Ultra-thin, high strength, drug-eluting sutures for prevention of thrombosis in microvascular surgery

用于预防微血管手术中血栓形成的超薄、高强度药物洗脱缝线

• 批准号: 10672287
• 负责人: Kunal S Parikh
• 金额: $ 38.06万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10672287
• 关键词: Affect; Anastomosis - action; Animal Model; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Anticoagulant therapy; Anticoagulants; Aspirin; Blood Cell Count; Blood Platelets; Blood Vessels; Blood flow; Body Weight; Body part; Calcineurin inhibitor; Clinical; Complication; Cosmetics; Data; Devices; Diameter; Drug Delivery Systems; Drug Kinetics; Endothelium; Ensure; Failure; Family suidae; Fibrinolytic Agents; Formulation; Fright; Health Care Costs; Hospitals; Hour; Hyperplasia; In Vitro; Infection; Inflammation; Inflammatory; Injury; Inpatients; Legal patent; Lipids; Literature; Maintenance; Malignant Neoplasms; Metabolic; Methods; Microsurgery; Modeling; Monitor; Morbidity - disease rate; Morphology; Operative Surgical Procedures; Patients; Pharmaceutical Preparations; Postoperative Complications; Postoperative Period; Prevention; Procedures; Production; Rattus; Recommendation; Repeat Surgery; Reporting; Reproducibility; Risk; Secure; Sirolimus; Site; Skin; Sodium; Specific qualifier value; Spleen; Surgeon; Surgical Instruments; Surgical Replantation; Surgical sutures; Tacrolimus; Technology; Tensile Strength; Testing; Therapeutic; Thick; Thrombophilia; Thrombosis; Time; Tissue Transplantation; Tissues; Toxic effect; Training Programs; Transplantation; Trauma; Triclosan; Vascular Patency; Vascularization; abdominal aorta; care burden; clinically relevant; clopidogrel; controlled release; cytokine; dosage; drug efficacy; efficacy evaluation; fondaparinux; healing; improved; improved outcome; liver function; local drug delivery; manufacture; nanofiber; nanopolymer; novel; prevent; repaired; risk mitigation; safety testing; side effect; small molecule; success; surface coating; thrombotic; tissue repair; wound

PROJECT SUMMARY More than 550,000 microsurgery cases are conducted each year in the US to repair tissue following trauma, cancer, or congenital deficiencies via transplantation of tissue from one part of the body to another (free flaps) or reattachment of amputated body parts (replantation). The maintenance of patent vascular anastomoses is critical to the success of any free tissue transfer, and as such, intra- or post- operative thrombosis is the most feared complication for the surgeon and patient, and is the primary cause of free flap failure. Free flap failure can lead to re-operations, extended inpatient stay, potentially-devastating functional and cosmetic morbidity, and increased healthcare costs.3 Despite the advent of improved microsurgical instruments and training programs, literature reports have indicated that anywhere from 6 to up to 25% of microsurgical cases result in re-operation due to thrombosis at the microvascular anastomosis site. In each case, microvascular thrombosis caused by hypercoagulability, blood flow stasis, and vessel wall injury (caused in part by damage to the vessel wall during the surgical procedure, often using non-absorbable sutures) is the primary cause of failure. The use of sutures for microvascular anastomosis and their placement directly at the wound site make them an ideal platform for local, sustained drug delivery (no change in surgical practice and mitigates the risks of systemic drug administration). We hypothesize that local delivery of anti-thrombotic drugs from sutures directly at the site of the anastomosis can reduce the rate of thrombosis while securely and reliably connecting all types of vessels. We describe a novel, highly versatile manufacturing platform capable of producing sutures composed of hundreds of drug-loaded, polymeric nanofibers. Our preliminary data demonstrates manufacture of microsurgical sutures capable of surpassing clinical strength specifications when loaded with a wide range of small molecules. In particular, tacrolimus-eluting sutures demonstrated sustained drug delivery, suitable vascular repair, and safe and significant inhibition of neointimal hyperplasia in comparison to systemic tacrolimus. We believe tacrolimus- eluting sutures may also have potential to prevent post-operative thrombosis, and have identified additional drug classes with potential to inhibit thrombosis via multiple mechanisms. Here, we aim to determine which drug class: anti-coagulant (fondaparinux sodium), anti-platelet (acetylsalicylic acid, clopidogrel), or anti-inflammatory (sirolimus, tacrolimus) provides optimal prevention of thrombosis via local drug delivery, and further optimize formulations and manufacturing parameters to provide optimal drug loading and release. Anti-thrombotic sutures will be evaluated in rat models of microvascular anastomosis thrombosis, and the most promising candidates will be tested for safety, pharmacokinetics, and efficacy in a swine free flap model. If successful, our suture platform could improve outcomes across a range of surgical procedures in microsurgery and beyond.

项目摘要 每年在美国每年进行超过550,000例显微外科手术病例，以修复创伤后的组织 通过将组织从身体的一个部分移植到另一部分（游自由皮瓣），癌症或先天性缺陷 或重新截肢身体部位（重新种植）。专利血管吻合的维护是 对于任何自由组织转移的成功至关重要，因此，手术内或手术后血栓形成最为重要 害怕外科医生和患者的并发症，是造成自由皮瓣失败的主要原因。自由皮瓣故障 可能导致重新运营，住院住院延长，潜在的功能性和美容发病率以及 3医疗保健成本增加。3尽管有改进的微型手术器械和培训计划的出现，但 文献报告表明，从6至25％的微型外科案件中，任何地方都会重新手术 由于微血管吻合部位的血栓形成。在每种情况下，由 高凝性，血液流动和容器壁损伤（部分是由于在船只壁上损坏而造成的 手术程序通常使用不可吸收的缝合线）是失败的主要原因。缝合线的使用 对于微血管吻合术及其直接在伤口部位的位置，它们成为理想的平台 局部，持续的药物输送（手术实践没有改变，并减轻全身药物的风险 行政）。我们假设直接在 吻合术可以降低血栓形成速率，同时可靠地连接所有类型的血管。 我们描述了一个新颖的，高度的制造平台，能够生产由缝合线组成的 数百种药物的聚合物纳米纤维。我们的初步数据证明了微神经的生产 缝合缝线时，缝合物充满了各种小分子时，可以超过临床强度规格。 尤其是，克莫司的缝合线表现出持续的药物输送，合适的血管修复和安全 与全身性他克莫司相比，对新内膜增生的显着抑制作用。我们相信他克莫司 - 洗脱缝合线也可能有可能预防术后血栓形成，并确定了其他药物 具有通过多种机制抑制血栓形成的潜力的类别。在这里，我们旨在确定哪种药物类别： 抗凝蛋白（酪蛋白蛋白糖钠），抗血小板（乙酰水杨酸，氯吡格雷）或抗炎 （克莫司人的西罗莫司）通过局部药物提供最佳预防血栓形成，并进一步优化 配方和制造参数可提供最佳的药物加载和释放。抗血栓形成缝合线 将在微血管吻合血栓形成的大鼠模型中评估，最有前途的候选者 将在无猪瓣模型中测试安全性，药代动力学和功效。如果成功，我们的缝合 平台可以改善微型外科手术及其他地区的一系列外科手术的结果。