Microfabricated thin film strain gage sensor with telemetry microprocessor embedded in a soft contact lens for minimally invasive intraocular pressure monitoring

Increased intraocular pressure (IOP) is the leading cause and the hallmark of Glaucoma, an asymptomatic and irreversible degenerative disease that, undetected or untreated, progresses to blindness due to optic nerve atrophy. Glaucoma is the second cause of blindness and visual impairment worldwide. Peripheral visual field is first affected, often unnoticed by the patient, progressing towards the loss of the central visual field and ultimately towards blindness. Continuous monitoring of the IOP is of major importance both for a better management of Glaucoma treatment, and for a more efficient and earlier screening of Glaucoma patients amongst risk groups. Currently, the only way to get data on the dynamic behavior of the IOP is to repeat punctual measurements several times a day. No available technology can perform uninterrupted 24-hour IOP measurements during sleep or during daily activities. Consequently, the ophthalmologist does not have the tool that permits widespread, cost-effective, and precise recording of the IOP for the full 24-hour period, in the case of Glaucoma patients or for Glaucoma screening. As a result, the disease remains under-diagnosed and many Glaucoma patients are kept on insufficient or inappropriate medication. This research work was focused on the development, characterization and testing of a novel minimal invasive microsystem for the monitoring of IOP, based on a new measurement principle. The research work presented in this thesis combines microtechnology, microelectronic and biomaterials. The method of indirect continuous monitoring of IOP presented here is based on the detection of spherical deformations of the eyeball (changes in cornea curvature) due to IOP. We developed and patented a soft contact lens with a microfabricated thin film strain gage sensor embedded, which is capable of measuring cornea deformations due to IOP variations- the Contact Lens Sensor (CLS). To power the sensor and retrieve data from the contact lens wirelessly, telemetry based on absorption modulation has been investigated and integrated in the CLS. The fabrication technology is based on a well known polyimide-based technology that has been widely used to fabricate implantable microelectronics, but two critical fabrication steps have been addressed and improved: metal adhesion on polyimide and structures release from wafer after fabrication. As the application is related to the medical field, great importance has been given in the choice of biocompatibility materials. The developed fabrication technology in combination with telemetry by absorption modulation, the flip-chip-on-flex assembly technology and the silicone biocompatible encapsulation and insulation technique open up new possibilities for the development of implantable microsystems for human biometric parameters monitoring and animal long term monitoring and testing, where small wireless sensors and no battery are needed. Prototypes of the CLS have been tested on pig-enucleated eyes, under simplified physiological conditions in order to verify our novel measurement principle for the IOP monitoring. Moreover the first wired prototype has also been tested on humans to study and investigate all issues related to safety, comfort, stability and reliability of the CLS. The results presented show that the device is sufficiently sensitive to measure a signal equivalent to the human ocular pulsation (OP) and follows well the IOP variations in a reproducible way, in static and dynamic mode, validating therefore the measurement principle and theoretical calculations. Next step will be extensive clinical trials to validate the systems and its reproducibility on humans. The wireless CLS would allow for the first time minimally invasive continuous IOP monitoring over periods up to 24 hours, regardless of patient position and activities. It would permits 24-hour continuous IOP measurements performed during sleep and various independent activities without the involvement of the patient, thus opening up new diagnostic and therapeutic methods to manage Glaucoma.

Design and Implementation of CMOS Image Sensors for Biomedical Applications

Gözen Köklü

Since the first introduction of digital cameras, the camera market has been taking tremendous interest from many fields. This trend has even accelerated when the cost, size, and power consumption of such devices were reduced with the introduction of camera on a chip concept. This concept is achieved by integrating photoactive and electronics parts of digital cameras on a single chip with Complementary Metal Oxide Semiconductor (CMOS) technology but resulted in reduced photon collection efficiency and increased noise. Since then, scientists and researchers have been putting a huge effort to improve the quality of CMOS image sensors with advancements in lithography and fabrication process, by finding alternative ways of increasing the fill factor, designing lower noise circuits, and putting additional on chip features. Despite these efforts and cost, integration, and power consumption advantages of CMOS image sensors, they have still not been preferred in many application fields such as biomedical imaging, where high quality imaging is targeted. Recently, with the process related technological advancements, the cost of CMOS image sensors have increased and this has made the CMOS image sensors loose their cost advantage and attractiveness for low cost applications. In this thesis, I summarize my research effort in integrating the low-cost CMOS image sensors in biomedical applications and improving their performance with novel circuits fabricated with standard CMOS process, while maintaining their cost advantage. Towards this aim, I propose possible ways of implementing pixel array sensors and noise reduction and read-out related circuits with standard CMOS technology in order to make these low-cost sensors applicable for biomedical applications. For this purpose, this research started by fabricating a characterization chip that uses standard CMOS process compatible photodiodes and pixels. Using this chip, I obtained characterization data for an n-well 0.18μm standard CMOS technology and made it available for designers using similar technologies. Later, I developed a small camera prototype by using the characterization data of the first chip. This small camera chip includes efficient pixel circuits with column parallel fully differential noise reduction circuits, and horizontal and vertical access circuits. After obtaining good quality images using this camera prototype, I designed a larger array camera chip, which offers Video Graphics Array (VGA) resolution, using the same technology. This third camera chip uses pixel sharing technique, which results in 1.75 transistors per pixel. Moreover, this design provides the flexibility of changing the pixel array resolution with respect to the pixel size, aiming to optimize the performance according to the application. In order to result in highest possible fill factor, all of these fabricated chips use Active Pixel Sensor (APS) technique. Within the scope of this thesis, I also propose novel Digital Pixel Sensor (DPS) designs, which would bring chip-level additional functions for biomedical imaging applications and hold the potential for future devices.

EPFL2014

Design and Implementation of CMOS Image Sensors for Biomedical Applications

Gözen Köklü

EPFL2014