Abstract
Neurological disorders are the leading cause of disability and the second largest cause of death worldwide. Despite significant research efforts, neurology remains one of the most failure-prone areas of drug development. The complexity of the human brain, boundaries to examining the brain directly in vivo, and the significant evolutionary gap between animal models and humans, all serve to hamper translational success. Recent advances in microfluidic in vitro models have provided new opportunities to study human cells with enhanced physiological relevance. The ability to precisely micro-engineer cell-scale architecture, tailoring form and function, has allowed for detailed dissection of cell biology using microphysiological systems (MPS) of varying complexities from single cell systems to “Organ-on-chip” models. Simplified neuronal networks have allowed for unique insights into neuronal transport and neurogenesis, while more complex 3D heterotypic cellular models such as neurovascular unit mimetics and “Organ-on-chip” systems have enabled new understanding of metabolic coupling and blood–brain barrier transport. These systems are now being developed beyond MPS toward disease specific micro-pathophysiological systems, moving from “Organ-on-chip” to “Disease-on-chip.” This review gives an outline of current state of the art in microfluidic technologies for neurological disease research, discussing the challenges and limitations while highlighting the benefits and potential of integrating technologies. We provide examples of where such toolsets have enabled novel insights and how these technologies may empower future investigation into neurological diseases.
| Original language | English |
|---|---|
| Pages (from-to) | 1276-1307 |
| Number of pages | 32 |
| Journal | Journal of Neuroscience Research |
| Volume | 99 |
| Issue number | 5 |
| Early online date | 13 Feb 2021 |
| DOIs | |
| Publication status | Published - 31 May 2021 |
Funding
We gratefully acknowledge support from the UK Organ‐on‐a‐Chip Technologies Network ( www.organonachip.org.uk/ ), which is funded by UKRI via the Technologies Touching Life Scheme (Grant reference MR/R02569X/1). As members of the Organ‐on‐a‐Chip Technologies Network from diverse fields in both academic and industrial sectors, the authors of this review were brought together in an initiative to surmise the key development, challenges, and unmet needs within the field. MPS are currently providing new insights into physiological and pathophysiological phenomena in the context of a specific functional unit of an organ or tissue, yet they fall short in modeling systemic responses and multi‐organ interactions which typically necessitate the use of animal models, such as in the study of the gut brain axis, brain cancer metastasis, and neuro‐immune networks. There have been a number of efforts to link multiple MPS to mimic key organ–organ reciprocal actions and more ambitiously in “Body on Chip” projects, such as the $37 million Defense Advanced Research Projects Agency (DARPA) backed “Body on chip” project at the Wyss Institute for Biologically Inspired Engineering to integrate 10 human organ‐on‐chips. The MINERVA (MIcrobiota‐Gut‐BraiN EngineeRed platform to eVAluate intestinal microflora impact on brain functionality) project, funded by the European Research Council represents a specifically brain focused attempt to connect multiple microfluidic cultures (microbiota, gut epithelial barrier, immune cells, BBB, and brain) aiming to study the impact of intestinal microflora on neurodegeneration (Raimondi et al., 2019 ). A discussion of such programs is beyond the scope of this review, but Sung et al. provide a detailed analysis of how such ambitious large‐scale projects may in future prove useful in delineating the contribution of organ–organ cross‐talk in health and disease (Sung et al., 2019 ). While linking multiple MPS comes with a unique set of challenges along with significantly increased complexity and expense, specific interactions between defined functional units are already being used to provide physiologically relevant insights, such as BBB‐brain metabolic coupling (Maoz et al., 2018 ) and brain metastasis (Yi et al., 2019 ).
Keywords
- Alzheimer's
- CNS
- MPS
- organ-on-chip
- Parkinson's
- stroke