The overall goal of this project is to develop histotripsy as a minimally invasive treatment for intracerebral hemorrhage (ICH).
Intracerebral hemorrhage (ICH) is a devastating form of stroke, leading to a 30-day survival rate of 40-50% and significant disability for those that survive. ICH is characterized by the rupture of vessels resulting in bleeding and clotting inside the brain. The presence of the clot causes two forms of injury: primary injury (i.e., mechanical disruption), immediately following the onset of hemorrhage, and secondary injury (i.e., toxic effects) developing in the days to weeks following hemorrhage. Minimally invasive approaches, such as intracranial catheter methods using thrombolytic drugs to liquefy the clots, have been used for treating ICH. However, these methods cannot remove the clot volume fast enough to reduce the primary and secondary brain injury associated with ICH and can cause asymptomatic bleeding. Magnetic resonance guided focused ultrasound (MRgFUS) has recently been developed as a minimally invasive ICH treatment. MRgFUS provides faster liquefaction rates without the need for thrombolytic drugs but is hindered by its inability to treat large volumes and regions close to the skullcap and its need for treatment targeting via continuous MRI. Histotripsy can overcome the limitations of MRgFUS and rapidly treat large volumes at a range of locations within the brain, without damaging the intervening or surrounding brain tissue or overheating the skull. ICH liquefied with histotripsy can be drained via catheter inserted through a small hole in the skull. This allows removal of liquefied clot with minimal collateral damage. The catheter can be integrated with a miniature acoustic hydrophone (catheter hydrophone) that can be used to correct the ultrasound distortion through the skull. With the development of the catheter hydrophone and the use of already existing neuronavigation techniques to co-register the physical location of the skull in the histotripsy array transducer with the pretreatment CT scan used to diagnose the ICH, the need for MRI can be overcome, with only the insertion of a catheter necessary to target, treat and drain the liquefied volume. This allows the potential for histotripsy to be applied in a standalone system and thus increases the potential for adoption of histotripsy into widespread clinical use.
We have demonstrated volume liquefaction of clots through excised human skulls using electronic focal steering with our large (30 cm diameter) hemisphere arrays. Clot liquefaction was achieved and drained with a catheter in range of 4.1 – 54.1 mL in 0.9 – 42.4 minutes, resulting in liquefaction rates of 0.5 – 12.6 mL/min. Monitoring the temperature increase within the skull during these in-vitro experiments showed a temperature rise that remained below 4 °C, which is reported as significantly below the threshold required to cause damage bone or the surrounding tissue.
Catheter Hydrophone Aberration Correction
Due to the sound speed and thickness inhomogeneities inherent to the skull, the ultrasound pulses propagated through the skull experience aberration, resulting in the significantly reduced focal pressure amplitude. For minimally invasive ICH treatment, a catheter needs to be inserted into the clot through a small bur hole in the skull to drain the liquefied clot. We have developed and validated a catheter hydrophone prototype, which can be used to measure ultrasound signals from each of the transducer array elements to correct for the aberration induced by the skull.
The need for developing a catheter hydrophone (CH) that can be stereotactically positioned through a small bur hole in the skull into the sound field, is two-fold, (1) it establishes a minimally invasive insertion procedure similar to those used in clinics and (2) it provides a range of skull insertion points across the hemisphere array scaffold and thus an ability to avoid critical neurological features in planning the catheter insertion path. We have developed a guiding mount that fits in place of one of the modular array elements, establishing 256 potential insertion trajectories that allow reaching a range of clot locations within the skull.
By performing catheter hydrophone aberration correction, the pressure at the geometric focus can be increased dramatically which extends the steering range at which histotripsy can be applied with electronic focal steering and improves the overall treatment efficacy in volume treatments. This effect can be observed in the figure below.
To begin testing the safety of histotripsy treatment of ICH in-vivo we used a well-accepted porcine ICH model. The focus of a histotripsy transducer was mechanically scanned through the clot to liquefy the central portion of the clot. A small amount of intact clot was left around the perimeter of the clot to avoid damaging the brain. MR images histology slides of the treated brains show that the histotripsy-liquefied volume was confined inside the clot, leaving 0.5 – 1mm rim of clot untreated purposely. No damage or hemorrhage to the surrounding brain tissue was observed.
 T. Gerhardson, J. R. Sukovich, A. S. Pandey, T. L. Hall, C. A. Cain, Z. Xu, “Effect of frequency and focal spacing on transcranial histotripsy clot liquefaction, using electronic focal steering,” Ultrasound Med Biol, vol. 43, no. 10, pp. 2302-2317, Oct. 2017.
 T. Gerhardson, J. R. Sukovich, A. S. Pandey, T. L. Hall, C. A. Cain, Z. Xu, “Catheter Hydrophone Aberration Correction for Transcranial Histotripsy Treatment of Intracerebral Hemorrhage: Proof-of-Concent,” IEEE Trans Ultrason Ferroelectr Freq Control, vol. 64, no. 11, pp. 1684-1697 Nov. 2017.
 Sukovich J, Xu Z, Kim Y, Cao H, Nguyen TS, Pandey A, Hall T, Cain C. Targeted Lesion Generation Through the Skull Without Aberration Correction Using Histotripsy. IEEE Trans Ultrason Ferroelectr Freq Control. 2016;63(5):671-82.