D. Silvestri

Molecularly imprinted poly(ethylene-co-vinyl alcohol) membranes for the specific recognition of phospholipids.

In this paper we concentrated on the possibility of adopting molecular imprinting technology for the preparation of polymeric membranes imprinted with phosphatidylcholine, one of the main phospholipids found in the cell membrane and lipoproteins, via phase inversion, with the intention of applying this method in the ongoing research into the regression of atherosclerosis. The polymer matrix was based on poly(ethylene-co-vinyl alcohol) with an ethylene molar content of 44% and the amount of template molecule was varied so as to obtain three different kinds of membrane. We found that they possessed elevated binding capabilities (78.6% of the initial amount of phosphatidylcholine was found to be adsorbed by the membrane) united with a very high selectivity. Similar phospholipids (phosphatidylinositol and phosphatidylethanolamine) were found to be adsorbed only in very small quantities and mostly due to the porosity of the membrane itself and not to molecular imprinting.

Combined drug release from biodegradable bilayer coating for endovascular stents.

In this work, the characterization of a biodegradable bilayer system, used as controlled and combined drug delivery platform, is reported. For this aim, a bilayer system, composed of poly(lactic-co-glycolic acid) and poly(3-hydroxybutyric-co-3-hydroxyvaleric acid), was investigated under physicochemical and functional aspects by evaluating polymer/polymer and polymer/stent material interactions, the kinetic of in vitro degradation, and drug release properties, comparing results with the monolayer reference systems. Obtained results showed that the bilayer system allowed increasing the total amount of eluted Tacrolimus and Paclitaxel drugs with respect to the monolayer systems in the considered testing period and conditions. This evidence was associated to a faster degradation of the tested copolymers in the bilayered configuration, excluding a synergic effect of two drugs on delivery performance. In addition, a macromolecular relaxation process was identified to govern the PLX release from poly(lactic-co-glycolic acid), whereas a pure Fickian diffusion occurred in the delivery of Tacrolimus from poly(3-hydroxybutyric-co-3-hydroxyvaleric acid).

Macromolecular composition and drug-loading effect on the delivery of paclitaxel and folic acid from acrylic matrices

Drug delivery systems based on synthetic polymers are widely employed in the treatment of several pathologies. In particular, the use of implantable devices able to release one or more active principles in a topic site with a controlled delivery kinetic represents an important improvement in this field. However, the release kinetic, that could be affected by different parameters, like polymer composition or chemical nature and initial drug loading, represents one of the problems related to the implantation of delivery systems. In this study, acrylic membranes with different macromolecular composition were prepared and studied analyzing delivery kinetic properties. Drug delivery systems were prepared using as matrix the copolymer poly(methylmethacrylate-co-butylmethacrylate) in three different compositions and folic acid (less hydrophobic) or Paclitaxel (more hydrophobic) as drugs, to evaluate the effect of macromolecular composition and hydrophilicity degree on the release properties. In addition, the effect of the initial drug loading was considered, loading drug delivery systems with four different initial drug percentages. Results showed a direct dependence of kinetics from macromolecular composition, hydrophilicity degree of solutes, and initial drug loading, allowing one to conclude that it is possible to design and to develop drug delivery systems starting from poly(methylmethacrylate-co-butylmethacrylate) matrices with specific properties by varying these three parameters.

Poly(ethylene‐co‐vinyl alcohol) Membranes with Specific Adsorption Properties for Potential Clinical Application

Abstract The preparation of novel polymeric systems through Molecular Imprinting Technology (MIT) for potential application in extracorporeal blood purification is described. Membranes based on poly(ethylene‐co‐vinyl alcohol) material, produced through a phase inversion method, were modified introducing in their structure specific binding sites for lipid and/or protein molecules. Membranes prepared are intended to selectively remove low density lipoproteins and cholesterol (LDL) from the plasma, by using interactions at a molecular level, between the molecularly imprinted membrane and specific target molecules, created during the preparation procedure. The binding performances of membranes and their potentiality as adsorbents for two different model target compounds, a phospholipid (phosphotidylcholine, PC) and a protein (α‐amylase enzyme) were investigated, showing improved adsorption capacity with respect to unmodified control membranes. In addition, molecularly imprinted poly(ethylene‐co‐vinyl alcohol) materials in the shape of microparticles, using the same templates, were prepared and studied for their potential use as adsorbers into a column.

The relevance of the transfer of molecular information between natural and synthetic materials in the realisation of biomedical devices with enhanced properties

Past and recent attempts to introduce in synthetic polymers molecular information from natural substances through simple blending, template polymerization and molecular imprinting are reviewed. The most promising approaches that can open the way to the realisation of new materials with improved biocompatibility, antibody- or enzyme-like performances are analysed more deeply. The realisation of bioartificial blends from natural and synthetic polymers, molecularly imprinted nanospheres or membranes that can act as recognition element in (bio)sensing devices, as synthetic enzymes or as key constituents of body fluids purification tools is presented in order to make the reader aware of the fascinating possibilities that these techniques make available to the biomedical science and engineering in the close future. The last part of the paper describes recent attempts to insert recognition elements for large molecules as proteins, DNA segments, viruses or whole cells in synthetic polymer systems, in order to develop new systems in the treatments of diseases and for tissue-engineering applications.

Molecularly imprinted bioartificial membranes for the selective recognition of biological molecules. Part 2: release of components and thermal analysis

Molecularly imprinted membranes imprinted for a large-molecular-weight protein were realised using a blend of natural and synthetic polymers. Bioartificial membranes of synthetic (poly(ethylene-co-vinyl alcohol)–EVAL, Clarene®) and biological (Dextran) polymers, molecularly imprinted with α-amylase as the template, were prepared and investigated. Dimethyl sulfoxide (DMSO) solutions of the α-amylase template, Clarene and Dextran were mixed under stirring in the desired proportions and dipped in DMSO (solvent)/water (non solvent) mixture, to obtain the phase separation. The release of Clarene, Dextran and α-amylase in the inversion baths was quantified by spectrophotometric methods and final composition of membranes was established. To study the interactions between the polymer components and between polymeric materials and the template, differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) were carried out. Results indicated that stable and continuous bioartificial membranes of Clarene and Dextran can be obtained, whereby calorimetric analysis suggested the presence of high interaction between α-amylase and the Clarene component.

BIODEGRADABLE BIOARTIFICIAL MATERIALS MADE BY CHITOSAN AND POLY(VINYL ALCOHOL). PART II: ENZYMATIC DEGRADABILITY AND DRUG-RELEASING ABILITY

Bioartificial biodegradable materials were prepared mixing chitosan (CHI) and poly(vinyl alcohol) (PVA), then manufactured as films, and finally cross-linked with glutaraldehyde (GTA), both in the absence and in the presence of the edible hexa-alcohol sorbitol (SOR), as a plasticizer. The release of the components into water was tested by high performance liquid chromatography (HPLC); no release of CHI and scarce release of PVA were found. The water uptake was tested by measuring the swelling of the materials, after incubating them for 20 h in an atmosphere saturated with water vapor at 37°C. The swelling percentage increases with increasing CHI content in the blends, although it is the less hydrophilic polymer. This behavior was attributed to the difficulty of water to diffuse through the crystalline PVA structure, which is partially altered in the blends. The addition of SOR enhances the water sorption, as expected. The biodegradability of the materials was tested using the specific enzyme chitosanase, and was found to depend on the blend composition, as well as to be enhanced by the addition of SOR. The initial degradation rates were calculated; the maximum rates were found when the CHI to PVA ratio was 80:20 for all systems. The results of the enzymatic degradation generally agree with those of the swelling. The cross-linked blends were also tested as drug-delivery systems. The drugs chosen were the vitamin L-ascorbic acid (AsA) and the anti-cancer drug paclitaxel (PTX). The effective diffusion coefficients, Deff, were evaluated for the release of both the drugs from each material. Those of AsA are greater, of many powers of ten, than those of PTX, owing mainly to the hydrophilic nature of the first drug and to the hydrophobic of the second one. In conclusion, these materials seem available for biomedical use.

Acrylic copolymers as candidates for drug-eluting coating of vascular stents.

The aim of the present work is the synthesis and characterization of polymer materials showing good adhesion, drug loading, and delivery properties, for potential cardiovascular application. In particular, poly(methylmethacrylate-co-acrylic acid) copolymers are prepared in different compositions by a radical polymerization and investigated as potential materials to coat metallic stents and to carry out a local drug release. Films obtained by dissolving the copolymer in an appropriate organic solvent (also loaded with an anti-restenosis drug, such as tacrolimus) are investigated: physicochemical properties, adhesiveness to metallic stent material, and kinetics of drug release in physiological environment are studied.

Synthesis and characterization of copolymers of methylmethacrylate and 2-hydroxyethyl methacrylate for the aqueous solubilization of Paclitaxel

The aim of the present work is the modification of a hydrophobic polymeric macromolecule, polymethylmethacrylate, by introducing hydrophilic moieties of 2-hydroxyethyl methacrylate within the polymer chain. Synthesis, characterization, and drug delivery control capabilities exerted on a highly hydrophobic drug (Paclitaxel) are illustrated. In particular, the dependency of the drug delivery kinetic on the fraction of hydrophilic units inserted in the copolymer chain was studied. Results showed that it is possible to have an increase of the kinetic delivery introducing hydrophilic units. In addition, a double control, diffusive and due to the relaxation of the molecules, on drug delivery was obtained.

BIODEGRADABLE BIOARTIFICIAL MATERIALS MADE BY CHITOSAN AND POLY(VINYL ALCOHOL) PART III: MATERIALS TOUGHENED BY MEANS OF A DEHYDROTHERMAL TREATMENT

The bioartificial chitosan–poly(vinyl alcohol) blends were toughened by means of a dehydrothermal treatment (DHT), to facilitate the formation of hydrogen bonds between the macromolecules. The materials were characterized by stress–strain test, contact angle measurement, spotlight Fourier transform infrared spectroscopy and chemical imaging, weight loss in water, swelling in water vapor saturated atmosphere, Alamar blue test to evaluate the indirect cytotoxicity, and the diffusive permeation, through membranes made with the blends, of D(+)glucose, vitamin B12, and bovine serum albumin. The results were compared with those of the blends crosslinked by glutaraldehyde (GTA). The Youngs modulus ranges between 10.56 and 16.12 MPa, and it is higher for the blends subjected to DHT than for those crosslinked by GTA, a fact explainable by the elasticity of the latter, due to the flexible bridges connecting the different chains. The contact angles indicate a scarce wettability, and then a scarce hydrophilicity, which is confirmed by the chemical imaging of the surfaces, made in the total reflection (microATR) mode, of the films toughened by DHT: the ν(OH) band in the 4000–3000 cm-1 is nearly absent in all the regions of the maps. Moreover, the correlation maps indicate a homogeneous distribution of the two components within the blends. The weight loss in water is generally less than 15%, and increases with the content of the ionizable macromolecule chitosan in the blends, a trend shown also by the swelling after exposure to water vapors. Alamar blue test shows that none of the eluates, after being in contact with the materials up to seven days, appears cytotoxic toward murine fibroblasts. As concerning the diffusive permeation, it appears good for D(+)glucose, quite good for vitamin B12, and scarce for bovine serum albumin. In conclusion, the chitosan–poly(vinyl alcohol) blends studied appear to be suitable for their use as biomaterials.