Novel Guidewire Design and Coating for Adenosine Delivery

用于腺苷输送的新型导丝设计和涂层

• 批准号: 10699444
• 负责人: Mervyn B. Forman
• 金额: $ 25万
• 依托单位: ADENOPAINT, LLC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-10 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10699444
• 关键词: Accreditation; Adenosine; Adhesions; Advanced Development; Affect; American; Animal Model; Area; Attenuated; Blood; Blood Platelets; Blood Vessels; Cardiotonic Agents; Cardiovascular Diseases; Cause of Death; Cessation of life; Chemistry; Classification; Clinical Research; Clinical Trials; Complex; Coronary; Coronary Arteriosclerosis; Data; Development; Devices; Diffusion; Documentation; Drug Delivery Systems; Engineering; Evaluation; FDA approved; Funding; Goals; Good Manufacturing Process; Grant; Guidelines; Half-Life; Heart failure; Human; Hydrogels; In Vitro; Intellectual Property; Intervention; Intravenous; Laboratories; Laboratory Research; Manufacturer; Marketing; Mechanics; Medical; Medical Device; Methods; Myocardial; Myocardial Infarction; Nucleosides; Obstruction; Outcome; Outsourcing; Pathway interactions; Patients; Performance; Pharmaceutical Preparations; Phase; Practice Guidelines; Procedures; Quality Control; Regulatory Pathway; Research; Risk Factors; Safety; Secure; Seminal; Small Business Innovation Research Grant; Sterilization; Surface; System; Technology; Testing; Therapeutic; Vasodilation; Vendor; biomaterial compatibility; commercialization; design; first-in-human; hydrophilicity; improved outcome; innovation; manufacture; manufacturing scale-up; member; mortality; novel; percutaneous coronary intervention; preclinical evaluation; preclinical study; programs; randomized trial; research and development; supply chain; tissue injury; vasoconstriction

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.

冠状动脉疾病 (CAD) 影响了 1,400 万美国人，导致约 90 万心肌梗塞 每年有 65 万人死于梗塞 (MI)。经皮介入治疗 (PCI) 是最常进行的治疗 治疗 CAD 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危险因素。当前的 设备在缓解 MI 之后的 PCI 后的 MVO 和 NRF 方面仅部分有效。负责的机制 MVO 是复杂且多因素的。腺苷是一种内源性核苷，可减弱许多 负责 MVO 的机制。我们实验室的开创性研究表明，静脉注射腺苷 导致显着的心肌保护作用，这一发现已在大型临床试验中得到证实。腺苷的全面治疗 由于其在人体血液中的半衰期超短（约 1 秒），因此其潜力受到影响。通过结合 导丝设计、表面化学、腺苷喷射研磨以及新型亲水性药物装载和制备 扩散屏障涂层，我们开发了一个导丝平台（Adenwire），可以连续输送 整个 PCI 过程中腺苷的含量。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验证，其中强烈的血管舒张和血管收缩的快速逆转 确定。新型惰性涂层还提供抗血小板作用，通过添加可增强抗血小板作用 涂层中的腺苷。台架研究表明，线材性能和涂层质量与惰性线材相当 亲水性市售导丝。虽然我们的第二阶段 SBIR 资助和后续开发 虽然产品安全且功能齐全，但在该设备投入使用之前仍存在巨大的资金缺口 商业化。 Adenwires 的制造和涂层并未受到 FDA 严格监管 要求并使用非灭菌产品。 Adenwire 被归类为组合产品，两者 腺苷和导丝已获得 FDA 批准。监管顾问提​​交的 IND 前申请 确定批准将通过 CDRH（设备）部门利用“从头”途径进行。为了 进行临床试验，需要以下协助：1）后期研究和开发 利用良好生产规范（GMP）和评估进行导丝制造和涂层应用 灭菌产品的生物相容性和功能参数； 2) 监管援助包括 战略、文件、提交 IDE 申请以及确定临床需求规模 试验。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 产品允许发布 IDE 并启动首次人体 (FIM) 临床试验。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 是一种变革性设备 价格低廉，将拥有广阔的目标市场，代表着治疗 CAD 的重大技术进步 接受 PCI 的患者。