Histotripsy

Histotripsy is the first noninvasive, non-ionizing, and non-thermal ablation technology guided by real-time imaging. Using focused ultrasound delivered from outside the body, histotripsy mechanically destroys tissue through cavitation, rendering the target into acellular debris.

• Overcoming the Blood-Brain Barrier: Focused Ultrasound in Glioblastoma Treatment
• Acoustic Cavitation Emissions Predict Near-complete/complete Histotripsy Treatment in Soft Tissues
• A pre-clinical MRI-guided all-in-one focused ultrasound system for murine brain studies
• Rescue Stenting for Failed Mechanical Thrombectomy in Acute Basilar Artery Occlusions: Analysis of the PC-SEARCH Registry
• State of Practice on Transcranial MR-Guided Focused Ultrasound: A Report from the ASNR Standards and Guidelines Committee and ACR Commission on Neuroradiology Workgroup
• Treatment envelope of transcranial histotripsy: challenges and strategies to maximize the treatment location profile
• Boiling Histotripsy in Ex Vivo Human Brain: Proof-of-concept
• Future Directions of MR-guided Focused Ultrasound

A in vitro study investigated the effects of ultrasound frequency and focal spacing on blood clot liquefaction via transcranial histotripsy. Histotripsy pulses were delivered using two 256-element hemispherical transducers of different frequency (250 and 500 kHz) with 30-cm aperture diameters. A 4-cm diameter spherical volume of in vitro blood clot was treated through 3 excised human skullcaps by electronically steering the focus with frequency proportional focal spacing: λ/2, 2 λ/3 and λ with 50 pulses per location. The pulse repetition frequency across the volume was 200 Hz, corresponding to a duty cycle of 0.08% (250 kHz) and 0.04% (500 kHz) for each focal location. Skull heating during treatment was monitored. Liquefied clot was drained via catheter and syringe in the range of 6-59 mL in 0.9-42.4 min. The fastest rate was 16.6 mL/min. The best parameter combination was λ spacing at 500 kHz, which produced large liquefaction through 3 skullcaps (23.1 ± 4.0, 37.1 ± 16.9 and 25.4 ± 16.9 mL) with the fast rates (3.2 ± 0.6, 5.1 ± 2.3 and 3.5 ± 0.4 mL/min). The temperature rise through the 3 skullcaps remained below 4°C ¹⁾

Duclos et al. studied the effect of various histotripsy dosages on tumor cell kill and associated bleeding in a murine glioma model (glioma [Gl261] and lung metastasis [LL/2-Luc2]).

GL261 or LL/2-Luc2 cells were cultured and implanted into the brains of C57BL/6 mice. Histotripsy (1-cycle pulses, 5 Hz PRF, 30 MPa-P) was performed using a 1 MHz transducer for five different dosages for each cell line: 5, 20 or 200 pulses per location (PPL) at a single treatment point, or 5 or 10-20 PPL at multiple treatment points. MRI, bioluminescence imaging and histology were used to assess tumor ablation and treatment effects within 4-6 h post-treatment.

All treatment groups resulted in a reduction of BLI intensity for the LL/2-Luc2 tumors, with significant signal reductions for the multi-point groups. The average pre-/post-treatment BLI flux (photons/s, ×108) for the different treatment groups were: 4.39/2.19 (5 PPL single-point), 5.49/1.80 (20 PPL single-point), 3.86/1.73 (200 PPL single-point), 2.44/1.11 (5 PPL multi-point) and 5.85/0.80 (10 PPL multi-point). MRI and H&E staining showed increased tumor damage and hemorrhagic effects with increasing histotripsy dose for both GL261 and LL/2-Luc2 tumors, but the increase in tumor damage was diminished beyond 10-20 PPL for single-point treatments and outweighed by increased hemorrhage. In general, hemorrhage was confined to be within 1 mm of the treatment boundary for all groups ²⁾

1: Duclos S, Golin A, Fox A, Chaudhary N, Camelo-Piragua S, Pandey A, Xu Z. Transcranial histotripsy parameter study in primary and metastatic murine brain tumor models. Int J Hyperthermia. 2023;40(1):2237218. doi: 10.1080/02656736.2023.2237218. PMID: 37495214.

2: Choi SW, Duclos S, Camelo-Piragua S, Chaudhary N, Sukovich J, Hall T, Pandey A, Xu Z. Histotripsy Treatment of Murine Brain and Glioma: Temporal Profile of Magnetic Resonance Imaging and Histological Characteristics Post-treatment. Ultrasound Med Biol. 2023 Aug;49(8):1882-1891. doi: 10.1016/j.ultrasmedbio.2023.05.002. Epub 2023 Jun 3. PMID: 37277304.

3: Hersh AM, Bhimreddy M, Weber-Levine C, Jiang K, Alomari S, Theodore N, Manbachi A, Tyler BM. Applications of Focused Ultrasound for the Treatment of Glioblastoma: A New Frontier. Cancers (Basel). 2022 Oct 8;14(19):4920. doi: 10.3390/cancers14194920. PMID: 36230843; PMCID: PMC9563027.

4: Raghuram H, Looi T, Pichardo S, Waspe AC, Drake JM. A robotic MR-guided high- intensity focused ultrasound platform for intraventricular hemorrhage: assessment of clot lysis efficacy in a brain phantom. J Neurosurg Pediatr. 2022 Sep 16;30(6):586-594. doi: 10.3171/2022.8.PEDS22144. PMID: 36115058.

5: Kim C, Lim M, Woodworth GF, Arvanitis CD. The roles of thermal and mechanical stress in focused ultrasound-mediated immunomodulation and immunotherapy for central nervous system tumors. J Neurooncol. 2022 Apr;157(2):221-236. doi: 10.1007/s11060-022-03973-1. Epub 2022 Mar 2. PMID: 35235137; PMCID: PMC9119565.

6: Meng Y, Pople CB, Budiansky D, Li D, Suppiah S, Lim-Fat MJ, Perry J, Sahgal A, Lipsman N. Current state of therapeutic focused ultrasound applications in neuro-oncology. J Neurooncol. 2022 Jan;156(1):49-59. doi: 10.1007/s11060-021-03861-0. Epub 2021 Oct 18. PMID: 34661791.

7: Lu N, Gupta D, Daou BJ, Fox A, Choi D, Sukovich JR, Hall TL, Camelo-Piragua S, Chaudhary N, Snell J, Pandey AS, Noll DC, Xu Z. Transcranial Magnetic Resonance-Guided Histotripsy for Brain Surgery: Pre-clinical Investigation. Ultrasound Med Biol. 2022 Jan;48(1):98-110. doi: 10.1016/j.ultrasmedbio.2021.09.008. Epub 2021 Oct 4. PMID: 34615611; PMCID: PMC9404674.

8: Pandey AS, Gerhardson T, Sukovich JR, Xu Z. Histotripsy: Potential Noninvasive Management of Intracerebral Hemorrhage. World Neurosurg. 2020 Jul;139:614-615. doi: 10.1016/j.wneu.2020.05.006. Epub 2020 May 8. PMID: 32561356; PMCID: PMC9357461.

9: Ho YJ, Li JP, Fan CH, Liu HL, Yeh CK. Ultrasound in tumor immunotherapy: Current status and future developments. J Control Release. 2020 Jul 10;323:12-23. doi: 10.1016/j.jconrel.2020.04.023. Epub 2020 Apr 14. PMID: 32302759.

10: Izadifar Z, Izadifar Z, Chapman D, Babyn P. An Introduction to High Intensity Focused Ultrasound: Systematic Review on Principles, Devices, and Clinical Applications. J Clin Med. 2020 Feb 7;9(2):460. doi: 10.3390/jcm9020460. PMID: 32046072; PMCID: PMC7073974.

11: Gerhardson T, Sukovich JR, Chaudhary N, Chenevert TL, Ives K, Hall TL, Camelo-Piragua S, Xu Z, Pandey AS. Histotripsy Clot Liquefaction in a Porcine Intracerebral Hemorrhage Model. Neurosurgery. 2020 Mar 1;86(3):429-436. doi: 10.1093/neuros/nyz089. PMID: 30924501; PMCID: PMC7308653.

12: Sukovich JR, Cain CA, Pandey AS, Chaudhary N, Camelo-Piragua S, Allen SP, Hall TL, Snell J, Xu Z, Cannata JM, Teofilovic D, Bertolina JA, Kassell N, Xu Z. In vivo histotripsy brain treatment. J Neurosurg. 2018 Oct 1:1-8. doi: 10.3171/2018.4.JNS172652. Epub ahead of print. PMID: 30485186; PMCID: PMC6925659.