Ultrasonic transducer-guided electrochemical impedance spectroscopy to assess lipid-laden plaques

Plaque rupture causes acute coronary syndromes and stroke. Intraplaque oxidized low density lipoprotein (oxLDL) is metabolically unstable and prone to induce rupture. We designed an intravascular ultrasound (IVUS)-guided electrochemical impedance spectroscopy (EIS) sensor to enhance the detection reproducibility of oxLDL-laden plaques. The flexible 2-point micro-electrode array for EIS was affixed to an inflatable balloon anchored onto a co-axial double layer catheter (outer diameter = 2 mm). The mechanically scanning-driven IVUS transducer (45 MHz) was deployed through the inner catheter (diameter = 1.3 mm) to the acoustic impedance matched-imaging window. Water filled the inner catheter to match acoustic impedance and air was pumped between the inner and outer catheters to inflate the balloon. The integrated EIS and IVUS sensor was deployed into the ex vivo aortas dissected from the fat-fed New Zealand White (NZW) rabbits (n = 3 for fat-fed, n = 5 normal diet). IVUS imaging was able to guide the 2-point electrode to align with the plaque for EIS measurement upon balloon inflation. IVUS-guided EIS signal demonstrated reduced variability and increased reproducibility (p < 0.0001 for magnitude, p < 0.05 for phase at <15 kHz) as compared to EIS sensor alone (p < 0.07 for impedance, p < 0.4 for phase at <15 kHz). Thus, we enhanced topographic and EIS detection of oxLDL-laden plaques via a catheter-based integrated sensor design to enhance clinical assessment for unstable plaque

Ultrasonic transducer-guided electrochemical impedance spectroscopy to assess lipid-laden plaques

Plaque rupture causes acute coronary syndromes and stroke. Intraplaque oxidized low density lipoprotein (oxLDL) is metabolically unstable and prone to induce rupture. We designed an intravascular ultrasound (IVUS)-guided electrochemical impedance spectroscopy (EIS) sensor to enhance the detection reproducibility of oxLDL-laden plaques. The flexible 2-point micro-electrode array for EIS was affixed to an inflatable balloon anchored onto a co-axial double layer catheter (outer diameter = 2 mm). The mechanically scanning-driven IVUS transducer (45 MHz) was deployed through the inner catheter (diameter = 1.3 mm) to the acoustic impedance matched-imaging window. Water filled the inner catheter to match acoustic impedance and air was pumped between the inner and outer catheters to inflate the balloon. The integrated EIS and IVUS sensor was deployed into the ex vivo aortas dissected from the fat-fed New Zealand White (NZW) rabbits (n = 3 for fat-fed, n = 5 normal diet). IVUS imaging was able to guide the 2-point electrode to align with the plaque for EIS measurement upon balloon inflation. IVUS-guided EIS signal demonstrated reduced variability and increased reproducibility (p < 0.0001 for magnitude, p < 0.05 for phase at <15 kHz) as compared to EIS sensor alone (p < 0.07 for impedance, p < 0.4 for phase at <15 kHz). Thus, we enhanced topographic and EIS detection of oxLDL-laden plaques via a catheter-based integrated sensor design to enhance clinical assessment for unstable plaque

Electrical Impedance Based Spectroscopy and Tomography Techniques for Obesity and Heart Diseases

Despite advances in diagnosis and therapy, atherosclerosis cardiovascular disease remains the leading cause of morbidity and mortality. Predicting metabolically active atherosclerotic lesions has remained an unmet clinical need. Specially, atherosclerotic plaques that are prone to rupture are of extremely high-risk and can cause detrimental heart attacks and/or strokes, leading to sudden death. It has been shown that atheroscleroses is correlated to the level of obesity of an individual [1] Usually in clinical practice, the doctor will assess a patient's "risk factor" based on his or her Body Mass Index (BMS), and measurement of the waist circumference. Meanwhile the level of fatty droplet deposits in the liver is an important bio-marker to assess the patient's risk factor, however the patient will need to undergo radiation imaging such as CT scan or MRI scan. For the vulnerable plaques that can lead to sudden rupture, the ability to distinguish them at an early stage remains largely lacking. Therefore it is of great clinical interest to find improved diagnostic techniques to identify and localize such vulnerable plaques. Meanwhile, lipid has significantly lower electrical impedance than the rest of the vessel tissues in certain frequency bands [2]. In this thesis we explore spectroscopic and tomographic methods to characterize such plaques. In addition, with the Electrical Impedance Tomography method we will propose a novel method to detect fatty liver in an early stage with non-radiating and non-invasive manner.</p

Three-Dimensional Impedance Tomographic Mapping of Metabolically Active Endolumen

Real-time detection of vulnerable atherosclerotic lesions, characterized by a high content of oxidized low-density lipoprotein (oxLDL)-laden macrophages or foam cells, remains an unmet clinical need. While fractional flow reserve (FFR)-guided revascularization in angiographically intermediate stenoses is utilized to assess hemodynamic significance, in vivo detection of oxLDL-rich plaques may provide a new paradigm for treating metabolically unstable lesions. Herein, we have demonstrated endoluminal mapping of lipid-laden lesions using 3-D electrical impedance spectroscopy-derived impedance tomography (EIT) in a pre-clinical swine model. We performed surgical banding of the right carotid arteries of Yucatan mini-pigs, followed by 16 weeks of high-fat diet, to promote the development of lipid-rich lesions. We implemented an intravascular sensor combining an FFR pressure transducer with a 6-point micro-electrode array for electrical impedance spectroscopy (EIS) measurements. 3-D EIT mapping was achieved using an EIS-based reconstruction algorithm. We demonstrated that EIT mapping corresponds to endoluminal histology for oxLDL-laden lesions. We further used computational models to theoretically predict and validate EIS measurements. Thus, our 3-D EIS-derived EIT provides in vivo detection of metabolically active plaques with the goal of guiding optimal intravascular intervention

Two-Point Stretchable Electrode Array for Endoluminal Electrochemical Impedance Spectroscopy Measurements of Lipid-Laden Atherosclerotic Plaques

Four-point electrode systems are commonly used for electric impedance measurements of biomaterials and tissues. We introduce a 2-point system to reduce electrode polarization for heterogeneous measurements of vascular wall. Presence of endoluminal oxidized low density lipoprotein (oxLDL) and lipids alters the electrochemical impedance that can be measured by electrochemical impedance spectroscopy (EIS). We developed a catheter-based 2-point micro-electrode configuration for intravascular deployment in New Zealand White rabbits. An array of 2 flexible round electrodes, 240 µm in diameter and separated by 400 µm was microfabricated and mounted on an inflatable balloon catheter for EIS measurement of the oxLDL-rich lesions developed as a result of high-fat diet-induced hyperlipidemia. Upon balloon inflation, the 2-point electrode array conformed to the arterial wall to allow deep intraplaque penetration via alternating current (AC). The frequency sweep from 10 to 300 kHz generated an increase in capacitance, providing distinct changes in both impedance (Ω) and phase (ϕ) in relation to varying degrees of intraplaque lipid burden in the aorta. Aortic endoluminal EIS measurements were compared with epicardial fat tissue and validated by intravascular ultrasound and immunohistochemistry for plaque lipids and foam cells. Thus, we demonstrate a new approach to quantify endoluminal EIS via a 2-point stretchable electrode strategy

A basic study of electrical impedance spectroscopy for intravascular diagnosis and therapy monitoring of atherosclerosis

The thesis reports about the feasibility of electrical impedance spectroscopy with microsystems for the intravascular diagnosis of atherosclerosis. Based on a basic investigation on the cellular level, it describes how the impedance of vessel walls on the microscale is determined and how the cellular alteration related with atherosclerosis affects the measured impedance. For an intravascular impedance characterization of vessels, it shows the development of a balloon impedance catheter (BIC) equipped with a flexible microelectrode structure. BIC measurement proved to be sensitive enough to detect the thickness of vessel walls or plaque positions. From in situ animal experiments, it demonstrates the potential of BIC to characterize atheromatous vessels.Die vorliegende Arbeit beschäftigt sich mit Untersuchungen zum Einsatz von Mikrosystemen, basierend auf elektrischer Impedanzspektroskopie, für die intravaskuläre Diagnose von Atherosklerose. Auf zellulärer Ebene konnte zum einen die Impedanz von Gefäßwänden bestimmt sowie die Auswirkungen von zellulären Veränderungen auf diese gezeigt werden. Für die intravaskuläre Impedanzspektroskopie wurde ein Ballon-Katheter mit integrierten Mikroelektroden entwickelt. Durchgeführte Messungen zeigen eine ausreichend hohe Empfindlichkeit zur Detektion von Gefäßwandstärken oder zur Lokalisierung von Plaques. Abschließend konnte im Tierversuch die Charakterisierung von atherosklerotischen Gefäßen gezeigt werden

Harmonic Intravascular Ultrasound

Medical ultrasound is a popular imaging modality in cardiology. Harmonic Imaging is a technique that has been shown to increase the image quality of diagnostic ultrasound at frequencies below 10 MHz. However, Intravascular Ultrasound, which is a technique to acoustically investigate arteries from within the lumen by means of a catheter, typically transmits at higher ultrasound frequencies ( >20 MHz). This dissertation describes studies showing the feasibility and potential of Harmonic Imaging for Intravascular Ultrasound. Harmonic Intravascular Ultrasound can reduce undesired image artefacts, and shows the potential to detect ultrasound contrast agents from within the lumen. This makes Harmonic Intravascular Ultrasound a promising tool in cardiovascular research

Integrated Electronics for Wireless Imaging Microsystems with CMUT Arrays

Integration of transducer arrays with interface electronics in the form of single-chip CMUT-on-CMOS has emerged into the field of medical ultrasound imaging and is transforming this field. It has already been used in several commercial products such as handheld full-body imagers and it is being implemented by commercial and academic groups for Intravascular Ultrasound and Intracardiac Echocardiography. However, large attenuation of ultrasonic waves transmitted through the skull has prevented ultrasound imaging of the brain. This research is a prime step toward implantable wireless microsystems that use ultrasound to image the brain by bypassing the skull. These microsystems offer autonomous scanning (beam steering and focusing) of the brain and transferring data out of the brain for further processing and image reconstruction. The objective of the presented research is to develop building blocks of an integrated electronics architecture for CMUT based wireless ultrasound imaging systems while providing a fundamental study on interfacing CMUT arrays with their associated integrated electronics in terms of electrical power transfer and acoustic reflection which would potentially lead to more efficient and high-performance systems. A fully wireless architecture for ultrasound imaging is demonstrated for the first time. An on-chip programmable transmit (TX) beamformer enables phased array focusing and steering of ultrasound waves in the transmit mode while its on-chip bandpass noise shaping digitizer followed by an ultra-wideband (UWB) uplink transmitter minimizes the effect of path loss on the transmitted image data out of the brain. A single-chip application-specific integrated circuit (ASIC) is de- signed to realize the wireless architecture and interface with array elements, each of which includes a transceiver (TRX) front-end with a high-voltage (HV) pulser, a high-voltage T/R switch, and a low-noise amplifier (LNA). Novel design techniques are implemented in the system to enhance the performance of its building blocks. Apart from imaging capability, the implantable wireless microsystems can include a pressure sensing readout to measure intracranial pressure. To do so, a power-efficient readout for pressure sensing is presented. It uses pseudo-pseudo differential readout topology to cut down the static power consumption of the sensor for further power savings in wireless microsystems. In addition, the effect of matching and electrical termination on CMUT array elements is explored leading to new interface structures to improve bandwidth and sensitivity of CMUT arrays in different operation regions. Comprehensive analysis, modeling, and simulation methodologies are presented for further investigation.Ph.D