Ординатура / Офтальмология / Английские материалы / Visual Prosthesis and Ophthalmic Devices New Hope in Sight_Rizzo, Tombran-Tink, Barnstable_2007

that ultimately produced great success in helping many deaf patients. It is suspected that intensive study of biological methods will provide more detailed insights into methods to lower stimulation thresholds and to create better vision, even in retinas that have undergone degeneration.

At this point in the evolution of the field of visual prostheses research, it is reasonable to experience a cognitive dissonance about the potential value of these devices. There are compelling reasons to have substantial optimism, and there are substantial unresolved questions that can raise uncertainty about the long-term prospects of these devices. The substantial critical mass of investigators that are contributing to the field makes it likely that, at the least, severely blind patients will experience functionally useful benefits from visual prosthetics.

REFERENCES

1.Margolis M, Coyne K, Kennedy-Martin T, Baker T, Schein O, Revicki D. Vision-Specific Instruments for the Assessment of Health-Related Quality of Life and Visual Functioning. Pharmacoeconomics 2002;20:791–811.

2.Dowling J. Artificial Human Vision. Expert Rev Med Devices 2005;2:73–85.

3.Huang Q, Xu P, Xia X, Hu H, Wang F, Li H. Subretinal transplantation of human fetal lung fibroblasts expressed cliliary neurotrophic factor gene prevent photoreceptor degeneration in RCS rats. Zhonghua Yan Ke Za Zhi 2006;42:127–130.

4.Bennett J. Gene therapy for Leber congential amaurosis. Novartis Found Symp 2004; 255:195–202.

5.Humayun MS, Prince M, de Juan E, et al. Morphometric analysis of the extramacular retina from postmortem eyes with retinitis pigmentosa. Invest Ophthalmol Visual Sci 1999;40:143–148.

6.Santos A, Humayun MS, de Juan E Jr, et al. Preservation of the inner retina in retinitis pigmentosa. A morphometric analysis. Arch Ophthalmol 1997;115.

7.Stone JL, Barlow WE, Humayun WS, et al. Morphometric analysis of macular photoreceptors and ganglion cells in retinas with retinitis pigmentosa. Arch Ophthalmol 1992;110:1634–1639.

8.Humayun MS, Weiland JD, Fujii GY, et al. Visual perception in a blind subject with a chronic microelectronic retinal prosthesis. Vision Res 2003;43:2573–2581.

9.Chow A, Chow VY, Packo K, Pollack J, Peyman GA, Schuchard R. The artifical silicon retina microchip for the treatment of vision loss from retinitis pigmentosa. Arch Ophthalmol 2005;122:460–469.

10.Gekeler F, Szurman P, Grisanti S, et al. Compound subretinal prostheses with extra-ocular parts designed for human trials: successful long-term implantation in pigs. Graefes Arch Clin Exp Ophthalmol 2006 [Epub ahead of print].

11.Hornig R, Laube T, Walter P, et al. A method and technical equipment for an acute human trial to evaluate retinal implant technology. 2005;2:S129–S134.

12.Hubel D, Wiesel TN. Receptive fields, binocular interactions, and functional architeture in the cat’s visual cortex. J Physiol 1962;160:106–154.

13.Penfiled W, Perot P. The brain’s record of auditory and visual experience. A final summary and discussion. Brain 1963;86:595–696.

14.Douglas R, Mahowald M, Mead C. Neuromorphic Analogue VLSI. Ann Rev Neurosci 1995; 18:255–281.

15.Tassiker G. US Patent 2,760,483, 1956.

16.Brindley GS. Effects of electrical stimulation of the visual cortex. Hum Neurobiol 1982;1:281–283.

17.Brindley GS, Lewin WS. The sensations produced by electrical stimulation of the visual cortex. J Physiol 1968;196:479–493.

18.Dobelle WH, Mladejovsky MG, Evans JR, Roberts TS, Girvin JP. “Braille” reading by a blind volunteer by visual cortex stimulation. Nature 1976;259:111–112.

19.Donoghue J, Nurmikko A, Friehs G, Black M. Development of neuromotor prostheses for humans. Suppl Clin Neurophysiol 2004;57:592–606.

20.Hambrecht FT. Neural prostheses. Ann Rev Biophys Bioeng 1979;8:239–267.

21.Bradley D, Troyk P, Berg J, et al. Visuotopic mapping through a multichannel stimulating implant in primate V1. J Neurophysiol 2005;93:1659–1670.

22.Marc RE, Jones BW, Watt CB, Strettoi E. Neural remodeling in retina degeneration. Prog Retinal Eye Res 2003;22:607–655.

23.Jensen RJ, Rizzo JF. Thresholds for activation of rabbit retinal ganglion cells with a subretinal electrode. Exp Eye Res 2005;submitted.

24.Jensen RJ, Ziv OR, Rizzo JF. Responses of rabbit retinal ganglion cells to electrical stimulation with an epiretinal electrode. J Neural Eng 2005;2:S16–S21.

25.Fried S, Hsueh H, Werblin F. A method for generating precise temporal patterns of retinal spiking using prosthetic stimulation. J Neurophysiol 2006;95:970–978.

26.Sekirjinak C, Hottowy P, Sher A, Dabrowski W, Chichilnisky E. Electrical stimulation of mammalian retinal ganglion cells with multi-electrode arrays. J Neurophysiol 2006; 95:3311.

27.Normann RA, Maynard EM, Rousche PJ, Warren DJ. A neural interface for a cortical vision prosthesis. Vision Res 1999;39:2577–2587.

28.Rizzo J. Embryology, anatomy, and physiology of the afferent visual pathway. In: Miller N, Newman N, eds. Walsh and Hoyt’s Clinical Neuro-Ophthalmology 6th ed., Philadelphia: Lippincott, Williams, and Wilkins, 2005;3–82.

29.Theogarajan LS. A low power wireless 15-channel implantable retinal stimulatorchip. Cambridge, MA: Massachusetts Institute of Technology Department of Electrical Engineering and Computer Science, 2005.

30.Kelly S, Wyatt J. A power-efficient voltage-based neural tissue stimulator with energy recovery. IEEE Int Solid-State Circuits Conf: (ISSCC), 2004.

31.Gingerich M, Shire D, Karcich K, Schulz C, Wyatt J, Rizzo J. Assembly and packaging developments for an ab externo retinal prosthesis. ARVO. Fort Lauderdale, FL, 2004.

32.Robblee LS, Lefko JL, Brummer SB. Activated Ir: An electrode suitable for reversible charge injection in saline solution. J Electrochem Soc 1983;130:731–732.

33.Jensen R, Rizzo JF, Ziv O, Grumet A, Wyatt J. Thresholds for activation of rabbit retinal ganglion cells with an ultra-fine, extracellular microelectrode. Invest Ophthalmol Visual Sci 2003;44:3533–3543.

34.Grumet AE, Wyatt JL, Rizzo JF. Multi-electrode stimulation and recording in the isolated retina. J Neurosci Methods 2000;101:31–42.

35.Grumet A. Electric stimulation parameters for an epi-retinal prosthesis. 1999.

36.Humayun MS, de Juan E Jr, Dagnelie G, Greenberg RJ, Propst RH, Phillips DH. Visual perception elicited by electrical stimulation of retina in blind humans. Arch Ophthalmol 1996;114:40–46.

37.Rizzo J, WJ, Loewenstein J, Kelly S, Shire D. Methods and perceptual thresholds for shortterm electrical stimulation of human retina with microelectrode arrays. IOVS 2003.

38.Rizzo JF, Wyatt J, Loewenstein J, Kelly S, Shire D. Perceptual efficacy of electrical stimulation of human retina with a microelectrode array during short-term surgical trials. Invest Ophthalmol Visual Sci 2003;44:5362–5369.

39.Montezuma SR, Loewenstein J, Scholz C, Rizzo JF. Biocompatibility of Subretinal Materials in Yucatan Pigs. Invest Ophthalmol Visual Sci 2004; submitted.

40.Zrenner E. Will Retinal Implants Restore Vision. Science 2002;295:1022.

41.McCall MA, DeMarco PJ, Crosby AL, et al. Visually Evoked Activity from a Subretinally placed artificial silicon retina. Assoc Res Vision Ophthalmol 2005.

42.Ball SL. Temporary trophic effect in two animal models (Chow group). In: Rizzo JF, ed., 2005.

43.Cheng Y, Yin H, Fernandes A, et al. Long-term neuroprotective effect of the subretinal implant in the RCS rat. Assoc Res Vision Ophthalmol 2004.

44.LaVail MM, Yasumura D, Matthes MT, et al. Protection of mouse photoreceptors by survival factors in retinal degenerations. Invest Ophthalmol Visual Sci 1998;39:592–602.

45.Husson-Danan A, Leveillard S, Mohand-Said S, Chalmel F, Poch O, Sahel JA. Rod-derived cone viability factor/Txnl-6 expression in the transgenic P23H rat, an autosomal dominant model of retinitis pigmentosa. Invest Ophthalmol Visual Sci 2005;46:E-Abstract 5185.

46.Wickelgren I. A Vision for the Blind. Science 2006;312:1124–1126.

47.Zrenner E. Subretinal stimulation for retinal prosthesis. ARVO. Fort Lauderdale, FL, 2006.

48.Loewenstein J, Montezuma S, Rizzo JF. Outer retinal degeneration: an electronic retinal prosthesis as a treatment strategy. Arch Ophthalmol 2003.

49.Loewenstein J, Montezuma SR, Rizzo JF. Outer retinal degeneration: an electronic retinal prosthesis as a treatment strategy. Arch Ophthalmol 2004;122:587–596.

stable implant position, and a reasonable threshold for cortical responses at a current level of 30 µA and a charge transfer of 2.4 × 10–8 C, respectively. At that time furthermore development was discontinued for technological reasons.

With recent technological breakthroughs in the production of silicone chip devices and the creation of new applicable microelectrodes and biocompatible encapsulation materials, the past two decades have witnessed a renaissance in the development of visual system implants. These new premises led to the creation of new concepts for suband epiretinal implants in the first half of the 1990s (14–18). Initial activities were followed by the establishment of a series of worldwide collaborative groups projecting epiretinal (19–24), subretinal (25–31), intrapapillary (32), suprachoroidal (33), extraocular (34–36), or complex (37) retina implant systems. Besides using electrical charge to stimulate the retina, other concepts were designed focusing on the microinjection of retinal neurotransmitters to mediate visual information (28,38–40).

RETINAL PROSTHESIS: CONCEPTS AND UNSOLVED PROBLEMS

The common principle of all retina implant concepts is that of a functional bypass of distal retinal cell layer degeneration. There are at least four basic requirements to be met in order to provide a clinically useful device:

1.A sufficient and long-lasting survival of contactable proximal retinal neurons.

2.The possibility to elicit visual qualities of perception by electrical stimulation or neurotransmitter release that will provide more than unstructured visual sensations.

3.Technical feasibility of implantation, mechanical fixation, and explantibility of implants with acceptable risk profile.

4.Biocompatibility of the devices with survival of the contacted retina, and a permanently reproducible visual perception.

The survival of contacted retinal neurons and RPE (retinal pigment epithelium) has broadly been discussed elsewhere (41–50). Although, data about this issue are by far not completely conclusive, it can be summarized that probably there will be a sufficient proportion of retinal neurons surviving distal retinal degenerative diseases for a long time. Nearly the same level of evidence is provided concerning the question of visual sensations. Stimulation was tested in acute quasi-realistic human and animal stimulation experiments (51–56) and first data with permanently implanted electrode arrays are available (57,58). Recent results of human in vivo and simulation tests show that devices with very few electrodes can mediate a surprising quality of visual perception (57,59,60).

Implantation, mechanical stabilization, potential secondary reactions toward a foreign structure and the survival of contacted retina are crucial biomedical issues for any kind of retinal implant. The new challenge to intraocular surgery is to place solid implants epior subretinally in a precise, long-term highly stable, and atraumatic way. It seems that many of the essential surgical techniques and concepts for the implantation of epior subretinal implants were successfully developed and tested so far and that there is a series of modified and combined surgical procedures at hand (24,61–68). In contrast to the successful search for primary surgical solutions it seems that problems of intraocular implant biocompatibility and tissue reactivity are still unsolved, especially, when large-scale intraocular implants are applied (69,70). Successful longterm results are only available for relatively small, or electrically inactive, or incomplete

suband epiretinal implants or for implants, which leave main components outside the globe (24,62,64,66,70). Experimental series applying complete epiretinal implants with anterior segment IOL-receivers and posterior segment microelectrode arrays (MA) were resulting in a relatively high percentage of severe intraocular complications like cyclitic, retroiridal, or retrociliary membrane formation, severe PVR (proliferative vitreoretinopathy) and/or total retinal detachment (69–71). Severe tissue reactions against large diameter anterior segment implants are well known from the experimental and clinical use of intraocular lenses or iris diaphragms (72). It seems that implants extending the diameter of conventional intraocular lenses with major contact to the iris or ciliary body tend to cause adversive reactions in the anterior segment or in the anterior part of the posterior segment. Problems obviously are potentiated by implants extending to the posterior segment as can be concluded from a series of experimental implantations showing especially intensive proliferations along microcables extending to the posterior segments (69).

Facing the problems that may be caused by these large scale retina implant system are probably the reason why several groups have changed their implant design in a way so that the need of intraocular deposition of implant material is reduced considerably (57,67,68,73,74). In these attempts the intraocular components of the system were limited to a stimulating device (microelectrode or multiphotodiode arrays) placed either subor epiretinally. The disadvantage of this technology is the necessity to connect intraocular structures by trans-scleral/trans-choroidal cables with other electronic components outside the eye. The penetration of cables again may cause severe local proliferative reactions and necessitate perhaps a limitation of ocular motility.

A maximal reduction of intraocular implant material is the design principle of a suprachoroidal or extraocular device designed by two groups (35,75). Here, stimulating electrodes are positioned in the suprachoroidal space, a scleral pocket, or in episcleral position leaving any intraocular structures untouched. This approach reminds of the early trial of external stimulation by Brindley (11). Theoretical disadvantages are the increasing distance between electrodes and target neurons probably resulting in a lower resolution and higher necessary charge delivery to reach stimulation thresholds (76).

MINIMAL INVASIVE RETINAL IMPLANT

The intention of the minimal invasive retinal implant (miRI) is to combine the need for a close spatial contact of stimulating electrodes with retinal neurons and the intention to minimize the intraocular deposition of implant components. The only way of combining these two basic criteria at a maximum level is the design of an implant with all components outside the eye and stimulating electrodes penetration the sclera and choroid. This principle is obviously in conflict to the general paradigm that the choroid has to be regarded as a critical structure, which might cause severe complications after single and even more multiple penetration. It was the aim of the miRI project to examine the feasibility of the retina implant system with these characteristic features and, if possible, to develop medical devices for the rehabilitation of blind people with distal retinal degenerations. Early results of feasibility studies and experimental data will be mentioned later. Before that the basic technological concept will be exemplified.

Fig. 1. Principle construction of the miRI.

Fig. 2. Functional construction of the EU.

The principle construction of the miRI is demonstrated in Fig. 1. It consists of two main components: the external unit (EU) and the implant unit (IU). The EU (Figs. 1 and 2) includes a camera (CAM), the external electronic unit (EEU), a transmitter coil (t-coil), and energy supply. The CAM is completely integrated into a normal-style glass frame. Image microcables within the temples are connecting the CAM with the EEU. The EEU can be fixated underneath and covered by normal cloths. Transmitter microcables return parallel to image microcables through the temples connecting the t-coil. The t-coil is integrated into a distension of the temple so that it is centered to the horizontal midline axis of the globe. Minor frame modifications and a cable leaving the end of the temple behind the auricle will be the only visible signs of the implant carrier status. The dimension of the EEU can be minimized so that the patient will not have to carry any bulky or noticeable equipment.

The IU (Figs. 1 and 3) consists of the receiver coil (r-coil), microcable connections (mc), the internal electronic units, microelectrode carrier (MC), and penetrating stimulating microelectrodes. Stimulating electrodes are the only component of the implant that penetrates the sclera. The rest of the IU is placed on the outer surface of the sclera and in this position mechanically stabilized by conventional intrascleral sutures comparable with those used in buckling procedures.

Fig. 3. Functional construction of the IU.

Figures 2 and 3 depict the functional construction of the miRI schematically. The external CAM uses a photosensor array consisting of 10,000–50,000 pixel units at the input side and transmits the data stream of primary image information through a cable connection to the EEU. The EEU transforms the primary image information into a stream of data that can be transmitted wirelessly through the t-coil to the IU. In principle the EEU represents a strong reduction of the natural information processing in the bypassed retinal layers. It has to include sophisticated information technology reducing possible image ambiguity and simulating small eye movements (17,77) The technical information process is primarily based on the assumption of virtual bypassed retinal layers with normal function, but has to be corrected for the deviant connectivity and processing of diseased retina, especially, in the contacted afferent retinal structures that naturally have changed with the progress of disease (48,49,78). The necessary modality is implemented in the functional layers of the retinal parallel processor (RPP). First the parallel retinal encoder recalculates the two dimensional matrix of image information. Then the primary matrix information undergoes a process of parallel retinal image encoding in the RPP. Each layer of parallel processing retinal parallel filter (RPF) provides a set (n > F × Σ stimulation electrodes, F = 1–8) of filter functions that represent approximated implementations of the normal primate retina function at different cellular layers. One of the main differences in layer modality is the specific use of either bipolar or ganglion cell receptive field function. A very important feature of the RPF is the tuning and learning modality. This allows a selection of different characteristic filter functions in the first layer of the RPF and a modulation of filter parameters in the second layer, the transfer function modulator. Filter selection and parameter tuning can be performed during training sessions with patients after implantation and at any time of implant use. It is the aim of these training sessions to match a reported subjective perception elicited by the implant so that it will come close to an expected or optimized visual sensation.

Signal output of the RPP is combined in the signal filter integrator in order to synthesize a temporal arrangement of transmitted information for each stimulating microelectrode. Then data are transferred to the data integrator, which combines all incoming

streams of information and a clock signal that is transferred to the signal and information transmitter. The transmitter combines the transfer of data and necessary energy to run the IU and is connected with the t-coil as demonstrated in Fig. 3.

The coil in the IU (r-coil), which is positioned directly opposite and in close approximation to the t-coil (r-coil), and the receiver unit are receiving the electromagnetically transferred energy and encoded data stream. The energy to run the implant is supplied by the basic wave of electromagnetic transmission, which is processed and stored in the internal energy unit. Transmitted data and clock signals are decoded in the signal and clock decoder. The microelectrode stimulation unit transforms the incoming data into a definite stimulation signal for each microelectrode, which will be realized by the current source and applied to the MA. The definite current curve applied by single microelectrodes is representing a combination of slow basal amplitudes directed to outer retinal (mainly bipolar cells) and fast spike trains for inner retinal neurons (mainly ganglion cells).

By the injection of complex patterns of stimulation one electrode can be used to elicit different visual effects. With the introduction of more complex electrodes consisting of independent conductive layers, which can individually be connected, the multiuse function of each penetrating electrode can be expanded so that the principle of “one electrode–one pixel” can be overcome and the number of resulting stimulation effects will be the number of electrodes multiplied by a factor X of multiuse capacity.

The construction of the miRI-system allows the use of more than one MC. By this the penetration of larger numbers of electrodes can be facilitated. Microelectrode choice and application can be individualized to meet the needs of implant carriers. The number and density of microelectrodes supported by each MC can be modified.

miRI DEVELOPMENT AND FIRST RESULTS

The idea of a miRI with penetrating electrodes was evolved from data generated in several experimental series performed in our laboratories. One of these was focussing on the long-term outcome of completely intraocular implanted epiretinal devices with an anterior IOL-receiver and a posterior MA. Results of this series were rather disappointing, as mentioned earlier, with severe complications, like proliferative vitreoretinopathy, retinal detachment, or cyclitic membrane formation in the majority of cases (69). A meta-analysis of several approaches using different epiretinal devices was supporting these results indicated that only isolated posterior segment epiretinal implants or small diameter implants could be applied without major complications (70). Still a high percentage of local adversive effects (fibrous interface formation, secondary retinal damage) were observed in the series with small epiretinal devices.

The second input for the creation of the miRI concept was generated from experiments focussing on biocompatibility test of devices for the intraocular mechanical fixation of epiretinal retina implant systems (79–81). In these experiments large diameter conventional retinal tacks and newly designed small diameter microtacks were inserted ab interno in a way that the retina, choroid, and sclera were completely penetrated and the peak of the device was positioned outside the eye. Long-term observations showed that theses structures, although permanently penetrating all layers were relatively well tolerated. Surprisingly, the insertion of these devices could be performed without significant

choroidal hemorrhage, choroidal detachment, or severe proliferative vitreoretinal reactions postoperatively. Furthermore testing of smaller elements in the micrometer scale clearly provided evidence that intraocular and especially, retinal reactions decreased in first approximation exponentially with the reduction in implant diameter. The retina remained intact according to histological criteria in the vicinity of implants when applying these devices ab interno (81) although still some undesired epiretinal proliferations were observed. The next step of progression was the penetration of the eye ab externo and this was leading to further reduction of secondary proliferations and retinal disintegration of neuronal structures (82). As the preliminary results of ab externo implantation of microelectrodes in rabbits were favorable, a study program was worked out for the development of a definitive miRI.

Shape and dimension of microelectrodes with a relatively high aspect ratio (ratio of length divided by diameter) were optimized in several series of biomechanical analysis using scleral tissue of different species (rabbit, pig, monkey, human donor eyes). Selection criteria were the force necessary for the penetration of electrodes and on the other hand the mechanical stability of electrodes. Deformation of electrodes or the apex of electrodes during scleral penetration was valuated as absolute exclusion criterion. It was demonstrated in these experiment that the examined scleral tissue can be simultaneously penetrated by multielectrode arrays (83). As expected, the number and density of electrodes proved to be a critical parameter severely limiting the range of applicable array designs. Anyhow, forced ad hoc penetration of electrodes revealed to be relatively traumatic, leading to immediate retinal damage around the site of penetration. A solution to this was found in the principle of very slow electrode penetration. It is applied by suturing electrode arrays to the scleral surface in way that a continuous force into the direction of desired penetration is applied so that a slow invasion of electrodes is resulting. The process of electrode penetration is finalized once the inner surface of the electrode carrier, which is a precise negative of the eye curvature, gets into touch with the outer scleral surface.

One of the most critical questions of the project so far was the problem of principle biocompatibility of the implantation procedure and long-term tissue reactions toward the implant. In order to examine this, a surgical standard procedure was successfully developed and tested in a series of in vitro procedures (83). In order to come as close as possible to the biology of human eyes in these experiments, it was decided to test electrically inactive multielectrode implants in nonhuman monkeys. The focus of these experiments was to study if the principle of slow penetration of electrodes is feasible, if chorioidal hemorrhages or detachment may develop during penetration, if undesired retinal effects might occur or vitreoretinal proliferations would set a critical limit. Electrode length in these experiments was chosen so that a proportion of elements were totally penetrating all layers extending into the posterior vitreal cortex. Results of this series of experiments so far indicate that the surgical procedure and penetration of electrodes are very well tolerated (83). Figure 4 shows an example of a 10 electrode implant 2 mo after implantation. The principle of slow electrode penetration, covering a postoperative period of several weeks in individual cases proved to be a well-working principle and revealed to be very atraumatic (84,85). The retina around slowly penetrating electrodes was relatively well preserved and the vitreous did not develop adverse proliferative