Chronic, non-healing wounds are a major health problem with more than 10 million Americans per annum receiving treatment, at a cost of greater than 10 billion dollars. Exogenous growth factor therapy for the treatment of chronic and acute wounds has shown promising results in accelerating the rate of healing in in-vitro and in vivo models. Unfortunately, inadequate methods of locally delivering active growth factors in a timely order limit the widespread utilization of growth factor therapy in a clinical wound management setting. A major challenge lies in the development of sophisticated peptide delivery systems that mimic the endogenous release profiles of growth factor production during the natural tissue repair process. We hypothesize that bioactive scaffolds impregnated with multiple growth factors that are released at controlled rates, offer the possibility of augmenting the rate of healing to a greater extent than a single growth factor therapy. This study is sought to a) understand how we can predictably modulate the sequential delivery of multiple growth factors from a single polymeric scaffold by manipulating the scaffold's properties and b) evaluate the synergistic effects of dual controlled growth factor delivery in cutaneous repair. We propose two Specific Aims.
In AIM 1 a we will synthesize biodegradable, polyethylene glycol-heparin (PEG-heparin) hydrogel scaffolds with tunable physical properties that release at controlled rates two well-known tissue repair factors, namely epidermal growth factor (EGF) and basic fibroblast growth factor (b-FGF).
In AIM 1 b we will determine the significance of controlled delivery on peptide bioactivity in an in vitro milieu and in AIM 2 we will assess the ability of the growth factor releasing scaffolds to promote cutaneous regeneration in a partial thickness wound model. The sequential delivery of these factors will be programmed by: a) controlling the physical properties of the scaffold (e.g. light exposure, gel composition), b) altering the growth factor loading capacity and c) pre-encapsulating each one of these factors (i.e. depending upon the preferred order of release) within biodegradable poly (lactide-co-glycolide) (PLG) microspheres before they are loaded into the gel scaffold. The heparin content of the gel scaffold will stabilize EGF and b-FGF and serve as a docking station for the prolonged release of the peptides to the wound area.
|Layman, Hans; Spiga, Maria-Grazia; Brooks, Toby et al. (2007) The effect of the controlled release of basic fibroblast growth factor from ionic gelatin-based hydrogels on angiogenesis in a murine critical limb ischemic model. Biomaterials 28:2646-54|
|Andreopoulos, Fotios M; Persaud, Indushekhar (2006) Delivery of basic fibroblast growth factor (bFGF) from photoresponsive hydrogel scaffolds. Biomaterials 27:2468-76|
|Gattas-Asfura, Kerim M; Weisman, Eric; Andreopoulos, Fotios M et al. (2005) Nitrocinnamate-functionalized gelatin: synthesis and ""smart""hydrogel formation via photo-cross-linking. Biomacromolecules 6:1503-9|