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.

项目总结