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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：
10521864
负责人：
Kunal S Parikh
金额：
$ 36.91万
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/10521864
关键词：
Affect Amputation Anastomosis - action Animal Model Animals Anti-Bacterial Agents Anti-Inflammatory Agents Anticoagulant therapy Anticoagulants Antiplatelet Drugs Aspirin Blood Cell Count Blood Vessels Blood flow Body Weight Body part Calcineurin inhibitor Caliber Clinical Complication Cosmetics Data Devices 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 Lead Legal patent Lipids Literature Maintenance Malignant Neoplasms Metabolic Methods Microsurgery Modeling Monitor Morbidity - disease rate Morphology Operative Surgical Procedures Patients Pharmaceutical Preparations Polymers Postoperative Complications Postoperative Period Prevention Procedures Production Rattus Reporting Reproducibility Risk Secure Sirolimus Site Skin Sodium Spleen Surgeon Surgical Flaps Surgical Replantation Surgical sutures Tacrolimus Technology Tensile Strength Testing Therapeutic Thick Thinness Thrombophilia Thrombosis Time Tissue Transplantation Tissues Toxic effect Training Programs Transplantation Trauma Triclosan Vascularization abdominal aorta base clinically relevant clopidogrel controlled release cytokine dosage drug efficacy efficacy evaluation fondaparinux healing improved improved outcome instrument liver function local drug delivery nanofiber novel operation prevent repaired safety testing side effect small molecule success surface coating 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.

项目总结