Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2009. / Includes bibliographical references. / Protein molecules are being widely used as pharmaceuticals for treating diseases ranging from diabetes and haemophilia to various types of cancers due to their great potency and specificity. However, these macromolecules are intrinsically unstable in aqueous solutions, due to the existence of various physical and chemical degradation pathways. Degraded protein molecules have much reduced biological functions, and may also have adverse effects such as immunogenriicity or pharmacokinetic issues. Thus, understanding the underlying mechanisms of these degradation pathways is essential for rationally devising better ways to stabilize protein pharmaceuticals and extends their applicability. In this thesis, two important types of chemical degradation pathways, the oxidation of methionine residues and the hydrolysis of peptide bonds in monoclonal antibody molecules, are investigated from a mechanistic point of view. In the first half of the thesis, oxidation 'of methionine residues in a model protein G-CSF (Granulocyte-Colony Stimulating Factor) was studied to address the issue of how protein structure affects its reactivity. Comparative oxidation studies were performed where the kinetics of oxidation of methionine residues by hydrogen peroxide (H₂0₂) in G-CSF and corresponding chemically synthesized peptides thereof were measured at different temperatures. To assess structural effects, equilibrium denaturation experiments also were conducted on G-CSF to obtain the free energy of unfolding as a function of temperature. / (cont.) A comparison of the relative rates of oxidation of methionine residues in short peptides with those of corresponding methionine residues in rhG-CSF yields an understanding of how protein tertiary structure affects oxidation reactions. For the temperature range studied, 4°C to 45°C, the oxidation rate constants followed an Arrhenius equation quite well, suggesting the lack of temperature-induced local structural perturbations that affect chemical degradation rates. One out of the four methionine residues, Met122, showed an activation energy significantly different than that of the corresponding peptide. Extrapolation of kinetic data predicts non-Arrhenius behavior around the melting temperature. Phenomenological modeling trying to understand the temperature dependence of rate constants was pursued. Finally, we show that the data obtained from accelerated oxidation can be used in conjunction with our models to get predictions about the long-term shelf-life oxidation comparable with experimental results. In the latter half of this thesis, three approaches in a hierarchical order were taken in order to explain the higher rate of un-catalyzed hydrolysis of peptide bonds only in the hinge region of antibody molecules. First, ab initio molecular dynamic simulations were performed to understand the reaction mechanism of the hydrolysis of peptide bonds. The system solvated in explicit water molecules was modeled quantum mechanically and dynamic transition trajectories of the chemical reaction were computed at ambient conditions. / (cont.) Since no unique pathway can be used to describe the reaction process due to fluctuations at finite temperature, path sampling technique was applied to obtain an ensemble of trajectories. A statistical tool, likelihood maximization, was used to extract physically important degrees of freedom by screening a large number of reaction coordinate models. The same approach was applied to the hydrolytic reactions under both acidic and neutral pH conditions, which are the most relevant to the formulation of antibody molecules. In both cases, changes in local bonding pattern close to the reaction center, as well as the solvent network, showed importance in determining the reaction dynamics of the hydrolysis of the peptide bond. Then classical molecular dynamic simulations were performed to study the dynamics of a free hinge fragment and -the hinge fragments in the antibody molecule. Important structural and dynamic differences between the two situations were revealed, especially the observation that the free hinge fragment takes on configurations much less frequently accessed by the hinge fragment when situated inside the antibody molecule. In the third approach, a coarse-grained reaction rate model was proposed in order to explain the experimentally observed higher rate of hydrolysis of peptide bonds. A hypothesis involving a mechano-chemical mechanism was motivated by the essential constraining effect of Fab and Fc domains on the hinge region in the antibody molecule revealed in the second approach. / (cont.) Combining the information obtained from the previous two approaches, force was calculated along the reaction coordinate direction that was determined and verified previously. This information was integrated into a reaction rate model in order to compute the reaction rate constants. The computational results show that the mechano-chemical mechanism can yield reasonable rate constants comparable with available experimental data. / by Bin Pan. / Ph.D.

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemical Engineering, 2015. / Cataloged from PDF version of thesis. / Includes bibliographical references. / Artificial protein hydrogels have attracted interest as injectable fillers and scaffolds for tissue engineering and regeneration, but the same features that enable minimally-invasive implantation of these biomaterials typically make them susceptible to mechanical degradation in the tissue environment. Achieving a rapid and sufficiently large increase in gel toughness post-injection is a crucial challenge for developing load-bearing injectable implants that persist for the needed lifetime of the implant. To address these complex goals, the objective of this thesis has been to engineer physical hydrogels that shear-thin at low temperatures but responsively assemble into a nanostructured, reinforced state at body temperature. For this purpose, the thermoresponsive aggregation of poly(N-isopropylacrylamide) (PNIPAM) and elastin-like polypeptides (ELPs) was leveraged to assemble nanostructured hydrogels from dual-associative block copolymers. Hybrid protein-polymers or protein fusions were formed by fusing PNIPAM or ELPs to the termini of a soluble artificial polypeptide decorated with self-associating [alpha]-helical domains. In cold solutions, these polypeptide block copolymers formed weak, injectable gels due to helix-associations alone; upon heating to physiological temperatures, the endblocks aggregated to form a reinforcing network of close-packed micelles throughout the gel, leading to over a 10-fold increase in elastic modulus and over 10³-fold increase in the longest stress relaxation time. Micelle packing and morphology could be tuned by endblock chemistry and block architecture, allowing for orthogonal control of gel viscoelasticity over timescales separated by four orders of magnitude. Furthermore, through the discovery of a new gelation mechanism for ELPs, simple but tough hydrogels were engineered and explored as biocompatible substrates for tissue engineering. Unlike solutions of other ELPs that have been studied extensively for decades, ELPs that have an alanine mutation in the third position of the repeat unit (i.e. VPAVG) were found to undergo arrested phase separation upon heating when formulated above a critical concentration. Solidification resulted in a bicontinuous, nanoscale network that could be manipulated by ELP design. Critically, this reversible mechanism produced extremely stiff physical gels with a relaxation time greater than 10³ seconds and shear moduli almost 10 MPa, nearly that of natural rubber despite consisting of 70% water. These ELPs were chain-extended via reversible coupling of terminal cysteine residues, leading to oxidatively-responsive increases in gel extensibility and overall toughness. Biofunctionalized gels maintained the viability of mesenchymal stem cells and chondrocytes in 2D and 3D, respectively, making these simple gel formulations a promising platform for biomedical applications. Ultimately, through controlled macromolecular synthesis and functionalization, combined with a fundamental understanding of the structure and mechanics of these new materials, this thesis has led to the development of responsively tough biomaterials that are promising for long-term performance under physiological conditions. / by Matthew James Glassman. / Ph. D.

Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 1999. / Includes bibliographical references (p. 201-209). / by R. Robert Balcarcel. / Ph.D.

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.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 1995. / Includes bibliographical references. / by Carlos Rojas-Guzmán. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 1997. / Includes bibliographical references (p. 267-282). / by Jonathan O. Allen. / Ph.D.

Thesis (B.S.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 1980. / Includes bibliographical references (leaves 61-62). / by Mark Ramond Naber. / B.S.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 1998. / Includes bibliographical references. / by Ravi Srinivasan. / Ph.D.

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemical Engineering, 2018. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 313-324). / Natural gas is one of the world's leading sources of fuel in terms of both global production and consumption. The abundance of reserves that may be developed at relatively low cost, paired with escalating societal and regulatory pressures to harness low carbon fuels, situates natural gas in a position of growing importance to the global energy landscape. However, the nonuniform distribution of readily-developable natural gas sources around the world necessitates the existence of an international gas market that can serve those regions without reasonable access to reserves. International transmission of natural gas via pipeline is generally cost-prohibitive beyond around two thousand miles, and so suppliers instead turn to the production of liquefied natural gas (LNG) to yield a tradable commodity. While the production of LNG is by no means a new technology, it has not occupied a dominant role in the gas trade to date. However, significant growth in LNG exports has been observed within the last few years, and this trend is expected to continue as major new liquefaction operations have and continue to become operational worldwide. Liquefaction of natural gas is an energy-intensive process requiring specialized cryogenic equipment, and is therefore expensive both in terms of operating and capital costs. However, optimization of liquefaction processes is greatly complicated by the inherently complex thermodynamic behavior of process streams that simultaneously change phase and exchange heat at closely-matched cryogenic temperatures. The determination of optimal conditions for a given process will also generally be nontransferable information between LNG plants, as both the specifics of design (e.g. heat exchanger size and configuration) and the operation (e.g. source gas composition) may have significantly variability between sites. Rigorous evaluation of process concepts for new production facilities is also challenging to perform, as economic objectives must be optimized in the presence of constraints involving equipment size and safety precautions even in the initial design phase. The absence of reliable and versatile software to perform such tasks was the impetus for this thesis project. To address these challenging problems, the aim of this thesis was to develop new models, methods and algorithms for robust liquefaction process simulation and optimization, and to synthesize these advances into reliable and versatile software. Recent advances in the sensitivity analysis of nondifferentiable functions provided an advantageous foundation for the development of physically-informed yet compact process models that could be embedded in established simulation and optimization algorithms with strong convergence properties. Within this framework, a nonsmooth model for the core unit operation in all industrially-relevant liquefaction processes, the multi-stream heat exchanger, was first formulated. The initial multistream heat exchanger model was then augmented to detect and handle internal phase transitions, and an extension of a classic vapor-liquid equilibrium model was proposed to account for the potential existence of solutions in single-phase regimes, all through the use of additional nonsmooth equations. While these initial advances enabled the simulation of liquefaction processes under the conditions of simple, idealized thermodynamic models, it became apparent that these methods would be unable to handle calculations involving nonideal thermophysical property models reliably. To this end, robust nonsmooth extensions of the celebrated inside-out algorithms were developed. These algorithms allow for challenging phase equilibrium calculations to be performed successfully even in the absence of knowledge about the phase regime of the solution, as is the case when model parameters are chosen by a simulation or optimization algorithm. However, this still was not enough to equip realistic liquefaction process models with a completely reliable thermodynamics package, and so new nonsmooth algorithms were designed for the reasonable extrapolation of density from an equation of state under conditions where a given phase does not exist. This procedure greatly enhanced the ability of the nonsmooth inside-out algorithms to converge to physical solutions for mixtures at very high temperature and pressure. These models and submodels were then integrated into a flowsheeting framework to perform realistic simulations of natural gas liquefaction processes robustly, efficiently and with extremely high accuracy. A reliable optimization strategy using an interior-point method and the nonsmooth process models was then developed for complex problem formulations that rigorously minimize thermodynamic irreversibilities. This approach significantly outperforms other strategies proposed in the literature or implemented in commercial software in terms of the ease of initialization, convergence rate and quality of solutions found. The performance observed and results obtained suggest that modeling and optimizing such processes using nondifferentiable models and appropriate sensitivity analysis techniques is a promising new approach to these challenging problems. Indeed, while liquefaction processes motivated this thesis, the majority of the methods described herein are applicable in general to processes with complex thermodynamic or heat transfer considerations embedded. It is conceivable that these models and algorithms could therefore inform a new, robust generation of process simulation and optimization software. / by Harry Alexander James Watson. / Ph. D.

Thesis (Sc. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 1992. / Includes bibliographical references (p. 783-789). / by Jarvis Tat-Yin Cheung. / Sc.D.