High Frequency Ultrasound Imaging System Research Articles

Murine cardiac fibrosis localization using adaptive Bayesian cardiac strain imaging in vivo

An adaptive Bayesian regularized cardiac strain imaging (ABR-CSI) algorithm for in vivo murine myocardial function assessment is presented. We report on 31 BALB/CJ mice (n = 17 females, n = 14 males), randomly stratified into three surgical groups: myocardial infarction (MI, n = 10), ischemia–reperfusion (IR, n = 13) and control (sham, n = 8) imaged pre-surgery (baseline- BL), and 1, 2, 7 and 14 days post-surgery using a high frequency ultrasound imaging system (Vevo 2100). End-systole (ES) radial and longitudinal strain images were used to generate cardiac fibrosis maps using binary thresholding. Percentage fibrotic myocardium (PFM) computed from regional fibrosis maps demonstrated statistically significant differences post-surgery in scar regions. For example, the MI group had significantly higher PFMRadial (%) values in the anterior mid region (p = 0.006) at Day 14 (n = 8, 42.30 ± 14.57) compared to BL (n = 12, 1.32 ± 0.85). A random forest classifier automatically detected fibrotic regions from ground truth Masson’s trichrome stained histopathology whole slide images. Both PFMRadial (r = 0.70) and PFMLongitudinal (r = 0.60) results demonstrated strong, positive correlation with PFMHistopathology (p < 0.001).

Abstract LBA051: Importance of drug osmotic pressure and viscosity for efficient drug delivery using lymphatic drug delivery system

Abstract Metastasis is known to be the prime cause of cancer associated fatality. It is therefore imperative to treat and prevent metastasis in order to curb cancer-associated morbidity and mortality. Metastatic lymph nodes (MLNs) are known to be crucial diagnostic and prognostic indicators. Furthermore, as per the lymph node mediated hematogenous theory, due to extant communication between the lymphatic network and the venous system, the lymphatic network facilitates the passage and subsequent colonization of tumor cells to distant sites, thus, serving as a starting point for distant metastasis even during the initial stages. Treatment of MLNs, therefore, is imperative. Proposed in 2015, the Lymphatic Drug Delivery System (LDDS) is a novel and promising drug delivery system for the treatment of MLNs that overcomes the limitations of conventional chemotherapy. Unlike systemic chemotherapy, LDDS entails a direct intranodal drug administration to sentinel lymph node, post its identification using radioisotopes and fluorescent molecules, in order to treat it and its downstream lymph nodes. Previous studies have documented the superior efficacy of LDDS as a MLN management strategy as compared to conventional therapy. Higher drug delivery to target sites and prolonged retention with lower systemic toxicity, and thereby stronger anti-tumor effect have been reported to have been achieved upon drug administration via LDDS. In the present study, MXH10/Mo/lpr mice and FM3A-Luc, mouse mammary carcinoma cells expressing the firefly luciferase gene, have been utilized for the establishment of a mouse model of Lymph node metastasis (LNM) to investigate the effect of drug osmotic pressure and viscosity on therapeutic efficacy of the LDDS. Two lymph nodes, exhibiting systemic lymphadenopathy, in the subiliac and axillary region, the subiliac lymph node (SiLN) and proper axillary lymph node (PALN) have been used to model a network of interconnected human lymph nodes. Drug solution of varying osmotic pressure and viscosity were administered via LDDS to the murine model of LNM and subsequently therapeutic efficacy was monitored using the high frequency ultrasound system, VEVO and bioluminescent imaging system, IVIS, and confirmed through histology. The study revealed an optimized window of drug osmotic pressure and viscosity (π = 1000 - 2000 kPa; µ = 0.9 - 11.5 mPa·s.) where a significantly stronger anti-tumor response was observed. Venturing below or beyond the optimized range results in decreased therapeutic efficacy. The study therefore concluded that drug osmotic pressure and viscosity are important fluid parameters that require careful consideration prior to preparation of drug cocktails as they can severely impact the prognosis. The findings of this study have the potential for translation to clinics and we anticipate that these results can be replicated in clinical trials, positively altering the fate of many cancer patients. Citation Format: Radhika Mishra, Ariunbuyan Sukhbaatar, Sora Shouta, Maya Sakamoto, Shiro Mori, Tetsuya Kodama. Importance of drug osmotic pressure and viscosity for efficient drug delivery using lymphatic drug delivery system [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA051.

Synthetic Aperture Imaging Using High-Frequency Convex Array for Ophthalmic Ultrasound Applications.

High-frequency ultrasound (HFUS) imaging has emerged as an essential tool for pre-clinical studies and clinical applications such as ophthalmic and dermatologic imaging. HFUS imaging systems based on array transducers capable of dynamic receive focusing have considerably improved the image quality in terms of spatial resolution and signal-to-noise ratio (SNR) compared to those by the single-element transducer-based one. However, the array system still suffers from low spatial resolution and SNR in out-of-focus regions, resulting in a blurred image and a limited penetration depth. In this paper, we present synthetic aperture imaging with a virtual source (SA-VS) for an ophthalmic application using a high-frequency convex array transducer. The performances of the SA-VS were evaluated with phantom and ex vivo experiments in comparison with the conventional dynamic receive focusing method. Pre-beamformed radio-frequency (RF) data from phantoms and excised bovine eye were acquired using a custom-built 64-channel imaging system. In the phantom experiments, the SA-VS method showed improved lateral resolution (>10%) and sidelobe level (>4.4 dB) compared to those by the conventional method. The SNR was also improved, resulting in an increased penetration depth: 16 mm and 23 mm for the conventional and SA-VS methods, respectively. Ex vivo images with the SA-VS showed improved image quality at the entire depth and visualized structures that were obscured by noise in conventional imaging.

High-Resolution All-Digital Transmit Beamformer for High-Frequency and Wearable Ultrasound Imaging Systems

In this article, we present a high delay resolution and all-digital transmit-beamforming circuit for use in high-frequency and wearable ultrasound imaging systems. The proposed transmit beamformer comprises an all-digital delay-locked loop (ADDLL), a cycle-based beamforming delay line (CBDL), and a pulse controller. ADDLL can provide specific digital control code for the CBDL to generate stable and suitable delays to excite array transducer elements without variations in process, voltage, and temperature. CBDL not only provides a finer delay resolution for high-frequency ultrasound imaging systems but also requires a few delay cells to maintain the duty cycle of long prorogation signals, thereby significantly reducing hardware costs. The pulse controller can adjust the number and width of output pulses to meet the requirements of different ultrasonic transducers and Doppler ultrasound color imaging. The proposed transmit beamformer uses a 0.18- $\mu \text{m}$ CMOS technology for a 30-MHz high-frequency linear array with 256 elements, and the focusing depth is from 3.5 to 8.1 mm. The measurement results indicate that the proposed transmit-beamforming design can achieve a maximum time delay of 562.6 ns with an average time resolution of 535 ps. The proposed design offers a smaller volume and finer delay resolution, and it is highly suitable for wearable ultrasound imaging systems.

Investigation of early effects of combination of mild aerobic exercise and angiotensin‐II type‐I receptor blocker losartan on aortic function in a mouse model of Marfan Syndrome.

Marfan syndrome (MFS) is a connective tissue disorder that causes complications throughout the body. However, the cardiovascular effects of MFS, specifically aortic aneurysms, are the leading cause of morbidity and mortality in patients. Both the transforming growth factor beta (TGF‐β) and angiotensin II type I receptor (AT1R) signaling pathways are known to contribute to the progression of MFS aneurysms. Recently, our laboratory reported that low‐intensity mild exercise could improve aortic function and structure in the mouse model of MFS. Losartan, an AT1R blocker, has been shown to slow down the progression of MFS aneurysms in both the mouse model and human patients. In this study, we have explored the potential of a combinational therapy of exercise and losartan in a well‐established mouse model of MFS associated aortic aneurysm in order to determine if there are additive protective and delaying effects on the progression of aortic aneurysm in the mouse model. Treatment consisted of 0.6 g/L (full dose) or 0.3 g/L (half dose) of losartan in drinking water combined with a 55% VO2 max exercise regimen (8 m/min, 30 min/day, 5 days/week). Mice were divided into experimental groups: control, MFS, MFS + exercise, MFS + 0.6 g/L losartan, MFS + 0.3 g/L losartan, MFS + exercise + 0.6 g/L losartan, and MFS + exercise + 0.3 g/L losartan. The biophysical properties of the aorta, such as the aortic diameter and pulse wave velocity (PWV), were determined by high resolution high frequency ultrasound imaging system (Vevo2100, FUJIFILM VisualSonics) in 3‐month‐old MFS and control mice. Aortic diameter measurements of the sinus of Valsalva were significantly higher in 3‐month‐old MFS mice as compared to control. However, losartan treatment, mild exercise, or combination of both had no effects on aortic root growth in MFS mice. In addition, measurements of the aortic annulus and sinotubular junction were not significantly different among experimental groups. MFS mice exhibited higher PWV as compared to control mice, indicating increased stiffness of aortic wall in these mice. Combination of mild aerobic exercise with full and half dose of losartan seems to have some effects on the aortic wall by decreasing the aortic diameter, although no statistical significant differences were observed among the treated and non‐treated groups. This study presents the effects of combination of mild exercise and losartan during the early stage of aneurysm progression in MFS mice. With the continuation of the longitudinal study at 6 and 9 months of age and as the aneurysm progresses, we will be able to continue our evaluation of aortic and cardiac function and structure in MFS mice subjected to exercise only, losartan only, or the combinational therapy. This study provides additional information on the most effective therapeutic approach to delay the progression of aneurysm in MFS.Support or Funding InformationThis study is supported by funding from The Marfan Foundation.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Temperature dependence of acoustic harmonics generated by nonlinear ultrasound beam propagation in ex vivo tissue and tissue-mimicking phantoms

Purpose: Hyperthermia is a cancer treatment technique that could be delivered as a stand-alone modality or in conjunction with chemotherapy or radiation therapy. Noninvasive and real-time temperature monitoring of the heated tissue improves the efficacy and safety of the treatment. A temperature-sensitive acoustic parameter is required for ultrasound-based thermometry. In this paper the amplitude and the energy of the acoustic harmonics of the ultrasound backscattered signal are proposed as suitable parameters for noninvasive ultrasound thermometry.Materials and methods: A commercial high frequency ultrasound imaging system was used to generate and detect acoustic harmonics in tissue-mimicking gel phantoms and ex vivo bovine muscle tissues. The pressure amplitude and the energy content of the backscattered fundamental frequency (p1 and E1), the second (p2 and E2) and the third (p3 and E3) harmonics were detected in pulse-echo mode. Temperature was increased from 26° to 46 °C uniformly through both samples. The amplitude and the energy content of the harmonics and their ratio were measured and analysed as a function of temperature.Results: The average p1, p2 and p3 increased by 69%, 100% and 283%, respectively as the temperature was elevated from 26° to 46 °C in tissue samples. In the same experiment the average E1, E2 and E3 increased by 163%, 281% and 2257%, respectively. A similar trend was observed in tissue-mimicking gel phantoms.Conclusions: The findings suggest that the harmonics generated due to nonlinear ultrasound beam propagation are highly sensitive to temperature and could potentially be used for noninvasive ultrasound tissue thermometry.

Maternal Anti-Platelet β3 Integrin Antibodies Impair Angiogenesis and Cause Intracranial Hemorrhage in Fetal and Neonatal Alloimmune Thrombocytopenia

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a life-threatening disease in which intracranial hemorrhage (ICH) is the major risk. Although thrombocytopenia caused by maternal antibodies against β3 integrin and occasionally against other platelet antigens (e.g. GPIbα) has long been assumed to be the cause of bleeding, the mechanism of ICH has never been adequately explored. Utilizing murine models of FNAIT and a high frequency ultrasound imaging system, we found that ICH only occurred in fetuses and neonates with anti-β3 integrin- but not anti-GPIbα-mediated FNAIT, despite similar thrombocytopenia in both groups. Only anti-β3 integrin-mediated FNAIT reduced brain and retina vessel density, impaired angiogenic signalling, and increased endothelial cell apoptosis; which were abrogated by maternal administration of intravenous immunoglobulin (IVIG). ICH and impairment of retinal angiogenesis was further reproduced in neonates by injection of anti-β3 integrin- but not anti-GPIbα-antisera. Utilizing cultured human endothelial cells, we found that cell proliferation, network formation, and Akt phosphorylation were inhibited only by murine anti-β3 integrin-antisera and human anti-HPA-1a IgG purified from mothers with FNAIT children. Our data suggest fetal hemostasis is unique in that impairment of angiogenesis rather than thrombocytopenia is likely the cause of ICH; importantly maternal IVIG therapy can effectively prevent this devastating disorder. DisclosuresNo relevant conflicts of interest to declare.

Development of 15 MHz 2-2 piezo-composite ultrasound linear array transducers for ophthalmic imaging

High frequency (>15MHz) ultrasound imaging is capable of producing high spatial resolution B-mode and color Doppler images for the efficient diagnosis of ocular diseases. However, commercial high frequency ultrasound imaging systems cannot currently provide its full capability for ophthalmic applications because either single element or annular array transducers are used in conjunction with mechanical scanning. To overcome the current limitations, 15MHz 128-element linear array transducers were developed, which are suitable to cover the whole eye from the eyelid in anterior segment to orbital fundus in posterior segment. To achieve the highest electromechanical coupling coefficient, 2-2 piezo-composite was designed and fabricated as an active layer. For the design, the simple model of the thickness-mode oscillation was derived and used in the 1-D model simulator such as PiezoCAD. Also, the usability of the simple model was verified by comparing its simulation results with those by finite element model-based PZFlex. In addition, easy fabrication procedure for the high frequency 2-2 piezo-composite arrays was proposed. In performance evaluation, the pulse-echo response of a representative composite element showed the center frequency of 14.4MHz and the −6dB fractional bandwidth of 69.4%. Measured insertion loss was achieved higher than −33.9dB and crosstalk level between elements less than −30dB. From the evaluation results, it is expected that the linear array transducer developed using the proposed design and fabrication methods can provide a potential alternative for high frequency ophthalmic imaging with the desired capability.

Bipolar-power-transistor-based limiter for high frequency ultrasound imaging systems

High performance limiters are described in this paper for applications in high frequency ultrasound imaging systems. Limiters protect the ultrasound receiver from the high voltage (HV) spikes produced by the transmitter. We present a new bipolar power transistor (BPT) configuration and compare its design and performance to a diode limiter used in traditional ultrasound research and one commercially available limiter. Limiter performance depends greatly on the insertion loss (IL), total harmonic distortion (THD) and response time (RT), each of which will be evaluated in all the limiters. The results indicated that, compared with commercial limiter, BPT-based limiter had less IL (−7.7dB), THD (−74.6dB) and lower RT (43ns) at 100MHz. To evaluate the capability of these limiters, they were connected to a 100MHz single element transducer and a two-way pulse-echo test was performed. It was found that the −6dB bandwidth and sensitivity of the transducer using BPT-based limiter were better than those of the commercial limiter by 22% and 140%, respectively. Compared to the commercial limiter, BPT-based limiter is shown to be capable of minimizing signal attenuation, RT and THD at high frequencies and is thus suited for high frequency ultrasound applications.

Novel power MOSFET-based expander for high frequency ultrasound systems

The function of an expander is to obstruct the noise signal transmitted by the pulser so that it does not pass into the transducer or receive electronics, where it can produce undesirable ring-down in an ultrasound imaging application. The most common type is a diode-based expander, which is essentially a simple diode-pair, is widely used in pulse-echo measurements and imaging applications because of its simple architecture. However, diode-based expanders may degrade the performance of ultrasonic transducers and electronic components on the receiving and transmitting sides of the ultrasound systems, respectively. Since they are non-linear devices, they cause excessive signal attenuation and noise at higher frequencies and voltages. In this paper, a new type of expander that utilizes power MOSFET components, which we call a power MOSFET-based expander, is introduced and evaluated for use in high frequency ultrasound imaging systems. The performance of a power MOSFET-based expander was evaluated relative to a diode-based expander by comparing the noise figure (NF), insertion loss (IL), total harmonic distortion (THD), response time (RT), electrical impedance (EI) and dynamic power consumption (DPC). The results showed that the power MOSFET-based expander provided better NF (0.76dB), IL (−0.3dB) and THD (−62.9dB), and faster RT (82ns) than did the diode-based expander (NF (2.6dB), IL (−1.4dB), THD (−56.0dB) and RT (119ns)) at 70MHz. The −6dB bandwidth and the peak-to-peak voltage of the echo signal received by the transducer using the power MOSFET-based expander improved by 17.4% and 240% compared to the diode-based expander, respectively. The new power MOSFET-based expander was shown to yield lower NF, IL and THD, faster RT and lower ring down than the diode-based expander at the expense of higher dynamic power consumption.

Development of a Bipolar Pulse Generator for High-Frequency Ultrasound Imaging System

The pulse generator is the critical component in high-frequency ultrasound imaging systems. Currently, there still exist some shortcomings about commercial ultrasound image systems and devices such as 5900 PR …etc.. However, to achieve a higher sensitivity and high performance, a programmable pulser generator is desired to match the requirements of high frequency ultrasound image system. In this study, we utilized a novel bipolar pulse generator method to overcome those issues in developed high resolution image system. As the needs of application in clinic, a real –time of high-frequency ultrasound imaging systems, including pulse generator, high speed scanning mechanism, high voltage protection and FPGA trigger control circuit, was developed in our Laboratory. This paper will focus to compare the performance of the bipolar generator and unipolar generator as used in pulse generator device respectively. Finally, the developed bipolar pulse generator show the better performance than the unipolar generator does. The bipolar system can generate clean N-cycle bipolar pulses and improve the center frequency of transducer up to 60 MHz. The axial resolution of scan system has been improved to around 60 μm. In addition, the result indicated that the proposed bipolar pulser could increase 4 dB for pulse/echo waveforms amplitude.

Optimization of Acoustic Liposomes for Improved In Vitro and In Vivo Stability

Liposomes encapsulating perfluoropropane gas, termed acoustic liposomes (ALs), which can serve both for ultrasound (US) imaging and US-mediated gene delivery, have been reported. However, the echogenicity of ALs decreases within minutes in vivo due to gas diffusion and leakage, hindering time-consuming procedures such as contrast-enhanced 3D US imaging and raising the need for improvement of their stability. The stability of ALs preparations incorporating increasing ratios of anionic / unsaturated phospholipids, polyethylene glycol (PEG)ylated phospholipid and cholesterol was investigated by measurement of their reflectivity over time using a high-frequency US imaging system, both in vitro and in vivo. The retention of echogenicity of ALs in vitro is enhanced with increasing molar ratios of PEGylated lipids. Addition of 10 molar percent of an anionic phospholipid resulted in a 31% longer half-life, while cholesterol had the opposite effect. Assessment of the stability of an optimized composition showed a more than 2-fold increase of the detection half-life in mice. Presence of a PEG coating not only serves to provide "stealth" properties in vivo, but also contributes to the retention of the encapsulated gas. The optimized ALs reported here can be used as a contrast agent for lengthier imaging procedures.

Detection of changes of scar thickness under mechanical loading using ultrasonic measurement

The intervention of pressure therapy on management of hypertrophic scar (HS) after burn is based on the theoretical assumption that the mechanical force added onto the scar tissue will reduce the growth of myofibroblasts which create the collagen clusters and the interstitial space, and to realign fibrous tissues, thus reducing the thickness of HS. In this experimental study, a high frequency ultrasound imaging system (12MHz) was applied to measure the real time changes of thickness of the post burn HS under a mechanical loading system with similar pressure generated to the scar tissue. The validity of the ultrasound system in measurement of the changes of scar thickness underneath the tissue was tested on the porcine skin in vitro followed by measurement of human skin in vivo. Results showed that the ultrasound measurement of thickness had both good validity (r2=0.98, p<0.0001) and good intra-rater reliability (ICC=0.89). Then, the system was used to test the thickness of 14 human HS samples in vivo among 7 subjects. External loading force with similar pressure range (10–45mmHg) was then applied to these scar samples via ultrasound probe with rectangular contacting area at 4cm2 and each loading force was maintained unchange for 2min over the scar tissue. The real time scar thickness was documented. Results showed that the mean scar thickness was found to be significantly decreased when the loading force applied was increased from 5 to 35mmHg (with 10mmHg interval) (p<0.001). A significant negative correlation between the pressure level and scar thickness was observed (r2=0.96, p=0.005). The decline of thickness was found more significant between 0mmHg and 15mmHg. The findings were in line with the postulate that pressure therapy is effective in reducing the thickness of HS. A long term followup study should be administered to determine the prolonged effect of pressure intervention.

Volumetric and Angiogenic Evaluation of Antitumor Effects with Acoustic Liposome and High-Frequency Ultrasound

Acoustic liposomes (AL) have their inherent echogenicity and can add functionality in serving as drug carriers with tissue specificity. Nonuniform vascular structures and vascular branches/bends are evaluated by imaging the intravascular movement locus of ALs with high-frequency ultrasound (HF-US) imaging. However, the evaluation of antitumor effects on angiogenesis by ALs and HF-US imaging has not been reported. Here, we show that the combination of ALs and an HF-US imaging system is capable of noninvasively evaluating antitumor volumetric and angiogenic effects in preclinical mouse models of various cancers. In this study, the antitumor effects of cisplatin on tumor growth and angiogenesis in mice bearing two different types of tumor cells were assessed. By tracking each AL flowing in the vessel and transferring the images to personal computers, microvessel structures were mapped and reconstructed using the color difference based on SD method. The antitumor effects were confirmed with an in vivo bioluminescence imaging system and immunohistochemical analysis. Our results show that cisplatin inhibits tumor growth by decreasing intratumoral vessel area but does not affect the angiogenesis ratio in the tumor. The vascular occupancy in the outer region of the tumor was larger than that in the inner region; however, both occupancies were similar to those of the control tumor. We propose that this method of mapping microvessels with ALs and an HF-US system can serve as a new molecular imaging method for the assessment of angiogenesis and can be applied to evaluate the antitumor effects by various therapeutic agents.

Evaluation of antitumor effects following tumor necrosis factor‐α gene delivery using nanobubbles and ultrasound

The antitumor effects of tumor necrosis factor (TNF-α) were evaluated following transfection of TNF-α plasmid DNA into solid mouse tumors using the nanobubbles (NBs) and ultrasound (US) gene delivery system. Murine breast carcinoma (EMT6) cells expressing luciferase (1 × 10(6) cells) were injected intradermally into the flanks of 6-7-week-old male SCID mice on day 0. Ten microliters of TNF-α (5 μg/μL) or TNF-α mock plasmid DNA (5 μg/μL) with/without NBs (15 μL) and saline was injected intratumorally in a total volume of 30 μL, and tumors were exposed to US (frequency, 1 MHz; intensity, 3.0 W/cm(2); duty cycle, 20%; number of pulses, 200; and exposure time, 60 s) on days 2, 4, 7, and 9. Changes in tumor size were measured with an in vivo bioluminescent imaging system and a mechanical caliper. Changes in tumor vessel area were quantified using contrast-enhanced US imaging with Sonazoid and a high frequency US imaging system (40 MHz) and immunohistochemistry (CD31). At the mRNA level, expression of TNF-α, caspase-3, and p53 were quantified using real-time quantitative RT-PCR. At the protein level, expression of caspase-3 and p53 were confirmed by immunohistochemistry. We show that repeated TNF-α gene delivery using NBs and US can lead to the local production of TNF-α. This results in antitumor effects, including activation of p53-dependent apoptosis, decrease in tumor vessel density, and suppression of tumor size. In this study, we showed the effectiveness of using NBs and US for TNF-α gene delivery into tumor cells.

A high-frequency ultrasound imaging system combining limited-angle spatial compounding and model-based synthetic aperture focusing

High-frequency ultrasound (HFUS) imaging systems are routinely used for medical diagnostics (skin, eyes) and for medical research (small animal imaging). Although systems with array transducers are already commercially available, imaging systems with single-element transducers are still of interest and available as well, because this type of transducer is less complex, less expensive, and technically mature. Nevertheless, drawbacks exist, for example, the need for mechanical scanning units and the limited depth of field. In this paper, we present a high-frequency (20 MHz) ultrasound imaging system equipped with a spherically focused transducer. Limited-angle spatial compounding is utilized to improve the image contrast, to suppress speckle and noise, and to reduce imaging artifacts. To overcome the limitation in depth of field, the system uses a novel synthetic aperture focusing technique based on the correlation of the recorded echo signals with the simulated point spread function of the imaging system. This method results in lower side lobe levels and greater noise reduction compared with delay-and-sum focusing, which is demonstrated by wire phantom measurements. When used in combination with limited-angle spatial compounding, as presented in this paper, the resulting image quality is superior to conventional single-element HFUS imaging systems and to array systems. Examples of measurements on tissue phantoms and small animals (ex vivo) are presented and discussed in detail.

Comparison of articular cartilage images assessed by high-frequency ultrasound microscope and scanning acoustic microscope

The purpose of this study was to compare images of a newly developed high-frequency ultrasound imaging system (HFUIS) and scanning acoustic microscope (SAM) and to calculate their Pearson product moment correlations with a view to applying HFUIS for clinical use. Cylindrical cartilage-bone complexes from adult male Sprague-Dawley rats were obtained. The specimens were immersed in normal saline and scanned by HFUIS. Intensity by HFUIS was normalised by reflection from a steel plate at the same distance. After the scanning, specimens were fixed with paraformaldehyde, decalcified and embedded in paraffin. Thinly sliced tissues were prepared for SAM evaluation. After the scanning, three layers of articular cartilage (superficial, middle and deep) were independently evaluated and their relationships calculated. The superficial and deep layers indicated high relative intensity, whereas the middle layer showed nonhomogeneous relative intensity by HFUIS. A high relative intensity by HFUIS and high sound speed area by SAM had strong correlations (Pearson product moment correlation, superficial layer 0.704, middle layer 0.731). HFUIS produced high-resolution images of the articular cartilage and its intensity was strongly correlated with sound speed by SAM.

Ultrasonic microscanning

A detailed review is given of the application of high-frequency ultrasound (HFUS) at frequencies of 20 MHz and above for high-resolution, cross-sectional imaging of biological soft tissue. The state of the art of HFUS imaging systems is discussed with respect to the underlying engineering concepts, system designs, and available transducer technology. Furthermore, the dependency of the spatial resolution on the system's parameters is analysed. Skin imaging, eye imaging, small animal imaging for preclinical research, and intravascular ultrasound in coronary arteries for arteriosclerotic disease diagnostics are presented as examples for the application of HFUS imaging in medical diagnostics. It is shown that, in the frame of the indicated applications, ultrasound in the frequency range 20-100MHz gives a good compromise between the contrary demands for a good spatial resolution and a sufficiently large penetration depth of ultrasound waves into the tissue. Scanning schemes for the imaging of tissue morphology are considered, including spatial compounding as a multidirectional imaging technique.

J0201-1-3 表在性膀胱がんに対する薬剤送達法の開発(ドラッグデリバリーシステムとその周辺技術の基礎と展開(1))

Seventy percent of patients with bladder cancer present superficial tumors with high recurrence rate. In order to develop effective superficial bladder cancer gene therapy, effective gene delivery using nanobubbles (NBs) and ultrasound (US) is our ultimate goal. To achieve this goal, we propose localized gene delivery in bladder using NBs and low-high-intensity US (LHUS) while low-intensity US direct NBs proximate to targeted cells in the bladder and high-intensity US collapse NBs to increase cell membrane permeability resulting the entry of exogenouse molecules into proximate cells. In the present study, to demonstrate the effectiveness of NBs and LHUS to localize the gene delivery to a designated bladder wall, we have assessed: i) in vivo local delivery and fragmentation of NBs with high frequency US imaging system; ii) localized molecular delivery of fluorescent molecules and quantification of the transfection efficacy; and iii) transfection of plasmid DNA and quantification of the transfection efficacy.

Digital High Frequency Coded Imaging System

Coded transmission is an approach to solve the inherent compromise between penetration and resolution required in ultrasound imaging. It is universally acknowledged that this technique gives major improvement in SNR. A novel high frequency (20-35 MHz) ultrasound real-time imaging system for research and evaluation was developed. The digital programmable coder-digitizer module based on the field programmable gate array (FPGA) supports arbitrary waveform coded transmission and RF echoes sampling up to 200 MSPS, as well as real-time streaming of digitized RF data via a high speed USB interface to the PC. All RF and image data processing were implemented in the software. A novel balanced software architecture using CPU and GPU processing supports real-time processing and display at rates up to 30 frames/sec. The system was used to acquire data for sine burst and 16-bit Golay code excitation using a single element scanning head with thick film focused spherical transducer 25 MHz center frequency and 56% system bandwidth. SNR gain for the Golay codes (referenced to single burst) of 15 dB for 20 MHz and 16 dB for 35 MHz were obtained. In water the axial resolution for both single burst and the Golay codes was the same FWMH=20 ns at 20 MHz and FWMH=15 ns at 35 MHz.