Microelectronic stimulator array

Description of equivalent WO 03067516 A2

Inventor: Scribner PATENT APPLICATION

Serial No. PCT No.

MICROELECTRONIC STIMULATOR ARRAY

BACKGROUND OF THE INVENTION

Field of the Invention

This invention deals generally with neural prosthesis, specifically the concept of

achieving a retinal prosthesis for blind patients through the creation of an electrical interface

between a high-density electrode array and the curved surface of the retina.

Description of the Related Prior Art

There is a great deal of recent interest in the area of neural prosthesis, specifically the

concept of achieving a retinal prosthesis for blind patients has been hypothesized by a number of researchers and is an active area of medical research. In a normal eye, in a basic concept

10, Figures la and lb shows a ray trace of two photons 12 focused on a retina 21. Note that

the incoming photons 12 pass through several layers of transparent retinal cells 16 and 18

before being absorbed by the photoreceptors 22. In a damaged eye, a retinal prosthesis

device 24, as shown in Figures lc and Id, is positioned against the retina 21. In this case, the

photons 12 are absorbed by a microelectronic stimulating array or device 26 that is

hybridized to a glass piece 28 containing an embedded array of microwires. The glass has a

curved surface that conforms to the inner radius of the retina 21. The microelectronic

imaging device 26 is made of thin silicon containing very large scale integrated (NSLI)

circuitry and photon detectors that convert the incident photons 12 to an electronic charge. Inventor: Scribner PATENT APPLICATION

Serial No. PCT No. The charge is then converted to a proportional amount of electronic current which is input to the nearby retinal cell layer 18. The cells fire and a signal is sent to the optic nerve 28.

A typical retinal prosthesis device combines two technologies: first, nanochannel glass (NGC) electrode arrays and secondly a two-dimensional (2-D) multiplexer array. NGC technology employs fiber optic fabrication techniques to produce thin wafers of glass with very small channels perpendicular to the plane of the wafer. Typical NGC wafers that will be required for retinal prosthesis devices are several millimeters in diameter and can contain millions of channels with channel diameters on the order of one micron. The channels are filled with a good electrical conductor and one surface of the glass is ground to a spherical shape consistent with the radius of curvature of the inside of the retina. The electrical conductors on the curved surface should protrude slightly to form efficient electrodes.

The 2-D multiplexer array is similar to infrared focal plane array (IRFPA) multiplexers that are microelectronic devices fabricated at silicon foundries. An IRFPA multiplexer is a 2-D array that reads out the infrared (IR) image captured by a complimentary detector array that converts photons into electrical charge. The charge is integrated and stored in each unit cell for a few milliseconds. The full image is then multiplexed off the array at frame rates compatible with commercial video. For a retinal prosthesis test device that obtains its input image from an external camera, the process is essentially reversed and the device acts as a de-multiplexer. That is, the prosthesis devices will perform de-multiplexing operations, but will be referred to here simply as a multiplexer. The basic concept is straightforward: visual images can be produced in the brain by Inventor: Scribner PATENT APPLICATION

Serial No. PCT No. electrical stimulation of retinal cells. Two-dimensional arrays of retinal cells, such as ganglion or bipolar cells, can be stimulated using two-dimensional arrays of electrical impulses with the spatial form of an image. The axons of the ganglion cells then transmit the image through the optic nerve and on to the visual cortex. This is in lieu of the normal photo- transduction process that occurs in a healthy retina. In approximately 90 percent of blind patients, the photoreceptors are diseased, but the other retinal layers are still responsive to electrical stimulation.

Experimental test procedures, such as shown in Figure 2, use standard retinal surgical

techniques performed in an operating room environment by an ophtalmologist. It is necessary that the patient be administered local anesthesia rather than general anesthesia so that visual perceptions can be orally recorded during the procedure.

There are a number of technical issues to be addressed in designing and fabricating a retinal prosthesis device, particularly if the device is to generate a high resolution image. First, there is the issue of creating an electrical interface between the high-density electrode array and the curved surface of the retina. The electrode array must have a spherical, convexed shape in order to conform to the spherical concaved surface of the retina. The electrode array must be bio-compatible and safe for permanent implantation. Second, the electrical stimulation pulse shapes and repetition rates, while generally well known, may need to be optimized for each individual recipient of a prosthesis device. The pulse amplitude is of course modulated within the retina to be proportional to the pixel value. Third, direct electrical stimulation of the ganglion cells precludes certain image processing functions that Inventor: Scribner PATENT APPLICATION

Serial No. PCT No. normally would have occurred in earlier layers of the retina. Therefore, computationally

based image preprocessing operations may need to be performed on the image before

stimulation of the retina. Fourth, supplying power to a permanent implant will need to be

engineered in a manner such that there are no wires or cables through the eye wall. Fifth,

because a normal retina processes image information created by the photoreceptors in a

simultaneous manner, it is assumed that a prosthesis device should similarly excite retinal

cells in a simultaneous manner, as opposed to sequential raster scan that might cause

synchronicity problems downstream in the lateral geniculate nucleus (LGN) or visual cortex.

SUMMARY OF THE INVENTION An object of this invention is to provide a device for achieving a retinal prosthesis for

blind patients.

Another object of this invention is to provide a retinal prosthesis test device for

providing visual images to the brain during acute human experiments to achieve electrical

stimulation of the retina tissue.

Another object of this invention is to provide a device for implant into the human eye

that will allow electrical stimulation of the retinal or any neural tissue so as to provide visual

images to the brain.

These and other objects are accomplished by the retinal prosthesis test device and

retinal implant device comprising two basic technologies — nanochannel glass (NGC)

electrode arrays and infrared focal plane array (IRFPA) multiplexers. In the retinal prosthesis Inventor: Scribner PATENT APPLICATION

Serial No. PCT No. test device, the device is positioned against the retina using standard retinal surgical

techniques in an operating room environment. The device is comprised of a thin wafer of

glass (NGC) with very small channels perpendicular to the plane of the wafer. The channels

are filled with a good electrical conductor forming microwires with one surface of the glass

being ground to a spherical shape consistent with the radius of curvature of the inside of the

retina. Electrical conductors protrude slightly from the NGC on the curved surface to form

electrodes. The NGC is hybridized to a silicon IRFPA multiplexer using indium bump

bonds. An image is serially input into the multiplexer via a very narrow, flexible micro-

cable. The multiplexer is mounted on a ceramic carrier such that interconnecting bond pads

on each are in close proximity to one another. A video image is read into each of the unit cells on the multiplexer in pixel-by-pixel manner. Discrete samples of the analog video are

input and stored as electrical charge on a MOS capacitor. After all unit cells have been loaded

with the pixel values for the current frame, a biphasic pulse is sent through each unit cell and

into the corresponding area of the retina. The biphase pulse is modulated in proportion to the

pixel value stored therein. Because the biphasic pulse flows in parallel from a global external

connection, the adjacent retinal neurons are all stimulated simultaneously, analogous to image

photons stimulating photoreceptors in a normal retina.

A permanent retinal implant device uses an NGC array hybridized to a silicon chip in

an identical manner to the retinal prosthesis test device, however, the image is no longer

multiplexed onto the chip through a wire from an external camera, but instead, the image is

simultaneously generated within each cell through a photon-to-electron conversion using a Inventor: Scribner PATENT APPLICATION

Serial No. PCT No. silicon photodiode. The photons propagate directly into the backside of the device. Electrical power and any control signals are transmitted through an inductively driven coil or antenna on the chip. The device collects the charge in storage capacitors via the photon-to- electron conversion process, stimulates the neural tissue with biphasic pulses in proportion to the stored charges, and resets the storage capacitors to repeat the process.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure la shows a general diagram of a ray trace of photons incident on a retina

without a prosthesis device (a normal eye).

Figure lb shows an interior view of a ray trace of photons incident on a retina

without a prosthesis device (a normal eye).

Figure lc shows a general diagram of a ray trace of photons incident on a retina with

a prosthesis device ( prosthesis device positioned against the retina).

Figure Id shows an interior view of a ray trace of photons incident on a retina with a

prosthesis device (prosthesis device positioned against the retina). Figure 2 shows a retinal prosthesis test device positioned against a retina.

Figure 3a shows a side-view of a fully packaged retinal prosthesis test device.

Figure 3b shows an enlarged view of a nano-channel glass (NCG) electrode array.

Figure 4 shows a conceptual layout (floor plan) of a silicon chip for the retinal test

prosthesis. Figure 5 shows a conceptual design of a unit cell for the retinal prosthesis test device Inventor: Scribner PATENT APPLICATION

Serial No. PCT No. showing the external inputs from off-chip.

Figure 6 shows a block diagram of ancillary electronics for the retinal prosthesis test

device.

Figure 7 shows a side-view of a permanent implant device.

Figure 8 shows a conceptual design of a unit cell for a permanent implant device.

Figure 9 shows a conceptual layout (floor plan) of a silicon chip for a permanent

implant device.

DESCRIPTION OF THE PREFERRED EMBODIMENT

In the preferred embodiment of a retinal prosthesis test device utilizing a

microelectronic stimulator array 30, as shown in Figure 3a, the nanochannel glass (NGC)

electrode arrays 32 is hybridized to silicon multiplexer 34 using indium bump bonds, a

technique from infrared (IR) focal plane array (IRFPA) multiplexers. An image is serially

input onto the multiplexer 34 via a very narrow, flexible micro-cable 36. The micro-cable 36

is approximately six inches in length and is custom made using gold leads patterned on

polyimide strips. A ceramic carrier 38 with gold-filled via holes 42 provides a mechanically

convenient means of routing interconnects from the top-side 44 of the ceramic carrier to the

back-side 46. By designing the ceramic carrier such that the top-side contacts to the via-holes

44 are in close proximity to bond pads 48 on the silicon multiplexer 34, the interconnection

may be made with conventional tab-bonds 52 (thin gold ribbons fused to interconnects with

mechanical pressure as is common practice in the microelectronics industry and is well Inventor: Scribner PATENT APPLICATION

Serial No. PCT No. known to those skilled in the art. This keeps all of the interconnects 52 from protruding

above the spherical curved envelop defined by the polished NCG 32 and therefore prevents

damage to the tab bond interconnects 52 or to a patients retina 54. A critical issue for any

neural prosthesis device is biocompatibility and safety. Because the duration of any tests with

the retinal prosthesis test device 30 are very short (less than an hour), biocompatibility issues

are primarily reduced to acute effects of the testing and need not address the more difficult

chronic issues that arise with permanent implants. Note that the surface of the packaging

shown in Figure 3a consists only of glass 32 , platinum (Pt) electrodes 56 , and silicon

encapsulation 58. However, as with any medical instrumentation, a major safety issue is

electrical shock hazard. Note that the purpose of the device is to provide minimal electrical

stimulation of retinal tissue using very low voltages and the smallest current possible, i.e.,

preferably about one volt and 1 μA per unit cell for about 1 millisecond (every frame at a

frame rate of 60 Hz). To protect a patient from any electrical shock, the patient is isolate from

high voltages using optocouplers (not shown) which are powered by low voltage electrical

batteries (not shown), a technique well known to those skilled in the art.

Specific requirements for the NCG 32 are that the channels 56 making up the NCG

32, as shown in Figure 3b, be small enough so that many microwires can be connected to

each unit cell of the multiplexer array. This is for redundancy and to help simplify the

hybridization alignment. If the NCG wires were to approach the size of the unit cell, then a

one-to-one alignment and hybridization would be required. This would be very problematic,

because of irregularities in the NCG periodicity and the possibility of shorting nearest Inventor: Scribner PATENT APPLICATION

Serial No. PCT No. neighbor cells (not shown). On the other hand, very narrow channels 56 imply very high

length-to-width aspect ratios of the channels 56 in the NCG 32. This makes it difficult to

fabricate large area NCG 32 samples with the proper thickness. It is expected that a

reasonable design size for the channels 56 should be on the order of a micron.

The NCG channels 56 must be filled with a high conductivity material 62, such as

platinum, to create microwires. Fabrication of the microwires can be performed using

electrodeposition or infusion of molten metal under pressure, techniques that are well known

to those skilled in the art. After the channels 56 have been filled with conductive material

and the continuity of the microwires has been confirmed, one side of the glass 32 must be

polished to create a spherical surface 64. This is accomplished by carefully grinding and

polishing of the glass/metal composite. The radius of curvature is nominally half an inch in

order to provide a conformal fit against the inside of the retina 54. This is critically important

as it allows positioning of the high-density electrodes in the NCG 32 against the retinal 54

tissue. The polishing process will create slightly recessed microwires with respect to the

curved NCG 32 surface. This is because the metal is softer than the glass. Therefore further

processing may be necessary to create electrodes that protrude slightly above the curved

surface 64 of the NCG 32. In preparation for hybridizing the NCG 32 to the multiplexer 34,

or the microwires may be hybridized directly to the indium bumps 66 on the multiplexer 34

or the glass is etched so the microwires protrude slightly from the NCG 32. This is similar to

the manner used to form the protruding electrodes on the curved side 64 of the NCG 32.

A conceptual layout of the multiplexer 34 is shown in Figure 4. The silicon Inventor: Scribner PATENT APPLICATION

Serial No. PCT No. multiplexer 34 performs several operations in a sequential order. During the first step, an

image is read onto the multiplexer 34, pixel-by-pixel to each unit cell 72. The row shift

register 74 and column shift register76 control the routing into each unit cell 72. The discrete

samples of analog video are input and stored as charge on MOS capacitor. This operation

occurs every 60^th of a second in a manner compatible with a RS-170 television format

allowing the use of the test prosthesis 30 with standard video equipment. A multiplexer 34

that has a read-on and read-off capability has several input signals including a pixel clock,

start-of-frame clock, bias voltage, ground, and analog input (RS-170). A digital electronics

block 78 is of major importance because it generates switching pulses that routes image data

into the unit cells 72 by controlling the row shift register 74 and the column shift register 76..

Without the on-chip digital electronics 78, there might be a dozen or more clocks that would

need to be input to the device. That would make the cable 27 from external drive electronics

25 through the eye wall 29 (as shown in Figure 2) much larger and more cumbersome. The

use of IRFPA multiplexer technology greatly simplifies cable 27 problems through the eye

wall 29.

Referring again to Figure 4, after all the unit cells 72 have been loaded with the pixel

values for the current frame, the next step is to send a biphasic pulse to that unit cell 72

which in turn is modulated in proportion to the pixel value stored in each unit cell 72.

Because the biphasic pulse flows in parallel from a global external connection, the adjacent

retinal neurons are all stimulated simultaneously. This is an important feature of the design

because it is synchronistic action analogous to imaged photons stimulating photoreceptors in Inventor: Scribner PATENT APPLICATION

Serial No. PCT No. a normal retina. Finally, the electrodes are all connected to ground to prevent any possible

charge build up at the electrode-neuron interface.

There are several important consideration in designing a device that performs all these

operations successfully. First the multiplexer 32 operation should be designed with many of

the requirements that exist for an IRFPA, for example, good uniformity, low noise, and high

dynamic range. Of course, the retinal prosthesis test device 30 moves image data in the

opposite direction than an IRFPA multiplexer, that is, image data moves onto the device

rather than off the device, but otherwise the specifications are analogous. Figure 5 shows a

generic design for a unit cell 72. Note that the unit cell 72 stores the pixel value and then

uses it to modulate the biphasic pulse 82 that is input to the retinal tissue 54 through the NCG

32. Note that the biphasic pulse 82 and the image data 84 are both generated off-chip. This

allows for greater flexibility during human testing as any image sequence can be input and

combined with any shape of biphasic pulse 82. The switch 86 at the bottom of Figure 5

provides the capability to connect the retinal tissue 54 to ground 88 to avoid any possibility of

charge build-up.

Referring to Figure 6, the operation of the retinal prosthesis test device 30 during

acute experiments is controlled and powered by external ancillary electronics 25. The input

signal is an image sequence at data rates fast enough to achieve 60 frames per second. The

multiplexer 34 is designed to sample the multiplexed input signal in a manner compatible

with the RS-170 format. This allows the retinal prosthesis test device 30 to be interfaced

directly with any standard video camera. This includes the use of a computer which stores Inventor: Scribner PATENT APPLICATION

Serial No. PCT No. digital imagery and can display sequential fields at a 60 Hz rate (RS-170 interlaces two fields

per frame at a rate of 30 frames per second). The actual control of the microelectronic

multiplexer 34 is done with precisely timed pulses generated by a set of signal clocking

boards 96 in a manner similar to that used in typical IRFPA' s. The sync pulse generator 92 is

used to synchronize the RS-170 signal 91 with the clocking pulses 96. Basically, the sync

pulse generator 92 detects the beginning of each RS-170 field and then sends a corresponding

pulse to the drive electronics 94 that triggers the clocking signals 96 required to control each

field of the image data input to the multiplexer 34, synchronizaton of the pulses can be

monitored with an oscilloscope 93. The isolated breakout box 98 electrically isolates the

human subject from high voltage power supplies. The box 98 contains opto-couplers that

isolate the clock 96 and biphasic pulse signals 82 and low voltage batteries supplying bias

potentials 102.

The biphasic pulses 82 used to stimulate the retinal tissue 54 may be programmable

such that any pulse shapes can be tested. This has several important implications for the

development process. First, because the input impedance to the retinal tissue 54 has both a

resistive and capacitive reactance associated with it, a square wave voltage pulse will not

produce the desired square wave current pulse. Neurobiologists tend to favor square wave

current pulses to achieve efficient neural stimulation. With knowledge of the output

impedance at the electrode-retina interface, a voltage shape can be computed that will provide

a square wave current pulse, thus providing efficient stimulation. Second, there is evidence

that various layers of the retina 54 can be stimulated with different shaped pulses - probably Inventor: Scribner PATENT APPLICATION

Serial No. PCT No. because of their differing frequency responses. Specifically, it is expected that either the

ganglion or bipolar cells can be selectively stimulated. Stimulating the bipolar cells instead

of the ganglion cells has the advantage of reaching more deeply into the retina 54, allowing a

more natural form of stimulation.

Direct electrical stimulation of the ganglion cells precludes certain processing

functions that normally would have occurred in the earlier layers of the retina 54. Therefore,

it may be necessary to perform certain functions on the incoming imagery before stimulation

to compensate for the missing processing. Unfortunately, a detailed model of human retinal

functions has never been confirmed. Nevertheless, it has been shown that many intracellular

recordings from the retinas of rabbits are very similar in mammailian vertebra species in

general.

In another preferred embodiment, a permanent implant device 40, as shown in Figure

7, that is fully self-contained and responds to incident photons naturally imaged through the

lens of the eye, similar to that shown in Figures lc and Id, is taught. The device 40 is

surgically implanted in a patients eye and has with no external connections passing through

the eye wall. The basic design of this device 40 is based extensively on the retinal prosthesis

test device 30 taught above. Specifically, the permanent implant device 40 would use a NCG

array 102 hybridized to a silicon chip 104 in an identical manner to the retinal prosthesis test

device 30. However, the unit cell 106 circuitry is redesigned because the image is no longer

being multiplexed onto the chip through a cable from an external camera, but instead, the

image is simultaneously generated within each unit cell 106 through a photon-to-electron Inventor: Scribner PATENT APPLICATION

Serial No. PCT No. conversion using a silicon photodiode 108, as shown conceptually in Figure 8. The photons

112 propagate directly into each unit cell 106 because the silicon chip 104 is used in a back-

illuminated configuration — essentially the photons 112 enter through the backside of the

silicon chip 104.

Packaging the device 40, obviously, differs from that of the retinal prosthesis test

device 30. Packaging the permanent implant device 40 requires that the photons 112 be

allowed to pass through the backside of the device 40. This is a simple matter of eliminating

the ceramic carrier taught in the retina prosthesis test device 30. Thinning the silicon chip

104 is necessary because of the need for good quantum efficiency. The packaging scheme for

the permanent implant device 40 is shown in Figure 7. Note that the silicon chip 104 can be thinned to a few tens of microns so that the overall mass of the object is primarily that of the

NCG array 102 making it more amenable for surgical attachment to the retina 114.

It will be noted that there is no need for any multiplexing functions in the permanent

implant device 40, therefore the design of the chip 104 is much simpler. Also there are no

ancillary electronics, however, the silicon chip 104 significantly differs from that previously set forth, as shown in Figure 9. Although there are no multiplexing requirements, there are

two new requirements, Specifically, these are external power and command signals necessary to adjust the operation of the device 40. Transmitting power and signals onto the device 40

are implemented with an inductively driven coil or antenna 116. The major on-chip electronic

adjustments needed are control of bias supplies 118 and biphasic pulse generator 122 plus the Inventor: Scribner PATENT APPLICATION

Serial No. PCT No. standard digital electronics 124 that supply timing for the simultaneous operation of the unit

cell 106 sequences. Again the operation of the device 40 is to collect charge in the storage

capacitors of the unit cells. The on-chip power receiver 126 provides conditioned power to

operate all the on-chip electronics. The frame rate would be nominally 60 frames per second,

but because there is no longer a need to be compatible with the RS-170 format, the frame rate

could be adjusted to anything desired.

Packaging of the permanent implant device 40 is very demanding. Along with issues

of biocompatibility is the question of device lifetime. Permanent implants might need to operate for several decades. Similar requirements exist for other electronic implants such as

cardiac pacemakers and cochlear prosthetics. The encapsulation of the permanent implant

device 40 is easier in one respect than that of the retinal prosthesis test device 30 there are no

connecting cables to the device 40. In the case of the latter device 30, encapsulation was not

a critical issue because the duration of the experiments are typically less than one hour.

Cables connected to any neural prosthesis are subject to mechanical forces that over time can

damage seals and ultimately cause failures. Because the permanent implant device 40 is

completely wireless (no cable connections), simple encapsulation should be achievable with

high integrity.

The specific teachings of this approach to neural implants is a new intra ocular device,

and has several extremely important advantages over any device taught by the prior art. First,

the use of the NCG enables the creation of a curved surface allowing the positioning of the

electrodes in extremely close proximity to the retinal cells over a large area. NCG also allows Inventor: Scribner PATENT APPLICATION

Serial No. PCT No. the creation of very small electrodes (on the order of a micron) with very high densities

(thousands of electrodes per square millimeter). Regarding the multiplexer for the retinal prosthesis test device 30, as well as the unit cell size for the permanent implant device 40, the

unit cell size can be made as small as practical based on the latest microelectronic design rules. The multiplexer technology taught in the retinal prosthesis test device 30 uses only a small number of electrical leads through the eye wall while allowing a high data rate to the retina. In essence, this allows the input of image sequences to the retina, at high resolution and rapid frame rates. The electrical leads may be fabricated on a small and flexible microcable. This is critical to performing human experiments and testing. This is in comparison to directly coupling all stimulating electrodes to individual leads. For example, a simple 8 x 8 test array when directly coupled to input electronics outside the eye would

require 64 input leads. The cabling and accompanying connectors for such a device becomes

very cumbersome.

The devices taught here 30 and 40 basically solves the technical problems of an earlier concept envisioned by the research group at the Wilmer Ophthalmological Institute working with North Carolina State University (NCSU). An approach similar to NCSU is also under study by an MIT/Harvard team. Other efforts are proceeding in the United States, Germany and Japan that build on the basic idea of stimulating retinal cells with a small number of electrodes on a microelectronic chip. However, none of these approaches addresses the difficult issue of high-density electrodes in close proximity to the retina for achieving very Inventor: Scribner PATENT APPLICATION

Serial No. PCT No. high-resolution imagery.

A second approach is to stimulate the retina with a microelectronic chip from behind

the retina, either replacing the diseased photoreceptors or positioning the chip just behind

them.

A third approach is to skip the retina altogether and stimulate the visual center of the brain.

In this approach, an array, with penetrating microelectrodes is positioned against a visual

cortex. This involves invasive brain surgery through the cranium. From a surgical point of

view, the intra ocular approach is the least invasive.

Although this invention has been described in relation to an exemplary embodiment

thereof, it will be understood by those skilled in the art that still other variations and

modifications can be affected in the preferred embodiment without detracting from the scope

and spirit of the invention as described in the claims.