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DC Bead is a FDA cleared embolisation device for the treatment of hypervascular tumours and arteriovenous malformations. This product is currently evaluated in a number of centres in Europe as an embolic device for transarterial chemoembolisation (TACE). The beads consist of poly(vinyl alcohol) microspheres modified with sulfonic acid groups and are available at different size ranges varying from 100 to 900 microm in diameter. The beads were shown to actively sequester doxorubicin hydrochloride (dox) from solution in a time dependent upon the dose of the drug and size of the beads. Drug uptake was by an ion-exchange mechanism, and in the absence of other ions in solution, the beads could load a maximum of around 40 mg dox/mL hydrated beads, with99% of drug being sequestered from the solution. A loading of 25 mg dox/mL beads was recommended as providing a practical therapeutic dose and optimum handling characteristics. There was a decrease in equilibrium water content of the beads with increasing dox loading, which resulted in a decrease in the average diameter of the beads and an increase in the compressive modulus. The deliverability properties, however, were not affected after drug loading. Using a variety of microscopic methods, the drug was shown to be distributed throughout the bead structure, but concentrated in the outer 20 microm surface layer, a feature related to the method of synthesis. This study characterises the properties of DC Bead loaded with dox with respect to important characteristics in embolisation and demonstrates the potential of this drug device combination for the treatment of hypervascular tumours such as hepatocellular carcinoma.

Background— Drug-eluting stents represent a useful strategy for the prevention of restenosis using various antiproliferative drugs. These strategies share the liability of impairing endothelial recovery, thereby altering the natural biology of the vessel wall and increasing the associated risk of stent thrombosis. Accordingly, we tested the hypothesis that local delivery via gene-eluting stent of naked plasmid DNA encoding for human vascular endothelial growth factor (VEGF)-2 could achieve similar reductions in neointima formation while accelerating, rather than inhibiting, reendothelialization. Methods and Results— phVEGF 2-plasmid (100 or 200 μg per stent)–coated BiodivYsio phosphorylcholine polymer stents versus uncoated stents were deployed in a randomized, blinded fashion in iliac arteries of 40 normocholesterolemic and 16 hypercholesterolemic rabbits. Reendothelialization was nearly complete in the VEGF stent group after 10 days and was significantly greater than in control stents (98.7±1% versus 79.0±6%, P 2 , P P Conclusions— Acceleration of reendothelialization via VEGF-2 gene–eluting stents provides an alternative treatment strategy for the prevention of restenosis. VEGF-2 gene–eluting stents may be considered as a stand-alone or combination therapy.

Copolymers of 2-methacryloyloxyethylphosphorylcholine (MPC) and lauryl methacrylate (LMA) of molar ratios MPC: LMAX where x = 1, 2 or 4, have been synthesised by two different free-radical polymerisation techniques. The solubility characteristics of the resulting materials were investigated in a variety of water: alcohol solvent mixtures and found to be influenced not only by the molar ratio of MPC: LMA, but also the method of synthesis. A window of solubility was observed for certain copolymers and the alcohol used in the solvent mixture was also found to have a profound influence on the solubility profile of the polymers. These materials were soluble in a wider range of aqueous methanol mixtures compared to aqueous mixtures of higher aliphatic alcohols, such as ethanol or isopropyl alcohol, which was rationalised in terms of the affinity of the phosphorylcholine headgroup for the various alcohols relative to water. 1H nuclear magnetic resonance spectroscopy was used to further examine the solution properties of the copolymers in various solvents. The copolymer MPC: LMA2 was coated onto a variety of substrates from both alcohol-only and water: alcohol solvent systems and the surface properties of the films compared by static and dynamic contact angle, atomic force microscopy (AFM) and attenuated internal reflectance Fourier transform infrared spectroscopy (ATR-IR). The coating formed from the water: alcohol solvent was found to be hydrophilic in nature, possessing spontaneous wettability, whereas films formed from alcohol-only solvents were hydrophobic, and only on conditioning with water were more wettable surfaces attained. This phenomenon was applied in the coating of leukocyte filtration material, where the aqueous-based systems demonstrated lower critical wetting surface tension (CWST) and shorter wetting times relative to both uncoated filters and those coated from alcohol-only systems. The haemocompatibility of the coated filters was equivalent for both coating solvent systems. employed, and far superior when compared to the uncoated control.

DC Bead is a sulfonate-modified, PVA-based microspherical embolisation agent approved for the treatment of hypervascular tumours and arterio-venous malformations. The beads have previously been shown to actively sequester oppositely charged drugs, such as doxorubicin hydrochloride (dox) by an ion-exchange mechanism. In order to characterise the release kinetics and predict the in vivo behaviour of drug eluting beads (DEB), two elution methods were utilised. The first, an application of the USP dissolution method Type II - Apparatus, enables study of the complete elution of loaded DC Bead in less than 4 h, allowing relatively rapid comparison to be made between different products and formulations. Release data obtained using this method were fitted to first order kinetics (R (2) > 0.998) and the elution constants shown to increase with the total surface area of the beads exposed to the elution medium. Diffusion coefficients were calculated adopting the Fickian diffusion model, which predicted slow elution rates under physiological conditions. The second method involved the use of a T-Apparatus where the drug experiences an element of diffusion through a static environment. This method was developed to resemble the in vivo situation in embolisation procedures more closely. Slow release of dox from DC Bead with half-lives over 1,500 h were predicted for all size ranges using a slow release model. A strong linear relationship was found between the release data from T-Apparatus and pharmacokinetic data obtained from patients treated with DC Bead loaded with dox in transarterial chemoembolisation (TACE) procedures. These data indicated a Level A in vitro-in vivo correlation (IVIVC) for the first 24 h post embolisation. Both systems developed were automated and good reproducibility was obtained for all samples, demonstrating the usefulness of these elution techniques for product development and comparative testing.

Drug eluting beads that release irinotecan in a controlled manner may be useful for application in the chemoembolization of colorectal cancer metastases to the liver. In this study, irinotecan drug eluting beads were prepared with loadings up to 50 mg drug/mL hydrated beads. Drug loading was via an ion-exchange mechanism with sulfonate binding sites in the bead. Release in vitro was shown to be sustained and dependent upon the presence of ions in the elution medium, drug loading and bead size. Drug elution in PBS was controlled by solute diffusion within the beads and gave rise to values for the diffusion coefficient, D, of between 2.4x10(-9) and 1.4x10(-7) cm(2)s(-1). The beads were shown to decrease in size (by a maximum 25-30%), and concomitantly their modulus of compression increased (from approximately 27 kPa to a maximum of about 49 kPa), with increasing drug loading. This did not however, influence their ability to be suspended homogeneously in contrast agent or delivered through a microcatheter. Following porcine hepatic artery embolization, maximum plasma levels were 70-75% lower for both irinotecan and SN-38 compared to intraarterial bolus administration, with peak levels observed at 2 and 5 min after completion of the embolization procedure. The in vivo data were shown to correlate well with the in vitro release measured using a T-apparatus model of embolization.

Phospholipid-like polymers based on 2-methacryloyloxyethyl phosphorylcholine containing varying amounts of the cationically charged monomer choline methacrylate (CMA) from 0 to 30 wt% have been prepared. Substrates coated with these materials were shown to bind significantly lower amounts of specific proteins compared to the uncoated control. ELISA assays demonstrated that fibrinogen did not bind appreciably to coatings containing 0-30% CMA, whereas albumin binding was seen to increase significantly as the CMA content of the coating increased. Platelet activation assays, measurement of plasma coagulation time and whole blood contact scanning electron micrography demonstrated that the haemocompatibility of the coatings was shown to be unaffected by the CMA component. The CMA polymer coatings have been shown to absorb/adsorb many different drug compounds covering a wide range of molecular weights and release these in a controlled fashion. The range of cationic polymers assessed can interact with the net negative charge found in many large therapeutic biomolecules, such as DNA fragments used in gene therapy, that may be of interest in the preventative treatment of conditions such as restenosis. Coronary stents coated with 6% or 20% CMA-containing polymers have been shown to load and release this type of genetic material irrespective of molecular weight of the biomolecule. Ex vivo and in vivo studies have shown that these compounds can be delivered to the stented section of the vessel with very low quantities delivered outside the vessel target area.

The preparation and characterisation of a new phosphorylcholine (PC)-coated silicone hydrogel contact lens for use in extended wear is described. The Michael-type addition of amines to acrylates forms the basis of the synthesis of a novel silicone-based macromer with hydrophilic functionality. It is demonstrated that this macromer can be combined with other silicone-based monomers, hydrophilic monomers and crosslinker to produce a contact lenses formulation. Examples of lenses with water contents of 33% and 46% are illustrated and their properties compared to other commercially available lenses. Materials with comparatively low modulus (0.3 MPa) and adequate tear strength (2-4MPa) with excellent elongation to break (200%) can be obtained using this technology. In addition to the mechanical aspects. both the oxygen and solute permeabilities of the material can be controlled by the hydrophilic: hydrophobic monomer balance in the formulation. to obtain materials with attributes suitable for extended wear use. The PC coating is achieved by means of an in-mould coating (IMC) technique that produces a uniform and stable surface as determined by staining and XPS. The coating imparts both improved lens wettability (advancing contact angle of approximately 50 with virtually no hysteresis) and lower protein adsorption relative to the uncoated lens.

2-Methacryloyloxyethyl phosphorylcholine (MPC) was synthesised and then used in the preparation of crosslinked polymer membranes with lauryl methacrylate, hydroxypropyl methacrylate and trimethoxysilylpropyl methacrylate (crosslinker) comonomers. Some physical aspects of the membrane properties were evaluated in order to establish the basis for the synthesis of a series of post-crosslinkable polymers. These materials were made by copolymerisation of the constituent monomers via a free radical method, and characterised using NMR, FT-IR, viscometry and elemental analysis. The optimum crosslink density and conditions required for curing coatings of these polymers were investigated using atomic force microscopy (AFM) and showed the inclusion of 5 mol% silyl crosslinking agent to be ideal. A nanoindentation technique was employed to determine if the coating developed elasticity upon crosslinking. The biological properties of the coatings were evaluated using a variety of protein adsorption assays and blood contacting experiments, and an enzyme immunoassay was developed to detect E. coli in order to assess the level of bacterial adhesion to these biomaterials. Polymers of this type were shown to be very useful as coating materials for improving the biocompatibility of, or reducing the levels of adherent bacteria to medical devices.