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The incorporation of drugs into phosphorylcholine (PC) polymers coated onto coronary stent surfaces is one potential method of treatment for reducing restenosis, the reclosure of the artery after angioplasty treatment. This work on the characterisation of the swelling performance of thin PC polymer films represents a further extension of the study on biocompatible polymers. The broad aim of this work is to relate the PC polymer structure and film processing conditions to their swelling, drug loading and release kinetics. As the two highly sensitive and powerful techniques in film structure determination, both ellipsometry and neutron reflection have proved to be useful in characterising PC polymer films and drug release processes. Following an established ellipsometry measurement method, a two stage process consisting of diffusion and relaxation has been observed during the PC film swelling: this suggests an anomalous mechanism, and this performance is well described by the coupled diffusion and relaxation model developed by Berens and Hopfenberg. Furthermore, the swelling of PC polymer films was investigated as a function of cross-linking, annealing temperature, chemical composition, hydrophilic/hydrophobic ratios, film thickness and environmental conditions by ellipsometry measurements, and their effects on swelling kinetics well quantified. The structures of the PC polymer films (PC100B) with cross-linking groups have been further characterised by neutron reflection. The segregation of hydrophobic and hydrophilic domains was found in the PC films with different dimensions. The PC100B with deuterated dodecyl chains was used to highlight the interfacial structures of the PC films. The hydrophilic segments, including phosphorylcholine groups and hydroxypropyl groups, are preferentially adsorbed at the polymer/substrate interface. The hydrophobic dodecyl chains are expelled away from the silicon oxide surface. The main part of PC100B films is the middle uniform region with 40% of water in the sample annealed at 150°C, and 55% of water in the sample annealed at 50°C. The combination of the ellipsometry results and the drug release profiles from UV measurements indicates that the drug release pattern is strongly affected by the film swelling kinetics when the drug molecules and polymer matrix interact weakly. Otherwise, a strong interaction between the drug and the polymer will dominate the drug release behaviour from the PC polymer films.

Chemical sensors and biosensors are important devices that are capable of providing real-time analytical information, widely applicable to problems ranging from point-of-care diagnostics to the detection of explosive or toxic gases. This dissertation will discuss a few different liquid- and gas-phase sensors developed during my time in the Penner Lab. Electrodeposition and electropolymerization have emerged as versatile tools for the fabrication of chemical sensors and biosensors. Electropolymerization allows for the ability to entrain receptors such as antibodies, engineered virus particles, and metal chelating agents into a conductive polymer sensing element and has proven to be a versatile method of preparing sensors for a variety of analyses. Meanwhile, electrodeposition has been utilized to fabricate nanostructured metal indicator microelectrodes as well as for rapid and sensitive hydrogen gas sensors. Chapter 2 will discuss the optimization of the Virus BioResistor (VBR) to allow for the detection of larger proteins. The VBR is a conductive polymer thin-film biosensor utilizing an electropolymerized virus-PEDOT composite bioaffinity layer, engineered specifically to bind proteins of interest. The VBR previously demonstrated fast and reproducible response to small proteins, but larger proteins, such as antibodies, exhibited minimal signal responses. An electrochemical overoxidation process to unlock the ability for the VBR to detect two different IgG antibodies is described and discussed. Chapter 3 details the fabrication of a nanojunction pH sensor, where a nanogap is fabricated within a single gold nanowire and is then subsequently bridged via the electropolymerization of polyaniline (PANI), which is pH responsive. The nanogap is created in a facile manner via electromigration, and thefabricated nanojunction sensor is able to reliably detect a range of pH from 1 to 9 within 30 s via impedance. This serves as a first step towards fabricating a VBR that is on the nanometer scale in all three dimensions. Chapter 4 then explores chemiresistive gas sensing for the detection of ethylene gas utilizing a single platinum nanowire, fabricated using lithographically patterned nanowire electrodeposition (LPNE). Platinum nanowires exhibit a reversible decrease in resistance upon exposure to H2 due to the increase in the specularity of electron surface scattering by the formation of Pt – H. We test if this surface scattering modality is also observed to also occur in the presence of ethylene exposure. A simple platinum nanowire transducer capable of detecting ppm concentrations of ethylene in air is described and a mechanism involving the combustion of ethylene causing changes in electron surface scattering is proposed. Finally, Chapter 5 details a unique and collaborative urology project investigating the encrustation of ureteral stents. Stents are an indispensable tool in the medical field to relieve obstruction and preserve kidney function. However, these devices lose their efficacy over time as they become obstructed by encrustation. In this final chapter, I describe and compare the encrustation formation on 2-hydroxyethy methacrylate (HEMA)-coated Pellethane to that formed on commercially available polymer-based stents.

Cardiac pacemakers have evolved over the years from the original version with external leads to the miniaturized leadless version that is implanted completely inside the ventricle. The leadless pacemakers offer advantages in simpler surgical procedures, easier device operation, and better patient comfort. However, the reduced size of the pacemaker substantially restricts battery capacity, reducing the battery life from 13-16 years to as few as 5-8 years. The reduced battery longevity often requires the patient to return for a pacemaker replacement surgery. This could result in increased medical cost, inconvenience, and potential risk to the patients. To address this issue, many researchers have examined different methods of harvesting energy for the pacemaker, mainly focusing on piezoelectric energy conversion. The results, however, were not promising due to the low energy conversion efficiency and potential material failure of the brittle piezoelectric materials.This thesis is aimed at exploring an alternative solution based on electromagnetic induction to convert mechanical energy generated at each systolic and diastolic cycle into electricity. The human heart is an inexhaustible mechanical energy source that is constant and consistent in its mechanical motion. Taking this into our advantage, the research aimed at utilizing the heart’s own mechanical motion to generate electrical energy to power the pacemaker. During the course of the research, multiple design iterations, experimenting with solid magnet cores, ferrofluid, and finally, the concentric double ring magnet design were developed. Many proof-of-concept testing and feasibility testing have been conducted to prove the viability of the design and the structural materials. The research will continue with more simulation testing on the materials and electrical circuit design for signal amplification and storage.

Cardiovascular stents are one of the most widely implanted medical devices, with over 1 million implanted each year in the United States alone. While stent failure modes of restenosis and thrombosis have been widely examined, there is an increasing appreciation of the propensity for stents to fracture and break after implantation. It remains unclear however what causes these fractures, which patients and devices are most susceptible, and whether fracture results in failure of device function.

Coronary artery disease (CAD) is the leading cause of death in the world. Most acute coronary events such as heart attacks and sudden deaths are due to the rupture of atherosclerotic plaques inside the arteries. Intravascular Optical Coherence Tomography (IVOCT), a high resolution (10-20µm) imaging modality that performs cross-sectional imaging of coronary arteries by measuring echoes of backscattered light, is rapidly becoming a promising imaging modality for diagnosis of CAD. Compared to alternative technologies such as intravascular ultrasound (IVUS), IVOCT with better resolution allows characterization of atherosclerotic plaques and evaluation of coronary stenting with unprecendented details. Currently, analysis of OCT images has been typically conducted manually in an extremely time-consuming manner. The aim of this PhD dissertation is to develop advanced image processing algorithms and software to automate the task and thereby reduce the image analysis time drastically.In this dissertation, we developed image analysis algorithms for a variety of IVOCT applications, including: (1) 3-D lumen boundary segmentation, (2) Guide wire artifact segmentation, (3) Automated calibration of IVOCT images, (4) Volumetric quantification of fibrous caps, (5) Automated segmentation of calcified plaques, (6) Automated quantification of macrophages and (7) Automated stent analysis, covering almost all the essential tasks performed in the Cardiovascular Imaging Core Laboratories (Core Lab). The algorithms we have developed have been extensively validated using a large number of data sets, and are robust to be used for real world clinical data analysis. Furthermore, we developed the prototype software OCTivat (intravascular OCT image visualization and analysis toolkit) for IVOCT image visualization and analysis, and it is being used by the interventional cardiologists in the Core Lab at the University Hospitals Case Medical Center. These image analysis methods, as well as OCTivat, can reduce the IVOCT image analysis time from tens of hours down to minutes. This may enable large clinical trial analysis and real-time feedback during clinical procedures, and may potentially improve patient care.

Cardiovascular diseases (CVD) are the leading cause of death in the world. According to the World Health Organization (WHO) 17.3 million people died from cardiovascular disease in 2008, representing 30% of all global deaths. The most common modality of treatment of occluded arteries is the use of stents. Despite the widespread use of stents, the incidence of post-stent restenosis is still high. The study of stents in conditions that are similar to in-vivo conditions is limited. This work tries to address the behavior of stents in conditions similar to in-vivo conditions in a generalized framework, thus providing insights for stent design and deployment. Three dimensional, time accurate computational fluid dynamics (CFD) simulations in a pulsatile flow with fluid-structure interaction (FSI) were carried out in realistic coronary arteries, with physiologically relevant flow parameters and dynamics due to induced motion of the heart. In addition, the geometric effects of the stent on the artery were studied to point towards possible beneficial stent deployment strategies. The results suggest that discontinuities in compliance and dynamic geometry cause critical changes in local hemodynamics, namely altering the local pressure and velocity gradients. Increasing the stent length, reducing the transition length and increasing the overexpansion caused adverse flow conditions. From this work, detailed flow characteristics and hemodynamic characteristics due to the compliance mismatch and applied motion were obtained that gave insights towards better stent design and deployment.

Drug-eluting stents are used routinely in coronary arteries, and are increasingly being considered for non-coronary vascular beds. Yet, mechanisms governing the efficacy of the drug-eluting stent are still being understood, in particular those physiologic and device related factors that determine the arterial distribution of therapeutic agents. The primary aim of this thesis is to determine the role of vascular-bed dependent luminal flow in dictating the extent of arterial drug deposition from endovascular stents. An integrated framework comprising computational and bench-top models has been formulated to explore the relative contributions of key hemodynamic parameters intrinsic to a vascular bed. Using a novel, dynamically similar bench-top model, we determine that arterial drug patterns are sensitive to the net luminal flow environment, created by mean flow rate and strut geometry. This analysis is then extended to consider the mechanisms that govern the pulsatile nature of blood flow, and how they modulate arterial drug distribution. A coupled framework comprising a computational fluid dynamics and mass transfer model, along with the custom-designed bench-top model allowed us to investigate scenarios that are not possible with animal models alone. Model-based simulations predicted that when stent struts were fully-apposed only the time-averaged blood flow through the lumen (or the mean blood flow rate defined by Reynolds number) dictated the pattern of drug distribution, and not the factors that quantify the unsteady nature of blood. Contrastingly, when struts were malapposed from the wall, arterial drug uptake was found to be directly dependent on the unsteady flow effects. Finally the effects of geometry-induced changes to the core flow were investigated, with focus on stent position at the aorta-renal ostia. The results showed that further to those local flow alterations induced by the stent strut, tissue drug uptake at the aorta-renal ostia is also modulated by both relative stent position with respect to the ostia and changes to the core flow due to bifurcation and curvature at the ostia.

A novel synthetic analog of curcumin, the active ingredient in the commonly used spice turmeric, was recently synthesized. The drug shows promise, both as an anti-proliferative agent against restenosis in bare-metal stents and as a cytotoxin against ovarian cancer, following direct administration. However, a major limitation is its insolubility in aqueous media, and limited solubility in most organic solvents. The inability to safely deliver this drug in a soluble form presents a major challenge to further in vivo validation and eventual clinical applicability.Poly(lactic-co-glycolic acid) (PLGA) is a well-known biodegradable polymer that is widely used as a sustained-release vehicle for various drugs. We hypothesized that the controlled release of the drug from a PLGA matrix would provide an alternative route for its administration in vivo. To improve dosage while limiting systemic cytotoxicity, localized release from disease-specific constructs was proposed, in which the mode of delivery is adapted to suit the different pathologies presented by the disease in vivo. Hence, drug-eluting films, PLGA-coated drug-eluting stents and drug-encapsulating nanoparticles were developed for evaluation in proliferative cardiovascular disease and ovarian cancer.Fourier transform infrared spectroscopy and electron paramagnetic resonance spectroscopy were used for physical characterization of the biodegradable constructs. Additionally, dynamic light scattering and transmission electron microscopy were used for size characterization of the drug-encapsulating nanoparticles. Viability assays established the dose- and time-dependent anti-proliferative and cytotoxic effects of the biodegradable constructs. Western blot analysis on drug-eluting PLGA films and PLGA-coated PET matrices validated that the cellular mechanism of the action of the drug was conserved between direct administration and sustained release. TEM studies confirmed the internalization of the nanoparticles in vitro. Nanoparticles directly injected into murine ovarian cancer xenograft tumors in vivo were tracked for 14 days without any evidence of systemic toxicity.These results validate the hypothesis that the sustained release of the drug from a PLGA matrix conserves its pharmacological action when compared to direct administration. This study established proof-of-concept for the localized and sustained release of a novel curcumin analog from biodegradable constructs, thus paving the way for its use as an effective therapeutic in two diseases of clinical significance.

Coronary stents have become a very popular treatment for cardiovascular disease, historically the leading cause of death in the United States. Stents, while successful in the short term, are subject to high failure rates (up to 24% in the first six months) due to wall regrowth and clotting, probably due to a combination of abnormal mechanical stresses and disruption of the arterial blood flow. The goal of this research was to develop recommendations concerning ways in which stent design might be improved, focusing on the problem of pressure wave reflections. A one-dimensional finite-difference model was developed to predict these reflections, and effects of variations in stent and vessel properties were examined, including stent stiffness, length, and compliance transition region, as well as vessel radius and wall thickness. The model was solved using a combination of Weighted Essentially Non-Oscillatory (WENO) and Runge-Kutta methods. Over 100 cases were tested. Results showed that reasonable variations in these parameters could induce changes in reflection magnitude of up to ±50%. It was also discovered that the relationship between each of these properties and the resulting wave reflection could be described simply, and the effect of all of them together could in fact be encompassed by a single non-dimensional parameter. This parameter was titled"Stent Authority," and several variations were proposed. It is believed this parameter is a novel way of relating the energy imposed upon the arterial wall by the stent, to the fraction of the incident pressure energy which is reflected from the stented region.

The use of bulk metals in micro-electro-mechanical systems (MEMS) can significantly broaden the possible applications of this technology. The investigation proposed in this report focuses on the development of batch-compatible bulk-metal micromachining based on micro-electro-discharge machining (muEDM) and its application to cardiovascular stents. In particular, this work explores batch muEDM using electrode arrays to achieve high parallelism and throughput in the machining. Constraints in the fabrication and use of high-aspect-ratio LIGA-fabricated electrode arrays as well as the limits imposed by the pulse discharge circuits on machining rates are studied. To increase the spatial and temporal multiplicity of discharge pulses, arrays of electrodes with lithographically fabricated interconnect and block-wise independent pulse control RC circuits are used, resulting in >100x improvement in throughput compared to the use of single electrodes. A modified electrode-circuit scheme that exploits the parasitic capacitance of the interconnect offers similarly high machining rates of 1.3 mum/s as well as smooth surfaces with tighter tolerance of 5 mum and is more amenable to integration. The batch mode muEDM concept is applied to the design and manufacturing of new cardiovascular stents. To form a tubular stent, a planar microstructure with overall dimensions of 7x2.6 mm2, which is cut from 50 mum thick stainless steel foil by muEDM, is plastically expanded to a cylindrical shape with diameter up to 3.5 mm by inflation of an angioplasty balloon. This planar approach potentially permits other planar microfabrication technologies based on lithographical processes to be exploited, offering opportunities to introduce additional functionality to the devices. The planar approach is extended to the development of stents serving as antennas (stentennas) for implementing the wireless monitoring of microsensors integrated with the stents. The stents are designed to form helical structures after the deployment. Wireless monitoring of a silicon-micromachined capacitive pressure sensor is successfully demonstrated by showing frequency shifts of the resonant impedance in a separate transmitting coil that is telemetrically coupled to the LC tank, i.e., a combination of the stentenna and the pressure sensor. With this capability, wireless flow sensing is explored by designing a dual-inductor stentenna integrated with two capacitive pressure sensors. A device with an emulated blockage shows flow response of 152--569 KHz per mL/min. The planar approach is also extended to the development of an intraluminal ring-shaped cuff for electromagnetic (EM) flow sensing in the presence of a magnetic field. Flow measurement with sensitivity of 50--70 ppm per cm/s is demonstrated using the EM cuff with flow of saline up to 180 cm/s and magnetic field of 0.25 T.

Cardiovascular diseases (CVD) afflict approximately 60 million Americans and are the leading causes of death in the United States. In 1995, more than 950,000 deaths were attributed to CVD with coronary artery disease comprising 50% of the deaths (American Heart Association, 1997). Percutaneous transluminal coronary angioplasty (angioplasty) and coronary stenting (stenting) are common revascularization treatments for coronary artery disease. Advances in cardiovascular technology have resulted in noninvasive treatment strategies in order to decrease symptoms, improve myocardial oxygenation, and improve HRQOL. The problem under investigation in this study is to determine if there is a difference in HRQOL following angioplasty or stenting. Health-related quality of life (HRQOL) refers to how well a person functions in life compared to what the person perceives to be possible or optimal (Cella & Cherin, 1988; Stewart et al., 1992). Health-related quality of life was measured by the Short Form-36 (SF-36) and the Seattle Angina Questionnaire (SAQ). TheSF-36 consisted of 36 questions measuring general health; the subscales were: physical functioning, role functioning-physical, role functioning-emotional, social functioning, bodily pain, mental health, vitality, and general health perception. The SAQ consisted of 19 questions measuring specific concepts of CAD; the subscales measured were: physical functioning limitations, anginal stability, anginal frequency, treatment satisfaction, and disease perception. Cronbach's alpha for the SF-36 subscales ranged fi-om 0.73 to 0.91; while the Cronbach's alpha of the SAQ subscales ranged from 0.58 to 0.89. A descriptive, comparative design was used to: (a) describe and determine if there was a difference in HRQOL scores one year after either coronary angioplasty, coronary stenting, or a combination of both procedures; (b) determine the relationships among the subjects' characteristics and HRQOL scores following angioplasty and/or stenting; and (c) determine the relationships among the domains/subscales of the SF-36 and SAQ. Fifty eight people, from two Midwest health care agencies, consented to serve as subjects by returning completed questionnaires. The findings revealed that the sample was fairly representative for gender, age, racial/ethnic background, educational history, and employment status of the cardiovascular population undergoing angioplasty or stenting. The SF-36 and SAQ subscale (HRQOL) scores one year post angioplasty, stenting, or combination of both procedures were diminished when compared to the general population; but similar to persons with angina and with those persons three and six months post angioplasty. The mean SF-36 and SAQ subscale scores for the subjects in the angioplasty or stenting procedures were not significantly different. After adjusting the mean SF-36 and SAQ scores for the covariate, rated affects of comorbid conditions on HRQOL, women were significantly different than their male counterparts in the subscales of: physical functioning, role functioning affected.