Human Visual System and Retinal Blindness•

• Retina is a light sensitive neural network

• Diseases such as Retinitis Pigmentosa (RP) and Age-related Macular Degeneration (AMD) primarily affect the photoreceptors, are both presently incurable, and render 100,000s blind each year

Webvision, Kolb, Fernandez, and Nelson, 2003.

Retinal Prosthesis - Epiretinal vs. Subretinal

EpiretinalLess disruptive to the retina.More flexibility in component placementMore complex stimulus algorithms required

SubretinalIn natural position of photoreceptorsDisruptive to retinaDevices relying on incident light for power cannot generate effective stimulus

State of the Art – Retinal Prostheses• Epiretinal and Subretinal at Investigational

Device Exemption Stage• Epiretinal - encouraging results, but better

technology required• Subretinal – No direct evidence demonstrating

functional electrical stimulation, but patients report subjective improvements in vision

Optobionics ASRTM Second Sight, Model ITM

Overview

Basics of Electrical Stimulation of NerveLimits on stimulating electrodes

Development of a Model 1 retinal prosthesisDisease targetsEarly clinical trialsPreclinical research to specify designClinical trial with implantable system

Future work

Electrical Stimulation of Nerve

Electrode-Retina Interface Design ParametersElectrode diameter.Electrode position.Stimulus waveform

Ganglion Cell LayerBipolar Cell Layer

Photoreceptor Layer

Stength Duration Curve

S1 - M2

0

100

200

300

400

500

600

0 2 4 6 8 10

ms

mic

roA

mps

Dose –Response Curve

M5, 6-27-02

0

2

4

6

8

10

12

0 100 200 300 400 500 600

pulse amplitude (uA)

Perc

eive

d Br

ight

ness

Is a retinal prosthesis feasible?

Electrical stimulation of globe in humans with RP can elicit flashes of light but….are any retinal cells left to stimulate? Or

does stimulation of the globe actually stimulate optic nerve?can focal perceptions be created? Or will

people see only flashes that make no sense?

Mean Cell Count from Post-Mortem RP Eyes

Intraocular Retinal Prosthesis Group © 2000

Group Age,y OuterNuclearLayer

InnerNuclearLayer

GanglionCell Layer

Moderate 73.56±11.19 12.91±17.59* 37.61±10.45 9.21±4.2*

Severe 76.17±8.89 2.33±2.95* 33.37±9.71* 5.72±4.13*

Normal 75.58±10.12 46.9±12.73 42.56±11.56 19.16±5.91

P (UsingF test ofVariance)

0.83 <0.01 0.08 <0.001

Ganglion Cell Layer

05

1015202530354045

-1500-1300-1100

-900-700-500-300-100 100 300 500 700 900110013001500

Eccentricity (µm)

Num

ber o

f Cel

ls

ControlGA

Inner Nuclear Layer

0

20

40

60

80

100

120

140

-1500-1300-1100

-900-700-500-300-100 100 300 500 700 900110013001500

Eccentricity (µm)

Num

ber o

f Cel

ls

ControlGA

Outer Nuclear Layer

0

10

20

30

40

50

60

70

-1500-1300-1100

-900-700-500-300-100 100 300 500 700 900110013001500

Eccentricity (µm)

Num

ber o

f Cel

ls

ControlGA

Condition of retina in RP

Cell counts indicate inner retina survivalMore recent studies of RP shows significant

alteration of retinal circuitry (Marc, 2003)Glial sheath between inner retina and subretinalspaceAnomalous rewiring and cell migration complicates transformation between image and stimulation pattern

Intraocular Retinal Prosthesis Group © 2000

Summary Data from Acute Trials

Intraocular Retinal Prosthesis Group © 2000

Charge (µC)ColorPerceptVisionConditionSubject

0.2WhiteFireflyLPRPJL

1.4WhiteBoxLPRPJT

1.2WhitePinLPRPHW

1.0YellowPinLPRPVO

2.4BluePinLPRPCS

0.3WhitePin20/400AMDAB

1.1WhitePinNLPRPBH

1.8YellowPinLPRPRJ

1.6YellowPinLPRPBC

2.8YellowPeaLPRPPS

6.0WhitePencilNLPAMDWG

3.2YellowPinLPRPRS

0.16YellowMatchheadNLPRPCC

0.95??LPRet-DegenAD

0.4Yellow-GreenLetterNLPRPHC

Electrical Stim in Normal Eyes

In eyes scheduled for removal (cancerous), artificial, focal photoreceptor loss created.Electrical stimulation in retina with

photoreceptors resulted in large, dark perceptionElectrical stimulation in retina without photoreceptors resulted in small, light percepts

Conclusions from Early Human Studies

Degeneration not uniform across retina, most severe in the photoreceptorsElectrical stimulation of retina in blind humans suggest retinal prosthesis possible:

Focal perceptsSpatial correlation between electrode position and percept location

Threshold stimulus current high: 600 uA for 1 ms on average.

Preclinical studies

Chronic implant studies to assess safety of implantation and stimulation, surgical attachment methodsIsolated retina studies to study stimulus thresholds

Chronic Stimulation

180 uA and 90 uA pulses applied, 8-10 hours/day, 60 pps.Histology shown from retina under electrode array after 60 days of stimulation over 4 months of implantation.Morphometric analysis underway on 3 normal and 3 RCD1 dogs that underwent 60-120 days of stimulation

Cortical Recording Methods

After completion of stimulation protocol, subdural electrode implanted.Synchronization of electrical stimulus with data acquisition system.100 averages, multi-channel stimulus.

EER elicited by retinal stimulator

-60

-40

-20

0

20

40

60

0 100 200 300 400 500 600

msec

mic

roV

olts A

BCD

Electrical stimulation of isolated retina

Measure threshold stimulus for retina ganglion cell responseCompare normal vs. diseased retinaJ.S. Shyu, M. Maia, T. O’Hearn

RecordingElectrodePair

1.5-2 mm

Optic Disc

StimulatingElectrodePair

RGC Axons

Isolated Retina: Electrode Position

Stimulating Multi-microelectrode Plate( MMEP)

retina

Recording electrodes

Stimulating Macroelectrodes

Isolated Retina: RGC responses

Electrical Stimulation and Induced Responserd Retina

-3

-2

-1

0

1

2

3

0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 11.0 12.0

Time (msec)

µVo

lts

cathodic(1mS)

interphase delay (3mS)

anodic(1mS)

measured response latency

Isolated Retina: Stimulus Thresholds

2.69 +/- 0.31 ms

2.11 +/- 0.43 ms

Stimulus Latency(P=0.0278)

111.2 uC/cm261.2 uC/cm2Charge Density

54.57+/-12.45 uA

30.04 +/-11.43 uA

Stimulus threshold(P=0.0597)

rdNormal

Results – Isolated Frog Retina

Stimulus Duration (msec)

0.01 0.10 1.00 10.00 100.00

Cur

rent

Thr

esho

ld (u

A)

10

100

1000

10000

Cadmium

Dark

Light

Summary from other studies

Humayun 200310-1000 nCPerceptionEpiretinal Blind Human, Chronic

Zrenner 200450 nCCortical responseSubretinal Stimulation, Normal Cat

Hesse 200014 nCCortical responseEpiretinal Stimulation, Normal Cat

Stett 19999 nCRGC responsesSubretina, isolated chick retina

Grumet 20002 nCRGC responsesEpiretinal, Isolated Normal Rabbit retina

Rizzo 2003300-500 nCPerceptionEpiretinal, Blind Human Acute

Humayun 1996600 nCPerceptionEpiretinal, Blind Human Acute

Lead AuthorThresholdDetection MethodModel

Conclusions from preclinical studies

Device can be safely implanted on the retinaElectrical stimulation up to 0.1 mC/cm2 does

not damage retinaStimulus thresholds in animal models 1 order of magnitude less than in humans

Prototype Human Retinal Prosthesis

Retinal Implant Surgery

OCTCan provide quantitative information about retina-implant interface.

ElectrophysiologySF VERs were non-recordable at every session. Sub-threshold EERs were non recordable when using lowest levels.

Electrophysiology

07/12/02

L7

L8

L5

L6

L4

L3

L2

M5

M7L1 M3

M6 M2

M1

M4M8 All at 10 cu-50 cu

-10 cu

baseline

Longitudinal Series – Baseline EER

N1-P14.49

N1-P16.05

N1-P18.78

7 electrod.base.-10cu691 µamp

(98.71)

8 electrod.1791 mamp

(223.87)

8 electrod.1111 µamp

(138.87)

Electrophysiology

03/12/02

06/19/02

07/09/02

HEC01 Spatial Map - Horizontal

M1M5

M6

M7

L5

L7

L1

L3

L2

L6

L4

L8

M2

M3

L6 L2

L1

L4

L3

M2

M4

M6

M8

M5 M1

M7 M3

L7

L5

L8

Patient Reported LocationsExpected Results based on Retinal Location

HEC01 Spatial Map - Vertical

M1M5

M6

M7

L5

L7

L1

L3

L2

L6

L4

L8

M2

M3L6 L2

L1

L4

L3

M2

M4

M6

M8

M5 M1

M7 M3

L7

L5

L8

Patient Reported LocationsExpected Results based on Retinal Location

Strength Duration CurvesS1 - M2

0

100

200

300

400

500

600

0 2 4 6 8 10

ms

mic

roA

mps

S1 - M5

020406080

100120140160

0 2 4 6 8 10

ms

mic

roA

mps

L2

0200400600800

1000

0 2 4 6 8 10ms

mic

ro A

mps

• Chronaxie 1-2 ms

Stimulus Thresholds

10 - 91CS

43 - 679YSL

28-949HEC

Threshold range, Day 1(in uA, 1 ms, biphasic pulse)

Subject

Response Thresholds

Computer Controlled TestingTest type HEC01 YSL02 CS03

Sequential activation

4AFC (25%) 16/24 (67%) 28/30 (93%) 20/40 (50%)

Form vision (Row vs. column)

2AFC (50%) 19/32 (59%) 29/30 (97%) 23/30 (77%)

Spatial Location 2AFC (50%) 79/109 (72%)

60/60 (100%) 40/60 (67%)

Object location

Object Recognition

Rows and Columns

Camera Tests

Camera still Test type HEC01 YSL02 CS03

Lights on/off 2AFC (50%) 10/10 (100%)

20/20 (100%)

9/10 (90%)

Moving directions

4AFC (25%) 4/8 (50%) 26/30 (87%) 12/30 (40%)

Camera Tests

19/30 (63%)22/30 (73%)5/10 (50%)4AFC (25%)L position

19/30 (63%)22/30 (80%)40/60 (67%)3AFC (33%)Objects recognition (plate, knife and cup)

31/40 (78%)34/40 (85%)23/30 (77%)4AFC (25%)Counting/finding objects (Ø, R, L, R+L)

23/30 (77%)30/30 (100%)9/10 (90%)3AFC (33%)Finding objects (Ø, R, L)

CS03YSL02HEC01Test TypeScanning

Multi-Pixel vs. Single Pixel

Camera set to either map a single pixel to all electrodes or to map individual pixels to individual electrodes12 cases (4 visual tasks x 3 subjects)

2 showed statistically higher accuracy with multi-pixel setting10 were not statistically different (5 better accuracy, 3 same, 2 worse)

Figure 8. Panel A. Height above the retina versus impedence. Panel B. Height above the retina versus threshold (on log axes). The shaded gray shows the amount of the height above the retina that can be attributed to the thickness of the electrode

S2aS2bS3

Height above retina (mm)

Impe

denc

e (kΩ

)

Height above retina (mm)0.2 0.5 1 1.5 20

10

20

30

40

50

60

0.2 0.5 1 1.5 25

1020

50

100200

5001000

Thre

shol

d (µ

Am

ps)

A. B.

Simulations of prosthetic vision

Cha, Horch, and Normann simulated pixelizedfoveal vision.

25x25 – easy mobility, 100 words/minute reading

Simulation of retinal implant16x16 macular pixels – 15 words/minute reading (Hayes, et al)10x10 face recognition above chance (Dagnelie, et al)32x32 80% face recognition (Dagnelie, et al)

Simulation of Prosthetic Vision

Retinal Prosthesis – Systems Level Description

External camera/image processor detects image and performs conversion to digital informationTelemetry link between external and implanted unitsImplanted unit recovers power and dataImplanted unit applies commanded stimulus patternto the retina via amicroelectrode array onthe surface of the retina

DOE Implants – PDMS electrode

Goal: To develop a PDMS substrate stimulating electrode Progress:

Four normal sighted dogs were implanted. Three of them have been followed for 3 months, 2 months and 1 month. Multilayer cable PDMS test devices were received and evaluated.

Implantation of LLNL device #4

Postoperative 1st month OCT imaging (horizontal scan)

Postoperative 1st month OCT imaging (vertical scan)

DOE Implants – PDMS Electrode

#2 LLNL dog, postoperative 2nd month, OCT imaging

#2 LLNL dog, postoperative 3rd month, OCT imaging

#3 LLNL dog, postoperative 1st month, OCT imaging

#3 LLNL dog, postoperative 2nd month, OCT imaging

DOE Implants – PDMS Electrode

DOE Implants – Spring arrayGoal: To develop silicon based electrode array with MEMS springs for z-axis alignment

Progress: Received two samples of PDMS frame without spring loaded electrodes

Plan: When spring devices received, perform acute and chronic experiments to assess mechanical interface and surgical biocompatibility

Retinal Implant – MEMS Component

microelectronics

electroplated or assembled electrodes

bulk micromachinedelectrode seats

surface micromachinedsprings(polymer) frame

flexible frame for attachment

micromachined electrode array (silicon substrate)

retina

posts for assembly and electrical interconnect

electrodes

flexibleinterconnecttack

antenna

inner-eyeelectronics

Conclusions

Current clinical trial has produced promising results

Low thresholds on some electrodesCorrelation with height from retinaSubjects can sense motion, recognize objects

Active research projects working towards higher density devices