Celiac Disease Diagnosis using Tethered Capsule Endomicroscopy

描述(申请人提供)：乳糜泻(CD)是一种对面筋蛋白的自身免疫反应，影响着美国的300万人和全球的5000万人。这些蛋白质会引发炎症反应，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，并增加其他自身免疫性疾病、糖尿病和癌症的发病率。根据十二指肠粘膜细胞和结构改变的显微镜检查结果，可通过随机的内窥镜活检确诊CD。坚持无麸质饮食(GFD)可以有效治愈CD。由于GFD是一个昂贵的、难以遵守的终生承诺，而且可能会产生心理社会影响，因此绝大多数患者不会接受这种方案，除非他们有经活检证实的疾病。十二指肠内窥镜活检是一种有许多缺陷的糟糕的黄金标准。因为内窥镜活检通常需要镇静，所以手术费用很高，而且很难耐受。随机的十二指肠活检也只对十二指肠壁的一小部分进行采样。由于这种疾病通常是斑片状的，所以对于那些患有这种疾病的人来说，有多个阴性的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组织检查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CD在人群中的大量延误和漏诊。这个问题必须解决，因为未经治疗的CD会导致死亡率增加2-4倍，在美国，每年的成本超过300亿美元。我们开发了一种名为栓系胶囊内窥镜(TCE)的新技术，它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)通过蠕动下降时捕捉到其三维显微图像。我们使用这项技术的第一个结果表明，整个食道的微结构可以在几分钟内以简单、快速和无痛的程序进行成像。在这项建议中，我们将进一步推进TCE技术，使其在整个十二指肠成像和CD诊断中得到优化。这种名为多模TCE(MM-TCE)的新设备将结合专门为在体CD诊断而设计的多种成像模式：1)光学相干断层扫描(OCT)，用于成像十二指肠钝化等随深度变化的结构变化；2)SECM，用于显示上皮中的淋巴细胞浸润物；以及3)视频成像，以便设备能够快速通过胃导航进入十二指肠。一旦MM-TCE系统和设备构建完成，将进行临床验证研究，以确定该设备与相应的组织学比较的准确性以及与十二指肠内窥镜活检相关的诊断率。这项研究的最终产品将是一种可吞咽的胶囊显微镜，它通过成像整个十二指肠来避免采样误差，比目前的护理标准更便宜，耐受性更好。除了对CD的直接临床影响外，这项胶囊技术还将改变我们获得上消化道其他疾病的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.