Novel Device for Sensitive, Small Sample Volume Assessment of Clot Elasticity

描述（由申请人提供）：我们建议开发一种用于测量血凝块弹性的新型装置，其具有更高的准确性和速度，并且需要更小的样品体积。从长远来看，这可以实现更好的护理点管理和诊断由广泛的心血管疾病引起的凝血病，包括心肌梗死、中风、冠状动脉疾病、静脉血栓栓塞和高血糖症。这种预期源于以下事实：在这些疾病中，凝块弹性模量（CEM）或相关凝块结构特性已显示与纤维蛋白溶解减退（破碎凝块的能力降低）强烈相关。我们假设，一个更准确的设备将提供一个更好的预测能力CEM作为一个相关的诊断参数，分析速度的提高可能是特别重要的术前监测抗凝治疗，减少样本量将使研究的遗传小鼠动物模型的心血管疾病。 我们的建议需要发展一种新兴的技术，用于小样品弹性测量的基础上共振声学光谱与光学振动检测（RASOV）。在RASOV中，血液样品的基本声共振模式通过在微珠换能器上扫描激发频率来测量，微珠换能器赋予样品可忽略的惯性。由于共振模式是与CEM直接相关的样品的固有特性，因此测量不需要校准程序。此外，对样本量没有限制，预计测量速度<0.2s。虽然初步数据表明RASOV可用于纤维蛋白凝块分析，但仍需要资源进行进一步改进，以便将该技术用于临床转化。我们的第一个目标是将几个硬件改进RASOV，包括一个更小的光学干涉仪，提高位移灵敏度，和一个微珠传感器具有较小的惯性质量。此外，我们将验证CEM测量与商业机械分析仪。我们的第二个目标是将强大的RASOV技术应用于健康献血者的全血样本分析。为了研究RASOV的能力，将向血液中添加额外的纤维蛋白原或抗体，以分别模拟高纤维蛋白原血症和血友病，我们预计这将分别导致CEM增加和减少。此外，我们将比较凝血过程中的时间依赖性CEM结果与商业凝块分析仪的结果，以了解RASOV的特殊优势。 在本研究结束时，将在全血中预期CEM的生理范围内对RASOV技术进行测试，并根据标准机械分析仪进行充分验证。这将平衡各种心血管疾病的临床试验技术，以建立CEM的诊断相关性，并将导致快速的临床转化。

DESCRIPTION (provided by applicant): We propose to develop a novel device for the measurement of blood clot elasticity with improved accuracy and speed, and requiring smaller sample volumes. In the long term, this may enable better point- of-care management and diagnoses of coagulopathies arising from a wide array of cardiovascular disorders including myocardial infarction, stroke, coronary artery disease, venous thromboembolism, and hyperglycemia. This expectation arises from the fact that the clot elastic modulus (CEM) or related clot structural properties have been shown to be strongly correlated with hypofibrinolysis (decreased ability to break up clots) in these diseases. We hypothesize that a more accurate device will provide a better predictive ability for CEM as a relevant diagnostic parameter, that the increased speed of analysis may be especially important for preoperative monitoring of anti-coagulant therapies, and that the decreased sample volume will enable studies of genetic murine animal models for cardiovascular disease. Our proposal entails the development of an emerging technique for small sample elasticity measurement based upon resonant acoustic spectroscopy with optical vibrometry-based detection (RASOV). In RASOV, the fundamental acoustic resonance modes of a blood sample are measured by sweeping the excitation frequency on a microbead transducer that imparts negligible inertia to the sample. Because the resonance modes are an intrinsic property of the specimen directly related to the CEM, the measurement requires no calibration procedures. Furthermore, there is no limitation to sample size, and measurement speeds <0.2s are anticipated. While preliminary data indicates the utility of RASOV for fibrin clot analysis, resources are needed for further improvements in order to position this technology for clinical translation. Our first aim is to incorporate several hardware improvements into the RASOV, including a smaller optical interferometer for improved displacement sensitivity, and a microbead transducer with smaller inertial mass. Also, we will validate CEM measurements with a commercial mechanical analyzer. Our second aim is to apply the robust RASOV technology to the analysis of whole blood samples from healthy donors. To investigate the capabilities of RASOV, additional fibrinogen or antibodies will be added to blood to simulate hyperfibrinogenemia and hemophilia, respectively, which we expect to result in increased and decreased CEM, respectively. Furthermore, we will compare the time-dependent CEM results during coagulation with that from a commercial clot analyzer, to understand the particular strengths of RASOV. By the conclusion of this study the RASOV technology will have been tested over the physiological range of expected CEM in whole blood and fully validated against a standard mechanical analyzer. This will poise the technology for clinical trials in a wide variety of cardiovascular diseases to establish the diagnostic relevance of CEM, and will lead to rapid clinical translation.