Browsing by Author "Sanati-Nezhad, Amir"

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    Asphaltene Mesoscale Aggregation Behavior in Organic Solvents
    (2019-01-10) Ahmadi, Mohammad; Abedi, Jalal; Hassanzadeh, Hassan; Chen, Zhangxin; Ponnurangam, Sathish; Sanati-Nezhad, Amir; Torabi, Farshid
    Asphaltenes have received significant attention over the past decade, primarily because of their complex self-assembly behavior that results in their aggregation and deposition either in the reservoir formation or the production facilities. The aggregation and deposition of asphaltenes causes severe problems in both upstream and downstream sectors of the petroleum industry. For this reason, significant effort has been expended in shedding light on the basic molecular and colloidal properties of asphaltenes to identify the key parameters controlling their stability in the crude oil mixture. Molecular simulations provided invaluable information on the main molecular mechanisms leading to the asphaltene aggregation and also the principal intermolecular forces governing this process. However, the high computational cost of these simulation approaches did not allow the scientists to fully produce the aggregation behavior of asphaltenes in the past. In this work, we aimed at studying the asphaltene self-assembly behavior at mesoscales wherein the primary colloidal particles portray the asphaltene nanoaggregates. The Brownian dynamics (BD) simulations have been utilized to investigate the aggregation behavior of asphaltenes in different solvent environments at various volume fractions of asphaltene nanoaggregates under no- and simple shear-flow conditions. The BD simulations enabled us to access significantly larger length and time scales compared to the molecular simulations resulting in complete reproduction of asphaltene aggregation hierarchy. The effects of asphaltene volume fraction, solvent quality, and the shear rate on the kinetics of aggregation, the internal structure of the formed aggregates, and the self-diffusion coefficients of asphaltenes were also discussed.
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    Bioprocessing of Mesenchymal Stem Cells and Their Derivatives: Toward Cell-Free Therapeutics
    (2018-09-12) Phelps, Jolene; Sanati-Nezhad, Amir; Ungrin, Mark; Duncan, Neil A.; Sen, Arindom
    Mesenchymal stem cells (MSCs) have attracted tremendous research interest due to their ability to repair tissues and reduce inflammation when implanted into a damaged or diseased site. These therapeutic effects have been largely attributed to the collection of biomolecules they secrete (i.e., their secretome). Recent studies have provided evidence that similar effects may be produced by utilizing only the secretome fraction containing extracellular vesicles (EVs). EVs are cell-derived, membrane-bound vesicles that contain various biomolecules. Due to their small size and relative mobility, they provide a stable mechanism to deliver biomolecules (i.e., biological signals) throughout an organism. The use of the MSC secretome, or its components, has advantages over the implantation of the MSCs themselves: (i) signals can be bioengineered and scaled to specific dosages, and (ii) the nonliving nature of the secretome enables it to be efficiently stored and transported. However, since the composition and therapeutic benefit of the secretome can be influenced by cell source, culture conditions, isolation methods, and storage conditions, there is a need for standardization of bioprocessing parameters. This review focuses on key parameters within the MSC culture environment that affect the nature and functionality of the secretome. This information is pertinent to the development of bioprocesses aimed at scaling up the production of secretome-derived products for their use as therapeutics.
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    Biosensors for Clinical Diagnosis and Mechanistic Study of Brain Injury
    (2021-06-21) Khetani, Sultan Noorddin; Sanati-Nezhad, Amir; Sen,Arindom;; Whelan,Patrick; Federico,Salvatore;
    Bodily fluid biomarkers predicting the type and level of central nervous system injury (CNS) have been extensively studied. However, these biomarkers would be helpful to practitioners and patients if appropriate detection tools are developed. The existing clinical procedure for diagnosing CNS injuries includes qualitative assessments, predominantly questionnaire-based tests, and various imaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI). These techniques are available only in tertiary care centers, and the cost of owning such is not affordable in lower or medium income countries and smaller clinics. Additionally, there is a wait time, sometimes stretching over a week, and it costs several hundred dollars. Conventional fluid-biomarker detection and monitoring techniques such as enzyme-linkedimmunosorbent assays (ELISA), Single-Molecule Array (SIMOA), as well as label-free biosensors, take longer time to compute the biochemical signals, thereby making them ineffective for point-of-care (POC) diagnostic. These technologies take a longer time (>1 hour) and require multiple biological sample processing steps. To address these technological challenges, the thesis focuses on inventing newer electrochemical biosensors capable of performing rapid detection and quantification of CNS injury biomarkers and use them for clinical CNS diagnosis and management as well as and in vitro modelling of CNS injury. Five different electrochemical biosensors were developed to detect CNS injury biomarkers, including S100 calcium-binding protein B (S100?), Glial fibrillary acidic protein (GFAP), Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), Cleaved Tau-Protein (C-Tau), Neuron filament light protein (NFL), and Total-Tau (T-Tau) within the blood samples of patients and three-(3D)- in-vitro neuron-injury-on-a-chip (NIOC) model. Conductive graphene, carbon, gold (Au)-electrodes were modified by various surface modification techniques such as electrochemical grafting of amine groups, drop-casting of amine-rich polymers, covalent polymerization of amine groups, and a self-assembled monolayer of carboxylic and amine groups to increase the biomarker detection range and reduce the sensor preparation steps. The biosensors were developed on these modified electrode surfaces by creating specific chemistries to tether target-specific antibodies. A ferrocene redox reporter molecule was used to measure the concentration of target biomarkers in an equivalent electrical signal. These biosensors detected the target biomarkers within the physiologically relevant range of 100 fg/mL – 1 ?g/mL. A field-ready device, ?Drop, was developed, and the dimensions of the biosensors were modified to be used as a true PoC, remotely sensing device, addressing the clinical and technological gaps. Overall, these findings show that electrochemical biosensors can reliably detect, monitor, and quantify CNS injuries from biomarkers. This thesis:(i) Reports a class of electrochemical biosensors that are better and sensitive in performance compared to existing biomolecular analysis techniques and others in the same category, (ii) Developed a portable hand-held device for detecting CNS injuries using a blood-test, (iii) Demonstrated the PoC and the field-study use by undertaking a clinical study, and(iv) Integrated the biosensors with in-vitro neuron injury model and investigated dynamic secretion of CNS injury biomarkers while comparing these biomarkers in human clinical studies. Together, this thesis demonstrates promising clinical and research outcomes of novel electrochemical biosensors.
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    Design and development of a microfluidic integrated electrochemical nanobiosensor for detection of SARS-CoV-2 Nucleocapsid protein biomarker
    (2021-12-13) Haghayegh, Fatemeh; Sanati-Nezhad, Amir; Dalton, Colin; Komeili, Amin
    The rapid spread of infectious disease outbreaks, such as the COVID-19 pandemic, once again emphasized the importance of deploying the potentials of biosensing technologies, as a key tool for controlling further transmission. Although the gold standard technique, Polymerase Chain Reaction (PCR), has become swiftly adopted, their limitations ask for more rapid, time-saving, and miniaturized approaches, such as all-in-one portable diagnostic platforms. Depending on the biosensing approach, the sensing element and the fluid-handling segment are considered as the most important elements of such platforms. As for the sensing methods, electrochemical immunosensing proved to have the sensitivity required for detecting the low amount of target proteins, which is favorable for early-disease detection, only if the surface of the sensor is modified to exhibit a high capacity for specific probe immobilization. Hence, introducing highly receptive surfaces is important for enhancing the sensitivity. For utilizing electrochemical immunosensors in point-of-care devices, the challenge of accommodating all of the conventionally lab-centralized sensing processes into one single chip also requires further research and investigation. To this end, the focus of the present thesis was to introduce an ultrasensitive nano-biosensor based on Zinc Oxide (ZnO) and Reduced Graphene Oxide (rGO) nanocomponents, which could successfully create a highly porous and stable sensing surface. The coated electrodes were functionalized with an L-cysteine cross-linker to provide abundant sources of carboxylic acid functional groups, an essential moiety for antibody immobilization. The morphology, physical and chemical characteristics of the sensing surface were thoroughly analyzed using spectroscopy and microscopy techniques. The electrochemical impedance spectroscopy (EIS) experiments confirmed the functionality of the immunosensor for detecting as low as 21 fg/mL SARS-CoV-2 biomarker, the Nucleocapsid (N-) protein, while it was further used for clinically detecting positive clinical swab samples. The integration of the biosensor into a microfluidic testing kit was also been explored, with a novel redox-contained chip automating all steps of immunosensing in one single kit. The platform successfully operated within 15 min for detecting N-proteins of the nasopharyngeal (NP) swab sample. This electrochemical biosensor integrated within the accompanying microfluidic chip provides a promising perspective towards the realization of a point-of-care platform.
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    Developing a microfluidic-microwave platform for real-time, non-invasive and sensitive monitoring of pathogens and antibiotic susceptibility testing
    (2020-06-25) Narang, Rakesh; Sanati-Nezhad, Amir; Murari, Kartikeya; Zarifi, Mohammad H,
    Microfluidics and microelectromechanical systems (MEMS) are areas of studies that have become highly valued for their point-of-care (POC) and high-throughput potential, particularly in healthcare and biomedical applications. However, lab-on-a-chip devices often require supplementary equipment to operate such as pumps, computers, analyzers, valves, etc. This creates a lab-around-a-chip environment. Therefore, capillary fluidics has been developed to eliminate the need of some external machines such as pumps and valves. By capitalizing upon geometric changes to create a specific hydrodynamic profile, capillary fluidics creates an autonomous fluid delivery system for microfluidics which renders devices simple to use in POC environments. Furthermore, it is easily implemented with various sensory methods, such as optical, electrochemical or microwave sensing. One application in which capillary fluidics can vastly improve the quality of service is infection diagnosis and antibiotic susceptibility testing. Due to issues with infection diagnosis and outdated antibiotic susceptibility testing (AST) methods, physicians are over-prescribing broad-spectrum antibiotics. This coupled with patients’ non-compliance in antibiotic administration gives pathogens the ability to evolve a resistance to antibiotics. The root of the underlying issue creates a critical need to focus on bacterial infection diagnosis and AST, as contemporary practices require up to two weeks, are expensive, labor intensive, and lack the potential for point-of-care testing. Therefore, diagnosis and AST are not performed in most cases leading to broad-spectrum antibiotic prescriptions being overused. For the application of monitoring pathogens and performing AST, microwave sensing was selected for highly sensitive and relatively inexpensive implementation. Microwave resonators generate electrical fields and detect dielectric shifts within their sensing zone to characterize bioassays in a real-time, sensitive and non-invasive manner. Currently, microwave sensors are being optimized with multiple resonators to further optimize sensitivity and selectivity for biomedical applications. This makes microwave sensing an attractive approach to couple with capillary microfluidics for infection diagnosis and AST. This work aims to provide a proof of concept in coupling capillary microfluidics with planar microwave resonators to create a sensing platform to monitor the growth and antibiotic susceptibility of E. coli.
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    Electrochemical Biosensors Based on Thiol and N-Heterocyclic Carbene Self-Assembled Monolayers
    (2019-04-29) Mayall, Robert Matthew; Birss, Viola I.; Amrein, Matthias W.; Sutherland, Todd C.; Sanati-Nezhad, Amir; Mauzeroll, Janine
    Monitoring for the presence of biological threats is of great importance from both a healthcare and military perspective. Traditional monitoring technologies fall into two categories, detection, which relies on quick (<20 minute) sensing of a potential threat agent, and identification, which provides specific information about the nature of the threat agent but takes longer to perform (typically ca. 1 hour). The focus of this thesis is to develop novel sensor platforms capable of performing both detection and identification methodologies utilizing an electrochemical biosensor approach. The fabrication of a detection biosensor was based on the specificity of Toll-Like Receptors (TLRs), which are a class of proteins found in the innate immune system of animals. These proteins detect specific markers for classes of biological agents, with TLR-4 detecting the presence of Gram-negative bacteria. TLR-4 was tethered to a Au electrode via an alkylthiol self-assembled monolayer (SAM) using an oriented approach to mimic the natural conformation that the protein adopts in the immune system. This sensor system was shown to detect the presence of Gram-negative bacteria (from 1 to 105 cells/mL) in phosphate buffer solutions, while remaining insensitive towards both Gram-positive and viral challenges. This sensor was then modified in order to increase the measured currents and enable the transition to a deployable instrumentation system. The incorporation of trace levels of ferrocene moieties into the SAM was studied, producing a simple method to increase the currents by >3 orders of magnitude. When applied to the TLR-4 biosensor platform, no loss of sensitivity or specificity was observed. The higher currents allowed for the translation of the TLR-4 biosensor onto an inexpensive open-source potentiostat system that is field-deployable. A novel SAM chemistry, utilizing ultra-stable N-heterocyclic carbenes (NHCs), was also studied for use as a platform in the development of biosensors. A sensor capable of detecting intact measles virions, without any pretreatment steps, was developed, for the first time, using either NHC or comparable alkanethiol SAMs. While both systems showed excellent specificity, the NHC system produced significantly larger signals over the same range of measles virus concentrations as the alkanethiol system. Importantly, the sensors based on the NHC SAMs were able to detect the presence of measles virions after two weeks of storage, whereas the alkanethiol SAMs could not. Overall, it is clear that these sensors are strong candidates for the monitoring of biological threat agents. The oriented approach to protein attachment and the incorporation of ferrocene into the SAMs demonstrated excellent detection on par or better than other published work. This thesis also represents the first report of an electrochemical biosensor based on NHC SAMs, showing a significantly better response than comparable alkanethiol SAMs and far superior stability towards storage of a pre-fabricated sensor. Combined, the work of this thesis demonstrates that electrochemical biosensors hold great promise as sensors for both detection and identification purposes in healthcare and military settings.
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    Experimental and numerical study of temperature-actuated droplets within microfluidics
    (2019-04-30) Ali Khater, Asmaa Ali ElAwadi; Mohamad, Abdulmajeed Abd; Sanati-Nezhad, Amir; Ren, Carolyn L.; Azaiez, Jalel; Johansen, Craig T.; Benneker, Anne M.
    Droplet microfluidics (DM), which involves the production of nano-/micro- droplets and particles using immiscible phases, reveals an impressive evolutionary trend that have been widely used to establish highly sensitive, robust, and flexible multitasking microsystems. Droplets generated by DM systems can operate thousands of parallel reactions without increasing device size or complexity which facilities the possibility of developing miniaturized fully integrated high‐throughput screening devices. The high surface-to-volume ratio offered by micro-drops ensures the rapid heat and mass transfer and makes thermal stimulation a powerful actuation technique to perform exquisite transporting, mixing, melting, and changing the volume formed droplets. The work aims to numerically and experimentally analyze the droplet generation and behavior when heat is applied to a flow-focusing microstructure under variable flow conditions. The study focused on two main topics; (1) Studying the effect of temperature variation on the behavior water droplets emulsified in mineral oil when heat is applied to the downstream channel. (2) Examining at 37C the size and generation regimes of agarose droplet dispersed in mineral oil. The study had several parts: designing and manufacturing a microchannel network to allow experimental investigation of the characteristics of the droplets, heater calibration and location determination to best fit the selected applications, and applying numerical simulations to understand the hydrodynamics and physics controlling the droplets. Results obtained from temperature alteration of water-in-oil micro-dispersions indicate that the temperature has a dominant effect on the size and the local stability of the droplets in the micro-channels. While, the results observed from exploring the formation of agar-in-oil emulsion demonstrate the significance of capillary number Ca and fluids flow rate ratios �� on the droplet size and the transformation from squeezing into dripping or jetting regimes. The findings of this work assist the future works of performance optimization of on-chip DNA amplification devices and encapsulating bacteria and live cells in agarose droplets for drug delivery applications.
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    Geomaterial-Functionalized Microfluidic Devices for Multiphase Flow in Porous Media
    (2020-03-23) Zhang, Yaqi; Hejazi, Seyed Hossein; Hejazi, Seyed Hossein; Aguilera, Roberto F.; Sanati-Nezhad, Amir; Oldenburg, Thomas B. P.; Torabi, Farshid
    Fluid flow, species transport, and chemical reactions in geological formations abound in the exploitation of fossil fuels and geothermal energy, the geological storage of carbon dioxide (CO2), and the disposal of hazardous materials. Reservoir rocks are made of grains, with an extensive surface area, where the physicochemical fluid-solid interactions greatly influence the multiphase flow behavior. The success of the design, implementation, and prediction of engineering activities related to subsurface systems depends on the understanding of the flowing fluids’ properties and their interactions with the surrounding rock surfaces. Microfluidics, which performs laboratory tests in miniaturized flow cells, has exhibited numerous functionalities and potentials to assess subsurface processes. However, a key constraint in the application of microfluidics to flow in porous rocks is the surface discrepancy between microfluidic chips and the actual rocks/soils. This research develops novel microfluidic devices (e.g., ‘surface-mimetic micro-reservoirs’ (SMMRs) functionalized with reflective rock surfaces), which represent multiscale and multi-type of natural rocks/soils. The advanced surface-functionalized microfluidic chips are applied to address the physics of fluids in porous media, which includes rock-fluid interactions. The novel layer-by-layer (LbL) assembly for surface modification is employed to produce rock-forming mineral coatings on microfluidic chip surfaces. Substrates of glass, quartz, and polydimethylsiloxane (PDMS), and the actual microscale flow channels made of glass and PDMS are successfully functionalized with geomaterials of clays and quartz. We characterize the coating stability, nanoscale structures, and wettability of the functionalized substrates and microfluidic chips using dynamic flooding experiments, scanning electron microscope (SEM), optical microscopy, profilometer, atomic force microscopy (AFM), and contact angle measurements. The surface modification technique generates a stable coated surface with tunable hydrophilicity in microfluidic chips and is shown to be universal, reliable, and material-independent. The microfluidic chips functionalized by clay particles are used in two-phase flow experiments, which illustrate the role of the coated clays on flow patterns. Functionalized microfluidic chips enable the real-time and multi-scale evaluation of transport processes in reservoir-mimetic visual models, thus unravelling the intricate interactions between the flowing fluids and rock minerals. The present study provides a path in the development of microfluidic technology-based applications for subsurface energy and environmental research.
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    Long-term co-culture of endothelial and cancer cells within biomimetic microfluidic chips for investigating juxtacrine and paracrine regulatory signaling pathways
    (2019-01) Soleimani, Shirin; Sanati-Nezhad, Amir; Rancourt, Derrick E.; Ungrin, Mark D.
    Emerging evidence on how angiocrine factors confer inductive signals to orchestrate a wide range of pathophysiological phenomena (e.g. tumorigenesis, self-renewal of hematopoietic stem cells, regenerative lung alveolization and liver regeneration) lends credence to the concept that endothelial cells are not only the building blocks of vascular networks but also serve as a rich resource of regulatory angiocrine factors. Cancer-associated endothelial cells initiate a series of signaling modes with cancer cells. These signallings determine cancer progression and response to drugs. While it is widely-believed that endothelial cells are only able to affect the cancer cells that are juxtaposed next to them, cells positioned five-cell diameters away from the sinusoid vessels have been shown to be ruled by angiocrine factors. Considering the distance dependency of cancer-endothelium crosstalk, there is a great demand for an in vitro system with high geometrical precision that offers a diverse range of cell-cell distance and cell-cell contact area for studying and distinguishing juxtacrine and paracrine signallings between cancer and endothelial cells in a spatiotemporal manner. In the present study, a three-layer microfluidic chip consisting of a top and a bottom channel separated via a porous membrane is devised, to enable studying the signalling pathways between cancer and endothelial cells under highly-controlled conditions. The porous membranes are variable in terms of pore size, thickness and porous surface area. However, transition from macroscopic to microfluidic platforms for reconstructing in vitro models brings with it a variety of challenges such as the effect of device material (Tissue culture Polystyrene vs. PDMS), surface coating, cell number/surface area unit, cell seeding method and cell culture media exchange schedule. The present work has tried to provide a comprehensive protocol to supply precisely controlled conditions along the microchannels for the cells to grow, using human umbilical vein endothelial cells, E4OR1 transduced endothelial cells and breast cancer MCF-7 cells.
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    Mesenchymal Stem Cell Therapy for Ischemic Tissues
    (2018-10-08) Yong, Kar Wey; Choi, Jane Ru; Mohammadi, Mehdi; Mitha, Alim P.; Sanati-Nezhad, Amir; Sen, Arindom
    Ischemic diseases such as myocardial infarction, ischemic stroke, and critical limb ischemia are immense public health challenges. Current pharmacotherapy and surgical approaches are insufficient to completely heal ischemic diseases and are associated with a considerable risk of adverse effects. Alternatively, human mesenchymal stem cells (hMSCs) have been shown to exhibit immunomodulation, angiogenesis, and paracrine secretion of bioactive factors that can attenuate inflammation and promote tissue regeneration, making them a promising cell source for ischemic disease therapy. This review summarizes the pathogenesis of ischemic diseases, discusses the potential therapeutic effects and mechanisms of hMSCs for these diseases, and provides an overview of challenges of using hMSCs clinically for treating ischemic diseases.
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    Nanoporous Microcantilevers with Plasmonic Absorbers for Photothermal Infrared Spectroscopy
    (2019-05-13) Simin, Nicholas; Kim, Seonghwan; Kim, Seonghwan; Dalton, Colin; Sanati-Nezhad, Amir; Park, Simon S.
    A nanoporous anodic aluminum oxide (AAO) bimetallic cantilever enhanced by a gold coating on the nanopores creates a plasmonic crystal structure. The fabricated sensor is used for photothermal cantilever deflection spectroscopy (PCDS). Explosive compounds tested, showed spectra identifying explosive compounds by their characteristic wavelengths. Through a two-step anodization process, photolithography, and bimetallic and plasmonic coatings, a sensitive photothermal microcantilever was fabricated. The bimetallic layer thickness was optimized through analytical calculations. The ideal plasmonic layer thickness was found through experimentation. Molecules adsorbed onto the cantilever surface had their mass quantified through a measured change in 2nd mode resonant frequency. Simultaneously, the molecules were identified by high power infrared (IR) spectroscopy. For standoff spectroscopy, a plasmonic enhanced AAO cantilever was shown to improve characteristic peak depth 10-fold and 7-fold compared to silicon and AAO bimetallic cantilevers, respectively. The limit of detection (LOD) of the plasmonic AAO cantilever was determined to be 63.42 ng/cm2.
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    A Power-Aware Reinforcement Learning Technique for Memory Allocation in Real-time Embedded Systems
    (2020-12-22) Karimi Fatemi, Masoud; Pahlevani, Majid; Far, Behrouz Homayoun; Sanati-Nezhad, Amir; Moshirpour, Mohammad
    Embedded systems are ubiquitous in today's world. They are used in a vast number of applications, from medical devices to spacecraft. Two of the main characteristics of such systems are real-time constraints and the lack of reliable energy sources. As cache memories negatively contribute to these two challenges, embedded systems have adopted a new concept called scratch-pad memories (SPMs). To further reduce power consumption, hybrid SPMs composed of Static RAMs (SRAMs) and non-volatile memories (NVMs) have been introduced. Compared to SRAMs, NVMs offer low leakage power and high density while suffering from high energy consumption during write activities. As such, numerous studies have been done on performing memory allocation in hybrid architectures. As memory allocation is an NP-complete problem, traditional approaches fall short due to their timing and memory complexities. Therefore, previous studies have offered alternative techniques to resolve this problem in significantly shorter times. In this work, I propose a reinforcement learning technique to tackle the memory allocation problem in a hybrid architecture. As the results showed, the proposed technique can provide a near-optimal solution - only 5.6% less efficient on average - in a substantially shorter time. To evaluate the algorithm's effectiveness, I compared the results with a greedy technique and a Genetic Algorithm (GA). The results showed that the proposed technique could reduce the average energy consumption by 35.84% and 5.1% compared to the greedy technique and GA, respectively. While the improvements gained by the proposed technique was negligible compared to the GA, it could outperform the GA in simulation time once the learning phase was complete. Particularly, the experiments on 15 soft real-time task frames showed a 35.1% reduction in the average simulation time.
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    SiPM-based Fiber Photometry and EIS for Cortisol Detection: Common Electronics, Distinct Applications
    (2024-01-25) Namazi, Mahrokh; Murari, Kartikeya; Sanati-Nezhad, Amir; Abassi, Zahra; Vyas, Rushi
    This thesis introduces two biomedical measurement systems utilizing the AD5934 impedance converter: a silicon photomultiplier (SiPM)-based low-light fiber photometry system for neural recordings in mice and a wireless electrochemical impedance spectroscopy (EIS) device designed for cortisol detection in human sweat. Despite their apparent differences, both systems share a common foundation—the AD5934 impedance converter chip, generating sinusoidal excitation signals and measuring corresponding system responses. Our fiber photometry system utilizes an SiPM as an alternative photodetector, addressing the power and sensitivity limitations of conventional counterparts. Additional optical excitation at an isosbestic point, often used for mitigating motion artifacts, was also used to correct for SiPM gain variations. Employing two impedance converters enables amplitude modulation with two carriers, which allows for distinguishing the main signal from the isosbestic control signal. Characterization tests confirmed the system's robustness to motion artifacts and temperature variations. In-vivo experiments demonstrated the system's functionality at significantly lower optical excitation powers comparing to commercial fiber photometry systems. In the EIS device, the AD5934 was used for its originally intended purpose of impedance spectroscopy. When used with a cortisol immunosensor, it can determine the concentration of cortisol in a sample by measuring its impedance at a range of frequencies. The device has a compact form-factor, and is wireless and battery-powered. Adaptive gain control was implemented to enhance the device's dynamic range. Characterization tests on resistors, capacitors, and electrochemical samples, and comparative experiments against a commercial potentiostat validated the system's suitability for cortisol concentration measurement. The device showed promise for adaptation into a wearable device for daily semi-continuous cortisol monitoring. The SiPM-based fiber photometry system and the compact EIS device stand as successful implementations of two biomedical measurement systems that benefit from the use of the AD5934 impedance converter chip. These two projects demonstrate the versatility of the AD5934 impedance converter, and meet their individual aims.
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    The Impact of Culture Environment on the Composition and Function of Mesenchymal Stem Cell Derived Extracellular Vesicles
    (2022-05-30) Phelps, Jolene; Sen, Arindom; Duncan, Neil A.; Ungrin, Mark; Sanati-Nezhad, Amir
    Mesenchymal stem cells (MSCs) have attracted research interest due to their ability to induce tissue repair and reduce inflammation. More recently, their therapeutic benefits have been attributed to small membrane bound vesicles called extracellular vesicles (EVs) that they release. The implantation of MSC-EVs offers significant advantages over the implantation of viable MSCs. Their nonliving nature eliminates many of the safety concerns related to cell therapies and enables them to be stored and transported more efficiently. There is a significant need to develop clinically applicable bioprocesses that can produce large numbers of therapeutically relevant MSC-EVs. This involves the translation of small-scale studies to large scale processes, which is limited by considerations such as the medium and platform in which the cells are cultured. Due to the novelty of the EV field, current research in this area is very limited, and thus the goal of this thesis was to evaluate the efficacy of producing MSC-EVs in a clinically relevant medium, and to gain insight into the impact of culture parameters needed for the scale-up of MSC-EVs. This thesis demonstrated, for the first time, that functional MSC-EVs could be produced using a clinically relevant serum-free culture medium for the applications of articular cartilage repair, cerebral ischemia, and intracranial aneurysm repair. Further, it was found that functional MSC-EVs could be produced in scalable stirred suspension bioreactors. These studies were among the first to evaluate the use of such a platform for EV production and were the first to present a scalable model for EV production specifically for the applications of articular cartilage repair and cerebral ischemia. In addition, the culture of MSCs at physiological oxygen conditions was evaluated and found to enhance their angiogenic potential, without damaging physiological function, in the application of cerebral ischemia. Finally, important considerations relevant to the upstream production of MSC-EVs were studied, including the confluence of cultured MSCs and the medium in which the EVs were isolated. This work enabled a proposed workflow for producing EVs in serum-free medium and will contribute highly to the development of clinically applicable bioprocesses aimed at producing MSC-EVs for applications in regenerative medicine.