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bioRxiv · 10.1101/2022.03.09.483580

Efficacy and safety of a patch containing adipose-derived stem cells for skin wound healing. Results form a comprehensive pre-clinical evaluation program

Brembilla, N.·Modarressi, A.·Andre Levigne, D.·Brioudes, E.·Lanza, F.·Vuagnat, H.·Durual, S.·Marger, L.·Boehncke, W.-H.·Krause, K.-H.·Preynat-Seauve, O.
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Abstract

Mesenchymal stem cell-based therapies are emerging as innovative approaches to treat chronic wounds. A common administration route used in clinical trials consists of local injections leading to uncontrolled/sub-optimal delivery. This study reports a comprehensive pre-clinical evaluation program on the mechanism of action, efficacy and safety of an easy-to-use patch that concentrates Adipose-derived Stem Cells (ASCs) in a clinical-grade sponge of porcine crosslinked-gelatin. ASCs were prepared from the fat of ischemic patients. Transcriptome and proteome of ASC-patches and ASC monolayers were assessed by microarrays, bio-arrays and mass spectrometry. Tumorigenesis was investigated in immunosuppressed mice according to the European Pharmacopeia. Angiogenesis was assessed in vivo in the chick chorioallantoic membrane model. Efficacy of the ASC-patch was tested in a rat model of ischemic full-thickness skin defect. Cell stability was assessed by luminescence using ASC-patches generated from ASCs stably transduced with firefly luciferase. ASCs from ischemic patients upregulated the transcription of multiple genes involved in skin wound healing when cultured within the ASC-patch formulation. The patch was not only a concentrator, but also a reservoir of both ASC-derived regenerative factors and sponge-derived soluble fragments having healing capacity. The secretome of the ASC-patch promoted dermal fibroblast survival and epidermal epithelialization. No tumor formation was observed in immunodeficient Nude mice subcutaneously transplanted with the ASC-patch. Transplanted patches were early invaded by new vessels in vivo, and a marked angiogenesis was confirmed in two independent animal models. Finally, ASC-patches prepared from syngeneic rats promoted faster healing and re-vascularization of full-thickness skin defects in a rat animal model. Of note, ASCs were viable and locally stable for at least two weeks in vivo. We provide here compelling pre-clinical evidence that patches concentrating ASCs within crosslinked gelatin may represent a convenient and effective tool for the management of chronic wounds.

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Brembilla, N., Modarressi, A., Andre Levigne, D., Brioudes, E., Lanza, F., Vuagnat, H., Durual, S., Marger, L., Boehncke, W.-H., Krause, K.-H., Preynat-Seauve, O.. 2022-03-11. Efficacy and safety of a patch containing adipose-derived stem cells for skin wound healing. Results form a comprehensive pre-clinical evaluation program. https://doi.org/10.1101/2022.03.09.483580

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