Multimodal Retinal Functional Imaging for Diabetic Retinopathy

描述（申请人提供）：糖尿病视网膜病变（Diabetic retinopathy， DR）是导致工作年龄成人不可逆性失明的主要原因，是糖尿病患者视网膜微血管损伤为特征的一种典型的缺血驱动视网膜疾病。DR的发展经历了一系列可识别的阶段，在早期临床症状出现之前，就开始了视网膜微循环的结构和功能紊乱。DR的早期临床表现为毛细血管周细胞和内皮细胞损伤引起的微动脉瘤和点状视网膜出血。这种毛细血管损伤导致视网膜血管通透性增加，毛细血管局部丧失导致缺血，并且在DR的最后阶段，异常视网膜血管的生长（病理性视网膜新生血管）称为增殖性糖尿病视网膜病变（PDR）。我们的长期目标是提供临床全面的功能和解剖评估视网膜血管在人类。在该项目中，我们首先通过开发基于功能光声眼科检查（PAOM）、光学相干断层扫描(OCT)/光学多普勒断层扫描（ODT）的多模态技术来解决技术需求。通过动物模型成像，对多模态成像技术进行验证和优化。然后，我们将验证基于PAOM和OCT/ODT的多模态成像技术可以在氧致视网膜病变（OIR）大鼠模型出现临床症状之前为DR的早期诊断提供全面的功能信息的假设。为了进一步验证这一假设，我们将在OIR大鼠模型上采用所提出的成像系统发现的血流动力学阈值（标志着DR的最早血流动力学变化）进行干预，以显示早期干预的益处——在血流动力学阈值时间点之后干预不能预防PDR。目的1。开发PAOM来测量视网膜血管中的二氧化硫。PAOM通过直接感知氧血红蛋白和脱氧血红蛋白的不同光学吸收，提供了视网膜血管中二氧化硫的准确定量。一种集成了超声波换能器的无动力隐形眼镜将被开发出来用于眼睛成像。目标2。开发双光束光谱域OCT成像视网膜血流动力学。OCT系统的特点是两个探测光束在视网膜上相隔一定距离。从而消除了多普勒角对血流测量的影响，可以实时测量绝对血流速度。目标3。结合POAM和OCT提供视网膜血管sO2和血流的多模态功能成像。通过对正常大鼠和家兔的幻影和眼睛进行成像，验证和优化集成系统。目标4。通过研究OIR大鼠模型中缺血性视网膜病变发展过程中视网膜血管功能的变化来验证这一假设。

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.