Advancing preclinical research with reconstructed in vitro skin models mimicking non-healing wounds

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

Chronic skin wounds remain a significant therapeutic challenge worldwide, primarily due to persistent inflammation, impaired function of fibroblasts and keratinocytes, defective angiogenesis, and the presence of complex polymicrobial biofilms. Conventional animal models only partially capture these human-specific pathophysiological mechanisms, limiting their predictive value for pharmacological development. Recent advances in human 3D in vitro skin models, including reconstructed human epidermis, full-thickness skin equivalents, vascularized and innervated constructs, and chronic wound-derived cell systems, provide opportunities to evaluate therapeutic strategies under controlled, human-relevant conditions. Here, we critically synthesize how engineered skin platforms recreate key pathological hallmarks of non-healing wounds, including IL-1/TNF-α-driven inflammation, RAGE-NOX4-mediated oxidative stress, MMP/TIMP imbalance, fibroblast and keratinocyte senescence, impaired HIF-1α/VEGF-dependent angiogenesis, immune polarization defects, and biofilm-associated antimicrobial tolerance. We examine scaffold-based, decellularized, and bioprinted approaches that enable the incorporation of adipocytes, endothelial cells, sensory neurons, and immune compartments, enhancing the mechanistic resolution with which chronic wound biology can be interrogated. By integrating cellular, biochemical

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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