Future of smart cardiovascular implants

Cardiovascular disease remains the leading cause of death in Western society. Recent technological advances have opened the opportunity of developing new and innovative smart stent devices that have advanced electrical properties that can improve diagnosis and even treatment of previously intractable conditions, such as central line access failure, atherosclerosis and reporting on vascular grafts for renal dialysis. Here we review the latest advances in the field of cardiovascular medical implants, providing a broad overview of the application of their use in the context of cardiovascular disease rather than an in-depth analysis of the current state of the art. We cover their powering, communication and the challenges faced in their fabrication. We focus specifically on those devices required to maintain vascular access such as ones used to treat arterial disease, a major source of heart attacks and strokes. We look forward to advances in these technologies in the future and their implementation to improve the human condition

An Optofluidic Lens Biochip and an x-ray Readable Blood Pressure Microsensor: Versatile Tools for in vitro and in vivo Diagnostics.

Three different microfabricated devices were presented for use in vivo and in vitro diagnostic biomedical applications: an optofluidic-lens biochip, a hand held digital imaging system and an x-ray readable blood pressure sensor for monitoring restenosis. An optofluidic biochip–termed the ‘Microfluidic-based Oil-Immersion Lens’ (mOIL) biochip were designed, fabricated and test for high-resolution imaging of various biological samples. The biochip consists of an array of high refractive index (n = 1.77) sapphire ball lenses sitting on top of an oil-filled microfluidic network of microchambers. The combination of the high optical quality lenses with the immersion oil results in a numerical aperture (NA) of 1.2 which is comparable to the high NA of oil immersion microscope objectives. The biochip can be used as an add-on-module to a stereoscope to improve the resolution from 10 microns down to 0.7 microns. It also has a scalable field of view (FOV) as the total FOV increases linearly with the number of lenses in the biochip (each lens has ~200 microns FOV). By combining the mOIL biochip with a CMOS sensor, a LED light source in 3D printed housing, a compact (40 grams, 4cmx4cmx4cm) high resolution (~0.4 microns) hand held imaging system was developed. The applicability of this system was demonstrated by counting red and white blood cells and imaging fluorescently labelled cells. In blood smear samples, blood cells, sickle cells, and malaria-infected cells were easily identified. To monitor restenosis, an x-ray readable implantable blood pressure sensor was developed. The sensor is based on the use of an x-ray absorbing liquid contained in a microchamber. The microchamber has a flexible membrane that is exposed to blood pressure. When the membrane deflects, the liquid moves into the microfluidic-gauge. The length of the microfluidic-gauge can be measured and consequently the applied pressure exerted on the diaphragm can be calculated. The prototype sensor has dimensions of 1x0.6x10mm and adequate resolution (19mmHg) to detect restenosis in coronary artery stents from a standard chest x-ray. Further improvements of our prototype will open up the possibility of measuring pressure drop in a coronary artery stent in a non-invasively manner.PhDMacromolecular Science and EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/111384/1/toning_1.pd

Inductive helical stent for wireless revascularization: finite element analysis

This paper reports simulation of a shape-memory-alloy (SMA) nitinol type active stent for wireless revascularization. The device comprises an inductive helical stent as an inductive component and a capacitive pressure sensor as a capacitive component. When the stent is coupled to an external coil with a radiofrequency (RF) signal, the stent can be expanded wirelessly by matching the signal with the device resonant frequency. By this approach, restenosis in a stented vessel can be potentially eliminated without a repeat stenting procedure. However, the calculation of important parameters is difficult using the conventional analytical method due to the unconventional structure of the helical stent which can be considered an irregular solenoid. In this work, finite element analysis (FEA) was performed using ANSYS HFSS to simulate the inductance, quality factor, and series resistance of the device at the initial crimped state and expanded state as a function of frequency

The future of cardiovascular stents: bioresorbable and integrated biosensor technology

Cardiovascular disease is the greatest cause of death worldwide. Atherosclerosis is the underlying pathology responsible for two thirds of these deaths. It is the age‐dependent process of “furring of the arteries.” In many scenarios the disease is caused by poor diet, high blood pressure, and genetic risk factors, and is exacerbated by obesity, diabetes, and sedentary lifestyle. Current pharmacological anti‐atherosclerotic modalities still fail to control the disease and improvements in clinical interventions are urgently required. Blocked atherosclerotic arteries are routinely treated in hospitals with an expandable metal stent. However, stented vessels are often silently re‐blocked by developing “in‐stent restenosis,” a wound response, in which the vessel's lumen renarrows by excess proliferation of vascular smooth muscle cells, termed hyperplasia. Herein, the current stent technology and the future of biosensing devices to overcome in‐stent restenosis are reviewed. Second, with advances in nanofabrication, new sensing methods and how researchers are investigating ways to integrate biosensors within stents are highlighted. The future of implantable medical devices in the context of the emerging “Internet of Things” and how this will significantly influence future biosensor technology for future generations are also discussed

AFM-based characterization method of capacitive MEMS pressure sensors for cardiological applications

Current CMOS-micro-electro-mechanical systems (MEMS) fabrication technologies permit cardiological implantable devices with sensing capabilities, such as the iStents, to be developed in such a way that MEMS sensors can be monolithically integrated together with a powering/transmitting CMOS circuitry. This system on chip fabrication allows the devices to meet the crucial requirements of accuracy, reliability, low-power, and reduced size that any life-sustaining medical application imposes. In this regard, the characterization of stand-alone prototype sensors in an efficient but affordable way to verify sensor performance and to better recognize further areas of improvement is highly advisable. This work proposes a novel characterization method based on an atomic force microscope (AFM) in contact mode that permits to calculate the maximum deflection of the flexible top plate of a capacitive MEMS pressure sensor without coating, under a concentrated load applied to its center. The experimental measurements obtained with this method have allowed to verify the bending behavior of the sensor as predicted by simulation of analytical and finite element (FE) models. This validation process has been carried out on two sensor prototypes with circular and square geometries that were designed using a computer-aided design tool specially-developed for capacitive MEMS pressure sensors.This research was funded by the Spanish Government’s “Ministerio de Economía, Industria y Competitividad” under the joint projects TEC2013-46242-C3-2-P and TEC2013-46242-C3, co-financed with FEDER

Development of a cell sensing and electrotherapeutic system for a smart stent

Cardiovascular diseases (CVD) is one of the main causes of death worldwide. Coronary heart disease (CHD) and strokes are the highest contributors to CVD deaths (46 % and 26 % respectively) in the UK. The condition which leads to CHD is Coronary artery disease (CAD). The main cause of CAD is coronary atherosclerosis, which involves an inflammatory response of the artery wall to chronic multifactorial injury, which then results into formation of atherosclerotic plaques. One of the main treatment strategies for CAD is Percutaneous Coronary Intervention (PCI). PCI is a procedure during which a balloon mounted catheter with an unexpanded stent is inserted into a peripheral artery and threaded up to the site of stenosis in the coronary artery of the heart to reopen the vessel. PCI usually involves stenting with a Bare Metal Stent (BMS) or Drug Eluting Stent (DES). The 9-month revascularisation rate is 12.32 % with BMS, and this rate has significantly decreased to 4.34 % with early generation DES. The latest generation of DES is associated with revascularisation rates of 2.91 %. Detection of this vascular hyperplasia is a common limitation of these devices which can be found across a number of vascular pathologies. In this project, we developed a new type of biosensor for detecting the changes associated with these blockages that could be mounted on these implantable medical devices. Our design and development led to a comprehensive characterisation of both the sensor and its cell interactions. Proof of concept experiments were performed that legitimised the concept of a smart self-reporting device, as a solution to remote detection of In-stent Restenosis (ISR). The proposed smart stent would have both diagnostic and therapeutic capabilities. Preliminary tests showed that the devices were minimally susceptible to changes in volume and conductivity of culture medium, during baseline measurements. Sensors of different dimensions were fabricated with the best version 16 times smaller but with 4.35 times higher sensitivity in cell detection compared to baseline. Our sensor could also distinguish between different cell types. Indeed the sensor coverage could be remotely monitored intermittently (at 24 h intervals) or continuously (at 15 min intervals) or on demand. Continuous monitoring allowed the gradual changes in cell phenotype to be monitored including cell adherence, proliferation and death which was then correlated with live cell sensor imaging. We found our sensors could be used for both cell detection and therapeutic intervention. As the fabricated biosensors are intended to be integrated onto a future smart stent, this would be implanted in vivo and would be subjected to blood flow. Therefore it was important to test the devices under flow conditions. Our data show that, when incorporated into microfluidic flow chambers, the sensors could exquisitely detect cell adherence under flow and static conditions. Moreover they were also suitable for monitoring the gradual migration and proliferation of vascular cells within a microfluidic channel. Future development of these proof-of-concept biosensors is critical for future commercialisation of this important novel device, which hopefully will provide a new class of diagnostic and therapeutic vascular devices

연성 및 생재흡수성 전자소자용 비휘발성 메모리 소자와 집적센서 구현

학위논문 (박사)-- 서울대학교 대학원 : 화학생물공학부, 2015. 8. 김대형.Over years, major advances in healthcare have been made through research in the fields of nanomaterials and microelectronics technologies. However, the mechanical and geometrical constraints inherent in the standard forms of rigid electronics have imposed challanges of unique integration and therapeutic delivery in non-invasive and minimally invasive medical devices. Here, we describe two types of multifunctional electronic systems. The first type is wearable-on-the-skin systems that address the challenges via monolithic integration of nanomembranes fabricated by top-down approach, nanotubes and nanoparticles assembled by bottom-up strategies, and stretchable electronics on tissue-like polymeric substrate. The system consists of physiological sensors, non-volatile memory, logic gates, and drug-release actuators. Some quantitative analyses on the operation of each electronics, mechanics, heat-transfer, and drug-diffusion characteristic validated their system-level multi-functionalities. The second type is a bioresorbable electronic stent with drug-infused functionalized nanoparticles that takes flow sensing, temperature monitoring, data storage, wireless power/data transmission, inflammation suppression, localized drug delivery, and photothermal therapy. In vivo and ex vivo animal experiments as well as in vitro cell researches demonstrate its unrecognized potential for bioresorbable electronic implants coupled with bioinert therapeutic nanoparticles in the endovascular system. As demonstrations of these technologies, we herein highlight two representative examples of multifunctional systems in order of increasing degree of invasiveness: electronically enabled wearable patch and endovascular electronic stent that incorporate onboard physiological monitoring, data storage, and therapy under moist and mechanically rigorous conditions.Contents Abstract Chapter 1. Introduction 1.1 Organic flexible and wearable electronics.................................................. 1 1.2 Inorganic flexible and wearable electronics............................................... 14 1.3 Flexible non-volatile memory devices.......................................................... 25 1.4 Bioresorbable materials and devices........................................................... 34 References Chapter 2. Multifunctional wearable devices for diagnosis and therapy of movement disorders 2.1 Introduction ................................................................................. 45 2.2 Experimental Section ......................................................................... 49 2.3 Result and Discussion ........................................................................ 65 2.4 Conclusion ................................................................................... 95 References Chapter 3. Stretchable Carbon Nanotube Charge-Trap Floating-Gate Memory and Logic Devices for Wearable Electronics 3.1 Introduction ................................................................................ 101 3.2 Experimental Section ........................................................................ 104 3.3 Result and Discussion ....................................................................... 107 3.4 Conclusion .................................................................................. 138 References Chapter 4. Bioresorbable Electronic Stent Integrated with Therapeutic Nanoparticles for Endovascular Diseases 4.1 Introduction ................................................................................ 148 4.2 Experimental Section ........................................................................ 151 4.3 Result and Discussion ....................................................................... 173 4.4 Conclusion .................................................................................. 219 References 국문 초록 (Abstract in Korean) .................................................................. 230Docto

A High-Yield Microfabrication Process for Sapphire Substrate Pressure Sensors with Low Parasitic Capacitances and 200 C Tolerance

Microelectromechanical systems (MEMS) can offer many benefits over conventional sensor assembly, especially as the desire for smaller and more effective instrumentation escalates in demand. While many industries continually strive for improved sensing capabilities, those invested in natural gas and oil extraction have a particular interest in miniaturized pressure sensing systems. These sensors need to operate autonomously in harsh environment (50 MPa, 125°C) fissures (≤1 cm) with at least 10 bit pressure resolution (≤0.05 MPa). The primary focus of this report is the development of a surface micromachining process to fabricate high performance capacitive pressures sensors, utilizing dielectric substrates to enable extremely low offset and parasitic capacitances and temperature coefficients. In contrast to conventional bulk silicon micromachining methods that use various kinds of etch stops such as electrochemical or dopant selective, dry additive processes are utilized to reduce manufacturing complexity, cost, and material consumption and have gained favor in recent years as the tools have matured. The fabricated devices must meet both pressure sensing and dimensional scaling requirements with a full scale range of ≥50 MPa, resolution of ≤50 kPa (>20 fF/MPa with a system resolution of 1 fF/code), and size of ≤2×1×0.5 mm3. In order to meet these goals while maximizing yield, particular attention has been given to the interplay between equipment limitations and device design. Process and design features have been refined over four process generations that together lead to a capacitance response of >450 fF/MPa over 50 MPa, provide a yield of >80%, permit an extreme span (>1000×) of full scale range designs, and allow automated system assembly. Devices have been tested at pressures and temperatures of up to ≥50 MPa and 200°C, representing downhole environments, demonstrating < 7.0 kPa (< 1 psi) resolution. Devices designed to operate over a much lower full scale range of < 50 kPa (≤350 Torr), representing biomedical applications, have been tested and demonstrate a resolution of < 80 Pa (< 0.6 Torr). Sensor response and design have been validated in the primary use case of autonomous microsystem integration. The system circuity includes a microcontroller, capacitance-to-digital converter, temperature sensor, photodiode, and battery. The readout electronics and sensor are mounted onto a flexible PCB, packaged into stainless steel or ceramic shells, sealed with silicone epoxy to permit pressure transmission while providing environmental protection, and measure < 9×9×7 mm3 in size. The systems have been successfully field tested in a brine well. While the capacitive pressure sensors have been developed primarily for active microsystems, there may be situations where a wired connection to the readout circuitry is not possible. A passive wireless pressure monitoring system utilizing short range inductive coupling has been developed to evaluate the performance of the sapphire substrate sensors for this use case. The passive sensing element consists of the capacitive pressure sensor and an inductor, packaged in a 3D printed biocompatible housing measuring ø12 x 24 mm3. Pressure monitoring within the GI tract has been targeted; an in situ resolution of 1.6 kPa (12 Torr) at 6 cm has been achieved through conductive saline. A practical application of the sensor has been demonstrated in vivo, having been ingested and successfully interrogated in a canine model to monitor stomach pressure for over two days.PHDElectrical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/149856/1/acbenken_1.pd