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.

Microphysiological systems (MPS) are advanced platforms that mimic the functions of human tissues and organs, aiding in drug development and disease modeling. Traditional MPS fabrication mainly depends on silicon-based microfabrication techniques, which are complex, time-consuming, and costly. In contrast, 3D printing technologies have emerged as a promising alternative, allowing for the rapid and precise creation of intricate three-dimensional structures, thereby opening new avenues for MPS research. This review examines the principles, characteristics, advantages, and limitations of key 3D printing techniques, including fused deposition modeling (FDM), stereolithography (SLA)/digital light processing (DLP), inkjet 3D printing, extrusion-based bioprinting, and laser-assisted bioprinting. Additionally, we discuss how these technologies are applied in MPS fabrication and their impact on MPS research, along with future prospects for advancements in the field.