Immunomodulation Following Severe Musculoskeletal Trauma to Improve Functional Regeneration

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Vantucci, Casey Elizabeth
Roy, Krishnendu
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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, morbidity and complication rates remain high with greater than 5-10% of patients experiencing complications with healing, most commonly non-unions and infections, resulting in longer rehabilitation times and increased treatment costs. Recently, systemic immune dysregulation and immunosuppression has been implicated as a main contributor to severe trauma patients who have complications in healing and who respond poorly to treatment strategies. A notable hallmark of systemic immune dysregulation is elevated levels of immune suppressor cells, including myeloid-derived suppressor cells (MDSCs), similar to immune suppression seen in many solid tumors. Despite awareness of systemic immune dysregulation in human trauma survivors, it is still poorly understood how these systemic cellular and molecular immune responses impact regenerative intervention strategies and outcomes. Further, whether such knowledge can enable design of effective immunoengineering strategies to improve functional regeneration has not been rigorously tested. Finally, well-characterized animal models that mimic these conditions and that could allow for a better understanding of the interaction between trauma-related immunosuppression and associated impaired regeneration responses have not been established. Previous clinical attempts at systemic immunomodulation following trauma have used systemic cytokine and growth factor therapies; however, they have had very little success to restore immune homeostasis and improve patient outcomes. Borrowing from cancer immunotherapy, a treatment to address immunosuppression at the cellular level rather than the protein level utilizes monoclonal antibodies (mAbs) to deplete MDSCs; however, they are limited by high dosage requirements and there are no mAbs that specifically target MDSCs. Therefore, in order to better understand systemic immune dysregulation following trauma, the first aim developed and characterized systemic immune dysregulation in pre-clinical animal models of severe trauma and identified predictive markers for immune dysregulation. The next aim developed a synthetic nanoparticle strategy that mimics the function of a mAb to target and deplete MDSCs. The last aim utilized the immunomodulatory MDSC-depleting therapeutic in order to evaluate the effect of systemic immune modulation on the immune system and local bone regeneration. The overall hypothesis was that (a) immunological markers indicative of systemic immune dysregulation can be used to predict functional regenerative outcomes in a previously developed rat composite trauma model and (b) depletion of MDSCs, a hallmark of systemic immune dysregulation, will restore immune homeostasis and lead to improved bone regeneration. The overall objectives were to investigate (i) how the development of systemic immune dysregulation relates to functional bone regeneration and (ii) how systemic immunomodulation impacts the immune system and regenerative outcomes following severe trauma. Overall, this thesis has investigated post-traumatic systemic immune dysregulation and immunosuppression in multiple different trauma models, developed and characterized a novel nanoparticle-based method to target and deplete aberrant immunosuppressive myeloid-derived suppressor cells, and increased the fundamental knowledge about the role of myeloid-derived suppressor cells on systemic immune function and healing following trauma. These results can be leveraged to more effectively treat challenging bone injuries by identifying patients at higher risk for complications and utilizing targeted and individualized treatment strategies that not only focus on local tissue engineering strategies but also on systemic immunomodulation strategies.
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