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Updated: Mar 31, 2026
Generation of a Three-dimensional Full Thickness Skin Equivalent and Automated Wounding
Published on: February 26, 2015
Advancing preclinical research with reconstructed in vitro skin models mimicking non-healing wounds
Regina Gomes Daré1,2, Luciana B Lopes1, Alke Petri-Fink2,3
1Institute of Biomedical Sciences, University of São Paulo, 1524 Professor Lineu Prestes Avenue, 05508-000 São Paulo, Brazil.
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.
Insights
Advanced 3D human skin models offer a better way to study chronic wounds and test new drugs. These engineered models mimic human disease, improving therapeutic development for non-healing skin conditions.
Area of Science:
- Biomedical Engineering
- Wound Healing Research
- Pharmacology
Background:
- Chronic skin wounds present significant challenges due to inflammation, impaired cell function, poor blood vessel formation, and biofilms.
- Existing animal models have limitations in replicating human-specific chronic wound pathophysiology, hindering drug development.
- 3D in vitro human skin models are emerging as powerful tools to overcome these limitations.
Purpose of the Study:
- To critically review how engineered human 3D skin platforms model key pathological features of chronic wounds.
- To examine how these advanced models can be used for mechanism-based drug discovery and preclinical screening.
- To provide guidelines for selecting and designing human skin models for therapeutic development.
Main Methods:
- Synthesis of literature on engineered human 3D skin models (reconstructed epidermis, full-thickness equivalents, vascularized/innervated constructs, chronic wound cells).
- Analysis of how these platforms recreate hallmarks like inflammation (IL-1/TNF-α), oxidative stress (RAGE-NOX4), senescence, impaired angiogenesis (HIF-1α/VEGF), and biofilm tolerance.
- Examination of scaffold-based, decellularized, and bioprinted approaches incorporating diverse cell types (adipocytes, endothelial cells, neurons, immune cells).
Main Results:
- Engineered skin platforms successfully recapitulate critical chronic wound pathologies, including inflammation, oxidative stress, senescence, and angiogenesis defects.
- Advanced models integrate cellular, biochemical, immune, vascular, and microbial components for mechanistic interrogation.
- These platforms enable pharmacological screening of numerous targets relevant to chronic wound healing.
Conclusions:
- Next-generation 3D human skin models bridge the gap between basic assays and clinical complexity for chronic wounds.
- These platforms provide a rational framework for mechanism-based drug discovery and preclinical evaluation of therapeutics.
- Utilizing advanced human skin models can accelerate the development of effective treatments for non-healing wounds.
