Optimizing Cardiovascular Device Thromboresistance for Eliminating Anticoagulants

描述(由申请人提供)：在我们的高风险/高影响特别应用计划资助的第一阶段项目中，成功开发了一种凝血活性预测技术-设备致血栓活性仿真器(DTE)-一种提高循环心血管设备抗血栓性能的通用方法，并展示了其在设计优化中的应用，以实现更高的性能。在这个量子二期项目中，将对来自不同制造商的一系列CVS设备进行测试和优化，最终目标是将它们的血栓形成能力降低到使设备接受者从复杂的药理抗凝治疗中解放出来的水平。在拟议的量子项目的第二阶段，DTE将用于优化CVS设备的各个子组的设计：人工心脏瓣膜(PHV)、室性辅助设备(VAD)、双室VAD以及FDA批准的第一台临时全人工心脏(THTT)。所有这些设备都将使用尖端的数值模拟技术在数值领域进行优化，并将连接到血液动力学剪切设备(HSD)，该设备模拟设备内的血流动力学-在该设备中测量设备促进血液凝结的潜力。重复这一过程，并对旨在降低设备血栓形成能力的设计修改进行优化，以最终消除这些设备所需的危险和复杂抗凝剂的使用。优化设备的原型将由本提案中的工业合作伙伴制造-其中包括一些领先的公司，他们已经向市场推出了几种突破性的机械循环支持(MCS)设备。优化后的原型将由我们在体外进行测试，以测试DTE优化是否达到了其声明的目标，并将在体内进行广泛的动物实验系列(在著名的亚利桑那州Sarver心脏中心进行)以及在各种参与设备制造商的设施中进行测试。我们将进一步为每个行业合作伙伴建立DTE系统，并对他们进行这一创新方法的培训。我们将与FDA互动，为设备血栓形成建立新的指南。我们的工业合作伙伴将进一步寻求FDA(PMA/IDE/HDE)的试验或研究要求，以满足设备类型和优化修改的要求，以促进首次人工演示和将优化设备推向市场。据设想，到第二阶段结束时，一些测试和优化的设备将展示消除抗凝的量子进步的潜力。对于寻求制造、重新设计和测试心血管设备的制造商来说，提供的技术将成为必不可少的工具。 与公共健康相关：美国每年有500多万患者患有心力衰竭。其中很大一部分将成为长期机械循环支持(MCS)的候选者。血栓栓塞症和随之而来的中风风险仍然是使用它们进行长期目的地治疗的关键障碍。DTE技术将有助于大幅降低研发和相关医疗成本的上升。使用抗凝剂消除困难和昂贵的药理管理有望为使用这些设备作为长期目的地治疗铺平道路，并拯救无数生命。

DESCRIPTION (provided by applicant): In our Phase I project which was funded under special high-risk/high-impact applications program, a thrombogenicity predictive technology - Device Thrombogenicity Emulator (DTE) - a universal methodology for improving the thromboresistance of circulatory cardiovascular devices was successfully developed, and its application to design optimization for achieving improved performance was demonstrated. In this Quantum Phase II project an array of CVS devices from various manufacturers will be tested and optimized, with the ultimate goal to reduce their thrombogenicity to a level that will liberate the device recipients from the need for complex pharmacological anticoagulation therapy. During the Phase II of the proposed quantum project, the DTE will be utilized to optimize the design of various sub-groups of CVS devices: Prosthetic Heart Valves (PHV), Ventricular Assist Devices (VAD), bi-ventricular VAD, and the first FDA approved temporary Total Artificial Heart (TAHt). All these devices will be optimized in the numerical domain, using cutting edge numerical simulation techniques, and will be interfaced to a Hemodynamic Shearing Device (HSD) that emulates the hemodynamics within the device- in which the potential of the device to promote blood clotting is measured. The process is reiterated, and design modifications aimed at reducing the device thrombogenicity are optimized to a level that will eventually eliminate the use of risky and complex anticoagulation these devices require. Prototypes of optimized devices will be manufactured by the industrial partners in this proposal- among them some of the leading companies who have introduced to the market several break-through mechanical circulatory support (MCS) devices. The optimized prototypes will be tested by us in vitro to test whether the DTE optimization achieved its stated goals, and will be further tested in vivo in an extensive animal experiments series (performed at the renowned Sarver Heart Center, U. Arizona), as well as in the various participating device manufacturers facilities. We will further build DTE systems for each of the industrial partners and train them in this innovative methodology. We will interact with the FDA for establishing new guidelines for device thrombogenicity. Our industrial partners will further seek trial or study requirements from the FDA (PMA/IDE/HDE), as required for the type of device and the optimization modifications, to facilitate first human demonstration and introduction of the optimized devices to the market. It is envisioned that by the end of phase II some of the devices tested and optimized will demonstrate the potential for a quantum advance of eliminating anticoagulation. The technology offered will become an essential tool for manufacturers that seek to create, redesign and test a cardiovascular device. PUBLIC HEALTH RELEVANCE: Over 5 million patients in the US suffer annually from heart failure. Of those a significant proportion will become candidates for longer-term mechanical circulatory support (MCS). Thromboembolism and the attendant risk for stroke remains the critical barrier to their use for long term destination therapy. The DTE technology will help in drastically reducing the R&D and escalating healthcare costs involved. Elimination of difficult and costly pharmacological management with anticoagulants is expected to pave the way for the use of these devices as long term destination therapy and save countless lives.