Bill Holton
If it’s true the eyes are the windows to the soul, then the corneas are the windowpanes. Unfortunately, these tiny disks of transparent tissue are not always clear as glass. Injuries, burns, birth defects, and diseases can cause corneas to turn opaque or damage them beyond repair.
Injuries and diseases affecting the cornea are a major cause of blindness worldwide, second only to cataracts. According to the World Health Organization, approximately 2 million new cases are reported each year. Over 50 million people in the world are blind in one or both eyes from corneal damage.
In this article I will describe two recent breakthroughs that could lead to significant improvements in the treatment of corneal injuries, defects, and disease.
Clearing Things Up
First let's take a quick anatomy lesson.
The cornea consists of several different layers, including the outermost epithelium, an underlying stroma, and the innermost endothelium. Briefly, the epithelium is a watertight barrier that protects the eye from the outside environment, whereas the stroma provides structural support and gives the cornea its curved shape. The endothelium, serves as a mediator to the passage of water and nutrients between the corneal stroma and the intraocular fluid.
So how does the healthy cornea remain transparent?
The cornea is one of two tissue types in the body that do not depend on tissue-clouding blood and vessels to supply nourishment (cartilage is the other). On the contrary, the cornea actually inhibits the growth of blood vessels because, according to recent research, of the presence of large amounts of the protein VEGFR-3 (vascular endothelial growth factor receptor-3) on the epithelial layer of normal, healthy corneas.
VEGFR-3 halts angiogenesis (blood vessel growth) by acting as a "sink" to bind or neutralize the growth factors sent by the body to stimulate the production of new vessels. This also happens in the retina, and it’s the breakdown of these processes that leads to the unchecked vessel growth associated with diabetic retinopathy, AMD, and other sight-destroying conditions.
Corneal cells, like most other cells in the body, need to be replenished and replaced. In the corneal epithelium, this turnover is a fundamental process made necessary due to the constant loss of cells caused by normal eye movement and blinking. The generation of new epithelial cells depends on the slow and constant proliferation of corneal epithelial stem cells, a self-renewing, immature cell type unique to this tissue.
Because corneal stem cells cannot be carried where they are needed by blood vessels, the cornea instead holds a reservoir of these immature cells in a well-defined region near the outer edges of the cornea known as the limbal stem cell niche. From there, the stem cells can migrate and mature into differentiated epithelial cells, and thus keep this layer of the cornea intact.
When the cornea is scratched, burned or otherwise injured this same process takes place on an accelerated scale. Unless, of course, the injury is so severe the stem cells never get the chance to create and replace the damaged tissue. This is why some serious corneal injuries simply will not heal and also may contribute to the failure of some corneal transplants.
Repairing the Damage
In these cases have these corneal stem cells actually been destroyed? “Not necessarily,” says Dr. Ricardo Gouveia, New Harvest Research Fellow and postdoctoral scientist at Newcastle University in the UK. Using living corneal tissue Gouveia and associates simulated the injuries caused by acid attacks and other chemical damage. “The stem cells in the niche did not always die. Instead, the cells differentiated in place, which is to say they changed into mature epithelial cells and lost their ability to proliferate before they could help heal the damage.”
Studying the effect even closer, Gouveia discovered what he believes is the cause of this early differentiation. “Normally, the tissue underlying stem cells in the limbus is considerably softer and more flexible than the tissue in the center of the cornea,” he describes. “We discovered that, when burned, the limbus becomes significantly stiffer, and this stiffening actually prompts the stem cell differentiation.”
Unwanted stiffening is common with ageing and also occurs in other tissue damage, such as fibrotic scarring after surgery, and contractures: a tightening or shortening of muscles that leads to joint pain and stiffness. Contractures can be treated with an enzyme formulation called collagenase, which cleaves connective tissue and makes it more elastic. Using small, localized doses of collagenase to restore the limbus tissue, the researchers made the burned areas of the cornea more pliable and able to support stem cells in their undifferentiated, proliferative state and once again promote healing.
“This is an exciting development in the field of corneal biology, and allows us to better understand how the eye works,” says Gouveia. “Even more importantly, it provides us with a new set of strategies to treat eye conditions which were until now inoperable. We show that the topical application of collagenase is safe and effective in restoring the normal softness of the limbus and enhances tissue regeneration by preventing the premature differentiation and loss of adult stem cells after such injuries.”
The collagenase would need to be administered in acute cases, because it only takes a few days for the stem cells to change in response to the stiffening of their niche. However this new knowledge may also help in the transplantation of stem cells from the still healthy eye, or even increase the success rate for donor corneal transplants.
New Hope for Corneal Melting
One of the lesser-discussed complications of rheumatoid arthritis is the possible development of necrotising keratitis, also known as corneal melting. The condition begins with corneal ulceration, but can lead to corneal perforation, even sight loss. Lupus and Stevens-Johnson syndrome can also lead to corneal melting, as can sterile infections of the eye, chemical burns, and even cataract removal or LASIK surgery.
“Basically, corneal melting is caused by a variety of hyperactive immune system responses,” says Kyung Jae Jeong, Assistant Professor at the College of Engineering and Physical Sciences at the University of New Hampshire. The disease occurs due to the uncontrolled production of certain zinc-dependent enzymes called matrix metalloproteinases (MMPs). These enzymes are found throughout the body, and are responsible for degrading and remodeling extracellular matrices, which offer structure and biochemical assistance to various cell types. When a hyperactive immune response is triggered, the production of these epithelial-destroying enzymes can grow out of control. They can destroy cell structure faster than it can be replaced, leading to ulceration, perforation, and, eventually, vision loss.
Normally, the body inhibits the over production of MMPs with natural protease inhibitors. Manmade inhibitors generally contain a chelating group that binds to the zinc ions, making this essential part of the enzyme from participating in the runaway MMP production.
“Most of the current MMP inhibitors used to treat corneal melting work by binding to the zinc ions within the MMPs," says Jeong. "However, once injected into the body, the MMP inhibitors travel through the blood stream into the entire body and can cause severe side effects because they are binding with and deactivating the zinc ions in other body tissue as well as the cornea."
Jeong and his research associate, Jung-Jae Lee, Assistant Professor of Chemistry at the University of Colorado, Denver, believe they have found a better way to deactivate the MMPs.
Instead of a protease inhibitor they use a molecule called dipicolylamine (DPA), which binds to zinc ions, steals them from the MMPs, and deactivates them.
The delivery method is also different. Instead of a pill or injection, the DPA can be built-into a hydrogel lens. Hydrogels are special water-permeable polymers that can hold up to 90 percent water. Extended wear contact lenses are made from hydrogels.
“Wearing a contact lens itself is known to be beneficial to corneal melting patients,” says Jeong. “The added benefit of incorporating DPA within the hydrogel is that this molecule will not be released into our body. Therefore, the therapeutic effect can be localized, and if the patient happens to have any side effects because of this contact lens, they can simply remove it.”
To date, DPA-infused hydrogels have only been tested on animal tissue, where the results demonstrated significant delay in corneal melting. As to the post-lab future of this potential breakthrough, the University of New Hampshire has a pending patent and will be placing the research in UNHInnovation, where outside companies can license the research and hopefully develop it into commercially available treatments and products.
This article is made possible in part by generous funding from the James H. and Alice Teubert Charitable Trust, Huntington, West Virginia.
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