Differential fracture response to traumatic brain injury suggests dominance of neuroinflammatory response in polytrauma.

Polytraumatic injuries, specifically long bone fracture and traumatic brain injury (TBI), frequently occur together. Clinical observation has long held that TBI can accelerate fracture healing, yet the complexity and heterogeneity of these injuries has produced conflicting data with limited information on underlying mechanisms. We developed a murine polytrauma model with TBI and fracture to evaluate healing in a controlled system. Fractures were created both contralateral and ipsilateral to the TBI to test whether differential responses of humoral and/or neuronal systems drove altered healing patterns. Our results show increased bone formation after TBI when injuries occur contralateral to each other, rather than ipsilateral, suggesting a role of the nervous system based on the crossed neuroanatomy of motor and sensory systems. Analysis of the humoral system shows that blood cell counts and inflammatory markers are differentially modulated by polytrauma. A data-driven multivariate analysis integrating all outcome measures showed a distinct pathological state of polytrauma and co-variations between fracture, TBI and systemic markers. Taken together, our results suggest that a contralateral bone fracture and TBI alter the local neuroinflammatory state to accelerate early fracture healing. We believe applying a similar data-driven approach to clinical polytrauma may help to better understand the complicated pathophysiological mechanisms of healing.

Stimulating Fracture Healing in Ischemic Environments: Does Oxygen Direct Stem Cell Fate during Fracture Healing?

Bone fractures represent an enormous societal and economic burden as one of the most prevalent causes of disability worldwide. Each year, nearly 15 million people are affected by fractures in the United States alone. Data indicate that the blood supply is critical for fracture healing; as data indicate that concomitant bone and vascular injury are major risk factors for non-union. However, the various role(s) that the vasculature plays remains speculative. Fracture stabilization dictates stem cell fate choices during repair. In stabilized fractures stem cells differentiate directly into osteoblasts and heal the injury by intramembranous ossification. In contrast, in non-stable fractures stem cells differentiate into chondrocytes and the bone heals through endochondral ossification, where a cartilage template transforms into bone as the chondrocytes transform into osteoblasts. One suggested role of the vasculature has been to participate in the stem cell fate decisions due to delivery of oxygen. In stable fractures, the blood vessels are thought to remain intact and promote osteogenesis, while in non-stable fractures, continual disruption of the vasculature creates hypoxia that favors formation of cartilage, which is avascular. However, recent data suggests that non-stable fractures are more vascularized than stable fractures, that oxygen does not appear associated with differentiation of stem cells into chondrocytes and osteoblasts, that cartilage is not hypoxic, and that oxygen, not sustained hypoxia, is required for angiogenesis. These unexpected results, which contrast other published studies, are indicative of the need to better understand the complex, spatio-temporal regulation of vascularization and oxygenation in fracture healing. This work has also revealed that oxygen, along with the promotion of angiogenesis, may be novel adjuvants that can stimulate healing in select patient populations.