The Design and Realization of a Dual Mode Photoacoustic and Ultrasound Imaging Camera

Prostate cancer is currently the second leading cause of cancer death in American men. Diagnosis of the disease is based on persisting elevated prostate-specific antigen (PSA) levels and suspicious lesion felt on digital rectal examination (DRE), prompting transrectal ultrasound (TRUS) imaging guided biopsy. This method, however, has long been criticized for its poor sensitivity in detecting cancerous lesions, leading to the fact that these biopsies generally are not targeted but systematic multi-core in nature that try to sample the entire gland. The thesis presents a new modality that, in combination of ultrasound (US) imaging with multi-wavelength photoacoustic (PA) imaging, improves the physician’s ability to locate the suspicious cancerous regions during biopsy. Here, building further on the innovation of an acoustic lens based focusing technology for fast PA imaging, a novel concept with the use of a polyvinylidene fluoride (PVDF) film that incorporates US imaging into our existing PA imaging probe is presented. The method takes advantage of the lens based PA signal focusing technology, while simultaneously incorporates US imaging modality without interfering with the current PA imaging system design and structure. Simulation and experimental support on tissue equivalent phantoms is provided in detail. The thesis also elaborates on the signal-to-noise ratio (SNR) improvement of the US imaging component by driving the film with frequency modulated (FM) signals. In addition, a custom-designed US simulation software that is developed to explore and evaluate various system design options is discussed. The dual modality transrectal probe is only intended as a first step. The long term goal of the study is to facilitate locating the cancer region in-vivo with PA imaging, transfer it to co-registered US image, and use the real-time US imaging for needle guidance during biopsy

Fast label-free multilayered histology-like imaging of human breast cancer by photoacoustic microscopy

The goal of breast-conserving surgery is to completely remove all of the cancer. Currently, no intraoperative tools can microscopically analyze the entire lumpectomy specimen, which results in 20 to 60% of patients undergoing second surgeries to achieve clear margins. To address this critical need, we have laid the foundation for the development of a device that could allow accurate intraoperative margin assessment. We demonstrate that by taking advantage of the intrinsic optical contrast of breast tissue, photoacoustic microscopy (PAM) can achieve multilayered histology-like imaging of the tissue surface. The high correlation of the PAM images to the conventional histologic images allows rapid computations of diagnostic features such as nuclear size and packing density, potentially identifying small clusters of cancer cells. Because PAM does not require tissue processing or staining, it can be performed promptly and intraoperatively, enabling immediate directed re-excision and reducing the number of second surgeries

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

Characterization of Lens Based Photoacoustic Imaging System

Some of the challenges in translating photoacoustic (PA) imaging to clinical applications includes limited view of the target tissue, low signal to noise ratio and the high cost of developing real-time systems. Acoustic lens based PA imaging systems, also known as PA cameras are a potential alternative to conventional imaging systems in these scenarios. The 3D focusing action of lens enables real-time C-Scan imaging with a 2D transducer array. In this paper, we model the underlying physics in a PA camera in the mathematical framework of an imaging system and derive a closed form expression for the point spread function (PSF). Experimental verification follows including the details on how to design and fabricate the lens inexpensively. The system PSF is evaluated over a 3D volume that can be imaged by this PA camera. Its utility is demonstrated by imaging phantom and an ex vivo human prostate tissue sample

Single-Shot Waterless Low-Profile Photoacoustic System: Near-Field Volumetric Imaging In Vivo for Blood Vessels Based on Capacitive Micromachined Ultrasonic Transducer (CMUT)

Intensive research on photoacoustics (PA) for imaging of the living human body, including the skin, vessels, and tumors, has recently been conducted. We propose a PA measurement system based on a capacitive micromachined ultrasonic transducer (CMUT) with waterless coupling, short measurement time (��1 s), backward light irradiation, and a low-profile ultrasonic receiver unit (��1 cm). We fabricate a 64-element CMUT ring array with 6.2 mm diameter and 10.4 MHz center frequency in air, and 100% yield and uniform element response. To validate the PA tissue characterization, we employ pencil lead and red ink as solid and liquid models, respectively, and a living body to target moles and vessels. The system implements a near-field imaging system consisting of a 6 mm polydimethylsiloxane (PDMS) matching layer between the object and CMUT, which has a 3.7 MHz center frequency in PDMS. Experiments were performed in a waterless contact on the PDMS and the laser was irradiated with a 1 cm diameter. The experimental results show the feasibility of this near-field PA imaging system for position and depth detection of skin, mole, vessel cells, etc. Therefore, a system applicable to a low-profile compact biomedical device is presented.National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP, Ministry of Science, ICT & Future Planning) (No. 2016R1E1A2915630); National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2018R1A5A7025522)

Photoacoustic tomography and sensing in biomedicine

Photoacoustics has been broadly studied in biomedicine, for both human and small animal tissues. Photoacoustics uniquely combines the absorption contrast of light or radio frequency waves with ultrasound resolution. Moreover, it is non-ionizing and non-invasive, and is the fastest growing new biomedical method, with clinical applications on the way. This review provides a brief recap of recent developments in photoacoustics in biomedicine, from basic principles to applications. The emphasized areas include the new imaging modalities, hybrid detection methods, photoacoustic contrast agents and the photoacoustic Doppler effect, as well as translational research topics

Multimodal photoacoustic and optical coherence tomography scanner using an all optical detection scheme for 3D morphological skin imaging

A noninvasive, multimodal photoacoustic and optical coherence tomography (PAT/OCT) scanner for three-dimensional in vivo (3D) skin imaging is described. The system employs an integrated, all optical detection scheme for both modalities in backward mode utilizing a shared 2D optical scanner with a field-of-view of ~13 × 13 mm2. The photoacoustic waves were detected using a Fabry Perot polymer film ultrasound sensor placed on the surface of the skin. The sensor is transparent in the spectral range 590-1200 nm. This permits the photoacoustic excitation beam (670-680 nm) and the OCT probe beam (1050 nm) to be transmitted through the sensor head and into the underlying tissue thus providing a backward mode imaging configuration. The respective OCT and PAT axial resolutions were 8 and 20 µm and the lateral resolutions were 18 and 50-100 µm. The system provides greater penetration depth than previous combined PA/OCT devices due to the longer wavelength of the OCT beam (1050 nm rather than 829-870 nm) and by operating in the tomographic rather than the optical resolution mode of photoacoustic imaging. Three-dimensional in vivo images of the vasculature and the surrounding tissue micro-morphology in murine and human skin were acquired. These studies demonstrated the complementary contrast and tissue information provided by each modality for high-resolution 3D imaging of vascular structures to depths of up to 5 mm. Potential applications include characterizing skin conditions such as tumors, vascular lesions, soft tissue damage such as burns and wounds, inflammatory conditions such as dermatitis and other superficial tissue abnormalities

Random-access optical-resolution photoacoustic microscopy using a digital micromirror device

We developed random-access optical-resolution photoacoustic microscopy using a digital micromirror device. This system can rapidly scan arbitrarily shaped regions of interest within a 40  μm×40  μm imaging area with a lateral resolution of 3.6 μm. To identify a region of interest, a global structural image is first acquired, then the selected region is scanned. The random-access ability was demonstrated by imaging two static samples, a carbon fiber cross and a monolayer of red blood cells, with an acquisition rate up to 4 kHz. The system was then used to monitor blood flow in vivo in real time within user-selected capillaries in a mouse ear. By imaging only the capillary of interest, the frame rate was increased by up to 9.2 times

Photoacoustic imaging in biomedicine

Photoacoustic imaging (also called optoacoustic or thermoacoustic imaging) has the potential to image animal or human organs, such as the breast and the brain, with simultaneous high contrast and high spatial resolution. This article provides an overview of the rapidly expanding field of photoacoustic imaging for biomedical applications. Imaging techniques, including depth profiling in layered media, scanning tomography with focused ultrasonic transducers, image forming with an acoustic lens, and computed tomography with unfocused transducers, are introduced. Special emphasis is placed on computed tomography, including reconstruction algorithms, spatial resolution, and related recent experiments. Promising biomedical applications are discussed throughout the text, including (1) tomographic imaging of the skin and other superficial organs by laser-induced photoacoustic microscopy, which offers the critical advantages, over current high-resolution optical imaging modalities, of deeper imaging depth and higher absorptioncontrasts, (2) breast cancerdetection by near-infrared light or radio-frequency–wave-induced photoacoustic imaging, which has important potential for early detection, and (3) small animal imaging by laser-induced photoacoustic imaging, which measures unique optical absorptioncontrasts related to important biochemical information and provides better resolution in deep tissues than optical imaging