Advances in in vitro modeling of skeletal muscle injury, dysfunction, and repair: From conventional cultures to functional microphysiological systems

Skeletal muscle injury involves complex interactions among inflammation, myogenic activation, extracellular matrix remodeling, and functional recovery. However, conventional models often fail to reproduce human injury responses and regenerative processes. Recent advances in biomaterials, biofabrication, and microphysiological systems have enabled more physiologically relevant in vitro muscle platforms. This review summarizes the evolution from two-dimensional cultures to engineered three-dimensional muscle tissues and microphysiological systems, highlighting how scaffold composition, tissue architecture, biophysical stimulation, and multicellular integration influence muscle maturation, injury responses, and repair. We distinguish injury from dysfunction, structural recovery from regeneration and functional recovery, and protective interventions from post-injury repair. We discuss current models of chemical, oxidative, mechanical, electrical, inflammatory, metabolic, and drug-induced muscle injury and dysfunction. A staged evaluation framework integrates structural, molecular, metabolic, and functional readouts across baseline characterization, injury or dysfunction assessment, and subsequent recovery. Finally, we present a decision matrix for aligning injury mechanisms with model design and functional assessment to improve reproducibility, interpretability, and translational relevance.