Immunomodulatory strategies for immune dysregulation following severe musculoskeletal trauma

Severe musculoskeletal trauma is one of the most prevalent types of trauma in both combat-wounded and civilian patients. However, despite advances in trauma care management, mortality and complication rates remain high. Recently, systemic immune dysregulation and immunosuppression has been implicated as a main contributor to unsatisfactory success of intervention strategies and poor outcomes in a subset of trauma patients. The importance of the immune system in wound healing and tissue regeneration suggests that for optimal success of regenerative medicine strategies, this underlying systemic immune dysregulation must be addressed, highlighting a strong need for immunomodulatory approaches to augment regenerative therapies. This review addresses what is currently known about systemic immune dysregulation following severe trauma, previous attempts at immunomodulation, considerations for the development of future immunomodulatory strategies, and animal models for testing these therapeutics. The severity of immune dysregulation over time, both systemically and locally, is impacted by injury severity and patient-specific factors, such as age and co-morbidities. Varying degrees of systemic immune dysregulation may require different and personalized approaches to restore immune homeostasis. Further, the timing of treatment and the site of delivery must be considered to determine the most safe and effective intervention strategy. In order to test and develop these immunomodulatory therapeutics aimed at improving outcomes of regenerative interventions, robust pre-clinical models are needed that recapitulate systemic immune dysregulation and clinical scenarios. Overall, more fundamental research is needed to better understand the complex interactions between the musculoskeletal system and the immune system, as well as the importance of systemic and local immune function on healing. Ultimately, this information could lead to new immunomodulatory strategies to enhance regeneration for severe musculoskeletal trauma patients.