Novel Guidewire Design and Coating for Adenosine Delivery

冠状动脉疾病（CAD）影响1400万美国人，导致约90万心肌梗死。 心肌梗死（MI）和每年650，000例死亡。经皮介入治疗（PCI）是最常见的 治疗CAD的程序。主要表现为微血管阻塞（MVO）和无复流现象（NRF 这些障碍阻碍了最佳结局，是死亡率和心力衰竭的独立风险因素。电流 器械仅部分有效缓解MI PCI后的MVO和NRF。负责的机制 MVO是复杂和多因素的。腺苷是一种内源性核苷， 负责MVO的机制。我们实验室的精液研究表明， 导致显著的心肌保护，这一发现在大型临床试验中得到证实。腺苷是完全治疗性的 由于其在人体血液中的半衰期极短（约1秒），潜在的危害。通过组合 导丝设计、表面化学、腺苷的喷射研磨和新型亲水性载药的产生， 扩散屏障涂层，我们开发了一种导丝平台（Adenowire），允许连续输送 在整个PCI过程中使用腺苷。体外研究证实了腺苷的理想洗脱曲线， 在大型动物模型中得到了验证，在这些模型中， 鉴定新型惰性涂层还提供抗血小板作用，该作用随着添加 包衣中的腺苷。台架研究表明，电线性能和涂层质量与惰性 亲水性市售导丝。虽然我们的第二阶段SBIR赠款和后续发展 虽然该设备是一种安全和功能性的产品，但在该设备能够投入使用之前，仍然存在巨大的资金缺口。 商业化。Adenowires的制造和涂层不受严格的FDA监管 要求，并使用非灭菌产品。Adenowire被归类为组合产品， 腺苷和导丝已经通过了FDA的认证监管顾问提交的IND前申请 确定批准将通过CDRH（器械）部门使用“从头”途径进行。为了 进行临床试验，需要以下援助：1）后期研究和开发 采用良好生产规范（GMP）的导丝制造和涂层应用及评价 灭菌产品的生物相容性和功能参数; 2）监管协助，包括 战略、文件、IDE申请的提交和临床要求规模的确定 审判从这些研究中获得的结果将是非常宝贵的，因为这些数据将最终确定 允许发布IDE和启动首次人体（First in Man，简称IDE）临床试验的产品。这将大大提升 我们获得额外资金和战略伙伴关系的能力。Adenowire是一种变革性设备， 价格低廉，将有一个大的目标市场，并代表了一个重大的技术进步，治疗CAD PCI患者

Coronary artery disease (CAD) effects 14 million Americans resulting in approximately 900,000 myocardial infarction’s (MI) and 650,000 deaths annually. Percutaneous intervention (PCI) is the most frequently performed procedure to treat CAD. Microvascular obstruction (MVO) and “no reflow phenomenon” (NRF) are major barriers that preclude optimal outcomes and are independent risk factors for mortality and heart failure. Current devices are only partially effective in mitigating MVO and NRF following PCI for MI. The mechanisms responsible for MVO are complex and multifactorial. Adenosine, an endogenous nucleoside, attenuates many of the mechanisms responsible for MVO. Seminal studies in our laboratory demonstrated that intravenous adenosine resulted in striking myocardial protection, a finding confirmed in large clinical trials. Adenosine’s full therapeutic potential is compromised due to its ultrashort half-life (approximately 1 second) in human blood. By combining guidewire design, surface chemistry, jet milling of adenosine and creation of novel hydrophilic drug-loading and diffusion barrier coatings, we developed a guidewire platform (Adenowire) which allows for continuous delivery of adenosine throughout a PCI procedure. In vitro studies confirmed an ideal elution profile for adenosine that was verified in large animal models where robust vasodilatation and rapid reversal of vasoconstriction was identified. The novel inert coating also provides antiplatelet effects that are amplified with the addition of adenosine in the coating. Bench studies reveal that wire performance and coating quality are comparable to inert hydrophilic commercially available guidewires. While our phase 2 SBIR grant and subsequent development resulted in a safe and functional product, a significant funding gap remains before the device can be commercialized. Manufacturing and coating of Adenowires were not subjected to rigorous FDA regulatory requirements and utilized a non-sterilized product. Adenowire is classified as a combination product and both adenosine and guidewires are already FDA approved. A pre-IND submission by a regulatory consultant determined that approval would occur via CDRH (device) division utilizing a “de novo“ pathway. In order to proceed with clinical trials, the following assistance is needed: 1) Late Stage Research and Development on guidewire manufacturing and application of coating utilizing good manufacturing practice (GMP) and evaluation of biocompatibility and functional parameters on a sterilized product; 2) Regulatory Assistance to include strategy, documentation, submission of IDE application and determination of size of requirements for clinical trials. Results obtained from these studies would be invaluable since such data would result in finalization of the product allowing issuance of an IDE and initiation of a First in Man (FIM) clinical trial. This will greatly enhance our ability to obtain additional funding and strategic partnerships. Adenowire is a transformative device that is inexpensive, will have a large target market and represents a major technological advancement for treating CAD patients with PCI.