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Ultrasound induced microbubble cavitation can cause enhanced permeability across natural barriers of tumors such as vessel walls or cellular membranes, allowing for enhanced therapeutic delivery into the target tissues. While enhanced delivery of small (100 nm) therapeutic carriers into cancer remains unclear and may require a higher pressure for sufficient delivery. Enhanced delivery of larger therapeutic carriers such as FDA approved pegylated poly(lactic-co-glycolic acid) nanoparticles (PLGA-PEG-NP) has significant clinical value because these nanoparticles have been shown to protect encapsulated drugs from degradation in the blood circulation and allow for slow and prolonged release of encapsulated drugs at the target location. In this study, various acoustic parameters were investigated to facilitate the successful delivery of two nanocarriers, a fluorescent semiconducting polymer model drug nanoparticle as well as PLGA-PEG-NP into human colon cancer xenografts in mice. We first measured the cavitation dose produced by various acoustic parameters (pressure, pulse length, and pulse repetition frequency) and microbubble concentration in a tissue mimicking phantom. Next, in vivo studies were performed to evaluate the penetration depth of nanocarriers using various acoustic pressures, ranging between 1.7 and 6.9 MPa. Finally, a therapeutic microRNA, miR-122, was loaded into PLGA-PEG-NP and the amount of delivered miR-122 was assessed using quantitative RT-PCR. Our results show that acoustic pressures had the strongest effect on cavitation. An increase of the pressure from 0.8 to 6.9 MPa resulted in a nearly 50-fold increase in cavitation in phantom experiments. In vivo, as the pressures increased from 1.7 to 6.9 MPa, the amount of nanoparticles deposited in cancer xenografts was increased from 4- to 14-fold, and the median penetration depth of extravasated nanoparticles was increased from 1.3-fold to 3-fold, compared to control conditions without ultrasound, as examined on 3D confocal microscopy. When delivering miR-122 loaded PLGA-PEG-NP using optimal acoustic settings with minimum tissue damage, miR-122 delivery into tumors with ultrasound and microbubbles was 7.9-fold higher compared to treatment without ultrasound. This study demonstrates that ultrasound induced microbubble cavitation can be a useful tool for delivery of therapeutic miR loaded nanocarriers into cancer in vivo.

We developed a fully-populated 2-D capacitive micromachined ultrasonic transducer (CMUT) array for high intensity focused ultrasound (HIFU) treatment. The 2-D CMUT array, which consists of 20 × 20 square CMUT elements with an element-to-element pitch of 1 mm, was designed and fabricated using the thick-buried-oxide (BOX) fabrication process. It was then assembled on a custom interface board that can provide various array configurations depending on the desired applications. In this study, the interface board groups the CMUT array elements into eight channels, based on the phase delay from the element to the targeted focal point at a 20-mm distance from the array surface, which corresponds to an F-number of 1. An 8-channel phase generating system supplies continuous waves with eight different phases to the eight channels of the CMUT array through bias-tees and amplifiers. This array aperture, grouped into eight channels, gives a focusing gain of 6.09 according to field simulation using Field II. Assuming a...

High-intensity focused ultrasound (HIFU) has been used as noninvasive treatment for various diseases. For these therapeutic applications, capacitive micromachined ultrasonic transducers (CMUTs) have advantages that make them potentially preferred transducers over traditional piezoelectric transducers. In this paper, we present the design and the fabrication process of an $8 \times 8$ -mm $^{2}~32 \times 32$ -element 2-D CMUT array for HIFU applications. To reduce the system complexity for addressing the 1024 transducer elements, we propose to group the CMUT array elements into eight HIFU channels based on the phase delay from the CMUT element to the targeted focal point. Designed to focus at an 8-mm depth with a 5-MHz exciting frequency, this grouping scheme was realized using a custom application-specific integrated circuit. With a 40-V dc bias and a 60-V peak-to-peak ac excitation, the surface pressure was measured 1.2 MPa peak-to-peak and stayed stable for a long enough time to create a lesion. With this dc and ac voltage combination, the measured peak-to-peak output pressure at the focus was 8.5 MPa, which is expected to generate a lesion in a minute according to the temperature simulation. The following ex vivo tissue experiments successfully demonstrated its capability to make lesions in both bovine muscle and liver tissue.

Synthetic phased array (SPA) beamforming with Hadamard coding and aperture weighting is an optimal option for real-time volumetric imaging with a ring array, a particularly attractive geometry in intracardiac and intravascular applications. However, the imaging frame rate of this method is limited by the immense computational load required in synthetic beamforming. For fast imaging with a ring array, we developed graphics processing unit (GPU)-based, real-time image reconstruction software that exploits massive data-level parallelism in beamforming operations. The GPU-based software reconstructs and displays three cross-sectional images at 45 frames per second (fps). This frame rate is 4.5 times higher than that for our previously-developed multi-core CPU-based software. In an alternative imaging mode, it shows one B-mode image rotating about the axis and its maximum intensity projection, processed at a rate of 104 fps . This paper describes the image reconstruction procedure on the GPU platform and presents the experimental images obtained using this software.

Treatment options for patients with hepatocellular carcinoma (HCC) are limited, in particular in advanced and drug resistant HCC. MicroRNAs (miRNA) are non-coding small RNAs that are emerging as novel drugs for the treatment of cancer. The aim of this study was to assess treatment effects of two complementary miRNAs (sense miRNA-122, and antisense antimiR-21) encapsulated in biodegradable poly (lactic-co-glycolic acid) nanoparticles (PLGA-NP), administered by an ultrasound-guided and microbubble-enhanced delivery approach in doxorubicin-resistant and non-resistant human HCC xenografts. Proliferation and invasiveness of human HCC cells after miRNA-122/antimiR-21 and doxorubicin treatment were assessed in vitro. Confocal microscopy and qRT-PCR were used to visualize and quantitate successful intracellular miRNA-loaded PLGA-NP delivery. Up and down-regulation of miRNA downstream targets and multidrug resistance proteins and extent of apoptosis were assessed in vivo in treated human HCC xenografts in mice. Compared to single miRNA therapy, combination therapy with the two complementary miRNAs resulted in significantly (P < 0.05) stronger decrease in cell proliferation, invasion, and migration of HCC cells as well as higher resensitization to doxorubicin. Ultrasound-guided delivery significantly increased in vivo miRNA-loaded PLGA-NP delivery in human HCC xenografts compared to control conditions by 5–9 fold (P < 0.001). miRNA-loaded PLGA-NP were internalized in HCC cells and anti-apoptotic proteins were down regulated with apoptosis in ~27% of the tumor volume of doxorubicin-resistant human HCC after a single treatment with complementary miRNAs and doxorubicin. Thus, ultrasound-guided delivery of complementary miRNAs is highly efficient in the treatment of doxorubicin- resistant and non-resistant HCC. Further development of this new treatment approach could aid in better treatment of patients with HCC.

A ring array provides a very suitable geometry for forward-looking volumetric intracardiac and intravascular ultrasound imaging. We fabricated an annular 64-element capacitive micromachined ultrasonic transducer (CMUT) array featuring a 10-MHz operating frequency and a 1.27-mm outer radius. A custom software suite was developed to run on a PC-based imaging system for real-time imaging using this device. This paper presents simulated and experimental imaging results for the described CMUT ring array. Three different imaging methods--flash, classic phased array (CPA), and synthetic phased array (SPA)--were used in the study. For SPA imaging, two techniques to improve the image quality--Hadamard coding and aperture weighting--were also applied. The results show that SPA with Hadamard coding and aperture weighting is a good option for ring-array imaging. Compared with CPA, it achieves better image resolution and comparable signal-to-noise ratio at a much faster image acquisition rate. Using this method, a fast frame rate of up to 463 volumes per second is achievable if limited only by the ultrasound time of flight; with the described system we reconstructed three cross-sectional images in real-time at 10 frames per second, which was limited by the computation time in synthetic beamforming.

In 3-D ultrasound imaging where 2-D transducer arrays with more than hundreds of elements are used, sparse arrays can be used to reduce the number of active ultrasound channels. Under a restriction of desired number of active channels, we can maximize the image quality by optimally choosing the positions of active elements. Here we use the method of simulated annealing to find the optimal configuration of a 2-D sparse array. This algorithm tries to minimize the value of an objective function defined as the energy ratio between the non-focal and focal regions in the point spread function (PSF). Optimal configurations were found for the cases of choosing 16, 20, 24, 28, and 32 transmit and receive elements from a 16×16-element rectangular transducer array. With only 32 transmit and 32 receive elements, we could achieve an energy ratio of 16%, compared to 6% of the full array, which is the gold standard utilizing all the 256 elements for both transmit and receive. Using Field II, we simulated imaging with the optimal sparse arrays, for off-axis targets as well as on-axis targets, and the resulting images were compared with those from some other configurations, such as full-transmit full-receive, full-transmit x-receive, x-transmit boundary-receive, and so on.

Capacitive micromachined ultrasonic transducer (CMUT) arrays are conveniently integrated with frontend integrated circuits either monolithically or in a hybrid multichip form. This integration helps with reducing the number of active data processing channels for 2D arrays. This approach also preserves the signal integrity for arrays with small elements. Therefore CMUT arrays integrated with electronic circuits are most suitable to implement miniaturized probes required for many intravascular, intracardiac, and endoscopic applications. This paper presents examples of miniaturized CMUT probes utilizing 1D, 2D, and ring arrays with integrated electronics.