Zusammenfassung
Hintergrund: Derzeit gibt es keine Therapie für progressive Netzhautdystrophien. Durch Fortschritte
in der Herstellung extrem kleiner komplexer Mikrosysteme und durch ihre Integration
in biokompatible Strukturen erscheint die Fertigung einer implantierbaren Sehprothese
heute möglich. Material und Methoden: Die derzeitige Entwicklung elektronischer implantierbarer Sehprothesen beruht auf
der Herstellung von Stimulationselektrodenarrays, die in die jeweilige Zielregion
des visuellen Systems implantiert werden. Funktionsmuster und Prototypen solcher Systeme
wurden tierexperimentell erprobt und in Einzelfällen bereits bei Menschen eingesetzt.
Ergebnisse: Derzeit werden vier Konzepte verfolgt: 1. Epiretinales Implantat - Befestigung auf
der Netzhautoberfläche, 2. Subretinales Implantat - Implantation im subretinalen Raum,
3. Sehnervprothese - Cuffelektrode um den Sehnerven, 4. Cortexprothese - Implantation
von Oberflächenelektroden über dem visuellen Cortex. Alle Verfahren wurden bisher
in Pilotversuchen am Menschen eingesetzt. Die Ergebnisse bezüglich der Sehwahrnehmung
zeigen bisher hoffnungsvolle Ergebnisse. Schlussfolgerungen: Die Entwicklung implantierbarer elektronischer Sehprothesen stellt eine mögliche
Option in der Behandlung weit fortgeschrittener Netzhautdystrophien dar. Weitere Grundlagenuntersuchungen
zur funktionellen Stimulation des visuellen Systems sind ebenso erforderlich wie Pilotstudien
zur Stimulation beim Menschen zur genauen Charakterisierung der Stimulationsparameter
und Optimierung vorhandener Systeme.
Abstract
Background: Currently, no treatment is available for progressive retinal dystrophies. The fabrication
of an implantable visual prosthesis seems to be possible now as a result of advances
in the fabrication of extremely small micro-systems and their encapsulation in biocompatible
materials. Materials and Methods: The development of implantable visual prostheses is based on the fabrication of remotely
controlled microelectrode arrays which have to be implanted in different target regions
of the visual system. Prototypes of such systems have already been implanted in animal
experiments and also in pilot trials in humans. Results: Four concepts are pursued: 1. epiretinal implant - fixation onto the inner retinal
surface; 2. subretinal implant - implantation within the subretinal space; 3. optic
nerve stimulator - cuff electrode placed around the optic nerve; 4. cortical prosthesis
- implantation of surface electrodes in the region of the visual cortex. All these
concepts have already been applied in pilot trials in humans. The results show some
promising visual perception. Conclusions: The use of implantable electronic visual prostheses will become a possible option
in the treatment of currently untreatable retinal dystrophies. Further basic research
initiatives are necessary as well as further human trials to characterize the stimulation
parameters and to improve the currently available devices.
Schlüsselwörter
Aktive Implantate - Cortexprothesen - elektrische Stimulation - Erblindung - Retina
Implant - Retinitis pigmentosa - Sehnervprothesen - Sehprothesen
Key words
Active implants - blindness - cortical prosthesis - electrical stimulation - optic
nerve prosthesis - retina implant - retinitis pigmentosa - visual prosthesis
Literatur
- 1
Adolph A R, Zucker C L, Ehinger B. et al .
Function and structure in retinal transplants.
J Neural Transplant Plast.
1994;
5 (3)
147-161
- 2
Ali R A, Reichel M B, Trasher A J. et al .
Gene transfer into the mouse retina by an adeno associated viral vector.
Hum Mol Genet.
1996;
5
591-594
- 3
Alteheld N, Vobig M A, Marzella G. et al .
Biocompatibility tests on the intraocular vision aid IOVA.
Biomed Tech (Berl).
2002;
47 (Suppl 1 Pt 1)
176-178
- 4
Bennett J, Zeng Y, Bajwa R. et al .
Adenovirus mediated delivery of rhodopsin-promoted bcl-2 results in a delay in photoreceptor
cell death in the rd/rd mouse.
Gene Ther.
1998;
5
1156-1164
- 5
Berk H, Held S, Alteheld N. et al .
Explantation of Tack Fixated Epiretinal Microcontact Foils in Rabbits - Preliminary
Observations.
ARVO Abstract.
2002;
4456
- 6
Berson E L, Juancho F, Remulla C. et al .
Evaluation of patients with retinitis pigmentosa receiving electric stimulation, ozonated
blood, and ocular suergery in Cuba.
Arch Ophthalmol.
1996;
114
560-563
- 7
Berson E L, Rosner B, Sandberg M A. et al .
A randomized trial of vitamin A and vitamin E supplementation for retinitis pigmentosa.
Arch Ophthalmol.
1993;
111
761-772
- 8
Brindley G S.
Sensations produced by electrical stimulation of the occipital poles of the cerebral
hemispheres, and their use in constructing visual prostheses.
Ann R Coll Surg Engl.
1970;
47 (2)
106-108
- 9
Brindley G S, Lewin W S.
The sensations produced by electrical stimulation of the visual cortex.
J Physiol.
1968;
196
479-493
- 10
Chow A Y, Chow V Y.
Subretinal electrical stimulation of the rabbit retina.
Neurosci Lett.
1997;
225 (1)
13-16
- 11
Chow A Y, Packo K H, Pollack J S. et al .
Subretinal Artificial Silicon Retina Microchip Implantation in Retinitis Pigmentosa
Patients: Long Term Follow-Up.
ARVO Abstract.
2003;
4205
- 12
Chow A Y, Pardue M T, Chow V Y. et al .
Implantation of silicon chip microphotodiode arrays into the cat subretinal space.
IEEE Trans Neural Syst Rehabil Eng.
2001;
9 (1)
86-95
- 13
Crampon M A, Brailovski V, Sawan M. et al .
Nerve cuff electrode with shape memory alloy armature: design and fabrication.
Biomed Mater Eng.
2002;
12 (4)
397-410
- 14
Dawson W W, Radtke N D.
The electrical stimulation of the retina by indwelling electrodes.
Invest Ophthalmol Vis Sci.
1977;
16 (3)
249-252
- 15
Delbeke J, Wanet-Defalque M C, Gerard B. et al .
The microsystems based visual prosthesis for optic nerve stimulation.
Artif Organs.
2002;
26 (3)
232-234
- 16
Delbeke J, Oozeer M, Veraart C.
Position, size and luminosity of phosphenes generated by direct optic nerve stimulation.
Vision Res.
2003;
43 (9)
1091-1102
- 17
Dobelle W H.
Artificial vision for the blind. The summit may be closer than you think.
ASAIO J.
1994;
40 (4)
919-922
- 18
Dobelle W H.
Artificial vision for the blind by connecting a television camera to the visual cortex.
ASAIO J.
2000;
46 (1)
3-9
- 19
Dryja T P, McGee T L, Hahn L B. et al .
Mutations within the rhodopsin gene in patients with autosomal dominant retinitis
pigmentosa.
N Engl J Med.
1990;
323 (19)
1302-1307
- 20 Eckmiller R. Towards retina implants for improvement of vision in human with RP
- challenges and first results. Proc WCNN. Vol. 1. Hillsdale; INNS Press, Lawrence
Earlbaum Assoc 1995: 228-233
- 21
Eckmiller R.
Retina Implants with adaptive Retina Encoders.
RESNA Research Symposium.
1996;
21-24
- 22
Eckmiller R.
Learning retina implants with epiretinal contacts.
Ophthalmic Res.
1997;
29 (5)
281-289
- 23
Eysel U T, Walter P, Gekeler F. et al .
Optical Imaging Reveals 2-Dimensional Patterns of Cortical Activation After Local
Retinal Stimulation With Sub- and Epiretinal Visual Prostheses.
ARVO Abstract.
2002;
4486
- 24
Ford M, Bragadottir R, Rakoczy P E. et al .
Gene transfer in the RPE65 null mutation dog: relationship between construct volume,
visual behavior and electroretinographic (ERG) results.
Doc Ophthalmol.
2003;
107 (1)
79-86
- 25
Fuortes M GF.
Initiation of impulses in visual cells of Limulus.
J Physiol.
1959;
148
14-28
- 26
Gouras P, Tanabe T.
Survival and integration of neural retinal transplants in rd mice.
Graefes Arch Clin Exp Ophthalmol.
2003;
241 (5)
403-409
- 27
Guenther E, Troger B, Schlosshauer B. et al .
Long-term survival of retinal cell cultures on retinal implant materials.
Vision Res.
1999;
39 (24)
3988-3994
- 28
Hartline H K, Wagner H G, MacNichol E F jr.
The peripheral origin of nervous activity in the visual system.
Cold Spr Harb Symp Quant Biol.
1952;
17
125-141
- 29
Humayun M, Greenberg R J, Mech B V. et al .
Chronically Implanted Intraocular Retinal Prosthesis in Two Blind Subjects.
ARVO Abstract.
2003;
4206
- 30
Humayun M S, de Juan E, Dagnelie G. et al .
Visual perception elicited by electrical stimulation of retina in blind subjects.
Arch Ophthalmol.
1996;
114
40-46
- 31
Humayun M S, Prince M, de Juan E Jr. et al .
Morphometric analysis of the extramacular retina from postmortem eyes with retinitis
pigmentosa.
Invest Ophthalmol Vis Sci.
1999;
40 (1)
143-148
- 32 Huppertz J, Hausschild R, Hosticka B J. et al .Fast CMOS imaging with high dynamic
range. Bruges Workshop Proceedings Charge coupled devices and advanced image sensors
IEEE Piscataway 1997
- 33
Kajiwara K, Hahn L B, Mukai S. et al .
Mutations in the human retinal degeneration slow gene in autosomal dominant retinitis
pigmentosa.
Nature.
1991;
354 (6353)
480-483
- 34
Kohler K, Hartmann J A, Werts D. et al .
Histological studies of retinal degeneration and biocompatibility of subretinal implants.
Ophthalmologe.
2001;
98 (4)
364-368
- 35
Kohn D B, Sadelain M, Glorioso J C.
Occurrence of leukaemia following gene therapy of X-linked SCID.
Nat Rev Cancer.
2003;
3 (7)
477-488
- 36
Krumpaszky H G, Klauss V.
Epidemiology of blindness and eye disease.
Ophthalmologica.
1996;
210
1-84
- 37
Lau D, McGee L H, Zhou S. et al .
Retinal degeneration is slowed in transgenic rats by AAV-mediated delivery of FGF-2.
Invest Ophthalmol Vis Sci.
2000;
41
3622-3633
- 38
Lawrence J M, Keegan D J, Muir E M. et al .
Transplantation of Schwann cell line clones secreting GDNF or BDNF into the retinas
of dystrophic Royal College of Surgeons rats.
Invest Ophthalmol Vis Sci.
2004;
45 (1)
267-274
- 39
Lund R D, Ono S J, Keegan D J. et al .
Retinal transplantation: progress and problems in clinical application.
J Leukoc Biol.
2003;
74 (2)
151-160
- 40
Luthert P J, Chong N H.
Photoreceptor rescue.
Eye.
1998;
12 (Pt 3b)
591-596
- 41
Majji A B, Humayun M S, Weiland J D. et al .
Long-term histological and electrophysiological results of an inactive epiretinal
electrode array implantation in dogs.
Invest Ophthalmol Vis Sci.
1999;
40 (9)
2073-2081
- 42
Morimura H, Fishman G A, Grover S A. et al .
Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa
or leber congenital amaurosis.
Proc Natl Acad Sci USA.
1998;
95 (6)
3088-3093
- 43
Normann R A, Maynard E M, Rousche P J. et al .
A neural interface for a cortical vision prosthesis.
Vision Res.
1999;
39 (15)
2577-2587
- 44
Pelaez O.
Evaluation of patients with retinitis pigmentosa receiving electric stimulation, ozonated
blood, and ocular surgery in Cuba.
Arch Ophthalmol.
1997;
115
133-134
- 45
Peyman G, Chow A Y, Liang C. et al .
Subretinal semiconductor microphotodiode array.
Ophthalmic Surg Lasers.
1998;
29
234-241
- 46
Rizzo J F 3rd, Wyatt J, Humayun M. et al .
Retinal prosthesis: an encouraging first decade with major challenges ahead.
Ophthalmology.
2001;
108 (1)
13-14
- 47
Rizzo J F 3rd, Wyatt J, Loewenstein J. et al .
Methods and perceptual thresholds for short term electrical stimulation of human retina
with microelectrode arrays.
Invest Ophthalmol Vis Sci.
2003;
44 (12)
5355-5361
- 48
Sagdullaev B T, Aramant R B, Seiler M J. et al .
Retinal transplantation-induced recovery of retinotectal visual function in a rodent
model of retinitis pigmentosa.
Invest Ophthalmol Vis Sci.
2003;
44 (4)
1686-1695
- 49
Sampaio E, Maris S, Bach-y-Rita P.
Brain plasticity: ’visual’ acuity of blind persons via the tongue.
Brain Res.
2001;
908 (2)
204-207
- 50
Santos A, Humayun M S, de Juan E Jr. et al .
Preservation of the inner retina in retinitis pigmentosa. A morphometric analysis.
Arch Ophthalmol.
1997;
115 (4)
511-515
- 51
Schanze T, Greve N, Hesse L.
Towards the cortical representation of form and motion stimuli generated by a retina
implant.
Graefes Arch Clin Exp Ophthalmol.
2003;
241 (8)
685-693
- 52
Schanze T, Wilms M, Eger M. et al .
Activation zones in cat visual cortex evoked by electrical retina stimulation.
Graefes Arch Clin Exp Ophthalmol.
2002;
240 (11)
947-954
- 53
Schwahn H N, Gekeler F, Kohler K. et al .
Studies on the feasibility of a subretinal visual prosthesis: data from Yucatan micropig
and rabbit.
Graefes Arch Clin Exp Ophthalmol.
2001;
239 (12)
961-967
- 54
Skogstad M, Bast-Pettersen R, Tynes T. et al .
Treatment with hyperbaric oxygen. Illustrated by the treatment of a patient with retinitis
pigmentosa.
Tidsskr Nor Laegeforen.
1994;
114
2480-2483
- 55
Takahashi M, Miyoshi H, Verma I M. et al .
Rescue from photoreceptor degeneration in the rd mouse by human immunodeficiency virus
vector mediated gene transfer.
J Virol.
1999;
73
7812-7816
- 56
Tomita T.
Mechanism of lateral inhibition in the eye of Limulus.
J Neurophyiol.
1958;
21
419-429
- 57
Veraart C, Raftopoulos C, Mortimer J T. et al .
Visual sensations produced by optic nerve stimulation using an implanted self-sizing
spiral cuff electrode.
Brain Res.
1998;
813 (1)
181-186
- 58
Veraart C, Wanet-Defalque M C, Gérard B. et al .
Pattern Recognition with the Optic Nerve Visual Prosthesis.
Artificial Organs.
2003;
27 (11)
996
- 59
Walter P, Heimann K.
Evoked cortical potentials after electrical stimulation of the inner retina in rabbits.
Graefes Arch Clin Exp Ophthalmol.
2000;
238 (4)
315-318
- 60
Walter P, Szurman P, Vobig M. et al .
Successful long-term implantation of electrically inactive epiretinal microelectrode
arrays in rabbits.
Retina.
1999;
19 (6)
546-552
- 61
Walter P, Kisvarday Z F, Roessler G F. et al .
Optical imaging of the visual cortex in the cat demonstrating local cortical activation
after epiretinal stimulation with a completely implanted wireless epiretinal prosthesis.
ARVO Abstract.
2004;
4225
- 62
Warren D J, Fernandez E, Normann R A.
High-resolution two-dimensional spatial mapping of cat striate cortex using a 100-microelectrode
array.
Neuroscience.
2001;
105 (1)
19-31
- 63
William L L, Shannon B T, Chambers R B. et al .
Systemic immunostimulation after retinal laser treatment in retinitis piogmentosa.
Clin Immunol Immunopathol.
1992;
64 (1)
78-83
- 64
Wolff J G, Delacour J, Carpenter R H. et al .
The patterns seen when alternating electric current is passed through the eye.
Q J Exp Psychol.
1968;
20 (1)
1-10
- 65
Zrenner E, Stett A, Weiss S. et al .
Can subretinal microphotodiodes successfully replace degenerated photoreceptors?.
Vision Res.
1999;
39 (15)
2555-2567
Prof. Dr. Peter Walter
Universitätsklinikum Aachen, Augenklinik
Pauwelsstr. 30
52074 Aachen
Phone: 02 41/8 08 81 91
Fax: 02 41/8 08 24 08
Email: pwalter@ukaachen.de
