Engineering Commons^™

Reactive Chemistries For Protein Labeling, Degradation, And Stimuli Responsive Delivery, Myrat Kurbanov

Doctoral Dissertations

Reactive chemistries for protein chemical modification play an instrumental role in chemical biology, proteomics, and therapeutics. Depending on the application, the selectivity of these modifications can range from precise modification of an amino acid sequence by genetic manipulation of protein expression machinery to a stochastic modification of lysine residues on the protein surface. Ligand-Directed (LD) chemistry is one of the few methods for targeted modification of endogenous proteins without genetic engineering. However, current LD strategies are limited by stringent amino acid selectivity. To bridge this gap, this thesis focuses on the development of highly reactive LD Triggerable Michael Acceptors (LD-TMAcs) …

Optimizing Channel Formation In Peg Maleimide Hydrogels, Bakthavachalam Kannadasan

Masters Theses

Blood vessels including the arteries, veins, and capillaries are a critical and indispensable component of various organisms. Some studies estimate that if all the blood vessels present in our body are arranged in line, they would amount to a total length of approximately 60,000 miles. This distance is enough to circle the world two and a half times! In addition to being all pervasive, blood vessels perform certain key functions such as delivery of oxygen and nutrients to various tissues in the body. They also assist in the spread of diseases such as cancer. Therefore, it is important to study …

Electrostatic Effects On Lipid Bilayer Physicochemal Properties And Vesicle Adhesion, Oscar Zabala-Ferrera

Doctoral Dissertations

Lipids are an integral part of cells, being the principal component of the cell membrane, and contributing to the function and regulation of biological processes. Lipid nanoparticles mimicking a cell’s endosomes or exosomes are of particular interest within the pharmaceutical industry for their ability to deliver cargo such as RNA into target cells. The delivery process faces a multitude of challenges, so a rational design approach for vesicles that considers a lipid’s physicochemical contribution to the membrane is desired. To that end, this thesis explores the creation of large area biomembranes along with the development of electromechanical and optical characterization …

Enabling Daily Tracking Of Individual’S Cognitive State With Eyewear, Soha Rostaminia

Doctoral Dissertations

Research studies show that sleep deprivation causes severe fatigue, impairs attention and decision making, and affects our emotional interpretation of events, which makes it a big threat to public safety, and mental and physical well-being. Hence, it would be most desired if we could continuously measure one’s drowsiness and fatigue level, their emotion while making decisions, and assess their sleep quality in order to provide personalized feedback or actionable behavioral suggestions to modulate sleep pattern and alertness levels with the aim of enhancing performance, well-being, and quality of life. While there have been decades of studies on wearable devices, we …

Unobtrusive Assessment Of Upper-Limb Motor Impairment Using Wearable Inertial Sensors, Brandon R. Oubre

Doctoral Dissertations

Many neurological diseases cause motor impairments that limit autonomy and reduce health-related quality of life. Upper-limb motor impairments, in particular, significantly hamper the performance of essential activities of daily living, such as eating, bathing, and changing clothing. Assessment of impairment is necessary for tracking disease progression, measuring the efficacy of interventions, and informing clinical decision making. Impairment is currently assessed by trained clinicians using semi-quantitative rating scales that are limited by their reliance on subjective, visual assessments. Furthermore, existing scales are often burdensome to administer and do not capture patients' motor performance in home and community settings, resulting in a …

Frontiers In The Self-Assembly Of Charged Macromolecules, Khatcher O. Margossian

Doctoral Dissertations

The self-assembly of charged macromolecules forms the basis of all life on earth. From the synthesis and replication of nucleic acids, to the association of DNA to chromatin, to the targeting of RNA to various cellular compartments, to the astonishingly consistent folding of proteins, all life depends on the physics of the organization and dynamics of charged polymers. In this dissertation, I address several of the newest challenges in the assembly of these types of materials. First, I describe the exciting new physics of the complexation between polyzwitterions and polyelectrolytes. These materials open new questions and possibilities within the context …

Extracellular Matrix Stiffness As A Cue To Shape Phenotypic Evolution Of Triple Negative Breast Cancer, Ning-Hsuan Tseng

Doctoral Dissertations

Accumulation of epigenetic and genetic changes results in oncogenic transformation of epithelial cells. During breast cancer metastasis, while the extracellular matrix (ECM) becomes stiffer, breast cancer cells transmit mechanical forces into intracellular tension and activate signaling pathways influencing growth, migration, and metastasis. Once cancer cells detach from the primary tumor, they intravasate into the vasculature, survive in the circulation, extravasate and adapt to a new microenvironment of a secondary site. Throughout the process, only a very small population of cancer cells survive, and they are likely to reside at the metastatic sites for several years. The most frequent metastatic sites …

Development Of In Vitro Bone Organoid Models For The Recapitulation Of Bone Complexity, Yongkuk Park

Doctoral Dissertations

Osteoporosis is the most common skeletal disorder that thins and weakens the bones, yet the detailed mechanisms remain poorly understood and limited therapeutic options are available. This can be attributed to the lack of relevant experimental models that can recapitulate the bone complexity and bone remodeling. Mouse models have identified many critical genes and molecules regulating bone metabolism but are limited to studying detailed cellular and molecular processes due to anatomical inaccessibility and restricted ability to manipulate bone structure. Considerable efforts have been made to generate physiologically relevant models by using synthetic and biomaterial-based 3D scaffolds. However, there are no …

The Influence Of Flow Mechanotransduction On Endothelial Cells In The Lymphatic Valve Sinus, Joshua Daniel Hall

Doctoral Dissertations

Fluid flow in the cardiovascular and lymphatic systems influences the phenotype of endothelial cells that line the interior to the vessel via mechanotransduction. Geometric features in a vessel such as curvature, bifurcation, and valves promote heterogeneous fluid flow profiles, inducing a heterogeneous endothelial phenotype within a vessel region. Certain flow conditions are associated with vascular dysfunction, and diseases such as atherosclerosis preferentially develop in areas of flow disturbance. Lymphatic vessels are highly analogous to blood vessels, although lymphatic flow characteristics and its effect on lymphatic endothelial cells (LECs) via mechanotransduction have been comparatively less examined. The most significant geometric features …

Characterizing Mechanical Regulation Of Bone Metastatic Breast Cancer Cells, Boyuan Liu

Doctoral Dissertations

Breast cancer most frequently metastasizes to the skeleton. Bone metastatic cancer is incurable and induces wide-spread bone osteolysis, resulting in significant patient morbidity and mortality. Mechanical stimuli in the skeleton are an important microenvironmental parameter that modulates tumor formation, osteolysis, and tumor cell-bone cell signaling, but which mechanical signals are the most beneficial and the corresponding molecular mechanisms are unknown. This work focused on bone matrix deformation and interstitial fluid flow based on their well-known roles in bone remodeling and in primary breast cancer. The goal of our research was to establish a platform that could define the relationship between …

Controlled Codelivery Of Mir-26a And Antagomir-133a With Osteoconductive Scaffolds To Promote Healing Of Large Bone Defects, Cole J. Ferreira

Masters Theses

Often caused by trauma or tumor removal, large bone defects frequently result in delayed or non-union. The current gold standard for treatment is autograft. However, due to limitations, such as the size and location of the defect, these cannot always be utilized. A common alternative to autograft is the use of BMP-2 with a collagen scaffold, however, this treatment is limited by numerous side effects. In recent years, genetic materials such as microRNAs (miRNAs) have offered possible alternative therapies. MiRNAs are small non-coding RNA molecules that generally range from 20-24 nucleotides, serve as repressors of gene expression, and are involved …

Visuomotor Adaptation During Asymmetric Walking, Charles Napoli

Masters Theses

Necessary for effective ambulation, head stability affords optimal conditions for the perception of visual information during dynamic tasks. This maintenance of head-in-space equilibrium is achieved, in part, by the attenuation of the high frequency impact shock resulting from ground contact. While a great deal of experimentation has been done on the matter during steady state locomotion, little is known about how head stability or dynamic visual acuity is maintained during asymmetric walking.

In this study, fifteen participants were instructed to walk on a split-belt treadmill for ten minutes while verbally reporting the orientation of a randomized Landolt-C optotype that was …

A Novel Intervention To Prevent Post-Traumatic Osteoarthritis Following Knee Joint Injury, Gerardo E. Narez

Doctoral Dissertations

The knee joint is the most commonly injured body part in the human body. Injuries as a result of participation in sports, or other recreational activities, often leads to damage to the anterior cruciate ligament (ACL) and meniscus. Injury to these tissues is strongly associated with subsequent knee post-traumatic osteoarthritis (PTOA), which is considered a serious disease because it greatly impacts a patient’s quality of life and significantly increases their risk of premature death. To return stability to the joint, the current clinical treatment is to perform reconstruction of the torn ACL and a meniscal debridement, or meniscectomy, when needed. …

Enhancing The Intracellular Availability Of Protein Cargoes In Polymer-Mediated Delivery, Christopher R. Hango

Doctoral Dissertations

Protein drugs, including antibodies, are rapidly emerging as the top-selling pharmaceuticals worldwide owing to their unparalleled specificity and biocompatibility. However, none of the currently-approved protein therapeutics act intracellularly, despite the vast majority of potential drug targets residing within the cell. This is due mainly to the paramount challenge of transporting hydrophilic macromolecular cargoes across the plasma membrane. As such, effective protein carriers are essential for the advancement of modern medicine. Despite significant advances, many challenges still plague protein delivery. Following membrane transduction, delivery vectors must preserve the structure and activity of their cargoes while transporting them to the correct subcellular …

Surface Enhanced Raman Spectroscopy (Sers) As An Approach For The Emerging Liquid Biopsy Diagnostics, Nariman Banaei

Doctoral Dissertations

Large Molecule bioanalysis and biosensor development are essential techniques that are required in many applications, including biotherapeutic development, in vitro diagnostic, biomarker detection, and early detection. These techniques should be highly specific and sensitive enough to identify and quantify an analyte of interest with minimum sample pretreatment requirements. This work explores the development and application of chip-scale bioassays based on surface-enhanced Raman scattering (SERS). It introduces sensing techniques to quantify various disease biomarkers, specifically pancreatic cancer. Blood is the best source of information about our body's function. There are many biomarkers in the blood, and each biomarker's high expression level …

A Generalized Method For Predictive Simulation-Based Lower Limb Prosthesis Design, Mark Price

Doctoral Dissertations

Lower limb prostheses are designed to replace the functions and form of the missing biological anatomy. These functions are hypothesized to improve user outcome measures which are negatively affected by receiving an amputation – such as metabolic cost of transport, preferred walking speed, and perceived discomfort during walking. However, the effect of these design functions on the targeted outcome measures is highly variable, suggesting that these relationships are not fully understood. Biomechanics simulation and modeling tools are increasingly capable of analyzing the effects of a design on the resulting user gait. In this work, prothesis-aided gait is optimized in simulation …

Design And Biomechanical Evaluation Of A Clutch-Based Energy Storage And Release Assistive Knee Brace, Ericber Jimenez Francisco

Doctoral Dissertations

Knee osteoarthritis (OA) is a serious degenerative disease affecting over 240 million people around the world. The most disabling symptoms are joint pain, joint stiffness, and reduction in joint functionality. Medial compartment knee OA is the most common case of unicompartmental knee OA, and pain and progression have been associated with tibiofemoral alignment in early to moderate knee OA patients, mainly due to its association with knee loading as measured by knee adduction moment (KAM) and tibiofemoral contact forces (KCF). Valgization knee braces have been developed to correct the malalignment at the tibiofemoral joint, but they have no direct effect …

Engineering Stimuli-Responsive Polymeric Nanoassemblies: Rational Designs For Intracellular Delivery Of Biologics, Kingshuk Dutta

Doctoral Dissertations

Biologic drugs have gained enormous research attention in recent years as reflected by the development of multiple candidates to the clinical pipelines and an increased percentage of FDA approval. This is reasoned by the fact that biologics have been proven to deliver more predictive and promising benefits for many hard-to-cure diseases by ‘drugging the undruggable’ targets. However, the challenges associated with biologic drug development are multi-fold, viz, poor encapsulation efficacy, systemic instability, low cellular internalization and endosomal escape capability. Thus, it is essential to develop new molecular strategies that can not only address the associated drug delivery challenges, but also …

Controlled Membrane Remodeling By Nanospheres And Nanorods: Experiments Targeting The Design Principles For Membrane-Based Materials, Sarah Zuraw-Weston

Doctoral Dissertations

In this thesis we explore two experimental systems probing the interactions of nanoparticles with lipid bilayer membranes. Inspired by the ability of cell membranes to alter their shape in response to bound particles, we report two experimental studies: one of nanospheres the other of long, slender nano-rods binding to lipid bilayer vesicles and altering the membrane shape. Our work illuminates the role of particle geometry, particle concentration, adhesion strength and membrane tension in how membrane morphology is determined. We combine giant unilamellar vesicles with oppositely charged nanoparticles, carefully tuning adhesion strength, membrane tension and particle concentration. In the case of …

Micro-Physiological Models To Mimic Mucosal Barrier Complexity Of The Human Intestine In Vitro, Abhinav Sharma

Doctoral Dissertations

The mucosal barrier in the intestine is vital to maintain selective absorption of nutrients while protecting internal tissues and maintaining symbiotic relationship with luminal microbiota. This bio-barrier consists of a cellular epithelial barrier and an acellular mucus barrier. Secreted mucus regulates barrier function via in situ biochemical and biophysical interaction with luminal content that continually evolves during digestion and absorption. Increasing evidence suggests that a mucus barrier is indispensable to maintain homeostasis in the gastrointestinal tract. However, the importance of mucus barrier is largely underrated for in vitro mucosal tissue modeling. The major gap is the lack of experimental material …

Engineering Mesothelin-Binding Proteins As Targeted Cancer Diagnostics And Therapeutics, Allison Rita Sirois

Doctoral Dissertations

Cancer is a significant global health concern; and traditional therapies, including chemotherapeutics, are often simultaneously toxic yet ineffective. There is a critical need to develop targeted cancer therapeutics which specifically inhibit molecules or molecular pathways essential for tumor growth and maintenance. Furthermore, a targeted therapy is only effective when a patient's tumor expresses the molecular target; therefore, companion diagnostics, including molecular imaging agents, are a necessary counterpart of targeted therapies. Mesothelin (MSLN) is a cell surface protein overexpressed in numerous cancers, including triple-negative breast, pancreatic, ovarian, liver, and lung, with limited expression in normal tissues. Aberrant MSLN expression promotes tumor …

Elucidating Mechanisms Of Metastasis With Implantable Biomaterial Niches, Ryan Adam Carpenter

Doctoral Dissertations

Metastasis is the leading cause of cancer related deaths, yet it remains the most poorly understood aspect of tumor biology. This can be attributed to the lack of relevant experimental models that can recapitulate the complex and lengthy progression of metastatic relapse observed in patients. Mouse models have been widely used to study cancer, however they are critically limited to study metastasis. Most models generate aggressive metastases in the lung without the use of unique cell lines or specialized injection techniques. This limits the ability to study disseminated tumor cells (DTCs) in other relevant metastasis prone tissues. Prolonged observation of …

Predictive Simulation Of Human Movement And Applications To Assistive Device Design And Control, Vinh Nguyen

Doctoral Dissertations

Predictive simulation based on dynamic optimization using musculoskeletal models is a powerful approach for studying biomechanics of human gait. Predictive simulation can be used for a variety of applications from designing assistive devices to testing theories of motor controls. However, one of the challenges in formulating the predictive dynamic optimization problem is that the cost function, which represents the underlying goal of the walking task (e.g., minimal energy consumption) is generally unknown and is assumed a priori. While different studies used different cost functions, the qualities of the gaits with those cost functions were often not provided. Therefore, this dissertation …

Bioinspired Complex Nanoarchitectures By Dna Supramolecular Polymerization, Laura A. Lanier

Doctoral Dissertations

Bioinspired nanoarchitectures are of great interest for applications in fields such as nanomedicine, tissue engineering, and biosensing. With this interest, understanding how the physical properties of these complex nanostructures relate to their function is increasingly important. This dissertation describes the creation of complex nanoarchitectures with controlled structure and the investigation of the effect of nanocarrier physical properties on cell uptake for applications in nanomedicine. DNA self-assembly by supramolecular polymerization was chosen to create complex nanostructures of controlled architectures. We demonstrated that the supramolecular polymerization of DNA known as hybridization chain reaction (HCR) is in fact a living polymerization. The living …

Engineering Nanomaterials For Imaging And Therapy Of Bacteria And Biofilm-Associated Infections, Akash Gupta

Doctoral Dissertations

Infections caused by multidrug-resistant (MDR) bacteria pose a serious global burden of mortality, causing thousands of deaths each year. The “superbug” risk is further exacerbated by chronic infections generated from antibiotic-resistant biofilms that are highly resistant to available treatments. Synthetic macromolecules such as polymers and nanoparticles have emerged as promising antimicrobials. Moreover, ability to modulate nanomaterial interaction with bacterial cellular systems plays a pivotal role in improving the efficacy of the strategy. In the initial studies on engineering nanoparticle surface chemistry, I investigated the role played by surface ligands in determining the antimicrobial activity of the nanoparticles. In further study, …

Walking For Object Transport: An Examination Of The Coordinative Adaptations To Locomotor, Perceptual, And Manual Task Constraints, Avelino Amado

Doctoral Dissertations

The goal of this dissertation was to understand how the intrinsic dynamics of gait adapt to support the performance of an ecologically relevant object transport task. A common object transport task is walking with a cup of water. Because the water can move relatively independent of the cup, the cup and water system is classified as a complex object. To model this task participants carried a cup with a wooden lid placed on top. On the lid there was a circular region with the same circumference as the cup and a ball. The object of the task was to keep …

Direct Printing/Patterning Of Key Components For Biosensor Devices, Yiliang Zhou

Doctoral Dissertations

Recently, biosensor devices, especially wearable devices for monitoring human health, have attracted significant interests and meanwhile, they have a huge market. These wearable biosensor devices usually consist of several key components, including microfluidics, biosensing elements and power supply. Though advanced sensing platforms have been extensively explored, high manufacturing fee and lack of practical functions are the main reasons that most of devices and techniques are still out of reach for potential users. This dissertation focuses on fabricating these key components for biosensor devices via advanced printing/patterning techniques, such as inkjet-printing and nanoimprinting. These fabrication techniques can be potentially extended to …

Building The Outer Membrane Protein G (Ompg) Nanopore Library: From The Discrimination Of Biotin-Binding Proteins In Serum To Resolving Human Carbonic Anhydrase From Human Red Blood Cells, Bib Yang

Doctoral Dissertations

The use of pore-forming proteins (PFPs) in nanopore sensing has been fruitful largely due to their nanoscale size and the ease with which protein nanopores can be manipulated and consistently reproduced at a large scale. Nanopore sensing relies heavily on a steady ionic current afforded by rigid nanopores, as the change in current is indicative of analyte detection, revealing characteristics of the analyte such as its relative size, concentration, and charge, as well as the nanopore:analyte interaction. Rigid PFPs have been used in applications such as DNA sequencing, kinetic studies, analyte discrimination, and protein conformation dynamics at the single-molecule level. …

Biophysical Features Of The Extracellular Matrix Direct Breast Cancer Metastasis, Alyssa Schwartz

Doctoral Dissertations

Breast cancer is plagued by two key clinical challenges; drug resistance and metastasis. Most work to date probes these events on an extremely rigid plastic surface, which recapitulates few aspects of these processes in humans. A malignant cell first resides in breast tissue, then likely travels to the bone, brain, liver, or lung, each of which has a distinct mechanical and biochemical profile. Cells transmit mechanical forces into intracellular tension and biochemical signaling events, and here we hypothesize that this mechanotransduction influences drug response, growth, and migration. To probe the impact of extracellular matrix on drug resistance, we defined a …

Polymeric Peptide Mimics For Protein Delivery, Coralie Backlund

Doctoral Dissertations

The plasma membrane is a major obstacle in the development and use of biomacromolecules for intracellular applications. Consequently, proteins with intracellular targets represent an enormous, yet under studied avenue for therapeutics. Extended research has aimed at facilitating intracellular delivery of exogenous proteins using protein transduction domains (PTDs), which allow transport of bioactive molecules into cells. Synthetic polymers, inspired by PTDs, provide a well-controlled platform to vary molecular architecture for structure activity relationship studies. Specifically, this thesis focuses on the use of ring-opening metathesis, a facile and efficient polymerization technique, through which we can vary structural parameters to optimize delivery of …