SBIR-STTR Award

Approximately 700,000 people in the United States have been diagnosed with a primary brain tumor. Of these, malignant gliomas (MGs) account for approximately 40% of all intracranial tumors, with an overall patient survival rate of only ~34%. More than any other cancer, brain cancer has lasting physical, cognitive, and psychological impacts on a patient’s life, and the highest per-patient initial cost of care. Surgical resection remains the cornerstone of therapy and the extent of resection correlates with patient survival. A limiting factor for resection, however, is the surgeon’s ability to differentiate the tumor from normal tissue. In pursuit of intraoperative guidance for the safe and maximal resection, fluorescence-guided surgery has emerged as an advanced adjunctive technique. The uses of surgical operative microscopes with FDA-approved fluorescein dye have shown significantly higher tumor resection rates (75-100%) in MGs than conventional surgeries (30-55%). However, most clinical-grade fluorescence microscopes (e.g., PENTERO® 900 microscope with YELLOW 560™ fluorescein module, Carl Zeiss Meditec AG) are hampered by high costs (~$330K), limited portability (~800 lbs), and lack of operation flexibility. 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. To overcome limitations of currently available surgical imaging techniques, we have preliminarily demonstrated safety and feasibility of an innovative wearable fluorescence prototype that piggybacks on eye loupes for identifying MGs (Pending Patent: PCT/US2018/41418). In this Phase-I study, we will collaborate with a startup company (Bioptics Technology, LLC) to miniaturize, optimize, and validate this low-cost device (~$8K) with user experience (e.g., ease of wearing, alignment, and operation) for easy and accurate fluorescent identification of MGs during resection. Compact LEDs and a small CMOS camera with dedicated optical filters will be optically integrated into different functional modules for florescence excitation and detection. These lightweight, compact, and inexpensive modules will be attached to the eye loupes to form an integrated wearable device, allowing for real-time ocular observation and video recording of fluorescence and color images. The device operating system will be optimized to be “up and running” so that neurosurgeons can easily use it without much specialized training. To ensure appropriate performance and sufficient accuracy, this device will be first optimized and calibrated using tumor-simulating phantoms against the PENTERO® 900 microscope with YELLOW 560™ (Aim 1), and then validated in patients with MGs against histopathological analyses of biopsied samples taken from the surgical tumor margin (Aim 2). The potential market size of this device would be tens of millions of dollars in the US alone, providing a significant opportunity for commercialization. Ultimately, this affordable, wearable, and ergonomic device will significantly increase the ability of more surgeons to conduct fast and thorough operations, and thus improve surgical outcomes and reduce the burden on healthcare systems.

Public Health Relevance Statement:
PROJECT NARRATIVE The goal of this STTR Phase-I project is to develop and commercialize an innovative low-cost, wearable, fluorescence imaging device that can be attached to the standard surgical eye loupes for helping neurosurgeons to easily and accurately identify brain tumors for safe and maximal resection. This wearable ergonomic device will result in a wide range of movement and fast/easy operation, thus providing a novel way to image fluorescing brain tumors without a large expensive operative microscope. The potential market size of this affordable device are tens of millions of dollars in the US alone, and potential customers are neurosurgeons working across a wide range of surgical units, especially at regional and mobile army surgical hospitals.

Project Terms:
Accounting; Area; base; Biopsy Specimen; Blinded; Blood - brain barrier anatomy; Brain Neoplasms; care costs; Clinical; Cognitive; Color; Color Visions; commercialization; contrast enhanced; Conventional Surgery; cost; Custom; Data; design; Detection; Development; Devices; Diagnosis; Dyes; Ensure; Excision; experience; Eye; FDA approved; flexibility; Fluorescein; Fluorescence; fluorescence imaging; fluorescence microscope; fluorescence-guided surgery; Goals; Gold; Halogens; Healthcare Systems; Hospitals; Hour; Image; Image-Guided Surgery; Imagery; Imaging Device; imaging system; Imaging Techniques; improved; innovation; Intracranial Neoplasms; Intravenous; Legal patent; Life; Light; light weight; Lighting; Magnetic Resonance Imaging; Malignant Glioma; Malignant neoplasm of brain; Malignant Neoplasms; Measurement; Microscope; miniaturize; Movement; Neurosurgeon; Normal tissue morphology; novel; Obstruction; off-patent; Operating System; operation; Operative Surgical Procedures; optical imaging; Optics; Outcome; Patients; Performance; performance tests; Phase; phase 1 study; phase 2 study; portability; Primary Brain Neoplasms; prototype; Psychological Impact; research and development; Running; safety and feasibility; Small Business Technology Transfer Research; Sports; Surgeon; surgery outcome; Surgical margins; Survival Rate; System; Techniques; Technology; Testing; Time; Training; tumor; Tumor Tissue; United States; Universities; Video Recording; wearable device; Work

Approximately 700,000 people in the United States are diagnosed with a primary brain tumor. Of these, malignantgliomas (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 aresignificantly higher than conventional surgeries with GTR rates of 30-55%. However, most clinical-grade imagingsystems are hampered by high costs, limited portability, and lack of operation flexibility. Some neurosurgicalfluorescence microscopes cost upwards of ~$500K and weigh ~800 pounds (PENTERO® 900 with fluorescencekits, Carl Zeiss). Many surgeons prefer, and continue to use wearable surgical eye loupes, which allow forconvenient and fast operation, but are not capable of fluorescence visualization. Supported by the STTR Phase1 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 forintraoperative identification of fluorescent MGs. We have tested FLoupe™ prototypes to image fluorescent MGsduring surgery in a small group of patients. Comparable results are observed against the PENTERO® 900system. 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™ devicein terms of weight, size, imaging quality, and ease to wear/operate (Aim 1). The optimized FLoupe™ device willbe calibrated and validated against the PENTERO® 900 system for equivalence to image fluorescent MGs in alarge group of patients (Aim 2). We expect that fluorescence images taken at the surgical site and from biopsiedsamples by both devices will be equivalent and agree with the blinded histopathological analyses (the goldstandard). Resulting data will be used for FDA clearance via the pre-market notification 510(k) submission withthe 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 ofneurosurgeons to conduct fast and thorough operations, thus improving patient safety and outcomes. At the endof this Phase 2, a clinical-grade FLoupe™ device will be generated as a pre-manufactured product forintraoperative identification of MGs. Moreover, the FLoupe™ device with a modular design is easily modifiedwith 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 braintumor resection based on the fluorescence characteristics of cancers, thereby expanding its market share.

Public Health Relevance Statement:
PROJECT NARRATIVE Fluorescent imaging of cancers during surgery allows real-time cancer-specific detection for guiding tumor removal, often resulting in significant improvements in patient survival; however, it is hampered by large expensive equipment. Bioptics Technology (BOT) is developing an innovative, low-cost, wearable fluorescence imaging device (FLoupe™, BOT brand) that attaches to standard surgical eye loupes to help neurosurgeons easily and accurately identify brain tumors for safe and maximal removal. This affordable and wearable device will significantly increase the ability of more surgeons to conduct fast and thorough operations, and thus improving patient safety and outcomes.

Project Terms:
<5-ALA><5-Amino-4-oxopentanoic Acid><5-Aminolevulinic Acid><5-amino-4-oxo-pentanoic acid>