Lentiviral Gene Transfer of SDF-1 to Wounds Improves Diabetic Wound Healing Andrea T. Badillo, M.D., Sophie Chung, B.S., Liping Zhang, M.S., Philip Zoltick, M.D., and Kenneth W. Liechty, M.D. 1 The Center for Fetal Research at The Children’s Hospital of Philadelphia, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania Submitted for publication January 3, 2007 Background. Chronic wounds continue to be a ma- jor clinical problem and novel therapeutic ap- proaches are needed. We have previously demon- strated that treatment of diabetic mouse wounds with local application of stromal progenitor cells results in improved healing and increased produc- tion of stromal-derived growth factor-1 (SDF-1). We hypothesized that lentiviral-mediated increased production of SDF-1 in the wound environment could also improve diabetic wound healing. Materials and methods. Full-thickness excisional wounds were created in Db/Db mice and immediately treated with 10 6 , 10 8 , or 10 9 plaque-forming units of a lentiviral construct containing GFP-SDF-1 or GFP alone. At 7 and 14 days post wounding, wounds were harvested for histological and molecular analysis. Results. At 7 days, Db/Db wounds treated with lenti GFP-SDF-1 exhibited a decrease in wound sur- face area for all doses tested. Morphologically, SDF- treated wounds were more cellular with increased granulation tissue volume compared to controls (P < 0.05). GFP expression was maintained in treated tissue at 7 days post wounding, but little expression was observed at 14 days. While we did not observe a differ- ence in the gross wound surface area at 14 days, his- tological analysis revealed that SDF-treated wounds were fully epithelialized (n  6) compared to only one of six controls. Conclusions. Lentiviral-mediated overproduction of SDF-1 is sufficient to correct the pathophysiologic ab- normalities in diabetic wound healing resulting in com- plete epithelialization at 2 weeks. SDF-1-mediated im- provement in diabetic wound healing has significant implications for the development of novel therapeutic strategies to facilitate wound closure which target pro- genitor cell mobilization and recruitment. © 2007 Elsevier Inc. All rights reserved. Key Words: SDF-1; gene therapy; wound healing; diabetes. INTRODUCTION Chronic wounds continue to be a major clinical problem. Non-healing wounds may result from a va- riety of causes including diabetes, ischemia, pres- sure, complications from corticosteroid therapy, or complications from radiation therapy. Failure to re- solve these wounds results in prolonged hospitaliza- tion and lost time from work and constitutes a multi- billion dollar health care expenditure each year. With the incidence of diabetes alone increasing 54% from 1997 to 2004 and a 4% risk of developing diabetic- wound-related complications, the healthcare impact of this problem will only continue to grow [1]. Various strategies have been used to enhance healing of chronic wounds including growth factor therapy [2] and ag- gressive local wound care [3] with variable results. To date, effective therapies for chronic non-healing wounds and diabetic-related wound healing impair- ments are lacking. We have previously shown that local application of stromal progenitor cells enhances wound closure in a diabetic mouse model. Furthermore this effect appears to be due, in part, to increased production of stromal- derived growth factor-1 (SDF-1) in wounds. SDF-1 is a CXC chemokine important in the mobilization and recruitment of hematopoietic progenitor cells and other CXCR4+ cells to bone marrow and other tissues [4]. SDF-1 secretion has also been shown to be up- 1 To whom correspondence and reprint requests should be ad- dressed at 3615 Civic Center Blvd., Abramson Research Center, Room 1116E, Philadelphia, PA 19104. E-mail: liechty@email.chop.edu. Journal of Surgical Research 143, 35– 42 (2007) doi:10.1016/j.jss.2007.03.051 35 0022-4804/07 $32.00 © 2007 Elsevier Inc. All rights reserved.