Immunoengineering Strategies for Musculoskeletal Trauma

项目总结 肌肉骨骼创伤在战斗伤员和平民患者中都非常普遍，尽管取得了进展 在创伤护理中，死亡率和并发症发生率仍然非常高。对药物无反应的病人 治疗或出现并发症，愈合不良，住院时间延长，治疗费用增加， 以及长期的残疾。最近，全身性免疫失调和免疫抑制被认为是可能的。 目前干预策略的成功有限，对创伤患者的结果不佳。系统免疫 调节失调和免疫抑制导致循环促炎细胞因子水平下降和 循环免疫效应细胞的减少，如效应T细胞。系统性的另一个显著标志 免疫失调是指免疫抑制细胞水平升高，包括髓系来源的抑制细胞 (MDSCs)。我们的总体目标是研究(I)全身免疫失调的发展 免疫抑制与功能性骨再生有关，以及(Ii)全身免疫调节 严重肌肉骨骼创伤后对免疫系统和再生结果的影响。我们会相遇的 这些目标通过以下具体目标实现。具体目标1：描述发展的特征 临床前复合创伤模型中的全身免疫失调和免疫抑制 确定预测愈合不良的免疫学标志物。使用复合骨/肌肉创伤前 临床模型，我们将通过流式细胞术纵向表征系统免疫失调生物标志物 和多分析血清蛋白质组图谱，然后利用非线性进化多变量分析 建立功能性骨再生的预测模型。具体目标2：制造和优化 针对和耗尽MDSCs的免疫调节治疗。我们将开发人造金纳米颗粒 功能化的Fc模拟和MDSC靶向配体可以模拟mAb功能(SNAbs)和 针对MDSC耗尽优化其多价性、Janus方向和大小。具体目标3：评估 全身免疫调节对体内免疫系统状态和骨再生的影响 在严重的肌肉骨骼创伤之后。我们将测试定向耗尽MDSCs的假设 恢复免疫动态平衡，促进功能性骨再生。

PROJECT SUMMARY Musculoskeletal trauma is highly prevalent in both combat-wounded and civilian patients, and despite advances in trauma care, mortality and complication rates remain remarkably high. Patients who do not respond to treatment or suffer from complications, experience poor healing, longer hospital stays, increased treatment costs, and prolonged disability. Recently, systemic immune dysregulation and immunosuppression has been implicated in the limited success of current intervention strategies and poor outcomes in trauma patients. Systemic immune dysregulation and immunosuppression results in decreased levels of circulating pro-inflammatory cytokines and a decrease in circulating immune effector cells, such as effector T cells. Another notable hallmark of systemic immune dysregulation is elevated levels of immune suppressor cells, including myeloid-derived suppressor cells (MDSCs). Our overall objectives are to investigate (i) how the development of systemic immune dysregulation and immunosuppression relates to functional bone regeneration and (ii) how systemic immunomodulation impacts the immune system and regenerative outcomes following severe musculoskeletal trauma. We will meet these objectives through the following specific aims. SPECIFIC AIM 1: Characterize the development of systemic immune dysregulation and immunosuppression in a pre-clinical composite trauma model and identify immunological markers predictive of poor healing. Using a composite bone/muscle trauma pre- clinical model, we will longitudinally characterize systemic immune dysregulation biomarkers via flow cytometry and multi-analyte serum proteomic profiling and then utilize nonlinear evolutionary multivariate analytics to develop predictive models of functional bone regeneration. SPECIFIC AIM 2: Fabricate and optimize an immunomodulatory therapeutic to target and deplete MDSCs. We will develop synthetic gold nanoparticles functionalized with both Fc-mimicking and MDSC-targeting ligands that can mimic mAb function (SNAbs) and optimize their multivalency, Janus orientation, and size for MDSC depletion. SPECIFIC AIM 3: Evaluate the effect of systemic immunomodulation on the immune system status and bone regeneration in vivo following severe musculoskeletal trauma. We will test the hypothesis that targeted depletion of MDSCs will restore immune homeostasis and promote functional bone regeneration.