Tornado-inspired acoustic vortex tweezer for trapping and manipulating microbubbles.

Spatially concentrating and manipulating biotherapeutic agents within the circulatory system is a longstanding challenge in medical applications due to the high velocity of blood flow, which greatly limits drug leakage and retention of the drug in the targeted region. To circumvent the disadvantages of current methods for systemic drug delivery, we propose tornado-inspired acoustic vortex tweezer (AVT) that generates net forces for noninvasive intravascular trapping of lipid-shelled gaseous microbubbles (MBs). MBs are used in a diverse range of medical applications, including as ultrasound contrast agents, for permeabilizing vessels, and as drug/gene carriers. We demonstrate that AVT can be used to successfully trap MBs and increase their local concentration in both static and flow conditions. Furthermore, MBs signals within mouse capillaries could be locally improved 1.7-fold and the location of trapped MBs could still be manipulated during the initiation of AVT. The proposed AVT technique is a compact, easy-to-use, and biocompatible method that enables systemic drug administration with extremely low doses.

Enhancing Doxorubicin Delivery in Solid Tumor by Superhydrophobic Amorphous Calcium Carbonate-Doxorubicin Silica Nanoparticles with Focused Ultrasound.

The current approach of delivering chemotherapy via pH-sensitive amorphous calcium carbonate-doxorubicin silica nanoparticles (ADS NPs) faces the challenge of insufficient drug dose due to drug instability within the bloodstream and poor tumor penetration. To overcome these long-standing obstacles, we proposed a superhydrophobic coating on the surface of the ADS NPs that could be easily modified via fluorination (ADSF NPs). The surface of fluorinated ADS NPs was further modified with a phospholipid layer to reduce aggregation and improve biocompatibility (ADSFL NPs). The contact angle and mean size of ADSFL NPs were 30.2 ± 4.4° and 353.1 ± 54.2 nm, respectively. The superhydrophobic layer generated interfacial nanobubbles on the outer shell of the NPs that reduced water-induced leakage of doxorubicin (DOX) sevenfold compared with the uncoated group and induced a cavitation effect upon ultrasound (US) sonication. Moreover, release of DOX from the ADSFL NPs could be triggered by US, and this release was further improved 1.6-fold in acidic aqueous conditions, indicating that the ADSFL NPs retained pH responsiveness. Enhanced sonography contrast and histological examination demonstrated that US could trigger cavitation activities from ADSFL NPs in vivo to induce vessel disruption and enhance the fluorescence intensity of DOX within the tumor region threefold under US imaging guidance compared with the ADSFL NPs-only group.

Ultrasonic technologies in imaging and drug delivery.

Ultrasonic technologies show great promise for diagnostic imaging and drug delivery in theranostic applications. The development of functional and molecular ultrasound imaging is based on the technical breakthrough of high frame-rate ultrasound. The evolution of shear wave elastography, high-frequency ultrasound imaging, ultrasound contrast imaging, and super-resolution blood flow imaging are described in this review. Recently, the therapeutic potential of the interaction of ultrasound with microbubble cavitation or droplet vaporization has become recognized. Microbubbles and phase-change droplets not only provide effective contrast media, but also show great therapeutic potential. Interaction with ultrasound induces unique and distinguishable biophysical features in microbubbles and droplets that promote drug loading and delivery. In particular, this approach demonstrates potential for central nervous system applications. Here, we systemically review the technological developments of theranostic ultrasound including novel ultrasound imaging techniques, the synergetic use of ultrasound with microbubbles and droplets, and microbubble/droplet drug-loading strategies for anticancer applications and disease modulation. These advancements have transformed ultrasound from a purely diagnostic utility into a promising theranostic tool.

Sonogenetic-Based Neuromodulation for the Amelioration of Parkinson's Disease.

Sonogenetics is a promising strategy allowing the noninvasive and selective activation of targeted neurons in deep brain regions; nevertheless, its therapeutic outcome for neurodegeneration diseases that need long-term treatment remains to be verified. We previously enhanced the ultrasound (US) sensitivity of targeted cells by genetic modification with an engineered auditory-sensing protein, mPrestin (N7T, N308S). In this study, we expressed mPrestin in the dopaminergic neurons of the substantia nigra in Parkinson's disease (PD) mice and used 0.5 MHz US for repeated and localized brain stimulation. The mPrestin expression in dopaminergic neurons persisted for at least 56 days after a single shot of adeno-associated virus, suggesting that the period of expression was long enough for US treatment in mice. Compared to untreated mice, US stimulation ameliorated the dopaminergic neurodegeneration 10-fold and mitigated the PD symptoms of the mice 4-fold, suggesting that this sonogenetic strategy has the clinical potential to treat neurodegenerative diseases.

Sonogenetic Modulation of Cellular Activities Using an Engineered Auditory-Sensing Protein.

Biomolecules that respond to different external stimuli enable the remote control of genetically modified cells. We report herein a sonogenetic approach that can manipulate target cell activities by focused ultrasound stimulation. This system requires an ultrasound-responsive protein derived from an engineered auditory-sensing protein prestin. Heterologous expression of mouse prestin containing two parallel amino acid substitutions, N7T and N308S, that frequently exist in prestins from echolocating species endowed transfected mammalian cells with the ability to sense ultrasound. An ultrasound pulse of low frequency and low pressure efficiently evoked cellular calcium responses after transfecting with prestin(N7T, N308S). Moreover, pulsed ultrasound can also noninvasively stimulate target neurons expressing prestin(N7T, N308S) in deep regions of mouse brains. Our study delineates how an engineered auditory-sensing protein can cause mammalian cells to sense ultrasound stimulation. Moreover, our sonogenetic tools will serve as new strategies for noninvasive therapy in deep tissues.

Monitoring of acoustic cavitation in microbubble-presented focused ultrasound exposure using gradient-echo MRI.

BACKGROUND: Gadolinium-based contrast agents can be used to identify the blood-brain barrier (BBB) opening after inducing a focused ultrasound (FUS) cavitation effect in the presence of microbubbles. However, the use of gadolinium may be limited for frequent routine monitoring of the BBB opening in clinical applications. PURPOSE: To use a gradient-echo sequence without contrast agent administration for monitoring of acoustic cavitation. STUDY TYPE: Animal and phantom prospective. PHANTOM/ANIMAL MODEL: Static and flowing gel phantoms; six normal adult male Sprague-Dawley rats. FIELD STRENGTH/SEQUENCE: 3T, 7T; fast low-angle shot sequence. ASSESSMENT: Burst FUS with acoustic pressures = 1.5, 2.2, 2.8 MPa; pulse repetition frequencies = 1, 10,100 Hz; and duty cycles = 2%, 5%, 10% were transmitted to the chamber of a static phantom with microbubble concentrations = 10%, 1%, 0.1%. MR slice thicknesses = 3, 6, 8 mm were acquired. In flowing phantom experiments, 0.1%, 0.25%, 0.5%, 0.75%, and 1% microbubbles were infused and transmitted by burst FUS with an acoustic pressure = 0.4 and 1 MPa. In in vivo experiments, 0.25% microbubbles was infused and 0.8 MPa burst FUS was transmitted to targeted brain tissue beneath the superior sagittal sinus. The mean signal intensity (SI) was normalized using the mean SI from pre-FUS. STATISTICAL TESTS: Two-tailed Student's t-test. P < 0.05 was considered statistically significant. RESULTS: In the static phantom, the time courses of normalized SI decreases to minimum SI levels of 70-80%. In the flowing phantom, substantial normalized SI of 160-230% was present with variant acoustic pressures and microbubble concentrations. Compared with in vivo control rats, the brain tissue of experimental rats with transmission of FUS pulses exhibited considerable decreases of normalized SI (P < 0.001) because of the cavitation-induced perturbation of flow. DATA CONCLUSION: Observing gradient-echo SI changes can help monitor the targeted location of microbubble-enhanced FUS, which in turn assists the monitoring of the BBB opening. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2020;51:311-318.

Efficacy of Quantitative Muscle Ultrasound Using Texture-Feature Parametric Imaging in Detecting Pompe Disease in Children.

Pompe disease is a hereditary neuromuscular disorder attributed to acid α-glucosidase deficiency, and accurately identifying this disease is essential. Our aim was to discriminate normal muscles from neuropathic muscles in children affected by Pompe disease using a texture-feature parametric imaging method that simultaneously considers microstructure and macrostructure. The study included 22 children aged 0.02-54 months with Pompe disease and six healthy children aged 2-12 months with normal muscles. For each subject, transverse ultrasound images of the bilateral rectus femoris and sartorius muscles were obtained. Gray-level co-occurrence matrix-based Haralick's features were used for constructing parametric images and identifying neuropathic muscles: autocorrelation (AUT), contrast, energy (ENE), entropy (ENT), maximum probability (MAXP), variance (VAR), and cluster prominence (CPR). Stepwise regression was used in feature selection. The Fisher linear discriminant analysis was used for combination of the selected features to distinguish between normal and pathological muscles. The VAR and CPR were the optimal feature set for classifying normal and pathological rectus femoris muscles, whereas the ENE, VAR, and CPR were the optimal feature set for distinguishing between normal and pathological sartorius muscles. The two feature sets were combined to discriminate between children with and without neuropathic muscles affected by Pompe disease, achieving an accuracy of 94.6%, a specificity of 100%, a sensitivity of 93.2%, and an area under the receiver operating characteristic curve of 0.98 ± 0.02. The CPR for the rectus femoris muscles and the AUT, ENT, MAXP, and VAR for the sartorius muscles exhibited statistically significant differences in distinguishing between the infantile-onset Pompe disease and late-onset Pompe disease groups (p < 0.05). Texture-feature parametric imaging can be used to quantify and map tissue structures in skeletal muscles and distinguish between pathological and normal muscles in children or newborns.

Theranostic nanosensitizers for highly efficient MR/fluorescence imaging-guided sonodynamic therapy of gliomas.

Glioma is the most frequent primary brain tumour of the central nervous system. Its high aggressiveness and deep-seated brain lesion make it a great challenge to develop a non-invasive, precise and effective treatment approach. Here, we report a multifunctional theranostic agent that can integrate imaging and therapy into a single nano-platform for imaging-guided sonodynamic therapy (SDT). The SDT agents were fabricated by encapsulation of sinoporphyrin sodium (DVDMS) chelating with manganese ions into nanoliposomes (DVDMS-Mn-LPs). DVDMS-Mn-LPs are physiologically stable and biologically compatible, and they can produce singlet oxygen upon ultrasound irradiation to kill cancer cells. Both cell and animal studies demonstrated that SDT with DVDMS-Mn-LPs can significantly improve the antitumour growth efficiency even in the presence of skull. In addition, DVDMS-Mn-LPs are good for MR and fluorescence imaging. Thus, DVDMS-Mn-LPs reported here may provide a promising strategy for imaging-guided modality for glioma treatment.

Roles of Textural and Surface Properties of Nanoparticles in Ultrasound-Responsive Systems.

Acoustic inertial cavitation (IC) is a crucial phenomenon for many ultrasound (US)-related applications. This study aimed to investigate the roles of textural and surface properties of NPs in IC generation by combining typical IC detection methods with various types of silica model NPs. Acoustic passive cavitation detection, optical high-speed photography, and US imaging have been used to quantify IC activities (referred to as the IC dose, ICD) and describe the physical characteristics of IC activities from NPs. The results showed that the ICDs from NPs were positively correlated to their surface hydrophobicity and that their external surface hydrophobicity plays a much more crucial role than do the textural properties. The high-speed photography revealed that the sizes of IC-generated bubbles from superhydrophobic NPs ranged from 20-40 µm at 4-6 MPa and collapsed in several microseconds. Bubble clouds monitored with US imaging showed that IC from NPs was consistent with the surface hydrophobicity. The simulation results based on the crevice model of cavitation nuclei correlated well with the experimental results. This study has demonstrated that the surface property, instead of the textural property, of NPs dominated the IC generation, and surface nanobubbles adsorbed on the NP surface have been proposed to be cavitation nuclei.

Ultrasound Entropy Imaging of Nonalcoholic Fatty Liver Disease: Association with Metabolic Syndrome.

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of advanced liver diseases. Fat accumulation in the liver changes the hepatic microstructure and the corresponding statistics of ultrasound backscattered signals. Acoustic structure quantification (ASQ) is a typical model-based method for analyzing backscattered statistics. Shannon entropy, initially proposed in information theory, has been demonstrated as a more flexible solution for imaging and describing backscattered statistics without considering data distribution. NAFLD is a hepatic manifestation of metabolic syndrome (MetS). Therefore, we investigated the association between ultrasound entropy imaging of NAFLD and MetS for comparison with that obtained from ASQ. A total of 394 participants were recruited to undergo physical examinations and blood tests to diagnose MetS. Then, abdominal ultrasound screening of the liver was performed to calculate the ultrasonographic fatty liver indicator (US-FLI) as a measure of NAFLD severity. The ASQ analysis and ultrasound entropy parametric imaging were further constructed using the raw image data to calculate the focal disturbance (FD) ratio and entropy value, respectively. Tertiles were used to split the data of the FD ratio and entropy into three groups for statistical analysis. The correlation coefficient r, probability value p, and odds ratio (OR) were calculated. With an increase in the US-FLI, the entropy value increased (r = 0.713; p < 0.0001) and the FD ratio decreased (r = -0.630; p < 0.0001). In addition, the entropy value and FD ratio correlated with metabolic indices (p < 0.0001). After adjustment for confounding factors, entropy imaging (OR = 7.91, 95% confidence interval (CI): 0.96-65.18 for the second tertile; OR = 20.47, 95% CI: 2.48-168.67 for the third tertile; p = 0.0021) still provided a more significant link to the risk of MetS than did the FD ratio obtained from ASQ (OR = 0.55, 95% CI: 0.27-1.14 for the second tertile; OR = 0.42, 95% CI: 0.15-1.17 for the third tertile; p = 0.13). Thus, ultrasound entropy imaging can provide information on hepatic steatosis. In particular, ultrasound entropy imaging can describe the risk of MetS for individuals with NAFLD and is superior to the conventional ASQ technique.

Real-time monitoring of inertial cavitation effects of microbubbles by using MRI: In vitro experiments.

PURPOSE: To investigate the feasibility of half-Fourier acquisition single-shot turbo spin-echo (HASTE) for real-time monitoring of signal changes because of water flow induced by inertial cavitation (IC) during microbubbles (MBs)-present focused ultrasound (FUS) exposure. THEORY AND METHODS: Strong turbulence produced in MB solution at the onset of IC results in the difficulty to refocus signal echoes and thus the decrease in signal intensity (SI). Fundamental investigations were conducted using an agar phantom containing MB dilutions exposed to 1.85-MHz FUS. The effects of various experimental conditions including MB concentrations, imaging slice thicknesses, chamber diameters, acoustic pressures, duty cycles, and pulse repetition frequencies (PRFs) were discussed. RESULTS: Continuous 2.8 MPa FUS exposure resulted in SI changed from 11% to 55% when MBs concentrations increased from 0.025% to 0.1%. When slice thickness increased from 3 mm to 6 or 8 mm, smaller SI changes were observed (84%, 59%, and 46%). Images acquired with chamber diameter of 6 and 3 mm showed SI changes of 84% and 35%, respectively. In burst modes, higher duty cycles exhibited higher SI changes, and lower PRFs exhibited smaller and longer SI decrease. CONCLUSION: Under various conditions, substantial signal changes were observable, suggesting the feasibility of applying HASTE to real-time monitor IC effect under FUS exposure. Magn Reson Med 77:102-111, 2017. © 2015 Wiley Periodicals, Inc.

Acoustic-actuated optical coherence angiography.

Optical coherence tomography (OCT) angiography requires high sensitivity and image penetration for detailed microvascular monitoring. Unfortunately, no effective contrast-medium-enhanced scheme is currently available for imaging improvement. We here propose the simultaneous use of gas-filled microbubbles (MBs) and acoustic actuation to enhance the imaging contrast of OCT angiography. OCT-synchronized acoustic actuation was applied in the presence of MBs, and different moving object tracking angiographic algorithms were tested in in vitro tubing and in vivo mouse experiments. This scheme significantly enhanced the OCT angiography performance, including its sensitivity and penetration, and should advance the utilization of OCT as an effective microvascular diagnostic tool.

Carpal tunnel syndrome: US strain imaging for diagnosis.

PURPOSE: To determine the feasibility of two-dimensional (2D) ultrasonographic (US) strain imaging for quantifying and mapping mechanical behaviors of the median nerve, flexor retinaculum, and flexor tendons within the carpal tunnel in normal and carpal tunnel syndrome (CTS) disease states during active finger motion. MATERIALS AND METHODS: This prospective study was approved by the institutional review board; all subjects gave written informed consent and had both of their hands examined. Ten wrists in 10 healthy volunteers (age range, 35-51 years) and 16 wrists in 12 patients with CTS (age range, 37-55 years) were examined. In the patients, CTS had been confirmed on the basis of clinical symptoms and results of electrophysiologic studies. Raw US signals were acquired and were cross correlated to enable estimation of 2D incremental displacements, from which 2D strains were computed. The median nerve was characterized by the axial normal strain, while the flexor tendons and the flexor retinaculum were characterized by the shear strain. Temporal mean values (mean cumulative strain [MCS] values) and standard deviations (standard deviations of the cumulative strain [SDCS]) of the spatially averaged cumulative strains in each tissue region over the entire cycle of finger motion were compared by using an unpaired two-tailed Student t test. RESULTS: MCS for patients with CTS and volunteers was similar. The SDCS for the shear strain of the flexor retinaculum was significantly lower (P < .001) in patients with CTS than in healthy volunteers, while that for the axial strain of the median nerve was higher in healthy volunteers than in patients with CTS (P = .0065). CONCLUSION: US strain imaging can be used to quantify and map tissue kinematics in the carpal tunnel and to differentiate abnormal from normal median nerves in the wrist.

The relationship between surface drug distribution of Dox-loaded microbubbles and drug release/cavitation behaviors with ultrasound.

Ultrasound (US)-triggered microbubbles (MBs) drug delivery is a promising tool for noninvasive and localized therapy. Several studies have shown the potential of drug-loaded MBs to boost the delivery of therapeutic substances to target tissue effectively. Nevertheless, little is known about the surface payload distribution affecting the cavitation activity and drug release behavior of the drug-loaded MBs. In this study, we designed a common chemodrug (Doxorubicin, Dox)-loaded MB (Dox-MBs) and regulated the payload distribution as uniform or cluster onto the outer surface of MBs. The Dox distribution on the MB shells was assessed by confocal fluorescence microscopic imaging. The acoustic properties of the Dox-MBs with different Dox distributions were evaluated by their acoustic stability and cavitation activities. The payload release and the fragments from Dox-MBs in response to different US parameters were measured and visualized by column chromatography and cryo-electron microscopy, respectively. By amalgamating these methodologies, we found that stable cavitation was sufficient for triggering uniform-loaded MBs to release their payload, but stable cavitation and inertial cavitation were required for cluster-loaded MBs. The released substances included free Dox and Dox-containing micelle/liposome; their portions depended on the payload distribution, acoustic pressure, cycle number, and sonication duration. Furthermore, we also revealed that the Dox-containing micelle/liposome in cluster-loaded MBs had the potential for multiple drug releases upon US sonication. This study compared uniform-loaded MBs and cluster-loaded MBs to enhance our comprehension of drug-loaded MBs mediated drug delivery.

Focused ultrasound stimulation of infralimbic cortex attenuates reinstatement of methamphetamine-induced conditioned place preference in rats.

Methamphetamine (MA) use disorder poses significant challenges to both the affected individuals and society. Current non-drug therapies like transcranial direct-current stimulation and transcranial magnetic stimulation have limitations due to their invasive nature and limited reach to deeper brain areas. Transcranial focused ultrasound (FUS) is gaining attention as a noninvasive option with precise spatial targeting, able to affect deeper areas of the brain. This research focused on assessing the effectiveness of FUS in influencing the infralimbic cortex (IL) to prevent the recurrence of MA-seeking behavior, using the conditioned place preference (CPP) method in rats. The study involved twenty male Sprague-Dawley rats. Neuronal activation by FUS was first examined via electromyography (EMG). Rats received alternately with MA or saline, and confined to one of two distinctive compartments in a three compartment apparatus over a 4-day period. After CPP test, extinction, the first reinstatement, and extinction again, FUS was applied to IL prior to the second MA priming-induced reinstatement. Safety assessments were conducted through locomotor and histological function examinations. EMG data confirmed the effectiveness of FUS in activating neurons. Significant attenuation of reinstatement of MA CPP was found, along with successful targeting of the IL region, confirmed through acoustic field scanning, c-Fos immunohistochemistry, and Evans blue dye staining. No damage to brain tissue or impaired locomotor activity was observed. The results of the study indicate that applying FUS to the IL markedly reduced the recurrence of MA seeking behavior, without harming brain tissue or impairing motor skills. This suggests that FUS could be a promising method for treating MA use disorder, with the infralimbic cortex being an effective target for FUS in preventing MA relapse.

Feasibility of in vitro calcification plaque disruption using ultrasound-induced microbubble inertial cavitation.

Percutaneous transluminal coronary angioplasty (PTCA) is a clinical method in which plaque-narrowed arteries are widened by inflating an intravascular balloon catheter. However, PTCA remains challenging to apply in calcified plaques since the high pressure required for achieving a therapeutic outcome can result in balloon rupture, vessel rupture, and intimal dissection. To address the problem with PTCA, we hypothesized that a calcified plaque can be disrupted by microbubbles (MBs) inertial cavitation induced by ultrasound (US). This study proposed a columnar US transducer with a novel design to generate inertial cavitation at the lesion site. Experiments were carried out using tubular calcification phantom to mimic calcified plaques. After different parameters of US + MBs treatment (four types of MBs concentration, five types of cycle number, and three types of insonication duration; n = 4 in each group), inflation experiments were performed to examine the efficacy of cavitation for a clinically used balloon catheter. Finally, micro-CT was used to investigate changes in the internal structure of the tubular plaster phantoms. The inflation threshold of the untreated tubular plaster phantoms was > 11 atm, and this was significantly reduced to 7.4 ± 0.7 atm (p = 5.2E-08) using US-induced MBs inertial cavitation at a treatment duration of 20 min with an acoustic pressure of 214 kPa, an MBs concentration of 4.0 × 108 MBs/mL, a cycle number of 100 cycles, and a pulse repetition frequency of 100 Hz. Moreover, micro-CT revealed internal damage in the tubular calcification phantom, demonstrating that US-induced MBs inertial cavitation can effectively disrupt calcified plaques and reduce the inflation threshold of PTCA. The ex vivo histopathology results showed that the endothelium of pig blood vessels remained intact after the treatment. In summary, the results show that US-induced MBs inertial cavitation can markedly reduce the inflation threshold in PTCA without damaging blood vessel endothelia, indicating the potential of the proposed treatment method.

Using microbubbles as an MRI contrast agent for the measurement of cerebral blood volume.

The susceptibility differences at the gas-liquid interface of microbubbles (MBs) allow their use as an intravascular susceptibility contrast agent for in vivo MRI. However, the characteristics of MBs are very different from those of the standard gadolinium-diethylenetriaminepentaacetic acid (Gd-DPTA) contrast agent, including the size distribution and hemodynamic properties, which could influence MRI outcomes. Here, we investigate quantitatively the correlation between the relative cerebral blood volume (rCBV) derived from Gd-DTPA (rCBV(Gd)) and the MB-induced susceptibility effect (ΔR(2*MB)) by conventional dynamic susceptibility contrast MRI (DSC-MRI). Custom-made MBs had a mean diameter of 0.92 µm and were capable of inducing 4.68 ± 3.02% of the maximum signal change (MSC). The MB-associated ΔR(2*MB) was compared with rCBV(Gd) in 16 rats on 4.7-T MRI. We observed a significant effect of the time to peak (TTP) on the correlation between ΔR(2*MB) and rCBV(Gd), and also found a noticeable dependence between TTP and MSC. Our findings suggest that MBs with longer TTPs can be used for the estimation of rCBV by DSC-MRI, and emphasize the critical effect of TTP on MB-based contrast MRI.

Enhanced sonodynamic therapy by carbon dots-shelled microbubbles with focused ultrasound.

Sonodynamic therapy involving the non-invasive and local generation of lethal reactive oxygen species (ROS) via ultrasound (US) with sonosensitizers has been proposed as an emerging tumor therapy strategy. However, such therapy is usually associated with inertial cavitation and unnecessary damage to healthy tissue because current sonosensitizers have insufficient sensitivity to US. Here, we report the use of a new proposed sonosensitizer, carbon dots (C-dots), to assemble microbubbles with a gas core (C-dots MBs). As the C-dots were directly integrated into the MB shell, they could effectively absorb the energy of inertial cavitation and transfer it to ROS. Our results revealed the appearance of 1O2, •OH, and H2O2 after US irradiation of C-dots MBs. In in vitro experiments, treatment with C-dots MBs plus US induced lipid peroxidation, elevation of intracellular ROS, and apoptosis in 32.5%, 45.3%, and 50.1% of cells respectively. In an animal solid tumor model, treatment with C-dots MBs plus US resulted in a 3-fold and 2.5-fold increase in the proportion of ROS-damaged cells and apoptotic cells, respectively, compared to C-dots MBs alone. These results will pave the way for the design of novel multifunctional sonosensitizers for SDT tumor therapy.

Application of Ultrasound to Enhancing Stem Cells Associated Therapies.

Pluripotent stem cell therapy exhibits self-renewal capacity and multi-directional differentiation potential and is considered an important regenerative approach for the treatment of several diseases. However, insufficient cell transplantation efficiency, uncontrollable differentiation, low cell viability, and difficult tracing limit its clinical applications and treatment outcome. Ultrasound (US) has mechanical, cavitation, and thermal effects that can produce different biological effects on organs, tissues, and cells. US can be combined with different US-responsive particles for enhanced physical-chemical stimulation and drug delivery. In the meantime, US also can provide a noninvasive and harmless imaging modality for deep tissue in vivo. An in-depth evaluation of the role and mechanism of action of US in stem cell therapy would enhance understanding of US and encourage research in this field. In this article, we comprehensively review progress in the application of US alone and combined with US-responsive particles for the promotion of proliferation, differentiation, migration, and in vivo detection of stem cells and the potential clinical applications.

Electrowetting-driven liquid lens for ultrasound: Enabling controllable focal length and flexible beam steering.

Focused ultrasound is an increasingly popular non-invasive treatment modality. Still, its fixed focal point requires an array ultrasound transducer or scanning system to cover different therapeutic scenarios. To address this limitation, we developed an electrically-controlled liquid lens that enables dynamic beam focusing and steering of the incident plane ultrasound beam. The lens was carefully optimized for low-energy attenuation and low-voltage driving. We evaluated the performance of the lens using a homemade 5.5-MHz planar transducer with a 7.5-mm aperture. Our results demonstrate that the planar ultrasound beam can be adjusted to a focused beam with a focal length from 27 mm to 32 mm within 1 s by increasing the electric input (0-60 V) to the lens. Additionally, the beam angle of the ultrasound is tunable from -5 to 5° by adjusting the charge distribution on the lens. Our design enables real-time, fast-response, on-demand changing of focal length and beam angle for a single-element planar transducer. Our study presents a promising technology for altering the ultrasound beam of a planar single-element transducer for different ultrasound applications. The development of this electrically-controlled liquid lens has the potential to enhance the efficacy of focused ultrasound treatment and improve patient outcomes.