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Comparison of Delivery Methods of Adipose-Derived Stem Cells Reveal Differential Survival and Wound Healing Outcomes
Michael S. Hu, MD, MPH, MS, Wan Xing Hong, MS, Mika Esquivel, N/A, Robert C. Rennert, BA, Michael T. Chung, BS, Andrew S. Zimmermann, BS, Jayakumar Rajadas, PhD, Dominik Duscher, MD, Adrian McArdle, MB, BCh, BAO(NUI), MRCSI, Graham G. Walmsley, AB, Geoffrey C. Gurtner, MD, Michael T. Longaker, MD, MBA, H. Peter Lorenz, MD.
Stanford University, Stanford, CA, USA.
PURPOSE:Cutaneous defects resulting from burns, trauma, or surgical procedures present a continuing challenge to the field of reconstructive surgery. The onset of stem cell-based therapies, however, promises to promote enhanced wound healing and optimize outcomes. In particular, the application of autologous adult stem cells has emerged as a promising approach, and allows for the utilization of nonimmunogenic cells for the treatment of many soft tissue disorders. In the past decade adipose-derived stem cells (ASCs), adult multipotent stem cells found in the stroma of adipose tissues, have been identified as an attractive donor cell source. Not only can ASCs be harvested through minimally invasive procedures such as liposuction, they are also an abundant stem cell population, and have the potential for stimulating neovascularization after transplantation into ischemic tissues, further enhancing wound healing.
However, in the clinical setting, the route of administration of ASCs plays a critical role in determining how efficient the treatment ultimately is. Optimizing administration is a crucial factor in prolonging the survival and functionality of the delivered therapeutic cells. Thus, the goal of our study is to compare several methods for administration of ASCs to excisional wounds in order to determine the delivery method through which the maximal therapeutic efficacy of ASCs, as determined by wound healing rates and resulting scar size, might be attained.
METHODS:Two 6mm full thickness excisional wounds were created on the dorsum of each wild-type (WT) FVB mouse. ASCs harvested from the inguinal fat pads of transgenic FVB-L2G mice were applied to each wound via different cell delivery methods. In all, four different methods for delivering ASCs were studied: cell suspension in PBS injected under the wound, ASCs in matrigel injected under the wound, ASCs in matrigel placed over the wound, and ASCs in bioengineered pullulan-collagen composite dermal hydrogel placed over the wound. Wounds with no therapeutic cells were used as control. As the ASCs from the L2G transgenic mice luminesce when interacting with injected luciferin, this enabled the quantification of ASCs in vivo through bioluminescent imaging (BLI). The effectiveness of the treatments was recorded over a period of two weeks using three parameters: the survival of ASCs in vivo using BLI, quantification of the rate of wound healing and comparison of scar formation.
RESULTS:Cutaneous wounds treated with ASCs delivered with hydrogel displayed the highest therapeutic cell survival on day 5 as well as the fastest wound healing. Wounds treated with ASCs delivered with hydrogel scaffold achieved full closure on day 11.4 versus day 14 for no treatment (*p<0.001). This was significantly earlier than excisional wounds treated with all other delivery methods, which fully closed on day 12.9 (*p<0.004).
CONCLUSION:We conclude that ASC delivery into wounds via hydrogel scaffolds is the superior method based upon cell survival, wound healing and scar formation. As the precise mechanisms by which hydrogel acts to preserve cell function remains undefined, future studies will be geared towards improving understanding of the characteristics of this technique for stem cell delivery.
Acknowledgment: Support was provided by the Sarnoff Foundation and CIRM.
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