Celiac Disease Diagnosis using Tethered Capsule Endomicroscopy

描述（由申请人提供）：乳糜泻（CD）是一种对麸质蛋白的自身免疫反应，在美国影响300万人，在全球影响5000万人。这些蛋白质引发炎症反应，最终破坏十二指肠的吸收绒毛，导致胃肠道症状，吸收不良，营养不良，并增加其他自身免疫性疾病，糖尿病和癌症的发病率。随机内镜下活检发现十二指肠黏膜细胞和结构改变，可明确诊断乳糜泻。坚持无麸质饮食（GFD）可以有效地治愈乳糜泻。由于GFD是一项终身承诺，费用昂贵，难以遵守，并可能产生社会心理影响，除非活检证实疾病，否则绝大多数患者不会接受这种方案。十二指肠内窥镜活检是一种糟糕的金标准，存在许多缺陷。由于内窥镜活检通常需要镇静，因此手术费用昂贵且难以忍受。随机十二指肠活组织检查也只抽取很小一部分十二指肠壁的样本。由于这种疾病通常呈斑块状，因此对于患有这种疾病的人来说，多次活检结果呈阴性是很常见的。组织处理伪影和缺乏获取和解释活检的标准也导致了诊断的不确定性。在很大程度上，内窥镜活检的这些问题导致了人群对乳糜泻的大量延误和诊断不足。这个问题必须得到解决，因为未经治疗的CD与死亡率增加2-4倍有关，在美国每年的成本超过300亿美元。我们已经开发了一种新技术，称为系绳胶囊内窥镜检查（TCE），它克服了内窥镜活检的局限性。TCE包括吞下一种光学机械工程药丸，当它通过蠕动下降时，它可以捕捉胃肠道的三维显微图像。我们使用这项技术的第一个结果表明，整个食道的微观结构可以在几分钟内成像，这是一个简单、快速、无痛的过程。在本提案中，我们将进一步推进TCE技术，使其在整个十二指肠成像和诊断CD方面得到优化。这种被称为多模态TCE （MM-TCE）的新设备将结合多种专门为体内CD诊断设计的成像模式：1)光学相干断层扫描（OCT）用于成像十二指肠钝化等深度相关的结构变化，2)SECM用于显示上皮内淋巴细胞浸润，3)视频成像使设备可以快速通过胃进入十二指肠。一旦MM-TCE系统和设备构建完成，将进行临床验证研究，以确定该设备相对于相应组织学的准确性以及相对于内镜十二指肠活检的诊断率。这项研究的最终产品将是一种可吞咽的胶囊显微镜，通过对整个十二指肠进行成像来避免采样误差，比目前的标准护理更便宜，而且耐受性更好。除了对乳糜泻的直接临床影响外，这种胶囊技术还将改变我们对其他上消化道疾病进行显微组织诊断的方式。

DESCRIPTION (provided by applicant): Celiac disease (CD) is an autoimmune response to gluten proteins that affects 3M people in the US and 50M worldwide. These proteins incite an inflammatory reaction that eventually destroys the absorptive villi in the duodenum, resulting in gastrointestinal symptoms, malabsorption, malnutrition, and an increased incidence of other autoimmune diseases, diabetes, and cancer. A definitive diagnosis of CD is made by random endoscopic biopsy with microscopic findings of cellular and architectural changes in the duodenal mucosa. CD can be effectively cured by adherence to a gluten free diet (GFD). Since a GFD is a lifelong commitment that is expensive, difficult to comply with, and can have psychosocial implications, the vast majority of patients are not placed on this regimen unless they have biopsy-confirmed disease. Duodenal endoscopic biopsy is a poor gold standard that suffers from many flaws. Because endoscopic biopsy typically requires sedation, the procedures are expensive and can be difficult to tolerate. Random duodenal biopsy also only samples a very small portion of the duodenal wall. Since the disease is often patchy, it is very common for those with the disease to have multiple negative biopsy results. Tissue processing artifacts and lack of standards for acquiring and interpreting the biopsies also contribute to diagnostic uncertainty. To a large part, these problems with endoscopic biopsy have led to massive delays and underdiagnosis of CD in the population. This problem must be solved because untreated CD is associated with a 2-4x increase in mortality, the cost of which exceeds $30B/year in the US. We have developed a new technology called tethered capsule endomicroscopy (TCE) that overcomes the limitations of endoscopic biopsy. TCE involves swallowing an optomechanically-engineered pill that captures three-dimensional microscopic images of the gastrointestinal (GI) tract as it descends via peristalsis. Our first results with this technology demonstrated that the microstructure of the entire esophagus can be imaged in just a few minutes in a simple, rapid, and painless procedure. In this proposal, we will advance TCE technology further so that it is optimized for imaging the entire duodenum and diagnosing CD. The new device, termed multimodality TCE (MM-TCE) will incorporate multiple imaging modalities that are specifically designed for CD diagnosis in vivo: 1) optical coherence tomography (OCT) for imaging the depth-dependent architectural changes such as duodenal blunting, 2) SECM for visualizing the lymphocytic infiltrate in the epithelium, and 3) video imaging so that the device can be quickly navigated through the stomach into the duodenum. Once the MM-TCE system and device has been constructed, clinical validation studies will be conducted to determine the accuracy of this device compared to corresponding histology and the diagnostic yield relative to endoscopic duodenal biopsy. The end product of this research will be a swallowable capsule microscope that avoids sampling error by imaging the entire duodenum, is less expensive, and better tolerated than the current standard of care. Beyond its immediate clinical impact for CD, this capsule technology will also transform how we obtain microscopic tissue diagnoses for other disorders of the upper GI tract.