Developing Three-Dimensional (3D) Skin Models to Study the Interaction Between the Skin Microbiome and Immune Cells in Chronic Wounds

Developing three-dimensional (3D) skin models provides a physiologically relevant platform to investigate the dynamic interactions between the skin microbiome and immune cells in chronic wounds, offering insights into delayed healing, persistent inflammation, and microbial dysbiosis. Traditional in vitro models fail to replicate the complex architecture of human skin and its immune-microbiome crosstalk, motivating the development of biomimetic systems that incorporate stratified epidermal layers, dermal fibroblasts, and innate immune components such as macrophages and neutrophils. Engineered 3D skin constructs inoculated with wound-associated microbiota, including Staphylococcus aureus, Pseudomonas aeruginosa, and Cutibacterium acnes, can reveal how biofilm formation, quorum sensing, and microbial metabolites influence immune cell recruitment and cytokine secretion. Dysregulated immune responses within these models, characterized by excessive interleukin-1 beta, tumor necrosis factor alpha, and reactive oxygen species production, mirror aspects of the inflammatory milieu observed in nonhealing wounds and highlight candidate pathways for therapeutic intervention. The incorporation of patient-derived immune cells into 3D co-culture systems further enables personalized modeling of wound-healing deficiencies and antimicrobial-resistance patterns. Applications of 3D skin models extend to the development of antibiofilm agents, immune-modulating therapies, and microbiome-targeted interventions. It is important to emphasize that the current evidence base is predominantly preclinical and in vitro; accordingly, these platforms should be viewed as a promising foundation for advancing precision-medicine approaches to chronic wound management, contingent on rigorous cross-laboratory and clinical validation.