Biomimicking scaffolds for neural tissue regeneration and innate immunomodulation

• Main Author: Lin, Junquan
• Other Authors: CHEW Sing Yian
• Format: Thesis-Doctor of Philosophy
• Language: English
• Published: Nanyang Technological University 2020
• Subjects: Engineering::Bioengineering
• Online Access: https://hdl.handle.net/10356/138686
• Institution: Nanyang Technological University

The application of tissue engineering for replacing damaged, injured or diseased tissues has come a long way since conceived in the late 1980s. Currently, scaffold-based treatments, as compared to cell-based treatments, pose minimal risks following implantation and enable versatile fabrication procedures. Electrospun synthetic fibers are one of the many avenues for attaining a scaffold and be easily modified to affect neural cell behaviour and function. For example, polycaprolactone fibers coated with poly-DOPA, a mussel-inspired bioadhesive, for affixing Protein A and subsequently recombinant L1 Cell Adhesion Molecule (L1CAM) through specific interactions led to enhanced axonal growth. Additionally, when L1CAM was replaced with Neuregulin-1 type III (Nrg1 type III), a known enhancer of myelination, oligodendrocytes (OLs) began to display better myelination in terms of myelin sheath length. The reverse, where OLs myelinated poorly, occurred when Nrg1 type III is further replaced with Junctional Adhesion Molecule 2 (JAM2), a known inhibitor of myelination. Besides surface modification, these electrospun synthetic fibers can also be assembled into a 3 dimensional (3D) scaffold which can delivery therapeutics in a sustained fashion when implanted into spinally injured rats. Therapeutics delivered, such as microRNA-219 (miR-219) and microRNA-338 (miR-338), which have been shown to promote the differentiation of oligodendrocyte progenitor cells (OPCs) during development, were further demonstrated to be able to increase the differentiation and myelination of OPCs in an injury. When the scaffold was loaded with a pro-regenerative factor (Neurotrophin-3 (NT-3)) instead and coupled with rehabilitation, animals showed increased motor recovery and force exertion. Lastly, these fibers can also be encapsulated with miRs for directing macrophage polarization, which may possibly be associative with the formation of fibrous capsule. With the delivery of miR-124, it was observed that fibrous encapsulation and blood vessels formation can be limited and enhanced respectively, which are indicative of host-implant integration. This thesis describes the endeavour towards treating spinal cord injury. It is hoped that through this series of experiments, readers will be able to gain some insight into not only the difficulties present but also most importantly, a possible way forward. In this work, I have chosen biocompatible, synthetic electrospun fibers as the scaffolding material for supporting all the biological components (cells and tissues). I show that these fibers can be loaded with small nucleic acids such as microRNAs and, depending on their orientation (aligned or randomly oriented), can be used for directing cellular behaviour. Taken together, tissue engineering has limitless potential for tackling neural-related deficits.