An Engineered Anisotropic Skeletal Muscle Organoid‐on‐a‐Chip for Deciphering Muscle Response under Intermittent Hypoxia

作者：Jiao Li, Weihua Zhang, Anqi Liu, Yun Lu, Liming Yu, Xue Liu, Liangyan Sun, Bingjiao Zhao, Xianqin Tong, Tingjiao Liu, Yuehua Liu · 发表于：Advanced Functional Materials · 年份：2024 · DOI：10.1002/adfm.202401564 · 被引用次数：11 · 研究领域：Muscle Physiology and Disorders、Advanced Sensor and Energy Harvesting Materials、3D Printing in Biomedical Research

Abstract Generating highly organized skeletal muscle tissues that mimics the cellular alignment, maturation, and contraction of native skeletal muscle remains a challenge in disease modeling and regenerative therapies. Existing methodologies are constrained by complexity in fabrication and difficulty in achieving aligned 3D myofibers. Here, a functional skeletal muscle organoid‐on‐a‐chip (SMO) is engineered by establishing mechanical boundary constraints at either end of the cell‐laden extracellular matrix hydrogel within polydimethylsiloxane microstructures to promote the formation of an anisotropic biophysical microenvironment in tissues. The linearly aligned tissue, featuring multinucleated myofibers with distinct cross‐striations, exhibited a positive force‐frequency relationship and stable calcium transients under electrical stimulation. SMOs applicability is demonstrated by systematically evaluating muscle response to varying degrees of intermittent hypoxia. Murine‐ or human‐derived SMOs revealed that, with increasing hypoxia severity, muscles transitioned from a compensatory phase‐characterized by enhanced contractile function, vacuolation and hypertrophic‐like changes in myofibers, fiber type switching, and metabolic shift, to a decompensatory stage, paralleling in vivo muscle responses and highlighting interspecies differences. Human‐derived SMOs are also utilized to assess self‐repair capabilities and pharmaceuticals protective effects on damaged muscle. Together, t...