H. HE1,2, T. Foster1, R. Assi1, K. Stamati3, H. Bai1, Y. Huang4, F. Hyder4, D. Rothman4, C. SHU5, S. Homer-Vanniasinkam3, U. Cheema3, A. Dardik1,6, A. Dardik1,6 1Yale University School Of Medicine,Vascular Biology And Therapeutics Program And The Department Of Surgery,New Haven, CT, USA 2The Third Xiangya Hospital Of Central South University,Department Of Vascular Surgery,changsha, HUNAN, China 3University College London,Division Of Surgery And Interventional Science,London, LONDON, United Kingdom 4Yale University,Departments Of Diagnostic Radiology And Biomedical Engineering,NEWHAVEN, CONNECTICUT, USA 5The Second Xiangya Hospital Of Central South University,Department Of Vascular Surgery,Changsha, HUNAN, China 6VA Connecticut Healthcare System,Department Of Surgery,West Haven, CT, USA
Introduction: Lower extremity wounds remain an important complication in patients with diabetes. Mesenchymal stem cells (MSC) are known to enhance wound healing. We hypothesize that delivery of MSC in a biomimetic collagen scaffold improves wound healing in a diabetic mouse model.
Methods: Bone marrow derived MSC were suspended in high density type I collagen scaffold sheets and rolled into a spiral configuration. Real-time oxygen measurements confirmed cells in the core having restricted oxygen exposure. These scaffolds were implanted adjacent to lower extremity wounds in diabetic C57BL/6 mice; a splinted excisional back wound model was used to test wound healing without contraction. Daily rates of wound healing were measured and immunohistochemical analysis was performed to identify changes in cell composition and growth factor expression. Nanoparticle labeling of MSC was used to monitor cell retention within the scaffold.
Results:The scaffold core was confirmed to be hypoxic with a resultant increase in VEGF release. Diabetic mice with leg wounds showed significantly increased wound healing with the scaffold compared to controls (64% closure vs. 49% with MSC alone vs. 37% with acellular scaffold; day 1; p=0.004). Diabetic mice with splinted back wounds also showed enhanced wound healing compared to controls (36% MSC scaffold vs. 31% acellular scaffold; day 4; p≤0.0001). Examination of cells surrounding the scaffolds showed increased proliferation without increased apoptosis, increased VEGF expression and capillary density, and increased numbers of macrophages, fibroblasts, and smooth muscle cells in mice treated with MSC containing scaffolds. Wound healing was further enhanced with the addition of laminin to the collagen scaffold.
Conclusion:MSC within a biomimetic collagen scaffold enhance wound healing in a translationally relevant diabetic mouse model. Tissue engineering approaches can create niche-like environments that promote stem cell survival and function, increasing their potential applications for therapeutic use.