Fibrin-Based Nanoparticles as a Novel Sealant for Vascular Anastomosis

基于纤维蛋白的纳米颗粒作为血管吻合的新型密封剂

基本信息

批准号：
10806127
负责人：
Nina Alexandra Moiseiwitsch
金额：
$ 3.99万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10806127
关键词：
Address Adhesives Air Embolism Anastomosis - action Angiography Benchmarking Biocompatible Materials Biological Biological Assay Blood Vessels Cardiovascular Diseases Cardiovascular Surgical Procedures Carotid Arteries Cells Cellular Infiltration Characteristics Clinical Skills Coagulation Process Cold Chains Colloids Consumption Coronary Artery Bypass Cryopreservation Drug Delivery Systems Drug vehicle Endothelium Evaluation Exhibits FGF2 gene Fibrin Fibrin Tissue Adhesive Fibrinogen Fibroblast Growth Factor Fibroblasts Formulation Freeze Drying Gel Glues Growth Factor Hemorrhage Hemostatic function Histologic Hyperplasia In Vitro Infiltration Lead Left Life Ligation Link Marketing Mechanics Medical Microfluidics Microscopy Modality Modeling Morphology Natural Disasters Operative Surgical Procedures Organ Transplantation Organ failure Oryctolagus cuniculus Outcome Patients Pharmaceutical Preparations Phase Physicians Physiological Play Polymers Porosity Postoperative Period Procedures Process Property Public Health Recovery Research Research Technics Risk Role Safety Scientist Shapes Site Skin wound healing Stenosis Stimulant Structure Surgical sutures Techniques Technology Temperature Testing Thrombin Thrombosis Time Tissue Sample Training Transplantation Trauma War Work career cofactor density design flexibility global health healing health application histological specimens improved in vivo innovation mechanical properties nanoparticle novel novel therapeutics particle polymerization practical application pressure release factor repaired restenosis sealant success surgery outcome wound closure wound healing

项目摘要

PROJECT SUMMARY Vascular anastomosis is an important surgical technique whereby closely spaced stitches are used to connect blood vessels. This process is used frequently in organ transplantation, trauma repairs, and cardiovascular surgery. However, vascular anastomosis is time consuming and associated with serious complications and long recovery times. Use of fibrin glue in anastomosis has led to improved surgical outcomes and shorter operating times, but these glues are frequently impractical as their concentrated formulations create high-density gels with short working times, low cellular infiltration, and cold storage limitations. We have developed fibrin-based nanoparticles (FBNs) which we have used to deliver growth factors and promote healing in vivo. Unlike traditional fibrin glues, FBNs are pre-polymerized and use physiologically relevant fibrin/thrombin concentrations. Owing to their colloidal structure and the aforementioned properties, FBNs exhibit tunable gelation, increased cellular infiltration, room temperature storage, and enhanced drug delivery capabilities – including of fibroblast growth factor 2 (FGF2), a known stimulant of vascular repair. The objective of this proposal is the optimization, characterization and in vivo analysis of paintable and patch formulations of an FBN surgical sealant with tunable growth factor release. It is expected that these FBN sealants will demonstrate better functionality than current fibrin glues, with the benefit of longer work time, extended stability at room temperature, targeted growth factor delivery, and improved healing outcomes. Aim 1 will optimize the formulation of patch and flowable FBN glues. This will occur through characterization of the effects of changes in FBN concentration, thrombin concentration, and cofactor used, on the mechanics and functionality of the glues. Testing will probe polymerization and degradation dynamics, structure, mechanical properties, sealant ability, and safety profile. Modalities used will include rheometry, microscopy, mechanical testing, and novel ex vivo and microfluidic assays. Aim 2 will optimize the loading/release of FGF2 by FBNs and characterize the effects of FGF2-FBN sealants on vascular wound healing in vitro. FGF2 loading efficiency and release characteristics of FBN sealants will be determined and compared to high-density bulk fibrin glues. Endothelial and fibroblast scratch tests and wound closure assays will be used to assess healing outcomes in vitro. Aim 3 will compare FBN formulations (gel and patch; unloaded and loaded with FGF2) to current fibrin glues using an in vivo leporine model of carotid artery anastomosis. Angiography will be use to characterize vascular morphology and histology of sampled tissues will be used to evaluate signs of healing, restenosis, and hyperplasia. This proposal’s use of FBNs will lead to a novel surgical sealant with improved work time and tunable drug delivery profiles that boasts superior wound healing – allowing for faster operating times, fewer complications, and improved recovery. This technology will also increase the accessibility of surgical glues by removing cold-chain requirements, opening up their use in varied global health applications. Training in the associated research techniques and clinical skills required for this project will contribute to the success of the applicant during the next phases of her career on the path to becoming an independent physician scientist.

项目概要血管吻合术是一种重要的外科技术，通过紧密间隔的缝合来连接血管。该过程经常用于器官移植、创伤修复和心血管手术。吻合术非常耗时，并且会导致严重的并发症和较长的恢复时间。吻合术改善了手术效果并缩短了手术时间，但这些胶水通常不切实际因为其浓缩配方可形成高密度凝胶，工作时间短、细胞渗透低且冷我们开发了基于纤维蛋白的纳米粒子（FBN），用于传递生长因子。与传统的纤维蛋白胶不同，FBN 是预聚合的，并且具有生理相关性。由于其胶体结构和上述特性，FBN 表现出可调节的纤维蛋白/凝血酶浓度。凝胶化、增加细胞渗透、室温储存和增强的药物输送能力 - 包括成纤维细胞生长因子 2 (FGF2)，一种已知的血管修复刺激物，该提案的目的是优化，具有可调节生长的 FBN 手术密封剂的可涂漆和贴片配方的表征和体内分析预计这些 FBN 密封剂将比目前的纤维蛋白胶表现出更好的功能。具有更长的工作时间、延长室温稳定性、靶向生长因子输送以及改进的优点目标 1 将优化贴片和可流动 FBN 胶的配方。表征 FBN 浓度、凝血酶浓度和所用辅因子变化对测试将探讨胶水的聚合和降解动力学、结构、机械性能、密封剂能力和安全特性将包括流变测定、显微镜、机械。测试，以及新颖的离体和微流体测定，目标 2 将优化 FBN 和 FGF2 的加载/释放。表征 FGF2-FBN 密封剂对体外血管伤口愈合的影响。 FBN 密封剂的特性将被确定并与高密度块状纤维蛋白胶进行比较。划痕测试和伤口闭合试验将用于评估体外愈合结果，Aim 3 将比较 FBN。使用体内兔素模型将配方（凝胶和贴片；卸载和装载 FGF2）转化为当前的纤维蛋白胶颈动脉吻合术将用于表征采样组织的血管形态和组织学。将用于评估愈合、再狭窄和增生的迹象。该提案对 FBN 的使用将产生一种新颖的效果。手术密封剂具有改善的工作时间和可调节的药物输送曲线，具有卓越的伤口愈合能力 - 允许更快的手术时间、更少的并发症和更好的恢复。该技术还将提高可及性。通过消除冷链要求，开放其在各种全球健康应用中的使用。该项目所需的相关研究技术和临床技能将有助于申请人的成功在她职业生涯的下一阶段，她将成为一名独立的医师科学家。