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Adipose-derived Stem Cell (adsc)-derived Exosomes And Collagen Constitute An Efficient Combination Therapy For Trauma Wound Healing
Alexa Rivera del Rio Hernandez, MD, Ethan Banks, Undergraduate, Naresh Mahajan, PhD, Jeffrey A. Gusenoff, MD, Francesco M. Egro, MBChB, MSc, MRCS, J. Peter Rubin, MD, Asim Ejaz, PhD.
University of Pittsburgh, Pittsburgh, PA, USA.
PURPOSE: Chronic wound healing remains a major clinical challenge with limited therapies. Collagen supports structural repair, while ADSC exosomes carry proteins, DNA and RNA molecules that regulate inflammation, angiogenesis, and tissue repair. Although these agents have been separately evaluated, a combination approach has not been tested. In this study we evaluated ADSC exosomes, collagen, and their combination in our novel full-thickness human skin perfusion trauma model using histology, immune profiling, and RNA sequencing, to identify molecular mechanisms and therapeutic potential.
METHODS: ADSC exosomes were isolated and characterized, then applied to standardized 0.8 mm full-thickness wounds in human skin. Treatment groups included collagen, exosomes, collagen plus exosomes, and untreated controls. Wound repair was assessed via histology, immunohistochemistry (Ki67, Vimentin, CD68/CD163), and next-generation RNA sequencing to identify transcriptional pathways driving regeneration, angiogenesis, and extracellular matrix remodeling.
RESULTS: Collagen preserved skin architecture, while exosomes promoted epidermal regeneration, fibroblast activation, and macrophage infiltration. Combination therapy produced the strongest effect: organized epidermal layers, high cellular migration, and enhanced immune recruitment. Macrophage profiling indicated an M1-skewed inflammatory-remodeling state. RNA sequencing confirmed activation of reparative and angiogenic genes (FOXF1, APLNR, MEG9) and proliferation/migration regulators (SOX2) versus control.
CONCLUSION: This study provides the first mechanistic demonstration in human skin that collagen and ADSC exosomes synergistically enhance wound healing. This first-of-its-kind platform bridges the translational gap, showcasing that collagen drives structural repair while exosomes amplify cellular and immune activation, together activating regenerative molecular pathways. These findings highlight exosome-collagen therapy as a powerful and translational strategy to accelerate wound healing.
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