sensors

Review
Retinal Prostheses: Engineering and Clinical Perspectives for
Vision Restoration
Kevin Y. Wu 1,† , Mina Mina 2,† , Jean-Yves Sahyoun 3 , Ananda Kalevar 1 and Simon D. Tran 4, *

1 Department of Surgery, Division of Ophthalmology, University of Sherbrooke,

Sherbrooke, QC J1G 2E8, Canada; [Link]@[Link] (K.Y.W.)
2 Department of Mechanical and Manufacturing Engineering, University of Calgary,
Calgary, AB T2N 1N4, Canada
3 Faculty of Medicine, University of Montreal, Montreal, QC H3T 1J4, Canada
4 Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montreal, QC H3A 1G1, Canada
* Correspondence: [Link]@[Link]
† These authors contributed equally to this work.

Abstract: A retinal prosthesis, also known as a bionic eye, is a device that can be implanted to
partially restore vision in patients with retinal diseases that have resulted in the loss of photorecep-
tors (e.g., age-related macular degeneration and retinitis pigmentosa). Recently, there have been
major breakthroughs in retinal prosthesis technology, with the creation of numerous types of im-
plants, including epiretinal, subretinal, and suprachoroidal sensors. These devices can stimulate
the remaining cells in the retina with electric signals to create a visual sensation. A literature re-
view of the pre-clinical and clinical studies published between 2017 and 2023 is conducted. This
narrative review delves into the retinal anatomy, physiology, pathology, and principles underlying
electronic retinal prostheses. Engineering aspects are explored, including electrode–retina alignment,
electrode size and material, charge density, resolution limits, spatial selectivity, and bidirectional
closed-loop systems. This article also discusses clinical aspects, focusing on safety, adverse events,
visual function, outcomes, and the importance of rehabilitation programs. Moreover, there is ongoing
debate over whether implantable retinal devices still offer a promising approach for the treatment of
retinal diseases, considering the recent emergence of cell-based and gene-based therapies as well as
optogenetics. This review compares retinal prostheses with these alternative therapies, providing
Citation: Wu, K.Y.; Mina, M.;
a balanced perspective on their advantages and limitations. The recent advancements in retinal
Sahyoun, J.-Y.; Kalevar, A.; Tran, S.D.
prosthesis technology are also outlined, emphasizing progress in engineering and the outlook of
Retinal Prostheses: Engineering and
retinal prostheses. While acknowledging the challenges and complexities of the technology, this
Clinical Perspectives for Vision
Restoration. Sensors 2023, 23, 5782.
article highlights the significant potential of retinal prostheses for vision restoration in individuals
[Link] with retinal diseases and calls for continued research and development to refine and enhance their
s23135782 performance, ultimately improving patient outcomes and quality of life.

Academic Editor: Antonios Kelarakis

Keywords: flexible electronic devices; implantable electronic devices; flexible sensors; human–
Received: 20 April 2023 machine interface; retinal prosthesis; vision restoration; retinal disease; ophthalmology
Revised: 4 June 2023
Accepted: 19 June 2023
Published: 21 June 2023
1. Introduction
1.1. Overview of Retinal Prostheses
Copyright: © 2023 by the authors. In recent years, the field of retinal prosthetics has gained considerable attention due to
Licensee MDPI, Basel, Switzerland. its potential to restore some useful vision to individuals suffering from retinal diseases that
This article is an open access article have resulted in the loss of photoreceptors, such as age-related macular degeneration and
distributed under the terms and retinitis pigmentosa. These conditions can lead to significant vision loss, severely impacting
conditions of the Creative Commons patients’ quality of life and ability to perform daily tasks. Retinal prostheses, also known as
Attribution (CC BY) license (https:// bionic eyes, offer a promising solution by stimulating the remaining retinal cells to produce
[Link]/licenses/by/ visual sensations.
4.0/).

Sensors 2023, 23, 5782. [Link] [Link]

Sensors 2023, 23, x FOR PEER REVIEW 3 of 37
Sensors 2023, 23, 5782 2 of 35

Horizontal cells make synaptic connections with rod spherules and cone pedicles,
The development of retinal prosthetic devices has been marked by significant tech-
while bipolar
nological cells are vertically
advancements, includingoriented, synapsing with
the introduction either rod
of various or cone
implant synaptic
designs suchbod-as
ies. Their axons make synaptic contact with ganglion cells
epiretinal, subretinal, and suprachoroidal sensors. These innovations have expandedand amacrine cells in the inner
plexiform
the range oflayer. The axons
possibilities forofenhancing
ganglion cells formvisual
patients’ the nerve
acuity fiber
andlayer and later
improving thethe optic
overall
nerve, containing over one million
functionality of retinal prosthetic devices. optic nerve fibers [1].
This comprehensive review delves into the pre-clinical and clinical studies conducted
between 2017 of
1.3. Overview andRetinal
2023, Physiology
exploring the andretinal
Pathology
anatomy, physiology, pathology, and principles
Retinal electronic
underlying prosthesesretinal
aim to prostheses.
restore vision in degenerate
Engineering eyes by
aspects suchreplacing the function
as electrode–retina
of the photoreceptors.
alignment, electrode size In the
andnormal
material, eye, the photoreceptors
charge density, resolution in the outerspatial
limits, layers selectivity,
of the ret-
ina contain
and light-sensitive
bidirectional closed-loop pigments
systems thataretrigger the phototransduction
examined. cascade, generat-
This article also discusses clinical
ing neuronal
aspects, signals
focusing upon light
on safety, stimuli.
adverse These
events, signals
visual are processed
function, outcomes, by and
a complex network
the importance
of neurons withinprograms.
rehabilitation the middleMoreover,
layers of this the retina
reviewbefore reaching
addresses retinal ganglion
the ongoing debate overcells
the viability
(RGCs) in theofinner
implantable retinal processes
layers. Axonal devices infrom lightRGCs
of emerging
form the cell-based
optic nerve, andtransmitting
gene-based
therapies as well
light-evoked as optogenetics,
neuronal signals to comparing retinal prostheses
the visual cortex. However, in to these alternative
congenital retinaltherapies
dystro-
and
phiesproviding a balanced
such as retinitis perspective
pigmentosa, the on their advantages
photoreceptors in theand limitations.
outer layers areThe recent
gradually
advancements in retinal visual
lost, causing progressive prosthesisloss, technology
while the inner are outlined, emphasizing
retinal layers, includingprogress
RGCs and in
engineering
bipolar cells,andare the futurespared
partially outlook [2].of retinal prostheses. In particular, the introduction of
wireless technologyvision
Theoretically, and artificial
restorationintelligence
could beto improvebythe
achieved processing
creating retinal and transmission
prostheses that
of electrical signals to the retinal is discussed.
receive and process incoming light, transmitting the information as electrical impulses to
the remaining inner retinal layers for visual function. However, the retina’s complex phys-
1.2. Overview of Retinal Structure and Function
iology poses significant challenges for retinal prostheses, as devices must replicate intri-
The retina,
cate retinal a thin and
processing. transparent
Currently, structure,
electrical embryologically
or photovoltaic originates
stimulation is from the inner
provided in a
and outer layers
relatively of the optic
unspecified manner, [Link]
It comprises 10 activating
distinct layers, each cell
multiple playing a crucial
types. role
The chal-
in the visual processing pathway. In a cross section, these layers
lenge lies in developing more selective stimulation to optimize device resolution and pa- can be identified from the
inner to the
tient [Link] retina as follows (Figure 1).

Figure 1. Retinal anatomy. The illustration highlights the different layers of the retina and its main
Figure 1. Retinal anatomy. The illustration highlights the different layers of the retina and its main
cell types. (BioRender, [Link] accessed on 16 February 2023).
cell types. (BioRender, [Link] accessed on 16 February 2023).
Sensors 2023, 23, 5782 3 of 35

• Nerve fiber layer: This layer contains the axons of retinal ganglion cells that coalesce
to form the optic nerve.
• Ganglion cell layer: This layer is composed of the cell bodies of retinal ganglion cells,
which transmit visual information to the brain.
• Inner plexiform layer: This layer consists of the synapses between bipolar and ganglion
cells, facilitating signal processing and integration.
• Inner nuclear layer: This layer houses the cell bodies of bipolar, horizontal, and amacrine
cells, which play essential roles in processing and transmitting visual information.
• Outer plexiform layer: This layer contains synapses between photoreceptors, bipolar
cells, and horizontal cells, allowing for the initial processing of visual signals.
• Outer nuclear layer: This layer is made up of the cell bodies of rod and cone photore-
ceptors, which are responsible for capturing and converting light into neural signals.
• Rod and cone inner and outer segments: These segments are part of the photoreceptor
cells, which include rods and cones. The inner segments contain vital cellular compo-
nents, such as mitochondria, while the outer segments contain stacked discs rich in
photopigments, which are essential for absorbing light and initiating the phototrans-
duction cascade to produce neuronal signals.
• Retinal pigment epithelium (RPE): This is the outermost layer of the retina, located
just beneath the photoreceptor cells. The RPE has several crucial functions in visual
processing. Its cells absorb stray light, preventing light scatter and enhancing visual
acuity. They also play a vital role in recycling photopigments and shuttling nutrients
to the photoreceptors. Additionally, they facilitate the transport of metabolic waste
products from the photoreceptors to the choroidal blood supply, thereby helping to
maintain the health of the photoreceptor cells.
Horizontal cells make synaptic connections with rod spherules and cone pedicles,
while bipolar cells are vertically oriented, synapsing with either rod or cone synaptic
bodies. Their axons make synaptic contact with ganglion cells and amacrine cells in the
inner plexiform layer. The axons of ganglion cells form the nerve fiber layer and later the
optic nerve, containing over one million optic nerve fibers [1].

1.3. Overview of Retinal Physiology and Pathology

Retinal prostheses aim to restore vision in degenerate eyes by replacing the function of
the photoreceptors. In the normal eye, the photoreceptors in the outer layers of the retina
contain light-sensitive pigments that trigger the phototransduction cascade, generating
neuronal signals upon light stimuli. These signals are processed by a complex network of
neurons within the middle layers of the retina before reaching retinal ganglion cells (RGCs)
in the inner layers. Axonal processes from RGCs form the optic nerve, transmitting light-
evoked neuronal signals to the visual cortex. However, in congenital retinal dystrophies
such as retinitis pigmentosa, the photoreceptors in the outer layers are gradually lost,
causing progressive visual loss, while the inner retinal layers, including RGCs and bipolar
cells, are partially spared [2].
Theoretically, vision restoration could be achieved by creating retinal prostheses that
receive and process incoming light, transmitting the information as electrical impulses
to the remaining inner retinal layers for visual function. However, the retina’s complex
physiology poses significant challenges for retinal prostheses, as devices must replicate
intricate retinal processing. Currently, electrical or photovoltaic stimulation is provided
in a relatively unspecified manner, simultaneously activating multiple cell types. The
challenge lies in developing more selective stimulation to optimize device resolution and
patient outcomes.

2. Principles of Electronic Retinal Prostheses

At the intersection of science and engineering, the field of visual prosthetics is driven
by an ambition–to restore vision to the blind. The epitome of success in the field would
be to create vision comparable to that of a healthy retina. Natural vision is made possible
Sensors 2023, 23, 5782 4 of 35

through complex, highly orchestrated, temporally synchronized electrical signals fired by

retinal ganglion cells [3]. This, then, becomes the goal of retinal prosthesis–to receive a
light stimulus, convert it to an electric pulse, and deliver that pulse to the retina through a
microelectrode array. Through this electric signal, prostheses aim to stimulate the structures
of the retina that remain capable of conveying signals to the optic nerve, which transmits
them to the brain for interpretation.
Mainly, two main mechanisms were described that allow prostheses to provide elec-
trical stimulation to retinal cells [4]. The first mechanism works through external light
detection and internal impulse delivery. In this mechanism, a microelectrode array is
intraocularly implanted. This electrode array cannot convert light signals to electrical
impulses by itself. Thus, it depends on an external camera system, such as one mounted on
a set of glasses, to receive an image from the surroundings. That image is then processed
(i.e., the image is converted to electrical impulses) and sent to a periocular implant (Figure 2).
Finally, the periocular implant sends the electrical signal to the implanted microelectrode
via cables. The microelectrode array then conveys it to the retinal cells. An example of one
such system is the ARGUS II prosthetic (Figures 2 and 3) [5]. In the second mechanism, a
photodiode electrode array that can act directly as the image receiver is implanted. This
photodiode electrode is able to directly receive light energy and transduce it to an electrical
signal (Figure 4) [6]. The light-induced signal can then be used to stimulate retinal cells.
These photodiode-based systems aim to replace the lost photoreceptors of the retina, and
they can often fulfill their function without having processing units or external cameras. In
some cases, however, external components including external power were used to amplify
the light waves and produce suitably strengthened impulses [7]. Generally, prostheses
using the second mechanism are activated directly by light and can depend on photovoltaic
processes, such as creating a voltage drop, to produce an electric field which can then be
used to stimulate target cells [8]. Photodiode systems have multiple advantages. (1) Due to
their photovoltaic process, photodiode-based prostheses can avoid the use of implanted
cables. Consequently, the surgical implantation tends to be less complex for photodiode-
based prostheses than for implants requiring cable connections. (2) These systems can
directly transduce light stimuli to electric signals and are, thus, often functional without
the use of an external camera. Eliminating the need for an external camera
Sensors 2023, 23, x FOR PEER REVIEW 5 of maintains
37 the
link between eye movements and visual stimuli [9].

Figure 2. Components of the ARGUS II system. Schematic representation of the main components
Figure 2. Components
of the ARGUS of the ARGUS
II retinal prosthesis system,IIincluding
system. the
Schematic representation
camera, video processing of theand
unit, main components of
elec-
the ARGUS
trode array. II retinal prosthesis system, including the camera, video processing unit, and electrode array.

Regardless of the mechanism of action, however–whether the prosthesis has internal

non-light-sensitive electrodes or photodiodes–both systems must fulfill common engi-
neering design criteria. Hereafter in this review, the general term microelectrode array
(MEA) is used to refer to both types of arrays, since both systems use electrodes to convey
electric impulses to retinal cells [10].
 trode array.

Regardless of the mechanism of action, however–whether the prosthesis has internal

non-light-sensitive electrodes or photodiodes–both systems must fulfill common engi-
neering design criteria. Hereafter in this review, the general term microelectrode array
Sensors 2023, 23, 5782 5 of 35
(MEA) is used to refer to both types of arrays, since both systems use electrodes to convey
electric impulses to retinal cells [10].

Sensors 2023, 23, x FOR PEER REVIEW 6 of 37

[Link]
Figure Intraocularcomponents
components of of
thethe ARGUS
ARGUS II system.
II system. Diagram
Diagram showing
showing the internal
the internal compo-
components
nents of the ARGUS II retinal prosthesis system that are implanted within
of the ARGUS II retinal prosthesis system that are implanted within the eye. the eye.

Figure
Figure 4.4. Prototypical
Prototypical design
design configuration
configuration ofof aa photodiode,
photodiode, consisting
consisting ofofan
aninner
innerelectrode
electrode(red),
(red),a
aphotodiode
photodiode(green),
(green),
anan insulating
insulating layer
layer (yellow),
(yellow), andand an outer
an outer ground
ground electrode
electrode (dark
(dark gray).
gray). (A.
(A. Side
Side view of multiple photodiodes in an array. B. Cross-sectional view of the photodiode at position
view of multiple photodiodes in an array. B. Cross-sectional view of the photodiode at position A-A,
A-A, at the location specified in the top view. C. Top-orientation view of photodiode. D. Isometric
at the location specified in the top view. C. Top-orientation view of photodiode. D. Isometric view of
view of the photodiode with a bipolar cell in close relation to the inner electrode. Due to the voltage
the photodiode
drop between thewith innera bipolar cellelectrodes,
and outer in close relation to the inner
the photodiode electrode.
generates Due to the
an electric fieldvoltage drop
that can be
used for cell stimulation. (Figure 4 was partly generated using Servier Medical Art, providedused
between the inner and outer electrodes, the photodiode generates an electric field that can be by
for cell stimulation.
Servier, licensed under(Figure 4 wasCommons
a Creative partly generated using3.0
Attribution Servier Medical
Unported Art, provided by Servier,
License.)
licensed under a Creative Commons Attribution 3.0 Unported License.)
3. Engineering of Retinal Prostheses
Regardless of the mechanism of action, however–whether the prosthesis has internal
The performance of retinal prostheses is dependent on a few outcomes. Fulfilling
non-light-sensitive electrodes or photodiodes–both systems must fulfill common engineer-
these outcomes is important to drive their adoption in the market and by patients. Each
ing design criteria. Hereafter in this review, the general term microelectrode array (MEA)
of the outcomes for retinal prostheses is closely related to an engineering design challenge,
is used to refer to both types of arrays, since both systems use electrodes to convey electric
namely, a constraint (Figure 5). This review describes the four main outcomes and their
impulses to retinal cells [10].
corresponding engineering design constraints.
Firstly, retinal prostheses must provide effective electrical stimulation to the retina to
enable formation of light percepts. To achieve this outcome, the microelectrode array of
prostheses must directly contact the retina for successful stimulation. Even small separa-
tions between the microelectrode array and the retina can reduce a prosthetic’s efficacy.
Sensors 2023, 23, x FOR PEER REVIEW 7 of 37

Sensors 2023, 23, 5782 6 of 35

able to both convey electrical pulses and be able to record the impact of such stimulation
on the retina. Thus, a description of the incorporation of bidirectional retinal prostheses is
3. Engineering of Retinal Prostheses
given.
It The
is mainly these design
performance criteria
of retinal that guide
prostheses the manufacturing
is dependent on a fewofoutcomes.
retinal prostheses
Fulfilling
and dictate their future market adoption. Thus, each of the criteria is described
these outcomes is important to drive their adoption in the market and by patients. in detail
Each of
tothe
allow the reader
outcomes to understand
for retinal theischallenges,
prostheses learntoabout
closely related recent advancements,
an engineering and
design challenge,
contemplate the prospects
namely, a constraint of retinal
(Figure prostheses.
5). This review describes the four main outcomes and their
corresponding engineering design constraints.

Figure 5. The performance of retinal prostheses is dependent on a few outcomes. Fulfilling these
Figure 5. The performance of retinal prostheses is dependent on a few outcomes. Fulfilling these
outcomes is important to drive their adoption in the market and by patients. These outcomes are (1) to
outcomes is important to drive their adoption in the market and by patients. These outcomes are (1)
provide effective electrical stimulation of the retina; (2) to produce a high-resolution image; (3) to
to provide effective electrical stimulation of the retina; (2) to produce a high-resolution image; (3) to
selectively
selectively activate
activate desired
desired retinalcells,
retinal cells,thereby
therebyavoiding
avoidingimageimagedistortion;
distortion;and
and (4)
(4) to
to be
be customiza-
customizable
for different patients. To achieve these requirements, retinal prostheses are designed
ble for different patients. To achieve these requirements, retinal prostheses are designed with with fourfour
main
design
main criteria:
design (1) the
criteria: electrode-to-retina
(1) the electrode-to-retina distance, (2) having
distance, smaller
(2) having electrode
smaller size, (3)
electrode implementing
size, (3) imple-
menting techniques
techniques to produce
to produce spatial spatial selectivity,
selectivity, and (4) and (4) implementing
implementing bidirectional
bidirectional [Link].

Firstly, retinal(ER)
3.1. Electrode–Retina prostheses must provide
Topographical Alignmenteffective electrical stimulation to the retina to
enable formation of light percepts. To achieve this outcome, the microelectrode array of
MEAs directly interface with the retina to deliver electrical stimuli. Signals delivered
prostheses must directly contact the retina for successful stimulation. Even small separa-
by MEAs are either directly or indirectly received by the retinal ganglion cells (RGCs). In
tions between the microelectrode array and the retina can reduce a prosthetic’s efficacy.
the case of epiretinal prostheses, the electrical signals are directly received, since the pros-
Thus, this review discuses some of the challenges and solutions proposed to ensure that
theses are in direct contact with the RGCs. In the case of subretinal/suprachoroidal pros-
retinal prostheses can meet the design consideration.
theses, however, the signals are first received by cells in the posterior retina, which then
Secondly, it is important for retinal prostheses to produce a high-resolution image that
convey them to the RGCs through the physiologic pathways. The received signal is then
can then be interpreted by the recipient. To attain higher resolution, one main consideration
conveyed by the RGCs, through the optic nerve, to the brain, where they are interpreted
is to minimize the size of the individual microelectrodes on the array such that each
as images [11]. The transmission of an electric stimulus to retinal neurons requires a close
electrode can stimulate a single retinal cell and maximize the resolution limit of prostheses.
topographical
However, there fit between the MEA
are technical of the retinal
challenges with suchprostheses and theofretinal
miniaturizing tissue [12]. The
microelectrodes. These
lack of conformity between implants and retinal tissue can cause gaps
challenges are described here, along with some of the solutions proposed to overcome up to several hun-them.
dred micrometers,
Thirdly, anotherwhich result
design in an impaired
consideration or lost
of retinal signal inisthese
prostheses their areas
abilityand, conse-
to selectively
quently,
target theimpact thecells
desired effectiveness of the
in the retina. deviceretinal
Different (Figure 6, produce
cells A) [13]. Thus, researchers
different perceptionspro-
that
posed a variety of solutions to overcome this topographical misalignment
directly impact the patient outcomes. As such, this review delves into a description of twothat can occur
between
techniquesthe retina andbethe
that can implant.
used to selectively target retinal cells, namely, (1) current steering,
which uses return electrodes,developed
Firstly, many researchers MEAs that the
and (2) manipulating incorporate three-dimensional
electric stimulation (3D)
parameters.
geometries. Within the retina, experiments showed that cells of the inner neuron
Finally, an important design consideration is a prosthetic’s ability to be customizable layer
(INL) can migrate
to every and
recipient’s integrateneeds.
individual with 3D geometry
To achieve MEAs
such (Figure prostheses
an outcome, 6, B) [14]. must
Since besub-
able
retinal prostheses are located in the INL, they are the ones that benefit the most
to both convey electrical pulses and be able to record the impact of such stimulation on the from such
integration
retina. Thus,of cells into the 3D
a description ofgeometry of [Link]
the incorporation was shown that both
retinal the protruding
prostheses is given.
and recessed 3D geometries
It is mainly these design of criteria
subretinal
thatimplants
guide thebenefit from this of
manufacturing retinal migration,
retinal prostheses
and dictate their future market adoption. Thus, each of the criteria is described in detail
Sensors 2023, 23, 5782 7 of 35

to allow the reader to understand the challenges, learn about recent advancements, and
contemplate the prospects of retinal prostheses.

3.1. Electrode–Retina (ER) Topographical Alignment

MEAs directly interface with the retina to deliver electrical stimuli. Signals delivered
by MEAs are either directly or indirectly received by the retinal ganglion cells (RGCs).
In the case of epiretinal prostheses, the electrical signals are directly received, since the
prostheses are in direct contact with the RGCs. In the case of subretinal/suprachoroidal
prostheses, however, the signals are first received by cells in the posterior retina, which
then convey them to the RGCs through the physiologic pathways. The received signal
is then conveyed by the RGCs, through the optic nerve, to the brain, where they are
interpreted as images [11]. The transmission of an electric stimulus to retinal neurons
requires a close topographical fit between the MEA of the retinal prostheses and the retinal
tissue [12]. The lack of conformity between implants and retinal tissue can cause gaps up to
several hundred micrometers, which result in an impaired or lost signal in these areas and,
consequently, impact the effectiveness of the device (Figure 6, A) [13]. Thus, researchers
Sensors 2023, 23, x FOR PEER REVIEW
proposed a variety of solutions to overcome this topographical misalignment that can9 occur
of 37

between the retina and the implant.

Figure 6.
Figure 6. (A)
(A) The
The lack
lack of
of the
the topographical
topographical alignment between
between a planar epiretinal
epiretinal microelectrode
microelectrode
array and
array and the
the retinal
retinal ganglion
ganglion cells.
cells. (B)
(B) Migration
Migration and
and integration
integration of
of the
the cells
cells in
in the
the Inner
Inner Nuclear
Nuclear
Layer to
Layer to3D
3Dprotruding
protrudinggeometries
geometriesininsubretinal
subretinalmicroelectrode
microelectrode array.
array. (Figure
(Figure 6 was
6 was partly
partly gener-
generated
ated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribu-
using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0
tion 3.0 Unported License.)
Unported License.)

3.2. Electrode Size and

Firstly, many Material, Charge
researchers Density,
developed MEAs andthat
Resolution Limit three-dimensional (3D)
incorporate
While most
geometries. clinical
Within resultsexperiments
the retina, from human-implanted
showed thatprostheses
cells of theshowed positivelayer
inner neuron out-
comes,can
(INL) themigrate
visual resolution
and integrateobtained from
with 3D prostheses
geometry MEAshas, (Figure
nevertheless, remained
6, B) [14]. Since lim-
sub-
ited. The recognition of simple objects and facial identification can still be challenging
retinal prostheses are located in the INL, they are the ones that benefit the most from [25].
Similarly,
such the restoration
integration of cells of visual
into acuity
the 3D in patients
geometry with retinal
of MEAs. prosthesis
It was has been,
shown that both de-
the
spite pioneering success in human trials, quite limited. Clinically, to describe visual acu-
ity, the Snellen scale is often used. The scale has a large range, but specific acuities are
defined—“normal” vision is defined as 20/20, and an acuity of 20/200 is defined as legally
blind. The recent clinical trials of the PRIMA system, which is described in further detail
Sensors 2023, 23, 5782 8 of 35

protruding and recessed 3D geometries of subretinal implants benefit from this retinal
migration, which reduces the separation distance between the INL and the implanted
electrodes [14–18]. However, while this advantage applies to subretinal prostheses, both
epiretinal and suprachoroidal implants were reported to have a gradually increasing ER
distance over time. This observed phenomenon was attributable to fibrosis and to evoked
inflammatory responses [19]. Since this time-based change in ER distance is particularly
evident in epiretinal and suprachoroidal prostheses, these prostheses had more studies
monitor this measurement, compared to studies of subretinal implants, in which device
trials never measured the ER distance [19]. It is also worth noting that while it might be
possible for retinal migration to decrease the ER distance in subretinal implants, epiretinal
implants require mechanical pressure to achieve close proximity to the MEA [18]. All in all,
due to the benefits of incorporating 3D geometries, these MEA designs were considered for
subretinal devices. However, epiretinal and suprachoroidal MEAs rely on other methods
that are more effective with their implant location.
Secondly, to decrease the electrode–retina distance, researchers considered integrating
pneumatic cavities that enable dynamic, real-time control of the electrode position. In
MEAs, pneumatic cavities can be placed under the electrodes [12], and, by adjusting
the pneumatic pressure, it then becomes possible to change the electrode position and
reduce the distance to the retinal surface. Like the proposed design of pneumatic systems,
hydraulic systems can also be tested for incorporation, especially in epiretinal devices, to
improve the topographical alignment.
Thirdly, researchers developed flexible MEA substrates that can be used to achieve
topographical alignment. Beyond their use in brain neuron stimulation, flexible probes
were suggested for use in epiretinal electrode arrays [20,21]. Such flexible designs can
better fit the surface topographies and can, therefore, permit the creation of larger and
higher-density devices, which can extend over the curvature of the retina. These flexible
designs were also shown to be safe and effective [22,23]. Finally, the flexibility of these
MEAs was considered beneficial in reducing the acute insertion footprint of the electrodes,
an outcome often measured by retinal cell viability after the implantation [24]. However,
while these MEAs are advantageous in many facets, including that they provide better
topographical alignment, it can still be challenging for these microelectrode arrays to fill
smaller gaps and sharp corners [12].
All in all, as an important engineering consideration, a variety of solutions were sug-
gested to decrease the electrode–retina distance in the different types of retinal prostheses.
The advantages and disadvantages of each of the solutions should be weighed, and, based
on implant location, the appropriate feature should be incorporated.

3.2. Electrode Size and Material, Charge Density, and Resolution Limit
While most clinical results from human-implanted prostheses showed positive out-
comes, the visual resolution obtained from prostheses has, nevertheless, remained limited.
The recognition of simple objects and facial identification can still be challenging [25].
Similarly, the restoration of visual acuity in patients with retinal prosthesis has been,
despite pioneering success in human trials, quite limited. Clinically, to describe visual
acuity, the Snellen scale is often used. The scale has a large range, but specific acuities
are defined—“normal” vision is defined as 20/20, and an acuity of 20/200 is defined as
legally blind. The recent clinical trials of the PRIMA system, which is described in further
detail in the succeeding sections, reported the best visual acuities of retinal prostheses yet,
in the range of 20/460–20/565 [26]. While these acuities remain within the definition of
legal blindness, a closer look reveals that there is a close match between the prosthetic
acuity and the fundamental sampling limit set by the pixel size [27]. Quantitatively, it was
reported that the visual acuity corresponded to 1.17 ± 0.13 of the pixel size [28]. From this
observation, it can be inferred that the pixel size of the microelectrodes in the prosthesis
was limiting the stimulation of adjacent points on the retina and, thereby, limiting acuity.
Sensors 2023, 23, x FOR PEER REVIEW 10 of 37
Sensors 2023, 23, 5782 9 of 35

[30]. Therefore, both given the clinical results of the PRIMA system and to emulate phys-
This closeprocesses,
iological match between the acuity
it is logical and the
to develop fundamental
MEAs sampling
with smaller, morelimit of the
densely prosthetic
packed elec-
consequently
trodes. indicates that smaller pixels may provide higher resolution (Figure 7) [27].

Figure 7. Demonstrating
Figure 7. Demonstratingthe theimpact
impactof
ofsmaller
smallerelectrodes.
[Link] the1515×× 15
comparisontotothe 15 grid
grid(A),
(A), the
the
55 ×
× 5 grid (B) produces a lower image resolution and enables less object object recognition.
recognition. Additionally,
since each
since eachsquare
squareininthe
thegrid
gridrepresents
representsthethesize
sizeofofanan electrode,
electrode, having
having larger
larger electrodes
electrodes correlates
correlates to
to larger activation of retinal cells—i.e., less selective activation of desired, target retinal
larger activation of retinal cells—i.e., less selective activation of desired, target retinal cells. cells.

From
In an engineering
addition perspective,
to this clinical observation, onephysiologically,
of the primaryto challenges with miniaturizing
restore natural vision, retinal
MEAs and should
prostheses decreasing pixel
ideally size is the
stimulate corresponding
individual retinalincrease
neuronsin[11].
charge
Theredensity [31]. than
are more With
decreasing
1.5 million RGCs pixel electrode
in the human size, retina,
there isof less surface
which the area available
largest soma has to transfer
a diametercharge to the
of about
surrounding
30 µm [29]. Intissue. However,
comparison, the retinal
smallest cells requiresize
electrode a minimum amount
of the retinal of charge
prostheses that to have
meet
been applied in
the activation clinical trials
threshold needed is the 50 × 50
in order µm electrode
to relay of the Alpha
visual information IMS
[32]. system [30].
Consequently,
Therefore,
to provideboth givenelectric
a similar the clinical
fieldresults of the depth,
penetration PRIMAasystemhigher and to emulate
electrode charge physiological
density per
processes, it is logical to develop MEAs with smaller, more densely
surface area is necessary when using smaller electrodes [33]. Due to the limitations of ma- packed electrodes.
terialFrom an engineering
properties and safetyperspective,
requirements, oneitofis,the primary challenges
nevertheless, challenging withto miniaturizing
accommodate
MEAs and decreasing
this increased pixel size requirement
charge-density is the corresponding
[34,35]. increase in charge
Conventional densityelectrodes,
platinum [31]. With
decreasing
widely used pixel
for electrode size, thereexceed
visual prostheses, is less the
surface
chargeareainjection
available to transfer
limits for safecharge to the
stimulation
surrounding
with decreased pixel size [31]. To overcome this challenge, innovations in the field ofmeet
tissue. However, retinal cells require a minimum amount of charge to ma-
the activation
terial science havethreshold needed
proposed in order to relay
modifications visualprostheses’
to retinal information [32]. Consequently,
MEAs. For instance, re- to
provide a similar electric field penetration depth, a higher
searchers manufactured nanocone-shaped platinum–iridium oxide neural microelec- electrode charge density per sur-
face area
trodes toisincrease
necessary thewhen usingsurface
electrode smallerareaelectrodes [33]. Due
[36]. Others to the limitations
incorporated of material
high-conductivity
properties
materials such and assafety requirements,
graphene, materialsit with
is, nevertheless,
superior charge challenging
injectionto accommodate
such as polymer/car- this
increased charge-density requirement [34,35]. Conventional
bon nanotubes, and carbon nanotube-modified gold [31,37,38]. These innovations made itplatinum electrodes, widely
used for to
possible visual
haveprostheses,
efficient charge exceed the charge
injection injection
and opened thelimits for to
horizon safe stimulation
decreasing the with
elec-
decreased pixel size [31]. To overcome this challenge, innovations
trode size on MEAs, with a final objective of improving the resolution limit of retinal pros- in the field of material
science haveHowever,
theses [39]. proposed withmodifications
each of the to proposed
retinal prostheses’
materials,MEAs. For instance,manufactur-
biocompatibility, researchers
manufactured
ability, and batch-to-batch consistency are still important considerations that to
nanocone-shaped platinum–iridium oxide neural microelectrodes needincrease
to be
the electrode surface area [36]. Others incorporated high-conductivity
studied to maximize the benefits while ensuring that the risks and variability are materials such as
graphene, materials with superior charge injection such as polymer/carbon nanotubes,
and carbon nanotube-modified gold [31,37,38]. These innovations made it possible to
 basic unit of artificial vision, defined as a subjective “visual percept” experienced by re-
cipients of retinal prostheses. Unsurprisingly, in an ethnographic, qualitative account of
how the current implementation of retinal prostheses translates into the perceptual expe-
rience of patients, the recipients of retinal prostheses described their vision as distinctly
Sensors 2023, 23, 5782 different from that of natural vision and as most closely resembling a “light show”10[41]. of 35
These manifest differences between artificial and natural vision can be attributed to the
coarse pattern of retinal activation caused by the MEA stimulation of many neighboring
cells
havewithout
efficientcoordination
charge injection [40].and
However,
openeditthe is not necessarily
horizon the difference
to decreasing from natural
the electrode size on
vision that is concerning, rather, it is the unreliable and irregularly
MEAs, with a final objective of improving the resolution limit of retinal prostheses shaped phosphenes [39].
that are produced
However, with each as aofresult of such coarse
the proposed and unselective
materials, activation
biocompatibility, [42]. When an elec-
manufacturability, and
tric field is produced
batch-to-batch by a stimulating
consistency are still importantelectrode, the shape ofthat
considerations theneed
electric
to befield and its
studied to
strength
maximizedirectly impact
the benefits the visual
while ensuring percept
that theof risks
the recipient. If the electric
and variability field spreads
are minimized. A more in
acomprehensive
lateral direction with distance
discussion above the
concerning the innovation
electrode, itwithin
can simultaneously activate
the field of material many
sciences,
retinal cells and cause a loss of spatial selectivity
as it relates to retinal prostheses, is presented in Section 7. (Figure 8) [25].
In epiretinal devices, MEAs inadvertently activate a bundle of RGC axons in the
3.3. Spatial
nerve Selectivity
fiber layer. This bundle activation happens since the axons of RGCs lie closer to the
electrodes thanstimulation
Electrical the underlying RGC soma
by MEAs allowsthatsurviving
are the intended
RGCs totargets of stimulation
depolarize and transmit[43].
The result
visual of this
signals activation
to the brain [40].is elongated
The outcome or arc-like
achievedphosphenes that negatively
by these signals impact the
is a phosphene–the
visual quality
basic unit [44]. Similarly,
of artificial vision,while
defined subretinal prosthesis
as a subjective are largely
“visual percept”spared from the in-
experienced by
terference
recipients of by retinal
RGC axons,
[Link] unwanted
Unsurprisingly, excitation
in anfrom these electrodes
ethnographic, can result
qualitative account in
highly variable phosphene shapes across electrodes and between
of how the current implementation of retinal prostheses translates into the perceptual subjects [45]. This phe-
nomenon
experiencehappens
of patients,duethe torecipients
the activation of many
of retinal cells and
prostheses cell types,
described their including tertiary
vision as distinctly
retinal
differentneurons
from thatsuchofasnatural
amacrine cellsand
vision [46,47].
as most closely resembling a “light show” [41].
These If manifest
the singledifferences
electrodes between
of retinalartificial
prostheses andcannatural
reliablyvision can be
produce anattributed
individual, toiso-
the
coarse
lated pattern
point of retinal
of light, whichactivation
the brain caused
can then byassemble
the MEAinto stimulation of many
objects similar neighboring
to an electronic
cells withoutthe
scoreboard, coordination [40]. However,
spatial resolution and consequentit is notvision
necessarily
can bethe difference
drastically from natural
improved [48].
vision that is concerning, rather, it is the unreliable and irregularly
However, this is not yet possible due to unselective and imprecise retinal stimulation. The shaped phosphenes that
are produced
engineering as a result
solutions of such
to this coarsehave
challenge and unselective
varied, and activation
two predominant [42]. When an electric
methods have
field is
been producedFirstly,
proposed. by a stimulating
there is the electrode, the shape
use of return of the electric
electrodes fieldthe
to localize andelectric
its strength
field
directly
and, impact
thereby, the visual
selectively percept cells.
stimulate of theSecondly,
[Link]
If theiselectric field spreads
the manipulation in aelectric
of the lateral
direction with
stimulation distance such
parameters, aboveasthe theelectrode,
amplitudeitand canfrequency,
simultaneously whichactivate many retinal
can selectively target
cells and cause a loss of spatial selectivity (Figure
cells that only respond to those specific parameters and not to others. 8) [25].

Figure 8. (Left) Electric field of a bipolar configuration causing lateral spread and unselectively
stimulating many retinal cells. (Right) A 3D geometry electrode with circumferential returns generates
locally confined electric fields, reducing electrode cross-talk and permitting more selective activation
of retinal cells. (Figure 8 was partly generated using Servier Medical Art, provided by Servier, licensed
under a Creative Commons Attribution 3.0 Unported License.)

In epiretinal devices, MEAs inadvertently activate a bundle of RGC axons in the

nerve fiber layer. This bundle activation happens since the axons of RGCs lie closer to the
electrodes than the underlying RGC soma that are the intended targets of stimulation [43].
The result of this activation is elongated or arc-like phosphenes that negatively impact
the visual quality [44]. Similarly, while subretinal prosthesis are largely spared from
the interference by RGC axons, the unwanted excitation from these electrodes can result
in highly variable phosphene shapes across electrodes and between subjects [45]. This
Sensors 2023, 23, 5782 11 of 35

phenomenon happens due to the activation of many cells and cell types, including tertiary
retinal neurons such as amacrine cells [46,47].
If the single electrodes of retinal prostheses can reliably produce an individual, isolated
point of light, which the brain can then assemble into objects similar to an electronic
scoreboard, the spatial resolution and consequent vision can be drastically improved [48].
However, this is not yet possible due to unselective and imprecise retinal stimulation. The
engineering solutions to this challenge have varied, and two predominant methods have
been proposed. Firstly, there is the use of return electrodes to localize the electric field
and, thereby, selectively stimulate cells. Secondly, there is the manipulation of the electric
stimulation parameters, such as the amplitude and frequency, which can selectively target
cells that only respond to those specific parameters and not to others.

3.3.1. Return Electrodes for Electric Field Localization and Current Steering
The stimulation of retinal cells is mainly achieved by depolarizing cells in an elec-
tric field, instead of direct current injection into cells [25]. By accumulating charge at
the synaptic terminals of retinal cells, the membrane depolarization exceeds a threshold,
and action potentials can be fired. Confining the electric field and controlling its shape
is important to ensure the stimulation selectivity of the desired target cells. To achieve
such control, researchers manipulated MEAs to incorporate adjacent return or grounding
electrodes. Return electrodes serve as the electrical counterpart to the active electrodes
that are implanted in the retina, and, through them, it is possible to limit current spread
and produce a well-controlled, directed electric field. A variety of return electrodes were
widely investigated for use in retinal prostheses including monopolar, bipolar, tripolar,
and hexapolar configurations. As seen in Figure 9, in the monopolar configuration, a
single stimulating electrode is used to activate retinal cells. The bipolar configuration has
an active electrode with an adjacent return electrode, which allows for current steering
and localization. In the tripolar configuration, two electrodes at the opposite sides of the
stimulating electrode function as the return electrodes. Finally, in the hexapolar configu-
ration, an active electrode is centrally located and is surrounded by six return electrodes
that form a “guard” around the active electrode [25]. In addition to these main designs,
more complex configurations were recently explored and proposed for further testing. For
instance, a 3D multilayered, concentric bipolar electrode was designed with the purpose of
achieving highly focused electric stimulation [49]. Another research group developed a
method that enables dynamic electric field confinement, by turning the designated active
pixels into transient returns [46]. In addition to these designs, researchers also developed a
computational implant simulator that can model electric fields of MEAs [27]. This simulator
was able to compute the electric field in the retina generated by thousands of electrodes as
well as with various pixel configuration [27]. It is through such computational models as
well as through the unique ideation and implementation of return electrodes that it can be
possible to confine the electric field and selectively target desired cells [40].
However, while current steering is important to ensure that small-sized electrodes can
target one cell at a time, it does not overcome the challenge of bundle activation in the nerve
fiber layer. Especially in epiretinal electrodes, where the nerve fiber layer more proximally
lies to the electrode than to the more distal RGC somas, another method of cell stimulation is
needed to selectively activate the somas [25]. Control of the electric stimulation parameters
was proposed as a solution, which is discussed in the following section.

3.3.2. Electric Stimulation Parameters for Selective Cell Activation and Chromatic Vision
An alternative approach to the selective activation of retinal cells is to manipulate the
electric impulses sent by the electrodes [25]. That is, instead of manipulating the electric
field shape and confinement to optimize selective cell activation, electrical stimulation
strategies were proposed to optimally target specific cells and leave other cells inactivated.
This stimulation strategy requires finding the pattern of electrical stimulation, including the
amplitude and frequency of the electrical pulse, which permits targeted retinal activation.
Sensors 2023, 23, 5782 12 of 35

Then, these impulses are sent through the MEAs to activate the retinal cells. Two main
reasons were suggested that favor this approach over electric field confinement. Firstly,
researchers showed that there may be more than 40 types of RGCs, and each may be
responsible for different aspects of visual information processing [50]. Selectively stimulat-
ing each of these types of RGCs would be desirable for the full restoration of vision [48].
Individualized electrical stimuli from the independent electrodes on MEAs can be used
to target different types of cells, such as ON- and OFF- cells. Moreover, researchers found
that the response to an electric pulse produced by RGCs is also dependent on the patient
disease genotype [51]. Patients with varying genotypes of retinitis pigmentosa would,
therefore, have varying quality of prosthetic vision, even though the same device may
be implanted in all patients. Through their study, the authors asserted the importance
of exploring novel stimulation strategies to enhance the response ratio between ON- and
OFF- cell responses, such that these strategies can be customized for different genotypes. If
only electric field confinement was used, it would not be possible to obtain the desirable
output responses for the different cell types and different disease genotypes. The second
reason for using electrical stimulation parameters in retinal prostheses is that researchers
found that frequency-modulated electrical stimulation can provide hope for chromatic
vision restoration in blind patients [52]. Stanga et al. (2011) first discovered that color
perception could be evoked by changing the relevant stimulation parameters [53]. In their
clinical trial, nine subjects with retinitis pigmentosa were equipped with the Argus II retinal
prosthesis system [53]. The study methodology involved the simultaneous stimulation of
various electrode pairs using different permutations of cathodic–anodic pulses [53]. The
subjects reported eight different colors including orange, red, blue, green, and white; blue,
yellow, and white were perceived the most [53]. A subsequent study in 2012 enrolled four
blind subjects diagnosed with retinitis pigmentosa, who were equipped with the Argus II
retinal prosthesis system [54]. The findings of this study demonstrated that it is possible to
simultaneously evoke two distinct colored flashes, a significant difference from the first
study [54]. In total, the patients perceived seven color combinations: gray–white, yellow–
gray, orange–white, white–blue, brown–white, yellow–white, and yellow–blue [54]. The
authors then concluded that manipulating the stimulation parameters can provide rudi-
mentary color vision to blind patients and allow them to simultaneously perceive multiple
colors, depending on stimulation parameters [53,54]. More recently, V L Towle et al. (2021)
reached a similar conclusion and suggested that color hue development in prostheses
may be dependent on stimulus intensity [55]. Paknahad and colleagues designed a study
and were able to demonstrate an “amplitude-frequency” stimulation strategy to encode
color vision, which was validated with experimental data [56]. Additionally, a case series
study that followed seven subjects blinded by advanced RP and fitted with an epiretinal
prosthesis showed that five/seven subjects perceived chromatic vision when frequency-
modulated electrical stimulation of the retina was tested [52]. In all cases, color vision was
achieved by selectively targeting small bistratified cells [52]. The knowledge that targeting
specific cell types with specific parameters can restore some color percepts to patients
creates an immense value for implementing the electric stimulation parameters that can
selectively activate those cells. Moreover, unlike the electric field confinement method,
the incorporation of electric stimulation can preferentially activate RGCs’ somas (versus
passing axons in the nerve fiber layer) by manipulating the stimulus’ durations, phases,
and waveforms [57].
While the two methods for selective stimulation are presented in comparison with
each other, it should be noted that the use of one method does not exclude the use of the
other. Indeed, both methods can and have been amalgamated to achieve higher selective
activation. Activation through current steering avoids lateral stimulation and cross-talk,
while using electric stimulation strategies can aid in targeting certain cells that are only
responsive to that stimulus [30]. For instance, Jepson et al. (2014) investigated the usage
of current steering in retinal prosthetics using multiple, densely packed suprachoroidal
electrodes in the macaque retina, while providing simultaneous stimulation parameters
Sensors 2023, 23, 5782 13 of 35

for these electrodes [58]. Jepson and colleagues identified that when a current is applied
to two adjacent electrodes, a peak current is produced at an equidistant point, termed
a virtual electrode. Modulating the current ratio creates biased electric fields; in other
words, if one electrode receives a higher current, the virtual electrode shifts toward that
electrode. The authors predicted that by using current steering to optimize the stimulation
Sensors 2023, 23, x FOR PEER REVIEW 13 of 38
intensity, frequency, and number of electrodes, it could be possible to increase target cell
selectivity while reducing the response probability of non-target cells. Since it is challenging
to document every stimulus pattern permutation, the authors proposed a piecewise linear
stimulation
model. They is needed
then to selectively
measured activate
the produced patternthe
andsomas
found [25].
that itControl of the
was almost electric
identical to
stimulation parameters
the spatial pattern was by
predicted proposed as a“allowing
the model, solution, for
which
0.90 is discussed
[~90%] in theprobability
activation following
section.
of the target cell with only 0.11 [~11%] probability of activating the neighboring cell [58]”.

Figure [Link]
Active(red) andand
(red) return (green)
return electrodes
(green) arranged
electrodes in different
arranged configurations.
in different (A) Monopo-
configurations. (A)
Monopolar configuration;
lar configuration; (B) bipolar(B) bipolar configuration;
configuration; (C) tripolar (C) tripolar configuration;
configuration; (D) hexapolar(D) hexapolar
configuration.
configuration.
These These configurations
configurations impact the shapeimpact
of thethe shapefield,
electric of theandelectric field, electrode
the return and the return electrode
is used to limit
is used to limit current spread and produce a well-controlled,
current spread and produce a well-controlled, directed electric [Link] electric field.

3.4. Bidirectional/Closed-Loop
3.3.2. Retinal Prostheses
Electric Stimulation Parameters for Selective Cell Activation and Chromatic Vision
Onealternative
An of the recent advances
approach in the
to the field of
selective retinal prostheses
activation is the
of retinal cells is design and devel-
to manipulate the
opment of bidirectional and closed-loop systems. These systems are
electric impulses sent by the electrodes [25]. That is, instead of manipulating the electricable to both send
electric
field impulses
shape and to retinal cellsto
confinement and record the
optimize electriccell
selective responses evoked
activation, by stimulation
electrical [59].
stimulation
The increased emphasis on this area in recent research can be attributed
strategies were proposed to optimally target specific cells and leave other cells inactivated. to several rea-
[Link]
This The first reason
strategyis requires
the neural plasticity
finding of the of
the pattern retina. Withstimulation,
electrical disease progression,
including
photoreceptors
the amplitude within the retina of
and frequency canthedegrade. In response,
electrical the retina
pulse, which remodels,
permits altering
targeted the
retinal
electrophysiologic properties of the retinal pathways [60]. Due to this
activation. Then, these impulses are sent through the MEAs to activate the retinal cells. dynamic change in
the electrophysiologic properties over the disease course and the consequent
Two main reasons were suggested that favor this approach over electric field confinement. interpatient
differences,
Firstly, the electrical
researchers showedpatterns
that thereused
may tobestimulate
more than retinal cellsofneed
40 types RGCs,to and
be iteratively
each may
be responsible for different aspects of visual information processing [50]. as
manipulated to produce an optimal outcome for patients [61]. For instance, recently
Selectively
demonstrated by Caravaca-Rodriguez et al. (2022), the progressive
stimulating each of these types of RGCs would be desirable for the full restoration degeneration of the
of
retina resulted in an increased electrical threshold needed by subretinal
vision [48]. Individualized electrical stimuli from the independent electrodes on MEAs and epiretinal
prostheses
can be used [62].
to The second
target reason
different driving
types innovation
of cells, such as in ON-
the development
and OFF- [Link] bidirectional
Moreover,
systems is that these systems can enable fully representative, personalized, and iterative
researchers found that the response to an electric pulse produced by RGCs is also
stimulation strategies. Often, to test stimulation parameters, including stimulus amplitude,
dependent on the patient disease genotype [51]. Patients with varying genotypes of
width, and time, experiments are conducted in ex vivo conditions. These conditions, how-
retinitis pigmentosa would, therefore, have varying quality of prosthetic vision, even
ever, lack the metabolic environment of the eye, upon which the true electrophysiologic
though the same device may be implanted in all patients. Through their study, the authors
properties are dependent [59]. Thus, in vivo, bidirectional systems can provide a more
asserted the importance of exploring novel stimulation strategies to enhance the response
complete reflection of the retinal response to stimulation and fill in any areas of uncertainty
ratio between ON- and OFF- cell responses, such that these strategies can be customized
for different genotypes. If only electric field confinement was used, it would not be
possible to obtain the desirable output responses for the different cell types and different
disease genotypes. The second reason for using electrical stimulation parameters in retinal
prostheses is that researchers found that frequency-modulated electrical stimulation can
Sensors 2023, 23, 5782 14 of 35

of ex vivo testing. Finally, bidirectional systems are important, since, as mentioned in previ-
ous sections, there is often a variable electrode–retina distance upon implantation [13]. This
variability in electrode–retina distance impacts the stimulation ability and the produced
phosphenes [45]. Thus, having closed-loop systems that guide the required stimulation of
individual electrodes based on the evoked cell response can significantly improve patient
outcomes. These closed-loop systems would enable such post-implantation customization.
In addition to these factors, closed-loop systems also help address some of the pre-
viously mentioned biological challenges. For instance, Tandon et al. (2021) implemented
bidirectional epiretinal prostheses to develop an algorithm for detecting axon bundle acti-
vation [42]. Similarly, Ghaffari et al. (2021) developed a closed-loop neural network (NN)
model of RGC spatial activity and used it to create a real-time optimization method to
search for stimulation parameters that elicit focal responses from in vitro retina [63].
The incorporation of bidirectional closed-loop systems into retinal prostheses requires
an understanding of how the recorded cell response can then be used to feedback stim-
ulation strategies to target cells [40]. As such, there has been an influx of computational
models that allow researchers and engineers to understand the electrical activity of the
retina and the impact that different stimulation parameters have on different cell types at
varying levels of degeneration [64–68].

4. Clinical Considerations for Retinal Prostheses

4.1. Importance of Patient Selection and Screening
The Argus II is currently the only FDA-approved retinal prosthesis device in North
America. However, despite FDA approval, its effectiveness has not been confirmed. On the
other hand, the Alpha AMS is CE-approved, and its efficacy is still being evaluated. This
subsection specifically focuses on the Argus II and Alpha AMS.
Successful outcomes with retinal prostheses, such as the Argus II and Alpha AMS
devices, rely heavily on proper patient selection and screening.
Indications for Argus II implantation include [69]
• Aged 25 years or older;
• A prior history of useful vision;
• Profound visual loss resulting from the loss of photoreceptors (e.g., retinitis pigmen-
tosa) that limits visual acuity to hand motion or bare light or no light perception in
both eyes;
• A patient with no light perception must demonstrate retinal ability to respond to
electrical stimulation, which can be confirmed through a dark-adapted flash test and
visual evoked potential (VEP) testing;
• A patient must be in pseudophakic or aphakic status or have phakic status requiring
cataract surgery or lensectomy prior to retinal prosthesis implantation;
• A patient must be able to attend post-implant clinical follow-up, device fitting, and
visual rehabilitation.
Contraindications for Argus II implantation include [70]
• Vision better than counting fingers in one of the eyes;
• Ocular conditions that prevent adequate visualization of internal structures, such as
corneal opacification;
• Ocular conditions that affect device functionality, such as optic neuropathy, central reti-
nal artery occlusion (CRAO), central retinal vein occlusion (CRVO), retinal detachment,
severe strabismus, and amblyopia;
• Systemic conditions that contraindicate general anesthesia;
• Presence of metallic or other implantable devices in the head (e.g., cochlear implants);
• Hearing impairments that can interfere with a patient’s interaction with the Argus
II device;
• Inability to comply with post-operative follow-up and rehabilitation due to cognitive
decline or other conditions such as dementia or developmental disability.
Sensors 2023, 23, 5782 15 of 35

The indications and contraindications of the retinal prosthesis Alpha AMS are similar
to those of the Argus II, with the exception that there is no age specification mentioned in
the literature for Alpha AMS implants. However, it is important to note that for the Alpha
AMS, the retina must have a thickness of >100 µm to require functionality. More precisely,
the indications for Alpha AMS implantation include [71]
• Light perception without projection or no light perception in hereditary retinal diseases
(retinitis pigmentosa, choroideremia, and Usher syndrome);
• Primary rod cone or cone rod dystrophies in their end-stage diseases;
• A prior history of normal visual function for >12 years.;
• A prior history of pseudophakia or aphakic status prior to retinal prosthesis implantation;
• A fluorescein angiography showing retinal vascular perfusion in all four quadrants of
the macula;
• Evidence of inner retinal function (ganglion cells and optic nerve function) observed
by the ability to elicit phosphene thresholds;
• Ability to give written informed consent and to attend follow-up and visual rehabilitation.
Contraindications for Alpha AMS implantation include [70,72]
• Ophthalmic conditions with relevant effects upon visual function (glaucoma, diabetic
neuropathy, retinal detachment, optic neuropathies, heavy clumped pigmentation at
posterior lobe, and cystoid macular edema);
• Retina < 100 µm or no layering of the inner retina shown by OCT;
• Scar tissue (epiretinal, intraretinal, subretinal, and macular pucker);
• Occipital stroke;
• Congenital blindness and severe amblyopia;
• Substantial corneal opacity or any opacification of ocular structures that prevent clear
image transmission;
• Active inflammation (uveitis);
• Systemic conditions that could pose significant risks during general anesthesia (car-
diovascular/pulmonary/severe metabolic conditions such as diabetes);
• Life expectancy < 1 year;
• Inability to comply with post-operative follow-up and rehabilitation due to psychi-
atric/neurological diseases (Parkinson’s, dementia, MS, epilepsy, and severe depres-
sion and anxiety).

4.1.1. Pre-Operative Assessment, Examination, and Imaging

A thorough pre-operative assessment is crucial for identifying suitable candidates for
retinal prostheses. This assessment should include a clinical examination and ancillary
testing. A clinical examination involves a complete ophthalmic examination, including an
anterior segment examination and a dilated fundus examination. This examination helps
to assess the overall ocular health of the patient and detect any contraindications to device
placement. Optical coherence tomography (OCT), ultrasonography, and optical biometry
for axial length measurements are also performed to help evaluate the retinal health and
ocular anatomy, ensuring optimal conditions for device functionality [73,74].

4.1.2. Post-Operative Rehabilitation

Post-operative rehabilitation plays a significant role in maximizing the benefits of
retinal prostheses. Patients must learn to interpret the artificial vision generated by the
device, which is different from natural sight. This situation is comprehensively covered
in the following sections of this article. Rehabilitation focuses on enhancing the patient’s
quality of life and independence by teaching them to use the limited vision provided by
the device in conjunction with their existing auditory and tactile function skills. Family
members and a social support network are crucial in facilitating the rehabilitation process,
by providing encouragement and motivation to the patient [75,76].
Sensors 2023, 23, 5782 16 of 35

As with any surgical procedure, it is valuable to weigh the benefits of treatment in

comparison to the possible risks. The following section aims to provide a risk-to-benefit
analysis for retinal prostheses by discussing their clinical outcomes.

4.2. Safety and Adverse Events

4.2.1. Epiretinal Prostheses
Shaffrath et al. (2019) conducted a study on the Argus II prosthesis system, in which
47 adults were followed for a period of 12 months. The study revealed a total of 13 serious
adverse events, of which 9 were related to the implant, and 4 were related to the procedure.
The reported adverse events were conjunctival erosions (n = 4), hypotony (n = 2), and
explantation (n = 2) [77]. Other adverse events included ocular inflammation (n = 1) as
well as tractional (n = 1) and rhegmatogenous retinal detachment (n = 1) [78]. While, in
total, 13 adverse events were observed, 11 of these were resolved while 2 cases persisted
(hypotony with a duration of eight months and the rhegmatogenous retinal detachment,
which was deemed permanent) [78]. In another study by Stanga et al., which studied the
same implants, the authors followed five patients who received implants. Out of those,
three cases of retinal detachment were reported; however, all of them were successfully
treated [77]. Finally, in a more recent (2021) study by Delyfer et al., which followed 17 sub-
jects over two years after implantation of the Argus II, the authors reported two serious
adverse events. One of these included a vitreous hemorrhage, a consequence of the device
itself, and the other was endophthalmitis, a consequence of the implantation procedure.
Other adverse events included macular edema (n = 1), choroidal detachment (n = 1), con-
junctival cyst (n = 1), keratitis (n = 1), bilateral phlebitis (n = 1), and ptosis (n = 1). All the
adverse events were resolved, except for the ptosis [79].
The IRIS 2, another epiretinal device, was the subject of clinical trials that reported
a total of 17 adverse events. Of these, 11 were non-serious adverse events that included
phlebitis (n = 1) and tack detachment requiring refixation (n = 1). All the non-serious events
were resolved. The remaining six events were classified as serious and included hypotony,
secondary to fluid leak from the sclerotomy site (n = 2); vitreoretinal preretinal traction
(n = 1); and persistent pain (n = 1) [80].
Epiretinal device implantation is a procedure that is similar to routine vitreoretinal
surgery. Due to this similarity, the process of implantation and the explanation of the
procedure are relatively simple. As a result, it is not surprising that the overall rate of
complications associated with this type of surgery is well-controlled [81].

4.2.2. Subretinal Prostheses

Subretinal implants were reported to be technically more challenging due to the
presence of adhesions between the retina and retinal pigment epithelium from degeneration
and lack of familiarity of the surgical approach [82].
Older studies on Alpha IMS subretinal implants noted adverse events that included
increased intraocular pressure resolved without sequelae and retinal detachment resolved
with explantation, with retinal fibrotic changes [83]. A study evaluating the safety of a
newer edition, the Alpha AMS, reported four cases of surgical dehiscence, two cases of
implant displacement, one case of partial loss of the silicone oil tamponade (n = 1), and one
case of pain (n = 1) [72]. Once again, all these complications were self-limiting or surgically
well-managed.
A study evaluating the PRIMA device, a subretinal retinal prosthesis, reported adverse
events related to procedural complications. These events included a choroidal hemorrhage,
secondary to inadvertent insertion into the choroid, caused by patient movement under
local anesthesia; focal subretinal hemorrhage; and the displacement of the device follow-
ing non-adherence to post-op movement limitations. Post-op medication non-adherence
also led to increased intraocular pressure in one patient that was successfully treated [28].
Adverse events of another subretinal device, the Alpha AMS, included two cases of conjunc-
Sensors 2023, 23, 5782 17 of 35

tival erosion, one case of peripheral retinal detachment, and one case of contact dermatitis,
which were subsequently well-managed [84].

4.2.3. Suprachoroidal Prostheses

Suprachoroidal implants are unique in that they are considered less technically and
surgically challenging compared to other implant types, and they limit the need for retinal
incisions [85]. Recent clinical trials following patients 56 weeks post-implantation found
expected non-serious adverse events such as pain, swelling, tenderness, conjunctival
injection, ocular pressure sensation, and local inflammation [86]. One case of increased
ocular pressure associated with topical steroid use for eyelid edema was reported but was
resolved by weaning of the medication and appropriate treatment [86]. These findings of
limited complications appeared to echo an earlier study on suprachoroidal devices [85].
All in all, these overall trends corresponded with older reports of adverse events in reti-
nal prostheses, where events were either few or well-managed [87]. The complication type
and frequency corresponded to the categories of implants according to the invasiveness of
the procedure, with suprachoroidal retinal prostheses reporting the least adverse outcomes.
Nonetheless, retinal prostheses continue to be safe and effective tools for restoring visual
function in individuals with macular degeneration.

4.3. Visual Function and Outcomes

4.3.1. Epiretinal Prostheses
Recent studies demonstrated interesting findings regarding visual function. A study
on the Argus II analyzed visual function through localization squares generated at random
and direction of motion. While some demonstrated improved visual function, an important
proportion saw no difference or benefit from having the device off [78]. More specifically,
square localization found 45% benefitting versus 55% having no difference or benefit with
the device off, while the identifying the direction of motion results were split, 35% versus
65% [78]. One way that researchers evaluate the functional outcomes of the device is
through the use of a self-report questionnaire, called the functional low-vision observer-
rated assessment (FLORA). The researchers that studied epiretinal retinal prosthetic use
in individuals with age-related macular degeneration found similar mixed benefits on
screen-based tasks but noted improvements on all tasks evaluated by the FLORA with the
device on versus off [77]. On the other hand, the evaluation of the visual function in the
IRIS 2 saw an improvement in the square localization and direction of motion detection at
the 3-month and 6-month marks. This same study also found enlarged visual fields and
enhanced picture recognition with the device on [80].

4.3.2. Subretinal Prostheses

The investigation of basic visual screen tasks with the Alpha IMS displayed improved
scores in light source perception in 86% of participants, which dropped to 59% when it
came to localizing, while motion detection was more difficult, with only 21% passing,
including one that attributed their success to chance [83]. The facilitation of daily living
activities such as identifying items on a dining table, telling the time, and reading letters
with the device on were also evaluated in this study. In total, 45% found the device to be
useful, 27% found little benefit, and 28% saw no benefit in completing these tasks [83].
Edwards et al. investigated the Alpha AMS and found improvement in tabletop
object identification and grayscale contrast detection; however, they found that participants
continued to have difficulty telling the time with or without the device. As for screen-
based tasks, participants of this study found more success with light localization and
perception with the device on; whereas for motion detection, there was no benefit from
having the device on versus the device off [84]. Analysis of the PRIMA subretinal device
also found improvements in eccentric natural acuity and the accurate identification of bar
orientation [28].
Sensors 2023, 23, 5782 18 of 35

4.3.3. Suprachorodial Prostheses

A study investigated the improvement in task accomplishment over two years in
patients with late-stage retinitis pigmentosa and found that the extent to which supra-
choroidal retinal implants facilitated daily activity varied. Tasks relying on vision, such
as washing dishes, folding and organizing laundry, and identifying doorways and people
in non-crowded spaces showed the greatest benefits over time, with peak improvement
between 17 and 44 weeks post-implantation [88]. Of note, identifying food on a plate
remained very difficult, attesting to the device’s limited visual information and quality [88].
On the other hand, walking around the home and independently walking up and down
stairs were reported as having no difference with or without the use of the device [88].
Laboratory-based functional visual tasks were also evaluated. Of note, participants scored
significantly higher on square localization and displayed improved motion discrimination
with the device on versus the device off [86].
Individuals with prosthetic vision also demonstrated oculomotor behavior post-
implantation in motion discrimination tasks with smooth pursuit and an altered opto-
kinetic reflex, which presented with upbeat nystagmus regardless of the stimulus mo-
tion [89]. The presence of these “naturalistic oculomotor responses” left room to further
develop these devices by augmenting their complexity and incorporating this finding [89].
In summary, studies on retinal prostheses, including epiretinal, subretinal, and supra-
choroidal devices, showed mixed results in improving visual function and facilitating
daily activities in individuals with macular degeneration. While some individuals may see
improvements in tasks such as square localization and the direction of motion detection,
others may not see a significant difference in visual function with the device off. Self-
report questionnaires such as the FLORA showed improvements in tasks evaluated with
the device on versus the device off, but the benefits may vary depending on the specific
functional tasks being evaluated and the type of prosthesis being used. Further research is
needed to fully evaluate the potential benefits and limitations of retinal prostheses and to
optimize their use in clinical practice. Additionally, studies showed that retinal implants
can generally facilitate daily activities such as washing dishes and identifying doorways
and people in non-crowded spaces, while identifying food on a plate remains difficult.
Table 1 summarizes the adverse events, visual function, and outcomes of the different
retinal prostheses available to patients.

4.4. Rehabilitative Programs

As part of the clinical implementation of retinal prostheses, rehabilitative programs are
essential to improve patient outcomes. Retinal prostheses showed a steep learning curve,
requiring resiliency from patients to achieve success [41]. Users of retinal prostheses often
described the visualized phosphenes as stressful and cognitively fatiguing [41]. Without
rehabilitation, recipients sometimes stop using the device within years, due to reasons such
as user familiarity with their home environment and, thus, no longer needing the device;
general disappointment; or the inconvenience of the device [41,90]. Furthermore, even
with adequate disclosure about the difference from natural vision, participants remained
unprepared for how different this vision was from what they had once known [41]. Those
that reported continued use of the device adjusted the conditions to decrease the intensity
and activity of the signals or used the device as visual entertainment [41].
Additionally, there are often obstacles that interfere with vision and emphasize the
importance of rehabilitation. These include a phenomenon where phosphenes persist for a
duration after a stimulation is complete or another phenomenon where they fade in certain
areas of the retina even with stimulation, possibly due to desensitization of the RGCs that
requires correction with head movements. Phosphene persistence and perceptual fading
onset differ from person to person, so it is suggested that these factors should be taken into
account during patient rehabilitation in order to optimize prosthesis’ efficacy [91]. While
some modifications to the technology were proposed, particularly with regard to specific
spatiotemporal stimulation strategies, as mentioned earlier, the strategies implemented
Sensors 2023, 23, 5782 19 of 35

throughout rehabilitation training are considered valuable to counteract some of the current
challenges posed by prostheses [92]. It was found, for instance, that retinal prostheses users
were able to improve visual search and perception with auditory cueing by emphasizing
the importance of including audio-visual training in future rehabilitation protocols [93].
Additionally, postoperatively, the use of head movements was recommended in certain
prostheses to “refresh the visual field viewed by the camera”, allowing for improved
outcomes [92].

Table 1. Adverse events, visual function, and outcomes of the different retinal prostheses.

Resolution of
Prosthesis Type Adverse Events Visual Function and Outcomes
Adverse Events
Successfully treated
Conjunctival erosions, hypotony, or managed, except Mixed visual function outcomes,
Epiretinal Argus II explantation, ocular inflammation, for hypotony and self-report improvements in
and retinal detachment. permanent retinal functional tasks.
detachment.
Improved square localization,
Non-serious events: phlebitis, tack
Successfully treated direction of motion detection,
IRIS 2 detachment, etc.; serious events:
or managed. visual fields, and picture
hypotony and persistent pain.
recognition with the device on.
Alpha IMS: increased intraocular
pressure, retinal detachment, and
Improved light source perception
retinal fibrotic changes; newer
Alpha IMS Successfully treated but difficulties with localizing and
Subretinal Alpha AMS: surgical dehiscence,
and AMS or managed. motion detection tasks; mixed
implant displacement, partial
benefits for daily living activities.
silicone oil tamponade loss,
and pain.
Choroidal hemorrhage, subretinal
Improved eccentric natural acuity
hemorrhage, device displacement, Successfully treated
PRIMA and accurate identification of
and increased intraocular pressure or managed.
bar orientation.
due to medication non-adherence.
Facilitated daily activities such as
washing dishes, folding and
Fewer adverse outcomes
organizing laundry, and
compared to other types of
identifying doorways and people
implants; Non-serious events:
Successfully treated in non-crowded spaces; difficulties
Suprachoroidal pain, swelling, conjunctival
or managed. remained in tasks such as
injection, and local inflammation;
identifying food on a plate;
one case of increased
improved square localization and
ocular pressure.
motion discrimination with the
device on.

A pilot study looked at the feasibility of the Computer Assisted Rehabilitation Envi-
ronment System (CAREN), an interdisciplinary approach comprised of visual exercises
and dual-task training (i.e., motor and visual tasks) adjusted to individual ability, with the
goals of improving visual function and safety [94]. Following biweekly 60-min sessions for
four weeks, the pilot study found CAREN to be safe, feasible, and effective in improving
functional outcomes [94]. The importance of a multidisciplinary approach in order to
manage patient expectations was also echoed in other case studies [90].

5. Comparison of Alternative Emerging Therapies to Retinal Prostheses

Retinal prostheses have emerged as a promising technology for restoring vision in
patients with retinal diseases. However, the safety and efficacy of these devices are still
being evaluated through clinical trials, and their high cost limits their widespread adop-
tion. Considering these limitations, it is essential to explore the alternative therapeutic
Sensors 2023, 23, 5782 20 of 35

approaches on the horizon for treating retinal diseases. In this section, we provide a brief
overview of some of the latest developments in cell-based and gene-based therapies for
retinal diseases. By examining these new treatments, we aim to assess whether retinal
prostheses are losing favor as a therapeutic option.

5.1. Cell-Based Therapies

Cell-based therapies typically involve the use of stem cells to replace or restore dys-
functional cells in the retina, often with the help of trophic factors to promote cell survival
and growth [95]. Several types of stem cells have been explored as potential sources for
cell-based therapies, including pluripotent and embryonic stem cells, bone marrow stem
cells, stem-cell-derived retinal progenitor cells, and retinal pigment epithelium (RPE) cells.
Pluripotent stem cells, which are capable of differentiating into any cell type in the
body, offer a promising option for cell-based therapies in retinal diseases. While human
embryonic stem cells (hESCs) have been a commonly studied type of pluripotent stem cell,
their use raises ethical concerns, as they are derived from human embryos. Alternatively,
induced pluripotent stem cells (iPSCs) can be generated from somatic cells, avoiding the
ethical concerns associated with hESCs. iPSCs can be directed to differentiate into retinal
pigment epithelium (RPE) cells, which play a crucial role in supporting photoreceptor
function in the retina. In retinal diseases where the RPE layer is damaged, the replacement
of this layer using PSC-derived RPE cells showed potential to delay disease progression
and restore vision loss [96].
Bone marrow stem cells (BMSCs), including mesenchymal stem cells (MSCs) and
hematopoietic stem cells (HSCs), are extracted from the bone marrow. Since BMSCs are
multipotent stem cells, their capacity of differentiation is more limited than that of PSCs.
However, BMSCs are able to generate cells that are specific to a certain type of tissue.
Setting BMSCs apart is their ability to transdifferentiate, to migrate toward lesion sites [97].
It has not yet been proven that BMSCs can fully differentiate into photoreceptors, but
recent preclinical studies showed their ability to release anti-angiogenic and neurotrophic
factors and many other molecules such as insulin-like growth factor-1 (IGF-1), Th2-related
cytokines, and the class II major histocompatibility complex (MHC II) [98].
As previously mentioned, damage to the RPE layer affects photoreceptor function and
can lead to vision loss. Stem-cell-derived RPE offers an interesting treatment option by
providing trophic support to the remaining photoreceptors [99]. Since RPE is composed
of a single layer with a morphology and a physiology that are well-known, it becomes a
relatively good candidate for stem cell therapies. Furthermore, because of its small size
and given its immune privilege, the eye offers a great microenvironment for stem cell
therapies [100]. By simultaneously transplanting fetal retinal pigment epithelium and
MSCs in mice, their electroretinograms (ERGs) were found to have improved. Due to the
expression of a protein-activating rhodopsin (Crx), an increase in rhodopsin levels, and
a decrease in caspase-3 expression, the survival rate of the transplanted cells was shown
to significantly improve. Therefore, coculture transplantation proved to be better than
single-cell transplantation, which opens up future possibilities for the development of better
treatments for retinal diseases [101]. Stem-cell-based therapies show potential as a treat-
ment option for retinal diseases caused by RPE dysfunction and loss, such as age-related
macular degeneration (AMD) and Stargardt’s macular dystrophy (SMD). While the safety
of stem-cell-derived RPE transplantation has been confirmed, the efficacy in terms of visual
outcomes still requires further investigation. The timing of RPE transplantation is crucial
for the success of the procedure, as it plays a key role in preserving photoreceptor function.
Researchers suggest that RPE transplantation should occur following RPE dysfunction but
preceding photoreceptor injury, in order to achieve optimal visual outcomes. However,
stem-cell-based therapies require systemic immunosuppression to prevent rejection, which
may limit their use in patients with other comorbidities. As a result, many patients may
not be candidates for this therapy [100].
Sensors 2023, 23, 5782 21 of 35

The developing neural retina of human fetuses aged between 16 and 20 weeks of
gestation generates another type of stem cells: retinal progenitor cells (RPCs) [102]. These
mitotically active MSCs were shown to express photoreceptor markers in vitro, which
would enable them to differentiate into the neural cells of the retina [103]. RPCs stand out
by their ability to secrete trophic factors that would increase retinal survival and enable
researchers to replace photoreceptors [104]. With ongoing preclinical studies, stem cells
have proved themselves as having the potential to regenerate the retina. Given their ability
to turn RPCs into photoreceptors and to form functioning synapses with the host, stem
cells could possibly stabilize or even reverse vision loss.
An example of how stem-cell-based implants have contributed to vision restora-
tion is the “California Project to Cure Blindness Retinal Pigment Epithelium” (CPCB-
PRE1) [105,106]. This implant system is composed of a monolayer of human embryonic
stem cells, which are derived from retinal pigment epithelium cultured on a media that
mimics the Bruch’s membrane. CPCB-RPE1 implants were shown to improve vision and
slow down progressive vision loss in a phase I/IIa clinical study [107].

5.2. Gene-Based Therapies

Gene therapy has emerged as a promising approach for treating retinal diseases such as
retinitis pigmentosa (RP) that are caused by genetic mutations. By targeting the root cause
of the disease, gene therapy offers the potential to restore vision in affected individuals.
Different approaches can be used depending on whether the inherited retinal disease is
caused by a recessive or dominant genetic mutation.
For recessive mutations, a gene complementation approach is typically used, while for
dominant mutations, gene suppression with or without gene complementation is generally
preferred. To implement gene therapy, various techniques were developed, including the
use of viral and non-viral vectors and CRISPR-cas9 gene editing. These approaches allowed
for targeted delivery and the expression of corrective genes to the retina [108].
Viral vectors used for gene therapy can be divided into three subtypes: adenovirus
(Ad), adeno-associated virus (AAV), and lentivirus (LV). Of these, AAV attracted the most
attention for treating inherited retinal diseases due to its small size (25 nm), which allows
for efficient targeting of the retinal layers, and low immunogenicity, which makes it a good
candidate for long-acting treatment [109]. However, AAV has limited capacity to clone a
large genome (packaging capacity of 4.7 kb), which restricts its use to treating recessive
diseases such as Stargardt’s disease [109].
Non-viral vectors were also studied for gene delivery, as they reduce the risk of an
immune response and can deliver larger genes compared to viral vectors. However, non-
viral vectors have not yet been shown to efficiently deliver genetic material into cells, unlike
viral vectors that have developed efficient ways for nucleus entry [110].
The gene-editing system known as CRISPR-cas9 has emerged as an important tool
for gene expression and suppression. It showed promising results in silencing dominant
mutations using the non-homologous end-joining pathway in inherited retinal diseases.
However, the success of CRISPR-cas9 is highly dependent on guide RNA design, the type
of target cell, whether a viral or non-viral vector is used, and host-related factors [111].
Currently, the only gene therapy approved for treating a retinal disease is Luxturna,
which targets the RPE65 gene and uses an AAV vector to treat Leber Congenital Amaurosis
type 2 (LCA2). LCA2 is a good candidate for gene therapy, as it involves an enzyme
expressed in the RPE layer, which is an easier target for AAV than the photoreceptor layer.
However, most other IRDs involve gene transfer to the photoreceptor layer, which poses a
challenge for gene therapy [110].
Despite the potential of gene therapy for treating IRDs, its application in practice is
complicated by the wide variety of gene mutations causing these diseases. An in-depth
understanding of pathogenesis is required, and further research is still needed to assess the
long-term outcomes and safety of the therapy [112].
Sensors 2023, 23, 5782 22 of 35

5.3. Optogenetics
Another field that recently gained attention for treating inherited retinal diseases
(IRDs) is optogenetics. Unlike gene therapy, which aims to restore the function of mutated
genes, optogenetics involves introducing photosensitive optic proteins (i.e., opsins) to the
degenerated retina to restore function and provide photosensitivity to the remaining retinal
cells. The primary goal is to turn non-light-sensitive cells, such as bipolar and retinal
ganglion cells, into photoreceptors.
Two types of opsins are used: microbial opsins (type 1) and animal opsins (type 2).
The choice of opsin depends on the desired effect, with depolarized opsins mimicking
an “off” response in dormant cells and hyperpolarized opsins mimicking an “on” re-
sponse [113]. The two types of opsins differ in light sensitivity, function, and utility for
vision restoration [114]. Type 1 opsins cause a conformational shift and directly affect ion
channels or pumps, while type 2 opsins indirectly affect ion channels through intracellular
G-protein-coupled receptor (GPCR) signaling cascades when absorbing light [115].
Currently, there are phase I/II clinical trials underway for optogenetic therapy, since
proof of concept was established. However, further research is needed to understand the
structure, molecular transport modes, dynamics, and optical properties of photosensitive
proteins [112].

5.4. Verdict
After reviewing the different treatment options for inherited retinal diseases (IRDs), it
is possible to consider whether retinal prostheses may become less attractive compared to
cell-based and gene-based therapies. However, each therapeutic avenue has its strengths
and challenges, and having more options available means that each option’s strengths can
be used to overcome others’ weaknesses. For example, a study by Nascimento-dos-Santos
et al. demonstrated the synergy between gene therapy (AAV2-pigment epithelium-derived
factor (PEDF)) and cell therapy (human mesenchymal stem cell) in increasing Tuj1-positive
cells, demonstrating retinal ganglion cell (RGC) layer neuroprotection and promoting
axonal outgrowth. Combining these therapies provided greater neuroprotection and
axonal outgrowth compared to gene therapy alone [116].
Optogenetics may also be an interesting solution for improving retinal prostheses, as
noted in a study by Lagali et al. Optogenetic prostheses would not require invasive surgery,
and the need for biocompatibility would be reduced. Using optogenetics could also be a
possible solution for overcoming the challenge of the low restoration of vision seen in retinal
implants, since optogenetics would only require a high brightness display and the right
optics [117]. Additionally, a study by Gongxin Li et al. showed that ChR2-expressing cells
could produce a mechanically responsive signal out of a light stimulation by using the size
of cellular deformation as an indicator. This study demonstrated that implants integrating
optogenetics offered better resolution than existing implants, potentially opening up the
possibility of a new generation of retinal prostheses [118].
While retinal prostheses face challenges in terms of vision quality and surgical risks,
combining them with other treatment options such as cell, gene, or optogenetics therapy
could potentially provide greater neuroprotection and improve the quality of vision restora-
tion. Therefore, the continued research and development of various therapeutic avenues is
essential to provide the best possible treatment for inherited retinal diseases. To achieve this,
interdisciplinary collaboration is essential between ophthalmologists, geneticists, stem cell
biologists, and engineers, among others, to continue developing and refining therapeutic
approaches that can provide optimal patient outcomes.
Table 2 provides a comparative overview of the emerging treatment modalities for retinal
diseases, including retinal prostheses, cell-based therapies, gene-based therapies, and optoge-
netics, highlighting their core mechanisms, potential advantages, and current limitations.
Sensors 2023, 23, 5782 23 of 35

Table 2. Comparative analysis of emerging therapies for retinal diseases.

Treatment Modality Description Advantages Limitations

This technology works by artificially Can restore some vision in Safety and efficacy are still
stimulating the retinal nerve cells to patients with advanced being evaluated. High
Retinal Prostheses
mimic the function of lost or retinal diseases, such as cost may limit
damaged photoreceptors. retinitis pigmentosa. widespread adoption.
Therapies involve the use of stem Potential to delay disease
cells (pluripotent stem cells, bone progression and restore
Potential risk of
Cell-Based Therapies marrow stem cells, and retinal vision loss, and can
immune rejection.
progenitor cells) to replace or restore provide trophic support to
dysfunctional cells in the retina. remaining photoreceptors.
Therapies involve the use of viral and Limited by the variety of gene
Targets the root cause of
non-viral vectors and CRISPR-cas9 mutations, so long-term
Gene-Based Therapies the disease, potentially
gene editing to correct genetic outcomes and safety still
restoring vision.
mutations causing retinal diseases. require further investigation.
This technique involves introducing Requires further research on
photosensitive proteins to the Can restore the structure, transport modes,
Optogenetics degenerated retina to restore function photosensitivity to dynamics, and optical
and provide photosensitivity to non-light-sensitive cells. properties of
remaining retinal cells. photosensitive proteins.

6. Recent Advancements in Retinal Prosthesis Technology

6.1. Advances in Engineering of Prostheses
Retinal prostheses must meet challenging design criteria. Researchers have pioneered
advancements in the field, such as improvements in material science, visual field size,
and the integration of artificial intelligence for optimizing image processing. Some of the
prominent advances are discussed in this section to reflect on the progress and innovation
in the field, leading to a discussion on the outlook of retinal prostheses.

6.1.1. Material Science

There are two categories of electrode materials proposed for retinal prostheses:
inorganics—such as metals, silicones, and carbon-based materials, and organics—such as
polyimide and polydimethylsiloxane (PDMS) [119]. The literature consistently demon-
strated that smaller-sized electrodes optimize electrical signaling due to comparable di-
mensionality to their neural targets; however, the innate physical limitations with current
electrodes require further inquiry [120].
Metal microwires typically involve conducting metals; in fact, the five most commonly
used metals in retinal prosthetics are iridium, gold, titanium, tin, and platinum [121]. They
are chemically inert, have desirable electrical properties, and have tested biocompatibility
and applicability in neural interfaces [119]. Planar microelectrodes are commonly used
for retinal prosthetics due to their relatively high spatial resolution capacity [119]. How-
ever, metal microwiring has certain intrinsic limitations, namely, its propensity for high
impedance and lower charge storage capacities [119]. Moreover, its rigidity makes it chal-
lenging to fixate, and the need to assemble transcutaneous wire connections increases the
probability of adverse surgical and long-term progressive physiological complications [119].
Microelectromechanical system (MEMS)-based silicon materials may be considered
to combat the above issues. These techniques adopt microfabrication techniques that can
conform a rigid planar structure into context-specific layouts. Consequently, they allow for
higher density recording sites [122]. However, a significant drawback with these materials
is a lack of conformity between the rigidity of the silicon electrodes and native tissue.
Furthermore, even after reducing the electrode thickness to improve bending rigidity, the
smallest MEMS-based electrodes are still too large for optimal conformability [119]. For
the above reasons, conductive polymers, carbon-based materials, and nanomaterials are
promising alternatives.
Sensors 2023, 23, 5782 24 of 35

Conductive and semi-conductive polymers are organic materials with intrinsic electri-
cal and optical characteristics. They demonstrated efficacy in electrode–tissue interfaces and
were better than purely metal-based materials because of their chemical stability, improved
biocompatibility, and high conductivity [123,124]. The most popular examples include
poly(3,4-ethylene dioxythiophene) (PEDOT), polyaniline, polythiophene, and polypyrrole
(PPy)—the lattermost being the most used in brain–machine interfaces [119]. Similarly,
PEDOT treated with polystyrene sulfonate also demonstrated superiority on the previously
mentioned metrics [124]. However, due to the weak interactions of the conductive polymer
coating with the electrode, there was a high risk of delamination—areas where there is
little to no bonding between the coating and the electrode—causing disruptions in how the
signal is registered [125].
Ouyang and colleagues (2017) proposed surface functionalization–modifying the sur-
face properties of the electrode–as a solution to these issues [126]. In their investigation,
they functionalized PEDOT with (2,3-dihydrothieno [3,4-b] [1,4] dioxin-2-yl) methenamine
(EDOT-NH2)—a methylamine-functionalized EDOT derivative—onto a metal substrate
using electrografting techniques. Electrografting involves creating strong covalent bonds
between organic materials with solid substrates. Their findings demonstrated better adhe-
sion with the P(EDOT-NH2) anchoring layer and improved electrode durability.
Green et al. (2010) demonstrated that PEDOT was significantly more efficient at charge
transfers compared to traditional metal electrodes [127]. The first aspect of their study
was in vitro, coating PEDOT on platinum microelectrode arrays and performing biphasic
stimulation protocols. Their preliminary findings demonstrated a 15-fold greater charge
injection limit than platinum, and PEDOT significantly reduced the potential excursion at
the platinum electrode. Upon completion of the investigation, PEDOT also demonstrated
a reduction in possible excursions when implanted into the suprachoroidal space of a
cat retina.
Carbon-based materials are of growing interest in the literature because of their low
modulus and electrical impedance [119]. Carbon nanotubes (CNT) accommodate sizeable
effective surface areas in electrode–tissue interfaces; as a result, they provide greater charge
transfer capacity and low interfacial impedance [128]. Additionally, Eleftheriou et al. (2017)
assessed the structural and functional integration of CNTs in retinal prosthetics [129]. Over
three days, stimulation thresholds decreased, and cellular recruitment increased [129].
These results indicated an increase in CNT–electrode–RGC coupling, while bypassing a
negative glial response [129]. These novel findings indicate a potential therapeutic benefit
of using CNTs in retinal prosthetics.
A lot is still unknown about the application of CNTs in retinal prosthetics; the most
prominent criticism against them and other carbon-based materials, such as graphenes,
is their potential for biotoxicity [119]. However, like conductive polymers, CNTs and
graphenes can be functionalized to make them more biocompatible and optimize electrode–
tissue interfaces [130,131]. In fact, graphene-based materials show promise as a viable
alternative to current brain–machine interface electrodes because they are conformable, can
be easily functionalized, are mechanically stable, and offer excellent electrical conductiv-
ity [131,132]. Moreover, Nguyen et al. (2021) performed an in vivo biocompatibility study
using a novel graphene electrode on P23H rat model retinas [37]. Their results demonstrated
a reduction in inflammation—as defined by microglial labeling—in the graphene-based
electrodes compared to the biocompatible polymer-based electrodes [37]. However, further
investigations assessing graphene-based electrodes on stimulation capacities in retinal
prosthetics are needed to evaluate efficacy.
Nanowires were another pillar of investigation, given their ability to stimulate neu-
rons at the axonal and dendritic levels [119]. Studies investigating the applicability of
two- and three-dimensional nanowire electrodes demonstrated improved sensitivity and
signal-to-noise ratio by virtue of an increased surface-to-volume ratio and increased den-
sity of neuron–nanowire electrodes [133]. Yang and colleagues (2019) discussed a novel
biomimetic electrode technology, called neuron-like electronics (NeuE), which are probes
Sensors 2023, 23, 5782 25 of 35

that have high structural and mechanical comparability to neuron targets—the more signif-
icant variance between the neuron and electrode occasions disruptions in signal recording
and damage to surrounding tissue [134]. Preliminary studies of NeuE in cerebral mouse
models also demonstrated minimal immune provocation [134]. In addition, NeuE also
showed some pro-regenerative properties; like a substrate, it seemed to be able to direct
cells toward damaged tissue sites in need of repair [134].

6.1.2. Visual Field Size

Advancements have recently been made in improving the visual field (or angle) size
of retinal prostheses. Felauto and colleagues in Switzerland developed a novel foldable
and photovoltaic wide-field epiretinal prosthetic called POLYRETINA [22]. POLYRETINA
significantly improved retinal prosthetic technology because it improves the currently
limited visual field [22,135]. A wide visual angle is required for optimal visual perception;
it is involved in a myriad of processes ranging from attention and spatial recognition to
estimating the layout space and interacting with the environment [136]. Therefore, for
retinal prosthetics to demonstrate better artificial vision, they must allow the recipient to
have a large visual angle size (VAS) [136].
Visual angle directly correlates with retinal coverage; however, current prosthetics,
such as the Argus II, provide a VAS of up to only 20 degrees [23,137]. This coverage is inad-
equate for mobility tasks and navigation-related activities such as object identification [137].
Hence, current prosthetics require patients to scan their environment to continually mitigate
the restrictions in VAS—the scanning and continual processing of visual information are
known as space decomposition [137]. Patients report that the device’s need for contin-
ual space decomposition is mechanically and cognitively cumbersome [137]. Preliminary
studies investigating the minimal visual field requirement to perform daily tasks—using
simulated prosthetic models in sighted individuals—is approximately 30 degrees, but this
is an underestimate [137]. Due to individual variations in vision and learning, a higher VAS
is required to appropriately adapt to the prosthetic [137]. Current retinal prosthetics are
lacking because they are too small, stimulate a small portion of the retina, and are difficult
to surgically fixate on the retina [137].
In addition to improving VAS, POLYRETINA improves the spatial resolution of the
prosthetic, as its wireless photovoltaic technology accommodates higher electrode number,
density, and coverage to optimize artificial vision [23]. The retina’s function is to absorb
the incident light entering the pupil and transmit that information to the brain as electrical
and chemical messages to inform visual image processing [136]. POLYRETINA’s wireless
photovoltaic technology serves a similar function: artificial light is projected onto the retina
and absorbed by a semiconductor layer embedded into the stimulating electrodes [22,136].
Each pixel in the device converts incident light into information that is later processed by the
brain [22,136]. The device contains 10,498 photovoltaic pixels and is densely packaged over
an approximate area of 43 degrees [22,136]. Increased electrode density reduces the need for
frequent environmental scanning and significantly improves spatial resolution [23]. Current
prosthetics typically directly activate the nerve fiber, but this can alter the retinotopic map
due to the residual activation of surrounding axons [137]. However, with POLYRETINA,
direct activation is bypassed through network-mediated stimulation, preventing visual
distortions [137]. In addition, the prosthetic can accommodate a high electrode number
and density because its wireless capabilities omit the need for space-consuming hardware
such as trans-scleral connectors, pulse generators, and other cables within the array [137].
While a high pixel density does not necessarily correlate with higher visual discrimination,
emerging studies using POLYRETINA in ex vivo mouse models with retinitis pigmentosa
demonstrate its ability to produce a high spatial resolution [22].
Another advantage of using a conformable device such as POLYRETINA is the ease
of surgical fixation [23,137]. Implants designed to provide a greater VAS require large
implants, producing more invasive incision sites. POLYRETINA, on the other hand, is
foldable and injectable, and it only requires a 6 mm scleral incision. The added benefit of
Sensors 2023, 23, 5782 26 of 35

high conformability makes the device a safer option than non-conformable implants. In
addition, wired implants observe greater risks of lead-wire damage—leading to implant
dysfunction—and tissue scarring due to the added pressure of the mechanical wiring.
POLYRETINA’s wireless technology bypasses these issues by eliminating the need for
superfluous hardware.

6.1.3. Artificial Intelligence

Artificial-intelligence-based imaging protocols are emerging as promising solutions
to combat low sampling resolution. While phosphene optimization is an ongoing area
of inquiry, advancements in AI research demonstrate the potential for devices to adopt
computer vision algorithms to conduct preprocessing maximization of image quality. For
instance, Ge et al. (2017) developed an obstacle-avoidance AI system, called NeuCube,
using a spiking neural network [138]. The NeuCube architecture conducts real-time ob-
stacle analysis and provides meaningful guidance to prosthetic wearers. In addition, it is
significantly more stable and accurate than current navigation systems and does not rely
on sensors or additional image-capturing hardware.
Deep learning models are now becoming integral to improving saliency mapping.
DeepGaze II, created by Kümmerer et al. (2016), is a trailblazer in this space [139]. This
model leverages developments in deep neural networks—namely VGG-19, a trained convo-
lutional neural network (CNN)—to recognize objects and improve saliency prediction [139].
One area of improvement with deep learning models is integrating depth estimation pro-
tocols [140]. However, collecting per-pixel ground truth depth information to inform
supervised learning is cumbersome [140]. Godard and colleagues (2019) developed mon-
odepth2, a self-supervised model that can approximate per-pixel monocular depth, to
address this gap [140]. It demonstrated significant improvements in reducing the pres-
ence of visual artifacts, reducing pixelations that infringe on camera motion assumptions,
and reducing reprojection loss [140]. The caveat with the above-mentioned models is the
scarcity of their usage in validated computational models of the retina. Han et al. (2021)
used different deep-learning-based scene simplification algorithms on psychophysically
validated retina models to address this deficiency [141]. Their findings revealed that these
models could be utilized to accurately predict stimulation patterns, which would help
inform refined algorithms to evoke responses at the desired tissue targets [141].
While CNNs, such as DeepGaze II, provide advanced improvements in two-dimensional
image processing, they are inefficacious when consolidating three-dimensional videos [142].
An emerging alternative is a convolution recurrent neural network (CRNN), which inte-
grates convolutional and recurrent processing to optimize spatiotemporal feature extraction.
However, the recording and processing framework utilized by CRNN is energy-demanding,
making it unfeasible for application in retinal prosthetics. Wang and colleagues (2022) devel-
oped an energy-efficient version called SpikeSEE, which uses a dynamic scene-processing
framework [142]. It has improved prediction accuracy compared to a traditional CRNN,
and it uses a spike processing protocol that helps decrease power consumption.

6.1.4. Preserving Residual Visual Field

Currently, one of the primary concerns when implanting retinal prostheses is the
possibility that they would impact the residual, functional, retinal cells in patients who
have remaining peripheral vision. This concern is significant, in that it directly limits the
scope of retinal prostheses, since those who have not had complete vision loss would be
ineligible or unenthusiastic for implantation. Recently, a study was completed to improve
central vision in atrophic age-related macular degeneration without threatening the residual
peripheral field [28]. This study was carried out in humans and aimed to develop a wireless
photovoltaic retinal implant (PRIMA) where pixels can convert images that are projected
from video glasses using near-infrared light into electric current to induce inner retinal
neurons without disrupting peripheral vision [28]. The clinical trial was performed on five
patients suffering from a geographic atrophy zone of at least 3 optic disc diameters with no
Sensors 2023, 23, 5782 27 of 35

foveal light perception. By using a subretinal, 2mm wide, 30 µm thick chip that displayed
378 pixels implanted in the area of atrophy, it was shown that, in all five patients, the
prosthesis was successfully implanted under the macula, and the photovoltaic subretinal
implants were able to demonstrate visual acuity up to 20/460. All five patients were able
to perceive white–yellow prosthetic visual patterns with adjustable brightness. The study
also demonstrated that the implantation of PRIMA did not decrease the residual natural
acuity in any patient [143]. Since the PRIMA did not negatively impact vision, further
studies were conducted to improve PRIMA durability and estimate the device’s lifespan
in vivo. These studies showed that these implants are robust, with in vitro reliability of
at least 10 years, and are resistant to corrosion and water ingress [144]. Another clinical
trial involving retinal implants was based on investigating the changes in neurosensory
macular structures and the thickness associated with subretinal implantation in geographic
atrophy [145]. In this study, changes in distance between electrodes and the retinal inner
nuclear layer (INL) and alterations in the thickness of retinal layers were assessed using
optical coherence tomography near the implanted subretinal chip within the atrophic area.
It was shown that, in three out of five patients, the distance between the implant and the
target cells remained stable over a long-term follow-up of 36 months [145]. The total retinal
thickness located above the subretinal implant decreased on average by 39 ± 12 µm for
3 months post-implantation. However, it was also reported that no significant changes
were observed after that. In addition, the retinal thickness decreased near the temporal
entry point areas located outside of the subretinal implantation, following the surgical
trauma of retinal detachment. All in all, this study demonstrated that the surgical delivery
of photovoltaic subretinal implants promoted minor retinal thickness three months post-
implantation, which remained stable over the long term with no disadvantageous structural
or functional effects.

6.2. Outlook on Retinal Prostheses

Retinal prosthesis technology has been gaining much interest in recent years and is
continuously for the target of further improvements [146]. As mentioned in earlier sections,
the engineering design criteria need to be finely balanced to achieve the most optimal
patient outcomes. A retinal prothesis can be influenced by several factors such as the
electrode–retina topographical alignment, electrode size and material, factors that impact
spatial selectivity, and, finally, incorporation of bidirectional systems. These factors should
be considered when improving the previously reported, low visual acuities [147]. All these
setbacks demand more research in the field of retinal implants, with a particular focus on
visual processing in the retina and psychophysical performance.
The clinical application of retinal prostheses faces several bottlenecks that limit their
widespread use. These include the following:
– Limited effectiveness: While retinal prostheses can provide some degree of visual
perception, the quality and resolution of the restored vision are still limited; cur-
rent prosthetic devices cannot fully replicate the complexity and functionality of the
natural retina;
– Surgical complexity: Implanting retinal prostheses requires delicate and technically
challenging surgical procedures with inherent trisks;
– Patient eligibility: Selection criteria are crucial to ensure that candidates have specific
visual and anatomical characteristics that can benefit from the device; factors such as
residual vision, retinal health, and overall eye condition need to be carefully evaluated,
leading to a limited pool of eligible candidates;
– Long-term durability: The longevity of retinal prostheses poses significant challenges;
over time, the implant may encounter issues such as mechanical failure, degradation,
or tissue response that can affect its performance, which are still unknown for now; we
still do not know if a prostheses already implanted in a patient’s body can be repaired
or replaced by a newer more developed version in the future;
Sensors 2023, 23, 5782 28 of 35

– Cost and accessibility: Retinal prostheses are currently expensive due to the advanced
technology involved and the complexity of the surgical procedure; the high costs can
restrict access to these treatments for many patients, limiting their availability and
adoption in clinical practice; reducing costs and increasing accessibility are important
considerations for the broader application of retinal prostheses.
Addressing these bottlenecks requires further advancements in technology, surgical
techniques, and the understanding of retinal physiology.
The future prospects of retinal prostheses are dependent on improvements in clinical
trial results that will then support the devices’ approval as well as increase their adoption
amongst users. Bioelectronic implants such as the Argus II, Alpha IMS (Retina Implant AG,
Reutlingen, Germany), BVT Bionic Eye System (Bionic Vision Technologies, Melbourne,
Australia), and IMIE 256 were used in clinical trials [148]. Although PRIMA is currently
under a clinical trial in patients with geographic atrophy, Argus II is the only retinal implant
approved by the Food and Drug Administration, as it has restored some degree of vision
in patients with advanced retinitis pigmentosa. However, Argus II implants hold a major
disadvantage related to high stimulation that requires large electrodes, which results in
either wide electrode spacing or low electrode density [79]. With these challenges, the
IMIE 256 was recently upgraded to exhibit a smaller size and higher number of electrodes,
which compensated for the limitations in the Argus II system. The IMIE 256 consists of an
episcleral electronic implant body with an antenna for telemetry, 248 larger electrodes of
210 µm diameter, and 8 small electrodes of 160 µm diameter. As mentioned before, the IMIE
256 has been so far implanted in five patients with favorable outcomes in safety and clinical
efficacy profiles. Additionally, results were reported regarding the risk of conjunctival
breakdown and exposure of the episcleral electronic packaging being low with the IMIE
256, unlike with the Argus II system. The continuous iteration of such devices and their
improvement will dictate whether retinal prostheses become widely adopted or replaced
by other therapeutics.
Finally, the future outlook on retinal prostheses will be based on parallel growth
in the field of artificial intelligence and the development of deep learning algorithms.
Recently, there was a substantial breakthrough in the field of processing algorithms for
retina prostheses, especially with the combination of the discovery of the retina’s working
principle and state-of-the-art computer vision models [149]. This combination is resulting
in remarkable progress and enhancement regarding the existing limitations in the field of
retinal prostheses aimed to improve visual perception. AI-based image processing methods
have a stronger extraction ability, providing greater convenience for patients with retinal
diseases [150].

7. Conclusions
Overall, the field of retinal prosthetics has made significant strides in recent years,
with advancements in wireless technology and artificial intelligence and the introduction
of various implant designs. While challenges remain in improving visual resolution and
image quality, minimizing surgical risks, and optimizing rehabilitation programs, the
potential for retinal prostheses to restore vision in individuals with significant vision loss
is promising.
The overview of different types of retinal prostheses, including epiretinal, subretinal,
and suprachoroidal sensors, and the principles of electronic retinal prostheses, such as
electrode size and material and charge density, were examined in detail. The clinical aspects
of retinal prostheses, including safety and adverse events, visual function and outcomes,
and rehabilitative programs, were also discussed.
While alternative therapies, including cell-based, gene-based, and optogenetic treat-
ments, have gained prominence, retinal prostheses still maintain their significance in the
management of retinal diseases. Future research focusing on the integration of various
treatment modalities, including cell, gene, or optogenetics therapy, may potentially lead to
enhanced vision restoration outcomes.
Sensors 2023, 23, 5782 29 of 35

Collaboration across different disciplines, including bioengineering, electrical engi-

neering, computer science, materials science, and ophthalmology, is critical to advancing
the field of retinal prosthetics. Continued research and development in this area are vital
for addressing the ongoing debate over the viability of implantable retinal devices and for
bringing this life-changing technology to a larger population.
In conclusion, while retinal prostheses face challenges, their potential to restore vision
and improve patients’ quality of life cannot be overlooked. With interdisciplinary collab-
oration, continued research and development, and a patient-centered approach, we can
work toward achieving this goal and ultimately provide a life-changing solution for those
who are affected.

Author Contributions: Conceptualization, K.Y.W.; writing—original draft preparation, K.Y.W., M.M.

and J.-Y.S.; writing—review and editing, K.Y.W., M.M., A.K. and S.D.T.; visualization, K.Y.W. and
M.M.; supervision, K.Y.W., A.K. and S.D.T. All authors have read and agreed to the published version
of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Acknowledgments: Jonathan Lin and Tracy Aoun—contributed to Section 5; Gerard K. Kim—
referencing and formatting; Ashley Jong—provided artwork figures.
Conflicts of Interest: The authors declare no conflict of interest.

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