Dual-Delivery of Bioactive and Anti-Microbial Nanowires for Accelerated Bone Repair

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ABSTRACT Fractures are one of the most common injuries worldwide with an estimated 15 million fractures each year in the United States alone. Complications in bone healing, such as delayed and non-unions, are estimated to occur in approximately 10-15% of fractures. Delayed healing rates increase to ~50% when the fracture involves vascular damage or are coupled with high co-morbidity burdens. Current standard of care for impaired healing is surgical intervention to increase stability or promote healing through application of bone grafts. There are currently no pharmacological agents approved to accelerate fracture healing or treat malunions. As such there exists an unmet clinical need for osteoinductive therapeutics that could stimulate bone regeneration through a non-surgical delivery platform. This proposal builds on recently published work from our group demonstrating that Nerve Growth Factor (NGF) given therapeutically during the cartilaginous phase of fracture repair promoted endochondral ossification and accelerated fracture healing. While NGF has not been rigorously studied in long bone fractures, NGF is well established as a potent regenerative factor within the central and peripheral nervous system. Multiple clinical trials suggested a therapeutic potential for NGF in treating Alzheimer’s disease and neuropathies, but the therapy failed to translate due to pain (hyperalgesia) noted upon injection. Recently, our team has isolated a novel NGF isoform identified from patients that lack nociception due to a point mutation in the protein (NGFR100W) that fails to transduce pain through an inability to activate the p75NTR signaling pathway. Since NGFR100W retains TrkA mediated trophic activity, this “painless” NGF presents an exciting opportunity to revisit the translational potential of NGF. The long-term goal of this grant is to develop and validate a translationally relevant, non-surgical, therapeutic platform to accelerate fracture repair based on the use of biodegradable nanowires to provide local and sustained release of “painless” NGF. We accomplish this through three specific aims. In Aim 1 we tune heparin-coated polycaprolactone-nanowires for the delivery of NGFR100W and validate this platform can achieve functional activation of the TrkA pathway to promote neuronal regeneration, while decreasing nociception relative to wild type NGF (NGFWT). We then rigorously test efficacy of the NGFR100W-nanowires in our clinical target of fracture repair (Aim 2). In parallel we also probe the mechanism by which NGF/TrkA signaling stimulates fracture repair. This is done in Aim 3 by genetically deleting the TrkA receptor from specific cell populations to determine whether this pathway is essential for endochondral fracture repair and if it can be rescued by NGF treatment. These aims allow us to test the central hypothesis that NGFR100W nanowires will accelerate fracture repair by acting through TrkA signaling to stimulate chondrocyte-to-osteoblast transformation. Our multidisciplinary team of experts in fracture healing, biomaterials, and NGF/TrkA signaling uniquely positions us to successfully accomplish the proposed study with the ultimate goal of significantly improving patient outcomes following a fracture.