Although sensory nerves are known to be present in mature bone, relatively little is understood about their function in the skeleton, aside from pain. In this project, we are investigating the role of NGF-TrkA signaling in sensory nerves. Nearly all of the nerves in bone express TrkA, the high affinity receptor for nerve growth factor (NGF). Furthermore, sensory nerves blanket the surfaces of bone in a mesh-like network, a privileged location for the acquisition of mechanical signals. Using both in vivo and in vitro methods, we have demonstrated that NGF is robustly expressed by mature osteoblasts in response to non-damaging mechanical loads. Inhibition of NGF-TrkA signaling impairs load-induced bone formation whereas administration of exogenous NGF increases relative bone formation rates. These effects appear to be facilitated through altered Wnt/β-Catenin signaling, which we are currently investigating by using mice which lack NGF in the osteoprogenitor and osteoblast lineages. In addition, we have identified a compound which may provide long-term activation of TrkA to increase load-induced bone formation without the painful side effects of NGF.

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly consumed medication in the world, with over 30 million daily users in the United States alone. NSAIDs are effective in reducing pain and inflammation by preventing the synthesis of prostaglandin E2 (PGE2) through the blockade of the cyclooxygenase (COX) enzyme isoforms, COX1 and COX2. However, PGE2 is part of an inflammatory signaling pathway that is known to be critical for load-induced bone formation. In collaboration with our partners at the US Army Research Institute of Environmental Medicine and the Rothman Institute, we have identified a clear link between NSAID usage and stress fracture susceptibility. Furthermore, we have observed in mice that NSAIDs may increase stress fracture risk through two independent mechanisms – diminished load-induced bone formation and decreased bone toughness. In addition, we have identified NSAIDs which can provide analgesia without affecting stress fracture risk or repair. We are currently analyzing the mechanisms by which NSAIDs affect the skeleton, with the aim of uncovering novel therapeutic targets for relieving musculoskeletal pain without affecting bone health.

The main cause of large bone graft failure is poor vascularization which leads to inner graft necrosis. Although this issue has been recognized for some time, developing bone grafts with adequate vascular function has proven to be a difficult problem to address and has prevented the widespread clinical use of engineered bone constructs. In this research area, we utilize 3D bioprinting to generate vascularized bone graft using patient-specific imaging data. First, we are developing a new computational tools to provide semi-automated generation of vascular structures within volume generated from standard clinical imaging. Next, we are optimizing the parameters used for extrusion bioprinting to improve outcomes and reproducibility using a type II fuzzy system. Our ultimate goal is to use bioprinting to generate patient-specific vascularized bone grafts for repair of carpal bones and other small bones with complex geometry and articulating surfaces.