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Localized neurotrophin delivery via microparticles for enhanced bone fracture repair

  • Author(s): Rivera, Kevin Omar
  • Advisor(s): Alliston, Tamara
  • et al.

Biological approaches to accelerate endochondral fracture healing could be an exciting alternative to bone grafting by stimulating the conversion of cartilage to bone rather than strictly osteogenesis. The most widely studied biologic for fracture repair is bone morphogenetic protein (BMP), However, high cost and adverse side effects, such as ectopic bone formation, have led to a significant decline in clinical application. This limited clinical success is likely due to the incomplete understanding of the underlying mechanisms driving endochondral ossification and poor drug delivery platforms utilized for BMP. Therefore, developing novel therapeutic targets of endochondral bone regeneration with appropriate drug delivery platforms to achieve local and sustained release could significantly improve clinical outcomes in fracture healing. This dissertation explores the use of a complete therapeutic system consisting of a novel orthobiologic and drug delivery platform for use in accelerating endochondral fracture repair. Herein, we first present a review that describes the most commonly-targeted pathways that potentially stimulate cartilage-to-bone version during endochondral fracture repair. Moreover, we describe the dynamic regenerative process that proceeds throughout bone fracture healing (in murine models). In our subsequent research article, we investigate nerve growth factor (NGF) in the context of endochondral repair. In this study, our major work focused on i) determining spatiotemporal parameters of endogenous NGF and its receptor tropomyosin receptor kinase A (TrkA) expression during tibial fracture repair ii) determining optimal administration window of local β-NGF injections iii) demonstrating osteogenic effect following β-NGF stimulation and (iv) therapeutic efficacy of local β-NGF injections to accelerate endochondral fracture repair. Utilizing this foundational work, in our subsequent study we (i) engineer injectable polyethylene glycol dimethacrylate (PEGDMA) microrods that can be loaded with β-NGF ii) demonstrate bioactivity of β-NGF eluted from PEGDMA microrods iii) localize the presence of injected PEGDMA microrods within fracture calluses and iv) test the therapeutic efficacy of the injectable system: β-NGF-loaded PEGDMA microrods for accelerating endochondral fracture repair. Here we present a promising drug delivery platform for sustained and local delivery of orthobiologics to accelerate fracture repair furthermore, our mechanistic studies lay the foundation for further exploration of NGF therapy and endogenous NGF signaling in the context of endochondral fracture repair.

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