Physics and Astronomy

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This is the collection for the University of Waterloo's Department of Physics and Astronomy.

Research outputs are organized by type (eg. Master Thesis, Article, Conference Paper).

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400 kHz Spectral Domain Optical Coherence Tomography for Corneal Imaging
(University of Waterloo, 2021-12-23) Chen, Lin Kun; Bizheva, Kostadinka
The cornea is the transparent, outermost layer of the human eye that contributes approximately 70% of the refractive power of the eye in air. It is composed of five major tissue layers: the epithelium, the Bowman’s membrane, the stroma, the Descemet’s membrane, and the endothelium. Corneal diseases such as Keratoconus and Fuchs’ dystrophy can change the morphology of some or all of the corneal layers, which can lead to vision impairment and eventually blindness. For example, Keratoconus causes localizes thinning and thickening of the corneal epithelium, damage to the collagen structure of the corneal stroma (scarring) and alteration of the corneal curvature. All of these changes result in blurred and double vision, and in severe cases can lead to corneal blindness that would require corneal replacement surgery. Fuchs’ dystrophy is a genetic disease that damages the endothelium cell. Since the endothelial cells are responsible for maintaining the fluid level in the stroma, impairment or death of the endothelial cells leads to dehydration or edema of the cornea that results in partial or full corneal blindness. Systemic diseases such as diabetes also affect the physiology and morphology of the cornea. Diabetes affects all the corneal cells and leads to abnormalities such as neuropathy, keratopathy, stromal edema, decrease in endothelial cell density, low tear secretion etc. Although there have been many clinical studies of these diseases, knowledge of the early-stage changes in the corneal morphology at the cellular level remains unclear. Understanding the early stage of disease development with the help of high speed and ultra-high resolution optical coherence tomography (UHR-OCT) corneal imaging can improve the early diagnostics of corneal diseases and well as monitoring the effectiveness of different therapies such as surgical intervention or administration of pharmaceutical drugs. The main objectives of my research project were: a) to upgrade the 34 kHz OCT system with a new camera that offered a 400 kHz data acquisition rate and 8192-pixel linear array sensor, b) test the performance of the 400 kHz OCT system for ex-vivo and in-vivo corneal imaging, and c) develop pre-processing for the interferogram and post-processing algorithms for the images. Implementing a camera with a faster acquisition rate will help to reduce the motion artifact caused by involuntary eye motions. Also, compared to 4500 pixels used in the 34 kHz camera, the new system utilizes approximately 7500 pixels, resulting in a larger scanning range. Although new camera has smaller sensor size (30% smaller), vertical binning is applied to ensure the light signal is all captured. However, due to the faster acquisition rate (~11 times faster), about 10 dB of SNR will suffers from the reduced integration time. Doubling the sample arm power while keep all other conditions the same can boost the SNR by about 3 dB. Therefore, incident power at the sample arm will be raised carefully according to the maximum permissible exposure calculated using the American National Standard for Ophthalmics – Light Hazard Protection for Ophthalmics instruments provided by ANSI. The result from the technical tests shows that the 400 kHz SD-OCT system offers 1 µm axial resolution in biological tissue with an extended scanning range of 2.8 mm (compared to 1.2 mm of the 34 kHz system). It has a lateral resolution of 1.04 μm/pix and can resolve group 7 element 6 of the USAF target with a 20x objective. It can provide 83 dB SNR with 0.95 mW of incident power at a 400 kHz image acquisition rate which should be sufficient to image semi-transparent biological tissues such as the human retina and cornea. However, given the much higher image acquisition rate (> 10x higher), the imaging power can be increased safely to ~ 4 mW, which will increase the system’s SNR to ~ 90 dB. So far, the performance of the 400 kHz OCT system has been tested by imaging plant tissues (cucumber) and ex-vivo pig corneas, due to the cancellation of all in-vivo human and animal studies imposed by COVID-19.
Evaluation and Correlation of Morphological, Blood Flow and Physiological Retinal Changes in a Rat Model of Glaucoma with a Combined Optical Coherence Tomography and Electroretinography System
(University of Waterloo, 2017-08-29) Tan, Bingyao; Bizheva, Kostadinka
Glaucoma is a chronic disease associated with progressive dysfunction of the retinal ganglion cells (RGC), reduction of the retinal blood flow, thinning of the retinal nerve fiber layer (RNFL) and deformation of the optical nerve head (ONH). It is the second leading cause of blindness worldwide, with an estimate of 64.3 million people between the ages of 40 to 80 years affected in 2013, 76.7 million by 2020, and 111.8 million by 2040. Currently, there is no cure for glaucoma and any clinically available pharmaceutical or surgical approaches to treating the disease can only slow its progression. Therefore, early detection and treatment are essential for managing the glaucoma progression. Elevated intraocular pressure (IOP) is one of the most well studied and documented pathogenic risk factors for open-angle glaucoma (OAG), and as such, numerous animal models have been developed to study the acute and chronic IOP elevation effect on the ONH structure, retinal blood perfusion and RGC function. However, most of these studies utilized static chronic IOP elevation, while the relation between the IOP dynamics and the progression of glaucoma is still poorly understood. Joos et al proposed a rat model of glaucoma that utilized a dynamic approach to IOP elevation by use of a vascular loop that consists of short duration (~1h), intermittent IOP elevation. This model resembles closely the daily IOP spiking observed in glaucomatous patients, especially during the early stages of the disease. Better understanding of how the retina (human and animal) responds to such intermittent spikes of the IOP can provide ophthalmologists with valuable information on the origins and early stages of glaucoma development when treatment would be most efficient, as well as insights into developing new therapeutic approaches for glaucoma. Over the past few decades, a number of ex-vivo and in-vivo optical imaging modalities ranging from histopathology to confocal microscopy and optical coherence tomography (OCT) have been used to image changes in the morphology of the retina and the optic nerve head (ONH) in human subjects and animal models of OAG. Laser Doppler Flowmetry, Doppler OCT (DOCT) and Optical Coherence Angiography (OCTA) have been utilized to image and quantify changes in the total retinal blood flow and the blood perfusion in retinal capillaries during IOP elevation. Furthermore, electroretinography (ERG) has been used to assess changes in the retinal function (response to visual stimulation) during elevated IOP. However, all previous studies collected information about the morphological, functional and blood flow / perfusion changes in the retina during elevated IOP separately, at different time points, which prevented the researchers from correlating those changes and uncovering the relationship between them, typically referred to as neurovascular coupling. Since OCT provides both intensity and phase information in a single acquisition, this imaging technology is able to assess changes in the retinal morphology, function and blood flow/perfusion in-vivo and simultaneously. Therefore, the main goals of this PhD project were to: • Develop a combined OCT+ERG imaging system that can image in-vivo and record simultaneously, changes in the retinal morphology, retinal response to visual stimulation and retinal blood flow / perfusion at normal and elevated IOP. • Test the performance of the OCT+ERG system in a rat model of glaucoma. • Utilize the OCT+ERG technology and the dynamic IOP rat model of glaucoma based on the vascular loop, to investigate the effects of acute and chronic IOP elevation to ischemic and non-ischemic IOP levels on the rat retina. • Utilize the OCT+ERG technology to investigate neurovascular coupling in the rat retina at normal and abnormal IOP levels. Results from this PhD research have been published or summarized in manuscripts that are currently under review. Therefore, this PhD thesis was prepared in such a way that individual manuscripts represent separate thesis chapters.
Line-Field Spectral Domain Optical Coherence Tomography: Design and Biomedical Applications
(University of Waterloo, 2024-05-10) CHEN, KEYU; Bizheva, Kostadinka
Corneal diseases such as keratoconus and Fuchs' dystrophy lead to the dysfunction of the cornea, which can result in vision loss. Early-stage detection at the cellular level provides the opportunity for treatment that slows or stops disease progression and potentially for disease cure. Optical coherence tomography (OCT), often described as the optical equivalent of ultrasound imaging, enables high-speed, non-invasive volumetric imaging at a cellular resolution. These advantages of OCT have made it a useful tool in ophthalmology and beyond. High-speed OCT data acquisition is desirable, particularly for volumetric imaging, to reduce involuntary eye and body motion and suppress motion-induced artifacts. Line-scan OCT (LS-OCT) utilizes a 2D lens, such as a cylindrical lens, as the line generator to project a line-shaped detection beam onto the sample instead of the focused pencil beam traditionally used in OCT systems. Combined with high-speed 2D cameras, LS-OCT systems allow for a data acquisition speed that is 1 to 2 orders of magnitude higher than conventional point-scanning OCT systems. The three main goals of this thesis research are: (i) to develop a novel Powell lens-based line-scan OCT system, (ii) to optimize the performance of the Powell lens-based line-scan OCT system for in vivo human studies, and (iii) to develop a line-scan OCT protocol for conducting dynamic OCT (dOCT) studies on various biological tissues. A Powell lens is used in a line-field spectral domain OCT (PL-LF-SD-OCT) system to generate a line-shaped imaging beam with an almost uniform distribution of optical power along the line direction. This design overcomes the significant sensitivity loss of approximately 10 dB that is observed along the line length direction (B-scan) in LF-OCT systems based on cylindrical lens line generators. The PL-LF-SD-OCT system offers almost isotropic spatial resolution (∆x and ∆y approximately 2 µm, ∆z approximately 1.8 µm) in free space and a sensitivity of approximately 87 dB with only about 1.6 dB loss along the line length for an imaging power of 2.5 mW at an imaging rate of 2,000 frames per second (fps). Images acquired with the PL-LF-SD-OCT system allow for the visualization of cellular and sub-cellular structures of biological tissues. Following the development of the first PL-LF-OCT system, we present a second-generation system that combines sufficiently high: spatial resolution (2.4 μm × 2.2 μm × 1.7 μm (x × y × z)) to resolve individual cells; sensitivity (approximately 90 dB) to image the semi-transparent human cornea; and image acquisition rate (≥ 2,400 fps) to suppress most involuntary eye motion artifacts. In summary, the second-generation system allows for contactless, in vivo imaging of the cellular structure of the human cornea. Volumetric images acquired in vivo from the corneas of healthy subjects show corneal epithelial, endothelial, and keratocytes cells, as well as sub-basal and stromal corneal nerves. The system's high axial resolution also allows for clear identification and morphometry of the corneal endothelium, Descemet's membrane, and the pre-Descemet’s (Dua) layer. By characterizing time-dependent signal intensity fluctuations, dOCT enhances contrast in OCT images and indirectly probes cellular metabolic processes. Almost all of the dOCT studies published so far are based on the acquisition of 2D dOCT images (B-scans or C-scans) via point-scanning spectral-domain/swept-source OCT or full-field OCT respectively, due to limitations in the image acquisition rate. Here we introduce a novel high-speed Line-Field dOCT (LF-dOCT) system and image acquisition protocols designed for volumetric dOCT imaging of biological tissues. The imaging probe is based on an exchangeable telecentric lens pair that enables a selection of transverse resolution (1.1 µm to 6.4 µm) and field of view (FOV) (250×250 µm² to 1.4×1.4 mm²) suitable for different biomedical applications. The system offers an axial resolution of 2.6 µm in free space, corresponding to approximately 1.9 µm in biological tissue assuming an average refractive index of 1.38. A maximum sensitivity of 90.5 dB is achieved for 3.5 mW optical power at the tissue surface and camera acquisition rate of 2000 fps. Volumetric dOCT images acquired with the novel LF-dOCT system from plant tissue (English cucumber) and animal tissues (mouse liver and prostate tumor spheroids) allow for volumetric visualization of the tissues’ cellular and sub-cellular structure.
Line-Scan Spectral-Domain Optical Coherence Tomography for Cellular Resolution Structural and Vascular Imaging of Biological Tissues
(University of Waterloo, 2022-06-07) Han, Le; Bizheva, Kostadinka
Optical coherence tomography (OCT) is an optical interferometric technique for non-invasive contactless imaging of the cellular-level structures of biological tissues. However, the application of OCT for in-vivo volumetric cellular resolution imaging of the human anterior eye is challenging due to artifacts induced by involuntary eye motion and the contradictory requirements for high lateral resolution and extended depth of focus. This thesis addresses these challenges by developing: (i) a broadband line-scan (LS) spectral-domain (SD) OCT system that combines micrometer-scale spatial resolution and ultrafast image acquisition rate; (ii) an image reconstruction method for restoring the diffraction-limited lateral resolution of the LS SD-OCT system along a large depth range. In addition, a novel flow velocimetry method is developed for extending the LS SD-OCT system's functionality. The novel LS SD-OCT system combines a broadband light source and an ultrafast area camera to achieve a nearly isotropic spatial resolution of ~2.3 𝜇m in free space and an image acquisition rate of up to 3000 frames/second. The central sensitivity of the system is 92 dB near the zero optical delay with a 6 dB rolloff depth range of 0.78 mm. The system's performance was evaluated by imaging in-vivo a healthy volunteer's cornea and limbus. The motion artifacts are not noticeable in most volumetric images. Cornea epithelial cells, sub-basal corneal nerves, keratocytes in the stroma, cornea endothelial cells, palisaded of Vogt (POV) in the limbus, limbal epithelial cells between the POVs, and hyperreflective line structures underneath POVs are resolved in the 3D images within a limited depth range. Digital adaptive optics (DAO) is commonly used to correct the monochromatic wavefront aberrations in heterodyne imaging techniques. We show that interference-induced phase destruction, spatial-spectral crosstalk, and chromatic aberrations are the three primary artifacts obscuring diffraction-limited resolution restoration with standard DAO in images acquired with the broadband LS SD-OCT system. We demonstrate that phase destruction can be minimized with appropriate optics alignment. In addition, we show that spatial-spectral crosstalk and chromatic aberrations can be efficiently suppressed by registration of monochromatic aberration corrected sub-band tomograms. The image reconstruction method for recovering the diffraction-limited lateral resolution has been validated using different test objects such as standard resolution target, microbeads phantom, and different biological tissues imaged ex-vivo. The novel decorrelation-based transverse flow velocimetry, developed specifically for LS SD-OCT, extends the current dynamic light scattering flow speed measurement techniques. We take advantage of the phase stability within each B-scan and digitally generate a low-resolution OCT signal. By introducing the lateral resolution contrast in the temporal autocorrelation function of the OCT signals, this method allows for precisely measuring the transverse intralipid flow velocity in the low time resolution and low SNR conditions. The proposed method was validated by comparing with the phasebased OCT velocity measurement methods in phantom-based experiments. The combination of the broadband LS SD-OCT system and the proposed image reconstruction method allows aberration-free volumetric cellular resolution imaging of biological tissues. The high image acquisition rate suppresses the motion-induced image artifacts, making high-resolution in-vivo imaging of the human eye in an extended depth of focus possible. The novel flow velocimetry can be used to monitor the flow dynamic, which extends the LS SD-OCT's functionality.
Neurovascular Coupling in healthy human retina evaluated with Optical Coherence Tomography
(University of Waterloo, 2024-12-21) Dhaliwal, Khushmeet; Bizheva, Kostadinka
Retinal neurodegenerative diseases such as glaucoma, age-related macular degeneration (AMD), diabetic retinopathy, and retinitis pigmentosa affect millions of people worldwide and pose a significant burden on public health and the economy. Glaucoma, impacting approximately 80 million people globally, is a leading cause of irreversible blindness. In 2019, an estimated 19.8 million Americans (12.6%) were living with AMD, of which about 1.49 million people faced vision-threatening conditions. An estimated 9.6 million people were living with diabetic retinopathy in 2021, with about 1.84 million of them experiencing vision-threatening stages. In the United States alone, vision impairments- including those resulting from these retinal diseases- cost an estimated $139 billion annually. Retinal neurodegenerative diseases not only cause progressive damage to the retinal morphology and vascular network, but also cause acute and transient metabolic, physiological, and blood flow changes at the early stages of the disease development which become permanent and chronic at the advanced stages of the disease. Neurovascular Coupling (NVC) refers to the transient vasodilation and increased retinal blood flow resulting from the increased metabolic activity of retinal neurons in response to visual stimulation. Over the past few decades, a range of imaging techniques from clinical ophthalmoscope and confocal microscopy to adaptive optics scanning laser ophthalmoscope and optical coherence tomography (OCT) have been used ex vivo and in vivo to study components of the neurovascular coupling and its underlying mechanisms. Techniques such as Laser Doppler Velocimetry, Optical Coherence Tomography Angiography (OCTA), and Doppler Optical Coherence Tomography (D-OCT) have been used to observe the vascular responses of the retina caused by visual stimulation. Additionally, Electroretinography (ERG) has been widely used in clinical settings to evaluate the electrical activity of the neuronal retina. More recently, an optical equivalent to ERG, Optoretinography (ORG) was developed and OCT technology, imaging protocols, and image processing algorithms were designed to conduct OCT-based ORG studies in the human and animal retina. However, most of the Doppler OCT, OCTA, and ORG studies have examined components of the neurovascular coupling separately, potentially overlooking the dynamic interactions and comprehensive responses inherent in neurovascular coupling. OCT, which acquires simultaneously both intensity and phase information, is particularly well-suited for investigating neurovascular coupling in the retina, as it enables a completely non-invasive approach for simultaneous monitoring of retinal blood flow dynamics and neuronal responses. The integration of a commercial ERG system with a research-grade OCT modality adds further value by offering easy control of the visual stimulus, use of clinically established ERG protocols designed to elicit responses from specific types of retinal neuronal cells, and using the ERG recordings to validate the visually-evoked neuronal responses. The main objectives of this PhD thesis were: 1. To develop a combined OCT+ERG imaging system to conduct in vivo and simultaneously morphological and functional imaging that can be utilized for investigating neurovascular coupling in the human retina. 2. To evaluate the performance and capabilities of the OCT+ERG system, imaging protocols, and image processing algorithms by conducting a pilot study on healthy human subjects. 3. To utilize the OCT+ERG technology to explore the neurovascular coupling mechanisms in the healthy human retina by extracting vascular and neuronal responses from different retinal layers simultaneously. 4. To examine the effects of different wavelengths and flicker frequencies on the dynamic retinal blood flow changes evoked by visual stimulation, providing deeper insights into the mechanisms of neurovascular coupling. Results from this PhD research have been summarized in three manuscripts that are either under review or under preparation for submission. Therefore, this PhD thesis was prepared in such a way that individual manuscripts represent separate thesis chapters.
Powell Lens-based Line-Scan Spectral Domain Optical Coherence Tomography for Cellular Resolution Imaging of Biological Tissues
(University of Waterloo, 2022-09-28) Song, Weixiang; Bizheva, Kostadinka
A line-scan spectral-domain optical coherence tomography system was developed for corneal imaging. It utilizes a Powell lens to achieve a better line illumination power distribution than the conventional use of cylindrical lenses. It achieves a lateral resolution of <2.1 microns and ~4.1 microns in the x and y directions and an axial resolution of ~1.5 microns in tissue.

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