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 数以百万计的动脉或静脉之间的吻合或外科连接是在血管中进行的， 每年在美国进行移植和重建手术。新生内膜增生症，或增殖性和 血管平滑肌细胞迁移到血管腔内，在血管腔内立即发育。 因手术造成局部损伤的吻合术。由此导致的狭窄，或缩小 吻合后的血管是动脉、静脉、动静脉和假体移植物的主要来源。 失败了。预防吻合口狭窄是各种血管手术长期疗效的关键，以及 将改善患者的预后。吻合手术的黄金标准是使用不可吸收的缝合线， 比如尼龙或聚丙烯。我们假设可以生产局部释放抗增殖剂的缝合线 在吻合口放置药物数周或更长时间，从而防止新生内膜过度生长和 在不中断正常手术流程的情况下进行狭窄。在吻合术中使用，缝合线将 提供持续数周或更长时间的药物释放，以防止新生内膜过度生长。 我们描述了一种新型的静电纺丝平台，可以同时生产不可吸收药物和可吸收药物。 血管外科洗脱缝线：(I)包裹在药物洗脱和可降解聚合物中的尼龙缝线 以及(Ii)完全可吸收、高强度、药物洗脱、扭曲的聚合物纳米纤维缝合线。我们有 用雷帕霉素填充这些缝合线，雷帕霉素是一种很有前途的抗增殖药物，已用于 支架联合应用预防支架内再狭窄。我们的初步结果表明，纳米纤维- 涂层尼龙缝线提供雷帕霉素的持续释放，减少大鼠的新生内膜增生 以药物剂量依赖的方式建立吻合口模型数周。在这里，我们的目标是进一步优化我们的 用于药物加载和药物释放的缝线配方，以防止新的内膜增生，同时保持 吻合口修复，将全身副作用降至最低。缝合线将在我们的大鼠吻合术中进行评估 最有希望的候选者将在被认为是最好的大型动物模型中进行测试 重述一下人类的血管系统。如果成功，我们的缝合线可以作为一种平台技术 防止任何类型的器官吻合中的狭窄。