The Journal of Bone and Joint Surgery (American). 2006;88:132-139.
doi:10.2106/JBJS.F.00892
© 2006 The Journal of Bone and Joint Surgery, Inc.
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Thrombin Peptide TP508 Stimulates Cellular Events Leading to Angiogenesis, Revascularization, and Repair of Dermal and Musculoskeletal Tissues

James T. Ryaby, PhD, Michael R. Sheller, MS, Benjamin P. Levine, MD, Dale G. Bramlet, MD, Amy L. Ladd, MD and Darrell H. Carney, PhD

Corresponding author:
James T. Ryaby, PhD
OrthoLogic Corp, 1275 West Washington Street, Tempe, AZ 85281.
E-mail address: jryaby{at}olgc.com

NOTE: The authors gratefully acknowledge the contributions of the following investigators: Phase 1/2 Diabetic Ulcer Clinical Trial—Drs. Leon Brill, Caroline Fife, Jon T. Mader (deceased), Kathleen Satterfield, and Jeffery Stone; Phase 1/2 Distal Radius Fracture Trial— Drs. Charles Cassidy, Bharat Desai, Philipp Lang, Charles Leinberry, Wadih Macksoud, Alan Ward, Joel Faden, Larry Muenz, David He, and Susanne Smith. The authors also thank Drs. Antonella Naldini, Andrea Norfleet, Shyam Ramakrishnan, and Janet Stiernberg for their contributions.

In support of their research for or preparation of this manuscript, one or more of the authors received grants or outside funding from OrthoLogic Corp. In addition, one or more of the authors received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity (OrthoLogic Corp). No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

The thrombin peptide, TP508, also known as Chrysalin (OrthoLogic, Tempe, Arizona), is a twenty-three-amino-acid peptide that represents a portion of the receptor-binding domain of the native human thrombin molecule that has been identified as the binding site for a specific class of receptors on fibroblasts and other cells. Preclinical studies with this peptide have shown that it can accelerate tissue repair in both soft and hard tissues by mechanisms that appear to involve up-regulation of genes that initiate a cascade of healing events. These events include recruitment and activation of inflammatory cells, directed migration of cells (chemotaxis), cell proliferation, elaboration of extra-cellular matrix, and accelerated revascularization of the healing tissues.

Early preclinical dermal wound-healing studies showed that TP508 accelerated healing of both incisional wounds and full-thickness excisional wounds in normal and ischemic skin. In all of these studies, the accelerated healing was associated with increased neovascularization across the incision or in the granulating wound bed. Studies in a rat fracture model have also shown that TP508 accelerates the rate of fracture repair. Gene array analysis of fracture callus from control and TP508-treated fractures indicated that TP508 treatment was associated with an up-regulation of early response elements, inflammatory mediators, and genes related to angiogenesis. Similar to what had been seen in dermal wounds, histology from rat fracture callus twenty-one days after treatment indicated that fractures treated with TP508 had significantly more large functional blood vessels than did fractures in the control animals. In vitro studies support these in vivo data and indicate that TP508 may have a direct angiogenic effect by promoting the rate of new vessel growth.

The results from phase-1 and phase-2 human clinical studies have shown a positive stimulatory effect of TP508 in the healing of diabetic ulcers and in the repair of fractures to the distal aspect of the radius. Collectively, these studies suggest that TP508 accelerates tissue repair by initiating a cascade of events that lead to an increased rate of tissue revascularization and regeneration.


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