Therapeutic Injectable Iron-Chelating Hydrogels, Debbie Campbell-Rance

Theses and Dissertations

ABSTRACT

Therapeutic Injectable Iron-Chelating Hydrogels for Improved Central Nervous System Regeneration

By

Debbie S. Campbell-Rance

A dissertation submitted in partial fulfillment of the requirements of the degree of Doctor of Philosophy at Virginia Commonwealth University 2021.

Director: Xuejun Wen, M.D., Ph.D., AIMBE Fellow, Alice T. and William H. Goodwin Jr. Endowed Chair Professor in Regenerative Medicine, Institute for Engineering and Medicine, Department of Chemical and Life Science Engineering

Severe traumatic brain and spinal cord injuries are major global public health and socioeconomic problems in terms of mortality and morbidity. Currently there are two main lines of treatment under development for …

Theta Burst Brain Stimulation In Painful Diabetic Neuropathy Patients: Investigating Neural Mechanisms, Bhushan Thakkar

Theses and Dissertations

Chronic pain (CP) is a significant contributor to disability and disease burden globally. In 2019, approximately 50.2 million adults (20.4% of the US population) experienced chronic pain, contributing to $560-635 billion in direct medical costs. In addition, the worldwide prevalence of diabetes mellitus has reached epidemic proportions and is set to increase to 629 million by 2045. Almost 50% of patients with diabetes present with diabetic neuropathy (DN), and one in five patients with diabetes presents with painful DN (pDN) which is the most common cause of neuropathic pain (NP) in the US. Symptomatic treatment is the mainstay of management …

Evaluating Neuromuscular Function Of The Biceps Brachii After Spinal Cord Injury: Assessment Of Voluntary Activation And Motor Evoked Potential Input-Output Curves Using Transcranial Magnetic Stimulation, Thibault Roumengous

Theses and Dissertations

Activation of upper limb muscles is important for independent living after cervical spinal cord injury (SCI) that results in tetraplegia. An emerging, non-invasive approach to address post-SCI muscle weakness is modulation of the nervous system. A long-term goal is to develop neuromodulation techniques to reinnervate (i.e. resupply nerve to) muscle fiber and thereby increase muscle function in individuals with tetraplegia. Towards this goal, developing monitoring techniques to quantify neuromuscular function is needed to better direct neurorehabilitation. Assessment of voluntary activation (VA) is a promising approach because the location of the stimulus can be applied cortically using transcranial magnetic stimulation (TMS) …

Nebulizer-Based Systems To Improve Pharmaceutical Aerosol Delivery To The Lungs, Benjamin M. Spence

Theses and Dissertations

Combining vibrating mesh nebulizers with additional new technologies leads to substantial improvements in pharmaceutical aerosol delivery to the lungs across therapeutic administration methods. In this dissertation, streamlined components, aerosol administration synchronization, and/or Excipient Enhanced Growth (EEG) technologies were utilized to develop and test several novel devices and aerosol delivery systems. The first focus of this work was to improve the poor delivery efficiency, e.g., 3.6% of nominal dose (Dugernier et al. 2017), of aerosolized medication administration to adult human subjects concurrent with high flow nasal cannula (HFNC) therapy, a form of continuous-flow non-invasive ventilation (NIV). The developed Low-Volume Mixer-Heater (LVMH) …

Computational Analysis And Prediction Of Intrinsic Disorder And Intrinsic Disorder Functions In Proteins, Akila I. Katuwawala

Theses and Dissertations

COMPUTATIONAL ANALYSIS AND PREDICTION OF INTRINSIC DISORDER AND INTRINSIC DISORDER FUNCTIONS IN PROTEINS

By Akila Imesha Katuwawala

A dissertation submitted in partial fulfillment of the requirements for the degree of Engineering, Doctor of Philosophy with a concentration in Computer Science at Virginia Commonwealth University.

Virginia Commonwealth University, 2021

Director: Lukasz Kurgan, Professor, Department of Computer Science

Proteins, as a fundamental class of biomolecules, have been studied from various perspectives over the past two centuries. The traditional notion is that proteins require fixed and stable three-dimensional structures to carry out biological functions. However, there is mounting evidence regarding a “special” class …

Nature-Inspired Material Strategies Towards Functional Devices, Sayantan Pradhan

Theses and Dissertations

Naturally sourced, renewable biomaterials possess outstanding advantages for a multitude of biomedical applications owing to their biodegradability, biocompatibility, and excellent mechanical properties. Of interest in this dissertation are silk (protein) and chitin (polysaccharide) biopolymers for the fabrication of functional biodevices. One of the major challenges restricting these materials beyond their traditional usage as passive substrate materials is the ability to combine them with high-resolution fabrication techniques. Initial research work is directed towards the fabrication of micropatterned, flexible 2D substrates of silk fibroin and chitin using bench-top photolithographic techniques. Research is focused on imparting electrochemical properties to silk proteins using conducting …

A Mechanism Behind The Mechanotransduction Of Surface Characteristics In Osteoblasts, Otto J. Juhl Iv

Theses and Dissertations

Biomaterials for use in bone regeneration and healing range from metal and metal alloy implants to hydrogel-based solutions. These materials can be optimized to increase bone healing and integration by improving the mechanical and biological properties. Regardless of the material itself, the cell-substrate interaction is key to the success of the biomaterial once implanted. Substrate surface characteristics such as roughness, wettability, and particle density are well-known contributors to a substrate’s overall osteogenic potential, and therefore the substrate's overall success. Unfortunately, it is still unknown how these substrate surface characteristics are transduced into intracellular signals by cells, preventing specific tailoring of …

Mathematical Models Of Cellular Signaling And Supramolecular Self-Assembly, Pratip Rana

Theses and Dissertations

Synthetic biologists endeavor to predict how the increasing complexity of multi-step signaling cascades impacts the fidelity of molecular signaling, whereby cellular state information is often transmitted with proteins diffusing by a pseudo-one-dimensional stochastic process. We address this problem by using a one-dimensional drift-diffusion model to derive an approximate lower bound on the degree of facilitation needed to achieve single-bit informational efficiency in signaling cascades as a function of their length. We find that a universal curve of the Shannon-Hartley form describes the information transmitted by a signaling chain of arbitrary length and depends upon only a small number of physically …

The Impact Of Aging And Mechanical Injury On Alveolar Epithelial And Macrophage Responses In Acute Lung Injury And Inflammation, Michael S. Valentine

Theses and Dissertations

Patients with severe lung pathologies, such as Acute Respiratory Distress Syndrome (ARDS), often require mechanical ventilation as a clinical intervention; however, this procedure frequently exacerbates the original pulmonary issue and produces an exaggerated inflammatory response that potentially leads to sepsis, multisystem organ failure, and mortality. This acute lung injury (ALI) condition has been termed Ventilator-Induced Lung Injury (VILI). Alveolar overdistension, cyclic atelectasis, and biotrauma are the primary injury mechanisms in VILI that lead to the loss of alveolar barrier integrity and pulmonary inflammation. Stress and strains during mechanical ventilation are believed to initiate alveolar epithelial mechanotransduction signaling mechanisms that contribute …

Higher Tensile Forces Across Cellular Junctions And An Intact Nuclear Linc Complex Is Required For Epithelial Function And Stability, Fnu Vani Narayanan

Theses and Dissertations

Recent advances in three-dimensional (3D) cell culture systems have provided key insights into the understanding of biochemical and physiological states of native tissue. A significant progress in the field of mechanobiology involves measuring cellular traction forces in a more native 3D environment. However, the effects of mechanical forces exerted across cellular junctions and the nuclear LINC complex, in an organized 3D system has not been investigated thus far. Epithelial cells spontaneously form acini (also known as cysts or spheroids) with a single, fluid-filled central lumen, when grown in 3D matrices. The size of the lumen is dependent on apical secretion …

The Role Of Kras In Mechanosensing In Non-Small Cell Lung Cancer, Krista M. Powell

Theses and Dissertations

Lung cancer is the number one cause of cancer related death worldwide, with more than 1.6 million fatalities each year. Non-small cell lung cancer (NSCLC) accounts for 80-85% of all lung cancers, with KRAS being one of the most prevalent oncogenic driver mutations. Therapeutic approaches for KRAS-mutated NSCLC have been extensively explored due to the US National Cancer Institute RAS Initiative, but methods of directly targeting KRAS or downstream effectors, such as MEK, still have poor results. Previous reports have shown that KRAS-mutated NSCLC activate distinct receptor tyrosine kinases (RTKs) depending on the epithelial or mesenchymal state. Epithelial-to-mesenchymal transition (EMT) …

The Role Of The Mechanical Environment On Cd117+ Endothelial Cell Angiogenesis, Patrick Link

Theses and Dissertations

Angiogenesis is a complex process coordinating cell migration, proliferation, and lumen formation. Changes to the microenvironment regulate angiogenesis through mechanotransduction and cytokine signals. In pulmonary hypertension, something in the process becomes abnormal, resulting in changes to the microenvironment and the formation of a glomerulus of dysfunctional capillaries, called a plexiform lesion. Endothelial cells, expressing CD117 (CD117+ EC clones) increase in the plexiform lesions of pulmonary hypertension, independent of pro-angiogenic VEGF signaling. We hypothesize that the mechanical environment and the macromolecular composition of the extracellular matrix, both, contribute to the aberrant angiogenesis. When we changed the mechanical environment, we changed the …

Eralpha Isoforms Modulate The Tumorigenicity Of 24r,25(Oh)2d3 In Estrogen-Responsive Cancer, Anjali Verma

Theses and Dissertations

Over 200,000 cases of breast cancer are diagnosed every year. Nearly 20% of these patients supplement their diets with some form of vitamin D. This high frequency of vitamin D supplement use may be due in part to research suggesting that cancer patients with higher serum vitamin D₃ levels have better prognoses than patients with low serum vitamin D_3. However, double-blind clinical trials on the efficacy of vitamin D₃ supplementation in breast cancer have been inconclusive. A recent meta-analysis showed evidence of reduced cancer recurrence in patients taking vitamin D₃ supplements who had ‘estrogen receptor positive’ …

Investigating Smoke Exposure And Chronic Obstructive Pulmonary Disease (Copd) With A Calibrated Agent Based Model (Abm) Of In Vitro Fibroblast Wound Healing., James A. Ratti

Theses and Dissertations

COPD is characterized by tissue inflammation and impaired remodeling that suggests fibroblast maintenance of structural homeostasis is dysregulated. Thus, we performed in vitro wound healing experiments on normal and diseased human lung fibroblasts and developed an ABM of fibroblasts closing a scratched monolayer using NetLogo to evaluate differences due to COPD or cigarette smoke condensate exposure. This ABM consists of a rule-set governing the healing response, accounting for cell migration, proliferation, death, activation and senescence rates; along with the effects of heterogeneous activation, phenotypic changes, serum deprivation and exposure to cigarette smoke condensate or bFGF. Simulations were performed to calibrate …

Engineering Surface Properties To Modulate Inflammation And Stem Cell Recruitment Through Macrophage Activation, Kelly M. Hotchkiss

Theses and Dissertations

Biomaterials are becoming the most commonly used therapeutic method for treatment of lost or damaged tissue in the body. Metallic materials are chosen for high strength orthopaedic and dental applications. Titanium (Ti) implants are highly successful in young, healthy patients with the ability to fully integrate to surrounding tissue. However the main population requiring these corrective treatments will not be healthy or young, therefore further research into material modifications have been started to improve outcomes in compromised patients. The body’s immune system will generate a response to any implanted material, and control the final outcome. Among the first and most …

Exogenous Fniii 12-14 Regulates Tgf-Β1-Induced Markers, Hilmi M. Humeid

Theses and Dissertations

The extracellular matrix protein Fibronectin (FN) plays an important role in cell contractility, differentiation, growth, adhesion, and migration. The 12th -14th Type III repeats of FN (FNIII 12-14), also referred to as the Heparin-II domain, comprise a highly promiscuous growth factor (GF) binding region. This binding domain aids in cellular signaling initiated from the ECM. Additionally, FN has the ability to assemble into fibrils under certain conditions, mostly observed during cell contractile processes such as those that initiate due to upregulation of Transforming Growth Factor Beta 1 (TGF-β1) [1], [2]. Previous work from our lab has shown that self-assembly of …

Behavioral Responses Of Sub-Adult Atlantic Sturgeon (Acipenser Oxyrinchus Oxyrinchus) To Electromagnetic And Magnetic Fields Under Laboratory Conditions, Andrew Mcintyre Iii

Theses and Dissertations

Electromagnetic fields (EMF) produced by high voltage (HV), submarine transmission cables leading from offshore wind energy generation facilities could affect foraging or migratory behaviors of electro-receptive fishes, including endangered Atlantic Sturgeon. However, no published studies have quantitatively evaluated the possible behavioral effects of EMF exposure on sturgeon during residence in coastal waters. This study evaluated behavioral responses by sub-adult Atlantic Sturgeon to electromagnetic and magnetic fields under controlled laboratory conditions. Fabricated EMF generators were used to emulate a range of field EMF conditions that migratory fishes could encounter in proximity to submarine HV sources. Sensor arrays and digital video recorders …

Modulating The Innate Immune Response To Electrospun Scaffolds And Polymer Degradative Byproducts, Daniel Abebayehu

Theses and Dissertations

Implanted biomaterials often induce inflammation that frequently leads to the foreign body response, fibrosis, and the failure of the implant. Thus, it is important to evaluate how cells interact with materials to promote a more regenerative response. It is critical to determine how to modulate the response of tissue resident innate immune cells, as they are among the first cells to interact with implanted materials. Among tissue resident innate immune cells are mast cells, which are inflammatory sentinels that degranulate and orchestrate the fate of other cell populations, such as monocytes/macrophages and lymphocytes. Mast cells have also been reported to …

Fabrication Of Flexible, Biofunctional Architectures From Silk Proteins, Ramendra K. Pal

Theses and Dissertations

Advances in the biomedical field require functional materials and processes that can lead to devices that are biocompatible, and biodegradable while maintaining high performance and mechanical conformability. In this context, a current shift in focus is towards natural polymers as not only the structural but also functional components of such devices. This poses material-specific functionalization and fabrication related questions in the design and fabrication of such systems. Silk protein biopolymers from the silkworm show tremendous promise in this regard due to intrinsic properties: mechanical performance, optical transparency, biocompatibility, biodegradability, processability, and the ability to entrap and stabilize biomolecules. The unique …

Optimizing Cobalt Carbide Based Nanomaterials By Using Nucleating Agents And Statistical Routes, Turki I. Almugaiteeb

Theses and Dissertations

The continuous high demand on permanent magnets in industries opened new research plateau to develop alternative magnetic material. The current used permanent magnet materials in the market still suffer from high cost and insufficient magnetic or thermal properties. The central focus of this dissertation work is the optimization of cobalt carbide based nanomaterial by means of modifying polyol synthesis assisted by nucleation agent and systematic statistics using JMP software tool. In most existing literatures, producing cobalt carbide (Co₂C or Co₃C) lack reproducibility and consistency resulting in nonsolid magnetic properties results. The practical requirements for cobalt carbide …

The Role Of E-Cadherin Force In The Maintenance Of Homeostasis In Epithelial Acini, Fnu Vani Narayanan

Theses and Dissertations

Numerous three-dimensional model systems have emerged for emulating the biochemical and physiological states of native tissue. Yet little is known about the effects of mechanical forces on cell behavior in the context of an organized tissue structure in three-dimensional cell-culture. Epithelial cells cultured in a three-dimensional environment comprised of extracellular matrix proteins form spheroids of polarized cells. Cellular responses to mechanical cues, generated from dynamic interactions with the extracellular matrix and neighboring cells, are known to influence cellular behavior to a great extent. Previous studies have shown that tumorigenic progression has been frequently linked to the down regulation of E-cadherin, …

Integrated Nanoscale Imaging And Spatial Recognition Of Biomolecules On Surfaces, Congzhou Wang

Theses and Dissertations

Biomolecules on cell surfaces play critical roles in diverse biological and physiological processes. However, conventional bulk scale techniques are unable to clarify the density and distribution of specific biomolecules in situ on single, living cell surfaces at the micro or nanoscale. In this work, a single cell analysis technique based on Atomic Force Microscopy (AFM) is developed to spatially identify biomolecules and characterize nanomechanical properties on single cell surfaces. The unique advantage of these AFM-based techniques lies in the ability to operate in situ (in a non-destructive fashion) and in real time, under physiological conditions or controlled micro-environments.

First, AFM-based …

Multi-Platform Arabinoxylan Scaffolds As Potential Wound Dressing Materials, Donald C. Aduba Jr

Theses and Dissertations

Biopolymers are becoming more attractive as advanced wound dressings because of their naturally derived origin, abundance, low cost and high compatibility with the wound environment. Arabinoxylan (AX) is a class of polysaccharide polymers derived from cereal grains that are primarily used in food products and cosmetic additives. Its application as a wound dressing material has yet to be realized. In this two-pronged project, arabinoxylan ferulate (AXF) was fabricated into electrospun fibers and gel foams to be evaluated as platforms for wound dressing materials. In the first study, AXF was electrospun with varying amounts of gelatin. In the second study, AXF …

Ex Vivo Dna Cloning, Adam B. Fisher

Theses and Dissertations

Genetic engineering of microbes has developed rapidly along with our ability to synthesize DNA de novo. Yet, even with decreasing DNA synthesis costs there remains a need for inexpensive, rapid and reliable methods for assembling synthetic DNA into larger constructs or combinatorial libraries. While technological advances have resulted in powerful techniques for in vitro and in vivo assembly of DNA, each suffers inherent disadvantages. Here, an ex vivo DNA cloning suite using crude cellular lysates derived from E. coli is demonstrated to amplify and assemble DNA containing small sequence homologies. Further, the advantages of an ex vivo approach are …