Enhancement of Neurite Outgrowth by Warming Biomaterial Ultrasound Treatment.

Ultrasound is a method for enhancing neurite outgrowth because of its thermal effect. In order to reach the working temperature to enhance neurite outgrowth, long-time treatment by ultrasound is necessary, while acknowledging that the treatment poses a high risk of damaging nerve cells. To overcome this problem, we developed a method that shortens the ultrasonic treatment time with a warming biomaterial. In this study, we used Fe3O4 nanoparticle-embedded polycaprolactone (PCL) as a sonosensitized biomaterial, which has an excellent heating rate due to its high acoustic attenuation. With this material, the ultrasonic treatment time for enhancing neurite outgrowth could be effectively shortened. Ultrasonic treatment could also increase neuronal function combined with the warming biomaterial, with more promoter neuronal function than only ultrasound. Moreover, the risk of overexposure can be avoided by the use of the warming biomaterial by reducing the ultrasonic treatment time, providing better effectiveness.

Self-Supplying O2 through the Catalase-Like Activity of Gold Nanoclusters for Photodynamic Therapy against Hypoxic Cancer Cells.

Photodynamic therapy (PDT) typically involves oxygen (O2 ) consumption and therefore suffers from greatly limited anticancer therapeutic efficacy in tumor hypoxia. Here, it is reported for the first time that amine-terminated, PAMAM dendrimer-encapsulated gold nanoclusters (AuNCs-NH2 ) can produce O2 for PDT via their intrinsic catalase-like activity. The AuNCs-NH2 not only show optimum H2 O2 consumption via the catalase-like activity over the physiological pH range (i.e., pH 4.8-7.4), but also extend such activity to acidic conditions. The possible mechanism is deduced from that the enriched tertiary amines of dendrimers are easily protonated in acidic solutions to facilitate the preadsorption of OH on the metal surface, thereby favorably triggering the catalase-like reaction. By taking advantage of the exciting feature on AuNCs-NH2 , the possibility to supply O2 via the catalase-like activity of AuNCs-NH2 for PDT against hypoxia of cancer cells was further studied. This proof-of-concept study provides a simple way to combine current O2 -dependent cancer therapy of PDT to overcome cancer cell hypoxia, thus achieving more effective anticancer treatments.

A Coaxial Dual-element Focused Ultrasound Probe for Guidance of Epidural Catheterization: An Experimental Study.

Ultrasound guidance for epidural block has improved clinical blind-trial problems but the design of present ultrasonic probes poses operating difficulty of ultrasound-guided catheterization, increasing the failure rate. The purpose of this study was to develop a novel ultrasonic probe to avoid needle contact with vertebral bone during epidural catheterization. The probe has a central circular passage for needle insertion. Two focused annular transducers are deployed around the passage for on-axis guidance. A 17-gauge insulated Tuohy needle containing the self-developed fiber-optic-modified stylet was inserted into the back of the anesthetized pig, in the lumbar region under the guidance of our ultrasonic probe. The inner transducer of the probe detected the shallow echo signals of the peak-peak amplitude of 2.8 V over L3 at the depth of 2.4 cm, and the amplitude was decreased to 0.8 V directly over the L3 to L4 interspace. The outer transducer could detect the echoes from the deeper bone at the depth of 4.5 cm, which did not appear for the inner transducer. The operator tilted the probe slightly in left-right and cranial-caudal directions until the echoes at the depth of 4.5 cm disappeared, and the epidural needle was inserted through the central passage of the probe. The needle was advanced and stopped when the epidural space was identified by optical technique. The needle passed without bone contact. Designs of the hollow probe for needle pass and dual transducers with different focal lengths for detection of shallow and deep vertebrae may benefit operation, bone/nonbone identification, and cost.

Temporal course of streptozotocin-induced diabetic polyneuropathy in rats.

The temporal course of diabetic polyneuropathy in a rat model plays a critical role in studies on diabetic polyneuropathy treatment. In this study, the temporal course of neuropathic symptoms was investigated in diabetic rats induced by streptozotocin and evaluated by nerve conduction velocity and behavioral assays, including the von Frey test for mechanical allodynia and the hot plate test for hyperalgesia. The results revealed that both mechanical allodynia and heat hyperalgesia started on the 2nd week, while nerve conduction velocity significantly decreased from the 1st week. In addition, the severity of allodynia did not change after the 3rd week. Hyperalgesia and nerve conduction velocity progressively aggravated even to the 8th week. Transmission electron microscopy showed that loss of unmyelinated axons, loosening of the myelin structure, and thickening of the perineurium layer were visible from the 4th week and worsened on the 8th week. Differences in the temporal course of neuropathic symptoms are discussed.

A new method for characterizing piezoelectric properties of hexagonal boron nitride nanoflakes activated by focused ultrasound.

Piezoelectric nanomaterials wirelessly activated by ultrasound have been studied for biomedical applications. However, the quantitative measurement of piezoelectric effects in nanomaterials and the correlation between the ultrasound dose and the piezoelectric amplitude are still explored. We demonstrated the synthesis of boron nitride nanoflakes by mechanochemical exfoliation and employed the electrochemical method to quantitatively evaluate the piezoelectric performance of the nanoflakes under ultrasonic circumstances. The change of voltametric charge, current, and voltage in response to different acoustic pressure was obtained in the electrochemical system. The charge was reached up to 69.29 µC with a net increase of 49.54 µC/mm2 under 2.976 MPa. The output current was measured up to 597 pA/mm2 and positive shift of output voltage shifted from -600 mV to -450 mV. Additionally, the piezoelectric performance linearly increased with acoustic pressure. The proposed method could be a standardized evaluation test bench for characterization of ultrasound-mediated piezoelectric nanomaterials.

Ultrasound Stimulation Potentiates Management of Diabetic Hyperglycemia.

OBJECTIVE: Glucose homeostasis is the only way to manage diabetic progression as all medications used do not cure diabetes. This study was aimed at verifying the feasibility of lowering glucose with non-invasive ultrasonic stimulation. METHODS: The ultrasonic device was homemade and controlled via a mobile application on the smartphone. Diabetes was induced in Sprague-Dawley rats through high-fat diets followed by streptozotocin injection. The treated acupoint CV12 was at the middle of the xiphoid and umbilicus of the diabetic rats. Parameters of ultrasonic stimulation were an operating frequency of 1 MHz, pulse repetition frequency of 15 Hz, duty cycle of 10% and sonication time of 30 min for a single treatment. DISCUSSION: The diabetic rats exhibited a significant decrease of 11.5% ± 3.6% in blood glucose in 5 min of ultrasonic stimulation (p < 0.001). After the single treatment on the first day, third day and fifth day in the first week, the treated diabetic rats had a significantly small area under the curve of the glucose tolerance test (p < 0.05) compared with the untreated diabetic rats in the sixth week. Hematological analyses indicated that the serum concentrations of ß-endorphin were significantly increased by 58% ± 71.9% (p < 0.05) and the insulin level was increased by 56% ± 88.2% (p = 0.15) without statistical significance after a single treatment. CONCLUSION: Therefore, non-invasive ultrasound stimulation at an appropriate dose can produce a hypoglycemic effect and improve glucose tolerance for glucose homeostasis and may play a role as adjuvant therapy with diabetic medications in the future.

Large-Volume Focused-Ultrasound Mild Hyperthermia for Improving Blood-Brain Tumor Barrier Permeability Application.

Mild hyperthermia can locally enhance permeability of the blood-tumor barrier in brain tumors, improving delivery of antitumor nanodrugs. However, a clinical transcranial focused ultrasound (FUS) system does not provide this modality yet. The study aimed at the development of the transcranial FUS technique dedicated for large-volume mild hyperthermia in the brain. Acoustic pressure, multiple-foci, temperature and thermal dose induced by FUS were simulated in the brain through the skull. A 1-MHz, 114-element, spherical helmet transducer was fabricated to verify large-volume hyperthermia in the phantom. The simulated results showed that two foci were simultaneously formed at (2, 0, 0) and (-2, 0, 0) and at (0, 2, 0) and (0, -2, 0), using the phases of focusing pattern 1 and the phases of focusing pattern 2, respectively. Switching two focusing patterns at 5 Hz produced a hyperthermic zone with an ellipsoid of 7 mm × 6 mm × 11 mm in the brain and the temperature was 41-45 °C in the ellipsoid as the maximum intensity was 150 W/cm2 and sonication time was 3 min. The phased array driven by switching two mode phases generated a 41 °C-contour region of 10 ± 1 mm × 8 ± 2 mm × 13 ± 2 mm in the phantom after 3-min sonication. Therefore, we have demonstrated our developed FUS technique for large-volume mild hyperthermia.

Vasomodulation of peripheral blood flow by focused ultrasound potentiates improvement of diabetic neuropathy.

OBJECTIVE: Effective treatment methods for diabetic peripheral neuropathy are still lacking. Here, a focused ultrasound (FUS) technique was developed to improve blood flow in diabetic peripheral vessels and potentially treat diabetic peripheral neuropathy. RESEARCH DESIGN AND METHODS: Male adult Sprague-Dawley rats at 4 weeks poststreptozotocin injections were adopted as models for diabetic neuropathic rats. For single FUS treatment, blood perfusion in the skin of the pad of the middle toe was measured before, during, and after the medial and lateral plantar arteries were treated by FUS. For multiple FUS treatments, blood perfusion measurements, von Frey and hot plate testing and nerve conduction velocity measurements were performed before ultrasonic treatment on the first day of each week, and the microvascular and neural fiber densities in the pad of the toe were measured on the first day of the last week. RESULTS: The blood perfusion rate significantly increased for 7-10 min in the control and neuropathic rats after a single ultrasound exposure. Multiple ultrasound treatments compared with no treatments significantly increased blood perfusion at the second week and further enhanced perfusion at the third week in the neuropathic rats. Additionally, the paw withdrawal force and latency significantly increased from 34.33±4.55 g and 3.96±0.25 s at the first week to 39.10±5.02 g and 4.77±0.71 s at the second week and to 41.13±2.57 g and 5.24±0.86 s at the third week, respectively. The low nerve conduction velocity in the diabetic rats also improved after the ultrasound treatments. Additionally, ultrasound treatments halted the decrease in microvessel and neural fiber densities in the skin of the diabetic toes. Histologic analysis indicated no damage to the treated arteries or neighboring tissue. CONCLUSIONS: FUS treatment can increase upstream arterial blood flow in diabetic feet, ameliorate the decrease in downstream microvessel perfusion and halt neuropathic progression.

Feasibility study of greater occipital nerve blocks by focused ultrasound - an animal study.

OBJECTIVE: Greater occipital nerve (GON) block may provide substantial relief for headache in the occipital location. This study tested the feasibility of focused ultrasound (FUS) to induce the conduction block of GONs in rats. APPROACH: For in vitro experiments, the nerve was dissected and cut from C2 to the site near the ear of the rats and preserved in Ringer's solution. Pulsed FUS was used for the block, and sensory action potentials were recorded in the GON. For in vivo experiments, the GONs of the rats were surgically exposed for precise ultrasonic treatment. All data are expressed as the mean ± the standard deviation. MAIN RESULTS: A single ultrasonic treatment temporarily suppressed the amplitude of action potentials of the in vitro nerves to 42 ± 14% of the baseline values, and the time to recovery was 55 min. The in vivo results showed that FUS acutely inhibited the amplitude of action potentials to 41 ± 8% of the baseline value in rat GONs, and the time to recovery was 67 min. Histological examination revealed no appreciable changes in the nerve morphology caused by FUS. Therefore, FUS reversibly blocked the conduction of the rat GON when the sonication parameters were appropriate. SIGNIFICANCE: Noninvasive FUS may be a novel treatment paradigm for occipital headache by blocking the occipital nerve, and the procedure is repeatable if indicated.

High-Intensity Focused Ultrasound Ablation Combined with Electrical Passive Exercise for Fast Removal of Body Fat.

BACKGROUND: High-intensity focused ultrasound (HIFU) lipolysis still lacks treatment efficacy. The authors hypothesized that electrical stimulation of muscular groups can enhance the metabolism of free lipids released from HIFU-ablated adipocytes. METHODS: Five-month-old, male Landrace swine, with an average initial weight of 95 kg, were divided randomly into sham, HIFU only, HIFU plus electrical stimulation I, and HIFU plus electrical stimulation II groups. Subcutaneous adipose tissue of the porcine abdomen was treated once by HIFU on days 1 of weeks 1, 3, and 5, and electrical stimulation of the quadriceps was performed once on the day 1 of weeks 1 through 6. The numbers of ultrasonic sonications were 70 per treatment for the HIFU-only and HIFU plus electrical stimulation I groups and 400 for the HIFU plus electrical stimulation II group. The measured data are expressed as medians (ranges). RESULTS: The body weights of all pigs increased gradually with time. The waist circumferences below the sheath decreased from 97.7 ± 6.0 cm in week 1 and 97.9 ± 5.3 cm in week 3 to 96.4 ± 10.0 cm in week 6, and from 105.3 ± 5.1 cm and 101.2 ± 7.4 cm to 100.5 ± 6.1 cm for the HIFU plus electrical stimulation I and II groups, respectively, whereas they increased for the sham and HIFU-only groups. The reductions in the adipose tissue thickness were 0.59, 1.46, and 2.18 mm for the HIFU-only, HIFU plus electrical stimulation I, and HIFU plus electrical stimulation II groups, respectively, when the sham group increased by 1.42 mm. Follow-up blood analyses demonstrated no significant changes in lipid panel parameters from baseline values. CONCLUSION: HIFU plus electrical stimulation can induce a substantial reduction in the waist circumference of pigs.

An MRI-Guided Ring High-Intensity Focused Ultrasound System for Noninvasive Breast Ablation.

High-intensity focused ultrasound (HIFU) has been used for noninvasive treatment of breast tumors, but the present magnetic resonance imaging (MRI)-guided HIFU (MRI-HIFU) systems encounter skin burn. In this study, a novel MRI-HIFU breast ablation system was developed to improve the above problem. The system consisted of the ring HIFU phased-array transducer, a commercial power amplifier, the mechanical positioner, and the graphical user interface control software. MRI thermometry was also established to monitor the temperature in the HIFU-treated tissue. Ablation of pork and the in vivo rabbit leg were carried out to validate the developed system. Results of fat-surrounding pork ablation showed that the ring HIFU system reached a safe margin of 3 mm without fat burn. Moreover, precision of the positioner moving the HIFU focal zone was within 6% error under MRI circumstances. The representative MRI temperature images show that the peak temperatures among the five ablations ranged between 66 °C and 91 °C, and their thermal doses were over 10000. The system could also ablate the biceps femoris of a rabbit without skin burn to form a lesion of 2.5 mm beneath the skin. With the HIFU dose of 315 W/10 s, the MRI temperature map revealed that the maximum temperature and the thermal dose were 60 °C and 3380, respectively. The MRI-guided ring HIFU system can ablate the target tissue near subcutaneous fat without fat burn. The system prototype is a promising tool for clinical implementation.

Using C-doped TiO2 Nanoparticles as a Novel Sonosensitizer for Cancer Treatment.

Sonodynamic therapy is an effective treatment for eliminating tumor cells by irradiating sonosentitizer in a patient's body with higher penetration ultrasound and inducing the free radicals. Titanium dioxide has attracted the most attention due to its properties among many nanosensitizers. Hence, in this study, carbon doped titanium dioxide, one of inorganic materials, is applied to avoid the foregoing, and furthermore, carbon doped titanium dioxide is used to generate ROS under ultrasound irradiation to eliminate tumor cells. Spherical carbon doped titanium dioxide nanoparticles are synthesized by the sol-gel process. The forming of C-Ti-O bond may also induce defects in lattice which would be beneficial for the phenomenon of sonoluminescence to improve the effectiveness of sonodynamic therapy. By dint of DCFDA, WST-1, LDH and the Live/Dead test, carbon doped titanium dioxide nanoparticles are shown to be a biocompatible material which may induce ROS radicals to suppress the proliferation of 4T1 breast cancer cells under ultrasound treatment. From in vivo study, carbon doped titanium dioxide nanoparticles activated by ultrasound may inhibit the growth of the 4T1 tumor, and it showed a significant difference between sonodynamic therapy (SDT) and the other groups on the seventh day of the treatment.

Development of an MRI-Compatible High-Intensity Focused Ultrasound Phased Array Transducer Dedicated for Breast Tumor Treatment.

High-intensity focused ultrasound (HIFU) under magnetic resonance imaging (MRI) guidance can achieve a noninvasive and precise ablation of the solid tumor. In the study, an MRI-compatible 1-MHz 16-channel ring-shaped transducer was developed to minimize the burn risk of breast skin and perform volumetric ablation for short treatment time. The measured electroacoustic conversion efficiency of the transducer was 50.90% ± 5. The transducer could produce a point and a quasi-hollow-cylinder lesion in a thermal-sensitive phantom or an ex vivo pork by tuning the phase of each element. It may achieve volumetric ablation of 1.5 cm3 when the point lesion is located inside the hollow lesion. Ex vivo ablation experiments showed that the transducer could cause a coagulative necrosis in the pork from the surrounded subcutaneous fat by 5 mm without fat damage. The temperature and region of the pork ablation were quantified by MRI technique. There was no MRI interference from HIFU and vice versa while both systems operated concurrently.

An Ultrasonic Tool for Nerve Conduction Block in Diabetic Rat Models.

Nerve conduction block with a high intensity-focused ultrasound (HIFU) transducer has been performed in normal and diabetic animal models recently. HIFU can reversibly block the conduction of peripheral nerves without damaging the nerves while using an appropriate ultrasonic parameter. Temporary and partial block of the action potentials of nerves shows that HIFU has the potential to be a useful clinical treatment for pain relief. This work demonstrates the procedures for suppressing the action potentials of neuropathic nerves in diabetic rats in vivo using an HIFU transducer. The first step is to generate adult male diabetic neuropathic rats by streptozotocin (STZ) injection. The second step is to evaluate the peripheral diabetic neuropathy in STZ-induced diabetic rats by an electronic von Frey probe and a hot plate. The final step is to record in vivo extracellular action potentials of the nerve exposed to HIFU sonication. The method showed here may benefit the study of ultrasound analgesic applications.

Synergistic Effects of Nanodrug, Ultrasound Hyperthermia, and Thermal Ablation on Solid Tumors-An Animal Study.

OBJECTIVE: Delivery barriers of nanodrug in large tumors due to heterogeneous blood supply, elevated interstitial pressure, and long transport distances can degrade the efficacy of cancer treatment. In this study, we proposed a therapeutic strategy to improve the tumor growth inhibition by injecting pegylated liposomal doxorubicin (PLD), and then applying a short time of ultrasound hyperthermia (HT) on the entire solid tumor, and inflicting ultrasound thermal ablation (Ab) in the low-perfused tumor region. METHODS: BALB/c female mice with an average weight of 20 g were adopted and murine breast cancer cells 4T1 were subcutaneously implanted into the flank. A 1.0-MHz planar and a 0.47-MHz focused ultrasound transducers were used, respectively, for the HT and Ab treatment. RESULTS: For a PLD dose of 5 mg/kg, the PLD + HT(42 °C, 10 min) group caused a significant decrease in the tumor size as compared with the control and the PLD group, but there were no significant differences between the PLD + HT group and the PLD + Ab(56 °C, 49 s) + HT group. For a PLD dose of 3 mg/kg, the tumor sizes among the four groups were mutually significant. The level of reduction in tumor was PLD + Ab + HT > PLD + HT > PLD > control. CONCLUSION: The combination of anticancer nanodrug and ultrasound thermal treatment could remarkably suppress cancer tumor growth with a minimum compromise of side effects. SIGNIFICANCE: The strategy of using thermal Ab in locations that are not reached by nanodrug with mild HT shows a promising potential for the entire tumor treatment.

A new design method for extracorporeal high-intensity focused ultrasound annular array.

Considering the damage to normal tissues during the high-intensity focused ultrasound ablation of the tumor is important. The purpose of this work was to design the annular array under the considerations of preventing the skin burn and damage to normal tissues behind the tumor target. Based on the Rayleigh-Summerfield pressure integral, the numerical acoustic intensity field of a spherical bowl annular array with a diameter of 12 cm and a radius of curvature of 12 cm was obtained by using the MATLAB software. An absorbed intensity ratio of the normal tissue to target was proposed to define the allowable grating lobe for determining the focusing range. The analytic results showed that for the treatment of uterine fibroids, the focusing range increased as the number of the element increased from 9 to 22 and the 14-ring array at the operating frequency of 0.8, 0.9 or 1.0 MHz had a focusing range larger than 5.5 cm when the range was only 4 cm at 1.2 MHz. For the treatment of medullary carcinoma and scirrhous carcinoma in breast, the focusing range of the 0.9-MHz, 14-ring annular array was 8-12 and 8-14 cm, respectively.

High-intensity focused ultrasound attenuates neural responses of sciatic nerves isolated from normal or neuropathic rats.

Patients with diabetic neuropathy often have neuropathic pain. The purpose of our work was to investigate the effects of high-intensity focused ultrasound (HIFU) on the conduction block of normal and neuropathic nerves for soothing pain. Adult male Sprague-Dawley rats were used, and diabetes was induced by streptozotocin injection. Diabetic neuropathy was evaluated with animal behavior tests. Sciatic nerves of both control and neuropathic rats were dissected from the starting point of the sciatic nerve to the point where the sural nerve ends near the ankle. The nerves were stored in Ringer's solution. The in vitro nerve was placed on a self-developed experimental platform for HIFU exposure. Stimulation and recording of the compound action potentials (CAPs) and sensory action potentials (SAPs) were performed. Control and neuropathic nerves exposed or not exposed to HIFU were submitted to histologic analysis. For the control and neuropathic nerves, suppression of CAPs and SAPs started 2 min post-HIFU treatment. Maximum suppression of SAPs was 34.4 ± 3.2% for the control rats and 11.6 ± 2.0% and 9.8 ± 3.0% for rats 4 wk post-injection and 8 wk post-injection, respectively. Time to full recovery was 25, 70 and 80 min, respectively. Histologic analysis revealed that the nerves in which CAPs and SAPs did not fully recover were damaged thermally or mechanically by HIFU. It is feasible to reversibly block nerves with appropriate HIFU treatment. Diabetic nerves were less suppressed by HIFU and were more vulnerable to permanent damage.

Measurement of ultrasonic attenuation in diabetic neuropathic sciatic nerves for diagnostic and therapeutic applications.

Measurements of ultrasonic attenuation in the sciatic nerves of rats were performed to verify the feasibility of ultrasound diagnosis of peripheral neuropathy and to avoid damage to the nerves caused by overheating in pain management applications. A rat model of diabetic peripheral neuropathy was established. The proximal-segment and middle-segment sciatic nerves of control and neuropathic rats were dissected for the attenuation measurement. Two commercial ultrasound transducers and a self-developed experimental platform were used in the measurements. Using H&E staining and transmission electron (TE) microscopy, morphological analysis of the control and neuropathic nerves was performed to determine the relationship between attenuation and the histology of the nerves. The experimental results showed that the attenuation coefficients of the control, second-week, fourth-week, and eighth-week neuropathic nerves were -6.68 ± 0.50, -5.61 ± 0.34, -6.27 ± 0.40, and -7.10 ± 0.35 dB/cm at 2.68 MHz, respectively. The respective values at 7.50 MHz were -14.96 ± 0.79, -12.65 ± 0.28, -13.98 ± 1.07, and -16.00 ± 0.54 dB/cm. The changes in the attenuation coefficients were significantly different among the second-week, fourth-week, and eighth-week DN nerves. Additionally, the ultrasonic attenuation coefficient of the rat sciatic nerve was fourfold that of the cat brain and cow liver and twofold that of human muscle.

Focused ultrasound simultaneous irradiation/MRI imaging, and two-stage general kinetic model.

Many studies have investigated how to use focused ultrasound (FUS) to temporarily disrupt the blood-brain barrier (BBB) in order to facilitate the delivery of medication into lesion sites in the brain. In this study, through the setup of a real-time system, FUS irradiation and injections of ultrasound contrast agent (UCA) and Gadodiamide (Gd, an MRI contrast agent) can be conducted simultaneously during MRI scanning. By using this real-time system, we were able to investigate in detail how the general kinetic model (GKM) is used to estimate Gd penetration in the FUS irradiated area in a rat's brain resulting from UCA concentration changes after single FUS irradiation. Two-stage GKM was proposed to estimate the Gd penetration in the FUS irradiated area in a rat's brain under experimental conditions with repeated FUS irradiation combined with different UCA concentrations. The results showed that the focal increase in the transfer rate constant of Ktrans caused by BBB disruption was dependent on the doses of UCA. Moreover, the amount of in vivo penetration of Evans blue in the FUS irradiated area in a rat's brain under various FUS irradiation experimental conditions was assessed to show the positive correlation with the transfer rate constants. Compared to the GKM method, the Two-stage GKM is more suitable for estimating the transfer rate constants of the brain treated with repeated FUS irradiations. This study demonstrated that the entire process of BBB disrupted by FUS could be quantitatively monitored by real-time dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).

Pharmacokinetic changes induced by focused ultrasound in glioma-bearing rats as measured by dynamic contrast-enhanced MRI.

Focused ultrasound (FUS) combined with microbubbles has been shown to be a noninvasive and targeted drug delivery technique for brain tumor treatment. The purpose of this study was to measure the kinetics of Gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) in glioma-bearing rats in the presence of FUS-induced blood-brain barrier disruption (BBB-D) by magnetic resonance imaging (MRI). A total of ten glioma-bearing rats (9-12 weeks, 290-340 g) were used in this study. Using dynamic contrast-enhanced (DCE)-MRI, the spatial permeability of FUS-induced BBB-D was evaluated and the kinetic parameters were calculated by a general kinetic model (GKM). The results demonstrate that the mean Ktrans of the sonicated tumor (0.128±0.019 at 20 min and 0.103±0.023 at 24 h after sonication, respectively) was significantly higher than (2.46-fold at 20 min and 1.78-fold at 24 h) that of the contralateral (non-sonicated) tumor (0.052±0.019 at 20 min and 0.058±0.012 at 24 h after sonication, respectively). In addition, the transfer constant Ktrans in the sonicated tumor correlated strongly with tissue EB extravasation (R = 0.95), which suggests that DCE-MRI may reflect drug accumulation in the brain. Histological observations showed no macroscopic damage except for a few small erythrocyte extravasations. The current study demonstrates that DCE-MRI can monitor the dynamics of the FUS-induced BBB-D process and constitutes a useful tool for quantifying BBB permeability in tumors.