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

## TL;DR

This paper reviews how 3D human skin models can better mimic chronic wounds and improve drug testing compared to animal models.

## Contribution

The paper provides a comprehensive review of advanced human skin models for chronic wound research and drug discovery.

## Key findings

- 3D skin models replicate key chronic wound features like inflammation and impaired angiogenesis.
- Human-relevant models outperform animal models in preclinical screening for wound therapeutics.
- Next-generation models integrate immune, vascular, and microbial components for better mechanistic insights.

## Abstract

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, immune, vascular, and microbial components, next-generation models allow pharmacological interrogation of targets such as IL-1/IL-1R, IL-6/STAT3, TNF-α/TNFR, RAGE–NOX4, Nrf2/KEAP1, ERK/AKT, Ang/Tie2, ferroptosis regulators, senescence pathways, and neuroimmune modulators. Collectively, these platforms bridge the gap between reductionist assays and clinical complexity, offering a rational framework for mechanism-based drug discovery and preclinical screening. This review provides guidelines for selecting and designing advanced human skin models to accelerate the development of effective therapeutics for chronic non-healing wounds.

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•Human 3D skin models reproduce the chronic wound microenvironment beyond acute injury.•Advanced skin equivalents enable mechanism-based screening of wound therapeutics.•Human-relevant models improve preclinical screening beyond conventional animal assays.•Model complexity can be tailored to specific drug development questions.•Ideal multicellular platforms integrate immune, vascular, neural and microbial components.

Human 3D skin models reproduce the chronic wound microenvironment beyond acute injury.

Advanced skin equivalents enable mechanism-based screening of wound therapeutics.

Human-relevant models improve preclinical screening beyond conventional animal assays.

Model complexity can be tailored to specific drug development questions.

Ideal multicellular platforms integrate immune, vascular, neural and microbial components.