Search

International audience; Mesoporous silica (MPS) carriers are considered as a promising strategy to increase the solubility of poorly soluble drugs and to stabilize the amorphous drug delivery system. The development by the authors of a solvent-free method (milling-assisted loading, MAL) made it possible to manipulate the physical state of the drug within the pores. The present study focuses on the effects of the milling intensity and the pore architecture (chemical surface) on the physical state of the confined drug and its release profile. Ibuprofen (IBP) and SBA-15 were used as the model drug and the MPS carrier, respectively. It was found that decreasing the milling intensity promotes nanocrystallization of confined IBP. Scanning electron microscopy and low-frequency Raman spectroscopy investigations converged into a bimodal description of the size distribution of particles, by decreasing the milling intensity. The chemical modification of the pore surface with 3-aminopropyltriethoxisylane also significantly promoted nanocrystallization, regardless of the milling intensity. Combined analyses of drug release profiles obtained on composites prepared from unmodified and modified SBA-15 with various milling intensities showed that the particle size of composites has the greatest influence on the drug release profile. Tuning drug concentration, milling intensity, and chemical surface make it possible to easily customize drug delivery.

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; The capabilities of the recent MAL (Milling-Assisted Loading) method were analyzed for the geometric confinement of amino acids within mesoporous silica matrices. The present study has shown a high filling degree (45 wt%) of L-tryptophan into unmodified MCM-41 pores. It was shown that the low-frequency Raman spectroscopy is a suited technique to determine that molecular materials are actually confined into silica-based ordered mesoporous materials from the analysis of lattice mode region, and to probe the molecular conformation of confined materials and their interaction with the pore surface from the analysis of internal vibrations.

We report the influence of treatment time of electrospun chitosan nanofibers (CHT NFs) in dopamine hydrochloride bath (2 mg.mL−1 in 10 mM Tris buffer, pH 8.5) on the extent of the polydopamine (pDA) coating on NFs surface. The reaction was characterized by FTIR and SEM analysis and the cytocompatibility of the scaffolds toward MT3C3-E1 cells was assessed. Biomimetic deposition of hydroxyapatite (HA) in 1.5xSBF batch was investigated by SEM-EDS and XRD. Samples treated in dopamine bath during 2 h promoted the structural stability of NFs in PBS, provided optimal cytocompatibility and induced the in vitro biomineralization from 6 days in 1.5xSBF. The XRD and SEM-EDS investigations confirmed formation of spherical-shaped particles composed of apatitic phase. Finally, this study shows that these NFs-pDA scaffolds prepared in the optimal experimental conditions defined here are promising candidates for application as osteoinductive scaffolds for bone regeneration applied to orthopedic and dental applications.

International audience; The solubility of the scarcely water-soluble molecule tetrahydrocurcumin (THC), a promising curcumin derivative to be used as biopesticide, was enhanced through the formation of inclusion complexes with different cyclodextrins (CDs). Randomly methylated β-cyclodextrin (MeβCD) gave the best results among the different CDs whose size, substituent or structure was changing. Differential scanning calorimetry as well as 1H- and 2D-Nuclear Magnetic Resonance (NMR) proved the inclusion of THC in MeβCD. Rotating-frame Overhauser effect spectroscopy NMR especially illustrated specific interactions of aromatic protons of THC and protons located inside the CD cavity. The complex formation between THC and MeβCD was studied using the Higuchi and Connor method, giving an association constant of 591 M−1. THC-loaded MeβCD did not show any growth inhibition of the target fungus Fusarium graminearum. However, THC-loaded MeβCD polymers exhibited 25 % inhibition of the fungal growth, thus making them promising material for solvent-free, aqueous and bio-based fungicide formulations.

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.

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; Using the Milling-Assisted Loading (MAL) solid-state method for loading a poorly water-soluble drug (ibuprofen, IBP) within the SBA-15 matrix has given the opportunity to manipulate the physical state of drugs for optimizing bioavailability. The MAL method makes it easy to control and analyze the influence of the degree of loading on the physical state of IBP inside the SBA-15 matrix with an average pore diameter of 9.4 nm. It was found that the density of IBP molecules in an average pore size has a direct influence on both the glass transition and the mechanism of crystallization. Detailed analyzes of the crystallite distribution and melting by Raman mapping, x-ray diffraction, and differential scanning calorimetry have shown that the crystals are localized in the core of the channel and surrounded by a liquid monolayer. The results of these complementary investigations have been used for determining the relevant parameters (related to the SBA-15 matrix and to the IBP molecule) and the nature of the physical state of the confined matter.

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 elaboration of catalytic composite nanofibers (NFs) by electrospinning through a one-pot strategy is described. First, aqueous colloidal suspensions of ruthenium nanoparticles (Ru NPs) formed by reduction of a Ru(III) salt with NaBH4 and stabilized by poly(cyclodextrin citrate) (PCD) were prepared. Then, poly(vinyl alcohol) (PVA) of different molecular weights was dissolved in the colloidal suspensions that were electrospun. SEM analyses of the resulting nanowebs displayed uniform NFs, whose diameters ranged between 300 and 700 nm and enlarged upon increasing (i) PVA molecular weight, (ii) nanosuspension viscosity, (iii) the amount of NaBH4 and (iv) the PCD/Ru NP concentration. TEM analysis confirmed that Ru NPs with a mean diameter of around 2 nm were observed at the surface of NFs, embedded in the PVA matrix of NFs. HAADF-STEM and EDS mapping clearly showed that Ru NPs were homogeneously distributed onto and into the matrix of NFs. After their electrospinning, the prepared nanowebs were submitted to a heat post-treatment at 160 °C which was shown to trigger the PVA crystallization. In addition, the physical crosslinking of PVA chains by NaBO2 resulting from NaBH4 oxidation in the precursor suspension was also observed. Interestingly, an SEM study evidenced that the thermal post-treatment in combination with the presence of NaBO2 clearly improved the thermal stability of the synthesized composite nanowebs. Finally, catalytic hydrogenation tests showed the absence of Ru NPs leaching from NFs in the reaction medium, and displayed good conversion of styrene into ethylbenzene.

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.

International audience; The effect of the post-annealing process on different properties of poly (L-lactic acid) (PLLA) nanofibers has been investigated in view of their use in energy-harvesting devices. Polymeric PLLA nanofibers were prepared by using electrospinning and then were thermally treated above their glass transition. A detailed comparison between as-spun (amorphous) and annealed (semi-crystalline) samples was performed in terms of the crystallinity, morphology and mechanical as well as piezoelectric properties using a multi-technique approach combining DSC, XRD, FTIR, and AFM measurements. A significant increase in the crystallinity of PLLA nanofibers has been observed after the post-annealing process, together with a major improvement of the mechanical and piezoelectric properties.

Current investigations deal with new surface functionalization strategy of nanocrystalline cellulose-based substrates to impart active molecule release properties. In this study, cellulose nanocrystals (CNC) were surface-functionalized with β-cyclodextrin (β-CD) using succinic acid (SA) and fumaric acid (FA) as bridging agents. The main objective of this surface modification performed only in aqueous media was to obtain new active materials able to release antibacterial molecules over a prolonged period of time. The reactions were conducted by immersing the CNC film into a solution composed of β-CD, SA and FA, leading to CNC grafting. The materials were characterized by infrared spectroscopy (FT-IR), Quartz crystal microbalance-dissipation (QCM-D), AFM and phenolphthalein (PhP) was used to determine the efficiency of CNC grafting with β-CD. The results indicated that β-CD was successfully attached to the CNC backbone through the formation of ester bonds. Furthermore, carvacrol was entrapped by the attached β-CD and a prolonged release was confirmed. In particular, CNC grafted to β-CD in the presence of FA was selected as the best solution. The antibacterial activity and the controlled release were studied for this sample. Considerably longer bacterial activity against B. subtilis was observed for CNC grafted to β-CD compared to CNC and CNC-FA, confirming the promising impact of the present strategy.

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.

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; This work firstly aimed to synthesize mono-and di-sulfonic derivatives of chitosan by reductive amination reaction using respectively 2-formyl benzene sulfonic acid and 2,4 formyl benzene sulfonic acid sodium salts. The influence of the reactants molar ratio (R), aryl - substituted amino groups versus chitosan free amino groups, on the degree of substitution (DS) of both sulfonated chitosans was assessed by H-1 NMR, elemental analysis, coupled conductometry-potentiometry analysis and UV spectrometry and FTIR. The influence of pH on sulfonated chitosans' properties in solution were investigated by solubility and zeta potential (ZP) studies, size exclusion chromatography equipped with MALLS detection (SEC-MALLS) and Taylor dispersion analysis (TDA). The polyampholytic character of both series was evidenced and strongly modified the solutions properties compared to chitosan. Then, the anticoagulant properties of mono-and di-sulfonic polymers were investigated by the measurement of the activated partial thromboplastin time (aPTT), Prothrombin-time (PT) and anti-(factor Xa).

The influence of HPβCD on the thermal denaturation of lysozyme was analyzed mainly from microcalorimetry and Raman investigations carried out in the molecular fingerprint and the low-frequency regions. It was shown that Raman spectroscopy investigations performed on a wide spectral range give the opportunity to describe the influence of HPβCD on the mechanism of protein denaturation. Using D2O as solvent allowed us to show that HPβCD mainly destabilizes the tertiary structure of lysozyme by enhancing the protein flexibility and thus inducing the destabilization of the secondary structure. Principal components analysis (PCA) was used for spectra treatment, providing important information about inclusion complex formation between protein hydrophobic residues and CDs molecules. Combining PCA and classical technics (curve fitting) of data analysis allowed a better understanding of the influence of HPβCD on the protein denaturation that seems to be related to the CDs capacity to form inclusion complex. It was observed that these interactions prevent the formation of new strong H-bonds between β-sheet structures thereby inhibiting protein aggregation. This study reveals that CDs are promising systems for inhibiting protein aggregation without protein denaturation, only if designing derivative CDs is carefully controlled.

International audience; Oxidized cellulose nanocrystals with sodium carboxylate groups (TOCNC-COONa) and with free carboxyl groups (TOCN-COOH) were prepared and then chemically modified with beta-cyclodextrin (βCD) and hydroxypropyl-beta-cyclodextrin (HPβCD) to prepare materials able to load and release antibacterial molecules over a prolonged period of time. The materials were characterized by infrared spectroscopy, and the CD content of modified TOCNCs determined by phenolphthalein colorimetry. The extent of grafting was also assessed by QCM-D and microscopy was used to ascertain and compare the morphology of both TOCNC-COONa/HPβCD and TOCNC-COOH/HPβCD. Then, carvacrol and curcumin were entrapped by the attached HPβCD and their prolonged release confirmed, as compared to neat material. The combined effects of HPβCD and carvacrol on the antimicrobial properties of TOCNC-COOH films were finally evaluated.

International audience; From 20th century, chitosan, a natural polysaccharide, has received much attention for use in biomedical applications thanks to its remarkable properties, such as biodegradability, biocompatibility, hemostasis and antibacterial activity. Over the last decades, many researchers have attempted to generate new chitosan derivatives-based biomaterials though chemical modifications, especially through sulfonation or sulfation reactions in order to tailor the physicochemical and biochemical properties. Due to the presence of residual amino groups, the generated polyampholytic derivatives are characterized by convenient biological properties, such as anti-oxidation, antiviral activity, anticoagulation and bone regeneration, expanding their application scope. This paper provides an overview of the strategies used to chemically modify chitosan by introduction of sulfonate groups on chitosan backbone, focusing on various sulfonating or sulfating agents used and substitution regioselectivity, and highlights their applications in biomedical field.

International audience; Chitosan (CS) presents antibacterial, mucoadhesive and hemostatic properties and is an ideal candidate for wound dressing applications. This work reports the development of sponge-like materials obtained from physical hydrogels after the interaction between CS and a p-cyclodextrin polymer (PCD) in acidic conditions to provoke immediate gelation. Characterization consisted of zeta potential (ZP) measurements, rheology analysis, Fourier transform infrared (FTIR), Raman spectroscopy, wide angle Xray scattering (WAXS) and scanning electron microscopy (SEM). Swelling behavior, cytotoxicity, drug sorption and drug delivery properties of sponges were assessed. ZP indicated that CS and PCD presented opposite charges needed for physical crosslinking. Rheology, swelling, and cytotoxicity of sponges depended on their CS:PCD weight ratios. Increasing PCD in the mixture delayed the gel time, reduced the swelling and increased the cytotoxicity. FTIR and Raman confirmed the physical crosslinking between CS and PCD through ionic interactions, and WAXS showed the amorphous state of the sponges. Finally, the efficiency of chlorhexidine loaded sponge against S. aureus bacteria was proved for up to 30 days in agar diffusion tests.

International audience; A water-soluble beta-cyclodextrin polymer synthesized by crosslinking beta-cyclodextrin with epichlorohydrin and glycidyltrimethylammonium chloride allowed the stabilization of ruthenium nanoparticles not only in basic aqueous medium but also in acidic medium. The aqueous ruthenium colloidal suspensions obtained with this polymer were active as catalysts for the hydrogenation of a large variety of unsaturated compounds including aromatic or fatty acids. The recycling of this catalytic system was attested through ten consecutive runs without loss of stability and activity, demonstrating its robustness.

In this paper, we propose a green route to prepare insoluble poly(vinyl alcohol) (PVOH) cast films with potential application as antimicrobial packaging. First PVOH films were cast from different aqueous solutions and analyzed by Dif- ferential Scanning Calorimetry (DSC) and Dynamic Mechanical Analysis (DMA) to determine their physical properties under two storage conditions. In order to obtain insoluble films, PVOH was then crosslinked by citric acid (CTR) as con- firmed by Nuclear Magnetic Resonance (NMR) analyses. The crosslinking reaction parameters (curing time, crosslinker content) were studied by comparing the characteristics of PVOH/CTR films, such as free COOH content and glass transi- tion temperature (Tg) value, as well as the impact of the crosslinking reaction on mechanical properties. It was found that for 40 and 10 wt% CTR contents, 120 and 40 min of crosslinking times were necessary to bind all CTR respectively. Brittle films were obtained for 40 wt% CTR whereas 10 wt% CTR content led to ductile films. Finally, films containing hydrox- ypropyl-!-cyclodextrin (HP!CD), chosen as a potential vector of antimicrobial agent, were prepared. The obtained results show that the incorporation of HP!CD in the PVOH matrix does not mainly influence the physical and mechanical proper- ties of the films.

Objective Transversus abdominis plane (TAP) block is commonly used for postcesarean section analgesia and compares favorably with other systemic and regional analgesia techniques. No major complications of ultrasound-guided TAP block have previously been reported in this indication. We report 2 cases of systemic local anesthetic toxicity in this context leading to seizures and treated with lipid emulsion. Case Report The first event occurred 10 minutes after ultrasound-guided bilateral injections, each consisting of 20 mL of levobupivacaine 3.75 mg/mL. Two episodes of tonic-clonic seizure required resuscitation measures and 200 mL of lipid emulsion. The second case 25 minutes after a 20-mL bilateral injection of ropivacaine 7.5 mg/mL. One generalized tonic-clonic seizure required bag-mask ventilation and 250 mL of lipid emulsion. In both cases, patients were successfully treated and fully recovered. Conclusions These cases cast a cautionary note for the use of TAP blocks after cesarean delivery. The risk of systemic local anesthetic toxicity after this procedure remains unknown in this population and plasma concentration of local anesthetics should be measured in case of suspected toxicity. To limit this risk, a low concentration of local anesthetic solution should be chosen when a “20 mL bilaterally” regimen is necessary to achieve the required spread for a successful block.

The progress in bone cancer surgery and multimodal treatment concept achieve only modest improvement in the overall survival, due to failure in clearing out residual cancer cells at the surgical margin and extreme side-effects of adjuvant postoperative treatments. Our study aims to propose a new method based on cyclodextrin polymer (polyCD) functionalized hydroxyapatite (HA) for achieving a high local drug concentration with a sustained release profile and a better control of residual malignant cells via local drug delivery and promotion of the reconstruction of bone defects. PolyCD, a versatile carrier for therapeutic molecules, can be incorporated into HA (bone regeneration scaffold) through thermal treatment. The parameters of polyCD treatment on the macroporous HA (porosity 65%) were characterized via thermogravimetric analysis. Good cytocompatibility of polyCD functionalized bioceramics was demonstrated on osteoblast cells by cell vitality assay. An antibiotic (gentamicin) and an anticancer agent (cisplatin) were respectively loaded on polyCD functionalized bioceramics for drug release test. The results show that polyCD functionalization leads to significantly improved drug loading quantity (30% more concerning gentamicin and twice more for cisplatin) and drug release duration (7 days longer concerning gentamicin and 3 days longer for cisplatin). Conclusively, this study offers a safe and reliable drug delivery system for bioceramic matrices, which can load anticancer agents (or/and antibiotics) to reduce local recurrence (or/and infection).

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.

A β-cyclodextrin (β-CD) polymer obtained by crosslinking β-CD with citric acid in its water-insoluble (PCD-I) and soluble (PCD-S) forms was used as a multifunctional direct compression excipient for tablet designing. PCD-I powder was obtained after grinding the solid fraction through a 200μm grid. PCD-S powder was recovered after lyophilization or spray drying of the PCD-S aqueous solutions, eventually followed by a wet granulation step. Both PCD-I and PCD-S powders were characterized, separately and mixed in variable ratios, based on dynamic water vapor sorption, SEM, particle size distribution, tapped density, compressibility, and flowability. PCD-I and spray dried and lyophilized/wet granulated PCD-S, as well as the mixture PCD-I/PCD-S=90/10, presented optimal free flowing characteristics. Then, PCD-I or PCD-S powders - separately or mixed in variable ratios - were used for tablets preparation by direct compression without adding any other excipient (e.g. binder, lubricant, disintegrant etc). As PCD-I decreased, tablets resistance to crushing and disintegration time increased from 15s to 15min (against 30min for β-CD), showing the improved disintegrant functionality of PCD-I, that rapidly swelled once in contact with water. Finally, PCD was force-fed to Sprague-Dawley rats (2g/kg) which were then observed during 14days for any clinical signs of toxicity.

The aim of this work was to determine the main physical characteristics of β-cyclodextrin polymers, well known for improving complexation capacities and providing enhanced and sustained release of a large panel of drugs. Two polymers were investigated: a polymer of β-cyclodextrin (polyβ-CD) and a polymer of partially methylated (DS=0.57) β-cyclodextrin (polyMe-β-CD). The physical characterizations were performed by powder X-ray diffraction and differential scanning calorimetry. The results indicate that these polymers are amorphous and that their glass transition is located above the thermal degradation point of the materials preventing their direct observation and thus their full characterization. We could however estimate the virtual glass transition temperatures by mixing the polymers with different plasticizers (trehalose and mannitol) which decreases Tg sufficiently to make the glass transition observable. Extrapolation to zero plasticizer concentration then yield the following Tg values: Tg (polyMe-β-CD)=317°C±5°C and Tg (polyβ-CD)=418°C±6°C.

A textile polyester vascular graft was modified with methyl-β-cyclodextrin (MeβCD) to obtain a new implant capable of releasing antibiotics directly in situ at the site of operation over a prolonged period and thereby prevent post-operative infections. We investigated the influence of the curing parameters (time and temperature) that allow control of the degree of functionalization (DF) of the support by MeβCD. The inclusion of ciprofloxacin (CFX) in the MeβCD cavity was observed in solution by two-dimensional 1H NMR spectroscopy. The amount of CFX loaded on the modified graft increased with DF. Depending on the release medium (water, phosphate-buffered saline, or human plasma) and the DF of the prostheses, different kinetic profiles of release of CFX were obtained. The sustained release of CFX in human plasma was shown by microbiological assays that indicated prolonged antimicrobial activity against Staphylococcus aureus and Escherichia coli. Viability tests demonstrated the non-toxicity of MeβCD to an epithelial cell line (HPMEC), although a decrease in endothelial cell number was observed on the functionalized prosthesis, probably due to the roughness of the coating and also to the nature of the MeβCD polymer present on the surface of the fibers.

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.

A polyelectrolyte multilayer film (PEM) based on cationic and anionic β-cyclodextrin polyelectrolytes was coated onto a textile substrate for future drug delivery purposes. We firstly synthesized a novel cationic β-cyclodextrin polymer (polyEPG-CD) by crosslinking β-cyclodextrin (βCD) with epichlorohydrin (EP) under basic conditions, in the presence of glycidyltrimetrylammonium chloride (GTMAC) as cationizing group. The influence of preparation conditions has been investigated in order to preferably obtain a water soluble fraction whose charge density and molecular weights were optimal for the layer-by-layer (LbL) deposition process. The different cationic cyclodextrin polymers obtained were characterized by FTIR, NMR, colloidal titration, conductimetry, thermogravimetric analysis and size exclusion chromatography. Besides, the counterpart polyelectrolyte was a β-cyclodextrin polymer crosslinked with citric acid, polyCTR-CD, whose synthesis and characterization have been previously reported. Finally we realized the Layer by Layer (LbL) build-up of the PEM coating onto the textile support, using the dip coating method, by alternatively soaking it in cationic polyEPG-CD and anionic polyCTR-CD solutions. This multilayer self-assembly was monitored by SEM, gravimetry and OWLS in function of both polyelectrolytes concentrations and ratios. Solutions parameters such as pH, ionic strenght were also discussed.

To compare the effect of different treatments (heat capsule, ultrasound, and dual treatments) on the setting kinetics and maturation properties of a conventional GIC (EQUIA, GC) to that of standard setting.The optimal durations of the heat and ultrasonic treatments were determined by monitoring changes in the COO-/COOH ratio, surface hardness, and temperature within the samples. The influence of optimal treatments on the maturation properties of the GIC (microhardness, and 3-point flexural strength) were assessed using GIC samples incubated in artificial saliva for 24 hours, 1 month, and 3 months.The optimal durations of the heat and ultrasonic treatments for accelerating setting were 5 minutes and 35 seconds, respectively. The dual treatment using the optimal conditions of the individual treatments further enhanced the setting kinetics. A temperature peak (49°C) within the GIC was detected during setting. Only the dual treatment increased the mechanical properties of the GIC after 24 hours compared to the control, while no significant difference was observed after 1 and 3 months.

In the field of implantable titanium-based biomaterials, infections and inflammations are the most common forms of postoperative complications. The controlled local delivery of therapeutics from implants through polyelectrolyte multilayers (PEMs) has recently emerged as a versatile technique that has shown great promise in the transformation of a classical medical implant into a drug delivery system. Herein, we report the design and the elaboration of new biodegradable multidrug-eluting titanium platforms based on a polyelectrolyte multilayer bioactive coating that target infections. These systems were built up in mild conditions according to the layer-by-layer (L-b-L) assembly and incorporate two biocompatible polysaccharides held together through electrostatic interactions. A synthetic, negatively charged β-cyclodextrin-based polymer (PCD), well-known for forming stable and reversible complexes with hydrophobic therapeutic agents, was exploited as a multidrug reservoir, and chitosan (CHT), a naturally occurring, positively charged polyelectrolyte, was used as a barrier for controlling the drug delivery rate. These polyelectrolyte multilayer films were strongly attached to the titanium surface through a bioinspired polydopamine (PDA) film acting as an adhesive first layer and promoting the robust anchorage of PEMs onto the biomaterials. Prior to the multilayer film deposition, the interactions between both oppositely charged polyelectrolytes, as well the multilayer growth, were monitored by employing surface plasmon resonance (SPR). Several PEMs integrating 5, 10, and 15 bilayers were engineered using the dip coating strategy, and the polyelectrolyte surface densities were estimated by colorimetric titrations and gravimetric analyses. The morphologies of these multilayer systems, as well as their naturally occurring degradation in a physiological medium, were investigated by scanning electron microscopy (SEM), and their thicknesses were measured by means of profilometry and ellipsometry studies. Finally, the ability of the coated titanium multilayer devices to act as a drug-eluting system and to treat infections was validated with gentamicin, a relevant water-soluble antibiotic commonly used in medicine due to its broad bactericidal spectrum.

This study aims to develop a high-performance delivery system using microfibrillated cellulose (MFC)-coated papers as a controlled release system combined with the well-known drug delivery agent, β-cyclodextrin (βCD). Chlorhexidine digluconate (CHX), an antibacterial molecule, was mixed with a suspension of MFC or a βCD solution or mixed with both the substances, before coating onto a cellulosic substrate. The intermittent diffusion of CHX ( i.e. , diffusion interrupted by the renewal of the release medium periodically) was conducted in an aqueous medium, and the release mechanism of CHX was elucidated by field emission gun-scanning electron microscopy, SEM, NMR, and Fourier transform infrared analyses. According to the literature, both βCD and MFC are efficient controlled delivery systems. This study indicated that βCD releases CHX more gradually and over a longer period of time compared to MFC, which is mainly due to the ability of βCD to form an inclusion complex with CHX. Furthermore from the release study, a complementary action when the two compounds were combined was deduced. MFC mainly affected the burst effect, while βCD primarily controlled the amount of CHX released over time. In this paper, two different types of controlled release systems are proposed and compared. Depending on the final application, the use of βCD alone would release low amounts of active molecules over time (slow delivery), whereas the combination of β-cyclodextrin and MFC would be more suitable for the release of higher amounts of active molecules over time (rapid delivery).