Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2005. / Includes bibliographical references (leaves 131-140). / (cont.) strains to characterize the bioreactor environment. The ability to reproducibly sacrifice microbioreactors mid-run is exploited to demonstrate the feasibility of linking microbioreactors to genome-wide expression studies using DNA microarrays. The potential of the microbioreactor for investigating different growth conditions is confirmed by comparing bacterial growth, as evaluated by the measured parameters, under conditions of different medium and oxygen concentration. It is shown that statistical differences can be observed, and that these differences are similar to those observed at a larger scale. The demonstrated functionality of the microbioreactor could potentially have a large impact in the numerous fields in which fermentations are used. In bioprocess development, the batch microbioreactor could be used to select strains at all stages of metabolic engineering and to explore and optimize growth conditions during scale-up. The microbioreactor could also be an effective tool in screening applications ranging from toxicology studies that use bacterial reporter strains, to studies that attempt to elucidate metabolic pathways, to intensification of genome-wide expression profiling using either direct links to DNA microarrays or screens of libraries carrying transcription reporters. / This thesis presents the design, fabrication, and characterization of a batch microbioreactor with integrated, automated sensors and aeration through a permeable polymer membrane as a step towards establishing high-throughput bioprocessing platforms. In particular, the thesis demonstrates the feasibility of culturing bacterial cells in microliter volumes and obtaining reproducible results similar to those shown at larger scales. A microbioreactor designed to provide sufficient oxygen to a growing culture is fabricated out of PDMS and glass. Models are developed to understand oxygen transport and consumption as well as the kinetics of growth within the microbioreactor. Sensors are integrated to measure the growth parameters optical density (OD), dissolved oxygen (DO), and pH. Based on these measurements as well as cell morphology and total and viable cell counts, reproducibility is established and comparisons to bench-scale bioreactors are made. It is demonstrated that the behavior of bacteria at the two scales is very similar. It is further demonstrated that off-line analysis of the medium can be carried out by serial sacrifice of microbioreactors operating under identical conditions. The test case of HPLC analysis of the fermentation medium to measure glucose consumption and organic acid production is used. Additional sensing capabilities in the form of in situ measurements for luminescence and fluorescence are demonstrated, and a potential glucose sensor is modeled to explore feasibility. Once reproducibility in fabrication, experimental protocol, and experimental results is established, the microbioreactor is used for several applications. The ability to monitor luminescence and fluorescence on-line enables the use of bacterial reporter / by Andrea Zanzotto. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2009. / Cataloged from PDF version of thesis. / Includes bibliographical references. / Photoinitiated chemical vapor deposition (piCVD) is developed as a simple, solventless, and rapid method for the deposition of swellable hydrogels and functional hydrogel copolymers. Mechanistic experiments show that piCVD is predominantly a surface reaction, allowing it to coat non-planar geometries such as particles. The process is gentle enough to coat delicate optical sensors without degrading their function. Chemically functional hydrogels can be synthesized by incorporating a comonomer, and this functionality can be nanoconfined to the near surface region. Random amphiphilic copolymer films deposited via piCVD represent a novel polymer film system, and these surfaces present molecular-scale compositional heterogeneities that interfere with protein adsorption events. Also described is the mechanism by which thin films form on non-planar geometries via initiated chemical vapor deposition (iCVD) . The conformality of these films in microtrenches is assessed and an analytical model is developed in order to quantify the sticking probability of the initiating radical. Mechanistic insight from these experiments is used to predict the conformality based on the fractional saturation of the monomer vapor. / by Salmaan Husain Baxamusa. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2009. / Includes bibliographical references. / Effective separation and purification of biopharmaceutical products from the media in which they are produced continues to be a challenging task. Such processes usually involve multiple steps and the overall product loss can be significant. As an integrative technique, high gradient magnetic separation (HGMS), together with the application of functional magnetic particles, provides many advantages over traditional techniques. However, HGMS has a number of drawbacks; and its application is limited because it is inherently a batch process and it is difficult to recycle the magnetic nanoparticles. This thesis explores the development of a new type of continuous magnetic separation process, called magnetically enhanced centrifugation (MEC), which exploits the interactions of magnetic particles with magnetic field gradients, forced convective flows and large centrifugal forces. Magnetically susceptible wires in a uniform magnetic field facilitate the capture and aggregation of magnetic particles on wires, and a centrifugal force perpendicular to the magnetic force conveys the particle sludge parallel to the wires in a continuous mode. The primary focus of this thesis is multi-scale modeling and simulation to understand the underlying physics of MEC processes. The potential of MEC as an effective unit operation for biopharmaceutical downstream processing has been demonstrated. Unlike traditional batch-mode HGMS, MEC has a great advantage in that it can be operated continuously as magnetic particles captured on wire surface are constantly removed. / (cont.) A dimensionless model for simulating the trajectories of magnetic particles in combined magnetic and flow fields has been developed. The model was first applied to single wire configurations and then extended to multi-wire arrays. It was shown that modified rhombic arrays can provide high capture efficiency while maintaining low pressure drop. It is also shown that capture efficiencies based on results for clean, particle-free wires, may be seriously in error because the particle buildup that accumulates on the wire significantly distorts the flow and the magnetic fields and thus influences the particle trajectories. The dynamic buildup growth process was treated as a moving-boundary problem. Simulation results have shown that the capture efficiency decreases dramatically as particle buildup volume increases. In addition, the influence of particle chaining under magnetic dipole-dipole forces on separation efficiency has been investigated. Magnetic particles form chains as soon as they enter a background magnetic field, and are captured in the form of particle chains. The hydrodynamic force on particle chains was calculated using a 3-D CFD simulation. The capture radius calculated with considering the chaining effect is few times as great as the capture radius calculated assuming individual particles. Bench-top MEC experiments have shown that magnetic particle buildup generally comprises two layers with distinct structures: a spiky layer with all chains parallel to the magnetic field, and a densely-packed layer near the wire. / (cont.) This unique structure reflects the dominance of magnetic forces near the wire and of magnetic dipole-dipole interactions at locations further from the wire. As more and more particles accumulate on the wire surface, the centrifugal force can overcome the cohesion of the layer or the adhesion of the layer to the wire, leading to movement of the buildup material. The onset of such movement can be achieved either by increasing the centrifugal force or by increasing the buildup height. Energy and force analyses have been carried out to study various scenarios of buildup movement. For monodisperse magnetic particles, four scenarios can be expected: chain-like layer collapsing down (I), rigid body movement (II), buildup breakage (III), and mixed behavior of rigid body movement and buildup breakage (IV). A set of design formulas were derived to predict buildup structure and different scenarios. Useful scenario and operating regime diagrams were obtained. A discrete element modeling (DEM) package was developed to study the dynamics and rheological behavior of highly concentrated magnetic particle systems. For monodisperse magnetic particles, simulation results confirmed the four regions of the scenario diagram as predicted by force arguments. For polydisperse magnetic particles, DEM simulations showed that the buildup exhibits solid-like behavior when centrifugal effects are small, and liquid-like behavior with a continuous velocity profile when centrifugal effects are large. / (cont.) DEM simulations were able to predict the three dimensional effects, including the buildup profiles at the wire tip. Taken together, the results of this work provide a general strategy that can be used as a starting point for the design, evaluation, and optimization of magnetically enhanced processes that are suitable for biopharmaceutical downstream processing. / by Fei Chen. / Ph.D.

Thesis (B.S.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 1942. / Includes bibliographical references (leaf 74). / by Fredrich Herbert Olsen. / B.S.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 1993. / Includes bibliographical references (v. 2, leaves 326-333). / by Christopher James Pope. / Ph.D.

Thesis (Sc.D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2002. / Includes bibliographical references. / In this thesis, chemically-induced transdermal transport enhancement has been examined as one of the many techniques currently used to increase the skin permeability to a broader range of pharmaceutically relevant drugs. By taking advantage of the current developments in instrumentation technology, the mechanisms underlying the well-known chemical enhancer action of oleic acid have been examined using novel applications of Two-Photon Microscopy (TPM). For the first time, TPM was used to visualize and quantify the oleic acid-induced three-dimensional spatial distributions of rhodamine B hexyl ester (RBHE), a model hydrophobic fluorescent probe, and of sulforhodamine B (SRB), a model hydrophilic fluorescent probe, based on a sampling of 4 to 6 different skin sites per skin sample. The fluorescent probe intensity profiles, that capture the fluorescent probe concentrations as a function of skin depth, were further evaluated using fundamental transport equations to quantify the oleic acid-induced changes in the vehicle to skin partition coefficient, the concentration gradient, the skin diffusion coefficient, and the skin barrier diffusion length. The application of the quantification methodology revealed that oleic acid-induced increases in the probe vehicle to skin partitioning was the primary effect for both the hydrophobic and the hydrophilic model fluorescent probes. The validity of the transport property enhancement values calculated based on the sample sizes examined (4-6 skin sites), was then addressed, in light of the inherent heterogeneity of the skin morphology. / (cont.) The increased sampling efficiency provided by High-Speed Two-Photon Microscopy (HTPM) enables the imaging of clinically more relevant skin areas over shorter times. Using HTPM, the fluorescent probe spatial distributions in 400 consecutive skin sites, comprising a total skin area of 2mm by 2mm, were quantified for the control (no oleic acid exposure) and the enhancer (oleic acid exposure) cases of RBHE and SRB. Following the application of a randomized skin site sampling subroutine, the optimum number of skin sites needed to accurately represent the globally-induced changes in transdermal transport properties was determined. For the hydrophobic probe, a limited sampling of 4-6 skin sites was found to be sufficient, whereas for the hydrophilic probe, 12-24 skin sites was recommended. Furthermore, the oleic acid-induced variations in the wide-area spatial distributions of two transdermal transport parameters- the probe surface intensity and the probe intensity gradient- were evaluated to determine the rate-limiting steps in transdermal transport for each fluorescent probe examined. Lateral diffusion through the lipid multilamellae, for the hydrophobic fluorescent probe, and probe partitioning from the vehicle into the skin, for the hydrophilic fluorescent probe, were determined to be the rate-limiting steps in transdermal transport. In the final application of TPM presented in this thesis, the oleic acid-induced changes in the fluorescent probe spatial distributions with respect to the skin structural features were examined, for the first time, utilizing dual-channel HTPM, where the skin autofluorescence intensity and the probe intensity spatial distributions are simultaneously visualized... / by Betty Yu. / Sc.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 1986. / MICROFICHE COPY AVAILABLE IN ARCHIVES AND SCIENCE. / Bibliography: leaves 242-245. / by Peter Martin Adornato. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2009. / Includes bibliographical references. / In this work we studied the focusing and trapping of submicron, nonmagnetic species immersed in a magnetic nanofluid under applied magnetic fields. Focusing was achieved using two pairs of permanent magnets, which forced submicron fluorescently-tagged polystyrene beads to focus in the region between the two magnet pairs. Size-based trapping was achieved using a microchip that produced spatially increasing magnetic field gradients that trapped flowing polystyrene beads at different locations, depending on their relative sizes. In the focusing experiments, a mixture of magnetic nanoparticles and nonmagnetic, fluorescently tagged latex beads (435 nm and 910 nm in diameter) were loaded into a capillary tube and placed in-between the magnet pairs. The concentration profiles of the latex beads were measured using fluorescence imaging and simulated results were obtained using continuum modeling. Good quantitative agreement was found between experiments and theory for both latex-bead sizes at various experimental conditions. Size-based trapping of latex beads was accomplished by balancing drag and magnetic buoyancy forces in such a way that smaller and larger nonmagnetic species were trapped at different locations. A microfabricated device with two external magnets was used to generate the trapping forces, and a syringe pump was used to flow the mixture of magnetic fluid and nonmagnetic particles through the device. Size-based trapping was achieved for a feed mixture of 435 nm and 865 nm latex beads, as measured using fluorescence imaging. Semi-quantitative agreement was found between experiments and Brownian-dynamics simulations. Our work shows that negative magnetophoresis in magnetic nanofluids can be used to size-selectively trap and focus submicron, nonmagnetic species. / by Lino A. Gonzalez. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2004. / Includes bibliographical references (p. 65-66). / Gene expression arrays are a technology used to measure quantities of messenger ribonucleic acid (mRNA). Application of the technology involves a variety of physical processes beginning with the acquisition of mRNA samples and ending with the fluorescence imaging of a gene expression array. This thesis examines these physical processes, develops a mechanistic model, and derives the analysis procedure based on the model. Chief advantages of this approach are that it accounts for certain previously unexplained array phenomena and is based in a clear way on physical knowledge allowing non-arbitrary determination of both the probability that any given gene has altered expression ratio relative to a control as well as the magnitude of this induction or repression. We demonstrate its use on simulated and real array data, and show that a considerable amount of previously unrecognized information concerning gene expression differences is inherent in the array measurements. / by Keith Howard Duggar. / Ph.D.

Thesis (Sc. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 1973. / Leaf 122 used twice in part 1. Leaf 249 used twice in part 2. Vita. / Includes bibliographical references. / by Joseph E. L. Rogers. / Sc.D.