Development of Microplatforms to Mimic the In Vivo Architecture of CNS and PNS Physiology and Their Diseases

Abstract

Understanding the mechanisms that govern nervous tissues function remains a challenge. In vitro two-dimensional (2D) cell culture systems provide a simplistic platform to evaluate systematic investigations but often result in unreliable responses that cannot be translated to pathophysiological settings. Recently, microplatforms have emerged to provide a better approximation of the in vivo scenario with better control over the microenvironment, stimuli and structure. Advances in biomaterials enable the construction of three-dimensional (3D) scaffolds, which combined with microfabrication, allow enhanced biomimicry through precise control of the architecture, cell positioning, fluid flows and electrochemical stimuli. This manuscript reviews, compares and contrasts advances in nervous tissues-on-a-chip models and their applications in neural physiology and disease. Microplatforms used for neuro-glia interactions, neuromuscular junctions (NMJs), blood-brain barrier (BBB) and studies on brain cancer, metastasis and neurodegenerative diseases are addressed. Finally, we highlight challenges that can be addressed with interdisciplinary efforts to achieve a higher degree of biomimicry. Nervous tissue microplatforms provide a powerful tool that is destined to provide a better understanding of neural health and disease.

Keywords: blood-brain barrier; brain cancer; cell co-cultures; metastasis; nervous tissues; neurodegenerative diseases; organ-on-a-chip.

Figure 1

Schematic showing the laminar and turbulent flow. The Reynolds number (Re) describes the physical characteristics of the fluid flow in microfluidic channels. In laminar flow (Re < 2300), the two streams move in parallel to the flow direction and mixed based on the diffusion (Left). In turbulent flow (Re > 4000), fluids move in all three-dimensions without correlation with the flow direction (Right). The transition region (2300 < Re < 4000) shares the features of laminar and turbulent flow.

Figure 2

A schematic diagram of traditional two-dimensional (2D) monolayer cell culture and three-dimensional (3D) microfluidic cell culture systems.

Figure 3

Schematic diagrams of blood-brain barrier (BBB)-on-chip models. (A) microchip BBB model [161]; (B) Neonatal BBB-on-chip [163]; (C) µBBB system [164]; (D) Neurovascular microfluidic bioreactor [165]; (E) 3D microfluidic neurovascular unit platform [166].

Figure 4

Schematic diagrams of BBB disruption models. (A) BBB chip. Figure adapted from [170]; (B) 3D in vitro BBB model [130]; (C) 3D microfluidic BBB chip [171]; (D) Neurovascular unit microfluidic device [172].

Figure 5

Schematic diagrams of axonal injury and regeneration models. (A) Two-chamber CMD. Figure adapted from [230]; (B) Pulsed laser microbeam integrated microfluidic device. Figure adapted from [230]; (C) Three-chamber CMD [232]; (D) Multi-chamber CMD controlled with valves. Figure adapted from [233].