Thesis: Sc. D., Massachusetts Institute of Technology, Department of Chemical Engineering, June 2015. / Cataloged from PDF version of thesis. "May 21, 2015." / Includes bibliographical references. / The complexity of growth, survival, and death signaling pathways in cancer continues to motivate extensive investigations using systems biology approaches to better inform treatments. Many of these drugs and drug combinations, however, are highly toxic, due to lack of targeting and poor pharmacokinetics, and are not easily delivered together due to solubility issues - requiring high levels of patient compliance over the course of treatment whereby lower, less efficacious doses of therapies are administered during multiple intravenous infusions. To address this problem, development of delivery systems that are safe/less toxic, yet capable of housing and delivering higher, more efficacious doses with sophisticated levels of control over the delivery, timing, and/or sequence of release, in order to therapeutically re-wire these signaling pathways, is essential to translate these drug combinations to the clinic. Work detailed herein addresses this challenge by developing controlled approaches for engineering and manufacturing translational nanoscale delivery systems for more efficacious, targeted treatment of cancer - specifically using layer-by-layer nanoscale assembly and liposomal manufacture. Layer-by-Layer (LbL) assembly of polyelectrolytes on solid substrates, including colloidal systems, is a well characterized, tunable approach for generating functional thin films for a variety of applications, including drug and gene delivery, tissue engineering, and bone regeneration. On the basis of electrostatics, this assembly method allows for incorporation of a broad range of materials; and due to its water-based synthesis, it allows for incorporation of a broad range of therapeutics without significant alteration of biological function. Using this approach, work described in Chapters 2-4 detail the utility of this approach. In Chapter 2, we demonstrate the ability to coat materials atop drug-loaded PLGA nanoparticle substrates that control drug release and nanoparticle pharmacokinetics in a systemic environment. In Chapter 3, we incorporate ligand-functionalized materials atop a drug-loaded liposomal core to promote tissue-level specificity for targeted treatment of cancer. In Chapter 4, we further adapt this approach towards addressing the challenge of scalably and reproducibly manufacturing LbL-functionalized nanoparticle systems by collaborating with Joseph DeSimone at UNC-Chapel Hill. In this work, we combine scalable methods, PRINT® particle fabrication, and spray-LbL deposition, to generate uniform and functional nanotechnologies that are built-to-order with precise control over composition, size, shape, and surface functionality. In Chapters 5-7, targeted liposomal technologies were synthesized to deliver drug combinations with different solubilities. Liposomes, representing the first nanomedicine systems approved and employed in the clinic, are well-characterized, simple and versatile platforms for manufacture of functional and tunable drug-carrier systems. Further, functionalization of these systems for tissue-level specificity is readily achieved by ligand conjugation of a lipid that is subsequently inserted into the dual drug-loaded liposomal vesicular membrane. Utilizing the hydrophobic and hydrophilic compartments of liposomes, we achieved high loadings of both hydrophobic and hydrophilic therapies within a singular tissue-targeted (e.g. folate) liposomal system. The resultant nature of compartmentalization inside the vesicular structure promoted the desired sequence of drug release for synergistic cancer therapy, improving tumor cell killing in vitro and significant tumor shrinkage in in vivo murine triple-negative breast cancer and non-small cell lung cancer models. In Chapters 6 and 7, we applied this approach for targeted combination therapeutic delivery for additional drug therapies (e.g. cisplatin-quisinostat (HDAC inhibitor) in a folate-targeted liposome; (+)-JQ1-temozolomide in a transferrin-targeted liposome) and disease targets (non-small cell lung cancer; brain stem gliomas). Using both LbL and liposomal manufacture, work detailed herein represents a broad skill set for engineering and manufacturing translational targeted multi-therapeutic delivery systems with high levels of control. / by Stephen Winford Morton. / Sc. D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2002. / Includes bibliographical references. / Nanocrystalline perovskites (Lal-xAMnl-yByO3) were successfully synthesized with higher surface area and smaller grain size by chemical co-precipitation compared to solid-state and complexation/combustion synthesis routes. The choice of solvent, base and suspension pH in co-precipitation was found to strongly affect the chemical stoichiometry of the resulting material. Stoichiometric La0.5Sr0.sMnO3 was successfully obtained at a high pH using isopropanol as the solvent and tetraethylammonium hydroxide as the base. La0.sSr0.sMnO3 was derived with a ultrafine grain size of 13 nm and a high surface area of 43 m2/g at 650⁰C, and maintained its nanocrystalline microstructure on heating to 1000⁰C, with a grain size of 25 nm and a surface area of 19 m2/g. The catalytic activity of these perovskites was investigated for different A- and B-site substitutions. Among LaBO3 perovskites, the catalytic activity was found to decrease in the order: Mn > Fe [approx.] Ni > Co, with LaMnO3 showing the lowest light-off temperature of 420⁰C. The intrinsic catalytic activity at 650C decreased in the order: Ni > Co > Fe > Mn. Substitution of Group IIA metals for La3+ was found to increase the reaction rate of LalxAxMnO3, while higher valency dopants did not change or decreased catalyst activity. In the case of Ca2+ and Sr +dopants, intrinsic activity of Lal-xAxMnO3 was found to increase with doping level until x = 0.4 and 0.6, respectively. La0.4Sr0.6MnO3 exhibited the lowest light-off temperature of 3800C, with a reaction rate that was 2.5 times higher than LaMnO3. Methane TPR experiments showed that methane oxidation over the perovskites occurred by methane adsorption on the catalyst surface via hydrogen abstraction. / (cont.) Substitution of Group IIA metals for La3+ enhanced catalytic activity by increasing the rate of methane activation, but lowered activity at high doping levels due to slow carbonate decomposition. Mixed conducting BalxSrCol-yMyO3- perovskite membranes were developed for oxygen separation applications. Ba0.75Sr0.25Coo.8Feo.203- showed a very high oxygen flux of [approx.] 3.8 cm3[STP]/min/cm2 at 900⁰C. Bao.25ro.75Co0sTio.2036 exhibited an oxygen flux of [approx.] 1.4 cm3[STP]/min/cm2 at 750⁰C with excellent stability over time. These oxygen fluxes were [approx.] 2 times higher than those reported for the best existing membrane materials. High oxygen fluxes were obtained by creating a high oxygen vacancy concentration ([approx.] 15% of oxygen lattice sites) via extrinsic doping, and by increasing the unit cell free volume to allow facile oxide ion hopping. The challenge in developing these membranes was to prevent the phase transformation of the vacancy-disordered perovskite to a poorly conductive vacancy-ordered structure in the desired temperature range of 750-900⁰C. This was accomplished by doping various cations in place of cobalt at the B site. Iron was found to be the most effective dopant for stabilizing the perovskite phase, followed by titanium and tin. A novel approach was developed to stabilize the vacancy-disordered perovskite phase of BaCoo.8M0.203 on cooling to room temperature, so that significantly higher oxygen fluxes could be achieved at low temperatures with excellent stability. When a single type of dopant cation was introduced at the B site, the vacancy-disordered phase could not be ... / by Neeraj Sangar. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 1995. / Includes bibliographical references. / by Colin Andrew Wolden. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, February 2007. / "January 2007." / Includes bibliographical references. / The primary objective of this work has been the advancement of selective adsorption techniques by use of new interactions and development of new approaches to the directed assembly of colloidal species. The ability to control the assembly from solution of complex and composite surface arrays by chemical patterning of surfaces is of great interest for the creation of nano- and micro-scale features without the costs and constraints of traditional lithography. Previous work in this group having demonstrated the patterning of polyelectrolyte multilayers by assembly on chemically-patterned surfaces, this thesis features a variation of selective adsorption in which polyelectrolytes of known substrate selectivity control the adsorption of the colloids onto which they are layered. The first section of this thesis will describe the evolution of this technique in response to certain limitations inherent to the patterning of multilayered films. Perfluorinated surfaces, proposed as potential adsorption resists, were found to display only partial or relative selectivity to common polyelectrolytes in the context of layer-by-layer assembly, an observation consistent with trends predicted by free-energy modeling. However, when these same polymers were layered on colloids, absolute selectivity could be more easily achieved. / (cont.) Polyamine-directed colloidal assembly was studied first, demonstrating that layer-by-layer selectivity observations still held in this new approach and illustrating some unique advantages with regards to multicomponent assembly. To expand the reach of selective adsorption, specific recognition via multiple hydrogen bonding was explored as a guiding interaction. Nucleic base pairing, the MHB system at the heart of molecular biology, proved highly effective for selectivity. In particular, the mutual indifference of non-complementary groups makes MHB ideally suited to side-by-side deposition of different species. Natural RNA homopolymers were used at first for surface and colloidal modification, but proved too fragile and costly for extensive use. Instead, novel biomimetic polymers combining nucleic base side chains and stable backbone charge were synthesized, along with nucleic base-terminated triethoxysilanes for facile microcontact printing of nucleic base patterns. These new materials successfully replaced RNA as directors of selective assembly while improving reproducibility; in particular, their stability allowed exploration of new approaches to asymmetric functionalization. / (cont.) Multilayered films of these polymers were also studied and found to exhibit interesting responses to changes in chemical environment. In the last section of this thesis, the synthesis and characterization of the nucleic base-grafted polyelectrolytes and triethoxysilanes will be reported. / by Marianne S. Terrot. / Ph.D.

Thesis (Sc. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 1996. / Includes bibliographical references (leaves 151-155). / by Glibert Lee Huppert. / Sc.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 1998. / Includes bibliographical references (p. 449-454). / by Kevin D. Dahm. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, February 2003. / Includes bibliographical references (v. 2, leaves 351-363). / Knowing and understanding the dynamics and molecular configurations of polymer molecules is important for efficient process design and novel product development. Much research has been focused on combining molecular simulations and traditional fluid mechanics computations to simulate the behavior of polymeric liquids in a fabrication process. These simulation approaches require solution of the coupled set of the equations of change, the governing equations from kinetic theory, and the flux expressions that map molecular configurations to macroscopic quantities. Most complex flow simulations so far make use of a mixed finite element method to calculate the velocity field, with stress tensor evaluated by using a stochastic simulation method. This so-called CONNFFESSIT approach suffers from both a large memory requirement and stochastic noise. This thesis focuses on the development and application of a fully deterministic numerical approach for computing viscoelastic flows with constitutive descriptions based directly on diffusion equations from kinetic theory. The numerical approach is based on an operator splitting time integration method that decouples the calculation of microstructure by solution of a hyperbolic diffusion equation from the velocity and pressure field evolution, which is obtained by solution of a generalized Stokes problem. The generalized Stokes problem is written in the DEVSS-G formulation, where a direct interpolation of the components of the velocity gradient tensor is introduced. The efficiency and robustness of this numerical method is demonstrated through calculating the viscoelastic flows of a modified Doi model for liquid crystalline polymer and a number of reptation models for polymer melts in different flow geometries. / (cont.) Simulations of the original Doi model with the Maier-Saupe potential in a pressure-driven channel flow by Nayak showed disclination formation due to the shear-rate-dependent frequencies of the tumbling/wagging states of the Doi model in a shear or mixed shear flow. The lack of an instrinsic length scale in the model leads to an infinitesimal structure refinement that eventually causes numerical instabilities. In this thesis, the effect of concentration variation is incorporated to develop a modified Doi model for introducing an intrinsic length scale through translational diffusion. This changes the mathematical characteristics of the spatial variation of the underlying diffusion equation from that of a hyperbolic equation to that of an elliptic equation. The resulting elliptic diffusion equation is then solved by using a local discontinuous Galerkin method, where an auxillary variable is introduced to rewrite the elliptic diffusion equation into a pair of formal, hyperbolic equations, which in turn is solved by the standard discontinuous Galerkin method. Unlike the original Doi model, a steady state is reached for a variety of De. Although there is structure variation across the channel width, the director profiles point uniformly along the flow direction. The lack of disclination formation may be rectified by introducing Frank elasticity into the modified Doi model ... / by Jason Ka-Chun Suen. / Ph.D.

Massachusetts Institute of Technology. Dept. of Chemical Engineering. Thesis. 1966. Sc.D. / Bibliography: leaves 192-199. / Sc.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, February 2012. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 181-199). / Catalytic processes are ubiquitous in both research and industrial settings. As continuous flow processes continue to gain traction in research labs and fine and pharmaceutical chemical processes, new opportunities exist for implementing previously difficult catalytic transformations. The major goal of this thesis is to expand and evaluate techniques for immobilized catalyst systems relevant to continuous flow. Fundamental studies in characterizing mixing, dispersion, and residence time distributions in small scale continuous flow systems are also presented. Given the numerous benefits associated with studying chemical processes at small length scales, microfluidic devices are the tool of choice for most studies in this thesis. Thermomorphic solvents offer the potential for homogeneous catalytic processes with biphasic catalyst recovery and recycle. A major limitation of these processes is the number of synthetically useful thermomorphic solvent combinations demonstrated in literature. A screening program using the modified UNIFAC (Dortmund) activity coefficient model to evaluate phase splitting behavior has been developed to predict thermomorphic behavior. Calculation of 861 binary solvent combinations results in 43 potential thermomorphic and 44 biphasic solvent combinations. Extension of the program to ternary solvents resulted in a new class of ternary solvents that display thermomorphic behavior with tunable critical solution temperatures. Evaluation of thermomorphic processes as a general method is presented. Traditional catalyst immobilization techniques rely on covalent grafting and are well suited to continuous flow processing due to the strong interactions of the catalyst to the support. Fluorous physisorption, which relies on interactions between a fluorous support and a fluorous-tagged catalyst, is characterized and presented as an immobilization technique for flow chemistry. The use of a fluorous-tagged Co(III)-salen catalyst to effect the ring opening of epoxyhexane with water is presented. Application of the platform to the ring closing metathesis of N,Ndiallyltosylamide using a fluorous-tagged Hoveyda-Grubbs metathesis catalyst results in significantly accelerated loss of activity over time compared to the salen catalyst. Use of continuous flow selective adsorption reactors to enhance catalytic processes is presented. Continuous feeds of a homogeneous catalyst into a sorbent where the catalyst displays an affinity for the sorbent results in accumulation of the catalyst in the packed bed. The net effect is an enhancement in turnover frequency and turnover number relative to homogeneous flow. Application of this platform to a Lewis acid catalyzed Diels-Alder reaction results in an order of magnitude improvement in turnover frequency compared to batch and homogeneous flow. / by Kevin David Nagy. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2012. / "June 2012." Cataloged from PDF version of thesis. / Includes bibliographical references. / An injectable hydrogel for controlled release of methylprednisolone was designed based on the inflammatory response during acute spinal cord injury. The gel is injectable through a small gauge needle, cross-links under physiological conditions, and releases methylprednisolone over a time period on the order of weeks. Swelling properties were characterized to address potential safety concerns for potential clinical use. Two studies are presented towards the development of a model Brown-Sequard syndrome and accompanying behavioral and pathological outcome measures for evaluation of biomaterials in vivo. A modified poly(glycerol-co-sebacic acid) membrane was developed using electrospun poly(s-caprolactone) nanofibers. Retinal adhesion and histology was evaluated in vitro. Membranes were evaluated in vivo for their ability to selectively remove photoreceptors in situ and promote survival and integration of retinal transplants. Viscoelastic poly(ethylene glycol) sols were evaluated as potential vitreous substitutes. Finally, a business plan outlines the strategy towards clinical trials for a hydrogel vitreous substitute. / by Christopher D. Pritchard. / Ph.D.