Development of a handheld confocal microscope for fluorescence-guided neurosurgery

Abstract

Surgery remains a critical step in the standard-of-care of many brain tumors, and the ability to identify tumor margins intraoperatively is central to achieving maximal tumor resection with minimal neurological damage. Unfortunately, the tumor boundary is often ambiguous under current imaging techniques for neurosurgical guidance (e.g. MRI and wide-field microscopy) due to their limited resolutions, and the assessment of tumor-brain interface can only be definite via slide-based histopathology, an invasive and laborious post-operative procedure. In recent years, there is a growing interest in developing handheld confocal fluorescence microscopy as a non-invasive and real-time imaging tool to distinguish normal and abnormal tissue with sub-cellular precision, ultimately improving the completeness of tumor resection. Although intraoperative confocal microscopes are commercially available, they typically provide either limited frame rates or suboptimal resolutions. In light of these concerns, we have developed a novel handheld confocal microscope for neurosurgical guidance based on the line-scanned dual-axis confocal (LS-DAC) architecture, a more recent optical-sectioning design that provides both high-speed and high-resolution tissue imaging. This manuscript documents the development of the device, including 1) an early-stage feasibility study utilizing a tabletop prototype, 2) hardware and software development of the handheld device, with fully packaging into a clinically viable imaging system, 3) performance evaluation and optimization using animal models, and 4) a pilot clinical study collaborating with neurosurgeons to image human brain tumors. In the final chapter, a proposed surgical workflow is provided for the future clinical use of this device, along with a detailed discussion on the remaining challenges for the clinical acceptance of this new technology as a routine imaging tool for neurosurgical guidance.