In Vitro Skin Models for Pigmentary Disorders: From Reconstructed Tissues to Skin-on-a-Chip Platforms

Abstract

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 (NAMs), are discussed.