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要的临床问题， 平民和战场创伤的死亡原因如果实现止血，创伤后伤口修复 可能会受到几种并发症的阻碍，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 创伤后，并与感染的高风险相关。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 止血和改善创伤后伤口愈合。血凝块的形成对止血至关重要 并涉及嵌入纤维蛋白网内的血小板栓的形成。血小板与多种纤维蛋白纤维结合 积极发力收缩网络，稳定发展态势。此外，血小板- 介导的血凝块收缩被认为在出血停止后通过重新建立 血液流向下游组织并向周围细胞提供机械刺激。我们最近 开发了血小板样颗粒（PLPs），由高度可变形的微凝胶（微凝胶）与伤口结合而成， 靶向基序，其通过高亲和力结合到临时的 基质蛋白纤维蛋白。我们先前的研究表明，PLPs概括了许多自然的功能， 血小板，包括体外增强成人血浆凝血，减少啮齿动物模型的出血时间 创伤性损伤，特异性归巢至损伤部位，诱导凝块收缩和增强伤口 皮肤损伤的啮齿动物模型中的修复。我们还在TBI的啮齿动物模型中显示，PLPs减少血液中的 损伤后的脑屏障（BBB）通透性和神经炎症。 该项目的长期目标是开发静脉内止血PLP， 凝血因子可通过体内的天然凝血级联反应促进凝血，并在止血后促进伤口愈合。我们的中央 假设PLP介导的凝块收缩和抗菌纳米银的递送的组合将 通过提供机械刺激， 周围的细胞和预防/治疗感染。这份提案将专门评估稳定性和安全性 含有抗菌纳米银的PLPs。然后将在小鼠中评估这些颗粒的有效性 出血和愈合的模型，在没有或存在感染。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性创伤模型中评价免疫系统调节 (TBI)和出血。