Ultrasound Imaging

This book provides an overview of ultrafast ultrasound imaging, 3D high-quality ultrasonic imaging, correction of phase aberrations in medical ultrasound images, etc. Several interesting medical and clinical applications areas are also discussed in the book, like the use of three dimensional ultrasound imaging in evaluation of Asherman's syndrome, the role of 3D ultrasound in assessment of endometrial receptivity and follicular vascularity to predict the quality oocyte, ultrasound imaging in vascular diseases and the fetal palate, clinical application of ultrasound molecular imaging, Doppler abdominal ultrasound in small animals and so on

Imaging Sensors and Applications

In past decades, various sensor technologies have been used in all areas of our lives, thus improving our quality of life. In particular, imaging sensors have been widely applied in the development of various imaging approaches such as optical imaging, ultrasound imaging, X-ray imaging, and nuclear imaging, and contributed to achieve high sensitivity, miniaturization, and real-time imaging. These advanced image sensing technologies play an important role not only in the medical field but also in the industrial field. This Special Issue covers broad topics on imaging sensors and applications. The scope range of imaging sensors can be extended to novel imaging sensors and diverse imaging systems, including hardware and software advancements. Additionally, biomedical and nondestructive sensing applications are welcome

Overview of biofluids and flow sensing techniques applied in clinical practice

This review summarizes the current knowledge on biofluids and the main flow sensing techniques applied in healthcare today. Since the very beginning of the history of medicine, one of the most important assets for evaluating various human diseases has been the analysis of the conditions of the biofluids within the human body. Hence, extensive research on sensors intended to evaluate the flow of many of these fluids in different tissues and organs has been published and, indeed, continues to be published very frequently. The purpose of this review is to provide researchers interested in venturing into biofluid flow sensing with a concise description of the physiological characteristics of the most important body fluids that are likely to be altered by diverse medical conditions. Similarly, a reported compilation of well-established sensors and techniques currently applied in healthcare regarding flow sensing is aimed at serving as a starting point for understanding the theoretical principles involved in the existing methodologies, allowing researchers to determine the most suitable approach to adopt according to their own objectives in this broad field.This research was supported by the Consejo Nacional de Ciencia y Tecnología (CONACYT) of México through Ph.D. grant 472102 and by the Ministerio de Economía y Competitividad through grant FIS2017-89850R.Peer ReviewedPostprint (author's final draft

Towards clinical photoacoustic imaging: developing next-generation endoscopy systems and exploring new contrast agents

Photoacoustic imaging holds great clinical promise because it achieves high-resolution tomographic imaging at depths. Moreover, its strong spectroscopic imaging capability provides a wealth of molecular and functional information based on. Still, despite recent advances, existing photoacoustic systems cannot be readily applied in the clinical environment. This dissertation aims to push the frontier of clinical photoacoustic imaging from both technological and applicational perspectives. The first part of this dissertation describes the development of photoacoustic endoscopy (PAE) systems for imaging human Barrett\u27s esophagus and studying preterm birth. We have developed optical resolution-PAE, which significantly improved lateral resolutions, laparoscopic-PAE, which can guide minimally-invasive surgeries, and catheter-based-PAE, which opens up new opportunities to image the human esophagus. For each system, we tested and optimized the imaging performance in phantom and animal experiments, and then validated them in humans. The second part of the dissertation describes advanced photoacoustic imaging aided by contrast agents. Specifically, gold nanoparticles were used to quantify biological diffusion photoacoustically. In addition, ion nanosensors were applied for continuously monitoring therapeutic lithium concentration in deep tissue in vivo

Cervical weakness and preterm birth: The structure and function of the internal cervical os

The cervix is integral to the maintenance of pregnancy and timely delivery of the baby. Mechanical failure of the cervix resulting in spontaneous preterm birth presents with collapse of the internal os, yet little is known about why the cervix behaves in this way. This may in part be due to research being technically limited and/or limited to punch biopsies of the distal cervix that did not include tissue from the internal os. The aim of this thesis was to re-evaluate cervical anatomy using novel laboratory and imaging methods to gain further insight into the structure of the cervix and how this may influence function during pregnancy. To achieve this, whole cervical samples were obtained from women undergoing hysterectomy for benign pathology. Uterine tissue was subsequently fixed and analysed using 2D and 3D histological methods. Cervical anatomy was characterised using markers for smooth muscle and collagen and analysed using computer-assisted quantification methods. Sequential tissue slices were then reconstructed to produce 3D models of the proximal, middle and distal cervix. High-resolution diffusion-tensor imaging was used to determine whether complex cervical anatomy could be visualised using radiological methods. Tissue was assessed using quantitative and qualitative diffusion methods, and directly compared to immunohistochemically stained tissue. The results obtained demonstrated that diffusion-tensor imaging accurately assessed cervical anatomy and provided further detail in terms of fibre volume, density and organisation. Ex vivo endoscopic ultrasound was used to assess whether current, established medical imaging technology could discern cervical smooth muscle and collagen fibres. Although this method could be used to identify gross anatomical structures, it was not an appropriate method to identify cervical microanatomy. The results described in this thesis provide further insight into how the cervix resists intrauterine forces throughout pregnancy, and then dilates and effaces to allow for delivery of a fetus. Diffusion-tensor imaging accurately assessed cervical anatomy, which may have implications for in vivo characterisation of cervical remodelling during pregnancy and identifying those at risk of delivering early. Finally, observations in this thesis encourage continued re-examination of the cervix using high-resolution imaging to provide insight into function and to develop strategies to discern cervical insufficiency from other known causes of preterm birth

Lower Urinary Tract Dysfunction

Lower urinary tract dysfunction (LUTD) is an umbrella diagnosis that covers the abnormalities of anatomy and function in the bladder, urethra, and, in men, the prostate. People with LUTD face a number of social, mental, and physical health effects due to the symptoms. Despite the increasing evidence in the assessment and management of lower urinary tract symptoms, it remains a challenge to bridge the gap between research evidence and clinical practice. In this book, each and every one of the authors presents a remarkable work for how to apply the evidence to clinical practice from different aspects. I hope this book is a key for every reader to open the door to LUTD

Co-registered photoacoustic and ultrasound tomographic imaging of human colorectal and ovarian cancer: light delivery, system development, and clinical study

Ovarian cancer remains the deadliest of all the gynecological malignancies. Conventional screening tests, including pelvic examination, transvaginal ultrasound (TVUS), and blood testing for cancer antigen 125 (CA-125), lack sufficient specificity for early ovarian cancer diagnosis. Imaging modalities such as computed tomography (CT), positron emission tomography (PET), and magnetic resonance imaging (MRI) have been used for surgical guidance. However, all of these modalities have limitations in detecting small lesions. Globally, colorectal cancer is the second most commonly diagnosed malignancy and the fourth most common cause of cancer mortality. Accurate staging and post-treatment surveillance of this prevalent disease are critical because treatment strategies are predicated upon the stage at presentation and the patient’s response to pre-surgical therapy – in some instances, detailed imaging allows certain patients to avoid surgery altogether. While colonoscopy and biopsy are the gold-standard diagnostic tests for colorectal cancers, multiple imaging modalities are also utilized, including optical imaging, endoscopic ultrasound (EUS), pelvic magnetic resonance imaging (MRI), computed tomography (CT), and positron emission tomography (PET). Unfortunately, each of these modalities has critical weakness in evaluating colorectal tumors. In staging colorectal tumors and evaluating their therapeutic response, more precise imaging modalities could transform the standard of care. This dissertation explores co-registered photoacoustic and ultrasound tomographic imaging of two fatal cancers: ovarian cancer and colorectal cancer. It is composed of three main parts: light delivery optimization/fiber optics, system development and optimization, and pilot patient and sample study. To begin, we designed, optimized, and evaluated an hand-held photoacoustic and ultrasound probe suitable for endo-cavity subsurface tumor imaging. Compared to previous designs, the prototype probe, consisting of four 1 mm multi-mode optical fibers attached to 1.5 mm diameter ball-shaped fiber tips sandwiched between a transvaginal ultrasound transducer and a custom-made sheath, demonstrated a higher light output and better beam homogeneity on the tissue subsurface. Second, we developed a novel fiber diffuser tip using microspheres dispersed within an ultraviolet (UV) adhesive to scatter light. This diffuser keeps the skin surface fluence under the maximum permissible exposure (MPE), while enabling higher laser energy injection to enhance the photoacoustic (PA) signal generated from the tissue. Third, we proposed an improved beamformer, named lag-based delay multiply and sum combined with coherence factor (DMAS-LAG-CF). Simulations and phantom experiments demonstrate that compared with conventional delay and sum (DAS), the proposed algorithm can provide 1.39 times better resolution and 10.77 dB higher contrast. For patient data, similar improvements in contrast ratios have been observed. However, since diagnostic accuracy in distinguishing between cancer and benign/normal groups is the significant measure, we have extracted the photoacoustic histogram features of mean, kurtosis, and skewness. When mean and skewness are used as features, DMAS-LAG-CF can improve cancer diagnosis, with an AUC of 0.91 in differentiating malignant from benign ovarian lesions. Fourth, to investigate the ability of co-registered photoacoustic and ultrasound tomographic imaging to assess human colorectal cancer, we conducted a pilot study on 23 ex-vivo human colorectal tissue samples that were collected immediately after surgical resection. Co-registered photoacoustic images of malignancies showed significantly increased PAT signals compared to normal regions of the same sample. We found statistically significant differences between untreated colorectal tumors and normal tissues, based on the quantitative relative total hemoglobin concentration (rHbT) computed from four optical wavelengths, spectral features such as the mean spectral slope and 0.5 MHz intercept extracted from PAT and US spectral data, and image features such as the first and second order statistics along with the standard deviation of the mean radon transform of PAT images. Using either a logistic regression model or a support vector machine, the best set of parameters of rHbT and PAT intercept achieved AUC values of 0.97 and 0.95 for the training and testing data sets, respectively, in predicting histologically confirmed invasive carcinoma. One limitation of the current system is its poor image resolution (~ 250 μm axial resolution) limited by the commercial endo-cavity ultrasound transducer array (6 MHz central frequency, 80% bandwidth). For better image resolution in high frequency PAT/US imaging, we first decoded the pin configuration of a high-frequency transducer array (15 MHz central frequency, 9-18 MHz bandwidth) and adapted it to our home-made 128 channel ultrasound pulsing and receiving system (sampling rate: 40 MHz). To further improve the performance, we are building a 64-channel FPGA-based high frequency photoacoustic imaging system with a sampling rate of 80 MHz and signal-to-noise ratio (SNR) of 40 dB. For in-vivo patient study, this system will be integrated with an endo-rectal probe with a side-firing fiber tip. Fifth, we investigated the laser safety of photoacoustic imaging, in preparation for its use in clinical reproductive medicine. Using preimplantation mouse blastocyst stage embryos, we assessed potential DNA damage from photoacoustic laser exposure. Different embryo groups were exposed to either 5- or 10- minute 15-Hz laser doses (typical clinical doses), or a 1-minute 1-kHz laser dose (a significantly higher dose). We demonstrated that typical lasers and exposure times used for photoacoustic imaging do not induce increased cell death in mouse blastocysts. Sixth, we demonstrated a novel fiber endface photoacoustic generator using IR 144 laser dye dispersed within an ultraviolet (UV) adhesive. The generator provides wide acoustic bandwidth in the transducer frequency range of 2-7 MHz, high thermal conversion efficiency (\u3e 90%), good PA intensity controllability (via the easily controlled IR 144 concentration), and high feasibility (simple procedures). Through a series of experimental validations, we show this fiber-based endface photoacoustic generator can be a useful tool for a broad range of biomedical applications, such as calibrating the local absorption coefficient of biological tissue for quantitative photoacoustic tomography

Photoacoustic Elastography and Next-generation Photoacoustic Tomography Techniques Towards Clinical Translation

Ultrasonically probing optical absorption, photoacoustic tomography (PAT) combines rich optical contrast with high ultrasonic resolution at depths beyond the optical diffusion limit. With consistent optical absorption contrast at different scales and highly scalable spatial resolution and penetration depth, PAT holds great promise as an important tool for both fundamental research and clinical application. Despite tremendous progress, PAT still encounters certain limitations that prevent it from becoming readily adopted in the clinical settings. This dissertation aims to advance both the technical development and application of PAT towards its clinical translation. The first part of this dissertation describes the development of photoacoustic elastography techniques, which complement PAT with the capability to image the elastic properties of biological tissue and detect pathological conditions associated with its alterations. First, I demonstrated vascular-elastic PAT (VE-PAT), capable of quantifying blood vessel compliance changes due to thrombosis and occlusions. Then, I developed photoacoustic elastography to noninvasively map the elasticity distribution in biological tissue. Third, I further enhanced its performance by combing conventional photoacoustic elastography with a stress sensor having known stress–strain behavior to achieve quantitative photoacoustic elastography (QPAE). QPAE can quantify the Young’s modulus of biological tissues on an absolute scale. The second part of this dissertation introduces technical improvements of photoacoustic microscopy (PAM). First, by employing near-infrared (NIR) light for illumination, a greater imaging depth and finer lateral resolution were achieved by near-infrared optical-resolution PAM (NIR-OR-PAM). In addition, NIR-OR-PAM was capable of imaging other tissue components, including lipid and melanin. Second, I upgraded a high-speed functional OR-PAM (HF-OR-PAM) system and applied it to image neurovascular coupling during epileptic seizure propagation in mouse brains in vivo with high spatio-temporal resolution. Last, I developed a single-cell metabolic PAM (SCM-PAM) system, which improves the current single-cell oxygen consumption rate (OCR) measurement throughput from ~30 cells over 15 minutes to ~3000 cells over 15 minutes. This throughput enhancement of two orders of magnitude achieves modeling of single-cell OCR distribution with a statistically meaningful cell count. SCM-PAM enables imaging of intratumoral metabolic heterogeneity with single-cell resolution. The third part of this dissertation introduces the application of linear-array-based PAT (LA-PAT) in label-free high-throughput imaging of melanoma circulating tumor cells (CTCs) in patients in vivo. Taking advantage of the strong optical absorption of melanin and the unique capability of PAT to image optical absorption, with 100% relative sensitivity, at depths with high ultrasonic spatial resolution, LA-PAT is inherently suitable for melanoma CTC imaging. First, with a center ultrasonic frequency of 21 MHz, the LA-PAT system was able to detect melanoma CTCs clusters and quantify their sizes based on the contrast-to-noise ratio (CNR). Second, I developed an LA-PAT system with a center ultrasonic frequency of 40 MHz and imaged melanoma CTCs in patients in vivo with a CNR greater than 12. We successfully imaged 16 melanoma patients and detected melanoma CTCs in 3 of them. Among the CTC-positive patients, 67% had disease progression despite systemic therapy. In contrast, only 23% of the CTC-negative patients showed disease progression. This study lays a solid foundation for translating CTC detection to bedside for clinical care and decision-making

Image analytic tools for tissue characterization using optical coherence tomography

Optical coherence tomography (OCT) has been emerging as a promising imaging technique, with a strong capability of non-invasive, in vivo, high resolution, depth-resolved imaging. There is a great potential to use OCT to guide the treatment of arrhythmias, to prevent preterm birth, and to detect breast cancer. To facilitate the clinical applications, this thesis presents three image analytic tools to characterize biological tissue: 1) automated fiber direction analysis; 2) automated volumetric stitching; 3) automated tissue classification. The fiber direction analysis consists of a particle-filter-based 3D tractography scheme and a pixel-wise fiber analysis scheme. The stitching algorithm enlarges the field of view of current OCT system from millimeter to centimeter level by volumetric stitching using scale-invariant feature transform. Based on relevance vector machine, a region-based classification scheme and a grid-based classification scheme are developed to automatically identify tissue composition in human cardiac tissue and human breast tissue. These tools are collaboratively used to study OCT images from cardiac, cervical, and breast tissue. In cardiac tissue, we apply the fiber orientation analysis to reconstruct 3D cardiac myofibers tractography and perform pixel-wise fiber analysis on the collagen region within human heart. In addition, we apply the region-based algorithm to segment and classify tissue compositions, such as collagen, adipose tissue, fibrotic myocardium, and normal myocardium, over a single or a stitched OCT volume. Using our algorithm, we observe fiber directionality change over depths and find that the fiber orientation changes more dramatically in atria than in ventricle. We also observe different dispersion patterns within collagen layer. In cervical tissue, our stitching algorithm enables a paramount 3D view of entire axial slices. Together with pixel-wise fiber orientation scheme, we analyze the difference of dispersion property within inner/outer regions of four quadrants. We observe two dispersion patterns in pregnant and non-pregnant cervical tissue at the location close to upper cervix. In addition, we discover that an increasing trend of dispersion and an increasing trend of penetration depth from internal orifice (os) to external os. In breast tissue, we visualize various features in both benign and malignant tissues such as invasive ductal carcinoma (IDC), ductal carcinoma in situ, cyst, and terminal duct lobule unit in stitched OCT images. Focusing on the automated detection of IDC, we propose a hierarchy framework of classification model and apply our classifier in two OCT systems and achieve both reasonable sensitivity and specificity in identifying cancerous region