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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要美国每年进行超过 550,000 例显微外科手术来修复创伤后的组织，癌症，或通过将组织从身体的一个部位移植到另一部位（游离皮瓣）而导致的先天性缺陷或重新连接截肢的身体部位（再植）。血管吻合术的维持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外科医生和患者都担心出现并发症，并且是游离皮瓣失败的主要原因。自由瓣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发病率，以及医疗保健成本增加。3尽管出现了改进的显微手术器械和培训计划，文献报告表明，6% 到 25% 的显微手术病例会导致再次手术由于微血管吻合部位血栓形成。在每种情况下，微血管血栓都是由高凝状态、血流停滞和血管壁损伤（部分是由于手术过程中血管壁损伤造成的）手术过程（通常使用不可吸收的缝合线）是失败的主要原因。缝合线的使用用于微血管吻合术并将其直接放置在伤口部位使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，并减轻了全身药物的风险行政）。我们假设，通过缝线直接在血栓部位进行局部递送抗血栓药物吻合可降低血栓形成率，同时安全可靠地连接各类血管。我们描述了一种新颖的、高度通用的制造平台，能够生产由以下材料组成的缝合线：数百种载药聚合物纳米纤维。我们的初步数据表明显微外科手术的制造当装载各种小分子时，缝线能够超越临床强度规格。特别是，他克莫司洗脱缝合线表现出持续的药物输送、适当的血管修复和安全与全身性他克莫司相比，显着抑制新内膜增生。我们相信他克莫司- 洗脱缝线也可能具有预防术后血栓形成的潜力，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（磺达肝素钠）、抗血小板剂（乙酰水杨酸、氯吡格雷）或抗炎剂（西罗莫司、他克莫司）通过局部给药提供最佳的血栓形成预防，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。抗血栓缝线将在微血管吻合血栓形成的大鼠模型中进行评估，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。如果成功的话，我们的缝合平台可以改善显微外科及其他领域的一系列外科手术的结果。