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A porous polyurethane vascular prosthesis with an internal diameter of 5 mm was studied. The graft carries a coating of immobilized dipyridamole (Persantin(R)) on the surface of its lumen. Dipyridamole is a potent nontoxic inhibitor of platelet activation/aggregation, and also a strong inhibitor of vascular smooth muscle cell proliferation. The polyurethane material is also known as Chronoflex(R), and already finds use as a vascular access graft. The coated vascular graft was studied in vitro (hemocompatibility, interaction with blood platelets and cultured endothelial cells), as well as in two established in vivo models. In the first in vivo study, coated grafts were implanted in goats, as a bypass of the carotid artery (four animals, eight grafts, length of the graft was approximately 12 cm). Four uncoated grafts were used as controls in otherwise identical experiments. In the second in vivo experiment, eight sheep were used. Each animal received one coated and one uncoated prosthesis as an interposition graft in the carotid artery (length of the graft was 4 cm). The in vitro experiments revealed that the dipyridamole coating has three beneficial effects: reduced thrombogenicity, reduced adherence of blood platelets, and accommodation of a confluent monolayer of endothelial cells. The goat experiments showed patency of the coated grafts in three of the eight cases. The sheep experiments were not useful for the evaluation of the dipyridamole coating because deterioration of the polyurethane material was observed. The in vivo results indicate that the dipyridamole coating may positively influence the patency rate, probably because the coating promotes the growth of an endothelial cell lining. The sheep data show, however, that the limited stability of the Chronoflex(R) material precludes its issue for the construction of permanent small-bore vascular grafts.

A new methodology to improve the hemocompatibility of polyurethane (medical grade Pellethane D-55) surfaces is reported. The approach is essentially based on a photochemical immobilization reaction. Two new conjugate molecules, compounds 2 and 3, were prepared. They consist of (i) dipyridamole, a well-known inhibitor of platelet activation, and a vasodilating drug with clinical application, for instance before and during pecutaneous transluminar coronary angioplasty (Dottering); and (ii) an aryl azide, a moiety that exhibits marked photoreactivity. In 2, the dipyridamole unit is directly linked to the aryl azide (via an ester bond), while a short spacer chain separates both units in 3. Upon irradiation of 2 or 3, adsorbed onto the polyurethane foil, the aryl azide is converted into a highly reactive species which reacts with a nucleophilic group on the polymer surface. In this way, the dipyridamole is covalently linked to the polymer. The underlying principle is also used in photoaffinity labeling, a well-known technique in biochemical studies on enzyme structure and function. From UV extinction experiments it could be deduced that the surface-density of immobilized 2 is 4.9 nmol/cm2. The surface density for 3 was 14.6 nmol/cm2. The surfaces were subjected to an in vitro thrombin generation assay. This assay gives a valuable impression about the hemocompatibility of artificial surfaces. These experiments revealed that the clotting times were substantially prolonged as a result of the photoimmobilization of dipyridamole. This was especially the case for immobilized 3. This effect cannot be readily explained. Possibly, the enhanced activity of immobilized 3 is due to the spacer chain. An alternative explanation is that the surface density is larger for 3 than for 2. In addition, the photomodified surfaces were incubated with platelet-rich blood plasma (37 degrees C, 30 min) and subsequently examined by scanning electron microscopy. The morphology of the blood platelets adhered to the surface also showed that hemocompatibility increased in the order untreated polyurethane < polyurethane with immobilized 2 < polyurethane with immobilized 3. Future work will concentrate on evaluation of the role of the spacer (length, hydrophilicity, etc.), as well as on the possible use of this approach with respect to the construction of biomaterials with improved in vivo biocompatibility, in particular hemocompatibility.

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The copolymer of methyl methacrylate (MMA) and 2-[2',3',5'-triiodobenzoyl]oxoethyl methacrylate (1), ratio 3:1 (mass:mass), was prepared via a free-radical polymerization in bulk. The copolymer (M(w) = 97.8 kD and M(n) = 41.5 kD) was dissolved in chloroform and subsequently transformed into beads with a diameter in the micrometer range, using a solvent evaporation technique. The resulting microbeads were characterized by different techniques, including NMR spectroscopy, differential scanning calorimetry, gel permeation chromatography, and scanning electron microscopy. The latter technique was used as the basis for statistical analysis of the bead size. Typically, an average diameter of 96 microm and a standard deviation of 21 microm were obtained. The beads were also subjected to some preliminary tests regarding cytotoxicity. The copolymer of MMA and 1 contains covalently bound iodine. Therefore, the material is intrinsically radiopaque, i.e., capable of absorbing X-radiation while no contrast additive is needed. Our interest in these microspheres stems primarily from their possible utility as injectable and afterward traceable (radiopaque) bulking agents, e.g., for use in urology for the treatment of female stress incontinence due to sphincter deficiency. As a first test into this direction, a sample of the microbeads was mixed with ethylene glycol, and the resulting suspension was studied with respect to injectability and radiopacity. The results suggest that the radiopaque microbeads may provide access to improved bulking agents. Further modification of the surface may be necessary in order to suppress the migratory aptitude of the radiopaque polymeric microspheres in vivo.

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Developments in membrane based blood purification therapies often come with longer treatment times and therefore longer blood-material contact, which requires long-term membrane biocompatibility. In this study, we develop for the first time membranes for blood purification using the material SlipSkinÔ, which is a copolymer, made from N-vinylpyrrolidone (NVP) and butylmethacrylate (BMA). Specific attention is focused on understanding the mechanism of pore formation and the tailoring of the membrane mechanical and transport properties to obtain the optimal membrane for blood purification therapies. Polymer composition, solvent type and solvent evaporation time influence membrane morphology and membranes with sieving properties of cascade filters in plasma fractionation applications are developed. The new membranes have very good blood compatibility properties; in fact compared to benchmark flat membranes currently used in the clinic, they have lower platelet adhesion while all other properties (contact activation, thrombogenicity, leukocyte adhesion, hemolysis and complement activation) are also very good and comparable to the benchmarks.