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Abstract
Grant Number: 1R01DK068401-01 Project Title: Wound Repair by Stimulation of Specific Tissue Ingrowth
PI Information: Name Title CHEN, WEILIAM ASSISTANT PROFESSOR Abstract: DESCRIPTION (provided by applicant): Diabetes is the 6th leading cause of medically related death in the United States. Development of foot ulcer is one of the most serious complications, affecting up to 3% of the diabetic population each year, with 15% of all diabetic individuals experiencing one episode during their life-time. Most current treatments (e.g., off-weighting, debridement and ischemic reversal) provide only limited benefits. Recombinant human platelet derived growth factor (PDGF-BB) (becaplerrnin 0.01% gel, Regranex TM) has been approved by the FDA for topical use in treating diabetic ulcer. Compared to placebo, the incidence of complete ulcer closure was increased in some clinical trials, but not all. Non-optimal dosing was likely a major contributory factor to the discrepancy observed. We intend to engineer a biodegradable composite bioactive matrix that mimics the initial provisional matrix formed after acute wounds to achieve better healing response for chronic wounds. The initial function of this matrix is not to achieve prolonged release of bioactive agents into the wound site; rather, the therapeutic moieties will largely be confined to the matrix. This system will be constructed from Hyaluronan (HA) and a heparin stabilized cell adhesion molecule Fibronectin (FN), capable of stimulating cell migration, will be integrated into the HA structure. Both HA and FN are the main components of the provisional matrix. Additionally, heparin stabilized Vascular Endothelial Growth Factor (VEGF), with limited diffusion potential, will be incorporated to locally stimulate the endothelial cells to form blood vessels; setting the stage for granulation tissue formation. An integral component of the matrix will contain DNA encoding PDGF intended for delayed release and expression, which helps to promote the formation of robust and mature blood vessels. Migration of cells into the matrix in conjunction with blood vessel growth will precede PDGF gene transfer and subsequent PDGF expression, which will enhance granulation tissue formation. HA is truly biocompatible and does not induce inflammatory and immunogenic responses, and has mechanical properties compatible with soft tissues. Additionally, the HA matrix structure will eventually be integrated into the tissue formed during the healing process. We will first formulate and optimize these bioactive matrices using photocrosslinkable HA. The dosing information will be derived using mouse cremaster muscle models followed by a test of efficacy in diabetic mice full-thickness dermal wound models. We will use a noninvasive optical biopsy technique (Optical Coherence Tomography, OCT) to monitor the recovery of the wounds.
Public Health Relevance:
This Public Health Relevance is not available.Thesaurus Terms:
angiogenesis, angiogenesis factor, artificial membrane, artificial skin, biomaterial compatibility, biomaterial development /preparation, biomaterial evaluation, cell migration, diabetes mellitus, fibronectin, hyaluronate, platelet derived growth factor, skin ulcer, tissue engineering, vascular endothelial growth factor, wound healing
disease /disorder model, gene therapy, nonhuman therapy evaluation
laboratory mouse, optical tomography
Institution: STATE UNIVERSITY NEW YORK STONY BROOK STONY BROOK, NY 11794 Fiscal Year: 2004 Department: BIOCHEMISTRY AND CELL BIOLOGY Project Start: 01-SEP-2004 Project End: 30-JUN-2008 ICD: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES IRG: SAT