Biomedical Engineering and Bioengineering 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) …

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 …

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 …

Brain Inspired Organic Electronic Devices And Systems For Adaptive Signal Processing, Memory, And Learning., Subhadeep Koner

Doctoral Dissertations

A new class of electronic device has emerged which bear the potential for low powered brain like adaptive signal processing, memory, and learning. It is a non-linear resistor with memory coined as memristor. A memristor is a two-terminal electrical device which simultaneously changes its resistance (processing information) and store the resistance state pertaining to the applied power (memory). Therefore, it can collocate memory and processing much like our brain synapse which can save time and energy for information processing. Leveraging stored memory, it can thereby help future engineered systems to learn autonomously from past experiences. There has been a growing …

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 …

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 …

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 …

Effect Of Ambient Oxidation On Chemical Composition And Structural Properties Of Iron Nanoparticles For Hyperthermia And Medical Imaging, Adam Wesley Evans

Doctoral Dissertations

With magnetization saturation roughly twice that of iron oxide nanoparticles, metallic iron nanoparticles (also termed zero-valent iron nanoparticles) have desirable properties for use as a magnetic resonance imagining (MRI) contrast agent as well as a medium for hyperthermia treatment of cancer. Metallic iron nanoparticles, however, are difficult to synthesize and maintain due to their high degree of reactivity and proclivity for oxidation. The main goal of this study was to investigate how ambient oxidation affects the chemical composition and structural properties of metallic iron nanoparticles initially synthesized through a facile reduction reaction of iron (III) chloride with sodium borohydride. A …

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 …

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, …

Two And Three-Dimensional Models For Material And Cells Interaction, Nam H. Nguyen

Doctoral Dissertations

Three-dimensional (3D) cell spheroid model has been long considered a better model to mimic in vivo physiology compared to two-dimensional (2D) cell culture model. Traditional 2D cell models provide a simple, convenient and quick technique for drug screening but fail to simulate the complexity and heterogeneity of cells in the in vivo environment. The last few decades have remarked substantial progress toward the advancement of three-dimensional (3D) cell cultures as systems which better mimic cellcell and cell-matrix interaction in the in vivo physiology. Nowadays, 3D cell models have been emerging, not only as an important approach in drug discovery and …

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 …

Structure-Property Relationships Of Polymer Films And Hydrogels To Control Bacterial Adhesion, Kristopher W. Kolewe

Doctoral Dissertations

The emergence and spread of antibiotic resistance across microbial species necessitates the need for alternative approaches to mitigate the risk of infection without relying on commercial antibiotics. Biofilm-related infections are a class of notoriously difficult to treat healthcare-associated infections that frequently develop on the surface of implanted medical devices. As biofilm formation is a surface-associated phenomenon, understanding how the intrinsic properties of materials affect bacterial adhesion enables the development of structure-property relationships that can guide the future design of infection-resistant materials. Despite lacking visual, auditory, and olfactory perception, bacteria still manage to sense and attach to surfaces. Previously, it has …

Analyses Of Densely Crosslinked Phenolic Systems Using Low Field Nmr, Jigneshkumar Patel

Doctoral Dissertations

A uniform dispersion of reactants is necessary to achieve a complete reaction involving multi-components, especially for the crosslinking of rigid high-performance materials. In these reactions, miscibility is crucial for curing efficiency. This miscibility is typically enhanced by adding a third component, a plasticizer. For the reaction of the highly crystalline crosslinking agent hexamethylenetetramine (HMTA) with a strongly hydrogen-bonded phenol formaldehyde resin, furfural has been traditionally used as the plasticizer. However, the reason for its effectiveness is not clear. In this doctoral thesis work, miscibility and crosslinking efficiency of plasticizers in phenolic curing reactions are studied by thermal analysis and spectroscopic …

Tissue-Guided Engineering Of Polyethylene Glycol Hydrogels, Lauren Jansen

Doctoral Dissertations

Polyethylene glycol (PEG) hydrogels are tunable cell culture platforms that recapitulate tissue geometry, water content, and bulk modulus. Despite these benefits, PEG hydrogels elicit an acute immune response, limiting their use in regenerative medicine, and they critically underrepresent the cell-instructive proteins found in the extracellular matrix (ECM). Here, I developed a new class of tissue-specific PEG-based materials and provided biocompatible strategies to improve the user handling and cell viability post-encapsulation when using these hydrogels. I also demonstrated that decreasing the protein fouling to PEG does not decrease the foreign body response to implanted hydrogels, a common misconception in the field. …

Crafting Nanostructured Neural Interfaces With Hydrogel Particles, Emily Ann Morin

Doctoral Dissertations

Central nervous system neural device functionality hinges on effective communication with surrounding neurons. This depends on both the permissiveness of the device material to promote neuron integration and the ability of the device to avoid a chronic inflammatory response. Here, a facile approach has been developed exploring the multiple functionalities of hydrogel particles to provide cues to impart neural integration for such materials. Three distinct, yet interconnected tasks were undertaken: investigating hydrogel particle-modified substrate neuron integration and central nervous system inflammatory response, investigating guided hydrogel particle adsorption, and investigating hydrogel particles as local reservoirs for counteracting adverse effects from oxidative …

Biopolymer Electrospun Nanofiber Mats To Inactivate And Remove Bacteria, Katrina Ann Rieger

Doctoral Dissertations

The persistence of antibiotic resistance in bacterial pathogens remains a primary concern for immunocompromised and critically-ill hospital patients. Hospital associated infections can be deadly and reduce the successes of medical advancements, such as, cancer therapies and medical implants. Thus, it is imperative to develop materials that can (i) deliver new antibiotics with accuracy, as well as (ii) uptake pathogenic microbes. In this work, we will demonstrate that electrospun nanofiber mats offer a promising platform for both of these objectives because of their high surface-to-volume ratio, interconnected high porosity, gas permeability, and ability to contour to virtually any surface. To provide …

Extracellular Matrix Control Of Breast Cancer Metastasis And Dormancy, Lauren Barney

Doctoral Dissertations

To metastasize, a cell must travel through circulation to a secondary tissue, and this process causes 90% of all cancer deaths. Although inefficient, metastasis is not random, and only capable seeds in hospitable soils are capable of outgrowing into detectable metastases. The overall hypothesis in this work is that the secondary tissue microenvironment, particularly the extracellular matrix (ECM), mediates metastasis. We posit that the ability of metastatic cells to survive dormancy, exit quiescence, and colonize a tissue depends upon the ability of the soil to sustain survival, and subsequently trigger outgrowth. We created a simple biomaterial platform with systematic control …

Bioengineered Platforms To Study Carcinoma Cell Response To Drug Treatment, Thuy V. Nguyen

Doctoral Dissertations

The tumor extracellular matrix (ECM) plays an important role in facilitating tumor growth and mediating tumor cells' resistance to drugs. However, during drug development, potential chemotherapeutics are screened in plastic plates, which lack relevant ECM physicochemical cues. In order to improve drug development process, this dissertation includes the development of relevant 2D and 3D biomaterial systems that can be used to study carcinoma cell response to drug treatment. A novel poly(ethylene glycol)-phosphorylcholine (PEG-PC) high-throughput biomaterial platform was developed to study how the ECM mechanochemical properties affect cancer cells' response to drug. The PEG-PC biomaterial is optically transparent, has a mechanical …

Structure And Dynamics Of Charged Colloidal Disks In Colloid-Polymer Mixtures, Suhasini Kishore

Doctoral Dissertations

Complex fluid mixtures of colloids and polymers are extensively used in several conventional and emerging technological applications. Particles self-assemble under different conditions to form colloidal glasses and gels and it often leads to the development of unusual viscoelastic features. In the case of aspherical particles, shape anisotropy and physical aging effects add to the existing complexities so the implementation of a strategic formulation method to improve performance and stability remains a critical challenge. This thesis presents a comprehensive analysis of particle interactions in mixtures of charged disk-shaped colloids and weakly-adsorbing polymers like poly(ethylene oxide) (PEO). Here, we discuss the behavior …

Inter-Droplet Membranes For Mechanical Sensing Applications, Nima Tamaddoni Jahromi

Doctoral Dissertations

This dissertation combines self-assembly phenomena of amphiphilic molecules with soft materials to create and characterize mechanoelectrical transducers and sensors whose sensing elements are thin-film bioinspired membranes comprised of phospholipids or amphiphilic polymers. We show that the structures of these amphiphilic molecules tune the mechanical and electrical properties of these membranes. We show that these properties affect the mechanoelectrical sensing characteristic and range of operation of these membrane transducers. In the experiments, we construct and characterize a membrane-based hair cell embodiment that enables the membrane to be responsive to mechanical perturbations of the hair. The resulting oscillations of membranes formed between …

Mimicking The Arterial Microenvironment With Peg-Pc To Investigate The Roles Of Physicochemical Stimuli In Smc Phenotype And Behavior, William G. Herrick

Doctoral Dissertations

The goal of this dissertation was to parse the roles of physical, mechanical and chemical cues in the phenotype plasticity of smooth muscle cells (SMCs) in atherosclerosis. We first developed and characterized a novel synthetic hydrogel with desirable traits for studying mechanotransduction in vitro. This hydrogel, PEG-PC, is a co-polymer of poly(ethylene glycol) and phosphorylcholine with an incredible range of Young’s moduli (~1 kPa - 9 MPa) that enables reproduction of nearly any tissue stiffness, exceptional optical and anti-fouling properties, and support for covalent attachment of extracellular matrix (ECM) proteins. To our knowledge, this combination of mechanical range, low …

Engineering The “Pluripotency” Of Zr-Based Bulk Metallic Glasses As Biomedical Materials, Lu Huang

Doctoral Dissertations

Bulk metallic glasses (BMGs) are a family of novel alloys with amorphous microstructures. The combination of their excellent mechanical properties, good chemical stability, high thermal formability, and general biocompatibility has brought up new opportunities for biomaterials. Research in this dissertation was focused on exploring multiple biomedical functionalities of Zr-based BMGs over a wide spectrum, combining materials and biological characterizations, through experimental and computational approaches. Four distinct yet interconnected tasks were endeavored, involving inflammation, hard-tissue implant, soft-tissue prosthesis, and pathogenic infection.

The inflammation that can be potentially triggered by Zr-based BMGs was investigated using macrophages. Lower level or comparable macrophage activations …

Cell Adhesion Biophysics On Dynamic Polymer Constructs, Andreas Kourouklis

Doctoral Dissertations

The biophysical characteristics of cell adhesion from single protein to cell length scales have primarily been studied using purely elastic substrates. However, natural extracellular matrix (ECM) is viscoelastic and contains mobile components. In this work, we combined chemistry and cell biology tools to design and characterize laterally mobile viscoelastic polymer films that promote receptor-specific cell adhesion. Moreover, we used amphiphilic block copolymers that are end-labeled with RGD peptide ligands to allow for integrin-mediated cell adhesion. The addition of a trace hydrophobic homopolymer in the supported bilayer block-copolymer films is used to tune the lateral mobility of the films. NIH 3T3 …