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 在美国，每年有超过55万例显微外科手术用于修复创伤后的组织， 癌症，或通过将组织从身体的一部分移植到另一部分（游离皮瓣）的先天性缺陷 或截肢的身体部位的重新连接（再植）。维持通畅的血管闭塞是 对于任何游离组织移植的成功至关重要，因此，术中或术后血栓形成是最重要的。 这是外科医生和患者担心的并发症，也是游离皮瓣失败的主要原因。游离皮瓣失败 可能导致再次手术、住院时间延长、潜在的破坏性功能和美容疾病，以及 增加了医疗费用。3尽管出现了改进的显微外科器械和培训计划， 文献报道指出，任何地方从6%到高达25%的显微外科病例导致再次手术 因为微血管吻合处血栓形成在每种情况下，微血管血栓形成引起的 高凝性、血流停滞和血管壁损伤（部分由在血管形成过程中对血管壁的损伤引起）。 外科手术，通常使用不可吸收的缝线）是失败的主要原因。使用缝线 用于微血管吻合术，并且它们直接放置在伤口部位，使它们成为 局部、持续给药（手术实践无变化，并减轻全身药物风险） 管理）。我们假设，直接在血栓形成部位通过缝线局部递送抗血栓药物， 该吻合术可以降低血栓形成率，同时安全可靠地连接所有类型的血管。 我们描述了一种新型的、高度通用的制造平台，能够生产由以下组成的缝线： 数百种载药聚合物纳米纤维我们的初步数据表明， 当装载各种小分子时，缝线能够超过临床强度规格。 特别是，他克莫司洗脱缝线证明了持续的药物输送，合适的血管修复， 和显著抑制新生内膜增生。我们认为他克莫司- 洗脱缝线也有可能预防术后血栓形成，并且已经确定了其他药物 具有通过多种机制抑制血栓形成的潜力的类别。在这里，我们的目标是确定哪种药物类别： 抗凝剂（磺达肝癸钠）、抗血小板（乙酰水杨酸、氯吡格雷）或抗炎药 （西罗莫司，他克莫司）通过局部药物递送提供血栓形成的最佳预防，并进一步优化 制剂和制造参数以提供最佳的药物装载和释放。抗血栓缝线 将在大鼠微血管吻合血栓形成模型中进行评估，最有希望的候选者 将在猪游离皮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 该平台可以改善显微手术及其他手术的结果。