Application of MEMS in Optobionics: Retinal
Implant
Beghini Alessandro
6
ABSTRACT
MEMS technology has been attracting increasing attention in several medical fields for its possible applications in curing diseases, which were considered intractable until few years ago. A typical application, as example, regards the MEMS based cochlear implant, which is meant to give hearing to deaf people through a wireless communication device. Moreover, MEMS accelerometer are widely applied to detect movement, heat flow, skin temperature, heart rate, etc...
Among all these applications, one in particular attracts the attention of researchers: the microchip retinal implant. Extended studies have been conducted in several places of the world (USA, Japan, Australia, etc…) in order to develop a microchip able to stimulate damaged retinal cells. This is very important for patients affected by Retinitis Pigmentosa (RP) and Age related Macular Degeneration (AMD).
In this research, the structure of the eye and the basic principle of the eye’s view will be investigated. The focus will be in particular on the function of the retina on the process of sight and the characteristics of the macula, the part of the retina, which gives the highest resolution for the images. The possible diseases and abnormal retinal conditions will also be briefly considered, especially the aforementioned Retinitis Pigmentosa and Age related Macular Degeneration.
In the second part of the project, the possible approaches to cure the retinal degeneration will be analyzed (i.e.: epiretinal and subretinal implant). In particular the study will focus on the microdevices applied in both the aforementioned approaches. On one side the epiretinal system is based on a retina encoder, a telemetry link and a stimulator device. On the other side the subretinal implant is based on a silicon microchip of 2mm diameter, which contains microscopic solar cells called microphotodiodes. These are designed to convert the light energy from images into electrochemical impulses that stimulate the remaining functional cells of the retina in patients with AMD and RP. Moreover, it is designed to produce visual signals similar to those produced by the photoreceptor layer in order to subsequently induce biological signals in the remaining functional retinal cells.
The research will also point out the main aspects in the microfabrication of these microchips and the possible alternatives in the process. Another important issue is the biocompatibility of the various component involved in the fabrication, with a particular concern for the biocompatibility of silicon.
Finally, some important results from the application of these new techniques will be addressed. In fact, pre-clinical laboratory testing showed that animal models with the retinal implant responded to light stimuli with electrical signals and sometimes brain wave signals. The induction of these biological signals indicated that visual responses had occurred. Besides, the subretinal device has been implanted in some patients with RP to study its safety and feasibility in treating retinal vision loss. Until now no patient has shown signs of implant rejections, inflammation or other problems.
INTRODUCTION
Retina Physiology
The human eye is composed by several parts but the most important is definitely the retina, which converts light information into neural electrical signals. These signals are transported to the visual cortex of the brain by the optic nerve. The visual cortex then decodes the neural signals into a meaningful image.
The retina is composed of approximately 126 million photoreceptors (size: 2-3 mm), which provide an analog electronic signal to the attached bipolar neural cell layer. The bipolar cells convert the signal into electrical pulse train. Signal processing and convergence is performed in all neural cell layers comprising horizontal cell, bipolar cells, amacrine cells and ganglion. Approximately one million axons of the ganglion cells form the optic nerve, which extends into the visual cortex of the brain. The light passes through the eye and through the 200 µm thin retina neural layer before reaching the photoreceptors (Fig. 1 in next page).
Fig. 1: Structure of the retina.
This description of the retina is definitely simplified, in fact there are many interneurons in the central part of the retina section between the photoreceptors and the ganglion cells. However, the concepts introduced can adequately support the scope of this research.
Retinal diseases
A group of diseases that may affect the retina is the Retinitis Pigmentosa (RP) and the Age-related Macular Degeneration (AMD). These diseases are characterised by a gradual breakdown and degeneration of the photoreceptor cells. Depending on which type of cell is mainly affected, the symptoms vary, and include night blindness, lost peripheral vision (tunnel vision) and loss of the ability to discriminate colour. Symptoms of RP are most often recognised in adolescents and young adults, with progression of the disease usually continuing throughout the individual's life. The rate of progression and degree of visual loss are variable.
So far, there is no known cure for RP. However, intensive research is currently under way to discover the cause, prevention and treatment. At this time, RP researchers have identified a first step in managing RP: certain doses of vitamin A have been found to slightly slow the progression of the disease in some individuals. Researches have also found some of the genes that cause RP.
There are other inherited retinal degenerative diseases that share some of the clinical symptoms of RP. Some of these conditions are complicated by other symptoms besides the loss of vision. The most common of these is Usher Syndrome, which causes both hearing and vision loss. Other rare syndromes that researchers are studying include Bardet-Biedl syndrome, Best Disease, Leber Congenital Amaurosis and Stargardt Disease.
Approaches to cure retinal diseases
In order to cure retinal diseases the possible approaches are the subretinal implant and the epiretinal implant. These two methods differ because they substitute different physiological functions.
An epiretinal implant stimulates directly the ganglion cells. The device generates spike trains at defined sites of the retina. The epiretinal device does not rely on the natural data processing of the neural compartments in the retina. Hence, the epiretinal approach requires an encoder for mapping visual patterns onto pulse trains as inputs for electronic stimulation.
A subretinal implant is meant to replaces the degenerated photoreceptors with photodiodes and electrodes. Hence, the technical implant must provide an analog signal to the adjacent neural layers. In this case the neural retina must be partly intact and it must be able to maps the visual pattern into pulse trains. The signals are processed and converged in the functional neural layers of the retina before they are transmitted through the optic nerve into the visual cortex.
THE EPIRETINAL MICROIMPLANT
Components
The epiretinal device introduced previously is composed by three major elements: the retina encoder, a telemetry link for power and data transmission, and the implantable stimulator device (Fig. 2). The image sensor, the implantable power and data receiver as well as the stimulator are fabricated using standard CMOS technology.
Fig. 2: The epiretinal system and its 3 functional units.
Description
In this device, the image is received by a CMOS photodiode based sensor chip with light sensitivity exceeding seven decades (>140 dB). The photodiodes are arranged in a hexagonal grid structure to obtain a quasi circular symmetric spatial filter kernel.
At first, spatial filtering is performed on a receptive field utilizing the interface of the CMOS image sensor (this is a digital-memory like interface). Then, a multiply-add unit carries out hardware convolution of pixel parameters with the filter coefficients. A chip digital signal processor is applied for temporal filtering and to generate spike trains. The DSP unit is also meant to control the external telemetry data transmission, implemented as an amplitude modulated signal (ASK-signal) running at a carrier frequency of 13.5 MHz. Modulated data contain stimulation parameters, encoded spike duration, polarity, and the electrode address.
The implantable receiver chip is powered by the RF signal. The receiver unit carries out rectification, clock extraction, demodulation, and decoding of the signal. A thin polyimide cable with embedded Platinum conductors connects the receiver chip with the stimulator die. The stimulator electronics provides a pulse time, a current source and a microelectrode selector addressing a field of 5 x 5 microelectrode pads. The chip generates pulses with a programmable pulse width (10 - 300 µs), pulse polarity (including bipolar pulses), pulse current (10 - 100 µA) and a pulse rate (500 Hz).
Microfabrication
In order to develop the epiretinal implant, a special micro machining process has been developed for embedding platinum microstructures into 15 µm thin polyimide (PI) films. The flexible PI foils serve as carrier and insulation layers that hold the platinum/ gold/ iridium based microelectrodes, conductive lines, and interconnection pads. Fig. 3 is sketching the micromachining process for fabricating the PI films with via holes, double layered conducting tracks, and contact pads. Micromachining of PI allows the fabrication of retina contact designs that adhere smoothly to the concave shape of the retina. Concentric ring electrodes were fabricated employing a double metal layer insulated by a 5 µm PI layer.
A special microflex interconnection (MFI) technology has been developed to integrate bare silicon chips mechanically and electrically on the substrate without consuming any additional space for wiring. The MFI technology enables high-density interconnects with a center to center pitch of contacting pads less than 100 µm.
The basic process of this new technology is utilizing a common thermosonic ball wedge bonder to form just the gold ball. This serves as a rivet that technically and electrically interconnects the thin PI foil with the bare chip.
Fig. 3: Microfabrication of flexible 15 µm thin polyimide film.
Surface mount devices (SMD capacitor, SMD diodes) and a receiver coil for signal and data transmission were soldered to corresponding contact pads on the PI foil. Complete epiretinal devices have been built on flexible foils using the MFI technology and hybrid assemblies.
Parylene was used to protect the electronic components. A mold was designed to house the complete device in medical graded silicone with the shape of an intraocular lens at the signal receiving end (Fig. 4).
Fig. 4: An epiretinal implant packaged in silicone.
THE SUBRETINAL MICROIMPLANT
Description
The subretinal implant is based on the studies of Chow V. and Chow A. who suggested to place a silicon based microphotodiode array (MPDA) in the subretinal space. The device resembles the function of degenerated photoreceptor. Therefore, the retina must be only partially degenerated in order the device to work. Each photodiode cell generates a photovoltaic charge which is transferred to the adjacent microelectrode for stimulation of the bipolar cells.
Ultra thin and flexible devices have been designed as well as CMOS-based chips with different pixel sizes and electrode configurations. Several prototypes have been developed holding between 2000 – 5000 photodiode microelectrode cells on a single device (Fig. 5).
Fig. 5: Schematic cross section of a microphotodiode (MPD) and SEM micrograph of the MPD chip surface.
Microfabrication
Microphotodiode arrays (MPDA) are manufactured on a silicon wafer using CMOS process technology. The first device produced was essentially a single photosensitive pixel, approximately 3 mm in diameter. The current microphotodiode array includes a regular array of individual photodiode subunits, each approximately 20×20 µm2 and separated by 10 µm channel stops. The resulting microphotodiode density is approximately 1,100/m2. Across the different generations examined, the implants have decreased in thickness, from ~250 µm (earlier devices), to approximately 50 µm (devices currently used). Because implants are designed to be powered solely by incident light, there are no connections to an external power supply or other device. In their final form, devices generate current in response to a wavelength range of 500 to 1100 nm.
The device is obtained starting with the deposition on the silicon wafer of a passivation layer of silicon oxide. This consists of a thin layer of high temperature oxide and about 0.5µm of TEOS (tetra-ethyl-ortho-silicate). Subsequently, microelectrodes are fabricated onto the wafer.
Firstly, a photoresist layer is applied and micropatterned. Then, contact holes are etched into the passivation layer in order to provide for an electrical connection of the microelectrodes to the microphotodiodes. A layer of titanium nitride is applied and finally micropatterned by lift-off to release the microelectrodes.
Grooves for chip separation are etched in the front part of the wafer. Individual chips are obtained by grinding the wafer from the rear side up to a final thickness of 30 to 70µm. Chip diameter is typically 1 to 3mm, thickness 30 to 70 µm. Even though electrical active chips are fabricated using standard CMOS process technology, non-standard processes are necessary to obtain individual implantable microchips. Titanium is sputtered at high pressure in a nitrogen atmosphere to obtain nanoporous titanium nitride (TiN) stimulation electrodes on the implant. The TiN deposition enhances electrode surface area by a factor of up to 100 which is a critical prerequisite for efficient charge transfer from chip to the retinal tissue.
Photodiode cells have been fabricated in various MPD area sizes: 20 x 20 µm2, 100 x 100 µm2, and 200 x 200 µm2 holding monopolar and bipolar microelectrode configurations.
The key issue for stimulating retina cells with technically generated photocurrents is an optimum capacitive coupling to the bipolar cells. Several contact layers (p-doped a- Si:H, microcrystalline Si, metal-induced crystallization) have been investigated which provide high perpendicular conductivity with reduced lateral parasitic losses to the surrounding tissue.
Experimental Results
The studies conducted on electrostimulation have elucidated that a pure photovoltaic current is not sufficient to provide charge capacities for stimulating the bipolar cells. Therefore, an additional energy input is provided by near-infrared radiation or radio frequency power transmission.
The devices have been implanted in pigs and rabbits to prove the biocompatibility, general function and local stability of the implants. The inner retina architecture is well preserved, however in vivo experiments revealed a decay of the passivation layer of the device when implanted for more than six month (Fig. 6). Titanium nitride electrodes proved to be biostable over an implantation period exceeding 18 months. Biostable passivation and packaging will be a major concern in on-going experiments.