Immunoengineering Strategies for Musculoskeletal Trauma

项目摘要 肌肉骨骼创伤在战斗伤员和平民患者中非常普遍，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。对以下药物无反应的患者 治疗或患有并发症，愈合不良，住院时间延长，治疗费用增加， 长期残疾。最近，全身性免疫失调和免疫抑制已牵连 目前的干预策略的成功有限，创伤患者的结局不佳。全身免疫 失调和免疫抑制导致循环促炎细胞因子水平降低， 循环免疫效应细胞如效应T细胞的减少。另一个显著的系统性特征是 免疫失调是免疫抑制细胞水平升高，包括髓源性抑制细胞 （MDSC）。我们的总体目标是研究（i）系统性免疫失调的发展如何影响 和免疫抑制与功能性骨再生有关，以及（ii）系统性免疫调节 影响免疫系统和严重肌肉骨骼创伤后的再生结果。我们将满足 通过以下具体目标实现这些目标。具体目标1：描述 临床前复合创伤模型中全身免疫失调和免疫抑制， 鉴定预测不良愈合的免疫学标志物。使用复合骨/肌肉创伤， 临床模型，我们将通过流式细胞术纵向表征全身免疫失调生物标志物 和多分析物血清蛋白质组学分析，然后利用非线性进化多变量分析， 开发功能性骨再生的预测模型。具体目标2：构建和优化 免疫调节治疗剂以靶向和耗尽MDSC。我们将开发合成金纳米粒子 用Fc模拟和MDSC靶向配体两者官能化，其可以模拟mAb功能（SNAb）， 优化它们的多价性、Janus取向和大小以用于MDSC耗竭。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 严重的肌肉骨骼创伤我们将检验MDSC的靶向耗竭将 恢复免疫稳态，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.