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- All Subjects: Biomedical Engineering
- All Subjects: Medical Imaging
- Creators: Kodibagkar, Vikram
Description
Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide, causing nearly 25% of deaths in the United States. Despite the efforts to create in vitro models for the study and treatment of CVDs, these are still limited in their recapitulation of the heart tissue. Thus, the engineering of accurate cardiac models is imperative to gain more understanding and improve the outcome of CVDs. This Ph.D. dissertation focuses on the development and characterization of isogenic cardiac organoids derived from human induced pluripotent stem cells (hiPSCs). Additionally, the integration of chemical and biological cues for enriching their microenvironment and promoting their maturation state and function were studied. First, hiPSC-derived cardiac cells were utilized for the fabrication of multicellular spherical microtissues, namely isogenic cardiac organoids. The cellular composition and culture time of the engineered tissues were optimized to induce cellular aggregation and the formation of cell-cell interactions. Also, ribbon-like gold nanoparticles, namely gold nanoribbons (AuNRs), were synthesized, characterized, and biofunctionalized for their integration into the isogenic cardiac organoids. In-depth biological evaluation of the organoids showed enhanced cardiac maturation markers. Furthermore, a supplement-free cell culture regime was designed and evaluated for fabricating isogenic cardiac organoids. Mechanistic, cellular, and molecular-level studies demonstrated that the presence of hiPSC-derived cardiac fibroblasts (hiPSC-CFs) significantly improves the morphology and gene expression profile of the organoids. Electrophysiological-relevant features of the organoids, such as conduction velocity (CV), were further investigated utilizing a microelectrode array (MEA) platform. It was shown that MEA offers a simple, yet powerful approach to assessing electrophysiological responses of the tissues, where a trend in decreased CV was found due to the presence of hiPSC-CFs. Overall, this dissertation has a broad impact casting light on the development strategy and biological mechanisms that govern the formation and function of isogenic cardiac organoids. Moreover, this study presents two unique approaches to promote maturation of stem cell-derived cardiac organoids: 1) through the integration of novel biofunctionalized nanomaterials, and 2) through a cell culture regime, leading to enhanced function of the organoids. The proposed micro-engineered organoids have broad applications as physiologically relevant tissues for drug discovery, CVDs modeling, and regenerative medicine.
ContributorsPatino, Alejandra (Author) / Nikkhah, Medhi (Thesis advisor) / Blain-Christen, Jennifer (Committee member) / Kodibagkar, Vikram (Committee member) / Vernon, Brent (Committee member) / Zhu, Wuqiang (Committee member) / Arizona State University (Publisher)
Created2023
Description
Among electrical properties of living tissues, the differentiation of tissues or organs provided by electrical conductivity is superior. The pathological condition of living tissues is inferred from the spatial distribution of conductivity. Magnetic Resonance Electrical Impedance Tomography (MREIT) is a relatively new non-invasive conductivity imaging technique. The majority of conductivity reconstruction algorithms are suitable for isotropic conductivity distributions. However, tissues such as cardiac muscle and white matter in the brain are highly anisotropic. Until recently, the conductivity distributions of anisotropic samples were solved using isotropic conductivity reconstruction algorithms. First and second spatial derivatives of conductivity (∇σ and ∇2σ ) are integrated to obtain the conductivity distribution. Existing algorithms estimate a scalar conductivity instead of a tensor in anisotropic samples.
Accurate determination of the spatial distribution of a conductivity tensor in an anisotropic sample necessitates the development of anisotropic conductivity tensor image reconstruction techniques. Therefore, experimental studies investigating the effect of ∇2σ on degree of anisotropy is necessary. The purpose of the thesis is to compare the influence of ∇2σ on the degree of anisotropy under two different orthogonal current injection pairs.
The anisotropic property of tissues such as white matter is investigated by constructing stable TX-151 gel layer phantoms with varying degrees of anisotropy. MREIT and Diffusion Magnetic Resonance Imaging (DWI) experiments were conducted to probe the conductivity and diffusion properties of phantoms. MREIT involved current injection synchronized to a spin-echo pulse sequence. Similarities and differences in the divergence of the vector field of ∇σ (∇2σ) among anisotropic samples subjected to two different current injection pairs were studied. DWI of anisotropic phantoms involved the application of diffusion-weighted magnetic field gradients with a spin-echo pulse sequence. Eigenvalues and eigenvectors of diffusion tensors were compared to characterize diffusion properties of anisotropic phantoms.
The orientation of current injection electrode pair and degree of anisotropy influence the spatial distribution of ∇2σ. Anisotropy in conductivity is preserved in ∇2σ subjected to non-symmetric electric fields. Non-symmetry in electric field is observed in current injections parallel and perpendicular to the orientation of gel layers. The principal eigenvalue and eigenvector in the phantom with maximum anisotropy display diffusion anisotropy.
Accurate determination of the spatial distribution of a conductivity tensor in an anisotropic sample necessitates the development of anisotropic conductivity tensor image reconstruction techniques. Therefore, experimental studies investigating the effect of ∇2σ on degree of anisotropy is necessary. The purpose of the thesis is to compare the influence of ∇2σ on the degree of anisotropy under two different orthogonal current injection pairs.
The anisotropic property of tissues such as white matter is investigated by constructing stable TX-151 gel layer phantoms with varying degrees of anisotropy. MREIT and Diffusion Magnetic Resonance Imaging (DWI) experiments were conducted to probe the conductivity and diffusion properties of phantoms. MREIT involved current injection synchronized to a spin-echo pulse sequence. Similarities and differences in the divergence of the vector field of ∇σ (∇2σ) among anisotropic samples subjected to two different current injection pairs were studied. DWI of anisotropic phantoms involved the application of diffusion-weighted magnetic field gradients with a spin-echo pulse sequence. Eigenvalues and eigenvectors of diffusion tensors were compared to characterize diffusion properties of anisotropic phantoms.
The orientation of current injection electrode pair and degree of anisotropy influence the spatial distribution of ∇2σ. Anisotropy in conductivity is preserved in ∇2σ subjected to non-symmetric electric fields. Non-symmetry in electric field is observed in current injections parallel and perpendicular to the orientation of gel layers. The principal eigenvalue and eigenvector in the phantom with maximum anisotropy display diffusion anisotropy.
ContributorsAshok Kumar, Neeta (Author) / Sadleir, Rosalind J (Thesis advisor) / Kodibagkar, Vikram (Committee member) / Muthuswamy, Jitendran (Committee member) / Arizona State University (Publisher)
Created2015
Description
Magnetic resonance spectroscopic imaging (MRSI) is a non-invasive technique that offers a unique ability to provide the spatial distribution of relevant biochemical compounds (metabolites). The ‘spectrum’ of information provided by MRSI is used as biomarkers for the differential diagnosis of several diseases such as cancer or neurological disorders. Treatment responsive brain tumors can appear similar to non-responsive tumors on conventional anatomical MR images, earlier in the therapy, leading to a poor prognosis for many patients. Biomarkers such as lactate are particularly of interest in the oncological studies of solid tumors to determine their energy metabolism, blood flow, and hypoxia. Despite the capability of nearly all clinical MRI scanners to perform MRSI only limited integration of MRSI into routine clinical studies has occurred to date. The major challenges affecting its true potential are the inherently long acquisition time, low signal-to-noise (SNR) of the signals, overlapping of spectral lines, or the presence of artifacts. The goal of this dissertation work is to facilitate MRSI in routine clinical studies without affecting the current patient throughput.
In this work, the Compressed Sensing (CS) strategy was used to accelerate conventional Point RESolved Spectroscopy (PRESS) MRSI by sampling well below the Shannon-Nyquist limit. Two undersampling strategies, namely the pseudo-random variable density and a novel a priori method was developed and implemented on a clinical scanner. Prospectively undersampled MRSI data was acquired from patients with various brain-related concerns. Spatial-spectral post-processing and CS reconstruction pipeline was developed for multi-channel undersampled data. The fidelity of the CS-MRSI method was determined by comparing the CS reconstructed data to the fully sampled data. Statistical results showed that the a priori approach maintained high spectral fidelity compared to the fully sampled reference for an 80% reduction in scan time. Next, an improvement to the CS-MRSI reconstruction was achieved by incorporating coil sensitivity maps as support in the iterative process. Further, a CS-MRSI-based fast lactate spectroscopic imaging method was developed and implemented to achieve complete water and fat suppression for accurate spatial localization and quantification of lactate in tumors. In vitro phantoms were developed, and the sequence was tested to determine the efficacy of CS-MRSI for low SNR signals, the efficacy of the CS acceleration was determined with statistical analysis.
ContributorsBikkamane Jayadev, Nutandev (Author) / Kodibagkar, Vikram (Thesis advisor) / Chang, John (Committee member) / Robison, Ryan (Committee member) / Smith, Barbara (Committee member) / Sohn, Sung-Min (Committee member) / Arizona State University (Publisher)
Created2021
Description
This thesis describes the development, characterization, and application of new biomedical technologies developed around the photoacoustic effect. The photoacoustic effect is defined as optical absorption-based generation of ultrasound and provides the foundation for a unique method of imaging and molecular detection. The range of applications of the photoacoustic effect have not yet been fully explored. Photoacoustic endoscopy (PAE) has emerged as a minimally invasive tool for imaging internal organs and tissues. One of the main themes of this dissertation involves the first reported dual-intrauterine photoacoustic and ultrasound deep-tissue imaging endoscope. This device was designed to enable physicians at the point-of-care to better elucidate overall gynecological health, by imaging the lining of the human uterus. Intrauterine photoacoustic endoscopy is made possible due to the small diameter of the endoscope (3mm), which allows for complete, 360-degree organ analysis from within the uterine cavity. In certain biomedical applications, however, further minimization is necessary. Sufficiently small diameter endoscopes may allow for the possibility of applying PAE in new areas. To further miniaturize the diameter of our endoscopes, alternative imaging probe designs were investigated. The proposed PAE architecture utilizes a hollow optical waveguide to allow for concentric guiding of both light and sound. This enables imaging depths of up to several millimeters into animal tissue while maintaining an outer diameter of roughly 1mm. In the final focus of this dissertation, these waveguides are further investigated for use in micropipette electrodes, common in the field of single cell electrophysiology. Pulsed light is coupled with these electrodes providing real-time photoacoustic feedback, useful in navigation towards intended targets. Lastly, fluorescence can be generated and collected at the micropipette aperture by utilizing an intra-electrode tapered optical fiber. This allows for a targeted robotic approach to labeled neurons that is independent of microscopy.
ContributorsMiranda, Christopher (Author) / Smith, Barbara S. (Thesis advisor) / Kodibagkar, Vikram (Committee member) / LaBaer, Joshua (Committee member) / Frakes, David (Committee member) / Barkley, Joel (Committee member) / Arizona State University (Publisher)
Created2021
Description
Allogeneic islet transplantation has the potential to reverse Type 1 Diabetes in patients. However, limitations such as chronic immunosuppression, islet donor numbers, and islet survival post-transplantation prevent the widespread application of allogeneic islet transplantation as the treatment of choice. Macroencapsulation devices have been widely used in allogeneic islet transplantation due to their capability to shield transplanted cells from the immune system as well as provide a supportive environment for cell viability, but macroencapsulation devices face oxygen transport challenges as their geometry increases from preclinical to clinical scales. The goal of this work is to generate complex 3D hydrogel macroencapsulation devices with sufficient oxygen transport to support encapsulated cell survival and generate these devices in a way that is accessible in the clinic as well as scaled manufacturing. A 3D-printed injection mold has been developed to generate hydrogel-based cell encapsulation devices with spiral geometries. The spiral geometry of the macroencapsulation device facilitates greater oxygen transport throughout the whole device resulting in improved islet function in vivo in a syngeneic rat model. A computational model of the oxygen concentration within macroencapsulation devices, validated by in vitro analysis, predicts that cells and islets maintain a greater viability and function in the spiral macroencapsulation device. To further validate the computational model, pO2 Reporter Composite Hydrogels (PORCH) are engineered to enable spatiotemporal measurement of oxygen tension within macroencapsulation devices using the Proton Imaging of Siloxanes to map Tissue Oxygenation Levels (PISTOL) magnetic resonance imaging approach. Overall, a macroencapsulation device geometry designed via computational modeling of device oxygen gradients and validated with magnetic resonance (MR) oximetry imaging enhances islet function and survival for islet transplantation.
ContributorsEmerson, Amy (Author) / Weaver, Jessica (Thesis advisor) / Kodibagkar, Vikram (Committee member) / Sadleir, Rosalind (Committee member) / Stabenfeldt, Sarah (Committee member) / Wang, Kuei-Chun (Committee member) / Arizona State University (Publisher)
Created2023