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的血液凝块弹性测量设备，以提高精度和速度，并需要较小的样本量。从长远来看，这可能使更好的护理点管理和凝血疾病的诊断产生广泛的心血管疾病，包括心肌梗死、中风、冠状动脉疾病、静脉血栓栓塞症和高血糖。这一预期源于这样一个事实，即血栓弹性模数(CEM)或相关的血栓结构属性已被证明与这些疾病中的纤溶功能低下(血栓分解能力降低)密切相关。我们假设，更准确的设备将为CEM作为相关的诊断参数提供更好的预测能力，分析速度的提高可能对抗凝治疗的术前监测特别重要，样本量的减少将使心血管疾病的小鼠遗传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谱和基于光学振动法的检测(RASOV)的小样本弹性测量的新兴技术。在RASOV中，通过扫描微珠换能器上的激励频率来测量血液样本的基波声学共振模式，微珠换能器赋予样本可以忽略的惯性。由于共振模式是与CEM直接相关的样品的固有属性，因此测量不需要校准程序。此外，对样本大小没有限制，预计测量速度为0.2秒。虽然初步数据表明RASOV用于纤维蛋白凝块分析的实用性，但需要资源来进一步改进，以便将这项技术定位于临床翻译。我们的第一个目标是在RASOV中加入几项硬件改进，包括用于提高位移灵敏度的更小的光学干涉仪，以及具有更小惯性质量的微珠换能器。此外，我们还将使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，将向血液中添加额外的纤维蛋白原或抗体，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随时间变化的CEM结果与商用血块分析仪的结果，以了解RASOV的特殊优势。通过这项研究的结论，RASOV技术将在全血中预期的CEM的生理范围内进行测试，并在标准的机械分析仪上进行充分验证。这将使这项技术在各种心血管疾病的临床试验中建立起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.