In Vitro Investigation of the Individual Contributions of Ultrasound-Induced Stable and Inertial Cavitation in Targeted Drug Delivery.

Ultrasound-mediated targeted drug delivery is a therapeutic modality under development with the potential to treat cancer. Its ability to produce local hyperthermia and cell poration through cavitation non-invasively makes it a candidate to trigger drug delivery. Hyperthermia offers greater potential for control, particularly with magnetic resonance imaging temperature measurement. However, cavitation may offer reduced treatment times, with real-time measurement of ultrasonic spectra indicating drug dose and treatment success. Here, a clinical magnetic resonance imaging-guided focused ultrasound surgery system was used to study ultrasound-mediated targeted drug delivery in vitro. Drug uptake into breast cancer cells in the vicinity of ultrasound contrast agent was correlated with occurrence and quantity of stable and inertial cavitation, classified according to subharmonic spectra. During stable cavitation, intracellular drug uptake increased by a factor up to 3.2 compared with the control. Reported here are the value of cavitation monitoring with a clinical system and its subsequent employment for dose optimization.

Measurement of proton resonance frequency shift coefficient during MR-guided focused ultrasound on Thiel embalmed tissue.

PURPOSE: To estimate the value of proton resonance frequency (PRF) shift coefficient of explanted Thiel embalmed animal and human tissue used as a preclinical model for treatment with MR-guided focused ultrasound (FUS). METHODS: Thiel embalmed human liver, ovine liver, and porcine muscle were heated using two methods: bulk heating and FUS-induced heating. Phase-referenced PRF thermometry was applied during cooling of the tissue to obtain a series of phase difference, ΔΦ, maps. A fiber-optic thermocouple was inserted in the tissue to measure the temperature difference, ΔT. The PRF shift coefficient was calculated from the measured ΔΦ, ΔT. RESULTS: In the case of bulk heating, the mean values (±SD) of the PRF coefficient for Thiel embalmed ovine liver, porcine muscle, and human liver were: 0.017 (5 × 10-4 ) ppm/°C, 0.015 (6 × 10-4 ) ppm/°C, and 0.012 (6 × 10-4 ) ppm/°C, respectively. Similar values were found in tissues heated with FUS. CONCLUSION: The values of PRF coefficient measured for the Thiel embalmed tissue were higher than the values for fresh tissue, suggesting that embalming a tissue with Thiel fluid can affect PRF thermometry. The chemical composition of the Thiel fluid and the electrical conductivity may explain these results. Magn Reson Med 74:260-265, 2015. © 2014 Wiley Periodicals, Inc.

Magnetic resonance-guided focused ultrasound treatment of facet joint pain: summary of preclinical phase.

STUDY DESIGN: A phantom experiment, two thermocouple experiments, three in vivo pig experiments, and a simulated treatment on a healthy human volunteer were conducted to test the feasibility, safety, and efficacy of magnetic resonance-guided focused ultrasound (MRgFUS) for treating facet joint pain. OBJECTIVE: The goal of the current study was to develop a novel method for accurate and safe noninvasive facet joint ablation using MRgFUS. SUMMARY OF BACKGROUND DATA: Facet joints are a common source of chronic back pain. Direct facet joint interventions include medial branch nerve ablation and intra-articular injections, which are widely used, but limited in the short and long term. MRgFUS is a breakthrough technology that enables accurate delivery of high-intensity focused ultrasound energy to create a localized temperature rise for tissue ablation, using MR guidance for treatment planning and real-time feedback. METHODS: We validated the feasibility, safety, and efficacy of MRgFUS for facet joint ablation using the ExAblate 2000® System (InSightec Ltd., Tirat Carmel, Israel) and confirmed the system's ability to ablate the edge of the facet joint and all terminal nerves innervating the joint. A phantom experiment, two thermocouple experiments, three in vivo pig experiments, and a simulated treatment on a healthy human volunteer were conducted. RESULTS: The experiments showed that targeting the facet joint with energies of 150-450 J provides controlled and accurate heating at the facet joint edge without penetration to the vertebral body, spinal canal, or root foramina. Treating with reduced diameter of the acoustic beam is recommended since a narrower beam improves access to the targeted areas. CONCLUSIONS: MRgFUS can safely and effectively target and ablate the facet joint. These results are highly significant, given that this is the first study to demonstrate the potential of MRgFUS to treat facet joint pain.

Ultrasound-mediated targeted drug delivery with a novel cyclodextrin-based drug carrier by mechanical and thermal mechanisms.

Various mechanisms for ultrasound-mediated targeted drug delivery have been investigated in the past several decades. Cyclodextrins are already known for their ability to encapsulate various drugs in their lipophilic cavity; this paper reports evaluation of the potential of a cyclodextrin-based nanocarrier as a drug delivery vehicle, using cell monolayers in vitro in conjunction with ultrasound as the release mechanism. The application of ultrasound to the cell monolayers results in both thermal and mechanical effects; a current challenge is to differentiate between these effects. In this study, the cell uptake routes of doxorubicin encapsulated in the cyclodextrin-based carrier were investigated, examining individually the thermal and the mechanical effects of focused ultrasound for drug release. Exploiting mechanical effects, the uptake of encapsulated doxorubicin into cancer cells was increased by a factor of up to 5.5 when ultrasound was applied. Thermal application of FUS increased the cellular uptake of encapsulated doxorubicin by a factor of up to 9.6. Hyperthermia without focused ultrasound resulted in an increase by a factor of up to 5.7.

Pain palliation in patients with bone metastases using MR-guided focused ultrasound surgery: a multicenter study.

BACKGROUND: Noninvasive thermal ablation using magnetic resonance (MR)-guided focused ultrasound (MRgFUS) has been shown to be clinically effective in uterine fibroids, and is being evaluated for ablation of breast, liver, and brain lesions. Recently MRgFUS has been evaluated for palliation of pain caused by bone metastases. We present the clinical results of a multicenter study using MRgFUS for palliation of bone metastases pain. METHODS: A multicenter study to evaluate the safety and efficacy of MRgFUS palliative treatment of bone metastases was conducted in patients suffering from painful metastatic bone lesions for which other treatments were either ineffective or not feasible. Thirty-one patients with painful bone metastases underwent the MRgFUS procedure in three medical centers. Treatment safety was evaluated by assessing the device-related complications. Effectiveness of pain palliation was evaluated using the visual analog pain score (VAS), and measurable changes in the intake of opioid analgesics. RESULTS: Thirty-six procedures were performed on 31 patients. Mean follow-up time was 4 months. 25 patients underwent the planned treatment and were available for 3 months post-treatment follow-up. 72% of the patients (18/25) reported significant pain improvement. Average VAS score was reduced from 5.9 prior to treatment to 1.8 at 3 months post treatment. 67% of patients with recorded medication data reported a reduction in their opioid usage. No device-related severe adverse events were recorded. CONCLUSION: The results suggest that MRgFUS has the ability to provide an accurate, effective, and safe noninvasive palliative treatment for patients with bone metastases.

Magnetic resonance imaging findings of spinal intramedullary spirocercosis.

Spirocerca lupi is a nematode infecting dogs in tropical and subtropical areas. Aberrant S. lupi migration to different body organs, including the spinal cord, has been documented. To date, the diagnosis of aberrant spinal cord migration was made at post-mortem examination or as an incidental finding, during spinal surgery. We describe two dogs with acute asymmetric paraparesis that were subsequently diagnosed with spinal cord spirocercosis. In magnetic resonance (MR) images of the spine, T2 hyperintense lesions were seen in the spinal cord of both dogs. The lesions appeared isointense on T1-weighted images and focal enhancement was detected after gadolinium administration. The MR imaging findings were compatible with focal inflammation, presumably along the parasite migration tract. Gross and microscopic pathologic findings confirmed the diagnosis of aberrant spinal intramedullary migration of S. lupi in one dog, and in the other dog, the clinical and imaging findings were supportive of this diagnosis.