title: 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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, United States.
authors.forename: Siddhesh D
authors.initials: SD
authors.lastname: Patil
authors.forename: Fotios
authors.initials: F
authors.lastname: Papadmitrakopoulos
authors.forename: Diane J
authors.initials: DJ
authors.lastname: Burgess
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000494:pharmacology*; D003907:Dexamethasone / Q000008:administration & dosage* / Q000494:pharmacology*; D004337:Drug Carriers; D005355:Fibrosis; D020100:Hydrogels; D007249:Inflammation / Q000473:pathology; D007275:Injections, Intravenous; D019344:Lactic Acid; D008863:Microspheres; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers; D011145:Polyvinyls; D051381:Rats; D012709:Serum Albumin; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage* / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D004337:Drug Carriers; D020100:Hydrogels; D011108:Polymers; D011145:Polyvinyls; D012709:Serum Albumin; D042461:Vascular Endothelial Growth Factor A; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D003907:Dexamethasone