Methods for fabrication and evaluation of a 3D microengineered model of myelinated peripheral nerve

Parastoo Khoshakhlagh,Daniel W Sazer,Lauren A Pace,Michael J Moore,Ashwin Sivakumar

doi:10.1088/1741-2552/aae129

Parastoo Khoshakhlagh, Daniel W Sazer + Show 3 more

Open Access

https://doi.org/10.1088/1741-2552/aae129

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Abstract

Objective. The cost and low success rates of the neurological drug development pipeline have diverted the pharmaceutical industry to ‘nerve-on-a-chip’ systems as preclinical models to streamline drug development. We present a novel micro-engineered 3D hydrogel platform for the culture of myelinated embryonic peripheral neural tissue to serve as an effective in vitro model for electrophysiological and histological analysis that could be adopted for preclinical testing. Approach. Dorsal root ganglions (DRG) from 15 d old embryonic rats were cultured in 3D hydrogel platforms. The interaction between Schwann cells (SC) and neurons during axonal development and regeneration affects the direction of growth and the synthesis of myelin sheaths. Induction of myelination was performed with two approaches: the addition of exogenous SC and promoting migration of endogenous SC. Main results. Histological analysis of the preparation utilizing exogenous SC showed aligned, highly fasciculated axonal growth with noticeable myelin sheaths around axons. Separately, electrophysiological testing of the preparation utilizing endogenous SC showed increased amplitude of the compound action potential and nerve conduction velocity in the presence of ascorbic acid (AA). Significance. This platform has immense potential to be a useful and translatable in vitro testing tool for drug discovery and myelination studies.

Highlights

Plagued with skyrocketing costs and low success rates of the drug development pipeline, the pharmaceutical industry is increasingly turning toward microphysiological systems, or “organs-on-chips”, as preclinical models for drug development[1,2]
This model offered spatiotemporally controlled incorporation of exogenous Schwann cells (SC) by visible light photocrosslinking encapsulation with myelin sheaths observed around axons in histological sections
In Method B, a methacrylated heparin (MeHp) hydrogel was utilized and the endogenous SC were encouraged to migrate from dorsal root ganglion (DRG) explants and form myelin sheaths in a directed manner

Summary

Introduction

Plagued with skyrocketing costs and low success rates of the drug development pipeline, the pharmaceutical industry is increasingly turning toward microphysiological systems, or “organs-on-chips”, as preclinical models for drug development[1,2]. This approach could be beneficial for neurological applications, where the failure rate of drugs entering Phase I clinical trials is as high as 92%3. Such high attrition rates have motivated accelerated development of neural microphysiological systems in recent years[4,5]. The need for preclinical models that can recapitulate certain key physiological aspects of the nervous system remains acute

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