Heparin releasing thermosensitive hydrogels

Thermosensitive hydrogels (TSH) based on N-isopropyl acrylamide (NiPAAm) were synthesized and investigated as heparin releasing polymers for the prevention of surface induced thrombosis. The rationale of using TSH as heparin releasing polymers is based on the unique, temperature dependent swelling of these materials. Below the lower critical solution temperature (LCST) NiPAAm based TSH gels exhibit high swelling that allow for simple solution sorption loading of hydrophilic macromolecules, such as heparin. Above the LCST, e.g., at body temperature, NiPAAm gels deswell abruptly and release absorbed macromolecules. The release process is controlled initially by the deswelling kinetics the gels (mechanical squeezing of drug) and subsequently by diffusion of macromolecules within the dense polymer network. TSH were synthesized as: 1) crosslinked NiPAAm copolymers with butyl methacrylate (BMA), acrylamide (AAm) and/or acrylic acid (AAc); 2) crosslinked NiPAAm copolymer coatings; 3) semiinterpenetrating polymer networks (semi-IPNs) containing NiPAAm and copoly(ether-urethane-urea) (Biomer); 4) and Biomer/poly(NiPAAm) polymer blend coatings. Equilibrium swelling and deswelling kinetics of the synthesized gels were examined at various temperatures. Heparin loading into the different gels was studied as a function of temperature, solution concentration, and gel composition. The partition coefficients of heparin within the networks decreased with increasing temperature and gel hydrophobicity. The release kinetics of heparin correlated with the networks deswelling kinetics and were found to be influenced by gel composition and loading temperature. The shortterm antithrombogenicity of intravenous polyurethane catheters coated with Biomer/poly(NiPAAm) thermosensitive coatings was evaluated in a canine animal model after room temperature heparin loading. It was shown that heparin release from Biomer/poly(NiPAAm) coated surfaces resulted in a significant reduction of thrombus formation on test surfaces in contact with venous blood as compared to control surfaces. The results obtained in this study demonstrate the feasibility of macromolecular loading and release from NiPAAm based TSH, including the novel thermosensitive Biomer/poly(NiPAAm) semi-IPNs and Biomer/poly(NiPAAm) thermosensitive coatings.