Celiac Disease Diagnosis using Tethered Capsule Endomicroscopy

描述（由申请人提供）：乳糜泻（CD）是一种对谷蛋白的自身免疫反应，影响美国300万人和全球5000万人。这些蛋白质引起炎症反应，最终破坏十二指肠中的吸收绒毛，导致胃肠道症状、吸收不良、营养不良和其他自身免疫性疾病、糖尿病和癌症的发病率增加。CD的明确诊断是通过随机内镜活检和十二指肠粘膜细胞和结构变化的显微镜检查结果进行的。CD可以通过坚持无麸质饮食（GFD）有效治愈。由于GFD是一个终身的承诺，是昂贵的，难以遵守，并可能有心理社会影响，绝大多数患者不放在这个方案，除非他们有活检证实的疾病。十二指肠内镜活检是一个有许多缺陷的金标准。因为内窥镜活检通常需要镇静剂，所以手术费用昂贵并且难以耐受。随机十二指肠活组织检查也仅对十二指肠壁的一小部分进行取样。由于这种疾病通常是斑片状的，所以对于患有这种疾病的人来说，多个阴性活检结果是非常常见的。组织处理伪影和缺乏获取和解释活检的标准也会导致诊断的不确定性。在很大程度上，内镜活检的这些问题导致了人群中CD的大量延迟和诊断不足。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倍相关，在美国每年的成本超过300亿美元。我们开发了一种称为栓系胶囊显微内镜（TCE）的新技术，克服了内窥镜活检的局限性。TCE涉及吞咽一种光学机械工程药丸，该药丸在胃肠道（GI）通过消化道下降时捕获胃肠道（GI）的三维显微图像。我们使用该技术的第一个结果表明，整个食管的微观结构可以在短短几分钟内以简单，快速和无痛的方式成像。在本提案中，我们将进一步推进TCE技术，使其优化用于整个十二指肠成像和诊断CD。新设备称为多模态TCE（MM-TCE），将包含专门为体内CD诊断设计的多种成像模式：1）光学相干断层扫描（OCT），用于成像深度依赖性结构变化，例如十二指肠变钝，2）SECM，用于可视化上皮中的淋巴细胞浸润，以及3）视频成像，使得该装置可以快速地通过胃进入十二指肠。一旦构建了MM-TCE系统和器械，将进行临床确认研究，以确定该器械与相应组织学相比的准确性以及与内镜十二指肠活检相关的诊断率。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，比目前的护理标准更便宜，耐受性更好。除了其对CD的直接临床影响外，这种胶囊技术还将改变我们如何获得上消化道其他疾病的显微组织诊断。

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.