2012年4月17日 星期二

Retinal Implants, Still in Their Infancy, Provide a New Vision of the Future

The challenge of restoring sight is immense, and the advances in this area seem to go hand in hand with advances in technology. As with most electrical prostheses, these advances cross many scientific disciplines, from biophysics to electrical engineering. Of equal importance is the surgical aspect of being able to successfully implant such devices.

Two approaches are being employed. One is the subretinal implant, which is implanted at the level of the photoreceptors. Several thousand photodiodes are arrayed in a sheet and are connected to microelectrodes that in turn stimulate ganglion cells (the output neurons) in the retina. Light shining on this array generates a current that depolarizes the ganglion cells, via these microelectrodes. The second approach is the epiretinal implant, which is placed on the inner or opposite layer of the retina. In this, a conventional (external) camera and processing unit are connected to a readout chip that is secured to the inner retina, at the level of the ganglion cells.

Complexity and Inaccessibility

Given the hard-to-access location of the retina, at the back of the eye, and the inherent complexity of this nervous structure, the procedure is incredibly delicate. The retina is only 0.5 mm thick, and neuroscientists consider it to be the most complex sensory organ we have. Several neuronal cell types constitute the retina, including photoreceptors, bipolar cells, horizontal cells and ganglion cells.

Key to vision is the transduction of photons by the photoreceptors, which have some exceptional properties. Among those is the "dark current," which is a constant depolarization in the dark. That, in turn, releases glutamate, at the synaptic terminals of photoreceptors. In darkness, the membrane of the outer segment is permeable to sodium ions. The higher concentration of sodium ions outside the cell allows positively charged sodium ions to enter the cell in darkness, causing the cell to be partially depolarized. Light decreases the permeability of the outer segment membrane to sodium, thereby decreasing the flow of positive ions into the cell and causing the inside of the cell to become more negative (i.e., to hyperpolarize).

All vertebrate photoreceptors hyperpolarize in response to light (i.e., the inside of the cell becomes more negative). This is a unique situation that is then relayed to vertical or lateral pathways, within the retina. The final output is the ganglion cells, which lie on the inner surface of the retina. The light passes through several neuronal layers before reaching the photoreceptors, and the retina relays all the information collected by the photoreceptors in the form of coded streams of action potentials. This coded information includes form, movement, contrast and color. These signals are then transferred via the optic nerves to various brain regions, finally ending in the visual cortex.

Sight Disorders and the Retina

Many disorders of the eye are related to the retina; for instance age-related macular degeneration, retinitis pigmentosa, and diabetic retinopathy. They often involve serious disruptions in the collection of light, and may lead to blindness. Some, such as retinitis pigmentosa, in which there is a gradual deterioration of rods within the retina, eventually leaving only the central fovea intact (which is concentrated with cones), have no known cure.

Currently much of the focus is on the subretinal implant, and many groups are investing in this technology. The hurdles are huge, of course, not least of which is the surgical implantation onto the back of the retina. In general, two surgical approaches are currently employed; the first is through the cornea and into the vitreous humor, and the second is through the sclera. Both techniques are challenging, as can be imagined. The biggest challenges involve maintaining internal pressure within the eye and contrast illumination of the surgical site during the procedure.

Once in place, there is about 50 to 100 ¼m between the subretinal implant array and the ganglion cells, which is sufficient to excite these cells. Even so, most of the other important neuronal elements that refine the retinal image in normal sight within the retina are bypassed. In animal models, the subretinal implants seem to produce action potentials in the visual cortex of the brain, and the spatial resolution is around 1 degree-a remarkable achievement. Nonetheless, the electrical stimulation of the ganglion cells is crude, and there is concurrent stimulation of their optic nerves, resulting in distorted images and cancellations of output from the photodiodes. Additionally, spatial resolution is adequate, at best, to achieve a recognizable image.

Boston Project Sees Progress

The Boston Retinal Implant Project, which is a collaborative effort with multiple academic, clinical and research institutions throughout the nation, has a novel engineering solution to treat blinding diseases with retinal implants (see http://www.bostonretinalimplant.org/). Their current prosthesis includes an external camera that is mounted onto a pair of eyeglasses. The camera transmits images wirelessly through a coil within the glasses. The scene captured by the camera is then relayed to receiving coils on the prosthesis. The retinal stimulating array consists of a row of several hundred electrodes that are capable of stimulating ganglion cells in their immediate vicinity. The result is a pixilated array of lights that appear much like a large scoreboard image, at best. With such information, however, it is anticipated that a blind person will not require the use of a guide dog or cane.

Surgical methods have been applied in animal models and so far have shown reliable success using a combination of vitreoretinal surgery and ab externo procedures. The project's retinal implant has been tested in six humans, and several of the patients who had been legally blind for decades were able to distinguish small spots of light upon low level stimulation of parts of the electrode array. (The original paper can be found at http://www.bostonretinalimplant.org/pdf/20031200-preceptual-thresholds.pdf.)

It is also noteworthy that close to 300 patents have been filed and granted on this topic. Over the past 12 months, 15 patents were filed naming various assignees, such as the Doheny Eye Institute, Neurosystec Corporation, The Pennsylvania College of Optometry, Retina Implant GMBH, Second Sight Medical Products Inc., W.C.Heraeus GMBH & Co., and Wayne State University.

Implants Currently Offer Best Hope

So, will these implants be the pathway to restoring sight in the future? In the absence of other approaches, they offer the best hope of restoring sight. Nonetheless, we are a long way off from achieving this goal. The retina is an exquisitely complex nervous structure that has many intricate levels of image processing. Our achievements to date represent a very crude approach at imitating its capabilities.

Nonetheless, several research institutes and companies, such as the Doheny Retina Institute, and Intelligent Medical Implants AG, are making truly remarkable headway in this area, and they may indeed achieve some significant milestones in the coming years. However, until micro-engineering approaches that employ either transplant technologies or neural-electrode interfaces at the single cell level are developed, science will not get close to anything capable of restoring full vision within the blind.

Alternately, it is quite likely that future advances in the current microelectrode array design will be large enough to significantly improve the visual image. I see that advance being related to the integration of smaller, more numerous electrodes and probably multiplying the current density by a factor of 10. Before that happens, however, it is premature to talk about restoring the ability to read or recognize faces, for instance. In the meantime, I suspect that we may see FDA-approved retinal implants within the not-too-distant future, with these exciting bio-prostheses continuing to improve with each additional clinical trial.

Nerac Inc. is a global research and advisory firm for companies developing innovative products and technologies. Nerac Analysts deliver custom assessments of product and technology development opportunities, competitor intelligence, intellectual property strategies, and compliance requirements through a proven blended approach to custom analysis: review of technical knowledge, investigation of intellectual property, and appraisal of business impacts. Nerac deploys analysts in diverse disciplines to help clients discover new applications, serving as a catalyst for new thinking and creative approaches to business problems or identifying strategic growth opportunities. On the web at http://www.nerac.com

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