Microfluidic Manipulation for Biomedical Applications in the Central and Peripheral Nervous Systems

Abstract

Physical injuries and neurodegenerative diseases often lead to irreversible damage to the organizational structure of the central nervous system (CNS) and peripheral nervous system (PNS), culminating in physiological malfunctions. Investigating these complex and diverse biological processes at the macro and micro levels will help to identify the cellular and molecular mechanisms associated with nerve degeneration and regeneration, thereby providing new options for the development of new therapeutic strategies for the functional recovery of the nervous system. Due to their distinct advantages, modern microfluidic platforms have significant potential for high-throughput cell and organoid cultures in vitro, the synthesis of a variety of tissue engineering scaffolds and drug carriers, and observing the delivery of drugs at the desired speed to the desired location in real time. In this review, we first introduce the types of nerve damage and the repair mechanisms of the CNS and PNS; then, we summarize the development of microfluidic platforms and their application in drug carriers. We also describe a variety of damage models, tissue engineering scaffolds, and drug carriers for nerve injury repair based on the application of microfluidic platforms. Finally, we discuss remaining challenges and future perspectives with regard to the promotion of nerve injury repair based on engineered microfluidic platform technology.

Keywords: damage models; drug-delivery system; microfluidic platforms; nerve injury repair; tissue engineering scaffold.

Figure 1

Comparing the role of Schwann cells and oligodendrocytes in nerve regeneration. Adapted with permission from Ref. [16]. Copyright 2021, Future Medicine Ltd.

Figure 2

Increased growth capacity of PNS versus CNS neurons. CNS, central nervous system; EFA-6, exchange factor for ADP-ribosylation factor 6; PNS, peripheral nervous system; PTEN, phosphatase and tensin homolog; RAG, regeneration-associated gene; SOCS3, suppressor of cytokine signaling 3. Adapted with permission from Ref. [32]. Copyright 2014, Wiley-Blackwell.

Figure 3

Engineering neural damage models using microfluidics. (A) Paclitaxel induced local axonal degeneration. Axons led to degeneration upon the axonal administration of paclitaxel for 24 h (a,b), but not with paclitaxel application to the soma chamber (c,d) ((a,c) = before paclitaxel; (b,d) = after paclitaxel). (B) A brain-on-a-chip to model mechanical axonal injury. Schematic of the uniaxial axonal strain device (a). Representative images of axonal beading (arrows) observed before (i) and after (ii) the strain injury (b). (C) A neuro-optical microfluidic device for precise axotomy. Reproducible spot damage (arrows) (a1,a2). Severity of spot damage using different laser energies (arrows) (b1,b2). (D) A 3D tri-culture microfluidic platform to model in vitro Alzheimer’s disease (AD). Schematic of the differentiation of neural progenitor cells (NPCs) to Alzheimer’s disease neurons and astrocytes (a). Schematics showing the multicellular interactions in the microfluidic AD model (b) and in the AD brain tissue (c). (E) A 3D microfluidic cell culture system to model in vitro Parkinson’s disease. Representative images of the 3D distribution of differentiated dopaminergic neurons. Top view of the entire culture chamber (a). Inside view (b) and side view (c) of a selected area. Top view of the selected area (d), reconstruction of the neuronal filaments of tyrosine hydroxylase (TH) and TUBβIII-positive neurons in the selected area (e), and overlap (f) of (d,e). (A) Adapted with permission from Ref. [82]. Copyright 2009, Elsevier; (B) Adapted with permission from Ref. [85]. Copyright 2014, World Scientific Publishing Co.; (C) Adapted with permission from Ref. [86]. Copyright 2009, the Royal of Society of Chemistry; (D) Adapted with permission from Ref. [88]. Copyright 2018, Nature; (E) Adapted with permission from Ref. [89]. Copyright 2015, the Royal of Society of Chemistry.

Figure 4

(A) A microfluidic device to study neurite guidance under chemogradients. Typical time-dependent snapshots of the gradient obtained with a 40 kDa FITC-dextran in the device (a). Neurite guidance of hippocampal neurons by chemoattractants (b). (B) NGN2 mRNA-based transcriptional programming. The NGN2-mediated transcriptional programming experiment of human-derived neural stem cells (hiPSCs) in microscale (a). Representative image of a single microfluidic channel of hiPSCs of NGN2 mmRNA transcriptional programming (b). (C) Differentiation of mouse embryonic stem cells (mESC) into neuron-like cells and Schwann cell-like cells in a microfluidic device. Photomicrographs (a) of the areas of the device, depicted as boxes in the cartoon (b). The top three rows (I–III) show significant neuronal differentiation and the directional outgrowth of neurites toward the “Schwann cell” sectors. The bottom two rows (IV,V) show no significant differentiation into any specific lineage. (D) A multi-compartment co-culture microfluidic platform. Schematic of the high-throughput microfluidic multi-compartment CNS neuron co-culture platform (a). Schematic of fabrication steps for the multi-compartment PDMS microfluidic device (b). (A) Adapted with permission from Ref. [91]. Copyright 2011, the Royal of Society of Chemistry; (B) Adapted with permission from Ref. [92]. Copyright 2021, Frontiers Media S.A.; (C) Adapted with permission from Ref. [94]. Copyright 2016, Wiley Periodicals, Inc.; (D) Adapted with permission from Ref. [95]. Copyright 2009, MYJoVE Corporation.

Figure 5

(A) Schematic of a complex hydrogel microfiber for guiding cell proliferation and forming intercellular networks. (B) The printed droplets connected by adhesive droplet interface bilayers (DIBs) using a lipid-bilayer-supported printing technique to form patterned droplet networks. (C) Schematic diagram of the brain organoids-on-a-chip device. The key factors of the brain microenvironment in vivo (a). The development process of brain organoids derived from hiPSCs in vitro (b). Configuration of the brain organoids-on-a-chip device (c). Enlarged view of the procedures for brain organoids generation on the chip (d). (D) A microfluidic blood–brain barrier model for evaluating drug permeability and cytotoxicity for central nervous system drug screening (a). Schematic illustration of the microfluidic platform (b). (A) Adapted with permission from Ref. [99]. Copyright 2014, IOP Publishing Ltd.; (B) Adapted with permission from Ref. [104]. Copyright 2020, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim; (C) Adapted with permission from Ref. [96]. Copyright 2018, the Royal of Society of Chemistry; (D) Adapted with permission from Ref. [98]. Copyright 2016, Elsevier.

Figure 6

(A) Two-pronged cytokine suppressive strategy for promoting the functional recovery of the injured spinal cord by capturing the released cytokines and inhibiting the secretion of new ones (a). Representative footprint images of rats for assessing the recovery of motor function at day 28 post-injury (b). (B) Schematic of the intranasal administration of mpEVs in mice bearing orthotopic glioblastomas (GBMs) (a). The delivered mpEVs monitored using optical imaging, MRI, and photoacoustic imaging (b). (C) A sTable 3D scaffold formed by mixing oppositely charged building blocks via interaction (a). Schematic of adaptable microporous hydrogel (AMH) with the gradient propagation of NGF for directed and accelerated axonal regeneration in vivo (b). (A) Adapted with permission from Ref. [100]. Copyright 2021, American Chemical Society; (B) Adapted with permission from Ref. [101]. Copyright 2021, American Chemical Society; (C) Adapted with permission from Ref. [102]. Copyright 2019, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.