A Murine Model of Polytrauma: Understanding the molecular basis of accelerated bone repair with concomitant traumatic brain injury

Investigator: Theodore Miclau, MD
Sponsor: NIH Natl Inst Arthr, Musculoskel & Skin

Location(s): United States


High velocity injuries, such as in those seen from combat or in automobile accidents, often result in combined brain and bone fractures. An unexplained clinical phenomenon is that brain trauma often accelerates fracture healing and increases incidence of heterotopic ossification, however, the mechanisms underlying this altered repair paradigm are unknown. The goal of this proposal is to define a clinically relevant murine model of combined brain and bone injury, and then utilize an interdisciplinary research team composed of orthopaedic traumatologist and neurologist to determine how these reciprocal events result in changed healing patterns and how to improve care for polytraumatized patients.

 This proposal represents an interdisciplinary team that has tremendous potential to impact trauma patient care. San Francisco General Hospital (SFGH) is one of four main campuses comprising UCSF, and it is the only Level 1 Trauma Center that serves the city of San Francisco. Research at SFGH is varied, but includes a large investment in trauma-related research both clinically and experimentally. However, until now, there has not been a concerted effort among basic scientists to leverage individual expertises and develop integrated animal models that correspond to commonly observed clinical polytrauma conditions. The interdisciplinary team assembled here represents a team of Neurosurgery and Orthopaedic Surgery researchers and clinicians that have collaborated to address the clinical challenges associated with understanding and treating polytrauma. For this proposal we have developed a mouse model of combined brain and bone injury in order to study the mechanisms by which injury in one tissue affects healing in another tissue. We chose to combine a traumatic brain injury (TBI) with a long bone fracture because this is a common combination of injuries observed during high velocity traumas. Furthermore, clinical data shows that brain injury accelerates fracture healing and increases incidence of heterotopic ossification, but the mechanism underlying this altered repair dynamic is unknown. While the description of these phenomena are engrained in the clinical literature, animal models to examine this combination of injuries are not common as they require expertise in divergent fields. The research proposed here will promote valuable interdisciplinary collaborations within our institution. As indicated, we chose to pair brain and bone injuries as an initial project, because there are well-described clinical outcomes for which the underlying molecular mechanisms are not understood. However, SFGH has a multitude of researchers studying a large variety of trauma including brain injuries and spinal cord injuries, cutaneous wounds, gastrointestinal and lung injuries. All of these models are currently being studied as isolated injuries, which is not commonly the clinical condition. To address this we have created the SFGH Polytrauma Research Initiative which is committed to expanding our understanding of molecular basis underlying combined injuries that occur during trauma in order to accelerate improvements in clinical practice to treat polytrauma patients. These goals are directly in line with the mission of NIAMS.