Visual prostheses use neurotransmitter retinal chips to stimulate retinal function

By Dan Keller

WASHINGTON, DC - Two new investigational neurotransmitter retinal chips should provide better vision more safely than other candidate prostheses currently undergoing clinical trials.

Retinal chip researchers are focusing efforts on diseases such as retinitis pigmentosa and age-related macular degeneration (AMD) where the retina retains some function, allowing for the transmission of signals to the visual cortex, according to researchers at a symposium organised by the Research to Prevent Blindness Foundation.

It is the man-machine interface to convey these signals to the brain that is the remaining hurdle, explained Raymond Iezzi MD.

Calling this tissue interface the "Holy Grail" of any visual prosthesis, he attributed the failure to achieve useful prosthetic vision over the last 50 years of research to deficiencies in the interfaces tried.

Dr Iezzi described a new system using microfluidic delivery of neurotransmitters to the retina.

It consists of three components - a digital camera, a computer and a computer-tissue interface.
The computer processes signals from the camera, defining edges and contrasts. It then sends signals to a microchip on the retina. The chip contains microfluidic orifices that form a two-dimensional array of chemical delivery "pixels" analogous to the output of an inkjet printer.

In practice, Dr Iezzi foresees a reservoir, possibly implanted behind the ear, to supply the prosthesis with a continuous flow of inactive neurotransmitters similar to a pro-drug.
The inactive forms of the neurotransmitters, which he described as "caged" molecules, are released by ultraviolet (UV) light. Prior to photolysis, the caged molecules are physiologically inactive.

UV light cleaves the cage and releases the active molecule. The neurotransmitters' gamma-aminobutyric acid (GABA), glycine and glutamate have been caged and tested in vitro.

Since the release of molecules is controlled optically, no fluidic valves are needed in the orifices. Like a showerhead, one fluidic input is routed to many outputs. Gallium nitride light emitting diodes (LEDs) provide photons.

A fibre optic waveguide in the chip directs the activating light to each orifice and no toxic UV radiation reaches the retina.

In addition, adjuvant neuroprotective molecules such as dextromethorphan may help minimise glutamate excitotoxicity that can lead to apoptosis.
When activated, the ideal caged molecule will react in a predictable manner on a sub-nanosecond timescale, resulting in a biologically active neurotransmitter and an inactive, nontoxic cage.

Dr Iezzi has tested several photo triggered caging molecules, including hydroxy-
phenacylglutamates, carboxynitrobenzyl and dimethoxynitrobenzyl-glutamate.
So far, his lab has fabricated multiple-orifice arrays and is using them to stimulate cultured neurons and retinal whole mounts in vitro.

Stanford researcher Harvey Fishman MD, PhD, is striving for even tighter integration of the man-machine interface - by growing retinal neurons right onto the implant chip. The idea is to stimulate any one specific cell with just the right signal.

He cited the example of "on" and "off" ganglion cells, one transmitting a light signal and the other a dark signal to the brain. A stimulus spanning the two would give a null response. So cell specificity is very important.

"The key to making a neurotransmitter chip work is you have to have spatial confinement," Dr Fishman noted.

His approach is to induce single retinal cell dendrites and axons to grow onto a sub- or epi-retinal chip in the vicinity of a microfabricated aperture, thereby delivering excitatory or inhibitory neurotransmitters.

The neurotransmitter is delivered to such a confined area that any diffusion would dilute it and render it inactive for nearby neurons.

Using microlithographic fabrication techniques from the computer chip industry, Dr Fishman made patterns of neural growth factors on chips.
Neurites from isolated rat retinal ganglion cells grew onto the chips in a directed manner, creating an artificial synapse at the aperture.

Picolitre volumes of neurotransmitters confined stimulation to a 5.0 micrometer radius of the aperture. By controlling the concentration, the volumes and flow rate, this can actually occur at the single cell level, he said.

Just as in nature, Dr Fishman said 20/20 vision is entirely feasible with the possibility of single-cell stimulation.
Using the right camera and lens system on the front end to send signals to the chip, the possibilities are endless.

"You could have super vision. You could actually look at stars in the distance," he said.
The Stanford work is in its early stages. Dr Fishman is beginning in vivo experiments and has implanted a flexible chip in a rabbit retina.

The new approaches to vision prostheses could overcome some of the potential disadvantages of the first generation of electrode-based systems. One of these, a subretinal microphotodiode-based silicon chip retinal prosthesis, is now in a phase I clinical trial in patients with retinitis pigmentosa (RP).

Developer Alan Chow MD and colleagues reported at the Association for Research in Vision and Ophthalmology (ARVO) conference earlier this year that the device had proven safe and stable for up to 18 months in six patients, producing some improvement in visual function.

The 2.0 mm diameter Artificial Silicon Retina chips (ASR™, Optobionics) are 25 microns thick and contain approximately 3,500 independent microphotodiodes.
They were implanted successfully in all patients approximately 20º superior and temporal to the macula. The ASR microchip is powered solely by incident light and does not require the use of external wires or batteries.

Dr Iezzi voiced reservations about the ASR system: "Dr Chow designed a device with a series of photocells that produce about 10,000 times too little electrical current to create electrical-type pixels, but they're asserting the electrical stimulation has some form of positive effect on the retina.

"So their device actually doesn't function in the way it's designed. They designed it to create electrical pixels and admit it doesn't work in that way - that they are undershooting the amount of current."

German researcher Eberhart Zrenner MD and colleagues at the University Eye Hospital, Tübingen, are developing an active subretinal implant that may help solve this problem. It utilises an external energy source they say provides sufficient current to generate neuron activity.

Another system under development by researchers at the Doheny Eye Institute in Los Angeles uses very high currents of the order of 300 microamperes to 1.0 milliampere for threshold detection of stimulation.

The system combines a wireless a receiver/transmitter that sends signals received from a digital camera to an electrode array affixed to the retina.
The first patient received this implant earlier this year. Reporting at ARVO conference, Mark Humayun MD and colleagues said the retinitis pigmentosa patient went from no light perception preoperatively to seeing spots of light that correlated with stimulation of the device postoperatively.

The problem with that approach, Dr Iezzi noted, is that the currents used by the device require large diameter electrodes, about 0.5 mm, because they exceed the charge capacity of smaller electrodes. Therefore, the system is stuck with large electrodes and poor spatial resolution.

He asserts that neurotransmitter chips should overcome many of the problems inherent in electrode-stimulation devices, including biocompatibility.
Because of the precision with which neurotransmitters can be delivered and the selectivity of specific molecules for different cell types, spatial resolution should be much better than with the wider, non-selective fields of electrical stimulation.

Furthermore, because of the currents needed, chronic electrical stimulation can cause thermal tissue damage, electrode oxidative breakdown and metal deposition in tissue. The latter problem could be avoided by using the neurotransmitter approach.

As competing retinal implants get closer to clinical trials, sceptics have emphasised the need for careful placebo-controlled protocols and reliable quantitative visual acuity testing before and after implantation.

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