title: Engineering strategies to control vascular endothelial growth factor stability and levels in a collagen matrix for angiogenesis: the role of heparin sodium salt and the PLGA-based microsphere approach.
abstract: New vessel formation is the result of the complex orchestration of various elements, such as cells, signalling molecules and extracellular matrix (ECM). In order to establish the suitable conditions for an effective cell response, the influence of vascular endothelial growth factor (VEGF) complexation with heparin sodium salt (Hp) on its pro-angiogenic activity has been evaluated by an in vitro capillary-like tube formation assay. VEGF with or without Hp was embedded into collagen gels, and the activated matrices were characterized in terms of VEGF activity and release kinetics. Taking into account the crucial role of Hp in VEGF stability and activity, VEGF/Hp complex was then encapsulated into microspheres based on poly(lactide-co-glycolide) (PLGA), and microsphere properties, VEGF/Hp release kinetics and VEGF in vitro activity over time were evaluated. Integrated microsphere/collagen matrices were developed in order to provide a continuous release of active VEGF/Hp inside the matrix but also a VEGF gradient at the boundary, which is an essential condition for endothelial cell attraction and scaffold invasion. The results confirmed a strong influence of Hp on VEGF configuration and, consequently, on its activity, while the encapsulation of VEGF/Hp complex in PLGA-microspheres guaranteed a sustained release of active VEGF for more than 30days. This paper confirms the importance of VEGF stability and signal presentation to cells for an effective proangiogenic activity and highlights how the combination of two stabilizing approaches, namely VEGF/Hp complexation and entrapment within PLGA-based microspheres, may be a very effective strategy to achieve this goal.
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Via D Montesano 49, 80131 Naples, Italy. ivana.dangelo@unina.it
authors.forename: Ivana
authors.initials: I
authors.lastname: d'Angelo
authors.forename: Olimpia
authors.initials: O
authors.lastname: Oliviero
authors.forename: Francesca
authors.initials: F
authors.lastname: Ungaro
authors.forename: Fabiana
authors.initials: F
authors.lastname: Quaglia
authors.forename: Paolo Antonio
authors.initials: PA
authors.lastname: Netti
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000008:administration & dosage / Q000737:chemistry; D002214:Capsules / Q000008:administration & dosage / Q000138:chemical synthesis; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000737:chemistry*; D004058:Diffusion; D004343:Drug Implants / Q000008:administration & dosage* / Q000737:chemistry; D004355:Drug Stability; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D006493:Heparin / Q000737:chemistry*; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry*; D008422:Materials Testing; D008863:Microspheres; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D012492:Salts; D054457:Tissue Scaffolds; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D043925:Angiogenesis Inducing Agents; D002214:Capsules; D004343:Drug Implants; D012492:Salts; D042461:Vascular Endothelial Growth Factor A; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D006493:Heparin; D003094:Collagen