Assessing biomarkers of intestinal fibrosis and inflammation in Crohn's Disease via an endoscopic imaging catheter

通过内窥镜成像导管评估克罗恩病肠道纤维化和炎症的生物标志物

• 批准号: 10033948
• 负责人: Peter D.R. Higgins
• 金额: $ 53.08万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10033948
• 关键词: Acute; Affect; Animal Model; Animals; Anti-Inflammatory Agents; Balloon Dilatation; Biological Markers; Biopsy; Catheters; Chronic; Clinical; Clinical Management; Collagen; Colonoscopes; Complement; Crohn' s disease; Diagnostic; Diagnostic Imaging; Diagnostic Procedure; Digestive System Disorders; Disease; Endoscopic Biopsy; Endoscopy; Excision; Extracellular Matrix; Fibrosis; Future; Gastroenterology; Genes; Hemoglobin; Histopathology; Human; Hyperplasia; Hypertrophy; Image; Imaging Techniques; Imaging technology; Inflammation; Inflammatory; Intestinal Diseases; Intestinal Fibrosis; Intestinal Obstruction; Intestines; Length; Magnetic Resonance Imaging; Measurement; Mechanics; Modality; Modeling; Molecular; Monitor; Morphology; Mucous Membrane; Multivariate Analysis; Muscle; Myofibroblast; Operative Surgical Procedures; Optics; Oryctolagus cuniculus; Outcomes Research; Pathologic; Pathology; Patient-Focused Outcomes; Patients; Performance; Phenotype; Pilot Projects; Procedures; Prognostic Marker; Publishing; Research; Resected; Sampling; Sensitivity and Specificity; Signal Transduction; Small Intestines; Stenosis; Techniques; Technology; Testing; Time; Tissue Sample; Tissues; Translations; Ultrasonic Transducer; Ultrasonography; United States; X-Ray Computed Tomography; absorption; accurate diagnosis; base; chronic autoimmune disease; clinical translation; clinically relevant; elastography; experimental study; human subject; human tissue; imaging approach; imaging biomarker; imaging modality; improved; in vivo; in vivo Model; inflammatory disease of the intestine; innovation; instrument; molecular marker; molecular pathology; novel; personalized therapeutic; photoacoustic imaging; pressure; prognostic; success; tool

ABSTRACT Crohn’s disease (CD) produces chronic intestinal bowel damage and stenosis in the majority of patients. Accurate characterization of these strictures is critical, as acute inflammatory strictures can respond to anti- inflammatory therapy, but chronic strictures, which include both fibrosis and muscular hypertrophy, require surgical resection. Intestinal fibrosis is an important predictor of future intestinal obstruction and penetrating complications of CD. The standard diagnostic procedure for CD is endoscopic biopsy, in which small pieces of tissue are removed from the innermost layer of the intestine for histopathology. Due to limited sampling depth, endoscopic biopsy does not assess fibrosis in submucosal and muscular layers. Conventional non-invasive modalities, such as MRI, CT and ultrasound (US), have shown limited sensitivity for intestinal fibrosis. Intestinal strictures are often a mixture of chronic fibrosis and acute inflammation, which are respectively correlated with increased collagen and hemoglobin in tissues, which act as molecular markers of distinct CD pathologies. In addition, extensive previous studies of compressional US elastography have documented that increased stiffness is a mechanical marker of chronic fibrotic strictures. These molecular and mechanical markers complement each other, providing orthogonal diagnostic information. A diagnostic imaging procedure that can simultaneously assess these phenotypes of CD is highly desirable for personalized therapeutic planning and improved patient outcomes. Our preliminary studies in animals in vivo, human tissue samples ex vivo, and in human subjects have validated that the molecular and mechanical markers of CD stricture pathology can be characterized by advanced photoacoustic (PA)-US dual modality imaging approaches, including spectroscopic PA imaging, US elastography, and our recent innovation of strain-PA imaging. An imaging catheter probe compatible with standard ileocolonoscopy procedures, integrating all these imaging technologies, has been developed and validated with tissue samples and in animals in vivo. Encouraged by our exciting preliminary results, we propose to fill this long-standing prognostic gap with accurate characterization of molecular and mechanical phenotypes of CD. In the proposed project, we will first objectively assess the sensitivity and specificity of each molecular and mechanical marker quantified by the proposed imaging technology through experiments on clinically relevant rabbit models. In addition, to pave the road to clinical translation, we will examine the feasibility and identify the limitations of the proposed technique for use during clinical ileocolonoscopy via a pilot study in CD patients. The success of this project will advance these molecular and mechanical biomarkers of distinct pathologies in CD strictures to practical clinical measurement with PA-US dual modality endoscopic imaging, enabling accurate prognostic assessment and treatment monitoring in CD.

抽象的 克罗恩病 (CD) 会对大多数患者造成慢性肠道损伤和狭窄。 这些狭窄的准确表征至关重要，因为急性炎症狭窄可以对抗 炎症治疗，但慢性狭窄（包括纤维化和肌肉肥大）需要 surgical resection.肠纤维化是未来肠梗阻和穿透性肠梗阻的重要预测因素 complications of CD. CD 的标准诊断程序是内窥镜活检，其中小片 从肠道最内层取出组织进行组织病理学检查。由于采样深度有限， 内窥镜活检不能评估粘膜下层和肌肉层的纤维化。传统非侵入式 MRI、CT 和超声（美国）等检查手段对肠道纤维化的敏感性有限。肠 狭窄通常是慢性纤维化和急性炎症的混合体，它们分别与 组织中胶原蛋白和血红蛋白增加，它们是不同 CD 病理学的分子标记。在 此外，之前对压缩超声弹性成像的大量研究已经证明，增加 僵硬是慢性纤维化狭窄的机械标志。这些分子和机械标记 相互补充，提供正交诊断信息。诊断成像程序可以 同时评估 CD 的这些表型对于个性化治疗计划和 改善患者治疗效果。 我们对动物体内、人体离体组织样本以及人类受试者的初步研究已经 验证了 CD 狭窄病理学的分子和机械标志物可以通过以下方式表征 先进的光声 (PA)-US 双模态成像方法，包括光谱 PA 成像、US 弹性成像，以及我们最近的应变 PA 成像创新。成像导管探头兼容 已经开发并整合了所有这些成像技术的标准回肠结肠镜检查程序 通过组织样本和动物体内进行验证。 受到我们令人兴奋的初步结果的鼓舞，我们建议用以下方法来填补这一长期存在的预后差距： CD 的分子和机械表型的准确表征。在拟议的项目中，我们首先将 客观评估每个分子和机械标记物量化的敏感性和特异性 通过对临床相关的兔子模型进行实验提出了成像技术。 In addition, to pave the 在通往临床转化的道路上，我们将检查可行性并确定所提出技术的局限性 通过 CD 患者的试点研究用于临床回肠结肠镜检查。该项目的成功将推进 这些 CD 狭窄中不同病理的分子和机械生物标志物应用于实际临床 使用 PA-US 双模态内窥镜成像进行测量，从而实现准确的预后评估和 CD 中的治疗监测。