Development of a Wearable Fluorescence Imaging Device for IntraoperativeIdentification of Brain Tumors

摘要 在美国，大约有70万人被诊断患有原发性脑肿瘤。其中，恶性 神经胶质瘤（MG）约占所有颅内肿瘤的40%，总生存率仅为20%。 约34%。手术切除仍然是治疗的基石，切除程度与生存率相关。 荧光成像已经成为一种快速的技术，允许实时癌症特异性检测。 荧光成像引导的外科手术实现了75- 100%的大体全切除率（GTR）， 显著高于传统手术，GTR率为30- 55%。然而，大多数临床级成像 系统受到高成本、有限的便携性和缺乏操作灵活性的阻碍。一些神经外科的 荧光显微镜的成本高达约50万美元，重量约为800磅（PENTERO® 900荧光显微镜 试剂盒，Carl Zeiss）。许多外科医生更喜欢，并继续使用可穿戴的手术放大镜，这允许 操作方便快捷，但不能荧光可视化。由STTR阶段提供支持 1奖（R41 CA 243600）和肯塔基州国家匹配基金，生物光学技术（BOT）已经开发出一种低- 成本可穿戴FLoupe™设备（美国专利申请#62/530，613，2017），其附接到手术用目镜， 荧光MG的术中鉴定。我们已经测试了FLoupe™原型，以成像荧光MG 在一小群病人的手术中。观察到与PENTERO® 900相当的结果 系统根据第一阶段神经外科医生的反馈，第二阶段项目将进一步优化大灯 （LED）、摄像机、发射滤波器、电气控制系统和FLoupe™装置的机械设计 在重量、尺寸、成像质量和易于佩戴/操作方面（目标1）。经过优化的FLoupe™设备将 根据PENTERO® 900系统进行校准和验证，以确定其与成像荧光MG的等效性。 大组患者（目标2）。我们希望在手术部位和活检部位拍摄的荧光图像 两种器械的样本将是等同的，并与盲态组织病理学分析一致（金 标准）。所得数据将通过上市前通知510（k）提交用于FDA批准， PENTERO® 900系统作为主要同品种器械。与PENTERO® 900系统相比， 设备明显更便宜（单位销售价格<1万美元），更紧凑（可穿戴），更易于操作 (hand免费无线控制）。这款价格实惠且可穿戴的设备将显着提高 神经外科医生进行快速和彻底的手术，从而提高病人的安全性和结果。年底 在第2阶段，临床级FLoupe™设备将作为预制造产品生产， MG的术中识别。此外，采用模块化设计的FLoupe™设备易于修改 利用优化的激发光和发射滤光器来成像各种可见染料（例如，荧光素，5-ALA， 亚甲蓝）。因此，我们的产品有可能被纳入其他外科设置以外的大脑 根据癌症的荧光特性进行肿瘤切除，从而扩大其市场份额。

ABSTRACT Approximately 700,000 people in the United States are diagnosed with a primary brain tumor. Of these, malignant gliomas (MGs) account for approximately 40% of all intracranial tumors, with an overall survival rate of only ~34%. Surgical resection remains the cornerstone of therapy and the extent of resection correlates with survival. Fluorescence imaging has emerged as an adjunctive technique, allowing for real-time cancer-specific detection. Surgeries guided by fluorescence imaging achieve gross-total-resection (GTR) rates of 75-100%, which are significantly higher than conventional surgeries with GTR rates of 30-55%. However, most clinical-grade imaging systems are hampered by high costs, limited portability, and lack of operation flexibility. Some neurosurgical fluorescence microscopes cost upwards of ~$500K and weigh ~800 pounds (PENTERO® 900 with fluorescence kits, Carl Zeiss). Many surgeons prefer, and continue to use wearable surgical eye loupes, which allow for convenient and fast operation, but are not capable of fluorescence visualization. Supported by the STTR Phase 1 Award (R41CA243600) and Kentucky State Matching Fund, Bioptics Technology (BOT) has developed a low- cost wearable FLoupe™ device (US Patent Application #62/530,613, 2017) attached to surgical eye loupes for intraoperative identification of fluorescent MGs. We have tested FLoupe™ prototypes to image fluorescent MGs during surgery in a small group of patients. Comparable results are observed against the PENTERO® 900 system. Based on neurosurgeons’ feedback in Phase 1, this Phase 2 project will further optimize the headlights (LEDs), video camera, emission filters, electrical control system, and mechanical design of the FLoupe™ device in terms of weight, size, imaging quality, and ease to wear/operate (Aim 1). The optimized FLoupe™ device will be calibrated and validated against the PENTERO® 900 system for equivalence to image fluorescent MGs in a large group of patients (Aim 2). We expect that fluorescence images taken at the surgical site and from biopsied samples by both devices will be equivalent and agree with the blinded histopathological analyses (the gold standard). Resulting data will be used for FDA clearance via the pre-market notification 510(k) submission with the PENTERO® 900 system as the primary predicate. Compared to the PENTERO® 900 system, the FLoupe™ device is significantly less expensive (<$10K unit sale price), more compact (wearable), and easier to operate (hand free with wireless control). This affordable and wearable device will significantly increase the ability of neurosurgeons to conduct fast and thorough operations, thus improving patient safety and outcomes. At the end of this Phase 2, a clinical-grade FLoupe™ device will be generated as a pre-manufactured product for intraoperative identification of MGs. Moreover, the FLoupe™ device with a modular design is easily modified with optimized excitation lights and emission filters to image a variety of visible dyes (e.g., fluorescein, 5-ALA, methylene blue). Thus, our product has the potential to be incorporated in other surgical settings beyond brain tumor resection based on the fluorescence characteristics of cancers, thereby expanding its market share.