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Poly-N-Acetyl Glucosamine Nanofibers: A New Bioactive Material to Enhance Diabetic Wound Healing by Cell Migration and Angiogenesis

Scherer, Saja Sandra MD*; Pietramaggiori, Giorgio MD*; Matthews, Jasmine*; Perry, Samuel; Assmann, Anke MD; Carothers, Adelaide PhD§; Demcheva, Marina PhD; Muise-Helmericks, Robin C. PhD; Seth, Arun PhD**; Vournakis, John N. PhD; Valeri, Robert C. MD††; Fischer, Thomas H. PhD‡‡; Hechtman, Herbert B. MD; Orgill, Dennis P. MD, PhD*

doi: 10.1097/SLA.0b013e3181ae9d45
Original Articles

Introduction: In several fields of surgery, the treatment of complicated tissue defects is an unsolved clinical problem. In particular, the use of tissue scaffolds has been limited by poor revascularization and integration. In this study, we developed a polymer, poly-N-acetyl-glucosamine (sNAG), with bioactive properties that may be useful to overcome these limitations.

Objective: To develop a scaffold-like membrane with bioactive properties and test the biologic effects in vitro and in vivo in diabetic wound healing.

Methods: In vitro, cells–nanofibers interactions were tested by cell metabolism and migration assays. In vivo, full thickness wounds in diabetic mice (n = 15 per group) were treated either with sNAG scaffolds, with a cellulosic control material, or were left untreated. Wound healing kinetics, including wound reepithelialization and wound contraction as well as microscopic metrics such as tissue growth, cell proliferation (Ki67), angiogenesis (PECAM-1), cell migration (MAP-Kinase), and keratinocyte migration (p 63) were monitored over a period of 28 days. Messenger RNA levels related to migration (uPAR), angiogenesis (VEGF), inflammatory response (IL-1β), and extracellular matrix remodeling (MMP3 and 9) were measured in wound tissues.

Results: sNAG fibers stimulated cell metabolism and the in vitro migratory activity of endothelial cells and fibroblasts. sNAG membranes profoundly accelerated wound closure mainly by reepithelialization and increased keratinocyte migration (7.5-fold), granulation tissue formation (2.8-fold), cell proliferation (4-fold), and vascularization (2.7-fold) compared with control wounds. Expression of markers of angiogenesis (VEGF), cell migration (uPAR) and ECM remodeling (MMP3, MMP9) were up-regulated in sNAG treated wounds compared with controls.

Conclusions: The key mechanism of the bioactive membranes is the cell-nanofiber stimulatory interaction. Engineering of bioactive materials may represent the clinical solution for a number of complex tissue defects.

Poor vascular supply and impaired cell activity limit the indication of tissue substitutes in complex tissue defects. We developed a scaffold based on a new bioactive nanofiber that shows a profound activation of tissue healing. Cell-nanofiber interaction lead to in vitro and in vivo VEGF mediated angiogenesis and cell migration that clinically stimulated reepithelialization and tissue growth.

From the *Division of Plastic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; †Department of Surgery, Vascular Biology Program, Children’s Hospital Boston, Harvard medical School, Boston, MA; ‡Joslin Diabetes Center, Harvard Medical School, Boston, MA; §Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; ¶Marine Polymer Technologies, Danvers, MA; ∥Department of Cell Biology and Anatomy, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC; **Molecular and Cellular Biology Research, Sunnybrook Health Science Center, Toronto CA; ††Naval Blood Research Laboratory, Inc, Boston, MA; and ‡‡Francis Owen Blood Laboratory, University of North Carolina, Chapel Hill, NC.

Supported by Marine Polymer Technologies, Inc., Danvers, MA (material and financial) and R01 HL84565 (to R.M.H.).

J.N.V and M.D. are employees of Marine Polymer Technologies, Inc., Danvers, MA.

Reprints: Dennis P. Orgill, MD, PhD, Division of Plastic Surgery, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115. E-mail: dorgill@partners.org.

In the article by Scherer et al. Ann Surg. 2009; 250(2)322-330, the academic degree for co-author Jasmine C. Mathews, MS, was not listed. Also, there is no figure 3D, and the 3rd sentence on page 5 should refer to Figure 4D. The authors apologize for the errors.

© 2009 Lippincott Williams & Wilkins, Inc.