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Retinal prostheses: current challenges

and future outlook
a b c
Jessica O. Winter , Stuart F. Cogan & Joseph F. Rizzo
a
Center for Innovative Visual Rehabilitation, VA Medical Center,
Boston, MA, USA; Department of Chemical and Biomolecular
Engineering, The Ohio State University, 140 West 19th
Avenue, Columbus, OH 43210, USA; Department of Biomedical
Engineering, The Ohio State University, 140 West 19th Avenue,
Columbus, OH 43210, USA
b
EIC Laboratories, Norwood, MA, USA
c
Center for Innovative Visual Rehabilitation, VA Medical Center,
Boston, MA, USA; Department of Ophthalmology, Harvard
Medical School and the Massachusetts Eye and Ear Infirmary,
Boston, MA, USA
Published online: 02 Apr 2012.

To cite this article: Jessica O. Winter , Stuart F. Cogan & Joseph F. Rizzo (2007) Retinal
prostheses: current challenges and future outlook, Journal of Biomaterials Science, Polymer
Edition, 18:8, 1031-1055, DOI: 10.1163/156856207781494403

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 J. Biomater. Sci. Polymer Edn, Vol. 18, No. 8, pp. 1031– 1055 (2007)
 VSP 2007.
Also available online - www.brill.nl/jbs

Review

Retinal prostheses: current challenges and future outlook

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JESSICA O. WINTER 1,2,3,∗ , STUART F. COGAN 4 and JOSEPH F. RIZZO III 1,5

1 Center for Innovative Visual Rehabilitation, VA Medical Center, Boston, MA, USA
2 Department of Chemical and Biomolecular Engineering, The Ohio State University,
140 West 19th Avenue, Columbus, OH 43210, USA
3 Department of Biomedical Engineering, The Ohio State University, 140 West 19th Avenue,
Columbus, OH 43210, USA
4 EIC Laboratories, Norwood, MA, USA
5 Department of Ophthalmology, Harvard Medical School and the Massachusetts Eye and Ear
Infirmary, Boston, MA, USA

Received 1 November 2006; accepted 28 March 2007

Abstract—Blindness from retinal diseases, including age-related macular degeneration (AMD) and
retinitis pigmentosa (RP), usually causes a significant decline in quality of life for affected patients.
Currently there is no cure for these conditions. However, over the last decade, several groups
have been developing retinal prostheses which hopefully will provide some degree of improved
visual function to these patients. Several such devices are now in clinical trials. Unfortunately, the
possibility of electrode or tissue damage limits excitation schemes to those that may be employed with
electrodes that have relatively low charge densities. Further, the excitation thresholds that have been
required to achieve vision to date, in general, are relatively high. This may result in part from poor
apposition between neurons and the stimulating electrodes and is confounded by the effects of the
photoreceptor loss, which initiates other pathology in the surviving retinal tissue. The combination
of these and other factors imposes a restriction on the pixel density that can be used for devices that
actively deliver electrical stimulation to the retina. The resultant use of devices with relatively low
pixel densities presumably will limit the degree of visual resolution that can be obtained with these
devices. Further increases in pixel density, and therefore increased visual acuity, will necessitate either
improved electrode-tissue biocompatibility or lower stimulation thresholds. To meet this challenge,
innovations in materials and devices have been proposed. Here, we review the types of retinal
prostheses investigated, the extent of their current biocompatibility and future improvements designed
to surmount these limitations.

Key words: Visual prosthesis; retina; biocompatibility; electrode.

∗ To whom correspondence should be addressed. E-mail: winter.63@osu.edu

 1032 J. O. Winter et al.

INTRODUCTION
Recent estimates indicate that over 937 000 Americans suffer profound vision loss,
while an additional 2.4 million display some degree of visual impairment [1].
A direct link between decreased visual acuity and age has been established, with up
to 12% of individuals over age 80 being affected by low vision, usually as a result
of age-related macular degeneration (AMD) [2]. As the US population continues to
age, it is likely that the total number of affected individuals will increase, perhaps
up to 50% by 2020 [3]. AMD, and other forms of neural blindness, cannot be
treated by any available means. Numerous strategies are being tried to treat neural
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blindness, including: transplantation of retinal neurons, retinal pigment epithelium

or stem cells, molecular genetic repair and retinal prostheses. Retinal [4 –8], cortical
[9, 10] and optic nerve [11, 12] visual prostheses use microfabricated electronic
components to stimulate neural circuitry that is still available despite whatever
neural damage has caused blindness. This approach is attractive in that prostheses
can directly stimulate surviving nerve cells and does not require the implant to
establish proper neural connections with the host tissue. Additionally, devices with
an analogous purpose have proven to be enormously successful in restoring hearing
to the deaf [13]. However, despite decades of research [14 –25], visual prostheses
have not advanced beyond early clinical trials and have not yet produced a level
of vision that has been demonstrated to improve the ability of patients to perform
visual tasks related to daily activities.
The reasons for slow development of visual prosthetic devices are numerous.
Among these is the fact that visual prostheses will almost certainly have to have
a moderately large number of stimulating electrodes to have any hope of providing
detailed visual perception. However, simply having a relatively large number of
electrodes does not guarantee that the nerve tissue can be stimulated in a way that
would faithfully transmit impulses (via electrical fields) that would correspond to
the intended pattern of stimulation based upon the visual scene. Although cochlear
implants can produce hearing with as few as 8 electrodes [13], visual prostheses
have not enjoyed the same success. The purpose of this review is to identify some
of the challenges facing the development of high pixel density visual prostheses.
Differences in the various visual prostheses under investigation are discussed in this
context, and future directions for overcoming these challenges and improving the
performance of the prostheses are suggested.

RESTORING VISUAL FUNCTION

Physiological visual processing
In a healthy individual, vision begins when the lens focuses light entering the eye
onto the retina (Fig. 1) [26]. At the level of the photoreceptors, the incoming light
rays are detected by some fraction of the about 190 million photoreceptors (i.e., rods
and cones). The photoreceptors are not distributed evenly; there is a substantially
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Retinal prostheses

Figure 1. Retinal anatomy and retinal prosthesis implant locations. The retina consists of several organized layers of cells and tissue. In normally sighted
individuals, light impinging on the retina is received by photoreceptors (lower left), which convert light into an electrical signal. That signal is processed by
the bipolar and ganglion cells, and transmitted to the brain. Nutrients to the retina are supplied by the retinal pigment epithelium (RPE) and the choroid, a
dense network of blood vessels. Epi-retinal implants are designed to interact with the retina from the vitreous side and are in closest proximity to ganglion
cells. Sub-retinal implants would be placed between the retina and the choroid, in the place normally occupied by photoreceptors. This figure is published
1033

in colour at http://www.ingenta.com
 1034 J. O. Winter et al.

greater density of photoreceptors within the central retina (i.e., macula). Capture of
light rays by photoreceptors causes a hyperpolarization of these cells, which reduces
the release of neurotransmitter at their synaptic terminals. This generates a graded
electrical signal at the level of the inner nuclear layer, which is transmitted through
bipolar cells to the retinal ganglion cells (RGC). Within the inner retina where RGCs
reside, the graded electrical signal is converted into a series of electrical spikes,
known as action potentials. Axonal extensions from the RGCs, the only output cells
from the eye, form the optic nerve, which transmits the electrical signals related to
visual input to the brain. The signal is transmitted along the RGC axons until it
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reaches the lateral geniculate nucleus (LGN), where the axons synapse. The final
relay along this retinocalcarine visual pathway begins at the LGN and extends to the
primary visual cortex. From here, the information is passed forward to numerous
“higher cortical” visual pathways. Visual perception is created by the collective
activity of these widely-distributed visual cortical regions.
Vision loss can occur from deficits at any stage in the vision processing system.
Retinal and optic nerve prostheses are designed to treat diseases of the retina,
primarily retinitis pigmentosa (RP, which accounts for 5% of cases of neural visual
loss among younger Caucasian patients within the industrialized world [27]) and
age-related macular degeneration (AMD, which accounts for 47% of visual loss
among older Caucasian patients within the industrialized world [27]). Cortical
prostheses could theoretically address these conditions plus those that occur because
of damage further along the retino-calcarine visual pathway. A cortical prosthesis
could provide visual assistance to patients with glaucoma (which accounts for 29%
of cases of visual loss among older Caucasian patients [27]) and diabetic retinopathy
(which accounts for 8% of cases of visual loss among older Caucasian patients [27]).
The requirements for device resolution will likely vary for each type of disease and
also differ from one patient to another with the same disease. For example, RP may
eventually result in no light perception, thus a low resolution device can improve
patient quality of life, whereas AMD patients typically retain normal vision in the
periphery. A resolution of 20:200–20:400 [28, 29] is the generally accepted goal
for visual acuity for this patient group, but only clinical tests can reveal the true
threshold for patient acceptance.

Clinical results related to the development of retinal prostheses

The concept of prosthetic vision is simple; electronic components are used to
convert light into an electrical signal that stimulates neurons in the visual pathway.
The neural signal is then processed by the brain to generate phosphenes (i.e.,
flashes of light). In practice, the realization of prosthetic vision has proven
complex and challenging. Two basic types of retinal prosthetic devices have
evolved. The most straightforward type of device consists of a multiphotodiode
array (MPDA) implanted in the sub-retinal space (i.e., between the retinal pigment
epithelium and the retina, Fig. 1). However, this type of device has a very limited
electrical output, which is arguably insufficient to drive retinal neurons (see below),
 Retinal prostheses 1035

especially diseased neurons that have higher-than-normal activation thresholds

as a consequence of a retinal degeneration. However, it would be possible to
provide supplemental electrical power to implanted MPDAs by including additional
hardware in the system design.

MPDA devices. Sub-retinal MPDAs were first proposed in 1956 by Tassiker

[14], who envisioned a selenium photodiode that would provide stimulation to the
retina. More recently, sub-retinal MPDAs have been studied by two independent
groups: German Southern Consortium/Retinal Implant (Reutlingen, Germany) [6]
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and Optobionics (Chicago, IL, USA) [4]. MPDAs convert light impinging on
the retina into an electrical signal, which is received by the cells of the inner
retina. MPDAs possess several advantages over other types of retinal implants.
MPDA devices and other sub-retinal implants provide functional replacement at the
earliest possible level, substituting for damaged photoreceptors. MPDA power is
provided by incident light, reducing the number of external and implanted electronic
components. Also, little signal processing is needed because sub-retinal devices
replace the first component in the visual cascade.
However, practical implementation has proved difficult. Incident light does
not appear to provide sufficient power to drive the devices [30, 31], requiring
the addition of external power components. Devices without external power
components have been used in clinical trials sponsored by Optobionics [4]. Ten
patients with retinitis pigmentosa have been implanted to date; testing has reportedly
produced visual images, including in areas of the visual field that were not being
directly driven by the implant [32]. Although the exact increase in visual acuity
is not described and varied across patients, visual improvement has apparently
persisted over 3.5 years with only a small decline in quality over time [4, 33].
However, the evidence of success is far from conclusive. Much of the reported
success is based on subjective patient reports. Similar sub-retinal MPDA devices,
but with additional supplemental power, have also been chronically implanted in
four patients by Retinal Implant.

MEA devices. MEAs consist of planar microelectrode arrays connected to an im-

plantable signal processor (Fig. 2). In one configuration, visual images are collected
with a digital camera and interpreted by the signal processor, which develops and
transmits a stimulation pattern to the electrodes. MEAs have been investigated at a
number of implant sites, including the retina, optic nerve and visual cortex, each re-
quiring varying levels of upstream signal processing that must be replicated. Retinal
devices based on this platform have been developed by three groups: USC/Second
Sight (Sylmar, CA, USA) [8], Intelligent Medical Implants (Bonn, Germany) [7],
which evolved from the Northern German Consortium, and our group, the Har-
vard Medical School/Massachusetts Institute of Technology/Veterans Administra-
tion consortium (Boston, MA, USA) [5]. The Second Sight and Intelligent Medical
Implant devices target epi-retinal implant locations, whereas the Harvard/MIT/VA
 1036 J. O. Winter et al.

Figure 2. (Left) Artist’s conception of Harvard/MIT/VA sub-retinal prosthesis. The image

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obtained by an external camera is translated into an electromagnetic signal that is transmitted wire-
lessly to the implanted secondary data coil attached to eye. Power is transmitted similarly. Essen-
tially the entire volume of the implant lies outside the eye. (Right) This perspective reveals that
only the electrode array (arrow) penetrates the wall of the eye. This figure is published in colour at
http://www.ingenta.com

device targets a sub-retinal implant location. Although there is substantial disagree-

ment, there may be some benefit of the sub-retinal implant location in lower electri-
cal thresholds [6, 34 –38].
Epi-retinal devices have been implanted by USC/Second Sight in three patients
with retinitis pigmentosa and showed no overt signs of toxicity for up to 21
months [8, 39, 40]. The devices have generated phosphenes and have allowed
repeated determinations of perceptual thresholds [41]. Their subjects were able
to discriminate between two objects and in some cases observe object movement
[42, 43]. Implantation of these devices in animals has been shown to drive the
pupillary light reflex [44] and to cause suppression of plasma melatonin, which
is under the control of a retino-hypothalamic pathway that subserves circadian
rhythms [45]. The implanted devices to date have contained roughly 16 functional
electrodes, which would at best seemingly provide only relatively coarse vision,
perhaps in the range of 20:1200 [29, 46].

Device resolution
Among devices currently in clinical trials, the MPDA devices have the smallest
electrode sizes (approximately 20 µm diameter). However, electrodes of this
size, powered by ambient light, are unlikely to provide sufficient charge to reach
threshold for neural excitation [30, 31]. The devices that have reportedly provided
the best vision for patients have employed approximately 20 electrodes with
diameters of approximately 500 µm [8, 29, 46]. Given that most neuronal cell
diameters are approximately 10 µm within the central retina, there is a relatively
high ratio of neurons to stimulating electrodes, which would presumably degrade
the specificity and spatial resolution of any induced images. The technology to
create smaller, more numerous electrodes certainly exists [47], but safety concerns
(see section on Effects of electrical stimulation on the electrode–tissue interface),
electrical cross-talk [48] and power requirements [48] have limited prostheses to a
 Retinal prostheses 1037
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Figure 3. Maximum pixel density as a function of the distance between electrodes and cells. Limits
are imposed by maximum charge density on Pt, TiN and IrOx electrodes. Figure reprinted with
author (Dr. D. Palanker, Stanford University, Stanford, CA, USA) and publisher (Institute of Physics)
permission from Ref. [29]. This figure is published in colour at http://www.ingenta.com

small number of large electrodes. Of these, safety concerns are the major limiting
factor on electrode size. Additionally, at this point in development, it is not clear
that having access to a larger number of stimulating electrodes would necessarily
translate into being able to improve the quality of induced visual percepts.
Estimates of the number of electrodes that would be required to yield various
levels of visual acuity with a retinal prosthesis have been studied by several groups.
These studies have provided estimates that range between 256 and 625 electrodes,
which theoretically might yield best visual acuity of 20/420 and 20/30, respectively
[49 –51]. However, the number of electrodes required depends on the ability of
electrode materials to safely transmit charge and also on the proximity of the target
tissue to those electrodes (Fig. 3) [29].

CHALLENGES TO ACHIEVING USEFUL VISION

The barriers in restoring vision to the blind are substantial. In addition to the
usual biomaterial issues such as toxicity, tissue encapsulation and cellular/immune
responses that might be incited by the foreign materials, an electrical prosthesis
must also provide long-term stability of the metal electrodes while minimizing any
tissue damage that occurs as a result of the electrical stimulation. Induced tissue
damage will reduce the excitability of the tissue and limit the potential for vision
restoration.
At the electrode–tissue interface, electrochemical reactions and heat production
generally accompany charge injection. These factors constrain maximum charge
injection levels and stimulation electrode area, which ultimately constrains the
 1038 J. O. Winter et al.

spatial resolution that could be achieved by electrical stimulation. The potential

biocompatibility and long-term functional stability of a retinal prosthesis are further
complicated by ongoing anatomical and physiological changes that inevitably occur
within the retina in patients with retinitis pigmentosa [52], which is the primary
disease that we hope to treat in the early years of visual prosthetic implantations. To
develop a clinically viable implant, these concerns must be satisfactorily addressed
over time scales of 10 years or more following implantation. Much work has
been done to explore these issues; however, there remains a notable absence of
knowledge in key areas, including perceptual thresholds, tissue damage thresholds
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and the impact of disease progression on the potential for vision restoration.

Charge thresholds for vision perception

One of the most critical needs in the development of visual prostheses is a
determination of the stimulation threshold that is required to produce a visual
percept (usually measured as charge/phase during current pulsing). The amount of
charge required to reach threshold is at least a function of the pulse duration, pulse
strength and the particular waveform applied [53]. As pulse duration decreases,
the current required to solicit a response increases dramatically. However, at long
pulse durations, the stimulation threshold approaches a constant value, known as the
rheobase. Electrical thresholds for eliciting a perceptual response in the human have
been measured during acute (i.e., hours-long) and chronic studies with electrodes
implanted either on the retina, the optic nerve, the surface of the visual cortex, or
intracortically, within the visual cortex (Table 1).
The data in Table 1 reveal marked differences in thresholds between healthy
patients and those who are blind because of retinal disease, which includes all of
the diseased citations, except those by Hambrecht who reports on a patient with
Table 1.
Comparison of human visual perceptual thresholds and corresponding waveforms for retinal, optic
nerve and cortical stimulation

Placement Type Charge/phase Charge density Sight Waveform Ref.

(µC/ph) (µC/cm2 )
Epi-retinal Surface 0.2–1.8 1630–14 680 RP/AMD PW
2 ms, 1 Hz [54]
Epi-retinal Surface 0.1–5.5 160–70 000 RP/AMD PW
4 ms,
10 Hz [20]
Epi-retinal Surface 0.33–1.9 320–12 230 RP/AMD PW 0.25–16 ms, 20 Hz [25]
Epi-retinal Surface 0.024–0.1 80–306 Normal PW 2 ms, 20 Hz [25]
Epi-retinal Surface 0.13 NA RP PW 1 ms [55]
Epi-retinal Surface 0.05–0.5 24–240 RP PW 1 ms [8]
Epi-retinal Surface 0.006–1.12 5–570 RP PW 1 ms [56]
Optic nerve Surface 0.007–0.124 4–62 RP PW 25–400 µs, 0–160 Hz [57]
Intracortical Penetrating 0.0004–0.0046 190–2300 Glaucoma PW = 200 µs, 200 Hz [58]
Intracortical Penetrating 0.004 2000 Normal PW = 200 µs, 100 Hz [58]
Cortical Surface 200 11 Normal PW = 200 µs, 100 Hz [58]

NA = not available.
 Retinal prostheses 1039

glaucomatous optic neuropathy. Rizzo et al. [5] observed charge/phase thresholds

for the normal retina that are four times less than the lowest threshold observed in
the RP retina. Interestingly, despite significant degeneration of the retinal ganglion
cells that form the optic nerve, perceptual thresholds of optic nerve stimulation in
RP patients are similar to those of normal patients [57]. This finding differs from
those of groups stimulating what are presumably the same axons at an epi-retinal
location.
Higher thresholds in diseased versus healthy retina have also been measured in
experiments using stimulating electrodes placed on the surface of the eyeball [59].
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It is possible that stimulation thresholds will increase progressively as the disease

process advances, which might require the use of adjustable stimulation parameters.
Examination of epi-retinal thresholds obtained by Rizzo et al. [5], Weiland et
al. [55], Humayun et al. [8] and Mahadevappa et al. [56], excluding data from
normally-sighted patients, reveals an average mid-range value of the perceptual
threshold in the diseased retina of approximately 0.5 µC/phase.

Causes of high perceptual threshold

The causes of high perceptual thresholds are not known but presumably relate to
several factors. Some likely explanations include: the anatomical and physiological
changes that accompany retinal degeneration; lack of understanding about the pre-
ferred methods of applying electrical stimulation; use of relatively large stimulating
electrodes that might create large inhibitory electrical fields; and the challenge for
the brain to learn how to make use of this new information that is being generated
by such artificial means. Some plausible factors that might be relevant also include:
formation of scar tissue on or around the stimulating electrodes, and the difficulty in
achieving intimate electrode–neuron contact. Mitigating any of these factors could
lead to significant advances in prosthesis resolution.

Device biocompatibility: gliosis. In general, the gross biocompatibility of

implanted devices has been good. Tissue reactions to implantation in general seem
not to be destructive. There is, for instance, a lack of any real encapsulation of the
foreign material [60, 61], which we (reasonably) expected to see. There is some
degree of “immune privilege” enjoyed by the eye, which might account for some
of these favorable outcomes [62, 63]. Furthermore, when an inflammatory reaction
does occur, it is typically related to the trauma of surgical implantation.
The field has collectively produced evidence of uneventful placement of a variety
of foreign materials at the levels of the retina [64, 65] and optic nerve [66] for
up to 4 years. However, some studies have shown up-regulation of glial fibrillary
acidic protein (GFAP) in the Müller cells of the retina. In addition, in the case of
sub-retinal implants, there has always been some degeneration of photoreceptors
with chronic sub-retinal implantation, given that the blood circulation of the
choriocapillaris, which is beneath the retina, is required to sustain the health
of photoreceptors. The photoreceptors also depend upon an integral anatomical
 1040 J. O. Winter et al.

relationship with the retinal pigment epithelium, which also underlies the retina
[67 –70]. There is also undoubtedly some degree of trauma to the outer retina when
a sub-retinal implant is performed.
Although it has not been explicitly observed in the retina, gliosis is also expected
to occur. Persistent gliosis has been observed with CNS microelectrodes, accom-
panied by a loss of neuronal cells [71]. Although the gliosis is localized to within
50–100 µm of the implant, this spatial extent is sufficient to interfere with the neural
recording and, probably, the stimulation capabilities of the electrodes. Minimizing
gliosis at the electrode-neural interface would presumably improve device perfor-
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mance. Certain types of scar tissue increase electrical resistance to current flow
[72]. Additionally, accumulation of scar tissue can expand the separation between
electrodes and target cells. Both factors increase the power required to achieve
threshold levels of charge injection. However, scar tissue can also have a beneficial
effect, by securing the implant to the target site, which may be especially useful for
epi-retinal implants [73].

Neuron–electrode interfacing. A significant contributing factor to high patient

thresholds is the proximity of the device to target cell populations. In many cases,
it is not possible to situate the implant near cells of interest. For example, in dogs,
epi-retinal arrays designed to rest on the retina surface actually displayed a mean
distance of 20–50 µm from the retina [74]. These arrays targeted retinal ganglion
or bipolar cell bodies located beyond the inner limiting membrane and nerve fiber
layer (approximately 100–200 µm thick [75]). Given that activation thresholds
increase significantly with distance from the retina [54, 76], these separations can
substantially elevate thresholds over those measured in vitro.
Increased electrode separation also decreases the likelihood that specific cell
classes or relatively small collections of neurons could be driven by electrical
stimulation. There was original speculation [47] and later in vivo evidence that
axons of retinal ganglion cells are driven by electrical stimulation applied to the
epi-retinal surface [77], although patients almost never report visual percepts that
might be reasonably ascribed to axonal stimulation. Perhaps an effect of decreased
specificity of excitation may simply be the generation of “noise” during neuronal
signal processing, which might compromise perceptual resolution. These issues are
not limited to retinal devices. For example, one version of the optic nerve prosthesis
consists of only 4 electrodes, and highly selective excitation of interior axons would
not be possible with such limited hardware [78]. Currently, the clinical [20] and
theoretical [79, 80] evidence seems to suggest that limited selective excitation of
cell bodies may be possible, but further in vivo study is required.

Effects of electrical stimulation on the electrode–tissue interface

Electrical stimulation of nerve requires charge injection across the electrode–
tissue interface, which exposes tissue to electrical current and any products of
the electrochemical reactions at the interface. The effects can have wide-reaching
 Retinal prostheses 1041

consequences on the tissue and the device. Excessive levels of charge may damage
tissue [81], the electrode [82, 83] and, in some instances, suppress the electrical
excitability of neuronal tissue even in the absence of histologically apparent damage
[84 –86]. The need to employ stimulation charge densities that are believed to
be acceptable (<100–200 µC/cm2 for platinum electrodes) has mandated the use
of relatively large electrodes for retinal prosthetic devices. The large electrodes
employed have not produced any definable histological damage [87], but may be
limiting the visual resolution of the devices that have been implanted.
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Charge-injection waveforms and limits. Electrical stimulation initiates a func-

tional response by depolarizing membrane potentials in excitable tissue. Depolar-
ization is achieved by the flow of ionic current between two or more electrodes, one
of which is usually in fairly close proximity to the target tissue. Charge-injection
for neural stimulation is typically applied in the form of rectangular current pulses,
with each pulse having cathodal and anodal components possessing current ampli-
tudes and durations that result in an overall zero net charge (i.e., charge-balance) for
the pulse. A typical pulse waveform with pulse parameters is provided in Fig. 4.
The majority of electrodes are metallic conductors and reactions at the electrode–
tissue interface are required to mediate the transition from electron flow in the
metal to ion flow in the tissue. These reactions are both capacitive, charging and
discharging the electrolyte double-layer, and Faradaic, in which surface-confined
species are reversibly oxidized and reduced. The maximum charge that an electrode
can inject into tissue without irreversible reactions is termed the “safe charge-
injection limit”. This limit is usually defined as the amount of charge that can be
injected without polarizing the electrode beyond the potential limits for reduction or
oxidation of water. This limit is based on the premise that irreversible reactions will
produce toxic by-products that damage tissue near the electrode. Charge injection
limits depend on the current density, which is a direct measure of the rate of the

Figure 4. A biphasic, charge-balanced current pulse typical of those used in neural stimulation. For
charge balance, I c × t c = I a × t a . The parameters and normal range for each value are: I c , cathodic
current (1 µA–10 mA); I a , anodic current (1 µA–10 mA); t c , cathodic half-phase period (50 µs–
10 ms); t d , interphase dwell (0–1 ms); t a , anodic half-phase period (50 µs–10 ms); frequency (not
shown), pulses per second (10–250 Hz).
 1042 J. O. Winter et al.

double-layer charging and reduction-oxidation processes, the pulse frequency and

the relative magnitudes of Ic and Ia . The geometry and porosity of the electrode
also impact the uniformity and magnitude of the polarization [88, 89].

Electrode corrosion. In addition to avoiding tissue damage, it is also desirable

to avoid reactions that can lead to electrode dissolution, or corrosion. In the absence
of an imposed stimulus pulse, all materials presently used as stimulation electrodes
resist corrosion when implanted into the body. However, during charge injection
an electrode may be polarized to a potential at which irreversible degradation in
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the form of electrode dissolution or delamination of electrode coatings occurs. The

potential for and the severity of corrosion depends on many factors including the
quantity of charge delivered, the rate of charge delivery (i.e., current density), the
shape of the pulse waveform, and the strategy used to balance the cathodal and
anodal charges in the pulse. Even when stimulus pulses are delivered with charge-
balanced waveforms, electrode degradation can occur.
For example, intracortical microelectrodes coated with activated iridium oxide
(AIROF) were severely damaged by polarization more negative than about −0.6 V
(vs. Ag|AgCl) when pulsed in cat cortex [83]. The AIROF coatings delaminated
from the electrode and were deposited into the tissue around the tip of the
microelectrode. Platinum and PtIr-alloys, which are the most commonly used
electrode materials for implantable devices, exhibit some dissolution in vitro even at
very low levels of charge-injection (20–50 µC/cm2 ) [90, 91]. Other in vitro studies
have shown that the presence of protein greatly reduces the dissolution rate, so in
vivo dissolution is likely to be less than that revealed by in vitro studies, especially
when performed in inorganic media [92]. Nonetheless, corrosion has occurred in
vivo with Pt electrodes in as little as 3 years of use in a cochlear implant, and Pt
was found in tissue around surface cortical electrodes pulsed at 100 µC/cm2 after
pulsing for only 36 h [90, 93]. In the cortical surface electrode study by Robblee
et al. [90], the rate of Pt dissolution decreased over 36 h of pulsing and very low
dissolution rates for Pt electrodes may be expected at approximately 100 µC/cm2
once the electrode–tissue interface has stabilized.
The preferred list of candidate electrode materials for a visual prosthesis includes
Pt, PtIr-alloys, iridium oxide and titanium nitride. Platinum electrodes have
been used for epi-retinal stimulation studies by Humayun et al. [20, 54] and
Mahahdevappa et al. [56]. Activated iridium oxide electrodes have been used
by Rizzo et al. [5, 25] in epi-retinal studies and sputtered iridium oxide has
been used by Chow et al. [70] in sub-retinal photodiode arrays. Titanium
nitride electrodes have been used by Zrenner et al. [69] in studies of sub-
retinal microphotodiode stimulation of degenerated rat retina. Interestingly, even
in the absence of imposed currents, the titanium nitride was poorly biocompatible
compared with iridium, SiO2 or Si3 N4 , as judged by retinal neuron cell survival
in disassociated cell cultures. The charge-injection capacities of these materials
have been evaluated in vitro by several investigators and the range of values is
 Retinal prostheses 1043

presented in Table 2. Activated iridium oxide has the highest reported charge-
injection capacity. However, the measured capacities can vary greatly with the
thickness, morphology and preparation method of an electrode surface or coating;
the values in Table 2 are specific to those features of the electrodes used in the
studies reported.

Electrical-stimulation-induced tissue damage. Although tissue damage is possi-

ble from the accumulation of toxic products from irreversible reactions at the elec-
trode, not all tissue damage is the result of such electrochemical reactions. For
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instance, a comparison of Faradaic and capacitive electrodes pulsed with charge

densities of 80–100 µC/cm2 for 7 h showed equivalent tissue damage [97]. The
cause of this type of tissue damage, which is manifested as tissue necrosis, vac-
uole formation and disruption of the plasma membranes (Fig. 5), is not known
Table 2.
In vitro charge injection capacities of stimulation electrode materials

Material Charge limit (mC/cm2 ) Reference

Pt and PtIr-alloys 0.05–0.15 [91]
Iridium oxide 1–3.5 [94, 95]
Titanium nitride approximately 1 [96]

Figure 5. Nissl-stained tissue sections of cat cortex exposed to (A) an unpulsed microelectrode
and (B) a microelectrode pulsed at 60 nC per phase for 7 h. The microelectrode track is indicated
with (T). Neurons near the unpulsed electrode appear as ovoid entities with small spot(s) (nucleoli).
In most cases, these are accompanied by smaller, darkly-stained satellite cells (oligodendrocytes).
Near the pulsed electrode, the damage from the stimulation is manifested as a loss most of the
neurons within 50 µm of the electrode and by an aggregate of inflammatory cells (darkly-stained,
globular entities) around the electrode site. From their morphology, these cells are most likely
macrophages phagocytosing remnants of cells or cellular processes damaged by the electrical
stimulation. Macrophages originate from blood vessels and a number of them can be seen closely
surrounding the large blood vessel at the upper right (“perivascular cuffing”). Figure courtesy
of Dr. D. McCreery, Huntington Medical Research Institute, Pasadena, CA, USA. This figure is
published in colour at http://www.ingenta.com
 1044 J. O. Winter et al.

[98, 99]. One hypothesis is that damage occurs as a result of excessive neuronal
firing, which can increase neurotransmitter release and subsequent Ca2+ uptake that
leads to cell death [85]. Another possibility is that the imbalance between normal
and excitation-induced intracellular concentrations of K+ and Na+ may produce
cellular edema that leads to cell damage. Finally, high stimulus currents have been
linked to a breakdown of the blood-brain barrier [100], and it is possible that an
increased number of immune cells enter the tissue and incite tissue damage.
Damage increases with charge density [81, 84] and charge per phase [76, 100]. In
fact, when histological results of stimulation studies are plotted on a charge per
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phase versus charge density graph (Fig. 6, black and white circles representing
damaging and non-damaging stimulation, respectively), a damage threshold can
be estimated. An approximate boundary between damaging and safe thresholds
is identified by the dashed line in Fig. 6, which is derived from the tissue-damage
model proposed by Shannon [101], for which we have selected k = 1.85 to match
the histologically observed boundary. Above the k = 1.85 line, damage occurs,
while below the line damage is not seen [81, 84]. The model considers surface
electrodes in sufficiently close proximity to the excitable tissue that elevated, non-
uniform current distributions at the edges of the electrodes are the primary cause of
tissue damage. This geometry is similar to that encountered with the planar, circular

Figure 6. A comparison of electrical thresholds for perception in human volunteers using epi-retinal
stimulation in three acute [5, 20, 54] and two chronic studies [8, 56]. Thresholds for Humayun [8]
are 10 weeks post-implant. Included are data and model predictions for tissue damage. The data
points from Rizzo et al. [5] marked with * are from a normally seeing subject. Two horizontal dashed
lines indicate the charge density limits for platinum and AIROF electrodes. Tissue damage: black
closed circle [81], black inverted triangle [100]. No tissue damage: black open circle [81]. Perceptual
thresholds: blue triangle [20], cyan squre [54], red diamond [5], green circle [56], brown square [8].
This figure is published in colour at http://www.ingenta.com
 Retinal prostheses 1045

electrodes employed in the epi-retinal studies reported in Table 1, and should be

applicable to either epi-retinal or sub-retinal placements when planar electrodes are
employed. The Shannon model relies on histological assessments of tissue damage
from studies involving extended periods of pulsing (7 h) and it should be noted
that the perceptual thresholds reported in Fig. 6 were obtained in acute studies
using single pulses or short pulse trains and those perceptual thresholds that exceed
the tissue damage boundary are unlikely to have caused tissue damage. However,
damage thresholds for long-term chronic pulsing remain to be determined and it
seems likely that more conservative limits than those defined in Fig. 6 will need to
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be adopted for long-term implants.

Although not directly comparable, some guidelines for safe stimulation may be
taken from cochlear implant studies [102]. High current densities can produce
histological evidence of nerve damage [103, 104], and some psychophysical studies
have revealed increased perceptual thresholds when high current densities are used
[104 –106]. However, even intermediate current densities may produce transient
elevations in thresholds, which suggest that mild dysfunction can be followed by
tissue repair. These results are dependant on the type and geometry of the electrode,
and on the species used in the animal model. It should also be noted that some
cochlear implants have demonstrated a neuroprotective effect (increased survival
of spiral ganglion neurons) in response to electrical stimulation that might lower
thresholds [107]. This factor may mitigate some of the features discussed above.
One of the principle reasons that relatively large electrodes (>400 µm diameter)
are employed for retinal prosthetic devices is concern that high charge densities
will damage neighboring tissue or the electrode. However, to our knowledge, a
firm relationship between charge/phase threshold and electrode size in target tissues
for visual prostheses has not been established, perhaps because the amount of
charge needed to damage the retina has not yet been determined. It is possible
that thresholds decrease for smaller electrodes as the specificity of the stimulation
applied increases. Examining this relationship is an ongoing area of research for the
visual prosthesis community.

A LOOK TO THE FUTURE

Device resolution is presently restricted by many factors. Among the electronic

concerns microelectronic design, packaging, electrode technology, power transmis-
sion and dissipation in tissue, and data telemetry rates figure prominently. From a
biocompatibility perspective, charge density limits for electrode or tissue damage
are a major contributor. If perceptual thresholds could be lowered, electrode size
could be reduced without increasing charge density to unsafe levels. If this goal
could be realized, it would make it possible to use a higher area-density of elec-
trodes, which should theoretically improve the selectivity of neural stimulation and,
presumably, the spatial detail of the induced visual images. A number of approaches
 1046 J. O. Winter et al.

to address the biocompatibility concern of decreasing charge thresholds for stimu-

lation are being investigated. The strategy taken by most investigators is to decrease
the spatial separation of the electrode and target population of neurons. In theory,
this approach should reduce stimulation thresholds, which might make stimulation
safer and hopefully produce better visual outcomes.

Alternative electrode designs

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Alternative electrode configurations may decrease electrode–tissue separation dis-

tances and thereby lower thresholds. For example, glass microwires have been used
to create surface electrode arrays that can be curved to conform to the shape of the
retina [108]. In preliminary experiments, activation thresholds of approximately
0.5–0.8 µC have been measured for retina, which is near the low end of reported
results for surface stimulation electrodes (see Table 1). Unfortunately, this device
employs electro-deposited nickel, which is known to be toxic to tissues, although
the nickel could be protected with a layer of gold or platinum that would enhance
biocompatibility.
However, an approach that will likely be more successful is the use of penetrating
arrays. Studies of visual cortical stimulating electrodes consistently have shown
that penetrating electrodes have lower charge thresholds than surface electrodes
(Table 1). However, retinal and optic nerve prostheses presently use only a
surface electrode design. In one conception of a penetrating array, networks of
carbon nanotubes (CNT) have been used to penetrate the retina. CNT pillar
arrays with a diameter of 50 µm and a height of 100 µm can perforate the
retina without disruption of their mechanical integrity [109], and they have been
shown to be “biocompatible” in retinal ganglion cell cultures, at least for 9 days
[110]. However, electrical thresholds generated with such devices have not yet
been determined. Although additional study is needed to further characterize
these designs, penetrating electrodes that improve device-tissue proximity should
certainly decrease thresholds and permit the use of smaller electrode sizes. The
value created by penetrating electrodes in lowering activation thresholds is clearly
evident from a comparison of the thresholds in Table 1 for surface and penetrating
electrodes at the level of the visual cortex.
Another approach designed to decrease the separation distance between electrodes
and target cells is in situ polymerization of electrically conducting polymers.
Polypyrrole and polyethylenedioxythiophene (PEDOT) can be used as electrode
materials for neural prostheses. Martin et al. [111 –113] propose that these
polymers can be injected into the target area and electrochemically polymerized
from the electrode surface outward. Although there are substantial hurdles to
clinical implementation (including potential aversion to in situ electro-deposition
in the brain), this technique may allow electrodes to be grown directly in target
tissue, improving separation distance.
 Retinal prostheses 1047

Surface coatings
Another method for improving tissue–device contact is the use of surface coatings
composed of patterned chemical cues. These coatings, which may include bio-
mimetic chemicals (i.e., mimicking native tissue with non-native molecules) or bio-
molecules, can reduce thresholds through two mechanisms. Surface modification
can diminish immune response and, therefore, the formation of scar tissue. The di-
minished tissue responses will decrease the thickness and the electrical resistance of
tissue lying between the electrodes and the target cells, which should substantially
reduce thresholds and enhance implant performance. Alternatively, surface mod-
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ification can promote neuronal attachment to the electrode surface, which should
enhance the integration of the device with the host tissue and presumably lower
thresholds. Unfortunately, bio-active molecules generally do not attract or promote
adhesion of specific neurons. Undesirable glia (i.e., Müller cells, astrocytes) may
be equally attracted, fouling the electrode surface and increasing the electrical re-
sistance.
Studies using biomimetic surfaces are still in early phases, and potential improve-
ments in threshold have not yet been demonstrated. However, alumina/zirconia
ceramics have improved the biocompatibility of retinal implant packaging materi-
als [114] and amorphous carbon deposited on sub-retinal implant materials virtually
eliminated the fibrotic capsule [61]. Unfortunately, the exact mechanism for these
beneficial responses is unknown. Coatings may either diminish the initial immune
response or play a more active role in chronic implant tolerance. If it is the lat-
ter case, these results could be difficult to maintain, as creating coatings stable for
the life of an implant may prove challenging. However, in pacemaker studies of
biomimetic self-assembled monolayers (SAMs) of dodecanethiol, reduced acute in-
flammatory reactions promoted long-term improvement in pacing efficiency [115],
suggesting that even acute changes in inflammatory response may diminish thresh-
olds.
Biomimetic coatings have also been used to promote cell adhesion. For exam-
ple, nanostructured porous silicon, which mimics microtubules found in the ex-
tracellular matrix, enhanced PC12 cell adhesion while reducing astrocytes adhesion
[116]. Composite biomimetic-natural coatings, such as layer-by-layer films of poly-
ethyleneimine and laminin, increased chick cortical neuron adhesion [117] while
maintaining a low physical profile (approximately 3–11 nm). Thus, electrode–tissue
separation distance resulting from the film itself was minimized. However, thresh-
olds have not been measured for these systems.
The development of biomolecular coatings is more advanced. Surfaces coated
with polylysine, laminin, or laminin peptides encouraged neuronal attachment to
micropatterned substrates [118 –122]. For visual prostheses in particular, laminin
has produced neurite extension from PC12 cells and rat RGCs over patterns as
small as 5 µm in width [123]. Subsequent migration of RGC axons toward the
site of a stimulating electrode reduced thresholds by an order of magnitude [124].
This method supported neurite outgrowth from retinal explants for up to one month
 1048 J. O. Winter et al.

[122]. Nonetheless, as stated above, many biological coatings lack specificity in

promoting cell adhesion, and the potential that a coating may encourage attachment
of glial cells is a major concern [122, 125 – 127]
One limitation of these results is that threshold reductions were measured in vitro.
The situation in vivo can be markedly different. In vivo conditions are very unlikely
to provide direct contact of cells to tethered factors. Typically, target cells are
embedded in several hundred micrometers of intervening tissue (e.g., approximately
100 µm [75]), and it is unlikely that tethered factors alone will successfully interact
with cells across these distances.
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Tissue-engineered devices
Tissue-engineering approaches, which attempt to reconstruct or mimic native tissue,
may have more success in sustaining long-range interactions between target cells
and the electrode surface. Several exploratory approaches for the merger of
tissue engineering and implantable devices are being considered for use with
a visual prosthesis. Electrode surfaces can be modified using techniques from
tissue engineering to promote nerve growth to a target. For example, implanted
cells cultured on micropatterned electrodes could extend neurites to the retina or
brain [128]. Alternatively, physical or chemical cues may encourage growth of
existing cells toward electrode surfaces [129, 130]. In either case, proposed devices
would encourage cells to extend neurites over large distances. These extensions
should produce more intimate contacts between electrodes and their targets, with
the possibility of reducing thresholds, which have been quite high for patients
with retinal degenerations (Table 1), who are the intended recipients for a visual
prosthesis.
It has also been suggested that grafts of implanted cells and tissue could produce
a synthetic “optic nerve” connecting a device to the lateral geniculate nucleus
[128, 131 –133]. This device, known as the hybrid retinal implant, would not
require retinal ganglion cells or the optic nerve and, thus, could treat a wide variety
of ailments. The concept is exciting, but underscores one of the larger issues in
tissue engineering today. Implantation of foreign cells and tissue will likely create
an immune response in the host. While the immune system can be suppressed
pharmacologically, it is unclear that the benefits of the device would outweigh the
risks of immune suppression therapy. The hope is that suppression of interference
by the immune system could be achieved locally, i.e., at the site of implantation
or transplantation. For instance, membranes could be used to exclude immune
elements [134], but the porosity required would likely be insufficient to permit
regeneration of the implanted neurons to target tissue. Alternatively, allogeneic host
cells and tissue, which would not evoke an immune response, could be cultured
ex vivo and implanted with the device. However, it is improbable that adequate
quantities of cells could be obtained, and function at the donor site would be lost.
Technologies are currently not sufficiently advanced for a device using cellular
 Retinal prostheses 1049
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Figure 7. Histological sections of the RCS rat retina 9 days after implantation. Retinal tissue (INL)
migrates through the aperture of 40 µm in a 13-µm-thick Mylar membrane and spreads above the RPE.
Scale bar is 50 µm. Figure reprinted with author (Dr. D. Palanker, Stanford University, Stanford, CA,
USA) and publisher (Institute of Physics) permission from Ref. [29]. This figure is published in
colour at http://www.ingenta.com

implantation to find acceptance in the clinic. Although, as stem cell techniques

advance, it may become possible to isolate cells from a patient for later implantation.
Other methods can circumvent these issues by utilizing physical and chemical
cues to attract existing cells to the electrode surface. One device proposes to use
the physical guidance of a micro-channel network to link cells with electrodes
[135]. The premise is intriguing, as the researchers have already shown that
retinal tissue will migrate through perforations in a Mylar membrane implanted sub-
retinally (Fig. 7) [136 –138]. It has also been suggested that electrodes coated with
hydrogels partially comprised of extracellular matrix components (e.g., laminin,
collagen) could release neurotrophic factors (e.g., NGF) that attract cells to the
device surface [130]. In ongoing work in our laboratory, we have observed neurite
extension in PC12 cells (Fig. 8) [129] and retinal explants (data not shown) in
 1050 J. O. Winter et al.
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Figure 8. Neurite extension from PC12 cells exposed to neurotrophin-eluting polymer hydrogels.
After 9 days of culture, cells exposed to neurotrophin-eluting hydrogel boluses (A) display substantial
neurite extension comparable to that of a positive control (B) receiving neurotrophin directly in
solution. (C) Control cells receiving no neurotrophin display few, if any, neurites.

the presence of neurotrophin-eluting hydrogels. Neurites extended in response to

released neurotrophins retract with neurotrophin removal; however, in the presence
of cell adhesion molecules (i.e., laminin, collagen, or polylysine) extensions not
only persist, but continue to grow.
Either method will probably be successful in promoting nerve growth; however,
several issues will need to be addressed in future research. Glia may also be attracted
to electrode surfaces, which would likely diminish neuronal proximity to the
electrodes and increase electrical resistance. It is unclear if neuronal function would
remain unaltered after growth. Biochemical changes may modify neurotransmitter
expression or cell firing. Further, regenerating neurons may create new synaptic
connections, altering the visuotopic map in the retina or cortex.

SUMMARY
Great strides have been made in the visual prosthetic field over the two decades
since its conception. Four companies are already performing long-term implants
into blind human patients. The results of clinical testing are promising enough
that continued work in the field is assured. However, many challenges remain
for implementation in large patient populations. The electrical signal used will
need to be non-damaging and contain the appropriate level of signal processing
 Retinal prostheses 1051

for the targeted cell type, and all of this must be accomplished using an adequate
number of pixels for the desired acuity level. Pixel density is limited by high
activation thresholds, resulting in part from the large separation distances between
electrodes and target cells and the progression of degenerative diseases in target
patients. Stimulation values sufficient to achieve these thresholds may exceed
electrode charge injection limits and, therefore, require compensating increases in
electrode area and concomitant decrease in pixel density and device resolution.
Comparisons to the cochlear prosthesis, which has had a very successful track
record of restoring hearing to the deaf, provide hope and insight. The success of the
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cochlear prosthesis is particularly interesting in light of the fact that a relatively

small number of electrodes (i.e., 6–18) are generally used. This suggests that
plasticity of the cortex is able to accommodate the artificial electrical inputs to
produce useful hearing. It is hoped that the brain will also contribute to the success
of visual prosthetic devices. The success of a visual prosthesis may partly depend
upon the ability to lower the relatively high stimulation thresholds that are found in
patients with retinal degenerations, who are the primary intended recipients.
Emerging attempts to lower activation thresholds with bioengineering techniques
are in the early development stage. These strategies primarily attempt to provide
more intimate contact between the target cells and the device. Managing non-
neuronal cell growth on these prostheses will be important to preserving the close
proximity, and presumed threshold reduction, of the neural cells and electrodes.
Polymeric coatings and drug-eluting polymers are likely to be involved in moder-
ating both acute and chronic inflammatory responses to retinal prostheses and their
development is being actively pursued. As these methods and materials advance,
the potential for success for visual prosthetic devices will likely increase.

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