WO2000056244A2 - Logarithmic light intensifier for use with photoreceptor-based implanted retinal prosthetics and those prosthetics - Google Patents
Logarithmic light intensifier for use with photoreceptor-based implanted retinal prosthetics and those prosthetics Download PDFInfo
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- WO2000056244A2 WO2000056244A2 PCT/US2000/005753 US0005753W WO0056244A2 WO 2000056244 A2 WO2000056244 A2 WO 2000056244A2 US 0005753 W US0005753 W US 0005753W WO 0056244 A2 WO0056244 A2 WO 0056244A2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
- A61N1/36046—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation of the eye
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F9/00—Methods or devices for treatment of the eyes; Devices for putting-in contact lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
- A61F9/08—Devices or methods enabling eye-patients to replace direct visual perception by another kind of perception
Definitions
- This invention relates generally to retinal prosthetics and more particularly to a method and apparatus for enhancing retinal prosthetic performance.
- This invention relates to directly modulating a beam of photons of sufficient energy onto retinal prosthetic implants of patients who have extreme vision impairment or blindness.
- a healthy eye is has photosensitive retinal cells (e.g. rods and cones) which react to specific wavelengths of light to trigger nerve impulses. Complex interconnections among the retinal nerves assemble these impulses which are carried through the optic nerve to the visual centers of the brain, where they are interpreted. Certain forms of visual impairment are primarily attributable to a malfunction of the photosensitive retinal cells. In such cases, sight may be enhanced by a retinal prosthesis implanted in a patient's eye. Michelson (U.S. Patent No.4, 628,933) and Chow (U.S. Patent Nos.
- 5,016,633; 5,397.350; 5,556,423) teach a retinal implant, or implants, of essentially photoreceptors facing out of the eye toward the pupil, each with an electrode which can stimulate a bipolar, or similar, cell with an electrical impulse.
- This bipolar cell is acted upon by the electrical stimulus, to send appropriate nerve impulses essentially through the optic nerve, to the brain.
- This invention is postulated as a necessary complement to this type of prosthesis, because the photoreceptors do not appear to be sensitive enough to the ordinary levels of light entering the eye in that not enough current is produced to sufficiently stimulate the retinal cells. Consequently, a light amplifier, or "helper" device would be needed. That device is the invention herein described, which also includes special characteristic implants.
- Fumess. et al. teach a "virtual retinal display”.
- U.S. Patent No. 5,659.327. where "The virtual retinal display...utilizes photon generation and manipulation to create a panoramic, high resolution, color virtual image that is projected directly onto the retina of the eye...there being no real or aerial image that is viewed via a mirror or optics.”
- Richard, et al. teach, U.S. Patent No. 5.369,415.
- * '...a direct retinal scan display including the steps of providing a directed beam of light, modulating the beam of light to impress video information onto the beam of light, deflecting the beam in two orthogonal directions, providing a planar imager including an input for receiving a beam of light into the eye of an operator which involves a redirection diffractive optical element for creating a virtual image from the beam of light on the retina of the eye, and directing the beam of light scanned in two orthogonal directions and modulated into the input of the planar imager and the output of the planar imager into the eye of an operator.” Sighted individuals can use these devices above for their intended uses.
- retinal threshold damage is 0.4 Joules per square centimeter.
- the present invention is directed to a method and apparatus for providing enhanced retinal prosthetic performance. More particularly, the invention is directed to a light amplifier and electrical circuitry for driving an implanted retinal prosthesis to maximize electrical stimulation of the retinal nerves or cells, while avoiding damage thereto. The invention is also directed to improved implanted retinal prostheses, which maximize the advantages of the light amplifier.
- light reflected from a viewed image i.e.. input image
- a light amplifier to produce an output image which is applied to the photoreceptor array of a retinal prosthesis.
- the gain (or "transfer function " ) of the light amplifier enables the photoreceptor array to drive output electrodes for producing retinal e impulses ot sufficient magnitude to enhance perceived sight
- the light amplifier preferably compresses the range of light intensity, e g . logarithmically, to enable maximum light amplification without overdm mg the prosthetic photoreceptors
- the electrical stimulation of the retinal nerves is preferably pulsed, 1 e . periodically interrupted to avoid any damage attributable to peak magnitude electrical signals Pe ⁇ odic interruption can be implemented mechanically by a shutter periodically interrupting the light incident on the photoreceptor array and/or electrically via an approp ⁇ ate wave shaping circuit
- the implanted prosthetic's electrodes generate a sequence of positive and negative pulses to avoid producing a net charge in the eye
- Successive pulses are preferably spaced m time by an interval ⁇ t
- a single wavelength is relied upon to activate a combined photodetector-electronics-electrode implanted unit which then produces a negative pulse, followed by a time delay, followed by a positive pulse
- a photoreceptor implanted in the eye acts to produce an electrical stimulation with an equal amount of positive and negative charge
- a single light wavelength is received by the photoreceptor That single wavelength
- This second set of photoreceptors is connected so that the stimulation of the attached, oi associated, electrodes results in a positive pulse
- the net charge introduced into the retinal cells must balance So the positive charge introduced by the positive pulse must equal the negative charge introduced by the negative pulse.
- the shutter cuts in and stops light transmission.
- An aspect of the second embodiment is using an electro-optic, electronic or mechanical shutter to provide a period of no electrical stimulation to the retinal cells targeted for elect ⁇ cal stimulation.
- a third embodiment which is a cross, so to speak, between the first and second embodiments two different wavelengths and two different types of
- each responsive to a corresponding wavelength are used in this embodiment, one wavelength is used to pump in a high constant level of light to supply power to the electronics component
- the other wavelength is used to send m information via amplitude, frequency, phase, pulse-width modulation, or combinations thereof.
- the stimulation pulse from the electronics to the electrode to the retinal cell is generated m
- a fourth embodiment is that of the logarithmic light amplifier itself, without any special implantable photoreceptors. This last embodiment may require a low duty cycle when used with photoreceptors connected to a diode without any electronics It
- oxidizable electrode 25 may be able to rely sufficiently upon the intrinsic capacitance of an oxidizable electrode, which acquires capacitance with the buildup of an insulating oxidized layer toward the lonizable fluid present in the eye as vitreous fluid, or fluid directly associated with the eye
- An image receiver with a first convener for the image converts the image into
- An aspect of the embodiments of the inv ention is that an amplified electrical signal is converted by a second conv erter into a photon-based display, the photons of this display entei an eye through the pupil of the eye Moreov ei . while the embodiments ol the logarithmic ampli fier inv ention hav e sufficient output light power, advantageouslv . the output light lev el still remains at a safe lev el
- This aspect of the invention corresponds to aspects of the action of the ins, as w ell as the biochemistry of retinal cells, in the human eve in making possible sight over many oiders of magnitude of ambient b ⁇ ghtness
- An aspect of the embodiments of the invention is incorporation of both optical and electronic magnification of the image, as for example, the incorporation of an optical zoom lens, as well as electronic magnification Consequently, it is feasible to focus in on items of particular interest or necessity With proper adjustment, proper threshold amplitudes of apparent b ⁇ ghtness would obtain, as well as comfortable maximum thresholds of apparent brightness Therefore, to adjust for these, an adjustment aspect is incorporated in each embodiment, such that proper adjustment for the threshold amplitudes and maximum comfortable thresholds are made
- Another aspect of the invention which may be incorporated in all embodiments, is oriented toward making color vision available, at least to a degree
- individual stimulation sites e g , retinal cells generally, bipolar cells specifically
- the color of selected pixels of the viewed scene is correlated with a specific photoreceptor-electronics-electrode units located so as to electncally stimulate a specific type of bipolar cell to provide the perception of color vision
- the logarithmic light amplifier also incorporates within itself, a data processmg unit which, semi-autonomously. cycles through the various photodetector-electrode and combinations thereof, inteirogates the patient as to what the patient sees, the patient then supplies the answers, setting up proper apparent brightness, proper apparent color and proper perception
- This setup mode is done by the use of a keyboard, display, and auxiliary processor, which are plugged into the data processing unit of the logarithmic light amplifier during the setup proceduie
- a scanning laser feedback is provided in different embodiments of the invention to keep the scanner laser scanning the correct locations
- An imaging of the reflected scanning laser reflected back from the retinal implant is used to provide real-time feedback information, utilizing a second imager v iew ing into the eye and a data processor unit tied into the scanning laser scan control unit BRIEF DESCRIPTION OF THE DRAWINGS
- Figure 1 shows the logarithmic light amplifier with shutter, showing the incoming scene or view photons on the right and the eye on the left;
- Figure 2a shows a laser being modulated by a video signal and scanning the full extent of the implanted retinal prosthesis
- Figure 2b shows a photoreceptor. associated electronics, and an associated electrode
- Figure 2c shows the apparatus of Figure 2b but in a more rounded, smoother packaged form, likely more amenable for implantation into the eye;
- Figure 3 depicts tuned photodetectors on an implanted retinal prosthesis;
- Figure 4 shows a sample waveform possible with the apparatus shown in Figure
- Figure 5 shows two different wavelengths, one to send in power, the other to send in information, to a single unit with two differently sensitive photoreceptors, one electronics package and one electrode;
- Figure 6 summarizes three embodiments as shown previously;
- Figure 7 shows the external logarithmic amplifier (as “glasses”), a portable computer with mouse and joystick as setup aids;
- Figure 8 shows an implant unit (old in the art) with a photoreceptor and an electrode
- Figure 9a shows a light-electronic feedback loop for knowing location on implant being scanned
- Figure 9b shows one of different possible fiduciary markings including here points and lines for aiding knowing location on implant being scanned.
- This inv ention provides amplified light for artificial photoreceptors implanted in the eye of a patient who has lost the use of his/her normal photoreceptor retinal cells
- the purpose of this amplified light is to effectively stimulate the artificial photoreceptors
- the artificial photoreceptors provide electrical stimulation through associated electrodes, usually via some electronics, to retinal cells, which are normally stimulated by living retinal photoreceptors such as cones and rods.
- the retinal cells which get electncally stimulated by vvay of the artificial photoreceptors, are typically bipolar cells This stimulation to these non-photoreceptor retinal cells allows the patient to have at least some perception of what a normal eye would see
- light is fed to the photoreceptor-electrode stimulators m the following ways Four preferred embodiments are descnbed
- a single wavelength is relied upon to activate a combined photodetector-electronics-electrode implanted unit which then produces a negative pulse, followed by a time delay, followed by a negative pulse
- a photoreceptor implanted m the eye acts to produce an electncal stimulation with an equal amount of positive and negative charge
- a single light wavelength is received by the photoreceptor.
- the photoreceptor activates an electrode with associated electronics
- the electronics produces a negative pulse followed by a time delay followed by a positiv e pulse
- a net charge of zero is introduced into the eye by the electrode-originating electncal pulses
- the preferred delay time is in the range 0 1 millisecond to 10 milliseconds, with the delay time of 2 milliseconds is most prefened
- an image receiver with a first converter for the image com erts the image into electrical signals
- the signals are amplified, basically logarithmically, so as to provide brightness compression toi the patient
- the amplified electrical signal is conv erted by a second conv erter into a photon-based display, w herein said photons of said display enter an eye through a pupil of said eye
- Photons ( 102) from a v le ed scene ( not shown ) enter the logarithmic amplifier ( 1000) bv w av of the lens ( 101 )
- the light amplifier ( 1000) has an image receiv er ( 1 ).
- the imager ( 1 ) is a type of video camera, the image recei er and conv ersion to electrical signals may occur in a package (old in the art)
- a display (7) that is a source of photons such as a laser (coherent light source) (7), or a non-coherent source such as colored LEDs (7) or a plasma display (7), is used to send photons directly to an implant near the retina
- These displays (7) are made very b ⁇ ght, but not such as to impact negativ elv on the ey e
- the patient has sufficient retinal degeneration so as to be unable to see without the aid of a retinal prosthetic
- the display (photon source) is a laser (7), that laser is scanned over the implanted photodetector-electro cs-electrode array ( Figure 2, (8) in accordance with the scene being displayed to the eye
- a scanning laser is a laser with scanning means (old in the art)
- the video signal (6) is applied to a scanning laser (7), a scanning laser being a laser with scanning means (old in the art)
- the scanning laser (7) is scanned over the retinal prosthesis m a square or rectangular pattern or m a raster pattern with an exact fit to the prosthesis (8)
- the v ideo signal (6) supplies amplitude from the data processor ( Figure 1 , (2)), and if desired (see Figure 1 ), color information, of the scene being viewed, from the individual color amplifiers (3) to the laser (7), which information is used to modulate the laser
- the light amplifier ( 1000) is a loga ⁇ thmic amplifier.
- the amplifier amplifies according to a different function than the logarithmic function or a modified logarithmic function, for example, an algebraic function such as a polynomial function multiplied bv the logarithmic function
- the imager or camera lens is sho n schematically as ( 101 )
- the signal is loga ⁇ thmicallv amplified as a w hole at the electronic processor (2), or the individual RGB (led, green, blue) or RGBY (red. gieen.
- This feature includes shifting the wavelength toward oi to the near infrared 01 toward or to the near ultraviolet, according to what is needed to optimize the response of the implanted photosensitive elements Consequently, a mapping of the incoming image data to an appropriate output is possible
- This mapping could be complex, for example, producing b ⁇ hasic waveforms as shown Figure 4 by appropriate timing of two lasers operating at different wavelengths and photosensitive elements uniquely sensitive to these wavelengths
- individual RGB (red, green, blue) or RGBY (red, green, blue, yellow) color components are amplified separately (3), or amplified together (2) and separated out (3) after the amplification
- These color components may be used to stimulate particular photosensitive elements of the retinal ⁇ mplant(s) For example, a cell (“blue-sensation") producing a sensation of blue color is stimulated when the scene being transmitted to the eye has blue, which in the projected (into the eye) scene would have blue in the vicinity of that
- the loganthmic amplification is necessary to compress the range of onginal b ⁇ ghtness
- the normal eye does this automatically of closing down the pupil size, squinting and employing other electrochemical cellular mechanisms
- This light amplifier accomplishes this necessary task by electronic loganthmic light amplification
- the light amplifier also includes an adjustable transformer or magnification of image size
- a shutter or electronically turning the scanning laser on and off are not a necessary part of this embodiment
- two or more wavelengths are used to communicate light energy to the eye to allow balanced biphasic stimulation with no net charge injection into the eye
- a first wavelength is used to stimulate a first set of photoreceptors
- These photoreceptors are connected so that the stimulation of the attached, or associated, electrodes results in a negative pulse
- This negative pulse provides retinal cell stimulation
- the shutter cuts in and stops light transmission to the eye
- the time of this light interruption is prefe ⁇ ed in the range 0 1 millisecond to 10 milliseconds, with the time of 2 milliseconds most preferred
- the retinal cell is in a rest and recov ery state so that it returns, electrically to the state it was in prior to stimulation by the first particular wavelength of light ⁇ second wavelength of light then stimulates a second set of photoi eceptors w hich ate sensiti e to that wavelength of light; while the first set of photoreceptors are not affected.
- This second set of photoreceptors is connected so that the stimulation of the attached, or associated, electrodes results in a positive pulse.
- the net charge introduced into the retinal cells must balance, or equal, the net charge introduced by the negative pulse.
- the shutter cuts in and stops light transmission. Again, the retinal cells rest and recover and the process repeats.
- FIG 3 A two scanning lasers, (9) and (10), are supplied with video signals, with each laser operating at a different wavelength.
- two or more photoreceptors ( 13), ( 14) are on the implant.
- the two types of photoreceptors (13), (14), are tuned to different frequencies of light, each of the frequencies being that of one of the emitting frequencies of the external lasers (9), (10).
- Figure 3B shows two incoming frequencies of light, (301 ) and (302).
- the light sources for the dual light frequencies (301), (302) is a unit (304) which is downstream in the information flow from the imager ( Figure 1 , ( 101 ), (1), (103)) and amplifiers ( Figure 1 , (2), (3)).
- the final output from the amplification stages is connected electrically or electromagnetically to the dual light frequency sources (304), in particular, dual scanning lasers operating with different wavelengths of light output.
- Pairs (303) of different frequency (i.e., wavelength) photoreceptors are placed on the eye-implant, each pair associated with an electrode (not shown).
- the two types of photoreceptors e.g., photodiodes
- Figure 4 the biphasic current at each electrode (not shown). Initially the rest state appears (40). Next, one of the photoreceptors (13) has been activated by its corcesponding laser (9). The current amplitude is negative. (41).
- a shutter (4) is part of the second embodiment.
- the shutter ( Figure 1. (4)) is of a mechanical design (old in the art), or an electronic shutter (4) (old in the art) or an electro-optical shutter (4) (old in the art).
- the shutter (4) cuts off light from the logarithmic light amplifier ( 1000) to the pupil ( 105) of the eye (5). This decreases the total time that light strikes the photoreceptors ( Figure 3a. ( 13) ( 14)) ( Figure 3b.
- a third embodiment that is a cross, so to speak, between the first and second embodiments uses two different wavelengths and two different types of diodes, each responsive to a corresponding wavelength
- one wavelength is used to pump in a high constant level of light to supply power to the electronics component
- the other wavelength is used to send in information via amplitude, frequency, phase, pulse-width modulation, or combinations thereof
- the stimulation pulse from the electronics to the electrode to the retinal cell is generated in a fashion similar to the pulses generated in the first embodiment, with a single wavelength
- the third embodiment uses two different wavelengths and two different types of diodes, each responsive to a corcesponding wavelength (See Figure 3b (301 ), (302))
- one wavelength ( Figure 5, (501 )) is used to pump in a high constant level of light to supply power to the electronics component (502)
- the other wavelength (503) is used to send in information via amplitude, frequency, phase, pulse- width modulation or combinations thereof to the electronics component (502)
- the stimulation pulse from the electronics (502) to the electrode (504) to the retinal cell is generated in a fashion similar to the pulses generated in the first embodiment, with a single wavelength
- theie is one w avelength (601 ) input to a single diode (602) ith electronics (603) and electrode (604)
- Eithei digitallv or bv analogue means old in the art a d c signal occurring after the absorption of photons by the photoreceptoi is converted by the electronics to a signal (600) of the type shown in Figure 4.
- a signal 600 of the type shown in Figure 4.
- the electrode for two diffei ent w avelengths (610), (61 1 ), both carrying pow er and information impinging on two different photoreceptors (612), (613).
- the electionics (6033), digital oi analogue again produce the waveform (600) of Figure 4 at the electrode (604)
- the third embodiment for two different photoreceptors (620). (621 ). the first receiving a steady state power wavelength (622). the second receiving a signal wav elength (623), the electronics (6034). digital or analogue, produces the signal (600) of Figure 4 at the electrode (604)
- the electronic circuitry of (603), (6033) and (6034) may be different
- a fourth embodiment is that of the logarithmic light amplifier (1000) itself, without any special implantable photoreceptors
- This last embodiment may require a low duty cycle w hen used with photoreceptors ( Figure 8, (81 )) connected to an electrode (82) ithout any electronics It relies upon the intrinsic capacitance of an oxidizable electrode, which acquires capacitance with the buildup of an insulating oxidized layer toward the lonizable fluid present in the eye as vitreous fluid, or fluid directly associated with the eye
- the addition of a shutter ( Figure 1 , (4)) with an off time of from 0 5 ms to 10 ms, most preferably 2 ms provides a mechanism to provide that off time ( Figure 4, (47), (48))
- the time each laser is on can be controlled by electronic means (old in the art) within the laser to provide equal positive pulses and negative pulses, I e , equal with respect to total signed charge introduced into a retinal cell
- the first and second sets of embodiments may be completely or partially coincident
- Another aspect of all of the embodiments is incorporation of both optical and electronic magnification of the image, as for example, the incorporation of an optical zoom lens, as w ell as electronic magnification
- Optical magnification of the image is accomplished by use of a zoom lens for the camera lens ( 101 )
- Electronic magnification is accomplished electronically in an electronic data processing unit (2) or (3) Consequentlv.
- the logarithmic amplifier also incorporates within itself, a data processing unit which cycles electncal pulses of varying amplitude and/or frequency and/or phase and/or pulse width through the vanous photodetector-electrodes and spatial combinations thereof, and, interrogates the patient, who then supplies the answers, setting up proper apparent brightness and apparent color
- a plug m accessory data processor (Figure 7, (71 )) with display (72) and data input device or devices such as a keyboard (73), mouse (74), or joystick (75)
- Figure 7 show the plug in unit (71 ) which plugs (76) into the loganthmic light amplifier (1000) to provide additional data processing ability as well as expanded data input and data display capability
- FIG. 9a An imaging ( Figure 9a) of the retinal implant from the reflected (92) incoming scanning laser beam (91 ), see Figure 9a, (7), ( Figure l and Figure 2a, (7)), ( Figure 3a, (9,), ( 10)) reflected back from the retinal implant ( Figure 9, (8)) can be used to provide real-time feedback information, utilizing a second imager (93) viewing into the eye (5) and a data processor unit (94) tied into the scanning laser's scan control unit (95)
- Figure 9b utilizes multiple fiduciary reflectiv e or light absorptive points (96) and/or lines ( 97) on the retinal implant (8) such that the frequency and signal pattern, mote genei allv. (98). (99) ( 100) of the high reflectivity from these reflectiv e, or absorptive lines/point for a given rate of scanning by the scanning laser (7) can be used to correct the scanning direction from the different frequency patterns, some indicating correct scanning, others indicating an incorrect scanning.
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Abstract
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Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2000606153A JP4384363B2 (en) | 1999-03-24 | 2000-03-03 | Logarithmic photomultiplier for use with a photoreceptor-based transplanted retinal prosthesis and the prosthesis |
AU38671/00A AU780183B2 (en) | 1999-03-24 | 2000-03-03 | Logarithmic light intensifier for use with photoreceptor-based implanted retinal prosthetics and those prosthetics |
DE60034678T DE60034678T2 (en) | 1999-03-24 | 2000-03-03 | LOGARITHMIC LIGHT AMPLIFIERS FOR USE WITH PHOTORE-CASE BASED IMPLANTED RETINAL PROSTHESIS |
EP00917743A EP1194083B1 (en) | 1999-03-24 | 2000-03-03 | Logarithmic light intensifier for use with photoreceptor-based implanted retinal prosthetics and those prosthetics |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12587499P | 1999-03-24 | 1999-03-24 | |
US60/125,875 | 1999-03-24 |
Publications (2)
Publication Number | Publication Date |
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WO2000056244A2 true WO2000056244A2 (en) | 2000-09-28 |
WO2000056244A3 WO2000056244A3 (en) | 2002-01-24 |
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PCT/US2000/005753 WO2000056244A2 (en) | 1999-03-24 | 2000-03-03 | Logarithmic light intensifier for use with photoreceptor-based implanted retinal prosthetics and those prosthetics |
Country Status (7)
Country | Link |
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US (4) | US6507758B1 (en) |
EP (1) | EP1194083B1 (en) |
JP (1) | JP4384363B2 (en) |
AT (1) | ATE361041T1 (en) |
AU (1) | AU780183B2 (en) |
DE (1) | DE60034678T2 (en) |
WO (1) | WO2000056244A2 (en) |
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Also Published As
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US20090204212A1 (en) | 2009-08-13 |
ATE361041T1 (en) | 2007-05-15 |
EP1194083B1 (en) | 2007-05-02 |
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JP2002538936A (en) | 2002-11-19 |
US20030181957A1 (en) | 2003-09-25 |
US7539544B2 (en) | 2009-05-26 |
WO2000056244A3 (en) | 2002-01-24 |
US7133724B2 (en) | 2006-11-07 |
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EP1194083A4 (en) | 2005-02-02 |
US6507758B1 (en) | 2003-01-14 |
US8046078B2 (en) | 2011-10-25 |
EP1194083A2 (en) | 2002-04-10 |
US20070016294A1 (en) | 2007-01-18 |
JP4384363B2 (en) | 2009-12-16 |
AU3867100A (en) | 2000-10-09 |
DE60034678D1 (en) | 2007-06-14 |
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