Dissertations / Theses on the topic 'Chemical engineering'
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Schultheisz, Daniel Joseph. "Exercises in chemical engineering using GPSS." Thesis, Georgia Institute of Technology, 1988. http://hdl.handle.net/1853/19913.
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Lindgren, Joel. "Chemical Engineering of Small Affinity Proteins." Doctoral thesis, KTH, Proteinteknologi, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-141014.
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Small robust affinity proteins have shown great potential for use in therapy, in vivo diagnostics, and various biotechnological applications. However, the affinity proteins often need to be modified or functionalized to be successful in many of these applications. The use of chemical synthesis for the production of the proteins can allow for site-directed functionalization not achievable by recombinant routes, including incorporation of unnatural building blocks. This thesis focuses on chemical engineering of Affibody molecules and an albumin binding domain (ABD), which both are three-helix bundle proteins of 58 and 46 amino acids, respectively, possible to synthesize using solid phase peptide synthesis (SPPS). In the first project, an alternative synthetic route for Affibody molecules using a fragment condensation approach was investigated. This was achieved by using native chemical ligation (NCL) for the condensation reaction, yielding a native peptide bond at the site of ligation. The constant third helix of Affibody molecules enables a combinatorial approach for the preparation of a panel of different Affibody molecules, demonstrated by the synthesis of three different Affibody molecules using the same helix 3 (paper I). In the next two projects, an Affibody molecule targeting the amyloid-beta peptide, involved in Alzheimer’s disease, was engineered. Initially the N-terminus of the Affibody molecule was shortened resulting in a considerably higher synthetic yield and higher binding affinity to the target peptide (paper II). This improved variant of the Affibody molecule was then further engineered in the next project, where a fluorescently silent variant was developed and successfully used as a tool to lock the amyloid-beta peptide in a β-hairpin conformation during studies of copper binding using fluorescence spectroscopy (paper III). In the last two projects, synthetic variants of ABD, interesting for use as in vivo half-life extending partners to therapeutic proteins, were engineered. In the first project the possibility to covalently link a bioactive peptide, GLP-1, to the domain was investigated. This was achieved by site-specific thioether bridge-mediated cross-linking of the molecules via a polyethylene glycol (PEG)-based spacer. The conjugate showed retained high binding affinity to human serum albumin (HSA) and a biological activity comparable to a reference GLP-1 peptide (paper IV). In the last project, the possibility to increase the proteolytic stability of ABD through intramolecular cross-linking, to facilitate its use in e.g. oral drug delivery applications, was investigated. A tethered variant of ABD showed increased thermal stability and a considerably higher proteolytic stability towards pepsin, trypsin and chymotrypsin, three important proteases found in the gastrointestinal (GI) tract (paper V). Taken together, the work presented in this thesis illustrates the potential of using chemical synthesis approaches in protein engineering.QC 20140207
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Molaro, Mark Christopher. "Computational statistical methods in chemical engineering." Thesis, Massachusetts Institute of Technology, 2016. http://hdl.handle.net/1721.1/111286.
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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemical Engineering, 2016.Cataloged from PDF version of thesis.
Includes bibliographical references (pages 175-182).
Recent advances in theory and practice, have introduced a wide variety of tools from machine learning that can be applied to data intensive chemical engineering problems. This thesis covers applications of statistical learning spanning a range of relative importance of data versus existing detailed theory. In each application, the quantity and quality of data available from experimental systems are used in conjunction with an understanding of the theoretical physical laws governing system behavior to the extent they are available. A detailed generative parametric model for optical spectra of multicomponent mixtures is introduced. The application of interest is the quantification of uncertainty associated with estimating the relative abundance of mixtures of carbon nanotubes in solution. This work describes a detailed analysis of sources of uncertainty in estimation of relative abundance of chemical species in solution from optical spectroscopy. In particular, the quantification of uncertainty in mixtures with parametric uncertainty in pure component spectra is addressed. Markov Chain Monte Carlo methods are utilized to quantify uncertainty in these situations and the inaccuracy and potential for error in simpler methods is demonstrated. Strategies to improve estimation accuracy and reduce uncertainty in practical experimental situations are developed including when multiple measurements are available and with sequential data. The utilization of computational Bayesian inference in chemometric problems shows great promise in a wide variety of practical experimental applications. A related deconvolution problem is addressed in which a detailed physical model is not available, but the objective of analysis is to map from a measured vector valued signal to a sum of an unknown number of discrete contributions. The data analyzed in this application is electrical signals generated from a free surface electro-spinning apparatus. In this information poor system, MAP estimation is used to reduce the variance in estimates of the physical parameters of interest. The formulation of the estimation problem in a probabilistic context allows for the introduction of prior knowledge to compensate for a high dimensional ill-conditioned inverse problem. The estimates from this work are used to develop a productivity model expanding on previous work and showing how the uncertainty from estimation impacts system understanding. A new machine learning based method for monitoring for anomalous behavior in production oil wells is reported. The method entails a transformation of the available time series of measurements into a high-dimensional feature space representation. This transformation yields results which can be treated as static independent measurements. A new method for feature selection in one-class classification problems is developed based on approximate knowledge of the state of the system. An extension of features space transformation methods on time series data is introduced to handle multivariate data in large computationally burdensome domains by using sparse feature extraction methods. As a whole these projects demonstrate the application of modern statistical modeling methods, to achieve superior results in data driven chemical engineering challenges.
by Mark Christopher Molaro.
Ph. D.
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Hackel, Benjamin Joseph. "Fibronectin domain engineering." Thesis, Massachusetts Institute of Technology, 2009. http://hdl.handle.net/1721.1/57701.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2009.Vita. Cataloged from PDF version of thesis.
Includes bibliographical references.
Molecular recognition reagents are a critical component of targeted therapeutics, in vivo and in vitro diagnostics, and biotechnology applications such as purification, detection, and crystallization. Antibodies have served as the gold standard binding molecule because of their high affinity and specificity and, historically, because of their ability to be generated by immunization. However, antibodies suffer from several shortcomings that hinder their production and reduce their efficacy in a breadth of applications. The tenth type III domain of human fibronectin provides a small, stable, single-domain, cysteine-free protein scaffold upon which molecular recognition capability can be engineered. In the current work, we provide substantial improvements in each phase of protein engineering through directed evolution and develop a complete platform for engineering high affinity binders based on the fibronectin domain. Synthetic combinatorial library design is substantially enhanced through extension of diversity to include three peptide loops with inclusion of loop length diversity. The efficiency of sequence space search is improved by library focusing with tailored diversity for structural bias and binding capacity. Evolution of lead clones was substantially improved through development of recursive dual mutagenesis in which each fibronectin gene is subtly mutated or the binding loops are aggressively mutated and shuffled. This engineering platform enables robust generation of high affinity binders to a multitude of targets. Moreover, the development of this technology is directly applicable to other protein engineering campaigns and advances the scientific understanding of molecular recognition. Binders were engineered to tumor targets carcinoembryonic antigen, CD276, and epidermal growth factor receptor as well as biotechnology targets human serum albumin and goat, mouse, and rabbit immunoglobulin G. Binders have demonstrated utility in affinity purification, laboratory detection, and cellular labeling and delivery. Of particular interest, a panel of domains was engineered that bind multiple epitopes of epidermal growth factor receptor. Select non-competitive heterobivalent combinations of binders effectively downregulate receptor in a non-agonistic manner in multiple cell types. These agents inhibit proliferation and migration and provide a novel potential cancer therapy.
by Benjamin Joseph Hackel.
Ph.D.
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Akpa, Belinda Sena Akosua. "Quantitative, chemically-resolved study of chemical engineering systems using nuclear magnetic resonance." Thesis, University of Cambridge, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.612860.
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Torbensen, Kristian. "Physico-Chemical and Microfluidic Approaches Toward Engineering Oscillating and Communicating Chemical Droplets." Thesis, Paris 6, 2016. http://www.theses.fr/2016PA066707/document.
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La génération, propagation et la réception d’informations (bio/chimiques) entre les organismes individuels sont la clé de voûte de nombreux systèmes communicants intelligents et sont omniprésents dans la nature. Les colonies de lucioles synchronisent leurs flashs, et la contraction et l’expansion des muscles cardiaques sont quelques exemples parmi d’autres, où les signaux bio / chimiques générés par des sources synchronisées produisent un comportement coopératif. L’objectif final de cette thèse est de développer une plateforme fiable pour générer des réseaux de communication de liposomes, en encapsulant la réaction de Belousov-Zhabotinsky (BZ) en tant que source d’information ou un signal transmis, et d’étudier la dynamique d’un tel système. Pour atteindre cet objectif, plusieurs questions ont été abordées par une approche “bottom-up” et multi-échelle. Tout d’abord, nous avons étudié l’interaction entre des liposomes de DMPC dopés et non-dopés avec le cholestérol, l’acide myristique, tétradécylsulfate, tétradécylamine, et les espèces impliquées dans la reaction BZ en utilisant la diffusion de rayons X aux petits angles et par spectrophotométrie UV-visible. Des rangées 1D de micro-gouttelettes ont été fabriquées en encapsulant la réaction BZ en microgouttelettes au moyen de la microfluidique et la communication entre les gouttelettes adjacentes a été étudiée. Plus tard, nous avons démontré un système microfluidique facile à monter / démonter avec une conception robuste et une géométrie modulable pour générer des emulsions doubles d’eau dans l’huile dans l’eau (E/ H / O). Enfin, le comportement de ces doubles emulsions générées dans système microfluidique en utilisant des phosphoplipides comme tensioactif et du chloroforme comme phase huileuse, est rapporté. Nous avons montré, avec cette composition de la phase d’huile, que le comportement dynamique des émulsions doubles sous écoulement donne lieu à des phénomènes riches incluant la déformation et du “tip-streaming”Generation, propagation and reception of (bio/chemical) information between individual organisms are the keystone of many intelligent communicating systems, and are ubiquitous in Nature. Colonies of fireflies synchronize their flashes, and contraction and expansion of heart muscles are few examples among others, where bio/chemical signals generated by synchronized sources produce a cooperative behaviour. The final objective of this thesis is to develop a reliable platform for generating communicative networks of liposomes, encapsulating the Belousov-Zhabotinsky (BZ) reaction as source of information or transmitted signals, and to study the dynamics of such a system. To reach this goal, several issues were addressed by following bottom-up and multi-scale approaches. First we investigated the interaction between both bulk DMPC liposomes, and liposomes doped with cholesterol, myristic acid, tetradecylsulfate, tetradecylamine, and the species involved in the BZ-reaction by using small angle X-ray scattering (SAXS) and UV-visible spectrophotometry. Than 1D arrays of micro-droplets were fabricated by encapsulating the BZ reaction into microdroplets by means of microfluidics, and the communication between adjacent droplets was studied. Later, we demonstrated an easy to assemble/disassemble and robust design for a microfluidic device with adjustable geometry, for generating monodisperse water-in-oil-in-water (w/o/w) double emulsions. Finally, the behavior of w/o/w double emulsions generated in a microfluidic device, using phospholipids as surfactant and chloroform as the oil phase, was reported. We showed, with this composition of the oil phase, that the dynamic behaviour of the double emulsions under flow gave rise to different phenomena, such as deformation and tip-streaming
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Jarvis, Richard Barry. "Robust dynamic simulation of chemical engineering processes." Thesis, Imperial College London, 1993. http://hdl.handle.net/10044/1/7309.
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Shen, Xin. "Applications of Fractional Calculus In Chemical Engineering." Thesis, Université d'Ottawa / University of Ottawa, 2018. http://hdl.handle.net/10393/37577.
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Fractional calculus, which is a generalization of classical calculus, has been the subject of numerous applications in physics and engineering during the last decade. In this thesis, fractional calculus has been implemented for chemical engineering applications, namely in process control and in the modeling mass transfer in adsorption.
With respect to process control, some researchers have proposed fractional PIλDμ controllers based on fractional calculus to replace classical PI and PID controllers. The closed-loop control of different benchmark dynamic systems using optimally-tuned fractional PIλDμ controllers were investigated to determine for which dynamic systems this more computationally-intensive controller would be beneficial. Four benchmark systems were used: first order plus dead time system, high order system, nonlinear system, and first order plus integrator system. The optimal tuning of the fractional PIλDμ controller for each system was performed using multi-objective optimization minimizing three performance criteria, namely the ITAE, OZ, and ISDU. Conspicuous advantages of using PIλDμ controllers were confirmed and compared with other types of controllers for these systems. In some cases, a PIλ controller was also a good alternative to the PIλDμ controller with the advantage of being less computationally intensive.
For the optimal tuning of fractional controllers for each benchmark dynamic system, a new version of the non-dominated sorting genetic algorithm (NSGA-III) was used to circumscribe the Pareto domain. However, it was found that for the tuning of PIλDμ controllers, it was difficult to circumscribe the complete Pareto domain using NSGA-III. Indeed, the Pareto domain obtained was sometimes fragmentary, unstable and/or susceptible to user-defined parameters and operators of NSGA-III. To properly use NSGA-III and determine a reliable Pareto domain, an investigation on the effect of these user-defined operators and parameters of this algorithm was performed. It was determined that a reliable Pareto domain was obtained with a crossover operator with a significant extrapolation component, a Gaussian mutation operator, and a large population. The findings on the proper use of NSGA-III can also be used for the optimization of other systems.
Fractional calculus was also implemented in the modeling of breakthrough curves in packed adsorption columns using finite differences. In this investigation, five models based on different assumptions were proposed for the adsorption of butanol on activated carbon. The first four models are based on integer order partial differential equations accounting for the convective mass transfer through the packed bed and the diffusion and adsorption of an adsorbate within adsorbent particles. The fifth model assumes that the diffusion inside adsorbent particles is potentially anomalous diffusion and expressed by a fractional partial differential equation. For all these models, the best model parameters were determined by nonlinear regression for different sets of experimental data for the adsorption of butanol on activated carbon. The recommended model to represent the breakthrough curves for the two different adsorbents is the model that includes diffusion within the adsorbent particles. For the breakthrough experiments for the adsorption of butanol on activated carbon F-400, it is recommended using a model which accounts for the inner diffusion within the adsorbent particles. It was found that instantaneous or non-instantaneous adsorption models can be used. Best predictions were obtained with fractional order diffusion with instantaneous adsorption. For the adsorption of butanol on activated carbon Norit ROW 0.8, it is recommended using an integer diffusion model with instantaneous adsorption. The gain of using fractional order diffusion equation, given the intensity in computation, was not sufficient to recommend its use.
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Quantrille, Thomas E. "Prolog and artificial intelligence in chemical engineering." Diss., This resource online, 1991. http://scholar.lib.vt.edu/theses/available/etd-06062008-170029/.
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Yasmin, Samina. "Engineering of P450cam for fine chemical synthesis." Thesis, University of Oxford, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.497160.
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Nguyen, Kieu Lien. "Terahertz spectroscopy and imaging in chemical engineering." Thesis, University of Cambridge, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.612895.
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Sullivan, Simon Philip. "Lattice Boltzmann development for chemical engineering applications." Thesis, University of Cambridge, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.614213.
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Baughman, D. Richard. "Neural Networks in Bioprocessing and Chemical Engineering." Diss., This resource online This resource online, 1995. http://scholar.lib.vt.edu/theses/available/etd-09222008-135734/restricted/LD5655.V856_1995.B384.V1.pdf.
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Tudisco, Cristina. "Chemical Engineering of Silicon for Supramolecular Recognition." Doctoral thesis, Università di Catania, 2012. http://hdl.handle.net/10761/938.
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This thesis discusses some strategies to anchor functional molecules on silicon-based substrates in order to introduce onto a solid surface specific functionalities. Two main typologies of silicon-based substrates both of technological interest have been functionalized through synthetic routes based on the hydrosilylation reaction. First typology consists of flat monocrystalline Si(100) which is the surface of election for the development of commercial microelectronic devices, while second substrate typology consists of porous silicon which represents an interesting candidate for novel devices due to its specific properties such as high surface area and luminescence. In particular, the attention is focused on the surface grafting of cavitand-based molecules, synthetic organic compounds with rigid cavities of molecular dimensions, which are interesting and versatile receptors. A key point of this thesis has been the study of the recognition properties of these receptors after surface anchoring. The obtained hybrid materials consisting of cavitand monolayer bonded to silicon surface combined the technological advantages of either Si(100) or porous silicon substratetes with the recognition properties of cavitand, thus allowing various applications ranging from sensing to surface hierarchical nanoassembly.
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Moro, Lorenzo <1985>. "Complex chemical dynamics through engineering-like methods." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2014. http://amsdottorato.unibo.it/6202/1/TesiDoc_Moro.pdf.
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Most of the problems in modern structural design can be described with a set of equation; solutions of these mathematical models can lead the engineer and designer to get info during the design stage. The same holds true for physical-chemistry; this branch of chemistry uses mathematics and physics in order to explain real chemical phenomena. In this work two extremely different chemical processes will be studied; the dynamic of an artificial molecular motor and the generation and propagation of the nervous signals between excitable cells and tissues like neurons and axons. These two processes, in spite of their chemical and physical differences, can be both described successfully by partial differential equations, that are, respectively the Fokker-Planck equation and the Hodgkin and Huxley model. With the aid of an advanced engineering software these two processes have been modeled and simulated in order to extract a lot of physical informations about them and to predict a lot of properties that can be, in future, extremely useful during the design stage of both molecular motors and devices which rely their actions on the nervous communications between active fibres.
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Moro, Lorenzo <1985>. "Complex chemical dynamics through engineering-like methods." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2014. http://amsdottorato.unibo.it/6202/.
Full textAbstract:
Most of the problems in modern structural design can be described with a set of equation; solutions of these mathematical models can lead the engineer and designer to get info during the design stage. The same holds true for physical-chemistry; this branch of chemistry uses mathematics and physics in order to explain real chemical phenomena. In this work two extremely different chemical processes will be studied; the dynamic of an artificial molecular motor and the generation and propagation of the nervous signals between excitable cells and tissues like neurons and axons. These two processes, in spite of their chemical and physical differences, can be both described successfully by partial differential equations, that are, respectively the Fokker-Planck equation and the Hodgkin and Huxley model. With the aid of an advanced engineering software these two processes have been modeled and simulated in order to extract a lot of physical informations about them and to predict a lot of properties that can be, in future, extremely useful during the design stage of both molecular motors and devices which rely their actions on the nervous communications between active fibres.
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Liu, David Victor. "Protein engineering for cancer therapy." Thesis, Massachusetts Institute of Technology, 2011. http://hdl.handle.net/1721.1/73796.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, February 2012.Cataloged from PDF version of thesis.
Includes bibliographical references.
The immunosuppressive effects of CD4⁺CD25⁺ regulatory T cells (Tregs) interfere with anti-tumor immune responses in cancer patients. In the first part of this work, we present a novel class of engineered Interleukin-2 (IL-2) analogues that antagonize the IL-2 receptor, for inhibiting Treg suppression. These antagonists are engineered for high affinity to the IL-2 receptor a subunit and low affinity to either the [beta] or [gamma] subunit, resulting in a signaling-deficient IL-2 analogue that sequesters the IL-2 receptor a subunit from wild type IL-2. Using this design, human and mouse IL-2 antagonists were generated with inhibition constants ranging from 200 pM to 5 nM in vitro. Genetic fusions with IgG2a Fc enhanced serum half-life up to 30 hours. In order to study the effects of IL-2 antagonism, Fc fragments with disrupted effector functions were used. Fc-antagonist fusions bound to but could not deplete peripheral Tregs. They downregulated CD25 on Tregs, but could not perturb Treg function in a syngenic tumor model, presumably due to the high sensitivity of the IL-2 receptor and a high threshold for antagonism in vivo. In the second part of this work, we present a novel multi-agent protein-based system for targeted siRNA delivery that provides potential advantages over other nanoparticle- and proteinbased delivery vehicles. In the first agent, the double stranded RNA binding domain (dsRBD) of human protein kinase R is used as an siRNA carrier, in fusion proteins that target epidermal growth factor receptor (EGFR). Targeted dsRBD proteins deliver large amounts of siRNA to endosomal compartments in an EGFR expressing cell line, but efficient gene silencing is limited by endosomal escape. The use of a second agent that contains the cholesterol dependent cytolysin, perfringolysin 0, enhances endosomal escape of siRNA. Targeted delivery of perfringolysin 0 induces gene silencing in a dose-dependent and EGFR-dependent manner. However, cytotoxicity of the cytolysin creates a narrow therapeutic window. Multiepitopic EGFR binders that induce EGFR clustering are explored as tools for enhancing gene silencing efficiency. Interestingly, they not only enhance gene silencing potency but also protect against toxicity from EGFR-targeted cytolysins, thus significantly widening the therapeutic window of this method.
by David Victor Liu.
Ph.D.
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Choi, Siwon (Siwon Chloe). "Microfluidic engineering of water purification." Thesis, Massachusetts Institute of Technology, 2017. http://hdl.handle.net/1721.1/111415.
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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemical Engineering, 2017.Cataloged from PDF version of thesis.
Includes bibliographical references.
The demand for clean water has been increasing for several reasons, such as rapid industrialization of developing countries, environmental pollution and climate change, and development of biofuels and the resulting irrigation growth. To meet the needs for this growing demand for clean water, desalination has become an appealing solution as saline water (brackish water, seawater and brine) are the most abundant water source for most of the world. However, desalination is energy and capital intensive compared to other water treatment processes, and oftentimes it is not economically feasible. Current desalination technologies require further engineering and development to become more sustainable in the long term. My Ph.D thesis is focused on engineering of electromembrane desalination, which is a set of electrically driven desalination technologies that utilize ion transport through ion exchange membranes. We employed microfluidic platforms and numerical modeling tools for the study, for they help reveal novel insights regarding the micro-scale details that are difficult to be discovered from the conventional large-scale systems. In this thesis, we consider three topics: i) engineering of structures that enhance mass transport in electrodialyis (ED), ii) techno-economic analysis of ion concentration polarization (ICP) desalination for high salinity brine treatment, and iii) development of electrocoagulation (EC) - ion concentration polarization (ICP) desalination hybrid that removes dissolved ions and non-ionic contaminants from water in a single device. First, we employed an electrodialysis (ED) system as a model to investigate the mass transport effects of embedded microstructures, also known as spacers, in electromembrane desalination systems. The spacer engineering is especially critical for low salinity (i.e., brackish water) desalination, where the mass transport in the solution is a dominant contributor to the electrical energy consumption in the system. Parametric studies of the spacer design revealed that small cylindrical structures effectively re-distribute the local flow velocity and enhance mass transport in the system. Furthermore, we found that relative diffusivities of cation and anion in the solution should be considered in designing the spacer and that the optimal design should maximize the mass transport while keeping the effect on the hydrodynamic resistance small. Next, we built an empirical model to estimate an electrical energy consumption of ICP desalination and utilized it to obtain the water cost and optimal operating parameters for high salinity applications. We performed cost analyses on two specific cases (i.e., partial desalination of high salinity brine to the seawater level, and brine concentration for salt production) and compared the performance with mainstream desalination technologies for each application. Lastly, we combined two electrical water treatment technologies and created an EC-ICP hybrid for total water treatment, which removes dissolved ions and non-ionic contaminants from the feed solution. We demonstrated a continuous EC-ICP operation that successfully removed salt and suspended solids. Our system is flexible in terms of the system size, and the type and concentration of contaminants it can handle, and thus it can find applications as a portable water treatment system.
by Siwon Choi.
Ph. D.
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Graff, Christilyn Paula. "Antibody engineering for tumor immunotherapy." Thesis, Massachusetts Institute of Technology, 2002. http://hdl.handle.net/1721.1/29279.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2002.Vita.
Includes bibliographical references (leaves 130-140).
Antibodies have been used as cancer therapeutics for several decades. One area in which this therapy may be improved is the retention time of antibody in the tumor relative to normal tissue. In this Thesis, we have attempted to elucidate the mechanisms that are most influential to improving antibodies as cancer therapeutics. Carcinoembryonic antigen (CEA) has long been identified as a tumor-associated antigen. CEA is also quite stable, with a cell-surface shedding half-life of approximately 7 days. Directed evolution methodology has been utilized to design an antibody fragment with properties that would improve tumor retention. Specifically, antibody engineering methods were used to produce a humanized, extremely high affinity and stable single chain antibody fragment (scFv) against CEA. Several mutant scFv libraries were constructed and screened against soluble CEA with yeast surface display and fluorescent activated cell sorting (FACS). A series of antibodies were engineered that span three orders of magnitude in off-rate improvement. These antibody fragments show excellent stability at physiologically relevant temperatures. In addition, soluble protein expression levels were greatly improved. The final product has a dissociation half-life of approximately 7 days, currently the longest engineered half-life of an scFv against a tumor-associated antigen. Binding and diffusion in micrometastases was also modeled to gain an improved understanding of the quantitative interplay among the rate processes of diffusion, binding, degradation, and plasma clearance in tumor microspheroids.
(cont.) Modeling studies illuminated the importance of targeting stable tumor-associated antigens. The elimination rate of the antigen was of critical importance to the change in the therapeutic effect of antibodies with increasing affinity. The significance of this result in the context of previous experimental studies will be discussed. By affinity maturing an antibody with a dissociation half-life equal to the turnover half-life of the antigen, we have engineered an antibody with effectively irreversible binding to CEA. Differences in retention for the series of scFvs will thus be dominated by the off-rate of the antibody and not the half-life of CEA. With this in mind, the molecules designed in this study can be used to reconcile the issue of affinity's impact on efficacy in tumor therapy.
by Christilyn Paula Graff.
Ph.D.
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Kunjapur, Aditya Mohan. "Microbial engineering for aldehyde synthesis." Thesis, Massachusetts Institute of Technology, 2015. http://hdl.handle.net/1721.1/98710.
Full textAbstract:
Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemical Engineering, 2015.Cataloged from PDF version of thesis.
Includes bibliographical references (pages 140-151).
Microbes have been engineered to produce many useful classes of chemicals from renewable carbon sources instead of from finite petroleum reserves. Aldehydes represent a class of chemicals that has been challenging to obtain using microbes given the rapid conversion of aldehydes into their corresponding alcohols that occurs naturally. Microbes are thought to have evolved numerous endogenous enzymes responsible for catalyzing these conversions in order to alleviate the negative effect of many aldehydes on cellular processes. In this thesis, we investigate several aspects of microbial aldehyde synthesis. Driven first by the hypothesis that targeted gene deletions could decrease endogenous aldehyde reduction in a model E. coli host strain, we demonstrate that benzaldehyde accumulation occurs upon deletion of a combination of genes encoding enzymes known to have benzaldehyde reductase activity in vitro. Using deletion subset studies and quantitative real-time PCR, we discover that deletion of many, but not all, of these genes is required to curtail endogenous reduction. We also show that the same engineered strain has a significantly decreased rate of reduction of other aromatic aldehydes. As an added benefit, cell growth rate is unaffected by these deletions. We demonstrate the utility of this strain for two applications: (i) conversion of glucose into vanillin, which is the most widely used flavoring additive; and, (ii) conversion of benzaldehyde and glucose into L-phenylacetylcarbinol, which is a chiral pharmaceutical intermediate. We next explore the ability to produce and retain non-aromatic aldehydes with the specific objective of studying the conversion of fatty aldehydes into gasoline-range alkanes. We find that a carboxylic acid reductase (Car) from Nocardia iowensis achieves biosynthesis of aldehydes from free fatty acid substrates ranging in carbon chain length from C4 to C10. The use of Car, the engineered host strain, and previously elucidated pathways to free fatty acids enables production of alkanes ranging from C3 to C9. Although alcohol byproduct formation significantly decreases, it does not significantly increase alkane titer because of poor aldehyde decarbonylase kinetics. Additional work presented in this thesis seeks to identify and surmount limitations in aldehyde biosynthesis in vitro and in E. coli de novo vanillin biosynthesis.
by Aditya Mohan Kunjapur.
Ph. D.
21
Yeung, Yik Andy. "Antibody engineering for cancer therapy." Thesis, Massachusetts Institute of Technology, 2005. http://hdl.handle.net/1721.1/32325.
Full textAbstract:
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2005.Vita.
Includes bibliographical references (leaves 131-141).
Antibodies targeting various tumor-associated antigens have been developed successfully to treat cancer. In this Thesis, novel antibodies and antibody-conjugate against two tumor antigens, AF-20 antigen and human aspartyl (asparaginyl) [beta]- hydroxylase (HAAH), were developed. Previously, these two tumor antigens have been shown to be present on a variety of tumor cells, while they have minimal expression on normal tissues, rendering them excellent targets for antibody therapy. For the AF-20 work, the variable region (V) gene of a previously isolated mouse monoclonal antibody (mAb) AF-20 was cloned from hybridoma mRNA and used to construct an AF-20 single-chain Fv (scFv). The AF-20 scFv was shown to bind specifically to the same epitope as mAb AF-20 with a binding affinity of 4nM. The AF- 20 scFv was also internalized into tumor cells in a manner identical to that of the original mAb AF-20. The scFv was later employed for cellular internalization of virus-sized fluorescent quantum dots. In addition, to demonstrate the versatility of this antibody, an immunotoxin composed of AF-20 scFv fused to the highly cytotoxic recombinant toxin gelonin was constructed, and its in-vitro efficacy against three different tumor cell lines were evaluated. The IC50 of the AF-20 scFv-gelonin fusion was consistently one to two logs lower than the IC50 of free gelonin on FOCUS (liver), L3.6pl (pancreas) and PC3 (prostate) cells, further demonstrating the capability of the AF-20 scFv as a targeting module. Therefore, this AF-20 scFv is a potential internalization vector for toxins, enzymes, radionuclides and virus for targeted therapy of AF-20-antigen expressing tumor cells.
For the HAAH study, twelve novel human scFv against HAAH were isolated from a human non-immune scFv library displayed on the surface of yeast. Five of the twelve scFv were reformatted as human IgG 1. One of the reformatted IgG, 6-22, showed significant binding to recombinant HAAH protein in ELISA, tumor cell lines, and tumor tissues. 6-22 IgG was also shown to target the catalytic domain of HAAH, and its apparent dissociation constant was determined to be 1.OnM. 6-22 IgG alone does not exhibit significant cytotoxicity toward the tumor cells. However, 6-22 IgG internalizes into tumor cells and can therefore be employed to deliver cytotoxic moieties into tumor cells. A goat anti-human IgG-saporin conjugate was delivered into tumor cells by 6-22 IgG and hence elicited cytotoxicity toward the tumor cells in vitro. Meanwhile, the monovalent affinity of 6-22 scFv was too low for therapeutic or diagnostic application, so 6-22 scFv was affinity matured using directed evolution and yeast surface display. After two rounds of mutagenesis, a mutant, C4-18, with an affinity of 0.6nM was isolated. Overall, these human [gamma]-HAAH scFv and IgG can potentially be used in the diagnosis and therapeutic treatment of HAAH-expressing tumor cells.
by Yik Andy Yeung.
Ph.D.
22
Khan, Imran Ullah. "CHEMCAD as a tool when teaching Chemical Engineering." Thesis, Karlstads universitet, Fakulteten för teknik- och naturvetenskap, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:kau:diva-8643.
Full textAbstract:
The aim of this project was to design different chemical processes using Chemcad software. Following five Chemcad models that had industrial relevance were designed and discussed, production of nitric acid by ammonia oxidation process, Production of sodium carbonate by Solvay process, production of hydrogen by steam reforming of natural gas, production of sulphuric acid by Contact process and production of sulphur by Claus process. Equilibrium reactor, Gibbs reactor, absorption tower, heat exchangers, condensers, separators, pumps, compressors and mixers are designed on flow sheet diagram using Chemcad software. Mass balances and energy balances of Chemcad models were compared with bachelor thesis work and their differences and similarities were discussed in detail. In all processes reasonable results were obtained. Mostly in all cases results are the same as in the bachelor thesis. It was seen that equilibrium reactors give better results as compare to Gibbs reactors because when conversion factor of the chemical reaction was not known, Gibbs reactor was used and it adjust the conversion by itself according to equilibrium concentrations of the compounds. SI unit system was used in Chemcad models because in Sweden the SI system is very well established.
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Pogiatzis, Thomas. "Application of mixed-integer programming in chemical engineering." Thesis, University of Cambridge, 2013. https://www.repository.cam.ac.uk/handle/1810/245023.
Full textAbstract:
Mixed-Integer Programming has been a vital tool for the chemical engineer in the recent decades and is employed extensively in process design and control. This dissertation presents some new Mixed-Integer Programming formulations developed for two well-studied problems, one with a central role in the area of Optimisation, the other of great interest to the chemical industry. These are the Travelling Salesman Problem and the problem of scheduling cleaning actions for heat exchanger networks subject to fouling. The Travelling Salesman Problem finds a plethora of applications in many scientific disciplines, Chemical Engineering included. None of the mathematical programming formulations proposed for solving the problem considers fewer than O(n^2) binary degrees of freedom. The first part of this dissertation introduces a novel mathematical description of the Travelling Salesman Problem that succeeds in reducing the binary degrees of freedom to O(nlog2(n)). Three Mixed-Integer Linear Programming formulations are developed and the computational performance of these is tested through computational studies. Sophisticated methods are now available for scheduling the cleaning actions for networks of heat exchangers subject to fouling. In the majority of these, only one form of cleaning is used, which restores the performance of the exchanger back to its clean level. A recent study revised the scheduling problem for the case where there are several cleaning methods available. The second part of this dissertation extends their approach, developed for individual units, to heat exchanger networks and explores the concept of selection of cleaning techniques further. Mixed-Integer Programming formulations are proposed for the scheduling task, for two fouling scenarios: (i) chemical reaction fouling and (ii) biological fouling. A series of results are presented for the implementation of the scheduling formulations to networks of different sizes.
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Rivera, Michael Kirn. "Protection, exposure, and recovery for chemical field engineering." Thesis, California State University, Long Beach, 2015. http://pqdtopen.proquest.com/#viewpdf?dispub=1604869.
Full textAbstract:
This project is a compilation of information from public sources as well as from private unclassified military sources combined with first hand field engineering knowledge. This report should be read prior to any and all who will be entering any Superfund site and/or Formally Used Defense Site (FUDS). Reading of this report should be done in order to make the individual aware of the risk they are under taking by entering a Superfund and FUD site. Primarily the health risks that include but are not limited the development of cancer and death. It should be noted that this report does not cover all contaminates, but focuses on the most detrimental to human health and widely found hazards. Primarily the effects Radiation, Lead, Cyanobacteria Blooms, and MTBE have on the human body and how these chemicals came to be in the environment. Ways to prevent exposure and treatment for when exposure occurs.
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Koshi, Yoichiro. "Development of New Chemical Methods toward Lectin Engineering." 京都大学 (Kyoto University), 2008. http://hdl.handle.net/2433/57283.
Full textAbstract:
Kyoto University (京都大学)0048
新制・課程博士
博士(工学)
甲第13851号
工博第2955号
新制||工||1436(附属図書館)
26067
UT51-2008-C767
京都大学大学院工学研究科合成・生物化学専攻
(主査)教授 濵地 格, 教授 森 泰生, 教授 白川 昌宏
学位規則第4条第1項該当
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Yildirir, Eyup. "Chemical engineering of waste plastics via hydrothermal processing." Thesis, University of Leeds, 2015. http://etheses.whiterose.ac.uk/10704/.
Full textAbstract:
Utilizing a simple, cost effective, feasible and efficient recycling process for waste plastics, which are largely produced from non-renewable sources, is strategically important for a sustainable environment and economy. In Europe, landfilling is still the major waste management method; therefore new routes for recycling are being researched to increase the recycling rates. In this research, hydrothermal processing was used for recycling of waste carbon fibre reinforced plastics (CFRP) and printed circuit boards (PCB) in a batch reactor were investigated. Also, the applicability of the hydrothermal process was tested on refuse derived fuel (RDF), as it is a good representative of municipal solid waste which is a complex waste mixture consisting of plastics, other biodegradable materials and inorganic materials. The ability of supercritical water to degrade the resins and plastics in the composite wastes was largely influenced by the presence of different additives and/or co-solvents. Water at supercritical conditions was able to remove 92.6% of the resin from the CFRP waste in the presence of KOH and 10 wt% H2O2. In the work with PCB, 94% of the resin removal was achieved with alkalis, at zero residence time. The carbon fibre was recovered by preserving 78 % of its tensile strength due to the loss in the mechanical properties as a result of oxidation on the carbon fibre surface. When mixtures of ethylene glycol and water were used as solvent, without any addition of a catalyst, 97.6 % resin removal was achieved at 400oC. The liquid obtained from hydrothermal processing of PCB mainly composed of phenol, and phenolic compounds, which are the precursors of the original thermosetting resin. The liquid effluent from the degradation of CFRP with water and ethylene glycol mixture became too complex for recovery and so was gasified under supercritical water conditions. In the presence of NaOH and ruthenium oxide as catalysts the produced fuel gas consisted of H2, CH4, CO2, CO and C2-4 hydrocarbon gases. The carbon fibres recovered using ethylene glycol co-solvent preserved its mechanical properties and used for the manufacture of new composite materials. The mechanical tests showed that the new composites with recovered carbon fibres had enhanced mechanical properties similar to those made from virgin carbon fibres. Finally RDF was subjected to hydrothermal gasification process to produce fuel gas. Up to 93% carbon gasification efficiency was achieved in the presence of 5 wt% RuO2/γ-Al2O3 catalyst, producing a fuel gas mostly consisting of H2, CH4, and CO2 with a heating value of 22.5 MJ/Nm3. The gross calorific value of the product gas increased to 32.4 MJ/Nm3 in the presence of NaOH, as a result of carbon dioxide fixation as sodium carbonate. Also, high yields of hydrogen were obtained in the presence of both the NaOH and ruthenium catalysts, as both promoted the water-gas shift reaction.
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TESTA, STEFANO. "Engineering musculoskeletal tissue upon mechanical and chemical inducement." Doctoral thesis, Università degli Studi di Roma "Tor Vergata", 2016. http://hdl.handle.net/2108/201710.
Full text
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Radisic, Milica. "Biomimetic approach to cardiac tissue engineering." Thesis, Massachusetts Institute of Technology, 2004. http://hdl.handle.net/1721.1/28665.
Full textAbstract:
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2004."September 2004."
Includes bibliographical references.
(cont.) biochemical and morphological properties in the pretreated group. Finally, in order to mimic capillary structure cardiac fibroblasts and myocytes were co-cultured on a scaffold with a parallel channel array that was perfused with culture medium supplemented with synthetic oxygen carrier (PFC emulsion). Presence of the PFC emulsion resulted in significantly higher cell density and improved contractile properties compared to the constructs cultivated in the culture medium alone, by increasing total oxygen content and effective diffusivity.
Heart disease is the leading cause of death in the Western world. Tissue engineering may offer alternative treatment options or suitable models for studies of normal and pathological cardiac tissue function in vitro. Current tissue engineering approaches have been limited by diffusional oxygen supply, lack of physical stimuli and absence of multiple cell types characteristic of the native myocardium. We hypothesized that functional, clinically sized (1-5 mm thick), compact cardiac constructs with physiologic cell densities can be engineered in vitro by mimicking cell microenvironment present in the native myocardium in vivo. Since cardiac myocytes have limited ability to proliferate we developed methods of seeding cells at high densities while maintaining cell viability. Cultivation of cardiac constructs in the presence of convective-diffusive oxygen transport in perfusion bioreactors, maintained aerobic cell metabolism, viability and uniform distribution of cells expressing cardiac markers. To improve cell morphology and tissue assembly cardiac constructs were cultivated with electrical stimulation of contraction in a physiologically relevant regime. Electrical stimulation enabled formation of tissue with elongated cells aligned in parallel and with organized ultrastructure remarkably similar to the one present in the native heart. To investigate the effect of multiple cell types on the properties of engineered cardiac tissue cardiac fibroblasts and cardiac myocytes were cultivated synchronously, separately or serially (pretreatment of scaffolds with fibroblasts followed by the addition of myocytes). Presence of fibroblasts remarkably improved contractile response of the engineered cardiac constructs with the superior
by Milica Radisic.
Ph.D.
29
Hilmer, Andrew J. (Andrew Joseph). "Engineering nanocarbon interfaces for electron transfer." Thesis, Massachusetts Institute of Technology, 2013. http://hdl.handle.net/1721.1/83783.
Full textAbstract:
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.
30
Carrier, Rebecca Lyn 1973. "Cardiac tissue engineering : bioreactor cultivation parameters." Thesis, Massachusetts Institute of Technology, 1999. http://hdl.handle.net/1721.1/8999.
Full textAbstract:
Thesis (Sc.D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2000.Includes bibliographical references.
Tissue engineering may be useful in fighting heart disease since it offers the possibility of creating functional tissue equivalents for scientific studies and tissue repair. In the present work, we examined how variations in cultivation parameters of a model tissue engineering system influenced cardiac tissue morphogenesis. The central hypothesis was that using a tissue engineering system consisting of isolated cardiac cells, polymer scaffolds, and tissue culture bioreactors, we could engineer cardiac muscle mimicking native tissue in structure and function in the presence of appropriate biochemical and physical signals. The specific objectives were to: ( 1) vary key parameters of the model tissue engineering system, and (2) structurally and functionally characterize engineered cardiac muscle so that effects of parameter variations could be assessed and engineered tissue could be compared to native tissue. Effects of key cultivation parameters, including (I) cell source, (2) cell seeding density, (3) cell seeding vessel, and (4) tissue culture bioreactor on structure and function of engineered cardiac cell-polymer constructs were studied. Advantages of seeding mammalian cells at high densities (6-Sx 106 cells/Smm diameter x 2mm thick scaffold) under mixed conditions and culturing constructs in rotating laminar flow bioreactors were demonstrated, but constructs had interiors (> IOOμm tissue depth) consisting of mostly empty space due to diffusional mass transport limitations. We attempted to overcome diffusional limitations by directly perfusing culture medium through the constructs. Perfusion significantly improved the uniformity of the cell distribution and enhanced expression of a differentiated cell phenotype in comparison to non-perfused (i.e. flask) cultures. Control of the cell microenvironment in the perfusion system was also used to study relationships between oxygen tension and properties of cardiac constructs. Oxygen tension was directly correlated with DNA and protein contents (r=0.88 and 0.89, respectively), aerobic metabolism (r=0.97), muscle protein expression, and ultrastructural differentiation. Characterization of cardiac construct structure, composition, cell phenotype, and in vitro function demonstrated cardiac specific protein expression, metabolic activity similar to that of native tissue, and differentiated ultrastructural features (e.g. sarcomeres). The results support the utility of engineered cardiac muscle as a native tissue model for in vitro studies and eventually for in vivo tissue repair.
by Rebecca Lyn Carrier.
Sc.D.
31
Givens, Rassoolkhani Brittany Estelle. "Engineering variable particles for pharmaceutical applications." Diss., University of Iowa, 2019. https://ir.uiowa.edu/etd/6950.
Full textAbstract:
Polymeric-based drug and gene delivery is advantageous for a number of reasons. Polymers can increase the circulation time of the cargo, protect the cargo from enzymatic degradation, and improve localization at the target site. The present work focuses on three different polymers for drug and gene delivery: poly-lactic-co-glycolic acid (PLGA), polyethyleneimine (PEI) and polystyrene-co-poly(N-isopropylacrylamide) (PS-co-NIPAM). Each of these polymers has a niche within the drug and gene delivery field, and each has its own advantages and disadvantages. Formulations were prepared using each of the aforementioned polymers with an ultimate goal of translating the formulations to clinical applications.
The drug PD98059, which has been identified as a potential treatment following myocardial infarction or for leukemia, has been loaded into PLGA nanoparticles, microparticles, or pellets. Each of these formulations was characterized based on size and surface morphology, as well as the release rate of the PD98059. Additionally, an HPLC-UV method was developed for detecting PD98059 at low concentrations using the wavelength of maximum absorption. Included with this HPLC-UV method was a method for extracting PD98059 and an internal standard (7-hydroxyflavone) from murine plasma to promote future biodistribution studies.
Formulations were also prepared using PEI and plasmid DNA (pDNA). PEI is a cationic polymer that can improve the circulation time and cellular uptake of pDNA compared with naked pDNA alone. The PEI-pDNA complexes (nanoplexes) were delivered to two endometrial cancer cell lines: Ishikawa H and KLE. The pDNA encoded for mutations to the PLAC1 gene, which is a potential onco-target for endometrial cancers using the CRISPR-Cas9 delivery system. The relative gene expression of PLAC1 was measured after transfection, as well as the relative cell viability. In the Ishikawa cells, there was no improvement in transfection efficiency (decrease in PLAC1 expression) incurred by the PEI, and the cells did not undergo decreases in relative viability. However, in the KLE cells there were large decreases in relative cell viability in response to the nanoplexes, which also made it difficult to determine relative gene expression following transfection.
Transfection was also paired with a genotoxic engineered nanomaterial (ENM) to investigate how co-delivery of nanoplexes and ENMs may influence the efficacy of gene therapy. The relative viability of A549 and Ishikawa H cells indicated that co-delivery was less toxic to cells compared with mono-delivery of either agent. Furthermore, relative expression of the cell cycle regulating p53 gene was increased after 48 hours in Ishikawa cells that received as little as 10 µg/mL CuO ENMs. Further toxicity investigations of CuO ENMs, ZnO ENMs, and SiO2 ENMs were conducted in the two lung epithelial cell lines A549 and Beas-2B, which indicated that the A549 cells are more susceptible to changes in viability as a function of ENM dose than the Beas-2B cells. Furthermore, the A549 cells likely internalized the SiO2 ENMs through the caveolae-mediated endocytosis mechanism.
The uptake and toxicity of PS-co-NIPAM microgels, which are a thermo-responsive polymer, was assessed in HepG2 liver adenocarcinoma cells, which was ~3 µg/mL total (maximum) for a 90 µg/mL dose. As such, the endocytosis mechanism could not be determined for these investigations. The results also indicated that these microgels did not induce any toxicity at 150 µg/mL after 24 hour exposure, which is promising for their development as a biocompatible delivery system.
The overarching goal of this research was to use polymeric formulations, which are known to be both biocompatible and highly tunable, for improved drug and gene delivery. The breadth of applications in this thesis highlights the many potential applications of polymeric formulations, as well as the interdisciplinary advantages to using polymers as carriers for sustained- and/or controlled-delivery.
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Chen, Tianjiao S. M. Massachusetts Institute of Technology. "Experimental characterization and chemical kinetics study of chemical looping combustion." Thesis, Massachusetts Institute of Technology, 2014. http://hdl.handle.net/1721.1/87957.
Full textAbstract:
Thesis: S.M., Massachusetts Institute of Technology, Department of Mechanical Engineering, 2014.Cataloged from PDF version of thesis. "February 2014."
Includes bibliographical references (pages 106-110).
Chemical looping combustion (CLC) is one of the most promising technologies to achieve carbon capture in fossil fuel power generation plants. A novel rotary-bed reactor concept was proposed by Zhao et. al. [1] in 2013. It is a compact gas fueled CLC reactor that could achieve high fuel conversion and carbon separation efficiencies. It is different from the widely applied and tested fluidized-bed reactor that employs metal oxides coated on particle shaped support materials as the reaction median. In the new reactor, the active metal oxidizes are coated on the surfaces of channel shaped structural material in the new reactor. Due to the different reaction mechanism, an alternative experimental platform with the capability of performing reaction kinetic analysis for disk or channel shaped samples was required needed. The sample selection, characterization and preparation methods are discussed, followed by the introduction of the experimental system design and initial calibration and tuning results. Preliminary oxidation kinetic studies are carried out using the real-time gas analysis system to obtain the concentration contours of the effluent gas species. Commercial 13 wt% copper(II) oxide particles prepared through impregnation method are used as the reaction median. The reactant gas used in the oxidation cycles is 8%, 13% and 21% oxygen in argon, operated at 700 - 800 *C; and 10% hydrogen in argon is used for the reducing cycles.
by Tianjiao Chen.
S.M.
33
Schmidt, Daniel J. Ph D. Massachusetts Institute of Technology. "Engineering electroresponsive layer-by-layer thin films." Thesis, Massachusetts Institute of Technology, 2011. http://hdl.handle.net/1721.1/62735.
Full textAbstract:
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2011.Cataloged from PDF version of thesis.
Includes bibliographical references.
Electroresponsive layer-by-layer (LbL) polymer films and polymer nanocomposite films were investigated as model systems for electrically triggered drug delivery applications and "mechanomutable" surface coating applications. Two strategies were implemented in the design of these electroresponsive films: the use of redox-active, chargeshifting nanoparticles and the control over local pH utilizing the electrochemical reduction of dissolved oxygen. These strategies and the multiple materials systems explored are described below. Redox-active Prussian Blue (PB) nanoparticles exhibit multiple, stable oxidation states and can shift their charge in response to mild electric potentials. The inherently negatively charged particles may be self-assembled into LbL films along with positively charged polyelectrolytes. When the PB in an LbL film is oxidized to its neutral state, dissolution of the film occurs as cohesive ionic crosslinks are broken and excess charge in the film brings in ions and water for electroneutrality, which solubilize the film components. The release of the polyanion dextran sulfate and the small molecule antibiotic gentamicin sulfate were precisely controlled with an electric potential. When PB is reduced, the negative charge on the particle is doubled, which results in film swelling and a decrease in stiffness. In films comprising PB and linear polyethyleneimine, reversible thickness changes on the order of 5-10% and reversible elastic modulus changes on the order of 50% (between 3.40 GPa and 1.75 GPa) were observed. Employing the second strategy mentioned above, the local pH near an electrode surface may be increased to more basic values when dissolved oxygen is electrochemically reduced to hydroxide ions. In the first model system explored, hydrogen bonded (H-bonded) films comprising polyvinylpyrrolidone (PVPON) and tannic acid (TA), were dissolved at constant bulk pH by applying mild potentials (-0.25 V to -1.00 V vs. Ag/AgCl). The dissolution mechanism and kinetics could be tuned with the magnitude of the applied voltage and the concentration of dissolved oxygen. In the second model system explored, films comprising polyallylamine hydrochloride (PAH) and sulfonated polystyrene (SPS) were found to undergo reversible and dramatic swelling/deswelling transitions on the order of roughly 300 vol% and mechanical transitions on the order of 600-800% (shear modulus between 230 kPa and 1.9 MPa and loss modulus between 90 kPa and 620 kPa). This thesis contributes to the applied materials science branch of chemical engineering. New polymer and polymer nanocomposite thin films were developed that can be further engineered and incorporated into implantable drug delivery devices for electrically triggered drug delivery or incorporated into MEMS and microfluidic systems for flow control or biomedical applications. Furthermore, the model systems presented here open doors for fundamental work on the transport of electrons, ions, and water through these electroresponsive films and the implications of transport phenomena on the control over film dissolution and swelling responses.
by Daniel J. Schmidt.
Ph.D.
34
Abel, Matthew J. "Process systems engineering of continuous pharmaceutical manufacturing." Thesis, Massachusetts Institute of Technology, 2009. http://hdl.handle.net/1721.1/58446.
Full textAbstract:
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, February 2010.Cataloged from PDF version of thesis.
Includes bibliographical references (p. 290-299).
Continuous manufacturing offers a number of operational and financial benefits to pharmaceutical companies. This research examines the critical blending step for continuous pharmaceutical manufacturing and the characteristics of continuous downstream pharmaceutical manufacturing systems. Discrete element method (DEM) simulations were used to develop novel insights into the mechanism of mixing for continuous blending of cohesive pharmaceutical powders and to examine the effects of particle properties, blender design and operating conditions on blend homogeneity. To place continuous blending into the context of pharmaceutical manufacturing, the scope of the analysis was expanded to process system models of continuous downstream pharmaceutical manufacturing. DEM simulations were used to study the mechanisms of mixing in the continuous blending of pharmaceutical powders. Diffusive mixing from the avalanching particles appears to be the dominant mechanism of mixing in both the axial and radial direction for the double helical ribbon blender. This result can guide the development of future continuous pharmaceutical powder blenders by optimizing the mixing elements to increase the amount of particles transported to a position where they can avalanche/flow and diffusively mix. A range of particle properties, blender designs and operating conditions were examined for their effects on flow behavior and blend homogeneity. Three particle properties were examined: particle size, polydispersity and cohesive force.
(cont.) Particle size was observed to be positively correlated to both flow rates and blend homogeneity. Polydispersity had no effect on flow rate and was negatively correlated to homogeneity. Cohesive force was negatively correlated to flow rate and had little to no effect on homogeneity. Two modifications of blender design were analyzed: changes in blender size and changes in shaft design. Blender size was observed to be positively correlated to flow rate and negatively correlated to homogeneity. The paddle shaft designs created a more homogeneous powder blend than the double helical ribbon shaft. Two operating parameters were also studied: rotation rate and fill fraction. Rotation rate was positively correlated to both flow rate and homogeneity. Fill fraction had the interesting result of being positively correlated to the absolute flow rate, but negatively correlated to the fill mass normalized flow rate. In addition, fill fraction has a clear negative correlation to homogeneity above fill fractions of 0.55, but is inconsistent for fill fractions lower than this. This research on particle properties, blender designs and operating conditions will help to guide the operation of continuous pharmaceutical blenders and the design of continuous pharmaceutical manufacturing systems. Process simulations comparing model batch and continuous downstream pharmaceutical manufacturing systems have quantified some of the potential size, cost and performance benefits of continuous processes. The models showed significant reductions in process equipment sizes for continuous manufacturing particularly in the blending step.
(cont.) This reduction in equipment size translates to capital cost (CAPEX) savings for both the continuous process equipment and manufacturing facilities. The steady state operation of continuous processing also reduces the labor requirements and gives the continuous processes an operating cost (OPEX) advantage over batch processes. This research has contributed to the understanding of continuous pharmaceutical powder blending and quantified some of the benefits of continuous downstream pharmaceutical manufacturing. This work is being continued by the Novartis-MIT Center for Continuous Manufacturing whose work is providing the foundation for future industrial scale pharmaceutical continuous manufacturing systems.
by Matthew J. Abel.
Ph.D.
35
Ngantung, Frederyk Anthonius. "Engineering mammalian cell line to improve sialylation." Thesis, Massachusetts Institute of Technology, 2005. http://hdl.handle.net/1721.1/33719.
Full textAbstract:
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2005.Includes bibliographical references (p. 209-231).
One of the key problems faced by many biotechnology companies is the cleavage of terminal sialic acid on the glycans of the therapeutic glycoproteins. This is caused by the degradative action of sialidase released to supernatant when the cell starts to die. This phenomenon is undesirable because the loss of terminal sialic acid results in a product which is rapidly removed from the plasma by the interaction with asialoglycoprotein receptors in the liver. Many studies have been done in this area for decades and no general approach has been produced thus far. In this study, RNA interference is utilized as a genetic approach to knock down the activity of sialidase which is responsible for cleaving terminal sialic acid. At the first stage of the studies, 21-nt double stranded siRNA sequences capable of knocking down sialidase are identified. The best sialidase siRNA sequence transiently knocks down sialidase mRNA by 9 folds and accompanied by a 4 fold reduction in sialidase activity. The most potent sialidase siRNA was located in UTR region and did not follow the widely-used Tuschl's rule. At the second stage of the studies, a siRNA sequence is integrated into CHO cells using a plasmid with a drug selection marker to produce stable cell lines. It is found that the Pol III promoter is not strong enough to generate sialidase siRNAs. The modified CMV promoter is more appropriate for knocking down sialidase activity as clones with over 50% sialidase activity reduction can be isolated. We have isolated stable clones with over 60% sialidase knock down during the course of the cell cultivation. Growth rate and glycoprotein specific productivity of stable clones with reduced sialidase activity are not affected by siRNA activity or reduced sialidase expression. Glycan site occupancy of IFN[gamma] produced by stable clones remains relatively unchanged. Two of the stable clones successfully maintain constant sialic acid content of IFN[gamma] during prolonged cell culture even though cells are dying during these periods while the parent cell line loses the sialic acid at the rate of 0.05 mole sialic acid /mole IFN[gamma]/day. This result is comparable to when sialidase inhibitor is used to deactivate sialidase. Microheterogeneity analysis reconfirms the consistent fraction of asialo, monosialyl, and bisialyl form of IFN[gamma] for cell lines with reduced sialidase level during prolonged cell culture. On the other hand, parent cells are found to have more asialo and monosialyl form of IFN[gamma] as the cells dies demonstrating the effect of sialidase release on glycoproteins during prolonged cell culture. Maximal sialic acid content during growth phase is found to be slightly altered by sialidase knock down. This could be due to clonal variation of parent cells or due to sialic acid salvage pathway disruption by reduced sialidase activity. At the third stage of the studies, we develop a GFP-based method to rapidly and effectively isolate cells which express high amounts of sialidase siRNA. Subpopulations of CHO cells with a high level of mean fluorescence intensity have lower sialidase mRNA level and activity. This implies a positive correlation between GFP fluorescence intensity and siRNA generated to silence sialidase. For similar fluorescent intensity, cells transfected with GFP-based Pol II-driven plasmid exhibits sialidase knock down 1-3 folds stronger than those transfected with GFP-based Pol III-driven plasmid. We have successfully knocked down sialidase using a siRNA approach and produced not only stable cell line, but also functional and viable cell where cell growth is not affected by sialidase knock down. This method is a generic method that can be adopted by any biotech companies to reduce the sialidase degradative activity, producing a more consistent protein quality over the cell cultivation.
by Frederyk Anthonius Ngantung.
Ph.D.
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Rao, Balaji Madhav 1978. "Interleukin-2 Engineering for improved therapeutic effectiveness." Thesis, Massachusetts Institute of Technology, 2004. http://hdl.handle.net/1721.1/28664.
Full textAbstract:
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2004.Vita.
Includes bibliographical references (p. 97-103).
(cont.) (K[d] [approximately] 10pM) for its private alpha receptor subunit, unlike wild-type IL-2 (K[d] [approximately] 10 nM). IL-2 mutants with picomolar affinity for IL-2Rα stimulate T cell growth responses quantitatively equivalent to those mediated by IL-15. Our results suggest that the contrasting effects of IL-2 and IL-15 on T cells in vivo are largely due to the 1,000-fold different affinities of wild-type IL-2 and IL-15 for their respective private alpha receptor subunits.
Interleukin-2 (IL-2) is an immunomodulatory cytokine that is clinically relevant for the treatment of metastatic renal cell carcinoma and melanoma. The primary objective of the research presented in this thesis was to generate IL-2 mutants with potentially improved therapeutic effectiveness. Based on qualitative considerations and simple mathematical modeling, we hypothesized that IL-2 mutants with increased affinity for the alpha subunit of the IL-2 receptor (IL-2Rα) would have increased potency for proliferation of activated T cells and hence potentially improved therapeutic value. Yeast surface display and directed evolution were used to generate a class of IL-2 mutants with enhanced IL-2Rα affinity. In a novel pulsed bioassay designed to approximate the rapid systemic clearance pharmacokinetics of IL-2, these mutants exhibit significantly increased potency for T cell proliferation, thus validating our hypothesis. Our results underscore the critical nature of the choice of appropriate bioassays to evaluate engineered proteins and other drugs. Conventional bioassays not only fail to reveal the increased potency resulting from enhanced IL-2Rα affinity (false negatives), but also suggest improved potency for a mutant without enhanced activity in the pulsed bioassay (false positive). Cell-surface IL-2Rα acts as a ligand reservoir for the IL-2 mutants, leading to increased cell-surface persistence of the IL-2 mutants with increased IL-2Rα affinity and consequently increased integrated growth signal. This is analogous to the prolonged persistence of IL-15 on cell surface IL-15Rα reservoirs. IL-2 and IL-15 signal through the IL-2Rβ and IL-2R[gamma] subunits while each have a private non-signaling alpha receptor subunit. IL-15 has a high affinity
by Balaji Madhav Rao.
Ph.D.
37
Gai, Shuning. "Engineering persistent interleukin-2 for cancer immunotherapy." Thesis, Massachusetts Institute of Technology, 2012. http://hdl.handle.net/1721.1/76957.
Full textAbstract:
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2012.Cataloged from PDF version of thesis.
Includes bibliographical references (p. 102-109).
Mobilizing the immune system to recognize and destroy tumor cells is a promising strategy for treating cancer. In contrast to standard therapeutic approaches such as surgery, radiation, and chemotherapy, immunotherapy offers the possibility of systemic yet tumor-specific cell killing as well as long-lasting cancer protection. A significant mode of tumor rejection is direct tumor cell killing by immune cells, such as cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. These cell types are stimulated to proliferate by the cytokine interleukin-2 (IL-2). Consequently, IL-2 has been actively pursued as an agent for immunotherapy, either alone or in combination with other therapeutic strategies. IL-2 is characterized by rapid systemic clearance, with a fast-phase serum half-life of 13 minutes and a slow-phase half-life of 85 minutes. We hypothesized that prolonging the persistence of IL-2 at the cell surface or extending its circulation lifetime would increase its immunostimulatory potency. Therefore, we evolved murine IL-2 to bind the alpha subunit of its receptor, known as IL-2Ra or CD25, with 500-fold higher affinity; tethered IL-2 to the surface of T cells via streptavidin sandwiches; and fused IL-2 to the antibody Fc fragment, designated Fc/ IL-2, which extended the slow-phase serum half-life by 15 hours. Compared to free IL-2, Fc/IL-2 fusions induced superior control of solid tumors in mice. Interestingly, combining Fc/IL-2 with an anti-tumor antibody led to potent suppression of tumor growth during treatment. Furthermore, combination therapy protected two of three mice from subsequent tumor re-challenge. Depletion of CTLs or NK cells completely or partially, respectively, abrogated treatment efficacy, suggesting these immune cell types contribute to the anti-tumor response. In the context of Fc fusion, increasing the affinity of IL-2 for CD25 did not further improve efficacy. Ablation of CD25 binding, however, significantly reduced efficacy and also increased treatment toxicity. Since we employed a mutant Fc with disrupted FcyR binding, and hence reduced effector function, and fused IL-2 to mutant Fc monovalently, the significant therapeutic benefit of Fc/IL-2 over free IL-2 likely results from the extension of IL-2 circulation lifetime. We hypothesize that long-circulating IL-2 would potently synergize with other anti-tumor antibodies for effective cancer immunotherapy.
by Shuning Gai.
Ph.D.
38
Zhang, Mi. "Engineering In Vitro Vascularization On A Chip." Case Western Reserve University School of Graduate Studies / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=case1549976951359121.
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Woolston, Benjamin Michael. "Enabling Cl-Based bioconversion with metabolic engineering." Thesis, Massachusetts Institute of Technology, 2017. https://hdl.handle.net/1721.1/127713.
Full textAbstract:
Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemical Engineering, May, 2017Cataloged from the official PDF of thesis.
Includes bibliographical references (pages 235-261).
Single-carbon (C) substrates, such as synthesis gas and methanol, are attractive feedstocks for biochemical processes, as they are widely available, can be produced renewably, and do not compete with food supply. However, their use in industrial bioprocessing remains limited, primarily because microbes that utilize these substrates are poorly characterized biochemically, and limited tools exist for their genetic modification. This leaves the metabolic engineer with a choice: to develop genetic tools to enable engineering in the desired host, or to import the relevant catabolic pathway into a more tractable organism, such as Escherichia coli. This thesis explores both options within the context of developing strains for the conversion of C1 substrates into value-added chemicals and fuels.
Clostridium ljungdahlii is an acetogen that grows autotrophically on synthesis gas (CO, H₂ , and CO₂) using the Wood-Ljungdahl pathway, and is a promising candidate for non-photosynthetic CO₂ fixation. In the first section, we extended its primitive genetic tools by developing a CRISPRi system for the targeted knockdown of specific genes. Constitutive downregulation of several genes with putative roles in energy conservation and carbon flux by up to 30-fold was demonstrated, and the associated phenotypes analyzed. Optimization of the promoter controlling dCas9 expression allowed for inducible knockdown, paving the way for dynamic metabolic control strategies to redirect carbon flux in engineered strains. To demonstrate this concept, several variants of a heterologous pathway for the biosynthesis of 3-hydroxybutyrate (3HB) were constructed, to probe 3HB production in the wild-type background and with various CRISPRi plasmids.
The CRISPRi system represents a valuable contribution to the metabolic engineering field for its ability to redirect carbon flux, and is also useful to the microbiology community to probe gene function to answer open questions in the biochemistry underlying the Wood-Ljungdahl pathway. Efforts to develop genetic tools for the related acetogen Moorella thermoacetica are also described. To explore the alternative approach of importing a single-carbon catabolic pathway into a tractable host, in the second section E. coli was engineered to metabolize methanol. Screening various candidates of the three heterologous pathway enzymes enabled robust incorporation of 3 C-labeled methanol into central carbon metabolism. To further improve methanol assimilation, a kinetic-thermodynamic modeling framework was developed and combined with novel isotopic tracing experiments to probe potential pathway limitations.
Flux leakage from the cyclical ribulose monophosphate (RuMP) pathway was identified as the primary bottleneck, as this led to the build-up of the toxic intermediate formaldehyde and ablation of the thermodynamic driving force for methanol oxidation. Strategies were developed to re-wire central metabolism accordingly, which restored the driving force and led to the identification of the kinetics of the first enzyme of the pathway - methanol dehydrogenase (MDH) - as the next limitation. These results represent the first systematic analysis of flux limitations in E. coli engineered for methanol metabolism, and provide clear targets for further metabolic engineering to enable synthetic methylotrophy. Finally, the development of a formaldehyde biosensor in support of evolutionary approaches to enhance MDH activity and partition carbon flux between formaldehyde assimilation and growth is described.
by Benjamin Michael Woolston.
Ph. D.
Ph.D. Massachusetts Institute of Technology, Department of Chemical Engineering
40
Wang, Cheng 1971. "Parametric uncertainty analysis for complex engineering systems." Thesis, Massachusetts Institute of Technology, 1999. http://hdl.handle.net/1721.1/9507.
Full textAbstract:
Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 1999.Includes bibliographical references (p. 259-275).
With the rapid advancement of computational science, modeling and simulation have become standard methods to study the behavior of complex systems. As scientists and engineers try to capture more detail, the models become more complex. Given that there are inevitable uncertainties entering at every stage of a model's life cycle, the challenge is to identify those components that contribute most to uncertainties in the predictions. This thesis presents new methodologies for allowing direct incorporation of uncertainty into the model formulation and for identifying the relative importance of different parameters. The basis of these methods is the deterministic equivalent modeling method (DEMM), which applies polynomial chaos expansions and the probabilistic collocation approach to transform the stochastic model into a deterministic equivalent model. By transforming the model the task of determining the probability density function of the model response surface is greatly simplified. In order to advance the representation method of parametric uncertainty. a theoretical study of polynomial chaos representation of uncertain parameters has been performed and an Adomian polynomial expansion for functions of random variables has been developed. While DEMM is applied to various engineering systems to study the propagation of uncertainty in complex models, a systematic framework is introduced to quantitatively assess the effect of uncertain parameters in stochastic optimization problems for chemical product and process design. Furthermore, parametric uncertainty analysis techniques for discrete and correlated random variables have been developed such that the deterministic equivalent modeling method can be applied to a broader range of engineering problems. As a result of these developments, uncertainty analysis can now be performed 2 to 3 orders faster than conventional methods such as Monte Carlo. Examples of models in various engineering systems suggest both the accuracy and the practicality of the new framework for parametric uncertainty analysis established in this thesis.
by Cheng Wang.
Ph.D.
41
Chatzivasileiou, Alkiviadis Orfefs. "Engineering a novel pathway for isoprenoid synthesis." Thesis, Massachusetts Institute of Technology, 2019. https://hdl.handle.net/1721.1/123243.
Full textAbstract:
Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemical Engineering, 2019Cataloged from PDF version of thesis.
Includes bibliographical references.
Isoprenoids comprise a large class of chemicals, of significant interest due to their diverse properties. Most isoprenoids are plant secondary metabolites and are of commercial importance due to their varied applications in fields spanning medicine, agriculture, flavors, fragrances, cosmetics and nutrition. Biological production of isoprenoids in microbes is considered to be the most efficient and commercially viable way for their large-scale production. Thus far, isoprenoid biosynthesis has been performed through pathways inextricably linked to glycolysis. Furthermore, these pathways are inherently limited due to their extensive cofactor requirements, complex regulation and large number of steps. In this thesis we present a novel pathway for isoprenoid synthesis, the Isopentenol Utilization Pathway (IUP), which aims to overcome these limitations.
This pathway functions through the double phosphorylation of an isopentenol, either isoprenol or prenol, to produce the main precursors to isoprenoid synthesis, isopentenyl diphosphate (IPP) or dimethylallyl diphosphate (DMAPP). This pathway is radically different from naturally-occurring pathways or their engineered variants because it is only two steps long, uses an externally-provided isoprenol as its substrate instead of a glucose-derived catabolite, and uses only a single co-factor, ATP. We identify suitable enzymes, construct the pathway and proceed to demonstrate an in vivo proof of concept. After optimizing the pathway feedstock, we proceed to show that IUP is decoupled from central carbon metabolism. We demonstrate that the IUP can quickly produce copious amounts of IPP & DMAPP and can be used for the production of a variety of isoprenoids.
The IUP flux exceeded the capacity of almost all downstream pathways tested, was competitive with the highest isoprenoid fluxes reported as well as against state-of-the art isoprenoid pathways. Furthermore, we elaborate on our progress towards improving the capacity of a downstream farnesene synthesis pathway, to catch up with and fully utilize IUP's production capacity. Finally, we propose a new scheme for the use of the IUP to produce functionalized isoprenoids using functionalized isopentenols to introduce functionalizations in isoprenoid backbones, and we show preliminary results of this application.
by Alkiviadis Orfefs Chatzivasileiou.
Ph. D.
Ph.D. Massachusetts Institute of Technology, Department of Chemical Engineering
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Inampudi, Narendra Kumar Pinhero Patrick J. "Developing, implementing, and assessing coupled-tank experiments in an undergraduate chemical engineering curriculum." Diss., Columbia, Mo. : University of Missouri--Columbia, 2009. http://hdl.handle.net/10355/6489.
Full textAbstract:
Title from PDF of title page (University of Missouri--Columbia, viewed on Feb 18, 2010). The entire thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file; a non-technical public abstract appears in the public.pdf file. Thesis advisor: Dr. Patrick J. Pinhero. Includes bibliographical references.
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Papamichail, Ioannis. "Global optimisation of dynamic systems for chemical engineering applications." Thesis, Imperial College London, 2002. http://hdl.handle.net/10044/1/8950.
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Thornham, S. A. "The mathematical modelling of two problems in chemical engineering." Thesis, University of Manchester, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.382778.
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Jian, Hongbing. "Understanding unsteadiness and turbulence in two chemical engineering systems." Thesis, Heriot-Watt University, 2002. http://hdl.handle.net/10399/1158.
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Brad, Robert Boyd. "Reduced kinetic mechanisms for chemical and process engineering applications." Thesis, University of Leeds, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.421444.
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Brownbridge, George Peter Edward. "Computer assisted model development applied to chemical engineering systems." Thesis, University of Cambridge, 2015. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708972.
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Severson, Kristen Ann. "Machine learning for applications in chemical and biological engineering." Thesis, Massachusetts Institute of Technology, 2018. http://hdl.handle.net/1721.1/117914.
Full textAbstract:
Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemical Engineering, 2018.Cataloged from PDF version of thesis.
Includes bibliographical references (pages 187-210).
Chemical and biological systems are increasingly implemented with advanced sensor systems that collect large amounts of data. For example, a single microarray can measure thousands of genes and a typical offshore oil platform generates 1 to 2 TB of data per day. New algorithms are needed to efficiently and effectively use these datasets to increase predictive capability and improve system understanding. In this thesis, algorithmic advances to bridge the gap between data and system insights are addressed in a series of case studies. In the first case study, the problem of predicting critical quality attributes for a monoclonal antibody using data from the manufacturing process is addressed. In this setting, the main challenge is that there is only a limited dataset available for modeling. To tackle this issue, Monte Carlo sampling was used in conjunction with an elastic net approach to subset selection. The second case study is also within the biological domain but considers a discrete outcome. The proposed algorithm addresses two common issues when building classification models for biological studies: learning a sparse model, where only a subset of a large number of possible predictors is used, and training in the presence of missing data. The resulting algorithm leverages expectation-maximization to tackle both issues simultaneously. In the third case study, the goal was to identify anomalous operating periods using production data from an oil and gas well without access to historical examples of such periods. The proposed approach recasts the problem as a semi-supervised problem and leverages approaches from the positive and unlabeled literature. The final case study considers the task of prediction lithium-ion battery cycle life. Cycle life is defined as the number of charge and discharge cycles the battery undergoes before 80% capacity fade. Several, difficult to identify factors can contribute to capacity fade. Even in batteries with the same chemistry, operated using the same conditions, there is considerable cycle life variability. Therefore, the challenge was to build a model to capture individual capacity trajectories. Each case study is benchmarked using state-of-the-art approaches. In all settings, the value of data-driven methods is demonstrated.
by Kristen Ann Severson.
Ph. D.
49
Rahman, I. "Application of artificial intelligence techniques to chemical engineering problems." Thesis(Ph.D.), CSIR-National Chemical Laboratory, Pune, 2005. http://dspace.ncl.res.in:8080/xmlui/handle/20.500.12252/2437.
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Atkinson, John Karl. "Thick film chemical sensors." Thesis, University of Southampton, 1998. https://eprints.soton.ac.uk/47474/.
Full textAbstract:
The development of thick film sensors is described from their early stages, where thick film technology was employed primarily for the fabrication of interface circuits and as a sensor support medium, through to their complete fabrication as screen printed sensor arrays. The concept of processing signal data from sensor arrays as a means of improving sensor performance is also introduced and examples given. These examples include the reduction of the effects of 1/f noise in thick film conductimetric sensors and the use of pattern recognition techniques applied to arrays of low specificity gas sensors to improve their selectivity to particular analyte gases. Examples of various thick film gas sensors are given and the fabrication methods and associated techniques for their use in the detection of a variety of toxic, flammable and environmental gases are described. Various sensors for liquids are described and, in particular, arrays of sensors for water quality determination. The investigation of useful lifetimes and operational performance of these devices is reported with particular reference to sensors for the measurement of temperature, conductivity, redox potential, pH and dissolved oxygen concentration in water.