Subretinal prostheses show promise in preliminary studies, author says

Subretinal implants have been successfully tested in animals. Further research and development is needed, however, according to the authors.

TÜBINGEN, Germany — Subretinal prostheses have demonstrated long-term stability, biocompatibility and functional performance in numerous animal studies, according to researchers here.

“Implants could potentially restore vision in the next few years. Just like a hearing aid for those who are hearing-impaired, or a pacemaker for those with heart disease, a retinal prosthesis will be implanted into the eye to support or replace defective tissues,” Eberhart Zrenner, MD, told Ocular Surgery News.

Since 1996, investigators here have been developing a subretinal micro-photodiode, an electrical retinal implant that produces images by replacing the damaged photoreceptors in the retina of a person with vision loss. Studies in cat, pig and chicken retinas have been promising. Researchers found that prosthetic stimulation achieved partial image resolution of 1° visual angle and better, which would allow useful object location.

“The subretinal implants are working quite well, but there are still many obstacles to overcome. For now, were are on the right track,” said Dr. Zrenner, a professor and chair of the department of pathophysiology of vision and neuro-ophthalmology at the University Eye Hospital Tübingen.

In addition to subretinal prostheses, epiretinal prostheses are also in development in other research centers. Investigators in Germany, the United States and Japan have been working on prototypes of both types of devices to restore vision.

“We are hoping that our developments will help those who are blind or with low vision to have useful vision again one day,” he added.

Subretinal implants

“There are advantages and disadvantages to both the subretinal and the epiretinal implants,” Dr. Zrenner said.

The subretinal microphotodiode is an electrical retinal implant that produces images by replacing the damaged photoreceptors in the retina of a person with vision loss.

The prosthesis Dr. Zrenner and colleagues have been developing is stimulated by light. The device is implanted between the pigment epithelial layer and the outer layer of the retina.

“It becomes suctioned by a vacuum effect. This permits for high stability, so the implant will not shift,” he said.

The implant is a thin plate 2 mm to 3 mm in diameter and 50 µm to 100 µm thick. It carries thousands of light-sensitive microphotodiodes. When placed in the subretinal area, the chip responds to the rays of light that fall on each microphotodiode.

“The microelectrodes on the plate are activated by the photodiodes in the eye after light comes in through the pupil,” Dr. Zrenner said.

Once the microelectrodes on the chip are activated, they stimulate retinal sensory neurons that transmit signals to the optic nerve, he added.

According to Dr. Zrenner, subretinal prostheses will have a number of advantages.

“In addition to easy fixation, the microphotodiodes directly replace damaged photoreceptor cells and utilize the retina’s remaining intact neural network, which is capable of processing electrical signals,” he said.

Artificial energy needed

One weakness of the subretinal chips was discovered during animal testing. Researchers found the implants could not sufficiently stimulate the retinal sensory neurons with the amount of light available in a natural environment.

“We have learned with our experience in animals that there is just not enough energy generated from natural ambient light. You have to put additional energy into the chip,” Dr. Zrenner said.

In the past year, Dr. Zrenner and his research team have developed an active subretinal implant supported by an external energy source, which provides the amount of current needed to generate neuron activity.

“We can amplify the signals by putting transpupillary infrared illumination into the chip,” he explained. “This has given us enough light voltage and current to properly stimulate the retinal neurons in regular ambient light. Only with the aid of an additional energy source can the subretinal chip become effective by light and function as it was intended to perform.”

Epiretinal implants

In contrast, the epiretinal implant the other research groups are investigating contains no light-sensitive elements.

“It has a small field sensor — like a camera — that is placed outside the eye or in an IOL. This sensor sends signals to an electrode array positioned on top of the inner layer of the retina,” Dr. Zrenner said.

The electrode array chip is attached to the sensor by foil-bound wires. It receives encoded messages of visual information from the external sensor. These electrical impulses are then transferred from the array chip to ganglion cells and their axons, which unite to form the optic nerve, he said.

“At the end of the process the visual data has to be translated into a spatiotemporal stimulation pattern of electrical impulses that have to be understood by the brain’s visual cortex,” he explained.

There is a much larger need for processing with this implant than there is with the subretinal chip, he said.

“The subretinal chip uses the remaining neural network of the retina, while the epiretinal implant does not; it works autonomously. Therefore, this chip must provide considerable additional processing to prepare the visual information,” he noted.

More research needed

Consequently, a higher chance of malfunction and complications exist with the epiretinal prostheses because they are designed to perform alone without the aid of the retinal system.

“The epiretinal implant has to ‘tap wires,’ ie, to stimulate the axons of ganglion cells that may be far away, and this can result in a missed transmission or disorder of stimulation patterns,” Dr. Zrenner explained.

Additionally, there are problems with the fixation of the array chip.

The subretinal implant is a thin plate 2 mm to 3 mm in diameter and 50 µm to 100 µm thick. It carries thousands of light-sensitive microphotodiodes. When placed in the subretinal area, the chip responds to the rays of light that fall on each microphotodiode. Once the microelectrodes on the chip are activated, they stimulate retinal sensory neurons that transmit signals to the optic nerve.

“Another problem with the epiretinal implant is the difficulty in getting it to fixate,” he said.

He said it is difficult for the chip to adhere to the inner layer of the retina. This difficulty carries an additional risk of potentially stimulating cellular proliferation, he added.

An advantage of this system, Dr. Zrenner noted, is that the strict information-transfer characteristics of the epiretinal implant make it more amenable to external control, especially when the sensor is outside the eye.

However, before clinical trials can take place for the epiretinal prostheses, these functional and design problems must be fully overcome, he said.

Long-term stability, biocompatibility

Long-term stability of both the subretinal and epiretinal chips is still under observation.

“The long-term stability of subretinal prostheses has been for tested for 30 months in pig retinas,” Dr. Zrenner said. “Unfortunately, this is not long enough. We really need to test biocompatibility for longer periods to fully evaluate how the retina tolerates the implant and how the implant tolerates the retina.”

An investigator in the United States, Alan Y. Chow, MD, cofounder of the Optobionics Corporation in Illinois, has tested the tolerance of subretinal implants for 18 months in humans. His team of researchers received approval from the Food and Drug Administration to implant subretinal chips in the retinas of three blind patients to test biocompatibility.

“In his experiences, the implants were well tolerated, so there seems to be no problem with biocompatibility,” Dr. Zrenner said. Dr. Chow and colleagues are currently in the process of releasing the data from the first phase of this trial.

Dr. Zrenner and colleagues will take Dr. Chow’s research one step further.

“We not only will be testing long-term stability and biocompatibility in humans, but we want to see the function of an active powered device and the visual abilities that the chip allows the patient to perceive objects,” he said.

For Your Information:

• Eberhart Zrenner, MD, can be reached at the University Eye Hospital Tübingen, Department of Pathophysiology of Vision and Neuro-Ophthalmology, Schleichstr. 12, D-72076, Tübingen, Germany; (49) 707-1298-4786; fax: (49) 707-1295-038; e-mail: ezrenner@uni-tuebingen.de. Dr. Zrenner has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.