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

抗菌血小板样颗粒可治疗内出血并促进后续愈合

• 批准号: 10666168
• 负责人: Ashley Carson Brown
• 金额: $ 57.29万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666168
• 关键词: Adult; Affinity; Area; Binding; Biodistribution; Biological Assay; Bleeding time procedure; Blood Coagulation Disorders; Blood Platelets; Blood flow; Brain; Brain hemorrhage; Cause of Death; Cells; Circulation; Clinical; Coagulation Process; Contracts; Dryness; Economics; Effectiveness; Evaluation; Excretory function; Family suidae; Fiber; Fibrin; Gel; Goals; Hemorrhage; Hemostatic Agents; Hemostatic function; Home; Homing; Immune; Immune system; Impairment; In Vitro; Incidence; Infection; Injury; Intravenous; Keloid; Laceration; Liver; Mechanical Stimulation; Mediating; Methods; Mission; Modeling; Morbidity - disease rate; Morphology; Multiple Trauma; Mus; Particle Size; Patients; Plasma; Pre-hospital setting; Predisposition; Prognosis; Proteins; Public Health; Publishing; Rattus; Reporting; Rodent; Rodent Model; Safety; Saline; Site; Skin injury; Technology; Testing; Thrombosis; Time; Tissues; Transportation; Trauma; Traumatic Brain Injury; Traumatic injury; United States National Institutes of Health; antimicrobial; aqueous; base; blood product; blood-brain barrier permeabilization; controlled cortical impact; cytotoxicity; design; efficacy evaluation; femoral artery; fighting; healing; high risk; improved; in vivo; infection risk; innovation; mortality; mouse model; nanosilver; nerve injury; neuroinflammation; novel; particle; preclinical evaluation; prevent; prothrombin complex concentrates; response; systemic inflammatory response; tissue repair; wound; wound environment; wound healing

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.

项目摘要 创伤后不受控制的出血是一个重大的临床问题。解血是主要的 平民和战场创伤的死亡原因。如果达到止血，则创伤后的伤口修复 可能会受到几种并发症的阻碍 免疫系统受损。外伤性脑损伤（TBI）也经常与出血同时发生 创伤后，与高感染风险有关。感染是死亡的主要原因， 发病率和世界各地的经济破坏，强调需要更好的方法来实现 创伤后止血并改善伤口愈合。凝块形成对于止血至关重要 并涉及形成纤维蛋白网中嵌入的血小板塞。血小板结合多个纤维蛋白纤维 并积极使用力量与网络收缩，从而稳定了发展中的凝块。此外，血小板 - 介导的凝块收缩被认为可以通过重新建立出血后增加伤口愈合 血液流向下游组织，并通过向周围细胞提供机械刺激。我们最近有 发达的血小板样颗粒（PLP）是由高度可变形的微凝胶（凝胶）产生的。 针对基序，该基序是通过高亲和力与临时性结合而专门针对伤口环境的 基质蛋白纤维蛋白。我们先前的研究表明，PLP概括了许多自然功能 血小板，包括体外成年血浆衣服的增强，在啮齿动物模型中精制出血时间 创伤性损伤，特异性归巢对损伤部位，凝块收缩的诱导以及伤口的增强 修复真皮损伤模型。我们还在TBI的啮齿动物模型中显示了PLPS减少血液 受伤后的脑屏障（BBB）渗透性和神经炎症。 该项目的长期目标是开发由该项目触发的静脉止血PLP 人体的本地服装级联，以促进衣服，并随着止血性增强伤口愈合。我们的中心 假设是PLP介导的凝块收缩和抗菌纳米粒细胞的递送的组合将 通过提供机械刺激来显着改善创伤性损伤后伤口愈合 周围细胞并防止/治疗感染。该建议将专门评估稳定性和安全性 含有PLP的抗菌纳米粒细胞。然后将在小鼠中评估这些颗粒的有效性 在不存在或存在感染的情况下出血和愈合的模型。另外，粒子效率，安全性和 免疫系统调节将在啮齿动物的啮齿动物多发性脑损伤模型中评估 （TBI）和出血。