Optical microscopes are  a key tool in biological studies. But because they are limited by approximately half the wavelength of light used (200 to 400 nanometers), they can’t resolve molecules that are typically much smaller than these dimensions. While electron microscopes can reach resolutions far below an optical microscope, they are large, expensive pieces of equipment that require a vacuum to operate, limiting the ability to examine live samples.

Now researchers at the University of Missouri have developed a way to make an optical microscope resolve images down to 65 nanometers. In the process, they may have extended access to high resolution imaging to a much larger group of scientists who may not have access to electron microscopes.

“Usually, scientists have to use very expensive microscopes to image at the sub-microscopic level,” said Shubra Gangopadhyay, an electrical and computer engineering in the University of Missouri College of Engineering, in a press release. “The techniques we’ve established help to produce enhanced imaging results with ordinary microscopes. The relatively low production cost for the platform also means it could be used to detect a wide variety of diseases, particularly in developing countries.”

The key to getting the optical microscopes to overcome the wavelength limitations is plasmonics. The field of plasmonics exploits the oscillations in the density of electrons that are generated when photons hit a metal surface.

In this application, the Mizzou researchers used the interaction between light and the surface of a metal grating to generate a surface plasmon resonance and combined this with nano-protrusions on the surface of the grating to create “hot spots” that have very high fluorescence intensity.

diagram of regular and plasmonic gratingNano-protrusions create on plasmonic grating create “hot spots.”Illustration: University of Missouri-Columbia

The nano-protrusions act as an excitation source with an enhanced signal-to-noise ratio. When they are combined with localization microscopy, which is performed with fluorophores, it becomes possible to achieve higher localization precision. This means that in a disease study you can reach single-molecule super-resolution imaging in a wide range of fluorophores that are required to study biological interactions and activity.

In research described in the journal Nanoscale, the Mizzou researchers employed a technique known as glancing angle deposition to control silver growth on polymer gratings that were replicated from HD-DVD and Blu-Ray grating molds. Depositing the silver at a specific angle relative to the surface creates a high density of silver nano-protrusions on the grating surface and nanogaps in the shadowed region of the plasmonic grating. Because the patterns originate from a widely used technology, the researchers claim that the manufacturing process should remain relatively inexpensive.

“In previous studies, we’ve used plasmonic gratings to detect cortisol and even tuberculosis,” Gangopadhyay said. “Additionally, the relatively low production cost for the platform also means it could be used to further detect a wide variety of diseases, particularly in developing countries. Eventually, we might even be able to use smartphones to detect disease in the field due to signal enhancement as well as super-resolution imaging capability.”

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Restoring Hearing With Beams of Light

Gene therapy and optoelectronics could radically upgrade hearing for millions of people

13 min read
A computer graphic shows a gray structure that’s curled like a snail’s shell. A big purple line runs through it. Many clusters of smaller red lines are scattered throughout the curled structure.

Human hearing depends on the cochlea, a snail-shaped structure in the inner ear. A new kind of cochlear implant for people with disabling hearing loss would use beams of light to stimulate the cochlear nerve.

Lakshay Khurana and Daniel Keppeler

There’s a popular misconception that cochlear implants restore natural hearing. In fact, these marvels of engineering give people a new kind of “electric hearing” that they must learn how to use.

Natural hearing results from vibrations hitting tiny structures called hair cells within the cochlea in the inner ear. A cochlear implant bypasses the damaged or dysfunctional parts of the ear and uses electrodes to directly stimulate the cochlear nerve, which sends signals to the brain. When my hearing-impaired patients have their cochlear implants turned on for the first time, they often report that voices sound flat and robotic and that background noises blur together and drown out voices. Although users can have many sessions with technicians to “tune” and adjust their implants’ settings to make sounds more pleasant and helpful, there’s a limit to what can be achieved with today’s technology.

8 channels

64 channels

Since optogenetic therapies are just beginning to be tested in clinical trials, there’s still some uncertainty about how best to make the technique work in humans. We’re still thinking about how to get the viral vector to deliver the necessary genes to the correct neurons in the cochlea. The viral vector we’ve used in experiments thus far, an adeno-associated virus, is a harmless virus that has already been approved for use in several gene therapies, and we’re using some genetic tricks and local administration to target cochlear neurons specifically. We’ve already begun gathering data about the stability of the optogenetically altered cells and whether they’ll need repeated injections of the channelrhodopsin genes to stay responsive to light.

Our roadmap to clinical trials is very ambitious. We’re working now to finalize and freeze the design of the device, and we have ongoing preclinical studies in animals to check for phototoxicity and prove the efficacy of the basic idea. We aim to begin our first-in-human study in 2026, in which we’ll find the safest dose for the gene therapy. We hope to launch a large phase 3 clinical trial in 2028 to collect data that we’ll use in submitting the device for regulatory approval, which we could win in the early 2030s.

We foresee a future in which beams of light can bring rich soundscapes to people with profound hearing loss or deafness. We hope that the optical cochlear implant will enable them to pick out voices in a busy meeting, appreciate the subtleties of their favorite songs, and take in the full spectrum of sound—from trilling birdsongs to booming bass notes. We think this technology has the potential to illuminate their auditory worlds.

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