Advances in Nerve Injury Models on a Chip

Abstract

Regeneration and functional recovery of the damaged nerve are challenging due to the need for effective therapeutic drugs, biomaterials, and approaches. The poor outcome of the treatment of nerve injury stems from the incomplete understanding of axonal biology and interactions between neurons and the surrounding environment, such as glial cells and extracellular matrix. Microfluidic devices, in combination with various injury techniques, have been applied to test biological hypotheses in nerve injury and nerve regeneration. The microfluidic devices provide multiple advantages over the in vitro cell culture on a petri dish and in vivo animal models because a specific part of the neuronal environment can be manipulated using physical and chemical interventions. In addition, single‐cell behavior and interactions between neurons and glial cells can be visualized and quantified on microfluidic platforms. In this article, current in vitro nerve injury models on a chip that mimics in vivo axonal injuries and the regeneration process of axons are summarized. The microfluidic‐based nerve injury models could enhance the understanding of the physiological and pathophysiological mechanisms of nerve tissues and simultaneously serve as powerful drug and biomaterial screening platforms.

A new microfluidic model to study dendritic remodeling and mitochondrial dynamics during axonal regeneration of adult zebrafish retinal neurons

“…While current microfluidic models cannot yet fully replicate the complexity of neuronal networks, they provide a simplified recapitulation of in vivo microenvironments, as they enable physical and fluidic separation of dendrites and somata from axons. Moreover, due to this fluidic isolation, they allow to precisely monitor and manipulate individual neuronal compartments, which is crucial within our objective to study intraneuronal reallocation of mitochondria in individual RGCs ( Harink et al, 2013 ; Kim et al, 2014 ; Dai et al, 2022 ; Lee et al, 2023 ). As MFDs require only small amounts of medium or cells, reducing not only the cost, but also the number of animals needed to answer specific research questions, microfluidics is becoming an increasingly popular research tool to complement existing in vivo and in vitro models ( Lee et al, 2023 ).…”

“…Moreover, due to this fluidic isolation, they allow to precisely monitor and manipulate individual neuronal compartments, which is crucial within our objective to study intraneuronal reallocation of mitochondria in individual RGCs ( Harink et al, 2013 ; Kim et al, 2014 ; Dai et al, 2022 ; Lee et al, 2023 ). As MFDs require only small amounts of medium or cells, reducing not only the cost, but also the number of animals needed to answer specific research questions, microfluidics is becoming an increasingly popular research tool to complement existing in vivo and in vitro models ( Lee et al, 2023 ). Here, we used open compartment MFDs (SOC450) that allow the creation of a densely seeded neuronal network in the SDC, which sustains fast, spontaneous axonal outgrowth of adult zebrafish RGC axons into the AC after only 3 days in culture (DIV 3).…”

“…Nevertheless, numerous papers confirmed the successful spatial isolation of axons from dendrites using MFDs. Firstly, the 450 μm barrier length allows axons from neurons seeded in the SDC to enter the AC, whereas dendrites, which grow significantly slower and shorter than axons, normally do not extend more than 400 μm ( Taylor et al, 2005 ; Taylor and Jeon, 2010 ; Cartoni et al, 2017 ; Lee et al, 2023 ). Moreover, as axons preferably grow toward higher concentrations of Laminin, the use of a Laminin concentration gradient from the AC to the SDC successfully targets axonal outgrowth toward the AC ( Dertinger et al, 2002 ; Virlogeux et al, 2018 ).…”

“…Although we cannot truly confirm the dendritic specification of neurites in our culture, we are confident that we identified axons in the AC, due to the combination of 450 μm microgrooves and the applied Laminin concentration gradient, (as discussed below) (Dertinger et al, 2002;Taylor et al, 2005Cartoni et al, 2017;Virlogeux et al, 2018;Lee et al, 2023). Furthermore, mixed gap43/ WT retinal cultures reveal completely isolated RGCs with a defined RGC-like architecture of one long axon-like neurite (the presumable axon) and multiple shorter dendrite-like processes (presumable dendrites) (Supplementary Figure S5C).…”

TPP-Based Microfluidic Chip Design and Fabrication Method for Optimized Nerve Cells Directed Growth

“…Cell growth regulation is one of the most promising methods in biomedical research such as tissue engineering [ 1 ], cancer research [ 2 ], and neuroscience [ 3 ]. As a typical cell growth regulation method, the directional growth of nerve cells has special significance for neurological medical research, especially for mechanism [ 4 ], intervention strategies [ 5 ], and drug testing [ 6 ] research of central nervous system (CNS) diseases (such as Alzheimer's disease, Huntington’s disease, and Parkinson’s disease). The structure and function of the CNS are affected by the precision and accuracy of nerve cell connections, which may lead to dysfunction [ 7 , 8 ].…”