Developing a melanoma-skin-on-a-chip integrated with vasculature using an edgeless skin reconstruction approach

Melanoma is the most aggressive form of skin cancer, characterized by high metastatic potential and frequent resistance to targeted therapies. Traditional 2D cultures and animal models often fail to accurately mimic the complexity of the human tumor microenvironment (TME). To improve the recapitulation of the cellular and mechanical microenvironmental cues, we bioengineered a melanoma-skin-on-a-chip platform using an edgeless 3D skin reconstruction strategy, which allows for creating mechanically relevant skin microenvironments. The platform integrates a dermis compartment made of primary dermal fibroblasts, human umbilical vein endothelial cells (HUVECs), and melanoma spheroids (generated using MeWo and A375 cell lines), and an epidermis compartment made of differentiated layers of primary keratinocytes. Melanoma spheroids consist of a mixture of melanoma cells, fibroblasts and endothelial cells in collagen droplets, and when incorporated into the engineered dermis, form morphologically heterogeneous structures that mimicked in vivo tumor masses and late vertical progression phase of melanoma. The model successfully recapitulated key aspects of the tumor microenvironment, including increased peritumoral cancer-associated fibroblast (CAF) marker expression and extracellular matrix (ECM) remodeling. To evaluate the therapeutic relevance of the model, we evaluated the effects of MEK and BRF inhibitors on tumor cell proliferation and apoptosis. By day 7 post-tumor integration, vascular organization differed between melanoma backgrounds, with the MeWo construct showing 2.3-fold higher vessel area fraction and 3.65-fold higher vascular length density than the A375 construct, indicating enhanced vascular coverage and network density. This vascularized melanoma-skin-on-a-chip provides a human-relevant platform for studying melanoma invasion, response to therapeutics, and tumor-microenvironment dynamics. It holds strong potential for preclinical drug screening and offers a foundation for developing personalized therapeutic strategies.