Grand Challenges at the Interface of Engineering and Medicine.

Over the past two decades Biomedical Engineering has emerged as a major discipline that bridges societal needs of human health care with the development of novel technologies. Every medical institution is now equipped at varying degrees of sophistication with the ability to monitor human health in both non-invasive and invasive modes. The multiple scales at which human physiology can be interrogated provide a profound perspective on health and disease.

Ultrasonic High-Resolution Imaging and Acoustic Tweezers Using Ultrahigh Frequency Transducer: Integrative Single-Cell Analysis.

Ultrasound imaging is a highly valuable tool in imaging human tissues due to its non-invasive and easily accessible nature. Despite advances in the field of ultrasound research, conventional transducers with frequencies lower than 20 MHz face limitations in resolution for cellular applications. To address this challenge, we employed ultrahigh frequency (UHF) transducers and demonstrated their potential applications in the field of biomedical engineering, specifically for cell imaging and acoustic tweezers.

Automated cell-type classification combining dilated convolutional neural networks with label-free acoustic sensing.

This study aimed to automatically classify live cells based on their cell type by analyzing the patterns of backscattered signals of cells with minimal effect on normal cell physiology and activity. Our previous studies have demonstrated that label-free acoustic sensing using high-frequency ultrasound at a high pulse repetition frequency (PRF) can capture and analyze a single object from a heterogeneous sample. However, eliminating possible errors in the manual setting and time-consuming processes when postprocessing integrated backscattering (IB) coefficients of backscattered signals is crucial.

Recent Advancements in Ultrasound Transducer: From Material Strategies to Biomedical Applications.

Ultrasound is extensively studied for biomedical engineering applications. As the core part of the ultrasonic system, the ultrasound transducer plays a significant role. For the purpose of meeting the requirement of precision medicine, the main challenge for the development of ultrasound transducer is to further enhance its performance.

Automated estimation of cancer cell deformability with machine learning and acoustic trapping.

Cell deformability is a useful feature for diagnosing various diseases (e.g., the invasiveness of cancer cells).

Manipulation and Mechanical Deformation of Leukemia Cells by High-Frequency Ultrasound Single Beam.

Ultrasound single-beam acoustic tweezer system has attracted increasing attention in the field of biomechanics. Cell biomechanics play a pivotal role in leukemia cell functions. To better understand and compare the cell mechanics of the leukemia cells, herein, we fabricated an acoustic tweezer system in-house connected with a 50-MHz high-frequency cylinder ultrasound transducer.

Super-Resolution Ultrasound Localization Microscopy for Visualization of the Ocular Blood Flow.

Objective: The ocular vascular system plays an important role in preserving the visual function. Alterations in either anatomy or hemodynamics of the eye may have adverse effects on vision. Thus, an imaging approach that can monitor alterations of ocular blood flow of the deep eye vasculature ranging from capillary-level vessels to large supporting vessels would be advantageous for detection of early stage retinal and optic nerve diseases.

Ultrasound Therapy, Chemotherapy and Their Combination for Prostate Cancer.

Prostate cancer is the second leading cause of cancer death in men. Its current treatment includes various physical and chemical approaches for the localized and advanced prostate cancer [e.g.

Prospective assessment of breast cancer risk from multimodal multiview ultrasound images via clinically applicable deep learning.

The clinical application of breast ultrasound for the assessment of cancer risk and of deep learning for the classification of breast-ultrasound images has been hindered by inter-grader variability and high false positive rates and by deep-learning models that do not follow Breast Imaging Reporting and Data System (BI-RADS) standards, lack explainability features and have not been tested prospectively. Here, we show that an explainable deep-learning system trained on 10,815 multimodal breast-ultrasound images of 721 biopsy-confirmed lesions from 634 patients across two hospitals and prospectively tested on 912 additional images of 152 lesions from 141 patients predicts BI-RADS scores for breast cancer as accurately as experienced radiologists, with areas under the receiver operating curve of 0.922 (95% confidence interval (CI) = 0.

2-D Ultrasonic Array-Based Optical Coherence Elastography.

Acoustic radiation force optical coherence elastography (ARF-OCE) has been successfully implemented to characterize the biomechanical properties of soft tissues, such as the cornea and the retina, with high resolution using single-element ultrasonic transducers for ARF excitation. Most currently proposed OCE techniques, such as air puff and ARF, have less capability to control the spatiotemporal information of the induced region of deformation, resulting in limited accuracy and low temporal resolution of the shear wave elasticity imaging. In this study, we propose a new method called 2-D ultrasonic array-based OCE imaging, which combines the advantages of 3-D dynamic electronic steering of the 2-D ultrasonic array and high-resolution optical coherence tomography (OCT).

FRET-Based Ca Biosensor Single Cell Imaging Interrogated by High-Frequency Ultrasound.

Fluorescence resonance energy transfer (FRET)-based biosensors have advanced live cell imaging by dynamically visualizing molecular events with high temporal resolution. FRET-based biosensors with spectrally distinct fluorophore pairs provide clear contrast between cells during dual FRET live cell imaging. Here, we have developed a new FRET-based Ca biosensor using EGFP and FusionRed fluorophores (FRET-GFPRed).

Focused Ultrasound Stimulates ER Localized Mechanosensitive PANNEXIN-1 to Mediate Intracellular Calcium Release in Invasive Cancer Cells.

Focused ultrasound (FUS) is a rapidly developing stimulus technology with the potential to uncover novel mechanosensory dependent cellular processes. Since it is non-invasive, it holds great promise for future therapeutic applications in patients used either alone or as a complement to boost existing treatments. For example, FUS stimulation causes invasive but not non-invasive cancer cell lines to exhibit marked activation of calcium signaling pathways.

Characterizing the Motility of Chemotherapeutics-Treated Acute Lymphoblastic Leukemia Cells by Time-Lapse Imaging.

Drug resistance is an obstacle in the therapy of acute lymphoblastic leukemia (ALL). Whether the physical properties such as the motility of the cells contribute to the survival of ALL cells after drug treatment has recently been of increasing interest, as they could potentially allow the metastasis of solid tumor cells and the migration of leukemia cells. We hypothesized that chemotherapeutic treatment may alter these physical cellular properties.

Investigation of cell mechanics using single-beam acoustic tweezers as a versatile tool for the diagnosis and treatment of highly invasive breast cancer cell lines: an in vitro study.

Advancements in diagnostic systems for metastatic cancer over the last few decades have played a significant role in providing patients with effective treatment by evaluating the characteristics of cancer cells. Despite the progress made in cancer prognosis, we still rely on the visual analysis of tissues or cells from histopathologists, where the subjectivity of traditional manual interpretation persists. This paper presents the development of a dual diagnosis and treatment tool using an in vitro acoustic tweezers platform with a 50 MHz ultrasonic transducer for label-free trapping and bursting of human breast cancer cells.

Classification of Breast Cancer Cells Using the Integration of High-Frequency Single-Beam Acoustic Tweezers and Convolutional Neural Networks.

Single-beam acoustic tweezers (SBAT) is a widely used trapping technique to manipulate microscopic particles or cells. Recently, the characterization of a single cancer cell using high-frequency (>30 MHz) SBAT has been reported to determine its invasiveness and metastatic potential. Investigation of cell elasticity and invasiveness is based on the deformability of cells under SBAT's radiation forces, and in general, more physically deformed cells exhibit higher levels of invasiveness and therefore higher metastatic potential.

Investigation of Ultrasound-Mediated Intracellular Ca Oscillations in HIT-T15 Pancreatic β-Cell Line.

In glucose-stimulated insulin secretion (GSIS) of pancreatic β-cells, the rise of free cytosolic Ca concentration through voltage-gated calcium channels (VGCCs) triggers the exocytosis of insulin-containing granules. Recently, mechanically induced insulin secretion pathways were also reported, which utilize free cytosolic Ca ions as a direct regulator of exocytosis. In this study, we aimed to investigate intracellular Ca responses on the HIT-T15 pancreatic β-cell line upon low-intensity pulsed ultrasound (LIPUS) stimulation and found that ultrasound induces two distinct types of intracellular Ca oscillation, fast-irregular and slow-periodic, from otherwise resting cells.

In Vivo Visualization of Eye Vasculature Using Super-Resolution Ultrasound Microvessel Imaging.

Objective: The choroidal vessels, which supply oxygen and nutrient to the retina, may play a pivotal role in eye disease pathogenesis such as diabetic retinopathy and glaucoma. In addition, the retrobulbar circulation that feeds the choroid shows an important pathophysiologic role in myopia and degenerative myopia. Owing to the light-absorbing retinal pigment epithelium (RPE) and optically opaque sclera, choroidal and retrobulbar vasculature were difficult to be observed using clinically accepted optical coherence tomography angiography (OCT-A) technique.

A combined ultrasonic B-mode and color Doppler system for the classification of breast masses using neural network.

Objectives: To develop a dual-modal neural network model to characterize ultrasound (US) images of breast masses.

Materials And Methods: A combined US B-mode and color Doppler neural network model was developed to classify US images of the breast. Three datasets with breast masses were originally detected and interpreted by 20 experienced radiologists according to Breast Imaging-Reporting and Data System (BI-RADS) lexicon ((1) training set, 103212 masses from 45,433 + 12,519 patients.

Integrin Antibody Decreases Deformability of Patient-Derived Pre-B Acute Lymphocytic Leukemia Cells as Measured by High-Frequency Acoustic Tweezers.

Objectives: This article reports a study of cell mechanics in patient-derived (primary) B-cell acute lymphocytic leukemia (ALL) cells treated with antibodies against integrins. Leukemia cell adhesion to stromal cells mediates chemotherapeutic drug resistance, also known as cell adhesion-mediated chemotherapeutic drug resistance. We have previously shown that antibodies against integrin α and α adhesion molecules can de-adhere ALL cells from stromal cells or counter-receptors.

Monitoring of Adult Zebrafish Heart Regeneration Using High-Frequency Ultrasound Spectral Doppler and Nakagami Imaging.

This paper reports the feasibility of Nakagami imaging in monitoring the regeneration process of zebrafish hearts in a noninvasive manner. In addition, spectral Doppler waveforms that are typically used to access the diastolic function were measured to validate the performance of Nakagami imaging. A 30-MHz high-frequency ultrasound array transducer was used to acquire backscattered echo signal for spectral Doppler and Nakagami imaging.

A One-Sided Acoustic Trap for Cell Immobilization Using 30-MHz Array Transducer.

Biological studies often involve the investigation of immobilized (or trapped) particles and cells. Various trapping methods without touching, such as optical, magnetic, and acoustic tweezers, have been developed to trap small particles. Here, we present the manipulation of a single cell or multiple cells using ultrasound-array-based single-beam acoustic tweezers (UA-SBATs).

Flexible piezoelectric ultrasonic energy harvester array for bio-implantable wireless generator.

Ultrasonic driven wireless charging technology has recently attracted much attention in the next generation bio-implantable systems; however, most developed ultrasonic energy harvesters are bulky and rigid and cannot be applied to general complex surfaces. Here, a flexible piezoelectric ultrasonic energy harvester (PUEH) array was designed and fabricated by integrating a large number of piezoelectric active elements with multilayered flexible electrodes in an elastomer membrane. The developed flexible PUEH device can be driven by the ultrasonic wave to produce continuous voltage and current outputs on both planar and curved surfaces, reaching output signals of more than 2 Vpp and 4 μA, respectively.

Fabrication and Characterization of a Miniaturized 15-MHz Side-Looking Phased-Array Transducer Catheter.

This paper describes the development of a miniaturized 15-MHz side-looking phased-array transducer catheter. The array features a 2-2 linear composite with 64 piezoelectric elements mechanically diced into a piece of PMN-30%PT single crystal and separated by non-conductive epoxy kerfs at a 50-μm pitch, yielding a total active aperture of 3.2 mm in the azimuth direction and 1.

Three-Dimensional Printed Piezoelectric Array for Improving Acoustic Field and Spatial Resolution in Medical Ultrasonic Imaging.

Piezoelectric arrays are widely used in non-destructive detecting, medical imaging and therapy. However, limited by traditional manufacturing methods, the array's element is usually designed in simple geometry such as a cube or rectangle, restricting potential applications of the array. This work demonstrates an annular piezoelectric array consisting of different concentric elements printed by Mask-Image-Projection-based Stereolithography (MIP-SL) technology.