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Ciprofloxacin (CFX) was loaded on Bana clay (Cameroon) and CFX loadedclays have been evaluated as drug delivery system. Raw clays and CFX loaded compounds have been characterized by some physico-chemicals methods. In vitro release studies have been done in gastric and phosphate buffer experimental mediums; bacteriological studies have been made up on Escherichia coli and Staphylococcus aureus. X-ray diffractometry patterns of loaded compounds show a basal spacing increasing due to CFX intercalation. On Fourier-Transformed Infrared spectrometry spectra, appearance of CFX characteristic bands and shifting of certain bands already presents on clay confirmed CFX intercalation. After 96 h of CFX released from release mediums, prolonged and continue profiles have been observed. Diffusion tests displayed an inhibition radius of ~2 cm on gelose seeded with Escherichia coli and Staphylococcus aureus due to CFX. The overall results show a modified release of ciprofloxacin with an effective antibacterial activity, giving the way for a new ciprofloxacin drug delivery system using Bana clay as carrier.

International audience; This study reports the in vitro efficacy of a mixture of plant extracts used as antibacterial agents loaded in a dressing to prevent infection in a wound. These natural compounds were extracted from avocado and mango.A mixture of equal proportions of petroleum ether extract from avocado kernels and methanolic extract from mango kernels was effective on the majority of 36 bacterial strains and presented excellent results against S. aureus. The Minimal Inhibitory Concentrations (MIC) measured on Staphylococcus aureus (ATCC 6538) were 0.019 mg/mL for the mixture compared to 0.039 mg/mL for the avocado or mango extract alone. This mixture was incorporated into a wound dressing composed of non-woven fabric and a gel. This gel consists of a plasticizer (starch/glycerin) and an absorbent (CMC/PCD) and is designed to have swelling properties and entrap plant extract. A formulation containing equal proportions of CMC and PCD enabled us to obtain 800% of swelling and a good adhesion of the gel to the non-woven fabric.The final dressing containing the mixture of avocado and mango extracts presented excellent antibacterial activity against S. aureus. Microbiological tests demonstrated that a wound dressing loaded with avocado/mango seed extract induced additional bacterial reduction of 3 Log10 and 2 Log10 against S. aureus and P. aeruginosa respectively but no additional bacterial reduction of C. albicans compared to the control.Our study demonstrated the scope for interest in plant species extracts provided by agricultural co-products in developing a new antibacterial wound dressing.

The goal of the study was to elaborate an antibacterial silver wound dressing covered by a protective coating that would prevent silver diffusion toward skin without losing its biocide properties. Therefore, non woven polyethyleneterephtalate (PET) textiles were pre-treated by two types of polysaccharides - chitosan and cyclodextrin - both crosslinked with citric acid by a pad/dry/cure process. Both types of resulting thermofixed textiles carrying the citrate crosslinks were then impregnated in silver solution followed by a thermal treatment and were finally coated by Layer-by-Layer (L-b-L) deposition of a polyelectrolyte multilayer (PEM) film consisting of anionic water-soluble poly-cyclodextrin and cationic chitosan. The influence of the process parameters was investigated in terms of silver adsorption capacity, PEM system build-up, silver kinetics of release and antibacterial activity. We demonstrate i) the utility of the intermediate thermal treatment step in the reduction of silver leakage in the polyelectrolyte solutions used in the L-b-L process, ii) that silver adsorption on the preliminary thermofixed layers did not affect the PEM system build-up, iii) the slowing down of silver release kinetic thanks to the PEM coating, iv) the preservation of the antibacterial activity despite the PEM coating.

Drug-eluting stents have demonstrated efficiency in in-stent restenosis (ISR) but induced a risk of late acute thrombosis by delaying strut re-endothelialization. Polydopamine (PDA), a biocompatible polymer inspired from adhesive proteins of mussels, has been reported to promote endothelial cell (EC) proliferation while limiting SMC proliferation in vitro, thus suggesting the pro-healing potential. This study aimed at evaluating in vivo the impact of the pro-healing PDA-coated stent on ISR and on the quality of the strut re-endothelialization in a rat model. PDA-coated stents demonstrated a significant reduction in ISR in vivo compared to bare metal stents (ratio neointima/media = 0.48 (±0.26) versus 0.83 (±0.42), p < 0.001). Western blot analyses identified a trend towards an increased activation of p38 MAPK phosphorylation and its anti-proliferative effects on vascular SMC that could explain the results observed in morphological analyses. This bioinspired and biocompatible polydopamine layer could intrinsically limit ISR. In addition, according to its latent reactivity, PDA offers the possibility to immobilize some relevant drugs on the PDA-functionalized stent to provide potential synergistic effects.

This study consisted of developing a dressing loaded with silver (Ag) and ibuprofen (IBU) that provides a dual therapy, antibacterial and antalgic, intended for infected painful wounds. Therefore, non-woven polyethyleneterephtalate (PET) textiles nonwovens were pre-treated by cyclodextrin crosslinked with citric acid by a pad/dry/cure process. Then, textiles were impregnated in silver solution followed by a thermal treatment and were then coated by Layer-by-Layer (L-b-L) deposition of a polyelectrolyte multilayer (PEM) system consisting of anionic water-soluble poly(betacyclodextrin citrate) (PCD) and cationic chitosan. Finally, ibuprofen lysinate (IBU-L) was loaded on the PEM coating. We demonstrated the complexation of IBU with native βCD and PCD by phase solubility diagram and 1H NMR. PEM system allowed complete IBU-L release in 6 h in PBS pH 7.4 batch (USP IV). On the other hand, microbiological tests demonstrated that loaded silver induced bacterial reduction of 4 Log10 against S. aureus and E. coli and tests revealed that ibuprofen lysinate loading did not interfere with the antibacterial properties of the dressing.

International audience; Infections represent a major medical concern and have severe impact on the public health economy. Antimicrobial coatings represent one major solution and are the subject of many investigations in academic and industrial research. Polyelectrolyte multilayers (PEMs) consist in the step-by-step deposition of polyanions and polycations films on surfaces. The wide range of disposable polyelectrolytes makes this approach among the most versatile methods as it allows to design surfaces that prevent bacterial adhesion, and kill bacteria by contact or by releasing antibacterial agents. The present work focused on the release-killing effect of an active PEM coating of a polyethylene terephthalate (PET) textile support. This activity was obtained thanks to the PEM film build up using cationic and anionic polyelectrolytes both based on cyclodextrins (PCD- and PCD+) that provided a reservoir property and prolonged release of triclosan (TCS). To this effect, a PET non-woven preliminarily modified with carboxylate groups by applying a thermofixation process was then treated by dip-coating, alternating soaking cycles in cationic PCD+ and in anionic PCD- solutions. Samples coated with such PEM film were then loaded with TCS whose release was assessed in dynamic mode in a phosphate buffered saline solution (PBS) at 37 °C. In parallel, TCS/PCD+ and TCS/PCD- interactions were investigated by Nuclear Magnetic Resonance (NMR) and phase solubility study, and the biocide activity was assessed against S. aureus and E. coli. Finally, the present study has demonstrated that our PCD+/PCD- PEM system presented release-killing properties that supplement the contact-killing effect of this system that was reported in a previous paper.

International audience; The main cause of failure of angioplasty stenting is restenosis due to neointimal hyperplasia, a too high proliferation of smooth muscle cells (SMC). The local and sustained delivery of selective pleiotropic drugs to limit SMC proliferation seems to be the hopeful solution to minimize this post surgery complication. The aim of this study is to develop a stent covered by nanofibers (NFs) produced by electrospinning, loaded with simvastatin (SV), a drug commonly used for restenosis prevention. NFs were prepared from the electrospinning of a solution containing SV and a mixture of chitosan (cationic) and β-cyclodextrin (CD) polymer (anionic) which form together a polyelectrolyte complex that makes up the NFs matrix. First, the SV/CD interactions were studied by phase solubility diagram, DRX and DSC. The electrospinning process was then optimized to cover a self-expandable NiTiNOL stent and the mechanical resistance of the NFs sheath upon its introduction inside the delivery catheter was considered, using a crimper apparatus. The morphology, coating thicknesses and diameters of nanofibers were studied by scanning electron microscopy. The SV loading rates on the stents were controlled by the electrospinning time, and the presence of SV in the NFs was confirmed by FTIR. NFs stability in PBS pH 7.4 buffer could be improved after thermal post-treatment of NFs and in vitro release of SV in dynamic conditions demonstrated that the release profiles were influenced by the presence of CD polymer in NFs and by the thickness of the NFs sheath. Finally, a covered stent delivering 3 µg/mm2 of SV within 6 h was obtained, whose efficiency will be investigated in a further in vivo study.

Diabetic foot infections are the most common complications requiring hospitalisation of patients with diabetes. They often result in amputation to extremities and are associated with high morbi-mortality rates, especially when bone is infected. Treatment of these complications is based on surgical procedures, nursing care and systemic antibiotic therapy for several weeks, with a significant risk of relapse. Due to low blood flow and damage caused by diabetic foot infection, blood supply is decreased, causing low antibiotic diffusion in the infected site and an increase of possible bacterial resistance, making this type of infection particularly difficult to treat. In this context, the aim of this work was to develop a medical device for local antibiotic release. The device is a lyophilized physical hydrogel, i.e a sponge based on two oppositely charged polyelectrolytes (chitosan and poly(cyclodextrin citrate)). Cyclodextrins, via inclusion complexes, increase drug bioavailability and allow an extended release. Using local release administration increases concentrations in the wound without risk of toxicity to the body and prevents the emergence of resistant bacteria. The hydrogel was characterised by rheology. After freeze-drying, a curing process was implemented. The swelling rate and cell viability were evaluated, and finally, the sponge was impregnated with a ciprofloxacin solution to evaluate its drug release profile and its antibacterial activity.

Introduction Les infections osteo-articulaires (IOA) sont un probleme de sante publique. Les therapies actuelles ne sont pas toujours efficaces et l’amputation est souvent la seule issue. De nouvelles strategies therapeutiques sont developpees : les systemes de liberation localisee. Dans notre cas, ce sont des eponges a base de chitosan (CHT) et de polymere de cyclodextrine (PCDs) impregnees de rifampicine (RFP). Cet antibiotique est actif sur les bacteries GRAM+. Des travaux anterieurs ont ete realises avec la ciprofloxacine (CFX), antibiotique actif sur les GRAM−. Notre objectif est d’evaluer in vitro la liberation en RFP de ces eponges et leur activite antibacterienne sur Staphylococcus aureus et Escherichia coli. Materiels et methodes Les eponges sont de ratios CHT/PCDs variables (3/0, 3/1, 3/3). On etudie l’impact des conditions d’impregnation (duree, concentration) via une liberation en mode dynamique. Pour le temps d’impregnation, on impregne les eponges dans 12 g/L de RFP (clinique) pendant 15 min, 30 min, 1 h, 2 h, 4 h, 24 h ou 72 h. Pour la concentration d’impregnation, on les impregne pendant 4 h dans 6, 12 ou 60 g/L de RFP. Les conditions optimales definies en fin d’etude permettent de realiser des kill-time sur S. aureus et E. coli. Resultats Pour l’impact du temps d’impregnation, le ratio 3/0 libere une quantite maximale a 24 h avec 4 h d’impregnation : 807 ± 79 mg/g. Les ratios 3/1 et 3/3 liberent une quantite maximale avec 72 h d’impregnation : 750 ± 287 mg/g et 512 ± 30 mg/g. L’analyse du profil de liberation montre une liberation plus lente avec l’augmentation du temps d’impregnation excepte pour le ratio 3 :0. Pour l’impact de la concentration d’impregnation, les eponges 3 :3 liberent a 24 h 20 ± 9 mg/g, 54 ± 8 mg/g et 171 ± 20 mg/g de RFP respectivement pour des impregnations a 6, 12 et 60 g/L. Les eponges 3/0 et 3/1 liberent 131 ± 16 mg/g et 91 ± 17 mg/g avec une impregnation a 6 g/ L contre 169 ± 12 mg/g et 172 ± 8 mg/g avec une impregnation a 12 g/L. Cet effet-dose dependant n’est plus visible pour ces deux ratios lorsqu’on impregne avec 60 g/L de RFP. Les quantites liberees avec une impregnation a 60 g/L sont de 17 2 ± 56 mg/g pour les eponges 3/0 et 171 ± 20 mg/g pour les eponges 3/1. L’analyse des profils de liberation montre la presence d’un burst initial pour les 3 ratios. Aux concentrations de 6 et 12 g/L, le burst est plus prononce pour les eponges 3/3. A 60 g/L, la quantite de RFP liberee a 24 h n’est pas differente significativement entre les 3 ratios et les profils de liberation sont similaires. La decroissance bacterienne des eponges impregnees avec 12 g/L de RFP pendant 4 h est importante sur S. aureus. A 6 h, on a une reduction de 6 Log10 pour les eponges 3/0 et 3/1, et de 4 Log10 pour les eponges 3/3. L’activite sur E. coli est faible avec une reduction de 2 Log10 pour le ratio 3/0 et inferieure a 1 Log10 pour les 2 autres ratios. Conclusion Les eponges 3/1 semblent etre adaptees au traitement des IOA. Le PCDs assure leur stabilite. D’autres tests doivent encore etre menes : l’efficacite in vitro sur les biofilms et l’etude sur l’animal…

Synthetic Vascular Graft Infection (SVGI) can be very serious for patients with dramatic consequences (up to 6%). Polyester vascular grafts (PET) were modified with polymerized cyclodextrin (Poly-MeβCD) and loaded with ciprofloxacin (CFX) for the prevention of postoperative infections. The aim of this study was to investigate the CFX/Poly-MeβCD interactions and the importance of the type of the dissolution technique. The solubility of CFX was significantly improved upon Poly-MeβCD, and the interaction between CFX and Poly-MeβCD were observed by NMR (Nuclear Magnetic Resonance). Drug release was measured in phosphate buffer saline pH 7.4 at 37 °C using: (i) agitated flasks, (ii) the paddle apparatus, (iii) the conventional flow-through cells, (iv) the modified flow-through cells with agarose gel at different flow rates. Importantly, CFX release depends on the flow rate as well as the experimental set-up in vitro. CFX release from virgin prostheses (PET) was faster than from functionalized prostheses (PET-MeβCD), irrespective of the flow rate, which indicates the superiority of Poly-MeβCD in the control of CFX release. The CFX diffusion from PET-MeβCD into agarose gel showed a continuously progressive diffusion during 7 days. Thus, this test can be highly appropriate for in vitro characterization of such drug delivery systems. 53

International audience; The aim of this work is to design a wound dressing able to release chlorhexidine (CHX) as antiseptic agent, ensuring long-lasting antibacterial efficacy during the healing. The textile nonwoven (polyethylene terephthalate) (PET) of the dressing was first modified by chitosan (CHT) crosslinked with genipin (Gpn). Parameters such as the concentration of reagents (Gpn and CHT) but also the crosslinking time and the working temperature were optimized to reach the maximal positive charges surface density. This support was then treated by the layer-by-layer (LbL) deposition of a multilayer system composed of methyl-beta-cyclodextrin polymer (PCD) (anionic) and CHT (cationic). After a thermal treatment to stabilize the LbL film, the textiles were loaded with CHX as antiseptic agent. The influence of the thermal treatment i) on the cytocompatibility, ii) on the degradation of the multilayer system, iii) on CHX sorption and release profiles and iv) on the antibacterial activity of the loaded textiles was studied.

In this paper, poly(vinyl alcohol) (PVOH) cast films were crosslinked with citric acid (CTR) and hydroxypropyl-β-cyclodextrin (HPβCD) and loaded with sodium benzoate (NaBz) as preservative agent, with different compositions of CTR (10–30 wt%) and NaBz (0–6 wt%) with or without HPβCD (10%). Permeability tests showed that the presence of CTR and HPβCD does not modify PVOH barrier properties. Before incorporation, the complex formation of HPβCD with NaBz was investigated through 2 dimensional Nuclear Magnetic Resonance, which revealed a 1:1 stoichiometry. Raman spectroscopy cartography showed that the NaBz distribution in the films was homogeneous, especially with HPβCD. The NaBz release in water is prolonged with HPβCD on one hand for high crosslinking times (360 min) and, on the second hand, in the assays carried out at low temperature (4 °C). The released quantity is increased from 40% to 70% when NaBz is included into HPβCD cavity. Antimicrobial assays were performed against Staphylococcus aureus, Escherichia coli and Candida. Without HPβCD, all films present a contact antimicrobial activity thanks to grafted CTR and the best diffusion activity was obtained for 6 wt% NaBz for the three microorganisms. With HPβCD, the antimicrobial activity by diffusion was increased with crosslinking times.

The coating of a nonwoven textile by polyelectrolyte multilayer film (PEM) issued from cationic and anionic β-cyclodextrin (βCD) polyelectrolytes according to the layer-by-layer (LbL) technique was successfully attempted. The tert-butyl benzoic acid (TBBA) was used as drug model to evaluate the loading capacity and sustained release properties of this PEM system. The build-up of the multilayer assembly was monitored in situ by optical waveguide lightmode spectroscopy (OWLS) on the one hand, and was assessed by gravimetry on the other hand when applied onto the textile substrate. In parallel, the complexation study of TBBA with both CD polyelectrolytes was also investigated by nuclear magnetic resonance (NMR) and isothermal titration calorimetry (ITC). The influence of thermal crosslinking of the multilayered coating on its stability and on TBBA release kinetics in phosphate buffered saline (PBS) at 37°C was studied. Finally, biological and microbiological tests were performed to investigate the cytocompatibility and the intrisic antibacterial activity of multilayer assemblies. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1408-1424, 2016.

International audience; The avoidance of post-herniorrhaphy pain can be challenging for hernia repair and has the greatest impact on patient's quality of life, health care utilisation and cost to society. Visceral meshes, functionalised with an efficient drug carrier system hydroxypropyl beta-cyclodextrin polymer (polyHP beta CD) coating, were developed to give a prolonged intraperitoneal analgesic drug release. We attempted to evaluate the in vivo pain-relief efficacy of ropivacaine loaded polyHP beta CD functionalised polyester meshes in a rat model of visceral pain induced by colorectal distension (CRD). In vivo safety, pharmacokinetic profile and biodegradation were measured via histological analysis and high-performance liquid chromatography, etc. The results confirmed that the polyHP beta CD on the functionalised meshes has a high adsorption capacity of ropivacaine and resulted in a sustained drug release in rats after mesh implantation. This was further reaffirmed by an elevated pain threshold (30%) up to 4 days after implantation in the rat CRD model, compared to 1-2 days for non-adapted meshes. Neither polyHP beta CD nor the loaded ropivacaine had a major impact on the inflammatory response. This evidence strongly suggests that polyHP beta CD functionalised visceral mesh could be a promising approach for post-operative pain control by improving the intraperitoneal drug delivery and bioavailability.

Infection still present as one of common complications after total hip replacement (∼2.5%), which may cause serious outcomes. For preventing such risk, loading antibiotics onto implants for increasing local drug concentration at targeted sites could be a solution. This study aims at modifying the surface of hydroxyapatite (HA) coated titanium hip implant material (Ti–HA) with polymer of cyclodextrin (polyCD) for loading antibiotics, to achieve a sustained local drug delivery. Two widely applied antibiotics (tobramycin and rifampicin) in orthopedic surgery were loaded alone or in combination. The drug adsorption isotherm, drug release kinetics and drug’s efficacy were thoroughly investigated. The results proved that polyCD coating significantly improved the affinity of both drugs to Ti–HA surface, while the mechanism of drug–polyCD interaction varies from the nature of drug, courtesy of the structural complex of polyCD. The advantage of dual-drug loading was highlighted by its strong efficacy against both Staphylococcus aureus and Enterobacter cloacae, which overcomes the limitation of mono-drug loading for an effective treatment against both bacterial strains. The prolonged antibacterial activity of antibiotic loaded Ti–HA-polyCD samples confirmed that polyCD could be a promising drug-delivery system, for sustained antibiotics release or other potential applications e.g., antimitotic agent release.

The aim of the study was to develop a polyester visceral implant modified with a cyclodextrin polymer for the local and prolonged delivery of ropivacaine to reduce post operatory pain. Therefore, we applied a coating of an inguinal mesh with a crosslinked polymer of hydroxypropyl-β-cyclodextrin (HPβCD) whose specific host–guest complex forming properties were expected to improve the adsorption capacity of the implant toward anesthetic, and then to release it within a sustained period. The modification reaction of the textile with cyclodextrin was explored through the study of the influence of the pad/dry/cure process parameters and the resulting implant (PET–CD) was characterized by solid state NMR and SEM. Besides, the inclusion complex between ropivacaine and CD was studied by NMR and capillary electrophoresis in PBS medium. Finally, ropivacaine sorption test showed that a maximum of 30 mg/g of ropivacaine could be adsorbed on the functionalized samples. In dynamic batch tests in PBS at pH 7.4, the release could be observed up to 6 h. The cytocompatibility of the PET–CD loaded with ropivacaine was also studied and reached 65% cell vitality after 6 days.

The use of textile meshes in hernia repair is widespread in visceral surgery. Though, mesh infection is a complication that may prolong the patient recovery period and consequently presents an impact on public health economy. Such concern can be avoided thanks to a local and extended antibiotic release on the operative site. In recent developments, poly- l -lactic acid (PLLA) has been used in complement of polyethyleneterephthalate (Dacron®) (PET) or polypropylene (PP) yarns in the manufacture of semi-resorbable parietal implants. The goal of the present study consisted in assigning drug reservoir properties and prolonged antibacterial effect to a 100% PLLA knit through its functionalization with a cyclodextrin polymer (polyCD) and activation with ciprofloxacin. The study focused i) on the control of degree of polyCD functionalization of the PLLA support and on its physical and biological characterization by Scanning Electron Microscopy (SEM), Differential Scanning Calorimetry (DSC) and cell viability, ii) on the understanding of drug/meshes interaction using mathematic model and iii) on the correlation between drug release studies in phosphate buffer saline (PBS) and microbiological evaluation of meshes and release medium against E. coli and S. aureus . All above mentioned tests highlighted the contribution of polyCD on the improved performances of the resulting antibacterial implantable material. Statement of Significance 1. We managed for the first time, with well-defined parameters in terms of temperature and time of treatment, to functionalize a bio-absorbable synthetic material to improve drug sorption and drug release properties without affecting its mechanical properties. 2. We analyzed for the first time the degradation of our coating products by mass spectroscopy to show that only citrate and cyclodextrin residues (and glucose units) without any cytotoxicity are formed. 3. We managed to improve the mechanical properties of the PLA with the cyclodextrin polymer to form a composite. The assembly (cyclodextrin polymer and PLLA) remains biodegradable.

Summary Objectives Synthetic vascular graft infection (SVGI) remains associated with high morbidity-mortality rates. Newly developed polyester vascular prostheses (PVP) functionalised with cyclodextrin (PVP-CD) allowed sustained-drug-eluting of several antibiotics. This study aimed to evaluate the efficacy of PVP-CD loaded with antibiotics against bacteria that are commonly responsible for SVGI in current practice. Methods Samples of PVP-CD loaded with antibiotics and uncoated-PVP were tested in-vitro for their ability to limit bacterial adhesion and prevent bacterial proliferation over time. Their anti-infectious properties were further evaluated in-vivo in a mouse model of SVGI. Both Gram-positive ( Staphylococcus aureus , Staphylococcus epidermidis , MRSA) and Gram-negative ( Escherichia coli , En. cloacae and Pseudomonas aeruginosa ) bacteria were tested. Results PVP-CD loaded with rifampin showed significant bacterial adhesion reduction and growth inhibition against Gram-positive bacteria. Similar results were obtained against Gram-negative bacteria with PVP-CD loaded with ciprofloxacin. In the mouse model, Gram-positive and Gram-negative bacterial proliferations were significantly prevented by PVP-CD loaded with rifampin or with ciprofloxacin respectively. A decrease in macroscopic infections correlated with the bacterial proliferation rates depicted on the samples (Spearman's rho = 0.61; P Conclusions We have demonstrated the efficacy of PVP-CD loaded with appropriate antibiotics both in-vitro and in-vivo against six of the most common bacteria involved in human SVGI.

This work focuses on the relevance of antibacterial nanofibers based on a polyelectrolyte complex formed between positively charged chitosan (CHT) and an anionic hydroxypropyl betacyclodextrin (CD)-citric acid polymer (PCD) complexing triclosan (TCL). The study of PCD/TCL inclusion complex and its release in dynamic conditions, a cytocompatibility study, and finally the antibacterial activity assessment were studied. The fibers were obtained by electrospinning a solution containing chitosan mixed with PCD/TCL inclusion complex. CHT/TCL and CHT-CD/TCL were also prepared as control samples. The TCL loaded nanofibers were analyzed by Scanning Electron Microscopy (SEM), Fourier Transformed Infrared spectroscopy (FTIR) and X-Ray Diffraction (XRD). Nanofibers stability and swelling behavior in aqueous medium were pH and CHT:PCD weight ratio dependent. Such results confirmed that CHT and PCD interacted through ionic interactions, forming a polyelectrolyte complex. A high PCD content in addition to a thermal post treatment at 90°C were necessary to reach a nanofibers stability during 15days in soft acidic conditions, at pH=5.5. In dynamic conditions (USP IV system), a prolonged release of TCL with a reduced burst effect was observed on CHT-PCD polyelectrolyte complex based fibers compared to CHT-CD nanofibers. These results were confirmed by a microbiology study showing prolonged antibacterial activity of the nanofibers against Escherichia coli and Staphylococcus aureus. Such results could be explained by the fact that the stability of the polyelectrolyte CHT-PCD complex in the nanofibers matrix prevented the diffusion of the PCD/triclosan inclusion complex in the supernatant, on the contrary of the similar system including cyclodextrin in its monomeric form.

Introduction: In stent restenosis (ISR) remains a major public health concern with an increased morbidity, mortality and health-related costs. Drug-eluting stents (DES) have reduced ISR, but are associated with healing-related issues or hypersensitivity reactions, leading to an increased risk of late acute stent thrombosis. Evaluations of new DES are based on animal models or in vitro release systems which show several limitations. The role of flow and shear stress on endothelial cell and ISR has also been emphasized. The aim of this work was to design and first evaluate an original bioreactor, reproducing ex vivo hemodynamic and biological conditions similar to human conditions, to further evaluate new DES. Methods & Results: This bioreactor was designed to study up to 6 stented arteries connected in bypass, immersed in a culture box, in which circulated a physiological systolo-diastolic resistive flow. Two centrifugal pumps drove the flow. The principal pump generated pulsating flows by modulation of rotation velocity, and the second pump worked at constant rotation velocity, ensuring the counter pressure levels and backflows. The flow rate, the velocity profile, the arterial pressure and the resistance of the flow were adjustable. The bioreactor was placed in an incubator to reproduce a biological environment. A first experience of feasibility was realized over a period of 24 days. Three rat aortic thoracic arteries were placed into the bioreactor, immersed in cell culture medium change every 3 days, and with a circulating systole diastolic flux circulating among the entire experimentation. There was no infection, no leak. At the end of experimentation, a morphometric analysis was performed confirming the viability of the arteries. Conclusion: We design and patent an original hemodynamic ex vivo model to further study new DES and ISR. We will next validate this ex vivo model of ISR reproducing this experimentation with stented arteries. Once validated, this bioreactor will allow characterization of the velocity field and drug transfers within a stented artery with new functionalized DES, with experimental means not available in vivo. Another main point will be the reduction of animal experimentation, and the availability of first results of new DES in human tissues (human infra popliteal or coronary arteries collected during human donation).

Objective After stent implantation, platelet aggregation and thrombus formation are thought to play a key role in the early phase of in-stent restenosis (ISR). Drug-eluting stents have reduced ISR, but are associated with healing-related issues or hypersensitivity reactions, leading to an increased risk of late acute stent thrombosis. EP224283 is a new dual-action antithrombotic molecule combining a GPIIbIIIa antagonist and a factor Xa inhibitor. We investigated its efficacy on restenosis in a rat model of ISR and on platelet adhesion. Methods and results Rat aortas were stented and the animals received either EP224283 or vehicle subcutaneously every 48 h. At day 7 and day 28 after surgery, the stented aortas were removed and processed for morphometric analysis or protein analysis. At day 28, EP224283 significantly reduced neointima growth (in the range of 20%). Protein analysis revealed that EP224283 reduced cell proliferation pathways: ERK1/2 and Akt were down-regulated and p38 up-regulated. Expression of Ki67 was also reduced. In vitro assessment depicted a reduction of platelet activation and platelet adhesion among treated rats. Conclusion These results show a beneficial effect of EP224283 on in-stent restenosis and on stent thrombogenicity that may improve results after stent implantation. Further investigations are required to assess the efficacy of a local delivery of EP224283 on both acute thrombosis and ISR.