by their low water solubilities and their toxicities. Carriers able to increase their apparent water solubilities are needed for these drugs and for other molecules with similar properties. Random amphiphilic copolymers derived from poly(dimethylmalic acid) were obtained using different hydrophobization ratios and side group sizes. Apparent water solubilities of pyrene, clofazimine, and AmB were increased up to 10 000, 20 000 and 1000 times, respectively, in aqueous solutions containing these polymers. The presence of sodium chloride in polymer solution increased pyrene solubility but decreased the solubilities of clofazimine and AmB, compared to the salt-free solutions. Synergy between hydrophobic and electrostatic interactions was observed for polar and cationic molecules. Degradation studies showed that the examined polymers were degradable, but none of them were totally degraded in 28 days. These polymers could be used as a new tool for drug solubilization.

A number of synthetic routes to the first pseudo-C-disaccharide ever prepared has been studied. The compound, methyl 7-(( 1S , 3R , 4R , 5S , 6S )-1-amino-3-hydroxymethyl-4,5,6trihydroxycyclohexyl) -6,7-dideoxy-α-D- gluco -heptopyranoside ( 1 ), is structurally related to cellobiose, but includes a crucial amino-functionality at the pseudoanomeric centre. It was prepared by 1,2-addition of the anion of methyl 6,7-dideoxy-2,3,4-tri- O -benzyl-α-D- gluco -hept-6ynopyranoside to ( 4R , 5S , 6R )-3-benzyloxymethyl-4,5,6-tribenzyloxy-2-cyclohexenone followed by stereoselective conversion of the tertiary alcohol to azide and finally reduction.

A number of synthetic routes to the first pseudo-C-disaccharide ever prepared has been studied. The compound, methyl 7-(( 1S , 3R , 4R , 5S , 6S )-1-amino-3-hydroxymethyl-4,5,6trihydroxycyclohexyl) -6,7-dideoxy-α-D- gluco -heptopyranoside ( 1 ), is structurally related to cellobiose, but includes a crucial amino-functionality at the pseudoanomeric centre. It was prepared by 1,2-addition of the anion of methyl 6,7-dideoxy-2,3,4-tri- O -benzyl-α-D- gluco -hept-6ynopyranoside to ( 4R , 5S , 6R )-3-benzyloxymethyl-4,5,6-tribenzyloxy-2-cyclohexenone followed by stereoselective conversion of the tertiary alcohol to azide and finally reduction.

We have synthesized new structures obtained from amphiphilic copolymers of dextran and polybutylmethacrylate with the aim of endothelialization of biomaterials. Grafting of butylmethacrylate onto dextran has been carried out using ceric ammonium nitrate as initiator. Three copolymers were obtained (11, 30 and 37 wt.% dextran) and homogeneous thin films were successfully prepared. In contrast to dextran, the resulting films were stable in water, and copolymers characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry and dynamic mechanical analysis showed evidence of hybrid properties between the parent homopolymers. Surfaces of films were smooth when analyzed by atomic force microscopy (roughness 2+/-1 nm) but greatly differed in their hydrophilicity by increasing the dextran content (water contact angle from 99 degrees to 57 degrees). In contrast to polybutylmethacrylate, where the proliferation of vascular smooth muscle cells (VSMCs) was excellent but that of endothelial cells was very low, the copolymer containing 11% of dextran was excellent for endothelial cells but very limited for VSMCs. An in vitro wound assay demonstrated that copolymer with 11% dextran is even more favorable for endothelial cell migration than tissue-culture polystyrene. Increasing the dextran content in the copolymers decreased the proliferation for both vascular cell types. Altogether, these results show that transparent and water-insoluble films made from copolymers of dextran and butylmethacrylate copolymers with an appropriate composition could enhance endothelial cell proliferation and migration. Therefore, a potential benefit of this approach is the availability of surfaces with tunable properties for the endothelialization of materials.

Hybrid materials constituted by hydrophobic and hydrophilic biocompatible macromolecules are useful for biomedical applications. In this context, a well-known acrylic monomer (methyl methacrylate) was polymerized and grafted onto the polysaccharide dextran by the use of ceric ammonium nitrate as a redox initiator in aqueous nitric acid medium. The effects of concentrations of dextran, acrylic monomer, and ceric ions on the copolymerization yields were investigated in detail. The obtained polymers were studied by solubility measurements, Fourier transform infrared spectrometry, (13)C nuclear magnetic resonance spectroscopy, and viscosimetric analysis. Interestingly, we found conditions to form transparent and homogeneous thin films or 3D structures with hybrid properties. Indeed, the copolymer, but not dextran or PMMA, could be dissolved in water/THF (20/80 v/v). The thermomechanical properties of the resulting copolymer analyzed by differential scanning calorimetry and dynamic mechanical analysis showed the occurrence of a single glass-transition temperature and a marked difference with the two homopolymers. The cytocompatibility of the copolymer with human endothelial cells was evidenced by the normal cell adhesion, proliferation, and morphology after 5 days in culture on these gels. In conclusion, this type of copolymer with hybrid properties of two biocompatible macromolecules could be of great interest as a 3D scaffold or for coating in biomedical applications.

Amphiphilic and biodegradable micelles and nanoparticles designed as potential drug carriers were prepared from biodegradable statistical and block copolyesters obtained by a living anionic ring-opening process. These novel materials display amphiphilic properties arising from the joint presence of hydrophilic poly((RS)-3,3-dimethylmalic acid) and hydrophobic poly(hexyl (RS)-3,3-dimethylmalate) segments. Micelles obtained from a well-defined block copolymer have been characterized by their critical aggregation concentration, and nanoparticles derived from statistical copolymer have been analyzed by transmission electron microscopy (TEM).

In polymer science, chemical modification has been early a large area of research and industrial development. The possibility of chemically fitting properties to specific applications has been often used in the case of natural macromolecules, such as cellulose or dextrans. In the biomedical and therapeutic domains, the necessity for smart temporary devices leads to an increase in the macromolecular structures complexity. The building of such polyvalent polymers can be achieved by copolymerization of monomers, by the tailor making of multiblock macromolecules or by chemical modification starting from a functional parent compound. The lactic and glycolic acids polymers and copolymers family, which have been the pioneer class of biocompatible and hydrolysable polymeric medical materials must be affixed by other polymers types for adjusting hydrophilic/hydrophobic balance, interactions, targeting, bioactive molecules attachment, degradation rate, suitable properties. Therefore, polymers with hydrolysable backbone and side functional groups have been selected: poly(amino acids), polyesteramides and polyesters1. Our choice has been concerned with synthetic, natural and artificial functionalized poly(hydroxyalkanoate)s. They have a cleavable ester bond in the macromolecular chain, one or more chiral centres in the monomer unit and a reactive group in the side chain. This group can hold an unsaturated bond, which will be turned to epoxy or carboxyl function by chemical modification, or an ester function, which will be turned to carboxyl group. Further reactions are conceivable.

A bioactive poly(beta-hydroxyalkanoate) derived from malic acid was prepared and tested on bone repair and muscle regeneration. This functionalized and hydrolyzable polymer was obtained after several steps, the first one being the anionic copolymerization of three malolactonic acid esters. Chemical modifications were carried out on the terpolymer to turn benzyl-protecting groups into carboxyl groups and allyl groups into sulfonate groups. The resulting polymer bore carboxylate, sulfonate, and sec-butyl pendent groups in 65/25/10 molar proportions and were aimed at interacting with heparan binding growth factors. This polymer did not present any toxic effect in cell viability of HepG2 cells, over a large range of concentrations (0.01-0.25 mgl(-1)). Its ability to improve wound healing was tested in vivo and positive results are reported. Furthermore, the bioactivity of this polymer was evaluated using the regeneration model of Extensor digitorum longus (EDL) rat muscle. The study displayed a significant increase in the muscle regeneration and maturation.

We have synthesized dextran derivatives called RGTAs (for regenerating agents) that were designed to mimic some of the properties of heparin or heparan sulfate to interact with and protect heparin binding growth factors. Some of these growth factors have been described to be involved in myogenesis control. In previous studies, we have shown that muscle regeneration in adults could be greatly enhanced in vivo by treatment with RGTA. Since muscle regeneration occurs through the activation of satellite cells, in the present study we have used primary cultures of rat satellite cells and treated them with the heparan sulfate analogue RGTA or heparin in order to stimulate their growth and differentiation. We also studied the effect of these substances on calpain (calcium-activated neutral proteases) expression in these cultures. Indeed, several reports, principally based on fetal myoblast cultures or myogenic cell lines, have suggested that calpains might be involved in myoblast fusion during myogenic differentiation. We therefore studied the expression of microcalpain (mu-calpain), millicalpain (m-calpain), and calpain 3 in the course of differentiation of these satellite cell cultures in the absence or in the presence of heparin or of a mimic compound (the RGTA RG1282). RGTA and heparin were shown to have a dual effect on satellite cell proliferation and differentiation: RGTA stimulated proliferation with a maximum dose effect at 1 microgam/ml. Heparin used at concentrations similar to those of RGTA was less efficient at stimulating proliferation. Both substances were shown, however, to induce precocious and enhanced differentiation of satellite cells. We showed by quantitative RT-PCR analysis that mu-calpain, m-calpain, and calpain 3 mRNAs were expressed in satellite cell cultures in proliferating myoblasts (day 3) and differentiating cultures (days 7 and 12). The level of mu-calpain mRNA was increased by a factor of 3 during differentiation of satellite cells, whereas the level of m-calpain mRNAs was slightly increased at day 12 only, and calpain 3 mRNA was slightly reduced in these differentiating cultures. Interestingly enough, RGTA and heparin, which both strongly increased differentiation, reduced the expression of the mu- and m-calpains and slightly increased that of calpain 3 in differentiating cultures. These results showed that there was no correlation between the extent of myoblast differentiation and the level of calpain expression in satellite cells grown in primary cultures and underscored the differences between these adult cells and fetal myoblasts.

Atherosclerosis, one of the frequent cardiovascular diseases, is treated by placing a metal stent inthe blocked artery. However, an intra-stent restenosis is observed in 20 to 30% of patients.The objective of this thesis is to develop a new bioactive polymer for cardiovascular stent coating,which would inhibit arterial restenosis. PDMMLAs are new biodegradable polyesters, synthesized through an anionic ring opening polymerization of α,α,β-tri-substituted β-lactones. The tailored synthesis of PDMMLAs allows to prepare amphiphilic copolymers with adjustable hydrophilicity proportions. As part of this thesis, after the multi-step synthesis of different PDMMLA derivatives, asurface physicochemical properties analysis was carried out by studying the adhesion profiles ofdifferent proteins on these surfaces. In parallel, the covalent grafting of molecules, especially of an activedrug was accomplished on PDMMLA derivatives. Promising results were obtained regarding the releaseprofile and kinetics of the grafted active drug and the biological studies, indicating that the drug-graftedPDMMLA is a good candidate for biological applications. This new polymer needs further studies toimprove its mechanical properties and other aspects, which are also important criteria in the developmentof medical devices, Le traitement de l’athérosclérose nécessite la pose d’un stent métallique dans la lumière d’un vaisseau sanguin endommagé. Cependant, le phénomène de resténose intra-stent est observé chez 20 à30% des patients. L’objectif de cette thèse est de développer un nouveau revêtement de stents, composé d’un polymère bioactif dans le but d’inhiber la resténose intra-stent. Les PDMMLAs sont de nouveaux polyesters biodégradables, synthétisés par une voie de polymérisation anionique par ouverture de cycle des β-lactones α,α,β-tri-substituées. La synthèse à façon des PDMMLAs permet d’obtenir des copolymères amphiphiles avec des proportions d’hydrophilie modulables. Dans le cadre de cette thèse, après la synthèse multi-étapes de différents dérivés de PDMMLA, une analyse des propriétés physicochimiques de surface a été réalisée en étudiant les profils d’adhésion des protéines sur ces surfaces. Parallèlement à ces études, le greffage covalent de molécules, notamment d’un principe actif sur les dérivés de PDMMLA a été effectué. Les résultats de l’étude de la libération du principe actif greffé, ainsi que les premiers résultats des études biologiques étant prometteurs, le PDMMLA, accompagné de son principe actif est un bon candidat pour des applications biologiques. Ce nouveau polymère greffé doit être davantage étudié afin d’améliorer ses propriétés mécaniques qui sont également des critères importants dans la conception des dispositifs médicaux

Atherosclerosis, one of the frequent cardiovascular diseases, is treated by placing a metal stent inthe blocked artery. However, an intra-stent restenosis is observed in 20 to 30% of patients.The objective of this thesis is to develop a new bioactive polymer for cardiovascular stent coating,which would inhibit arterial restenosis. PDMMLAs are new biodegradable polyesters, synthesized through an anionic ring opening polymerization of α,α,β-tri-substituted β-lactones. The tailored synthesis of PDMMLAs allows to prepare amphiphilic copolymers with adjustable hydrophilicity proportions. As part of this thesis, after the multi-step synthesis of different PDMMLA derivatives, asurface physicochemical properties analysis was carried out by studying the adhesion profiles ofdifferent proteins on these surfaces. In parallel, the covalent grafting of molecules, especially of an activedrug was accomplished on PDMMLA derivatives. Promising results were obtained regarding the releaseprofile and kinetics of the grafted active drug and the biological studies, indicating that the drug-graftedPDMMLA is a good candidate for biological applications. This new polymer needs further studies toimprove its mechanical properties and other aspects, which are also important criteria in the developmentof medical devices; Le traitement de l’athérosclérose nécessite la pose d’un stent métallique dans la lumière d’un vaisseau sanguin endommagé. Cependant, le phénomène de resténose intra-stent est observé chez 20 à30% des patients. L’objectif de cette thèse est de développer un nouveau revêtement de stents, composé d’un polymère bioactif dans le but d’inhiber la resténose intra-stent. Les PDMMLAs sont de nouveaux polyesters biodégradables, synthétisés par une voie de polymérisation anionique par ouverture de cycle des β-lactones α,α,β-tri-substituées. La synthèse à façon des PDMMLAs permet d’obtenir des copolymères amphiphiles avec des proportions d’hydrophilie modulables. Dans le cadre de cette thèse, après la synthèse multi-étapes de différents dérivés de PDMMLA, une analyse des propriétés physicochimiques de surface a été réalisée en étudiant les profils d’adhésion des protéines sur ces surfaces. Parallèlement à ces études, le greffage covalent de molécules, notamment d’un principe actif sur les dérivés de PDMMLA a été effectué. Les résultats de l’étude de la libération du principe actif greffé, ainsi que les premiers résultats des études biologiques étant prometteurs, le PDMMLA, accompagné de son principe actif est un bon candidat pour des applications biologiques. Ce nouveau polymère greffé doit être davantage étudié afin d’améliorer ses propriétés mécaniques qui sont également des critères importants dans la conception des dispositifs médicaux

In this work we synthesized derivatives of poly((R,S)-3,3-dimethylmalic acid) (PDMMLA).PDMMLA copolymers are mainly composed of two monomers: a hydrophobic monomercontaining a hydroxyl group and a hydrophilic monomer containing an acid group. Due to theproportion of each monomer in the final copolymer, the hydrophilic / hydrophobic balance ismodulated. Thus, six copolymers were obtained: three random copolymers PDMMLAHn-co-Hex100-n and three block copolymers: PDMMLAHn-b-Hex100-n.These copolymers are at the origin of nanoparticles without and with an active principle.Warfarin, which has been successfully encapsulated with both PDMMLAHn-co-Hex100-nand block, copolymer nanoparticles: PDMMLAHn-b-Hex100-n. The formed nanoparticlesshowed fairly high encapsulation efficiency for both types of copolymers.The PDMMLA nanoparticles are characterized in order to determine their shape, size andsurface charge. Thus nanoparticles of spherical shape, having less than 100 nm size andhaving a surface charge of less than -30 mV have been obtained. The PDMMLAH30-co-Hex70nanoparticles were chosen to study the controlled release of warfarin under physiologicaltemperature and pH conditions. Obtained results show a slow and progressive release ofwarfarin. Such nanoparticulate systems based on amphiphilic derivatives of PDMMLA wouldthus offer tools of interest for the encapsulation and controlled release of many hydrophobicactive principles such as the coumarin derivative thrombin inhibitor (DCBC) whoseantithrombin activity in purified system is higher than that of argatroban., Dans ce travail de thèse, nous avons synthétisé des dérivés de poly(acide (R,S)-3,3-diméthylmalique) (PDMMLA). Les copolymères de PDMMLA sont composésprincipalement de deux monomères: un monomère hydrophobe contenant un groupementhexylique et un monomère hydrophile contenant un groupement acide. Grâce à la proportionde chaque monomère dans le copolymère final, la balance hydrophile/hydrophobe est ajustée.Donc six copolymères ont été obtenus: trois copolymères statistiques PDMMLAHn-co-Hex100-n et trois copolymères à blocs PDMMLAHn-b-Hex100-n. Ces copolymères sont àl’origine de nanoparticules sans et avec un principe actif. La Warfarine a été encapsulée à lafois avec des nanoparticules de PDMMLAHn-co-Hex100-n et de PDMMLAHn-b-Hex100-n.Les nanoparticules formées sont caractérisées afin d'en déterminer la forme, la taille et lacharge de surface. Donc des nanoparticules de forme sphérique, ayant une taille inférieure à100 nm et ayant une charge de surface inférieure à -30 mV ont été obtenues. Lesnanoparticules de PDMMLAH30-co-Hex70, ont été choisies pour étudier la libérationcontrôlée de la warfarine dans des conditions de température et de pH physiologiques. Lesrésultats obtenus montrent une libération lente et progressive de la warfarine à partir dessystèmes nanoparticulaires ainsi conçus et réalisés. De tels systèmes nanoparticulaires à basede dérivés amphiphiles du PDMMLA offriraient ainsi des outils d'intérêt pour l'encapsulationet la libération contrôlée de nombreux principes actifs hydrophobes tels que le dérivécoumarinique inhibiteur de la thrombine (DCBC) dont l'activité antithrombine en systèmepurifié est plus élevée que celle de l'argatroban.

With the exception of bibliographic chapter, this thesis was written in the format of collection of articles with abstracts and discussions while comparing the results with other’s in the literature in the same research theme. This work is organized in three tasks: organic synthesis and stereochemistry of polymers, surface physicochemical properties and biological response and degradation study of polymers. The issue of this thesis is based on in-stent restenosis which represents the major complications of angioplasty with stent placement. Drug-eluting stents are currently the solution used for the restenosis treatment. These are metal stents coated with a polymer having a bioactive substance which is generally an antiproliferative agent. The polymer role is to create a protective barrier between the metal and the arterial wall. This barrier must improve the roughness and the chemical composition of the metallic stent, repair the endothelium by the proliferation of endothelial cells and inhibit the proliferation and the migration of smooth muscle cells which are responsible to the reformation of atheroma plaque. The surface properties confer to polymer a strong adhesiveness to the metal and biocompatibility vis-a-vis of the arterial wall. Interaction created between the polymer coating and vascular cells are modulated by the physicochemical properties of the surface. It is in this context that my thesis is organized into two themes.The first aim of my thesis is to develop a series of amorphous polymers and study their physicochemical (wettability, roughness ...) and biological properties (adhesion, cell behavior and proliferation) and then correlate these properties to choose the promising coating coronary stent. A degradation study was also conducted on elaborate systems. The second is dedicated to chemical synthesis and stereochemistry of polymers. Indeed, new optically active monomers and the corresponding stereopolyesters were synthesized and characterized in order to compare their physicochemical properties with those of amorphous polyesters studied as a coating of the stent and enhance the biomaterials field.; A l’exception du chapitre bibliographique, cette thèse a été rédigée sous forme d’articles avec des résumés et des discussions tout en comparant les résultats obtenus à d’autres résultats de la littérature dans la même thématique de recherche. Ce travail s’organise en trois axes de recherche : la synthèse organique et la chimie des polymères, la physicochimie de la surface et l’étude de la réponse biologique et de la dégradation des polymères. La problématique de ce sujet de thèse s’articule autour de la resténose intra-stent qui représente la complication majeure de l’angioplastie par pose de stent dans les artères sténosées. Les stents actifs restent la solution actuellement utilisée pour le traitement de la resténose. Ce sont des stents métalliques recouverts d’un polymère qui comporte une substance bioactive généralement un antiprolifératif. Le rôle du polymère est de créer une barrière protectrice entre le métal et la paroi artérielle. Cette barrière doit améliorer la rugosité et la composition chimique du stent métallique, réparer l’endothélium par la prolifération des cellules endothéliales et inhiber la prolifération et la migration des cellules musculaires lisses qui sont responsables d’une façon directe de la reformation de la plaque d’athérome. Les propriétés de surface du polymère lui confèrent un fort pouvoir d’adhérence au métal et de biocompatibilité vis-à-vis de la paroi artérielle. Les interactions créées entre le revêtement polymère et les cellules vasculaires sont modulées par les propriétés physicochimiques de la surface. C’est dans cette optique que mon sujet de thèse est organisé en deux thématiques.

With the exception of bibliographic chapter, this thesis was written in the format of collection of articles with abstracts and discussions while comparing the results with other’s in the literature in the same research theme. This work is organized in three tasks: organic synthesis and stereochemistry of polymers, surface physicochemical properties and biological response and degradation study of polymers. The issue of this thesis is based on in-stent restenosis which represents the major complications of angioplasty with stent placement. Drug-eluting stents are currently the solution used for the restenosis treatment. These are metal stents coated with a polymer having a bioactive substance which is generally an antiproliferative agent. The polymer role is to create a protective barrier between the metal and the arterial wall. This barrier must improve the roughness and the chemical composition of the metallic stent, repair the endothelium by the proliferation of endothelial cells and inhibit the proliferation and the migration of smooth muscle cells which are responsible to the reformation of atheroma plaque. The surface properties confer to polymer a strong adhesiveness to the metal and biocompatibility vis-a-vis of the arterial wall. Interaction created between the polymer coating and vascular cells are modulated by the physicochemical properties of the surface. It is in this context that my thesis is organized into two themes.The first aim of my thesis is to develop a series of amorphous polymers and study their physicochemical (wettability, roughness ...) and biological properties (adhesion, cell behavior and proliferation) and then correlate these properties to choose the promising coating coronary stent. A degradation study was also conducted on elaborate systems. The second is dedicated to chemical synthesis and stereochemistry of polymers. Indeed, new optically active monomers and the corresponding stereopolyesters were synthesized and characterized in order to compare their physicochemical properties with those of amorphous polyesters studied as a coating of the stent and enhance the biomaterials field., A l’exception du chapitre bibliographique, cette thèse a été rédigée sous forme d’articles avec des résumés et des discussions tout en comparant les résultats obtenus à d’autres résultats de la littérature dans la même thématique de recherche. Ce travail s’organise en trois axes de recherche : la synthèse organique et la chimie des polymères, la physicochimie de la surface et l’étude de la réponse biologique et de la dégradation des polymères. La problématique de ce sujet de thèse s’articule autour de la resténose intra-stent qui représente la complication majeure de l’angioplastie par pose de stent dans les artères sténosées. Les stents actifs restent la solution actuellement utilisée pour le traitement de la resténose. Ce sont des stents métalliques recouverts d’un polymère qui comporte une substance bioactive généralement un antiprolifératif. Le rôle du polymère est de créer une barrière protectrice entre le métal et la paroi artérielle. Cette barrière doit améliorer la rugosité et la composition chimique du stent métallique, réparer l’endothélium par la prolifération des cellules endothéliales et inhiber la prolifération et la migration des cellules musculaires lisses qui sont responsables d’une façon directe de la reformation de la plaque d’athérome. Les propriétés de surface du polymère lui confèrent un fort pouvoir d’adhérence au métal et de biocompatibilité vis-à-vis de la paroi artérielle. Les interactions créées entre le revêtement polymère et les cellules vasculaires sont modulées par les propriétés physicochimiques de la surface. C’est dans cette optique que mon sujet de thèse est organisé en deux thématiques.