Matching Items (42)
Description
Mechanical properties, in particular elasticity, of cancer cells and their microenvironment are important in governing cancer cell fate, for example function, mobility, adhesion, and invasion. Among all tools to measure the mechanical properties, the precision and ease of atomic force microscopy (AFM) to directly apply force—in the range of Pico to micronewtons—onto samples—with length scales from nanometers to tens of micrometers—has made it a powerful tool to investigate the mechanics of materials. AFM is widely used to measure deformability and stiffness of soft biological samples. Principally, these samples are indented by the AFM probe and the forces and indentation depths are recorded. The generated force-indentation curves are fitted with an elastic contact model to quantify the elasticity (e.g. stiffness). AFM is a precise tool; however, the results are as accurate as the contact model used to analyze them. A new contact model was introduced to analyze force-indentation curves generated by spherical AFM probes for deep indentations. The experimental and finite element analysis results demonstrated that the new contact model provides more accurate mechanical properties throughout the indentation depth up to radius of the indenter, while the Hertz model underestimates the mechanical properties. In the classical contact models, it is assumed that the sample is vertically homogenous; however, many biological samples—for example cells—are heterogeneous. A novel two-layer model was utilized to probe Polydimethylsiloxane hydrogel (PDMS) layers on PDMS substrates with stiffness mismatch. In this experiment the stiffness of the substrate was deconvoluted from the AFM measurements to obtain the stiffness of the layer. AFM and confocal reflectance microscopy were utilized along with a novel 3D microengineered breast cancer tumor model to study the crosstalk between cancer tumor and the stromal cells (CAFs) and the ECM remodeling caused by their interplay. The results showed that as the cancer cells invade into the extracellular matrix (ECM), they release PDGF ligands which enable Cafes to remodel the ECM and this remodeling increased the invasion rate of the cancer cells. Next, the effect of the ECM remodeling on anti-cancer drug resistant was investigated within the 3D microengineered cancer model. It was demonstrated that the combinatory treatment by anti-cancer and-anti-fibrotic drugs enhance the efficiency of the cancer treatment. A novel DNA-based 3D hydrogel model with tunable stiffness was investigated by AFM. The results showed the hydrogel stiffness can be enhanced by adding DNA crosslinkers. In addition, the stiffness was reduced to the control sample level by introducing the displacement DNA. Biophysical quantifications along with the in vitro microengineered tumor models provide a unique frame work to study cancer in more detail.
ContributorsRahmani Eliato, Kiarash (Author) / Ros, Robert (Thesis advisor) / Nikkhah, Mehdi (Committee member) / Ozkan, Sefika (Committee member) / Lindsay, Stuart (Committee member) / Arizona State University (Publisher)
Created2019
Description
Extracellular Vesicles (EVs), particularly exosomes, are of considerable interest as tumor biomarkers since tumor-derived EVs contain a broad array of information about tumor pathophysiology including its metabolic and metastatic status. However, current EV based assays cannot distinguish between EV biomarker changes by altered secretion of EVs during diseased conditions like cancer, inflammation, etc. that express a constant level of a given biomarker, stable secretion of EVs with altered biomarker expression, or a combination of these two factors. This issue was addressed by developing a nanoparticle and dye-based fluorescent immunoassay that can distinguish among these possibilities by normalizing EV biomarker level(s) to EV abundance, revealing average expression levels of EV biomarker under observation. In this approach, EVs are captured from complex samples (e.g. serum), stained with a lipophilic dye and hybridized with antibody-conjugated quantum dot probes for specific EV surface biomarkers. EV dye signal is used to quantify EV abundance and normalize EV surface biomarker expression levels. EVs from malignant (PANC-1) and nonmalignant pancreatic cell lines (HPNE) exhibited similar staining, and probe-to-dye ratios did not change with EV abundance, allowing direct analysis of normalized EV biomarker expression without a separate EV quantification step. This EV biomarker normalization approach markedly improved the ability of serum levels of two pancreatic cancer biomarkers, EV EpCAM, and EV EphA2, to discriminate pancreatic cancer patients from nonmalignant control subjects. The streamlined workflow and robust results of this assay are suitable for rapid translation to clinical applications and its flexible design permits it to be rapidly adapted to quantitate other EV biomarkers by the simple swapping of the antibody-conjugated quantum dot probes for those that recognize a different disease-specific EV biomarker utilizing a workflow that is suitable for rapid clinical translation.
ContributorsRodrigues, Meryl (Author) / Hu, Tony (Thesis advisor) / Nikkhah, Mehdi (Committee member) / Kiani, Samira (Committee member) / Smith, Barbara (Committee member) / Han, Haiyong (Committee member) / Arizona State University (Publisher)
Created2019
Description
The recording of biosignals enables physicians to correctly diagnose diseases and prescribe treatment. Existing wireless systems failed to effectively replace the conventional wired methods due to their large sizes, high power consumption, and the need to replace batteries. This thesis aims to alleviate these issues by presenting a series of wireless fully-passive sensors for the acquisition of biosignals: including neuropotential, biopotential, intracranial pressure (ICP), in addition to a stimulator for the pacing of engineered cardiac cells. In contrast to existing wireless biosignal recording systems, the proposed wireless sensors do not contain batteries or high-power electronics such as amplifiers or digital circuitries. Instead, the RFID tag-like sensors utilize a unique radiofrequency (RF) backscattering mechanism to enable wireless and battery-free telemetry of biosignals with extremely low power consumption. This characteristic minimizes the risk of heat-induced tissue damage and avoids the need to use any transcranial/transcutaneous wires, and thus significantly enhances long-term safety and reliability. For neuropotential recording, a small (9mm x 8mm), biocompatible, and flexible wireless recorder is developed and verified by in vivo acquisition of two types of neural signals, the somatosensory evoked potential (SSEP) and interictal epileptic discharges (IEDs). For wireless multichannel neural recording, a novel time-multiplexed multichannel recording method based on an inductor-capacitor delay circuit is presented and tested, realizing simultaneous wireless recording from 11 channels in a completely passive manner. For biopotential recording, a wearable and flexible wireless sensor is developed, achieving real-time wireless acquisition of ECG, EMG, and EOG signals. For ICP monitoring, a very small (5mm x 4mm) wireless ICP sensor is designed and verified both in vitro through a benchtop setup and in vivo through real-time ICP recording in rats. Finally, for cardiac cell stimulation, a flexible wireless passive stimulator, capable of delivering stimulation current as high as 60 mA, is developed, demonstrating successful control over the contraction of engineered cardiac cells. The studies conducted in this thesis provide information and guidance for future translation of wireless fully-passive telemetry methods into actual clinical application, especially in the field of implantable and wearable electronics.
ContributorsLiu, Shiyi (Author) / Christen, Jennifer (Thesis advisor) / Nikkhah, Mehdi (Committee member) / Phillips, Stephen (Committee member) / Cao, Yu (Committee member) / Goryll, Michael (Committee member) / Arizona State University (Publisher)
Created2020
Description
BioMEMS has the potential to provide many future tools for life sciences, combined with microfabrication technologies and biomaterials. Especially due to the recent corona 19 epidemic, interest in BioMEMS technology has increased significantly, and the related research has also grown significantly. The field with the highest demand for BioMEMS devices is in the medical field. In particular, the implantable device field is the largest sector where cutting-edge BioMEMS technology is applied along with nanotechnology, artificial intelligence, genetic engineering, etc. However, implantable devices used for brain diseases are still very limited because unlike other parts of human organs, the brain is still unknow area which cannot be completely replaceable.To date, the most commercially used, almost only, implantable device for the brain is a shunt system for the treatment of hydrocephalus. The current cerebrospinal fluid (CSF) shunt treatment yields high failure rates: ~40% within first 2 years and 98% within 10 years. These failures lead to high hospital admission rates and repeated invasive surgical procedures, along with reduced quality of life. New treatments are needed to improve the disease burden associated with hydrocephalus. In this research, the proposed catheter-free, completely-passive miniaturized valve is designed to alleviate hydrocephalus at the originating site of the disorder and diminish failure mechanisms associated with current treatment methods. The valve is composed of hydrogel diaphragm structure and polymer or glass outer frame which are 100% bio-compatible material. The valve aims to be implanted between the sub-arachnoid space and the superior sagittal sinus to regulate the CSF flow substituting for the obstructed arachnoid granulations.
A cardiac pacemaker is one of the longest and most widely used implantable devices and the wireless technology is the most widely used with it for easy acquisition of vital signs and rapid disease diagnosis without clinical surgery. But the conventional pacemakers with some wireless technology face some essential complications associated with finite battery life, ultra-vein pacing leads, and risk of infection from device pockets and leads. To solve these problems, wireless cardiac pacemaker operating in fully-passive modality is proposed and demonstrates the promising potential by realizing a prototype and functional evaluating.
A cardiac pacemaker is one of the longest and most widely used implantable devices and the wireless technology is the most widely used with it for easy acquisition of vital signs and rapid disease diagnosis without clinical surgery. But the conventional pacemakers with some wireless technology face some essential complications associated with finite battery life, ultra-vein pacing leads, and risk of infection from device pockets and leads. To solve these problems, wireless cardiac pacemaker operating in fully-passive modality is proposed and demonstrates the promising potential by realizing a prototype and functional evaluating.
ContributorsLee, Seunghyun (Author) / Christen, Jennifer (Thesis advisor) / Goryll, Michael (Committee member) / Nikkhah, Mehdi (Committee member) / Sohn, SungMin (Committee member) / Arizona State University (Publisher)
Created2020
Description
Glioblastoma Multiforme (GBM) is a grade IV astrocytoma and the most aggressive form of cancer that begins within the brain. The two-year average survival rate of GBM in the United States of America is 25%, and it has a higher incidence in individuals within the ages of 45 - 60 years. GBM Tumor formation can either begin as normal brain cells or develop from an existing low-grade astrocytoma and are housed by the perivascular niche in the brain microenvironment. This niche allows for the persistence of a population of cells known as glioma stem cells (GSC) by supplying optimum growth conditions that build chemoresistance and cause recurrence of the tumor within two to five years of treatment. It has therefore become imperative to understand the role of the perivascular niche on GSCs through in vitro modelling in order to improve the efficiency of therapeutic treatment and increase the survival rate of patients with GBM.
In this study, a unique three dimensional (3D) microfluidic platform that permitted the study of intercellular interactions between three different cell types in the perivascular niche of the brain was developed and utilized for the first time. Specifically, human endothelial cells were embedded in a fibrin matrix and introduced into the vascular layer of the microfluidic platform.
After spontaneous formation of a vascular layer, Normal Human Astrocytes and Patient derived GSC were embedded in a Matrigel® matrix and incorporated in the stroma and tumor regions of the microfluidic device respectively.
Using the established platform, migration, proliferation and stemness of GSCs studies were conducted. The findings obtained indicate that astrocytes in the perivascular niche significantly increase the migratory and proliferative properties of GSCs in the tumor microenvironment, consistent with previous in vivo findings.
The novel GBM tumor microenvironment developed herein, could be utilized for further
in-depth cellular and molecular level studies to dissect the influence of individual factors within the tumor niche on GSCs biology, and could serve as a model for developing targeted therapies.
In this study, a unique three dimensional (3D) microfluidic platform that permitted the study of intercellular interactions between three different cell types in the perivascular niche of the brain was developed and utilized for the first time. Specifically, human endothelial cells were embedded in a fibrin matrix and introduced into the vascular layer of the microfluidic platform.
After spontaneous formation of a vascular layer, Normal Human Astrocytes and Patient derived GSC were embedded in a Matrigel® matrix and incorporated in the stroma and tumor regions of the microfluidic device respectively.
Using the established platform, migration, proliferation and stemness of GSCs studies were conducted. The findings obtained indicate that astrocytes in the perivascular niche significantly increase the migratory and proliferative properties of GSCs in the tumor microenvironment, consistent with previous in vivo findings.
The novel GBM tumor microenvironment developed herein, could be utilized for further
in-depth cellular and molecular level studies to dissect the influence of individual factors within the tumor niche on GSCs biology, and could serve as a model for developing targeted therapies.
ContributorsAdjei-Sowah, Emmanuella Akweley (Author) / Nikkhah, Mehdi (Thesis advisor) / Plaisier, Christopher (Committee member) / Mehta, Shwetal (Committee member) / Arizona State University (Publisher)
Created2020
Description
One of the single-most insightful, and visionary talks of the 20th century, “There’s plenty of room at the bottom,” by Dr. Richard Feynman, represented a first foray into the micro- and nano-worlds of biology and chemistry with the intention of direct manipulation of their individual components. Even so, for decades there has existed a gulf between the bottom-up molecular worlds of biology and chemistry, and the top-down world of nanofabrication. Creating single molecule nanoarrays at the limit of diffraction could incentivize a paradigm shift for experimental assays. However, such arrays have been nearly impossible to fabricate since current nanofabrication tools lack the resolution required for precise single-molecule spatial manipulation. What if there existed a molecule which could act as a bridge between these top-down and bottom-up worlds?
At ~100-nm, a DNA origami macromolecule represents one such bridge, acting as a breadboard for the decoration of single molecules with 3-5 nm resolution. It relies on the programmed self-assembly of a long, scaffold strand into arbitrary 2D or 3D structures guided via approximately two hundred, short, staple strands. Once synthesized, this nanostructure falls in the spatial manipulation regime of a nanofabrication tool such as electron-beam lithography (EBL), facilitating its high efficiency immobilization in predetermined binding sites on an experimentally relevant substrate. This placement technology, however, is expensive and requires specialized training, thereby limiting accessibility.
The work described here introduces a method for bench-top, cleanroom/lithography-free, DNA origami placement in meso-to-macro-scale grids using tunable colloidal nanosphere masks, and organosilane-based surface chemistry modification. Bench-top DNA origami placement is the first demonstration of its kind which facilitates precision placement of single molecules with high efficiency in diffraction-limited sites at a cost of $1/chip. The comprehensive characterization of this technique, and its application as a robust platform for high-throughput biophysics and digital counting of biomarkers through enzyme-free amplification are elucidated here. Furthermore, this technique can serve as a template for the bottom-up fabrication of invaluable biophysical tools such as zero mode waveguides, making them significantly cheaper and more accessible to the scientific community. This platform has the potential to democratize high-throughput single molecule experiments in laboratories worldwide.
At ~100-nm, a DNA origami macromolecule represents one such bridge, acting as a breadboard for the decoration of single molecules with 3-5 nm resolution. It relies on the programmed self-assembly of a long, scaffold strand into arbitrary 2D or 3D structures guided via approximately two hundred, short, staple strands. Once synthesized, this nanostructure falls in the spatial manipulation regime of a nanofabrication tool such as electron-beam lithography (EBL), facilitating its high efficiency immobilization in predetermined binding sites on an experimentally relevant substrate. This placement technology, however, is expensive and requires specialized training, thereby limiting accessibility.
The work described here introduces a method for bench-top, cleanroom/lithography-free, DNA origami placement in meso-to-macro-scale grids using tunable colloidal nanosphere masks, and organosilane-based surface chemistry modification. Bench-top DNA origami placement is the first demonstration of its kind which facilitates precision placement of single molecules with high efficiency in diffraction-limited sites at a cost of $1/chip. The comprehensive characterization of this technique, and its application as a robust platform for high-throughput biophysics and digital counting of biomarkers through enzyme-free amplification are elucidated here. Furthermore, this technique can serve as a template for the bottom-up fabrication of invaluable biophysical tools such as zero mode waveguides, making them significantly cheaper and more accessible to the scientific community. This platform has the potential to democratize high-throughput single molecule experiments in laboratories worldwide.
ContributorsShetty, Rishabh Manoj (Author) / Hariadi, Rizal F (Thesis advisor) / Gopinath, Ashwin (Committee member) / Varsani, Arvind (Committee member) / Nikkhah, Mehdi (Committee member) / Tillery, Stephen H (Committee member) / Hu, Ye (Committee member) / Arizona State University (Publisher)
Created2019
Description
Magnetic resonance imaging (MRI) is a noninvasive imaging modality, which is used for many different applications. The versatility of MRI is in acquiring high resolution anatomical and functional images with no use of ionizing radiation. The contrast in MR images can be engineered by two different mechanisms with imaging parameters (TR, TE, α) and/or contrast agents. The contrast in the former is influenced by the intrinsic properties of the tissue (T1, T2, ρ), while the contrast agents change the relaxation rate of the protons to enhance contrast. Contrast agents have attracted a lot of attention because they can be modified with targeting groups to shed light on some physiological and biological questions, such as the presence of hypoxia in a tissue. Hypoxia, defined as lack of oxygen, has many known ramifications on the outcome of therapy in any condition. Hence its study is very important. The standard gold method to detect hypoxia, immunohistochemical (IHC) staining of pimonidazole, is invasive; however, there are many research groups focused on developing new and mainly noninvasive methods to investigate hypoxia in different tissues.Previously, a novel nitroimidazole-based T1 contrast agent, gadolinium tetraazacyclododecanetetraacetic acid monoamide conjugate of 2-nitroimidazole (GdDO3NI ), has been synthesized and characterized on subcutaneous prostate and lung tumor models. Here, its efficacy and performance on traumatic brain injuries and brain tumors are studied. The pharmacokinetic properties of the contrast agent the perfusion properties of brain tumors are investigated. These results can be used in personalized therapies for more effective results for patients.
Gadolinium (Gd), which is a strongly paramagnetic heavy metal, is routinely and widely used as an MR contrast agent by chelation with a biocompatible ligand which is typically cleared through the kidneys. While widely used, there are serious concerns for patients with impaired kidney function, as well as recent studies showed Gd accumulation in the bone and brain. Iron as a physiological ion is also capable of generating contrast in MR images. Here synthesis and characterization of an iron-based hypoxia targeting contrast agent is proposed to eliminate Gd-related complications and provide a cheaper and more economical alternative contrast agent to detect hypoxia.
ContributorsMoghadas, Babak (Author) / Kodibagkar, Vikram D (Thesis advisor) / Beeman, Scott (Committee member) / Muthuswamy, Jitendran (Committee member) / Nikkhah, Mehdi (Committee member) / Turner, Gregory (Committee member) / Arizona State University (Publisher)
Created2021
Description
Many medical procedures, like surgeries, deal with the physical manipulation of sensitive internal tissues. Over time, new medical tools and techniques have been developed to improve the safety and efficacy of these procedures. Despite the leaps and bounds of progress made up to the present day, three major obstacles (among others) persist, bleeding, pain, and the risk of infection. Advances in minimally invasive treatments have transformed many formerly risky surgical procedures into very safe and highly successful routines. Minimally invasive surgeries are characterized by small incision profiles compared to the large incisions in open surgeries, minimizing the aforementioned issues. Minimally invasive procedures lead to several benefits, such as shorter recovery time, fewer complications, and less postoperative pain. In minimally invasive surgery, doctors use various techniques to operate with less damage to the body than open surgery. Today, these procedures have an established, successful history and promising future. Steerable needles are one of the tools proposed for minimally invasive operations. Needle steering is a method for guiding a long, flexible needle through curved paths to reach targets deep in the body, eliminating the need for large incisions. In this dissertation, we present a new needle steering technology: magnetic needle steering. This technology is proposed to address the limitations of conventional needle steering that hindered its clinical applications. Magnetic needle steering eliminates excessive tissue damage, restrictions of the minimum radius of curvature, and the need for a complex nonlinear model, to name a few. It also allows fabricating the needle shaft out of soft and tissue-compliant materials.
This is achieved by first developing an electromagnetic coil system capable of producing desired magnetic fields and gradients; then, a magnetically actuated needle is designed, and its effectiveness is experimentally evaluated. Afterward, the scalability of this technique was tested using permanent magnets controlled with a robotic arm.
Furthermore, different configurations of permanent magnets and their influence on the magnetic field are investigated, enabling the possibility of designing a desired magnetic field for a specific surgical procedure and operation on a particular organ. Finally, potential future directions towards animal studies and clinical trials are discussed.
ContributorsIlami, Mahdi (Author) / Marvi, Hamid (Thesis advisor) / Berman, Spring (Committee member) / Lee, Hyunglae (Committee member) / Nikkhah, Mehdi (Committee member) / Sugar, Thomas (Committee member) / Arizona State University (Publisher)
Created2021
Description
Tumor-stroma interactions significantly influence cancer cell metastasis and disease progression. These interactions partly comprise crosstalk between tumor and stromal fibroblasts, but the key molecular mechanisms within the crosstalk governing cancer invasion are still unclear. Here we develop a 3D in vitro organotypic microfluidic to model tumor-stroma interaction by mimicking the spatial organization of the tumor microenvironment on a chip. We co-culture breast cancer and patient-derived fibroblast cells in 3D tumor and stroma regions respectively and combine functional assessments, including cancer cell migration, with transcriptome profiling to unveil the molecular influence of tumor-stroma crosstalk on invasion. This led to the observation that cancer associated fibroblasts enhanced invasion in 3D by inducing the expression of a novel gene of interest, GPNMB, in breast cancer cells resulting in increased migration speed. Importantly, knockdown of GPNMB blunted the influence of CAFs on enhancing cancer invasion. Overall, these results demonstrate the ability of our model to recapitulate patient specific tumor microenvironment to investigate cellular and molecular consequences of tumor-stroma interactions.
ContributorsBarrientos, Eric Salvador (Author) / Nikkhah, Mehdi (Thesis director) / Veldhuizen, Jaime (Committee member) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2019-05
Description
Stromal cells play an important role in facilitating disease progression of ductal carcinoma. Cancer associated fibroblasts (CAFs) are an important component of the extracellular matrix (ECM) which constitutes the microenvironment of breast tumor cells. They are known to participate in chemotherapeutic drug resistance by modulating various biochemical and biophysical factors that contribute to increased matrix stiffness and collagen I density of the tumor-adjacent stroma. To address these issues in terms of patient treatment, anti-cancer drug regimes have been assembled to incorporate both chemotherapeutic as well as anti-fibrotic drugs to both target tumor cells while also diminishing the elastic modulus of the microenvironment by targeting CAFs. The quantitative assessment of these drug regimes on tumor progression is missing in terms of CAFs role alone.
A high density 3D tumor model was utilized to recapitulate the tumor microenvironment of ductal carcinoma in vitro. The tumor model consisted of MDA-MB-231 tumors seeded within micromolded collagen wells, chemically immobilized upon a surface treated PDMS substrate. CAFs were seeded within the greater collagen structure from which the microwells were formed. The combinatorial effect of anti-fibrotic drug (Tranilast) and chemotherapy drug (Doxorubicin) were studied within 3D co culture conditions. Specifically, the combinatorial effects of the drugs on tumor cell viability, proliferation, and invasion were examined dynamically upon coculture with CAFs using the microengineered model.
The results of the study showed that the combinatorial effects of Tranilast and Doxorubicin significantly decreased the proliferative ability of tumor cells, in addition to significantly decreasing the ability of tumor cells to remain viable and invade their surrounding stroma, compared to control conditions.
A high density 3D tumor model was utilized to recapitulate the tumor microenvironment of ductal carcinoma in vitro. The tumor model consisted of MDA-MB-231 tumors seeded within micromolded collagen wells, chemically immobilized upon a surface treated PDMS substrate. CAFs were seeded within the greater collagen structure from which the microwells were formed. The combinatorial effect of anti-fibrotic drug (Tranilast) and chemotherapy drug (Doxorubicin) were studied within 3D co culture conditions. Specifically, the combinatorial effects of the drugs on tumor cell viability, proliferation, and invasion were examined dynamically upon coculture with CAFs using the microengineered model.
The results of the study showed that the combinatorial effects of Tranilast and Doxorubicin significantly decreased the proliferative ability of tumor cells, in addition to significantly decreasing the ability of tumor cells to remain viable and invade their surrounding stroma, compared to control conditions.
ContributorsSilva, Casey Rudolph (Author) / Nikkhah, Mehdi (Thesis director) / Saini, Harpinder (Committee member) / Harrington Bioengineering Program (Contributor, Contributor) / Barrett, The Honors College (Contributor)
Created2019-05