Novel Ultrasonic Technique for the Treatment of Hemorrhagic Stroke

Title: Novel Ultrasonic Technique for the Treatment of Hemorrhagic Stroke Project Summary This grant is a renewal of our previous R01 (NS108042) to develop neuronavigation-guided transcranial histotripsy (NaviTH) as the most minimally invasive, safe, and effective method for treatment of Intracerebral hemorrhage (ICH) to date. ICH is the most common type of hemorrhagic stroke caused by the rupture of vessels resulting in formation of a clot inside the brain. Standard clinical ICH treatments, including medical management and craniotomy-based surgery, have not shown improvements in patient outcome. The latest clinical trial shows that early, minimally invasive extraction of the ICH can significantly improve the clinical outcome. However, the current minimally invasive ICH treatment approaches still carry a high risk of damage to the normal brain tissue and rebleeding given that they require large burr hole and active penetration of normal brain parenchyma or the use of thrombolytic drugs. We propose to develop histotripsy as the most minimally invasive approach for ICH treatment. Using ultrasound applied from outside the skull and focused inside the ICH, histotripsy produces cavitation to liquefy the clot within minutes without thrombolytic drugs or damaging the surrounding cerebral tissue. The liquefied clot is drained via a small catheter. Our original project has been highly productive and we have developed a prototype NaviTH system and demonstrated its feasibility and safety with the following key accomplishments: 1) development of a prototype NaviTH system with a 700kHz, 360-element array; 2) aberration correction and focusing through the skull using a miniature catheter hydrophone ; 3) rapid liquefaction of ex vivo bovine blood clot and evacuation via a catheter through an excised human skull (>2cc/min); 4) real-time treatment monitoring using the transmit-receive capable histotripsy array; and 5) initial feasibility and safety in the in vivo swine ICH model and in the brain of full human cadavers. Even with these substantial achievements, two major challenges remain. 1) The current NaviTH system is limited to only treat deep locations for skulls with high density variation and large thicknesses. Our analysis of ICH patient head CT scans, corroborated by the literature, demonstrates the need to treat both deep and shallow locations. 2) There is always a high risk of rebleed post ICH treatment, especially in patients needing anticoagulants. This renewal is built upon the above achievements and will focus on solving the two challenges via the following three Aims. Aim 1: Develop a new NaviTH system that can treat a wide range of ICH locations in a set of patients, and test it using human ICH phantoms. Aim 2: Investigate the in vivo safety and efficacy of the new NaviTH system in a swine model with and without anticoagulant. Aim 3: Demonstrate the clinical feasibility of the ICH treatment using the new NaviTH system in a pilot human study. The successful completion of this R01 renewal will result in a NaviTH system designed to treat a set of human ICH patients with associated critical preclinical data and initial clinical data for rapid future clinical translation.