Thin-film impedimetric sensors for chronic in vivo use: design and application to hydrocephalus treatment

2018-08-05The ability to record physiological signals from inside the body without invasive surgery or dangerous testing was a revolutionary development in medicine that has accelerated our understanding of the human body and the ability to diagnose, manage, and cure diseases. However, many physiological signals cannot be accurately measured using non-invasive imaging techniques. These signals include hormones and biomarkers in blood, the neural signals which make up cognition, reason, and perception, and cerebrospinal fluid dynamics. Even for diseases which can be non-invasively monitored, several barriers exist that limit the usefulness of medical imaging. Imaging studies can only be performed during doctor’s visits, which generally occur once every six months or less. This limits a doctor’s ability to understand and manage chronic conditions. Patients can experience very different physiological responses in a doctor’s office compared to normal activity, a phenomenon colloquially known as “white coat syndrome”. Measurements made in a doctor’s office also preclude disease monitoring during exercise or strenuous activities. To improve medical care and advance our understanding of chronic diseases, techniques are needed to remotely monitor patients outside of the clinic, to acquire data on a disease state during periods of physical activity, to take measurements at time scales of minutes or hours instead of months, and to record biosignals that are not currently detectable using non-invasive medical imaging. This would give us unprecedented access to a patient’s disease state, enabling the detection or prediction of adverse events before the patient has any symptoms and leading to rapid, targeted treatment. It would also advance our scientific understanding of chronic diseases, allow high-precision trialing of therapies, and may lead to cures for diseases which are now considered life-long conditions. Continuous glucose monitoring in diabetes patients acts as early validation of continuous biosignal monitoring outside the clinic; numerous studies have shown that even self-monitoring of blood glucose by patients results in improved long-term outcomes. ❧ Since the invention of the transistor in 1947, the microelectronics field has exploded in size and scope, enabling the extreme miniaturization of complex devices and systems. The self-fulfilling prophecy of Moore’s Law has resulted in transistors with 7 nm or smaller features, enabling the creating of millimeter-sized microcontrollers and solid-state sensors. Piggybacking off silicon manufacturing techniques developed for integrated circuits, the development of microelectromechanical systems (MEMS) has brought physical actuation and sensing to the solid-state electronics world. Commercial MEMS devices include pressure sensors, accelerometers, and gyroscopes; these MEMS sensors are made by etching mechanical structures out of a monolithic silicon substrate. The combination of microelectronics and MEMS devices has enabled orientation detection, tactile feedback on cell phones, and tire pressure measurement in cars. Miniaturized MEMS sensors and ultra-low power microelectronics hold enormous potential for the medical field as well. Potential devices would allow doctors to remotely monitor a patient’s condition, catch disease progression before it becomes symptomatic, and intervene before complications occur. These remote medical sensors could be as simple as a fall-detector for elderly patients or as complicated as a flexible skin-based platform for monitoring multiple biomarkers in sweat. Recent manufacturing advances have led to the development of polymer MEMS sensors, which can be placed inside the body for long periods of time without corrosion or sensor drift. Polymer MEMS technology could enable novel sensors for monitoring blood or CSF dynamics, biomarkers in the blood, or neural signals. ❧ One group of patients which stand to benefit from continuous remote monitoring of their disease state is those with hydrocephalus. Hydrocephalus is an incurable, chronic disease characterized by an accumulation of excess cerebrospinal fluid in the brain’s ventricles. The disease affects 1 in every 500 children born in the US, and 1 million Americans live with hydrocephalus today. If left untreated, patients will experience brain damage, coma, and eventual death. Luckily, effective treatment involving drainage of excess fluid to the abdomen using an implanted hydrocephalus shunt has existed since the 1960s. These permanently implanted shunts have saved millions of lives since their introduction, but they fail at an alarming rate due to occlusion, infection, mechanical breakage, or improper drainage rate. The tools used by physicians to diagnose shunt failure are non-specific and inaccurate. The standard of care for shunt failure diagnosis involves one or more CT scans and a shunt tap, in which a doctor inserts a needle into the patient’s shunt to measure pressure. CT scans must be compared against past images to identify fluid build-up, and shunt taps often give incorrect pressure measurements when the shunt is clogged; often, physicians cannot truly diagnose shunt failure until the patients undergoes a shunt resection surgery. Shunt failure is a progressive process, and patients will experience non-specific symptoms such as headaches, irritability, and dizziness before progressing to more serious symptoms such as coma and brain damage. The ability to remotely monitor shunt status, and to diagnose or predict shunt failure before serious symptoms occur, would result in a huge improvement in the treatment of hydrocephalus and in the quality of life of patients. ❧ The following thesis describes work toward developing a wireless multi-sensor module for remote monitoring of hydrocephalus shunts status. This work focuses on the development of novel flow sensors and wireless catheter patency sensors for hydrocephalus shunts, as well as an ongoing clinical study of a multi-sensor module in external ventricular drains. Work toward improving hydrocephalus treatment has also inspired related projects in implantable sensors and biomedical monitoring. These projects include the development of a passive, wireless glucose sensor, a novel method of temperature measurement, the use of electrodeposited platinum-iridium coatings for improving sensors, and polymer strain sensors based on kirigami patterns. ❧ Chapter 1 describes hydrocephalus, including its history and the current standards of care. Hydrocephalus has been identified since ancient times, but it is only in the past century that patients were able to survive the disease. Patient survival is thanks to the hydrocephalus shunt, which revolutionized hydrocephalus treatment after its introduction in the 1960s. This chapter describes the pathophysiology of hydrocephalus and the early development of the hydrocephalus shunt. It then presents an overview of modern advances in hydrocephalus shunt technology, including gravimetric devices and magnetically adjustable valves. Shunt failure is introduced, and the causes and current state of shunt failure diagnosis is discussed. Finally, the chapter describes physicians’ desire for a “smart shunt” involving sensors and self-cleaning technology, and the technological issues which have thus far prevented a smart shunt from entering the market. ❧ Chapter 2 describes a novel flow sensor designed for chronic use in cerebrospinal fluid. Commercial MEMS flow sensors are composed of a microfabricated heater and multiple temperature sensors, and measure flow velocity via heat transfer through a fluid. However, these sensors utilize high overheat temperatures and are fabricated on silicon or other semiconductor materials, preventing their use in the body. This chapter first reports on a novel method of temperature measurement using the high-frequency electrochemical impedance between electrodes exposed to physiological fluid. The conductivity of a fluid is highly sensitive to temperature, so temperature can be transduced using an electrical signal through the fluid, with sensitivities an order of magnitude higher than the current state of the art. This temperature sensing technique was used to design a thermal flow sensor for physiological fluids that is highly sensitive to flow velocity in the range expected in hydrocephalus shunts while only using a 1℃ overheat temperature. A second-generation flow sensor is also described, which uses a slightly different measurement technique to improve sensitivity at ultra-low flow rates. This chapter closes with three projects investigating the practicality of flow sensor operation in vivo: sensor improvements after coating with electrodeposited platinum-iridium, an investigation of the major expected failure mode (delamination) during in vivo operation, and a long-term drift study using human cerebrospinal fluid. ❧ Chapter 3 describes a novel method for passive wireless transduction of electrochemical impedance. A high-frequency electric signal applied to a coil of wire generates an oscillating magnetic field, allowing energy transfer to a nearby coil. If a load is placed on the second coil, energy will be drawn from the shared magnetic field, changing the impedance of the primary, powered coil. If the load on the secondary coil is composed of a pair of electrodes immersed in physiological fluid, the solution resistance between those electrodes can be transduced by measuring the reflected impedance of the primary coil. This chapter describes the theory and simulation of this transduction method, as well as the fabrication and testing of thin-film biocompatible coils terminating in exposed gold electrodes. Both theory and experiment revealed that the solution resistance between the electrodes could be wirelessly transduced using reflected impedance. The effects of changing coil orientation and separation were also investigated. To apply the reflected impedance technique to hydrocephalus treatment, a patency sensor was developed which wirelessly measured the resistance between an electrode inside and an electrode outside a shunt, enabling direct transduction of shunt blockage. In addition to hydrocephalus treatment, the use of reflected impedance for biomarker detection is explored, and preliminary data on glucose sensing is presented. ❧ Chapter 4 describes a kirigami strain sensor that was inspired by colleague’s work on Parylene C microfabrication. Parylene C is a flexible, biocompatible polymer which can be used to create chronically implantable sensors. However, Parylene C does not stretch significantly when strain is applied. Kirigami refers to the ancient art of cutting paper to produce complex three-dimensional patterns. One kirigami technique which has recently been explored in the MEMS community is the use of offset rows of slits to allow normally stiff planar thin films to stretch. This chapter describes the development of a stretchable Parylene C device using a kirigami slit pattern created via oxygen plasma etching. Kirigami slits enabled devices to stretch to over four times their original size before mechanical failure occurred. Electrical traces on a Parylene C kirigami device were tested during stretching, and multiple electrical parameters were found to change with strain, suggesting the development of a novel biocompatible strain sensor. ❧ Chapter 5 describes a clinical study of a multi-sensor module in pediatric patients with external ventricular drains, or EVDs. EVDs are used in acute cases of hydrocephalus to drain excess fluid to an external collection bag. Integrating sensors into an EVD allows for sensor validation in human cerebrospinal fluid under real-world drainage conditions, without causing significant risk to the patient. For this study, the flow sensor described in Chapter 2 was combined with a pressure sensors and patency sensor developed by colleagues into a multi-sensor module. This module was paired with an electronic datalogger designed to record sensor measurements for up to 14 days. This chapter describes the design of the multi-sensor module and of the first-generation datalogger electronics. It then describes the results of patient enrollment, and the disappointing failure modes that were only uncovered after patient enrollment began. The chapter then describes work towards fixing these failure modes, the most important being the development of a second-generation datalogger with significantly higher sensitivity. The study is currently ongoing, and results using the new sensors and electronics are expected soon. ❧ The final chapter describes milestones and future plans for developing a wireless, chronically implantable multi-sensor module for hydrocephalus shunts. Preliminary work on the wireless electronics and packaging for implantation and integration with hydrocephalus shunts is described