Solyman Hatami

Introduction: Alzheimer’s disease (AD), the leading cause of dementia worldwide, is an irreversible neurodegenerative disease characterized by memory loss and executive dysfunction.¹  It is characterized by intracellular neurofibrillary tangles and extracellular amyloid beta (Aβ) plaques through improper cleavage of amyloid precursor protein by β-secretases. Aβ aggregation is known to cause neuronal cell death through oxidative stress, diminished metabolism, and local inflammation.²  Exact etiology and triggers are unknown. Existing solutions are limited to symptom targeting medications, thus lacking in disease modifying therapies. The drug development pipeline is extremely costly and time consuming, with a need to move away from animal tests and better understand pathogenesis.³  Organ-on-a-chip is an upcoming technology with significant potential to address these concerns. Methods: The premise of the technology is brain-on-a-chip, a microfluidics chip seeded with cells with potential for functional and structural modifications to suit the experiment. Basic technique involves creating a master mold using photolithography with photoresist layers on a silicon wafer. The polydimethylsiloxane (PDMS) prepolymer mix is poured into the master and thermally cured. Device variations discussed are interstitial flow modelling, subcellular toxicity, screening array, neural growth, and a triculture system.^4-8  These all allow for simulation of the neuronal microenvironment in a highly controlled and manipulable setting. Results: Modeling of neural interstitial flow and cytoarchitecture demonstrated synapse and neural network formation through levels of nestin, synapsin IIa, and β-III tubulin.⁴ Another device had axons and dendrites successfully isolated and growth directed in distinct compartments.  Toxicity, uptake, and secretion of Aβ measured at a subcellular level through engineered perfusion channels.⁵ Drug screening capabilities are also proven through a neurospheroid monitoring screening array.⁶  Neural growth was quantified in a chip through spatial and temporal manipulation of concentration gradients of iridoid glycosides.7 Microfluidic triculture system developed, displaying inflammatory markers, cell loss, and microglial recruitment in Aβ seeded groups.⁸  Conclusions: Device variations proven to grow neurospheroids, create neural networks, induce perfusion, direct growth, simulate the brain microenvironment, and modulate inflammation. All results indicate significant potential of brain-on-a-chip devices for drug discovery and disease modeling. There is an opportunity for major clinical translation in better understanding of disease pathogenesis and allowance of cheap, high throughput drug development. This will pave the way for the future of AD therapeutics.

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