The Development of Hydrogel Microfiber Scaffolds for Peripheral Nerve Repair

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Johns Hopkins University
This thesis provides a description of the development of electrospun hydrogel fiber strings, fiber sheets, and fiber tubes by characterizing their property changes with variations in spinning properties such as collector rotation speed, solution concentrations, and crosslinking conditions, for biologically derived materials such as alginate, fibrin, collagen, and hyaluronic acid. The basic, as spun, fibers were applied to several clinical applications including guidance of axons and Schwann cell outgrowth in peripheral nerve repair using fibrin and collagen fibers, where guidance by the collagen fiber sheets improved neurite outgrowth by 2.5 mm over 14 days compared to anisotropic collagen gels; alignment and maturation of cardiomyocytes, adipose-tissue derived stem cells (ASCs), and microvessel network formation in cardiac patches composed of fibrin; skeletal muscle implants formed through use of porous fibrin generated by removing co-spun alginate via sodium citrate treatment; and fibrin fiber-based vascular grafts to demonstrate the versatility and utility of the material for enhancing ECM deposition from vascular cell types and perfusibility. These hydrogel fibers were then modified to serve as growth factor delivery vehicles to enhance cellular interaction and provide the topographical guidance to promote neurite outgrowth for improving peripheral nerve regeneration through local release of GDNF. A robust protective nerve guide outer conduit, to serve as a carrier for hydrogel fibers, was developed in collaboration with a corporate partner, the Secant Group (Telford, PA, USA) using poly(glycolic acid) (PGA) braided tubes that were coated with a biodegradable elastomer, poly(glycerol sebacate) (PGS). The fibrin-loaded PGA/PGS conduits were implanted in a rat sciatic nerve defect model to assess their effect on nerve regeneration, the local inflammatory microenvironment, and improvement in coated tube mechanical properties to ease surgical handling of the guide. PGS-coated conduits improved the M2/M1 macrophage ratio and improved action potential amplitudes compared to the uncoated nerve guide group. In addition, PGS-coated conduits containing electrospun fibrin hydrogel fibers and collagen fibers with uniform and gradient presentation of loaded neurotrophic factor were evaluated in a rat sciatic defect model to determine the potential feasibility of hydrogel fibers for peripheral nerve repair. Nerve guide groups containing collagen fiber sheets showed high permissivity of cells through the aligned hydrogel structure. These studies demonstrate the broad potential and unique properties of the hydrogel fibers for regenerative engineering applications.
Hydrogels, electrospinning, nanofiber, microfiber, peripheral nerve repair, cardiac patch, skeletal muscle, vascular graft, tissue engineering