Retinal degenerative disorders such as Retinitis Pigmentosa, and especially Macular Degeneration are common nowadays. With a lack of natural drugs or treatments available, other alternative vision restoration methods are needed. Retinal implants are now becoming a focus of research as the idea of bypassing the damage instead of trying to repair it has great potential. Retinal implants nowadays are mostly divided into the epiretinal and subretinal groups, but newer technologies are being investigated as well . The Artifical Silicon Retina and the Argus 2 system are one of the more successful implants presently . Other emerging implants like optogenetics are currently stepping up to be another viable treatment to degenerative retinal diseases.
Introduction to the Retina
Retinal Degenerative Diseases
|An Eye with Retinitis Pigmentosa|
|Shows Pigment Deposits characteristic of RP|
Retinitis Pigmentosa (RP) is essentially inherited, retinal degradation with many symptoms. The symptoms include worsening night blindness, visual field decay, decrease in visual acuity, and electroretinographic decline. Pigment deposits, reduced retinal vessels, and abnormal pale look of the optic disks are signs of Retinitis Pigmentosa observed through ocular examinations. Genetics is also a big part as it can be traced back to family’s history . However, it has been seen to be autosomal dominant, recessive and sex linked in terms of inheritance. There has been no clear link between genotype and phenotype as of yet, but 12 loci have been identified as being the causative genes for RP. The following have been described as possible physical causes for RP: Rhodopsin mutation, peripherin mutation, alpha and beta subunit mutations in cGMP phosphodiesterase of the visual transduction cascade, and others which makes direct treatment quite difficult .
|Age Related Macular Degeneration|
|Wet and Dry Forms of Age Related Macular Degeneration|
Age-Related Macular Degeneration
Macular Degeneration or also known as Age-Related Macular Degeneration (ARMD) is visual impairment most frequent in older individuals especially in the 65 and older groups. ARMD comes in a dry and wet form: the dry form being increased degeneration and lipidization of the retinal pigment epithelial layer, and the wet form with increased choroidal neovascularisation. The clinical signs of Age-Related Macular Degeneration are the presence of drusen, which are dots of white to yellow in colour . Late stages of Age Related Macular Degeneration can lead to severe vision loss. The early symptoms of the dry form consist of hypopigmented spots next to the fovea accompanied by large choroidal vessels. Patients see gaps when presented with images, and letters that appear to be mislocated. The wet form has more serious symptoms which includes retinal pigment epithelium detaching from the Bruch’s membrane due to hemorrhagic fluid accumulation. The loss of attachment leads to metamorphosia , a form of image distortion. The hemorrhage becomes progressively worse and vessels extend and grow towards the fovea leading to gradual blindness till a legally blind state. The tendency is that patients have similar forms of Age-Related Macular Degeneration in both eyes, but it is not uncommon to see different types between the two eyes. Wet forms can become dry forms, and dry forms can become wet forms as their states are not permanent .
The idea of subretinal implants began with a study in 1956 where a light-sensitive selenium cell was implanted right behind the retina allowed a blind patient to see light. This then led to a lot of other research into devices which evolved alongside with microelectronics to allow the subretinal implants today to exist . The subretinal space is a very good spot for retinal stimulation because it’s very close to the inner nuclear layer that will provide direct simulation .
|Artificial Silicon Retina|
|The ASR installed into different Retinas|
Artificial Silicon Retina
One of the more successful and well known subretinal implants is the Artifical Silicon Retina (ASR) implant developed and tested by Chow et al. . The main idea of this device is to depolarize membrane potentials of retinal neurons damaged by Retinitis Pigmentosa to restore vision. This depolarization is done by a 2mm silicon chip with 5000 independently-acting microphotodiodes that are powered by light. They will depolarize the neurons in the places where light would normally stimulate specific neurons thus bypassing much of the damage from the degenerative disorder .
Patient testing have shown great success in terms of vision restoration. FDA approved trials for 6 patients with late stage Retinitis Pigmentosa has shown success. The following was improved in patients implanted with ASR: perception of contrast, resolution, shape, improved threshold sensitivities, increased brightness in visual fields, and other general improvements to pervious, degenerated vision. Follow ups of the patients were done to see the effects of long term use, and the effects ranged from stabilization to even further improvements. More impressively, during this entire process, patients felt little discomfort, and there were no signs of rejection, inflammation, neovascularisation, retinal detachment, migration, vessel disruption, and neovacularization. These results show promise for ASR [4.
Epiretinal Implants are devices installed in the epiretinal membrane right above the retina. This layer is made up of retinal pigment epithelial cells, vascular endothelial cells, fibroblasts, and glial cells . Previous tests showed through epiretinal stimulation showed that electrodes could be used to simulate, and that thresholds for stimulation were lower than in other eye diseases which allows for use of microelectrodes. The most important finding out of that study however was the fact that after stimulation, no images remained which together with others facts, allows for stimulation by electrodes to be used . Although it is great that the implants are not placed onto the retina, the distance thus demands more stimulation .
|How the Argus-2 Circuitry Works|
This retinal prosthesis designed by Second Sight Medical Products is composed of 2 parts, an internal and external component. The external component is a pair of glasses with a mounted camera, processor, and transmitter. There is also the battery which is placed on a worn belt. The internal component consists of receiver, transmitter, and an electrode array with 60 electrodes which stimulated the epiretinal membrane. The system works by first capturing the image with the camera, sending it to the processors which then transmit the information to the receiver wirelessly. The receiver then responds by causing the electrode array to stimulate accordingly to produce phosphenes or partial vision .
Clinical trials were done and the results in general were successful. 96% of the patients in one study were better able to perceive high-contrasts objects, 57% were better able to detect high contrast movement and 23% had shown improved acuity when the device was turned on. However, the safety of the device was a bit uncertain as initial placements had difficulties with increased incidents of serious adverse events (permanent damage, etc). The incidents of severe adverse events did decrease as they improved on better surgical and maintenance features . Another follow up study of patients with the Argus-2 implants showed improvements in spatial-motor task. Patients were asked to located a square when presented at random locations with the following results: 96% showed accuracy improvements while 93% could reproduce the results over and over again . The feasibility of this device is now very high as it is FDA approved with other studies showing that it is also MRI compatible and safe .
ChR2 and Optogenetics
Recent research has shown that optogenetics through the use of Channelrhodhopsin-2 can be used to restore vision. A really good explanation of optogenetics can be found here: Optogenetics. Channelrhodopsins are capable of depolarizing cells and as such, can be exploited to depolarized retinal neurons to bypass the damage by retinal degenerative disorders . However, there are many problems with this approach. First of all, this approach is still only done in rats so translation of results into humans is still in question. The next problem is with the delivery system which requires the adeno associated virus to be modified and used. This has been used in human ocular gene transfer, but not for optogenes. This could lead to possible undesired immune reactions, and oncogeneic results which have been proved safe in rats, but not as of yet in humans .
In a more recent study, a lot of success has been shown through the use of an optogenetics system. The prosthetic device consists of an encoder and a transducer. The encoder functions like the retina in which it converts visual information into a coding understood by the ganglion cells. The ganglion cells are stimulated by a transducer. The transducer is a Channelrhodopsin 2 protein which responds to light. The overall goal of this system is to provide the same action potentials fired by a healthy retina . The results through implants into blind mice were that the blind retinas were able to produce normal coded output. They were able to fire patterns similar to the scenic images they were shown through movies of landscapes, animals, people, faces who were doing activities such as playing and walking. The results closely matched normal retinas in terms of firing much better than other optogeentic systems and just blind mice itself. They also showed that the brain was able to map spike trains of action potentials just as it would with normal retina function at a reliable (90%) rate. The spike train was also shown to be reconstructed very effectively in the brain where a spike train of a baby’s face was reconstructed to be comparable to the actually picture. The next step will be to go onto clinical trials .