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，影响美国 300 万人和全球 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性绒毛，导致胃肠道症状、吸收不良、营养不良以及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窥镜活检并通过十二指肠粘膜细胞和结构变化的显微镜检查来做出的。坚持无麸质饮食 (GFD) 可以有效治愈 CD。由于 GFD 是一项终生承诺，费用昂贵、难以遵守，并且可能产生社会心理影响，因此绝大多数患者不会接受这种治疗方案，除非他们患有活检确诊的疾病。十二指肠内窥镜活检是一种较差的金标准，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耐受。随机十二指肠活检也仅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，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。组织处理伪影以及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中克罗恩病的大规模延误和诊断不足。这个问题必须得到解决，因为未经治疗的 CD 会导致死亡率增加 2-4 倍，在美国，其费用每年超过 30B 美元。我们开发了一种称为系留胶囊内窥镜检查 (TCE) 的新技术，它克服了内窥镜活检的局限性。 TCE 涉及吞咽一种光机械设计的药丸，该药丸可捕捉胃肠道 (GI) 通过蠕动下降时的三维显微图像。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通过简单、快速、无痛的过程成像。在本提案中，我们将进一步推进 TCE 技术，使其针对整个十二指肠成像和诊断 CD 进行优化。这种新设备被称为多模态 TCE (MM-TCE)，将结合专为 CD 体内诊断而设计的多种成像方式：1) 光学相干断层扫描 (OCT)，用于对十二指肠钝化等深度依赖性结构变化进行成像；2) SECM，用于可视化上皮中的淋巴细胞浸润；3) 视频成像，以便设备可以快速穿过胃进入十二指肠。一旦构建了 MM-TCE 系统和设备，将进行临床验证研究，以确定该设备与相应组织学相比的准确性以及相对于内窥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式胶囊显微镜，它通过对整个十二指肠进行成像来避免采样错误，并且比当前的护理标准更便宜且耐受性更好。除了对克罗恩病的直接临床影响之外，这种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.