Abstract
Nanofabrication can help us to emulate natural intelligence. Forward-engineering brain gained enormous momentum but still falls short in human neurodegenerative disease modeling. Here, organ-on-chip (OoC) implementation of tissue culture concepts in microfluidic formats already progressed with the identification of our knowledge gap in toxicology and drug metabolism studies. We believe that the self-organization of stem cells and chip technology is a key to advance such complex in vitro tissue models, including models of the human nervous system as envisaged in this review. However, current cultured networks of neurons show limited resemblance with the biological functions in the real nervous system or brain tissues. To take full advantage of scaling in the engineering domain of electron-, ion-, and photon beam technology and nanofabrication methods, more research is needed to meet the requirements of this specific field of chip technology applications. So far, surface topographies, microfluidics, and sensor and actuator integration concepts have all contributed to the patterning and control of neural network formation processes in vitro. However, when probing the state of the art for this type of miniaturized three-dimensional tissue models in PubMed, it was realized that there is very little systematic cross-disciplinary research with biomaterials originally formed for tissue engineering purposes translated to on-chip solutions for in vitro modeling. Therefore, this review contributes to the formulation of a sound design concept based on the understanding of the existing knowledge and the technical challenges toward finding better treatments and potential cures for devastating neurodegenerative diseases, like Parkinson's disease. Subsequently, an integration strategy based on a modular approach is proposed for nervous system-on-chip (NoC) models that can yield efficient and informative optical and electronic NoC readouts in validating and optimizing these conceptual choices in the innovative process of a fast growing and exciting new OoC industry.
Highlights
After more than 100 years of neural cultures[1] and the emergence of organ-on-chip (OoC) technology around 2010 pioneered by Huh et al.[2] in their lung-on-chip paper, technical developments in nano- and microfabrication methods exploiting manipulations that utilize electron, ion, and photon-beam material interactions can be applied to unravel the workings of the human brain
To thechemical nature relevant to all OoCs, for nervous system-on-chip (NoC) cultures, the visualization of the spatiotemporal morphological changes of single neurons are important markers of a healthy versus a disease state of a network, too, due to the extensive connectivity across central or peripheral nervous system components avs.scitation.org/journal/jvb and tissues of other organs of the human body, which at least rudimentarily need to be mimicked in a physiological relevant NoC to reveal meaningful signatures for a range of biomarkers to be registered in such a system
What else needs a microphysiological integrated system to enable models for the human nervous systems? we do not know the actual input-output functions yet since stem-cell-derived neural networks are still in their infancy for instructive microenvironments; one would like to implement simple geometric features in these wet tissue models to guide the process of data avs.scitation.org/journal/jvb collection for high- or at least medium throughput screening under controlled culture conditions, of which we summarize additional challenges in Sec
Summary
After more than 100 years of neural cultures[1] and the emergence of organ-on-chip (OoC) technology around 2010 pioneered by Huh et al.[2] in their lung-on-chip paper, technical developments in nano- and microfabrication methods exploiting manipulations that utilize electron-, ion-, and photon-beam material interactions can be applied to unravel the workings of the human brain. Beyond short-term cell-on-chip experiments utilizing, e.g., circulating cells in solution and integrated impedance sensors, disease modeling of the nervous system must include long-term culture formats including static and dynamic stimulating input functions to yield mature and complex microtissue assemblies in gaining functional resemblance to the human nervous system in vivo.[14] To this end in 2019, Black et al.[15] discussed these various engineering efforts as an emerging neurotechnology by defining novel models for a pharmaceutical approach in treating complex diseases such as pain disorders and concluded that there are great perspectives but still many challenges to solve before value can be created Henceforward, in this introduction (Sec. I), NoC technology is addressed by three additional sections: strategies in nanofabricating neural networks (Sec. II), advances in Parkinson’s disease (PD) modeling (Sec. III), and remaining challenges in this field of research (Sec. IV). V D) an overall conclusion to complete our outlook on further NoC technology research
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