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The design, synthesis, characterization, and mechanical testing of a novel degradable polymeric biomaterial for use as a bone substituteYaszemski, Michael Jerome January 1995 (has links)
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 1995. / Includes bibliographical references (p. 141-148). / by Michael Jerome Yaszemski. / Ph.D.
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Engineering persistent interleukin-2 for cancer immunotherapy / Engineering persistent interleukin-two for cancer immunotherapy / Engineering persistent IL-2 for cancer immunotherapyGai, Shuning January 2012 (has links)
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.
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Computational study of self-assembly in block copolymer/superparamagnetic nanoparticle composites under external magnetic fieldsRaman, Vinay January 2014 (has links)
Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemical Engineering, February 2014.. / Cataloged from PDF version of thesis. / Includes bibliographical references. / This computational and theoretical study investigates the self-assembly of superparamagnetic nanoparticles and block copolymers under external magnetic fields. A variety of morphological transitions are observed based on the field orientation, nanoparticle loading, and selectivity of the nanoparticles for the blocks. For symmetric block copolymers, chaining of superparamagnetic nanoparticles under in-plane magnetic fields is shown to achieve long range orientational order of the block copolymer nanodomains and is found to be dependent on nanoparticle size, volume fraction and magnetization strength. A critical selectivity of the particles for one nanodomain is observed, above which strong alignment results and below which comparatively disordered structures are formed. Higher magnetization strengths are found to reduce equilibrium defect densities in the nematic-isotropic ordering of lamellar thin films, as corroborated by scaling arguments. For asymmetric coil fractions forming hexagonal block copolymer nanostructure, the inplane field induced chaining of the nanoparticles selective for the minority block, leads to the formation of stripe phases oriented parallel to the magnetic field. Furthermore, in-plane field induced chaining of nanoparticles selective for the majority block leads to alignment of hexagonal morphology with <100> direction oriented parallel to the external magnetic field. Out of plane magnetic fields induce repulsive dipolar interactions between the nanoparticles that annihilate the defects in the hexagonal morphology of the block copolymer when the nanoparticle is selective for the minority block. Honeycomb lattices are obtained using nanoparticles selective for majority block under out of plane magnetic fields for certain specific nanoparticle loadings. Commensurability of nanoparticle size and loadings with the block copolymer structure is critical in optimizing the ordering of the final composite. Kinetics of alignment in block copolymer nanocomposites is studied using External Potential Dynamics (EPD) method, wherein an equivalent evolution equation for potential fields is solved instead of conservation equation for the monomer segments. The dynamics study reveals an interesting interplay of nanoparticle mobility, dipolar interaction strength and nanoparticle-polymer interaction strength on the rate of alignment of domains. / by Vinay Raman. / Ph. D.
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Concentration fluctuations in ducted jet-mixingBecker, Henry A January 1961 (has links)
Thesis (Sc. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 1961. / Includes bibliographical references. / by Henry A. Becker. / Sc.D.
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Biological applications of weal polyelectrolyte multilayersBerg, Michael C., Ph. D. Massachusetts Institute of Technology January 2005 (has links)
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2005. / Includes bibliographical references. / This thesis research focused on biological applications of ultra-thin weak polyelectrolyte multilayers with specific emphasis on cell patterning, drug delivery, and antibacterial coatings. All of these very different applications were studied using three different polymers - polyacrylic acid (PAA), poly(allylamine hydrochloride) (PAH), polyacrylamide (PAAm). The first part of this thesis focuses on patterning polyelectrolyte multilayers found to resist mammalian cell adhesion, with ligands that promote specific interactions for adhesion. It was found that by patterning PAH on polyelectrolyte multilayers, the patterned functional group density and thickness could be tuned through ink pH adjustment. By changing the surface density of amine groups in the PAH patterns, the ligand density could also be altered using specific chemistry to attach peptides containing the tri-peptide sequence, RGD, which is known to promote cell adhesion in a number of cell types. The RGD density in the patterned regions determined the number of cells attached and the amount of cytoskeletal protein organization. The second part is an evaluation of porous polyelectrolyte multilayers as a delivery system for controlled release of small molecule drugs. The loading and releasing properties of porous PAH/PAA multilayers were investigated using the two drugs, ketoprofen and cytochalasin D. It was determined that the amount of drug released was proportional to the number of porous layers. Nanoporous films showed zero-order release, whereas microporous films displayed Fickian diffusion. The efficacy of the released drugs was checked by monitoring the effect of released cytochalasin D on fibroblasts' division. / (cont.) In the final part of this thesis, the antibacterial properties of both silver-loaded polyelectrolyte multilayers and superhydrophobic multilayers are examined. It was found that silver loaded multilayers killed bacteria to an extent greater than 99.99% for both airborne and waterborne models. Superhydrophobic films showed excellent anti-fouling properties for proteins, mammalian cells, and bacteria. / by Michael C. Berg. / Ph.D.
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Injectable hyaluronic acid scaffolds for cartilage tissue engineeringRen, Cindy D January 2008 (has links)
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2008. / Includes bibliographical references. / Every year tens of millions worldwide suffer from cartilage damage, caused by mechanical degradation, trauma or disease. Because of the lack of blood supply and low cell concentration within the tissue, cartilage has very limited regenerative ability. Although current treatments can provide symptomatic relief, the results vary greatly among individuals, and newly formed tissue often does not duplicate the structure, composition or mechanical properties of normal cartilage. Therefore, in recent years, tissue engineering has emerged as an alternative therapy. Tissue engineering enhances the body's natural healing capacity by providing cells, signaling molecules, and an environment in the form of a scaffold that is conducive to tissue growth. This project has focused on the development of a tissue engineering scaffold for cartilage regeneration. Disadvantages to current scaffolds include the fact that they require surgery for implantation, and that they are difficult to mold to the exact shape of the defect site. Hence, the motivation of this thesis is to develop an injectable scaffold that can be administered in a minimally invasive manner, and that allows for scaffold formation in situ, naturally shaping the construct into the shape of the defect, and thus promoting integration and stability To this end, we have developed a thermoresponsive injectable scaffold for cartilage tissue engineering. The scaffold was injected as a liquid at room temperature, and gelled at the target site in response to the change to body temperature, resulting in a biocompatible, bioresorbable substrate for tissue growth. Our approach involved suspending thermoresponsive liposomes, which encapsulated a crosslinking agent, in a polymer solution. At room temperature, the crosslinking agent was separated from the polymer by the lipid membrane, hence the precursor solution remained a liquid and injectable. Upon injection and exposure to body temperature, the lipids experienced a phase transition, which significantly increased the membrane permeability and led to the release of the crosslinking agent and reaction with the polymer, forming a networked scaffold. / (cont.) The scaffold system that we have chosen is a hyaluronic acid-tyramine system (HA-Tyr) that crosslinked in the presence of H202 and horseradish peroxidase (HRP) to form a hydrogel. Since HA, Tyr, H202 and peroxidases all occur naturally in the body, scaffold formation could take place with minimal toxicity and in the presence of cells as well as in situ. In order to impart temperature sensitivity to this system, HRP was encapsulated within liposomes, and it was shown that HRP was successfully retained at 25°C and released at 37°C. Upon liposome addition to the HA-Tyr/H202 solution, the precursor solution remained a liquid for hours at 25°C, yet gelation could be induced within minutes when exposed to 37°C. Furthermore, it was shown that gelation times could be adjusted to meet various clinical needs by modulating HRP encapsulation, liposome concentration and HA-Tyr concentration. In order to test the potential of the HA-Tyr system for cartilage production, porcine chondrocytes were encapsulated within HA-Tyr/H202/HRP hydrogels and implanted subcutaneously in mice. Harvested constructs were shown to achieve a GAG content of 1.2 wt% and demonstrated 40% of the collagen content of normal articular cartilage. Matrix production was found to be influenced by the initial cell density, scaffold degradation rate and Type II collagen concentration. The means of HRP delivery, whether by simple addition or through thermoreponsive liposomes, was not shown to have an effect on matrix production. Injected scaffolds were shown to achieve GAG and collagen levels similar to that of implanted scaffolds. As signaling molecules have been demonstrated to be potent chondrogenic inducers, PLGA-hydroxyapatite nanocomposite microparticles were utilized for the controlled delivery of TGF-[beta]1 and IGF-1. The rate of growth factor release was modulated by the molecular weight of PLGA within the microparticles; increasing molecular weight led to decreasing release rate. The nanocomposite microparticles were encapsulated within HA-Tyr/H202/HRP/chondrocyte constructs, which were then implanted subcutaneously in mice. / (cont.) Growth factor-induced enhancement of GAG and collagen production was found to be determined by the release rates of TGF-31 and IGF-1, multifactor release, and the dosage of nanocomposite microparticles. Injection of the microparticles with an HA-Tyr/H202/HRP liposome/chondrocyte/collagen solution also showed that the microparticles did not interfere with in situ scaffold formation, and could induce significant improvements to GAG and collagen production in the injectable system. / by Cindy D. Ren. / Ph.D.
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Covalent end-immobilization of oligonucleotides onto solid surfacesLee, Ivan H. (Ivan Hao), 1967- January 2001 (has links)
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2001. / Includes bibliographical references. / With the completion of the Human Genome Project, the focus of genetics research has shifted towards functional genomics, with emphasis on gene expression and polymorphism studies. To this end, there is rapidly increasing interest in solid-phase, high-throughput, combinatorial microarrays for DNA assays. For this purpose I synthesized oligonucleotides (oligos) stepwise onto derivatized SiO2 surfaces. Then double-stranded (ds)DNA molecules with "dangling end" oligo overhangs were immobilized onto the oligo surface by hybridization. Photolysis of psoralen crosslinkers covalently immobilized the dsDNA molecules to the oligo surface. The covalently end-attached dsDNA formed brush-like structures where the dsDNA strand could react under conditions resembling the natural solution-state found in vivo. This method minimized the possibility of nonspecific surface interactions, and could be developed for site-specific segregation of mixed dsDNA sequences from solution onto surface microarrays. Oligo surfaces with different densities were synthesized to determine the conditions that optimize dsDNA hybridization. The oligo surface density was controlled by derivatizing the Si02 surface with mixed compositions of alkylsilane molecules (X-(CH2)11-SiCl3, X= OH or CH3). X-ray photoelectron spectroscopy was used in conjunction with commercially available iodine-labeled nucleotides for quantifying oligo surface densities and stepwise reaction (coupling) efficiencies. / (cont.) 32P-radiolabeled complementary oligos and dangling-end dsDNA sequences also were used to determine hybridization yields and efficiencies. The experimental results clearly indicated that oligo coupling efficiency increased with decreasing oligo surface density, and also with increased coupling time. Consequently, I maximized the yield of full-length surface oligos by manipulating these reaction conditions. In addition, hybridization efficiency was inversely related to oligo surface density, and total hybridization yield was achieved at an oligo surface density of between 2 and 4 x 10-13 moles/cm2. The oligo surfaces were found to be thermally stable and reusable for performing multiple hybridization experiments on glass slides. dsDNA with 5' oligo overhangs were generated by PCR with a customized oligo primer. The dsDNA molecules were successfully immobilized onto oligo surfaces, at surface densities of approximately 2 x 10-13 moles/cm2. The spatial addressability of patterned oligo surfaces was demonstrated. Psoralen crosslinking was observed to proceed at 30-80% efficiency, compared to optimal 50% efficiency in solution phase. Upon heating the end-immobilized dsDNA unraveled to form covalently end-immobilized ssDNA probes with sequence lengths up to 390 bp that were employed in hybridization studies. / by Ivan H. Lee. / Ph.D.
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Optimal control of dynamical systems with time-invariant probabilistic parametric uncertaintiesShen, Dongying Erin January 2018 (has links)
Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemical Engineering, February 2018. / Cataloged from PDF version of thesis. "September 2017." Handwritten on title page "February 2018." / Includes bibliographical references (pages 117-121). / The importance of taking model uncertainties into account during controller design is well established. Although this theory is well developed and quite mature, the worst-case uncertainty descriptions assumed in robust control formulations are incompatible with the uncertainty descriptions generated by commercial model identification software that produces time-invariant parameter uncertainties typically in the form of probability distribution functions. This doctoral thesis derives rigorous theory and algorithms for the optimal control of dynamical systems with time-invariant probabilistic uncertainties. The main contribution of this thesis is new feedback control design algorithms for linear time-invariant systems with time-invariant probabilistic parametric uncertainties and stochastic noise. The originally stochastic system of equations is transformed into an equivalent deterministic system of equations using polynomial chaos (PC) theory. In addition, the H2- and H[infinity symbol]-norms commonly used to describe the effect of stochastic noise on output are transformed such that the eventual closed-loop performance is insensitive to parametric uncertainties. A robustifying constant is used to enforce the closed-loop stability of the original system of equations. This approach results in the first PC-based feedback control algorithm with proven closed-loop stability, and the first PC-based feedback control formulation that is applicable to the design of fixed-order state and output feedback control designs. The numerical algorithm for the control design is formulated as optimization over bilinear matrix inequality (BMI) constraints, for which commercial software is available. The effectiveness of the approach is demonstrated in two case studies that include a continuous pharmaceutical manufacturing process. In addition to model uncertainties, chemical processes must operate within constraints, such as upper and lower bounds on the magnitude and rate of change of manipulated and/or output variables. The thesis also demonstrates an optimal feedback control formulation that explicitly addresses both constraints and time-invariant probabilistic parameter uncertainties for linear time-invariant systems. The H2-optimal feedback controllers designed using the BMI formulations are incorporated into a fast PC-based model predictive control (MPC) formulation. A numerical case study demonstrates the improved constraint satisfaction compared to past polynomial chaos-based formulations for model predictive control. / by Dongying Erin Shen. / Ph. D.
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Theoretical modeling of micellization and solubilization in ionic surfactant systemsSrinivasan, Vibha, 1976- January 2003 (has links)
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2003. / Includes bibliographical references (p. 365-389). / Ionic surfactants constitute a very important class of surfactants, both from an academic as well as from a commercial viewpoint. In most commercial applications involving ionic surfactants, the selection of the surfactant is based on its aqueous bulk solution properties, including its micellization characteristics and its micellar solubilization characteristics (that is, the capacity of the surfactant micelles to encapsulate hydrophobic solutes in their interior, leading to a significant increase in the aqueous solubility of the hydrophobic solutes). Accordingly, the development of comprehensive, predictive, molecularly-based theories that relate the bulk solution properties of an ionic surfactant to its chemical structure should facilitate significantly the rational design, selection, and optimization of commercial surfactant formulations. The first major contribution of this thesis was the development of a molecular-thermodynamic theory of micellization of ionic surfactant-electrolyte systems, which takes into account the possibility that counterions (inorganic or organic, monovalent or multivalent) released by the ionic surfactant polar heads and by any added electrolytes can bind onto the charged micelle surface. By minimizing the free energy of micellization, various micellar solution properties were predicted quantitatively in the context of this theory, including : (i) the degree of binding of each counterion species onto the charged micelle surface, (ii) the micelle surface electrostatic potential, (iii) the critical micelle concentrations (CMC's), and (iv) the optimal shapes and average sizes of the micelles formed in solution. / (cont.) The micellization theory was applied to surfactant solutions containing monovalent counterions (specifically, alkali metal ions), multivalent counterions (specifically, A13+ and Ca2+), and organic counterions having pendant hydrophobic groups that penetrate into the micelle core (specifically, the salicylate ion). For all the surfactant systems considered, the quantitative predictions made compared well with the relevant experimental results available in the literature. The second objective of this thesis was to study the effect of the surfactant tail (chain) molecular structure on the surfactant micellar solution properties, for surfactants having more complex tail structures than linear alkyl tails, including: (i) branched akyl tails, (ii) alkylbenzene tails, and (iii) fluorocarbon tails. For surfactants with branched alkyl tails and alkylbenzene tails, a single-chain mean-field theory of chain packing was combined with suitable Rotational Isomeric State (RIS) models describing the chain torsional conformations, and the chain conformational characteristics as well as the packing free energy were predicted. Although the micellar solution properties of these surfactants were not investigated, the predicted packing characteristics can be viewed as a valuable "first-step" in the development of a comprehensive, predictive, molecularly-based micellization theory for these surfactants. In the case of fluorocarbon surfactants, in addition to modeling chain packing within the micelle core using suitable RIS models for the fluorocarbon chains, the remaining free-energy changes associated with micelle formation were modeled as well ... / by Vibha Srinivasan. / Ph.D.
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Radiation from a line fireRochechouart, Charles-Louis de January 1961 (has links)
Thesis (M.S.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 1961. / Includes bibliographical references (leaf 62). / by Charles-Louis de Rochechouart. / M.S.
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