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.

Bioengineered skeletal muscle constructs that replicate the architectural, metabolic, and contractile characteristics of native tissue are becoming essential platforms for disease modeling and advancing regenerative medicine. The creation of these constructs relies heavily on cell-mediated gel compaction, a crucial process for facilitating tissue maturation. To ensure myotube alignment, muscle cell-laden hydrogels are typically embedded in 3D-printed molds with anchor structures. However, structural detachment or rupture often occurs during culture, which undermines the stability and functional differentiation of the engineered tissue. To address these challenges, we developed an improved anchor-type mold through a series of structural optimizations. We first compared two anchor geometries—linear and mushroom-shaped pillars—within rectangular frames, finding that the mushroom-shaped design provided better structural retention. However, the rectangular frames led to excessive gel compaction, causing detachment and disrupting cellular alignment, especially in central regions. To alleviate these issues, we introduced a dumbbell-shaped mold with a narrowed midsection to better distribute mechanical stress. This new mold effectively promoted aligned myotube formation, long-term construct maintenance, and functional maturation. Our findings underscore the benefits of structurally optimized molds in creating stable engineered muscle, with significant implications for regenerative therapies and preclinical testing platforms.