Presented By: Biomedical Engineering
Ph.D. Defense: Tyler Gerhardson
Transcranial Therapy for Intracerebral Hemorrhage and Other Brain Pathologies using Histotripsy
NOTICE: Will be held via BlueJeans.
Link: https://umich.bluejeans.com/924142541
Brain pathologies including stroke and cancer are a major cause of death and disability. Intracerebral hemorrhage (ICH) accounts for roughly 12% of all strokes in the US with approximately 200,000 new cases per year. ICH is characterized by the rupture of vessels resulting in bleeding and clotting inside the brain. The presence of the clot causes immediate damage to surrounding brain tissue via mass effect with delayed toxic effects developing in the days following the hemorrhage. This leads ICH patients to high mortality with a 40% chance of death within 30 days of diagnosis and motivates the need to quickly evacuate the clot from the brain. Craniotomy surgery and other minimally invasive methods using thrombolytic drugs are common procedures to remove the clot but are limited by factors such as morbidity and high susceptibility to rebleeding, which ultimately result in poor clinical outcomes.
Histotripsy is a non-thermal ultrasound ablation technique that uses short duration, high amplitude rarefactional pulses (>26 MPa) delivered via an extracorporeal transducer to generate targeted cavitation using the intrinsic gas nuclei existing in the target tissue. The rapid and energetic bubble expansion and collapse of cavitation create high stress and strain in tissue at the focus that fractionate it into an acellular homogenate. This dissertation presents the role of histotripsy as a novel ultrasound technology with potential to address the need for an effective transcranial therapy for ICH and other brain pathologies.
The first part of this work investigates the effects of ultrasound frequency and focal spacing on transcranial clot liquefaction using histotripsy. Histotripsy pulses were delivered using two 256-element hemispherical transducers of different frequency (250 and 500 kHz) with 30-cm aperture diameters. 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 (~30 mL) with fast rates (~2 mL/min). The temperature-rise through the 3 skullcaps remained below 4°C.
The second part addresses initial safety concerns for histotripsy ICH treatment through investigation in a porcine ICH model. 1.75-mL clots were formed in the frontal lobe of the brain. 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. Histotripsy was able to liquefy the core of clots without direct damage to the perihematomal brain tissue. An average volume of 0.9 ± 0.5 mL (~50%) 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.
The third part presents the development of a novel catheter hydrophone method for transcranial phase aberration correction and drainage of the clot liquefied with histotripsy. A prototype hydrophone was fabricated to fit within a ventriculostomy catheter. Improvements in focal pressure of up to 60% were achieved at the geometric focus and 27%-62% across a range of electronic steering locations. The sagittal and axial -6-dB beam widths decreased from 4.6 to 2.2 mm in the sagittal direction and 8 to 4.4 mm in the axial direction, compared to 1.5 and 3 mm in the absence of aberration. The cores of clots liquefied with histotripsy were readily drained via the catheter.
The fourth part focuses on the development of a preclinical system for translation to human cadaver ICH models. A 360-element, 700 kHz hemispherical array with a 30 cm aperture was designed and integrated with an optical tracker surgical navigation system. Calibrated simulations of the transducer suggest a therapeutic range between 48 – 105 mL through the human skull with the ability to apply therapy pulses at pulse-repetition-frequencies up to 200 Hz. The navigation system allows real-time targeting and placement of the catheter hydrophone via a pre-operative CT or MRI.
The fifth and final part of this work extends transcranial histotripsy therapy beyond ICH to the treatment of glioblastoma. This section presents results from an initial investigation into cancer immunomodulation using histotripsy in a mouse glioblastoma model. The results suggest histotripsy has some immunomodulatory capacity as evidenced by a 2-fold reduction in myeloid derived suppressor cells and large increases in interferon-γ concentrations (3500 pg/mL) within the brain tumors of mice treated with histotripsy.
Link: https://umich.bluejeans.com/924142541
Brain pathologies including stroke and cancer are a major cause of death and disability. Intracerebral hemorrhage (ICH) accounts for roughly 12% of all strokes in the US with approximately 200,000 new cases per year. ICH is characterized by the rupture of vessels resulting in bleeding and clotting inside the brain. The presence of the clot causes immediate damage to surrounding brain tissue via mass effect with delayed toxic effects developing in the days following the hemorrhage. This leads ICH patients to high mortality with a 40% chance of death within 30 days of diagnosis and motivates the need to quickly evacuate the clot from the brain. Craniotomy surgery and other minimally invasive methods using thrombolytic drugs are common procedures to remove the clot but are limited by factors such as morbidity and high susceptibility to rebleeding, which ultimately result in poor clinical outcomes.
Histotripsy is a non-thermal ultrasound ablation technique that uses short duration, high amplitude rarefactional pulses (>26 MPa) delivered via an extracorporeal transducer to generate targeted cavitation using the intrinsic gas nuclei existing in the target tissue. The rapid and energetic bubble expansion and collapse of cavitation create high stress and strain in tissue at the focus that fractionate it into an acellular homogenate. This dissertation presents the role of histotripsy as a novel ultrasound technology with potential to address the need for an effective transcranial therapy for ICH and other brain pathologies.
The first part of this work investigates the effects of ultrasound frequency and focal spacing on transcranial clot liquefaction using histotripsy. Histotripsy pulses were delivered using two 256-element hemispherical transducers of different frequency (250 and 500 kHz) with 30-cm aperture diameters. 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 (~30 mL) with fast rates (~2 mL/min). The temperature-rise through the 3 skullcaps remained below 4°C.
The second part addresses initial safety concerns for histotripsy ICH treatment through investigation in a porcine ICH model. 1.75-mL clots were formed in the frontal lobe of the brain. 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. Histotripsy was able to liquefy the core of clots without direct damage to the perihematomal brain tissue. An average volume of 0.9 ± 0.5 mL (~50%) 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.
The third part presents the development of a novel catheter hydrophone method for transcranial phase aberration correction and drainage of the clot liquefied with histotripsy. A prototype hydrophone was fabricated to fit within a ventriculostomy catheter. Improvements in focal pressure of up to 60% were achieved at the geometric focus and 27%-62% across a range of electronic steering locations. The sagittal and axial -6-dB beam widths decreased from 4.6 to 2.2 mm in the sagittal direction and 8 to 4.4 mm in the axial direction, compared to 1.5 and 3 mm in the absence of aberration. The cores of clots liquefied with histotripsy were readily drained via the catheter.
The fourth part focuses on the development of a preclinical system for translation to human cadaver ICH models. A 360-element, 700 kHz hemispherical array with a 30 cm aperture was designed and integrated with an optical tracker surgical navigation system. Calibrated simulations of the transducer suggest a therapeutic range between 48 – 105 mL through the human skull with the ability to apply therapy pulses at pulse-repetition-frequencies up to 200 Hz. The navigation system allows real-time targeting and placement of the catheter hydrophone via a pre-operative CT or MRI.
The fifth and final part of this work extends transcranial histotripsy therapy beyond ICH to the treatment of glioblastoma. This section presents results from an initial investigation into cancer immunomodulation using histotripsy in a mouse glioblastoma model. The results suggest histotripsy has some immunomodulatory capacity as evidenced by a 2-fold reduction in myeloid derived suppressor cells and large increases in interferon-γ concentrations (3500 pg/mL) within the brain tumors of mice treated with histotripsy.
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