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峰口内成像设备，用于评估口腔和 口咽粘膜用于检测瘤形成，有助于早期检测。口腔和口咽癌占 全球每年新增64万例癌症病例案件数量每年增加，部分原因是 人类乳头瘤病毒的传播5年生存率在几年内保持相对不变， 几十年来，尽管口腔和口咽的检查可及性。如果及早发现， 生存率增加到80%，提供了改善患者预后的希望， 早期检测方法。目前通过触诊进行视觉检查的临床方法， 引导活检采集不足以在最早、最可治疗的阶段可靠地检测肿瘤，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 和试点临床样本研究表明，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产生，是非常有前途的光学 活组织检查法它以亚细胞分辨率提供深层粘膜成像，并检测相关参数 与组织学相似的肿瘤除了光学组织学之外，NLOM还提供了额外的光谱分析。 基于代谢和生物化学微环境的度量，其可以添加到光学组织学度量。 我们评估NLOM的结果表明，对于肿瘤的检测具有高灵敏度和特异性， 与组织病理学高度一致。尽管有这些优点，显微镜的局限性是 固有地将图像视场限制在几百微米的数量级。另一方面，临床大面积 包括宽视野自体荧光（WF）成像的筛选方法提供了所需的视野 （厘米），检测灵敏度高，但缺乏特异性，无法在表面以下成像或评估 微观特征在这个项目中，我们将联合收割机的好处，这两种方法到一个单一的手持设备 口内成像装置，其将使用WF对疑似瘤形成的区域提供大面积筛查 再加上详细的，深度分辨地下成像的NLOM高度敏感和具体的检测， 高危病变（OED）和早期OSCC。为了实现这一目标，我们将1）构建一个生物模式的WF-NLOM 口内成像装置以及用于非侵入性评价口腔内肿瘤的最佳性能和适用性 人类口腔/口咽粘膜; 2）完善和转化临床前研究中定义方法和指标 用于人OSCC的口内装置;以及3）评估双峰口内成像装置 性能并进行初步研究，以在患者体内评价器械，获得有价值的反馈 关于肿瘤检测的潜力和临床适应性。

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.