Trends in Amyotrophic Lateral Sclerosis Microphysiological Systems and the Challenges

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by the progressive degeneration of motor neurons and muscle atrophy. Despite extensive clinical research, effective treatments remain scarce due to the complexity of the disease's mechanisms and the inadequacy of current preclinical models. Recent advancements in microphysiological systems (MPS) present promising alternatives to traditional animal models for studying ALS pathogenesis and evaluating potential therapies. This review outlines the latest developments in ALS MPS, including co-culture membrane-based systems, microfluidic compartmentalization, microarray platforms, and modular assembly approaches. We also discuss key studies that replicate ALS-specific pathologies, such as TDP-43 aggregation, neuromuscular dysfunction, and alterations in astroglial mitochondria. Additionally, we identify significant challenges that need to be addressed for more physiologically relevant ALS modeling: replicating neural fluid flow, incorporating immune responses, reconstructing the extracellular matrix, and mimicking the pathological microenvironment. Finally, we emphasize the potential of ALS MPS as valuable tools for preclinical screening, mechanistic studies, and personalized medicine applications.