Mitchell Kirby | University of Washington (original) (raw)

Papers by Mitchell Kirby

Scientific Reports

The cornea provides the largest refractive power for the human visual system. Its stiffness, alon... more The cornea provides the largest refractive power for the human visual system. Its stiffness, along with intraocular pressure (IOP), are linked to several pathologies, including keratoconus and glaucoma. Although mechanical tests can quantify corneal elasticity ex vivo, they cannot be used clinically. Dynamic optical coherence elastography (OCE), which launches and tracks shear waves to estimate stiffness, provides an attractive non-contact probe of corneal elasticity. To date, however, OCE studies report corneal moduli around tens of kPa, orders-of-magnitude less than those (few MPa) obtained by tensile/inflation testing. This large discrepancy impedes OCE’s clinical adoption. Based on corneal microstructure, we introduce and fully characterize a nearly-incompressible transversely isotropic (NITI) model depicting corneal biomechanics. We show that the cornea must be described by at least two shear moduli, contrary to current single-modulus models, decoupling tensile and shear respon...

APL Bioengineering

Recent progress in the production and maturation of iPSC-cardiomyocytes has facilitated major adv... more Recent progress in the production and maturation of iPSC-cardiomyocytes has facilitated major advances in building bioartificial heart tissue with functional cardiomyocytes. Despite this progress, vascularizing these constructs continues to be a barrier to clinical application. One emerging strategy for vascularization uses aligned "cords" of endothelial cells in tissue grafts to guide assembly of chimeric microvessels upon graft implantation. Here, we test whether this approach can guide vascularization of a bioartificial tissue implanted on the rat heart. We find that patterned cords of human endothelial cells anastomose and become perfused with host blood by 3 days post-implantation. Immunohistochemical staining confirmed that graft-derived micro-vessels persist in the patch for 7 days. Furthermore, we noted a shift in distribution of vessels in the patch from patterned cord-associated clustering at 3 days to a more diffuse distribution pattern at 7 days. This loss of patterning corresponded to an infiltration of CD68þ cells and an increase in collagen within the patch. Upon further engraftment of patches containing both cords and human cardiomyocytes, we identified human cardiomyocytes and graft derived vasculature at the time of explant. Our findings show that patterned endothelial cords guide transient vessel patterning on the rat heart. Our results also suggest that future work should be directed at further adapting vascularization strategies to the epicardial environment and add to an important emerging dialog in cardiac cell therapy that points to the need to characterize host response prior to or in parallel with efficacy studies.

Journal of Biomedical Optics

Dynamic optical coherence elastography (OCE) tracks elastic wave propagation speed within tissue,... more Dynamic optical coherence elastography (OCE) tracks elastic wave propagation speed within tissue, enabling quantitative three-dimensional imaging of the elastic modulus. We show that propagating mechanical waves are mode converted at interfaces, creating a finite region on the order of an acoustic wavelength where there is not a simple one-to-one correspondence between wave speed and elastic modulus. Depending on the details of a boundary's geometry and elasticity contrast, highly complex propagating fields produced near the boundary can substantially affect both the spatial resolution and contrast of the elasticity image. We demonstrate boundary effects on Rayleigh waves incident on a vertical boundary between media of different shear moduli. Lateral resolution is defined by the width of the transition zone between two media and is the limit at which a physical inclusion can be detected with full contrast. We experimentally demonstrate results using a spectraldomain OCT system on tissue-mimicking phantoms, which are replicated using numerical simulations. It is shown that the spatial resolution in dynamic OCE is determined by the temporal and spatial characteristics (i.e., bandwidth and spatial pulse width) of the propagating mechanical wave. Thus, mechanical resolution in dynamic OCE inherently differs from the optical resolution of the OCT imaging system.

Applied Physics Letters

We describe surface wave propagation in soft elastic media at speeds exceeding the bulk shear wav... more We describe surface wave propagation in soft elastic media at speeds exceeding the bulk shear wave speed. By linking these waves to the elastodynamic Green's function, we derive a simple relationship to quantify the elasticity of a soft medium from the speed of this supershear evanescent wave (SEW). We experimentally probe SEW propagation in tissue-mimicking phantoms, human cornea ex vivo, and skin in vivo using a high-speed optical coherence elastography system. Measurements confirm the predicted relationship between SEW and bulk shear wave speeds, agreeing well with both theoretical and numerical models. These results suggest that SEW measurements may be a robust method to quantify elasticity in soft media, particularly in complex, bounded materials where dispersive Rayleigh-Lamb modes complicate measurements.

Journal of Biomedical Optics

Dynamic elastography is an attractive method to evaluate tissue biomechanical properties. Recentl... more Dynamic elastography is an attractive method to evaluate tissue biomechanical properties. Recently, it was extended from US-and MR-based modalities to optical ones, such as optical coherence tomography for three-dimensional (3-D) imaging of propagating mechanical waves in subsurface regions of soft tissues, such as the eye. The measured group velocity is often used to convert wave speed maps into 3-D images of the elastic modulus distribution based on the assumption of bulk shear waves. However, the specific geometry of OCE measurements in bounded materials such as the cornea and skin calls into question elasticity reconstruction assuming a simple relationship between group velocity and shear modulus. We show that in layered media the bulk shear wave assumption results in highly underestimated shear modulus reconstructions and significant structural artifacts in modulus images. We urge the OCE community to be careful in using the group velocity to evaluate tissue elasticity and to focus on developing robust reconstruction methods to accurately reconstruct images of the shear elastic modulus in bounded media.

Journal of biomedical optics, Dec 1, 2017

Optical coherence elastography (OCE) can provide clinically valuable information based on local m... more Optical coherence elastography (OCE) can provide clinically valuable information based on local measurements of tissue stiffness. Improved light sources and scanning methods in optical coherence tomography (OCT) have led to rapid growth in systems for high-resolution, quantitative elastography using imaged displacements and strains within soft tissue to infer local mechanical properties. We describe in some detail the physical processes underlying tissue mechanical response based on static and dynamic displacement methods. Namely, the assumptions commonly used to interpret displacement and strain measurements in terms of tissue elasticity for static OCE and propagating wave modes in dynamic OCE are discussed with the ultimate focus on OCT system design for ophthalmic applications. Practical OCT motion-tracking methods used to map tissue elasticity are also presented to fully describe technical developments in OCE, particularly noting those focused on the anterior segment of the eye....

Dynamics and Fluctuations in Biomedical Photonics XIII, 2016

Journal of Biomedical Optics, 2016

Before laser speckle contrast imaging (LSCI) can be used reliably and quantitatively in a clinica... more Before laser speckle contrast imaging (LSCI) can be used reliably and quantitatively in a clinical setting, there are several theoretical and practical issues that still must be addressed. In order to address some of these issues, an electro-optical system that utilizes a nematic liquid crystal spatial light modulator (SLM) to mimic LSCI experiments was assembled. The focus of this paper is to address the issue of how incident intensity affects LSCI results. Using the SLM-based system, we systematically adjusted incident intensity on the SLM and assessed the resulting first-and second-order statistics of the imaged speckle to explain the corresponding spatial contrast values in both frozen and time-integrated speckle patterns. The SLM-based system was used to generate speckle patterns with a controlled minimum speckle size, probability intensity distribution, and temporal decorrelation behavior. By eliminating many experimental parameters, this system is capable of serving as a useful intermediary tool between computer simulation and physical experimentation for further developing LSCI as a quantitative imaging modality.

Journal of the Optical Society of America. A, Optics, image science, and vision, Apr 1, 2016

In this study, we developed a signal processing method for fixed pattern noise removal in fiber-b... more In this study, we developed a signal processing method for fixed pattern noise removal in fiber-bundle-based endoscopic imaging. We physically acquired the fixed pattern of the fiber bundle and used it as a prior image in an l₁ norm minimization (l₁-min) algorithm. We chose an iterative shrinkage thresholding algorithm for l₁ norm minimization. In addition to fixed pattern noise removal, this method also improved image contrast while preserving spatial resolution. The effectiveness of this method was demonstrated on images obtained from a dark-field illuminated reflectance fiber-optic microscope (DRFM). The iterative l₁-min algorithm presented in this paper, in combination with the DRFM system that we previously developed, enables high-resolution, high-sensitivity, intrinsic-contrast, and in situ cellular imaging which has great potential in clinical diagnosis and biomedical research.

Dynamics and Fluctuations in Biomedical Photonics XII, 2015

Optical Coherence Tomography and Coherence Domain Optical Methods in Biomedicine XIX, 2015

Three-Dimensional and Multidimensional Microscopy: Image Acquisition and Processing XXII, 2015

Biomedical optics express, 2014

In this work, we investigated how bulk motion degraded the quality of optical coherence tomograph... more In this work, we investigated how bulk motion degraded the quality of optical coherence tomography (OCT) angiography that was obtained through calculating interframe signal variation, i.e., interframe signal variation based optical coherence angiography (isvOCA). We demonstrated theoretically and experimentally that the spatial average of isvOCA signal had an explicit functional dependency on bulk motion. Our result suggested that the bulk motion could lead to an increased background in angiography image. Based on our motion analysis, we proposed to reduce image artifact induced by transient bulk motion in isvOCA through adaptive thresholding. The motion artifact reduced angiography was demonstrated in a 1.3μm spectral domain OCT system. We implemented signal processing using graphic processing unit for real-time imaging and conducted in vivo microvasculature imaging on human skin. Our results clearly showed that the adaptive thresholding method was highly effective in the motion ar...

Dynamics and Fluctuations in Biomedical Photonics XIII, 2016

Scientific Reports

The cornea provides the largest refractive power for the human visual system. Its stiffness, alon... more The cornea provides the largest refractive power for the human visual system. Its stiffness, along with intraocular pressure (IOP), are linked to several pathologies, including keratoconus and glaucoma. Although mechanical tests can quantify corneal elasticity ex vivo, they cannot be used clinically. Dynamic optical coherence elastography (OCE), which launches and tracks shear waves to estimate stiffness, provides an attractive non-contact probe of corneal elasticity. To date, however, OCE studies report corneal moduli around tens of kPa, orders-of-magnitude less than those (few MPa) obtained by tensile/inflation testing. This large discrepancy impedes OCE’s clinical adoption. Based on corneal microstructure, we introduce and fully characterize a nearly-incompressible transversely isotropic (NITI) model depicting corneal biomechanics. We show that the cornea must be described by at least two shear moduli, contrary to current single-modulus models, decoupling tensile and shear respon...

APL Bioengineering

Recent progress in the production and maturation of iPSC-cardiomyocytes has facilitated major adv... more Recent progress in the production and maturation of iPSC-cardiomyocytes has facilitated major advances in building bioartificial heart tissue with functional cardiomyocytes. Despite this progress, vascularizing these constructs continues to be a barrier to clinical application. One emerging strategy for vascularization uses aligned "cords" of endothelial cells in tissue grafts to guide assembly of chimeric microvessels upon graft implantation. Here, we test whether this approach can guide vascularization of a bioartificial tissue implanted on the rat heart. We find that patterned cords of human endothelial cells anastomose and become perfused with host blood by 3 days post-implantation. Immunohistochemical staining confirmed that graft-derived micro-vessels persist in the patch for 7 days. Furthermore, we noted a shift in distribution of vessels in the patch from patterned cord-associated clustering at 3 days to a more diffuse distribution pattern at 7 days. This loss of patterning corresponded to an infiltration of CD68þ cells and an increase in collagen within the patch. Upon further engraftment of patches containing both cords and human cardiomyocytes, we identified human cardiomyocytes and graft derived vasculature at the time of explant. Our findings show that patterned endothelial cords guide transient vessel patterning on the rat heart. Our results also suggest that future work should be directed at further adapting vascularization strategies to the epicardial environment and add to an important emerging dialog in cardiac cell therapy that points to the need to characterize host response prior to or in parallel with efficacy studies.

Journal of Biomedical Optics

Dynamic optical coherence elastography (OCE) tracks elastic wave propagation speed within tissue,... more Dynamic optical coherence elastography (OCE) tracks elastic wave propagation speed within tissue, enabling quantitative three-dimensional imaging of the elastic modulus. We show that propagating mechanical waves are mode converted at interfaces, creating a finite region on the order of an acoustic wavelength where there is not a simple one-to-one correspondence between wave speed and elastic modulus. Depending on the details of a boundary's geometry and elasticity contrast, highly complex propagating fields produced near the boundary can substantially affect both the spatial resolution and contrast of the elasticity image. We demonstrate boundary effects on Rayleigh waves incident on a vertical boundary between media of different shear moduli. Lateral resolution is defined by the width of the transition zone between two media and is the limit at which a physical inclusion can be detected with full contrast. We experimentally demonstrate results using a spectraldomain OCT system on tissue-mimicking phantoms, which are replicated using numerical simulations. It is shown that the spatial resolution in dynamic OCE is determined by the temporal and spatial characteristics (i.e., bandwidth and spatial pulse width) of the propagating mechanical wave. Thus, mechanical resolution in dynamic OCE inherently differs from the optical resolution of the OCT imaging system.

Applied Physics Letters

We describe surface wave propagation in soft elastic media at speeds exceeding the bulk shear wav... more We describe surface wave propagation in soft elastic media at speeds exceeding the bulk shear wave speed. By linking these waves to the elastodynamic Green's function, we derive a simple relationship to quantify the elasticity of a soft medium from the speed of this supershear evanescent wave (SEW). We experimentally probe SEW propagation in tissue-mimicking phantoms, human cornea ex vivo, and skin in vivo using a high-speed optical coherence elastography system. Measurements confirm the predicted relationship between SEW and bulk shear wave speeds, agreeing well with both theoretical and numerical models. These results suggest that SEW measurements may be a robust method to quantify elasticity in soft media, particularly in complex, bounded materials where dispersive Rayleigh-Lamb modes complicate measurements.

Journal of Biomedical Optics

Dynamic elastography is an attractive method to evaluate tissue biomechanical properties. Recentl... more Dynamic elastography is an attractive method to evaluate tissue biomechanical properties. Recently, it was extended from US-and MR-based modalities to optical ones, such as optical coherence tomography for three-dimensional (3-D) imaging of propagating mechanical waves in subsurface regions of soft tissues, such as the eye. The measured group velocity is often used to convert wave speed maps into 3-D images of the elastic modulus distribution based on the assumption of bulk shear waves. However, the specific geometry of OCE measurements in bounded materials such as the cornea and skin calls into question elasticity reconstruction assuming a simple relationship between group velocity and shear modulus. We show that in layered media the bulk shear wave assumption results in highly underestimated shear modulus reconstructions and significant structural artifacts in modulus images. We urge the OCE community to be careful in using the group velocity to evaluate tissue elasticity and to focus on developing robust reconstruction methods to accurately reconstruct images of the shear elastic modulus in bounded media.

Journal of biomedical optics, Dec 1, 2017

Optical coherence elastography (OCE) can provide clinically valuable information based on local m... more Optical coherence elastography (OCE) can provide clinically valuable information based on local measurements of tissue stiffness. Improved light sources and scanning methods in optical coherence tomography (OCT) have led to rapid growth in systems for high-resolution, quantitative elastography using imaged displacements and strains within soft tissue to infer local mechanical properties. We describe in some detail the physical processes underlying tissue mechanical response based on static and dynamic displacement methods. Namely, the assumptions commonly used to interpret displacement and strain measurements in terms of tissue elasticity for static OCE and propagating wave modes in dynamic OCE are discussed with the ultimate focus on OCT system design for ophthalmic applications. Practical OCT motion-tracking methods used to map tissue elasticity are also presented to fully describe technical developments in OCE, particularly noting those focused on the anterior segment of the eye....

Dynamics and Fluctuations in Biomedical Photonics XIII, 2016

Journal of Biomedical Optics, 2016

Before laser speckle contrast imaging (LSCI) can be used reliably and quantitatively in a clinica... more Before laser speckle contrast imaging (LSCI) can be used reliably and quantitatively in a clinical setting, there are several theoretical and practical issues that still must be addressed. In order to address some of these issues, an electro-optical system that utilizes a nematic liquid crystal spatial light modulator (SLM) to mimic LSCI experiments was assembled. The focus of this paper is to address the issue of how incident intensity affects LSCI results. Using the SLM-based system, we systematically adjusted incident intensity on the SLM and assessed the resulting first-and second-order statistics of the imaged speckle to explain the corresponding spatial contrast values in both frozen and time-integrated speckle patterns. The SLM-based system was used to generate speckle patterns with a controlled minimum speckle size, probability intensity distribution, and temporal decorrelation behavior. By eliminating many experimental parameters, this system is capable of serving as a useful intermediary tool between computer simulation and physical experimentation for further developing LSCI as a quantitative imaging modality.

Journal of the Optical Society of America. A, Optics, image science, and vision, Apr 1, 2016

In this study, we developed a signal processing method for fixed pattern noise removal in fiber-b... more In this study, we developed a signal processing method for fixed pattern noise removal in fiber-bundle-based endoscopic imaging. We physically acquired the fixed pattern of the fiber bundle and used it as a prior image in an l₁ norm minimization (l₁-min) algorithm. We chose an iterative shrinkage thresholding algorithm for l₁ norm minimization. In addition to fixed pattern noise removal, this method also improved image contrast while preserving spatial resolution. The effectiveness of this method was demonstrated on images obtained from a dark-field illuminated reflectance fiber-optic microscope (DRFM). The iterative l₁-min algorithm presented in this paper, in combination with the DRFM system that we previously developed, enables high-resolution, high-sensitivity, intrinsic-contrast, and in situ cellular imaging which has great potential in clinical diagnosis and biomedical research.

Dynamics and Fluctuations in Biomedical Photonics XII, 2015

Optical Coherence Tomography and Coherence Domain Optical Methods in Biomedicine XIX, 2015

Three-Dimensional and Multidimensional Microscopy: Image Acquisition and Processing XXII, 2015

Biomedical optics express, 2014

In this work, we investigated how bulk motion degraded the quality of optical coherence tomograph... more In this work, we investigated how bulk motion degraded the quality of optical coherence tomography (OCT) angiography that was obtained through calculating interframe signal variation, i.e., interframe signal variation based optical coherence angiography (isvOCA). We demonstrated theoretically and experimentally that the spatial average of isvOCA signal had an explicit functional dependency on bulk motion. Our result suggested that the bulk motion could lead to an increased background in angiography image. Based on our motion analysis, we proposed to reduce image artifact induced by transient bulk motion in isvOCA through adaptive thresholding. The motion artifact reduced angiography was demonstrated in a 1.3μm spectral domain OCT system. We implemented signal processing using graphic processing unit for real-time imaging and conducted in vivo microvasculature imaging on human skin. Our results clearly showed that the adaptive thresholding method was highly effective in the motion ar...

Dynamics and Fluctuations in Biomedical Photonics XIII, 2016