Abstract
ABSTRACTOrgans-on-chips are broadly defined as microfabricated surfaces or devices designed to engineer cells into microscale tissues with native-like features and then extract physiologically relevant readouts at scale. Because they are generally compatible with patient-derived cells, these technologies can address many of the human relevance limitations of animal models. As a result, organs-on-chips have emerged as a promising new paradigm for patient-specific disease modeling and drug development. Because neuromuscular diseases span a broad range of rare conditions with diverse etiology and complex pathophysiology, they have been especially challenging to model in animals and thus are well suited for organ-on-chip approaches. In this Review, we first briefly summarize the challenges in neuromuscular disease modeling with animal models. Next, we describe a variety of existing organ-on-chip approaches for neuromuscular tissues, including a survey of cell sources for both muscle and nerve, and two- and three-dimensional neuromuscular tissue-engineering techniques. Although researchers have made tremendous advances in modeling neuromuscular diseases on a chip, the remaining challenges in cell sourcing, cell maturity, tissue assembly and readout capabilities limit their integration into the drug development pipeline today. However, as the field advances, models of healthy and diseased neuromuscular tissues on a chip, coupled with animal models, have vast potential as complementary tools for modeling multiple aspects of neuromuscular diseases and identifying new therapeutic strategies.
Highlights
Neuromuscular diseases collectively affect 160 per 100,000 people worldwide and are generally characterized by progressive motor impairment and muscular atrophy (Deenen et al, 2015)
We describe the cell sources for neuromuscular disease models, which can be integrated into the two- (2D) and three-dimensional (3D) engineered tissue platforms described
Primary myoblasts can only be passaged a few times before their growth rate and myogenic capacity decline, leading to limited supply and passage-dependent variability. These supply and variability issues are especially problematic for human primary myoblasts, which are generally isolated from relatively small muscle biopsies
Summary
Neuromuscular diseases collectively affect 160 per 100,000 people worldwide and are generally characterized by progressive motor impairment and muscular atrophy (Deenen et al, 2015). Disease phenotypes in animals can vary widely from humans in terms of progression, severity and other characteristics (De Giorgio et al, 2019; Aartsma-Rus and van Putten, 2020; Babin et al, 2014) Another limitation of animal models is that it is difficult, if not impossible, to recapitulate the genotypic heterogeneity and allelic variation observed in individuals with neuromuscular diseases without generating an unreasonable number of animal strains (Juneja et al, 2019; Morrice et al, 2018). The muscle fiber propagates this action potential along its length, triggering the entry of extracellular calcium through voltage-sensitive ion channels in the membrane and subsequently a large release of calcium from the sarcoplasmic reticulum. Amyotrophic lateral sclerosis (ALS) is another neuromuscular disease that introduces unique challenges for modeling in animals
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