High-Speed Photoacoustic Microscopy In Vivo

The overarching goal of this research is to develop a novel photoacoustic microscopy: PAM) technology capable of high-speed, high-resolution 3D imaging in vivo. PAM combines the advantages of optical absorption contrast and ultrasonic resolution for deep imaging beyond the quasi-ballistic regime. Its high sensitivity to optical absorption enables the imaging of important physiological parameters, such as hemoglobin concentration and oxygen saturation, which closely correlate with angiogenesis and hypermetabolism--two hallmarks of cancer. To translate PAM to the clinic, both high imaging speed and high spatial resolution are desired. With high spatial resolution, PAM can detect small structural and functional changes early; whereas, high-speed image acquisition helps reduce motion artifacts, patient discomfort, cost, and potentially the risks associated with minimally invasive procedures such as endoscopy and intravascular imaging. To achieve high imaging speed, we have constructed a PAM system using a linear ultrasound array and a kHz-repetition-rate tunable laser. The system has achieved a 249-Hz B-scan rate and a 0.5-Hz 3D imaging rate: over ~6 mm × 10 mm × 3 mm), over 200 times faster than existing mechanical scanning PAM using a single ultrasonic transducer. In addition, high-speed optical-resolution photoacoustic microscopy: OR-PAM) technology has been developed, in which the spatial resolution in one or two dimension(s) is defined by the diffraction-limited optical focus. Using section illumination, the elevational resolution of the system has been improved from ~300 micron to ~28 micron, resulting in a significant improvement in the 3D image quality. Furthermore, multiple optical foci with a microlens array have been used to provide finer than 10-micron lateral resolution--enabling the system to image capillary-level microvessels in vivo--while offering a speed potentially 20 times faster than previously existing single-focus OR-PAM. Finally, potential biomedical applications of the developed technology have been demonstrated through in vivo imaging of murine sentinel lymph nodes, microcirculation dynamics, and human pulsatile dynamics. In the future, this high-speed PAM technology may be adapted for clinical imaging of diabetes-induced vascular complications or tumor angiogenesis, or miniaturized for gastrointestinal or intravascular applications

Low-cost, High-contrast, and Miniature Optical Imaging Systems for Clinical Applications

Reducing the cost and size and enhancing the contrast of optical imaging systems improve their potentials for clinical applications. In this dissertation, we describe our endeavors towards development of low-cost and compact photoacoustic microscopy and spatial frequency domain imaging systems as well as improvement of photoacoustic tumor imaging using a specifically designed photoacoustic contrast agent. Chapters two and three focus on the development of low-cost and compact laser diode based photoacoustic microscopy systems. We first provided an improvement in light delivery of laser diode based photoacoustic microscopy systems that enables imaging biological tissue with high signal to noise ratio. We then developed a laser scanning laser diode based photoacoustic microscopy system that provides substantial improvement of imaging speed and eliminates the need for mechanical scanning of the sample, hence improving the potentials of low-cost and compact laser diode based photoacoustic microscopy for clinical applications. Chapter four describes synthesis and evaluation of a monomeric porphyrin-based photoacoustic contrast agent for improvement of in vivo tumor imaging. Absorption in near infrared wavelength range, solubility, stability, nontoxicity, and high photoacoustic generation efficiency of the dye were demonstrated. The contrast agent was evaluated for enhancing the photoacoustic images of implanted murine tumors revealing a multi-fold stronger enhancement and a slower washout compared to the benchmark FDA approved indocyanine green (ICG) dye. Favorable filtration and tumor accumulation of the dye further demonstrated its potential as a photoacoustic contrast agent for in vivo tumor imaging. Finally, chapter 5 describes development of a very low-cost, handheld, and multispectral spatial frequency domain imaging system that incorporates nine different light emitting diodes and all illumination and detection optical components in a small 3D-printed probe. The system performance was evaluated on biological tissue to assess its potentials

Portable Ultrasound Imaging

This PhD project investigates hardware strategies and imaging methods for hand-held ultrasound systems. The overall idea is to use a wireless ultrasound probe linked to general-purpose mobile devices for the processing and visualization. The approach has the potential to reduce the upfront costs of the ultrasound system and, consequently, to allow for a wide-scale utilization of diagnostic ultrasound in any medical specialties and out of the radiology department. The first part of the contribution deals with the study of hardware solutions for the reduction of the system complexity. Analog and digital beamforming strategies are simulated from a system-level perspective. The quality of the B-mode image is evaluated and the minimum specifications are derived for the design of a portable probe with integrated electronics in-handle. The system is based on a synthetic aperture sequential beamforming approach that allows to significantly reduce the data rate between the probe and processing unit. The second part investigates the feasibility of vector flow imaging in a hand-held ultrasound system. Vector flow imaging overcomes the limitations of conventional imaging methods in terms of flow angle compensation. Furthermore, high frame rate can be obtained by using synthetic aperture focusing techniques. A method is developed combining synthetic aperture sequential beamforming and directional transverse oscillation to achieve the wireless transmission of the data along with a relatively inexpensive 2-D velocity estimation. The performance of the method is thoroughly assessed through simulations and measurements, and in vivo investigations are carried out to show its potential in presence of complex flow dynamics. A sufficient frame rate is achieved to allow for the visualization of vortices in the carotid bifurcation. Furthermore, the method is implemented on a commercially available tablet to evaluate the real-time processing performance in the built-in GPU with concurrent wireless transmission of the data. Based on the demonstrations in this thesis, a flexible framework can be implemented with performance that can be scaled to the needs of the user and according to the computing resources available. The integration of high-frame-rate vector flow imaging in a hand-held ultrasound scanner, in addition, has the potential to improve the operator’s workflow and opens the way to new possibilities in the clinical practice

Study and design of an ultrasonic flow tomographic front-end multi level measurement system

With the rapid evolution of electro-acoustical technology, ultrasonic tomography has made considerable progress in industry. An ultrasonic tomography system provides non-invasive and non-intrusive flow visualisation that enhances the understanding of fluid flow processes. The function of ultrasonic tomography is to continuously monitor the dynamics of liquid flow without interrupting the flow. The ultrasonic tomography technique is fully supported by a front-end hardware system. The front end is defined as all the hardware circuitries, including the ultrasonic transducer up to the Analogue-to-Digital Convertors (ADCs), even though the primary focus is the analogue signal processing components. We present here the challenges and trade-offs in the implementation of a front-end system by first explaining the basic operation of such a system, and then indicating what particular performance parameters are needed to ensure optimal system operation. Based on the results from our research studies, we propose an improved front-end multi-level solution that is more accurate than previous solutions and provides real-time measurement capability

Novel design and architecture development of fixed and variable focal length beamforming circuits for ultrasound scanners

Real-time ultrasonic imaging systems have been available for more than sixty years and are becoming an important tool in the practice of modern medicine. There are a lot of improvements occurred to the basic architecture and functions of these clinical systems and their beamformers, which are, in many ways, the most important components of these systems. In this thesis we proposed various Ultrasound Beamforming techniques that are used in biomedical applications, Beamforming circuits are used to steer the ultrasound waves to focus at desired location. Our main importance is to design and architecture development of low power and area efficient beamforming circuits.CMUT is used as transducer element is our beamforming approach which has better impedance matching with the medium, high sensitivity, low power consumption, high bandwidth when compared to conventional piezoelectric transducer elements which are usually used in ultrasound scanners

MEMS Technology for Biomedical Imaging Applications

Biomedical imaging is the key technique and process to create informative images of the human body or other organic structures for clinical purposes or medical science. Micro-electro-mechanical systems (MEMS) technology has demonstrated enormous potential in biomedical imaging applications due to its outstanding advantages of, for instance, miniaturization, high speed, higher resolution, and convenience of batch fabrication. There are many advancements and breakthroughs developing in the academic community, and there are a few challenges raised accordingly upon the designs, structures, fabrication, integration, and applications of MEMS for all kinds of biomedical imaging. This Special Issue aims to collate and showcase research papers, short commutations, perspectives, and insightful review articles from esteemed colleagues that demonstrate: (1) original works on the topic of MEMS components or devices based on various kinds of mechanisms for biomedical imaging; and (2) new developments and potentials of applying MEMS technology of any kind in biomedical imaging. The objective of this special session is to provide insightful information regarding the technological advancements for the researchers in the community

Ultrasound Guided Robot for Human Liver Biopsy using High Intensity Focused Ultrasound for Hemostasis

Percutaneous liver biopsy is the gold standard among clinician\u27s tool to diagnose and guide subsequent therapy for liver disease. Ultrasound image guidance is being increasingly used to reduce associated procedural risks but post–biopsy complications still persist. The major and most common complication is hemorrhage, which is highly unpredictable and may sometimes lead to death. Though the risk of mortality is low, it is too high for a diagnostic procedure. Post-biopsy care and additional surgical intervention to arrest hemorrhage make liver biopsy a costly procedure for health care delivery systems. Non-invasive methods to stop bleeding exist like electro–cautery, microwave, lasers, radio frequency, argon–beam, and High Intensity Focused Ultrasound (HIFU). All the methods except HIFU require direct exposure of the needle puncture site for hemostasis. HIFU is an ultrasound modality and uses mechanical sound waves for focused energy delivery. Ultrasound waves are minimally affected by tissue attenuation and focus internal targets without direct exposure. Human error in focusing HIFU renders it unusable for a medical procedure especially when noninvasive. In this project we designed and developed an ultrasound guided prototype robot for accurate HIFU targeting to induce hemostasis. The robotic system performs percutaneous needle biopsy and a 7.5 cm focal length HIFU is fired at the puncture point when the needle tip retracts to the liver surface after sample collection. The robot has 4 degrees of freedom (DOF) for biopsy needle insertion, HIFU positioning, needle angle alignment and US probe image plane orientation. As the needle puncture point is always in the needle path, mechanically constraining the HIFU to focus on the needle reduced the required functionality significantly. Two mini c-arms are designed for needle angle alignment and US probe image plane orientation. This reduced the contact foot print of the robot over the patient providing a greater dexterity for positioning the robot. The robot is validated for HIFU hemostasis by a series of experiments on chicken breasts. HIFU initiated hemorrhage control with robotic biopsy ensures arrest of post-biopsy hemorrhage and decreases patient anxiety, hospital stay, morbidity, time of procedure, and cost. This can also be extended to other organs like kidneys, lungs etc. and has widespread implications such as control of hemorrhage in post-biopsies in patients with reduced ability for hemostasis. This research opens a greater scope for research for automation and design making it a physician friendly tool for eventual clinical use

Front-end receiver for miniaturised ultrasound imaging

Point of care ultrasonography has been the focus of extensive research over the past few decades. Miniaturised, wireless systems have been envisaged for new application areas, such as capsule endoscopy, implantable ultrasound and wearable ultrasound. The hardware constraints of such small-scale systems are severe, and tradeoffs between power consumption, size, data bandwidth and cost must be carefully balanced. To address these challenges, two synthetic aperture receiver architectures are proposed and compared. The architectures target highly miniaturised, low cost, B-mode ultrasound imaging systems. The first architecture utilises quadrature (I/Q) sampling to minimise the signal bandwidth and computational load. Synthetic aperture beamforming is carried out using a single-channel, pipelined protocol in order to minimise system complexity and power consumption. A digital beamformer dynamically apodises and focuses the data by interpolating and applying complex phase rotations to the I/Q samples. The beamformer is implemented on a Spartan-6 FPGA and consumes 296mW for a frame rate of 7Hz. The second architecture employs compressive sensing within the finite rate of innovation (FRI) framework to further reduce the data bandwidth. Signals are sampled below the Nyquist frequency, and then transmitted to a digital back-end processor, which reconstructs I/Q components non-linearly, and then carries out synthetic aperture beamforming. Both architectures were tested in hardware using a single-channel analogue front-end (AFE) that was designed and fabricated in AMS 0.35μm CMOS. The AFE demodulates RF ultrasound signals sequentially into I/Q components, and comprises a low-noise preamplifier, mixer, programmable gain amplifier (PGA) and lowpass filter. A variable gain low noise preamplifier topology is used to enable quasi-exponential time-gain control (TGC). The PGA enables digital selection of three gain values (15dB, 22dB and 25.5dB). The bandwidth of the lowpass filter is also selectable between 1.85MHz, 510kHz and 195kHz to allow for testing of both architectural frameworks. The entire AFE consumes 7.8 mW and occupies an area of 1.5×1.5 mm. In addition to the AFE, this thesis also presents the design of a pseudodifferential, log-domain multiplier-filter or “multer” which demodulates low-RF signals in the current-domain. This circuit targets high impedance transducers such as capacitive micromachined ultrasound transducers (CMUTs) and offers a 20dB improvement in dynamic range over the voltage-mode AFE. The bandwidth is also electronically tunable. The circuit was implemented in 0.35μm BiCMOS and was simulated in Cadence; however, no fabrication results were obtained for this circuit. B-mode images were obtained for both architectures. The quadrature SAB method yields a higher image SNR and 9% lower root mean squared error with respect to the RF-beamformed reference image than the compressive SAB method. Thus, while both architectures achieve a significant reduction in sampling rate, system complexity and area, the quadrature SAB method achieves better image quality. Future work may involve the addition of multiple receiver channels and the development of an integrated system-on-chip.Open Acces