Photoacoustic (PA) imaging has the potential to overcome disadvantages of optical and ultrasonic imaging techniques by combining the two imaging modalities. This allows for exploitation of endogenous contrasts (variants of hemoglobin) to generate energy with light, and provides enhanced resolution by probing for resulting acoustic signals. The resulting platform has widespread applications ranging from structural (vasculature-based) to functional (oxygenation-based) point-of-care clinical imaging. This thesis has been aimed towards the development of a PA system for detection of intracranial hemorrhages. Simulations have been performed using a photon tracking Monte Carlo program and ultrasound wave propagation modeling software, k-wave to simulate light absorption and resultant acoustic signals in tissue. Furthermore, development of a PA imaging setup utilizes a 6-ns pulsed laser operating at 532-nm with a pulse repetition frequency of 28-Hz as the light source. Ultrasonic transducers with centre frequencies ranging from 1- to 5-MHz are used to receive acoustic signals produced from the object illuminated. The system is designed in a handheld, probe-like configuration to enable point-of-care detection and/or imaging. Acoustic signals are amplified and collected through a data acquisition system and processed through software to form an image. Simulations have shown sufficient penetration through superficial tissue, and absorption of light by blood at relevant wavelengths (near-infrared range). Black plastic resin phantoms have been used to characterize point-source PA signals, and complex geometries of phantoms have successfully been imaged and reconstructed with the PA system. Phantom geometries have also been imaged through gelatin and bone. The PA system has been successfully shown to image PA absorbers in different surrounding media, providing a promising first-step towards further development of the PA system for the detection of intracranial hemorrhages. This research has shown that photoacoustic detection of intracranial hemorrhages may be possible for adult human patients with brain injuries, and that the PA system design presented should be further developed to meet this goal. / Thesis / Master of Applied Science (MASc)

Photoacoustic imaging for biomedical application has attracted much research in recent years. To date, most of the work has focused on pulsed photoacoustics. Recent developments have seen the implementation of a radar pulse compression methodology into continuous wave photoacoustic modality, however very little theory has been developed in support of this approach. In this thesis, the one-dimensional theory of radar photoacousticsfor pulse compressedlinear frequency modulated continuous sinusoidal laserphotoacoustics is developed.The effect of the chirp parameters on the corresponding photoacoustic signal is investigated, and guidelines for choosing the chirp parametersfor absorber profilometric detectionare given based on the developed theory and simulations. Simulated results are also compared to available experimental results and show a good agreement.

Accurate insertion and monitoring of metal implants in-vivo is essential for clinical diagnosis and therapy of various diseases. Clinical studies and examples have demonstrated that the misplacement errors of these metal devices can have dramatic consequences. This thesis focuses on three main metal devices that are in widespread use today: needles, coronary stents and brachytherapy seeds. Each application requires proper image-guidance for correct usage. For needles, image guidance is required to ensure correct local injection delivery or needle aspiration biopsy. Fine needle aspiration biopsies are performed in order to avoid major surgical excisions when obtaining tissue biopsy procedures. However, because of the small biopsy sample, the risk is that the sample is collected outside of the tumorigenic region, resulting in a false negative result. Implantation of stents requires that confirmation that proper stent apposition has been achieved due to balloon inflation. Furthermore, it is important to guide the stent to shield the vulnerable region of an atherosclerotic plaque. With prostate brachytherapy seeds, the ability to monitor seed placement is crucial because needle deflections or tissue deformation can result in seed misplacement errors, decreasing the efficacy of the pre-established treatment plan. For the described applications and other possible clinical practices involving the use of metallic implants, an imaging technology that can accurately depict the location of the metal objects, relative to their respective backgrounds, in real-time, is necessary to improve the safety and the efficacy of these procedures. Currently, ultrasound is used because of its real-time capabilities, non-ionizing radiation, and soft tissue contrast. However, due to high acoustic scattering from tissue, the contrast of metal implants can be low. Photoacoustic imaging can be used as an alternative, or complementary, imaging method to ultrasound for imaging metal. This thesis focuses on the benefits and the pitfalls of using photoacoustic imaging for detecting three different metal implants, each having unique requirements. Overall, the goal of this work is to develop a framework for clinical applications using combined ultrasound and photoacoustic imaging to help guide, detect and follow-up on clinical metal implants introduced in-vivo. / text

archives@tulane.edu / Placental insufficiency is a term used to describe the reduced transport of gases and nutrients across the placenta. As a result of placental insufficiency, preeclampsia and intrauterine growth restriction (IUGR) can develop. Preeclampsia is diagnosed by the onset of high blood pressure and proteinuria after 20 weeks of gestation and complicates 2-8% of all pregnancies. Having preeclampsia is also a risk-factor for developing IUGR, which is defined as an estimated fetal weight below the 10th percentile. These conditions can negatively impact the immediate outcomes of pregnancy by reducing placental perfusion and causing placental ischemia. Currently, there is a need for reliable, inexpensive tools that can monitor placental function bedside. Spectral photoacoustic (PA) imaging presents a solution to this need. Photoacoustic imaging uses nanosecond light pulses to excite photoabsorbers within tissue. These photoabsorbers undergo thermal expansion and relaxation, emitting a pressure wave that can then be read by an ultrasound transducer. In this study, the photoabsorbers of interest include hemoglobin, deoxyhemoglobin, and indocyanine green (ICG). Various ultrasound contrast agents are available for clinical use; however, indocyanine green-loaded nanodroplets present various advantages over other contrast agents due to their smaller size and longer in vivo stability. Upon laser irradiation, these droplets experience a liquid-to-gas phase change and provide improved photoacoustic contrast. These nanodroplets are a focus of this work, as they have the ability to be targeted to specific tissues and can act as oxygen carriers. In this case, they are targeted to folate receptor α, which is highly expressed on the placenta. Thus, the first aim of this work is to validate the folate receptor α targeting mechanism using an in vitro tissue phantom model. As oxygen carriers, they are able to release oxygen once activated by the laser. The second aim is to validate localized oxygen delivery via these nanodroplets by using multiplex imaging to determine ICG accumulation and measure their effect on placental oxygen saturation in vivo. Another contrast agent, 2-Deoxy-D-Glucose (2DG-ICG), could be utilized in conjunction with photoacoustic imaging as a tool to monitor glucose transport, a major indicator of placental function. By conjugating ICG to 2DG, a glucose analog, it is possible to target glucose transporter 1, which is the primary glucose transporter on the placenta. The final aim of this work is to determine the feasibility of using 2DG-ICG as an indicator of glucose transport in the placenta using an in vitro model. / 1 / Sarah Nwia

Head trauma patients are susceptible to secondary injuries where afflicted tissues can propagate towards dysfunction after the initial injury is treated. Monitoring blood oxygenation (SpO2) below the skull is crucial for the early detection of secondary head injury such as hematoma. To obtain such information in a point-of-care setting, photoacoustic (PA) imaging can be used to differentiate optical contrast between hemoglobin (Hb) species by measuring resultant ultrasonic waves emitted by optically irradiated tissue. Given the ratio of Red:NIR light absorption, information regarding SpO2 can be determined in vivo. In this project, computer simulations involving PA imaging of tissue models have been performed and techniques tested using an optic fiber/transducer PA imaging system. In simulated and physical PA scans, Red:NIR ratio values are computed for various tissue models to evaluate optical contrast in target absorbers. Images reconstructed from simulations showed the ability to visualize differences in SpO2 across a layer of skull tissue using multi-spectral optical irradiation. Red:NIR ratios were calculated using PA signals produced by 750 nm light and 850 nm light. Physical image reconstructions were conducted using a 5 ns pulsed laser and near-infrared (NIR) optical parametric oscillator (OPO). The pulse energy used during physical PA raster scans reached up to 5.3 mJ/pulse. Tissue phantoms scanned consisted of optical absorbers surrounded by various tissue-mimicking materials. Images from physical acquisitions were acquired using a 2D CNC-controlled moving stage, but free-hand tracking using inertial and optical sensors have been investigated. At 5.3 mJ/pulse, images reconstructed from physical scans could not resolve optical absorbers positioned beneath a layer of skull-mimicking tissue. A limiting factor contributing to low signal-to-noise ratio (SNR) from inferior absorbers was the percentage of power lost during beam focusing. However, simulation results encourage future work to improve pulse energy output before simulation results can be validated. / Thesis / Master of Applied Science (MASc)

Cancer has been one of main causes of human deaths for many years. Early detection of cancer is essential to provide definitive treatment. Among many cancer treatment methods, nanoparticle-mediated photothermal therapy is considered as one of the promising cancer treatment methods because of its non-invasiveness and cancer-specific therapy. Ultrasound and photoacoustic imaging can be utilized for both cancer detection and photothermal therapy guidance. Ultrasound elasticity imaging can detect cancer using tissue elastic properties. Once cancer is diagnosed, spectroscopic photoacoustic imaging can be used to monitor nanoparticle delivery before photothermal therapy. When nanoparticles are well accumulated at the tumor, ultrasound and photoacoustic-based thermal imaging can be utilized for estimating temperature distribution during photothermal therapy to guide therapeutic procedure. In this dissertation, ultrasound beamforming, elasticity imaging, and spectroscopic photoacoustic imaging methods were developed to improve cancer detection and therapy guidance. Firstly, a display pixel based synthetic aperture focusing method was developed to fundamentally improve ultrasound image qualities. Secondly, an autocorrelation based sub-pixel displacement estimation method was developed to enhance signal-to-noise ratio of elasticity images. The developed elasticity imaging method was utilized to clinically evaluate the feasibility of using ultrasound elasticity imaging for prostate cancer detection. Lastly, a minimum mean square error based spectral separation method was developed to robustly utilize spectroscopic photoacoustic imaging. The developed spectroscopic photoacoustic imaging method was utilized to demonstrate ultrasound and photoacoustic image-guided photothermal cancer therapy using in-vivo tumor-bearing mouse models. The results of these studies suggest that ultrasound and photoacoustic imaging can assist both cancer detection and therapy guidance. / text

京都大学 / 0048 / 新制・課程博士 / 博士(人間健康科学) / 甲第21037号 / 人健博第53号 / 新制||人健||4(附属図書館) / 京都大学大学院医学研究科人間健康科学系専攻 / (主査)教授 杉本 直三, 教授 精山 明敏, 教授 安達 泰治 / 学位規則第4条第1項該当 / Doctor of Human Health Sciences / Kyoto University / DFAM

Providing molecular fingerprint information, vibrational spectroscopy is a powerful tool for chemical analysis. In the mid-infrared window, FT-IR spectroscopy and microscopy have been routinely used for sample characterization. In the near-IR window, near-infrared spectroscopy has been widely used for tissue analysis and for the detection of lipids in the arterial walls. Yet, these traditional linear spectroscopies have intrinsic limitations. FT-IR spectroscopy suffers from a poor spatial resolution and strong water absorption for the study of living systems. Near-infrared spectroscopy avoids water absorption, yet it suffers from a poor, millimeter-scale spatial resolution in tissue analysis. My thesis focuses on breaking these limitations through photoacoustic and photothermal detection approaches. The first part of my thesis is on improving the spatial resolution in catheter-based intravascular photoacoustic (IVPA) imaging. By near-infrared excitation of lipids and acoustic detection, IVPA allows depth-resolved identification of lipid-laden atherosclerotic plaque. Thus far, most IVPA endoscopes use multimode fibers, which do not allow tight focusing of photons. Recent experiments on pulse propagation in multimode graded-index fibers have shown a nonlinear improvement in beam quality. Here, we harness this nonlinear phenomenon for the fiber-delivery of nanosecond laser pulses. We built a photoacoustic catheter 1.4 mm outer diameter, offering a lateral resolution as fine as 30 μm within a depth range of 2.5 mm. Such resolution is one order of magnitude better than current multi-mode fiber-based intravascular photoacoustic catheters. At the same time, the delivered pulse energy can reach as high as 20 μJ, which is two orders of magnitude higher than that of an optical resolution photoacoustic endoscope built with single-mode fiber. These improvements are expected to promote the biomedical application of photoacoustic endoscopes which require both high resolution and high pulse energy. Based on the technical advances, my thesis work further demonstrated longitudinal imaging of the same plaque in the same living animal. Recently developed mid-infrared photothermal (MIP) microscopy overcomes the limitations in FT-IR microscopy by probing the IR absorption-induced photothermal effect using visible light. MIP microscopy yields sub-micrometer spatial resolution with high spectral fidelity and much-reduced water background. The second part of my thesis work pushes the physical limits of MIP microscopy in aspects of detection sensitivity and imaging speed using two approaches. First, taking advantage of the interference scattering effect, the scattering signal from the sample can be greatly enhanced. Together with the relatively large infrared absorption coefficient, the sensitivity of the infrared spectrum is greatly improved, and single virus detection is achieved. Second, by using fluorescence as a thermo-sensitive probe, the temperature raise by infrared absorption can be retrieved in a more efficient way and much higher imaging speed and sensitivity are thus accomplished.

Neuromodulation plays a crucial role in facilitating research into brain function and enabling treatments for neurological and psychiatric disorders. In brain research, current non-invasive tools face challenges when studying brain sub-regions due to their limited spatial resolution, which can barely reach a scale of 100 μm. Moreover, precise control over the volume of tissue activated (VTA) is needed to effectively target diverse-shaped brain regions, such as ocular dominance columns. Similarly, in disease treatment, the lack of sufficient spatial resolution poses obstacles in restoring normal vision using existing FDA-approved retina prostheses for retinitis pigmentosa. To address these challenges, my thesis work focuses on the development of optically-generated ultrasound devices for non-invasive brain stimulation and implantable retina prostheses. Firstly, to meet the need for non-invasive neuromodulation with ultrahigh precision, we have developed an optically-generated focused ultrasound device. By embedding candle soot nanoparticles in a curved polydimethylsiloxane pad, this device generates a transcranial ultrasound focus at 15 MHz with an ultrahigh lateral resolution of 83 μm. This resolution is two orders of magnitude smaller than conventional transcranial-focused ultrasound, enabling successful submillimeter transcranial stimulation in vivo targeting the mouse motor cortex. Addressing the requirement for a customized VTA in specific brain sub-regions, we have developed an optically-generated Bessel beam ultrasound device. This device was specifically designed to target brain columns with an elongated acoustic focus, and it successfully achieved a VTA with a lateral resolution of 152 μm and an axial resolution of 1.93 mm. The stimulation capability of the device has been confirmed through immunofluorescence imaging, which showed that the stimulation depth in mouse brains reached up to 2.2 mm. Furthermore, in order to address the need for an ultrahigh spatial resolution in retina prosthesis, we have developed an optically-generated ultrasound film as a subretinal prosthesis. In proof-of-concept experiments using blind rat retina, this film has successfully achieved retina stimulation ex vivo. In conclusion, optically-generated ultrasound devices offer promising opportunities for brain science research and disease treatments. They revolutionize non-invasive brain stimulation with ultrahigh precision and customized VTA for studying brain sub-regions. Additionally, they hold the potential for enhancing spatial resolution in retina prostheses, bringing hope to individuals with retinal disorders. / 2024-09-08T00:00:00Z

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