Frank L. Starr

HEPATIC CONTRAST-ENHANCING PROPERTIES OF MANGANESE-MESOPORPHYRIN AND MANGANESE-TPPS4 : A COMPARATIVE MAGNETIC RESONANCE IMAGING STUDY IN RATS

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 Mnmesoporphyrin indicate its potential as an intravenous contrast agent for liver imaging

Focused ultrasound to displace renal calculi: threshold for tissue injury

BackgroundThe 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.MethodsKidneys of 28 domestic swine were treated with exposures that ranged in duty cycle from 0%–100% and spatial peak pulse average intensities up to 30xa0kW/cm2 for a total duration of 10xa0min. The kidneys were processed for morphological analysis and evaluated for injury by experts blinded to the exposure conditions.ResultsAt a duty cycle of 3.3%, a spatial peak intensity threshold of 16,620xa0W/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.ConclusionsThe 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.

Intravenous manganese-mesoporphyrin as a magnetic resonance imaging contrast agent: An experimental model using VX-2 carcinoma in rabbits

RATIONALE AND OBJECTIVESnWe 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.nnnMETHODSnRabbits given VX-2 carcinoma liver implants (n = 8) were imaged before and after the intravenous (i.v.) 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 i.v. 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.nnnRESULTSnI.v. 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 i.v. Mn-mesoporphyrin injection demonstrated preferential distribution of Mn to normal liver tissue (57.8 +/- 15.3 micrograms Mn/g) compared with VX-2 tumor (4.28 +/- 1.48 micrograms Mn/g). No significant change was found in the serum chemistries of six normal rabbits over a 7-day period after the i.v. administration of 0.04 mmol/kg Mn-mesoporphyrin.nnnCONCLUSIONnI.v. Mn-mesoporphyrin improved lesion-to-liver contrast because of preferential distribution of Mn-mesoporphyrin to normal liver parenchyma and bile.

In vivo tissue emulsification using millisecond boiling induced by high intensity focused ultrasound.

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 suc...

Determination of tissue injury thresholds from ultrasound in a porcine kidney model

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.]

Targeted Long-Term Venous Occlusion Using Pulsed High-Intensity Focused Ultrasound Combined with a Pro-Inflammatory Agent

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 significant adverse effects. A more effective therapy that results in long-term vascular occlusion has the potential to improve patient outcomes. In this study, we investigated a new potential method for inducing long-term vascular occlusion by targeting segments of a rabbits 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 ultrasound microbubbles followed by local injection of fibrinogen and a pro-inflammatory agent (ethanol, cyanoacrylate 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 translational studies are needed to assess its clinical applicability.

Ultrasound-guided HIFU neurolysis of peripheral nerves to treat spasticity and pain

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.

Determination of thresholds for renal injury in a porcine model by focused ultrasound

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 29u2009000 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_...

Ultrasound‐guided high frequency focused ultrasound neurolysis of peripheral nerves to treat spasticity and pain

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 1480−1850u2009W/cm2 was effective in achieving complete conduction block in 100% of 22 nerves with HIFU treatment times of 36±14u2009s (mean±SD). Gross examination showed blanching of the nerve at the treatment site and lesion volumes of 2.8±1.4u2009cm3 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 1930u2009W/cm2, applied to 12 nerves for an average time of 10.5±4.9u2009s, enabled n...

Ultrasound‐Guided HIFU Neurolysis Of Peripheral Nerves to Treat Spasticity and Pain

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.