High-frequency shock wave lithotripsy: stone comminution and evaluation of renal parenchyma injury in a porcine ex-vivo model.

BACKGROUND: The electrohydraulic high-frequency shock wave (Storz Medical, Taegerwilen, Switzerland) is a new way to create small fragments with frequencies up to 100 Hertz (Hz). This study evaluated the efficacy and safety of this method in a stone and porcine model. MATERIALS AND METHODS: BEGO stones were put in a condom in a specifically designed fixture treated with different modulations to see stone comminution. Standardized ex vivo porcine model with perfused kidneys with 26 upper and lower poles of 15 kidneys was treated with the following modulations: voltage 16-24 kV, capacitor 12 nF and frequency up to 100 Hz. 2000-20,000 shock waves were applied to each pole. The kidneys were perfused with barium sulfate solution (BaSO4) and x-ray was performed to quantify the lesions using pixel volumetry. RESULTS: There was no correlation between the number of shock waves and the powdering degree or the applied Energy and the grade of pulverization in the stone model. Regarding the perfused kidney model, the number of shock waves, applied voltage and frequency had no direct correlation with the occurrence of parenchymal lesions The detected lesions of the renal parenchyma were minimal, technical parameters had no significant impact and the lesions did not differ from the results of former experiments using 1-1.5 Hz in the same model. CONCLUSIONS: High-frequency shock wave lithotripsy can produce small stone fragments to pass in a very short time. The injury to the renal parenchyma is comparable to the results of the conventional SWL using 1-1.5 Hz.

Transcranial Pulse Stimulation with Ultrasound in Alzheimer's Disease-A New Navigated Focal Brain Therapy.

Ultrasound-based brain stimulation techniques may become a powerful new technique to modulate the human brain in a focal and targeted manner. However, for clinical brain stimulation no certified systems exist and the current techniques have to be further developed. Here, a clinical sonication technique is introduced, based on single ultrashort ultrasound pulses (transcranial pulse stimulation, TPS) which markedly differs from existing focused ultrasound techniques. In addition, a first clinical study using ultrasound brain stimulation and first observations of long term effects are presented. Comprehensive feasibility, safety, and efficacy data are provided. They consist of simulation data, laboratory measurements with rat and human skulls and brains, in vivo modulations of somatosensory evoked potentials (SEP) in healthy subjects (sham controlled) and clinical pilot data in 35 patients with Alzheimer's disease acquired in a multicenter setting (including neuropsychological scores and functional magnetic resonance imaging (fMRI)). Preclinical results show large safety margins and dose dependent neuromodulation. Patient investigations reveal high treatment tolerability and no major side effects. Neuropsychological scores improve significantly after TPS treatment and improvement lasts up to three months and correlates with an upregulation of the memory network (fMRI data). The results encourage broad neuroscientific application and translation of the method to clinical therapy and randomized sham-controlled clinical studies.

Potential of shock waves to remove calculus and biofilm.

Effective calculus and biofilm removal is essential to treat periodontitis. Sonic and ultrasonic technologies are used in several scaler applications. This was the first feasibility study to assess the potential of a shock wave device to remove calculus and biofilms and to kill bacteria. Ten extracted teeth with visible subgingival calculus were treated with either shock waves for 1 min at an energy output of 0.4 mJ/mm(2) at 3 Hz or a magnetostrictive ultrasonic scaler at medium power setting for 1 min, which served as a control. Calculus was determined before and after treatment planimetrically using a custom-made software using a grey scale threshold. In a second experiment, multispecies biofilms were formed on saliva-preconditioned bovine enamel discs during 64.5 h. They were subsequently treated with shock waves or the ultrasonic scaler (N = 6/group) using identical settings. Biofilm detachment and bactericidal effects were then assessed. Limited efficiency of the shock wave therapy in terms of calculus removal was observed: only 5% of the calculus was removed as compared to 100% when ultrasound was used (P ≤ 0.0001). However, shock waves were able to significantly reduce adherent bacteria by three orders of magnitude (P ≤ 0.0001). The extent of biofilm removal by the ultrasonic device was statistically similar. Only limited bactericidal effects were observed using both methods. Within the limitations of this preliminary study, the shock wave device was not able to reliably remove calculus but had the potential to remove biofilms by three log steps. To increase the efficacy, technical improvements are still required. This novel noninvasive intervention, however, merits further investigation.

Extracorporeal shock wave therapy in inflammatory diseases: molecular mechanism that triggers anti-inflammatory action.

Shock waves (SW), defined as a sequence of single sonic pulses characterised by high peak pressure (100 MPa), a fast rise in pressure (< 10 ns) and a short lifecycle (10 micros), are conveyed by an appropriate generator to a specific target area at an energy density ranging from 0.03 to 0.11 mJ/mm(2). Extracorporeal SW (ESW) therapy was first used on patients in 1980 to break up kidney stones. During the last ten years, this technique has been successfully employed in orthopaedic diseases such as pseudoarthosis, tendinitis, calcarea of the shoulder, epicondylitis, plantar fasciitis and several inflammatory tendon diseases. In particular, treatment of the tendon and muscle tissues was found to induce a long-time tissue regeneration effect in addition to having a more immediate anthalgic and anti-inflammatory outcome. In keeping with this, an increase in neoangiogenesis in the tendons of dogs was observed after 4-8 weeks of ESW treatment. Furthermore, clinical observations indicate an immediate increase in blood flow around the treated area. Nevertheless, the biochemical mechanisms underlying these effects have yet to be fully elucidated. In the present review, we briefly detail the physical properties of ESW and clinical cases treated with this therapy. We then go on to describe the possible molecular mechanism that triggers the anti-inflammatory action of ESW, focusing on the possibility that ESW may modulate endogenous nitric oxide (NO) production either under normal or inflammatory conditions. Data on the rapid enhancement of endothelial NO synthase (eNOS) activity in ESW-treated cells suggest that increased NO levels and the subsequent suppression of NF-kappaB activation may account, at least in part, for the clinically beneficial action on tissue inflammation.

High-intensity focused ultrasound for the targeted destruction of uterine tissues: experiences from a pilot study using a mobile HIFU unit.

BACKGROUND: High intensity focused ultrasound (HIFU) is a novel method which offers the non-invasive ablation of tissues without harming overlying organs or skin. It has been introduced successfully in urology for the ablation of prostatic hyperplasia and seems to be promising in the treatment of uterine fibroids. In this study we aimed to examine the feasibility and possible side effects of HIFU treatment of uterine tissues using an experimental mobile HIFU unit with ultrasound guidance. METHODS: For these experiments, a 1.07 MHz ultrasound source was used which allows treatment depths between 0 and 10 cm. In 12 patients scheduled to have abdominal hysterectomy, 5-60 impulses of HIFU were applied through the intact skin upon uterine tissues directly prior to the surgical procedure. Tissue intensities lay between 3,200 and 6,300 W/cm(2) and a fixed pulse length of 4 s was used. RESULTS: No side effects were encountered other than one first-degree skin burn and the treatment was well tolerated. Histology showed clearly demarcated coagulative necrosis in the targeted tissues. Treatment was concluded in less than 45 min for each patient. CONCLUSION: Focused ultrasound is an effective method to selectively destroy tissue within the uterus and the transabdominal access route is very feasible. This study shows that a mobile ultrasound source can be used safely and effectively to destroy uterine tissues, such as fibroids, without major side effects.

Shock waves activate in vitro cultured progenitors and precursors of cardiac cell lineages from the human heart.

Postischemic cardiomyopathy remains one of the disorders in urgent need of effective noninvasive therapy. It is currently accepted that the isolation, expansion and application of resident cardiac stem cells may hold therapeutic promise for the future. Recently, it has been demonstrated that shock waves (SW) could enhance the expression of vascular endothelial growth factor (VEGF) and its receptor, Flt-1. As the development of angiogenic noninvasive therapy is very important for future therapeutic strategies in cardiovascular diseases, we examined in vitro, the effects of SW treatment on adult resident cardiac primitive cells isolated from bioptic fragments of normal human hearts and from explanted pathologic hearts with postischemic cardiomyopathy. This study demonstrates that SW have positive influence on both the proliferation and the differentiation of cardiomyocytes, smooth muscle and endothelial cells precursors, with a more obvious effect being evident in the cells from normal heart than in those taken from pathologic hearts. Our results suggest that SW treatment could inhibit or retard the pathologic remodeling and functional degradation of the heart if applied during the early stages of heart failure.

A new electromagnetic shock-wave generator "SLX-F2" with user-selectable dual focus size: ex vivo evaluation of renal injury.

Storz Medical AG (Kreutzlingen/Switzerland) has developed a new electromagnetic shockwave (SW) generator, the "SLX-F2", which allows the user to choose between a small-focus, high-pressure treatment regime or a wide-focus, low-pressure option. The aim of this study was to investigate, under standardized conditions, the impact of these two different treatment regimes on SW-induced renal injury. SW-induced renal injury was investigated by using the standardized model of the perfused ex vivo kidney. SWs were applied under ultrasound control in the parenchyma of a kidney pole. Different SW numbers (20, 50, 125, 250, 500, 1,000) were applied in three groups: group A was treated with a wider focus (80 MPa), groups B (60 MPa) and C (120 MPa) with a smaller focus (each parameter setting was repeated ten-fold). Disintegration capacity (measured by crater volume in cubes of plaster of Paris) was the same in groups A and C. After SW exposure, barium sulphate suspension was perfused through the renal artery. The maximum diameter (mm) of the extravasation in the cortex, representing the extent of vascular injury, was measured on X-ray mammography films. H&E staining was performed. In all three groups (A, B, C) a higher number of SWs caused the diameter of the extravasate to increase, with statistical significance appearing at 1,000 shots versus 20 shots (p < 0.05). Vascular injury was not influenced by the focal size and positive peak pressure at identical SW numbers applied. Histology of the focal area showed gap-like defects. Our ex vivo data show that renal vascular injury is independent of the focal diameter of the SW generator at the same peak positive pressure and disintegration power. This confirms the in vivo findings that show renal injury caused by SW as being related to the number of SWs administered. Clinical studies are needed to investigate whether there is any advantage to offering both treatment regimes in one SW machine-for example, by using the "wide-focus, low-pressure" option for kidney stones and the "small-focus, high-pressure" regimen for stones in the ureter. The renal injury caused by either regime remains comparable.

Ablation of clinically relevant kidney tissue volumes by high-intensity focused ultrasound: Preliminary results of standardized ex-vivo investigations.

PURPOSE: To investigate strategies to achieve confluent kidney-tissue ablation by high-intensity focused ultrasound (HIFU). MATERIALS AND METHODS: Our model of the perfused ex-vivo porcine kidney was used. Tissue ablation was performed with an experimental HIFU device (Storz Medical, Kreuzlingen, Switzerland). Lesion-to-lesion interaction was investigated by varying the lesion distance (5 to 2.5 mm), generator power (300, 280, and 260 W), cooling time (10, 20, and 30 seconds), and exposure time (4, 3, and 2 seconds). The lesion rows were analyzed grossly and by histologic examination (hematoxylin-eosin and nicotinamide adenine dinucleotide staining). RESULTS: It was possible to achieve complete homogeneous ablation of a clinically relevant tissue volume but only by meticulous adjustment of the exposure parameters. Minimal changes in these parameters caused changes in lesion formation with holes within the lesions and lesion-to-lesion interaction. CONCLUSIONS: Our preliminary results show that when using this new device, HIFU can ablate a large tissue volume homogeneously in perfused ex-vivo porcine tissue under standardized conditions with meticulous adjustment of exposure parameters. Further investigations in vivo are necessary to test whether large tissue volumes can be ablated completely and reliably despite the influence of physiologic tissue and organ movement.

Extracorporeally induced ablation of renal tissue by high-intensity focused ultrasound.

OBJECTIVE: To investigate the safety and the effects on healthy renal tissue of high-intensity focused ultrasound (HIFU) applied extracorporeally. PATIENTS, MATERIALS AND METHODS: Ultrasound waves (1.04 MHz) created by a cylindrical piezo-ceramic element were focused by a parabolic reflector to a physical focus size of 32 x 4 mm (-6 dB). For an in vivo study, HIFU was applied to the healthy tissue of 24 kidneys, monitored by ultrasonography, with a maximum power of 400 W and a spatially averaged intensity (ISAL) in the focus of 1192 W/cm(2). Fourteen kidneys were removed immediately after ablation to evaluate the side-effects and the effects in the focal zone, and 10 kidneys were removed delayed after 1, 7 and 10 days. The clinical study consisted of 19 patients requiring radical nephrectomy for a renal tumour. HIFU was applied to the healthy tissue of 19 kidneys (up to 1600 W, I(SAL) = 4768 W/cm(2)) before proceeding with the radical nephrectomy. RESULTS: There were no major complications after applying HIFU to the 43 kidneys. Side-effects included skin burns (grade 3) in two patients. During the follow-up there were no further HIFU-specific side-effects. In one case (in vivo study) there was a thermal lesion of the small intestine, which was due to mis-focusing. HIFU effects in the focal zone immediately after application were: interstitial haemorrhages, fibre rupture, shrinking of the collagen fibres, and coagulation necrosis. These effects occurred sporadically, and their number and size did not correspond to the number of HIFU pulses applied. After 7 and 10 days, there was a well-demarcated coagulation necrosis in vivo. CONCLUSION: Using this device, extracorporeally applied HIFU can ablate healthy kidney tissue in vivo in combination with diagnostic online ultrasonography. The technique is safe and resulted only in minor complications (skin burns). Refinements in the technology are essential to establish HIFU as a noninvasive treatment option that allows complete and reliable tissue ablation.

Nitric oxide mediates anti-inflammatory action of extracorporeal shock waves.

Here, we show that extracorporeal shock waves (ESW), at a low energy density value, quickly increase neuronal nitric oxide synthase (nNOS) activity and basal nitric oxide (NO) production in the rat glioma cell line C6. In addition, the treatment of C6 cells with ESW reverts the decrease of nNOS activity and NO production induced by a mixture of lipopolysaccharides (LPS), interferon-gamma (IFN-gamma) plus tumour necrosis factor-alpha (TNF-alpha). Finally, ESW treatment efficiently downregulates NF-kappaB activation and NF-kappaB-dependent gene expression, including inducible NOS and TNF-alpha. The present report suggests a possible molecular mechanism of the anti-inflammatory action of ESW treatment.

Multiple high-intensity focused ultrasound probes for kidney-tissue ablation.

BACKGROUND AND PURPOSE: To investigate kidney-tissue ablation by high-intensity focused ultrasound (HIFU) using multiple and single probes. MATERIALS AND METHODS: Ultrasound beams (1.75 MHz) produced by a piezoceramic element (focal distance 80 mm) were focused at the center of renal parenchyma. One of the three probes (mounted on a jig) could also be used for comparison with a single probe at comparable power ratings. Lesion dimensions were examined in perfused and unperfused ex vivo porcine kidneys at different power levels (40, 60, and 80 W) and treatment times (4, 6, and 8 seconds). RESULTS: At identical power levels, the lesions induced by multiple probes were larger than those induced by a single probe. Lesion size increased with increasing pulse duration and generator power. The sizes and shapes of the lesions were predictably repeatable in all samples. Lesions in perfused kidneys were smaller than those in unperfused kidneys. CONCLUSIONS: Ex vivo, kidney-tissue ablation by means of multiple HIFU probes offers significant advantages over single HIFU probes in respect of lesion size and formation. These advantages need to be confirmed by tests in vivo at higher energy levels.

Extracorporeal application of high-intensity focused ultrasound for prostatic tissue ablation.

OBJECTIVE: To investigate the efficacy and safety of extracorporeal prostatic tissue ablation using high-intensity focused ultrasound (HIFU) in vivo in animals, and in a clinical feasibility study in men, as this is an investigational minimally invasive treatment alternative for locally confined prostatic carcinoma, but may have significant side-effects. PATIENTS, MATERIALS AND METHODS: Ultrasound (1.04 MHz excitation frequency) was generated by an extracorporeal cylindrical piezo-ceramic element and focused by a paraboloidal reflector to a focal size of 32 x 4 mm. The focal distance and aperture diameter were both 100 mm. HIFU was applied extracorporeally at different intensities and pulse duration (up to 6 s) to 11 dog prostates in vivo (median intensity 1192 W/cm2) and eight patients (median intensity 3278 W/cm2, range 2384-3576) under general anaesthesia. The lesions were assessed macroscopically and histologically after HIFU and any side-effects evaluated. RESULTS: Thermoablation was feasible in vivo and in all patients. Macroscopic analysis and histology showed sharply demarcated coagulative necrosis. Side-effects, including skin and rectal burns, occurred only after transvesical application in the in vivo study. There were no side-effects in patients after perineal application. CONCLUSION: Extracorporeal HIFU is technically feasible and induces sharply demarcated tissue damage in the prostate. From the early results of this phase 1 study, the perineal approach seems to be safe.

Extracorporeal shock waves: from lithotripsy to anti-inflammatory action by NO production.

At low energy density (0.03 mJ/mm2), extracorporeal shock waves (ESW), originally developed for clinical lithotripsy, have successfully been used for anti-inflammatory treatment of soft tissues. Since nitric oxide plays a critical role in inflammation, we hypothesized for ESW to increase NO production in cells. Using human umbilical vein endothelial cells as a model system, we observed that ESW, at low energy density, rapidly induced an enhancement of eNOS activity. In these cells, eNOS activity is modulated by tyrosine- and serine-phosphorylation. ESW shifted eNOS to a less-tyrosine-phosphorylated form, without affecting its serine-phosphorylation, thus accounting for its rapid enzyme activation. LPS/IFN-gamma treatment of human umbilical vein endothelial cells induced a rapid inhibition of eNOS activity and concomitant NF-kappaB activation which were efficiently counteracted by ESW treatment. Therefore, the present results indicate that the molecular mechanism of clinically observed anti-inflammatory action of ESW should include tyrosine-dephosphorylation of eNOS, a successive increase in NO production and suppression of NF-kappaB activation.

High-intensity focused ultrasound for ex vivo kidney tissue ablation: influence of generator power and pulse duration.

BACKGROUND AND PURPOSE: The therapeutic application of noninvasive tissue ablation by high-intensity focused ultrasound (HIFU) requires precise physical definition of the focal size and determination of control parameters. The objective of this study was to measure the extent of ex-vivo porcine kidney tissue ablation at variable generator parameters and to identify parameters to control lesion size. MATERIALS AND METHODS: The ultrasound waves generated by a cylindrical piezoceramic element (1.04 MHz) were focused at a depth of 100 mm using a parabolic reflector (diameter 100 mm). A needle hydrophone was used to measure the field distribution of the sound pressure. The morphology and extent of tissue necrosis were examined at generator powers of up to 400 W (P(el)) and single pulse durations of as long as 8 seconds. RESULTS: The two-dimensional field distribution resulted in an approximately ellipsoidal focus of 32 x 4 mm (-6 dB). A sharp demarcation between coagulation necrosis and intact tissue was observed. Lesion size was controlled by both the variation of generator power and the pulse duration. At a constant pulse duration of 2 seconds, a generator power of 100 W remained below the threshold doses for inducing a reproducible lesion. An increase in power to as high as 400 W induced lesions with average dimensions of as much as 11.2 x 3 mm. At constant total energy (generator power x pulse duration), lesion size increased at higher generator power. CONCLUSIONS: This ultrasound generator can induce defined and reproducible necrosis in ex-vivo kidney tissue. Lesion size can be controlled by adjusting the generator power and pulse duration. Generator power, in particular, turned out to be a suitable control parameter for obtaining a lesion of a defined size.

High intensity focused ultrasound as noninvasive therapy for multilocal renal cell carcinoma: case study and review of the literature.

PURPOSE: Noninvasive tumor ablation can be achieved by extracorporeally induced high intensity focused ultrasound. Clinical high intensity focused ultrasound performed to date for renal tumors have only been experimental in nature. We present specific details on a patient with renal cell carcinoma who underwent high intensity focused ultrasound with curative intent and long-term followup examinations. MATERIALS AND METHODS: Ultrasound waves were generated by a cylindrical piezoelectric element focused by a paraboloid reflector. High intensity focused ultrasound was applied to 3 tumors in 3 sessions with the patient under general anesthesia or sedation analgesia, followed by magnetic resonance imaging for 6 months. RESULTS: After treatment magnetic resonance imaging showed necrosis in the 2 tumors in the lower kidney pole within 17 and 48 days, respectively. The necrotic tumor area shrank thereafter within 6 months. The tumor in the upper pole was not affected by treatment due to absorption of the ultrasound energy by the interposed ribs. General anesthesia was required to apply high energy levels of focused ultrasound. Absorption of high intensity focused ultrasound in the tissue induced sharply demarcated thermonecrosis. For 50 years patients have been treated with high intensity focused ultrasound for different indications, focusing on the brain, eyes, prostate, liver and bladder. For the kidney experimental but only few clinical studies indicate sufficient tissue ablation. CONCLUSIONS: In our case contactless noninvasive application of high intensity focused ultrasound to 2 renal carcinomas achieved thermal ablation. When high intensity focused ultrasound energy was coupled correctly, no lesions occurred outside of the target area. Successful high intensity focused ultrasound application depended on optimum energy coupling, a sufficiently high ultrasound energy level and general anesthesia.