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

摘要 克罗恩病（CD）在大多数患者中产生慢性肠损伤和狭窄。 这些狭窄的准确表征是至关重要的，因为急性炎症性狭窄可以对抗- 炎症治疗，但慢性狭窄，其中包括纤维化和肌肉肥大，需要 手术切除肠纤维化是未来肠梗阻和穿透性的重要预测因素 CD的并发症CD的标准诊断程序是内窥镜活检，其中小块 从肠的最内层取出组织用于组织病理学。由于取样深度有限， 内窥镜活检不能评估粘膜下层和肌肉层的纤维化。常规非侵入性 诸如MRI、CT和超声（US）的模态已经显示出对肠纤维化的有限敏感性。肠 狭窄通常是慢性纤维化和急性炎症的混合物，其分别与 组织中的胶原蛋白和血红蛋白增加，这是不同CD病理的分子标志物。在 此外，以前对压缩超声弹性成像的广泛研究已经证明， 硬度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，提供正交的诊断信息。一种诊断成像程序， 同时评估CD的这些表型对于个性化治疗计划是非常需要的， 改善患者的预后。 我们在动物体内、离体人体组织样品和人体受试者中的初步研究， 证实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 弹性成像和我们最近的应变PA成像创新。一种成像导管探头， 已经开发出整合了所有这些成像技术的标准回结肠镜检查程序， 用组织样品和动物体内进行验证。 在我们令人兴奋的初步结果的鼓舞下，我们建议用以下方法填补这一长期存在的预后空白： CD的分子和机械表型的准确表征。在拟议的项目中，我们将首先 客观地评估通过免疫组织化学定量的每个分子和机械标记物的灵敏度和特异性， 通过对临床相关兔模型的实验，提出了成像技术。此外，为了铺设 在临床翻译的道路上，我们将研究可行性，并确定所提出的技术的局限性 通过在CD患者中的初步研究，用于临床回结肠镜检查。该项目的成功将推动 这些CD狭窄中不同病理的分子和机械生物标志物用于实际临床 PA-US双模态内窥镜成像测量，实现准确的预后评估， CD中的治疗监测。

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.