Heparin-regulated delivery of osteoprotegerin promotes vascularization of implanted hydrogels

Localized, controlled delivery of pro-angiogenic agents is an important component of therapies for chronic wound treatment and regenerative medicine. Osteoprotegerin (OPG), a tumor necrosis factor receptor (TNFR) superfamily member has recently been shown to be pro-angiogenic in vitro, and we hypothesized that controlled delivery of OPG could induce angiogenesis in vivo. OPG contains a highly basic heparin-binding domain, suggesting that affinity interactions could be used to control the rate of its ion-exchange-driven release from drug-delivery devices. Here, we describe the use of a hydrogel consisting of thiol-modified heparin which can be readily and controllably cross-linked using a bi-functional PEG-diacrylate. These hydrogels were found to retain between 750 and 900 ng of immunoreactive OPG for up to 500 h in in vitro release studies. OPG containing hydrogels were evaluated in a subcutaneous mouse implant model, and exhibited little degradation and retained OPG as indicated by immunohistochemistry at 2 weeks post-implantation. Immunohistochemical analysis of implanted gels indicated that OPG induced nearly a 2-fold increase in vascular density in the surrounding foreign body capsule. These results suggest that the controlled delivery of OPG can stimulate angiogenesis in vivo and may be of use for wound healing therapies as well as other inflammatory and bone disorders in which OPG plays a role.