Navid Farr

Characterization of a multi-element clinical HIFU system using acoustic holography and nonlinear modeling

High-intensity focused ultrasound (HIFU) is a treatment modality that relies on the delivery of acoustic energy to remote tissue sites to induce thermal and/or mechanical tissue ablation. To ensure the safety and efficacy of this medical technology, standard approaches are needed for accurately characterizing the acoustic pressures generated by clinical ultrasound sources under operating conditions. Characterization of HIFU fields is complicated by nonlinear wave propagation and the complexity of phased-array transducers. Previous work has described aspects of an approach that combines measurements and modeling, and here we demonstrate this approach for a clinical phased-array transducer. First, low amplitude hydrophone measurements were performed in water over a scan plane between the array and the focus. Second, these measurements were used to holographically reconstruct the surface vibrations of the transducer and to set a boundary condition for a 3-D acoustic propagation model. Finally, nonlinear simulations of the acoustic field were carried out over a range of source power levels. Simulation results were compared with pressure waveforms measured directly by hydrophone at both low and high power levels, demonstrating that details of the acoustic field, including shock formation, are quantitatively predicted.

Endoscopic high-intensity focused US: technical aspects and studies in an in vivo porcine model (with video)

BACKGROUND High-intensity focused US (HIFU) is becoming more widely used for noninvasive and minimally invasive ablation of benign and malignant tumors. Recent studies suggest that HIFU can also enhance targeted drug delivery and stimulate an antitumor immune response in many tumors. However, targeting pancreatic and liver tumors by using an extracorporeal source is challenging due to the lack of an adequate acoustic window. The development of an EUS-guided HIFU transducer has many potential benefits including improved targeting, decreased energy requirements, and decreased potential for injury to intervening structures. OBJECTIVE To design, develop, and test an EUS-guided HIFU transducer for endoscopic applications. DESIGN A preclinical, pilot characterization and feasibility study. SETTING Academic research center. PATIENTS Studies were performed in an in vivo porcine model. INTERVENTION Thermal ablation of in vivo porcine pancreas and liver was performed with EUS-guided focused US through the gastric tract. RESULTS The transducer successfully created lesions in gel phantoms and ex vivo bovine livers. In vivo studies demonstrated that targeting and creating lesions in the porcine pancreas and liver are feasible. LIMITATIONS This was a preclinical, single-center feasibility study with a limited number of subjects. CONCLUSION An EUS-guided HIFU transducer was successfully designed and developed with dimensions that are appropriate for endoscopic use. The feasibility of performing EUS-guided HIFU ablation in vivo was demonstrated in an in vivo porcine model. Further development of this technology will allow endoscopists to perform precise therapeutic ablation of periluminal lesions without breaching the wall of the gastric tract.

Boiling histotripsy lesion characterization on a clinical magnetic resonance imaging-guided high intensity focused ultrasound system.

Purpose High intensity focused ultrasound (HIFU) is a non-invasive therapeutic technique that can thermally ablate tumors. Boiling histotripsy (BH) is a HIFU approach that can emulsify tissue in a few milliseconds. Lesion volume and temperature effects for different BH sonication parameters are currently not well characterized. In this work, lesion volume, temperature distribution, and area of lethal thermal dose were characterized for varying BH sonication parameters in tissue-mimicking phantoms (TMP) and demonstrated in ex vivo tissues. Methods The following BH sonication parameters were varied using a clinical MR-HIFU system (Sonalleve V2, Philips, Vantaa, Finland): acoustic power, number of cycles/pulse, total sonication time, and pulse repetition frequency (PRF). A 3×3×3 pattern was sonicated inside TMP’s and ex vivo tissues. Post sonication, lesion volumes were quantified using 3D ultrasonography and temperature and thermal dose distributions were analyzed offline. Ex vivo tissues were sectioned and stained with H&E post sonication to assess tissue damage. Results Significant increase in lesion volume was observed while increasing the number of cycles/pulse and PRF. Other sonication parameters had no significant effect on lesion volume. Temperature full width at half maximum at the end of sonication increased significantly with all parameters except total sonication time. Positive correlation was also found between lethal thermal dose and lesion volume for all parameters except number of cycles/pulse. Gross pathology of ex vivo tissues post sonication displayed either completely or partially damaged tissue at the focal region. Surrounding tissues presented sharp boundaries, with little or no structural damage to adjacent critical structures such as bile duct and nerves. Conclusion Our characterization of effects of HIFU sonication parameters on the resulting lesion demonstrates the ability to control lesion morphologic and thermal characteristics with a clinical MR-HIFU system in TMP’s and ex vivo tissues. We demonstrate that this system can produce spatially precise lesions in both phantoms and ex vivo tissues. The results provide guidance on a preliminary set of BH sonication parameters for this system, with a potential to facilitate BH translation to the clinic.

Noninvasive characterization of pancreatic tumor mouse models using magnetic resonance imaging

The preclinical models of pancreatic adenocarcinoma provide an alternative means for determining the mechanisms of malignancy and possibilities for treatments, thus representing a resource of immense potential for cancer treatment in medicine. To evaluate different tumor models, quantifiable magnetic resonance imaging (MRI) techniques can play a significant role in identifying valuable in vivo biomarkers of tumor characteristics. We characterized three models of pancreatic cancer with multiparametric MRI techniques. Tumor stromal density of each tumor was measured using diffusion‐weighted imaging and magnetization transfer (MT‐MRI). Histologic measurement showed a similar trend with tumor fibrosis levels. Results indicated that MRI measurements can serve as a valuable tool in identifying and evaluating tumor characteristics.

Boiling histotripsy: A noninvasive method for mechanical tissue disintegration

Boiling histotripsy is an experimental noninvasive focused ultrasound therapy that applies shocked ms-length pulses to achieve mechanical disintegration of a targeted tissue. Localized delivery of high-amplitude shocks causes rapid heating, resulting in boiling of the tissue. The interaction of incident shocks with the boiling bubble results in tissue disruption and liquefaction without significant thermal injury. Simulations are utilized to design and characterize therapy sources, predicting focal waveforms, shock amplitudes, and boiling times. Transducers have been developed to generate focal shock amplitudes >70 MPa and achieve rapid boiling at depth in tissue. Therapy systems including ultrasound-guided single-element sources and clinical MRI-guided phased arrays have been successfully used to create ex vivo and in vivo lesions at ultrasound frequencies in the 1–3 MHz range. Histological and biochemical analyses show mechanical disruption of tissue architecture with minimal thermal effect, similar to ...

Characterization of nonlinear ultrasound fields of 2D therapeutic arrays

A current trend in high intensity focused ultrasound (HIFU) technologies is to use 2D focused phased arrays that enable electronic steering of the focus, beamforming to avoid overheating of obstacles (such as ribs), and better focusing through inhomogeneities of soft tissue using time reversal methods. In many HIFU applications, the acoustic intensity in situ can reach thousands of W/cm2 leading to nonlinear propagation effects. At high power outputs, shock fronts develop in the focal region and significantly alter the bioeffects induced. Clinical applications of HIFU are relatively new and challenges remain for ensuring their safety and efficacy. A key component of these challenges is the lack of standard procedures for characterizing nonlinear HIFU fields under operating conditions. Methods that combine low-amplitude pressure measurements and nonlinear modeling of the pressure field have been proposed for axially symmetric single element transducers but have not yet been validated for the much more complex 3D fields generated by therapeutic arrays. Here, the method was tested for a clinical HIFU source comprising a 256-element transducer array. A numerical algorithm based on the Westervelt equation was used to enable 3D full-diffraction nonlinear modeling. With the acoustic holography method, the magnitude and phase of the acoustic field were measured at a low power output and used to determine the pattern of vibrations at the surface of the array. This pattern was then scaled to simulate a range of intensity levels near the elements up to 10 W/cm2. The accuracy of modeling was validated by comparison with direct measurements of the focal waveforms using a fiber-optic hydrophone. Simulation results and measurements show that shock fronts with amplitudes up to 100 MPa were present in focal waveforms at clinically relevant outputs, indicating the importance of strong nonlinear effects in ultrasound fields generated by HIFU arrays.

Tissue decellularization with boiling histotripsy and the potential in regenerative medicine

There have been major advances in the development of replacement organs by tissue engineering (TE); however, one of the holy grails is still in the development of biomimetic structures that replicate the complex 3-D vasculature. Creation of bioartificial organs by decellularization shows greater promise in reaching the clinic compared to TE. However, current decellularization techniques require the use of chemical and biological agents, often in combination with physical force, which could result in damage to the matrix. Here we evaluate the use of boiling histotripsy (BH) to selectively decellularize large volumes of tissue. BH lesions (10–20 mm diameter) were produced in bovine liver with a clinical 1.2 MHz MR-HIFU system (Sonalleve, Philips, Finland), using thirty 10 ms pulses, and pulse repetition frequencies of 1–10 Hz. Peak acoustic powers corresponding to an estimated in situ shock front amplitude of 65 MPa were used. Macroscopic and histological evaluation revealed treatment conditions that produc...

Hyperthermia-enhanced targeted drug delivery using magnetic resonance-guided focussed ultrasound: a pre-clinical study in a genetic model of pancreatic cancer

Abstract Purpose: The lack of effective treatment options for pancreatic cancer has led to a 5-year survival rate of just 8%. Here, we evaluate the ability to enhance targeted drug delivery using mild hyperthermia in combination with the systemic administration of a low-temperature sensitive liposomal formulation of doxorubicin (LTSL-Dox) using a relevant model for pancreas cancer. Materials and methods: Experiments were performed in a genetically engineered mouse model of pancreatic cancer (KPC mice: LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre). LTSL-Dox or free doxorubicin (Dox) was administered via a tail vein catheter. A clinical magnetic resonance-guided high intensity focussed ultrasound (MR-HIFU) system was used to plan treatment, apply the HIFU-induce hyperthermia and monitor therapy. Post-therapy, total Dox concentration in tumour tissue was determined by HPLC and confirmed with fluorescence microscopy. Results: Localized hyperthermia was successfully applied and monitored with a clinical MR-HIFU system. The mild hyperthermia heating algorithm administered by the MR-HIFU system resulted in homogenous heating within the region of interest. MR-HIFU, in combination with LTSL-Dox, resulted in a 23-fold increase in the localised drug concentration and nuclear uptake of doxorubicin within the tumour tissue of KPC mice compared to LTSL-Dox alone. Hyperthermia, in combination with free Dox, resulted in a 2-fold increase compared to Dox alone. Conclusion: This study demonstrates that HIFU-induced hyperthermia in combination with LTSL-Dox can be a non-invasive and effective method in enhancing the localised delivery and penetration of doxorubicin into pancreatic tumours.

Mechanical fractionation of tissues using microsecond-long HIFU pulses on a clinical MR-HIFU system

Abstract Purpose: High intensity focussed ultrasound (HIFU) can non-invasively treat tumours with minimal or no damage to intervening tissues. While continuous-wave HIFU thermally ablates target tissue, the effect of hundreds of microsecond-long pulsed sonications is examined in this work. The objective of this study was to characterise sonication parameter-dependent thermomechanical bioeffects to provide the foundation for future preclinical studies and facilitate clinical translation. Methods and materials: Acoustic power, number of cycles/pulse, sonication time and pulse repetition frequency (PRF) were varied on a clinical magnetic resonance imaging (MRI)-guided HIFU (MR-HIFU) system. Ex vivo porcine liver, kidney and cardiac muscle tissue samples were sonicated (3 × 3 grid pattern, 1 mm spacing). Temperature, thermal dose and T2 relaxation times were quantified using MRI. Lesions were histologically analysed using H&E and vimentin stains for lesion structure and viability. Results: Thermomechanical HIFU bioeffects produced distinct types of fractionated tissue lesions: solid/thermal, paste-like and vacuolated. Sonications at 20 or 60 Hz PRF generated substantial tissue damage beyond the focal region, with reduced viability on vimentin staining, whereas H&E staining indicated intact tissue. Same sonication parameters produced dissimilar lesions in different tissue types, while significant differences in temperature, thermal dose and T2 were observed between the parameter sets. Conclusion: Clinical MR-HIFU system was utilised to generate distinct types of lesions and to produce targeted thermomechanical bioeffects in ex vivo tissues. The results guide HIFU research on thermomechanical tissue bioeffects, inform future studies and advice sonication parameter selection for direct tumour ablation or immunomodulation using a clinical MR-HIFU system.

A multimodal evaluation of boiling histotripsy lesion properties in ex vivo bovine liver

New types of high intensity focused ultrasound (HIFU) therapy aiming at mechanical homogenization of tissue has shown great promise, namely, cavitation-cloud histotripsy and boiling histotripsy (BH). BH uses millisecond-long bursts of HIFU waves containing shocks to repeatedly induce boiling at the focus; the interaction of incident HIFU waves with vapor bubbles homogenizes tissue. In this study, degassed ex vivo bovine liver samples were sonicated using a 256-element 1.2 MHz array of a clinical MR-HIFU system. The BH lesions were produced using 10-ms long pulses with 80 MPa shocks in situ and pulse repetition frequencies (PRFs) of 1-10 Hz to cover a range of effects from pure mechanical homogenization to thermal ablation. Individual lesions were generated for the multimodal analysis of the lesion including ultrastructure (electron microscopy), molecular (biochemistry), and microstructure (histological) methods. The extent of homogenization and thermal denaturation was evaluated for each lesion. The resul...