High resolution high sensitivity photoacoustic imaging molecular guided brain tumor surgery with pilot clinical deployment

For the more than 700,000 people in the United States living with a primary brain tumor, surgery is the most important initial predictor of quality of life and overall survival. The neurosurgeon’s goal is to maximize extent of resection (EOR) while preserving adjacent normal brain tissue. However, the unclear boundary between normal brain tissue and tumor at the surface, subsurface, and in the depth poses a significant challenge for the neurosurgeon in achieving this goal. Current technologies for surgical image-guidance help neurosurgeons more accurately and safely resect brain tumors. Preoperative MRI provides a 3-dimensional (3D) view of tumor in relation to surrounding normal brain, and intraoperative MRI provides updated images at desired points during surgery. However, MRI does not provide real-time intraoperative feedback. Neuronavigation addresses this limitation by providing a real-time view of MRI images in relation to the intraoperative setting. However, because the brain can shift position during surgery, the MRI map used by neuronavigation is inaccurate (e.g., errors up to 3 cm). Intraoperative (iUS) is not limited by brain shift, providing real-time 3D intraoperative feedback, but it lacks tumor-specific molecular contrast, limiting its ability to accurately demarcate tumor. Fluorescence guided surgery (FGS), provides real-time visualization of tumor tissue with high tumor-to-normal molecular contrast, is not limited by brain shift, and increases EOR. However, the strong optical scattering and absorption of tissues limit FGS to surface visualization. Thus, current image-guidance technologies have intrinsic limitations for intraoperative use that reduce their ability to provide the surgeon with real-time, accurate, and 3D visualization of tumors and normal tissues. Photoacoustic imaging (PAI) is a hybrid imaging modality that harvests both optical and acoustic energies offering rich optical contrast and 3D high spatial resolution imaging deep inside tissues. We hypothesize that multi-contrast PAI of intrinsic molecules and extrinsic fluorescent agents can serve as a surgical adjunct to accurately demarcate normal brain from tumor tissue during surgery. The long-term goal of this project is to improve surgical outcomes by creating the first real-time intraoperative 3D PAI platform (i.e., intraoperative photoacoustic molecular image-guided surgery [iPMIGS]). We will use our expertise in developing photoacoustic and fluorescence imaging technologies to build a 3D real-time intraoperative photoacoustic and ultrasound tomography (iPAUST) system for multiplexed molecular image-guided brain tumor surgery (Aim 1). iPAUST will perform multi-contrast PAI of intrinsic (e.g., hemoglobin to visualize blood vessels) and extrinsic (e.g., fluorophores used in FGS of brain tumors) biomarkers. We will perform pre-clinical validation and optimization of iPAUST in ex vivo and in vivo rodent brain tumor models and in a cadaveric human brain fluorescence model (Aim 2). We will then translate iPAUST into an investigator-initiated feasibility clinical trial in patients undergoing FGS for brain tumors (Aim 3).