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Background: In multiply injured patients, bilateral femur fractures invoke a substantial systemic inflammatory impact and remote organ dysfunction. However, it is unclear whether isolated bone or soft tissue injury contributes to the systemic inflammatory response and organ injury after fracture., Questions/purposes: We therefore asked whether the systemic inflammatory response and remote organ dysfunction are attributable to the bone fragment injection, adjacent soft tissue injury, or both., Methods: Male C57/BL6 mice (8-10 weeks old, 20-30 g) were assigned to four groups: bone fragment injection (BF, n = 9) group; soft tissue injury (STI, n = 9) group; BF + STI (n = 9) group, in which both insults were applied; and control group, in which neither insult was applied. Animals were sacrificed at 6 hours. As surrogates for systemic inflammation, we measured serum IL-6, IL-10, osteopontin, and alanine aminotransferase (ALT) and nuclear factor (NF)-κB and myeloperoxidase (MPO) in the lung., Results: The systemic inflammatory response (mean IL-6 level) was similar in the BF (61.8 pg/mL) and STI (67.9 pg/mL) groups. The combination (BF + STI) of both traumatic insults induced an increase in mean levels of inflammatory parameters (IL-6: 189.1 pg/mL) but not in MPO levels (1.21 ng/mL) as compared with the BF (0.82 ng/mL) and STI (1.26 ng/mL) groups. The model produced little evidence of remote organ inflammation., Conclusions: Our findings suggest both bone and soft tissue injury are required to induce systemic changes. The absence of remote organ inflammation suggests further fracture-associated factors, such as hemorrhage and fat liberation, may be more critical for induction of remote organ damage., Clinical Relevance: Both bone and soft tissue injuries contribute to the systemic inflammatory response.

Following trauma there is an early hyper-reactive inflammatory response that can lead to multiple organ dysfunction and high mortality in trauma patients; this response is often accompanied by a delayed immunosuppression that adds the clinical complications of infection and can also increase mortality. Many studies have begun to assess these changes in the reactivity of the immune system following trauma. Immunologic studies are greatly supported through the wide variety of transgenic and knockout mice available for in vivo modeling; these strains aid in detailed investigations to assess the molecular pathways involved in the immunologic responses. The challenge in experimental murine trauma modeling is long term investigation, as fracture fixation techniques in mice, can be complex and not easily reproducible. This pseudofracture model, an easily reproduced trauma model, overcomes these difficulties by immunologically mimicking an extremity fracture environment, while allowing freedom of movement in the animals and long term survival without the continual, prolonged use of anaesthesia. The intent is to recreate the features of long bone fracture; injured muscle and soft tissue are exposed to damaged bone and bone marrow without breaking the native bone. The pseudofracture model consists of two parts: a bilateral muscle crush injury to the hindlimbs, followed by injection of a bone solution into these injured muscles. The bone solution is prepared by harvesting the long bones from both hindlimbs of an age- and weight-matched syngeneic donor. These bones are then crushed and resuspended in phosphate buffered saline to create the bone solution. Bilateral femur fracture is a commonly used and well-established model of extremity trauma, and was the comparative model during the development of the pseudofracture model. Among the variety of available fracture models, we chose to use a closed method of fracture with soft tissue injury as our comparison to the pseudofracture, as we wanted a sterile yet proportionally severe peripheral tissue trauma model. Hemorrhagic shock is a common finding in the setting of severe trauma, and the global hypoperfusion adds a very relevant element to a trauma model. The pseudofracture model can be easily combined with a hemorrhagic shock model for a multiple trauma model of high severity.