Ultrasound-assisted Drug Delivery Research Articles

High-frequency ultrasound-assisted drug delivery of chia, cress, and flax conjugated hematite iron oxide nanoparticle for sono-photodynamic lung cancer treatment in vitro and in vivo

BackgroundSono-photodynamic therapy (SPDT), which combines photodynamic (PDT) and sonodynamic (SDT) therapies with sensitizers, offers new avenues for cancer treatment. Even though new sensitizers for SPDT have been synthesized with great success, few of them are effectively used. The limited tumor-targeting specificity, inability to transport the sensitizers deeply intratumorally, and the deteriorating tumor microenvironment limit their anti-tumor effectiveness. The current study was carried out aiming at high-frequency ultrasound-assisted drug delivery of chia, cress and flax conjugated hematite iron oxide nanoparticles (CCF–HIONP) for photothermal–photodynamic lung cancer (LCA) treatment in vitro and in vivo as activated cancer treatment up-to-date modality.Materials and methodsThe study was conducted in vitro on human LCA cells (A-549) and the study protocol application groups in vivo on Swiss albino mice treated with benzo[a]pyrene only and were not received any treatment for inducing LCA, and only after LCA induction the study treatment protocol began, treatment was daily with CCF–HIONP as HIFU–SPDT sensitizer with or without exposure to laser (IRL) or high-frequency ultrasound (HIFU–US) or a combination of laser and/or high-frequency ultrasound for 3 min for 2 weeks.ResultsRevealed that HIONP can be employed as effective CCF delivery system that directly targets LCA cells. In addition, CCF–HIONP is a promising HIFU–SPS for HIFU–SPDT and when combined with HIFU–SPDT can be very effective in treatment of LCA–A549 in vitro (cell viability decreased in a dose-dependent basis, the cell cycle progression in G0/G1 was slowed down, and cell death was induced as evidenced by an increase in the population of Pre-G cells, an increase in early and late apoptosis and necrosis, and an increase in autophagic cell death) and benzo[a]pyrene LCA-induce mice in vivo (decreased oxidative stress (MDA), and ameliorated enzymatic and non-enzymatic antioxidants (SOD, GR, GPx, GST, CAT, GSH, and TAC) as well as renal (urea, creatinine) and hepatic (ALT, AST) functions, induced antiproliferative genes (caspase 3,9, p53, Bax, TNFalpha), suppressed antiapoptotic and antiangiogenic genes (Bcl2,VEGF respectively) and effectively reducing the growth of tumors and even leading to cancer cell death. This process could be attributed to photochemical and/or high-frequency sono-chemical activation mechanism HIFU–SPDT.ConclusionsThe results indicate that CCF–HIONP has great promise as an innovative, effective delivery system for selective localized treatment of lung cancer that is activated by HIFU–SPDT.

A unifying Rayleigh-Plesset-type equation for bubbles in viscoelastic media.

Understanding the ultrasound pressure-driven dynamics of microbubbles confined in viscoelastic materials is relevant for multiple biomedical applications, ranging from contrast-enhanced ultrasound imaging to ultrasound-assisted drug delivery. The volumetric oscillations of spherical bubbles are analyzed using the Rayleigh-Plesset equation, which describes the conservation of mass and momentum in the surrounding medium. Several studies have considered an extension of the Rayleigh-Plesset equation for bubbles embedded into viscoelastic media, but these are restricted to a particular choice of constitutive model and/or to small deformations. Here, we derive a unifying equation applicable to bubbles in viscoelastic media with arbitrary complex moduli and that can account for large bubble deformations. To derive this equation, we borrow concepts from finite-strain theory. We validate our approach by comparing the result of our model to previously published results and extend it to show how microbubbles behave in arbitrary viscoelastic materials. In particular, we use our viscoelastic Rayleigh-Plesset model to compute the bubble dynamics in benchmarked viscoelastic liquids and solids.

Preparation and Optimization of Ibrutinib-Loaded Nanoliposomes Using Response Surface Methodology.

The main aim of this study was to optimize the formulation and process variables for the preparation of ibrutinib nanoliposomes and to evaluate the stability of nanoliposomes. The influence of four formulations and process parameters, namely, the phosphatidylcholine-to-cholesterol ratio (A), conc. of ibrutinib (B), sonication time (C), and stirring time (D) on the drug encapsulation efficiency (Y1) and particle size (Y2) of ibrutinib nanoliposomes were investigated by using response surface methodology. Reverse-phase evaporation was used to prepare ibrutinib nanoliposomes. Twenty-nine trial experiments were performed as per the design and the response parameters were noted. Multiple linear regression analysis was used to assess each response parameter. The effect of each factor on the response parameters was depicted using perturbation, response surface, and contour plots. A numerical optimization technique was used to estimate the optimum process parameters to obtain the desired responses. Ibrutinib nanoliposomes prepared under optimal conditions were evaluated for stability at a different temperature, pH, and sonication time. It is evident from the results that the phosphatidylcholine-to-cholesterol ratio (A) was the major factor influencing the encapsulation efficiency. All the factors were found to have noteworthy influences on particle size. A statistical evaluation provided the information about the individual and interactive effects of independent factors on the response parameters in order to obtain optimum experimental conditions that lead to preparing nanoliposomes with improved characteristics. The optimum level of the independent variables was phosphatidylcholine:cholesterol (6.76:1), ibrutinib concentration (2 mg/mL), sonication time (15.13 min), and stirring time (45 min). At optimal conditions, Y1 and Y2 were found to be 90.76 ± 1.56% and 208.24 ± 3.16 nm, respectively. The ibrutinib nanoliposomes were found to be stable both in simulated gastric and intestinal fluids at 37 °C for 6 h. At elevated conditions of temperature and pH, the prepared nanoliposomes were found to be unstable. Sonication for shorter periods resulted in decreased particle size, whereas longer periods can be helpful for ultrasound-assisted drug delivery. The closeness between the obtained results and predicted results indicates the reliability of the optimization technique for the preparation of ibrutinib nanoliposomes.

Microbubbles Contrast Agents: General Overview as Diagnostics and Therapeutic Agent.

Recent discoveries have unfolded many powerful emerging applications in the field of drug delivery science. For the past few years, ultrasound mediated microbubble contrast agents have been an emerging modality for diagnostic and drug delivery applications. Microbubbles are small spherical bubbles composed of a gas core encapsulated by a shell with different materials. The composition of the microbubble determines its stiffness, encapsulation efficiency, stability, and clearance from the system. A gas-filled microbubble, when activated by an acoustic pulse, can produce large volumetric oscillations and, once administered intravenously, can act as a cavitating nuclei, allowing for a wide range of ultrasound-assisted drug delivery applications. Microbubbles offer a fantastic approach to ultrasound triggered drug delivery with various drug loading techniques and targeting strategies for the uptake of bioactive substances such as polynucleotides, proteins, genes, and small-molecule drugs. Microbubbles can be used for several diagnostic and therapeutic purposes for accurate detection and treatment of various life-threatening diseases.

Layer-by-Layer Assembly of Lipid Nanobubbles on Microneedles for Ultrasound-Assisted Transdermal Drug Delivery.

Microneedles as a typical device for transdermal drug delivery provide an alternative route for drug administration with minimal digestion by organs and better patient compliance. However, diffusion of passively released drug molecules within the skin tissue mainly depends on the interstitial fluid, which may be affected by different physiological conditions of individuals. Herein, we propose a nanobubble-modified microneedle patch for ultrasound-assisted drug delivery, which provides additional driving force for penetration and diffusion of the drug molecules. Layer-by-layer self-assembled drug-containing nanobubbles on the surfaces of microneedles trigger active drug release upon application of ultrasound. The concomitant microstreaming caused by cavitation effects facilitates the penetration and diffusion of drug molecules in the gelatin gel model and the ex vivo porcine skin model. The proposed drug delivery strategy holds great promise for rapid transdermal drug delivery with enhanced penetration and diffusion of the released drugs.

Nano-Enhanced Drug Delivery and Therapeutic Ultrasound for Cancer Treatment and Beyond.

While ultrasound is most widely known for its use in diagnostic imaging, the energy carried by ultrasound waves can be utilized to influence cell function and drug delivery. Consequently, our ability to use ultrasound energy at a given intensity unlocks the opportunity to use the ultrasound for therapeutic applications. Indeed, in the last decade ultrasound-based therapies have emerged with promising treatment modalities for several medical conditions. More recently, ultrasound in combination with nanomedicines, i.e., nanoparticles, has been shown to have substantial potential to enhance the efficacy of many treatments including cancer, Alzheimer disease or osteoarthritis. The concept of ultrasound combined with drug delivery is still in its infancy and more research is needed to unfold the mechanisms and interactions of ultrasound with different nanoparticles types and with various cell types. Here we present the state-of-art in ultrasound and ultrasound-assisted drug delivery with a particular focus on cancer treatments. Notably, this review discusses the application of high intensity focus ultrasound for non-invasive tumor ablation and immunomodulatory effects of ultrasound, as well as the efficacy of nanoparticle-enhanced ultrasound therapies for different medical conditions. Furthermore, this review presents safety considerations related to ultrasound technology and gives recommendations in the context of system design and operation.

Real-time visualization of instantaneous frequency from bubble cavitation using color Doppler ultrasound imaging

Time-resolved observations of acoustic cavitation emission signals are important in understanding bubble cavitation dynamics and monitoring sonoporation efficiencies of ultrasound-assisted drug delivery systems. Previous methods using back propagation of such signals measure frequencies with high time resolutions but require post-processing. We propose a method using color Doppler ultrasound to obtain instantaneous frequencies of these signals from the phase differences with an external reference signal. Standard color Doppler processing is applied to both emissions and reference signals to enable real-time observations of bubble cavitation generated by high-intensity ultrasound wave irradiation. A sinusoidal wave signal was used to confirm the accuracy of our method with an estimation error of 8.59%. Experiments were performed using Sonazoid suspensions of two different concentrations. With a sound pressure of 1.0 MPa for the ultrasound wave, the type of bubble cavitation that is dominant is different before and after irradiation of about ten pulses.

Advances in Ultrasound Mediated Transdermal Drug Delivery.

Low frequency ultrasound-assisted drug delivery has been widely investigated as a non-invasive method to enhance the transdermal penetration of drugs. Using this technique, a brief application of ultrasound is used to permeabilize skin for a prolonged time. In this review, an overview on ultrasound is detailed to help explain the parameters that could be modulated to obtain the desired ultrasound parameters for enhanced transdermal drug delivery. The mechanisms of enhancement and the latest developments in the area of ultrasound-assisted transdermal drug delivery are discussed. Special emphasis is placed on the effects of ultrasound when used in combination with microneedles, electroporation and iontophoresis, and penetration enhancers. Further, this review summarizes the effect of ultrasound on skin integrity and the regulatory requirements for commercialization of the ultrasound based transdermal delivery instruments.

Observing Bubble Cavitation by Back-Propagation of Acoustic Emission Signals.

Temporal- and spatial-resolved observations of microbubble cavitation generated through high-intensity ultrasound irradiation are key in improving both the efficiency and efficacy of ultrasound-assisted drug delivery systems. A method of measuring bubble cavitation applying an image-reconstruction technique of back-propagation of an acoustic cavitation emission (ACE) signal is proposed. A high-intensity focused ultrasound wave (pump wave) irradiates the bubble synchronously using ultrasound recording equipment to acquire the timing of the RF signal, which is produced when the bubble radiates a secondary wave during bubble cavitation. The ACE signal source is reconstructed through ultrasound-wave back-propagation followed by amplitude deconvolution. The proposed method was applied to microbubbles of an ultrasound contrast agent by changing the sound pressure of the pump wave. The method reliability of the temporal resolution was verified by simulating the amplitude-modulated signal of the virtual sound source. The temporal transition of the ACE signal exhibited sub-microsecond-order fluctuations in the signal intensity. From the amplitude signal image and the instantaneous frequency image reconstruction of the proposed method, two different ACE phenomena were visualized. One is the periodic pattern by the beat signals from the harmonic and ultraharmonic component of nonlinear oscillation under low-intensity ultrasound conditions. The other is the nonperiodic temporal and spatial distributions of this irradiation under high-intensity ultrasound conditions.

Passive acoustic mapping of extravasation following ultrasound-enhanced drug delivery

The amount and distribution of chemotherapeutic agents delivered to tumours can vary significantly due to tumour heterogeneity, even under focussed ultrasound (FUS) assisted drug delivery regimes. The ability to non-invasively localise cavitation nuclei of a similar size to therapeutic drugs, both within the vasculature and tumour tissue, may provide a useful marker of ultrasound-enhanced drug delivery and extravasation. Solid polymer based nanoscale cavitation nuclei, under FUS excitation, have previously been shown to extravasate into tissue-mimicking phantoms, and to increase drug delivery in murine tumour models in vivo. Here we show in a tissue-mimicking material that these nuclei, once extravasated under FUS excitation, are still acoustically active and can be non-invasively localised using passive acoustic mapping (PAM). By using a high resolution dual linear array setup in conjunction with adaptive beamformers, we demonstrate that the average ‘maximum distance’ of a PAM pixel to an extravasated particle across experiments is mm. Although the primary objective of the paper is to show that extravascular cavitation can be used as evidence of successful drug extravasation in a tissue-mimicking phantom, we also recognise the physical and computational limitations of using a high resolution dual array setup with adaptive beamformers. Thus as a secondary objective, we evaluate tradeoffs between adaptive and non-adaptive beamformers, as well as between dual and single array geometries. When compared to a conventional beamformer, adaptive beamformers reduce the maximum distance of PAM pixels to extravasated particles from an average of mm to mm in the single array case. The distance is further reduced to mm using the dual array configuration, thereby demonstrating that increasing the solid angle spanned by the PAM array aperture significantly improves drug delivery localisation. Future work will test the applicability of PAM-based monitoring of ultrasound-enhanced drug delivery in vivo.

Electrochemical generation of microbubbles by carbon nanotube interdigital electrodes to increase the permeability and material uptakes of cancer cells

Artificial cavitation as a prerequisite of sonoporation, plays an important role on the ultrasound (US) assisted drug delivery systems. In this study, we have proposed a new method of microbubble (MB) generation by local electrolysis of the medium. An integrated interdigital array of three-electrode system was designed and patterned on a nickel-coated quartz substrate and then, a short DC electrical pulse was applied that consequently resulted in distributed generation of microbubbles at the periphery of the electrodes. Growth of the carbon nanotube (CNT) nanostructures on the surface of the electrodes approximately increased the number of generated microbubbles up to 7-fold and decreased their average size from ∼20 µm for bare to ∼7 µm for CNT electrodes. After optimizing the three-electrode system, biocompatibility assays of the CNT electrodes stimulated by DC electrical micropulses were conducted. Finally, the effect of the proposed method on the sonoporation efficiency and drug uptake of breast cells were assessed using cell cycle and Annexin V/PI flow cytometry analysis. These results show the potential of electrochemical generation of MBs by CNT electrodes as an easy, available and promising technique for artificial cavitation and ultrasound assisted drug delivery.

Micro-cavitation on demand via the nanoparticle mediated interaction of light and sound

The safe utilization of controlled cavitation for HIFU therapy and ultrasound assisted drug delivery requires nucleation sites for bubble formation. We consider the potential for nucleating transient vapor cavities using laser-illuminated gold nanoparticles combined with high-intensity focused ultrasound. An transparent polyacrylamide gel phantom was seeded with 82-nm diameter gold particles and exposed to 20 ns pulses from a 532 nm Nd:Yag laser. Laser firing was synchronized with the arrival of a burst of 1.1 MHz focused ultrasound. Acoustic emissions from ensuing inertial cavitation were detected passively using a 15 MHz focused transducer. At a laser energy of 0.10 mJ/pulse, the resulting inertial cavitation nucleation threshold pressure (peak-negative focal pressure) was as low as 0.92 MPa. In comparison, a peak-negative focal pressure of 4.50 MPa was required to nucleate detectable cavitation without laser illumination (nano-particles were present in both cases). Experimental results agree well with a simple model for transient heating and cavity formation. Since the particles are durable, one can re-activate them as needed, essentially yielding cavitation nuclei “on demand.” [Work supported by the Dept. of the Army (Award No. DAMD17-02-2-0014) and the Center for Subsurface Sensing and Imaging Systems (NSF ERC Award No. EEC-9986821).]

Microvessels-on-a-Chip to Assess Targeted Ultrasound-Assisted Drug Delivery.

Microbubbles have been used in ultrasound-assisted drug delivery to help target solid tumors via blood vessels in vivo; however, studies to understand the phenomena at the cellular level and to optimize parameters for ultrasound or microbubbles in vivo are challenging and expensive to perform. Here, we utilize microfluidic microvessels-on-a-chip that enable visualization of microbubble/ultrasound-dependent drug delivery to microvasculature. When exposed to pulsed ultrasound, microbubbles perfused through microvessels-on-a-chip were observed to stably oscillate. Minimal cellular damage was observed for both microbubbles and untargeted doxorubicin-encapsulating liposomes (DOX-liposomes) perfused through chip microvessels. In contrast, passive and ultrasound-assisted perfusion of integrin-targeted DOX-liposomes induced cytotoxicity, which was only significantly enhanced for ultrasound-assisted perfusion when microbubbles were coperfused. These results suggest that stably oscillating microbubbles enhance targeted DOX-liposome internalization/cytotoxicity largely by stimulating integrin receptor endocytosis. Furthermore, our study demonstrates the utility of our microvessels-on-a-chip as a screening platform for optimizing drug dosage, targeting ligands and drugs.

Experimental verification of theoretical equations for acoustic radiation force on compressible spherical particles in traveling waves

Acoustophoresis uses acoustic radiation force to remotely manipulate particles suspended in a host fluid for many scientific, technological, and medical applications, such as acoustic levitation, acoustic coagulation, contrast ultrasound imaging, ultrasound-assisted drug delivery, etc. To estimate the magnitude of acoustic radiation forces, equations derived for an inviscid host fluid are commonly used. However, there are theoretical predictions that, in the case of a traveling wave, viscous effects can dramatically change the magnitude of acoustic radiation forces, which make the equations obtained for an inviscid host fluid invalid for proper estimation of acoustic radiation forces. To date, experimental verification of these predictions has not been published. Experimental measurements of viscous effects on acoustic radiation forces in a traveling wave were conducted using a confocal optical and acoustic system and values were compared with available theories. Our results show that, even in a low-viscosity fluid such as water, the magnitude of acoustic radiation forces is increased manyfold by viscous effects in comparison with what follows from the equations derived for an inviscid fluid.

Multi-functional biomedical ultrasound: Imaging, manipulation, neuromodulation and therapy

As a safe, low-cost, portable and fast imaging modality, ultrasound has been widely used in various clinical fields. Ultrasound imaging is used in every branch of medicine and can be used to visualize almost every organ. Recently, numerous new ultrasound technologies, such as microbubble-based nonlinear contrast imaging, ultrasound molecular imaging, ultrasound-assisted targeted drug delivery, ultrasonic neuro-modulation and theranostics-based integrative application, have been developed for early-stage diagnosis and treatment, based on the multi-disciplinary developments in physics, engineering, and biomedicine. The nature of biomedical ultrasound technology is also changing, from being an imaging technology into a multi-functional tool that allows both precise diagnosis and treatment. This review offers a critical analysis of the state-of-the-art biomedical ultrasound technology and its application in clinical diagnosis and drug delivery. In this paper, we first introduce some basic physical characteristics of biomedical ultrasound technology, including its wave and mechanical properties, the history of the development of ultrasound contrast agent microbubbles, and the biomedical effects of ultrasound, such as cavitation and heat deposition. Then, we review the recent progress and our research on the preparation and acoustic characterization of microbubbles, nonlinear ultrasound contrast imaging and ultrasound molecular imaging, and ultrasound-assisted drug delivery and treatment based on the large surface of a drug-loaded microbubble and on the surface modification-enabled elastic shell. In addition, we discuss the integrative applications of ultrasound diagnostics and therapeutics in clinical medicine. Moreover, we review the advances in ultrasound-based deep brain stimulation, which indicates that ultrasound technology might be used as a potential noninvasive tool in neuroscience and in the treatment of brain disorders. Finally, we review the challenges associated with the development of biomedical ultrasound technology, which include acoustic power thresholds in drug delivery and deep brain stimulation for the safety and precision control of acoustic fields in inhomogeneous media. In conclusion, besides assessing the conventional tissue anatomy and hemodynamics, we argue that biomedical ultrasound techniques can provide information on tissue elasticity, metabolic function, distribution of temperature, and even biochemical processes. Owing to its advantages such as acoustic radiation force, the use of ultrasound might open a new era in neuro-modulation in the neurosciences, in addition to its traditional areas of use such as imaging and thermal therapy.

Enhanced Therapeutic Anti-Inflammatory Effect of Betamethasone on Topical Administration with Low-Frequency, Low-Intensity (20 kHz, 100 mW/cm2) Ultrasound Exposure on Carrageenan-Induced Arthritis in a Mouse Model

The purpose of this work was to investigate whether low-frequency, low-intensity (20 kHz, <100 mW/cm2, spatial-peak, temporal-peak intensity) ultrasound, delivered with a lightweight (<100 g), tether-free, fully wearable, battery-powered applicator, is capable of reducing inflammation in a mouse model of rheumatoid arthritis. The therapeutic, acute, anti-inflammatory effect was estimated from the relative swelling induced in mice hindlimb paws. In an independent, indirect approach, the inflammation was bio-imaged by measuring glycolytic activity with near-infrared labeled 2-deoxyglucose. The outcome of the experiments indicated that the combination of ultrasound exposure and topical application of 0.1% (w/w) betamethasone gel resulted in statistically significantly (p < 0.05) enhanced anti-inflammatory activity in comparison with drug or ultrasound treatment alone. The present study underscores the potential benefits of low-frequency, low-intensity ultrasound-assisted drug delivery. However, the proof of concept presented indicates the need for additional experiments to systematically evaluate and optimize the potential of, and the conditions for, tolerable low-frequency, low-intensity ultrasound-promoted non-invasive drug delivery.

Ultra-fast bright field and fluorescence imaging of the dynamics of micrometer-sized objects.

High speed imaging has application in a wide area of industry and scientific research. In medical research, high speed imaging has the potential to reveal insight into mechanisms of action of various therapeutic interventions. Examples include ultrasound assisted thrombolysis, drug delivery, and gene therapy. Visual observation of the ultrasound, microbubble, and biological cell interaction may help the understanding of the dynamic behavior of microbubbles and may eventually lead to better design of such delivery systems. We present the development of a high speed bright field and fluorescence imaging system that incorporates external mechanical waves such as ultrasound. Through collaborative design and contract manufacturing, a high speed imaging system has been successfully developed at the University of Pittsburgh Medical Center. We named the system "UPMC Cam," to refer to the integrated imaging system that includes the multi-frame camera and its unique software control, the customized modular microscope, the customized laser delivery system, its auxiliary ultrasound generator, and the combined ultrasound and optical imaging chamber for in vitro and in vivo observations. This system is capable of imaging microscopic bright field and fluorescence movies at 25 × 10(6) frames per second for 128 frames, with a frame size of 920 × 616 pixels. Example images of microbubble under ultrasound are shown to demonstrate the potential application of the system.

Dynamic time reversal acoustic focusing of ultrasound for biomedical applications

Time Reversal Acoustic (TRA) system provides effective focusing in inhomogeneous media that can be used in various biomedical applications including high intensity ultrasound treatment, ultrasound-assisted drug delivery, ultrasonic battery charging of implants, etc. In many cases, the TRA focusing is conducted in tissues with time varied properties and variation in propagating media degrades the TRA focused signal. Dynamic focusing is required to maintain the same acoustic intensity in the focus. We suggest adjustment to the radiated signal in order to maintain the maximal amplitude in the focus using the inverse filtering technique with Tikhonov regularization. The suggested algorithm enables to determine the radiated signal based on the changes in the focused signal received by a beacon. Developed algorithm of TRA refocusing was tested in the experiments with a TRA system with an aluminum reverberator comprising ten piezotransducers with resonance around 1 MHz, DAC control system and a multi-channel binary amplifier. This system was built in Artann Laboratories for investigation of time reversal acoustic focusing for hyperthermia therapy and drug delivery. The dynamic TRA refocusing is shown to be effective even in the case of significant lateral shifts in the media and strong focused signal variation.

Modeling non-spherical oscillations and stability of acoustically driven shelled microbubbles

The oscillation and destruction of microbubbles under ultrasound excitation form the basis of contrast enhanced ultrasound imaging and microbubble assisted drug and gene delivery. A typical microbubble has a size of a few micrometers and consists of a gas core encapsulated by a shell. These bubbles can be driven into surface mode oscillations, which not only contribute to the measured acoustic signal but can lead to bubble destruction. Existing models of surface model oscillations have not considered the effects of a bubble shell. In this study a model was developed to study the surface mode oscillations in shelled bubbles. The effects of shell viscosity and elasticity on the surface mode oscillations were modeled using a Boussinesq-Scriven approach. Simulation was conducted using the model with various bubble sizes and driving acoustic pressures. The occurrence of surface modes and the number of ultrasound cycles needed for the occurrence were calculated. The simulation results show a significant difference between shelled bubbles and shell free bubbles. The shelled bubbles have reduced surface mode amplitudes and a narrower bubble size range within which these modes develop compared to shell free bubbles. The clinical implications were also discussed.

Novel contrast-enhanced ultrasound imaging in prostate cancer

PurposeThe purposes of this paper were to present the current status of contrast-enhanced transrectal ultrasound imaging and to discuss the latest achievements and techniques now under preclinical testing.ObjectiveAlthough grayscale transrectal ultrasound is the standard method for prostate imaging, it lacks accuracy in the detection and localization of prostate cancer. With the introduction of contrast-enhanced ultrasound (CEUS), perfusion imaging of the microvascularization became available. By this, cancer-induced neovascularisation can be visualized with the potential to improve ultrasound imaging for prostate cancer detection and localization significantly. For example, several studies have shown that CEUS-guided biopsies have the same or higher PCa detection rate compared with systematic biopsies with less biopsies needed.Materials and methodsThis paper describes the current status of CEUS and discusses novel quantification techniques that can improve the accuracy even further. Furthermore, quantification might decrease the user-dependency, opening the door to use in the routine clinical environment. A new generation of targeted microbubbles is now under pre-clinical testing and showed avidly binding to VEGFR-2, a receptor up-regulated in prostate cancer due to angiogenesis. The first publications regarding a targeted microbubble ready for human use will be discussed.ConclusionUltrasound-assisted drug delivery gives rise to a whole new set of therapeutic options, also for prostate cancer. A major breakthrough in the future can be expected from the clinical use of targeted microbubbles for drug delivery for prostate cancer diagnosis as well as treatment.