Minimally invasive photoacoustic imaging:Current status and future perspectives

Photoacoustic imaging (PAI) is an emerging biomedical imaging modality that is based on optical absorption contrast, capable of revealing distinct spectroscopic signatures of tissue at high spatial resolution and large imaging depths. However, clinical applications of conventional non-invasive PAI systems have been restricted to examinations of tissues at depths less than a few cm due to strong light attenuation. Minimally invasive photoacoustic imaging (miPAI) has greatly extended the landscape of PAI by delivering excitation light within tissue through miniature fibre-optic probes. In the past decade, various miPAI systems have been developed with demonstrated applicability in several clinical fields. In this article, we present an overview of the current status of miPAI and our thoughts on future perspectives.status: publishe

Photoacoustic Tomography: From Bench to Bedside

Photoacoustic imaging (PAI) is an emerging imaging modality that shows great potential for preclinical research and clinical practice. As a hybrid technique, PAI uniquely combines the advantages of optical excitation and of acoustic detection. Optical absorption provides a rich contrast mechanism from either endogenous chromophores or exogenous contrast agents. Because ultrasound scatters much less than light in tissue, PAI generates high-resolution images in both the optical ballistic and diffusive regimes, overcoming the limitations imposed by light scattering in deep biological tissues. PAI has led to a variety of exciting discoveries and applications from laboratory research to clinical patient care. To translate photoacoustic technology from the bench to the bedside, this thesis focuses on efforts to increase the imaging depth, provide clinically useful information (i.e., relevant imaging contrast), reduce system size, and improve system reliability. Assisted by powerful pulsed lasers and advanced data acquisition circuits, modern PAI has achieved applications such as functional imaging of the whole rat brain, revealing detailed angiography and functional connectivity at high spatiotemporal resolution. The advancement of deep imaging in small animal PAI has been transferred to human breast and brain imaging, showing early promise for clinical practice. To further extend the imaging depth and provide dielectric imaging contrast, microwave-based thermoacoustic tomography has been demonstrated in vivo. To map further physiological contrasts, spectroscopic PAI has been performed to image the oxygenation states of hemoglobin and myoglobin. In addition to the effort towards deep penetration and multiple contrasts, benchtop photoacoustic microscopy has been minimized to a handheld probe for human skin imaging. As a rapidly evolving imaging technology, PAI is being translated from the bench to the bedside and promises exciting and useful clinical applications.</p

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

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 evaluation of surfaces via pulsed evanescent field interaction

"May 2014."Dissertation Supervisor: Dr. John A. Viator.Includes vita.In recent years, major research funding and commercial development has been going toward the production and characterization of increasingly useful nanomaterials. These materials such as quantum dots, nanoparticles, and thin films can increase the efficiency of solar panels, create new treatments for cancer, and vastly improve the detection capabilities for various optical sensors for biosensing. Unfortunately, to date, very few methods of characterizing these types of materials exist such as scanning electron microscopy and ellipsometry. These techniques are prohibitively expensive, cannot be used with all materials, and require rigorous preparation schemes before scanning. Therefore, a new method to characterize thin films and detect the properties of nanomaterials is needed. This study proposes a newly revived method, Total Internal Reflection Photoacoustic Spectroscopy, along with related techniques, to deliver cost effective characterization and detection for nanomaterials and thin films.Includes bibliographical references (pages 122-143)

Row-Column Capacitive Micromachined Ultrasonic Transducers for Medical Imaging

Ultrasound imaging plays an important role in modern medical diagnosis. Recent progress in real-time 3-D ultrasound imaging can offer critical information such as the accurate estimation of organ, cyst, or tumour volumes. However, compared to conventional 2-D ultrasound imaging, the large amount of data and circuit complexity found in 3-D ultrasound imaging results in very expensive systems. Therefore, a simplification scheme for 3-D ultrasound imaging technology is needed for a more wide-spread use and to advance clinical development of volumetric ultrasound. Row-column addressing 2-D array is one particular simplification scheme that requires only N + N addressing lines to activate each element in an N × N array. As a result, the fabrication, circuit, and processing complexity dramatically decrease. Capacitive micromachined ultrasonic transducer (CMUT) technology was chosen to fabricate the array as it offers micro-precision fabrication and a wide bandwidth, which make it an attractive transducer technology. The objective of this thesis is to investigate and demonstrate the imaging potential of row-column CMUT arrays for RT3D imaging. First, the motivation, physics, and modelling of both CMUTs and row-column arrays are described, followed by the demonstration of a customized row-column CMUT pseudo-real-time 3-D imaging system. One particular limitation about row-column arrays discovered as part of this dissertation work is the limited field-of-view of the row-column arrays’ imaging performance. A curved row-column CMUT array was proposed to improve the field-of-view, and the resulting modelling of the acoustic field and simulated reconstructed image are presented. Furthermore, a new fabrication process was proposed to construct a curved row-column CMUT array. The resulting device was tested to demonstrate its flexibility to achieve the necessary curvature. Finally, a new wafer bonding process is introduced to tackle the next generation of RC-CMUT fabrication. Many of the new fabrication techniques reported in this work are useful for CMUT fabrication engineers. The analysis on row-column array also provides additional insights for 2-D array simplification research

Viscoelasticity Imaging of Biological Tissues and Single Cells Using Shear Wave Propagation

Changes in biomechanical properties of biological soft tissues are often associated with physiological dysfunctions. Since biological soft tissues are hydrated, viscoelasticity is likely suitable to represent its solid-like behavior using elasticity and fluid-like behavior using viscosity. Shear wave elastography is a non-invasive imaging technology invented for clinical applications that has shown promise to characterize various tissue viscoelasticity. It is based on measuring and analyzing velocities and attenuations of propagated shear waves. In this review, principles and technical developments of shear wave elastography for viscoelasticity characterization from organ to cellular levels are presented, and different imaging modalities used to track shear wave propagation are described. At a macroscopic scale, techniques for inducing shear waves using an external mechanical vibration, an acoustic radiation pressure or a Lorentz force are reviewed along with imaging approaches proposed to track shear wave propagation, namely ultrasound, magnetic resonance, optical, and photoacoustic means. Then, approaches for theoretical modeling and tracking of shear waves are detailed. Following it, some examples of applications to characterize the viscoelasticity of various organs are given. At a microscopic scale, a novel cellular shear wave elastography method using an external vibration and optical microscopy is illustrated. Finally, current limitations and future directions in shear wave elastography are presented

Enabling Technologies for Co-Robotic Translational Ultrasound and Photoacoustic Imaging

Among many medical imaging modalities, medical ultrasound possesses its unique advantages of non-ionizing, real-time, and non-invasive properties. With its safeness, ease of use, and cost-effectiveness, ultrasound imaging has been used in a wide variety of diagnostic applications. Photoacoustic imaging is a hybrid imaging modality merging light and ultrasound, and reveals the tissue metabolism and molecular distribution with the utilization of endo- and exogenous contrast agents. With the emergence of photoacoustic imaging, ultrasound and photoacoustic imaging can comprehensively depict not only anatomical but also functional information of biological tissue. To broaden the impact of translational ultrasound and photoacoustic imaging, this dissertation focuses on the development of enabling technologies and the exploration of associated applications. The goals of these technologies are; (1) Enabling Technologies for Translational Photoacoustic Imaging. We investigated the potential of maximizing the access to translational photoacoustic imaging using a clinical ultrasound scanner and a low-cost light source, instead of widely used customized data acquisition system and expensive high power laser. (2) Co-robotic Ultrasound and Photoacoustic Imaging. We introduced a co-robotic paradigm to make ultrasound/photoacoustic imaging more comprehensive and capable of imaging deeper with higher resolution and wider field-of-view.(3) Advancements on Translational Photoacoustic Imaging. We explored the new use of translational photoacoustic imaging for molecular-based cancer detection and the sensing of neurotransmitter activity in the brain. Together, these parts explore the feasibility of co-robotic translational ultrasound and photoacoustic imaging

Development and Applications of Advanced Ultrasound Techniques for Characterization and Stimulation of Engineered Tissues

Mechanobiology is central in the development, pathology, and regeneration of musculoskeletal tissues, in which mechanical factors play important roles. Therefore, there is a need for methods to characterize the composition and mechanical properties of developing musculoskeletal tissues over time. Ultrasound elastographic techniques have been developed for noninvasive imaging of spatial heterogeneity in tissue stiffness. However, their application for quantitative assessment of tissue mechanical properties, especially viscoelastic properties, has not been exploited. Additionally, ultrasound energy may be used to apply mechanical stimulation to engineered constructs at the microscale, and thereby to enhance tissue regeneration. We have developed a multimode ultrasound viscoelastography (MUVE) system for assessing microscale mechanical properties of engineered hydrogels. MUVE uses focused ultrasound pulses to apply acoustic radiation force (ARF) to deform samples, while concurrently measuring sample dimensions using coaxial high frequency ultrasound imaging. We used MUVE to perform creep tests on agarose, collagen, and fibrin hydrogels of defined concentrations, as well as to monitor the mechanical properties of cell-seeded constructs over time. Local and bulk viscoelastic properties were extracted from strain-time curves through fitting of relevant constitutive models, showing clear differences between concentrations and materials. In particular, we showed that MUVE is capable of mapping heterogeneity of samples in 3D. Using inclusion of dense agarose microbeads within agarose, collagen and fibrin hydrogels, we determined the spatial resolution of MUVE to be approximately 200 μm in both the lateral and axial directions. Comparison of MUVE to nanoindentation and shear rheometry showed that our ultrasound-based technique was superior in generating consistent, microscale data, particularly for very soft materials. We have also adapted MUVE to generate localized cyclic compression, as a means to mechanically stimulate engineered tissue constructs at the microscale. Selected treatment protocols were shown to enhance the osteogenic differentiation of human mesenchymal stem cells in collagen-fibrin hydrogels. Constructs treated at 1 Hz at an acoustic pressure of 0.7 MPa for 30 minutes per day showed accelerated osteogenesis and increased mineralization by 10 to 30 percent, relative to unstimulated controls. In separate experiments, the ultrasound pulse intensity was increased over time to compensate for changes in matrix properties over time, and a 35 percent increase in mineralization was achieved. We also extended the application of a previously-developed spectral ultrasound imaging (SUSI) technique to an animal model for early detection of heterotopic ossification (HO). The quantitative information on acoustic scatterer size and concentration derived from SUSI was used to differentiate tissue composition in a burn/tenotomy mice model from the control model. Importantly, HO foci were detected as early as one week after injury using SUSI, which is 3-5 weeks earlier than when using conventional micro-computed tomography. Taken together, these results demonstrate that ultrasound-based techniques can non-invasively and quantitatively characterize viscoelastic properties of soft materials in 3D, as well as their composition over time. Ultrasound pulses can also be used to stimulate engineered constructs to promote musculoskeletal tissue formation. MUVE, SUSI, and ultrasound stimulation can be combined into an integrated system to investigate the roles of matrix composition, static mechanical environment, and dynamic mechanical stimuli in tissue regeneration, as well as the interactions of these factors and their evolution over time. Ultrasound-based techniques therefore have promising potential in noninvasively characterizing the composition and biomechanics, as well as providing mechanical intervention in native and engineered tissues as they develop over time.PHDBiomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/144116/1/xho_1.pd

Optical Methods in Sensing and Imaging for Medical and Biological Applications

The recent advances in optical sources and detectors have opened up new opportunities for sensing and imaging techniques which can be successfully used in biomedical and healthcare applications. This book, entitled ‘Optical Methods in Sensing and Imaging for Medical and Biological Applications’, focuses on various aspects of the research and development related to these areas. The book will be a valuable source of information presenting the recent advances in optical methods and novel techniques, as well as their applications in the fields of biomedicine and healthcare, to anyone interested in this subject