In vitro skin models for pigmentary disorders: from reconstructed tissues to skin-on-a-chip platforms

Cutaneous pigmentary disorders, including vitiligo, melasma, post-inflammatory hyperpigmentation (PIH) and solar/senile lentigines (SL), are prevalent, chronic and recurrent conditions driven by interactions among melanocytes, keratinocytes, fibroblasts, immune cells, the extracellular matrix (ECM) and environmental stimuli. Conventional animal models and two-dimensional cultures incompletely reproduce the cellular heterogeneity, tissue architecture and the dynamic microenvironment that regulates human pigmentation. To address these challenges, this review evaluates human-relevant in vitro models through a framework integrating biomaterial engineering, disease-specific modeling and translational evaluation, based on principles of tissue engineering, pathological reconstruction and predictive assessment. We compare ex vivo explants, co-cultures, three-dimensional skin equivalents, bioprinted constructs, organoids and skin-on-a-chip platforms in terms of cell sources, engineered matrices, structural fidelity, functional readouts, disease specificity, reproducibility and suitability for mechanistic studies and therapeutic evaluation. We further distinguish pigmentation-capable systems from models that recapitulate disease-specific pathological processes, including immune-mediated melanocyte loss in vitiligo, chronic dermal-epidermal signaling alterations in melasma, inflammation-associated pigmentation in PIH and senescence-related microenvironmental remodeling in SL. Current bottlenecks, including vascular and immune integration, long-term stability, quantitative monitoring, reproducibility, standardization and regulatory acceptance within the framework of New Approach Methodologies, are discussed.