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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK068401-03
Application #
7074564
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Jones, Teresa L Z
Project Start
2004-09-01
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
3
Fiscal Year
2006
Total Cost
$326,542
Indirect Cost
Name
State University New York Stony Brook
Department
Biochemistry
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
Liao, Huijuan; Pastar, Irena; Chen, Weiliam (2012) Rosiglitazone modulates the behaviors of diabetic host-derived fibroblasts in a carboxymethyllysine-modified collagen model. Wound Repair Regen 20:435-43
Dewar, Anthony M; Clark, Richard A; Singer, Adam J et al. (2011) Curcumin mediates both dilation and constriction of peripheral arterioles via adrenergic receptors. J Invest Dermatol 131:1754-60
Georgi, Melissa K; Dewar, Anthony M; Frame, Mary D (2011) Downstream exposure to growth factors causes elevated velocity and dilation in arteriolar networks. J Vasc Res 48:11-22
Zhang, Hanwei; Qadeer, Aisha; Chen, Weiliam (2011) In situ gelable interpenetrating double network hydrogel formulated from binary components: thiolated chitosan and oxidized dextran. Biomacromolecules 12:1428-37
Pan, Hui; Jiang, Hongliang; Kantharia, Sarah et al. (2011) A fibroblast/macrophage co-culture model to evaluate the biocompatibility of an electrospun Dextran/PLGA scaffold and its potential to induce inflammatory responses. Biomed Mater 6:065002
Georgi, Melissa K; Vigilance, Jacqueline; Dewar, Anthony M et al. (2011) Terminal arteriolar network structure/function and plasma cytokine levels in db/db and ob/ob mouse skeletal muscle. Microcirculation 18:238-51
Pan, Hui; Zimmerman, Thomas; Zakhaleva, Julia et al. (2010) Embolization of a common carotid aneurysm with rhVEGF coupled to a pH-responsive chitosan in a rat model. J Neurosurg 112:658-65
Zeng, Qiong; Chen, Weiliam (2010) The functional behavior of a macrophage/fibroblast co-culture model derived from normal and diabetic mice with a marine gelatin-oxidized alginate hydrogel. Biomaterials 31:5772-81
Falabella, Christine A; Melendez, Mark M; Weng, Lihui et al. (2010) Novel macromolecular crosslinking hydrogel to reduce intra-abdominal adhesions. J Surg Res 159:772-8
Yuan, Zhijia; Zakhaleva, Julia; Ren, Hugang et al. (2010) Noninvasive and high-resolution optical monitoring of healing of diabetic dermal excisional wounds implanted with biodegradable in situ gelable hydrogels. Tissue Eng Part C Methods 16:237-47

Showing the most recent 10 out of 35 publications