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

摘要 克罗恩病(CD)在大多数患者中会导致慢性肠道损伤和狭窄。 对这些狭窄的准确描述是至关重要的，因为急性炎症性狭窄可以对 炎症治疗，但慢性狭窄，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肠梗阻的重要预测指标 CD的并发症。CD的标准诊断程序是内窥镜活检，在这种检查中，小块的 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， 内窥镜活检不评估粘膜下层和肌层的纤维化。常规无创手术 MRI、CT和超声(US)等方法对肠道纤维化的敏感性有限。肠道 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的增加，这是不同CD病理的分子标记。在……里面 此外，先前对压缩超声弹性成像的广泛研究已经证明， 僵硬是慢性纤维性狭窄的力学标志。这些分子和机械标记 相互补充，提供正交诊断信息。一种诊断成像程序，可以 同时评估CD的这些表型对于个性化治疗计划和 改善了患者的预后。 我们在动物体内、体外人体组织样本和人体受试者身上进行的初步研究 证实CD狭窄病理的分子和力学标记物可以表征 先进的光声(PA)-US双模式成像方法，包括光谱PA成像 弹性成像，以及我们最近的应变-PA成像的创新。与之兼容的成像导管探头 整合了所有这些成像技术的标准回结肠镜检查程序已经开发出来，并 用组织样本和活体动物进行了验证。 受到我们令人振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测空白 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 客观评价每个分子和机械标记物的敏感性和特异性 通过对临床相关的兔模型进行实验，提出了成像技术。此外，为了铺平 临床翻译之路，我们将研究该技术的可行性并确定其局限性。 用于CD患者的临床回肠结肠镜检查。这项工程的成功将会向前推进 CD狭窄不同病理类型的分子和力学生物标志物的临床应用 使用PA-US双模式内窥镜成像进行测量，实现准确的预后评估和 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.