In situ crosslinkable heparin-containing poly(ethylene glycol) hydrogels for sustained anticoagulant release

Low-molecular weight heparin (LMWH) is widely used in anticoagulation therapies and for the prevention of thrombosis. LMWH is administered by subcutaneous injection usually once or twice per day. This frequent and invasive delivery modality leads to compliance issues for individuals on prolonged therapeutic courses, particularly pediatric patients. Here, we report a long-term delivery method for LMWH via subcutaneous injection of long-lasting hydrogels. LMWH is modified with reactive maleimide groups so that it can be crosslinked into continuous networks with four-arm thiolated poly(ethylene glycol) (PEG-SH). Maleimide-modified LMWH (Mal-LMWH) retains bioactivity as indicated by prolonged coagulation time. Hydrogels comprising PEG-SH and Mal-LMWH degrade via hydrolysis, releasing bioactive LMWH by first-order kinetics with little initial burst release. Separately dissolved Mal-LMWH and PEG-SH solutions were co-injected subcutaneously in New Zealand White rabbits. The injected solutions successfully formed hydrogels in situ and released LMWH as measured via chromogenic assays on plasma samples, with accumulation of LMWH occurring at day 2 and rising to near-therapeutic dose equivalency by day 5. These results demonstrate the feasibility of using LMWH-containing, crosslinked hydrogels for sustained and controlled release of anticoagulants.