Sighting the Inner Ear
Understanding these serpentine spaces — and how substances move through them — promises safer, targeted drug delivery
Computer models of drug diffusion have potential for widespread benefit in treating inner ear disorders.
Most people are blissfully unaware of a pair of oddly shaped organs embedded in their skull behind their earlobes. Each of these organs is an inner ear, which looks a little like a three-tentacled squid emerging from a snail shell. The "squid" part of the inner ear contains the vestibular system, responsible for balance and motion sensing; the "snail shell" is the cochlea, where sensory cells for hearing are located.
Although seldom noticed when they are working correctly, the inner ears are hard to ignore when something goes wrong. Inner ear disorders can lead to hearing loss, ringing or buzzing sounds, dizziness, spinning sensations or nausea.
Not surprisingly, much remains to be learned about the complex and convoluted inner ear, also called the labyrinth, but Alec N. Salt, PhD, professor of otolaryngology, is offering a new view of its winding passages. He and colleagues have created two- and three-dimensional computer models to simulate the pharmacokinetics of the inner ear — how drugs move through the ear's fluid and supporting structures, both across distance and over time. Their work promises to make treatment of inner ear disorders safer and more effective.
Here's an example of what can happen when too little is known about drug diffusion in the inner ear: In the late 1970s, doctors began using the antibiotic gentamicin to treat an inner ear disorder called Meniere's disease, which is characterized by intermittent sudden hearing loss and severe attacks of vertigo. They found that although gentamicin can be toxic to the delicate sensory cells of the inner ear, the right dose of the drug could selectively knock out the cells responsible for balance, stopping the patient's vertigo attacks, while preserving the cells used for hearing. So gentamicin was — and still is — used to alleviate the debilitating spinning sensation experienced by Meniere's patients.
Fast forward several decades — in 2001, researchers running a medical study on Meniere's delivered what was considered a safe dose of gentamicin. But they used a different method than previously, applying gentamicin gradually through a catheter located in the middle ear where the drug could then diffuse into the inner ear. To their surprise, eight out of 10 patients in that study lost their hearing in the gentamicin-treated ears.
That result would have been predictable if our computer models had been used to simulate the protocol, Salt says. "Our models replicate the diffusion of a substance from the base of the inner ear through its various chambers and show how the dose is affected by the concentration of the drug and how it is applied," he explains.
Given the prevalence of inner ear problems, Salt's computer models of drug diffusion in the inner ear have the potential for widespread benefit. Meniere's disease affects millions worldwide, and even more people suffer from hearing loss caused by noise, age or their genetics. Tinnitus, a persistent ringing or humming that stems from inner ear defects, is found in about 10 to 15 percent of adults.
Salt's models meticulously account for the proximity of the inner ear's various loops, coils and sacs. They also incorporate the speed at which substances seep through the membranes and support tissues that separate the chambers and how fast they leak into adjacent blood vessels.
A researcher using the computer models virtually injects a defined dose of a specified drug at the base of the inner ear. Then a colored cloud representing the drug begins moving along the simulated inner ear passages at the same rate as in an actual inner ear. The researcher can sample the model's passages to find the drug's concentration at any place and time of interest.
Salt and colleagues studied inner ear fluids in laboratory animals to create their models. They pioneered more sensitive and less invasive ways to measure drug movements without creating the artificial fluid flows associated with taking fluid samples that had plagued prior research. Yet at first they found themselves somewhat hampered when trying to extrapolate to human anatomy because there wasn't as much data on the exact size and shape of the human inner ear; the delicate membranes and numerous open spaces make the inner ear notoriously difficult to dissect without distortion. But now, new laser-based techniques are giving more precise information that Salt is taking advantage of.
"We are creating a 3-D simulation of the human inner ear that you can rotate and 'fly' through," Salt says. "Until now, no one had ever done that."
Salt's computer models of the human inner ear show that there can be much larger gradients of drugs along the human cochlea than are in animal models, because the human cochlea is much longer. At the base of the cochlea, where high frequency sounds are sensed, the drug concentration may be a thousand times higher than at the apex, where low frequency sounds are heard.
That's a good thing when treating Meniere's disease — the steep concentration gradient protects most hearing cells from exposure to gentamicin — but not so helpful when treating other hearing problems, where drugs need to reach down the entire length of cochlea. Among the many new therapies for disorders of the cochlea are calcium channel blockers to stop tinnitus, antioxidants to prevent chemotherapy-related hearing loss, stem cell or gene therapy agents to correct noise-induced or age-related hearing loss and growth factors to induce nerve growth toward the electrodes of cochlear implants. Thanks to Salt's computer models, researchers can now more easily create methods that will get these substances precisely where they are needed.
"Drug companies and cochlear implant companies are asking us to do work for them so they can develop their applications scientifically instead of by trial and error," Salt says. "When it comes to inner ear modeling and pharmacokinetics, we are leading the world."