Bimodal Intraoral imaging device for detection of oral epithelial neoplasia

摘要 本项目的目标是开发一种新型的双模口腔内成像设备，用于评估口腔和 口咽粘膜用于肿瘤的检测，有助于早期发现。口腔和口咽癌帐户 全球每年有64万新的癌症病例。病例数量每年都在增加，部分原因是 人类乳头瘤病毒的传播。在过去的几年中，5年存活率相对保持不变。 几十年，尽管口腔和口咽部可以进行检查。及早发现，5年内 存活率提高到80%，提供了改善患者预后的希望，因为有效的发展 早期检测方法。目测触诊检测的临床应用现状 引导活检获取，不足以在最早、最可治疗的阶段可靠地发现肿瘤，包括 口腔上皮异型增生(OED)和早期口腔/口咽鳞状细胞癌(OSCC)。我们的临床前研究 初步的临床样本研究表明，无标记非线性光学显微镜(NLOM)包括 多光子自发荧光显微镜和二次谐波的产生，是一种极具前景的光学 活检法。它提供亚细胞分辨率的深层粘膜成像，并检测相关参数 与组织学相似的肿瘤。除了光学组织学，NLOM还提供了额外的光谱 基于代谢和生化微环境的指标，这可能会增加光学组织学指标。 我们评估NLOM在这一应用中的结果显示，对检测肿瘤具有很高的敏感性和特异性， 与组织病理学高度一致。尽管有这些优点，但显微镜的一个局限性是 固有的数百微米量级的有限图像视场。另一方面，临床大面积 由宽视野自发荧光(WF)成像组成的筛查方法提供了所需的视野 (厘米)具有很高的检测灵敏度，但缺乏特异性，无法在表面下成像或评估 显微特征。在这个项目中，我们将把这两种方法的优点结合到一个手持设备中 口腔内成像设备，将使用WF为肿瘤可疑区域提供大面积筛查 与NLOM的详细、深度分辨率地下成像相结合，可高度敏感和特异地检测 高危病变(OED)和早期口腔鳞癌。为了实现这一目标，我们将1)构建一个生物模式的WF-NLOM 口腔内成像设备和优化性能及其在无创性评估口腔肿瘤中的适用性 人类口腔/口咽粘膜；2)改进和翻译临床前定义的方法和指标 研究用于人类口腔鳞癌的口腔内装置；以及3)评价双模口腔内成像装置 在活体患者中评估该设备的性能并进行试点研究，获得有价值的反馈 关于肿瘤的检测潜力和临床适应性。

ABSTRACT The goal of this project is to develop a novel bimodal intraoral imaging device for assessment of the oral and oropharynx mucosa for detection of neoplasia, aiding in early detection. Oral and oropharyngeal cancers account for 640,000 new cases of cancer worldwide each year. The number of cases increases each year, in part due to the spread of human papillomavirus. The 5-year survival rate has remained relatively unchanged over several decades, despite accessibility of the oral cavity and oropharynx for examination. With early detection, the 5-year survival rate increases to 80%, providing hope of improved patient outcomes given development of effective early detection approaches. The current clinical approach of detection by visual examination with palpation to guide biopsy acquisition, is insufficient to reliably detect neoplasia at the earliest, most treatable stages, including oral epithelial dysplasia (OED) and early oral/oropharyngeal squamous cell carcinoma (OSCC). Our preclinical and pilot clinical sample studies indicate that label-free nonlinear optical microscopy (NLOM), consisting of multiphoton autofluorescence microscopy and second harmonic generation, is highly promising as an optical biopsy method. It provides deep mucosal imaging at subcellular resolution and detects parameters associated with neoplasia that parallel histology. In addition to optical histology, NLOM provides additional spectroscopic metrics based on the metabolic and biochemical microenvironment, which may add to optical histology metrics. Our results assessing NLOM for this application show high sensitivity and specificity for detection of neoplasia, and a high degree of agreement with histopathology. Despite these advantages, a limitation of microscopy is the inherently limited image field of view on the order of hundreds of microns. On the other hand, clinical large area screening methods comprised of widefield autofluorescence (WF) imaging provide the fields needed (centimeters) with high sensitivity for detection, but lack specificity and cannot image below the surface or assess microscopic features. In this project, we will combine the benefits of both approaches into a single handheld intraoral imaging device that will provide large area screening for regions of suspicion for neoplasia using WF coupled with detailed, depth-resolved subsurface imaging by NLOM for highly sensitive and specific detection of high risk lesions (OED) and early OSCC. To accomplish this goal we will 1) construct a biomodal WF-NLOM intraoral imaging device and optimize performance and suitability for noninvasive evaluation of neoplasia in human oral/oropharyngeal mucosa; 2) refine and translate methodology and metrics defined in preclinical studies, to the intraoral device for use in human OSCC; and 3) evaluate the bimodal intraoral imaging device performance and conduct a pilot study to evaluate the device in patients in vivo, obtaining valuable feedback regarding potential for detection of neoplasia and adaptability for the clinic.