Histotripsy Clot Liquefaction in a Porcine Intracerebral Hemorrhage Model

Abstract

BACKGROUND Intracerebral hemorrhage (ICH) is characterized by a 30-d mortality rate of 40% and significant disability for those who survive. OBJECTIVE To investigate the initial safety concerns of histotripsy mediated clot liquefaction and aspiration in a porcine ICH model. Histotripsy is a noninvasive, focused ultrasound technique that generates cavitation to mechanically fractionate tissue. Histotripsy has the potential to liquefy clot in the brain and facilitate minimally invasive aspiration. METHODS About 1.75-mL clots were formed in the frontal lobe of the brain (n = 18; n = 6/group). The centers of the clots were liquefied with histotripsy 48 h after formation, and the content was either evacuated or left within the brain. A control group was left untreated. Pigs underwent magnetic resonance imaging (MRI) 7 to 8 d after clot formation and were subsequently euthanized. Neurological behavior was assessed throughout. Histological analysis was performed on harvested brains. A subset of pigs underwent acute analysis (≤6 h). RESULTS Histotripsy was able to liquefy the center of clots without direct damage to the perihematomal brain tissue. An average volume of 0.9 ± 0.5 mL was drained after histotripsy treatment. All groups showed mild ischemia and gliosis in the perihematomal region; however, there were no deaths or signs of neurological dysfunction in any groups. CONCLUSION This study presents the first analysis of histotripsy-based liquefaction of ICH in vivo. Histotripsy safely liquefies clots without significant additional damage to the perihematomal region. The liquefied content of the clot can be easily evacuated, and the undrained clot has no effect on pig survival or neurological behavior.

Relevance of Porcine Stroke Models to Bridge the Gap from Pre-Clinical Findings to Clinical Implementation

“…A similar method has been used by Bimpis et al; in their approach a balloon is inflated and, while decompressed, the autologous blood is injected [ 184 , 185 , 186 ]. In a recent study, injection of blood to the target region of the brain was performed after a craniotomy, but this was only performed to apply focused ultrasounds to liquefy induced intracerebral blood clots [ 165 ]. However, the main method remains to be the surgical access to the target area and direct injection of the blood through a catheter or needle [ 158 , 159 , 187 , 188 , 189 , 190 , 191 , 192 , 193 , 194 , 197 , 199 , 200 , 201 , 202 , 203 , 204 , 205 , 206 , 207 , 208 , 209 , 210 , 211 , 212 ].…”

“…Curiously, this technique has been used as a potential therapy for ICH in swine models. Using intracerebral autologous blood injection models in pigs, MRgFUS can be directed to the blood clots within the brain to cause its thrombolysis, showing positive results [ 165 , 198 , 212 ].…”

“…Together with the latter, only the recently published article by Gerhardson et al clearly describes the use of a scaling system to evaluate the neurological state of pigs after ICH. Specifically, they use the Tanaka et al 25-point scale previous to and daily after the lobar WM injection of autologous blood [ 165 ].…”

“…Fractional anisotropy (FA) maps obtained by DTI analysis showed loss of WM integrity in the ipsilateral hemisphere (in the internal capsule and corpus callosum) [ 16 , 240 ] in a pig model of stroke. In addition, a stem cell vesicle-based treatment was found to preserve the integrity and functionality of WM [ 103 , 104 ].When focusing on the effects of hemorrhagic stroke, leakage of blood into the brain parenchyma of swine has been mostly measured using CT [ 180 , 206 , 208 , 214 ] or MRI FLAIR images or in T2*-weighted images [ 165 , 173 , 174 , 178 , 187 , 213 , 214 , 241 ]. To overcome possible artefacts, the iron from hemoglobin can be indirectly measured using the rate of transverse magnetization relaxation, R2*(1/T2*).…”

Transcranial activation and imaging of low boiling point phase‐change contrast agents through the temporal bone using an ultrafast interframe activation ultrasound sequence

“…9 In cases of ICH and large clots, researchers have recently demonstrated encouraging results through the use of high intensity, short ultrasound pulses to dissolve clots. 10 In other studies seeking to provide therapy for drug delivery or clot lysis, microbubbles have been used as agents for enhancing the mechanical effect during therapeutic applications, including drug delivery or clot lysis. [11][12][13][14][15][16][17][18] These cavitation-mediated approaches could allow rapid, localized treatment of ICH in patients for whom surgery is not a viable path.…”