Concurrent delivery of dexamethasone and VEGF for localized inflammation control and angiogenesis

Abstract

Localized elution of corticosteroids has been used in suppressing inflammation and fibrosis associated with implantation and continuous in vivo residence of bio-medical devices. However, these agents also inhibit endogenous growth factors preventing angiogenesis at the local tissue, interface thereby delaying the healing process and negatively impacting device performance. In this work, a combination of dexamethasone and vascular endothelial growth factor (VEGF) was investigated for concurrent localized delivery using PLGA microsphere/PVA hydrogel composites. Pharmacodynamic effects were evaluated by histopathological examination of subcutaneous tissue surrounding implanted composites using a rat model. The hydrogel composites were capable of simultaneously releasing VEGF and dexamethasone with approximately zero order kinetics. Composites were successful in controlling the implant/tissue interface by suppressing inflammation and fibrosis as well as facilitating neo-angiogenesis at a fraction of their typical oral or i.v. bolus doses. Implants containing VEGF showed a significantly higher number of mature blood vessels at the end of the 4 week study irrespective of the presence of dexamethasone. Thus, localized concurrent elution of VEGF and dexamethasone can overcome the anti-angiogenic effects of the corticosteroid and can be used to engineer inflammation-free and well-vascularized tissue in the vicinity of the implant. These PLGA microsphere/PVA hydrogel composites show promise as coatings for implantable bio-medical devices to improve biocompatibility and ensure in vivo performance.