A. James Clark School of Engineering
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The collections in this community comprise faculty research works, as well as graduate theses and dissertations.
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Item PREPARATION OF A NANOSUSPENSION OF THE PHOTOSENSITIZER VERTEPORFIN FOR PHOTODYNAMIC AND LIGHT-INDEPENDENT THERAPY IN GLIOBLASTOMA(2024) Quinlan, John Andrew; Huang, Huang-Chiao; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Photodynamic therapy (PDT) using verteporfin (VP) has treated ocular disease for over 20 years, but recent interest in VP’s light-independent properties has reignited interest in the drug, particularly in glioblastoma (GBM) (NCT04590664). Separate efforts to apply PDT to GBM using 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX) have also garnered attention (NCT03048240), but, unfortunately, clinical trials using 5-ALA-induced PpIX-PDT have yet to yield a survival benefit. Previous studies have shown VP to be a superior PDT agent than 5-ALA-induced PpIX. Our lab has shown that 690 nm light activates VP up to 2 cm into the brain, while 635 nm light only activates PpIX at depths <1 cm into the brain. Additionally, VP is a more effective photosensitizer than PpIX because it has a higher singlet oxygen yield and is active in the vasculature as well as target tumor cells. However, the hydrophobicity of VP limits effective delivery of the drug to the brain for treatment of GBM.In this context, this thesis aims to re-evaluate the delivery method for VP. VP traditionally requires lipids for delivery as Visudyne. Recent shortages of Visudyne and potential drawbacks of liposomal carriers motivated our development of a carrier-free nanosuspension of VP, termed NanoVP. Previous work has shown that cellular uptake of VP is greater when delivered as NanoVP rather than liposomal VP, resulting in improved cell killing after light activation. This thesis builds on this previous work by (1) evaluating synthesis and storage parameters for NanoVP, (2) determining the pharmacokinetics, biodistribution, and brain bioavailability of NanoVP, and (3) evaluating the potential efficacy of NanoVP as a PDT and a chemotherapy agent, and by supporting development of a zebrafish model of the blood-brain barrier (BBB) for mechanistic studies of improved drug delivery to the brain.Item Nanoparticle-assisted, image-guided laser interstitialthermal therapy for cancer treatment(Wiley, 2022-06-23) Pang, Sumiao; Kapur, Anshika; Zhou, Keri; Anastasiadis, Pavlos; Ballirano, Nicholas; Kim, Anthony J.; Winkles, Jeffrey A.; Woodworth, Graeme F.; Huang, Huang-ChiaoLaser interstitial thermal therapy (LITT) guided by magnetic resonance imaging (MRI) is a new treatment option for patients with brain and non-central nervous system (non-CNS) tumors. MRI guidance allows for precise placement of optical fiber in the tumor, while MR thermometry provides real-time monitoring and assessment of thermal doses during the procedure. Despite promising clinical results, LITT complications relating to brain tumor procedures, such as hemorrhage, edema, seizures, and thermal injury to nearby healthy tissues, remain a significant concern. To address these complications, nanoparticles offer unique prospects for precise interstitial hyperthermia applications that increase heat transport within the tumor while reducing thermal impacts on neighboring healthy tissues. Furthermore, nanoparticles permit the co-delivery of therapeutic compounds that not only synergize with LITT, but can also improve overall effectiveness and safety. In addition, efficient heat-generating nanoparticles with unique optical properties can enhance LITT treatments through improved real-time imaging and thermal sensing. This review will focus on (1) types of inorganic and organic nanoparticles for LITT; (2) in vitro, in silico, and ex vivo studies that investigate nanoparticles' effect on light–tissue interactions; and (3) the role of nanoparticle formulations in advancing clinically relevant image-guided technologies for LITT.Item Direct visualization of nanoparticle morphology in thermally sintered nanoparticle ink traces and the relationship among nanoparticle morphology, incomplete polymer removal, and trace conductivity(Institute of Physics, 2023-06-19) Chandel, Ghansham Rajendrasingh; Sun, Jiayue; Etha, Sai Ankit; Zhao, Beihan; Sivasankar, Vishal Sankar; Nikfarjam, Shakiba; Wang, Mei; Hines, Daniel R.; Dasgupta, Abhijit; Woehl, Taylor; Das, SiddarthaA key challenge encountered by printed electronics is that the conductivity of sintered metal nanoparticle (NP) traces is always several times smaller than the bulk metal conductivity. Identifying the relative roles of the voids and the residual polymers on NP surfaces in sintered NP traces, in determining such reduced conductivity, is essential. In this paper, we employ a combination of electron microscopy imaging and detailed simulations to quantify the relative roles of such voids and residual polymers in the conductivity of sintered traces of a commercial (Novacentrix) silver nanoparticle-based ink. High resolution transmission electron microscopy imaging revealed details of the morphology of the inks before and after being sintered at 150 °C. Prior to sintering, NPs were randomly close packed into aggregates with nanometer thick polymer layers in the interstices. The 2D porosity in the aggregates prior to sintering was near 20%. After heating at 150 °C, NPs sintered together into dense aggregates (nanoaggregates or NAgs) with sizes ranging from 100 to 500 nm and the 2D porosity decreased to near 10%. Within the NAgs, the NPs were mostly connected via sintered metal bridges, while the outer surfaces of the NAgs were coated with a nanometer thick layer of polymer. Motivated by these experimental results, we developed a computational model for calculating the effective conductivity of the ink deposit represented by a prototypical NAg consisting of NPs connected by metallic bonds and having a polymer layer on its outer surface placed in a surrounding medium. The calculations reveal that a NAg that is 35%–40% covered by a nanometer thick polymeric layer has a similar conductivity compared to prior experimental measurements. The findings also demonstrate that the conductivity is less influenced by the polymer layer thickness or the absolute value of the NAg dimensions. Most importantly, we are able to infer that the reduced value of the conductivity of the sintered traces is less dependent on the void fraction and is primarily attributed to the incomplete removal of the polymeric material even after sintering.Item Self-assembly of immune signals to program innate immunity through rational adjuvant design(Wiley, 2022-11-14) Bookstaver, Michelle L.; Zeng, Qin; Oakes, Robert S.; Kapnick, Senta M.; Saxena, Vikas; Edwards, Camilla; Venkataraman, Nishedhya; Black, Sheneil K.; Zeng, Xiangbin; Froimchuk, Eugene; Gebhardt, Thomas; Bromberg, Jonathan S.; Jewell, Christopher M.Recent clinical studies show activating multiple innate immune pathways drives robust responses in infection and cancer. Biomaterials offer useful features to deliver multiple cargos, but add translational complexity and intrinsic immune signatures that complicate rational design. Here a modular adjuvant platform is created using self-assembly to build nanostructured capsules comprised entirely of antigens and multiple classes of toll-like receptor agonists (TLRas). These assemblies sequester TLR to endolysosomes, allowing programmable control over the relative signaling levels transduced through these receptors. Strikingly, this combinatorial control of innate signaling can generate divergent antigen-specific responses against a particular antigen. These assemblies drive reorganization of lymph node stroma to a pro-immune microenvironment, expanding antigen-specific T cells. Excitingly, assemblies built from antigen and multiple TLRas enhance T cell function and antitumor efficacy compared to ad-mixed formulations or capsules with a single TLRa. Finally, capsules built from a clinically relevant human melanoma antigen and up to three TLRa classes enable simultaneous control of signal transduction across each pathway. This creates a facile adjuvant design platform to tailor signaling for vaccines and immunotherapies without using carrier components. The modular nature supports precision juxtaposition of antigen with agonists relevant for several innate receptor families, such as toll, STING, NOD, and RIG.Item 3D ENGINEERING OF VIRUS-BASED PROTEIN NANOTUBES AND RODS: A TOOLKIT FOR GENERATING NOVEL NANOSTRUCTURED MATERIALS(2018) Brown, Adam Degen; Culver, James N; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Technological innovation at the nanometer scale has the potential to improve a wide range of applications, including energy storage, sensing of environmental and medical signals, and targeted drug delivery. A key challenge in this area is the ability to create complex structures at the nanometer scale. Difficulties in meeting this challenge using traditional fabrication methods have prompted interest in biological processes, which provide inspiration for complex structural organization at nanometer to micrometer length scales from self-assembling components produced inexpensively from common materials. From that perspective, a system of targeted modifications to the primary amino acid structure of Tobacco mosaic virus (TMV) capsid protein (CP) has been developed that induces new self-assembling behaviors to produce nanometer-scale particles with novel architectures. TMV CPs contain several negatively charged carboxylate residues which interact repulsively with those of adjacent CP subunits to destabilize the assembled TMV particle. Here, the replacement of these negatively charged carboxylate residues with neutrally charged or positively charged residues results in the spontaneous assembly of bacterially expressed CP into TMV virus-like particles (VLPs) with a range of environmental stabilities and morphologies and which can be engineered to attach perpendicularly to surfaces and to display functional molecular patterns such as target-binding peptide chains or chemical groups for attachment of functional targets. In addition, the distinct electrostatic surface charges of these CP variants enable the higher-level coassembly of TMV and VLP into continuous rod-shaped nanoparticles with longitudinally segregated distribution of functionalities and surface properties. Furthermore, the unique, novel, environmentally responsive assembly and disassembly behaviors of the modified CPs are shown to act as simple mechanisms to control the fabrication of these hierarchically structured functional nanoparticles.Item Development of Nanoparticle-Based Intracellular Dual Sensing and Actuation Modalities(2017) Field, Lauren D.; White, Ian M; Medintz, Igor L; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)The integration of therapeutics with diagnostic agents, or theranostics, is vital for the development of novel and effective disease treatments. To effectively design new and efficient theranostic materials, a thorough understanding of the carrier ensemble, the interactions within the construct components, and the surrounding environment is required. This dissertation focuses on the development of new strategies to produce an effective ‘toolbox’ of nanoscale theranostics, namely through the use of a central NP scaffold and the visualization technique of Förster Resonance Energy Transfer (FRET). The NP scaffold used throughout this work, the semiconductor quantum dot (QD), is ideal for visualizing sensing modalities due to their high quantum yield (QY), tunable, narrow and symmetric emission profiles with broad, far-UV excitation, and resistance to photobleaching - making them optimal FRET donors. We first examined the intracellular assembly of QDs to proteins by injecting 545 nm emitting QDs, coated with various capping ligands, into cells transfected to express mCherry at two distinct intracellular locations: the cytosol and the plasma membrane. We found that the small, zwitterionic capping ligand CL4 and the cytosolically located mCherry protein assembled into the most efficient FRET complexes. We used this knowledge to design and implement a novel intracellular actuation modality for drug delivery that used a 520 nm emitting QD with the carrier maltose binding protein appended to the surface and carrying drug or dye conjugated to a maltose analog, -cyclodextrin in the binding pocket. Rather than relying on intracellular environmental changes or external stimuli to actuate release, the addition of the innocuous sugar maltose to the medium induced cargo actuation and could be visualized via FRET. Finally, the same methods were implemented to develop a novel pH sensor to report on the extracellular changes that occur in tumor development where the physiological pH is lowered dramatically. Using a 464 nm QD scaffold conjugated to pH-responsive FITC, we successfully monitored changes in extracellular pH and accurately determined unknown pH values. With the work in this thesis, we believe we have contributed greatly to the advancement and development NPs for the design and implementation of sensing and actuation complexes.Item PHYSICAL CHARACTERIZATION OF DNA CONDENSED WITH CATIONIC AGENTS(2016) Salgado, Eddy; Briber, Robert M; Material Science and Engineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Gene therapy using non viral vectors remains a challenging problem of maximizing efficiency while minimizing risks due to the multiple biological hurdles for a carrier agent to deliver its genetic cargo. The precise connection between the physical properties of the vectors and their transfection behaviors remains to be fully realized. We have used atomic force microscopy as well as dynamic light scattering and zeta potential measurements in order to image and characterize DNA complexes with polyethylenimine (PEI), histidine-lysine (HK) peptide, and triethylenetetramine (TETA)-functionalized gold nanoparticles. The resulting complex structures are analyzed as a function of amine to phosphate (N/P) ratios and as a function of sample preparation protocols. This work aims to not only characterize these specific complexes, but to aid in the general understanding of complex formation and how it relates to transfection observations to promote a more rational design of future gene delivery agents.Item Novel Interactions of Liquid Crystals with Coated Nanoparticles(2013) Taylor, Jefferson; Martinez-Miranda, Luz J; Material Science and Engineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Functionalized nanoparticles have a wide range of applications in liquid crystal systems, including displays, photovoltaics, and drug delivery. We need to understand the interactions between the nanoparticles and the liquid crystal molecules in order to utilize them fully and safely. We investigate the short-range interaction of coated nanoparticles with a liquid crystal membrane or bulk sample through the use of atomic force microscopy (AFM) and X-ray scattering techniques. We identify the role the functionalization plays in the phase behavior of the liquid crystal both as a thin film and in bulk. Our research produced three results. We identify differing behavior in thin film samples of liquid crystal and coated nanoparticles dependent upon particle functionalization using AFM. Using X-ray scattering we measure the alignment and smectic layer formation in the presence of coated nanoparticles, even above the smectic-A to nematic transition temperature. We find evidence of a "halo" that forms around coated nanoparticles, particularly with longer coating molecules.Item Research and Development of Liquid Phase Epitaxy Grown Iron Garnet Thin Films Utilizing Plasmon Resonances for Enhancement of Magneto-Optic Effects(2013) Lang, Garrett Seth; Mayergoyz, Isaak D; Electrical Engineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Plasmon resonance induced Faraday rotation enhancement in garnet films offers the promise for development of compact and higher performance polarization dependent optical devices. Enhancement of Faraday rotation has been achieved utilizing strong localized electric fields induced by the excitation of plasmon resonances in gold nanoparticles deposited on or in garnets. Experimental results are presented that reveal strong Faraday rotation enhancement in bismuth-doped garnet films with gold nanoparticles incorporated in or on the epitaxial films. The strength of the enhancement is governed by the thickness of the garnet films, the dimensions and separations of the nanoparticle assemblies, and the relative ratio between the height of the nanoparticles and the thickness of the films. For samples with embedded nanoparticles, there have been noticeable effects on the magnetic properties of the films due to the presence of the embedded gold nanoparticles. The embedding of nanoparticles in the films can be practically utilized to control the local anisotropy of the films. Special efforts have been made to improve the growth process and produce sub-micron thick films with thicknesses around 200nm to ensure that the induced electric fields are uniformly spread over the thickness of the films. At this thickness, nanoparticles have been incorporated on the surface of the liquid phase epitaxy grown garnet films rather than embedded in the films due to the low growth rate necessary to grow these films. New techniques have been developed to improve the accuracy of Faraday rotation enhancement measurements. Faraday rotation enhancement as high as 110% has been observed for samples with nanoparticle assemblies incorporated on the surfaces of the films but the enhancement depends on a number of factors and can be substantially lower. Stronger enhancement can be obtained by increasing the nanoparticle height to film thickness ratio as well as increasing the relative spacing between nanoparticles.Item Electrospray-Differential Mobility Analysis of Bionanoparticles(2012) Guha, Suvajyoti; Zachariah, Michael R; Mechanical Engineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)The growth of the multibillion dollar bionanoparticle industry has spurred the development of new physical characterization methods. One such method, electrospray-differential mobility analysis (ES-DMA) constitutes an electrospray for aerosolization of bionanoparticles (such as viruses, gold-nanoparticles, proteins, nanoparticle-protein complexes) and an ion mobility method that operates at atmospheric conditions, and separates bionanoparticles spatially. This dissertation identifies some relevant "problem" areas for ES-DMA by reviewing selected applications. Some such problems are: proteins while passing through ES capillaries are found to interact with it and thus produce time dependent size distributions. Further, it is thought that adsorbed proteins may subsequently desorb and influence size distributions with the ES-DMA which may concomitantly affect quantification of aggregates. These artifacts are studied systematically and it is demonstrated that ES-DMA can quantify adsorption-desorption of complex protein mixtures at high shear rates. Further, it is shown that desorbing proteins do not have a significant effect on size distributions. Another artifact of the ES takes place during the aersolization process. Two units (called monomers) of a bionanoparticle may get encapsulated in the same ES droplet and upon drying of the droplet create artificial dimers thus affecting quantification with ES-DMA. Assuming Poisson distribution, this thesis provides a systematic approach that can be undertaken to eliminate this artifact. A third artifact arises from the low sensitivity of the DMA to size increase. When a ligand (for e.g. protein) adsorbs to a bionanoparticle it creates an increase in the size of the later, which can be used to quantify the amount of ligand adsorbed per bionanoparticle. As ligands can change conformations upon adsorption, using ES-DMA for such applications may be flawed. This issue has been identified and a solution has been provided by integrating a mass analyzer after the ES-DMA. After correcting for these artifacts, this dissertation delves into characterization of different types of bionanoparticles and demonstrates that ES-DMA has several advantages over other traditional techniques such as transmission electron microscopy, size exclusion chromatography, analytical ultracentrifugation, dynamic light scattering and plaque assay and thus has immense potential to become a process analytical technique in biomanufacturing environments.