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Acoustic radiation force impulse (ARFI) imaging has been developed as a non-invasive method for quantitative illustration of tissue stiffness or displacement. Conventional ARFI imaging (2-10 MHz) has been implemented in commercial scanners for illustrating elastic properties of several organs. The image resolution, however, is too coarse to study m...
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... zebrafish embryo reaches the late blastula stage approximately 5 h after fertilization. In this experiment, most embryonic cells undergo epiboly, a process in which thinning blastula spreads around the yolk cell. An example image during embryogenesis 4 is given in Fig. 7, particularly indicating the blastula stage (v)-(vi). After displacement estimation, parametric images that represent the elastic properties are obtained and shown in Fig. 8 along with the corresponding B-mode image. Those images outline its anatomical structures such as chorion envelope, perivitelline space (PVS), and embryo ...
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... Hence, both structural and mechanical imaging of neural tube formation and closure is required to fully understand NTC. Techniques for mechanical imaging to understand tissue stiffness, like atomic force microscopy [8], acoustic radiation force elastography [9], and microindentation with optical coherence elastography (OCE) [10], have been used to determine the elasticity of developing embryos. However, these techniques have low resolution and are contact-based or invasive, which may affect the developing embryos. ...
To understand the dynamics of tissue stiffness during neural tube formation and closure in a murine model, we have developed a multimodal, coaligned imaging system combining optical coherence tomography (OCT) and Brillouin microscopy. Brillouin microscopy can map the longitudinal modulus of tissue but cannot provide structural images. Thus, it is limited for imaging dynamic processes such as neural tube formation and closure. To overcome this limitation, we have combined Brillouin microscopy and OCT in one coaligned instrument. OCT provided depth-resolved structural imaging with a micrometer-scale spatial resolution to guide stiffness mapping by Brillouin modality. 2D structural and Brillouin frequency shift maps were acquired of mouse embryos at gestational day (GD) 8.5, 9.5, and 10.5 with the multimodal system. The results demonstrate the capability of the system to obtain structural and stiffness information simultaneously.
... There have been several studies on accurately visualizing living tissue with minimal effects on normal physiology and structures with ultrasound, inaudible sound having the frequency range over 20 kHz and transmitted or detected by transducers employing piezoelectric materials [1][2][3][4]. By increasing the operational frequency of ultrasound technologies, the improved image resolution enables the exploration for the precisely quantitative indicator of arteriosclerosis using intravascular ultrasound (IVUS) imaging, highly detailed images of outer layers of skin, anterior segment of the eye, and measurement of the mechanical properties of small objects [5][6][7][8][9]. For the cellular applications, a working frequency range at least over 100 MHz is required to achieve the adequate acoustic beam size similar to the typical cell size [10][11][12]. ...
... Also, the device is applicable to the functional mode such as color, Doppler mode without the aid of noisier benchtop pulse generators due to its capability of generating multi-cycled sinusoidal bursts. Another remarkable characteristic of the system is the pulsing of waveforms at high PRF up to 1 MHz without degrading the output voltage level, which can be used for monitoring the very fast translation of living tissue/cells in response to the acoustic radiation force, which cannot be achieved by lower PRF [9,12]. ...
In this article, an approach to designing and developing an ultrahigh frequency (≤600 MHz) ultrasound analog frontend with Golay coded excitation sequence for high resolution imaging applications is presented. For the purpose of visualizing specific structures or measuring functional responses of micron-sized biological samples, a higher frequency ultrasound is needed to obtain a decent spatial resolution while it lowers the signal-to-noise ratio, the difference in decibels between the signal level and the background noise level, due to the higher attenuation coefficient. In order to enhance the signal-to-noise ratio, conventional approach was to increase the transmit voltage level. However, it may cause damaging the extremely thin piezoelectric material in the ultrahigh frequency range. In this paper, we present a novel design of ultrahigh frequency (≤600 MHz) frontend system capable of performing pseudo Golay coded excitation by configuring four independently operating pulse generators in parallel and the consecutive delayed transmission from each channel. Compared with the conventional monocycle pulse approach, the signal-to-noise ratio of the proposed approach was improved by 7–9 dB without compromising the spatial resolution. The measured axial and lateral resolutions of wire targets were 16.4 µm and 10.6 µm by using 156 MHz 4 bit pseudo Golay coded excitation, respectively and 4.5 µm and 7.7 µm by using 312 MHz 4 bit pseudo Golay coded excitation, respectively.
... Thus, an additional reliable method may be needed to detect tumors more accurately. High-frequency ARFI imaging or shear wave elasticity imaging (SWEI) have been shown to be a viable alternative to overcome the shortcomings of B-mode imaging by overlaying a map of the stiffness of tissues with an ultrasound B-mode image 27,28 . It uses high-intensity ultrasound pulses with short durations to apply acoustic radiation force to a target, which results in displacements of the target tissues, where the displacements depend on their mechanical properties. ...
We report a multimodal biomicroscopic system which offers high-frequency ultrasound B-mode, acoustic radiation force impulse (ARFI), and multispectral imaging for qualitative tumor characterization ex vivo. Examinations of resected tissues from diseased regions such as tumors are crucial procedures during surgical operations to treat cancer. Particularly, if tiny tumors remain at surgical sites after tumor resection, such tumors can result in unwanted outcomes, such as cancer recurrence or metastasis to other organs. To avoid this, accurate characterizations of tumors resected during surgery are necessary. To this end, we devised a multimodal biomicroscopic system including high-frequency ultrasound B-mode, ARFI, and multispectral imaging modalities to examine resected tumors with high levels of accuracy. This system was evaluated with tissue-mimicking phantoms with different mechanical properties. In addition, colorectal tumors excised from cancer patients were examined. The proposed system offers highly resolved anatomical, mechanical, chemical information pertaining to tumors, thus allowing the detection of tumor regions from the surface to deep inside tissues. These results therefore suggest that the multimodal biomicroscopic system has the potential to undertake qualitative characterizations of excised tumors ex vivo.
... Additionally, it has been confirmed that the ultrasound pulses used for separating RBCs and PNT1A cells and trapping one target cell are sufficiently short for determining its size based on the measured IB coefficient (Fig. 5); a size difference of 1.3 μm between the largest RBC (7.8 μm) and the smallest PNT1A cell (9.1 μm) were distinguished by an IB difference of 1.2 dB. Although it was demonstrated that the proposed label-free approach is capable of measuring the IB coefficient of a target cell under trapping as an example in this paper, we believe that this experimental result is a prominent stepping stone for the capture and the measurement of other physical properties of various cells such as the mechanical stiffness and shape of cancer cells 40,41 . Especially, the different slopes of the IB coefficient of RBCs and PNT1A cells shown in Fig. 5 indicate another possibility of measuring the mass density and compressibility of cells after separation; these are the secondary factors influencing the IB coefficient of cells. ...
Single-cell analysis is essential to understand the physical and functional characteristics of cells. The basic knowledge of these characteristics is important to elucidate the unique features of various cells and causative factors of diseases and determine the most effective treatments for diseases. Recently, acoustic tweezers based on tightly focused ultrasound microbeam have attracted considerable attention owing to their capability to grab and separate a single cell from a heterogeneous cell sample and to measure its physical cell properties. However, the measurement cannot be performed while trapping the target cell, because the current method uses long ultrasound pulses for grabbing one cell and short pulses for interrogating the target cell. In this paper, we demonstrate that short ultrasound pulses can be used for generating acoustic trapping force comparable to that with long pulses by adjusting the pulse repetition frequency (PRF). This enables us to capture a single cell and measure its physical properties simultaneously. Furthermore, it is shown that short ultrasound pulses at a PRF of 167 kHz can trap and separate either one red blood cell or one prostate cancer cell and facilitate the simultaneous measurement of its integrated backscattering coefficient related to the cell size and mechanical properties.
... The techniques used include AFM elastography, 39 optical coherence elastography (OCE), 30 and acoustic radiation force impulse (ARFI) imaging. 40 However, resolution constraints for subcellular imaging with OCE and ARFI and the need for external loading to induce deformations might have detrimental effects on the developing embryo or may cause external perturbations to the already existing mechanical forces. ...
Embryogenesis is regulated by numerous changes in mechanical properties of the cellular microenvironment. Thus, studying embryonic mechanophysiology can provide a more thorough perspective of embryonic development, potentially improving early detection of congenital abnormalities as well as evaluating and developing therapeutic interventions. A number of methods and techniques have been used to study cellular biomechanical properties during embryogenesis. While some of these techniques are invasive or involve the use of external agents, others are compromised in terms of spatial and temporal resolutions. We propose the use of Brillouin microscopy in combination with optical coherence tomography (OCT) to measure stiffness as well as structural changes in a developing embryo. While Brillouin microscopy assesses the changes in stiffness among different organs of the embryo, OCT provides the necessary structural guidance.
... In addition to its application in the clinical settings, more advanced ARFI imaging techniques with high-frequency ultrasound transducers were devised for preclinical applications. In particular, the stiffness of the internal micro-structures of a zebrafish embryo could be quantitatively determined by using high-frequency ARFI imaging at 100 MHz, offering a two-dimensional map of mechanical properties of the zebrafish embryo [13]. ...
We demonstrate a jitter noise reduction technique for acoustic radiation force impulse microscopy via photoacoustic detection (PA-ARFI), which promises to be capable of measuring cell mechanics. To reduce the jitter noise induced by Q-switched pulsed laser operated at high repetition frequency, photoacoustic signals from the surface of an ultrasound transducer are aligned by cross-correlation and peak-to-peak detection, respectively. Each method is then employed to measure the displacements of a target sample in an agar phantom and a breast cancer cell due to ARFI application, followed by the quantitative comparison between their performances. The suggested methods for PA-ARFI significantly reduce jitter noises, thus allowing us to measure displacements of a target cell due to ARFI application by less than 3 μm.
... Currently, a few ARFI imaging techniques have been utilized for various biological applications including in vivo discrimination of cysts from solid lesions by estimating the visco-elastic properties of the target [15], detection of lesions in the gastrointestinal tract [16], and assessment of the mechanical properties of coagulations with minimal disturbances [17]. More recently, we have shown that mechanical properties of the internal micro-structures of a zebrafish embryo of a size of ~800 µm could be successfully estimated with high frequency ARFI imaging at 100 MHz, yielding a 2D map of mechanical properties of the zebrafish embryo [18]. However, for ARFI imaging of a single cell, which typically have a dimension in the order of tens of micrometers, the operating frequency of a transducer needs to be further increased to beyond 300 MHz, which offers an axial resolution of ~5µm, to resolve a single cell from the cell culture substrate, which typically produces much stronger echo signals than a cell. ...
... Cross-correlation calculation between the reference and track PA signals was then performed to obtain the maximum displacement. A threshold of 0.8 was set for the correlation coefficient for data analysis [18]. ...
We demonstrate a novel non-contact method: acoustic radiation force impulse microscopy via photoacoustic detection (PA-ARFI), capable of probing cell mechanics. A 30 MHz lithium niobate ultrasound transducer is utilized for both detection of phatoacoustic signals and generation of acoustic radiation force. To track cell membrane displacements by acoustic radiation force, functionalized single-walled carbon nanotubes are attached to cell membrane. Using the developed microscopy evaluated with agar phantoms, the mechanics of highly- and weakly-metastatic breast cancer cells are quantified. These results clearly show that the PA-ARFI microscopy may serve as a novel tool to probe mechanics of single breast cancer cells.
... This work demonstrates that HFUMS elicits cytosolic calcium elevations in highly invasive breast cancer cells to a significantly greater extent than it does in weakly invasive breast cancer cells, suggesting that HFUMS may be a useful tool for identification of invasion potential of breast cancer cells. HFUMS has many advantages over other stimulation methods including chemical and non-chemical approaches (Brignani et al., 2008;Sekirnjak et al., 2006;Serena et al., 2009): (1) HFUMS is relatively noninvasive; (2) it may be suited for tumor biopsies in situ and tumors in vivo, possibly without tumor extraction; (3) it allows single cell stimulation at a micro scale (<~17 m); (4) it provides more versatilities in stimulation of breast cancer cells in terms of beam size, intensity level, and penetration depth; (5) it can be complementarily combined with other imaging modalities such as acoustic radiation force impulse imaging (Park et al., 2012), which enables the estimation of elastic properties of tumor cells in situ and in vivo. Notably, the elastic properties of cancer cells have been importantly considered as one of primary indicators in the determination of metastatic potential of breast cancer cells. ...
In this paper, we investigate the application of contactless high frequency ultrasound microbeam stimulation (HFUMS) for determining the invasion potential of breast cancer cells. In breast cancer patients, the finding of tumor metastasis significantly worsens the clinical prognosis. Thus, early determination of the potential of a tumor for invasion and metastasis would significantly impact decisions about aggressiveness of cancer treatment. Recent work suggests that invasive breast cancer cells (MDA-MB-231), but not weakly invasive breast cancer cells (MCF-7, SKBR3, and BT-474), display a number of neuronal characteristics, including expression of voltage-gated sodium channels. Since sodium channels are often co-expressed with calcium channels, this prompted us to test whether single-cell stimulation by a highly focused ultrasound microbeam would trigger Ca(2+) elevation, especially in highly invasive breast cancer cells. To calibrate the diameter of the microbeam ultrasound produced by a 200-MHz single element LiNbO3 transducer, we focused the beam on a wire target and performed a pulse-echo test. The width of the beam was ∼17μm, appropriate for single cell stimulation. Membrane-permeant fluorescent Ca(2+) indicators were utilized to monitor Ca(2+) changes in the cells due to HFUMS. The cell response index (CRI), which is a composite parameter reflecting both Ca(2+) elevation and the fraction of responding cells elicited by HFUMS, was much greater in highly-invasive breast cancer cells than in the weakly-invasive breast cancer cells. The CRI of MDA-MB-231 cells depended on peak-to-peak amplitude of the voltage driving the transducer. These results suggest that HFUMS may serve as a novel tool to determine the invasion potential of breast cancer cells, and with further refinement may offer a rapid test for invasiveness of tumor biopsies in situ. Biotechnol. Bioeng. © 2013 Wiley Periodicals, Inc.
... High-frequency ultrasound at 80 MHz has previously been used for ARFI imaging in the embryos of zebrafish [44]. The ARFI imaging performed in that study employed a singleelement transducer via mechanical scanning, and the same transducer was used for both pushing and imaging. ...
In ophthalmology, detecting the biomechanical properties of the cornea can provide valuable information about various corneal pathologies, including keratoconus and the phototoxic effects of ultraviolet radiation on the cornea. Also, the mechanical properties of the cornea can be used to evaluate the recovery from corneal refractive surgeries. Therefore, noninvasive and high-resolution estimation of the stiffness distribution in the cornea is important in ophthalmic diagnosis. The present study established a method for high-resolution acoustic-radiation-force-impulse (ARFI) imaging based on a dual-frequency confocal transducer in order to obtain a relative stiffness map, which was used to assess corneal sclerosis. An 11-MHz pushing element was used to induce localized displacements of tissue, which were monitored by a 48-MHz imaging element. Since the tissue displacements directly correlated with the tissue elastic properties, the stiffness distribution in a tiny region of the cornea can be found by a mechanical B/D scan. The experimental system was verified using tissue-mimicking phantoms that included different geometric structures. Ex vivo cornea experiments were carried out using fresh porcine eyeballs. Corneas with localized sclerosis were created artificially by the injection of a formalin solution. The phantom experiments showed that the distributions of stiffness within different phantoms can be recognized clearly using ARFI imaging, and the measured lateral and axial resolutions of this imaging system were 177 and 153 μm, respectively. The ex vivo experimental results from ARFI imaging showed that a tiny region of localized sclerosis in the cornea could be distinguished. All of the obtained results demonstrate that high-resolution ARFI imaging has considerable potential for the clinical diagnosis of corneal sclerosis.
... As an application of UM, two-dimensional cell manipulation has been experimentally demonstrated with 200 MHz sinusoidal bursts (PRF = 1 kHz, duty factor = 0.025%, and supplied voltage to the transducer = 2 V), showing that the beam is capable of trapping a leukemia cell at the focus without affecting other neighboring cells [10]. Elastic properties of zebrafish embryos are parametrically mapped through acoustic radiation force impulse imaging at 100 MHz [11]. ...
