Transcatheter aortic heart valve replacement (TAVR) is a procedure to replace a failing aortic valve and is becoming the new standard of care for patients that are not candidates for open-heart surgery [2]. However, this minimally invasive technique has shown to cause ischemic brain lesions, or “silent infarcts”, in 90% of TAVR patients, which can increase the patient’s risk for stroke by two to four times in future years [3]. Claret Medical Inc., a medical device company, has developed a cerebral protection system that filters and captures embolic debris released during endovascular procedures, such as TAVR. This thesis utilized CT scans from Claret Medical to create a physical construct of the aortic arch to experimentally validate a theoretical computer model through flow visualization. The hypothesis was that the empirical model can accurately mimic the fluid dynamic properties of the aortic arch in order validate an in silico model using the finite elements program COMSOL MultiPhysics® Modeling Software. The physical model was created from a patient CT scan of the aortic arch using additive manufacturing (3D printing) and polymer casting, resulting in the shape of the aortic arch within a transparent, silicone material. Fluid was pumped through the model to visualize and quantify the velocity of the fluid within the aortic arch. COMSOL MultiPhysics® was used to model the aortic arch and obtain velocity measurements, which were statistically compared to the velocity measurements from the physical model. There was no significant difference between the values of the physical model and the computer model, confirming the hypothesis. Overall, this study successfully used CT scans to create an anatomically accurate physical model that was validated by a computer model using a novel technique of flow visualization. As TAVR and similar procedures continue to develop, the need for experimental evaluation and visualization of devices will continue to grow, making this project relevant to many companies in the medical device industry.

The Cardiac Rhythm Management Division of St. Jude Medical specializes in the development of implantable cardioverter defibrillators that improve the quality of life for patients diagnosed with a variety of cardiac arrhythmias, especially for patients prone to sudden cardiac death. With the goal to improve detection of cardiac arrhythmias, this study explored the value in time-frequency analysis of intracardiac electrogram in four steps. The first two steps characterized, in the frequency domain, the waveforms that construct the cardiac cycle. The third step developed a new algorithm that putatively provides the least computationally expensive way to identifying cardiac waveforms in the frequency domain. Lastly, this novel approach to analyzing intracardiac electrogram was compared to a threshold crossing algorithm that strictly operates in the time domain and that is currently utilized by St. Jude Medical. The new algorithm demonstrated an equally effective method in identifying the QRS complex on the ventricular channel. The next steps in pursing time-frequency analysis of intracardiac electrogram include implementing the new algorithm on a testing platform that emulates the latest implantable cardioverter defibrillator manufactured by St. Jude Medical and pursuing a similar algorithm that can be employed on the atrial channel.

Medical devices used for surgical or therapeutic purposes require a high degree of safety and effectiveness. Software is critical component of many such medical devices. The software architecture of a system defines organizational structure and the runtime characteristic of the application used to control the operation of the system and provides a set of frameworks that are used to develop that. As such, the design of software architecture is a critical element in achieving the intended functionality, performance, and safety requirements of a medical device. This architecture uses object-oriented design techniques, which model the underlying system as a set of objects that interact to achieve their goals. The architecture includes a number of frameworks comprised of a set of classes that can be extended to achieve different functionality required for a medical device. The Input/ Output (IO) framework includes a number of core classes that implement periodic and a periodic input output with varying priority requirements, provides a hardware neutral interface to the application logic, and a set of classes that can be extended to both meet the hardware IO specifics of a target platform and create new sensor and actuator types for client applications. The Devices framework provides a blueprint to develop the controller logic of the medical device in terms of abstractions that parallel the hardware components of the medical device. The Configuration framework allows creation and configuration of a medical device from an XML (Extensible Markup Specification) specification that specifies the configuration of the device based on abstract factories that can be extended to meet requirements of a specific medical device. The Controller is the component of the architecture that defines classes that implement reception of commands from and transmission of status and data to a local or remote client and dictate the structure of threads, thread priorities and policies for this purpose. The Diagnostics package of the architecture defines a framework for developing components that monitor the health of the system and detect emergency conditions. The architecture is implemented in C++ and runs on a real-time LINUX operating system. At this time, the architecture is used in development of two of the St. Jude Medical Atrial Fibrillation Division’s medical devices; one of these has FDA class III and the other class II classification.

Pulmonary edema occurs when fluid leaks from the pulmonary capillary network into the lung interstitium and alveoli. When the heart is not able to pump blood to the body efficiently, fluid can back up into the veins that take blood through the lungs to the left atrium. This then builds up the pressure in the blood vessels and fluid is pushed into the alveoli in the lungs. The fluid reduces normal oxygen movement through the lungs and can cause impaired gas exchange and respiratory failure. There are many causes of congestive heart failure that may lead to pulmonary edema such as heart attack, any diseases of the heart that weaken or stiffen the heart muscle, a leaking or narrowed heart valve, and sudden, severe high blood pressure. Pulmonary edema is a strong indicator of congestive heart failure in patients and therefore can be used as a gauge for congestive heart failure. One way to diagnose cardiogenic pulmonary edema constantly is through the continuous monitoring of the transthoracic impedance throughout the day. One method to achieve this constant monitoring is through the use of a cardiac pacemaker or an implantable cardioverter defibrillator (ICD). Many patients who are at risk of heart failure have these medical devices implanted already. In these implantable cardiac devices, the connected cardiac leads can be utilized to continually screen several impedance vectors for decreases in impedance in the thoracic cavity. A pacemaker or ICD that implements Pulmonary Edema Monitoring is designed to continuously monitor these impedance vectors and alert the patient to seek medical attention. This thesis will discuss the implementation of Pulmonary Edema Monitoring via screening of multiple impedance vectors in a pacemaker or implantable cardioverter defibrillator and the effectiveness of this monitoring method. Furthermore, the design, implementation, and testing of this feature will be explored in greater detail.

ELECTROCHEMICAL IMPEDANCE SPECTROSCOPY (EIS) has been widely used to study the electrical properties of biological material due to its non-invasive nature and experimental reliability. However, most of the precision impedance analyzers used in EIS only provide single- or two-channel measurements which are inadequate for larger-scale multiplexed measurements, such as those found in modern microfluidic cell culture experiments. The Biomedical Microsystems Laboratory has developed a 16-channel cell culture platform with integrated electrode arrays for monitoring cell growth and electrical properties (i.e., the so-called “electrical phenotype”). In this paper, a system consisting of a 16-channel solid-state analog multiplexer (MUX)paired with a low-cost, impedance analyzer is developed to replace high-cost physical relay MUX and impedance analyzer systems. System requirements and design constraints for monitoring biological systems are considered and a prototype device was fabricated. Initial testing was performed on a breadboard to verify the feasibility of the design idea. Results identified measurement errors due to parasitic elements in the system. Software compensation successfully corrected for parasitic capacitance in the analog MUX design. The accuracy of the measurement system was evaluated on a developed Printed Circuit Board Assembly (PCBA) by comparing theoretical values to MUX compensated data. Finally, an EIS experiment was carried out with tap water with the PCBA system, and measurement results were analyzed using an equivalent Circuit Model (ECM). These results successfully captured the dynamics of charge transport in the electrical double layer, consistent with a modified-Randlecell ECM.

Since the advent of recommendations for placing infants in the supine position during sleep to reduce the incidence of sudden infant death syndrome, clinicians have noted an increase in the frequency of cranial asymmetry due to deformation of suture sections of the infants’ skulls as a result of constant concentrated stress in one area at the back of their head. This specific form of cranial deformation is known as positional plagiocephaly and its rate of occurrence has increased from 0.3% in 8.2% within the past 30 years. Current treatments and methodologies for preventing and correcting positional plagiocephaly such as stretching exercises, bedding pillows, and cranial molding are not optimized for effectiveness and comfort. Literature surrounding the implementation of these methodologies or devices often assesses the relative effectiveness of each treatment through statistical means, or studies complications associated with their use. There is a lack of quantified mechanical analysis for determining the effectiveness of each treatment or engineered solutions. In this study, a finite element model was created and validated to study the effect of wearing a cranial helmet, as the most effective non-surgical device for treatment of positional plagiocephaly, on reducing concentrated stress from the back of the baby’s head during sleep. The results from this model were then compared to two other finite element models with a healthy baby sleeping in supine position on a pillow, and a patient diagnosed with a severe case of positional plagiocephaly sleeping on the flat side of his head in supine position. The geometries representing the head of the babies in these models are the refined 3D laser-scanned file of a patient’s head contour at Hanger Clinic as well as the cavity inside the cranial helmet that was used for treatment of the baby. After successfully assigning section and contact properties to different regions of the models, applying proper loading and boundary conditions, and performing mesh convergence studies for each of the three models, the average Von Mises stress values of each of the 13 different suture segments of each model were summarized in tables and evaluated using mathematical and qualitative methods. The stress value data obtained from different suture regions of the model with the cranial helmet resulted in the smallest standard deviation among all three populations which supports that wearing the cranial helmet helps to reduce stress concentrations. Use of the cranial helmet during sleep also showed a significant decrease of the average Von Mises stress within the posterior fontanelle by 90% compared to the healthy baby sleeping in supine position and 73.4% compared to the deformed head sleeping on the flat surface of the head. The major limitations of this study are correlated with the simplifying assumptions and geometries in generating and validating the models. Future studies need to focus on overcoming these limitations and generating more complex models using a similar approach. The methods used in this study and the results obtained from the models can serve as a basis for future development of engineered solutions that are more effective than the existing solutions in the market and reduce the side-effects and complications associated with their use.

<p>Achieving control over the construction and operation of microfabricated label-free DNA biosensors would be a big leap in the quest for highly reliable clinical laboratory tests. Reliable outcomes of critical medical tests mean less need for repetitions and earlier isolation of outbreaks. Nanotechnology has lent itself well to this purpose, with a plethora of work that attempt to produce highly sensitive nano-biosensors for detection of DNA strands. The problem of achieving a repeatable outcome is crude at best. Additionally, the mechanism of sensing in label-free Field-Effect based DNA sensors is still a matter of dispute. Simulation of the sensors using physical models can shed light into these mechanisms and help answer this question. Computational calculations can also allow designers to assess the importance of several parameters involved in the fabrication.</p> <p>In this thesis, the problem of modeling FET-based DNA hybridization sensors (named BioFET) is approached. Using the Finite-Element Method, a scalable model for the BioFET is produced and solved in 3D. The results are compared to an earlier work and we find that higher dimension physical modeling is essential for more realistic results. Additionally, we present a model for the impedance of the BioFET which allows the calculation of parasitic components that can contaminate the impedance measurements.</p> <p>The issue of variations in the sensed signal from the BioFET is addressed by performing hybrid Finite-Element/Monte Carlo simulations on the conformation of single-stranded DNA. From electrostatic considerations alone, it is concluded that the change of conformation upon hybridization is a main contributor to the induced signal. We also simulate the positional variations of the DNA molecules on the sensitive surface. This computation yields an estimate for the amount of variation in the sensed signal due to the random placement of DNA molecules, and an estimate for the total signal-to-noise ratio is deduced.</p> / Doctor of Philosophy (PhD)

<p>This thesis provides new regression methods for the removal of structured noise in datasets. With multivariable data, the variables and the noise can be both temporally correlated (i.e. auto correlated in time) and contemporaneously correlated (i.e. cross-correlated at the same time). In many occasions it is possible to acquire measurements of the noise, or some function of it, during the data collection. Several new constrained latent variable methods (LVM) that are built upon previous LVM regression frameworks are introduced. These methods make use of the additional information available about the noise to decompose a dataset into basis for the noise and signal. The properties of these methods are investigated mathematically, and through both simulation and application to actual biomedical data.</p> <p>In Chapter Two, linear, constrained LVM methods are introduced. The performance of these methods are compared to the other similar LVM methods as well as ordinary PLS throughout several simulation studies. In Chapter Three, a NIPALS type algorithm is developed for the soft constrained PLS method which is also able to account for missing data as well as datasets with large covariance matrices. Chapter Four introduces the nonlinear-kernelized constrained LVM methods. These methods are capable of handling severe nonlinearities in the datasets. The performance of these methods are compared to nonlinear kernel PLS method. In Chapter Five the constrained methods are used to remove ballistocardiographic and muscle artifacts from EEG datasets in combined EEG-fMRI as well as single EEG experiments on patients. The results are shown and compared to the standard noise removal methods used in the field. Finally in Chapter Six, the overall conclusion and scope of the future work is laid out.</p> / Doctor of Philosophy (PhD)

<p>A microfluidic device capable of drug delivery to multiple wells in a concentration gradient was designed for automated high content and high throughput screening. The design was proposed to utilize a nanoporous polycarbonate membrane to spatially and temporally control drug dosage from the microchannels below to the wells above. Microchannels were to hold to the drugs or reagents, while wells were to culture cells. An array of 16 wells was to fit in the equivalent area of a single well of a 96 well plate. Two simpler devices were created to validate electrokinetic drug delivery to a single well and to characterize cell proliferation and viability in micro-wells. The first device tested drug delivery to a single well with methylene blue dye at applied voltages of 100V, 125V, and 150V. It was validated that the dosage of dye could be controlled by increasing the voltage and by increasing the duration the voltage was applied. The second devices were a series of 9-well arrays, each testing a different diameter (1.2 mm – 0.35 mm). These devices were cultured with MCF-7 breast cancer cells over 5 days. At the end of the 5 day study, all diameters except for 0.5 mm and 0.35 mm measured a cell viability of 99% and exhibited cell growth patterns similar to coverslip glass controls. The proposed integrated cell culture and drug delivery device could have application towards early stage drug discovery and could have compatibility with lab equipment originally designed for well plates.</p> / Master of Applied Science (MASc)

Total ankle replacement (TAR) implants are an effective option to restore the range of motion of the ankle joint for arthritic patients. An effective tool for analyzing these implants’ mechanical performance and longevity in-silico is finite element analysis (FEA). ABAQUS FEA was used to statically analyze the von Mises stress and contact pressure on the articulating surface of the bearing component in two newly installed fixed-bearing total ankle replacement implants (the Wright Medical INBONE II and the Exactech Vantage). This bearing component rotates on the talar component to induce primary ankle joint motion of plantarflexion and dorsiflexion. The stress response was analyzed on this bearing component since it is made of the least strong material in the implant assembly (ultra-high molecular weight polyethylene (UHMWPE). This bearing component commonly fails and is the cause for surgeon revisions. Six different FEA models for various gait percentages during stance (10%, 20%, 30%, 40%, 50%, and 60%) were created. They varied in magnitude of the compressive load and the ankle dorsiflexion/plantarflexion angle. This study captured the variation in stress magnitudes based on the portion of the stance phase. The results indicated that the stress distribution on the articulating surface increased as compressive load increased, and the largest magnitudes occurred at high dorsiflexion angles (15-30°). The von Mises stress and contact pressure tended to occur in regions where the thickness of the bearing was the least. Additionally, high contact pressures were examined in areas near the talar component's edge or at the bearing's edges. To the author’s knowledge, this is the first study available to the research community that analyzes the Vantage implant with FEA. This study lays an essential foundation for future researchers in presenting a thorough literature review of TAR and for a simple model setup to capture the stress distributions of two TAR implants. This study provides valuable information that can be beneficial to medical company designers and orthopedic surgeons in understanding the stress response of TAR patients.