Maria Butnaru

Chemical functionalization of hyaluronic acid for drug delivery applications

Functionalized hyaluronic acid (HA) derivatives were obtained by ring opening mechanism of maleic anhydride (MA). FTIR and H(1) NMR spectroscopy were used to confirm the chemical linkage of MA on the hyaluronic acid chains. Thermal analysis (TG-DTG and DSC) and GPC data for the new products revealed the formation of new functional groups, without significant changes in molecular weight and thermal stability. New gels based on hyaluronic acid modified derivatives were obtained by acrylic acid copolymerization in the presence of a redox initiation system. The resulted circular and interconnected pores of the gels were visualized by SEM. The release profiles of an ophthalmic model drug, pilocarpine from tested gels were studied in simulated media. Evaluation of the cytotoxicity and cell proliferation properties indicates the potential of the new systems to be used in contact with biological media in drug delivery applications.

Phosphorylated curdlan microgels. Preparation, characterization, and in vitro drug release studies.

Curdlan derivative with anionic phosphate groups was used for the first time to obtain hydrogel microspheres. The chemical cross-linking of the phosphorylated curdlan was performed with epichlorohydrin using the water-in-oil inverse emulsion technique. The optical and scanning electron microscopies were used to analyze the morphology of the microgels, whereas the FTIR spectroscopy was used to investigate their chemical structure. The main characteristics such as the swelling degree, the exchange capacity, and the thermal resistance were also studied. These new anionic microgels could be used as potential carriers for controlled release of opposite charged drugs retained through electrostatic forces. Diphenhydramine, a cationic model drug, was used to investigate the loading and the release processes in various pH media simulating physiological fluids. Several mathematical models were applied to evaluate the drug transport processes and to calculate the drug diffusion coefficients. The synthesized microspheres presented an excellent biocompatibility.

Evaluation of polyurethane based on cellulose derivative-ketoprofen biosystem for implant biomedical devices.

A polyether-urethane based on polytetrahydrofuran containing hydroxypropyl cellulose for biomedical applications was tested for its biocompatibility. Ketoprofen was incorporated (3% and 6%) in the polyurethane matrix as an anti-inflammatory drug. Dynamic vapour sorption method was employed for testing the water sorption/desorption behaviour of these materials with the determination of the surface isotherms, surface parameters and the kinetic curves of sorption/desorption processes. Cytotoxicity testing in vitro for quantifying cell proliferation was employed, and the results evidence noncytotoxicity for the studied polyurethane-drug systems. In vivo biocompatibility study was performed on 200 g weight male rats. It was found that after implantation of the polyether-urethane samples a reduced acute inflammation occurred, especially for polyurethane samples with added ketoprofen.

Crosslinked hydrogels based on biological macromolecules with potential use in skin tissue engineering

Zero-length crosslinked hydrogels have been synthesized by covalent linking of three natural polymers (collagen, hyaluronic acid and sericin), in the presence of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide. The hydrogels have been investigated by FT-IR spectroscopy, microcalorimetry, in vitro swelling, enzymatic degradation, and in vitro cell viability studies. The obtained crosslinked hydrogels showed a macroporous structure, high swelling degree and in vitro enzymatic resistance compared to uncrosslinked collagen. The in vitro cell viability studies performed on normal human dermal fibroblasts assessed the sericin proliferation properties indicating a potential use of the hydrogels based on collagen, hyaluronic acid and sericin in skin tissue engineering.

Poly(Acrylic Acid)–Poly(Ethylene Glycol) Nanoparticles Designed for Ophthalmic Drug Delivery

Poly(acrylic acid) (PAA) and poly(ethylene glycol) (PEG), four-arm, amine-terminated particles with nanometer size and spherical shape were obtained by the polymers cross-linking, via activation with 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide hydrochloride, in a w/o emulsion. The morphology and surface charge of the final particles are strongly dependent on the molar ratio of PAA-PEG and the PAA concentration. The physicochemical characteristics correlated with the drug-loading capacity, in vitro and ex vivo release kinetics of pilocarpine hydrochloride and biocompatibility results indicate that these nanoparticles exhibit the prerequisite behavior for use as carriers of ophthalmic drugs.

Preparation of electromechanically active silicone composites and some evaluations of their suitability for biomedical applications

Some films based on electromechanically active polymer composites have been prepared. Polydimethylsiloxane-α,ω-diols (PDMSs) having different molecular masses (Mv=60 700 and Mv=44 200) were used as matrix in which two different active fillers were incorporated: titanium dioxide in situ generated from its titanium isopropoxide precursor and silica particles functionalized with polar aminopropyl groups on surface. A reference sample based on simple crosslinked PDMS was also prepared. The composites processed as films were investigated to evaluate their ability to act as efficient electromechanical actuators for potential biomedical application. Thus, the surface morphology of interest for electrodes compliance was analysed by atomic force microscopy. Mechanical and dielectric characteristics were evaluated by tensile tests and dielectric spectroscopy, respectively. Electromechanical actuation responses were measured by interferometry. The biocompatibility of the obtained materials has been verified through tests in vitro and, for valuable films, in vivo. The experimental, clinical and anatomopathological evaluation of the in vivo tested samples did not reveal significant pathological modifications.

Characteristics of polyurethane-based sustained release membranes for drug delivery

AbstractThis paper is focused on the preparation and physicochemical characterization of two poly(ester ether urethane)s with rifampicin in their matrix and different molar concentrations of urethane groups. The polyurethanes with rifampicin were processed as asymmetrical microporous membranes by a phase inversion method and characterized by attenuated total reflection — Fourier transform infrared (ATR-FTIR) spectroscopy and differential scanning calorimetry (DSC). The influence of the surface morphology in the release of drug compounds was analyzed by scanning electron microscopy (SEM), atomic force microscopy (AFM), contact angle, and water uptake. The release of rifampicin depends on the molar concentration of urethane groups and also on the surface morphology of the polyurethane membranes. The antibacterial activity was evaluated with S. Epidermidis RP 62 A and P. Aeruginosa ATCC 1544. Finally, the biocompatibility of the polyurethane membranes was studied with human dermal fibroblasts (HDF) to evaluate the potential biomedical applications.

Surface topography effect on fibroblasts population on epiclon-based polyimide films

A polyimide based on alicyclic units, such as epiclon (5-(2,5-dioxotetrahydrofurfuryl)-3-methyl-3-cyclohexene-1,2-dicarboxylic acid anhydride), was investigated from the point of view of its surface features to check their suitability for cell culture applications. Atomic force microscopy data revealed fractal and isotropic surfaces with nanoscale roughness and peaks placed at much smaller distances comparing to the cell size scale, favoring a good compatibility of the synthesized material with the biological medium, particularly after plasma treatment. Surface tension properties were determined in order to evaluate the interactions at the bio-interface affecting the adherence behavior of cell-binding proteins to the sample surface. In vitro experiments regarding the cytocompatibility and population tendency reveal that polyimide allows cells to adhere and to proliferate onto the surface. These tests indicate that the studied epiclon-based polyimide is not cytotoxic and can be recommended as good candidate for cell culture substrate in tissue engineering, especially after plasma treatment.

Property peculiarities of the atelocollagen-hyaluronan conjugates crosslinked with a short chain di-oxirane compound.

Minimal amounts of a short-chain bifunctional crosslinker of about 1.3 nm length, the 1,4-butanediol-diglycidyl ether (BDDGE), were used to generate atelocollagen-hyaluronan conjugates in hydrogel state. Two a priori constraints were considered in recipe/procedure developing: (i) working in nondenaturing conditions, and (ii) ensuring a low cytotoxicity of the final product. Both atelocollagen (aK) and hyaluronan (NaHyal) were accurately purified to reduce their molecular-weight dispersity, in order to ensure the reproducibility of hydrogels characteristics. 1:5 aK:NaHyal weight ratios and 1:2.5 to 1:5 α-NH2:BDDGE molar ratios were found to be the most favorable recipe prescriptions that allow the obtaining of rheo-mechanically stable hydrogels, able to be manipulated during cell culturing protocols. Experiments revealed two unexpected effects due to the crosslinking reactions mediated by a short-chain molecule: (i) the occurrence of two thresholds in the rheological behavior of the hydrogels, related with the amount of added crosslinker, and (ii) a quasi-denaturation side-effect induced over the protein component by large or in excess amounts of crosslinker.

Biomimetic Composites Based on Calcium Phosphates and Chitosan - Hyaluronic Acid with Potential Application in Bone Tissue Engineering

Composites based on calcium phosphates (CP) and mixtures of biopolymers (chitosan and hyaluronic acid) have been prepared by a biomimetic co-precipitation method and tested as scaffolds for bone tissue engineering. The biomimetic strategy is inspired by natural mineralization processes, where the synthesized minerals are usually combined with proteins, polysaccharides or other mineral forms to form composite, in physiological conditions of temperature and pH. Fourier transformed infrared spectroscopy, scanning electron microscopy, X-ray diffraction and XPS analyses confirmed the porous morphology of the scaffolds and formation of various forms of calcium phosphates with amorphous nature. The in vitro degradation studies showed a slow degradation process for CP-biopolymers composites and limited swelling in simulated body fluids. The scaffolds compositions have no negative effect on osteoblasts cell, emphasizing a good biocompatibility.