<p> Mechanical signals affect virtually every fundamental single- and multi-cellular process in biology. The local responses of individual molecules to mechanical stimuli at the interface of cell with its adjacent microenvironment (extracellular matrix or material) elicit global responses at the cell and tissue scales. Understanding and manipulating the cell-material interaction can be leveraged to design biomaterials with unique characteristics tailored towards a wide variety of biological applications such as platforms that direct stem cell differentiation for tissue engineering, sensors that can record accurate electrical signals in single cells for neuroscience, and implants that are susceptible to cell adhesion for biomedical applications. In this thesis I present work characterizing the response of cells to mechanical stimuli at the single cell and single molecule scales. At the single cell scale, we provide insights into how mechanical signals such as micro- and nano-topography of metallic and metallic surfaces affect cell adhesion, both in mammalian and bacterial cells. Next we characterize the mechanical response of protein complexes involved in the transmission of mechanical signals across the cytoskeleton to the nucleus. </p><p> The four main contributions of the work presented in this thesis are as follows: 1) We used high resolution scanning electron microscopy to characterize the cell-nanostructure interface and provide insights into the response of individual mammalian cells to nanostructures with complex geometries. 2) We provide a first look at how individual bacterial cells adhere to metallic nanostructures, which could lead to new techniques to thwart infections. 3) We proposed a novel technique to control the growth and arrangements of bacterial cell communities. This method will allow precise small-scale mechanical manipulation of bacterial cells and could be utilized for unraveling the understudied mechanisms of bacterial mechanosensitivity. 4) We performed the first molecular dynamics study on the mechanisms of force transmission to the nucleus of eukaryotic cells through protein complexes known as linkers of the nucleoskeleton and cytoskeleton (LINC complexes). We showed that LINC complexes are highly stable under tensile forces, and that the transmission of force across the complex depends highly on the unique intermolecular covalent bonds formed between the two proteins that construct the complex. Finally, we presented a model for the molecular mechanisms of LINC complex activation and regulation at the nuclear envelope.</p><p>

Synthetic tri-leaflet heart valves generally fail in the long-term use (more than 10 years). Tearing and calcification of the leaflets usually cause failure of these valves as a consequence of high tensile and bending stresses borne on the material. The primary purpose of this study was to explore the possibilities of a new polymer composite to be used as synthetic tri-leaflet heart valve material. This composite was comprised of polystyrene-polyisobutylene-polystyrene (Quatromer), a proprietary polymer, embedded with continuous polypropylene (PP) fibers. Quatromer had been found to be less likely to degrade in vivo than polyurethane. Moreover, it was postulated that a decrease in tears and perforations might result from fiber-reinforced leaflets reducing high stresses on the leaflets. The static and dynamic mechanical properties of the Quatromer/PP composite were compared with those of an implant-approved polyurethane (PU) for cardiovascular applications. Results show that the reinforcement of Quatromer with PP fibers improves both its static and dynamic properties as compared to the PU. Hence, this composite has the potential to be a more suitable material for synthetic tri-leaflet heart valves.

The objective of this study is to design and development of an enzyme-linked biosensor for detection and quantification of phosphate species. Various concentrations of phosphate species were tested and completed for this study. Phosphate is one of the vital nutrients for all living organisms. Phosphate compounds can be found in nature (e.g., water sediments), and they often exist in aninorganic form. The amount of phosphates in the environment strongly influences the operations of living organisms. Excess amount of phosphate in the environment causes eutrophication which in turn causes oxygen deficit for the other living organisms. Fish die and degradation of habitat in the water occurs as a result of eutrophication. In contrast, low phosphate concentration causes death of vegetation since plants utilize the inorganic phosphate for photosynthesis, respiration, and regulation of enzymes. Therefore, the phosphate quantity in lakes and rivers must be monitored. Result demonstrated that phosphate species could be detected in various organisms via enzyme-linked biosensor in this research.

This thesis involves a procedure, which calculated and compared the sum of all the pixel counts, threshold pixel counts sum of a 3D PET image and mean and maximum pixel count of one single transaxial slice (2D) of simulated tumors for a chosen region of interest (ROI). A calibration factor was multiplied by the sum of the pixel counts, threshold pixel counts sum of all the transaxial slices, and the mean, and maximum pixel counts of one single transaxial slice in an ROI to calculate for the activity of the tumor. This activity calculated was compared with the real activity values. The results showed that the sum of all the pixel counts with applied threshold is better to calculate the activity of tumor with greater accuracy. These findings suggest that a 3D distribution of sum of all the pixel counts was able to calculate the activity of malignant tumors and lung lesions with better accuracy.

This dissertation presents dynamic flow experiments with fluorescently labeled platelets to allow for spatial observation of wall attachrent in inter-strut spacings, to investigate their relationship to flow patterns. Human blood with fluorescently labeled platelets was circulated through an in vitro system that produced physiologic pulsatile flow in (1) a parallel plate flow chamber that contained two-dimensional (2D) stents that feature completely recirculating flow, partially recirculating flow, and completely reattached flow, and (2) a three-dimensional (3D) cylindrical tube that contained stents of various geometric designs. Flow detachment and reattachment points exhibited very low platelet deposition. Platelet deposition was very low in the recirculation regions in the 3D stents unlike the 2D stents. Deposition distal to a strut was always high in 2D and 3D stents. Spirally recirculating regions were found in 3D unlike in 2D stents, where the deposition was higher than at well-separated regions of recirculation. Platelet deposition occurred through convective transport of platelets as defined by the instantaneous streamlines. The instantaneous streamlines were obtained from computational fluid dynamics models of the different stents used with the same experimental flow conditions. Platelet deposition was higher in areas where the blood flow was directed towards the wall and lower in areas where the blood flow was directed away from the wall. Though the platelet deposition patterns shown in this paper were a result of a short time-scale phenomena, convective transport plays an essential role in the interaction of blood cells with the endothelial or exposed underlying collagen layer, which In turn affects the development of Intimal hyperplasia (IH). These results could help in improved stent designs In future that prevent excessive platelet aggregation.

The purpose of this research was to develop a new diffuse reflectance model to facilitate rapid and accurate extraction of tissue physiological characteristics from diffuse reflectance spectra. The model used hybrid statistic formulas to describe the probability of a photon reemerging at the tissue surface and its weight attenuation during migration. Validations by Monte Carlo simulations indicate that the model is accurate for a wide range of optical parameters and short source-detector separations with an error less than 10%. Furthermore, the model was incorporated in the process of interpreting diffuse reflectance spectra from a set of tissue simulating phantoms; the dynamic changes in hemoglobin oxygenation of the phantoms were obtained accurately. Findings of this research demonstrate the utility of the new diffuse reflectance model for extracting physiological information from tissue diffuse reflectance spectra, and due to speed and accuracy advantages over existing models, applicability for use in the clinical setting.

Polymer trileaflet heart valves have been under investigation since the 1960's but their success has not been realized because of failure due to calcification, thrombogenicity, tensile stresses, and overall lack of durability. The purpose of this research was to assess Quatromer , a proprietary triblock co-polymer, for use in a trileaflet heart valve. Two specific aims were covered in this research endeavor: 1) Hydrodynamic assessment of a composite Quatromer valve and 2) Assessment of the thrombogenic potential of the QuatromerTM material by means of platelet deposition. Hydrodynamic tests proved that the QuatromerTM valve had equivalent performance when compared with two commercially available mechanical and bioprosthetic valves, while biocompatibility testing showed that the material's resistance to platelet aggravation was equivalent to that of polyurethane, the leading choice of polymer for trileaflet heart valves. In conclusion, the QuatromerTM trileaflet valve has been shown to have a promising design that warrants further investigation.

Fluorescence-enhanced optical imaging is an emerging non-invasive and non-ionizing modality towards breast cancer diagnosis. Various optical imaging systems are currently available, although most of them are limited by bulky instrumentation, or their inability to flexibly image different tissue volumes and shapes. Hand-held based optical imaging systems are a recent development for its improved portability, but are currently limited only to surface mapping. Herein, a novel optical imager, consisting primarily of a hand-held probe and a gain-modulated intensified charge coupled device (ICCD) detector, is developed towards both surface and tomographic breast imaging. The unique features of this hand-held probe based optical imager are its ability to; (i) image large tissue areas (5x10 sq. cm) in a single scan, (ii) reduce overall imaging time using a unique measurement geometry, and (iii) perform tomographic imaging for tumor three-dimensional (3-D) localization. Frequency-domain based experimental phantom studies have been performed on slab geometries (650 ml) under different target depths (1-2.5 cm), target volumes (0.45, 0.23 and 0.10 cc), fluorescence absorption contrast ratios (1:0, 1000:1 to 5:1), and number of targets (up to 3), using Indocyanine Green (ICG) as fluorescence contrast agents. An approximate extended Kalman filter based inverse algorithm has been adapted towards 3-D tomographic reconstructions. Single fluorescence target(s) was reconstructed when located: (i) upto 2.5 cm deep (at 1:0 contrast ratio) and 1.5 cm deep (upto 10:1 contrast ratio) for 0.45 cc-target; and (ii) 1.5 cm deep for target as small as 0.10 cc at 1:0 contrast ratio. In the case of multiple targets, two targets as close as 0.7 cm were tomographically resolved when located 1.5 cm deep. It was observed that performing multi-projection (here dual) based tomographic imaging using a priori target information from surface images. Improved the target depth recovery over using single projection based imaging. From a total of 98 experimental phantom studies, the sensitivity and specificity of the imager was estimated as 81-86% and 43-50%, respectively. With 3-D tomographic imaging successfully demonstrated for the first time using a hand-held based optical imager, the clinical translation of this technology is promising upon further experimental validation from in-vitro and in-vivo studies.

abstract: Muscular weakness is a common manifestation for Stroke survivors and for patients with Anterior Cruciate Ligament reconstruction leading to reduced functional independence, especially mobility. Several rigid orthotic devices are being designed to assist mobility. However, limitations in majority of these devices are: 1) that they are constrained only to level walking applications, 2) are mostly bulky and rigid lacking user comfort. For these reasons, rehabilitation using soft-robotics can serve as a powerful modality in gait assistance and potentially accelerate functional recovery. The characteristics of soft robotic exosuit is that it’s more flexible, delivers high power to weight ratio, and conforms with the user’s body structure making it a suitable choice. This work explores the implementation of an existing soft robotic exosuit in assisting knee joint mechanism during stair ascent for patients with muscular weakness. The exosuit assists by compensating the lack of joint moment and minimizing the load on the affected limb. It consists of two I-cross-section soft pneumatic actuators encased within a sleeve along with insole sensor shoes and control electronics. The exosuit actuators were mechanically characterized at different angles, in accordance to knee flexion in stair gait, to enable the generation of the desired joint moments. A linear relation between the actuator stiffness and internal pressure as a function of the knee angle was obtained. Results from this characterization along with the insole sensor outputs were used to provide assistance to the knee joint. Analysis of stair gait with and without the exosuit ‘active’ was performed, using surface electromyography (sEMG) sensors, for two healthy participants at a slow walking speed. Preliminary user testing with the exosuit presented a promising 16% reduction in average muscular activity of Vastus Lateralis muscle and a 3.6% reduction on Gluteus Maximus muscle during the stance phase and unrestrained motion during the swing phase of ascent thereby demonstrating the applicability of the soft-inflatable exosuit in rehabilitation. / Dissertation/Thesis / Masters Thesis Biomedical Engineering 2018

<p> Artificial pancreas (AP) systems are implemented as a treatment for type 1 diabetes (T1D) patients to regulate blood glucose concentration (BGC). With continuous glucose monitoring (CGM), information related to BGC can be measured at a high frequency. It is widely known that besides meals, BGC is also influenced by many other factors such as exercise, sleep, and stress. In order to get information about these factors, different kinds of measurements such as heart rate, acceleration and derived variables such as energy expenditure (EE) should also be collected using equipment like armband and chest band devices to be used as inputs for AP systems. With adequate information about patients, BGC, and other related factors, the controller in AP systems is able to calculate insulin infusion rate for patients based on the model and control algorithm. The insulin pump will deliver the calculated amount of insulin to patient's body to close the loop of BGC regulating. </p><p> For AP systems, the performance of model-based control systems depends on the accuracy of the models and may be affected when large dynamic changes in the human body occur or when the equipment performance varies. And those factors may move the operating conditions away from those used in developing the models and designing the control system. Sensor errors such as signal bias and missing data can mislead or stop the calculation of insulin infusion rate. All of these possible performance failures can make AP systems unreliable and endanger the safety of patients. </p><p> This project aims to develop additional modules focused on fault detection and diagnosis of the controller and the sensors of the AP system. A controller performance assessment module (CPAM) is developed to generate several indexes to monitor different aspects of controller performance and retune the controller parameters according to different types of controller performance deterioration. A sensor error detection and reconciliation module (SED&amp;RM) is developed to detect sensor error in CGM measurements. The SED&amp;RM is based on two model estimation technologies, outlier-robust Kalman filter (ORKF) and locally weighted partial least squares (LW-PLS) to replace the erroneous sensor signal with the model estimated value. A novel method, the nominal angle analysis (NAA) is introduced to solve problems of false positive and candidate selection for signal reconciliation. SED&amp;RM is extended to multi-sensor error detection and reconciliation module (MSED&amp;RM), which also includes error detection and reconciliation for other sensor signals such as galvanic skin response (GSR) and values derived from original sensor signals such as EE. A multi-level supervision and controller modification (ML-SCM) module integrates CPAM and MSED&amp;RM together and extends the controller modification into different time scales including sample level, period level, and day level. </p><p> CPAM is tested with a single input and single output (SISO) version of AP system in UVa/Padova simulator. The results indicate that a generalized predictive control (GPC) with the proposed CPAM has a safer range of glucose concentration variation and more reasonable insulin suggestions than a GPC without controller retuning guided by the proposed CPAM. The performance of SED&amp;RM and MSED&amp;RM is tested with data from clinical experiments. The results indicate that the proposed system can successfully detect most of the erroneous signals and substitute them with reasonable model estimation values. The ML-SCM is tested with both simulation and clinical experiments. The results indicate that the AP system with ML-SCM module has a safer range of glucose concentration distribution and more reasonable insulin infusion rate suggestions than an AP system without the ML-SCM module.</p><p>