Single‐Cell Resolution Mapping of Osteoarthritis‐Associated Chondrocyte Dynamics Using a High‐Density CMOS MEA Platform

ABSTRACT Fibrosis is a major cause of chronic tissue dysfunction and contributes substantially to morbidity and mortality worldwide. Osteoarthritis (OA), affecting over 590 million people, is a prevalent fibrotic joint disease for which disease‐modifying therapies remain lacking, partly because disease progression remains incompletely understood. As human‐relevant in vitro models, including organ‐on‐chip and microphysiological systems, become increasingly important, non‐invasive technologies capable of continuous cellular monitoring are urgently needed. Here, we implement high‐density complementary metal‐oxide‐semiconductor (CMOS) multielectrode array (MEA)‐based impedance profiling as a label‐free platform for longitudinal assessment of OA‐relevant chondrocyte remodeling. Human primary chondrocytes cultured on CMOS‐MEA chips exhibited impedance increases that correlated with electrode occupancy and extracellular matrix (ECM) deposition. Spatial impedance mapping enabled visualization of injury‐response dynamics, while oxidative stress induced progressive impedance decline accompanied by apoptosis, morphological remodeling, and chondrocyte dedifferentiation, evidenced by reduced collagen II and SOX9 expression and increased collagen I expression. In contrast, osteogenic de‐differentiation produced increased impedance associated with ECM remodeling and matrix mineralization. Together, these findings support high‐density CMOS‐MEA impedance profiling as a non‐invasive approach for monitoring cellular remodeling and provide a foundation for future integration of spatially resolved impedance sensing into advanced microphysiological systems for OA and other fibrotic diseases.