An Allogenic 3d Scaffold-free Tissue Engineered Product For Deep Thickness Skin Regeneration: In Vitro Development To In Vivo Proof Of Concept
Denis Dufrane1, Gaetan Thirion1, Sophie Vériter1, Valérie Lebrun1, Pierre-Yves Adnet1, Ali MODARRESSI2.
1Novadip Biosciences, Mont Saint Guibert, Belgium, 2Plastic, Reconstructive&Aesthetic Surgery department, University hospitals, Geneva, Switzerland.
Deep thickness skin wound remains a major challenge for reconstructive surgery. A novel approach of tissue engineering, based on an allogeneic adipose-derived 3D scaffold-free technology, was proposed.Adipose-derived stromal cells (ASCs) were isolated from human adipose tissue to constitute the 3D-graft (n=9). The ultrastructure was assessed by microtomography/SEM. The protein content was determined by proteomic/ELISA. The in vivo biocompatibility was assessed in nude and Wistar rats up to 4 weeks (n=20) as well as the safety in terms of tumorigenicity/toxicity/biodistribution (following GLP). The efficacy was then evaluated in a model of ischemic (vs. non-ischemic) wound in hyperglycemic Wistar rats (n=42).The 3D-graft is a translucid and malleable membrane to be easily handled and sutured in the wound bed. A mean of 175±86 cells/mm² was found to be embed in the extracellular matrix with a low level of mineralization (0.30±0.31%v/v). The expression of the biological pathways involved in early wound healing and the VEGF/SDF1a contents (181±12 and 663±27 ng/g, respectively) were over-expressed in the graft. The biocompatibility and the safety of the 3D-graft were confirmed at 4 and up to 24 weeks post-implantation, respectively. The 3D-graft was easily applied (by a simple bandage) on the ischemic/hyperglycemic wounds (on the leg) and promoted an earlier wound closure (27 vs. 34 days for sham, respectively) associated with dermis/epidermis reconstruction, transient aSMA positive staining and lymphocytes/macrophages recruitment after 10-15 days.In conclusion, the scaffold-free approach with allogenic 3D-graft (derived from ASCs) demonstrated the safety and efficacy in stringent model of hyperglycemic and ischemic deep-thickness wound.
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