A mechanomimetic model of skin fibrosis

Abstract

Skin fibrosis results from excessive extracellular matrix (ECM) deposition and tissue remodeling due to persistent inflammation and mechanotransduction dysregulation. Current in vivo animal models lack human relevance, while conventional 2D and 3D in vitro models misrepresent physiological mechanical forces. To address this gap, we developed a miniaturized Edgeless-Skin Chip (ESC) platform with gravity-driven perfusion, enabling enhanced biomechanical mimicry for fibrosis modeling. ESCs present bioengineered skin grown around a 3D-printed scaffold, mimicking the continuous geometry of human skin and in vivo mechanical balance. Compared to conventional skin constructs (CSCs) that have open boundaries on all sides, ESCs exhibited higher sensitivity to TGF-β1, leading to increased ECM deposition, myofibroblast activation, YAP signaling upregulation, matrix stiffness and reduced permeability. Inhibiting YAP signaling with verteporfin (VTP) reduced collagen deposition, prevented tissue stiffening, and attenuated several fibrosis markers, confirming the role of mechanotransduction in fibrosis progression using human cells. Transcriptome analysis revealed upregulation of fibrosis-associated genes, including COL10A1, COL11A1, and ACTA2, counterbalanced by elevation of anti-fibrotic regulators such as DKK2, which suggests the activation of negative feedback mechanisms. These findings establish the ESC platform as a robust human-relevant mechanomimetic model for studying fibrosis and evaluating anti-fibrotic therapies, addressing a critical need for translational drug discovery.