Hierarchically-Structured Conduits with Programmed Release of Neurotrophic Factors for Repairing Large Defects in Thick Nerves

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PROJECT SUMMARY/ABSTRACT This project aims to develop, validate, and translate a novel class of nerve guidance conduits (NGCs) for the surgical repair and healing of large defects in thick peripheral nerves by restoring their continuity and functions. The research team includes an innovative and productive expert in nanotechnology from the Department of Biomedical Engineering at the Georgia Institute of Technology and a top neurosurgeon and scientist from the Department of Neurosurgery at Emory University School of Medicine. Guided by the anatomic structure of peripheral nerve, as well as the biochemistry and cell biology involved in injury and repair, the investigators design, fabricate, and validate multi-tubular conduits (mNGCs) using fibers electrospun from a biocompatible and biodegradable polymer. The mNGC is typically constructed by wrapping a honeycomb array of 3 or 7 small, single-tubular conduits inside a large, single-tubular conduit. The wall of each conduit contains three layers: uniaxially-aligned fibers to longitudinally guide axonal extension for both the inner and outer layers, together with random fibers (welded at cross points) sandwiched in between to circumvent tearing or collapsing during surgery. Besides the topographic cue associated with the aligned fibers, the surface of each fiber in the inner layer is further engraved with longitudinal nanogrooves to accelerate neurite outgrowth by providing more sensing targets and contact pads to the filopodia in the growth cone. In addition, neurotrophic factors (NTFs) are loaded in hollow microparticles of natural fatty acids and then photo-cross-linked to create a unidirectional gradient in degradation half-life along the conduit. The proposed activities are broadly divided into three major thrusts: i) controlling the degradation rate of hollow microparticles made of natural fatty acids and thus release kinetics of NTFs through photo-cross-linking; ii) evaluating the 3-in-1 mNGCs for sciatic nerve repair in a rat model; and iii) assessing the 7-in-1 mNGCs for facial nerve repair in a porcine model. The NGCs are anticipated to augment nerve regeneration as a result of the synergistic effect arising from the aligned fibers, the nanogrooves on the surface of the fibers, and the steady supply of NTFs, improving the health and quality of life for individuals afflicted by peripheral nerve injuries.