| Description |
Despite being the current "gold standard" for repair of nerve gaps there are downsides to autografts, including: limited donor tissue availability, and size mismatch between graft and nerve stumps. Nerve conduits are a promising alternative to autografts. They act as guidance cues for the regenerating axons and allow for tension-free bridging. Separately, it has been shown that localized delivery of neurotrophic factors (NTF) such as NGF (nerve growth factor)/GDNF (Glial cell line derived neurotrophic factor)/FK506 (Tacrolimus) can enhance axon growth. This dissertation describes the design of a novel drug delivery apparatus integrated with a PLGA (poly lactic-co-glycolic acid) or PTFE (polytetrafluoroethylene)-based nerve conduit for controlled local delivery of neurotrophic factors. We have fabricated and verified the efficacy of a novel biocompatible nerve conduit to (1) continuously deliver a therapeutic dose of small molecules or growth factors locally, and (2) improve the degree of peripheral nerve regeneration and functional recovery following a peripheral nerve injury. First, a drug dosage curve was acquired to determine the minimum in vitro concentration for optimal neurite outgrowth of DRG (dorsal root ganglion) cells. Next, drug delivery devices were designed to release sufficient neurotrophins to enhance neurite outgrowth and finally tested in vitro and in vivo. Mathematical models were developed to identify the optimal design of the nerve conduit in both dimension and drug dosage with respect to final drug concentration at the proximal nerve stump. The mathematical diffusion model was verified using a microfluidic setup of the device. The drug delivery nerve guides were able to release adequate concentration of NGF/GDNF/FK506 for 28 days at concentrations (0.1-10 ng/mL) that were shown to enhance DRG neurite growth. Following these tests, drug-releasing nerve conduits were implanted across 15-mm sciatic nerve gaps in a rat model or 10-mm sciatic nerve gaps in a mouse model, where they demonstrated significant nerve regeneration in vivo as compared to empty nerve conduits. This drug delivery nerve guide can release drugs for extended periods of time and enhance axon growth in vitro and in vivo and has the potential to improve nerve regeneration following a peripheral nerve injury. |
