Novel Guidewire Design and Coating for Adenosine Delivery

冠状动脉疾病(CAD)影响着1400万美国人，导致大约90万人患上心肌梗死 每年有650,000人死于脑梗塞(MI)。经皮介入治疗(Pci)是最常用的治疗方法。 治疗冠心病的程序。微血管阻塞(MVO)和无复流现象(NRF)是主要的 阻碍最佳结果的障碍，是死亡率和心力衰竭的独立风险因素。当前 设备仅部分有效地缓解了MI后的MVO和NRF。负责的机制 对于MVO来说，是复杂和多因素的。腺苷是一种内源性核苷，可以减弱许多 负责MVO的机制。我们实验室的精液研究表明，静脉注射腺苷 导致显著的心肌保护，这一发现在大型临床试验中得到了证实。腺苷完全治疗性 由于其在人类血液中的超短半衰期(约1秒)，其潜力受到损害。通过组合 导丝设计、表面化学、腺苷的气流粉碎和新型亲水性载药材料的创建 对于扩散阻挡涂层，我们开发了一种导丝平台(Adenowire)，它允许连续输送 在整个经皮冠状动脉介入治疗过程中。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，在这些动物模型中，强大的血管扩张和快速逆转的血管收缩 已确认身份。新的惰性涂层还提供了抗血小板作用，通过添加 涂层中的腺苷。试验台研究表明，金属丝的性能和涂层质量与惰性金属相当 市面上有亲水性导轨。虽然我们的第二阶段SBIR拨款和后续开发 产生了安全和功能齐全的产品，但在该设备能够 商业化了。Adenowire的制造和涂层不受FDA严格监管 要求，并使用了一种非灭菌产品。Adenowire被归类为组合产品，并且 腺苷和导丝已经获得了FDA的批准。监管顾问提交的IND前意见书 确定将通过CDRH(设备)部门采用“从头开始”的方式进行批准。为了 进行临床试验，需要以下援助：1)后期研究和开发 利用GMP制造和评价涂层的导丝制造和应用 灭菌产品的生物兼容性和功能参数；2)监管援助，包括 策略、文档、IDE应用程序的提交和临床需求规模的确定 审判。从这些研究中获得的结果将是无价的，因为这些数据将导致最终确定 允许发布IDE并启动首个人中(FIM)临床试验的产品。这将大大增强 我们获得额外资金和战略伙伴关系的能力。Adenowire是一种变革性的设备， 价格低廉，将有一个巨大的目标市场，并代表着治疗CAD的重大技术进步 接受经皮冠状动脉介入治疗的患者。

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.