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

描述（由申请人提供）：我们建议开发一种新型设备，用于测量血凝块弹性，具有更高的准确性和速度，并且需要更小的样本量。从长远来看，这可能使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疾病，包括心肌梗死、中风、冠状动脉疾病、静脉血栓栓塞和高血糖。这一预期源于这样一个事实，即在这些疾病中，凝块弹性模量（CEM）或相关的凝块结构特性与低纤溶（分解凝块的能力下降）密切相关。我们假设，更精确的设备将为CEM提供更好的预测能力，作为相关的诊断参数，分析速度的提高可能对抗凝治疗的术前监测特别重要，并且减少的样本量将使心血管疾病遗传小鼠动物模型的研究成为可能。我们的建议需要开发一种基于共振声学光谱和基于光学振动测量的检测（RASOV）的小样本弹性测量新兴技术。在RASOV中，血液样本的基本声学共振模式是通过扫描微珠换能器上的激励频率来测量的，该换能器赋予样品可忽略不计的惯性。由于共振模式是与CEM直接相关的试样的固有属性，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用于纤维蛋白凝块分析，但为了将该技术定位于临床转化，还需要进一步改进资源。我们的第一个目标是将几个硬件改进纳入RASOV，包括一个更小的光学干涉仪，以提高位移灵敏度，以及一个具有更小惯性质量的微珠换能器。此外，我们将用商用机械分析仪验证CEM测量结果。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的功能，将在血液中添加额外的纤维蛋白原或抗体来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的增加和减少。此外，我们将比较凝固过程中随时间变化的CEM结果与商业血块分析仪的结果，以了解RASOV的特殊优势。通过本研究的结论，RASOV技术将在全血中预期的CEM生理范围内进行测试，并在标准机械分析仪上进行充分验证。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.