Development of an instrument to track oxygen from blood to mitochondria in vivo

描述(由申请人提供)：氧气是生命所必需的，大量的医疗治疗围绕着正常或稳定体内的氧气水平。市场上新的脉搏血氧仪和近红外光谱(NIRS)设备的爆炸性增长证明，光学光谱在许多医院的非侵入性组织监测中具有吸引力。但我们还没有做到这一点--现有的临床设备还没有克服准确量化对氧合敏感的细胞生物标记物的关键障碍。我们 建议开发一种用于人类的新型非侵入性细胞血氧仪，通过从光学反射光谱同时测量血红蛋白饱和度、肌红蛋白饱和度和细胞色素Aa3氧化，提供肌肉组织氧分布(TOP)的快照。三个不同的隔室将用光来询问：毛细血管、心肌细胞和线粒体。在这项建议中，我们将重点放在骨骼肌上，但一般的方法适用于任何距离探头表面足够近的组织，以便用光进行询问。TOP监测将打开评估氧气可获得性、输送和消耗的窗口。临床医生将能够识别细胞缺氧，当他们能够沿着代谢途径定位缺氧时，他们将能够更好地进行针对性治疗。这项建议的具体目的是：1)开发光谱预处理步骤，以消除皮肤和脂肪的吸收和散射效应；2)开发并验证体外局部加权回归(LWR)测量TOP；以及3)开发并验证体内LWR测量TOP。目标1和目标2将使用幻影在体外实现。将建造一种新的探测器来测量浅层和深层组织的光谱。光谱前处理步骤将被开发，并用已知的血红蛋白浓度的模体进行测试。光谱预处理的目标是从光谱中去除由于皮肤和脂肪以及散射效应引起的吸光度，留下主要包含与TOP相关的吸光度信息的光谱。LWR的TOP测量将在体外开发，使用模特儿模拟人类的手。最后，在目标3中，将在手臂缺血期间从健康受试者手中获取光谱。这些光谱将用于校准体内LWR模型。这些模型将实现从皮肤表面(例如手、手臂、腿和大脑)可访问的测量地点收集的新光谱的顶级实时监测。使用我们的新设备跟踪从血液到线粒体的氧气将在临床实践和临床研究中具有广泛的意义。我们预计，顶层监测将成为护理缺氧患者的关键组成部分，包括败血症、休克和心力衰竭患者。我们的长期目标是开发用于救护车、急诊科、重症监护病房和手术室的临床使用的细胞血氧仪。

DESCRIPTION (provided by applicant): Oxygen is essential for life, and an enormous amount of medical treatment centers around normalizing or stabilizing oxygen levels in the body. Evidenced by the explosion of new pulse oximetry and near infrared spectroscopy (NIRS) devices on the market, optical spectroscopy is attractive for noninvasive tissue monitoring in many hospital settings. But we are not there yet - no existing clinical device has overcome the critical hurdle of accurately quantifying cellular biomarkers that are sensitive to oxygenation. We propose to develop a novel, noninvasive cell oximeter for use in humans that will provide snapshots of tissue oxygen profiles (TOPs) in muscle by simultaneously measuring hemoglobin saturation, myoglobin saturation, and cytochrome aa3 oxidation from optical reflectance spectra. Three different compartments will be interrogated with light: capillaries, myocytes, and mitochondria. In this proposal we focus on skeletal muscle, but the general approach is applicable to any tissue that is close enough to the probe surface to be interrogated with light. TOP monitoring will open windows for assessment of oxygen availability, delivery, and consumption. Clinicians will be able to identify cellular oxygen insufficiency and will be able to target treatment better when they can localize oxygen deficits along the metabolic pathway. The specific aims of this proposal are to: 1) develop spectral preprocessing steps to remove skin and lipid absorbances and scattering effects; 2) develop and validate measurement of TOP by Locally Weighted Regression (LWR) in vitro; and 3) develop and validate measurement of TOP by LWR in vivo. Aims 1 and 2 will be accomplished in vitro using phantoms. A new probe will be built to measure spectra from superficial and deep tissue regions. Spectral preprocessing steps will be developed and tested with phantoms that have known hemoglobin concentrations. The goal of spectral preprocessing is to remove absorbances due to skin and fat and scattering effects from spectra, leaving spectra that primarily contain absorbance information relevant to TOPs. TOP measurement by LWR will be developed in vitro with phantoms that model a human hand. Finally, in Aim 3, spectra will be acquired from the hands of healthy subjects during arm ischemia. These spectra will be used to calibrate in vivo LWR models. The models will enable TOP monitoring in real time from new spectra collected from measurement sites that are accessible from the skin surface (e.g., hand, arm, leg, and brain). Tracking oxygen from blood to mitochondria with our new device will have broad implications in clinical practice and clinical research. We envision that TOP monitoring will become a critical component in the care of patients with oxygen insufficiency, including those with sepsis, shock, and cardiac failure. Our long-term goal is to develop the cell oximeter for clinical use in ambulances, emergency departments, intensive care units, and operating rooms.