Novel drug-eluting sutures to prevent vascular graft anastomosis stenosis

新型药物洗脱缝合线预防血管移植吻合口狭窄

• 批准号: 9899316
• 负责人: Laura Ensign
• 金额: $ 31.04万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899316
• 关键词: Adopted; Anastomosis - action; Animal Model; Animals; Arteries; Blood Cell Count; Blood Vessels; Body Weight; Bypass; Caliber; Cardiovascular Diseases; Cardiovascular Surgical Procedures; Characteristics; Childhood; Coronary; Devices; Dose; Drug Formulations; Electrospinning; Engineering; Ensure; Formulation; Functional disorder; Gel; Gold; Growth; Hemodialysis; Human; Hyperplasia; In Vitro; Incidence; Inflammation; Kidney; Lipids; Longevity; Metabolic; Methods; Modeling; Morbidity - disease rate; Morphology; Nylons; Obstruction; Operative Surgical Procedures; Organ; Organ Transplantation; Patients; Peripheral; Pharmaceutical Preparations; Physiologic arteriovenous anastomosis; Polymers; Polypropylenes; Procedures; Process; Prognosis; Prosthesis; Rattus; Sheep; Sirolimus; Site; Smooth Muscle Myocytes; Spleen; Stenosis; Stents; Surgical sutures; Technology; Tensile Strength; Testing; Therapeutic; Thinness; Time; Transplantation; Vascular Graft; Vascular Smooth Muscle; Veins; Venous; Wool; antiproliferative drugs; appropriate dose; biodegradable polymer; biomaterial compatibility; controlled release; dosage; drug efficacy; drug release kinetics; efficacy evaluation; graft failure; healing; improved; liver function; manufacturing process; migration; nanofiber; novel; novel therapeutics; prevent; reconstruction; repaired; restenosis; side effect; surgery outcome

Project Summary Millions of anastomoses, or surgical connections between arteries or veins, are performed in vascular, transplant, and reconstruction procedures in the US each year. Neointimal hyperplasia, or proliferation and migration of vascular smooth muscles cells into the vessel lumen space, develops immediately at the site of anastomosis due to the local damage caused by the surgical procedure. The resulting stenosis, or narrowing of the vessel after the anastomosis, is the main contributor to arterial, venous, arteriovenous, and prosthetic graft failure. Preventing anastomotic stenosis is the key to long-term efficacy of all types of vascular surgery, and will improve patient prognosis. The gold standard for anastomotic surgery is to use non-absorbable sutures, like nylon or polypropylene. We hypothesize that sutures can be produced that locally release anti-proliferative drugs at the site of anastomosis for several weeks or longer, thereby preventing neointimal overgrowth and stenosis without disrupting normal surgical workflow. Used during anastomosis procedure, the suture will provide sustained release of drugs for several weeks or longer to prevent neointimal overgrowth. We describe a novel electrospinning platform capable of producing both non-absorbable and absorbable drug- eluting sutures for vascular surgery: (i) nylon sutures that are wrapped in drug-eluting and degradable, polymer nanofibers, and (ii) fully absorbable, high-strength, drug-eluting, twisted polymer nanofiber sutures. We have loaded these sutures with rapamycin, which is a promising anti-proliferative drug that has been used in combination with stents for preventing in-stent restenosis. Our preliminary results demonstrate that nanofiber- coated nylon sutures provide sustained rapamycin release that decreases neointimal hyperplasia in a rat anastomosis model in a drug dose dependent fashion for several weeks. Here, we aim to further optimize our suture formulations for drug loading and drug release to prevent neointimal hyperplasia while maintaining anastomosis repair and minimizing systemic side effects. The sutures will be evaluated in our rat anastomosis model, and the most promising candidates will be tested in a large animal model that is considered to best recapitulate the human vasculature. If successful, our sutures could serve as a platform technology for preventing stenosis in any type of organ anastomosis.

项目摘要 在血管中进行数百万吻合或动脉或静脉之间的手术连接 每年在美国的移植和重建程序。新内膜增生或增殖和 血管平滑肌细胞迁移到容器腔空间中，立即在 由于手术程序造成的局部损害，吻合术。由此产生的狭窄或变窄 吻合后的血管是动脉，静脉，动静脉和假肢移植物的主要贡献者 失败。预防吻合式狭窄是所有类型的血管手术的长期功效的关键，并且 将改善患者预后。吻合手术的黄金标准是使用不可吸收的缝合线， 如尼龙或聚丙烯。我们假设可以生产缝合线，以局部释放抗增殖性 吻合部位的药物几周或更长时间，从而防止了新的过度生长和 狭窄而不会破坏正常的手术工作流程。在吻合过程中使用的缝合线将 提供数周或更长时间的持续释放药物，以防止新的过度生长。 我们描述了一个新型的静电平台，能够产生不可吸收和可吸收的药物 - 洗脱血管手术缝合线：（i）用药物洗脱和降解的聚合物包裹的尼龙缝合线 纳米纤维，以及（ii）完全吸收，高强度，药物洗脱，扭曲的聚合物纳米纤维缝合线。我们有 用雷帕霉素加载了这些缝合线，这是一种有希望的抗增殖药物 结合支架可预防支架内再狭窄。我们的初步结果表明纳米纤维 - 涂层尼龙缝合线提供持续的雷帕霉素释放，可降低大鼠的新内膜增生 以药物剂量依赖的方式吻合模型数周。在这里，我们旨在进一步优化我们的 药物加载和药物释放的缝合配方，以防止新的增生，同时保持 吻合修复并最大程度地减少全身副作用。缝合线将在我们的大鼠吻合中评估 模型和最有前途的候选人将在大型动物模型中进行测试，该模型被认为是最好的 概括人类脉管系统。如果成功，我们的缝合线可以作为平台技术 防止任何类型的器官吻合术的狭窄。