Background

History of Bionic Vision

Advances in medicine, surgery and electronics have set the stage for a fusion of the physical and biological sciences; one in which prosthetic devices may restore lost functional capacity to the disabled. For excellent reviews on the subject, see [1, 2, 3].

The Early Days

The end of the 18th century saw the introduction of electrophysiology as a scientific discipline, opening the door to many studies of cortical stimulation.

• 1752

  Benjamin Franklin theorized to the Royal Society of London that sight and hearing could be restored with the use of electricity [4].

• 

  1755

  Charles Le Roy, an 18th century French scientist, conducted the first attempt to cure blindness through electrical stimulation (presumably after reading Benjamin Franklin's theory). Le Roy was able to evoke flashes of light (phosphenes

  ) and other visual disturbances in a blind patient by sending electrical currents through a wire wrapped around the patient's head [5].

  Fig. 1: Method used by Charles Le Roy to evoke visual disturbances in a blind volunteer. A wire was wrapped around the patient's head with current applied through it. (reproduced with permission from [6])

• 1870

  Two German physicists called Gustav Theodor Fritsch and Eduard Hitzig performed a number of experiments involving systemic stimulation across the cerebral hemispheres of dogs. These studies demonstrated that cerebral hemispheres were excitable at a time when many scientists believed that they were not [7].

• 1884

  Victor Horsley, a British scientist, is credited as the first to use electrical stimulation of thecerebral cortex

  intraoperatively. Horsley electrically stimulated an occipital encephalocele in a 6-week old child [8], in response to which the child's eyes showed rapid conjugate deviations.

Treatment of Head Injuries in the World War Era

The beginning of the 20th century saw the introduction of cortical stimulation as a treatment option for epilepsy. With the increased occurrence of gunshot and battlefield wounds to the head, neurosurgeons reported a wide variety of phosphenes in response to cortical stimulation.

• 1918

  Kurt Löwenstein & Moritz Borchardt electrically stimulated the exposed visual cortex of a patient who suffered persistent seizures from a bullet wound on the left side of his head. The stimulation produced flickers of light that closely resembled the visual phenomena the patient would see preceding a seizure, showing that stimulation of the visual cortex could produce point sources of light [9].

• 1924

  Fedor Krause introduced surgical operations for treatment of epilepsy in Germany, performing over 400 operations on epileptic patients. When he stimulated the cortex of a gunshot wound victim, the patient reported seeing jagged rings of light and stars in different patterns. Krause observed that even though his patient washemianopic

  for nine years, he still experienced visual hallucinations in his blind hemifield preceding a seizure. Electrical stimulation could provoke similar visual imagery in the blind hemifield as well [10].

• 1929

  Otfried Förster, a German neurologist and neurosurgeon, examined a patient with a projectile injury that resulted in occipital seizures. He demonstrated that stimulation of theoccipital pole

  and its surrounding cortex produced phosphenes that were motionless and located at the center of the patient’s visual field [2].

• 1947

  The American-Canadian neurosurgeon Wilder Graves Penfield examined 17 years of visual cortex stimulation in about 330 operations. He stimulated a wide area of the visual cortex and also one area outside the occipital lobe, which still produced visual imagery. The observations of Penfield were unique in that patients reported seeing phosphenes of different colors [11].

The First Generation of "Bionic Vision" Devices

By the 1950s, it was well known that electrical stimulation of the occipital poles could produce punctate phosphenes in the centre of the visual field [3]. This knowledge, plus Krause's observation that it was possible for a blind patient to perceive visual imagery upon stimulation of the occipital cortex, prompted the suggestion that a visual prosthesis might be a practical possibility.

• 1962

  

  "I see a flash!" - Button (1958, p.54)

  John C. Button and Tracey Putnam at Cedars of Lebanon Hospital (now Cedars-Sinai) in Los Angeles created and implanted the first ever bionic vision device in a 36-year old woman who had been completely blind for 18 years. Two pairs of stainless steel wires were implanted into the cortex and connected to a simple stimulator. The patient reported seeing vivid flashes of light and (with the use of a photocell) was able to detect the presence and relative brightness of a light source [3].

  Fig. 2: Button's stimulating apparatus was connected to an array of four stainless steel wires implanted in the occipital cortex of a blind woman. (reproduced under CC BY-NC-ND 4.0 from [2])

• 1965

  Giles Brindley, a physiologist at the University of Cambridge, had been undertaking a programme of research to support the development of a fully implanted, multielectrode wireless visual cortex stimulation device developed a fully implanted, multielectrode, wireless visual cortex stimulation device with the goal of allowing prosthesis recipients to read printed or handwritten text [5].

• 1966

  The first Conference on Visual Prosthesis was held in Endicott House at the Massachusetts Institute of Technology. The conference chair Theodore Sterling explained that after initial difficulty in bringing together potential participants, the conference was finally held under the proviso that the proceedings would not be made publicly accessible [2].

• 1968

  

  Brindley and Lewin implanted their first cortical implant that consisted of an array of 80 small, square, platinum electrodes embedded in a silicone cap. Each electrode was hard-wired to a receiving coil that was part of an array of coils also embedded in silicone and implanted under the scalp. 39 electrodes in the implant produced phosphenes across the patient’s visual field when stimulated. Centrally evoked phosphenes were small and flickering whereas peripherally evoked phosphenes differed more in size, shape, brightness, and sharpness [12].

  Fig. 3: Brindley stimulating the visual cortex of his first implant recipient, placing a stimulating coil over a matched receiving coil implanted under her scalp. (reproduced under CC BY-NC-ND 4.0 from [2])

The Era of Government-Funded Research

The same year that Brindley & Lewin published their groundbreaking paper, the UK Medical Research Council formed the Neurological Prosthesis Unit, with Brindley as its director. In the US, the University of Utah instigated a sensory prosthesis research program with William Dobelle as director. In addition, the National Institute of Health (NIH) established a neuroprosthetic program at the US National Institute of Neurological Diseases and Blindness (NINDB, now known as NINDS). Thus began the era of government-funded research towards the development of a cortical visual prosthesis:

• 1969

  The second Conference on Visual Prosthesis was held at the University of Chicago, aimed at trying to find future directions necessary to explore a possible visual prosthesis [2].

• 1974

  

  William Dobelle and his group developed a removable multielectrode cortical surface array, which was tested on 36 sighted patients undergoing occipital surgery [13] and 2 blind volunteers who had been blind for 7 and 28 years, respectively [14]. The array contained 64 hexagonally arranged platinum discs placed only over the mesial occipital cortex, each of 1-mm² surface area. Their results in blind subject closely agreed with Brindley & Lewin's [12], noting that phosphenes could be elicited with stimulation of V2 and persisted with suprathreshold stimulation. The same was not true in sighted volunteers, where phosphenes did not always flicker and were occasionally coloured, always disappeared immediately upon cessation of stimulus, and gradually faded with continuous pulse trains [13].

  Fig. 4: Phosphene map in the visual field for case no. 36. Phosphenes indicated by dashed circles appear only at high amplitudes. The electrode array and numbering system are also shown, along with a dashed line showing the postulated position of the calcarine fissure. (reproduced with permission from [14]).

• 1974

  Over the same period, researchers from the Huntington Institute of Applied Medical Research also developed and tested a cortical array comprising smaller, "strip" arrays of 18 platinum surface electrodes, placed separately on both the occipital pole and mesial occipital cortex of normally sighted patients [2, 15]. The implant was able to elicit phosphenes, but could also cause seizures, which led the NIH to disbandon the group's effort in favor of research on "safe and effective methods for neural stimulation" [2].

• 1975

  Another group funded by the NIH and based at the Massachusetts General Hospital in Boston had been undertaking intraoperative visual cortex stimulations on five patients throughout the early 1970s. However, only three patients reported seeing phosphenes, with the two failures attributed to postoperative swelling and patient drowsiness [2].

• 1978

  

  Dobelle and colleagues continued to improve their implant design throughout the 1970s, adding a transcutaneous connector to permit chronic implantation of electrodes and spectacle-mounted cameras. One of Dobelle's early patients retained his implant for over 20 years, with no reported complications of infection or seizure [2].

  Fig. 5: Different views of a recipient of the Dobelle implant, first implanted in 1978. In 2000, his external hardware & software was upgraded, including the miniature camera shown, greatly enhancing the functionality of his prosthesis. (reproduced with permission from [6])

• 1982

  

  Determined to pursue the goal of reading conventional letterforms, Brindley's group continued developing improved implants into the 1980s including one with 151 electrodes [13], which unfortunately became infected and had to be removed [14].

  Fig. 6: "Miss Bonnett", recipient of the last visual cortex implant built by the MRC Neurological Prostheses Unit. (reproduced under CC BY-NC-ND 4.0 from [2])

The Era of Retinal Implants

The considerable risk associated with cortical prostheses led to the scientific community to explore other locations along the visual pathway capable of producing phosphenes, which led to a new era focused on the development of retinal prostheses.

• 1996

  Mark Humayun and colleagues showed that local electrical stimulation of the retinal surface in patients with outer retinal diseases resulted in focal light perception, even though the patients had been blind for many years [16].

• 2011

  

  Argus II, anepiretinal

  implant developed by Second Sight Medical Products, received approval for commercial use in the European Union (CE Mark). The device was initially available at a limited number of clinics in Switzerland, France, and the United Kingdom, at an EU market price of $115,000 [17].

  Fig. 7: Argus II Retinal Prosthesis System (Source: Second Sight). Camera images are processed and transferred to electrodes implanted in the back of the eye.

• 2013

  

  Alpha IMS, asubretinal

  implant developed by Retina Implant AG, received the CE Mark as well [18]. The device was initially available at around $130,000.

  Meanwhile in the US, Argus II became the first retinal implant to receive FDA approval [19].

  Fig. 8: Alpha IMS, a subretinal implant consisting of a 3x3mm2 microchip with 1,500 electrodes (Source: Retina Implant AG).

• 2019

  Retina Implant AG discontinued business activities quoting innovation-hostile climate of Europe's rigid regulatory and unsatisfactory results in patients.

• 2020

  Stricken by fundraising issues due to COVID-19, Second Sight announced massive lay-offs and an intent to wind down operations. The company would later attempt a (failed) business merger with Pixium Vision but ultimately rebound after raising ~$60M in a public offering.

• 2021

  

  Pixium Vision implanted their first of an expected 38AMD

  patients with PRIMA, a subretinal device, as part of their PRIMAvera clinical trial. This study is the last step before seeking market approval for dry AMD in Europe.

  In addition, Pixium expects to report 36-month data from the French feasibility study by early 2022, and is continuing clinical development in the US.

  Fig. 9: PRIMA, a subretinal implant consisting of ~400 photovoltaic cells (Source: Pixium Vision).

The Future

• 2020s - ?

  With dozens of next-generation devices in development that include retinal, optic nerve, and cortical approaches, a wide variety of bionic eye technologies should be available within a decade.

Causes of Vision Loss

Sight Restoration Technologies

Bionic Vision is not limited to computer interfaces but instead encompasses a wide range of vision restoration and/or rehabilitation techniques.

Electronic Neuroprostheses

Neuroprostheses, better known as "implants", have been a common focus of research and investments into curing blindness. These devices come in the form of a miniature chip which is placed into a specific location of the retina (retinal implants

Retinal implants function to replace damaged photoreceptor cell activation. However, if the disease has significantly interrupted the early visual pathway (i.e. the retina, optic nerve, or lateral geniculate nucleus), cortical implants may be the only option.

Optogenetic Neuroprostheses

Optogenetics is a technique that uses a combination of optical and genetic methods to restore vision loss. Once light-sensitive proteins are introduced to the area of the damaged photoreceptors, retinal neurons can be stimulated by using a specific range of light intensities and wavelengths.

Two types of optogenetic strategies have been studied: ion channel therapies and G-protein coupled receptor (GPCRs) therapies. Ion channel therapy research focuses on improving temporal sensitivity for vision. While slower than ion channels, GPCR therapies have demonstrated much promise for vision restoration given their higher sensitivity to light activation. Both have been used to study and treat retinal dystrophies and degenerative diseases.

There are a few companies in the process of developing accurate optogenetic studies for future use. The GenSight PIONEER preliminary trial combines optogenetic therapy with biomimetic goggles. These specially designed goggles help to compensate for spatiotemporally related visual distortions associated with optogenetic treatment.

Gene-Based Therapies

When there is a mutation of a gene, the synthesis of proteins that follows is affected such that there can be an increase or inhibition of function for that gene. Inhibiting the function of a protein within the retina can lead to diseases that cause blindness. Gene therapy and gene editing are two current genetic approaches being studied to prevent the spread of retinal disease and possibly restore vision.

Gene therapy involves using recombinant DNA to encode the desired DNA into a plasmid which is delivered into the cell by a vector. This is meant to cause the expression of the desired gene throughout the retina, and restore cellular function. A limitation of gene therapy is that it can only function to supplement the expression of a gene, not eliminate or suppress the desired genetic expression. There has been significant progress in gene therapy for treating Leber congenital amaurosis, which shows promise in treating more frequent diseases in vision such as AMD and RP.

Cell Therapy

Once they are successfully injected or transplanted into the retina, stem cells have the ability to form all cell types necessary for retinal regeneration. There are two types of stem cells that can do this: embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). ESCs and iPSCs can mature into pluripotent stem cells, and pluripotent cells are then able to differentiate into bipolar or photoreceptor cells.

Inserting stem cells within the retina may be conducted through an injection process or a transplantation. There have been multiple trials over the past ten years testing the usefulness of stem cell therapy within the retina, mostly yielding promising results. Research has focused on studying the effectiveness of stem cell therapy in creating retinal pigment epithelium (RPE) cells and photoreceptor cells. Data suggest that iPSC transplants can produce RPE cells and have potential to restore vision or even slow the progression of disease for AMD patients. There are currently no clinical trials that have demonstrated the effectiveness of stem cell therapy for photoreceptor cells.

Sensory Substitution

Sensory substitution devices change visual information to auditory or tactile information. What is most notable about these solutions is that they do not require invasive surgery for use, instead relying on the plasticity of other sensory modalities to adapt new strategies to compensate for vision loss. When paired with extensive training, people who are blind or have low vision can improve performance in navigation, object recognition, and more.

Devices in this category include the vOICE (visual to auditory) and BrainPort (visual to tactile).