Organ on a Chip: A Novel in vitro Biomimetic Strategy in Amyotrophic Lateral Sclerosis (ALS) Modeling

Abstract

Amyotrophic lateral sclerosis is a pernicious neurodegenerative disorder that is associated with the progressive degeneration of motor neurons, the disruption of impulse transmission from motor neurons to muscle cells, and the development of mobility impairments. Clinically, muscle paralysis can spread to other parts of the body. Hence it may have adverse effects on swallowing, speaking, and even breathing, which serves as major problems facing these patients. According to the available evidence, no definite treatment has been found for amyotrophic lateral sclerosis (ALS) that results in a significant outcome, although some pharmacological and non-pharmacological treatments are currently applied that are accompanied by some positive effects. In other words, available therapies are only used to relieve symptoms without any significant treatment effects that highlight the importance of seeking more novel therapies. Unfortunately, the process of discovering new drugs with high therapeutic potential for ALS treatment is fraught with challenges. The lack of a broad view of the disease process from early to late-stage and insufficiency of preclinical studies for providing validated results prior to conducting clinical trials are other reasons for the ALS drug discovery failure. However, increasing the combined application of different fields of regenerative medicine, especially tissue engineering and stem cell therapy can be considered as a step forward to develop more novel technologies. For instance, organ on a chip is one of these technologies that can provide a platform to promote a comprehensive understanding of neuromuscular junction biology and screen candidate drugs for ALS in combination with pluripotent stem cells (PSCs). The structure of this technology is based on the use of essential components such as iPSC- derived motor neurons and iPSC-derived skeletal muscle cells on a single miniaturized chip for ALS modeling. Accordingly, an organ on a chip not only can mimic ALS complexities but also can be considered as a more cost-effective and time-saving disease modeling platform in comparison with others. Hence, it can be concluded that lab on a chip can make a major contribution as a biomimetic micro-physiological system in the treatment of neurodegenerative disorders such as ALS.

Validation of Functional Connectivity of Engineered Neuromuscular Junction With Recombinant Monosynaptic Pseudotyped ΔG-Rabies Virus Tracing

“…Another study using a 3D microfluidic approach demonstrated that motor units using iPSC derived motor neurons from a patient with sporadic ALS produced weaker muscle cell contractions compared to healthy donor derived controls, and treatment with mTOR pathway inhibitors increased muscle contractile force and improved motor neuron survival in the ALS model ( Osaki et al, 2018 ). The potential incorporation of different cell types, such as various glial cells, can further improve the relevance of these models to the specific conditions of ALS or other diseases where the NMJ is selectively vulnerable ( de Jongh et al, 2021 ; Arjmand et al, 2022 ). Using an in-house developed microfluidic chip ( van de Wijdeven et al, 2018 , 2019 ), we have been able to reproducibly generate functional NMJs from human iPSC derived MNs and primary myotubes.…”

Advances in In Vitro Models of Neuromuscular Junction: Focusing on Organ‐on‐a‐Chip, Organoids, and Biohybrid Robotics

“…[55] The high-speed development of micro-manufacturing technology has promoted the emergence of second-generation compartment systems, termed microfluidic compartment systems. Microfluidic technology has the ability to accurately control, monitor, and manipulate the cell growth microenvironment and to easily add appropriate mechanical, biochemical, or electrical stimulation, [56] quickly becoming a tool to study NMJ models in vitro (Figure 4B). [57] The microfluidic compartment system combined with the 3D hiPSC culture technology can accurately reconstruct in vitro models of human NMJ.…”

“…[49,130] For example, specific and controllable responses can be achieved by adding peptides and growth factors, [131] whereas vascular endothelial growth factor and angiopoietin can be added to maintain endothelial growth and build vascular branching. [56] The main role of biochemical stimulation is to induce disease or drug validation after the establishment of an in vitro NMJ model.…”

Blood–Brain Barrier Breakdown in Neuroinflammation: Current In Vitro Models

“…In recent years, there has been a significant focus on using iPSCs to better understand the causes of ALS and to develop effective treatment approaches [ 317 ]. A recent review by Arjmand et al [ 318 ] provides an input about how an ALS organ-on-a-chip can be approached. Embryonic or neural stem cells or iPSCs can be derived from patient fibroblasts.…”