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

项目总结 在美国，每年有超过55万例显微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个部位移植到另一个部位而导致的先天性缺陷(游离组织瓣) 或截肢的身体部分重新附着(再植)。未闭血管吻合术的维护 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 外科医生和患者担心出现并发症，这是游离皮瓣失败的主要原因。游离襟翼失效 可能导致再次手术，延长住院时间，潜在破坏性的功能和美容并发症，以及 医疗费用增加。3尽管出现了改进的显微手术器械和培训方案， 文献报道表明，在任何地方，6%到25%的显微外科病例会导致再次手术。 由于微血管吻合部位的血栓形成。在每个病例中，由以下原因引起的微血管血栓 高凝、血流停滞和血管壁损伤(部分是由于在 手术过程，通常使用非吸收缝线)是失败的主要原因。缝合线的使用 用于微血管吻合，并将其直接放置在伤口处，使其成为治疗 局部、持续的药物输送(不改变外科实践并减轻全身用药的风险 行政管理)。我们假设直接从缝合部位注射抗血栓药物 吻合术可以降低血栓发生率，同时安全可靠地连接所有类型的血管。 我们描述了一种新的、高度通用的制造平台，能够生产缝合线，包括 数以百计的载药聚合物纳米纤维。我们的初步数据表明，制造显微外科手术 缝合线能够超过临床强度规格时，加载了广泛的小分子。 特别是，他克莫司洗脱缝合线显示出持续的药物输送、合适的血管修复和安全。 与全身性他克莫司相比，他克莫司显著抑制新生内膜增生。我们相信他克莫司- 洗脱缝线也有可能预防术后血栓形成，并已确定了其他药物。 具有通过多种机制抑制血栓形成的潜力的类。在这里，我们的目标是确定哪一类药物： 抗凝剂(磺达肝素钠)、抗血小板(乙酰水杨酸、氯吡格雷)或抗炎 (西罗莫司，他克莫司)通过局部给药提供最佳的血栓预防，并进一步优化 配方和制造参数，以提供最佳的药物装载和释放。抗血栓缝合线 将在微血管吻合血栓的大鼠模型中进行评估，并且最有希望的候选者 将在猪游离皮瓣模型中进行安全性、药动学和有效性测试。如果成功，我们的缝合线 Platform可以改善显微外科和其他领域的一系列手术程序的结果。

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.