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In the first-in-human trial of ultrasonic propulsion, subjects passed collections of residual stone fragments after repositioning with a C5-2 probe. Here, effectiveness and safety in moving multiple fragments is compared between the C5-2 and a custom SC-50 probe that produces a longer beam and burst duration.

Objective High-order multifetal pregnancies carry a significant risk of obstetric complications and poor pregnancy outcome. Selective reduction has traditionally been performed using transabdominal and transvaginal ultrasound-guided intracardiac injection of potassium chloride. We have previously shown that high-intensity focused ultrasound (HIFU) can create a coagulative tissue necrosis in the sheep fetus. The objective of this study was to investigate the feasibility of non-invasive selective fetal reduction using HIFU in a rabbit model. Methods A protocol for HIFU-induced tissue coagulation was developed in the rabbit model. The fetal heart was targeted with ultrasound-guided tissue ablation by a HIFU beam. Five time-mated does between 20–29 days' gestation underwent transabdominal fetal cardiac ablation in a total of 11 fetuses. The HIFU system consisted of a 7-MHz high-power transducer, operated at 2000 W/cm2. The fetal heart rate was observed using real-time ultrasound with Doppler flow velocimetry. All lesions were assessed macroscopically and by histological analysis. Results Severe bradycardia leading to asystole was observed in all targeted fetuses with ultrasound examination. Dissection of fetuses demonstrated a necrotic intrathoracic lesion similar in size to the HIFU focus (approximately 1 × 9 mm). None of the surrounding fetuses was found to have bradycardia during the procedure or a macroscopic lesion on dissection. Conclusion In this pilot study HIFU seems promising to ablate even highly vascularized tissue in the fetus. Copyright © 2005 ISUOG. Published by John Wiley & Sons, Ltd.

Objective: We have shown that High-Intensity Focused Ultrasound (HIFU) can effectively control bleeding from injuries to solid organs such as liver, spleen, and lung. Achievement of hemostasis was augmented when a homogenate of tissue and blood was formed. The objective of this study was to investigate quantitatively the effect of homogenate production on HIFU application time for hemostasis. Possible mechanisms involved in homogenate production were also studied. Methods: Ten anesthetized rabbits had laparotomy and liver exposure. Liver incisions, 15–25 mm long and 3–4 mm deep, were made followed immediately by HIFU application. Two electrical powers of 80 and 100 W corresponding to focal acoustic intensities of 2264 and 2829 W/cm2, respectively were used. Tissue and homogenate temperatures were measured. Smear and histological tissue sample analysis using light microscopy were performed. Results: In treatments with homogenate formation, hemostasis was achieved in 76 ± 1.3 s (Mean ± Standard Error Mean: SEM) at 80 W. In treatments without homogenate formation (at 80 W), hemostasis was achieved in 106 ± 0.87 s. At 100 W, hemostasis was achieved in 46 ± 0.3 s. The time required for homogenate formation, at 80 and 100 W were 60 ± 2.5 and 23 ± 0.3 s, respectively. The homogenate temperature was 83 °C (SEM 0.6 °C), and the non-homogenate tissue temperature at the treatment site was 60 °C (SEM 0.4 °C). The smear and histological analysis showed significant blood components and cellular debris in the homogenate, with some intact cells. Conclusion: The HIFU-induced homogenate of blood and tissue resulted in a statistically significant shorter HIFU application time for hemostasis. The incisions with homogenate had higher temperatures as compared to incisions without homogenate. Further studies of the correlation between homogenate formation and temperature must be done, as well as studies on the long-term effects of homogenate in achieving hemostasis.

Purpose Because of a potential impact on thrombus formation, this study determines the degree of blood back flow into catheters filled with different fluids. Materials and Methods Catheters filled with saline or non-ionic or ionic contrast medium were placed in pulsatile circulating human blood in vitro. Catheter orientation was varied, and blood back flow was recorded. Results When the leading end of the catheter was angled downward, blood back flow into a contrast material–filled catheter was far greater than that into a saline-filled catheter (7.0 vs 0.5 cm). Conversely, when the leading end of the catheter was horizontal, blood back flow was much greater when the catheter contained saline versus contrast media (3.6 vs 0.4 cm). Ionicity of contrast material did not affect back flow. Conclusion Back flow of blood into a catheter can be considerable and is dependent on the type of fluid within the catheter and orientation of the leading end of the catheter. Angiographic techniques adjusted to these findings are important to maintain patient safety.

Esophageal and gastric varices are associated with significant morbidity and mortality for cirrhotic patients. The current modalities available for treating bleeding esophageal and gastric varices, namely endoscopic band ligation and sclerotherapy, require frequent sessions to obtain effective thrombosis and are associated with significantadverse effects.Amoreeffectivetherapythat resultsin long-termvascularocclusionhasthepotentialto improve patient outcomes. In this study, we investigated a new potential method for inducing long-term vascular occlusion by targeting segments of a rabbit's auricular vein in vivo with low-duty-cycle, high-peak-rarefaction pressure (9 MPa), pulsed high-intensity focused ultrasound in the presence of intravenously administered ultra- sound microbubbles followed by local injection of fibrinogen and a pro-inflammatory agent (ethanol, cyanoacry- late or morrhuate sodium). The novel method introduced in this study resulted in acute and long-term complete vascular occlusions when injecting a pro-inflammatory agent with fibrinogen. Future investigation and transla- tional studies are needed to assess its clinical applicability. (E-mail: jooha@medicine.washington.edu) 2011 World Federation for Ultrasound in Medicine & Biology.

Objectives Manganese (III) mesoporphyrin (Mn-mesoporphyrin) was investigated for its pharmaceutical properties and magnetic resonance imaging characteristics as a potential hepatobiliary contrast agent. Methods Solubility, partition coefficient, plasma binding, proton relaxation enhancement, biodistribution, biliary excretion, liver extraction ratio, and liver enhancement were measured in various in-vitro and in-vivo systems. Results Mn-mesoporphyrin was soluble and stable at moderate alkaline pH in phosphate buffer. The octanol/water coefficient was 25.98, and the compound was highly protein bound. R1 for water and plasma were 1.94 and 2.35 L/mmol sec, respectively. R1 in liver was calculated to be 15.72 L/mmol sec. Biodistribution studies in rats and mice confirmed hepatotrophic properties and biliary excretion was 65% over 24 hours. First pass liver uptake was 15%. Magnetic resonance imaging studies showed persistent liver enhancement at 0.05 mmol/kg. Conclusion Mn-mesoporphyrin is a lipophilic compound that shows potential as a hepatobiliary magnetic resonance contrast agent.

OBJECTIVES Manganese (III) mesoporphyrin (Mn-mesoporphyrin), a synthetic and stable complex, was investigated for its hepatic magnetic resonance imaging (MRI) properties and compared with manganese tetrakis-(4 sulfonatophenyl) porphyrin (Mn-TPPS4). METHODS Liver abscesses (n = 10) and tumors (n = 14) were induced in rats. These rats then underwent MRI at 2.0 T. Animals received one of the two contrast agents, and measurement of lesion enhancement was performed. RESULTS At an intravenous dose of 0.035 mmol/kg, Mn-mesoporphyrin caused significant enhancement of normal liver parenchyma and increased the lesion-to-liver contrast in both the models of heptic liver abscess and metastatic liver disease. Mn-TTPS4 at an intravenous dose of 0.04 mmol/kg typically enhanced both lesion and normal liver parenchyma and therefore did not improve the lesion-to-liver contrast. CONCLUSIONS The hepatotrophic properties of Mn-mesoporphyrin indicate its potential as an intravenous contrast agent for liver imaging.

Spasticity, a major complication of disorders of the central nervous system (CNS) signified by uncontrollable muscle contractions, is difficult to treat effectively. We report on the use of ultrasound image-guided high-intensity focused ultrasound (HIFU) to target and suppress the function of the sciatic nerve of rabbits in vivo as a possible treatment of spasticity and pain. The image-guided HIFU device included a 3.2 MHz spherically curved transducer (focal dimensions of 5.1 mm/spl times/0.76 mm) integrated with an intraoperative imaging probe (CL10-5, Philips HDI-1000), such that the HIFU focus was within the image plane. The sciatic nerve was imaged in cross-section and identified between two muscle planes, and the HIFU treatment was directed to the nerve and monitored in real time. In situ focal acoustic intensity of 1480-1850 W/cm/sup 2/ was applied using a scanning method (scan rate of 0.5-0.6 mm/s). The force response of the plantarflexion muscles in the rabbit foot to electrical stimulation of the sciatic nerve was measured both before and after HIFU treatment using a force gauge perpendicularly coupled to the metatarsal joint of the rabbit foot. The force response was approximately 0.55 N before HIFU treatment, and complete suppression of this force was achieved after HIFU treatment, indicating complete conduction block. HIFU treatment time of 36/spl plusmn/14 s (mean /spl plusmn/ standard deviation) was effective in achieving complete conduction block in 100% of the 22 nerves treated (11 rabbits). Gross examination showed blanching of the nerves at the HIFU treatment site and lesion volumes of 2.8/spl plusmn/1.4 cm/sup 2/ encompassing the nerves. Histologic results indicated axonal demyelination and necrosis of Schwann cells as probable mechanisms of nerve block. With accurate localization and targeting of peripheral nerves using ultrasound imaging, HIFU could become a promising tool for the suppression of spasticity and pain.

Spasticity, a major complication of central nervous system disorders, signified by uncontrollable muscle contractions, is very difficult to treat effectively. We report on the use of ultrasound (US) image-guided high-intensity focused US (HIFU) to target and suppress the function of the sciatic nerve complex of rabbits in vivo, as a possible treatment of spasticity. The image-guided HIFU device included a 3.2-MHz spherically curved transducer and an intraoperative imaging probe. A focal acoustic intensity of 1480 to 1850 W/cm(2), applied using a scanning method, was effective in achieving complete conduction block in 100% of 22 nerve complexes with HIFU treatment times of 36 +/- 14 s (mean +/- SD). Gross examination showed blanching of the nerve at the HIFU treatment site and lesion volumes of 2.8 +/- 1.4 cm(3) encompassing the nerve complex. Histologic examination indicated axonal demyelination and necrosis of Schwann cells as probable mechanisms of nerve block. With accurate localization and targeting of peripheral nerves using US imaging, HIFU could become a promising tool for the suppression of spasticity.

Background The global prevalence and incidence of renal calculi is reported to be increasing. Of the patients that undergo surgical intervention, nearly half experience symptomatic complications associated with stone fragments that are not passed and require follow-up surgical intervention. In a clinical simulation using a clinical prototype, ultrasonic propulsion was proven effective at repositioning kidney stones in pigs. The use of ultrasound to reposition smaller stones or stone fragments to a location that facilitates spontaneous clearance could therefore improve stone-free rates. The goal of this study was to determine an injury threshold under which stones could be safely repositioned. Methods Kidneys of 28 domestic swine were treated with exposures that ranged in duty cycle from 0%–100% and spatial peak pulse average intensities up to 30 kW/cm2 for a total duration of 10 min. The kidneys were processed for morphological analysis and evaluated for injury by experts blinded to the exposure conditions. Results At a duty cycle of 3.3%, a spatial peak intensity threshold of 16,620 W/cm2 was needed before a statistically significant portion of the samples showed injury. This is nearly seven times the 2,400-W/cm2 maximum output of the clinical prototype used to move the stones effectively in pigs. Conclusions The data obtained from this study show that exposure of kidneys to ultrasonic propulsion for displacing renal calculi is well below the threshold for tissue injury.

PURPOSE To determine the in vitro feasibility of abciximab absorption and elution from a polymer-coated, silicone-covered stent, and to determine the in vivo effect of local delivery of abciximab concerning endothelialization of a polymer-coated, silicone-covered stent in a canine model. MATERIALS AND METHODS Six polymer-coated, silicone-lined Wallstents were soaked in 2 mg/mL of concentrated solution of I131-labeled abciximab for a period as long as 48 hours. Quantification of abciximab absorption was determined by photon emission. Six maximally drug-loaded devices were then washed continuously with normal saline with use of a pustule pump apparatus. The quantity of residual abciximab was determined by photon emission for a period as long as 16 days. Eight similar devices (as described previously) were then implanted within the iliac arteries of four adult canines. Devices were identical except that four of eight were maximally loaded with abciximab. For each animal, one control implant was placed in the right iliac artery and one experimental implant (drug loaded) was placed in the left iliac artery, via right carotid cutdown. Animals were allowed to recover and no chronic medications were given. After an interval of 6 weeks, the animals were killed. Implants were isolated and perfused with 10% buffered formalin at a pressure of approximately 100 mm Hg for a period of 1 hour. Each implant was encased in methacrylate, sectioned into six equal segments, ground and polished, and stained with hematoxylin and eosin. Each slide was projected on a screen and the thickness of the neointima quantified. The mean neointima was determined for control and experimental groups, and compared for a potential significant difference with a Student t test. RESULTS Mean absorption of abciximab was 21.53 μg ± 2.99 per device. Devices were fully saturated at 24 hours. Forty percent was absorbed at 1 hour, and 60% and 80% were absorbed at 4 hours and 12 hours, respectively. Regarding elution, 30% of abciximab was washed out after 1 hour. There was a gradual elution of the drug to 16 days, with approximately 40% remaining at the end of the term. Mean neointimal thickness was 995 μm ± 597 for the experimental group and 1,738 μm ± 1,042 for the control group. The difference was significant ( P CONCLUSIONS Absorption and elution of abciximab from the surface of a covered stent is feasible. Local delivery of abciximab from the surface of this covered stent reduced the thickness of endothelial lining in the canine iliac artery compared to control.

Therapeutic ultrasound has an increasing number of applications in urology, including shockwave lithotripsy, stone propulsion, tissue ablation, and hemostasis. However, the threshold of renal injury using ultrasound is unknown. The goal of this study was to determine kidney injury thresholds for a range of intensities between diagnostic and ablative therapeutic ultrasound. A 2 MHz annular array generating spatial peak pulse average intensities (ISPPA) up to 30,000 W/cm2 in water was placed on the surface of in vivo porcine kidneys and focused on the adjacent parenchyma. Treatments consisted of pulses of 100 μs duration triggered every 3 ms for 10 min at various intensities. The perfusion-fixed tissue was scored by three blinded independent experts. Above a threshold of 20,000 W/cm2, the majority of injury observed included emulsification, necrosis, and hemorrhage. Below this threshold, almost all injury presented as focal cell and tubular swelling and/or degeneration. These findings provide evidence for a wide range of potentially therapeutic ultrasound intensities that has a low probability of causing injury. While this study did not examine all combinations of treatment parameters of therapeutic ultrasound, tissue injury appears dose-dependent. [Work supported by NIH DK43881, DK092197, and NSBRI through NASA NCC 9-58.]

We investigated the interaction between manganese(III)mesoporphyrin (MnMeso), a metalloporphyrin, and liposome membranes containing oleic acid (OA; cis-9-octadecenoic acid). MnMeso associates preferentially with OA but minimally with egg phosphatidylcholine (EPC). Using small unilamellar vesicles, we characterized the MnMeso-OA binding at neutral pH. Our data suggest that MnMeso binds to the OA bilayer with Kd = 6.8 x 10(-4) M; the binding stoichiometry of MnMeso-OA was 1:3.4. This OA-MnMeso interaction was analyzed further for changes in the T1 relaxation property of MnMeso. OA increased the T1 of MnMeso significantly more than did EPC, suggesting that the OA-MnMeso interaction was stronger than that of PC-MnMeso. The side-chain specificity of the OA interaction with this porphyrin derivative was further supported in an experiment with manganese mesotetra(4-sulfonatophenyl)porphine, which lacks hydrophobic side chains for OA interaction. The association of MnMeso with the OA membrane was proposed according to the structure of MnMeso and OA and further verified using electron microscopy. A strong association of MnMeso with OA, an absorption enhancer of the gastrointestinal tract, may be useful for delivery of MnMeso as an oral contrast agent for magnetic resonance imaging.

Rationale and Objectives. We investigated the potential of manganese (III) mesoporphyrin (Mn-mesoporphyrin) as a hepatobiliary contrast agent for magnetic resonance (MR) imaging in rabbits given VX-2 carcinoma liver implants. Methods. Rabbits given VX-2 carcinoma liver implants (n = 8) were imaged before and after the intravenous (IV) administration of 0.04 mmol/kg Mn-mesoporphyrin. MR images were correlated with gross-specimen cross-sections. The distribution of Mn in various tissues following IV administration of 0.04 mmol/kg Mn-mesoporphyrin was determined using atomic absorption analysis. A standard panel of serum chemistries was followed over 7 days in six rabbits following this same dose of Mn-mesoporphyrin and compared with chemistries from two control rabbits. Results. IV administration of 0.04 mmol/kg (25 mg/kg) Mn-mesoporphyrin resulted in improvement of tumor-to-liver contrast, with enhancement of normal liver (99.7 ± 14.7%) and the gallbladder (442 ± 116%), but not VX-2 tumor tissue (14.8 ± 13.9%), (n = 8, p = .05). Analysis of tissue Mn levels 100 min after IV Mn-mesoporphyrin injection demonstrated preferential distribution of Mn to normal liver tissue (57.8 ± 15.3 μg Mn/g) compared with VX-2 tumor (4.28 ± 1.48 μg Mn/g). No significant change was found in the serum chemistries of six normal rabbits over a 7-day period after the IV administration of 0.04 mmol/kg Mn-mesoporphyrin. Conclusion. IV Mn-mesoporphyrin improved lesion-to-liver contrast because of preferential distribution of Mn mesoporphyrin to normal liver parenchyma and bile.

Recently, a system that uses focused ultrasound to expel renal stone fragments from the kidney by radiation force was developed by Shah etal. [Urol. Res. 38, 491–495 (2010)]. A worst-case treatment protocol using this system would require a total exposure time of 10 min, with a spatial peak pulse average intensity (I_SPPA) of 3600 W/cm2 in water (16 MPa peak positive pressure) and a 3% duty cycle. As the system operates above the FDA limits for diagnostic ultrasound, our goal is to verify the safety of the system by determining the threshold for renal injury. A 2-MHz annular array generating I_SPPA up to 29 000 W/cm2 in water was placed on the surface of in vivo porcine kidneys and focused in the proximal parenchyma. Exposures of 10 min duration with varying I_SPPAs and duty cycles were repeated at least 6 times. Mechanical tissue damage and cell viability were evaluated histologically using H&E, PAS, and NADH diaphorase stains. The proportion of samples showing injury was plotted versus duty cycle and I_SPPA. The results indicate that the system to expel renal stones operates below the threshold for kidney injury. [Work supported by NIH DK043881, DK086371, DK092197, and NSBRI through NASA NCC 9–58.]

Shock‐wave heating and millisecond boiling in high intensity focused ultrasound fields have been shown to result in mechanical emulsification of ex‐vivo tissue. In this work, the same in situ exposures were applied in vivo in pig liver and in mice bearing 5–7 mm subcutaneous tumors (B16 melanoma) on the hind limb. Lesions were produced using a 2‐MHz annular array in the case of pig liver (shock amplitudes up to 98 MPa) and a 3.4‐MHz single‐element transducer in the case of mouse tumors (shock amplitude of 67 MPa). The parameters of the pulsing protocol (1–500 ms pulse durations and 0.01–0.1 duty factor) were varied depending on the extent of desired thermal effect. All exposures were monitored using B‐mode ultrasound. Mechanical and thermal tissue damage in the lesions was evaluated histologically using H&E and NADH‐diphorase staining. The size and shape of emulsified lesions obtained in‐vivo agreed well with those obtained in ex‐vivo tissue samples using the same exposure parameters. The lesions were successfully produced both in bulk liver tissue at depths of 1–2 cm and in superficial tumors at depths less than 1 mm without damaging the skin. [Work supported by NIH (DK070618, EB007643, and DK007742) and NSBRI through NASA NCC 9‐58.]

Neovascularity in a VX2 carcinoma in rabbit liver was detectable, using an ultrasonic color Doppler flow imager. Intraportal infusion of heated saline increased the fractional area of color flow Doppler signals by at least 5% and as much as 30%, within and surrounding the tumors of all six rabbits studied. The effect of the fluid load was an increase in fractional area of color flow Doppler signals by 5 to 20% and was determined by the measurements following infusion and return to baseline temperature. The largest increment in color Doppler signal was observed in peritumoral vessels (10-40%). In contrast, the fractional area of color-coded pixels within the tumor was only slightly higher or lower (5-10%) at the peak temperature than at the baseline measurements. The temperature within the tumors was as much as 1 degree lower than parenchymal tissue in all animals measured. This was presumably due to the portal vein blood supply to normal tissue and predominantly hepatic artery supply to the pathological tissue. High velocities and persistent bidirectional flow were observed within the tumors only at the peak temperatures (> 43.5 degrees C). This experiment suggests that thermal stress may enhance tumor detectability by color Doppler imaging. Further development of a quantitative analysis method for color Doppler studies is needed.

Cyanoacrylate glue is a rapidly polymerizing agent used for vascular embolization. Polymerization occurs when the glue comes into contact with ions in the blood or on the vascular endothelium. Mixing iophendylate with cyanoacrylate causes slowing of polymerization, allowing flow-directed embolization into the nidus of an arteriovenous malformation (AVM) or the central neovascularity of a tumor or hemangioma. The authors attempted to define the relationship between the iophendylate-glue ratio and polymerization time with an in vivo swine model. In this model, glue setup occurred much more rapidly than predicted on the basis of in vitro studies. This appeared to be due to glue polymerizing on the endothelium at vessel bifurcations and at areas of acute angulation or marked vessel narrowing. On the basis of these data, the authors substantially increased the iophendylate-glue ratio in their most recent AVM embolization procedures and achieved nidus occlusion in each case. With use of the authors' guidelines, it is possible to achieve optimal distal flow-directed embolization with cyanoacrylate.

Spasticity, a complication of central nervous system disorders, signified by uncontrollable muscle contractions, is difficult to treat effectively. The use of ultrasound image‐guided high‐intensity focused ultrasound (HIFU) to target and suppress the function of the sciatic nerve of rabbits in vivo, as a possible treatment of spasticity and pain, will be presented. The image‐guided HIFU device included a 3.2‐MHz spherically‐curved transducer and an intraoperative imaging probe. A focal intensity of 1480−1850 W/cm2 was effective in achieving complete conduction block in 100% of 22 nerves with HIFU treatment times of 36±14 s (mean±SD). Gross examination showed blanching of the nerve at the treatment site and lesion volumes of 2.8±1.4 cm3 encompassing the nerve. Histological examination indicated axonal demyelination and necrosis of Schwann cells as probable mechanisms of nerve block. Long‐term studies showed that HIFU intensity of 1930 W/cm2, applied to 12 nerves for an average time of 10.5±4.9 s, enabled n...

A technique for producing a reliable, clinically applicable, and highly reproducible canine model of nonocclusive mesenteric ischemia was developed. Following left thoracotomy in 10 dogs, a 1 mm diameter soft polyethylene tube was inserted into the pericardial space via a small puncture site. This tube was sealed in place with cyanoacrylate tissue adhesive. A solution of 10% Dextran 40 in saline was infused into the pericardial space until a 50% reduction (as monitored by electromagnetic flowmeter) in superior mesenteric artery flow (SMAQ) was obtained. Without additional intrapericardial infusion of the Dextran solution, SMAQ was reduced 51 +/- 4% to 54 +/- 3% of control values during a 60 minute post-tamponade observation period. During the same time. Cardiac output was depressed between 40 +/- 8% and 54 +/- 3%, and right atrial pressure remained elevated between 164 +/- 15% and 171 +/- 15%. Systemic arterial pressure initially dropped 28 +/- 5% but compensated to within 11 +/- 5% of pre-tamponade level at 60 minutes. The stability of this model is well suited for evaluating new experimental diagnostic and therapeutic procedures.

Embolization for ablation of organs and tumor infarction requires uniform permanent occlusion of the distal vasculature. This is best accomplished through the use of solidifying liquids. The study on 15 dogs reported here compares the degree of peripheral vascular embolization and its relation to tissue infarction both acutely and chronically following embolization of the renal arteries with two solidifying liquids, a low viscosity silicone and the occlusion gel Ethibloc. Silicone produced quite uniform distal distribution including 50 to 80% (mean 66%) of renal glomeruli, whereas Ethibloc occluded more proximally and reached only 10 to 50% (mean 22%) of all glomeruli. After three months complete cortical infarction of all nine kidneys embolized with silicone was found, whereas two of the three kidneys embolized with Ethibloc retained nests of viable glomeruli. Balloon occlusion of the entire renal artery inflow during embolization prevented distal venous emboli whereas partial inflow occlusion allowed systemic venous embolization. It is concluded that due to its more uniform distal penetration low viscosity silicone is a more suitable embolization agent than Ethibloc for organ ablation. Total arterial inflow occlusion during embolization effectively prevents systemic venous embolization.