Thesis (Sc. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 1987. / Bibliography: leaves 187-190. / by Bernard L. Palowitch Jr. / Sc.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 1994. / Includes bibliographical references. / by Paul Franklin NEaley. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2004. / Includes bibliographical references. / In chromatography, the selective separation for large molecules, polymers, and proteins is of particular interest. To achieve quality separations, the stationary phase should exhibit pore diameters greater than 10 nm to facilitate the diffusion of large analytes throughout the stationary phase. In packed-bed applications, narrow particle and pore size distributions and uniform particle shape would lead to improved separations. Thus, spherical stationary phase particles are often preferred, but the challenge has been to combine spherical particle morphologies, high surface areas, large mesopores, and narrow pore size distributions. We have successfully created a new three-step synthesis of spherical MCF (S- MCF) particles utilizing sodium fluoride as a condensation catalyst. The approach allowed for independent control over S-MCF particle and pore size, and was extended to other non-ordered porous silicas. The S-MCF particles were engineered into a reverse- phase chromatographic column and achieved good separation ability for a mixture of aryl ketones. By relating chromatographic performance to S-MCF surface silanol chemistry, an improved S-MCF chromatographic support was realized, which rivaled the separation capability of a commercially available chromatographic support. The asymmetric Diels-Alder (ADA) reaction is very useful in building complex chiral molecules through the formation of chiral carbon ring structures, and it presents an excellent route for generating new therapeutic molecules. Although these compounds are of great importance, homogeneous ADA catalysts exhibit moderate activities and are not readily recovered and reused. This has prevented the ADA reaction from being widely practiced in the pharmaceutical industry. / (cont.) To create more attractive catalysts, MCF was used to anchor chiral bisoxazoline-copper(II) complexes for the ADA reaction. We have examined the effect of catalyst environment on activity and selectivity through the use of different catalyst ligands, linker groups, and silanol capping agents. The MCF-immobilized catalysts showed enhanced activity compared to their homogeneous counterparts, and the phenomenon was correlated to bisoxazoline ligand loading on the MCF surface. Batch recycling experiments and continuous ADA reactor trials showed that the MCF-anchored catalysts were reusable and stable. Catalytic performance was measured through in situ infrared spectroscopy, and a Michaelis-Menten kinetic model with product inhibition was applied to determine relevant kinetic parameters for the best heterogenized catalyst. The Heck reaction is a powerful synthetic tool in organic chemistry for C-C bond formation through a liquid-phase reaction between aryl halides and alkenes. It has great industrial potential, but the Heck coupling reaction catalysts have traditionally suffered from low oxygen tolerance and poor reusability due to palladium cluster growth, agglomeration and oxidation. In this work, a new mesoporous and crystalline carbon, carbon nanofoam (CNF), was examined as a Pd cluster support for the coupling of 4-bromoacetophenone and n- butyl acrylate. Using CNF as a support, we successfully synthesized Pd/CNF catalysts using a vapor grafting approach and demonstrated high activities for the Heck coupling at 140⁰C. The Pd/CNF catalysts showed remarkable performance enhancements compared to Pd/activated ... / by Thomas M. Lancaster. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2012. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 119-123). / The main body of this work considers the design and development of a microfluidic, continuous electrochemical sensor capable of measuring accurate potential differences. The key challenge in creating such a device is the implementation of a miniaturized reference electrode and salt bridge. The purpose of a salt bridge is to allow ionic conduction between the reference and working electrodes while maintaining a physical separation between the two systems. Macro reference electrode and salt bridge techniques are difficult to implement on a micro scale. Instead of attempting to conform one of these techniques to function in a micro system, new methods were developed that take advantage of the conditions in a continuous microfluidic device. In particular, laminar flow and slow relative diffusion times allow for a reference electrode that does not require a physical salt bridge. Ionic conduction is maintained between neighboring reference and analyte streams while slow mixing effectively separates the two systems. Several different device designs were investigated focusing on the prevention of reference electrode contamination. If the reference electrode is chemically contaminated it will no longer behave as expected and can not be used as a reference point. Contamination at the reference electrode was evaluated while varying flow rates and the geometry of the microfluidic device. Mathematical models were simulated in order to understand the mass transport in each device design. Based on these simulations, dimensionless groups were found that defined the dominant physics in each system. These dimensionless numbers were then validated experimentally and numerically over a range of device parameters. Subsequently, operation criteria were developed to ensure that the reference electrode remains stable and uncontaminated. By creating a stable reference electrode on chip, any homogeneous electrochemical system that was previously studied on the macro scale can now be studied continuously in a microfluidic device. A secondary portion of this work investigates the role of surface charge with respect to electrodynamics in a microchannel. As the surface area to volume ratio increases, the concentration of charge at a channel wall may begin to approach the electrolyte concentration in the bulk solution. This phenomenon is studied numerically, with and without convection, in particular as it relates to a possible mechanism for overlimiting current. Additionally, a potential de-ionization device is theorized based on this mechanism along with scaling arguments that can be used to aid device design. / by EthelMae Victoria Dydek. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2013. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 131-141). / Electron-transfer reactions at nanometer-scale interfaces, such as those presented by single-walled carbon nanotubes (SWCNTs), are important for emerging optoelectronic and photovoltaic technologies. Electron transfer also governs a primary means by which these interfaces are chemically functionalized and subsequently manipulated. This thesis explores several chemical approaches to understanding and controlling charge transfer at nanocarbon interfaces. In the first part of this thesis, we explore ground-state electron transfer via the chemical reaction of SWCNTs with selected diazonium salts as a means of controlling the number of moieties attached to a given nanotube. We initially explore this reaction theoretically using a kinetic Monte Carlo simulation, with rate parameters evaluated using Gerischer-Marcus theory, in order to examine the extent to which these reactions can be controlled stoichiometrically. These modeling results indicate that heterogeneities in SWCNT chiral population result in a large variance in the number of covalent defects, even at low conversions, thereby limiting the ability to control these reactions through stoichiometry. We then experimentally examine the ability to impart an additional degree of control over these reactions through utilization of the adsorbed surfactant layer. Surfactants are commonly employed in the processing of nanoparticles to impart colloidal stability to otherwise unstable dispersions. We find that the chemical and physical properties of adsorbed surfactants influence the diazonium reaction with SWCNT in several ways. Surfactants can impose electrostatic attraction or repulsion, steric exclusion, and direct chemical modification of the reactant. Electrostatic effects are most pronounced in the cases of anionic sodium dodecyl sulfate and cationic cetyltrimethylammonium bromide, where differences in surfactant charge can significantly affect the ability of the diazonium ion to access the SWCNT surface. For bile salt surfactants, with the exception of sodium cholate, we find that the surfactant wraps tightly enough that exclusion effects are dominant. Here, sodium taurocholate exhibits almost no reactivity under the explored reaction conditions, while for sodium deoxycholate and sodium taurodeoxycholate, we show that the greatest extent of reaction is observed among a small population of nanotube species, with diameters between 0.88 and 0.92nm. The anomalous reaction of nanotubes in this diameter range implies that the surfactant is less effective at coating these species, resulting in a reduced surface coverage on the nanotube. Contrary to the other bile salts studied, sodium cholate enables high selectivity toward metallic species and small band-gap semiconductors, which is attributed to surfactant-diazonium coupling to form highly reactive diazoesters. We subsequently move on to examine excited-state electron transfer events between SWCNTs and fullerenes. This electron transfer system is distinct from the diazonium system since it does not result in the formation of a covalent bond between the donor and acceptor species. To study this interface, we synthesized a series of methanofullerene amphiphiles, including derivatives of C60 , C70, and C84, and investigated their electron transfer with SWCNT of specific chirality, generating a structure/reactivity relationship. In the cases of lipid-C61-PEG and lipid-C 71-PEG, which are predicted to similar surfactant surface coverages, band-gap dependent, incomplete quenching was observed across all semiconducting species, indicating that the driving force for electron transfer from SWCNT is small. This is further supported by a Marcus theory model, which predicts that the energy offsets between the SWCNT conduction bands and the fullerene LUMO levels are less than the exciton binding energy of the SWCNT in these two systems. In contrast, the lipid-C 85-PEG derivative shows complete quenching of all SWCNT species utilized in this work. This enhancement in quenching efficiency is consistent with the fact that the LUMO level of C85 methanofullerene is approximately 0.35eV lower than that of the smaller fullerene adducts, resulting in energy offsets which exceed the exciton binding energy. This result, combined with the fact that C8 5 has much higher photo-stability than C61 and C71, makes this larger fullerene adduct a promising candidate for SWCNT-based sensors and photovoltaics. Finally, we design and synthesize fullerene derivatives that self-assemble into onedimensional arrays. We find that a dendritic fullerene, which possesses a Boc-L-Ser-L-Ala-OMe dipeptide sequence at its apex, selectively forms S-oriented, helical, one-dimensional nanowires upon cooling from an isotropic state in cyclohexane. These nanowires possess diameters of 3.76 ± 0.52nm, and can be several microns in length. Control molecules, which do not possess the dipeptide sequence, only produce poorly formed aggregates under identical conditions, indicating that dipeptide-dipeptide interactions are integral to assembly. These nanorods open new opportunities in the chiral assembly of novel electron acceptor materials for optoelectronic and photovoltatic applications. / by Andrew J. Hilmer. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2007. / Includes bibliographical references. / The lack of correlation between in vitro and in vivo gene delivery experiments presents a significant obstacle in the progress of gene therapy studies by preventing the extrapolation of successful cell culture results into animals. This phenomenon has also been documented in the specific case of liver where standard hepatocyte culture systems fail to reliably predict the in vivo performance of gene delivery vectors. This is possibly a consequence of the loss of differentiated phenotype that these cells undergo when they are dissociated from their in vivo environment and cultured in vitro. This problem underscores the necessity for better in vitro models that can mimic the physiological environment and responses of in vivo liver tissue. This thesis aimed at developing an alternative in vitro gene delivery assay based on the Tissue-Engineered Liver Microreactor, a culture system designed to facilitate the morphogenesis of three-dimensional tissue-like structures from isolated liver cells under continuous perfusion, maintain cell viability and hepatic functionality for long-term culture periods and enable repeated in situ observation with microscopy. We developed experimental assays to non-invasively detect and quantify gene delivery efficiency in the 3D environment of the microreactor culture based on the application of 2-photon microscopy and spectroscopy. / (cont.) These techniques provide a convenient platform for comparative analysis of different vectors. Our main objective was to compare the gene delivery efficiency of an adenoviral vector (Ad5-CMV-EGFP) in the microreactor system and 2D hepatocyte monolayer culture. Quantitative assays were developed based on Real-Time PCR and RT-PCR to measure the levels of Ad vector uptake and transgene expression. The Ad mass transport in both systems was mathematically modeled to estimate the Ad uptake constant as a basis for comparison of delivery efficiency. This parameter was found to be significantly higher in the microreactor system, suggesting a more efficient mechanism of Ad internalization. Moreover, gene expression was measured in terms of transgene mRNA levels; the ratio of gene expression relative to Ad uptake was estimated as the basis for comparison of vector transcription efficiency. No significant difference was found between the 2 systems. These results provide some evidence that a more physiological culture system can yield different information (potentially more relevant to the in vivo situation) compared to standard in vitro culture. / by Artemis Kalezi. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, February 2004. / MIT Science Library copy in pages. / Also issued in pages. / Includes bibliographical references (leaves 147-155). / In this work an optimization-based approach to kinetic model reduction was studied with a view to generating reduced-model libaries for reacting-flow simulations. A linear integer formulation of the reaction elimination problem was developed in order to allow the model reduction problem to be solved cheaply and robustly to guaranteed global optimality. When compared with three other conventional reaction-elimination methods, only the integer-programming approach consistently identified the smallest reduced model which satisfies user-specified accuracy criteria. The proposed reaction elimination formulation was solved to generate model libraries for both, homogeneous combustion systems, and 2-D laminar flames. Good agreement was observed between the reaction trajectories predicted by the full mechanism and the reduced model library. For kinetic mechanisms having many more reactions than species, the computational speedup associated with reaction elimination was found to scale linearly with the size of the derived reduced model. Speedup factors of 4-90 were obtained for a variety of different mechanisms and reaction conditions. The integer-programming based reduction approach was tested successfully on large-scale mechanisms comprising up to [approximately] 2500 reactions. The problem of identifying optimal (maximum) ranges of validity for point-reduced kinetic models was also investigated. A number of different formulations for the range problem were proposed, all of which were shown to be variants of a standard semi-infinite program (SIP). Conventional algorithms for nonlinear semi-infinite programs are essentially all lower-bounding methods which cannot guarantee the feasibility of an incumbent at finite termination. / (cont.) Thus, they cannot be used to identify rigorous ranges of validity for reduced kinetic models. In the second part of this thesis, inclusion functions were used to develop an inner approximation method which generates a convergent series of feasible upper bounds on the minimum value of a smooth, non-linear semi-infinite program. The inclusion-constrained reformulation approach was applied successfully to a number of test problems in the SIP literature. The new upper-bounding approach was then combined with existing lower-bounding methods in a branch-and-bound framework which allows smooth nonlinear semi-infinite programs to be solved finitely to [epsilon]-optimality. The branch-and-bound algorithm was also tested on a number of small literature examples. In the final chapter of the thesis, extensions of the existing algorithm and code to solve practical engineering problems, including the range identification problem, were considered. / by Binita Bhattacharjee. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2006. / Includes bibliographical references (p. 187-207). / The macroscopic metabolic phenotype of a cellular system, such as insulin resistance, is the result of the integration of many hundreds or thousands of preceding cellular events, which culminates in the cell's final response to a perturbation in the environment. The data provided by DNA microarrays and multiple types of metabolic measurements can be integrated to reconstruct the actions taken by a cellular system to arrive at a particular metabolic response to a stimulus, elucidating the underlying physiology. We employed this integrated approach for the characterization of hepatic metabolism. First, we implemented a novel method for functional genomics. The metabolic response of hepatoma cells to the depletion and repletion of glutamine was characterized in time course measurements of metabolic fluxes and metabolite pool sizes. DNA microarrays characterized the expression profiles. The metabolic data were correlated with the microarray data to identify coregulated clusters of genes. This study contributed to our understanding of glutamine metabolism in hepatomas, and advanced the field of functional genomics. Next, we identified the hexosamine biosynthetic pathway (HBP) as a mechanism for hyperglycemia-induced hepatic insulin resistance. / (cont.) Glycogen deposition and glucose production data in mouse hepatocytes confirmed that HBP activity was negatively correlated with insulin sensitivity. Metabolite profiling data confirmed that prolonged incubation in hyperglycemic conditions raised the levels of hexosamine intermediates by saturating upper glycolysis. Our data, along with previous work in muscle and adipose tissue, underline the increasingly important role of the HBP in regulating insulin action and energy homeostasis. A dysfunctional HBP may contribute to the pathophysiology of Type 2 diabetes. Finally, we analyzed the control structure of the glucose production bioreaction network. We systematically perturbed the network and analyzed the effects on the fluxes. We found that gluconeogenesis was the dominant flux, and therefore regulation of gluconeogenesis determined the glucose production phenotype. G6Pase was identified as the enzyme in gluconeogenesis controlling the glucose production phenotype, whereas PEPCK played a secondary role. Our conclusions here give insight into the physiology underlying the regulation and dysregulation of hepatic glucose production with possible application to the treatment of Type 2 diabetes. / by Matthew Sing Wong. / Ph.D.

Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 1999. / Includes bibliographical references (leaves 253-261). / A comprehensive hierarchical methodology has been developed to assist decision-makers allocate resources for experimentation during the initial-tages of pharmaceutical and chemical process development. The goal is to identify the most useful information that can be obtained for the least amount of effort and time. The allocation of resources for information gathering is based on Bayesian experimental design. Specifically, experimental designs for parameter estimation, model discrimination, and decisionmaking have been examined. Solving some of these design problems rigorously has not previously been attempted due to the mathematical complexity involved and sheer computational intensity of classical methods. The enabling technology is the use of polynomial chaos expansions to represent process and decisions models. A compact representation of uncertainty permits a rapid evaluation of expected values and variances in the decision models. In typical applications the computational burden was reduced by more than four orders of magnitude. The technique allows processes with industrial levels of complexity to be analyzed. The methodology takes a hierarchical approach. Initially the process subsystem that most adversely affects the objectives is identified. In this way resources are only allocated to studying the most important components. Metrics for measuring financial, environmental, and safety, objectives at different stages of the development process are suggested. The performance measures are unique to pharmaceutical and chemical manufacturing; however, the mathematical techniques developed are universally relevant. Examples showcase the experimental design approaches, the performance metrics, and the hierarchical modeling. A comprehensive case study, production of recombinant heparinase, highlights the most important aspects for an industrially relevant process. / by Morten Aleksandr Engel. / Ph.D.

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemical Engineering, 2015. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 180-203). / There is high demand for next-generation biomolecule detection platforms arising from clinical need for more robust point-of-care diagnosis systems, fundamental research need to characterize complex biological processes, and the emergence of personalized medicine. These detection systems should accordingly provide multiplexed, sensitive, and highly specific quantification of biomarkers from several types of biological fluids. Hydrogels, which are loosely crosslinked networks of polymer chains, are particularly favorable substrates for robust detection of clinical analytes due to their non-fouling properties, ability to immobilize high concentrations of probe molecules, and solution-like environment which often leads to lower free energies of target-probe binding relative to solid surfaces. In this thesis, a novel array of microfluidic gel-based diagnostic tools is created for interrogation of proteins and microRNAs (miRNAs) from a range of biologically complex samples. To this end, we developed two distinct systems that are each applicable in different clinical contexts and both make use of microfluidic photolithographic approaches: (1) well-mixed hydrogel particle arrays for high-throughput and multiplexed quantification of proteins from cell culture, serum, and tissue lysates, and (2) channel-immobilized hydrogel posts for high-sensitive and multiplexed detection of microRNAs in an entirely on-chip format. Graphically-encoded polyethylene glycol (PEG) hydrogel microparticles bearing distinct coding regions and probe regions have previously demonstrated superior detection properties relative to surface-based bead arrays or microarrays for detection of short nucleic acids such as microRNAs. They have also been interfaced with a custom microfluidic highthroughput scanner for real-time post-assay analysis. Now, this platform is extended to multiplexed endogenous protein detection using both aptamer and antibodies to capture and label targets. Through our development and optimization, gel particles could be suspended into several types of unprocessed biological media without fouling or losing detection capability and demonstrated sensitivities that are comparable to commercial standards without needing amplification. In particular, aptamer-based protein detection using gel particles was found to provide up to three orders of magnitude better sensitivity than competing platforms using the hydrated and flexible gel particles also without using signal amplification. The chemical and thermodynamically favorable properties of the gel scaffold were also exploited to engineer an entirely on-chip assay that could have applications in clinical settings. Probe-containing porosity-tuned PEG posts were immobilized into microfluidic channels using a spatial encoding scheme. We developed a novel enzymatic amplification scheme that made use of the unique properties of a laminar two-phase flow around a gel post in a channel to completely isolate the gel posts within a fluorinated oil phase without needing surfactants. These confined gel chambers could then be used to dramatically concentrate products from an enzymatic amplification reaction leading to large (up to 57-fold) increase in sensitivity relative to direct labeling. The platform was integrated with an existing scheme for multiplexed miRNA detection from low amounts (10 - 50 ng) of total RNA inputs to enable entirely on-chip detection that shows great promise for eventual clinical integration to measure these biomarkers for disease diagnosis. Together, the advances reported here have significantly furthered both gel particle arrays and immobilized hydrogel posts as platforms that could eventually be integrated into clinical and research settings for robust biomolecule quantification. / by Rathi Lakshmi Srinivas. / Ph. D.