Multimodal Retinal Functional Imaging for Diabetic Retinopathy

描述(申请人提供)：糖尿病视网膜病变(DR)是导致工作年龄成年人不可逆失明的主要原因，这是一种典型的由缺血引起的视网膜疾病，其特征是糖尿病患者的视网膜微血管损害。DR的进展经历了一系列可识别的阶段，这些阶段开始于视网膜微循环的结构和功能紊乱，甚至在早期临床症状出现之前。DR最早的临床症状是微动脉瘤和点状视网膜内出血，这是由于毛细血管周细胞和内皮细胞受损引起的。这种毛细血管损伤导致视网膜血管通透性增加，局部毛细血管丢失，导致缺血，在DR的末期，异常视网膜血管(病理性视网膜新生血管)生长，称为增殖性糖尿病视网膜病变(PDR)。我们的长期目标是为人类视网膜血管提供临床、全面的功能和解剖学评估。在拟议的项目中，我们首先通过开发基于功能光声眼底检查(PAOM)、光学相干断层扫描(OCT)/光学多普勒断层扫描(ODT)的多模式技术来解决技术需求。多模式成像技术将通过成像动物模型进行验证和优化。然后，我们将验证基于PAOM和OCT/ODT的多模式成像技术可以为氧诱导视网膜病变(OIR)大鼠在临床体征出现之前早期诊断DR提供全面的功能信息。为了进一步验证这一假设，我们将在OIR大鼠模型上对血流动力学阈值(最早的血液动力学变化表示DR)进行干预，以显示早期干预的好处-在血流动力学阈值干预的时间点之后无法预防PDR。目的1.建立检测视网膜血管中二氧化硫的PAOM。PAOM通过直接感知氧合和脱氧血红蛋白的不同光吸收，提供视网膜血管中SO2的准确定量。将开发一种集成了超声波换能器的无源隐形眼镜，用于对眼睛进行成像。目的2.建立用于视网膜血流动力学成像的双光束光谱域OCT。OCT系统的特点是两个探测光束在视网膜上以可控的距离分开。从而消除了多普勒角在血流测量中的影响，可以实时测量绝对血流速度。目的3.将POAM和OCT相结合，提供SO2和视网膜血管血流的多模式功能成像。通过对体模和正常大鼠、兔的眼睛进行成像，验证和优化了集成系统。目的4.通过研究OIR模型大鼠视网膜血管功能在缺血性视网膜病变发展过程中的变化，用发展起来的技术验证这一假说。

DESCRIPTION (provided by applicant): Diabetic retinopathy (DR) is a leading cause of irreversible blindness among working-age adults, which is a typical type of ischemia driven retinal disease characterized by microvascular damage to the retina in patients with diabetes. DR progresses through a sequence of recognizable stages, which begin with structural and functional derangement of the retinal microcirculation even before the early clinical signs occur. The earliest clinical signs of DR are microaneurysms and dot intraretinal hemorrhages resulting from damage to the capillary pericytes and endothelial cells. This capillary damage leads to an increase in retinal vascular permeability, localized loss of capillaries with resulting ischemia, and, in the final stage of DR, the growth of abnormal retinal blood vessels (pathological retinal neovascularization) known as proliferative diabetic retinopathy (PDR). Our long term goal is to provide clinical comprehensive functional and anatomical assessment of retinal vessels in humans. In the proposed project, we first address the need for technology by developing multimodal technologies based on functional photoacoustic ophthalmoscopy (PAOM), optical coherence tomography (OCT)/optical Doppler tomography (ODT). The multimodal imaging technology will be validated and optimized through imaging animal models. Then we will test the hypothesis that the multimodal imaging technology based on PAOM and OCT/ODT can provide comprehensive functional information for the early diagnosis of DR before clinical signs occur in the oxygen induced retinopathy (OIR) rat model. To further test the hypothesis we will apply intervention at the hemodynamic threshold (the earliest hemodynamic changes signifying DR) found by the proposed imaging system on the OIR rat model to show the early intervention benefits - after the time point of hemodynamic threshold interventions cannot prevent PDR. Aim 1. Develop a PAOM to measure sO2 in retinal vessels. PAOM provides accurate quantification of sO2 in retinal vessels by directly sensing the different optical absorption of oxy- and deoxy-hemoglobins. A powerless contact lens integrated with an ultrasonic transducer will be developed for imaging the eye. Aim 2. Develop a dual beam spectral domain OCT to image retinal hemodynamics. The OCT system features two probing beams separated by a controlled distance on retina. Thus, effects of the Doppler angle in blood flow measurement are eliminated and the absolute blood flow velocity can be measured in real-time. Aim 3. Integrate POAM and OCT to provide multimodal functional imaging of both sO2 and blood flow of retinal blood vessels. Validate and optimize the integrated system by imaging phantoms and the eyes of normal rats and rabbits. Aim 4. Test the hypothesis using the developed technology by studying the variation of retinal vascular functions during ischemic retinopathy development in the OIR rat model.