Noninvasive Ultrasound Therapy Research Articles

Safety and quality of life assessment at 6 months follow-up of the valvosoft pivotal study

Abstract Background Calcific Aortic stenosis (CAS) is currently the most common heart valve disease. Patients suffering from severe CAS are treated with invasive surgeries based on valve replacement. Symptoms heavily impact quality of life, including chest pain, shortness of breath, dizziness, fatigue, and major risks as heart failure or sudden death, and daily activities might also be strongly impacted. Purpose A prospective, multi-centre, single-arm, pivotal study (NCT05235568) was initiated in 2021 to treat severe CAS patients with Valvosoft, a medical device based on Non-Invasive Ultrasound Therapy (NIUT) intended to treat CAS in patients not eligible for immediate aortic valve replacement (SAVR/TAVR) or refusing such a treatment, to confirm safety and performance at 1-, 3-, 6- and 12 months. We present here the safety and quality of life results at 6M follow-up. Methods Valvosoft NIUT procedure is based on a trans-thoracic delivery of focused, high intensity short therapeutic ultrasound pulses, to precisely generate a cavitation bubble cloud on the aortic valve. Echocardiographic imaging enables to monitor the valve in real-time while cavitation causes both non-thermal tissue softening and calcification fractionation of the diseased valve. 60 planned subjects, suffering from severe calcific aortic stenosis, not recommended for aortic valve replacement or refusing such a procedure, were enrolled in 11 centres in Europe. Patients were awake or lightly sedated, NIUT was delivered during up to 70 minutes per patient per procedure. DSMB and CEC were installed to monitor safety, performance and effectiveness of Valvosoft device, and safety related to participation in the clinical investigation. Results Sixty high-risk patients advanced in age (85.2 ± 9.1) with multiple severe comorbidities were included. Primary safety endpoint (less than 25% MACE) was met at 30D (p=0.002). Furthermore patients experienced an overall quality of life improved. 6 minutes’ walk test increases from baseline towards 6 months with 10 %. At 6M follow-up, no stroke was reported, an average KCCQ score improvement of 17% was noticed, and NYHA class improved or stabilized for 78% of patients. The calcium score or volume on the aortic did not change pre- and post-procedure. Conclusion Valvosoft NIUT safety and quality of life improvement are proven at 6MFU, and the technology is presented as potentially disruptive, in the treatment of severe calcific aortic stenosis.

Ultrasound Therapy as a Treatment for Valvular Aortic Stenosis: A Review.

Calcific aortic stenosis is the most common form of aortic stenosis, and offers a poor prognosis in affected patients. Current treatment methods for aortic stenosis, including open surgical aortic valve repair and transcatheter aortic valve replacement, are invasive, and require the patient to undergo open-heart surgery with cardiopulmonary bypass. Ultrasound therapy offers a potential solution for patients ineligible for traditional surgical treatment. Noninvasive ultrasound therapy allows for decalcification of aortic valves without open sternotomy or cardiopulmonary bypass. This article reviews the use of ultrasound therapy for aortic stenosis, including this newer method of noninvasive ultrasound therapy.

TCT-892 Valvosoft Noninvasive Ultrasound Therapy in Patients With Severe Symptomatic Aortic Valve Stenosis: Safety and Performance Study, 6-Month Follow-Up Update

TCT-892 Valvosoft Noninvasive Ultrasound Therapy in Patients With Severe Symptomatic Aortic Valve Stenosis: Safety and Performance Study, 6-Month Follow-Up Update

Non-Invasive Ultrasound Therapy for Severe Aortic Stenosis: Early Effects on the Valve, Ventricle, and Cardiac Biomarkers (A Case Series).

Background: Transcatheter aortic valve replacement (TAVR) was developed for inoperable patients with severe aortic stenosis. However, despite TAVR advancements, some patients remain untreated due to complex comorbidities, necessitating less-invasive approaches. Non-invasive ultrasound therapy (NIUT), a new treatment modality, has the potential to address this treatment gap, delivering short ultrasound pulses that create cavitation bubble clouds, aimed at softening embedded calcification in stiffened valve tissue. Methods: In the prospective Valvosoft® Serbian first-in-human study, we assessed the safety and efficacy of NIUT and its impact on aortic valve hemodynamics, on the left ventricle, and on systemic inflammation in patients with severe symptomatic aortic stenosis not eligible for TAVR or surgery. Results: Ten patients were included. Significant improvements were observed in hemodynamic parameters from baseline to one month, including a 39% increase in the aortic valve area (from 0.5 cm2 to 0.7 cm2, p = 0.001) and a 23% decrease in the mean transvalvular gradient (from 54 mmHg to 38 mmHg, p = 0.01). Additionally, left ventricular global longitudinal strain significantly rose, while global wasted work significantly declined at one month. A dose-response relationship was observed between treatment parameters (peak acoustic power, intensity spatial-peak pulse-average, and mean acoustic energy) and hemodynamic outcomes. NIUT was safely applied, with no clinically relevant changes in high-sensitivity troponin T or C-reactive protein and with a numerical, but not statistically significant, reduction in brain natriuretic peptide (from 471 pg/mL at baseline to 251 pg/mL at one month). Conclusions: This first-in-human study demonstrates that NIUT is safe and confers statistically significant hemodynamic benefits both on the valve and ventricle.

Non-invasive ultrasound therapy for calcified aortic valve stenosis.

Non-invasive ultrasound therapy for calcified aortic valve stenosis.

Treatment of severe symptomatic aortic valve stenosis using non-invasive ultrasound therapy: a cohort study

Calcific aortic stenosis is commonly treated using surgical or transcatheter aortic valve replacement; however, many patients are not considered suitable candidates for these interventions due to severe comorbidities and limited life expectancy. As such, non-invasive therapies might offer alternative therapeutic possibilities in these patients. This study aimed to assess the safety of non-invasive ultrasound therapy and its ability to improve valvular function by softening calcified valve tissue. This prospective, multicentre, single-arm series enrolled 40 adult patients with severe symptomatic aortic valve stenosis at three hospitals in France, the Netherlands, and Serbia between March 13, 2019, and May 8, 2022. Patients were treated with transthoracically delivered non-invasive ultrasound therapy. Follow-ups were scheduled at 1, 3, 6, 12, and 24 months. The primary endpoints were procedure-related deaths within 30 days and improved valve function. We report the 6-month data. This study is registered at ClinicalTrials.gov, NCT03779620 and NCT04665596. 40 high-risk patients with a mean Society of Thoracic Surgeons score of 5·6% (SD 4·4) and multiple severe comorbidities were included. The primary endpoint, procedure-related mortality, did not occur; furthermore, no life-threatening or cerebrovascular events were reported. Improved valve function was confirmed up to 6 months, reflected by a 10% increase in mean aortic valve area from 0·58 cm2 (SD 0·19) at baseline to 0·64 cm2 (0·21) at follow-up (p=0·0088), and a 7% decrease in mean pressure gradient from 41·9 mm Hg (20·1) to 38·8 mm Hg (17·8; p=0·024). At 6 months, the New York Heart Association score had improved or stabilised in 24 (96%) of 25 patients, and the mean Kansas City Cardiomyopathy Questionnaire score had improved by 33%, from 48·5 (SD 22·6) to 64·5 (21·0). One serious procedure-related adverse event occurred in a patient who presented with a transient decrease in peripheral oxygen saturation. Non-serious adverse events included pain, discomfort during treatment, and transient arrhythmias. This novel, non-invasive ultrasound therapy for calcified aortic stenosis proved to be safe and feasible. Cardiawave.

Systematic brain magnetic resonance imaging and safety evaluation of non-invasive ultrasound therapy for patients with severe symptomatic aortic valve stenosis.

Systematic brain magnetic resonance imaging and safety evaluation of non-invasive ultrasound therapy for patients with severe symptomatic aortic valve stenosis.

Impact of the Scatterer Type on Ultrasound Wave Propagation in Microstructure Composites: Calculation and Application

This study is motivated to quantitatively analyze the differences among various multiple scattering models to determine the role played by the scatterer type in ultrasonic wave propagation. By calculating the transmission and reflection coefficients of the composites, the results of multiple scattering theoretical models of different scatterer types have been evaluated. The problem of acoustic properties in a fluid matrix containing different types of micron-scale scatterers operating in the ultrasound frequency range is considered. Theoretical calculations are conducted for composites with different mechanical properties. Meanwhile, the theoretical results have been compared with numerical finite element method simulations, which can be regarded as a benchmark to verify the validity of different theoretical models. The results show that the composites can achieve negative acoustic properties by selecting appropriate resonant scatterers, paving the way for searching ultrasonic metamaterials with desired negative acoustic properties. We further explored the application of microstructure ultrasonic metamaterials by enhancing the ultrasound transmitted energy through the high-impendence skull layer, having the potential for non-invasive ultrasound brain imaging and therapy.

Abstract 12626: Valvosoft Non-Invasive Ultrasound Therapy (NIUT) in Patients With Severe Symptomatic Aortic Valve Stenosis: First-in-Human Study - Twelve-Months Safety Update

Background: While aortic valve replacements (AVR) generally present favorable outcomes in severe calcific aortic stenosis (CAS), not all patients are eligible for an invasive treatment.Cardiawave © developed a novel non-invasive ultrasound therapy (NIUT) device, Valvosoft, to treat CAS. A prospective first-in-human study was conducted in two centers (Hôpital Européen Georges-Pompidou, France and Heart Center, Amphia Hospital, Netherlands) in 10 patients and a second study (University Clinical Center of Serbia) involving brain-MRI in 4 patients. All patients had symptomatic severe CAS and were ineligible for SAVR or TAVR according to local heart teams. Methods: Transthoracic NIUT was delivered on all 14 patients with Valvosoft. Clinical and echocardiographic evaluation was performed at baseline, discharge, 1-, 3-, 6- and 12-months follow-up (FUP). Additionally, the 4 patients of the second study had a brain-MRI performed before and after treatment. Results: Patients were advanced in age (82.4±5.3 years) with severe comorbidities (57% with heart failure and 50% with coronary heart disease). No adverse events (AE) occurred during the procedure other than isolated ventricular extrasystoles. No serious AE were adjudicated by a Clinical Event Committee (CEC) as device- or procedure-related at 1-month FUP. No death, stroke or transient ischemic attack or deterioration of neurological status were observed at 1-month FUP.During 12-months FUP, 5 deaths were reported (between 2 to 7 months after the procedure), all were adjudicated by CEC as non-procedure related. The survival rate was 100%, 93%, 79%, 64% at 1-, 3-, 6 and 12-months (to compare to the classic natural evolution of the disease survival rate of 94%, 73%, 73%, 54% respectively). No sign of cerebrovascular accident was detected in any of the 4 patients who had a brain-MRI before and after treatment. Conclusions: NIUT was feasible and safe in this small cohort of very frail, severe symptomatic CAS patients with severe comorbidities. Brain-MRIs performed before and after treatment ruled out silent cerebrovascular events. The survival rate of this cohort suggests that NIUT is beneficial for these patients and serves an unmet medical need.

Twelve-months safety of valvosoft non-invasive ultrasound therapy (NIUT) in patients with severe symptomatic aortic valve stenosis: a first-in-human study

Abstract Background Despite overall favourable outcome of surgical and transcatheter aortic valve replacement (SAVR/TAVR) in patients with severe calcific aortic stenosis (CAS), not all patients are eligible for an invasive treatment1 because of too high predicted mortality and complications. Cardiawave© has developed a novel non-invasive ultrasound therapy (NIUT) device called Valvosoft to treat calcific aortic stenosis (CAS). Based on preclinical results2,3, a prospective first-in-human study was conducted in two centres in 10 patients in 2019 and a second one in 4 patients in 2020. All patients had symptomatic severe CAS and were not eligible for aortic valve replacement according to local heart teams. Methods Fourteen patients with severe symptomatic CAS not eligible for valve replacement were enrolled. Transthoracic therapeutic ultrasound was delivered by the Valvosoft transducer coupled with an echocardiographic phased-array probe for real-time monitoring. Clinical and echocardiographic evaluation were performed at baseline, discharge, 1-, 3-, 6- and 12-months follow-up. Additionally, the 4 patients of the second study had a brain-MRI performed before and after treatment to rule out silent cerebrovascular events. Results Patients were advanced in age (82.4±5.3 years) with severe comorbidities (57% with heart failure and 50% with coronary heart disease) and severe CAS. No adverse events occurred during the procedure other than isolated ventricular extrasystoles. No device- or procedure-related SAEs were reported at 1-month follow-up as adjudicated by the Clinical Event Committee (CEC). No death, stroke or TIAs or deterioration of neurological status were observed at 1-month follow-up for all 14 patients. During 12-months follow-up, 5 out of the 14 patients died (from 2 to 7 months after the procedure). All deaths were adjudicated as non-procedure related. The survival rate was higher (100%, 93%, 79%, 64% at 1-, 3-, 6- and 12-months) comparing to the natural evolution of the disease on an equivalent studied population4 (94%, 73%, 73%, 54% at 1, 3, 6 and 12-months). No abnormality was detected in any of the 4 patients who had a brain-MRI before and after treatment. Conclusions NIUT seemed feasible and safe and in a small first cohort of very frail patients with severe comorbidities suffering from severe symptomatic CAS. Brain-MRIs performed before and after treatment ruled out silent cerebrovascular events. The survival comparison of the studied population contrasted to the natural evolution of the disease suggests that NIUT is beneficial for these patients with no other medical option. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): This study has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement 829492 and is supported by the French Government, managed by the National Research Agency (ANR) under the program “Investissements d'avenir” with the reference ANR-16-RHUS-0003 and ANR VALVOSOFT-17-CE19-0019-02.

Abstract 17142: Long Term Results of Non-Invasive Ultrasound Therapy (NIUT) in Severe Symptomatic Aortic Valve Stenosis - First-in-Man

Background: Not all patients with severe aortic valve stenosis are eligible for open-heart surgery or TAVR. CARDIAWAVE (Paris, France) has developed Valvosoft, a unique non-invasive ultrasound therapy device to treat aortic stenosis. The therapy aims to improve the opening of severely calcified aortic valves by cracking the calcium and reducing the stiffness in the aortic valve tissue by delivering transthoracically local shock waves on the valve leaflets. This study assesses the safety, feasibility and performance of this novel technique. Methods: This is a multi-center, prospective, first-in-man study designed to evaluate the safety and feasibility of the Valvosoft device. Ten patients with severe symptomatic calcific aortic stenosis and not eligible for SAVR/TAVR underwent a Valvosoft ultrasound therapy. Echocardiographic evaluation was performed by an independent core lab at baseline, discharge, and at 1, 3, 6 and 12 months along with clinical follow up. Results: Enrolled patients were advanced in age (84.1±6.5 yrs) with severe comorbidities (8 with heart failure, 5 with coronary heart disease and 5 with kidney failure). All had extensive aortic valve calcification with mean AVA of 0.61±0.17 cm2 and mean pressure gradient of 37.5±10.5 mmHg. At one-month follow-up, six patients had significantly improved their AVA with increase of 27.5% (p=0.03) and mean pressure gradient decrease of 23.2 % (p=0.025). These patients also received the highest dose and longest treatment duration. During one year follow up, 4 patients died due to progression of end stage heart failure not linked to the procedure and one patient had undergone a TAVR procedure. At 12 months, the five remaining patients has no device or procedure related major adverse events nor deterioration of neurological status. Echo, brain-MRI and clinical follow up will be presented. Conclusions: Non-invasive ultrasound therapy is feasible and safe in patients with severe aortic valve stenosis and can improve AVA and hemodynamic parameters. NIUT can be an important tool complementary to TAVI in treating patients with aortic valve stenosis.

Safety, feasibility and performance of Valvosoft non-invasive ultrasound therapy in patients with severe symptomatic calcific aortic valve stenosis. First-in-Man

Abstract Objectives We recently developed a unique transthoracic non-invasive ultrasound therapy device called Valvosoft to treat aortic stenosis. The therapy consists in delivering trans-thoracically precisely focused and controlled short ultrasound pulses (<20μsec) at a high acoustic intensity to produce non-thermal mechanical tissue softening of the calcified aortic valve with the ultimate aim of improving the valve opening. Ultrasound imaging enables to follow valve movements in real-time and thus targets the ultrasound waves on the valve with great precision. After having validated this concept in pre-clinical studies, we aimed at applying this technique in human. The primary objectives were to assess the safety and feasibility of this novel technique along with its performance by evaluation of the valve leaflets mobility and valve opening area. Methods This is a multi-center, prospective, controlled first-in-man study. Ten patients with severe symptomatic calcific aortic stenosis and not eligible for SAVR/TAVR underwent a Valvosoft ultrasound therapy. The therapy consists of 6 sessions of ultrasound therapy. The Valvosoft transducer is applied on the patient's chest and coupled at its center with an echocardiography phased array probe to allow real-time control of the therapy (cavitation bubble detection). Preselection of the region of interest is performed by echo still frame before each session. Ultrasonic evaluation was performed by an independent core lab at baseline, discharge, 30-day and 3 month follow-up along with clinical follow up. Results Enrolled patients were advanced in age (84.1±6.5 yrs) with severe comorbidities (8 with heart failure, 5 with coronary heart disease and 5 with kidney failure). All had extensive aortic valve calcification (mean calcification volume of 687.28 mm3) with mean AVA of 0.61±0.17 cm2 and mean pressure gradient of 37.5±10.5 mmHg (6 patients had SV<35ml/m2). No adverse events were recorded during the procedures other than some benign ventricular extrasystoles. The mean treatment time was 52 minutes. At 3 months follow-up, one patient had died due to end stage heart failure not linked to the procedure (9 weeks post procedure) and another got finally TAVI (45 days post procedure). Of the other 8 patients, 6 experienced an improvement of their NYHA status. No device or procedure related major adverse events nor deterioration of neurological status were observed at 3 months follow-up. Of the 7 patients that had echo follow-up at 3 months (one patient refused to get echo evaluation), 5 increased the AVA (between 14% and 46%) and 4 patients decreased the mean pressure gradient (from 6% to 44%). No AI or EF deterioration occurred during follow up. Conclusion Non-invasive ultrasound therapy is feasible and safe in patients with severe aortic valve stenosis and is able to improve AVA and pressure gradient in some patient. Larger studies with longer follow up will need to be conducted. Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): Cardiawave SA, Paris, France

Feasibility and safety of non-invasive ultrasound therapy (NIUT) on an porcine aortic valve

Calcific aortic stenosis (CAS) is associated with advanced age and comorbidities, therefore a non-invasive therapy for it would be beneficial. We previously demonstrated that ultrasound therapy improved calcified bioprosthetic valve function in an open chest model. For translational applications, we tested non-invasive ultrasound therapy (NIUT) transthoracically on swine aortic valves and investigated the need for antithrombotic treatment as a follow-up.Primary objective: feasibility and safety of NIUT. Secondary objectives: occurrence, severity and evolution of side effects during therapy and at 1 month follow-up.The device (Valvosoft, Cardiawave) consisted of an electronically steered multi-element transducer and a 2D echocardiographic probe. Three groups of swine received treatment on aortic valves: NIUT (group 1; n = 10); NIUT and 1 month antithrombotic treatment (group 2; n = 5); sham group (group 3; n = 4).Feasibility was successfully reached in all treated swine (n = 15) and no life-threatening arrhythmia were detected. Non-sustained ventricular tachycardia occurred during the procedure in seven swine. Decrease or interruption of NIUT ended arrhythmia. Histopathology revealed no valve or surrounding tissue damage and echocardiography revealed no valvular dysfunction. Only one animal had side effects [right ventricle (RV) dilatation], but the RV normalized after therapy cessation with no sequelae at follow-up. No disturbance in biological markers nor valve thrombosis were observed at follow-up. Antithrombotic treatment did not demonstrate any advantage. Survival at 30 d was 100%.We demonstrated, in vivo, the feasibility and safety of transthoracic NIUT on aortic valves in a swine model without serious adverse events. We expect this first-time transthoracic delivery of NIUT to pave the way towards a new non-invasive approach to valve softening in human CAS to restore valve function.

2381Low-intensity pulsed ultrasound ameliorates DES-induced coronary adventitial inflammation and hyperconstricting responses in pigs in vivo - A novel non-invasive therapy for coronary inflammation

Abstract Background We previously demonstrated that coronary adventitial inflammation plays important roles in the pathogenesis of coronary artery spasm, including drug-eluting stent (DES)-induced coronary hyperconstricting responses, in pigs and humans. Indeed, the coronary adventitia has recently attracted much attention as the important site for vascular inflammation. However, a direct therapeutic approach to the coronary adventitia remains to be developed. We have developed a non-invasive low-intensity pulsed ultrasound (LIPUS) therapy for angina, which exerts anti-inflammatory effects through improved coronary microcirculation. Purpose In this study, we aimed to examine whether our LIPUS therapy ameliorates DES-induced coronary hyperconstricting responses in pigs in vivo, and if so, what mechanisms are involved. Methods An everolimus-eluting stent (EES) was implanted into the left anterior descending (LAD) coronary artery in normal male pigs. They were randomly assigned to the LIPUS or the sham therapy groups. After EES implantation, in the LIPUS group, LIPUS (32 cycles, 193 mW/cm2) was applied to the heart at 3 different levels (proximal and distal stent edges and middle portion of the stent) through X-ray for 20 min at each level for every other day for 2 weeks (6 days in total) (Figs. 1A, 1B). The sham therapy group was treated in the same manner but without LIPUS. At 4 weeks after the procedure, we performed coronary angiography to examine coronary vasoconstricting responses to intracoronary serotonin in vivo. Finally, stented coronary vessels were harvested for immunohistochemistry of vasa vasorum, lymphatic vessels (LYVE-1), sympathetic nerve fibers (SNF), vascular inflammation (macrophages and IL-1β expression), Rho-kinase expression and activity as evaluated by phosphorylated myosin phosphatase target subunit-1 (pMYPT-1). Results Coronary vasoconstricting responses to intracoronary serotonin were significantly enhanced in the sham therapy group but were significantly suppressed in the LIPUS group at the DES edges in the LAD, whereas those responses were comparable at the non-DES implanted segments in the left circumflex (LCx) coronary arteries between the 2 groups. (Figs. 1C, 1D). Furthermore, in vivo lymph transport speed was significantly faster in the LIPUS group than in sham group (Figs. 1E–1G). Histological analysis showed that except vasa vasorum formation, the number of lymphatic vessels, adventitial inflammatory cells infiltration, Rho-kinase expression and activity were all significantly enhanced in the sham therapy group and were significantly suppressed in the LIPUS group (Figs. 1G–1K). Figure 1 Conclusion We were able to develop a non-invasive LIPUS therapy for coronary functional abnormalities caused by chronic adventitial inflammation in pigs in vivo, for which multiple beneficial effects appear to be involved (Fig. 1L).

Transcranial focused ultrasound with multielement arrays: Decreasing the number of transducers without compromising the focusing quality

Transcranial ultrasonic brain therapy at frequencies higher than 500 kHz requires adaptive focusing to compensate for the aberrations induced by the skull bone. This can be achieved by using multi-element arrays driven by a dedicated electronics. A growing number of elements was used to improve the focusing: 64 elements in 2000 [1], 300 in 2003 [2], 1024 in 2013 [3], and more to come. We will present some of the salient results obtained pre-clinically and clinically with such multi-element transcranial devices. Nevertheless, we will show that comparable transcranial focusing can be achieved with a novel approach in rupture with the current trend. It consists in a single-element transducer covered with a 3D silicone acoustic lens of variable and controlled thickness. Similar lenses have been introduced in the past to perform multiple focusing patterns in homogenous media [4] but recent 3d printing capabilities make 3D lenses a feasible option for transcranial adaptive focusing. We will show that the use of a lenses increases the acoustic intensity by 97 ± 56% on average, on three human skulls. [1] G. Clement et al., “A hemisphere array for non-invasive ultrasound brain therapy and surgery,” Phys. Med. Biol. 2000. [2] M. Pernot et al., “High power transcranial beam steering for ultrasonic brain therapy,” Phys. Med. Biol. 2003. [3] N. Lipsman et al., “MR-guided focused ultrasound thalamotomy for essential tremor: a proof-of-concept study,” The Lancet Neurology 2013. [4] T. Fjield et al., “Low-profile lenses for ultrasound surgery,” Phys. Med. Biol. 1999.

Robotic Platform for High-Intensity Focused Ultrasound Surgery Under Ultrasound Tracking: The FUTURA Platform

Focused Ultrasound Therapy Using Robotic Approaches (FUTURA) is a European seventh research framework programme project aimed at creating an innovative platform for Focused Ultrasound Surgery (FUS). Merging robotics together with noninvasive ultrasound monitoring and therapy has the goal to improve flexibility, precision and accuracy of the intervention, thus enabling a large use of FUS for the treatment of different pathologies. The FUTURA platform, based on FUS therapy under US tracking, has been set up with the first clinical target of kidney cancer treatment. Experiments for assessing the accuracy of the FUS delivery with the FUTURA platform have been carried out under in vitro static conditions and presented here as preliminary outcomes of this study.

Ultrasound-Stimulated Drug Delivery Using Therapeutic Reconstituted High-Density Lipoprotein Nanoparticles.

The abnormal tumor vasculature and the resulting abnormal microenvironment are major barriers to optimal chemotherapeutic drug delivery. It is well known that ultrasound (US) can increase the permeability of the tumor vessel walls and enhance the accumulation of anticancer agents. Reconstituted high-density lipoproteins (rHDL) nanoparticles (NPs) allow selective delivery of anticancer agents to tumor cells via their overexpressed scavenger receptor type B1 (SR-B1) receptor. The goal of this study is to investigate the potential of noninvasive US therapy to further improve delivery and tumor uptake of the payload from rHDL NPs, preloaded with an infrared dye (IR-780), aimed to establish a surrogate chemotherapeutic model with optical localization. Athymic nude mice were implanted orthotopically with one million breast cancer cells (MDA-MB-231/Luc). Three weeks later, animals were divided into seven groups with comparable mean tumor size: control, low, moderate, and high concentration of rHDL NPs alone groups, as well as these three levels of rHDL NPs plus US therapy groups (N = 7 to 12 animals per group), where low, moderate and high denote 5, 10, and 50 µg of the IR-780 dye payload per rHDL NP injection, respectively. The US therapy system included a single element focused transducer connected in series with a function generator and power amplifier. A custom 3D printed cone with an acoustically transparent aperture and filled with degassed water allowed delivery of focused US energy to the tumor tissue. US exposure involved a pulsed sequence applied for a duration of 5 min. Each animal in the US therapy groups received a slow bolus co-injection of MB contrast agent and rHDL NPs. Animals were imaged using a whole-body optical system to quantify intratumoral rHDL NP accumulation at baseline and again at 1 min, 30 min, 24 h, and 48 h. At 48 h, all animals were euthanized and tumors were excised for ex vivo analysis. We investigated a noninvasive optical imaging method for monitoring the effects of US-stimulated drug delivery of IR-780 dye-loaded rHDL NPs in living animals. No change in optical imaging data was found in the control animals. However, there was considerable dye accumulation (surrogate drug) within 48 h in the low (5 µg), moderate (10 µg), and high (50 µg) rHDL NP concentration-dosed group animals (p < 0.09). With US therapy added to the experimental protocol, there was an additional and significant increase in local tumor drug uptake at 48 h (p < 0.02). Optical image data collected from ex vivo tumor samples confirmed tumor retention of the IR-780 dye-loaded rHDL NPs and correlated positively with in vivo optical imaging results (R2 > 0.69, p < 0.003). IR-780 dye extraction from the tumor tissue samples confirmed the in vivo and ex vivo US therapy findings. Overall, the addition of US therapy considerably improved local rHDL NP accumulation in tumor tissue. This study concludes that US-mediated drug delivery can facilitate tumor uptake of rHDL NPs and more research is warranted to optimize the drug dosing schedule and the respective therapeutic protocols.

Carbon-Nanotube Optoacoustic Lens for Focused Ultrasound Generation and High-Precision Targeted Therapy

We demonstrate a new optical approach to generate high-frequency (>15 MHz) and high-amplitude focused ultrasound, which can be used for non-invasive ultrasound therapy. A nano-composite film of carbon nanotubes (CNTs) and elastomeric polymer is formed on concave lenses, and used as an efficient optoacoustic source due to the high optical absorption of the CNTs and rapid heat transfer to the polymer upon excitation by pulsed laser irradiation. The CNT-coated lenses can generate unprecedented optoacoustic pressures of >50 MPa in peak positive on a tight focal spot of 75 μm in lateral and 400 μm in axial widths. This pressure amplitude is remarkably high in this frequency regime, producing pronounced shock effects and non-thermal pulsed cavitation at the focal zone. We demonstrate that the optoacoustic lens can be used for micro-scale ultrasonic fragmentation of solid materials and a single-cell surgery in terms of removing the cells from substrates and neighboring cells.

Clinical Effects of Noninvasive Ultrasound Therapy for Circumferential Reduction

Introduction: Conventional body contouring techniques such as liposuction, although now far less invasive, still require extended periods of recuperation and the use of compression garments. Several noninvasive techniques for soft tissue, adipose, and dermal treatment have been reported in the literature as also producing circumferential measurement reductions in patients. These results can now be correlated to evidence-based scientific methodology versus anecdotal reports. Materials and Methods: Patients were treated using the VASER Shape (Sound Surgical Technologies, Louisville, Colo) as part of routine practice. Circumferential measurements were made before and after treatments. Results: Two hundred and four patients were treated in 741 treatment sessions at 12 centers in the United States beginning in June 2010. When measured immediately after treatment, the patients experienced a 0.8-in circumferential reduction in the abdomen and a 0.5-in reduction on the thighs. Circumferential reduction continued over the course of treatments, resulting in reductions of more than 2-in and 1-in, respectively, in the abdomen and thighs. In no cases were any analgesics or anesthesia provided to patients before or during treatment. In general, the patients reported that the treatment was pleasant and felt warm but not uncomfortable. After treatment, patients were able to continue with their normal daily routines. Patients reacted positively to the procedure and the immediacy of results, and many reported that their clothes fit better when they dressed after treatment. In addition to circumferential measurement changes, patients also reported the sensation of feeling tighter in the treated area and that the treated areas had smoother skin. Conclusions: The VASER Shape system presents a novel approach to achieving immediate circumferential measurement reduction noninvasively with no patient downtime.

Intermediate-Term Effects of Intracardiac Communications Created Noninvasively by Therapeutic Ultrasound (Histotripsy) in a Porcine Model

The authors have demonstrated that histotripsy (pulsed cavitational ultrasound) can create atrial septal defects and ventricular septal defects (VSDs) in an open-chest canine model transcutaneously through the intact chest of neonatal pigs. To assess the potential untoward effects of these applications, the clinical, systemic, and pathologic effects of histotripsy-induced intracardiac communications were analyzed. Six neonatal pigs received noninvasive ultrasound therapy to their ventricular septa, then were allowed to survive 1 month for evaluation of intermediate-term effects. The results were compared with those of six previous animals killed immediately and three others killed 2-3 days after the procedure. Brain magnetic resonance imaging (MRI) and an assessment of cardiac function were performed with long-term survivors, and pathologic specimens were obtained when the animals were killed. In all 15 animals, VSDs 2-6.5 mm wide were successfully created. No fatalities occurred, and all the animals thrived, achieving normal weight gain by the time they were killed. Brain MRI and lung pathology exhibited no evidence of thromboembolic events. No damage to intervening tissue was observed. Pathologic analysis showed demarcated damage to the ventricular septa. Flanking injury and hemorrhage observed acutely were resolved by 1 month, with tissue remodeling present. Transcutaneous histotripsy is a safe and effective technique for creating intracardiac communications noninvasively without intermediate-term untoward effects. With further refinement and development, histotripsy has the potential to become an effective tool for palliation of congenital heart disease.