Mu Chiao

Mechanical properties of biological tissues have been shown to vary in the presence of pathological disorders. This dissertation aims to investigate the effect of cancer on the viscoelastic properties of prostate gland. We use the quasi-linear viscoelastic model to characterize the elastic and viscous characteristics of thirty-five fresh prostate glands, removed within two hours of radical prostatectomy surgery. The viscoelastic properties of normal and cancerous prostates are compared to reveal the influence of cancer grade and tumor volume on the elasticity and viscosity of prostate tissue. We first present a novel method for describing the time-dependent behavior of soft materials using one-dimensional quasi-linear viscoelastic model. Our model derives the elastic (Young’s modulus) and viscous (shear relaxation modulus) properties by analyzing the stress response after a sudden uniaxial compression. The model is validated using experimental data on the phantoms that mimic the elasticity of normal and cancerous prostate tissues. The applicability of the model for material characterization is demonstrated by introducing a procedure for obtaining the mechanical properties via indentation test. Using three-dimensional equations and pre-calculated finite element analysis, the procedure introduces a fast and straightforward approach that is superior to inverse finite element methods. We evaluate our procedure by comparing the derived properties with those obtained from uniaxial compression test, where the results show high precision (standard deviation less than 10%) and good accuracy (error less than 20%). Finally, the procedure introduced for material characterization is used to characterize the viscoelastic properties of prostate gland. We test four different locations on fresh, unfixed prostate samples and compare the properties of locations where cancer spreads with those where cancer is not present. Our data-driven results demonstrate that tumor volume increases elastic and viscous properties of prostate with high statistical significance (p-value
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Systemic drug administration (i.e., intravenous injection), leading to drug circulation throughout the body can be associated with adverse side effects. Alternatively, localized drug delivery systems have been developed to focus drug concentrations at target sites. This method of delivery has been widely accepted in orthopedic infection management where the poor blood supply hampers antibiotics from reaching the infected site. Antibiotic-loaded bone cement beads have been approved for clinical delivery systems for the localized treatment of bone infections (osteomyelitis). The beads, however, have some shortcomings such as incompatibility with some antibiotics, and poor drug elution, which relies on unregulated passive diffusion. This dissertation proposes an on-demand drug delivery device that can control the release pattern using a controlled magnetic field application. The drug delivery device has the same configuration as conventional bone cement beads. It provides a sustained antibiotic discharge through a PMMA shell with multiple holes, while incorporating a magnetic porous PDMS at its core to manage the release profile via external magnetic fields. The magnetic sponge’s magneto-mechanical properties are investigated under non-uniform magnetic fields. Unlike proposed models that explore the effect of uniform magnetic fields, this study presents an analytical model that demonstrates the magnetic sponge response to the magnetic field gradient. The findings of this study and the development of the drug delivery device can provide adjustable released content controlled by the strength of the applied magnetic field. The in vitro experiments confirm the antibacterial efficacy of discharged gentamicin and silver against both gram-positive and gram-negative bacteria with extended bactericidal activity up to six days after drug combination. The ex vivo assessment demonstrated a successful drug discharge upon implantation with a controllable release profile using a magnet. Furthermore, to address the increasingly prevalent problem of antibiotic-resistant bacteria, a synergy study was conducted on gentamicin and silver nitrate. The results showed a significant improvement in the antibacterial efficiency once the two agents are combined, inhibiting the growth of MRSA and E. coli by more than 3log10CFU/mL. Exploiting the drug combination therapy in conjunction with a controllable localized drug delivery device may provide a more efficient therapy for treating osteomyelitis.

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Linear parameter-varying (LPV) control is a systematic way for gain-scheduling control of a nonlinear or time-varying system that has parameter-dependent dynamics variations in its operating region. However, when the dynamics variations are large, LPV control may give the conservative performance. One way to reduce the conservatism is switching LPV (SLPV) control, in which we partition the operating region into sub-regions, design one local LPV controller for each sub-region, and switch among those local controllers according to some switching rules. On the one hand, this thesis makes three theoretical contributions to the SLPV control theory. Firstly, this thesis proposes a new approach to designing SLPV controllers with guaranteed stability and performance even when the scheduling parameters cannot be exactly measured. Secondly, this thesis presents two algorithms to optimize the switching surfaces (SSs) that can further improve the performance of an SLPV controller. One algorithm is based on sequentially optimizing the SSs and the SLPV controller for the state-feedback case. The other one is based on particle swarm optimization and can be used for both state-feedback and output-feedback cases. Finally, this thesis introduces a novel approach to designing SLPV controllers that could yield significantly improved local performance in some sub-regions without much sacrifice of the worst-case performance. This is different from the traditional approach that often leads to similar performance in all the sub-regions.On the other hand, this thesis addresses two practical problems using the theoretic approaches developed in this thesis. One is control of miniaturized optical image stabilizers with product variations. Specifically, multiple parameter-dependent robust (MPDR) controllers are designed to adapt to the product variations, while being robust against the uncertainties in measurement of the scheduling parameters that characterize the dynamics variation. Experimental results validate the advantages of the proposed MPDR controllers over a conventional robust mu-synthesis controller. The other application is control of a floating offshore wind turbine on a semi-submersible platform. SLPV controllers are designed for regulating the power and the generator speed and reducing the platform motion. The superior performance of the SLPV controllers is demonstrated in high-fidelity simulations.

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The ability of living cells to sense and respond to mechanical cues from the surrounding environment has been the subject of much study. Over the past two decades, a variety of techniques have been used to apply mechanical stimuli and investigate cell response. Recently, with advances in the field of Microelectromechanical Systems, devices incorporating microscale actuators have been developed to apply forces and study the cell response of individual cells. Among these microdevices, micropillar arrays incorporating remotely actuated magnetic pillars have shown some success as combined actuation and sensing platforms for cell strain studies. However, issues associated with the complex fabrication techniques used, the low actuation forces generated and the high magnetic field gradients required for pillar actuation have hindered the wide-scale adoption of these devices by the general research community. Consequently, investigation into the use of these active micropatterned surfaces in eliciting or controlling specific cellular response on a multicellular level has yet to be undertaken. This thesis aims to investigate the application of remotely actuated micropillar surfaces in controlling the migration behavior of cells on a multicellular level. First, using a novel custom-made magnetically actuated cell strain assessment tool, conventional tests are performed on endothelial cells to determine the minimum strain requirements for eliciting cell response. Then, a new technique for fabrication and patterning of magnetic micropillar arrays is developed to overcome the complexities of previous fabrication methods. Using the newly developed fabrication technique, magnetic micropillar arrays of various dimensions are fabricated and their mechanical, magnetic and material properties are characterized. The fabricated magnetic micropillars generate forces of several hundred nanonewtons at moderate magnetic fields of 100mT and are favorable to previous state-of-the-art. Finally, a cell migration chip comprising various micropillar topologies is developed and the migration behavior and migration rates of sheets of cells on the micropillar surfaces in the presence and absence of micropillar actuation is studied using in-vitro experiments. We show that actuated micropillar surfaces significantly impede cell migration, reducing cell migration rates by up to 85%. The magnetically actuated micropillar surfaces could have possible in-vivo applications for preventing cell-migration induced biofouling of medical implants.

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Various optical microscopy techniques have been developed for micrometer level imaging of biological tissue samples. Among those techniques, confocal imaging provides superior image contrast and high resolution with a modest system cost. Confocal microscopy allows vertical optical sectioning (imaging a section perpendicular to the surface of tissue) or horizontal optical sectioning (imaging a section parallel to the surface of tissue) and provides high-resolution tissue morphology that is analogous to conventional histopathology images. This has brought up a tremendous potential for guiding surgical biopsies and in vivo non-invasive diagnosis of diseases such as cancer. The challenge in moving microscopic imaging modalities into clinical applications is miniaturization into a form of hand-held devices or catheters for endoscopic applications.In this thesis, micro-fabrication techniques such as Microelectromechanical Systems (MEMS) fabrication process and laser micromachining have been employed to develop magnetic actuators. The actuators are then used to move lenses and optical fibers in order to scan a laser beam across a sample. Lens and fiber actuators are integrated in catheter and hand-held devices for confocal thickness measurement and optical sectioning imaging of biological samples.Thickness measurement is performed by scanning the focal point of a microlens across the thickness of thin films or layered biological tissues and collecting the intensity signal of the single scattering light reflected back from the samples as a function of lens position. A catheter was developed and thickness measurements of polymer layers and biological tissues were demonstrated. The device has optical resolution of 32 µm with expanded uncertainty of measurement of 11.86 µm. Lens and fiber optic actuators have been coupled to form two-dimensional imaging devices. Direct and real-time vertical and horizontal cross-sectional imaging of biological samples has been demonstrated. Vertical imaging is performed by transverse (X-axis) and axial (Z-axis) scanning of a focused laser beam using an optical fiber and a microlens actuator respectively. Horizontal imaging is done by a 2-axis fiber optic scanner. All the developed actuators are driven by electromagnetic forces and require low driving voltages. Confocal imaging of biological samples, with lateral resolution of 1.55 µm, has been demonstrated.

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Drug therapy efficacy depends on therapeutic concentrations of drugs at disease sites. An ideal controlled and localized drug delivery system would deliver drugs to a target tissue and would locally maintain the required drug concentration. Furthermore, for many diseases, the delivery of therapeutic concentrations on an “on-demand” basis would be of tremendous benefit.In this thesis, a MEMS (Microelectromechanical Systems) based drug delivery device has been developed that provides on-demand release of defined drug quantities. The device consists of a drug-loaded microreservoir that is sealed with an elastic PDMS (polydimethylsiloxane) magnetic membrane with a laser-drilled aperture. The drug release is triggered in the presence of an external magnetic field by deforming the magnetic membrane and therefore discharging the drug solution. The use of magnetic actuation for on-demand and controlled dose sequencing eliminates the need for an on-board power source. A new magnetic membrane material has been developed for the proposed drug delivery device. The polymeric magnetic composites were developed by incorporating coated iron oxide nanoparticles within a PDMS matrix. The new composites show improvement in reducing particle agglomeration compared to existing polymeric magnetic materials. Free-standing PDMS magnetic membranes with a thickness of 35 µm have been fabricated and have shown to deflect in applied magnetic fields. The MEMS drug delivery device has been used to deliver an antiproliferative, taxane-based drug, docetaxel (DTX). On-demand and controlled release of DTX with a dosage suitable for treatment of diabetic retinopathy has been achieved for 35 days. Biological activity of the released DTX was investigated two months after the drug was packaged in the device. These studies confirmed that the antiproliferative effect of DTX can be maintained for 2 months, and the drug does not degrade within the device. This device is a proof-of-concept development for on-demand and controlled delivery of taxane-based agents for treatment of proliferative retinopathy, which requires accurate delivery of nanomolar drug concentrations.

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Kraft pulp digesters have been used to convert wood chips into pulp for manufacturing a wide variety of paper products. Inside a kraft digester, chemical reactions remove lignin from their wood matrix in a caustic environment (pH~13.5, 170°C, 2MPa). Data on actual internal operating conditions in a kraft digester is needed to optimize kraft digester operation and obtain maximum production quality. Currently, this information is limited to selected static locations on the periphery of the digester. The objective of this thesis is to develop miniature temperature, pressure, and liquid conductivity sensors for use in autonomous flow-following SmartChips to measure kraft process variables within the digester during their passage through the process. Combined capacitive pressure and temperature sensors were fabricated by bonding silicon and Pyrex chips using a new polymeric gap-controlling layer and a high temperature adhesive. A simple chip bonding technique involving insertion of the adhesive into the gap between two chips was developed. A silicon dioxide layer and a thin layer of Parylene were deposited to passivate the pressure sensor diaphragm against the caustic environment in kraft digesters. The sensors were characterized at both high temperatures and pressures and no signs of corrosion could be identified on the sensors.Integrated piezoresistive pressure and temperature sensors consisting of a square silicon diaphragm and high resistance piezoresistors were developed. A new Parylene and silicone conformal coating process were developed to passivate the pressure sensors against the caustic environment. The sensors were characterized up to 2MPa and 180°C in an environmental chamber. The sensors’ resistances were measured before and after testing in a kraft pulping cycle and showed no change in their values. SEM pictures and topographical surface analyses were also performed before and after pulp liquor exposure and showed no observable changes.Combined liquid conductivity and temperature sensor packages consisting of a platinum resistance temperature detector (RTD) and a four-electrode conductivity sensor formed by stainless steel electrodes and installed on a polyetheretherketone (PEEK) enclosure were developed. The sensors were characterized up to 180°C at NaOH concentrations of 10-100g/l in the presence of wood chips and survived with no signs of corrosion.

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A novel anti-biofouling mechanism based on the combined effects of electric field and shear stress was reported. The mechanism was observed in millimeter-scale piezoelectric plates coated with different metal materials and microfabricated Micro-Electro-Mechanical Systems (MEMS) devices. Experimental observation on the quantities of protein desorption and theoretical calculations on surface interactions (van der Waals, electrostatic, hydrophobic, shear stress) have been carried out. This anti-fouling mechanism can also be activated by a vibrating micromachined Si/SiO₂ membrane. The combined effect of polyethylene glycol (PEG) grafting and application of vibration on attenuation of protein adsorption was also investigated. Vibrating PEG-grafted surfaces significantly attenuate protein adsorption, especially at low PEG grafting densities. Polymer steric interaction dominates over vibration interaction with protein on surfaces with high PEG grafting densities.Monothiol-functionalized hyperbranched polyglycidols (HPG-SH) were synthesized and self-assembled on the gold surface. The characteristics of the polymer were studied and compared with linear PEG using various surface analysis techniques. This hyperbranched polyglycidol is more resistant to protein adsorption than is linear PEG of similar molecular weight. In addition, higher molecular weight HPG shows less protein adsorption than does lower molecular weight HPG.The hyperbranched polyglycidols (without a thiol group) were further modified to generate functionality for microchannel-based liquid chromatography applications. The microchannel surface was first amino modified by allylamine plasma, and amino groups then reacted with N-hydroxy succinimide-functionalized HPGs to form strong amide bonds. The grafted HPGs are resistant to nonspecific protein adsorption. The succinimidyl ester groups degrade in water to form carboxyl groups on HPGs. By giving extra carboxyl groups to each HPG, the HPG can selectively capture positive avidin from a mixture of avidin and bovine serum albumin (BSA). To increase the capture efficiency, the microchannel was integrated with micropillar arrays as the liquid chromatography column.

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