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Quantitative ultrasound (QUS) was used to classify rabbits that were induced to have liver disease by placing them on a fatty diet for a defined duration and/or periodically injecting them with CCl(4). The ground truth of the liver state was based on lipid liver percents estimated via the Folch assay and hydroxyproline concentration to quantify fibrosis. Rabbits were scanned ultrasonically in vivo using a SonixOne scanner and an L9–4/38 linear array. Liver fat percentage was classified based on the ultrasonic backscattered radio-frequency (RF) signals from the livers using either QUS or a 1D convolutional neural network (CNN). Use of QUS parameters with linear regression and canonical correlation analysis (CCA) demonstrated that the QUS parameters could differentiate between livers with lipid levels above or below 5%. However, the QUS parameters were not sensitive to fibrosis. The CNN was implemented by analyzing raw RF ultrasound signals without using separate reference data. The CNN output the classification of liver as either above or below a threshold of 5% fat level in the liver. The CNN outperformed the classification utilizing the QUS parameters combine with a support vector machine (SVM) in differentiating between low and high lipid liver levels, i.e., accuracies of 74% versus 59% on the testing data. Therefore, while the CNN did not provide a physical interpretation of the tissue properties, e.g., attenuation of the medium or scatterer properties, the CNN had much higher accuracy in predicting fatty liver state and did not require an external reference scan.

The use of wireless implanted medical devices (IMDs) is growing because they facilitate monitoring of patients at home and during normal activities, reduce the discomfort of patients, and reduce the likelihood of infection associated with trailing wires. Currently, radio frequency (RF) electromagnetic waves are the most commonly used method for communicating wirelessly with IMDs. However, due to the restrictions on the available bandwidth and the employable power, data rates of RF-based IMDs are limited to 267 kb/s. Considering standard definition video streaming requires data rates of 1.2 Mb/s and high definition requires 3 Mb/s, it is not possible to use the RF electromagnetic communications for high data rate communication applications such as video streaming. In this work, an alternative method that utilizes ultrasonic waves to relay information at high data rates is introduced. An advanced quadrature amplitude modulation (QAM) modem with phase-compensating, sparse decision feedback equalizer (DFE) is tailored to realize the full potential of the ultrasonic channel through biological tissues. The proposed system is tested in a variety of scenarios, including both simulations with finite impulse response (FIR) channel models, and real physical transmission experiments with ex vivo beef liver and pork chop samples as well as in situ rabbit abdomen. Consequently, the simulations demonstrated that video-capable data rates can be achieved with millimeter-sized transducers. Real physical experiments confirmed data rates of 6.7, 4.4, 4, and 3.2 Mb/s through water, ex vivo beef liver, ex vivo pork chop, and in situ rabbit abdomen, respectively.

The ultrasonic attenuation coefficient (ACE) can be used to classify tissue state. Pulse-echo spectral-based attenuation estimation techniques, such as the spectral-log-difference method (SLD), account for beam diffraction effects using a reference phantom having a sound speed close to the sound speed of the sample. Methods like SLD assume linear propagation of ultrasound and do not account for potential acoustic nonlinear distortion of the backscattered power spectra in both sample and reference. In this study, the ACE of a sample was computed and compared using the SLD with two independent references (high attenuating and low attenuating phantoms but with similar B/A values) and over several pressure levels. Both numerical and physical tissue-mimicking phantoms were used in the study. The results indicated that the biases in ACE increased when using a reference having low attenuation, whereas the high attenuating reference produced more consistent ACE. Furthermore, increments in ACE vs input pressure were correlated to the log-ratio of Gol'dberg numbers between the sample and reference ([Formula: see text] in simulations and [Formula: see text] in experiments). Therefore, the results suggest that to reduce bias in ACE using spectral-based methods, both the sound speed and the Gol'dberg number of the reference phantom should be matched to the sample.

In ultrasonic imaging, reduction of lateral sidelobes can result in an improved image with less distortion and fewer artifacts. In general, apodization is used to lower sidelobes in exchange for increasing the width of the main lobe, and thus decreasing lateral resolution. Null subtraction imaging (NSI) is a nonlinear image processing technique that uses different receive apodizations on copies of the same RF data to maintain low sidelobe levels while simultaneously improving lateral resolution. The images created with three different apodization functions are combined to form an image with low sidelobe levels and apparent improvements in lateral resolution compared to conventional rectangular apodization. To evaluate the performance of this technique for different imaging tasks, experiments were performed on an ATS539 phantom containing wire targets to assess lateral resolution and cylindrical anechoic and hyperechoic targets to assess contrast. NSI images were compared against rectangular apodized images and minimum variance beamformed images. In experiments, the apparent lateral resolution was observed to improve by a factor of more than $35\times $ when compared to rectangular apodization. Image quality was assessed by the estimation of lateral resolution (−6-dB receive beamwidth), main-lobe-to-sidelobe ratio, and contrast-to-noise ratio (CNR). Imaging with NSI using a focal number of 2 (f/2), the −6-dB beamwidth on receive as measured from a small wire target in the ATS phantom was $0.03\lambda $ compared to $2.79\lambda $ for rectangular apodization. Sidelobes were observed to decrease by 32.9 dB with NSI compared to rectangular apodization. However, the ability to observe the contrast of anechoic and hyperechoic targets reduced when utilizing the NSI scheme, i.e., the CNR decreased from −3.05 to −1.01 for anechoic targets and 1.65 to 0.45 for the hyperechoic targets.

In an increasing number of applications of focused ultrasound (FUS) therapy, such as opening of the blood–brain barrier or collapsing microbubbles in a tumor, elevation of tissue temperature is not involved. In these cases, real-time visualization of the field distribution of the FUS source would allow localization of the FUS beam within the targeted tissue and allow repositioning of the FUS beam during tissue motion. In this paper, in order to visualize the FUS beam in situ , a 6-MHz single-element transducer ( $f$ /2) was used as the FUS source and aligned perpendicular to a linear array which passively received scattered ultrasound from the sample. An image of the reconstructed intensity field pattern of the FUS source using bistatic beamforming was then superimposed on a registered B-mode image of the sample acquired using the same linear array. The superimposed image is used to provide anatomical context of the FUS beam in the sample being treated. The intensity field pattern reconstructed from a homogeneous scattering phantom was compared with the field characteristics of the FUS source characterized by the wire technique. The beamwidth estimates at the FUS focus using the in situ reconstruction technique and the wire technique were 1.5 and 1.2 mm, respectively. The depth-of-field estimates for the in situ reconstruction technique and the wire technique were 11.8 and 16.8 mm, respectively. The FUS beams were also visualized in a two-layer phantom and a chicken breast. The novel reconstruction technique was able to accurately visualize the field of an FUS source in the context of the interrogated medium.

The emergence of in-body medical devices has provided a means of capturing physiological or diagnostic information and streaming this information outside of the body. Currently, electromagnetic-based communications make up the bulk of in-body medical device communication protocols. Traditional electromagnetic-based solutions are limited in their data rates and available power. Recently, ultrasound was investigated as a communication channel for through-tissue data transmission. To achieve real-time video streaming through tissue, data rates of ultrasound need to exceed 1 Mbps. In a previous study, we demonstrated ultrasound communications with data rates greater than 30 Mbps with two focused ultrasound transducers using a large footprint laboratory system through slabs of lossy tissues. While the form factor of the transmitter is also crucial, it is obvious that a large, focused transducer cannot fit within the size of a small in-body medical device. Several other challenges for achieving high-speed ultrasonic communication through tissue include strong reflections leading to multipath effects and attenuation. In this work, we demonstrate ultrasonic video communications using a mm-scale microcrystal transmitter with video streaming supplied by a camera connected to a Field Programmable Gate Array (FPGA). The signals were transmitted through a tissue-mimicking phantom and through the abdomen of a rabbit in vivo . The ultrasound signal was recorded by an array probe connected to a Verasonics Vantage system and decoded back to video. To improve the received signal quality, we combined the signal from multiple channels of the array probe. Orthogonal frequency division multiplexing (OFDM) modulation was used to reduce the receiver complexity under a strong multipath environment.

The backscatter coefficient (BSC) quantifies the frequency-dependent reflectivity of tissues. Accurate estimation of the BSC requires knowledge of the attenuation coefficient slope (ACS) of tissues in the beam path between the transducer and the insonified region of interest, namely, the total attenuation. In this study, the total attenuation is calculated as the cumulative sum of values of a local attenuation map devised using full angular spatial compounding (FASC). The BSC was parameterized through the integrated backscatter coefficient (iBSC) obtaining iBSC maps. Experimental validation of the proposed approach consisted of scanning two cylindrical physical phantoms with off-centered inclusions having different ACS and BSC values than the background. Additional iBSC maps were computed assuming an uniform ACS map of 0.5 dB/cm/MHz (which is a value assumed for soft tissues) instead of the FASC-ACS map. Finally a iBSC map was obtained using an ideal ACS map formed with ground truth ACS values and knowledge of inclusion true position. The results were comparable when using the FASC-ACS map or the ideal ACS map in term of inclusion detectability and estimation accuracy. The use of the uniform ACS map resulted in some cases with very high fractional error (>;9 dB), which highlights the relevance of accurate compensation for total attenuation. These results suggest that BSCs can be reliably estimated using total attenuation compensation from FASC-ACS maps.

A future clinical goal of capsule endoscopy is to transmit high definition (HD) video in real time from inside the human body to an external device. Current electromagnetic wave approaches do not provide enough data rates to achieve video streaming let alone at HD. In a previous study, we verified highspeed communication through tissue using ultrasound with data rates up to 30 Mbps [1]. The system used single-element focused transducers operating at 5 MHz using a Tabor WW1281 arbitrary waveform generator and power amplifier. To move towards a capsule endoscopy system, a smaller hardware footprint is required. We designed an OFDM modulation scheme, which was compatible with an in-tissue ultrasound communication channel and verified the scheme with 2-mm sonomicrocrystal as the transmit transducer and IP103 linear array as receive transducer. A 3 Mbps data rate was achieved with this setup. Furthermore, we implemented the transmitter with an FPGA to achieve real-time video streaming through tissue.

We have demonstrated that exposing human breast tumour xenografts to ultrasound-stimulated microbubbles enhances tumour cell death and vascular disruption resulting from hyperthermia treatment. The aim of this study was to investigate the effect of varying the hyperthermia and ultrasound-stimulated microbubbles treatment parameters in order to optimize treatment bioeffects. Human breast cancer (MDA-MB-231) tumour xenografts in severe combined immunodeficiency (SCID) mice were exposed to varying microbubble concentrations (0%, 0.1%, 1% or 3% v/v) and ultrasound sonication durations (0, 1, 3 or 5 min) at 570 kPa peak negative pressure and central frequency of 500 kHz. Five hours later, tumours were immersed in a 43°C water bath for varying hyperthermia treatment durations (0, 10, 20, 30, 40, 50 or 60 minutes). Results indicated a significant increase in tumour cell death reaching 64 ± 5% with combined treatment compared to 11 ± 3% and 26 ± 5% for untreated and USMB-only treated tumours, respectively. A similar but opposite trend was observed in the vascular density of the tumours receiving the combined treatment. Optimal treatment parameters were found to consist of 40 minutes of heat with low power ultrasound treatment microbubble parameters of 1 minute of sonification and a 1% microbubble concentration.

This study proposes a new cancer drug delivery modality that allows for spatiotemporal control over activation of the therapeutic. Current standard cancer therapies of surgery, chemotherapy, and radiation therapy have their limitations, such as invasiveness and systemic toxicities. Developing a new modality that is localized and triggerable is becoming increasingly advantageous. Currently, photodynamic therapy (PDT) has been shown to be clinically effective but is limited by poor tissue penetration of light. Sonodynamic therapy (SDT) bypasses this pitfall with increased tissue penetration depth of ultrasound. However, PDT has limitations as it relies on the potentially damaging ultrasound cavitation effect and requires sonosensitizers or nanoparticles that have issues with bioavailability, biostability, and biosafety. In this study, we propose a novel ultrasound-based cancer treatment modality called mechanochemical dynamic therapy (MDT). In MDT, high intensity focused ultrasound (HIFU) delivers mechanical forces to force-responsive moieties of azo mechanophores that are embedded into biocompatible polyethylene glycol (PEG) hydrogel polymers. Upon focal sonication with HIFU, these mechanophores generate highly reactive free radicals (FRs) that are converted to reactive oxygen species (ROSs). The sonicated gels are then placed into in vitro cultures, allowing for the diffusion of ROSs into the cells to induce oxidative cytotoxicity and eventually cell death. Cell proliferation is monitored at 24-hour intervals, and by 72 hours, the sonicated gels produced cell killing effects comparable to lethal doses of H2O2 in both in vitro mouse melanoma (B16F10) and breast cancer (E0771) models. Sonication of control hydrogels that did not contain mechanophores showed minimal cytotoxicity. This study shows the potential of MDT as a drug delivery platform that overcomes the limitations of PDT and SDT and has the potential to be applied synergistically with other current cancer treatments. This is the first demonstration of using HIFU-activated mechanophores to non-invasively deliver cancer therapies with spatiotemporal control. Citation Format: Gun Kim, Qiong Wu, James L. Chu, Emily J. Smith, Michael L. Oelze, King C. Li, Jeffrey S. Moore. Mechanochemical dynamic therapy for focal cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1318.

The objective of this article is to demonstrate the feasibility of estimating the backscatter coefficient (BSC) using an in situ calibration source. Traditional methods of estimating the BSC in vivo using a reference phantom technique do not account for transmission losses due to intervening layers between the ultrasonic source and the tissue region to be interrogated, leading to increases in bias and variance of BSC-based estimates. To account for transmission losses, an in situ calibration approach is proposed. The in situ calibration technique employs a titanium sphere that is well-characterized ultrasonically, biocompatible, and embedded inside the sample. A set of experiments was conducted to evaluate the embedded titanium spheres as in situ calibration targets for BSC estimation. The first experiment quantified the backscattered signal strength from titanium spheres of three sizes: 0.5, 1, and 2 mm in diameter. The second set of experiments assessed the repeatability of BSC estimates from the titanium spheres and compared these BSCs to theory. The third set of experiments quantified the ability of the titanium bead to provide an in situ reference spectrum in the presence of a lossy layer on top of the sample. The final set of experiments quantified the ability of the bead to provide a calibration spectrum over multiple depths in the sample. All experiments were conducted using an L9-4/38 linear array connected to a SonixOne system. The strongest signal was observed from the 2-mm titanium bead with the signal-to-noise ratio (SNR) of 11.6 dB with respect to the background speckle. Using an analysis bandwidth of 2.5–5.5 MHz, the mean differences between the experimentally derived BSCs and BSCs derived from the Faran theory were 0.54 and 0.76 dB using the array and a single-element transducer, respectively. The BSCs estimated using the in situ calibration approach without the layer and with the layer and using the reference phantom approach with the layer were compared to the reference phantom approach without the layer present. The mean differences in BSCs were 0.15, 0.73, and −9.69 dB, respectively. The mean differences of the BSCs calculated from data blocks located at depths that were either 30 pulse lengths above or below the actual bead depth compared to the BSC calculated at bead depth were −1.55 and −1.48 dB, respectively. The results indicate that an in situ calibration target can account for overlaying tissue losses, thereby improving the robustness of BSC-based estimates.

The attenuation coefficient (AC) has demonstrated the ability to classify tissue state. Linear acoustic propagation is assumed when estimating the AC using spectral-based methods from the ultrasonic backscatter. However, the effects of acoustic nonlinearities can distort the backscattered power spectra versus depth. The distortion of the power spectra could result in a bias in the estimation of the AC. The goal of the study was to quantify the effects of nonlinear distortion on the estimation of AC from ultrasonic backscatter using spectral methods. We computed the AC from backscattered signals using the spectral log difference method and a reference phantom to account for diffraction effects. Computational simulations and experiments in phantoms were performed. In the experiments, three tissue-mimicking phantoms, named A, B and C having estimated AC values of 0.60, 0.90, and 0.20 dB/cm/MHz, respectively, and B/A ≈ 6.6 for each phantom were scanned using a single-element focused transducer (f/2) having a 0.5" diameter and 5-MHz center frequency. The phantoms were scanned using six excitation levels from a high-power (HP) pulsing apparatus (RAM-5000, Ritec, USA). The AC was estimated from phantom A using either phantom B (high attenuation) or phantom C (low attenuation) as the reference. The AC was estimated at each excitation level over the analysis bandwidth (− 6-dB criterion) to determine the effects of acoustic nonlinearity on estimation of AC. The presence of nonlinear distortion can be quantified through the Gol’dberg number, which is inversely proportional to the product of the nonlinearity coefficient and attenuation. We hypothesized that because the B/A values were approximately the same for each phantom, the effects of nonlinear distortion would be more pronounced when using phantom C, which had much lower attenuation. Specifically, increased excess attenuation due to transfer of energy from the fundamental to the harmonics would be observed more in phantom C. The AC estimate increased from 0.57 to 0.67 dB/cm/MHz as the excitation levels increased from level one to six when using phantom B as a reference. In contrast, when using phantom C as reference, the estimated AC slope of phantom A decreased from 0.57 to 0.43 dB/cm/MHz as the excitation levels increased from level one to six. Therefore, use of a reference with different attenuation resulted in increased bias of AC estimates due to nonlinear distortion being this deviation larger when using low attenuating media.

Conventional medical imaging technologies, including ultrasound, have continued to improve over the years. For example, in oncology, medical imaging is characterized by high sensitivity, i.e., the ability to detect anomalous tissue features, but the ability to classify these tissue features from images often lacks specificity. As a result, a large number of biopsies of tissues with suspicious image findings are performed each year with a vast majority of these biopsies resulting in a negative finding. To improve specificity of cancer imaging, quantitative imaging techniques can play an important role. Conventional ultrasound B-mode imaging is mainly qualitative in nature. However, quantitative ultrasound (QUS) imaging can provide specific numbers related to tissue features that can increase the specificity of image findings leading to improvements in diagnostic ultrasound. QUS imaging can encompass a wide variety of techniques including spectral-based parameterization, elastography, shear wave imaging, flow estimation, and envelope statistics. Currently, spectral-based parameterization and envelope statistics are not available on most conventional clinical ultrasound machines. However, in recent years, QUS techniques involving spectral-based parameterization and envelope statistics have demonstrated success in many applications, providing additional diagnostic capabilities. Spectral-based techniques include the estimation of the backscatter coefficient (BSC), estimation of attenuation, and estimation of scatterer properties such as the correlation length associated with an effective scatterer diameter (ESD) and the effective acoustic concentration (EAC) of scatterers. Envelope statistics include the estimation of the number density of scatterers and quantification of coherent to incoherent signals produced from the tissue. Challenges for clinical application include correctly accounting for attenuation effects and transmission losses and implementation of QUS on clinical devices. Successful clinical and preclinical applications demonstrating the ability of QUS to improve medical diagnostics include characterization of the myocardium during the cardiac cycle, cancer detection, classification of solid tumors and lymph nodes, detection and quantification of fatty liver disease, and monitoring and assessment of therapy.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and can often lead to fibrosis, cirrhosis, cancer and complete liver failure. Liver biopsy is the current standard of care to quantify hepatic steatosis, but it comes with increased patient risk and only samples a small portion of the liver. Imaging approaches to assess NAFLD include proton density fat fraction estimated via magnetic resonance imaging (MRI) and shear wave elastography. However, MRI is expensive and shear wave elastography is not proven to be sensitive to fat content of the liver (Kramer et al. 2016). On the other hand, ultrasonic attenuation and the backscatter coefficient (BSC) have been observed to be sensitive to levels of fat in the liver (Lin et al. 2015; Paige et al. 2017). In this study, we assessed the use of attenuation and the BSC to quantify hepatic steatosis in vivo in a rabbit model of fatty liver. Rabbits were maintained on a high-fat diet for 0, 1, 2, 3 or 6 wk, with 3 rabbits per diet group (total N = 15). An array transducer (L9-4) with a center frequency of 4.5 MHz connected to a SonixOne scanner was used to gather radio frequency (RF) backscattered data in vivo from rabbits. The RF signals were used to estimate an average attenuation and BSC for each rabbit. Two approaches were used to parameterize the BSC (i.e., the effective scatterer diameter and effective acoustic concentration using a spherical Gaussian model and a model-free approach using a principal component analysis [PCA]). The 2 major components of the PCA from the BSCs, which captured 96% of the variance of the transformed data, were used to generate input features to a support vector machine for classification. Rabbits were separated into two liver fat-level classes, such that approximately half of the rabbits were in the low-lipid class (≤9% lipid liver level) and half of the rabbits in the high-lipid class (>9% lipid liver level). The slope and the midband fit of the attenuation coefficient provided statistically significant differences (p value = 0.00014 and p value = 0.007, using a two-sample t test) between low and high-lipid fat classes. The proposed model-free and model-based parameterization of the BSC and attenuation coefficient parameters yielded classification accuracies of 84.11 %, 82.93 % and 78.91 % for differentiating low-lipid versus high-lipid classes, respectively. The results suggest that attenuation and BSC analysis can differentiate low-fat versus high-fat livers in a rabbit model of fatty liver disease.

The backscatter coefficient (BSC) has demonstrated the ability to classify disease state and to monitor changes in tissue due to therapy. However, traditional methods of estimating the BSC in vivo using a reference phantom technique do not account for transmission losses due to intervening layers between the ultrasonic source and tissue region to be interrogated. The intervening layers result in increases in bias and variance of BSC-based estimates. To accurately account for the transmission losses, an in situ calibration approach is proposed to obtain a more robust estimate of the BSC. The in situ calibration technique employs the use of a biocompatible sphere that is well-characterized ultrasonically and embedded inside a sample or tissue. Ultrasound scattered from the sphere encounters the same transmission loss and attenuation as the investigated sample and can be used as a reference spectrum to provide a more accurate estimate of the BSC. A 2-mm diameter titanium sphere was embedded inside a homogeneous phantom containing glass bead scatterers with diameters ≤ 90 μm placed spatially at random. A layer of fatty meat was placed on top of the phantom to produce transmission losses from a layer. The BSC was estimated from the phantom with and without the layer on top and compared using a traditional reference phantom technique and using the in situ sphere as a calibration target. Estimates of the effective scatterer diameter (ESD) were obtained for each condition and compared. The BSCs estimated using the in situ calibration approach with and without the layer present overlapped with the BSC estimated using the traditional reference phantom approach without the layer present. The BSC estimated using the traditional reference phantom approach with the layer present did not overlap with the other curves. Estimates of the ESD were 80 μm, 82 μm, 84 μm and 95 μm using the in situ calibration approach without the layer, with the layer and using the reference phantom approach without layer and with the layer present, respectively. The results indicate that an in situ calibration target can account for overlying tissue losses thereby improving the robustness of BSC-based estimates. This work was supported by a grant from the NIH (R21 EB020766).

Quantitative ultrasound estimates based on the backscatter coefficient (BSC) have demonstrated the ability to detect and classify disease beyond the capabilities of traditional B-mode imaging. Quantitative ultrasound has been able to differentiate live from apoptotic cells or oncotic cells in vitro with high-frequency ultrasound,1,2 monitor changes in tissue microstructure due to high-intensity focused ultrasound at high frequencies in a preclinical model,3 and monitor changes due to chemotherapy clinically at 6 MHz.4 Tumors have been characterized and differentiated using quantitative ultrasound at high frequencies in preclinical models of thyroid cancer,5 at high frequencies in clinical applications for ocular tumors,6,7 and at clinical frequencies in human patients for breast tumors8 and prostate cancers.9,10 Also, the BSC has been proven valuable for diagnosing fatty liver disease clinically11 and for monitoring physiologic and pharmacologic responses in renal function at clinical frequencies in an animal model.12,13 One of the BSC features that is often cited as an advantage is its system independence; ie, the same BSC value for a given tissue can be estimated from any imaging platform. Previous studies have demonstrated system independence of BSC estimates in well-characterized phantoms.14–17 These investigations applied single-element imaging systems measuring backscatter levels for strong glass bead scatterer phantoms (1–12 MHz),14,15 single-element imaging systems for probing weakly scattering agar-in-agar phantoms (1–13 MHz),16 and clinical array imaging systems for estimating BSC for phantoms with glass bead scatterers (1–15 MHz).17 Parametric estimates based on the BSC have demonstrated the ability to differentiate different types of orthotopic mouse tumors ex vivo (16–24 MHz),18 to identify regions of micrometastases within resected lymph nodes clinically (26.5 MHz center),19 and to identify dominant sources of backscattering in the renal cortex (frequencies covering 2.5–15 MHz).12,13,20,21 The frequency ranges in these studies cover the range being investigated in this study: namely, from the clinical frequencies to the lower end of the small-animal pre-clinical imaging frequencies, covering, for example, 1 to 21 MHz. This study addresses the need for demonstrating that in vivo interlaboratory measurements can be used to distinguish different types of tumors, while being able to obtain consistent BSC results from all systems. Previous studies22,23 examined BSC agreement across single-element and clinical imaging systems for an in vivo rodent fibroadenoma model over a frequency range of 1 to 14 MHz. The heterogeneity of the benign fibroadenomas provided a near worst-case scenario to evaluate quantitative ultrasound performance. The study presented herein seeks to expand on this work using clinical and preclinical array imaging systems to test their capability to detect known tissue differences while maintaining good agreement in BSC values across all systems. Mouse (4T1) and rat (MAT) mammary tumor models were used in a comparative experiment with 3 array-based ultrasound imaging systems (Siemens, Ultrasonix, and VisualSonics) and 5 different transducers covering a range of frequency bandwidths. Backscatter coefficient agreement between systems was assessed, as well as the ability to differentiate the two tumor types.

Quantitative ultrasound techniques are generally applied to characterize media whose scattering sites are considered to be small compared to a wavelength. In this study, the backscattered response of single weakly scattering spheres and cylinders with diameters comparable to the beam width of a 2.25 MHz single-element transducer were simulated and measured in the transducer focal plane to investigate the impact of physically large scatterers. The responses from large single spherical scatterers at the focus were found to closely match the plane-wave response. The responses from large cylindrical scatterers at the focus were found to differ from the plane-wave response by a factor of f(-1). Normalized spectra from simulations and measurements were in close agreement: the fall-off of the responses as a function of lateral position agreed to within 2 dB for spherical scatterers and to within 3.5 dB for cylindrical scatterers. In both measurement and simulation, single scatterer diameter estimates were biased by less than 3% for a more highly focused transducer compared to estimates for a more weakly focused transducer. The results suggest that quantitative ultrasound techniques may produce physically meaningful size estimates for media whose response is dominated by scatterers comparable in size to the transducer beam.

Tumor response to neoadjuvant chemotherapy in patients (n=30) with locally advanced breast cancer (LABC) was examined using quantitative ultrasound. Three ultrasound backscatter parameters, the integrated backscatter coefficient (IBC), average scatterer diameter (ASD), and average acoustic concentration (AAC), were estimated from tumors prior to treatment and at four times during neoadjuvant chemotherapy treatment (weeks 0, 1, 4, 8, and prior to surgery) and compared to ultimate clinical and pathological tumor responses. Results demonstrated that among all parameters, AAC was the best indicator of tumor response early after starting treatment. The AAC parameter increased substantially in treatment-responding patients as early as one week after treatment initiation, further increased at week 4, and attained a maximum at week 8. In contrast, the backscatter parameters from non-responders did not show any changes after treatment initiation. The two patient populations exhibited a statistically significant difference in changes of AAC (p

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and can often lead to fibrosis, cirrhosis, cancer and complete liver failure. Liver biopsy is the current standard of care to quantify hepatic steatosis, but it comes with increased patient risk and only samples a small portion of the liver. Imaging approaches to assess NAFLD include proton density fat fraction (PDFF) estimated via MRI and shear wave elastography. However, MRI is often prohibitively expensive and shear wave elastography is not sensitive to fat content of the liver [1]. On the other hand, ultrasonic attenuation and the backscatter coefficient (BSC) have been observed to be sensitive to levels of fat in the liver. In this study, we explored the use of attenuation and a principal component analysis (PCA) of the BSC to detect and quantify hepatic steatosis in vivo in a rabbit model of fatty liver. Rabbits were maintained on a high fat diet for 0, 1, 2, 3 or 6 weeks with three rabbits per diet group (total N = 15). For analysis, rabbits were separated into three classes based on the total lipid content of the livers estimated using the Folch method: low fat ( 10%). An array transducer L9-4 with center frequency of 4 MHz connected to a SonixOne scanner was used to gather RF backscattered data in vivo from rabbits. The RF signals were used to estimate an average attenuation and BSC for each rabbit. The first five principal components of the PCA from the BSCs were used as input features to a support vector machine (SVM) for classification and comparison to total liver lipid levels. The slope of the attenuation coefficient provided statistically significant differences (p < 0.00058, using two-sample t-test) between low and high lipid fat groups. The proposed PCA-SVM based classification system yielded a classification accuracy of 63.7%, 32.6% and 71.2% for the low, medium and high fat groups, respectively. The results suggest that attenuation and BSC analysis can differentiate low versus high fat livers in a rabbit model. This work was supported by a grant from NIH (R21EB020766).

It is now well established that for tumour growth and survival, tumour vasculature is an important element. Studies have demonstrated that ultrasound-stimulated microbubble (USMB) treatment causes extensive endothelial cell death leading to tumour vascular disruption. The subsequent rapid vascular collapse translates to overall increases in tumour response to various therapies. In this study, we explored USMB involvement in the enhancement of hyperthermia (HT) treatment effects. Human prostate tumour (PC3) xenografts were grown in mice and were treated with USMB, HT, or with a combination of the two treatments. Treatment parameters consisted of ultrasound pressures of 0 to 740 kPa, the use of perfluorocarbon-filled microbubbles administered intravenously, and an HT temperature of 43°C delivered for various times (0-50 minutes). Single and multiple repeated treatments were evaluated. Tumour response was monitored 24 hours after treatments and tumour growth was monitored for up to over 30 days for a single treatment and 4 weeks for multiple treatments. Tumours exposed to USMB combined with HT exhibited enhanced cell death (p

Improving spatial resolution of ultrasonic scanners would allow improved imaging performance. A lateral resolution is limited by diffraction and the width of the beam used to interrogate the medium. Techniques for improving the lateral resolution beyond the diffraction limit have utilized dilute concentrations of microbubbles (MBs) to localize MB locations. These approaches enable the mapping of microvasculature but do not allow improvements in general B-mode imaging. Null Subtraction Imaging (NSI) is a passive nonlinear image processing scheme that constructs images from the nulls in the beam pattern of an array rather than the main lobe. In NSI, envelopes reconstructed with different apodizations are combined to form an image with an improved apparent lateral resolution. NSI is computationally efficient compared to adaptive beamforming approaches and does not need MBs. Experiments have demonstrated improvements in a resolution of over 100 times compared to conventional delay-and-sum beamforming with no apodization. Engineering trade-offs associated with combining different apodization functions, angular steering, and interpolation were assessed using the NSI technique. The utilization of the NSI for specific imaging tasks was also evaluated. The results of the study suggest that NSI could provide improved performance for the detection of small microcalcifications, which has application in detecting and identifying malignant cancers.Improving spatial resolution of ultrasonic scanners would allow improved imaging performance. A lateral resolution is limited by diffraction and the width of the beam used to interrogate the medium. Techniques for improving the lateral resolution beyond the diffraction limit have utilized dilute concentrations of microbubbles (MBs) to localize MB locations. These approaches enable the mapping of microvasculature but do not allow improvements in general B-mode imaging. Null Subtraction Imaging (NSI) is a passive nonlinear image processing scheme that constructs images from the nulls in the beam pattern of an array rather than the main lobe. In NSI, envelopes reconstructed with different apodizations are combined to form an image with an improved apparent lateral resolution. NSI is computationally efficient compared to adaptive beamforming approaches and does not need MBs. Experiments have demonstrated improvements in a resolution of over 100 times compared to conventional delay-and-sum beamforming with no ...

The backscatter coefficient (BSC) has demonstrated the ability to classify disease state and identify the response of cancer to therapy. However, estimating the BSC in vivo using a reference phantom technique does not account for transmission losses due to intervening layers, leading to increase in bias and variance of BSC-based estimates from one sample to the next. To account for transmission losses, an in situ calibration approach is proposed using a titanium sphere that is well-characterized ultrasonically, biocompatible, and embedded inside the sample. Ultrasound scattered from the sphere encounters the same transmission loss and attenuation as the investigated sample and can be used as a reference spectrum. To test the calibration procedures, phantoms were scanned with and without lossy layers on top, and BSCs were estimated using the in situ calibration approach and the reference phantom approach and compared. The differences of the BSCs, using the BSC from the reference phantom without a layer as baseline, were 0.16 ± 2.29 dB, -1.95 ± 2.99 dB and -10.90 ± 3.64 dB using the in situ calibration approach without the layer, with the layer, and using the reference phantom approach with the layer, respectively. The results indicate that an in situ calibration target can account for overlaying tissue losses thereby improving the robustness of BSC-based estimates.The backscatter coefficient (BSC) has demonstrated the ability to classify disease state and identify the response of cancer to therapy. However, estimating the BSC in vivo using a reference phantom technique does not account for transmission losses due to intervening layers, leading to increase in bias and variance of BSC-based estimates from one sample to the next. To account for transmission losses, an in situ calibration approach is proposed using a titanium sphere that is well-characterized ultrasonically, biocompatible, and embedded inside the sample. Ultrasound scattered from the sphere encounters the same transmission loss and attenuation as the investigated sample and can be used as a reference spectrum. To test the calibration procedures, phantoms were scanned with and without lossy layers on top, and BSCs were estimated using the in situ calibration approach and the reference phantom approach and compared. The differences of the BSCs, using the BSC from the reference phantom without a layer as ...

The backscatter coefficient (BSC) is a fundamental property of tissues and can be parameterized for tissue characterization. The BSC requires a reference signal, which is estimated through either the planar reflector method (PRM) or the reference phantom method (RPM). In both methods, linear acoustic propagation is assumed. In this work, the BSC estimation methods are evaluated when nonlinear distortion is present. RF data were acquired from two physical phantoms, labeled A and B, with a 5 MHz single-element transducer using low power (1 excitation level) and high power (6 increasing excitation levels) excitation signals. Phantom A contained glass beads with diameters ranging from 75 to 90 μm and phantom B had glass beads with diameters ranging from 9 to 43 μm. The BSCs estimated using the low power setting and high power settings were compared for the both the PRM and RPM through a root mean square error (RMSE). Estimates of the effective scatterer diameter (ESD) were obtained using each method for each high power setting and compared to the low power setting. The RMSE increased as the power setting increased with much higher RMSEs using the PRM compared to RPM, i.e., a maximum of 7.3 times larger for phantom A and 8.6 times larger for phantom B. Estimates of ESD matched the ranges of glass beads sizes for both phantoms except when using the PRM at higher power settings. These findings suggest that the RPM is more robust to nonlinear distortion effects compare to the PRM.The backscatter coefficient (BSC) is a fundamental property of tissues and can be parameterized for tissue characterization. The BSC requires a reference signal, which is estimated through either the planar reflector method (PRM) or the reference phantom method (RPM). In both methods, linear acoustic propagation is assumed. In this work, the BSC estimation methods are evaluated when nonlinear distortion is present. RF data were acquired from two physical phantoms, labeled A and B, with a 5 MHz single-element transducer using low power (1 excitation level) and high power (6 increasing excitation levels) excitation signals. Phantom A contained glass beads with diameters ranging from 75 to 90 μm and phantom B had glass beads with diameters ranging from 9 to 43 μm. The BSCs estimated using the low power setting and high power settings were compared for the both the PRM and RPM through a root mean square error (RMSE). Estimates of the effective scatterer diameter (ESD) were obtained using each method for each ...

Wireless implanted medical devices (IMDs), which communicate data wirelessly from sensors within the body to a receiver outside of the body, are poised to be significant contributors to medical diagnostics and treatment procedures. Currently, radio frequency (RF) electromagnetic waves are the most frequently used communication method for wireless IMDs. However, high attenuation of RF in the body and strict regulations on the RF frequency spectrum limit the data rates to 267 kbps for in vivo applications. Considering standard definition video streaming requires 1.2 Mbps, and HD requires greater than 3 Mbps, it is not possible to use RF communication, for example, in applications that require real-time video transmission and, possibly, intervention such as real-time video capsule endoscopy. In our work, we use ultrasonic waves to communicate through tissue at video-capable data rates (>1.2 Mbps). Previously, we demonstrated a 4 Mbps data rate with BER less than 1 10-4through beef liver using small, 2-mm biocompatible transducers at 1.3 MHz. In this study, we will investigate the effects of target motion on data rates and demonstrate real-time communication links in situ in a dead animal and in vivo.

Currently, the evaluation of thyroid cancer relies on the use of fine needle aspiration biopsy as non-invasive imaging methods do not provide sufficient levels of accuracy for the diagnosis of this disease. In this study, the potential of quantitative ultrasound methods for characterizing thyroid tissues was studied using a rodent model ex vivo. A high-frequency ultrasonic scanning system (40 MHz) was used to scan thyroids extracted from mice that had spontaneously developed thyroid lesions (cancerous or benign). Three sets of mice were acquired having different predispositions to developing thyroid anomalies (a C-cell adenoma, a papillary thyroid carcinoma (PTC), and a follicular variant papillary thyroid carcinoma (FV-PTC)). A fourth set of mice did not develop thyroid anomalies (normal mice) and were used as controls. The backscatter coefficient was estimated from excised thyroid lobes for the different mice. From the backscatter coefficient versus frequency (25 to 45 MHz), the effective scatterer diameter (ESD) and effective acoustic concentration (EAC) were estimated. From the envelope of the backscattered signal, the homodyned K distribution was used to estimate the k parameter (ratio of coherent to incoherent signal energy) and the μ parameter (number of scatterers per resolution cell). Statistically significant differences were observed between the malignant thyroids and the normal thyroids based on the ESD, EAC and μ parameters. The mean values of the ESDs were 18.0 ± 0.92, 15.9 ± 0.81, and 21.5 ± 1.80 µm for the PTC, FV-PTC and the normal thyroids, respectively. The mean values of the EACs were 59.4 ± 1.74, 62.7 ± 1.61, and 52.9 ± 3.42 dB (mm−3) for the PTC, FV-PTC and the normal thyroids, respectively. The mean values of the μ parameters were 2.55 ± 0.37, 2.59 ± 0.43, and 1.56 ± 0.99 for the PTC, FV-PTC and the normal thyroids, respectively. Statistically significant differences were observed between the malignant thyroids and the C-cell adenomas based on the ESD and EAC parameters with estimated values for the ESD of 21.3 ± 1.50 µm and EAC of 54.7 ± 2.24 dB (mm−3) for the C-cell adenomas. These results suggest that high frequency quantitative ultrasound may enhance the ability to detect and classify diseased thyroid tissues.

Longitudinal imaging techniques are needed that can meaningfully probe the tumor microenvironment and its spatial heterogeneity. Contrast-enhanced ultrasound, shear wave elastography and quantitative ultrasound are ultrasound-based techniques that provide information on the vascular function and micro-/macroscopic tissue structure. Modifications of the tumor microenvironment induced by cytotoxic and anti-angiogenic molecules in ectopic murine Lewis lung carcinoma tumors were monitored. The most heterogenous structures were found in tumors treated with anti-angiogenic drug that simultaneously accumulated the highest levels of necrosis and fibrosis. The anti-angiogenic group presented the highest number of correlations between parameters related to vascular function and those related to the micro-/macrostructure of the tumor microenvironment. Results suggest how patterns of multiparametric ultrasound modifications can be related to provide a more insightful marker of changes occurring within tumors during therapy.

Remote monitoring of patients using wireless capabilities increasingly plays an important role in healthcare and the communication with implanted medical devices (IMDs). In the case of IMDs, transmission is characterized by low peak power and low duty cycle to reduce the potential for adverse bio-effects. Currently, most IMDs use radio-frequency (RF) electromagnetic waves to communicate through the body. The corresponding maximum bandwidth allowed is 300 kHz as regulated by the FCC, which inherently limits the communication rates of these devices (limiting to maximum data rates of 50 kb/s). Beyond bandwidth restrictions, the main limitation for using RF electromagnetic waves in the body is loss of signal because of attenuation in the body. For these reasons the output power of RF devices is limited to 25 µW, which also limits data rates to 50 kb/s. In this study, an ultrasonic communication channel is explored for IMD communications as an alternative to EM transmission. We demonstrate the ability to communicate through tissues using the ultrasonic communications channel while maintaining data rates necessary for streaming of high definition video. In our experiments we used a matched pair of 5-MHz f/3 single-element transducers operating in a pitch-catch configuration in a tank of degassed water. Between the transducers was placed either a slab of pork tenderloin or a slab of beef liver (each more than 2 cm thick). Quadrature amplitude modulation (QAM) and quadrature phase shift keying (QPSK) signals were coded for transmission into the transmitting transducer using an arbitrary waveform generator. Signals were transmitted and captured by sending 10 snapshots (packets) of 50,000 samples (10,000 training / 40,000 decision-directed) using a fractionally-spaced (2 samples per symbol) decision feedback equalizer with up to 40 taps in the feed forward section, and 40 taps in the feedback section. Signals were successfully decoded through the samples using QPSK, 16QAM and 64QAM codes with bit error rates of (BER) < 1e-4. A maximum data rate of 30 Mbps using the 64QAM was achieved through both the pork tenderloin and the beef livers. These experiments successfully demonstrate that communications through the ultrasonic channel can provide data rates capable of streaming high definition video.

Tumor microstructure can potentially be evaluated with quantitative ultrasound (QUS) during therapy, but parameters are influenced by a complex combination of components and modifications in the tumor. To better understand how QUS parameters reflect tumor response to therapy, we estimated effective scatterer diameter (ESD, μm) and effective acoustic concentration (EAC, dB/cm) from ultrasound backscatter measurements in a murine Lewis Lung Carcinoma model on days 7 to 13 after the start of therapy by administration of: anti-angiogenic (AA) agent to inhibit new blood vessels (n = 21); a cytotoxic agent (CA) to damage tumor cells (n = 24) and placebo (n = 24). At D7, there was no significant difference between ESD and EAC for the different therapy groups. At D13, the AA group had higher mean ESD than for CA and placebo (p < 0.005). At D13, the placebo group exhibited a significantly higher EAC compared to the AA (p < 0.005) and was elevated compared to the CA group. Histology showed higher (p < 0.05) necrosis and fibrosis in the AA group at D13 as compared to other groups but no significant differences at D7. Higher mean ESD and lower EAC in the AA group at D13 are consistent with thicker, more sparsely distributed fibrotic structures in the corresponding histology.

According to a 2013 report by the American Society of Civil Engineers, the infrastructure of the United States requires a $3.6 trillion investment to return it to a good condition by 2020[ 1]. A significant portion of the American infrastructure is composed of concrete, which undergoes microcracking damage over time, adversely affecting material mechanical strength, stiffness and permeability compromising the resilience and sustainability of the structural system. Although previous research identified that ultrasonic and other nondestructive approaches can characterize distributed damage content in concrete, the methods are either insensitive to early stages (low crack volumes) of damage, not repeatable, or inconsistent. We hypothesize that contactless, air-coupled ultrasonic techniques based on quantifying the extraction of backscatter energy from surface waves can provide a means of rapidly and robustly assessing microcrack damage in concrete. Ultrasonic surface guided waves in concrete were generated and detected using a fully contactless air-coupled system. Three concrete samples were prepared by varying the content of polymer fiber in the concrete samples to mimic varying degrees (0, 0.3 and 0.6%) of well-controlled and well-distributed microcracking. These samples were compared to a homogeneous sample, which was presumed to have negligible scattering from particulates or cracks in the sample. A 16 cycle tone burst at 50 kHz was transmitted into the concrete samples at an incidence angle of 8° using an electrostatic transducer (Senscomp, Livonia, MI). Contactless silicon-based miniature MEMS acoustic sensors were placed behind the ultrasonic transmitter insulated by a triple-layered acoustic baffle. The MEMS sensors were located a few millimeters above the surface and recorded backscatter from leaky waves traveling in the concrete samples. The energy in the backscattered signals (EB) from the different samples was quantified by integrating the square of the subtracted waves from spatially averaged received signals. These values were then normalized by dividing the energy in the forward propagating wave recorded by a matched MEMS sensor located in front of the transmitter. Normalized EB values for the PMMA, 0, 0.3 and 0.6% concrete samples were 0, 0.001, 0.06 and 0.15, respectively. Statistically significant differences (p < 0.05) were observed between EB values from the 0.3 and 0.6% concrete samples compared to PMMA and 0% and statistically significant differences were observed between the 0.3 and 0.6% concrete samples. By quantifying the EB from surface waves in concrete, the non-contact ultrasonic technique was able to differentiate between samples having different fiber content.

We describe an approach that utilizes ultrasonic surface wave backscatter measurements to characterize the volume content of relatively small distributed defects (microcrack networks) in concrete. A simplified weak scattering model is used to demonstrate that the scattered wave field projected in the direction of the surface wave propagation is relatively insensitive to scatterers that are smaller than the propagating wavelength, while the scattered field projected in the opposite direction is more sensitive to sub-wavelength scatterers. Distributed microcracks in the concrete serve as the small scatterers that interact with a propagating surface wave. Data from a finite element simulation were used to demonstrate the viability of the proposed approach, and also to optimize a testing configuration to collect data. Simulations were validated through experimental measurements of ultrasonic backscattered surface waves from test samples of concrete constructed with different concentrations of fiber filler (0.0, 0.3 and 0.6%) to mimic increasing microcrack volume density and then samples with actual cracking induced by controlled thermal cycles. A surface wave was induced in the concrete samples by a 50 kHz ultrasonic source operating 10 mm above the surface at an angle of incidence of 9°. Silicon-based miniature MEMS acoustic sensors located a few millimeters above the concrete surface both behind and in front of the sender were used to detect leaky ultrasonic surface waves emanating from concrete. A normalized backscattered energy parameter was calculated from the signals. Statistically significant differences in the normalized backscattered energy were observed between concrete samples with varying levels of simulated and actual cracking damage volume.

High frequency quantitative ultrasound techniques were investigated to characterize different forms of cell death in vitro. Suspension-grown acute myeloid leukemia cells were treated to cause apoptosis, oncosis, mitotic arrest, and heat-induced death. Samples were scanned with 20 and 40 MHz ultrasound and assessed histologically in terms of cellular structure. Frequency-domain analysis of 20 MHz ultrasound data demonstrated midband fit changes of 6.0 ± 0.7 dBr, 6.2 ± 1.8 dBr, 4.0 ± 1.0 dBr and -4.6 ± 1.7 dBr after 48-hour cisplatinum-induced apoptosis, 48-hour oncotic decay, 36-hour colchicine-induced mitotic arrest, and heat treatment compared to control, respectively. Trends from 40 MHz ultrasound were similar. Spectral slope changes obtained from 40 MHz ultrasound data were reflective of alterations in cell and nucleus size. Chromatin pyknosis or lysis trends suggested that the density of nuclear material may be responsible for observed changes in ultrasound backscatter. Flow cytometry analysis confirmed the modes of cell death and supported midband fit trends in ultrasound data. Scatterer-size and concentration estimates obtained from a fluid-filled sphere form factor model further corresponded with spectral analysis and histology. Results indicate quantitative ultrasound spectral analysis may be used for probing anti-cancer response and distinguishing various modes of cell death in vitro.

Ultrasound-stimulated microbubbles (MBs) were demonstrated to enhance cell kill from hyperthermia. Definity MBs were injected into wells containing 4T1 cells in culture media and scanned with 1-MHz ultrasound, an exposure duration of 30 s and a negative pressure of 0.5 or 1.3 MPa. Some cell samples were placed in a water bath heated to 42 °C for 5 min. Cell death was quantified. When combining MBs, ultrasound at 1.3 MPa and hyperthermia, more than 58.8% ± 7.21% of cells were nonviable. When exposed to hyperthermia alone or exposure to MBs and ultrasound but no hyperthermia, cell death was less than 10.1% ± 6.96% and 30.1% ± 10.8%, respectively.

Ultrasonic attenuation is important not only as a parameter for characterizing tissue but also for compensating other parameters that are used to classify tissues. Several techniques have been explored for estimating ultrasonic attenuation from backscattered signals. In the present study, a technique is developed to estimate the local ultrasonic attenuation coefficient by analyzing the time domain backscattered signal. The proposed method incorporates an objective function that combines the diffraction pattern of the source/receiver with the attenuation slope in an integral equation. The technique was assessed through simulations and validated through experiments with a tissue mimicking phantom and fresh rabbit liver samples. The attenuation values estimated using the proposed technique were compared with the attenuation estimated using insertion loss measurements. For a data block size of 15 pulse lengths axially and 15 beamwidths laterally, the mean attenuation estimates from the tissue mimicking phantoms were within 10% of the estimates using insertion loss measurements. With a data block size of 20 pulse lengths axially and 20 beamwidths laterally, the error in the attenuation values estimated from the liver samples were within 10% of the attenuation values estimated from the insertion loss measurements.

Ultrasound contrast agents (UCAs) have been explored as a means to enhance therapeutic techniques. Because the effectiveness of these techniques relies on the UCA concentration at a target site, it would be beneficial to estimate UCA concentration noninvasively. In this study, a noninvasive method for estimating UCA concentration was developed in vitro. Backscatter coefficients (BSCs) estimated from measurements of Definity(®) UCAs were fitted to a theoretical scattering model in the 15-25 MHz range using a Levenberg-Marquardt regression technique. The model was defined by the UCA size distribution and concentration, and therefore concentration estimates were extracted directly from the fit. Calculation of the BSC was accomplished using planar reference measurements from the back wall of a Plexiglas(®) chamber and an average of 500 snapshots of ultrasonic backscatter from UCAs flowing through the chamber. In order to verify the ultrasonically derived UCA concentration estimates, a sample of the UCAs was extracted from the flow path and the concentration was estimated with a hemacytometer. UCA concentrations of 1, 2, and 5 times the dose recommended by the manufacturer were used in experiments. All BSC-based estimates were within one standard deviation of hemacytometer based estimates for peak rarefactional pressures of 100-400 kPa.

Quantitative ultrasound (QUS) is an imaging technique that can be used to quantify tissue microstructure giving rise to scattered ultrasound. Other ultrasonic properties, e.g., sound speed and attenuation, of tissues have been estimated versus temperature elevation and found to have a dependence with temperature. Therefore, it is hypothesized that QUS parameters may be sensitive to changes in tissue microstructure due to temperature elevation. Ultrasonic backscatter experiments were performed on tissue-mimicking phantoms and freshly excised rabbit and beef liver samples. The phantoms were made of agar and contained either mouse mammary carcinoma cells (4T1) or chinese hamster ovary cells (CHO) as scatterers. All scatterers were uniformly distributed spatially at random throughout the phantoms. All the samples were scanned using a 20-MHz single-element f∕3 transducer. Quantitative ultrasound parameters were estimated from the samples versus increases in temperature from 37 °C to 50 °C in 1 °C increments. Two QUS parameters were estimated from the backscatter coefficient [effective scatterer diameter (ESD) and effective acoustic concentration (EAC)] using a spherical Gaussian scattering model. Significant increases in ESD and decreases in EAC of 20%–40% were observed in the samples over the range of temperatures examined. The results of this study indicate that QUS parameters are sensitive to changes in temperature.

Three-dimensional impedance maps (3DZMs) are virtual volumes of acoustic impedance values constructed from histology to represent tissue microstructure acoustically. From the 3DZM, estimations can be made for ultrasonic backscatter and scatterer properties, such as effective scatterer diameter (ESD). Additionally, the 3DZM can be exploited to visualize and identify possible scattering sites, which may aid in the development of more effective scattering models to better represent the ultrasonic interaction with underlying tissue microstructure. In this study, 3DZMs were created from several human fibroadenoma samples. ESD estimates were obtained using the fluid-filled sphere form factor model. These estimates were made using two regions of interest (ROIs) sizes: cubes of side length 300 µm and 150 µm. This estimation technique allowed a better understanding of the spatial distribution and variability of the estimates throughout the volume. For a collection of 33 3DZMs, the ESD was estimated to be 99±43 µm with the large ROI and 65±30 µm when using the small ROI. The 3DZMs were then investigated visually to identify possible scattering sources, which conformed to the estimated characteristic scatterer dimensions. This visualization and comparison resulted in the identification of possible ultrasonic scattering sources within human fibroadenomas.

The ultimate goal of quantitative ultrasound (QUS) imaging methods based on backscatter coefficient (BSC) estimates is to obtain system-independent structural information about samples. In the current study, three BSC estimation methods were compared and evaluated using the same backscattered pressure datasets in order to assess their consistency. BSC estimates were obtained from two phantoms with embedded glass spheres and compared to theoretical BSCs calculated using size distributions estimated using optical microscopy. Effective scatterer diameter and concentration estimates of the glass spheres were also obtained from the estimated BSCs. One estimation method needed to be compensated by more than an order of magnitude in amplitude in order to produce BSCs comparable to the other two methods. All calibration methods introduced different frequency-dependent effects, which could have noticeable effects on the bias of QUS estimates derived from experimental BSCs. Although in most cases the experimental QUS estimates obtained with all three methods were observed to differ by less than 10%, larger differences are expected depending on both the pressure focusing gain of the transducer (proportional to the ratio of the square of the aperture radius to the product of the wavelength and focal length) and ka range used in the estimation.

Quantitative imaging methods using high-frequency ultrasound (HFU) offer a means of characterizing biological tissue at the microscopic level. Previously, high-frequency, 3-D quantitative ultrasound (QUS) methods were developed to characterize 46 freshly-dissected lymph nodes of colorectal-cancer patients. 3-D ultrasound radiofrequency data were acquired using a 25.6 MHz center-frequency transducer and each node was inked before tissue fixation to recover orientation after sectioning for 3-D histological evaluation. Backscattered echo signals were processed using 3-D cylindrical regions-of-interest (ROIs) to yield four QUS estimates associated with tissue microstructure (i.e., effective scatterer size, acoustic concentration, intercept and slope). These QUS estimates, obtained by parameterizing the backscatter spectrum, showed great potential for cancer detection. In the present study, these QUS methods were applied to 112 lymph nodes from 77 colorectal and gastric cancer patients. Novel QUS methods parameterizing the envelope statistics of the ROIs using Nakagami and homodyned-K distributions were also developed; they yielded four additional QUS estimates. The ability of these eight QUS estimates to classify lymph nodes and detect cancer was evaluated using receiver operating characteristics (ROC) curves. An area under the ROC curve of 0.996 with specificity and sensitivity of 95% were obtained by combining effective scatterer size and one envelope parameter based on the homodyned-K distribution. Therefore, these advanced 3-D QUS methods potentially can be valuable for detecting small metastatic foci in dissected lymph nodes.

Quantitative ultrasound (QUS) techniques have been widely used to estimate the size, shape and mechanical properties of tissue microstructure for specified regions of interest (ROIs). For conventional methods, an ROI size of 4 to 5 beamwidths laterally and 15 to 20 spatial pulse lengths axially has been suggested to estimate accuracy and precision better than 10% and 5%, respectively. A new method is developed to decrease the standard deviation of the quantitative ultrasound parameter estimate in terms of effective scatterer diameter (ESD) for small ROIs. The new method yielded estimates of the ESD within 10% of actual values at an ROI size of five spatial pulse lengths axially by two beamwidths laterally, and the estimates from all the ROIs had a standard deviation of 15% of the mean value. Such accuracy and precision cannot be achieved using conventional techniques with similar ROI sizes.

The use of wireless implanted medical devices (IMDs), which communicate data wirelessly from sensors within the body to a receiver outside of the body, are gaining significant momentum in medical diagnosis and treatment procedures. Currently, radio frequency (RF) electromagnetic waves are the most frequently used communication method for wireless IMDs. However, there are various drawbacks of using RF electromagnetic waves in such applications such as high attenuation in the body and strictly regulated frequency spectrum, which consequently limit data rates of these devices. An alternative approach to RF transmission for IMDs uses ultrasonic waves, which experience lower attenuation in the body and have higher available bandwidth. In our work, we aim to demonstrate high data rate (>1.2 Mbps) through tissue communication using ultrasonic waves that will allow us to stream video with an IMD while actively controlling it inside the body. Initial experiments performed with 2mm biocompatible sonomicrometry transducers, where 2.4 Mbps data rate BER less than 5E-5 through water is achieved, demonstrating the capability of this method for high speed data transmission. Additional targets of this work include data transmission through beef liver and a live rabbit abdominal wall with high enough data rates capable of video streaming.The use of wireless implanted medical devices (IMDs), which communicate data wirelessly from sensors within the body to a receiver outside of the body, are gaining significant momentum in medical diagnosis and treatment procedures. Currently, radio frequency (RF) electromagnetic waves are the most frequently used communication method for wireless IMDs. However, there are various drawbacks of using RF electromagnetic waves in such applications such as high attenuation in the body and strictly regulated frequency spectrum, which consequently limit data rates of these devices. An alternative approach to RF transmission for IMDs uses ultrasonic waves, which experience lower attenuation in the body and have higher available bandwidth. In our work, we aim to demonstrate high data rate (>1.2 Mbps) through tissue communication using ultrasonic waves that will allow us to stream video with an IMD while actively controlling it inside the body. Initial experiments performed with 2mm biocompatible sonomicrometry tran...

To translate quantitative ultrasound (QUS) from the laboratory into the clinic, it is necessary to demonstrate that the measurements are platform independent. Because the backscatter coefficient (BSC) is the fundamental estimate from which additional QUS estimates are calculated, agreement between BSC results using different systems must be demonstrated. This study was an intercomparison of BSCs from in vivo spontaneous rat mammary tumors acquired by different groups using 3 clinical array systems and a single-element laboratory scanner system.Radio frequency data spanning the 1- to 14-MHz frequency range were acquired in 3 dimensions from all animals using each system. Each group processed their radio frequency data independently, and the resulting BSCs were compared. The rat tumors were diagnosed as either carcinoma or fibroadenoma.Carcinoma BSC results exhibited small variations between the multiple slices acquired with each transducer, with similar slopes of BSC versus frequency for all systems. Somewhat larger variations were observed in fibroadenomas, although BSC variations between slices of the same tumor were of comparable magnitude to variations between transducers and systems. The root mean squared (RMS) errors between different transducers and imaging platforms were highly variable. The lowest RMS errors were observed for the fibroadenomas between 4 and 5 MHz, with an average RMS error of 4 x 10(-5) cm(-1)Sr(-1) and an average BSC value of 7.1 x 10(-4) cm(-1)Sr(-1), or approximately 5% error. The highest errors were observed for the carcinoma between 7 and 8 MHz, with an RMS error of 1.1 x 10(-1) cm(-1)Sr(-1) and an average BSC value of 3.5 x 10(-2) cm(-1)Sr(-1), or approximately 300% error.This technical advance shows the potential for QUS technology to function with different imaging platforms.

Quantitative ultrasound (QUS) imaging can improve the diagnostic capabilities of ultrasound. Spectral-based QUS approaches utilize backscattered ultrasound signals to extract additional information about tissue state. These technique have traditionally relied on scattering models to differentiate tissue state. However, the use of machine learning approaches may obviate the need for models. A model-based and model-free (principle component analysis (PCA)) approach to spectral-based QUS were compared for their ability to differentiate fatty from non-fatty liver in a rabbit model. PCA was observed to provide better differentiation of fatty from non-fatty liver, i.e., PCA predicted fatty liver 86% of the time versus 36% for model-based. In addition, three calibration approaches for spectral-based QUS were compared: the traditional reference phantom, reference free, and an in situ calibration target. To test the calibration procedures, a phantom was scanned with and without a lossy layer placed on top and integrated backscatter coefficients (IBSCs) were calculated from the scattered data. Utilizing an in situ calibration target provided the ability to account for transmission losses and attenuation. The root mean square error between IBSCs estimated from the phantom with and without the lossy layer were 8.28 for the reference phantom versus 1.24 for the in situ calibration approach.

Objective Estimates of ultrasonic attenuation (the loss of energy as an ultrasonic wave propagates through tissue) have been used to evaluate the structure and function of tissues in health and disease. The purpose of this research was to develop a method to estimate ultrasonic cervical attenuation during human pregnancy using a clinical ultrasound system. Methods Forty women underwent a cervical scan once during pregnancy with the Zonare® z.one clinical ultrasound system using a 4–9-MHz endovaginal transducer. This ultrasound system provides access to radiofrequency (RF) image data for processing and analysis. In addition, a scan of a tissue-mimicking phantom with a known attenuation coefficient was acquired and used as a reference. The same settings and transducer used in the clinical scan were used in the reference scan. Digital data of the beam-formed image were saved in Digital Imaging and Communications in Medicine (DICOM) format on a flash drive and converted to RF data on a personal computer using a Matlab® program supplied by Zonare. Attenuation estimates were obtained using an algorithm that was independently validated using tissue-mimicking ultrasonic phantoms. Results RF data were acquired and analyzed to estimate attenuation of the human pregnant cervix. Regression analysis revealed that attenuation was: a predictor of the interval from ultrasound examination to delivery (β = 0.43, P = 0.01); not a predictor of gestational age at time of examination (β = − 0.23, P = 0.15); and not a predictor of cervical length (β = 0.077, P = 0.65). Conclusions Ultrasonic attenuation estimates have the potential to be an early and objective non-invasive method to detect interval between examination and delivery. We hypothesize that a larger sample size and a longitudinal study design will be needed to detect gestational age-associated changes in cervical attenuation. Copyright © 2010 ISUOG. Published by John Wiley & Sons, Ltd.

A novel coded-excitation method, resolution-enhancement compression (REC), increases the axial resolution and the echo signal-to-noise ratio (eSNR) for an ultrasonic imaging system. The REC technique was examined for its ability to improve lesion detectability. The REC technique was used to double the −3-dB fractional pulse-echo bandwidth of an ultrasonic source in both simulations and experiments. The increase in usable bandwidth increased lesion detectability compared to conventional pulsing (CP) techniques and coded excitation using a linear chirp (LC). Lesion detectibility was quantified through lesion signal-to-noise ratio (lSNR), which is a metric that quantifies the ability of an isolated observer to detect a focal lesion against a background. In simulations, a higher lSNR value was observed using the REC technique for lesions ranging in size from 1 mm to 8 mm in diameter. In addition, the eSNR was increased by almost 15 dB. To validate simulation results, a hydrogel-cone phantom was constructed to provide lesions with +6-dB contrast of different sizes. A transducer was scanned perpendicular to the major axis of the cone at different levels to provide lesions of 3, 5 and 8 mm in diameter. The lSNR was estimated for lesions of different sizes and using the three excitation techniques, i.e., CP, LC and REC. In experiments, the lSNR was observed to be higher using the REC technique than the other pulsing techniques. The lSNR scores for REC were higher by 15%, 45% and 40% for the 3, 5 and 8 mm over the other two excitation techniques. The eSNR was increased by 5.7 dB. Therefore, accrding to the lSNR metric, the improvement in spatial resolution from the REC technique resulted in improved detectability of small lesions.

The frequency-dependent ultrasound backscatter from tissues contains information about the microstructure that can be quantified. In many cases, the anatomic microstructure details responsible for ultrasonic scattering remain unidentified. However, their identification would lead to potentially improved methodologies for characterizing tissue and diagnosing disease from ultrasonic backscatter measurements. Recently, three-dimensional (3D) acoustic models of tissue microstructure, termed 3D impedance maps (3DZMs), were introduced to help to identify scattering sources [J. Mamou, M. L. Oelze, W. D. O’Brien, Jr., and J. F. Zachary, “Identifying ultrasonic scattering sites from 3D impedance maps,” J. Acoust. Soc. Am. 117, 413–423 (2005)]. In the current study, new 3DZM methodologies are used to model and identify scattering structures. New processing procedures (e.g., registration, interpolations) are presented that allow more accurate 3DZMs to be constructed from histology. New strategies are proposed to construct scattering models [i.e., form factor (FF)] from 3DZMs. These new methods are tested on simulated 3DZMs, and then used to evaluate 3DZMs from three different rodent tumor models. Simulation results demonstrate the ability of the extended strategies to accurately predict FFs and estimate scatterer properties. Using the 3DZM methods, distinct FFs and scatterer properties were obtained for each tumor examined.

Previous tomographic methods using ultrasound for reconstructing sound speed and attenuation images suffered from convergence issues for targets with moderate speed of sound contrast. Convergence problems can be overcome by the use of the multiple frequency, distorted Born iterative method (DBIM). The implementation of DBIM for measurement configurations in which receiver positions are fixed was studied, and a novel regularization scheme was developed. The regularization parameter needed to stabilize the inversion process initially was found through the Rayleigh quotient iteration, then relaxed according to the relative residual error between the measured and estimated scattered fields. The DBIM was successfully stabilized for both full and partial receiver angular coverage without a significant loss in spatial resolution. The effects of variable density in the reconstructions were briefly explored through simulations. The ability to reconstruct targets with moderate contrast was validated through experimental measurements. Speed of sound profiles for balloons filled with saline in a background of water were reconstructed using multiple frequency DBIM techniques. The mean squared error for speed of sound reconstructions of the balloon phantoms with 16.4% sound speed contrast was 1.1%.

A novel pulse compression technique is developed that improves the axial resolution of an ultrasonic imaging system and provides a boost in the echo signal-to-noise ratio (eSNR). The new technique, called the resolution enhancement compression (REC) technique, was validated with simulations and experimental measurements. Image quality was examined in terms of three metrics: the eSNR, the bandwidth, and the axial resolution through the modulation transfer function (MTF). Simulations were conducted with a weakly-focused, single-element ultrasound source with a center frequency of 2.25 MHz. Experimental measurements were carried out with a single-element transducer (f/3) with a center frequency of 2.25 MHz from a planar reflector and wire targets. In simulations, axial resolution of the ultrasonic imaging system was almost doubled using the REC technique (0.29 mm) versus conventional pulsing techniques (0.60 mm). The -3 dB pulse/echo bandwidth was more than doubled from 48% to 97%, and maximum range sidelobes were -40 dB. Experimental measurements revealed an improvement in axial resolution using the REC technique (0.31 mm) versus conventional pulsing (0.44 mm). The -3 dB pulse/echo bandwidth was doubled from 56% to 113%, and maximum range sidelobes were observed at -45 dB. In addition, a significant gain in eSNR (9 to 16.2 dB) was achieved.

In this pilot study, focused ultrasound (FUS) was used to produce hyperthermia in cervical lymph nodes of rats having experimental autoimmune encephalomyelitis (EAE) to alleviate symptoms associated with EAE. EAE was induced in dark agouti rats, and EAE scores were recorded over 21 d. At the onset of EAE symptoms, rats were treated with FUS to induce temperatures of 43–44°C for 20 min in the superficial cervical lymph nodes. An EAE remittance score was tallied for all rats, defined as the maximum EAE score observed minus the minimum EAE score observed after the maximum EAE was reached. On average, the peak remittance score for FUS-treated rats was 1.14 ± 0.48 versus 0.33 ± 0.27 for sham-treated rats. These differences were statistically significant ( p = 0.037). Therefore, FUS treatment of cervical lymph nodes in rats with EAE resulted in a significant reduction in EAE score.