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

• 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
• 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

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.

项目摘要 血管吻合是一种重要的外科手术技术，其缝隙紧密间隔用于连接血管。 此过程经常用于器官移植，创伤维修和心血管手术。但是，血管 吻合很耗时，并且与严重的并发症和较长的恢复时间有关。使用纤维蛋白胶 吻合术导致手术结果改善，工作时间较短，但是这些胶水经常不切实际 由于其浓缩配方会产生高密度凝胶，工作时间短，细胞浸润低和冷 存储限制。我们开发了基于纤维蛋白的纳米颗粒（FBN），我们用来提供生长因子 并在体内促进康复。与传统的纤维蛋白胶不同，FBN是预聚合并使用物理相关的 纤维蛋白/凝血酶浓度。由于其胶体结构和相关事项，FBN暴露了可调 凝胶化，细胞浸润增加，室温存储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剂。该建议的目的是优化， FBN手术密封剂的可涂有和斑块配方的表征和体内分析，可调节生长 因子释放。预计这些FBN密封剂将比电流纤维蛋白胶水表现出更好的功能，并具有 更长的工作时间的好处，在室温下延长稳定性，有针对性的生长因子交付并改善 治愈结果。 AIM 1将优化斑块和可流动FBN胶的配方。这将通过 表征FBN浓度，凝血酶浓度和辅助因子变化的影响，对 胶水的力学和功能。测试将探测聚合和降解动态，结构， 机械性能，密封剂能力和安全性。所使用的方式将包括风化，显微镜，机械 测试以及新型的离体和微流体测定。 AIM 2将优化FBN的加载/释放FGF2， 表征FGF2-FBN密封剂对体外血管伤口愈合的影响。 FGF2加载效率和释放 将确定FBN密封剂的特性并将其与高密度的纤维蛋白胶水进行比较。内皮和成纤维细胞 刮擦测试和伤口闭合测定将用于评估体外的愈合结果。 AIM 3将比较FBN 公式（凝胶和斑块；卸载并用FGF2卸载）使用的当前纤维蛋白胶，并使用体内麻风病模型的模型 颈动脉吻合。血管造影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。该提议的使用FBN将导致一本小说 手术密封剂，有改善的工作时间和可调的药物输送轮廓，可增强伤口愈合 - 允许 对于更快的运营时间，较少的并发症和改善的恢复。该技术还将增加可访问性 通过删除冷链要求，开放其在各种全球健康应用中的用途，可以通过手术进行。训练 在相关的研究技术和该项目所需的临床技能中，将有助于申请人的成功 在她职业生涯的下一个阶段中，成为一名独立物理科学家的道路。