Data Drop: Prof. Yossi Mandel on Merging Electrodes and Neurons for High-Acuity Vision Restoration

Interviewer (Michael Beyeler): In plain terms, what’s the big idea here—and why build a hybrid prosthesis?

Prof. Mandel: The big idea is to overcome the inherent limitations of current retinal prostheses by mimicking the natural retina. In the Hybrid Retinal Implant, the electrodes are positioned at the bottom of 10-micron microwells, where glutamatergic neurons are seeded. These cells translate the electrical current into the language of the retina, which is primarily glutamate. This, in theory, will enable selective stimulation of the various retinal neural circuits.

Interviewer: Your modeling suggests single-cell stimulation with picocoulomb charges. How is that possible?

Prof. Mandel: In our device, we achieved tight sealing and excellent electrode-neuron coupling through the microwell geometry. In this configuration, the close proximity between the neurons and the insulating microwell walls (on the order of nanometers) amplifies the injected electrical current by up to three orders of magnitude. Thus, significantly less charge is needed to activate the cells.

This situation is analogous to inflating a balloon: when the air blower is tightly sealed to the balloon opening, the air pressure efficiently inflates it, whereas when the blower is held farther away, much more air is needed.

This effect was demonstrated by our computer simulations and supported by patch-clamp recordings from cells positioned within the microwells and activated by electrical stimulation.

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“These cells translate the electrical current into the language of the retina, which is primarily glutamate.”

Interviewer: What did the in vitro studies show about real-world performance?

Prof. Mandel: In our in vitro studies, we optimized the microwell structures to achieve single-cell occupancy per microwell and close nanometric proximity between the cells and the microwell walls. Patch-clamp recordings validated the computer simulations, showing a significant reduction in the activation charge threshold compared with flat electrodes and with cells located at distances of several tens of micrometers (as is the case in current retinal prostheses).

Interviewer: And what happened when you implanted the device in degenerated rat eyes?

Prof. Mandel: Both imaging and histological analysis revealed good survival of the device’s cellular components (photoreceptor precursors). We were strongly encouraged to observe that many of the implanted cells extended neurites toward the host retinal neurons.

Interviewer: How close could this come to restoring normal visual acuity?

Prof. Mandel: Despite the significant advancements demonstrated in our recent publication, several major engineering and biological challenges must be overcome before vision can be restored using our device.

From an engineering perspective, the main challenge is the efficient transmission of information and energy to the implant in order to stimulate thousands of electrodes simultaneously. We believe that a photovoltaic approach, elegantly implemented by the Palanker group and Science Corporation, should be considered.

The main biological challenge involves improving functional connectivity with the host retina—specifically, the formation of synapses. This aspect is being extensively investigated in the context of photoreceptor precursor transplantation for cell replacement therapy. Our group is also actively working to enhance this function through several complementary approaches.

Interviewer: What drew you personally to combine electronic and cellular strategies?

Prof. Mandel: I’ve always believed that solving complex problems requires bringing together people with different kinds of expertise and knowledge. In the field of retinal prosthetics—and in brain-machine interfaces more broadly—I feel that direct electrical stimulation has its limitations. These can, at least in part, be overcome when the stimulation is translated into the brain’s own language through a hybrid approach. I also believe that nature often shows us the best way forward, and that’s the guiding principle behind our work.

In this project, I’ve had the unique opportunity to bring together everything I’ve learned throughout my career—my medical training, my expertise in ophthalmology, and my PhD in bioengineering—to try to follow nature’s path toward restoring vision.