- Histotripsy Mechanism – Cavitation Bubble Dynamics
- Non-invasive Atrial Septal Perforation in Treatment of Congenital Heart Diseases
- Noninvasive Image-Guided Thrombolysis Using Histotripsy
- Histotripsy for Noninvasive Liver Cancer Ablation
- Transcranial Histotripsy
- Nanodroplet-Mediated Histotripsy for Targeted Cancer Cell Ablation
- Advanced Histotripsy Image Guidance
- Non-invasive Therapy for Prenatal Surgery
- The Effects of Histotripsy on Tissues of Different Mechanical Properties
How exactly does the bubble activity result in cellular disruption and tissue fractionation? How can the bubble dynamics be controlled by ultrasound? These are key questions to understand the mechanism of histotripsy. Understanding of the physical mechanism would provide rationale to guide development and optimization of histotripsy for clinical applications. Bubble cloud formation and dynamic activity of individual bubbles within cloud are being studied using high speed imaging and acoustic and optical monitoring.
This project was motivated by a need to non-invasively create a flow channel between the left and right chambers of the heart in pediatric patients with different congenital heart diseases, such as Transposition of the Great Arteries (TGA) and Hypoplastic Left Heart Syndrome (HLHS). This flow channel usually comes in the form of a perforation of the atrial septum, clinically referred to as an ASD. The procedure to create an ASD is currently performed through a heart catheterization with a balloon atrial septostomy or open heart surgery. However, these approaches are invasive and carry inherent risks and potentially fatal complications. We are developing histotripsy to generate the ASD non-invasively to reduce the complication associated with the currently available invasive procedure. This project is currently funded by National Institute of Health (NIH R01 HL077629).
Deep vein thrombosis (DVT) is the formation of a blood clot in a deep vein usually in the legs, affecting nearly two million Americans per year. To treat DVT, blood clots need to be removed, a process generally termed thrombolysis. Current clinical thrombolysis methods include catheter-based surgical procedures and thrombolytic drugs, both of which have significant drawbacks including invasiveness and risks of bleeding and infection. We are developing an ultrasonic thrombolysis technique that is non-invasive and carries virtually no risks of bleeding and infection. Histotripsy breaks down blood clots into tiny debris particles that are smaller than red blood cells. The entire histotripsy thrombolysis treatment is guided and monitored by real-time ultrasound imaging. If tested successful for DVT treatment, it could potentially lead to the broader application of histotripsy to other clinical conditions requiring thrombolysis, including stroke, superficial vein thrombosis, pulmonary embolism, and dialysis grafts clotting. This project is currently funded by National Institute of Health (NIH R01 EB008998).
Hepatocellular carcinoma (HCC), a form of liver cancer, is one of the fastest growing cancers in the United States and is associated with poor survival rates. Surgical resection has long been the gold standard intervention, however surgery is not an option for many patients due to factors like tumor morphology, location, associated disease, and poor physiological condition. Several minimally invasive and noninvasive techniques have demonstrated efficacy comparable to surgical resection for tumors smaller than 2-3 cm in diameter, but rapidly diminishing efficacy thereafter. Current tumor ablation techniques are typically thermal-based and are size-limited as a result of perfusion-mediated convection (commonly referred to as the “heat-sink effect”) in which blood flow impedes heat transfer. Since more than 75% of patients presenting with tumors larger than 3 cm, there is an unmet clinical need for an ablation technique capable of effectively treating large-volume liver tumors. Because histotripsy relies on a non-thermal mechanism of action (acoustic cavitation), it is not affected by vascular perfusion. We are currently working to develop histotripsy as a non-invasive liver cancer ablation technique to overcome the limitations of contemporary techniques.
Treatment guided by real-time ultrasound imaging.
We are currently working on a number of projects related to the application of histotripsy in the brain. Particularly, we are working on developing transcranial histotripsy therapies for minimally-to-non-invasive treatment options in brain applications, where histotripsy may be applied from outside the skull to generate targeted lesions in the brain without requiring major invasive surgery. Potential applications include the treatment of intracerebral hemorrhage, where histotripsy may be used to rapidly liquefy large volume clots for drainage later to relieve intracranial pressure, and for tumor ablation, where histotripsy may be used to selectively destroy targeted volumes within the brain without requiring the surgical traversal of overlying tissues. Recent work has shown that histotripsy can be used to transcranially liquefy clot volumes of up to 40mL in under 25 minutes, and to generate targeted lesions as small as 1mm in diameter through the skull. We are also developing technologies and methods to improve the efficacy of transcranial histotripsy therapies, including schemes to rapidly and non-invasively correct for aberrations introduced to the ultrasound pulses by the skull during transcranial histotripsy therapies, and to guide cavitation generation during treatment to ensure accurate and rapid target ablation.
In addition, we are also conducting studies on the safety of applying histotripsy in the brain in vivo. We have recently shown that we can use real-time ultrasound guidance and monitoring during therapy to precisely generate compact lesions in individual gyri in the brain while avoiding damage to surrounding features. MRI and morphological and histological evaluation of lesions generated in the brain via histotripsy indicate that histotripsy in the brain does not lead to significant edema, hemorrhage, or other major complications, and that damage from histotripsy is well confined to within the treatment region, with sharp boundaries between treated and untreated tissues.
Block “M” created in a red blood cell phantom through an ex vivo human skull cap without aberration correction.
We are currently working to develop a nanodroplet-mediated histotripsy approach for targeted cancer cell ablation which would be able to treat multi-focal tumors even when those tumors may not be readily identified using currently available imaging techniques. By combining histotripsy with nanodroplets which can be delivered only to the tumor as a result of the leaky tumor vasculature, histotripsy can be used to selectively ablate cancer cells while leaving the surrounding healthy tissue intact. The reduced pressure required to generate histotripsy using nanodroplets will allow for simultaneous multi-focal tumor ablation. This treatment strategy would be a significant clinical advancement in the treatment of cancer and allow for the targeted ablation of multi-focal tumors even in instances when the tumors are unidentifiable using current imaging modalities.
Polymer encapsulated nanodroplets (A) were formed by self-assembly around a perfluoropentane core. The histotripsy pressure threshold was significantly reduced in the presence of nanodroplets (B) which suggests that nanodroplet-mediated histotripsy can be used for multi-focal ablation by generating cavitation only in locations within the focal region containing nanodroplets (C).
Congenital abnormalities (birth defects) are the leading cause of infant mortality in the U.S., accounting for more than 20% of all infant deaths according to a recent report. Several congenital abnormalities require that patients undergo some form of invasive surgery; these procedures are generally performed after birth due to the high risks of fetal surgery to both mother and fetus. However, because fetal diagnosis of many congenital anomalies can be made early in gestation, fetal intervention may be desirable in certain cases to prevent progression of severe congenital malformations such as hypoplastic left heart syndrome (HLHS).
This project is currently funded by The Hartwell Foundation.
Pictures of fetal sheep heart treated by histotripsy. The fetal heart was slightly larger than a US quarter coin. The ventricular septum of the fetal heart was treated by an external transducer outside the mother’s abdominal skin. This fetal heart was 8 cm deep from the mother’s abdominal wall. A: Outside the lesion the heart is intact, with no signs of damage to the external wall. No damage was observed in other overlying tissue. B: Inside the heart, two lesions were created across the septum separating the left ventricle (LV) and the right ventricle (RV).
Histotripsy is a non-invasive ablation method that depends on a cavitation bubble cloud to mechanically fractionate tissue. In this work, we are investigating the effects of tissue mechanical properties on the histotripsy process. Initial results have demonstrated tissues with increased mechanical strength require higher pressures to generate the dense bubble cloud required for tissue fractionation as well as an increased resistance to histotripsy induced tissue damage. Based on these results, a self-limiting vessel-sparing treatment strategy has been developed in an attempt to preserve major blood vessels with a higher mechanical strength while fractionating the surrounding target tissue with lower mechanical strength.
Blood vessels remained intact and functional within an in vivo porcine liver treated with histotripsy. Doppler ultrasound images before (A) and after (B) histotripsy demonstrated vessel remained functional after treatment. MRI images (A) and histological analysis (D) demonstrated blood vessels remained structurally intact within the histotripsy focal volume while surrounding liver tissue was completely ablated.