1 Eye-spots Bipolar cell Epithelial invaginated eye Octopus

2 compound eye Fish

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4 Anatomy of Eye Eye vs. Camera cornea lens iris iris lens lens sclera box retina film brain DP&E

5 Diagnosis & Treatment Diagnosis Treatment Symptom SignManifested Incipient Sign Structural; metamorphosis, dismorphysm, neoplasm Functional change; mechanical, neuronal Treatment Medication; various ‘anti-’s, neurotransmitters, enzymes,... Surgery; reconstruction, destruction, removal, ‘-plantation’ Genetic approach

6 Refractive system Cornea Aqueous Humor Pupil Lens Vitreous HumorRefractive surface 1st: cornea - refracts light the most (about 80% - 43D) 2nd: anterior surface of the lens 3rd: posterior surface of the lens

7 Focusing for Close VisionAccommodation contraction of the ciliary muscles releases tension in the suspensory ligaments and allows the lens to elastically recoil and bulge out on both of its sides

8 Focusing for Close VisionPupillary Constriction contraction of the circular muscles of the iris causes the pupil to constrict, reducing the amount of light entering the eye, increasing the clarity of the image

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11 Focusing for Close VisionConvergence medial rotation of the eyeballs by the medial rectus muscles directs the eyeballs toward the object being viewed

12 Stereoscopic vision Monocular clue Binocular clue HoropterMotion parallax Perspective Focus Occlusion Peripheral vision Binocular clue Retinal disparity Accommodation Convergence Horopter

13 Cornea Cornea covers the anterior portion of the eyeball (1/6th)transparent, avascular, allowing light to enter the eye Only tissue of the body that does not risk rejection by the recipient when transplanted from one person to another The cornea is supplied with many pain receptors (nerve endings)

14 Lens avascular, transparent, biconvex, flexiblealways increasing in size with age as new fibers are added to it so that it becomes denser and less elastic, and more convex so that it becomes less able to focus light properly

15 Retina Pigment epithelium(RPE): supporter Layer of photoreceptor cellsphotopigment regeneration, blood supply dark with melanin, decreasing light scatter Layer of photoreceptor cells outer segments and inner segments of rod /cone Outer limiting membrane Outer Nuclear Layer (ONL) cell bodies of rods & cones Outer Plexiform Layer (OPL) rod and cone axons/ horizontal cell dendrites/ bipolar dendrites Inner Nuclear Layer (INL) Nuclei of horizontal, bipolar and amacrine cells Inner Plexiform Layer (IPL) axons of bipolars (and amacrines)/ dendrites of ganglion cells Layer of Ganglion cells (GCL) nuclei of the ganglion cells / displaced amacrine cells Layer of optic nerve fibers fibers from ganglion cells traversing the retina to leave the eyeball at the optic disc Internal limiting membrane

16 Major diseases and treatmentartificial cornea ? disease; corneal burn, scar, perforation, etc penetrating keratoplasty (PKP), keratoprosthesis, cultured cornea artificial iris ? disease; iniridia, iridodialysis, etc iris contact lens, iris IOL artificial lens ? disease; cataract, aphakia, etc various intraocular lens (IOL) artificial retina ? retinitis pigmentosa (RP); 1/4000 in normal population age-related macular degeneration (AMD); 1/20 in over 65

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19 Treatment modalities Laser machine Phacoemusifier for cataract surgeryVitrectomy machine for retina surgery Operation microscope Microsurgical units

20 The failure comes from... Inconvenience to usertechnicians are not experts ophthalmologists are not technicians Inconvenience to patient patients are impatient How long can you keep your eyes without blinking? How much light can you tolerate? How much pain can you tolerate? Other chores stability durability reproducibility biocompatibility

21 Neuron Respond to environmental change (stimuli) by altering electrical potential differences (action potential). Motor / Sensory / Interneuron Synapse presynaptic membrane (axon terminal); contains synaptic vesicle postsynaptic membrane ; contains receptors neurotransmitter; acetylcholine, norepinephrine, epinephrine, glutamine, substance P, etc. gap junction by ion channel

22 Normal Vision viewing angle: 140 degree resolution: 1 arcminphotoreceptor : ganglion cell = 1:1(fovea) to 300:1(periphery) intensity shift by a factor of 108 spectroscopy by 3 different pigments rapid change and edge detector spatial depth difference by binocular vision

23 Visual pathway Sensory neuron; photoreceptor 1st order; bipolar cellCone; color discrimination Rod; scotopic vision 1st order; bipolar cell 2nd order; ganglion cell Interneurons horizontal cell amacrine cell

24 Contrast Information Convergence and Receptive Fieldsindividual receptors do not have private lines up to the visual cortex multiple receptors converge onto single higher order neurons on their way to the higher visual centers Border information begins within the retina itself result of specialized arrangements of interneurons into center -surround ganglion cell receptive fields

25 Center-Surround Receptive FieldBipolar cells(BC) center of the receptive field receive input from the photoreceptors feed excitatory input onto GC peripheral regions of the receptive field feel excitatory information onto inhibitory cells pass the inhibitory information to GC Ganglion cell(GC) "on-center, off-surround“: center is illuminated exclusively a large amount of stimulation to GC, and no inhibition “on-center, on-surround”: whole field were stimulated peripheral inhibitory influences would come into play

26 Interaction with brainVisual field; split in half and cross over Optic nerve  LGN  primary visual(striate) cortex Self-organization of the cortex: learning, organizing, testing Artificial Neural Network: associative memory, task assignment problem, back propagation Various "household chores" associated with vision saccadic motion and compensation for it the control of lens opening (pupillary reflex) distance accommodation binocular convergence

27 Visual pathway Course of axons of 2nd order neurons; Optic nerve - optic chiasm - optic tract 3rd order; lateral geniculate body (LGN) Course of axons of 3rd order neurons; geniculocalcarine tract (optic radiation) Visual cortex (area 17) Visual association area cortex (area 18,19)

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32 Visual Cortex Brain Crossover 4 layersbuilt-in memory + learned memory recognition of pattern moving object; hop the split gap in hemispheres Crossover crossover by lens + crossover by optic nerve: left half of an object in left hemisphere match the crossover of the eye lenses afferent; R-body  L-hemisphere efferent; L-hemisphere  R-body 4 layers complex(C), simple(S), geniculate(G) separation into R & L layers "ocular dominance” repeat in every millimeter repeat in front-to-back direction 50,000 neurons/mm3  600,000 neurons/12mm3

33 Visual Cortex Surface area of visual cortex105neurons/mm2  150x106neurons/15cm2 mainly in fovea; 150,000cones  1000neurons/cone Processing in primary visual cortex mainly orientation response: direction of edge and line of visual images fires when edge of particular orientation enters all possible orientation; short line(9 neurons long) Dissection and reconstruction of visual image face recognition dissection of smaller pieces of eyes, ears,nose see eyes, ears,nose  complete face  grandmother all in a fraction of second

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35 Diagnostic tools Subjective measurement Optical systemsvisual acuity, glare meter, contrast sensitivity, color test Optical systems Measuring cornea, anterior chamber, lens, vitreous to retina slit lamp photography, keratometry, aberrometry, topography, pupillography, tonometry, optical coherent tomography Radiological systems Orbit CT, MRI, Ultrasonography Electrophysiological systems EOG, ERG, pattern ERG, multifocal ERG, multifocal VEP, VEP

36 Electrooculogram Test of integrity of RPE & overlying photoreceptorarise from a depolarization of basal membrane of RPE measure voltage between the cornea (+) & RPE (-), i.e. change in potential caused by swinging movement of eye VEOG = VOsinθ clinical use Best’s vitelliform macular degeneration retinitis pigmentosa drug toxicity

37 Electrooculogram Signal acquisition InterpretationGain; 103 (~mV range) bandpass filter; Hz AgCl electrode ±30º saccade, 72cycle/min dark / light adaptation Interpretation Arden ratio = light peak / dark trough (normal; 180%) Gliem ratio = light peak / dark-adapted baseline drawback; takes more than 30 min

38 Electroretinogram Record response of retina to lightSignal acquisition Gain; 106 (~μV range) band filter; Hz light Ganzfeld +100D lens diffuser clinical use photoreceptor / inner retinal damage objective measurement of retinal function

39 Electroretinogram Source of waveform a wave; photoreceptorb wave; Müller cell c wave; RPE cell? oscillatory potential; bipolar cell

40 Electroretinogram 5 ISCEV standard recording“rod response”, in the dark-adapted eye maximal combined response in the dark adapted eye; rod + cone response oscillatory potentials; bipolar / amacrine response “Cone response”, in the light-adapted eye 30Hz flicker responses; R/G/B cone discrimination, full excitation of cone

41 Electroretinogram Comparison of electrodes Type Advantages Disadvantages DTL - cost effective poorer S/N ratio Electrode comfortable unipolar no anesthetics repeatability strongly dependent on operator Gold foil easy application signal is position dependable simple cleaning and not uniform unipolar, poor repeatability ERG-Jet reliable, most safe expensive (disposable) good repeatability unipolar partially compensates astigmatism Gold Lens bipolar, low noise not suited for binocular rec. easy cleaning expensive, irritation prevents blinking partially compensates astigmatism Burian-Allen bipolar, low noise not suited for binocular rec. partially compensates expensive, irritation astigmatism very cautious cleaning

42 Pattern ERG evoked by temporally modulated patterned stimulus of constant total luminance checkerboard / grating Pros; macula / inner retina dysfunction - conventional full-field ERG cannot detect them Cons; very small signal (0.5-8μV), technically more demanding

43 Multifocal ERG Patched visual stimulation by m-sequenceCalculation Example R(t)1=RC(t)+R1(t)+R2(t) R(t)2=R1(t)+R3(t)+RC(t) R(t)3=R2(t)+R3(t)+RC(t) R(t)4 = R1(t) + R2(t) + R3(t) R(t)1+R(t)2+R(t)3 =2(R1(t)+R2(t)+R3(t))+3RC(t) = 2R(t)4 + 3RC(t) RC(t) = 2/3 (R(t)1 + R(t)2 + R(t)3 - 2R(t)4) 1 2 1 c c 3 2 c 3 1 2 3 1 6 2 c 5 3 4

44 Multifocal ERG

45 Multifocal ERG “kernel” N1 = a wave? P1 = b wave?

46 Vision prosthesis Enhanced vision: process image for maximum visibility & present information to still viable retina Prosthetic vision: presents processed visual information to the inner retina or visual pathways Artificial vision: process & interpret visual information & presents the result through another sensory modality

47 Chronology 1890s Animal-to-human organ grafts are tried, but failed1906 Corneal transplantation succeeded 1918 Blood transfusions 1928 Iron lung developed for polio 1933 Human-to-human kidney transplant fails 1943 Kidney dialysis machine 1951 Artificial heart valve 1953 Heart-lung machine 1954 Kidney transplanted between identical twins; artificial hip implanted 1955 Heart-valve graft succeeded 1959 Kidney transplanted between nonidentical siblings 1962 Kidney transplanted from cadaver; silicone-filled breast implants

48 Chronology 1966 Kidney-pancreas transplant succeeds; titanium dental implants 1967 Heart and liver transplants succeed 1969 Cold-organ preservation 1973 All 50 states pass the Uniform Anatomical Gift Act 1978 Pancreas transplanted from living donor 1980 Cochlear implant

49 Chronology 1981 Heart-lung transplant succeeds1982 Jarvik artificial heart transplant 1983 Single-lung transplant succeeds; cyclosporine, potent antirejection drug, approved 1984 Baboon heart transplanted into child; patient lives 20 days 1988 Liver-small intestine transplant succeeded 1992 Baboon-to-human liver transplant succeeds 1990 Cure for cystic fibrosis attempted with lung transplant 1993 Left-ventricular assist approved for heart patients 2001 Experimental robotic pancreas demonstrated; Abiomed’s AbioCor artificial heart implanted

50 Artificial organ Transgenic xenotransplantationhuman HLA expression in transgenic animal lowering immune-associated adverse reaction Liver, Heart, etc Stem cell culture organogenesis human embryonic stem (ES) cell; plueripotent - unlimited differentiation under specialized cytokines biomedical organogenesis in biodegradable scaffold differentiated cell culture in bio-polymer skin, cartilage, bone, etc bionic artificial organ

51 Inside Out Clinically accepted organ replacementMechanical and organic replacement is available for several major organ systems. Established and experimental options for the lungs, heart, pancreas, kidney, and other organs are displayed here. Clinically accepted organ replacement Organ Organic Mechanical Heart Human heart transplant Heart-lung machine Pacemaker / Implantable defibrillator Pig heart valve Artificial heart valve Kidney Human or pig kidney TPL Hemodialysis machine Ear Cochlear implant Skin Lab-cultured skin patches Artificial skin Experimental/Conceptual organ replacement Heart N/A Artificial heart Lung Transplantable human lung Artificial lung Pancreas Biohybrid device made of Robotic pancreas tubes filled with islet cells Eyes N/A Artificial Eye SOURCE: Red Herring

52 Revolutionary Forces

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56 Electrophysiological stimulationHolmes (1918): disturbances of vision by cerebral lesions Foerster (1929): patient saw a small spotlight on electrical stimulation of visual cortex - 'phosphene' Krause & Schum (1931): similar localized and well-defined sensations of light in acquired hemianopia over 8 years Button & Putnam (1962): reconfirmation of experiment Brindley & Lewin(1968) first human experiment of indwelling type visual cortical stimulator in 52-year old blind patient no sharp flicker fusion frequency phosphene moves with the eye during voluntary eye movement Dawson & Radtke (1977); electrical stimulation of the retina by indwelling electrodes

57 What kinds of components are needed?image acquisition image processing image transfer neural stimulator power supply

58 Image acquisition in experiment in real trialDigital camera for still & motion image DV-graphic workstation for simultaneous DSP still image: more than 30 frames/seconds image acquisition in dim light(0 lux acquisition) auto-focus, auto-contrast gyroscope and accelerometer for camera positioning digital image archiving in real trial CCD in lightweight HMD auto-focusing by IR or microwave gyroscope and accelerometer for HMD positioning digital image processing computer is needed

59 Image processing: in experiment in real trialDVC / DV workstation for simultaneous DSP Image analysis and secondary processing software programming with MATLAB or C pixelization: resolution depth modification quantization: pixel signal design signal waveform design pixel overlapping and absolute/relative pixel modeling contrast leveling edge detection and enhancement tilt correction by gyroscope signal acceleration correction by accelerometer signal image stabilization by image comparison and temporal fusion color information and naming in real trial ASIC for CCD image processing under 3D position correction EEPROM for basic OS EEPROM for updating image processing program Smart Media or PCMCIA HDD for data personalization portable power supply

60 Image transfer HMD design Signal encoding and decodingglass shape, band shape, helmet shape mounting devices: gyroscope, accelerometer, pupil pursuit, signal transfer module Signal encoding and decoding encoding by image processor decoding by intraocular pocessor low heat generation and fast heat sink enough signal generation for various stimuli IR or laser signaling iris, lens problem harnessing according to eyeball movement or fixation of eyeball by EOM paralysis intraocular photosensor Mutual inductance coil material: copper, titan, platinum, gold, silver, etc coil shape: round, ovoid, etc coil position: intraocular, extraocular, periorbital coil efficiency: S/N Other transfer methods should be investigated

61 Neural stimulator biocompatibility stimulator fixation methodlong-term stable material: silicone rubber, polyimid, polycarbonate, PMMA, etc less foreign body response: non-inflammatory, minimal glial tissue growing stimulator fixation method retinal tack: titanium, folded polyimid, MEMS microelectrode biocompatible glue intraocular balloon or high-surface tension fluidsl stimulating electrode plate: shape, size, array density, wiring needle: shape, size, length, array density, wiring In vitro simulation multichannel stimulator and recorder, e.g. DAQ board micromanipulator with microscope Faraday cage and surgical kits In vivo test rabbit, dog, etc microsurgery lab: vitrectomy set VEP recording stimulating target ganglion cell body photoreceptor, bipolar/horizontal cell body retinal nerve fiber visual cortex neural cellular response to stimulation response recording from stimulating electrode response recording by VEP or other methods

62 Power supply microcomputer power supplyintraocular or cortical stimulator power supply IR or laser Mutual inductance others

63 Subretinal Doheny-SecondSight

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71 Epiretinal IIP technologie, Hamburg-Eppendorf

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73 Optic Nerve UCL

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77 50° field 10° / Div

78 Visual Cortex Dobelle Inst