Diagnostic Ultrasound Imaging Research Articles

Validation of a deep-learning modular prototype to guide novices to acquire diagnostic ultrasound images from urinary system

ImportanceArtificial intelligence (AI) application in guiding the acquisition of ultrasonography images represents a pioneering field of research. A new developed hybrid deep-learning (DL) algorithm, trained on more than high quality 60.000 curated and labelled reference images (distilled from a set of more than 600.000 abdominal ultrasound images) from La Paz Hospital, can provide real-time prescriptive guidance for novice operators to obtain standard planes images of the target organs. ObjectiveThis study aims to evaluate the capability of novice users to acquire diagnostic-quality abdominal ultrasound images of the urinary system using the deep-learning (DL)-based guiding research prototype provided by GMV. DesignSetting, and Participants: This prospective diagnostic study was conducted within the facilities of an academic hospital. A cohort of 24 technically-oriented volunteers, lacking prior knowledge in anatomy or medicine and without experience in conducting ultrasound examinations, was recruited. After a brief training session focused on various organs, each pair of volunteers performed scans of each other's urinary system, exclusively guided by AI support. These scans were subsequently repeated by experienced sonographers using identical ultrasound equipment but without AI assistance. Four radiologists, each with decades of experience, independently and blindly assessed the quality of each acquisition. ResultsOver 90.6 % of the images scanned by volunteers were identified as valuable clinical picture, using only an AI-based guidance system. This is nearly comparable to the results achieved by experienced radiologists, who attained a 98.6 % success rate. ConclusionsThis deep-learning (DL) prototype enables novices lacking experience in ultrasonography to acquire diagnostic ultrasound images suitable for subsequent expert evaluation. The modular prototype works on a large range of ultrasound device models and vendors. This advancement has the potential to extend the application of ultrasound beyond traditional clinical environments, particularly in situations requiring immediate anatomical and functional interrogation, as well as in resource-limited settings.

Comparative study of two diagnostic methods, ultrasound and Magnetic Resonance Imaging in measurement of the angle and depth of trochlear groove

Comparative study of two diagnostic methods, ultrasound and Magnetic Resonance Imaging in measurement of the angle and depth of trochlear groove

DIAGNOSIS AND TREATMENT OF ACUTE ACHILLES TENDON RUPTURE: A COMPREHENSIVE SYSTEMATIC REVIEW

Background: Achilles tendon rupture is a common orthopaedic injury that results in substantial functional limitations throughout a lengthy recovery time. The increasing incidence of Achilles tendon ruptures has been well documented in population-based studies. The delayed treatment of AT ruptures is usually attributable to either poor diagnosis upon injury or patients disregarding their injuries and not presenting to healthcare facilities. The aim: The aim of this study to show about diagnosis and treatment of acute achilles tendon rupture. Methods: By the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020, this study was able to show that it met all of the requirements. This search approach, publications that came out between 2014 and 2024 were taken into account. Several different online reference sources, like Pubmed, SagePub, and Google Scholar were used to do this. It was decided not to take into account review pieces, works that had already been published, or works that were only half done. Result: In the PubMed database, the results of our search get 17 articles, whereas the results of our search on SagePub get 299 articles, on Google Scholar 6990 articles. Records remove before screening are 5317, so we get 1989 articles fos screening. After we screened based on record exclude, we compiled a total of 12 papers. We included five research that met the criteria. Conclusion: Multiple evaluative techniques including the addition of diagnostic ultrasound imaging and continuous shear wave elastography (cSWE) to standard clinical tests and measures were used to assess patient-reported symptoms, tendon structure, and tendon functional performance. As treatment recommendations and strategies evolve, decisional conflict may arise when patients with Achilles tendon ruptures are faced with the need to choose a management option. There have been several reviews of management strategies, primarily focused on pairwise comparisons between individual operative and non-operative strategies.

Effects of Polyurethane Absorber for Improving the Contrast between Fascia and Muscle in Diagnostic Ultrasound Images

Effects of Polyurethane Absorber for Improving the Contrast between Fascia and Muscle in Diagnostic Ultrasound Images

Dosage dependent subharmonic response and ambient pressure sensitivity of sonazoid microbubbles for subharmonic aided pressure estimation

Microbubbles are micron-sized contrast-increasing agents for diagnostic ultrasound imaging. At half of the excitation frequency due to nonlinear oscillations, they generate a subharmonic response, the magnitude of which changes by the ambient pressure. Subharmonic Aided Pressure Estimation (SHAPE) is a noninvasive method to measure local in vivo pressure utilizing subharmonic emission from microbubbles using medical ultrasound. In this study, we investigated the in vitro dosage effect of Sonazoid, a commercially available microbubble, on SHAPE. We subjected Sonazoid microbubbles to acoustic excitations ranging from 100 to 700 kPa peak negative pressure (PNP) and at a frequency of 3 MHz. We increased the ambient pressure up to 20 kPa and investigated the change in subharmonic signal during eight pressurizing-depressurizing cycles. We observed two different behaviors of subharmonic responses over investigated parameters. Subharmonic response increased significantly with increasing ambient pressure under low PNP excitations for sufficiently high concentrations. Meanwhile, increased ambient pressure at higher PNPs drastically reduced the subharmonic response for sufficiently low concentrations. Reported findings are crucial for characterizing the SHAPE performance of Sonazoid microbubbles, offering valuable insights for improved, consistent, and cost-efficient practice.

Sonographic imaging education for sonographers versus health professionals: A literature review

AbstractBackgroundSonographers are tertiary qualified health professionals who acquire, measure, and interpret diagnostic ultrasound images. Ultrasound is also used by many health professionals other than sonographers. As the imaging objectives of these two groups differs, and in the interest of enhancing education, we performed a literature review.MethodResearch questions drove the literature search that initially yielded >4,000 articles: subject and theme relevance checks reduced this to a final selection of 44. Based on dominant themes within articles, the final 44 were placed into 7 categories, 3 in ‘skills development’ and 4 in ‘educational methods’ domains. In each category, articles were grouped by research participant type: 1. Sonographer or 2. Health Professional, and citation frequency used to measure impact.ResultSix sonographer‐focused and 16 health professional focused articles were assigned to the skills development domain. The highest impact sonographer‐focused article emphasised psychomotor skills for optimal development, the highest impact health professional focused article centered on rapid image acquisition and interpretation. Six sonographer‐focused and 16 health professional focused articles were assigned to the educational methods domain. The highest impact sonographer‐focused article identified a limitation of high‐fidelity simulators, the highest impact health professional focused article cited a limitation of education delivery.ConclusionDifferent sonographic imaging skills and educational methods are used for sonographers and health professionals. Sonographers utilise a wide range of imaging skills: teaching methods should be tailored accordingly. Health professionals rely on condensed imaging skills and standardised protocols: this requires a customised approach and may be enhanced by sonographer involvement.

The Value of Ultrasound Diagnostic Imaging of Anterior Crucial Ligament Tears Verified Using Experimental and Arthroscopic Investigations

This study investigates the potential of the ultrasound imaging technique in the assessment of Anterior Cruciate Ligament (ACL) pathologies by standardizing the examination process. We focused on four key ultrasound parameters: the inclination of the ACL; swelling or scarring at the ACL’s proximal attachment to the lateral femoral condyle; swelling or scarring of the ACL/posterior cruciate ligament (PCL) compartment complex with accompanying morphological changes in the posterior joint capsule; and dynamic instability, categorized into three ranges—0–2 mm, 3–4 mm, and ≥5 mm. The study group consisted of 25 patients with an ACL injury and 25 controls. All four tested parameters were found more frequently in the study group compared to the control (p < 0.0001). Our findings suggest that this standardized approach significantly augments the diagnostic capabilities of ultrasound, complementing clinical evaluation and magnetic resonance imaging (MRI) findings. The meticulous assessment of these parameters proved crucial in identifying subtle ACL pathologies, which might otherwise be missed in conventional imaging modalities. Notably, the quantification of dynamic instability and the evaluation of morphological changes were instrumental in early detection of ACL injuries, thereby facilitating more precise and effective treatment planning. This study underscores the importance of a standardized ultrasound protocol in the accurate diagnosis and management of ACL injuries, proposing a more comprehensive diagnostic tool for clinicians in the field of sports medicine and orthopedics.

Design of Preamplifier for Ultrasound Transducers

In diagnostic ultrasound imaging applications, preamplifiers are used as first-stage analog front-end amplifiers for ultrasound transducers because they can amplify weak acoustic signals generated directly by ultrasound transducers. For emerging diagnostic ultrasound imaging applications, different types of preamplifiers with specific design parameters and circuit topologies have been developed, depending on the types of the ultrasound transducer. In particular, the design parameters of the preamplifier, such as the gain, bandwidth, input- or output-referred noise components, and power consumption, have a tradeoff relationship. Guidelines on the detailed design concept, design parameters, and specific circuit design techniques of the preamplifier used for ultrasound transducers are outlined in this paper, aiming to help circuit designers and academic researchers optimize the performance of ultrasound transducers used in the diagnostic ultrasound imaging applications for research directions.

Task Space Compliant Control and Six-Dimensional Force Regulation Toward Automated Robotic Ultrasound Imaging

<italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">Objective:</i> We propose a general control framework for task space compliant motion and six-dimensional (6-D) force regulation towards automated robotic ultrasound (US) imaging. The framework endows a position-controlled robotic manipulator with the capability of accurate compliant motion in free space and accurate force control in motion-constrained environment. <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">Methods:</i> An intuitive six degree-of-freedom (6-DoF) admittance control model expressed in an arbitrary Cartesian body frame is mathematically derived with closed-form task space error mapping. Its practical implementation on widely-used collaborative manipulators is proposed to achieve full task space compliant behaviors and accurate 6-D force control. A hybrid control law is presented to achieve good motion accuracy in free space and improved coupled stability in motion-constrained environment. The coupled model of physical human-robot interaction is established and the reason for the improved coupled stability is analyzed through simulation. <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">Results:</i> Evaluation experiments on the proposed control framework were performed to show the effectiveness. The mean error of compliant trajectory following was less than 0.30 mm in free space. The mean relative force and moment control accuracy in three orthogonal directions was better than 0.5% and 0.8%, respectively. The improved coupled stability under the same model parameters was also confirmed by human-robot interaction experiments. Finally, an automated robotic US imaging experiment on a human volunteer in a real clinical scenario was carried out to show the potential application of our proposed framework. <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">Conclusion:</i> Experimental results have shown the advantages of the control framework, including satisfied force control accuracy, high accuracy of compliant motion, improved coupled stability, and system effectiveness on a human volunteer. <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">Note to Practitioners</i> —This paper was motivated by the increasing needs of automated ultrasound (US) scanning for both diagnostic and interventional purpose. Clinical sonographers suffer from repeated workload when performing diagnostic US imaging, which could benefit from automated robotic scanning. Robotic US imaging involves physical interaction between the robot end-effector (i.e., US transducer) and the human body. The dynamics of the interaction is regulated by the control law to guarantee the contact of the US transducer and the safety of the procedure. Most existing works have focused on regulating in-plane contact force in terms of the position without considering the compliance in other dimensions. However, it is not a trivial work to extend the positional compliance to six degree-of-freedom (6-DoF) compliance. As the prevalence of low-cost collaborative robotic arms in medical scenarios, how to perform 6-DoF compliant trajectory following and accurate six-dimensional (6-D) force control on these robotic arms becomes increasingly important. This paper gives a complete general solution to achieve 6-DoF compliant control and 6-D force regulation with accurate kinematics on a position-controlled robotic arm. A hybrid control law is proposed to switch the government of “instantaneous model” and “theoretical model” to achieve compliant motion accuracy in free space and improved coupled stability in motion-constrained environment. No expensive torque sensors and torque control interface are required. And no prior geometric knowledge about the scanning object is needed. We have demonstrated the application for robotic US imaging in a real clinical scenario.

Development and validation of a gel wax phantom to evaluate geometric accuracy and measurement of a hyperechoic target diameter in diagnostic ultrasound imaging.

Diagnostic ultrasound (US) scanners are generally evaluated using proprietary quality assurance (QA) phantoms, but their prohibitively high cost may prevent organizations to perform the necessary tests. This study aimed to develop a low-cost gel wax phantom with targets to determine the lateral and axial resolution and diameter of a hyperechoic target in an US scanner. The acoustic property (AP) of gel wax, which includes the speed of sound (cus), acoustic impedance (Z), and attenuation coefficient (µ), were determined for multiple transducers operating at 2.25, 5, 10, 15, and 30MHz. These results were compared to the AP of soft tissue. Two polytetrafluoroethylene (PTFE) rectangular frames with holes separated by 5, 10, and 20mm were constructed. Nylon filaments and stainless-steel disc (SS disc) (diameter = 16.8mm) were threaded through the frames and suitably placed in gel wax to obtain orthogonal targets in the phantom. The target dimensions obtained from computerized tomography (CT) and US images of the phantom were compared for phantom validation. The average cus=1431.4m/s, mass density ρ = 0.87g/cm3, Z = 1.24 MRayls, and µ ranged from 0.7 to 0.98 dB/cm/MHz for gel wax at 22°C. The US image measurement exhibited a maximum error in determining the diameter of the SS disc, resulting in a value of 18mm instead of its actual value of 16.8mm. The phantom volume decreased by 1.8% in 62 weeks. The present phantom is affordable, stable, customizable, and can be used to evaluate diagnostic US scanners across multiple centers.

Computed tomographic contrast tenography aids pre‐operative diagnosis in clinical conditions of the digital flexor tendon sheath

SummaryCommon pathology within the digital flexor tendon sheath (DFTS) includes tearing of the manica flexoria, marginal longitudinal lesions of the deep digital flexor tendon and fetlock canal constriction. These are a frequent cause of lameness in cob‐type breeds where skin thickness can make obtaining diagnostic ultrasound images difficult. Radiographic contrast tenography in the standing patient can be used to identify pathology but provides limited information on the exact lesion configuration. This report describes the use of computed tomographic contrast tenography under general anaesthesia to identify and detail the configuration of intrathecal DFTS pathology in four clinical cases (six limbs) subsequently assessed with DFTS tenoscopy. Computed tomography findings altered surgical planning in two cases, and in all cases computed tomography findings were confirmed by tenoscopy. Computed tomographic contrast tenography correctly predicted all lesions observed during tenoscopy: manica flexoria pathology including laterality (4/4 torn and 2/2 intact), fetlock canal constriction (3/3 limbs), deep digital flexor tendon injury (1/1) and intrathecal adhesions (5/5 limbs). Computed tomographic contrast tenography was a useful pre‐operative imaging modality which aided surgical planning. The technique may be applicable for use in standing computed tomography systems where it would provide the diagnostic benefits listed without the associated risk of prolonging anaesthesia.

A Multiscale Deep Encoder–Decoder with Phase Congruency Algorithm Based on Deep Learning for Improving Diagnostic Ultrasound Image Quality

Ultrasound imaging is widely used as a noninvasive lesion detection method in diagnostic medicine. Improving the quality of these ultrasound images is very important for accurate diagnosis, and deep learning-based algorithms have gained significant attention. This study proposes a multiscale deep encoder–decoder with phase congruency (MSDEPC) algorithm based on deep learning to improve the quality of diagnostic ultrasound images. The MSDEPC algorithm included low-resolution (LR) images and edges as inputs and constructed a multiscale convolution and deconvolution network. Simulations were conducted using the Field 2 program, and data from real experimental research were obtained using five clinical datasets containing images of the carotid artery, liver hemangiomas, breast malignancy, thyroid carcinomas, and obstetric nuchal translucency. LR images, bicubic interpolation, and super-resolution convolutional neural networks (SRCNNs) were modeled as comparison groups. Through visual assessment, the image processed using the MSDEPC was the clearest, and the lesions were clearly distinguished. The structural similarity index metric (SSIM) value of the simulated ultrasound image using the MSDEPC algorithm improved by approximately 38.84% compared to LR. In addition, the peak signal-to-noise ratio (PSNR) and SSIM values of clinical ultrasound images using the MSDEPC algorithm improved by approximately 2.33 times and 88.58%, respectively, compared to LR. In conclusion, the MSDEPC algorithm is expected to significantly improve the spatial resolution of ultrasound images.

Rib detection using pitch-catch ultrasound and classification algorithms for a novel ultrasound therapy device

BackgroundNoninvasive ultrasound (US) has been used therapeutically for decades, with applications in tissue ablation, lithotripsy, and physical therapy. There is increasing evidence that low intensity US stimulation of organs can alter physiological and clinical outcomes for treatment of health disorders including rheumatoid arthritis and diabetes. One major translational challenge is designing portable and reliable US devices that can be used by patients in their homes, with automated features to detect rib location and aid in efficient transmission of energy to organs of interest. This feasibility study aimed to assess efficacy in rib bone detection without conventional imaging, using a single channel US pitch-catch technique integrated into an US therapy device to detect pulsed US reflections from ribs.MethodsIn 20 healthy volunteers, the location of the ribs and spleen were identified using a diagnostic US imaging system. Reflected ultrasound signals were recorded at five positions over the spleen and adjacent ribs using the therapy device. Signals were classified as between ribs (intercostal), partially over a rib, or fully over a rib using four models: threshold-based time domain classification, threshold-based frequency domain classification, logistic regression, and support vector machine (SVM).ResultsSVM performed best overall on the All Participants cohort with accuracy up to 96.25%. All models’ accuracies were improved by separating participants into two cohorts based on Body Mass Index (BMI) and re-fitting each model. After separation into Low BMI and High BMI cohorts, a simple time-thresholding approach achieved accuracies up to 100% and 93.75%, respectively.ConclusionThese results demonstrate that US reflection signal classification can accurately provide low complexity, real-time automated onboard rib detection and user feedback to advance at-home therapeutic US delivery.

The Value of Ultrasound Diagnostic Imaging of Meniscal Knee Injuries Verified by Experimental and Arthroscopic Investigations.

(1) Introduction: Meniscal knee injuries may develop as the result of trauma or overloading. Ultrasound imaging is an observer-dependent modality, meaning that the assessment of structural damage depends on the investigator's experience.. None of the published papers provides a standardized method for ultrasound examination of knee menisci. The main goal of this study is to realize and standardize ultrasound imaging diagnostics of meniscal knee injuries based on individual features of ultrasound presentation and to evaluate the applicability of this modality in clinical practice. (2) Material and methods: This study consisted of two anatomical parts, including a clinical part that started with clinical examination of 50 patients with suspected meniscal knee injuries. After this we performed ultrasound examinations in patients with positive clinical test results, using sonographic confirmation for inclusion in the next stage. Finally, knee arthroscopy by two physicians in an operating room was performed, with procedures documented through photographs and video recordings, and analytic material obtained from patients in the control group documented similarly. (3) Results: In the clinical part of the study, arthroscopic examination revealed 13 longitudinal injuries (corresponding to 36% of all injuries in the group), 14 multidirectional injuries (corresponding to 28% of all injuries), 3 radial injuries (corresponding to 6% of all injuries), and 20 oblique injuries (corresponding to 40% of all injuries). The analysis of the sensitivity and specificity of the diagnostic test in terms of recognizing actual meniscal injuries on the basis of full-thickness or partial-thickness delamination, meniscal cyst oedema, and articular space stenosis revealed that the presence of at least two of these three characteristics was associated with the sensitivity of 88% and the specificity of 86% relative to the number of actual meniscal injuries as seen in arthroscopic examination. (4) Conclusions: Research results confirm that clinical examination combined with ultrasound imaging is a very efficient tool for evaluation of meniscal injuries.

A review of contrast-enhanced harmonic endoscopic ultrasonography for pancreatic solid tumors.

Endoscopic ultrasonography (EUS) is superior to other imaging modalities in the detection of pancreatic masses, although differentiating the types of pancreatic masses detected on EUS remains challenging. However, the value of contrast-enhanced harmonic EUS (CH-EUS) using ultrasound contrast agents for this differentiation has been reported. CH-EUS plays a pivotal role in analysis of small lesions that can only be detected with EUS. Recently, CH-EUS was used for staging and/or determining the resectability of pancreatic cancer in several clinical trials. In addition, it is used to estimate the response of pancreatic cancer to chemotherapy and to determine the prognosis in cases of pancreatic cancer and pancreatic neuroendocrine neoplasms. It is also postulated that CH-EUS improves the diagnostic performance of endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNAB) through complementary diagnoses using CH-EUS and EUS-FNAB, or CH-EUS-guided EUS-FNAB. Thus, CH-EUS has been employed for various qualitative diagnoses, including differentiation of pancreatic masses. Second-generation contrast agents such as Sonazoid are used clinically for ultrasound diagnostic imaging of liver and breast disease. The positioning of CH-EUS with Sonazoid as a test for the diagnosis of solid pancreatic tumors is an issue for further studies.

Detection of microcalcifications using nonlinear beamforming techniques.

Abundant research demonstrates that early detection of cancer leads to improved patient prognoses. By detecting cancer earlier, when tumors are in their primary stages, treatment can be applied before metastases have occurred. The presence of microcalcifications (MCs) is indicative of malignancy in the breast, i.e., 30-50% of all nonpalpable breast cancers detected using mammograms are based on identifying the presence of MCs. Therefore, improving the ability to detect MCs with modern imaging technology remains an important goal. Specifically, improving the sensitivity of ultrasound imaging techniques to detect MCs in the breast will provide an important role for the early detection and diagnosis of breast cancer. In this work, a novel nonlinear beamforming technology for ultrasonic arrays is investigated for its ability to detect MCs. The beamforming technique, called null subtraction imaging (NSI), utilizes nulls in the beam pattern to create images using ultrasound. NSI provides improved lateral resolution, a reduction in side lobes, and an accentuation of bright singular targets. Therefore, it was hypothesized that the use of NSI would result in identification of more MCs in rat tumors having a speckle background. To test this hypothesis, rats with tumors were injected with Hydroxyapatite (HA) particles to mimic MCs. Ultrasound was used to scan the rat tumors and images were constructed using conventional delay and sum and using NSI beamforming. Three readers with experience in diagnostic ultrasound imaging examined the 1,344 images and scored the presence or absence of MCs. In all, 336 different tumor image slices were recorded and each reconstructed using NSI or conventional delay and sum with Hann apodization. In every image where one or MCs were detected in the Hann reconstructions, MCs were detected in the NSI images. In nine rat tumor images, one or more MCs were detected in the NSI images but not in the Hann images. Statistically, the results did support the hypothesis that NSI would increase the number of MCs detected in the rat tumors.

Temperature-Controlled Hyperthermia with Non-Invasive Temperature Monitoring through Speed of Sound Imaging

Hyperthermia therapy (HT) is used to treat diseases through heating of high temperature usually in conjunction with some other medical therapeutics such as chemotherapy and radiotherapy. In this study, we propose a promising temperature-controlled hyperthermia method that uses high-intensity focused ultrasound (HIFU) for clinical tumor treatment combined with diagnostic ultrasound image guidance and non-invasive temperature monitoring through speed of sound (SOS) imaging. HIFU heating is realized by a ring ultrasound transducer array with 256 elements. In this study, tumors in the human thigh were set as heating targets. The inner structure information of thigh tissue is obtained by B-mode ultrasound imaging. Since the relationship between temperature and SOS in different human tissue is available, the temperature detection is converted to the SOS detection obtained by the full-wave inversion (FWI) method. Simulation results show that our model can achieve expected hyperthermia of constant temperature on tumor target with 0.2 °C maximum temperature fluctuation for 5 h. Through simulation, our proposed thermal therapy model achieves accurate temperature control of ±0.2 °C in human thigh tumors, which verifies the feasibility of the proposed temperature-controlled hyperthermia model. Furthermore, the temperature measurement can share the same ring ultrasound transducer array for HIFU heating and B-mode ultrasound imaging, which provides a guiding significance for clinical application.

Development and Evaluation of a Multifrequency Ultrafast Doppler Spectral Analysis (MFUDSA) Algorithm for Wall Shear Stress Measurement: A Simulation and In Vitro Study.

Cardiovascular pathology is the leading cause of death and disability in the Western world, and current diagnostic testing usually evaluates the anatomy of the vessel to determine if the vessel contains blockages and plaques. However, there is a growing school of thought that other measures, such as wall shear stress, provide more useful information for earlier diagnosis and prediction of atherosclerotic related disease compared to pulsed-wave Doppler ultrasound, magnetic resonance angiography, or computed tomography angiography. A novel algorithm for quantifying wall shear stress (WSS) in atherosclerotic plaque using diagnostic ultrasound imaging, called Multifrequency ultrafast Doppler spectral analysis (MFUDSA), is presented. The development of this algorithm is presented, in addition to its optimisation using simulation studies and in-vitro experiments with flow phantoms approximating the early stages of cardiovascular disease. The presented algorithm is compared with commonly used WSS assessment methods, such as standard PW Doppler, Ultrafast Doppler, and Parabolic Doppler, as well as plane-wave Doppler. Compared to an equivalent processing architecture with one-dimensional Fourier analysis, the MFUDSA algorithm provided an increase in signal-to-noise ratio (SNR) by a factor of 4-8 and an increase in velocity resolution by a factor of 1.10-1.35. The results indicated that MFUDSA outperformed the others, with significant differences detected between the typical WSS values of moderate disease progression (p = 0.003) and severe disease progression (p = 0.001). The algorithm demonstrated an improved performance for the assessment of WSS and has potential to provide an earlier diagnosis of cardiovascular disease than current techniques allow.

Synthesis and Evaluation of Clinically Translatable Targeted Microbubbles Using a Microfluidic Device for In Vivo Ultrasound Molecular Imaging.

The main aim of this study is to synthesize contrast microbubbles (MB) functionalized with engineered protein ligands using a microfluidic device to target breast cancer specific vascular B7-H3 receptor in vivo for diagnostic ultrasound imaging. We used a high-affinity affibody (ABY) selected against human/mouse B7-H3 receptor for engineering targeted MBs (TMBs). We introduced a C-terminal cysteine residue to this ABY ligand for facilitating site-specific conjugation to DSPE-PEG-2K-maleimide (M. Wt = 2.9416 kDa) phospholipid for MB formulation. We optimized the reaction conditions of bioconjugations and applied it for microfluidic based synthesis of TMBs using DSPE-PEG-ABY and DPPC liposomes (5:95 mole %). The binding affinity of TMBs to B7-H3 (MBB7-H3) was tested in vitro in MS1 endothelial cells expressing human B7-H3 (MS1B7-H3) by flow chamber assay, and by ex vivo in the mammary tumors of a transgenic mouse model (FVB/N-Tg (MMTV-PyMT)634Mul/J), expressing murine B7-H3 in the vascular endothelial cells by immunostaining analyses. We successfully optimized the conditions needed for generating TMBs using a microfluidic system. The synthesized MBs showed higher affinity to MS1 cells engineered to express higher level of hB7-H3, and in the endothelial cells of mouse tumor tissue upon injecting TMBs in a live animal. The average number (mean ± SD) of MBB7-H3 binding to MS1B7-H3 cells was estimated to be 354.4 ± 52.3 per field of view (FOV) compared to wild-type control cells (MS1WT; 36.2 ± 7.5/FOV). The non-targeted MBs did not show any selective binding affinity to both the cells (37.7 ± 7.8/FOV for MS1B7-H3 and 28.3 ± 6.7/FOV for MS1WT cells). The fluorescently labeled MBB7-H3 upon systemic injection in vivo co-localized to tumor vessels, expressing B7-H3 receptor, as validated by ex vivo immunofluorescence analyses. We have successfully synthesized a novel MBB7-H3 via microfluidic device, which allows us to produce on demand TMBs for clinical applications. This clinically translatable MBB7-H3 showed significant binding affinity to vascular endothelial cells expressing B7-H3 both in vitro and in vivo, which shows its potential for clinical translation as a molecular ultrasound contrast agent for human applications.

Focused ultrasound neuromodulation of the spleen activates an anti-inflammatory response in humans

Focused ultrasound stimulation (FUS) activates mechanosensitive ion channels and is emerging as a method of noninvasive neuromodulation. In preclinical studies, FUS of the spleen (sFUS) activates an anti-inflammatory neural pathway which suppresses acute and chronic inflammation. However, the relevance of sFUS for regulating inflammatory responses in humans is unknown. Here, we used a modified diagnostic ultrasound imaging system to target the spleen of healthy human subjects with 3 min of continuously swept or stationary focused pulsed ultrasound, delivered at three different energy levels within allowable safety exposure limits. Potential anti-inflammatory effects of sFUS were assessed by measuring sFUS-elicited changes in endotoxin-induced tumor necrosis factor (TNF) production in whole blood samples from insonified subjects. We found that stimulation with either continuously swept or focused pulsed ultrasound has an anti-inflammatory effect: sFUS lowers TNF production for >2 h, with TNF returning to baseline by 24 h following sFUS. This response is independent of anatomical target (i.e., spleen hilum or parenchyma) or ultrasound energy level. No clinical, biochemical, or hematological parameters are adversely impacted. This is the first demonstration that sFUS suppresses the normal inflammatory response in humans, with potential implications for noninvasive bioelectronic therapy of inflammatory disorders.