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Description
There is a strong medical need and important therapeutic applications for improved wireless bioelectric interfaces to the nervous system. Multichannel devices are desired for neural control of robotic prosthetics that interface to remaining nerves in limb stumps of amputees and as alternatives to traditional wired arrays used in for some

There is a strong medical need and important therapeutic applications for improved wireless bioelectric interfaces to the nervous system. Multichannel devices are desired for neural control of robotic prosthetics that interface to remaining nerves in limb stumps of amputees and as alternatives to traditional wired arrays used in for some types of brain stimulation. This present work investigates a new approach to ultrasound-powering of implantable microelectronic devices within the tissue that may better support such applications. These devices are of ultra-miniature size that is enabled by a wireless technique. This study investigates two types of ultrasound-powered neural interfaces for multichannel sensory feedback in neurostimulation. The piezoceramics lead zirconate titanate (PZT) ceramic and polyvinylidene fluoride (PVDF) polymer were the primary materials used to build the devices. They convert ultrasound to electricity that when rectified by a diode produce a current output that is neuro stimulatory to peripheral nerve or the neurons in the brain. Multichannel devices employ a form of spatial multiplexing that directs focused ultrasound towards localized and segmented regions of PVDF or PZT that allows independent channels of nerve actuation. Different frequencies of ultrasound were evaluated for best results. Firstly, a 2.25 MHz frequency signal that is reasonably penetrating through body tissue to an implant several centimeters deep and also a 5 MHz frequency more suited to application for actuation of devices within a less than a centimeter of nerve. Results show multichannel device performance to have a complex inter-relationship with frequency, size and thickness, angular incidence, channel separations, and number of folds (layers connected in series and parallel). The output electrical port impedances of PVDF devices were examined in relationship to that of stimulating electrodes and tissue interfaces. Miniature multichannel devices were constructed using an unreported method of employing state of the art laser cutting systems. The results show that PVDF based devices have advantages over PZT, because of better acoustic coupling with tissue, known better biocompatibility, and better separation between multiple channels. However, the PZT devices proved to be better overall in terms of compactness and higher outputs for a given ultrasound power level.
ContributorsNanda Kumar, Yashwanth (Author) / Towe, Bruce (Thesis advisor) / Muthuswamy, Jitendran (Committee member) / Nikkhah, Mehdi (Committee member) / Arizona State University (Publisher)
Created2015
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Description
Severe cases of congenital heart defect (CHD) require surgeries to fix the structural problem, in which artificial grafts are often used. Although outcome of surgeries has improved over the past decades, there remains to be patients who require re-operations due to graft-related complications and the growth of patients which results

Severe cases of congenital heart defect (CHD) require surgeries to fix the structural problem, in which artificial grafts are often used. Although outcome of surgeries has improved over the past decades, there remains to be patients who require re-operations due to graft-related complications and the growth of patients which results in a mismatch in size between the patient’s anatomy and the implanted graft. A graft in which cells of the patient could infiltrate, facilitating transformation of the graft to a native-like tissue, and allow the graft to grow with the patient heart would be ideal. Cardiac tissue engineering (CTE) technologies, including extracellular matrix (ECM)-based hydrogels has emerged as a promising approach for the repair of cardiac damage. However, most of the previous studies have mainly focused on treatments for ischemic heart disease and related heart failure in adults, therefore the potential of CTE for CHD treatment is underexplored. In this study, a hybrid hydrogel was developed by combining the ECM derived from cardiac tissue of pediatric CHD patients and gelatin methacrylate (GelMA). In addition, the influence of incorporating gold nanorods (GNRs) within the hybrid hydrogels was studied. The functionalities of the ECM-GelMA-GNR hydrogels as a CTE scaffold were assessed by culturing neonatal rat cardiomyocytes on the hydrogel. After 8 days of cell culture, highly organized sarcomeric alpha-actinin structures and connexin 43 expression were evident in ECM- and GNR-incorporated hydrogels compared to pristine GelMA hydrogel, indicating cell maturation and formation of cardiac tissue. The findings of this study indicate the promising potential of ECM-GelMA-GNR hybrid hydrogels as a CTE approach for CHD treatment.

As another approach to improve CHD treatment, this study sought the possibility of performing a proteomic analysis on cardiac ECM of pediatric CHD patient tissue. As the ECM play important roles in regulating cell signaling, there is an increasing interest in studying the ECM proteome and the influences caused by diseases. Proteomics on ECM is challenging due to the insoluble nature of ECM proteins which makes protein extraction and digestion difficult. In this study, as a first step to perform proteomics, optimization on sample preparation procedure was attempted.
ContributorsSugamura, Yuka (Author) / Nikkhah, Mehdi (Thesis advisor) / Smith, Barbara (Committee member) / Willis, Brigham (Committee member) / Arizona State University (Publisher)
Created2018
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Description
With an increased demand for more enzyme-sensitive, bioresorbable and more biodegradable polymers, various studies of copolymers have been developed. Polymers are widely used in various applications of biomedical engineering such as in tissue engineering, drug delivery and wound healing. Depending on the conditions in which polymers are used, they are

With an increased demand for more enzyme-sensitive, bioresorbable and more biodegradable polymers, various studies of copolymers have been developed. Polymers are widely used in various applications of biomedical engineering such as in tissue engineering, drug delivery and wound healing. Depending on the conditions in which polymers are used, they are modified to accommodate a specific need. For instance, polymers used in drug delivery are more efficient if they are biodegradable. This ensures that the delivery system does not remain in the body after releasing the drug. It is therefore crucial that the polymer used in the drug system possess biodegradable properties. Such modification can be done in different ways including the use of peptides to make copolymers that will degrade in the presence of enzymes. In this work, we studied the effect of a polypeptide GAPGLL on the polymer NIPAAm and compare with the previously studied Poly(NIPAAm-co-GAPGLF). Both copolymers Poly(NIPAAm-co-GAPGLL) were first synthesized from Poly(NIPAAm-co-NASI) through nucleophilic substitution by the two peptides. The synthesis of these copolymers was confirmed by 1H NMR spectra and through cloud point measurement, the corresponding LCST was determined. Both copolymers were degraded by collagenase enzyme at 25 ° C and their 1H NMR spectra confirmed this process. Both copolymers were cleaved by collagenase, leading to an increase in solubility which yielded a higher LCST compared to before enzyme degradation. Future studies will focus on evaluating other peptides and also using other techniques such as Differential Scanning Microcalorimetry (DSC) to better observe the LCST behavior. Moreover, enzyme kinetics studies is also crucial to evaluate how fast the enzyme degrades each of the copolymers.
ContributorsUwiringiyimana, Mahoro Marie Chantal (Author) / Vernon, Brent (Thesis director) / Nikkhah, Mehdi (Committee member) / Harrington Bioengineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
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Description
Several debilitating neurological disorders, such as Alzheimer's disease, stroke, and spinal cord injury, are characterized by the damage or loss of neuronal cell types in the central nervous system (CNS). Human neural progenitor cells (hNPCs) derived from human pluripotent stem cells (hPSCs) can proliferate extensively and differentiate into the various

Several debilitating neurological disorders, such as Alzheimer's disease, stroke, and spinal cord injury, are characterized by the damage or loss of neuronal cell types in the central nervous system (CNS). Human neural progenitor cells (hNPCs) derived from human pluripotent stem cells (hPSCs) can proliferate extensively and differentiate into the various neuronal subtypes and supporting cells that comprise the CNS. As such, hNPCs have tremendous potential for disease modeling, drug screening, and regenerative medicine applications. However, the use hNPCs for the study and treatment of neurological diseases requires the development of defined, robust, and scalable methods for their expansion and neuronal differentiation. To that end a rational design process was used to develop a vitronectin-derived peptide (VDP)-based substrate to support the growth and neuronal differentiation of hNPCs in conventional two-dimensional (2-D) culture and large-scale microcarrier (MC)-based suspension culture. Compared to hNPCs cultured on ECMP-based substrates, hNPCs grown on VDP-coated surfaces displayed similar morphologies, growth rates, and high expression levels of hNPC multipotency markers. Furthermore, VDP surfaces supported the directed differentiation of hNPCs to neurons at similar levels to cells differentiated on ECMP substrates. Here it has been demonstrated that VDP is a robust growth and differentiation matrix, as demonstrated by its ability to support the expansions and neuronal differentiation of hNPCs derived from three hESC (H9, HUES9, and HSF4) and one hiPSC (RiPSC) cell lines. Finally, it has been shown that VDP allows for the expansion or neuronal differentiation of hNPCs to quantities (>1010) necessary for drug screening or regenerative medicine purposes. In the future, the use of VDP as a defined culture substrate will significantly advance the clinical application of hNPCs and their derivatives as it will enable the large-scale expansion and neuronal differentiation of hNPCs in quantities necessary for disease modeling, drug screening, and regenerative medicine applications.
ContributorsVarun, Divya (Author) / Brafman, David (Thesis advisor) / Nikkhah, Mehdi (Committee member) / Stabenfeldt, Sarah (Committee member) / Arizona State University (Publisher)
Created2016
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Description
The pathophysiology of neurodegenerative diseases, such as Alzheimer’s disease (AD), remain difficult to ascertain in part because animal models fail to fully recapitulate the complex pathophysiology of these diseases. In vitro models of neurodegenerative diseases generated with patient derived human induced pluripotent stem cells (hiPSCs) and human embryonic stem cells

The pathophysiology of neurodegenerative diseases, such as Alzheimer’s disease (AD), remain difficult to ascertain in part because animal models fail to fully recapitulate the complex pathophysiology of these diseases. In vitro models of neurodegenerative diseases generated with patient derived human induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs) could provide new insight into disease mechanisms. Although protocols to differentiate hiPSCs and hESCs to neurons have been established, standard practice relies on two dimensional (2D) cell culture systems, which do not accurately mimic the complexity and architecture of the in vivo brain microenvironment.

I have developed protocols to generate 3D cultures of neurons from hiPSCs and hESCs, to provide more accurate models of AD. In the first protocol, hiPSC-derived neural progenitor cells (hNPCs) are plated in a suspension of Matrigel™ prior to terminal differentiation of neurons. In the second protocol, hiPSCs are forced into aggregates called embryoid bodies (EBs) in suspension culture and subsequently directed to the neural lineage through dual SMAD inhibition. Culture conditions are then changed to expand putative hNPC populations and finally differentiated to neuronal spheroids through activation of the tyrosine kinase pathway. The gene expression profiles of the 3D hiPSC-derived neural cultures were compared to fetal brain RNA. Our analysis has revealed that 3D neuronal cultures express high levels of mature pan-neuronal markers (e.g. MAP2, β3T) and neural transmitter subtype specific markers. The 3D neuronal spheroids also showed signs of neural patterning, similar to that observed during embryonic development. These 3D culture systems should provide a platform to probe disease mechanisms of AD and enable to generation of more advanced therapeutics.
ContributorsPetty, Francis (Author) / Brafman, David (Thesis advisor) / Stabenfeldt, Sarah (Committee member) / Nikkhah, Mehdi (Committee member) / Arizona State University (Publisher)
Created2016
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Description
Stromal cell-derived factor-1α (SDF-1α) and its key receptor, CXCR4 are ubiquitously expressed in systems across the body (e.g. liver, skin, lung, etc.). This signaling axis regulates a myriad of physiological processes that range from maintaining of organ homeostasis in adults to, chemotaxis of stem/progenitor and immune cell types after injury.

Stromal cell-derived factor-1α (SDF-1α) and its key receptor, CXCR4 are ubiquitously expressed in systems across the body (e.g. liver, skin, lung, etc.). This signaling axis regulates a myriad of physiological processes that range from maintaining of organ homeostasis in adults to, chemotaxis of stem/progenitor and immune cell types after injury. Given its potential role as a therapeutic target for diverse applications, surprisingly little is known about how SDF-1α mediated signaling propagates through native tissues. This limitation ultimately constrains rational design of interventional biomaterials that aim to target the SDF-1α/CXCR4 signaling axis. One application of particular interest is traumatic brain injury (TBI) for which, there are currently no means of targeting the underlying biochemical pathology to improve prognosis.

Growing evidence suggests a relationship between SDF-1α/CXCR4 signaling and endogenous neural progenitor/stem cells (NPSC)-mediated regeneration after neural injury. Long-term modulation of the SDF-1α/CXCR4 signaling axis is thus hypothesized as a possible avenue for harnessing and amplifying endogenous regenerative mechanisms after TBI. In order to understand how the SDF-1α/CXCR4 signaling can be modulated in vivo, we first developed and characterized a sustained protein delivery platform in vitro. We were the first, to our knowledge, to demonstrate that protein release profiles from poly(D,L,-lactic-co-glycolic) acid (PLGA) particles can be tuned independent of particle fabrication parameters via centrifugal fractioning. This process of physically separating the particles altered the average diameter of a particle population, which is in turn was correlated to critical release characteristics. Secondly, we demonstrated sustained release of SDF-1α from PLGA/fibrin composites (particles embedded in fibrin) with tunable burst release as a function of fibrin concentration. Finally, we contrasted the spatiotemporal localization of endogenous SDF-1α and CXCR4 expression in response to either bolus or sustained release of exogenous SDF-1α. Sustained release of exogenous SDF-1α induced spatially diffuse endogenous SDF-1/CXCR4 expression relative to bolus SDF-1 administration; however, the observed effects were transient in both cases, persisting only to a maximum of 3 days post injection. These studies will inform future systematic evaluations of strategies that exploit SDF-1α/CXCR4 signaling for diverse applications.
ContributorsDutta, Dipankar (Author) / Stabenfeldt, Sarah E (Thesis advisor) / Kleim, Jeffrey (Committee member) / Nikkhah, Mehdi (Committee member) / Sirianni, Rachael (Committee member) / Vernon, Brent (Committee member) / Arizona State University (Publisher)
Created2016
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Description
Breast cancer is the second leading cause of disease related death in women, contributing over

40,000 fatalities annually. The severe impact of breast cancer can be attributed to a poor

understanding of the mechanisms underlying cancer metastasis. A primary aspect of cancer

metastasis includes the invasion and intravasation that results in cancer cells

Breast cancer is the second leading cause of disease related death in women, contributing over

40,000 fatalities annually. The severe impact of breast cancer can be attributed to a poor

understanding of the mechanisms underlying cancer metastasis. A primary aspect of cancer

metastasis includes the invasion and intravasation that results in cancer cells disseminating from

the primary tumor and colonizing distant organs. However, the integrated study of invasion and

intravasation has proven to be challenging due to the difficulties in establishing a combined tumor

and vascular microenvironments. Compared to traditional in vitro assays, microfluidic models

enable spatial organization of 3D cell-laden and/or acellular matrices to better mimic human

physiology. Thus, microfluidics can be leveraged to model complex steps of metastasis. The

fundamental aim of this thesis was to develop a three-dimensional microfluidic model to study the

mechanism through which breast cancer cells invade the surrounding stroma and intravasate into

outerlying blood vessels, with a primary focus on evaluating cancer cell motility and vascular

function in response to biochemical cues.

A novel concentric three-layer microfluidic device was developed, which allowed for

simultaneous observation of tumor formation, vascular network maturation, and cancer cell

invasion/intravasation. Initially, MDA-MB-231 disseminated from the primary tumor and invaded

the acellular collagen present in the adjacent second layer. The presence of an endothelial network

in the third layer of the device drastically increased cancer cell invasion. Furthermore, by day 6 of

culture, cancer cells could be visually observed intravasating into the vascular network.

Additionally, the effect of tumor cells on the formation of the surrounding microvascular network

within the vascular layer was evaluated. Results indicated that the presence of the tumor

significantly reduced vessel diameter and increased permeability, which correlates with prior in vivo

data. The novel three-layer platform mimicked the in vivo spatial organization of the tumor and its

surrounding vasculature, which enabled investigations of cell-cell interactions during cancer

invasion and intravasation. This approach will provide insight into the cascade of events leading up

to intravasation, which could provide a basis for developing more effective therapeutics.
ContributorsNagaraju, Supriya (Author) / Nikkhah, Mehdi (Thesis advisor) / Ebrahimkhani, Mohammad (Committee member) / Kiani, Samira (Committee member) / Arizona State University (Publisher)
Created2017
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Description
A tumor is a heterogeneous combination of proliferating tumor cells, infiltrating immune cells and stromal components along with a variety of associated host tissue cells, collectively termed the tumor microenvironment (TME). The constituents of the TME and their interaction with the host organ shape and define the properties of tumors

A tumor is a heterogeneous combination of proliferating tumor cells, infiltrating immune cells and stromal components along with a variety of associated host tissue cells, collectively termed the tumor microenvironment (TME). The constituents of the TME and their interaction with the host organ shape and define the properties of tumors and contribute towards the acquisition of hallmark traits such as hypoxia. Hypoxia imparts resistance to cancer from chemotherapy and radiotherapy due to the decreased production of reactive oxygen species and also promotes angiogenesis, malignant progression and metastasis. It also provides a powerful physiological stimulus that can be exploited as a tumor-specific condition, allowing for the rational design of anticancer hypoxia-activated pro-drugs (HAP). Accurate evaluation of tumor oxygenation in response to therapeutics interventions at various stages of growth should provide a better understanding of tumor response to therapy, potentially allowing therapy to be tailored to individual characteristics. The primary goal of this research was to investigate the utility of prospective identification of hypoxic tumors, by two different Magnetic Resonance Imaging (MRI) based oximetry approaches, in successful treatment with hypoxia activated therapy. In the present study, I report the utility of these two techniques 1) PISTOL (Proton Imaging of Siloxanes to map Tissue Oxygenation Levels) and 2) use of a hypoxia binding T1 contrast agent GdDO3NI in reporting the modulations of hypoxia pre and post hypoxia activated therapies in pre-clinical models of cancer. I have performed these studies in non-small cell lung cancer (NSCLC) and epidermoid carcinoma (NCI-H1975 and A431 cell lines, respectively) as well as in patient derived xenograft models of NSCLC. Both the oximetry techniques have the potential to differentiate between normoxic and hypoxic regions of the tumor and reveal both baseline heterogeneity and differential response to therapeutic intervention. The response of the tumor models to therapeutic interventions indicates that, in conjunction with pO2, other factors such as tumor perfusion (essential for delivering HAPs) and relative expression of nitroreductases (essential for activating HAPs) may play an important role. The long term goal of the proposed research is the clinical translation of both the MRI techniques and aiding the design and development of personalized therapy (e.g. patient stratification for novel hypoxia activated pro-drugs) particularly for cancer.
ContributorsAgarwal, Shubhangi (Author) / Kodibagkar, Vikram D (Thesis advisor) / Inge, Landon J (Committee member) / Nikkhah, Mehdi (Committee member) / Pagel, Mark D. (Committee member) / Sadleir, Rosalind J (Committee member) / Arizona State University (Publisher)
Created2017
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Description
Chimeric antigen receptor (CAR)-T cell therapy is a type of cancer immunotherapy has shown promising results in engineering the T cells which targets a specific antigen. Despite their success rate, there are certain limitations to the use of CAR-T therapies that includes cytokine release syndrome (CRS), neurologic toxicity, lack of

Chimeric antigen receptor (CAR)-T cell therapy is a type of cancer immunotherapy has shown promising results in engineering the T cells which targets a specific antigen. Despite their success rate, there are certain limitations to the use of CAR-T therapies that includes cytokine release syndrome (CRS), neurologic toxicity, lack of response in approximately 50% of treated patients, monitoring of patients treated with CAR-T therapy. However, rapid point- of- care testing helps in quantifying the circulating CAR T cells and can enhance the safety of patients, minimize the cost of CAR-T cell therapy, and ease the management process. Currently, the standard method to quantify CAR-T cell in patient blood samples are flow cytometry and quantitative polymerase chain reaction (qPCR). But these techniques are expensive and are not easily accessible and suitable for point- of- care testing to assist real- time clinical decisions. To overcome these hurdles, here I propose a solution to these problems by rapid optical imaging (ROI)- based principle to monitor and detect CAR-T cells. In this project, a microfluidic device is developed and integrated with two functions: (1) Centrifuge free, filter- based separation of white blood cells and plasma; (2) Optical imaging- based technique for digital counting of CAR T- cells. Here, I carried out proof- of- concept test on the laser cut prototype microfluidic chips as well as the surface chemistry for specific capture of CAR-T cells. These data show that the microfluidic chip can specifically capture CAR-T positive cells with concentration dependent counts of captured cells. Further development of the technology could lead to a new tool to monitor the CAR-T cells and help the clinicians to effectively measure the efficacy of CAR-T therapy treatment in a faster and safer manner.
ContributorsElanghovan, Praveena (Author) / Wang, Shaopeng (Thesis advisor) / Forzani, Erica (Committee member) / Nikkhah, Mehdi (Committee member) / Arizona State University (Publisher)
Created2023
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Description
The blood-brain-barrier (BBB) is a significant obstacle for treating many neurological disorders. Bubble-assisted focused ultrasound (BAFUS) medicated BBB disruption is a promising technology that enables the delivery of large drug doses at targeted locations across the BBB. However, the current lack of an in vitro model of this process hinders

The blood-brain-barrier (BBB) is a significant obstacle for treating many neurological disorders. Bubble-assisted focused ultrasound (BAFUS) medicated BBB disruption is a promising technology that enables the delivery of large drug doses at targeted locations across the BBB. However, the current lack of an in vitro model of this process hinders the full understanding of BAFUS BBB disruption for better translation into clinics. In this work, a US-transparent organ-on-chip device has been fabricated that can be critical for the in vitro modeling of the BAFUS BBB disruption. The transparency of the device window to focused ultrasound (FUS) was calculated theoretically and demonstrated by experiments. Nanobubbles were fabricated, characterized by cryogenic transmission electron microscopy (cryo-TEM), and showed bubble cavitation under FUS. Human colorectal adenocarcinoma (Caco-2) cells were used to form a good cellular barrier for BAFUS barrier disruption, as suggested by the measured permeability and transepithelial electrical resistance (TEER). Finally, barrier disruption and recovery were observed in BAFUS disrupted US-transparent organ-on-chips with Caco-2 barriers, showing great promise of the platform for future modeling BAFUS BBB disruption in vitro.
ContributorsAkkad, Adam Rifat (Author) / Gu, Jian (Thesis advisor) / Nikkhah, Mehdi (Thesis advisor) / Belohlavek, Marek (Committee member) / Wang, Xiao (Committee member) / Arizona State University (Publisher)
Created2022