The overall goal of this study is to develop the first integrated transcranial MR-guided Histotripsy system and validate it in an anatomically realistic human brain phantom and in vivo pig brain, which is essential to enable future preclinical studies and clinical translation of this promising technique.
Currently, the major treatment option for many brain diseases including brain tumor is craniotomy-based surgical resection, which is highly invasive and associated with high risk of injury to surrounding cerebral parenchyma and morbidity. There is a clear unmet clinical need for a noninvasive, safe and effective treatment for brain applications.
Transcranial magnetic resonance guided focused ultrasound (tcMRgFUS) has been investigated for noninvasive ablation to treat neuro-disorders and brain tumors. Guided by magnetic resonance imaging (MRI), ultrasound is applied from outside the skull and focused to the target brain tissue to produce thermal necrosis, while the surrounding brain and the skull remain intact. However, the limitations on treatment location and volume are major roadblocks preventing tcMRgFUS to be a viable treatment for most brain tumors.
Unlike tcMRgFUS that relies on heating produced by continuous sonication, histotripsy uses short (several μsec), high-pressure ultrasound pulses (~26 MPa) to generate focused cavitation bubbles, which mechanically fractionate and liquefy the target tissue into acellular homogenate. With long cooling times between pulses (ultrasound duty cycle <0.2%), overheating to the skull and surrounding tissue can be avoided, while effectively ablating the target tissue. Our preliminary data have showed: 1) Applied through excised human skulls, histotripsy can treat locations from the skull base to 5 mm from the inner skull surface as well as volume targets, while keeping the temperature increase in the skull <4°C. 2) Specialized MRI sequences can be used to visualize histotripsy-induced cavitation and tissue fractionation in real-time. 3) Initial in vivo safety was demonstrated in the normal pig brain. Based on these strong results, our scientific premise is that transcranial MR-guided histotripsy (tcMRgHt) can overcome the location and volume limitations of tcMRgFUS, providing a noninvasive and effective treatment option for patients with brain tumors.
Part I. System Design & Development
In this study, a transcranial MR-guided histotripsy (tcMRgHt) system was developed, characterized, and tested through an excised human skull. A 700-kHz, 128-element MR-compatible phased-array ultrasound transducer with a focal depth of 15 cm was designed and fabricated in house. Support structures were also constructed to facilitate the transcranial treatment.
The tcMRgHt array was acoustically characterized with a peak negative pressure up to 137 MPa in free field, 72 MPa through an excised human skull with aberration correction, and 51 MPa without aberration correction. Using electronic steering only, the tcMRgHt system was able to create volume lesions in a range of 35 mm through the skull.
The MR-compatibility of the tcMRgHt system was assessed quantitatively using SNR, B0 field map, and B1 field map in a clinical 3T MRI scanner, showing sufficient image quality for treatment monitoring and evaluation.
The transcranial treatment using electronic focal steering was visualized using the RBC phantoms. The size of lesions on the sparse circular pattern (A) ranged from 0.6 mm to 2.3 mm due to the aberration and attenuation through the excised human skull, indicating the precision limits for histotripsy treatment. The 10-mm continuous square lesion in B demonstrated that tcMRgHt system can treat volume target using electronic focal steering through the excised human skull.
Part II. In vivo Pig Treatment (Acute Study)
The goal of this study is to demonstrate the feasibility and safety of in vivo transcranial MR-guided histotripsy in the pig brain through an excised human skullcap.
Methods: As the pig skull is too flat and thick for ultrasound propagation, a 60 mm diameter circular region of the pig skullcap was surgically removed to provide an acoustic opening. The skin was sutured over the pig brain after craniotomy. The craniotomy was performed 2 days prior to the histotripsy treatment to remove any air bubbles between the brain and the skin. On the day of the treatment, the ultrasound array was placed in a water bucket inside a 3T GE MRI scanner. The pig head was placed above an excised human skull held by a skull holder inside the array. The MR images were acquired using surface coil pads attached to left and right side of the pig head. Pre-treatment MRI scans were used to align the geometric focus of the array within the target brain tissue based on fiducial markers on the array. A target zone of 27-216 mm3 was treated by electronically steering the focus with 1-1.5 mm between adjacent focal locations. Each focal location was treated with 50 pulses with a pulse repetition frequency of 10 Hz. T2 and T2* images were acquired immediately after and 2 hours post-treatment to evaluate the treated zone and any off-target brain damage, including hemorrhage and edema. The pig brains were harvested for pathological examination.
Results: Histotripsy ablation was successfully generated in the brain of 8 pigs with target in a wide range of anatomical locations, as confirmed by MRI. T2-weighted MR images showed hyperintense histotripsy ablation zones compared to the surrounding untreated tissue. These hyperintense regions were well confined within the targeted volume and did not demonstrate significant brain edema. T2* images, as a measure of iron and hemosiderin in the brain, demonstrated no excessive bleeding in peri-target zones. Histology revealed complete cellular disruption within the ablation zones and great correlation to the identified treatment zones on MRI.
Conclusions: This study provides initial results demonstrating the feasibility and safety of transcranial MR-guided histotripsy. Through an excised human skull, tcMRgHt is capable of generating ablation in a wide range of anatomical locations (from cortex to deep targets such as basal ganglia) in the in vivo pig brain. MRI and histology results showed a well confined histotripsy ablation zone without significant hemorrhage or edema outside the target region.
Part III. Currently ongoing projects & Future work:
- Transcranial Aberration Correction
- Real-time Cavitation Mapping using acoustic cavitation emission signal
- Chronic pig study to further investigate the safety and outcome of tcMRgHt treatment
- Integrated human-scale tcMRgHt system with receiving capability
- Validate the performance of the tcMRgHt system in an anatomically realistic human brain tumor phantom ex vivo.
 N. Lu, T. L. Hall, D. Choi, D. Gupta, B. J. Daou, J. R. Sukovich, A. Fox, T. Gerhardson, A. S. Pandey, D. C. Noll, Z. Xu. “MR-guided Histotripsy System for Transcranial Treatment”. IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control. (Under review, 2020).
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