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Timestamp: 2019-04-26 14:56:47+00:00

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You searched for +publisher:"University of Michigan" +contributor:("Kopelman, Raoul"). Showing records 1 – 30 of 49 total matches.
1. Nguyen, Khoi Tan. Studies of Interactions between Peptides/Proteins and Lipid Bilayers using Sum Frequency Generation Vibrational Spectroscopy.
▼ The orientation of peptides and proteins on surfaces can have drastic implications on the function of these interfacial molecules. Interfacial proteins and peptides can play crucial roles in biological applications and processes such as antimicrobial selectivity, membrane protein activity, biocompatibility, and biosensing performance. The α-helical and β-sheet structures are the most widely encountered secondary structures in peptides and proteins. The orientation of interfacial α-helical and β-sheet structure can be determined using a combination of linear and second order nonlinear optical vibrational spectroscopies, namely Attenuated Total Reflectance Fourier Transformation Infrared Spectroscopy (ATR-FTIR) and Sum Frequency Generation (SFG) vibrational spectroscopy. Here in this dissertation, orientation determination methods of the interfacial α-helical, 3-10 helical and β-sheet structures, using the combined ATR-FTIR and SFG spectroscopic techniques, have been systematically developed. SFG was used to probe multiple amide I vibrational modes, which are related to their respective molecular hyperpolarizability tensor components through the orientation of the studied secondary structures. By implementing the bond additivity model along with group theory, the molecular hyperpolarizability tensor was determined for the SFG active vibrational modes of the secondary structures from the calculated IR transition dipole moment and the Raman polarizability tensor. The SFG susceptibility ratio of the signals collected in different polarization combinations, together with polarized ATR-FTIR amide I signals, can be used to determine the orientation angles of the interfacial secondary structures being studied. As an illustration of the methodology, the orientations of magainin 2 (an α-helical peptide), Cytochrome b5 (an α-helical structure containing protein), tachyplesin I (a β-sheet peptide), at various interfaces were determined. Advisors/Committee Members: Chen, Zhan (committee member), Kopelman, Raoul (committee member), Ramamoorthy, Ayyalusamy (committee member), Xi, Chuanwu (committee member).
Nguyen, Khoi Tan. “Studies of Interactions between Peptides/Proteins and Lipid Bilayers using Sum Frequency Generation Vibrational Spectroscopy.” 2010. Doctoral Dissertation, University of Michigan. Accessed April 26, 2019. http://hdl.handle.net/2027.42/76024.
Nguyen, Khoi Tan. “Studies of Interactions between Peptides/Proteins and Lipid Bilayers using Sum Frequency Generation Vibrational Spectroscopy.” 2010. Web. 26 Apr 2019.
Nguyen KT. Studies of Interactions between Peptides/Proteins and Lipid Bilayers using Sum Frequency Generation Vibrational Spectroscopy. [Internet] [Doctoral dissertation]. University of Michigan; 2010. [cited 2019 Apr 26]. Available from: http://hdl.handle.net/2027.42/76024.
2. Shirakura, Teppei. Development of Drug-loaded Nanoparticles for Targeted Chemotherapy.
▼ Cancer is the second highest cause of death in the US, and chemotherapy is one of the common cancer therapies. In order to reduce side effects and avoid cancer’s resistance to antitumor drugs, we use nanoparticle (NP)-assisted chemotherapy. This strategy can selectively deliver high concentrations of antitumor drugs to the tumor area, because NPs can encapsulate antitumor drugs, target the tumor area by active and passive targeting mechanisms, and release the drugs inside the cancer cells. This work focuses on three aspects of such NPs: high loading with antitumor drugs, controlled release of antitumor drugs, and high cellular uptake by the NPs. As a model system, polyacrylamide-based NPs were loaded with cisplatin. The effects of functional groups in the NPs, and the effects of matrix densities, were evaluated in terms of the NPs’ drug-loading, their release profile, and their cellular uptake. The carboxyl-functionalized NPs achieved 2 times higher loading and faster release of cisplatin than the amine-functionalized NPs. In contrast, the amine-functionalized NPs had 3.5 times better cellular uptake than the carboxyl-functionalized NPs. Tuning the matrix density of those NPs could control the release of cisplatin. Also, cisplatin-loaded, temperature-responsive NPs were synthesized so as to incorporate a trigger for cisplatin release in the cancer cells. The elevated temperature successfully enhanced the release of cisplatin from the synthesized NPs, especially under acidic conditions simulating lysosomes, which were the destination of the NPs inside the cells. Also, the in vitro cytotoxicity of the NPs is accelerated at high temperature. Finally, polyethylenimine (PEI) was incorporated into cisplatin-loaded PAA-NPs. Incorporation of PEI enhanced the cellular uptake of the PAA NPs 7 times, and resulted in significantly higher cytotoxicity. Other properties of these NPs, such as enhanced loading, enhanced release, and endosomal escape may contribute to their higher cytotoxicity. These results confirmed the importance of the following three factors when designing NPs for NP-assisted chemotherapy: (1) high loading with antitumor drugs, (2) controlled release of antitumor drugs, and (3) high cellular uptake of the NPs. Advisors/Committee Members: Kopelman, Raoul (committee member), Castro, Maria (committee member), Veatch, Sarah (committee member), Gafni, Ari (committee member).
Shirakura, Teppei. “Development of Drug-loaded Nanoparticles for Targeted Chemotherapy.” 2015. Doctoral Dissertation, University of Michigan. Accessed April 26, 2019. http://hdl.handle.net/2027.42/111622.
Shirakura, Teppei. “Development of Drug-loaded Nanoparticles for Targeted Chemotherapy.” 2015. Web. 26 Apr 2019.
Shirakura T. Development of Drug-loaded Nanoparticles for Targeted Chemotherapy. [Internet] [Doctoral dissertation]. University of Michigan; 2015. [cited 2019 Apr 26]. Available from: http://hdl.handle.net/2027.42/111622.
3. Hurst, Tamiika Kache. Development Of A Novel Protein Sensor For The Intracellular imaging of Zinc.
▼ Zinc is the second most abundant transition metal in the human body. In recent years, research on zinc homeostasis in mammalian cells has revealed distinct pools of zinc. Zinc is tightly bound to metalloproteins as a cofactor or structural component including metallothioneins that may provide a specific labile pool of zinc. The zinc-binding protein, Carbonic Anhydrase II (CA(II)) can be compartmentalized in intracellular organelles such as lysosomes, endosomes, endoplasmatic reticulum, mitochondria and the Golgi apparatus or in specialized organelles like synaptic vesicles and secretory granules. However, the concentration of “free” zinc inside cells is estimated to be at or below thepicomolar level. Disruption of cellular Zn2+ homeostasis is implicated in several major disorders including Alzheimer's disease, diabetes, and cancer. The molecular mechanisms of Zn2+ physiology and pathology are insufficiently understood, owing in part to the lack of tools for measuring changes in intracellular Zn2+ concentrations with high spatial and temporal fidelity. To address this critical need, we have designed, characterized, and applied an intracellular protein-based sensor expressed in BL21(DE3) cells for the ratiometric imaging of Zn2+ based on the carbonic anhydrase (CA(II)) platform. FRET excitation ratiometric detection of intracellular Zn2+ occurs through Zn2+- mediated energy transfer between dapoxylsulfonamide (Dps) bound to carbonic anhydrase and the fluorescent protein, mCherry fused to the C-termini of (CA(II)). The series of probes developed are expressible in various cell types, feature visible excitation and emission profiles, and show excellent selectivity responses for Zn2+ at intracellular concentrations. Furthermore, the ratio of the binding affinity for Zn2+/Cu2+ can be varied by mutations at Q92 and T199. We demonstrate the value of the (CA(II))_mCherry sensor for biological applications by imaging induced changes in intracellular [Zn2+] in E. coli..	We anticipate that (CA(II))_mCherry and related probes will prove useful for elucidating the biology of Zn2+ in a number of in vivo processes. Advisors/Committee Members: Fierke, Carol (committee member), Kopelman, Raoul (committee member), Matzger, Adam J. (committee member), Meyerhoff, Mark E. (committee member), Philbert, Martin A. (committee member).
Hurst, Tamiika Kache. “Development Of A Novel Protein Sensor For The Intracellular imaging of Zinc.” 2010. Doctoral Dissertation, University of Michigan. Accessed April 26, 2019. http://hdl.handle.net/2027.42/78843.
Hurst, Tamiika Kache. “Development Of A Novel Protein Sensor For The Intracellular imaging of Zinc.” 2010. Web. 26 Apr 2019.
Hurst TK. Development Of A Novel Protein Sensor For The Intracellular imaging of Zinc. [Internet] [Doctoral dissertation]. University of Michigan; 2010. [cited 2019 Apr 26]. Available from: http://hdl.handle.net/2027.42/78843.
4. Orozco, Michael B. Temperature-Dependent Studies of Condensed Phase Reaction Dynamics.
▼ Transient absorption spectroscopy was used to perform temperature-dependent studies of the reaction dynamics of cis-1,3,5-hexatriene (Z-HT), 7-dehydrocholesterol (DHC) and iso-bromoiodomethane (iso-CH2BrI) in various solvents. The activation barrier for the ground-state isomerization of cZt-1,3,5-hexatriene to tZt-1,3,5-hexatriene was measured in methanol/propanol (17.4 ± 2.4 kJ/mol), and in cyclohexane/hexadecane (23.5 ± 2.5 kJ/mol). It was found to be independent of which alcohol or alkane was used but dependent on solvent type. Calculations to replicate experimental results were performed in Gaussian 03. In methanol the calculations accurately predicted the barrier height within the error bars of the measurement, while in cyclohexane the calculated results were lower than experimental results. The discrepancy suggested that a more complex calculation was needed in order to explain the experimental results. The decay of the excited-state absorption (ESA) of DHC was studied in methanol, ethanol, 1-propanol, 1-butanol, 2-butanol, n-heptane and n-hexadecane. The decay of the ESA is biexponential, with a fast component of ca. 0.4 – 0.65 ps and a slow component 1.0 - 1.8 ps depending on the solvent. The relative amplitudes are also influenced by the solvent. Temperature dependent results suggested an intrinsic intramolecular barrier to ring-opening and a solvent dependent barrier arising from friction of the environment on the reaction coordinate. The low viscosity solvents set an upper limit for the intrinsic barrier of ca. 4 kJ/mol. A more complete analysis suggests that the intrinsic barrier is ca. 2 kJ/mol The decay of iso-CH2Br—I was studied in 1-butanol, 2-butanol, methanol and acetonitrile. The results are interpreted using a model consisting of a bimolecular reaction between iso-CH2Br-I and CH2BrI and a solvent-assisted unimolecular decay. Rate constants are calculated for the diffusion-controlled bimolecular reaction using three approximations for the diffusion coefficient of the solute particles. Comparison of calculated and measured values suggested that at ≤135 mM, iso-CH2Br – I decays primarily through a solvent-assisted isomerization in 2-butanol and ≥135 mM the decay is dominated by a diffusion-limited bimolecular collision with another species in 1-and 2-butanol. In methanol and acetonitrile, the decay is presumed to be a bimolecular reaction between contact-pairs and is essentially temperature independent. Advisors/Committee Members: Sension, Roseanne J. (committee member), Dunietz, Barry (committee member), Geva, Eitan (committee member), Kopelman, Raoul (committee member), Steel, Duncan G. (committee member).
Orozco, Michael B. “Temperature-Dependent Studies of Condensed Phase Reaction Dynamics.” 2011. Doctoral Dissertation, University of Michigan. Accessed April 26, 2019. http://hdl.handle.net/2027.42/84445.
Orozco, Michael B. “Temperature-Dependent Studies of Condensed Phase Reaction Dynamics.” 2011. Web. 26 Apr 2019.
Orozco MB. Temperature-Dependent Studies of Condensed Phase Reaction Dynamics. [Internet] [Doctoral dissertation]. University of Michigan; 2011. [cited 2019 Apr 26]. Available from: http://hdl.handle.net/2027.42/84445.
5. Kinnunen, Paivo. Asynchronous Magnetic Bead Rotation (AMBR) for Biosensors.
▼ As antibiotic resistance of pathogenic bacteria is now a declared global threat, dubbed by the US Centers for Disease Control (CDC) as one of the most pressing public health problems worldwide, faster, growth-based methods are needed to be able to treat infections more effectively. Here we present the latest developments in the Asynchronous Magnetic Bead Rotation (AMBR) biosensor toward this goal. Asynchronous rotation of a magnetic bead in a fluid occurs when a rotating magnetic field exceeds a critical driving frequency. The frequency of the asynchronously rotating magnetic bead is a linear function of its volume, as well as of the fluid’s viscosity, and can therefore be used as a volumetric sensor. These sensors, called here Asynchronous Magnetic Bead Rotation (AMBR) sensors, were first used for bio-applications in 2007. This dissertation shows the development of various aspects of the AMBR biosensor: (1) the effect of the sensor’s frequency on its sensitivity of detection is investigated, (2) an AMBR sensor is optimized for measuring the growth of individual bacterial (E. coli) cells, achieving an 80 nm sensitivity to the cell length, (3) an off-the-microscope method for the observation of AMBR sensor signals is demonstrated, and (4) self-assembled AMBR sensors are developed for potentially rapid and scalable antibiotic susceptibility testing of bacteria. AMBR offers a simple and robust method for translating nanoscale volumetric changes into easily measurable frequency changes. It is a platform technology applicable to a multitude of high resolution volumetric and viscosity measurements, one of the primary applications being in healthcare: bacterial growth can be measured even on the single cell level. Due to AMBR biosensors high sensitivity, the bacterial resistance to antimicrobials can be rapidly determined. The resistance was determined within one hour for a clinical E. coli isolate, potentially leading to faster information on what would be the appropriate therapy for the specific case/patient. Advisors/Committee Members: Kopelman, Raoul (committee member), Clarke, Roy (committee member), Doering, Charles R. (committee member), Hunt, Alan J. (committee member), Orr, Bradford G. (committee member).
Kinnunen, Paivo. “Asynchronous Magnetic Bead Rotation (AMBR) for Biosensors.” 2011. Doctoral Dissertation, University of Michigan. Accessed April 26, 2019. http://hdl.handle.net/2027.42/86488.
Kinnunen, Paivo. “Asynchronous Magnetic Bead Rotation (AMBR) for Biosensors.” 2011. Web. 26 Apr 2019.
Kinnunen P. Asynchronous Magnetic Bead Rotation (AMBR) for Biosensors. [Internet] [Doctoral dissertation]. University of Michigan; 2011. [cited 2019 Apr 26]. Available from: http://hdl.handle.net/2027.42/86488.
6. Kochi, Akiko. Development of Small Molecules to Target and Modulate Multiple Factors in the Neuropathogenesis of Alzheimer's Disease.
▼ Alzheimer’s disease (AD) is one of the leading cause of death; being the only cause to have increased attribution to death necessitates the understanding of its etiology. Several pathological features, including accumulation of misfolded proteins (i.e., amyloid-β; Aβ), metal ion dyshomeostasis, and loss of acetylcholine (ACh) neurotransmission, are suggested in AD pathogenesis. Current AD therapeutics focus on inhibition of acetylcholinesterase (AChE) for mitigating ACh breakdown. Extensive studies indicate a potential interconnection between Aβ and metal ions (i.e., Cu2+/Zn2+) as well as between Aβ and AChE. Aforementioned factors or their inter-relationships in neuropathogenesis are unclear, however. To understand the correlation between these factors, efforts have been made toward the development of small molecules as chemical tools, capable of targeting them and subsequently regulating their reactivity. For such purposes, in this thesis, diphenylpropynone (DPP; Aβ imaging probe) derivatives, bioapplicable molecules (i.e., curcumin, in curry and enediyne, framework used in cancer research), as well as a multifunctional hybrid molecule (hybrid 5) were developed and investigated toward their targets. DPP derivatives are observed to interact with Aβ species and metal ions. The bifunctionality (Aβ interaction and metal chelation) of these derivatives is able to influence the reactivity (metal-induced Aβ aggregation) of metal-associated Aβ (metal–Aβ) species in vitro. The GdIIIDTPA-curcumin conjugate, a synthesized, Aβ specific MRI agent, is also found to target metal–Aβ species and modulate metal-triggered Aβ aggregation. This study presents the potential to develop a theranostic (diagnostic and therapeutic) agent all-in-one. The enediyne derivative, with its proclivity to generate radicals, is shown to target metal–Aβ species and control the Aβ aggregation possibly via multiple properties (i.e., metal chelation, Aβ interaction, radical generation). Lastly, hybrid 5 interacts with various targets (Aβ, metals, and AChE), is able to inhibit AChE activity with and without Aβ and metals, and modulate metal-induced Aβ aggregation in the absence and presence of AChE. Through this finding, the feasibility of designing a single molecule for multiple functions was indicated. Taken together, the presented studies demonstrate the development of small molecules as chemical tools that can be used to understand the involvement of multiple factors in AD pathogenesis. Advisors/Committee Members: Lim, Mi Hee (committee member), Nikolovska-Coleska, Zaneta (committee member), Kuroda, Kenichi (committee member), Kopelman, Raoul (committee member).
Kochi, Akiko. “Development of Small Molecules to Target and Modulate Multiple Factors in the Neuropathogenesis of Alzheimer's Disease.” 2014. Doctoral Dissertation, University of Michigan. Accessed April 26, 2019. http://hdl.handle.net/2027.42/107244.
Kochi, Akiko. “Development of Small Molecules to Target and Modulate Multiple Factors in the Neuropathogenesis of Alzheimer's Disease.” 2014. Web. 26 Apr 2019.
Kochi A. Development of Small Molecules to Target and Modulate Multiple Factors in the Neuropathogenesis of Alzheimer's Disease. [Internet] [Doctoral dissertation]. University of Michigan; 2014. [cited 2019 Apr 26]. Available from: http://hdl.handle.net/2027.42/107244.
7. Zhang, Chi. The Development and Applications of Nonlinear Vibrational Spectroscopy for Material and Biological Studies.
▼ Nonlinear vibrational spectroscopy has been extensively developed and has found important applications in recent years. As a label free technique, vibrational spectroscopy has great advantages in material science, analytical chemistry and biological engineering. The theoretical and technical development, as well as application approaches in nonlinear vibrational spectroscopy can help to push this field towards a more prosperous future. The goal of this thesis is to demonstrate my personal contributions in these three directions of nonlinear vibrational spectroscopy. We mainly focused on a second order nonlinear spectroscopy sum frequency generation (SFG), and a third order nonlinear spectroscopy coherent anti-Stokes Raman scattering (CARS), supplemented by a linear attenuated total-internal reflection Fourier transformation IR (ATR-FTIR) spectroscopy and other techniques. The research focus of this thesis can be summarized in four parts: (1) the applications of SFG spectroscopy in understanding interfacial molecular structures of various adhesive materials, more specifically silicone and epoxy adhesives, to elucidate their adhesion mechanisms to different substrates; (2) the applications of SFG spectroscopy supplemented by ATR-FTIR spectroscopy for studying lipid dynamics in supported lipid bilayers used to mimic biological membranes, as well as elucidating cytotoxicity mechanisms of a certain polyelectrolyte; (3) the technical development of new analytical platforms to integrate SFG spectroscopy with other optical techniques (including CARS, optical microscopy or total-internal reflection fluorescence (TIRF) microscopy) for multimodal sample studies; (4) the quantitative interpretation of the spectral measurements in CARS spectroscopy with the help of bond additivity method and Raman depolarization ratio, which has significance in quantitative spectral analysis in modern CARS spectroscopy and microscopy. The theoretical advancement, technical development and extensive applications of SFG and CARS spectroscopy demonstrated in this thesis can help to improve nonlinear spectroscopy to be a more powerful and versatile tool in material science, biology, or other industry-driven interdisciplinary fields. Advisors/Committee Members: Chen, Zhan (committee member), Deng, Hui (committee member), Kopelman, Raoul (committee member), Kubarych, Kevin J. (committee member).
Zhang, Chi. “The Development and Applications of Nonlinear Vibrational Spectroscopy for Material and Biological Studies.” 2014. Doctoral Dissertation, University of Michigan. Accessed April 26, 2019. http://hdl.handle.net/2027.42/109058.
Zhang, Chi. “The Development and Applications of Nonlinear Vibrational Spectroscopy for Material and Biological Studies.” 2014. Web. 26 Apr 2019.
Zhang C. The Development and Applications of Nonlinear Vibrational Spectroscopy for Material and Biological Studies. [Internet] [Doctoral dissertation]. University of Michigan; 2014. [cited 2019 Apr 26]. Available from: http://hdl.handle.net/2027.42/109058.
8. Donehue, Jessica Erin. Plasmon-Enhanced Fluorescent Protein Emission: A New Paradigm for Improved Single-Molecule Bio-Imaging.
▼ Single-molecule fluorescence (SMF) microscopy is a powerful technique that provides high sensitivity and nanometer-scale resolution for biological imaging. The emission profile of an isolated fluorescent molecule allows the emitter position to be determined on a scale far smaller than the standard diffraction limit of light with a precision that improves with the number of detected photons. While in vitro implementations of SMF have achieved 1.5-nm localization precisions, an outstanding problem in the field is to improve the resolution of SMF imaging in live cells; this has been generally limited to 10 – 40 nm. The main problem is technological: fluorescent proteins (FPs), the genetically encodable labels widely used for biological imaging, are dimmer and shorter lived than the organic dyes employed in vitro. Increasing FP brightness and photostability will significantly improve the precision with which these fluorescent probes are localized in vivo down to a few nanometers, as well as increase average trajectory length for single-particle tracking, and these advances will enable studies of intracellular processes on the molecular scale. In this Thesis, we use SMF microscopy to characterize fluorescence and attain super-resolution images, and we demonstrate that nanoparticle plasmonics can improve both the brightness and photostability of FPs. The localized surface plasmon mode, or collective oscillation of free electrons, produces a highly enhanced field in the near field of a metal nanostructure. Here, by positioning FPs in the near field of gold nanorods via adsorption or immobilization, we use this coupling to more than double the emission rate of the red FP mCherry, and determine that coupled molecules of the photo-activatable FP PAmCherry emit three times more photons prior to photobleaching. We then extend our methods to in vivo experiments, in which gold nanotriangle arrays serve as extracellular imaging substrates to enhance the emission from membrane-bound proteins in live bacterial cells. Finally, we demonstrate selective excitation of the longitudinal mode of gold nanorods using polarization, and consequently tune the amount of plasmon-enhanced emission observed. The work in this Thesis demonstrates the power of plasmon-enhanced single-molecule fluorescence to strongly impact the bio-imaging field, with implications for human health and disease. Advisors/Committee Members: Biteen, Julie Suzanne (committee member), Ogilvie, Jennifer P. (committee member), Kopelman, Raoul (committee member), Maldonado, Stephen (committee member).
Donehue, Jessica Erin. “Plasmon-Enhanced Fluorescent Protein Emission: A New Paradigm for Improved Single-Molecule Bio-Imaging.” 2014. Doctoral Dissertation, University of Michigan. Accessed April 26, 2019. http://hdl.handle.net/2027.42/110406.
Donehue, Jessica Erin. “Plasmon-Enhanced Fluorescent Protein Emission: A New Paradigm for Improved Single-Molecule Bio-Imaging.” 2014. Web. 26 Apr 2019.
Donehue JE. Plasmon-Enhanced Fluorescent Protein Emission: A New Paradigm for Improved Single-Molecule Bio-Imaging. [Internet] [Doctoral dissertation]. University of Michigan; 2014. [cited 2019 Apr 26]. Available from: http://hdl.handle.net/2027.42/110406.
9. Cipolla, Cynthia Marie. Development and Application of Analytical Techniques for Evaluating Function in Pancreatic Islets of Langerhans.
▼ Type 1 diabetes is caused by autoimmune destruction of insulin-secreting beta-cells found in the islets of Langerhans of the pancreas. Severe cases can be treated in a minimally invasive way by islet transplantation; however, islet transplantation has been limited by an inability to measure islet viability and potency prior to transplant. To address this need, we have developed a microfluidic platform to measure both intracellular calcium flux and insulin secretion, two important indicators of beta-cell function, at high temporal resolution during glucose treatment. Combining these measures on islets required methods for measuring fluorescence at two separate locations on a microfluidic system. To accomplish this objective, we used a 2-chip system in which perfusate was collected in fractions while intracellular calcium was measured using fluorescence imaging. The perfusate was subsequently analyzed for insulin by microchip electrophoresis with laser-induced fluorescence detection (MCE-LIF) using the same fluorescence microscope. We were able to distinguish first and second phase insulin secretion from batches of 8-10 islets with 80 s temporal resolution. Measured basal and peak first phase insulin secretion correlated well with previously reported results. Total analysis time using this system was <90 min. For an alternative approach to islet evaluation, we developed a metabolomic method to identify potential biomarkers of islet health for transplant. Using a miniaturized sample preparation method and HPLC-TOF-MS, we were able to identify 62 metabolites reliably in whole islet samples. To mimic damage that can occur during islet transplant, we induced oxidative stress in islets using hydrogen peroxide and measured their immediate metabolomic response as well as their response 1-4 h following stress removal. Increased concentrations of pentose phosphates, glucose-6-phosphate, and fructose bisphosphate in the immediate response corresponded to glycolysis blockage and possibly increased flux through the pentose phosphate pathway. Post-stress responses included increased levels of free fatty acids, phospholipids, long chain CoAs, and HMG-CoA as well blunted malonyl CoA concentrations, potentially relating to alterations in the glycerolipid/free fatty acid cycle and mevalonate pathway. These metabolites could comprise a metabolic signature of stressed cells for islet evaluation prior to transplantation. Advisors/Committee Members: Kennedy, Robert T. (committee member), Satin, Leslie (committee member), Kopelman, Raoul (committee member), Meyerhoff, Mark E. (committee member).
Cipolla, Cynthia Marie. “Development and Application of Analytical Techniques for Evaluating Function in Pancreatic Islets of Langerhans.” 2015. Doctoral Dissertation, University of Michigan. Accessed April 26, 2019. http://hdl.handle.net/2027.42/113374.
Cipolla, Cynthia Marie. “Development and Application of Analytical Techniques for Evaluating Function in Pancreatic Islets of Langerhans.” 2015. Web. 26 Apr 2019.
Cipolla CM. Development and Application of Analytical Techniques for Evaluating Function in Pancreatic Islets of Langerhans. [Internet] [Doctoral dissertation]. University of Michigan; 2015. [cited 2019 Apr 26]. Available from: http://hdl.handle.net/2027.42/113374.
10. Cha, Kyoung Ha. Advances in Glucose Sensing Techniques: Novel Non-Invasive and Continuous Electrochemical Glucose Monitoring Systems.
▼ Diabetes mellitus (or diabetes) is a chronic, lifelong condition that affects the body's ability to utilize the stored chemical potential energy found in our food. Frequent measurement and tight control of blood glucose is essential to avoiding life-threatening hyper- and hypoglycemic events and associated serious, long-term complications. In this dissertation, a novel non-invasive tear glucose measurement approach and various continuous electrochemical glucose sensor-based monitoring devices with nitric oxide (NO) release are examined and evaluated for their potential application for diabetes management. Tear glucose measurements have been previously suggested as a potential alternative to blood glucose monitoring for diabetic patients, although this approach has not been thoroughly established. In Chapter 2, the first use of commercial blood glucose test strips to measure glucose in tears is examined. Roche AccuChek test strips are shown to exhibit the low detection limit required for quantitating glucose concentration in tears. Measurements of glucose in tears from nine normal (nondiabetic) fasting human subjects using strips yielded glucose values within the range of 5–148 μM, similar to glucose measurements for human tears reported by others via LC-MS methods. Chapter 3 evaluates the origin of the high sensitivity and selectivity of the Roche test strips and demonstrates that the use of pyrroloquinoline quinone (PQQ)-dependent glucose dehydrogenase (GDH) in combination with a nitrosoaniline derivative as an electron transfer mediator provides the low limits of quantitation (ca. 9 µM) and enhanced selectivity achieved with these strips. In Chapter 4, the test strips are used to measure glucose levels in tear fluids from human subjects with type 2 diabetes after fasting and then for 90 min after ingesting sugar while concurrently measuring the blood glucose values. A moderate correlation between tear and blood glucose levels is demonstrated. Tight glycemic control helps reduce life-threatening hyper- and hypoglycemic events that can cause serious long-term complications for hospitalized critically ill patients. Therefore, the development of continuous glucose monitoring systems to quantitate blood glucose levels intravascularly (IV) could improve patient outcomes. In Chapter 5, the compatibility of nitric oxide (NO) release coatings with implantable enzymatic glucose sensors based on osmium (III/II) mediated electrochemical detection is examined for the first time. Nitric oxide (NO) is a potent inhibitor of platelet activation and adhesion. NO-releasing osmium-mediated glucose sensors are prepared using a S-nitrosothiol impregnated outer tubing and are tested in vitro in both phosphate buffer (pH 7.4) and heparinized whole porcine blood. After 3 days of continuous NO release at or above physiological levels, no negative effects on the osmium mediated electrochemical currents are observed. These results suggest that improved performance of both intravascular and, potentially, subcutaneous Os(III/II) mediated… Advisors/Committee Members: Meyerhoff, Mark E (committee member), Lee, Kyung-Dall (committee member), Daniels, Rodney (committee member), Kopelman, Raoul (committee member), Maldonado, Stephen (committee member).
Cha, Kyoung Ha. “Advances in Glucose Sensing Techniques: Novel Non-Invasive and Continuous Electrochemical Glucose Monitoring Systems.” 2018. Doctoral Dissertation, University of Michigan. Accessed April 26, 2019. http://hdl.handle.net/2027.42/144018.
Cha, Kyoung Ha. “Advances in Glucose Sensing Techniques: Novel Non-Invasive and Continuous Electrochemical Glucose Monitoring Systems.” 2018. Web. 26 Apr 2019.
Cha KH. Advances in Glucose Sensing Techniques: Novel Non-Invasive and Continuous Electrochemical Glucose Monitoring Systems. [Internet] [Doctoral dissertation]. University of Michigan; 2018. [cited 2019 Apr 26]. Available from: http://hdl.handle.net/2027.42/144018.
11. Smith, Broc D. Ultrafast Optical Control of Ring-Opening and Isomerization in 7-Dehydrocholesterol and Stilbene.
▼ 7-dehydrocholesterol and stilbene are model systems for the molecules used within the fast-growing field of molecular motors and switches. One of the significant problems facing the development of effective motors and switches is the quantum yield of the photoisomerization reactions that these materials undergo. This dissertation describes the use of optical control methods to improve the yields of ring-opening and isomerization of 7-dehydrocholesterol and stilbene following UV excitation. The effects of both single-pulse and two-pulse control schemes using UV and visible excitation pulses were investigated. First, the dependence of the 7-dehydrocholesterol ring-opening on excess vibrational energy was studied by exciting with pump pulses tunable over a broad range of wavelengths. Based on these measurements, it appears that either the vibrational mode in which the excess energy is deposited does not play a role in the ring-opening reaction, or the excess energy is quickly dispersed to the remaining vibrational modes by intramolecular vibrational distribution. Next, the effect of chirp on the dynamics and photoproducts of 7-dehydrocholesterol and cis-stilbene was explored through the use of UV pump pulses with chirp between about 10000 fs2 and 10000 fs2. These experiments showed that there was no measurable change in the amount of photoproduct formed following excitation with these pulses. Finally, a two-pulse pump-repump design was used to first place a population of molecules into the lowest electronic excited state before re-exciting to an even higher state. This technique had little effect on the reaction dynamics of 7-dehydrocholesterol, but successfully modified the isomerization yield for both cis- and trans-stilbene. After the arrival of a visible repump pulse, cis-stilbene showed a small change in reaction dynamics, and the yield of trans-stilbene photoproduct was increased. Trans-stilbene showed a large depletion of the excited state population following repumping, and the yield of cis-stilbene photoproduct was increased. Trans-stilbene also demonstrated a distinct change in the recovery of the ground state population, indicating that the re-excited trans-stilbene molecules utilize a different decay pathway that bypasses the S1 state. These results show that a two-pulse excitation scheme may provide the means to modify the isomerization yield in stilbene based molecular motors. Advisors/Committee Members: Sension, Roseanne J (committee member), Ogilvie, Jennifer P (committee member), Kopelman, Raoul (committee member), Kubarych, Kevin J (committee member).
Smith, Broc D. “Ultrafast Optical Control of Ring-Opening and Isomerization in 7-Dehydrocholesterol and Stilbene.” 2015. Doctoral Dissertation, University of Michigan. Accessed April 26, 2019. http://hdl.handle.net/2027.42/116703.
Smith, Broc D. “Ultrafast Optical Control of Ring-Opening and Isomerization in 7-Dehydrocholesterol and Stilbene.” 2015. Web. 26 Apr 2019.
Smith BD. Ultrafast Optical Control of Ring-Opening and Isomerization in 7-Dehydrocholesterol and Stilbene. [Internet] [Doctoral dissertation]. University of Michigan; 2015. [cited 2019 Apr 26]. Available from: http://hdl.handle.net/2027.42/116703.
12. Lee, Chang. Utilization of Nanoparticles for Photoacoustic Chemical Imaging.
▼ Tumors are known to have unique chemical properties, such as low pH (acidosis), high K+ (hyperkalemia), and low O2 (hypoxia). Tumor acidosis has been known to influence therapeutic activities of chemotherapeutic drugs. Another conventional cancer treatment, radiation therapy, is highly dependent on local oxygen concentrations. Hyperkalemia has been recently reported to suppress the immune response of activated T-cells. It is also believed that the spatial distribution of these analytes and its heterogeneity, are of relevance. Despite the importance of such chemical information on tumors, there are no clinically available tools for “quantitative” pH, K+, or tissue O2 imaging. Here, photoacoustic (PA) imaging is employed to provide chemical imaging of all these target analytes for cancer (pH, O2 and K+). As for pH, we report on an in vivo pH mapping nanotechnology. This subsurface chemical imaging is based on tumor-targeted, pH sensing nanoprobes and multi-wavelength photoacoustic imaging (PAI). The nanotechnology consists of an optical pH indicator, SNARF-5F, 5-(and-6)-Carboxylic Acid, encapsulated into polyacrylamide nanoparticles with surface modification for tumor targeting. Facilitated by multi-wavelength PAI plus a spectral unmixing technique, the accuracy of pH measurement inside the biological environment is not susceptible to the background optical absorption of biomolecules, i.e., hemoglobins. As a result, both the pH levels and the hemodynamic properties across the entire tumor can be quantitatively evaluated with high sensitivity and high spatial resolution in in vivo cancer models. For K+, we extend this technique to ion-selective photoacoustic optodes (ISPAOs) that serve at the same time as fluorescence-based ISOs, and apply it specifically to potassium (K+). However, unfortunately, sensors capable of providing potassium images in vivo are still a future proposition. Here, we prepared an ion-selective potassium nanosensor (NS) aimed at in vivo photoacoustic (PA) chemical imaging of the extracellular environment, while being also capable of fluorescence based intracellular ion-selective imaging. This potassium nanosensor (K+ NS) modulates its optical properties (absorbance and fluorescence) according to the potassium concentration. The K+ NS is capable of measuring potassium, in the range of 1 mM to 100 mM, with high sensitivity and selectivity, by ISPAO based measurements. Also, a near infrared dye surface modified K+ NS allows fluorescence-based potassium sensing in the range of 20 mM to 1 M. The K+ NS serves thus as both PA and fluorescence based nanosensor, with response across the biologically relevant K+ concentrations, from the extracellular 5 mM typical values (through PA imaging) to the intracellular 150 mM typical values (through fluorescence imaging). Lastly, nano-enabled tissue O2 monitoring by PA, called lifetime-based PA (PALT) imaging, was introduced and demonstrated. A known PALT oxygen indicator, Oxyphor G2, is conjugated into polyacrylamide nanoparticles, called G2-PAA NP. The oxygen… Advisors/Committee Members: Kopelman, Raoul (committee member), Wang, Xueding (committee member), Sun, Duxin (committee member), Chen, Zhan (committee member), Kennedy, Robert T (committee member).
Lee, Chang. “Utilization of Nanoparticles for Photoacoustic Chemical Imaging.” 2018. Doctoral Dissertation, University of Michigan. Accessed April 26, 2019. http://hdl.handle.net/2027.42/143924.
Lee, Chang. “Utilization of Nanoparticles for Photoacoustic Chemical Imaging.” 2018. Web. 26 Apr 2019.
Lee C. Utilization of Nanoparticles for Photoacoustic Chemical Imaging. [Internet] [Doctoral dissertation]. University of Michigan; 2018. [cited 2019 Apr 26]. Available from: http://hdl.handle.net/2027.42/143924.
13. Karamchand, Leshern. Modulation of Signaling and Intracellular Trafficking Pathways by Surface-Engineered Hydrogel Nanoparticles in Tumor Cells.
▼ Surface engineering of a polyacrylamide (PAA) hydrogel nanoparticle (NP) with the tumor-targeting ligand, F3 peptide (KDEPQRRSARLSAKPAPPKPEPKPKKAPAKKC), confers binding specificity toward Nucleolin overexpressing tumor cells (9L rat gliosarcoma, and MDA-MB-435 human breast adenocarcinoma). In this study, the endocytic internalization, and intracellular trafficking of the non-targeted PAA-NPs (NTNPs), and F3-targeted PAA-NPs (F3NPs) in the above-mentioned cell lines, was investigated. Caveolae-mediated internalization of both types of PAA-NPs peaked at 2 hours post-delivery, although internalization of the NTNPs was ~2-fold greater than for the F3NPs. In contrast, clathrin-mediated internalization of both types of PAA-NPs was markedly faster; the NTNPs and F3NPs both reached similar peak colocalization levels with early endosome antigen-1 (EEA1, ~32%) at 30 minutes post-delivery. However, at 60 minutes post-delivery, the NTNPs exhibited faster egress from the early endosomes than the F3NPs, with a concomitant, sharp increase in trafficking to the lysosomes (acidic, degradative vesicles), whereas the F3NPs largely evaded trafficking to the lysosomes. Furthermore, the F3 peptides alone exhibited significantly higher accumulation within the lysosomes than both the NTNPs, and the F3NPs. The p38 Mitogen-Activated Protein Kinases (MAPKs), upon activation, promote (i) internalization of caveolae from the cell membrane, and (ii) rapid trafficking of early endosomes to the lysosomes by directly phosphorylating Caveolin1 and EEA1, respectively. Phospho-proteomic analyses, in MDA-MB-435 cells, revealed that the peak levels of activated p38β and p38δ MAPKs (at 2 hours post-delivery) elicited by the F3 peptides alone, and the NTNPs was ~2-fold greater than by the F3NPs. These data therefore provide compelling evidence that the intracellular trafficking behavior of the F3 peptides, NTNPs and F3NPs are attributable to their differential activation of the p38 MAPKs. Further analysis of the ERK MAPK, JNK MAPK, and Akt pathways revealed that the NTNPs elicit a pro-apoptotic signaling profile, whereas the F3 peptides, and F3NPs elicit proliferative profiles. The findings of this thesis suggest that the design of tumor-targeting nanoparticles also need to consider the MAPK signaling profiles that they elicit on the intended target cell type, due to the influence of the p38 MAPKs, in particular, on endocytic trafficking, and the survival status of the target tumor cell. Advisors/Committee Members: Kopelman, Raoul (committee member), Garcia, George A. (committee member), Glick, Gary D. (committee member), Gafni, Ari (committee member).
Karamchand, Leshern. “Modulation of Signaling and Intracellular Trafficking Pathways by Surface-Engineered Hydrogel Nanoparticles in Tumor Cells.” 2014. Doctoral Dissertation, University of Michigan. Accessed April 26, 2019. http://hdl.handle.net/2027.42/110348.
Karamchand, Leshern. “Modulation of Signaling and Intracellular Trafficking Pathways by Surface-Engineered Hydrogel Nanoparticles in Tumor Cells.” 2014. Web. 26 Apr 2019.
Karamchand L. Modulation of Signaling and Intracellular Trafficking Pathways by Surface-Engineered Hydrogel Nanoparticles in Tumor Cells. [Internet] [Doctoral dissertation]. University of Michigan; 2014. [cited 2019 Apr 26]. Available from: http://hdl.handle.net/2027.42/110348.
14. Hopkins, Thomas. Nanoconstructs for Advances in Photodynamic Therapy.
▼ Nanoparticle (NP) based systems have advanced the efficacy of treating cancer by enabling selective accumulation of drugs in tumors. Photodynamic therapy (PDT) is an exceptionally promising modality for its triple selectivity in treating cancer: requiring light, oxygen, and a photosensitizer (PS). The choice of a PS can become important not only for its absorption spectrum but also its relative aggression in causing oxidative stress; clinicians may prefer one PS over another depending on the type of response required to elicit optimal treatment. We show in Chapter 2 using polyacrylamide (PAAm) hydrogel NPs that chlorin e6 (Ce6) is a much more aggressive PDT agent than the classically applied methylene blue (MB). In addition to understanding the relative aggression of a PS in PDT, design of the NP is important to optimizing both the reactive oxygen species (ROS) producing capabilities and the means of effective delivery. Previously reported 8-arm polyethylene glycol amine (8PEGA) has been used to stop heart arrhythmia via PDT from conjugated Ce6. This NP is ideal for also targeting cancer due to the optimized ROS production, ease of changing targets, and its small size that would allow for deep tumor penetration in vivo. In Chapter 3, the tumor targeting peptide F3-cys was successfully grafted to 8PEGA-Ce6 and cancer cells efficiently ablated in vitro, demonstrating promise in translation to cancer in vivo. In addition, 8PEGA was shown to be a very promising diffusion weighted magnetic resonance (MR) imaging agent for cancer due to its long T2 lifetime and high molecular weight. 8PEGA may then potentially act as an efficient agent in MR of tumors in vivo without the use of toxic heavy metal atoms. Lastly, while NP-mediated PDT has been efficiently described in treating cancer and stopping heart arrhythmia, it may also be suitable to treating cancer-like diseases, such as choroidal neovascularization (CNV). In Chapter 4, the FDA-approved dyes indocyanine green (ICG) and the PS verteporfin (VP) were successfully encapsulated in pluronic micelles and shown to ablate cancer cells with low inherent toxicity. Given the cancer-like nature of CNV, NP-mediated PDT looks like a potential modality for treatment. The presented systems are effective in evaluation of their objectives and should further encourage clinical adoption of NPs for theranostics (PDT + imaging) by being simple to prepare, purify, and exceptionally biocompatible. Advisors/Committee Members: Kopelman, Raoul (committee member), Wang, Xueding (committee member), Biteen, Julie Suzanne (committee member), Goodson III, Theodore G (committee member).
Hopkins, Thomas. “Nanoconstructs for Advances in Photodynamic Therapy.” 2018. Doctoral Dissertation, University of Michigan. Accessed April 26, 2019. http://hdl.handle.net/2027.42/146108.
Hopkins, Thomas. “Nanoconstructs for Advances in Photodynamic Therapy.” 2018. Web. 26 Apr 2019.
Hopkins T. Nanoconstructs for Advances in Photodynamic Therapy. [Internet] [Doctoral dissertation]. University of Michigan; 2018. [cited 2019 Apr 26]. Available from: http://hdl.handle.net/2027.42/146108.
15. Curry, Taeyjuana Y. Nanoparticles for Biomedical Applications: Photothermal Therapy and Nuclear Delivery.
▼ Cancer is still a grand challenge faced by society today. Nanomedicine addresses many of the serious issues associated with conventional treatments. Nanoparticles (NPs) are advantageous for therapy because they are minimally invasive, have tunable characteristics and can be used as targeted and multifunctional treatment platforms. This thesis focuses on the use of both polymeric and gold NPs for photothermal therapy (PTT) of cancer cells, and describes the surface engineering of gold NPs for optimized, cell specific nuclear delivery. The first ever use of the FDA approved Coomassie Brilliant blue (CB) dye as a photosensitizer for PTT of cancer is detailed. The CB dye is covalently linked into the matrix of biologically compatible, hydrogel NPs. Also, a portable, inexpensive, low intensity LED is used as the light source. Incubation with moderate NP concentrations, combined with relatively low light levels, yielded nearly complete cell death within 3 hours of treatment. Another part of this dissertation research describes the stepwise surface engineering of specialty gold NPs for optimized delivery to cancer cell nuclei. These femtosecond laser ablation generated gold NPs have virgin surfaces to which cell-specific and nucleus-specific targeting peptides are directly attached. Efficient nuclear delivery was achieved using as little as 100pM of NPs solution, a concentration that is at least an order of magnitude lower than what has been previously reported in nuclear delivery studies involving gold NPs. The aforementioned nuclear-targeted gold NPs were also successfully utilized for PTT of cancer cells in vitro. A drastic difference in treatment efficacy was observed when the therapy was mediated by gold NPs delivered into the nucleus compared to when the NPs remained outside the nucleus. In the former case, the cell viability drops dramatically at early times and complete cell death is observed at six hours post-treatment. In the latter case, the viability decreases slowly over time and a maximum change of approximately 50% is observed 12 hours post-treatment. Overall this thesis provides several contributions to the field of Nanobiotechnology, through the presentation of highly effective, nanoparticle-mediated PTT. The latter can be easily incorporated into a multimodal approach for the treatment of cancer. Advisors/Committee Members: Kopelman, Raoul (committee member), Philbert, Martin A. (committee member), Orr, Bradford G. (committee member), Meiners, Jens-Christian (committee member), Goodson Iii, Theodore G. (committee member).
Curry, Taeyjuana Y. “Nanoparticles for Biomedical Applications: Photothermal Therapy and Nuclear Delivery.” 2013. Doctoral Dissertation, University of Michigan. Accessed April 26, 2019. http://hdl.handle.net/2027.42/97985.
Curry, Taeyjuana Y. “Nanoparticles for Biomedical Applications: Photothermal Therapy and Nuclear Delivery.” 2013. Web. 26 Apr 2019.
Curry TY. Nanoparticles for Biomedical Applications: Photothermal Therapy and Nuclear Delivery. [Internet] [Doctoral dissertation]. University of Michigan; 2013. [cited 2019 Apr 26]. Available from: http://hdl.handle.net/2027.42/97985.
16. Abeyasinghe, Neranga. Quantum Confined Noble Metal Monolayer Protected Clusters Investigated Using Linear and Nonlinear Microscopy.
▼ Elemental quantum confined nanocluster systems were previously demonstrated to have unusual optical, electronic, catalytic and magnetic properties suggesting to classify them as a new form of matter. Optical investigations in solution phase ensembles using monolayer protected nanoclusters (MPCs) allowed the community to experimentally confirm that the metal-to-insulator transition in gold occurs at ~300 gold atoms. However, investigations of single nanoclusters using optical microscopy and spectroscopy to determine effects of quantum confinement in MPCs were not reported until now. In my dissertation work, I interrogated isolated single quantum confined Au25 MPCs on a solid substrate. My observations made on isolated and aggregated MPCs on solid using two-photon excited fluorescence (TPEF) near-field scanning optical microscopy (NSOM) revealed that their native quantum confinement effects manifest primarily when they are isolated from aggregates and solution ensembles. This is consistent with the picture of narrowing of the density of states (DOS) when the quantum clusters are removed from aggregates and studied in isolation on solid. Also, it agrees with the enhancement expected for volume-normalized oscillator strengths (f12/V) of electronic transitions in the presence of quantum size effects. In order to obtain isolated single nanoclusters on solid, I devised a procedure where I synthesized MPCs, isolated them in solution phase and then deposited isolated single nanoclusters on solid substrate with ~160 nm average inter-nanocluster distances. Scanning transmission electron microscopy (STEM) confirmed the isolation of single nanoclusters on solid. The investigations of isolated MPCs on solid using aperture-based TPEF NSOM elicit ~30 nm point resolution which is ~5-fold better than the typical confocal point resolution. Also, my findings on possible local field enhancement for MPCs suggest the potential to use isolated MPCs, MPC arrays, meshes or lattices to obtain significantly enhanced TPEF properties that can be used in molecular computing, bioimaging,sensing, and data storage applications. On a separate investigation, I explored materials that can increase the theoretical efficiency limit of organic photovoltaics (OPV) via ntramolecular singlet exciton fission (iSEF). I interrogated a quinoidal bithiophene molecule in solution that revealed highly efficient ultrafast iSEF with ~180% singlet-to-triplet conversion efficiency. Our finding of iSEF in a small molecule invigorates theoretical and experimental investigations of small molecule iSEF materials to make highly efficient solar cells. Advisors/Committee Members: Goodson III, Theodore G (committee member), Schotland, John Carl (committee member), Geva, Eitan (committee member), Kopelman, Raoul (committee member), Walter, Nils G (committee member).
Abeyasinghe, Neranga. “Quantum Confined Noble Metal Monolayer Protected Clusters Investigated Using Linear and Nonlinear Microscopy.” 2016. Doctoral Dissertation, University of Michigan. Accessed April 26, 2019. http://hdl.handle.net/2027.42/135860.
Abeyasinghe, Neranga. “Quantum Confined Noble Metal Monolayer Protected Clusters Investigated Using Linear and Nonlinear Microscopy.” 2016. Web. 26 Apr 2019.
Abeyasinghe N. Quantum Confined Noble Metal Monolayer Protected Clusters Investigated Using Linear and Nonlinear Microscopy. [Internet] [Doctoral dissertation]. University of Michigan; 2016. [cited 2019 Apr 26]. Available from: http://hdl.handle.net/2027.42/135860.
17. Lesher-Perez, Sasha Cai. Development of Micro-actuators and Micro-sensors for the On-chip Interrogation of Cells and In Vitro Generated Tissues.
▼ Microscale systems enable interrogation of biological mechanisms beyond the capacity of conventional macroscale techniques. The large surface-to-volume ratio of microscale platforms allows investigators to better control the spatial and temporal microenvironment presented to biological samples, manipulating samples at scales reminiscent of their native microenvironments. This research describes microscale technologies to advance the design, complexity, and control of tissue culture microenvironments in three areas – chemical stimulation, regulating cell culture dimensionality, and oxygen monitoring. These tools improve in vitro models to better emulate the native biological response. To regulate temporal patterns of biochemical stimulation I developed an autonomous microfluidic oscillator circuit that enables dynamic control of delivered fluids without external control signals. This work produced to (1) a practical system to modulate the duty cycle of an applied stimulus in a user-defined manner without requiring modification of the device itself; and (2) a method to couple multiple independent oscillators together to ensure uniformity of experimental parameters, such as frequency and duty cycle, across multiple devices. In other work, reproducibility of three-dimensional spheroid cultures was achieved by culture additives to generate increasingly complex, and robust microscale cultures. We also developed dispersible microsensors for tissue culture oxygen measurements. When recreating physiologic microenvironments, it is critical to monitor and quantify the presence of oxygen. The untethered biocompatible oxygen sensors can be embedded or dispersed within diverse culture conditions for the real-time/continuous detection of oxygen in vitro. Dispersible microsensors were used to visualize the oxygen environment within in vitro tumor models, which allow for the informed generation of tumor models to more accurately capitulate the necessary oxygen environments. Advisors/Committee Members: Takayama, Shuichi (committee member), Luker, Gary D. (committee member), Kopelman, Raoul (committee member), Nagrath, Sunitha (committee member), Mycek, Mary-Ann (committee member), Burns, Mark A. (committee member).
Lesher-Perez, Sasha Cai. “Development of Micro-actuators and Micro-sensors for the On-chip Interrogation of Cells and In Vitro Generated Tissues.” 2015. Doctoral Dissertation, University of Michigan. Accessed April 26, 2019. http://hdl.handle.net/2027.42/113506.
Lesher-Perez, Sasha Cai. “Development of Micro-actuators and Micro-sensors for the On-chip Interrogation of Cells and In Vitro Generated Tissues.” 2015. Web. 26 Apr 2019.
Lesher-Perez SC. Development of Micro-actuators and Micro-sensors for the On-chip Interrogation of Cells and In Vitro Generated Tissues. [Internet] [Doctoral dissertation]. University of Michigan; 2015. [cited 2019 Apr 26]. Available from: http://hdl.handle.net/2027.42/113506.
18. Elbez, Remy A. Nanoparticle Induced Cell Magneto-Rotation for the Multiplexed Monitoring of Morphology, Stress and Drug Sensitivity of Suspended Single Cancer Cells.
▼ The metastatic process of a cancer relies on the transformation of some of the primary tumor cells into cells capable of migrating through the Extra-Cellular Matrix (ECM), surrounding the tumor, into the bloodstream and the lymph nodes, and then settle in distant tissue, growing new secondary tumors. By identifying, characterizing and quantifying these cells, the progression of cancer in a patient during therapy can be more accurately assessed. Here we describe the development of a new method for quantitative real time monitoring of cell size and morphology, on single live suspended cancer cells, unconfined in three dimensions. The enabling cell magnetorotation (CM) method is made possible by nanoparticle induced cell magnetization. Using a rotating magnetic field, the magnetically labeled cells are actively rotated, then imaged, using a high definition CCD camera. Under proper conditions, the rotation period of a magnetic object is proportional to its shape factor. We demonstrate first that the rotational period, when measured in real-time, can serve to track cellular response to drugs, cytotoxic agents and other chemical stimuli. In addition, while cells are rotated, they exhibit very specific morphological activities, even without a chemical stimulus. Described also is how to multiplex the CM method, to image several dozens to several thousands of cells simultaneously, and using morphology to classify cells into different phenotypic categories, with each phenotype being correlated with malignancy level. The intrinsic tumor heterogeneity, at the cellular level, can be visualized with relationship graphs. Shown is the ability to monitor cell morphological changes over long periods of time, in real time, in order to detect the metastatic potential for heterogeneous populations of cancer cells, using tools from statistical analysis methods. The method relies on unsupervised Machine Learning algorithms which do not require human inputs. Overall it is demonstrated that the CM method can be used as a diagnostic tool to evaluate the phenotypical heterogeneity in a cell population in general, and in a cancer cell population in particular. This fast and high throughput method promises to efficiently assess the efficacy of personalized therapeutic strategies. Advisors/Committee Members: Kopelman, Raoul (committee member), Hunt, Alan J. (committee member), Takayama, Shuichi (committee member), Ziff, Robert M. (committee member), Doering, Charles R. (committee member), Clarke, Roy (committee member).
Elbez, Remy A. “Nanoparticle Induced Cell Magneto-Rotation for the Multiplexed Monitoring of Morphology, Stress and Drug Sensitivity of Suspended Single Cancer Cells.” 2015. Doctoral Dissertation, University of Michigan. Accessed April 26, 2019. http://hdl.handle.net/2027.42/111434.
Elbez, Remy A. “Nanoparticle Induced Cell Magneto-Rotation for the Multiplexed Monitoring of Morphology, Stress and Drug Sensitivity of Suspended Single Cancer Cells.” 2015. Web. 26 Apr 2019.
Elbez RA. Nanoparticle Induced Cell Magneto-Rotation for the Multiplexed Monitoring of Morphology, Stress and Drug Sensitivity of Suspended Single Cancer Cells. [Internet] [Doctoral dissertation]. University of Michigan; 2015. [cited 2019 Apr 26]. Available from: http://hdl.handle.net/2027.42/111434.
19. Lhermitte, Charles. Kinetics of Competing Reactions on Metal Oxide Semiconductors during the Course of Photoelectrochemical Water Oxidation.
▼ Photoelectrochemical (PEC) water splitting is a sustainable and environmentally friendly method for the conversion of solar energy into a portable H2 fuel. However, in order to drive the paradigm shift toward these new sources of energy, the efficiency of this process must be improved. Because the oxygen evolution reaction (OER) is the kinetically slowest step for water splitting, it is imperative to develop materials that demonstrate high efficiencies and turnover frequencies for this reaction. This thesis focuses on developing metal oxides capable of using visible light to drive water oxidation in addition to obtaining a more fundamental understanding of the kinetics of the processes that take place on the electrode surface. The major contribution of the work presented in this thesis focuses on understanding how the catalysis of a few select metal oxides may be affected via doping or through the addition of co-catalysts. Additionally, particular emphasis is placed on understanding how competitive side reactions may affect the OER efficiency of metal oxide photoelectrodes. Improvements in the Faradaic efficiency and aqueous stability of WO3 electrodes were probed via the growth of a surface FeOOH layer. This surface layer increases the Faradaic efficiency for OER to nearly 100% in addition to dramatically improving the aqueous stability. Furthermore, the effects of competing side reactions on WO3 were investigated using a novel rotating ring disk photoelectrode and it was determined that significant competition with OER arises from the oxidation of reduced W sites present in the electrode. Furthermore, visible light absorbing ternary oxide phases were also investigated. Doping CuWO4 with Co was investigated as a means of improving OER kinetics, however, it was observed via a combination of UV-Vis spectroscopy, and electrochemistry that although Co2+ doping improves both dark catalysis and visible light absorption, these impurities produce trap states which quench the photocurrent. Finally, the 2.2 eV band gap material, PbCrO4, was investigated as a “trap-free” metal oxide due to its combination of d10/d0 transition metal cations. Unfortunately, electrodes of this material are unstable during the photoelectrolysis of water and decomposition reactions out compete OER which shuts down the electrode’s reactivity. Advisors/Committee Members: Bartlett, Bart (committee member), Sih, Vanessa (committee member), Kopelman, Raoul (committee member), Maldonado, Stephen (committee member).
Lhermitte, Charles. “Kinetics of Competing Reactions on Metal Oxide Semiconductors during the Course of Photoelectrochemical Water Oxidation.” 2017. Doctoral Dissertation, University of Michigan. Accessed April 26, 2019. http://hdl.handle.net/2027.42/137008.
Lhermitte, Charles. “Kinetics of Competing Reactions on Metal Oxide Semiconductors during the Course of Photoelectrochemical Water Oxidation.” 2017. Web. 26 Apr 2019.
Lhermitte C. Kinetics of Competing Reactions on Metal Oxide Semiconductors during the Course of Photoelectrochemical Water Oxidation. [Internet] [Doctoral dissertation]. University of Michigan; 2017. [cited 2019 Apr 26]. Available from: http://hdl.handle.net/2027.42/137008.
20. Vazquez, Anne V. Correlating Surface and Buried Interfacial Structures to Polymer Adhesion.
▼ Robust adhesion of polymers is necessary for applications in many industries; however, adhesion is poorly understood on a molecular level. Here, a surface and interface-sensitive nonlinear optical technique, sum frequency generation (SFG) vibrational spectroscopy was used to study polymer adhesive surfaces and polymer/adhesive interfaces to gain a better understanding of polymer adhesion mechanisms. Silane adhesion promoters are often used to enhance the adhesion of elastomeric materials to polymer substrates. The interfacial structures of a known silane adhesion promoting mixture at polymer/liquid, silicone elastomer/liquid and polymer/silicone elastomer buried interfaces were studied with SFG and correlated to adhesion testing results. The silane adhesion promoters exhibited orientational order at all buried interfaces, implying that interfacial ordering of silane adhesion promoters may be necessary to enhance adhesion. Silane adhesion promoters cannot be used in microfluidics fabrication. In these applications, surface treatments are used to oxidize the silicone surface prior to adhesion, but due to hydrophohbic recovery these effects are temporary. Hydrophobic recovery can be slowed by removing extractable short chain oligomers from the silicone bulk. SFG analysis of silicone surfaces before and after extractable materials were removed showed that the silicone surface methyl group orientation changed after extractions. Also, the surface flattened after extractable materials were removed. These changes in surface structure may slow hydrophobic recovery, and therefore improve adhesion enhancement by oxidative surface treatments. Lastly, the adhesion of a different class of polymer adhesives, epoxy resins, was investigated. Epoxy resins are used as underfills in flip-chip devices, and adhesion failure of underfills can cause the flip-chip device to fail. Here, SFG was used to study the surface structures of model epoxy compounds before cure, after cure and after moisture exposure. Surface structural changes were observed for all three conditions, which may affect adhesion of epoxy underfills. Further, the buried interfacial structures of the cured epoxies and a model polymer were investigated before and after moisture exposure and correlated to adhesion testing results. These studies showed that SFG is a powerful technique to study polymer adhesion mechanisms and the surface and interfacial structures required for adhesion. Advisors/Committee Members: Chen, Zhan (committee member), Guo, Lingjie (committee member), Kopelman, Raoul (committee member), Sension, Roseanne J. (committee member).
Vazquez, Anne V. “Correlating Surface and Buried Interfacial Structures to Polymer Adhesion.” 2010. Doctoral Dissertation, University of Michigan. Accessed April 26, 2019. http://hdl.handle.net/2027.42/77938.
Vazquez, Anne V. “Correlating Surface and Buried Interfacial Structures to Polymer Adhesion.” 2010. Web. 26 Apr 2019.
Vazquez AV. Correlating Surface and Buried Interfacial Structures to Polymer Adhesion. [Internet] [Doctoral dissertation]. University of Michigan; 2010. [cited 2019 Apr 26]. Available from: http://hdl.handle.net/2027.42/77938.
21. Hagedorn, Kevin V. Experimental Studies and Numerical Simulations on Light-Harvesting Devices.
▼ Obtaining high solar energy conversion efficiencies with materials that require minimal processing or refining is critical to next generation light-harvesting systems. Organic dyes and inorganic nanostructured semiconductors are two material types that address this need and are studied herein. Two sets of organic chromophore systems were characterized. First, triarylamine multi-chromophore dendrimers with purposely designed biphenyl-based trap sites were investigated using fluorescence upconversion spectroscopy. A rise in the fluorescence from the biphenyl site after the excitation pulse demonstrated that excitons were trapped with 99% efficiency. These data show that excitons can be directed to a specific site in a molecular chromophore. Separately, thiophene macrocycles were investigated to determine if molecular systems could show high energetic degeneracy. The chromophore coupling constants of two thiophene rings were quantified using time-resolved fluorescence anisotropy measurements. The calculated chromophore coupling constants for the cyclic system were an order of magnitude higher than linear chains. In addition, the cyclic system had a two photon absorption cross section of 1470 GM, which is over a thousand times greater than the linear chain and useful for applications in imaging and lithography. Nanostructured inorganic semiconductors were also the subject of study. In one set of experiments, the first example of macroporous p-GaP(100) was reported and its ability to perform photosynthetic water splitting was demonstrated and assessed. Macroporous films were prepared using a two-electrode cell with a halogen acid electrolyte and pulsed anodic etching voltage waveform. Control over the macroporous film morphology was explored by varying halogen acid type, concentration, and etching voltage. Macroporous p-GaP has applications in photonic and light-harvesting systems. To this end, the relationship between optoelectronic properties and the obtainable solar energy conversion efficiency was determined in nanostructured semiconductors. The photocurrent-potential response of lightly and heavily doped silicon nanowires were quantified, with the heavily doped semiconductors demonstrating superior energy conversion. For low dopant density nanowires, the low energy conversion efficiencies were attributed to a lack of an internal electric field, which resulted in a high majority carrier recombination at the interface. These data provide design principles for efficient solar energy conversion systems based on nanostructured semiconductors. Advisors/Committee Members: Maldonado, Stephen (committee member), Kopelman, Raoul (committee member), Matzger, Adam J. (committee member), Shtein, Max (committee member).
Hagedorn, Kevin V. “Experimental Studies and Numerical Simulations on Light-Harvesting Devices.” 2010. Doctoral Dissertation, University of Michigan. Accessed April 26, 2019. http://hdl.handle.net/2027.42/78903.
Hagedorn, Kevin V. “Experimental Studies and Numerical Simulations on Light-Harvesting Devices.” 2010. Web. 26 Apr 2019.
Hagedorn KV. Experimental Studies and Numerical Simulations on Light-Harvesting Devices. [Internet] [Doctoral dissertation]. University of Michigan; 2010. [cited 2019 Apr 26]. Available from: http://hdl.handle.net/2027.42/78903.
22. Suzer, Ozgun. Quantum Optical Applications in Spectroscopy: Investigations of Entangled Two-Photon Absorption and Entangled Two-Photon Excited Fluorescence in Organic Dendritic Systems.
▼ Entangled states of light have been utilized successfully in a wide variety of experiments and applications. This dissertation will discuss the application of entangled states of light toward spectroscopy wherein entangled pairs of photons generated via the process of spontaneous parametric down-conversion (SPDC) are utilized to excite entangled two-photon absorption (ETPA) in organic molecules. An enhancement of the brightness of the SPDC entangled photon source under focused pumping conditions is discussed for the purpose of maximizing the entangled-pair flux available in these experiments. The entangled-pair flux utilized in ETPA experiments, however, still constitutes approximately 10 orders of magnitude fewer photons than any classical counterpart requires. Further, the effects of various conditions under which entangled photons are generated via the process of SPDC, specifically the phase-matching conditions and their resulting impact on the interaction of said photons with matter is presented. It is shown that spatial indistinguishability of entangled photons generated via SPDC is a necessary requirement for ETPA in organic nonlinear optical materials. Investigations of the ETPA response of a wide range of organic dendritic materials with differing geometry, donor-acceptor strength, and charge-transfer character are also presented, where it was observed that materials whose classical TPA cross-section is attributed to a dipole transition, without involvement of an intermediate state, were nearly transparent to entangled photons. In addition, the premiere demonstration of fluorescence from an organic dendrimer subsequent to two-photon excitation by entangled pairs of photons is presented. A novel, high geometric efficiency, spherically-enclosed optical collection system for collection of fluorescence photons is introduced, which is utilized to circumvent any drawbacks related to the weak quantum yield of the organic materials, and it is observed that the dependence of the rate of fluorescence collected from the material on the entangled excitation flux follows that of the ETPA response of the material. This is the first ever demonstration of the ETPEF phenomenon in any kind of material, and these novel results have widespread impact in applications ranging from spectroscopy to chemical and biological sensing, where the demonstration of the ETPEF phenomenon enables advancement in fields such as quantum imaging and microscopy. Advisors/Committee Members: Goodson, Theodore G. (committee member), Green, Peter F. (committee member), Kopelman, Raoul (committee member), Winful, Herbert Graves (committee member).
Suzer, Ozgun. “Quantum Optical Applications in Spectroscopy: Investigations of Entangled Two-Photon Absorption and Entangled Two-Photon Excited Fluorescence in Organic Dendritic Systems.” 2010. Doctoral Dissertation, University of Michigan. Accessed April 26, 2019. http://hdl.handle.net/2027.42/78932.
Suzer, Ozgun. “Quantum Optical Applications in Spectroscopy: Investigations of Entangled Two-Photon Absorption and Entangled Two-Photon Excited Fluorescence in Organic Dendritic Systems.” 2010. Web. 26 Apr 2019.
Suzer O. Quantum Optical Applications in Spectroscopy: Investigations of Entangled Two-Photon Absorption and Entangled Two-Photon Excited Fluorescence in Organic Dendritic Systems. [Internet] [Doctoral dissertation]. University of Michigan; 2010. [cited 2019 Apr 26]. Available from: http://hdl.handle.net/2027.42/78932.
23. Dooley, Kathryn A. Raman Spectroscopic Studies of Bone Biomechanical Function and Development in Animal Models.
▼ Raman spectroscopy is a versatile technique for studying multiple aspects of bone health. Raman bands are sensitive to the composition and structural orientation of the material and to external mechanical forces. Through examination of bone tissue from various animal models, this dissertation demonstrates the ability of Raman spectroscopy to advance knowledge of bone biomechanical function and normal bone development. Stress was measured in an equine model for the early stages of bone fracture by analyzing band shifts in phosphate ν1, the most prominent mineral band in bone. Stresses were significantly higher in strained and failed regions than in control regions, and the pattern of stresses as calculated with Raman imaging was in agreement with the predicted stresses from a linear finite element analysis model of the fracture specimen. In an equine model for an extreme athlete, the third metacarpal bone from a racehorse was found to have an increased mineral to matrix ratio, an indicator of tissue mineralization, compared to a specimen from a nonathletic horse. Raman spectroscopy was also applied to evaluate bone tissue from genetically modified mice in which the Sprouty2 gene, a gene which regulates normal bone development, was deleted. Based on observed differences in the collagen cross link and mineral to matrix band ratios, Spry2 appears to regulate cross link formation and accrual of mineral during normal bone development. Another genetically modified mouse examined was the Brittle mouse, a model for osteogenesis imperfecta type IV. In this model, an amino acid point substitution prevents proper folding of the collagen triple helix. Polarized Raman spectroscopy was used to assess the orientations of bone mineral and collagen fibrils in Brittle and wild-type mice. Surprisingly, no significant differences between genotypes were detected. Finally, improvements to ex vivo, through the skin bone measurements on animal tissue are presented, along with an experimental study detailing the improvements to fiber spectra obtained by applying software corrections to coupling errors that arise in collection with fiber bundles. Advisors/Committee Members: Morris, Michael D. (committee member), Kopelman, Raoul (committee member), Kubarych, Kevin J. (committee member), McCauley, Laurie Kay (committee member).
Dooley, Kathryn A. “Raman Spectroscopic Studies of Bone Biomechanical Function and Development in Animal Models.” 2011. Doctoral Dissertation, University of Michigan. Accessed April 26, 2019. http://hdl.handle.net/2027.42/84467.
Dooley, Kathryn A. “Raman Spectroscopic Studies of Bone Biomechanical Function and Development in Animal Models.” 2011. Web. 26 Apr 2019.
Dooley KA. Raman Spectroscopic Studies of Bone Biomechanical Function and Development in Animal Models. [Internet] [Doctoral dissertation]. University of Michigan; 2011. [cited 2019 Apr 26]. Available from: http://hdl.handle.net/2027.42/84467.
24. Si, Di. PEBBLE Nanosensors for Intracellular Imaging and Analysis of Free Calcium and Zinc.
▼ Ca2+ is a universal second messenger and plays a major role in intracellular signaling, metabolism and a wide range of cellular processes. To date, the most successful approach for intracellular Ca2+ measurement involves the introduction of optically sensitive Ca2+ indicators into living cells, combined with digital imaging microscopy. However, the use of free Ca2+ indicators for intracellular sensing and imaging has several limitations, such as interference from cellular small ions and biomacromolecules, and unwanted sequestration of the indicator molecules. Zinc is the second most abundant trace element in the human body. It is an essential component of all six classes of enzymes and several families of regulatory proteins. Zinc deficiencies and excesses were found to be related to a number of health issues. Due to the importance of zinc in the human body, many fluorescent Zn2+ indicators have been developed. Among these indicators, carbonic anhydrase (CA) and its mutants are particularly useful for intracellular Zn2+ sensing, because of their outstanding and tunable sensitivity (picomolar level), selectivity and binding kinetics. In this work, PEBBLE nanosensors have been developed for intracellular measurements of free Ca2+ and Zn2+. The general design, matrices and the advantages of PEBBLE nanosensors are briefly reviewed in Chapter 1. Chapter 2 describes the preparation, characterization and intracellular application of PEBBLE nanosensors encapsulated with rhodamine based Ca2+ fluorescence indicators. The Kd of Rhod-2 inside PEBBLEs is determined to be 500~600 nM for in-solution calibration and 1 µM for in-cell calibration. Chapter 3 describes the preparation and purification of CA encapsulated PEBBLEs; the active CA encapsulation is about 28%. Chapter 4 describes zinc sensing performed by CA encapsulated and conjugated PEBBLEs. The Zn2+ binding affinity of the CA conjugated on PEBBLE surface is determined to be 9 pM, while the Zn2+ sensing by CA encapsulated PEBBLEs is not successful. Chapter 5 summarizes the conclusions and limitations of this work, and proposes future experiments for developing novel PEBBLE nanosensors. Advisors/Committee Members: Kopelman, Raoul (committee member), Fierke, Carol (committee member), Hakansson, Kristina I. (committee member), Philbert, Martin A. (committee member).
Si, Di. “PEBBLE Nanosensors for Intracellular Imaging and Analysis of Free Calcium and Zinc.” 2011. Doctoral Dissertation, University of Michigan. Accessed April 26, 2019. http://hdl.handle.net/2027.42/86474.
Si, Di. “PEBBLE Nanosensors for Intracellular Imaging and Analysis of Free Calcium and Zinc.” 2011. Web. 26 Apr 2019.
Si D. PEBBLE Nanosensors for Intracellular Imaging and Analysis of Free Calcium and Zinc. [Internet] [Doctoral dissertation]. University of Michigan; 2011. [cited 2019 Apr 26]. Available from: http://hdl.handle.net/2027.42/86474.
25. Tenney, Craig M. Molecular Simulation of Carbon Dioxide Adsorption for Carbon Capture and Storage.
▼ Capture of CO2 from fossil fuel power plants and sequestration in unmineable coal seams are achievable methods for reducing atmospheric emissions of this greenhouse gas. To aid the development of effective CO2capture and sequestration technologies, a series of molecular simulation studies were conducted to study the adsorption of CO2 and related species onto heterogeneous, solid adsorbents. To investigate the influence of surface heterogeneity upon adsorption behavior in activated carbons and coal, isotherms were generated via grand canonical Monte Carlo (GCMC) simulation for CO2 adsorption in slit-shaped pores with several variations of chemical and structural heterogeneity. Adsorption generally increased with increasing oxygen content and the presence of holes or furrows, which acted as preferred binding sites. To investigate the potential use of the flexible metal organic framework (MOF) Cu(BF4)2(bpy)2 (bpy=bipyridine) for CO2capture, pure- and mixed-gas adsorption was simulated at conditions representative of power plant process streams. This MOF was chosen because it displays a novel behavior in which the crystal structure reversibly transitions from an empty, zero porosity state to a saturated, expanded state at the “gate pressure”. Estimates of CO2 capacity above the gate pressure from GCMC simulations using a rigid MOF model showed good agreement with experiment. The CO2 adsorption capacity and estimated heats of adsorption are comparable to common physi-adsorbents under similar conditions. Mixed-gas simulations predicted CO2/N2and CO2/H2selectivities higher than typical microporous materials. To more closely investigate this gating effect, hybrid Monte-Carlo/molecular-dynamics (MCMD) was used to simulate adsorption using a flexible MOF model. Simulation cell volumes remained relatively constant at low gas pressures before increasing at higher pressure. Mixed-gas simulations predicted CO2/N2 selectivities comparable to other microporous adsorbents. To study the molecular processes relevant to storage of CO2 in unmineable coal seams with enhanced methane recovery, a representative bituminous coal was simulated using MD and a hybrid Gibbs-ensemble-Monte-Carlo/MD method. Simulation predicted a bulk density of 1.24 g/ml for the dry coal, which compares favorably with the experimental value of 1.3 g/ml. Consistent with known coal properties, simulation models showed stacking of macromolecular graphitic regions and preferential adsorption of CO2 relative to methane. Advisors/Committee Members: Lastoskie, Christian M. (committee member), Kopelman, Raoul (committee member), Weber, Jr., Walter J. (committee member), Wright, Steven J. (committee member).
Tenney, Craig M. “Molecular Simulation of Carbon Dioxide Adsorption for Carbon Capture and Storage.” 2009. Doctoral Dissertation, University of Michigan. Accessed April 26, 2019. http://hdl.handle.net/2027.42/62442.
Tenney, Craig M. “Molecular Simulation of Carbon Dioxide Adsorption for Carbon Capture and Storage.” 2009. Web. 26 Apr 2019.
Tenney CM. Molecular Simulation of Carbon Dioxide Adsorption for Carbon Capture and Storage. [Internet] [Doctoral dissertation]. University of Michigan; 2009. [cited 2019 Apr 26]. Available from: http://hdl.handle.net/2027.42/62442.
26. Slaney, Thomas R. Low-Flow Push-Pull Perfusion for Measuring Neurotransmitters with High Spatial and Temporal Resolution within the Living Brain.
▼ Low-flow push-pull perfusion is a technique for measuring neurotransmitters within the brain with ~200 μm resolution. Activity of neurotransmitters can vary on this size scale; therefore, low-flow push-pull may offer new insights into physiology. Flow rates used by this technique (50 nL/min) may present challenges for sample handling and assay sensitivity due to nL sample fractions. In this work, the temporal resolution of low-flow push-pull was advanced to 7 s in vivo, several different neurochemical assays were implemented, and gradients of neurotransmitters were mapped across sub-mm distances. To address collection and manipulation of 7 s fractions collected in vivo, push-pull samples were stored as 6 nL plugs in an oil carrier phase. A tee was developed to address each fraction discretely for reagent addition. L-glutamate was measured within the striatum of anesthetized rats by using a fluorogenic enzyme assay. Microinjection of a potassium solution at the probe tip evoked L-glutamate concentration transients that had maxima of 4.5 ± 1.1 μM and rise times of 22 ± 2 s. Nanospray ionization mass spectrometry was used to simultaneously measure three neurochemicals in plug samples. After microinjection of neostigmine at the push-pull probe tip, rapid extracellular concentration increases of neostigmine (14 ± 3 s), acetylcholine (35 ± 4 s) and a gradual decrease in choline (60 ± 13 s) were observed. This experiment highlights the ability of low-flow push-pull perfusion to observe drug-neurotransmitter dynamics in vivo. A GABA enzyme assay and capillary electrophoresis were demonstrated for analysis of push-pull perfusion plugs. A miniaturized push-pull probe was adapted for awake, freely moving animals and used to measure 13 neurotransmitters and metabolites. Concentration gradients were observed between proximate brain regions. For example, dopamine in the ventral tegmental area was 4.8 ± 1.5 nM, but in the red nucleus (200 µm apart) was 0.5 ± 0.2 nM. This collection of work illustrates that low-flow push-pull perfusion is a versatile tool for monitoring many different neurotransmitters within the brain with 200 μm spatial and 7 s or faster temporal resolution. Future research directions may include ms temporal resolution in vivo measurements and microfabricated probes. Advisors/Committee Members: Kennedy, Robert T. (committee member), Yoon, Euisik (committee member), Maldondo, Stephen (committee member), Kopelman, Raoul (committee member).
Slaney, Thomas R. “Low-Flow Push-Pull Perfusion for Measuring Neurotransmitters with High Spatial and Temporal Resolution within the Living Brain.” 2013. Doctoral Dissertation, University of Michigan. Accessed April 26, 2019. http://hdl.handle.net/2027.42/97958.
Slaney, Thomas R. “Low-Flow Push-Pull Perfusion for Measuring Neurotransmitters with High Spatial and Temporal Resolution within the Living Brain.” 2013. Web. 26 Apr 2019.
Slaney TR. Low-Flow Push-Pull Perfusion for Measuring Neurotransmitters with High Spatial and Temporal Resolution within the Living Brain. [Internet] [Doctoral dissertation]. University of Michigan; 2013. [cited 2019 Apr 26]. Available from: http://hdl.handle.net/2027.42/97958.
27. Yoon, Hyung Ki. Multifunctional Nanoplateforms for Biomedical Imaging and Photodynamic Therapy.
▼ Nanoplatforms have considerable potential for delivery of biomedical agents, so as to overcome inherent limitations of small molecule drugs or contrast agents, such as fast degradation, aggregation and lack of targeting ability. In this dissertation, we demonstrate improved imaging and therapy techniques using polyacrylamide (PAA) based nanoparticles (NPs) and star-shaped polyethylene glycol (PEG) platforms for cancer and cardiac arrhythmia treatment. The proposed albumin conjugated PAA NPs provided strong fluorescence and photoacoustic intensities for the Indocyanine Green (ICG) contrast agent for use in cancer imaging. These protein hybrid NPs not only enhanced the chemical stability of ICG but also showed in vitro cancer cell specificity, with the help of targeting moieties. We also developed methylene blue (MB) conjugated PAA NPs for photodynamic therapy (PDT). Its reactive oxygen species (ROS) productivity was enhanced by utilizing longer cross-linker than in previous PAA NPs and a newly designed microfluidic device contributes to faster tests on the cell killing efficacy of photo-drug NPs. Lastly, Chlorin e6 (Ce6) and cardiac targeting peptide (CTP) were conjugated to 8-arm PEG for extremely small sized nanoplatforms (CTP‒Ce6‒PEG); it showed great potential for treating cardiac arrhythmia by PDT, demonstrating selective ablation of arrhythmia causing myocyte cells. Overall, this dissertation, reporting on biomedical imaging and therapy based on nanotechnology, shows their potentialities towards further modifications for clinical usage and commercialization, not only for cancer but also for heart disease. Advisors/Committee Members: Kopelman, Raoul (committee member), Kim, Jinsang (committee member), Lim, Mi Hee (committee member), Matzger, Adam J. (committee member).
Yoon, Hyung Ki. “Multifunctional Nanoplateforms for Biomedical Imaging and Photodynamic Therapy.” 2014. Doctoral Dissertation, University of Michigan. Accessed April 26, 2019. http://hdl.handle.net/2027.42/107224.
Yoon, Hyung Ki. “Multifunctional Nanoplateforms for Biomedical Imaging and Photodynamic Therapy.” 2014. Web. 26 Apr 2019.
Yoon HK. Multifunctional Nanoplateforms for Biomedical Imaging and Photodynamic Therapy. [Internet] [Doctoral dissertation]. University of Michigan; 2014. [cited 2019 Apr 26]. Available from: http://hdl.handle.net/2027.42/107224.
28. Koh, Byumseok Eric. Dispersion of Single-Walled Carbon Nanotubes (SWCNTs) Iin Aqueous Solution and Reversion of SWCNT Aggregates.
▼ Due to their unique physical properties, single-walled carbon nanotubes (SWCNTs) have become increasingly important in applications as diverse as biosensors and building blocks for nano-electronics. SWCNTs are considered to be effective drug and gene carriers because they have the ability to either directly penetrate or be endocytosed into cells with relatively low or no toxicity. However, there is a limitation: in order to be used as drug or gene carriers, SWCNTs must be dispersed in aqueous solution. In fact, studies have shown that an aggregated form of SWCNTs induces a toxic response in vivo, thus limiting their use as delivery tools. This toxic response, consisting of aggregate accumulation in the lung and spleen and consequent inflammation and fibrosis, motivated us to study strategies for achieving effective SWCNT dispersion in aqueous solution. We investigated the mechanisms of SWCNT dispersion and aggregation and how certain SWCNT aggregates can be re-dispersed by addition of chelating or reducing agents. We also developed a method to re-disperse SWCNT aggregates by using enzymes, which has the potential to control the aggregation status of SWCNTs in solution. Our studies and findings can advance the development of SWCNTs for future applications in drug/DNA delivery. Advisors/Committee Members: Cheng, Wei (committee member), Kopelman, Raoul (committee member), Schwendeman, Steven P. (committee member), Lee, Kyung-Dall (committee member).
Koh, Byumseok Eric. “Dispersion of Single-Walled Carbon Nanotubes (SWCNTs) Iin Aqueous Solution and Reversion of SWCNT Aggregates.” 2013. Doctoral Dissertation, University of Michigan. Accessed April 26, 2019. http://hdl.handle.net/2027.42/102316.
Koh, Byumseok Eric. “Dispersion of Single-Walled Carbon Nanotubes (SWCNTs) Iin Aqueous Solution and Reversion of SWCNT Aggregates.” 2013. Web. 26 Apr 2019.
Koh BE. Dispersion of Single-Walled Carbon Nanotubes (SWCNTs) Iin Aqueous Solution and Reversion of SWCNT Aggregates. [Internet] [Doctoral dissertation]. University of Michigan; 2013. [cited 2019 Apr 26]. Available from: http://hdl.handle.net/2027.42/102316.
29. Smith, Ron Gordon. Photonic and Magnetic Nano- and Micro-Particles for Biomedical Applications: Detection and Distruction of Bacterial and Cancer Cells.
▼ Recently, many advances have been made on the use of micro- and nano-particles for photothermal therapy and photodynamic therapy, as well as for bacterial detection and growth dynamics. This thesis includes three projects on the utility of activated particles towards the eradication of tumor cells and bacteria. Recently our laboratory developed a biodegradable nanoparticle, copolymerized from acrylamide and a coomassie blue derivative. In this work we investigated the capability of the coomassie blue polyacrylamide (CB-PAA) nanoparticle to induce tumor cell death photothermally. Specifically, the dependence of cell death on mass concentration of nanoparticles, incubation time with nanoparticles, and the exposure time and intensity of the light source were determined. These CB-PAA nanoparticles were able to cause significant cell death, up to 97%, at fluencies as low as 61 J/cm2, when incubated with 1.2 mg/mL CB-PAA nanoparticles. Photodynamic cell kill of bacteria has been extensively studied as an alternative treatment to antibiotics. Previously, methylene blue loaded polyacrylamide nanoparticles have been shown to cause cell death in various bacterial strains. In this work, we investigated a methylene blue molecule covalently linked to polyacrylamide nanoparticles to determine if it could be used as a photodynamic agent on Escherichia coli O157:H7. A major goal was to determine if any increase in methylene blue loading by covalent linkages would increase mortality of the cells. However, this alternative approach to methylene loaded nanoparticles showed no cell death. The possible reasons for less activity are discussed. Bacteria detection and monitoring of their cell growth are important for determining the correct antibiotic to be administered for an infection. An innovative approach from our laboratory, involving the use of nonlinear rotation of magnetic microparticles, has led to the ability to detect binding events of a single bacterium. We showed a decrease in average rotation rate by a factor 3.8 when a bacteria was bound to the surface of the microparticle. This opened the way towards a simple method of monitoring cell growth and its application for rapid determination of drug sensitivity, e.g. antibiotic susceptibility. Advisors/Committee Members: Kopelman, Raoul (committee member), Philbert, Martin A. (committee member), Morris, Michael D. (committee member), Goodson, Theodore G. (committee member).
Smith, Ron Gordon. “Photonic and Magnetic Nano- and Micro-Particles for Biomedical Applications: Detection and Distruction of Bacterial and Cancer Cells.” 2013. Doctoral Dissertation, University of Michigan. Accessed April 26, 2019. http://hdl.handle.net/2027.42/102445.
Smith, Ron Gordon. “Photonic and Magnetic Nano- and Micro-Particles for Biomedical Applications: Detection and Distruction of Bacterial and Cancer Cells.” 2013. Web. 26 Apr 2019.
Smith RG. Photonic and Magnetic Nano- and Micro-Particles for Biomedical Applications: Detection and Distruction of Bacterial and Cancer Cells. [Internet] [Doctoral dissertation]. University of Michigan; 2013. [cited 2019 Apr 26]. Available from: http://hdl.handle.net/2027.42/102445.
30. Yau, Sung-Hei. Understanding Metal Nonoclusters through Ultrafast and Nonlinear Spectroscopy.
▼ In the past 20 years, nanomaterials studies have uncovered many new and interesting properties not found in bulk materials. Extensive research has focused on metal nanoparticles (> 2 nm) because of their potential applications, such as molecular electronics, image markers and catalysts. Moreover, the discovery of metal nanoclusters (< 2 nm) has greatly expanded the horizon of nanomaterial research. These nanosystems exhibit molecular-like characteristics as their size approaches the Fermi-wavelength of an electron. The relationships between size and physical properties of nanomaterials are intriguing. Metal nanosystems in this size regime have electronic properties that are determined by both size and shape. Remarkably, changes in the optical properties of nanomaterials have provided tremendous insight into the electronic structure of nanoclusters. The success of synthesizing monolayer protected clusters (MPCs) in the condensed phase has allowed scientists to study the metal core directly. Spectroscopic studies are carried out on two different metal nanosystems, gold and silver. Gold nanosystems are known for their high stability. Detailed characterization of gold nanosystems allows for modeling of the electronic and optical properties. Major optical and electronic differences between gold nanoparticles and nanoclusters can be observed around 2.2 nm, which was not known previously. Gold MPCs also exhibit emissions that are five orders of magnitude larger than bulk gold. Chemical dynamics such as electron-electron scattering and electron-phonon coupling can be used to explain the subtle differences between nanosystems. Silver and gold nanosystems are compared because of the similarity between their bulk properties. Silver MPCs exhibit similar optical properties as gold MPCs, but differ in key electronic transitions. The study of nanosystems aims to answer a few major questions. First, what is the effect of size on the electronic and optical properties of metal nanosystems? Second, what are the fundamental mechanisms that govern the electronic excitation? Can we take advantage of these new properties for optical and electronic applications? Finally, can we build better models to predict the properties of metal nanoclusters made and yet to be made? Nanosystem presents a new frontier in material science to be explored and exploited. Advisors/Committee Members: Goodson, Theodore G. (committee member), Geva, Eitan (committee member), Violi, Angela (committee member), Kopelman, Raoul (committee member).
Yau, Sung-Hei. “Understanding Metal Nonoclusters through Ultrafast and Nonlinear Spectroscopy.” 2013. Doctoral Dissertation, University of Michigan. Accessed April 26, 2019. http://hdl.handle.net/2027.42/99761.
Yau, Sung-Hei. “Understanding Metal Nonoclusters through Ultrafast and Nonlinear Spectroscopy.” 2013. Web. 26 Apr 2019.
Yau S. Understanding Metal Nonoclusters through Ultrafast and Nonlinear Spectroscopy. [Internet] [Doctoral dissertation]. University of Michigan; 2013. [cited 2019 Apr 26]. Available from: http://hdl.handle.net/2027.42/99761.

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