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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要外伤后失血过多是一个严重的临床问题；平民和战场创伤的死亡原因如果实现止血，创伤后的伤口修复。可能会受到多种并发症的阻碍，包括感染、疤痕疙瘩形成、血流不足和免疫系统受损（TBI）也经常与出血同时发生。创伤后并与高感染风险相关，是死亡的主要原因，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伤口愈合对于止血至关重要。并涉及嵌入纤维蛋白网内的血小板栓的形成血小板结合多个纤维蛋白纤维。并积极施加力量来收缩网络，从而稳定正在形成的血栓。介导的凝块收缩被认为可以通过重建伤口来促进出血停止后的伤口愈合。我们最近发现，血液流向下游组织并为周围细胞提供机械刺激。开发了由高度可变形的微凝胶（凝胶）与伤口结合而成的血小板样颗粒（PLP）靶向基序，通过与临时材料的高亲和力结合，专门针对伤口环境我们之前的研究表明，PLP 概括了天然纤维蛋白的许多功能。血小板，包括在体外增强成人血浆的凝血，减少啮齿动物模型的出血时间创伤性损伤的发生、对损伤部位的特异性归巢、诱导凝块收缩以及伤口的增强在啮齿动物皮肤损伤模型中的修复我们还在 TBI 啮齿动物模型中证明了 PLP 可以减少血液。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由以下因素触发的静脉止血PLP：身体的天然凝血级联可促进凝血，并在止血后增强伤口愈合。假设 PLP 介导的凝块收缩和抗菌纳米银的输送相结合将通过向伤口提供机械刺激，显着改善创伤后的伤口愈合该提案将专门评估稳定性和安全性。然后将在小鼠中评估这些颗粒的抗菌纳米银的有效性。另外，在没有或存在感染的情况下出血和愈合的模型，颗粒的功效、安全性和。将在联合创伤性脑损伤的啮齿动物多发伤模型中评估免疫系统调节（TBI）和出血。