Browsing by Author "Larin, Kirill V."
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Item Advances in Raman and Surface-Enhanced Raman Spectroscopy: Instrumentation, Plasmonic Engineering and Biomolecular Sensing(2014-08) Qi, Ji; Shih, Wei-Chuan; Wolfe, John C.; Han, Zhu; Larin, Kirill V.; Willson, Richard C.; Roysam, BadrinathRaman spectroscopy is a powerful technique for label-free molecular sensing and imaging in various fields. High molecular specificity, non-invasive sampling approach and the need for little or no sample preparation make Raman spectroscopy uniquely advantageous compared to other analytical techniques. However, Raman spectroscopy suffers from the intrinsic limitation of weak signal intensity. Therefore, time-sensitive studies such as diagnosis and clinical applications require improving the throughput of Raman instrumentation. Alternatively, surface-enhanced Raman scattering (SERS) improves the sensitivity by 10^6 to 10^14 times, making the weak Raman intensity no longer a limitation. Nevertheless, it is still a big challenge to engineer plasmonic substrates with high SERS enhancement, good uniformity and reproducibility. This thesis presents advances in: (1) Raman instrumentation towards high-throughput, environmental, biological and biomedical analysis; (2) SERS substrates with high enhancement factor (EF), uniformity and reproducibility; (3) biosensing applications including imaging of cell population and detection of biomolecules towards high time efficiency and sensitivity. In Raman instrumentation, we have built a high-throughput line-scan Raman microscope system and a novel parallel Raman microscope based on multiple-point active-illumination and wide-field hyperspectral data collection. Using the line-scan Raman microscope, we have performed chemical imaging of intact biological cells at the cell population level. We have also demonstrated more flexibility and throughput from the active-illumination Raman microscope in rapid chemical identification and screening of micro and nanoparticles and bacterial spores. Both Raman microscopes have been used to evaluate the large-area SERS uniformity of DC-sputtered gold nanoislands, a low-cost means to fabricate plasmonic substrates. In plasmonic engineering, we have introduced patterned nanoporous gold nanoparticles that feature 3-dimensional mesoporous network with pore size on the order of 10 nm throughput the sub-wavelength nanoparticles. We showed that the plasmonic resonance can be tuned by geometrical engineering of either the external nanoparticle size and shape or the nanoporous network. As an example, we have developed disk-shaped entities, also known as nanoporous gold disks (NPGD) with highly uniform and reproducible SERS EF exceeding 10^8. Label-free, multiplexed molecular sensing and imaging has been demonstrated on NPGD substrates. Using the line-scan Raman microscope and the NPGD substrates, we have successfully developed a label-free DNA hybridization sensor at the single-molecule level in microfluidics. We have observed discrete, individual DNA hybridization events by in situ monitoring the hybridization process using SERS. The advances and promising results presented in this thesis demonstrate potential impact in Raman/SERS imaging and sensing in environmental, biological and biomedical applications.Item Assessing Mouse Brain Elasticity Using Air-Pulse Based Optical Coherence Elastography(2017-10-12) Goh, Megan; Liu, Chih-Hao; Singh, Manmohan; Raghunathan, RakshaCurrent diagnostic methods are able to detect severe brain trauma but are unable to detect the microscopic brain injuries that regularly occur during a concussion. Our research aims to explore a potential alternative method to detect a wider range of severity in concussions through comparing the changes in the biomechanical properties of pre- and post-concussed brain tissue using optical coherence elastography (OCE). This study is a proof of concept to see if OCE can distinguish different regions within the brain based on biomechanical properties. In this study, we hope to distinguish the hippocampus, a complex structure located in the medial temporal part of the brain beneath the cerebral cortex, from the rest of the brain. Our results show that the hippocampus is softer than the cortex of the brain, which corresponds to currently available literature. In this study, we were able to show that OCE could detect differences in the biomechanical properties of different regions of the brain.Item Assessing Teratogen-Induced Changes in Murine Fetal Brain Vasculature Using In Utero Optical Coherence Tomography(2020-05) Raghunathan, Raksha; Larin, Kirill V.; Miranda, Rajesh C.; Gifford, Howard C.; Zhang, Yingchun; Mayerich, DavidThis dissertation reports the use of in utero optical coherence tomography to evaluate changes in vasculature in a developing murine fetal brain caused due to prenatal exposure to teratogens. Embryogenesis is a highly complex process that is extremely vulnerable to external factors. Proper visualization of embryonic development is crucial to understand the basic physiological processes and identify defects if any. This dissertation is divided into two major sections: 1) assessing teratogen induced changes in the murine fetal brain vasculature during the second trimester equivalent period (chapters 2-4) and 2) combining optical coherence tomography with Brillouin microscopy to image and evaluate changes in biomechanical properties during neural tube closure in order to study first trimester exposure to teratogens (appendix A3). The first section is further divided into the following sub-sections: 1) assessing alcohol induced changes in murine fetal brain vasculature, 2) assessing nicotine induced changes in murine fetal brain vasculature, and 3) assessing synthetic cannabinoid (SCB) induced changes in murine fetal brain vasculature. The advancement of algorithms to image and detect minute changes in vasculature are also detailed. The contributions of this work are significant to understand the effects of teratogens on development, as blood flow plays a major role in embryogenesis. Understanding the acute changes in vasculature caused within minutes of maternal exposure to a teratogen can open several new avenues to explore as blood flow drives organ development. Results from this dissertation have been published in 7 first author peer-reviewed publications.Item Assessing the Biomechanical Properties of Cornea using Optical Coherence Elastography(2016-05) Li, Jiasong; Larin, Kirill V.; Akay, Metin; Twa, Michael D.; Gifford, Howard C.; Wood, Lowell T.This dissertation reports on the development of measurement methods to assess the biomechanical properties of cornea based on low-coherence optical imaging, focusing on optical coherence elastographic techniques, to meet the growing demand for noninvasive high-resolution tissue characterization with improved diagnosis and treatment of ocular diseases. The research work was based on optical coherence tomography (OCT), a rapid, high-resolution, three-dimensional imaging modality that enables noninvasive depth-resolved imaging. The dissertation work is summarized in seven sections: 1) characterization the biomechanical properties of tissue mimicking phantoms, an ocular phantom, and mouse cornea in vivo using optical coherence elastography (OCE); 2) assessment the biomechanical properties of mouse corneas of different ages in vivo using air-pulse OCE; 3) the development of a method to spatially map the localized elasticity of the rabbit cornea in situ after partial riboflavin/UV-A corneal collagen cross-linking using OCE; 4) rapid characterization of the biomechanical properties of porcine corneas before and after UV-induced collagen cross-liking at different intraocular pressures by OCE; 5) the development of method to differentiate untreated and cross-linked porcine corneas of the same measured stiffness with OCE; 6) evaluation of the effects of Riboflavin/UV-A corneal collagen crosslinking on porcine corneal mechanical anisotropy with noncontact OCE; 7) a comparison of two non-contact methods to assess mechanical properties of tissue mimicking phantoms: optical coherence elastography and Michelson interferometric vibrometry. These techniques, methods and applications are demonstrated with the experiments performed on tissue mimicking phantoms (gelatin, agar, and silicone) and corneas (mouse, rabbit, porcine, both ex vivo, in situ, and in vivo) under different conditions (normal vs. cross-linking, various intraocular pressures, etc.). This dissertation represents the frontier and emerging research area of optical coherence elastography and is expected to contribute to the field of biomechanical assessment with research and clinical based applications.Item Assessing the Vasculature Changes in Murine Fetal Brain Upon Alcohol Exposure(2017-10-12) Nguyen, Jennifer; Raghunathan, Raksha; Wu, Chen; Singh, Manmohan; Liu, Chih-HaoFetal Alcohol spectrum disorder (FASD) refers to a broad spectrum of abnormalities that arise due to prenatal alcohol exposure (PAE). The severity of the abnormality depends on the amount of alcohol consumed and period of consumption during gestation. A large number of women continue to consume alcohol even during the second trimester of pregnancy, a critical period for fetal neurogenesis and angiogenesis. OCT is an optical analog of ultrasound. 3D non-invasive imaging technique with high spatial resolution. OCT has shown to be extremely useful in embryonic imaging. Speckle variance OCT (SVOCT), is a functional extension of OCT that has been used to study vasculature development in embryos. We use SVOCT, to detect vasculature changes in the embryonic brain in utero, minutes after maternal alcohol consumption. The results show that there is a decrease in fetal vessel diameter within the first 10 minutes and it persisted for 45 minutes after maternal alcohol consumption, indicating that ethanol is a possible vasoconstrictor on the fetal brain. This project was completed with contributions from Rajesh C. Miranda from the Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center.Item Assessing Tissue Biomechanical Properties with Noncontact Dynamic Optical Coherence Elastography(2018-05) Singh, Manmohan; Larin, Kirill V.; Akay, Metin; Twa, Michael D.; Gifford, Howard C.; Mayerich, DavidThis dissertation reports the development of noncontact techniques to quantify the biomechanical properties of various tissues utilizing optical coherence elastography. These techniques are critical for screening, detection, and monitoring of disease onset and progression as well as evaluating the effectiveness of various therapeutic procedures. The dissertation is divided into two major sections: 1) analyzing the localized dynamic deformation and 2) analyzing elastic wave propagation to quantify tissue biomechanical properties. Each of these sections is further divided. The localized dynamic tissue deformation analysis section has two sub-sections: a) real-time visual feedback and biomechanical assessment of dermal filler injections and b) evaluating the changes in local cardiac biomechanical properties after myocardial infarction. The elastic wave propagation analysis section has seven sub-sections: a) evaluating the changes in corneal biomechanical properties due to riboflavin/UV-A corneal collagen cross-linking, b) comparing the changes in corneal biomechanical properties induced by riboflavin/UV-A and rose-bengal/green light collagen cross-linking, c) quantifying the effects of tissue hydration on the stiffness of the cornea, d) assessing the elastic anisotropy of the cornea as a function of intraocular pressure, e) evaluating the changes in cardiac elastic anisotropy after myocardial infarction, f) development of an ultra-fast, single-shot, elastography technique, and g) development of a noncontact technique ca pable of assessing corneal geometry, eye-globe intraocular pressure, and corneal stiffness with a single instrument. Finally, the spatio-temporal properties of air-pulse induced displacement were characterized, and the repeatability and sensitivity of the OCE techniques described in this dissertation were compared to the “gold standard” of mechanical testing. The contributions of this work are crucial steps for the further development and clinical application of rapid, accurate, robust, and safe techniques capable of evaluating tissue biomechanical properties for early detection and monitoring of diseases.Item Assessment of Tissue Biomechanical Properties Using Ultrasound Elastography and Optical Coherence Elastography(2022-05-10) Rippy, Justin Randall; Larin, Kirill V.; Aglyamov, Salavat R.; Liu, Jingfei; Wu, Tianfu; Schultz, Jerome S.; Mayerich, DavidThis dissertation reports several significant contributions that further the field of elastography as a whole. Each chapter also represents a key step toward the realization of quantitative compression elastography (QCE). First, motion estimation algorithms were analyzed in chapter 2 to determine which algorithm allowed for the most accurate measurement of motion and subsequent elastic wave speed. This is significant for the entire field of elastography, as motion estimation algorithms are used regardless of choice of imaging modality or method. Following this, ultrasound shear wave elastography and transient optical coherence elastography were compared under similar conditions in chapter 3 to determine if they gave comparable results. This analysis proves that the results obtained from both modalities are comparable and that they can be used interchangeably. While this is important for the field of elastography, i.e., measurements taken with one can and should be compared to the other, it is absolutely crucial for the development of QCE. If the two methods cannot give comparable results, it follows that techniques used to obtain quantitative information from one cannot be used in the other. Chapter 4 contains the most significant contribution, which is the development of QCE. QCE is a simple, multi-modal, quantitative elastography technique that borrows the idea of a compliant stress sensor from optical coherence elastography and improves upon it by removing the need for calibration. Because strain imaging and wave excitation can be performed without moving the transducer, ultrasound has the unique ability to essentially calibrate the sensor in place during the act of compression. Furthermore, this allows for a more accurate measurement than is typically possible when using a compliant sensor because the exact sensor conditions can be known at the time of measurement instead of assumed from uniaxial compression testing. Overall, the contributions of this work serve to increase accuracy in elastographic measurements, further multimodal elastography, and serve as the genesis of quantitative compression elastography methods in ultrasound.Item Biomechanical Characterization of Crystalline Lens by Optical Coherence Elastography(2021-12) Zhang, Hongqiu; Larin, Kirill V.; Aglyamov, Salavat R.; Schultz, Jerome S.; Zhang, Yingchun; Manns, FabriceThis dissertation reports on the application of optical coherence tomography (OCT) based elastography technique to assess the biomechanical properties of crystalline lens tissue noninvasively quantitatively. This work is summarized in four sections: 1) Assessing the Effects of Storage Medium on the Biomechanical Properties of Porcine Lens with Optical Coherence Elastography; 2) Optical Coherence Elastography of Cold Cataract in Porcine Lens; 3) The Mechanical Properties of Oxidative Cataract and the Potential Medical Treatment Measured by Optical Coherence Elastography; 4) Age-Related Changes in Rabbit Lens Viscoelasticity by Surface Wave Dispersion Analysis. These methods and applications are demonstrated with experiments on both tissue-mimicking phantoms (gelatin and agar) and lens (porcine and rabbit) ex vivo and in situ under different conditions (medium preservation, cold cataract, oxidative cataract, aging). This dissertation represents the frontier and emerging research area of noninvasive optical coherence elastography. It is expected to contribute to the field of quantitative biomechanical assessment with research and clinical-based applications.Item Biomechanical Effects of Custom Corneal Cross-Linking Using Optical Coherence Elastography(2018-10-18) Smith, ChristopherKeratoconus is a progressive disease of the eye which causes the cornea to become weak and thin. If untreated, it may lead to corneal deformation and impaired vision. Corneal collagen cross-linking (CXL) is a recently FDA-approved treatment for keratoconus that stiffens the cornea by the combined use of a photoactivator and exposure to ultraviolet (UV) light. Normal CXL treats a large region of the cornea; in contrast, custom CXL only treats diseased portions of the cornea, minimizing patient exposure to harmful UV light. However, the effects of custom CXL on local corneal stiffness are not well understood. Using a porcine model, we investigated the biomechanical effects of custom CXL. Three dimensional optical coherence tomography (OCT) images of eyes were taken before and after CXL treatment and could distinguish the CXL regions from the untreated areas. To quantify the biomechanical effects of custom CXL, we used optical coherence elastography (OCE), which utilizes OCT imaging to measure air-pulse-induced displacements in the cornea. By varying the induced air pressure, the displacement as a function of applied pressures was quantified, which was a noncontact analog to traditional stiffness measurements by mechanical testing. The OCE measurements were made at points within the CXL and untreated regions. The results showed a statistically significant decrease in the air-pressure-induced displacement response in the CXL region as compared to untreated regions, indicating a significant increase in stiffness. Our work provides both qualitative and quantitative evidence that custom CXL is an effective method of inducing localized stiffening of the cornea.Item Biomechanics and Electromyography Inassessing Female Stress Urinary Incontinence(2016-12) Peng, Yun; Zhang, Yingchun; Boone, Timothy B.; Larin, Kirill V.; Ince, Nuri F.; Omurtag, AhmetIntroduction: Stress urinary incontinence (SUI), the involuntary urinary leakage associated with increases in intra-abdominal pressure, has a prevalence of 25–50% in U.S. women and the number of those who will undergo surgery will increase by half in the next forty years. SUI negatively affects the patient’s quality of life and places a great burden to the society. The functional anatomy of the continence mechanism remains vaguely understood. Hence my dissertation aims at offering a complete description of the pelvic floor muscles (PFM), the key contributor to the continence, thorough biomechanical and neurophysiological approaches. Methods: The biomechanical approach involves the development of a subject-specific finite element (FE) model of the female pelvic floor region. Subsequent computer simulations are targeted at finding the most contributive muscle to the urethral support function and evaluating current treatment strategies using a mini-sling. The neurophysiological approach involves the implementation of a novel surface electromyography (EMG) probe to acquire bioelectrical information of PFMs and the assessment of their innervations in healthy subjects and patients. Results: An FE pelvic floor model was developed which incorporates 40+ anatomical structural in the pelvis, representing the most complete model in the field. Simulation results showed that the vaginal walls, puborectalis, and pubococcygeus are the most important structures and that mid-distal post-urethral implantation represents the optimal location. Innervation zones of PFMs have been successfully identified and described for multiple PFMs. An high-density surface EMG-based motor unit number estimation approach was developed, providing a novel tool to evaluate the condition of neurologically impaired PFM. Conclusions: The combined information greatly advances our understanding of the physiology of PFM and would lay a firm foundation to novel, non-invasive, patient-specific interventional strategies in the future.Item Blood Flow Simulation in Stented Vessels and Flow Reversal Conditions(2012-05) Ionescu, Mircea; Metcalfe, Ralph W.; Kleis, Stanley J.; Franchek, Matthew A.; Larin, Kirill V.; Kakadiaris, Ioannis A.; Cohn, William E.; Naghavi, Morteza; Hartley, Craig J.Hemodynamics is one of the major factors involved in the development of cardiovascular diseases and adverse events associated with endovascular stent implantation such as in-stent restenosis and thrombosis. The first part of this work is dedicated to the imaging of stent deployment in graft tubes and ex vivo arterial segments and the investigation of in-stent hemodynamics through computational hemodynamic simulations, i.e., CHD, based on realistic in vitro stent and wall geometries. The second part is concerned with the parameterization of flow rate waveforms resembling physiologic waveforms and the description of waveform properties that lead to the occurrence of wall flow reversal in straight, cylindrical pipes. Stent reconstruction by high-resolution micro-computed tomography (microCT) is compared with reconstructions obtained from clinical CT: multislice CT (MSCT), C-arm flat detector CT (C-arm CT), and flat panel CT (FP-CT). The spatial resolution of current clinical CT for stent imaging is insufficient to visualize fine geometrical details as stent struts appear over-sized. Deployment characteristics such as stent strut prolapse into the lumen, strut vertex misalignment, underdeployment, wall prolapse, and wall creases at strut vertices of intracranial and coronary stents with open- and closed-cell designs are demonstrated by microCT imaging. In-stent hemodynamics are significantly altered by non-uniform deployment characteristics (misaligned strut vertices, malapposed struts, or wall creases), important effects not realistically captured in previous, computer generated stent models. Periodic waveforms with positive net flow rates can exhibit flow reversal. The physiological flow waveform is divided into acceleration and deceleration phases described by sinusoids, and two non-dimensional parameters to quantify wall flow reversal conditions are proposed. For waveforms typical of arterial blood flow, the wall shear stress reversal during the second deceleration phase is strongly influenced by the amplitude ratio of the preceding acceleration and deceleration phases and less by the relative time period of the deceleration phase. The method presented here can identify the occurrence of wall flow reversal and indicate the possibility of oscillatory wall shear stress that may negatively affect endothelial cell function due to blood flow waveform characteristics.Item Characterizing Corneal Biomechanical Properties Using Dynamic Optical Coherence Elastography(2016-08) Vantipalli, Srilatha; Frishman, Laura J.; Twa, Michael D.; Burns, Alan R.; Marsack, Jason D.; Larin, Kirill V.; Miller, William L.Purpose: Optical coherence elastography (OCE) quantifies the tissue’s biomechanical properties through mechanical loading and imaging the tissue response using optical coherence tomography (OCT). Current techniques evaluating corneal stiffness do not account for the influence of key physiological factors on the measured corneal biomechanical properties and either require contact, or create global deformations masking the localized variations: the hallmark of corneal ectasias, e.g., keratoconus. To implement OCE in the cornea, we developed a micro air-pulse stimulator that provides non-contact, dynamic, spatially localized, tissue stimulation. This dissertation determines a) the acute effects of tissue hydration and UV riboflavin cross-linking (CXL) treatment on the corneal ultrastructure, and evaluates the corneal biomechanical properties determined using OCE due to the effect of b) hydration and CXL treatment, c) deep stromal cross-linking treatments and d) in vivo application. Methods: a) Ex vivo de-epithelialized rabbit corneas (n=11) were cross-linked instilling 0.1% riboflavin solution for 30min across the whole cornea and UV irradiation (365nm, 3mW/cm2) to only the temporal half-region for 30min while instilling riboflavin and processed for light and transmission electron microscopy. Corneal thickness and collagen fibril separation computed as the average radial inter-fibrillar distance from the sampled fibril cross-sectional electron micrographs were recorded. b) OCE imaging was performed using phase-sensitive OCT imaging to quantify the tissue deformation dynamics resulting from a spatially discrete, low-force air-pulse (150μm spot size; 0.8ms duration; <10Pa (<0.08mmHg)). The time-dependent surface deformation is characterized by a viscoelastic tissue recovery response, quantified by an exponential decay constant—relaxation rate (RR). Higher RR is consistent with increased stiffness. Hydration influence was determined (n=10) instilling 0.9% saline every 5min for 60min and 20% dextran for another 60min. Measurements were made every 20min to determine central corneal thickness (CCT) and RR. Hydration and CXL effects were determined by obtaining OCE measurements on cross-linked corneas using isotonic (n=6) and hypertonic (n=7) riboflavin. c) OCE measurements were performed (n=10) at: the de-epithelialized stromal surface, 2/3rd corneal depth post-trephination, and after deep stromal cross-linking treatment. Rose bengal green light cross-linking (RGX) using 0.1% rose bengal solution for 20min (n=5) and 10min green light irradiation (565nm, 0.25W/cm2) and CXL treatment (n=5) was performed in the deep stroma. d) In vivo OCE was performed on anesthetized Dutch belted rabbits (n=20) recording within-session (IOP: 10, 20, 30, 40mmHg) and between sessions RR measurements before and after animal re-positioning (10mmHg). Results: a) Corneal thickness decreased significantly (−56%) after CXL treatment. Anterior collagen fibril spacing decreased significantly in the paired CXL treated region (−23%) showing that acute CXL treatment-induced changes are not only tonicity-driven. b) Corneal thickness was positively correlated (R2=0.9) with stiffness. CXL treatment using isotonic riboflavin (CCT: −1%) produced stiffer corneas (higher RR: +10%). However, CXL treatment using hypertonic riboflavin (reduced CCT: −31%) produced a tonicity-driven stiffness decrease that offset the expected stiffer material properties due to CXL treatment, resulting in no significant change in corneal material properties (RR: +6%). c) Deep stromal RGX (RR: +22%) and CXL (RR: +44%) treatments showed significantly stiffer corneas. d) In vivo RR showed excellent measurement precision for within and between session measures. Conclusion: OCE is a promising technique to quantify the corneal biomechanical properties while preserving the intact corneal shape and structure. We demonstrate the influence of hydration, and the modifications due to cross-linking treatments on the corneal ultrastructure and biomechanical properties using OCE methods. The observed excellent measurement precision is critical for in vivo application of OCE in clinical settings. Further development and future application of OCE to derive corneal material properties will allow us to quantify the magnitude of ectatic diseases, the effectiveness of CXL treatment and follow changes over time.Item Depth-resolved imaging and detection of microretroreflectors within biological tissue using Optical Coherence Tomography(Biomedical Optics Express, 2010) Ivers, Steven N.; Baranov, Stephan A.; Sherlock, Tim; Kourentzi, Katerina D.; Ruchhoeft, Paul; Willson, Richard C.; Larin, Kirill V.A new approach to in vivo biosensor design is introduced, based on the use of an implantable micron-sized retroreflector-based platform and non-invasive imaging of its surface reflectivity by Optical Coherence Tomography (OCT). The possibility of using OCT for the depth-resolved imaging and detection of micro-retroreflectors in highly turbid media, including tissue, is demonstrated. The maximum imaging depth for the detection of the micro-retroreflector-based platform within the surrounding media was found to be 0.91 mm for porcine tissue and 1.65 mm for whole milk. With further development, it may be possible to utilize OCT and micro-retroreflectors as a tool for continuous monitoring of analytes in the subcutaneous tissue.Item Detection and Monitoring of Microparticles Under Skin by Optical Coherence Tomography as an Approach to Continuous Glucose Sensing Using Implanted Retroreflectors(IEEE Sensors Journal, 2015-09) Wang, Shang; Sherlock, Tim; Salazar, Betsy; Sudheendran, Narandran; Manapuram, Ravi K.; Kourentzi, Katerina D.; Ruchhoeft, Paul; Willson, Richard C.; Larin, Kirill V.We demonstrate the feasibility of using optical coherence tomography (OCT) to image and detect 2.8 ?m diameter microparticles (stationary and moving) on a highly-reflective gold surface both in clear media and under skin in vitro. The OCT intensity signal can clearly report the microparticle count, and the OCT response to the number of microparticles shows a good linearity. The detect ability of the intensity change (2.9%�5%) caused by an individual microparticle shows the high sensitivity of monitoring multiple particles using OCT. An optical sensing method based on this feasibility study is described for continuously measuring blood sugar levels in the subcutaneous tissue, and a molecular recognition unit is designed using competitive binding to modulate the number of bound microparticles as a function of glucose concentration. With further development, an ultra-small, implantable sensor might provide high specificity and sensitivity for long-term continuous monitoring of blood glucose concentration.Item DEVELOPMENT OF PHASE STABILIZED SWEPT SOURCE OPTICAL COHERENCE TOMOGRAPHY FOR BIOMEDICAL IMAGING AND SENSING(2012-08) Manapuram, Ravi 1981-; Larin, Kirill V.; Sharma, Pradeep; Metcalfe, Ralph W.; Franchek, Matthew A.; Wood, Lowell T.Several life-threatening diseases could either be cured or be eased by diagnosing them during earlier stages. Currently, medical imaging is one of the most reliable methods of disease diagnostics. This dissertation describes the development of a medical imaging device that has a great potential for early diagnosis of various diseases. The developed system utilizes optical coherence tomography (OCT) and is capable of 3D imaging of tissues with near cellular resolution noninvasively. It is also capable of sensing minute changes in tissue refractive index or surface displacement via phase-sensitive measurements. The system showed an axial resolution of 8 µm, lateral resolution of 15 μm, an imaging depth of 9 mm, signal to noise ratio of 101 dB and a phase stability of 9 mrad. After development, the system was applied to several biomedical applications such as the detection of microbubbles in mice tails in vivo and mechanical wave propagation in mice corneas in vivo. In the live mice tails, microbubbles of sizes as small as 50 μm were detected, therefore indicating the capability of the system to serve as an early diagnostic tool for diseases caused by decompression sickness or gas emboli. Apart from imaging, this dissertation also describes a method to apply OCT for elastography applications. Results demonstrate that the system is capable of measuring amplitude of mechanical waves as small as 30 nm. The high sensitivity of the system was exploited to measure wave propagation in live mice corneas as a function of age. To the best of our knowledge, this is the first time OCT has been applied to measure wave parameters in ocular tissues in vivo.Item Distinguishing Colon Pathologies by Optical and Mechanical Contrast using Optical Coherence Elastography and Optical Coherence Tomography(2018-10-18) Le, TrietColon pathologies including colorectal cancer (CRC) and ulcerative colitis (UC) affect nearly 200,000 people per year. Early detection of these pathologies is crucial for positive prognoses. However, screening of CRC and UC by existing diagnostic tools such as white light endoscopy and sonography is limited due to their poor resolution, depth penetration, and contrast. Hence, additional contrast, such as biomechanical properties, may be necessary for accurate early detection. Existing techniques to evaluate tissue mechanical properties lack the resolution to distinguish CRC and UC in the early disease state. Optical coherence elastography (OCE) is a functional extension of optical coherence tomography (OCT) and is capable of micrometer-scale spatial resolution and nanometer-scale displacement sensitivity, making it an effective tool to distinguish small structural and mechanical changes in healthy tissue due to disease. In this work, murine colon samples from three distinct groups: healthy, CRC, and UC were tested to assess optical and elastic properties. An OCE system was used to image elastic waves that were induced by focused air-pulses in the samples. The elastic wave group velocity and dispersion of the elastic wave were translated to the viscoelastic properties of each sample. Additionally, the structural OCT image was analyzed as another method to differentiate between healthy and diseased samples. The result showed a significant difference in elasticity between CRC and UC as compared to healthy tissue and a significant difference in optical properties (p<<.05 in two-sample T-test).Item Evaluating changes in murine fetal brain vasculature due to maternal nicotine exposure using in utero optical coherence tomography(2019) Mussio, Kelsey; Raghunathan, RakshaNicotine is a commonly used substance of abuse during pregnancy. Previous research has shown that prenatal nicotine exposure (PNE) is harmful to a fetus. PNE is known to cause intrauterine and postnatal growth restriction, decrease in head circumference and biparietal diameter, and perinatal mortality and morbidity. Evidence of negative influences of nicotine on brain development has been seen in humans too. It is unknown whether the relationship between maternal smoking and behavior problems is due to physical brain deficits caused by nicotine. In this study, we use optical coherence tomography (OCT), a noninvasive optical imaging modality with high spatial and temporal resolution to image the changes in fetal brain vasculature caused due to maternal nicotine exposure. We use a functional extension of OCT called correlation mapping optical coherence angiography (cm-OCA) to image microvasculature in the fetal brain, in utero. Pregnant mice at 14.5 days post coitum were anesthetized and placed on a heated surgical platform. Abdominal fur was removed, and a small incision was made to expose the uterine horn for imaging. After initial cm-OCA measurements, the mother was administered nicotine via intragastric gavage, at a dose of 1mg/kg. Subsequent measurements were taken for a period of 45 minutes at 5-minute intervals. A drastic decrease in parameters quantifying vasculature was seen within 45 minutes of maternal nicotine exposure during the second trimester equivalent period. This project was completed with contributions from Rajesh C. Miranda from Texas A & M University College of Medicine.Item Heartbeat Optical Coherence Elastography: A Method for Passive Biomechanical Assessment of the Cornea(2022-05-12) Nair, Achuth; Larin, Kirill V.; Aglyamov, Salavat R.; Twa, Michael D.; Yoon, Geunyoung; Zhang, Yingchun; Ince, Nuri F.In this dissertation, the biomechanical properties of the cornea are explored using a novel, completely passive, biomechanical analysis technique termed heartbeat optical coherence elastography (Hb-OCE). This technology enables mechanical characterization of the cornea with applications in disease detection, staging, and therapeutic monitoring. This dissertation explores the development and evolution of the Hb-OCE technique and is divided accordingly. In the first chapter, the need for biomechanical analysis in ocular health and diagnostics and the tools available to perform that task are discussed. The second chapter describes the development of the Hb-OCE technique. Hb-OCE was initially demonstrated in a proof-of-concept ex vivo investigation. The mechanical properties of the cornea were measured in response to a simulated ocular pulse. The capabilities of the technique were initially demonstrated, including its ability to identify spatial mechanical contrast in a heterogenous sample. In the next chapter, the Hb-OCE technique is compared to better established optical elastography techniques to investigate the effects of collagen XII deficiency on the biomechanical properties of the murine cornea ex vivo. Hb-OCE was successfully used to distinguish collagen XII deficient tissue from the wild-type, and the ability of Hb-OCE to detect tissue elastic nonlinearity was demonstrated. In the fourth chapter, Hb-OCE is demonstrated in vivo, successfully illustrating that not only can the technique detect mechanical contrast in vivo, but corneal stiffness can be measured using only the heartbeat-induced ocular pulse as a source of displacement. The fifth chapter discusses how Hb-OCE was compared to a similar quasi-static but active elastography technique known as compression elastography. Furthermore, stiffness mapping using Hb-OCE was demonstrated for the first time. Finally, this dissertation concludes with closing thoughts on areas of technical improvements and future applications.Item Hemodynamic analysis of flow near cerebral aneurysms: Insight into aneurysm formation and effects of intervention(2012-05) Mantha, Aishwarya; Metcalfe, Ralph W.; Kleis, Stanley J.; Larin, Kirill V.; Franchek, Matthew A.; Hartley, Craig J.; Naghavi, MortezaThe purpose of this study is to investigate the role of hemodynamics in the initiation and progression of cerebral aneurysms. It is composed of two major sections, where the first part attempts at understanding the hemodynamic cause and effect linkages leading to aneurysm formation and it is shown that low and oscillatory shear could lead to aneurysm initiation. The second part consists of hemodynamic analysis inside the aneurysm. It is shown that stable flow patterns exist inside the aneurysm with distinct influx and efflux zones that remain unchanged during the cardiac cycle; application of this knowledge will aid in better design of flow diverting devices. In my Master’s thesis, it was demonstrated that low and oscillatory wall shear stresses (WSS) correlated with the aneurysm sites. This work is summarized and then a careful critique of some newer aneurysm formation theories involving high WSS and wall shear stress gradients (WSSG) and how they relate to the AFI (aneurysm formation indicator, proposed by our group) is presented. Second, a numerical experiment is performed to demonstrate the potential drawbacks of using WSSG and its variations as a hemodynamic indicator. Effects of various meshing schemes and resolutions are investigated systematically and the sensitivity of WSSG to image acquisition and reconstruction is demonstrated, along with its potential for misleading interpretation. Third, robustness and sensitivity of the proposed AFI is demonstrated by analyzing the effects of ageing reflected by the change in waveform shape as a result of degeneration of arterial tone. It is shown that AFI indeed captures the differences in the waveforms of an older and a younger adult. Fourth, hemodynamic influences on aneurysm stability under realistic physiological conditions are explored, and contrary to what has been reported in the literature, we have shown that flow patterns inside the aneurysm are relatively stable and insensitive to pulsatility. Two aneurysm types were considered: sidewall (paraclinoid) and bifurcation (basilar tip), with three specimens of each obtained from human patients via clinical 3D digital subtraction angiography. We identified stable large-scale flow patterns in the aneurismal flows. This knowledge of flow patterns is applied towards better design of stents and other flow diverting devices. In addition, potential use of hemodynamic simulations in clinical application is also established.Item Laser Optoacoustic Imaging System for Molecular and Functional Imaging Research in Small Animal Models(2021-05) Su, Richard; Oraevsky, Alexander A.; Larin, Kirill V.; Gifford, Howard C.; Roysam, Badrinath; Das, Mini; Emelianov, Stanislav Y.Optoacoustic tomography is an emerging field of medical imaging that is rapidly developing due to its unique capability to visualize and display molecular content of biological tissues with quantitative accuracy and excellent spatial resolution scalable with depth within live tissues. The main merit of optoacoustic tomography is in deep tissue imaging where resolution and contrast of pure optical imaging methods are limited by the strong optical scattering. The dominating tissue chromophores in the spectral range of laser wavelengths (650 nm to 1100 nm) that penetrate deep within tissues are hemoglobin and oxyhemoglobin of blood. Potential capability of functional optoacoustic tomography systems to measure concentrations of hemoglobin and oxyhemoglobin in humans provides for a variety of medical applications in the fields of diagnostics, therapeutic interventions and surgery. Using the methods of molecular imaging, it is also possible to visualize distribution of molecules that do not possess strong optical absorption in the near infrared spectral range, but can be targeted by special molecular and nano-particular contrast agents designed with strong optical absorption and high efficiency of acoustic wave emission through thermal expansion. In spite of great promises the full potential of optoacoustic tomography in functional and molecular imaging has not been realized yet. In order to achieve capabilities of functional and molecular imaging, the optoacoustic tomography system has to overcome the tradeoff between high sensitivity of detection and ultrawide-bandwidth of ultrasonic frequency detection. Furthermore, quantitative imaging is only possible with knowledge of the optical fluence distribution through the entire volume of interest at each of the multiple wavelengths of laser illumination. We took on a challenging task to develop such an advanced tomography system and enhance it with the methods of quantitative data analysis and image reconstruction. We designed and assembled a full view three-dimensional Laser Optoacoustic Imaging System (LOIS-3D) based on a 96-channel array of ultrawide band ultrasonic transducers and demonstrated its highest sensitivity to changes in the optical absorption coefficient ~0.03/cm compared with any academic or industrial system. We proposed and implemented a signal processing method of transducer impulse response deconvolution that enabled reversal of distortions in the detected optoacoustic signals, which in turn allowed the experimental approach to functional and molecular imaging in live laboratory animals. The system technical specifications were characterized in a number of molecular imaging experiments. Finally, we proposed and implemented a practical method of the optical fluence normalization through the entire imaged volume based on measurements of the voxel brightness in blood vessels with known optical absorption and without computations of light propagation through tissues with unknown optical properties. We reconstructed previously unattainable functional images of the total hemoglobin and blood oxygen saturation in a volume of live tissue showing separately arteries, veins and tissues.