Therapeutic Potential of Chlorhexidine-Loaded Calcium Hydroxide-Based Intracanal Medications in Endo-Periodontal Lesions: An Ex Vivo and In Vitro Study.

Endo-periodontal lesions are challenging clinical situations where both the supporting tissues and the root canal of the same tooth are infected. In the present study, chlorhexidine (CHX)-loaded calcium hydroxide (CH) pastes were used as intracanal medications (ICMs). They were prepared and tested on pathogens found in both the root canal and the periodontal pocket. Exposure to 0.5% and 1% CHX-loaded ICMs decreased the growth of Porphyromonas gingivalis and was effective in eradicating or inhibiting an Enterococcus faecalis biofilm. CH was injected into the root canal of extracted human teeth immersed in deionized water. CHX-loaded ICMs resulted in the transradicular diffusion of active components outside the tooth through the apex and the lateral dentinal tubules, as shown by the release of CHX (from 3.99 µg/mL to 51.28 µg/mL) and changes in pH (from 6.63 to 8.18) and calcium concentrations (from 2.42 ppm to 14.67 ppm) after 7 days. The 0.5% CHX-loaded ICM was non-toxic and reduced the release of IL-6 by periodontal cells stimulated by P. gingivalis lipopolysaccharides. Results indicate that the root canal may serve as a reservoir for periodontal drug delivery and that CHX-based ICMs can be an adjuvant for the control of infections and inflammation in endo-periodontal lesions.

Antiviral functionalization of a polypropylene nonwoven textile structure as a self-decontaminating layer for respiratory masks.

The aim of this work was to develop a filtering biocidal polypropylene (PP) nonwoven textile structure to block and inactivate airborne bacteria and viruses. PP filters were functionalized with a cyclodextrin (CD)-polycarboxylic acid-crosslinked polymer (PP-CD) through a pad/dry/curing process, and were then activated by padding in an alkyl dimethyl benzalkonium chloride (ADBAC) solution. The textile finishing process parameters were optimized with the perspective of mass production, considering the threshold temperature necessary for provoking crosslinking and the limitation of the low thermal stability of PP. The use of an aqueous solution containing hydroxypropyl-ß-cyclodextrin (HPßCD), 1,2,3,4-butanetetracarboxylic acid (BTCA), ammonium hypophosphite (AH), and a surfactant allowed immobilization of the optimal quantity of cyclodextrin polymer under curing for 5 minutes at 125 °C without affecting the nonwoven PP structure. The presence of CD drastically increased the sorption of ADBAC on the textiles. There was leaching of ADBAC at the first rinsing and then satisfactory fastness at the second and third rinsings, revealing adsorption mechanisms by weak physical interactions, ionic interactions, and inclusion of ADBAC inside the CD cavities. SEM revealed no clogging of the nonwoven pores, nor any increase in the air flow resistance, as evaluated by pressure drop measurements. The filtration efficiency of particulate matter PM3.0 and PM0.5 was moderately affected, in contrast to that of PM0.3, which greatly decreased due to the loss of the electrostatic charge of the filter upon the functionalization process. Bactericidal tests resulted in a reduction of 3 log10 against Staphylococcus aureus, and for virucidal tests on human coronavirus HCoV-229E, there was a reduction of 3.4 log10, with both strains undergoing 20 minutes of contact. Finally, the filter we developed is manufacturable by a scalable process, and because of its filtration and biocidal performances, it is a choice material as a self-disinfecting layer in the fabrication of facepiece respirators.

Injectable Chitosan-Based Hydrogels for Trans-Cinnamaldehyde Delivery in the Treatment of Diabetic Foot Ulcer Infections.

Diabetic foot ulcers (DFU) are among the most common complications in diabetic patients and affect 6.8% of people worldwide. Challenges in the management of this disease are decreased blood diffusion, sclerotic tissues, infection, and antibiotic resistance. Hydrogels are now being used as a new treatment option since they can be used for drug delivery and to improve wound healing. This project aims to combine the properties of hydrogels based on chitosan (CHT) and the polymer of ß cyclodextrin (PCD) for local delivery of cinnamaldehyde (CN) in diabetic foot ulcers. This work consisted of the development and characterisation of the hydrogel, the evaluation of the CN release kinetics and cell viability (on a MC3T3 pre-osteoblast cell line), and the evaluation of the antimicrobial and antibiofilm activity (S. aureus and P. aeruginosa). The results demonstrated the successful development of a cytocompatible (ISO 10993-5) injectable hydrogel with antibacterial (99.99% bacterial reduction) and antibiofilm activity. Furthermore, a partial active molecule release and an increase in hydrogel elasticity were observed in the presence of CN. This leads us to hypothesise that a reaction between CHT and CN (a Schiff base) can occur and that CN could act as a physical crosslinker, thus improving the viscoelastic properties of the hydrogel and limiting CN release.

Evaluation of a Medical Grade Thermoplastic Polyurethane for the Manufacture of an Implantable Medical Device: The Impact of FDM 3D-Printing and Gamma Sterilization.

Three-dimensional printing (3DP) of thermoplastic polyurethane (TPU) is gaining interest in the medical industry thanks to the combination of tunable properties that TPU exhibits and the possibilities that 3DP processes offer concerning precision, time, and cost of fabrication. We investigated the implementation of a medical grade TPU by fused deposition modelling (FDM) for the manufacturing of an implantable medical device from the raw pellets to the gamma (γ) sterilized 3DP constructs. To the authors' knowledge, there is no such guide/study implicating TPU, FDM 3D-printing and gamma sterilization. Thermal properties analyzed by differential scanning calorimetry (DSC) and molecular weights measured by size exclusion chromatography (SEC) were used as monitoring indicators through the fabrication process. After gamma sterilization, surface chemistry was assessed by water contact angle (WCA) measurement and infrared spectroscopy (ATR-FTIR). Mechanical properties were investigated by tensile testing. Biocompatibility was assessed by means of cytotoxicity (ISO 10993-5) and hemocompatibility assays (ISO 10993-4). Results showed that TPU underwent degradation through the fabrication process as both the number-averaged (Mn) and weight-averaged (Mw) molecular weights decreased (7% Mn loss, 30% Mw loss, p < 0.05). After gamma sterilization, Mw increased by 8% (p < 0.05) indicating that crosslinking may have occurred. However, tensile properties were not impacted by irradiation. Cytotoxicity (ISO 10993-5) and hemocompatibility (ISO 10993-4) assessments after sterilization showed vitality of cells (132% ± 3%, p < 0.05) and no red blood cell lysis. We concluded that gamma sterilization does not highly impact TPU regarding our application. Our study demonstrates the processability of TPU by FDM followed by gamma sterilization and can be used as a guide for the preliminary evaluation of a polymeric raw material in the manufacturing of a blood contacting implantable medical device.

Core-Sheath Electrospun Nanofibers Based on Chitosan and Cyclodextrin Polymer for the Prolonged Release of Triclosan.

This work focuses on the manufacture of core-sheath nanofibers (NFs) based on chitosan (CHT) as sheath and cyclodextrin polymer (PCD) as core and loaded with triclosan (TCL). In parallel, monolithic NFs consisting of blended CHT-PCD and TCL were prepared. Nanofibers were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), and Fourier Transform Infrared spectroscopy (FTIR). SEM displayed the morphology of NFs and the structure of the nanowebs, while TEM evidenced the core-sheath structure of NFs prepared by coaxial electrospinning. The core diameters and sheath thicknesses were found dependent on respective flow rates of both precursor solutions. Nanofibers stability and TCL release in aqueous medium were studied and correlated with the antibacterial activity against Staphylococcus aureus and Escherichia coli. Results showed that the release profiles of TCL and therefore the antibacterial activity were directly related to the type of nanofibers. In the case of monolithic nanofibers, the NFs matrix was composed of polyelectrolyte complex (PEC formed between CHT and PCD) and resulted in a prolonged release of TCL and a sustained antibacterial effect. In the case of core-sheath NFs, the PEC was formed only at the core-sheath interface, leading to less stable NFs and therefore to a faster release of TCL, and to a less extended antibacterial activity compared to monolithic ones.

Electrospun Filtering Membrane Designed as Component of Self-Decontaminating Protective Masks.

The 2019 coronavirus outbreak and worsening air pollution have triggered the search for manufacturing effective protective masks preventing both particulate matter and biohazard absorption through the respiratory tract. Therefore, the design of advanced filtering textiles combining efficient physical barrier properties with antimicrobial properties is more newsworthy than ever. The objective of this work was to produce a filtering electrospun membrane incorporating a biocidal agent that would offer both optimal filtration efficiency and fast deactivation of entrapped viruses and bacteria. After the eco-friendly electrospinning process, polyvinyl alcohol (PVA) nanofibers were stabilized by crosslinking with 1,2,3,4-butanetetracarboxylic acid (BTCA). To compensate their low mechanical properties, nanofiber membranes with variable grammages were directly electrospun on a meltblown polypropylene (PP) support of 30 g/m2. The results demonstrated that nanofibers supported on PP with a grammage of around only 2 g/m2 presented the best compromise between filtration efficiencies of PM0.3, PM0.5, and PM3.0 and the pressure drop. The filtering electrospun membranes loaded with benzalkonium chloride (ADBAC) as a biocidal agent were successfully tested against E. coli and S. aureus and against human coronavirus strain HCoV-229E. This new biocidal filter based on electrospun nanofibers supported on PP nonwoven fabric could be a promising solution for personal and collective protection in a pandemic context.

How Adding Chlorhexidine or Metallic Nanoparticles Affects the Antimicrobial Performance of Calcium Hydroxide Paste as an Intracanal Medication: An In Vitro Study.

The aim of our study was to explore the potential value of metallic (Ag, Cu, and Zn) salts, polymer/metallic nanoparticles, and chlorhexidine (CHX) for improving the antimicrobial activity of calcium hydroxide (CH) against E. faecalis and C. albicans, associated with persistent endodontic infections. A first screening was performed by determining minimum inhibitory/bactericidal concentrations (MIC/MBC). Antimicrobial activity of the CH paste mixed with metallic salts, chitosan or cyclodextrin polymer metallic nanoparticles was compared to the antimicrobial activity of CH paste alone and CH + CHX using a time-kill kinetics assay. The effect of the antimicrobials on the rheological and the key mechanical properties were also examined. Copper and zinc were discarded because of their MIC/MBC values and silver because of its kill time curve profile. Except for a slower setting time after 24 h and a higher weight loss after 1 week of incubation, the mechanical behavior of the CH paste was unaffected by the addition of CHX. Polymeric/metallic nanoparticles failed to potentiate the antimicrobial effect of CH. By contrast, CHX increased this effect and thus could help eradicate E. faecalis associated with persistent root canal infections without altering the desired key physical properties of the CH paste.

In Vitro Microbiological and Drug Release of Silver/Ibuprofen Loaded Wound Dressing Designed for the Treatment of Chronically Infected Painful Wounds.

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 ßCD 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.

In vivo evaluation of a pro-healing polydopamine coated stent through an in-stent restenosis rat model.

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.

Release-killing properties of a textile modified by a layer-by-layer coating based on two oppositely charged cyclodextrin polyelectrolytes.

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.

Stent coating by electrospinning with chitosan/poly-cyclodextrin based nanofibers loaded with simvastatin for restenosis prevention.

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 ß-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.

Evaluation of antibacterial textile covered by layer-by-layer coating and loaded with chlorhexidine for wound dressing application.

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 vivo evaluation of post-operative pain reduction on rat model after implantation of intraperitoneal PET meshes functionalised with cyclodextrins and loaded with ropivacaine.

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 (polyHPßCD) coating, were developed to give a prolonged intraperitoneal analgesic drug release. We attempted to evaluate the in vivo pain-relief efficacy of ropivacaine loaded polyHPßCD 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 polyHPßCD 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 polyHPßCD nor the loaded ropivacaine had a major impact on the inflammatory response. This evidence strongly suggests that polyHPßCD functionalised visceral mesh could be a promising approach for post-operative pain control by improving the intraperitoneal drug delivery and bioavailability.

In vitro evaluation of drug release and antibacterial activity of a silver-loaded wound dressing coated with a multilayer system.

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.

In vitro assessment of the influence of intravenous extension set materials on insulin aspart drug delivery.

Insulin is a frequently prescribed drug in hospitals and is usually administered by syringe pumps with an extension line which can be made of various materials. Two insulin solutions were studied: an insulin analogue, Novorapid® which contains insulin aspart and two phenolic preservatives (e.g. phenol and metacresol) and Umuline rapide® with human insulin and metacresol as preservative. Some studies have indicated interactions between insulin, polyvinyl chloride (PVC) and polyethylene (PE). The aim of this work was to study such interactions between Novorapid® or Umuline rapide® and infusion extension line materials (PVC, PE and coextruded (PE/PVC)). Insulin solution at 1 IU/mL was infused at 2 mL/h over 24 hours with 16 different extension lines (8 in PVC, 3 in PE and 5 in PE/PVC). Ultra-Fast Liquid Chromatography with diode array detection (UFLC-DAD) was performed to quantify insulin (human and aspart) and preservatives (metacresol and phenol). Limited human insulin sorption was observed thirty minutes after the onset of infusion: 24.3 ± 12.9%, 3.1 ± 1.6% and 18.6 ± 10.0% for PVC, PE and PE/PVC respectively. With insulin aspart, sorption of about 5% was observed at the onset of infusion for all materials. However, there were interactions between phenol and especially metacresol with PVC, but no interactions with PE and PE/PVC. This study shows that insulin interacts with PVC, PE and PE/PVC at the onset of infusion. It also demonstrates that insulin preservatives interact with PVC, which may result in problems of insulin conservation and conformation. Some more studies are required to understand the clinical impact of the latter during infusion.

Triclosan loaded electrospun nanofibers based on a cyclodextrin polymer and chitosan polyelectrolyte complex.

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.

Layer-by-layer coating of textile with two oppositely charged cyclodextrin polyelectrolytes for extended drug delivery.

The coating of a nonwoven textile by polyelectrolyte multilayer film (PEM) issued from cationic and anionic ß-cyclodextrin (ßCD) 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.

A New Hemodynamic Ex Vivo Model for Medical Devices Assessment.

BACKGROUND: In-stent restenosis (ISR) remains a major public health concern associated with an increased morbidity, mortality, and health-related costs. Drug-eluting stents (DES) have reduced ISR, but generate healing-related issues or hypersensitivity reactions, leading to an increased risk of late acute stent thrombosis. Assessments of new DES are based on animal models or in vitro release systems, which have 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, replicating ex vivo hemodynamic and biological conditions similar to human conditions, to further evaluate new DES. METHODS: 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 main 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. RESULTS: A first feasibility experience was performed over a 24-day period. Three rat aortic thoracic arteries were placed into the bioreactor, immersed in cell culture medium changed every 3 days, and with a circulating systolic and diastolic flux during the entire experimentation. There was no infection and no leak. At the end of the experimentation, a morphometric analysis was performed confirming the viability of the arteries. CONCLUSIONS: We designed and patented an original hemodynamic ex vivo model to further study new DES, as well as a wide range of vascular diseases and medical devices. 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 major benefit will be the reduction of animal experimentation and the opportunity to test new DES or other vascular therapeutics in human tissues (human infrapopliteal or coronary arteries collected during human donation).

Evaluation of sorption capacity of antibiotics and antibacterial properties of a cyclodextrin-polymer functionalized hydroxyapatite-coated titanium hip prosthesis.

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.

Evaluation of the anti-infectious properties of polyester vascular prostheses functionalised with cyclodextrin.

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 < 0.0001). 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.