Tuesday, April 15, 2014

Cable guys: Inside UAB's high-tech, custom-built approach to eye science

This machine, designed and built by UAB vision researcher Crawford Downs, is producing ultra-clear images of a key structure implicated in glaucoma, the world's second leading cause of blindness. See the machine in action in a video below.

The miracle of sight relies on a masterpiece of wiring. More than a million individual nerve cells scattered around the eye convert visual information into electricity. Then these individual cells are bundled together at the back of the eye into the optic nerve, which carries the signal to the brain.

Problems with this central cable are at the root of glaucoma, the world's second leading cause of blindness, after cataracts. The underlying causes of this optic nerve deterioration are still poorly understood. But a pioneering group of researchers and clinicians at UAB are exploring a new paradigm that could revolutionize our understanding of glaucoma and other eye conditions, including myopia and keratoconus.

The approach, known as ocular biomechanics, applies engineering principles to the eye. By creating detailed models of key eye structures, then stress-testing them in computer simulations, the scientists aim to identify the features of individual eyes that lead to glaucoma.

The work is led by J. Crawford Downs, Ph.D., vice chair of basic science research in the UAB Department of Ophthalmology and director of the new UAB Ocular Biomechanics and Biotransport Program, and Christopher Girkin, M.D., chair of the UAB Department of Ophthalmology. It has attracted the attention of the National Eye Institute, which awarded Downs and Girkin a $1.125-million grant in early 2013.

Zooming In on Glaucoma
Downs' efforts are focused on the lamina cribrosa, which acts as a mechanical seal at the optic nerve head where the optic nerve passes out of the back of the eye on its way to the brain. "The optic nerves go through pores in that structure," Downs explains. "It's also the place where the nerves get damaged in glaucoma. We want to understand the mechanics of the lamina cribrosa and what it looks like in three dimensions. That’s a key to understanding glaucoma biomechanics."

The problem is that this tiny structure—"it's about the size of a pencil lead," Downs explains—doesn't respond well to conventional microscopic imaging techniques. "Every time you put a section of the tissue on a slide for imaging, it's always warped or folded or stretched, so you can’t stack up successive images into a 3D structure" Downs says. So he built his own machine to do the job.

(See video below.)

This “fluorescent three-dimensional histologic reconstruction device” slices away tissue 1.5 micrometers at a time (about 1/100th the diameter of a human hair), snapping high-resolution pictures of the remaining tissues as it goes. With a volumetric resolution about 5 million times better than the best MRI, "I can see cell bodies with this technique," Downs says.

He reveals an engineer's pride in the clever details of his creation. For instance, the device automatically e-mails him a picture every 100 frames and texts him if it runs into problems. That way he can monitor the process remotely and allow the machine to run 24 hours a day. "There are only two in the world—the one here at UAB for eyes and one we built for colleagues at Imperial College London to study osteoarthritis in mouse knees," Downs says.

An individual image from Downs' machine

Image to Insights
Downs's first 3D rendering of the lamina, built from around 1,500 individual images, is just the beginning. Because everyone's lamina cribrosa is different, he is building a library of digitized models of laminas from the eyes of patients with and without glaucoma, as well as laminas from patients of different ages and ethnicities. "We can put the models in a computer, apply pressure to them, and simulate what happens mechanically," Downs says.

3D rendering of the lamina cribrosa

Downs was one of the first biomedical engineers to take up the study of the eye; now he is making UAB the hub of the rapidly growing field of ocular biomechanics. He has already recruited a team of fellow bioengineers to tackle complex problems in glaucoma and other eye diseases. Raphael Grytz, Ph.D., is studying the growth and remodeling of the sclera and lamina cribrosa; Massimo Fazio, Ph.D., is developing new, ultra-precise tools to measure scleral deformations with pressure and track deformations in images; and Vincent Libertiaux, Ph.D., is simulating how the optic nerve head reacts to different intraocular pressures. "We're one of the biggest groups in the world," Downs says.

Left to right: Massimo Fazio, Crawford Downs, Vincent Libertiaux, and Raphael Grytz

Defining Disparities
The gulf between surgeons and basic scientists isn't so wide in a specialty such as ophthalmology, where clinicians are used to doing their diagnosis at the tissue level. "I like to say that ophthalmologists are in vivo histopathologists," Girkin says.

Girkin's research is focused on health disparities in glaucoma, particularly in identifying why African Americans are at increased risk. Research by Downs and Girkin has helped uncover "some fundamental structural differences between the eyes of individuals with sub-Saharan African ancestry and those of individuals with European ancestry that may account for this elevated risk of glaucoma," Girkin says. "If we can define these differences we can target not just African Americans but anyone who is going to get glaucoma."

This basic research complements UAB's glaucoma service, which is among the nation’s busiest, Girkin notes. In addition to evaluating new treatment options, including laser therapy and minimally invasive surgeries, “our clinical research is looking at detection methods to allow us to find glaucoma earlier than ever, along with discovering novel pathways to treat this blinding disease," Girkin says.
In a pilot program led by Girkin, UAB's Department of Ophthalmology has installed sophisticated imaging devices in the offices of two central Alabama independent optometrists who are located adjacent to Walmart Vision Centers, with a centralized image-reading center housed at UAB.

(Learn more about the program in the video below.)

Toward Early Detection
The optical coherence tomography machines provide high-resolution images of the back of the eye. An optometrist can detect the earlier stages of glaucoma in those images, even before symptoms appear. Images of a patient’s eyes are electronically transmitted from the imaging machines at the optometrist’s office to the UAB center for confirmation of the diagnosis. UAB’s trained glaucoma specialists can then confer with the optometrist on complex cases to determine an appropriate treatment regimen. Patients who undergo the glaucoma testing also receive a dilated comprehensive eye exam and educational materials about glaucoma.

“This is an excellent example of the value of translating technology that has been evaluated and fine-tuned in the research setting and employing it in the field for the betterment of patients,” Girkin says. “This provides better access to care and better delivery of care within these hard-to-reach populations.”

The ultimate goal is to develop a noninvasive, image-based test "that a clinician can do in five minutes," Downs says. A human trial is at least a decade away, he predicts, but success would bring dramatic benefits: "You could cut the costs of treating glaucoma in half," saving billions of dollars per year.

Learn More
UAB Department of Ophthalmology

Ocular biomechanics at UAB

Research areas, UAB Department of Ophthalmology

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