Anti-microbial platelet-like-particles to treat internal bleeding and augment subsequent healing

项目总结 创伤后失控出血是一个重大的临床问题；失血是主要原因。 平民和战场创伤的死因。如果止血成功，创伤后的伤口修复 可被几种并发症所阻碍，包括感染、瘢痕疙瘩形成、血流不足和 免疫系统受损。创伤性脑损伤(TBI)也经常与出血同时发生 在创伤后，并与感染的高风险有关。感染是导致死亡的主要原因， 世界各地的发病率和经济混乱，突出表明需要更好的方法来实现 止血和促进创伤后的伤口愈合。血栓形成是止血的关键 并且涉及嵌入在纤维蛋白网中的血小板塞子的形成。血小板结合多个纤维蛋白纤维 并积极施力收缩网络，从而稳定正在发展的凝块。此外，血小板- 介导的凝块收缩被认为通过重建伤口来促进止血后的伤口愈合 血液流向下游组织，并向周围细胞提供机械刺激。我们最近做了 开发的血小板样粒子(PLP)是由高度变形的微凝胶(凝胶)结合到伤口上产生的- 靶向基序，通过与临时的高亲和力结合而特异性地靶向伤口环境 基质蛋白纤维蛋白。我们先前的研究表明，PLP概括了自然的许多功能 在啮齿动物模型中，血小板，包括在体外增加成人血浆的凝血，减少了出血时间 创伤性损伤、损伤部位的特定归巢、凝块收缩的诱导和伤口的强化 在啮齿动物皮肤损伤模型中进行修复。我们还在脑外伤的啮齿动物模型中证明了PLP能降低血液 脑屏障(BBB)通透性和损伤后的神经炎症。 该项目的长期目标是开发静脉止血PLP，该PLP由 体内天然的凝血级联以促进凝血，止血后，增加伤口愈合。我们的中央 假设PLP介导的血栓收缩和抗菌纳米银的传递相结合将 通过提供机械刺激显著改善创伤后的伤口愈合 并通过预防/治疗感染来实现。该提案将具体评估稳定性和安全性。 含有PLP的抗菌纳米银。这些颗粒的有效性随后将在小鼠身上进行评估 在没有或存在感染的情况下出血和愈合的模型。此外，颗粒的功效、安全性和 将在复合创伤性脑损伤的啮齿动物多发伤模型中评估免疫系统的调节 (颅脑损伤)和出血。

PROJECT SUMMARY Uncontrolled bleeding following trauma represents a significant clinical problem; exsanguination is the major cause of death in both civilian and battlefield traumas. If hemostasis is achieved, wound repair following trauma can be impeded by several complications including infection, keloid formation, insufficient blood flow and a compromised immune system. Traumatic brain injury (TBI) also frequently occurs concurrently with hemorrhage following trauma and is associated with high risks of infection. Infections are a leading cause of mortality, morbidity, and economic disruption around the world, highlighting the need for better methods to achieve hemostasis and improve wound healing following trauma. Clot formation is critical to the cessation of bleeding and involves the formation of a platelet plug embedded within a fibrin mesh. Platelets bind multiple fibrin fibers and actively apply forces to contract the network, thereby stabilizing the developing clot. Furthermore, platelet- mediated clot contraction is thought to augment wound healing following cessation of bleeding by reestablishing blood flow to downstream tissues and by providing mechanical stimulation to surrounding cells. We have recently developed platelet-like particles (PLPs) created from highly deformable microgels (gels) conjugated to wound- targeting motifs, which specifically target wound environments through high affinity binding to the provisional matrix protein fibrin. Our prior studies demonstrate that PLPs recapitulate a number of functions of natural platelets, including augmentation of clotting of adult plasma in vitro, decreased bleeding times in rodent models of traumatic injury, specific homing to injury sites, induction of clot contraction, and enhancement of wound repair in rodent models of dermal injury. We have also shown in a rodent model of TBI that PLPs decrease blood brain barrier (BBB) permeability and neuroinflammation after injury. The long-term goal of this project is to develop intravenous hemostatic PLPs that are triggered by the body’s native clotting cascade to promote clotting and, following hemostasis, augment wound healing. Our central hypothesis is that the combination of PLP-mediated clot contraction and delivery of antimicrobial nanosilver will significantly improve wound healing following traumatic injury by providing mechanical stimulation to surrounding cells and by preventing/treating infection. This proposal will specifically evaluate stability and safety of antimicrobial nanosilver containing PLPs. The effectiveness of these particles will then be evaluated in a mouse model of bleeding and healing in the absence or presence of infection. Additionally, particle efficacy, safety, and immune system modulation will be evaluated in a rodent polytrauma model of combined traumatic brain injury (TBI) and hemorrhage.