Bioengineered Corneal Transplant Procedure Improves Vision In Patients With Severe Damage, Minimal Vision

Before treatment at UC Davis Medical Center, all of the patients had damage to their ocular surface, many with poor vision, and had failed standard treatments, including conventional cornea transplants. After the new treatment, 10 of the patients regained some or most of their sight.

Only two other bioengineered tissue replacements are currently commercially available: Bioengineered skin is widely used to treat burns and chronic skin wounds, and bioengineered cartilage is increasingly used to treat certain knee injuries. UC Davis researchers believe that bioengineered cornea could very well become the third type of bioengineered replacement tissue for humans that's available.

"We learned about skin and then used that knowledge to create biological skin replacement for burn victims," says Dr. R. Rivkah Isseroff, a professor of dermatology at the UC Davis School of Medicine and Medical Center. "Now we have transplanted that knowledge to the eye. In the future, we hope to translate it to the lung, gastrointestinal tract, bladder and other epithelial tissues throughout the body."

Dr. Isseroff, who directs a laboratory that develops skin replacements, and Dr. Ivan R. Schwab, a professor of ophthalmology who specializes in disorders of the cornea, spent 10 years perfecting the new technique. They report their procedure in the July issue of the journal Cornea.

Ultimately, Dr. Schwab says tissue engineers may be able to produce readily available, "off-the-shelf" cornea replacements that can be easily transplanted into with severe damage to the cornea, "This is a unique and important step toward that goal," he says.

James Beebe, 78, a retired securities trader who lives in Brookings, Ore., began losing his sight a decade ago due to a rare reaction to the medicated eye drops he used to control his glaucoma. The reaction severely scarred his corneas, leaving him unable to drive a car or see a computer screen. He could read only with the help of a large magnifying glass, and could recognize faces only up close. He consulted ophthalmologists around the country, but none could help.

"I was practically unable to function before," says Beebe, who finally received a bioengineered corneal tissue transplant in his right eye at UC Davis Medical Center in August 1998. The two-hour procedure was performed under general anesthesia.

Today Beebe's vision in his right eye is 20/40 with a contact lens, enabling him to once more drive, read, and use his computer to write freelance feature articles for magazines and newspapers.

George Norman, 69, lost most of his vision in a 1973 chemical accident in which ammonia splashed in both his eyes. Over the next two decades Norman underwent six corneal transplants, all unsuccessful. "I saw everything like through a dark, cloudy fog," the Colusa, Calif., grandfather says. "Anything I'd see was brownish colored."

Last fall, Norman received yet another corneal transplant in his left eye, this time supplemented with corneal stem cells donated by his son, Robert, 38. Although Norman still doesn't see well enough to drive, the vision in his left eye is now better than it's been in almost 30 years. "Everything is bright again," he says. "More people need to know about this procedure."

Son Robert, who lives in nearby Sutter, was in his early teens when his dad lost his sight. "Watching him struggle with patches over his eyes all those years was hard," says Robert, who has 20/20 vision in both eyes. "I would have done anything to help him. He was totally against it at first -- he didn't want to see someone else lose sight for him. But I was all for it."

Donating the cells was painless and did not affect his 20/20 vision, says the younger Norman, who works for the Colusa County roads department. "It took five minutes. I was awake, watching everything out of my other eye. There was no pain whatsoever, and I'm kind of a sissy when it comes to pain."

Researchers at several other centers around the world are also exploring methods of producing bioengineered tissue to repair damaged corneal surfaces, but only one other group thus far has reported success in treating humans. That group, from Taiwan, reports its results in the July 13 issue of the New England Journal of Medicine. Drs. Isseroff and Schwab are authors of an editorial accompanying the article.

In the technique pioneered by Drs. Isseroff and Schwab, a few corneal stem cells are first removed from a healthy cornea. If a patient has one good cornea, the stem cells are removed from that cornea. If both of a patient's corneas are damaged, stem cells are taken from the cornea of a related donor.

Corneal stem cells are the "mother" cells of the cornea; they lie deep within a protected area adjacent to the cornea, continually giving birth to new corneal cells to replace aging corneal cells, and to repair corneal injuries. (Note: Corneal stem cells are distinct from fetal stem cells. Fetal stem cells possess the unique ability to develop into any tissue in the body. Corneal stem cells, in contrast, can produce only corneal cells).

Severe injuries to the cornea, such as a chemical, fire or radiation burn, can destroy corneal stem cells. So can certain diseases that affect the eye, including some tumors and a handful of rare disorders such as pemphigoid, an autoimmune condition, and Stevens-Johnson syndrome, which results from a severe allergic response. Without its stem cells, the cornea loses its ability to repair itself, and can become scarred and opaque, causing blindness.

Conventional corneal transplantation, in which a superficial layer of donor cornea is placed over a damaged cornea, does not transfer enough stem cells to be sufficient in these cases.

In the UC Davis technique, the harvested corneal stem cells are divided among multiple laboratory dishes. In the dishes, the stem cells produce a fragile film of corneal cells just one cell thick. Scientists transfer the corneal cells, including the surviving stem cells, to the surface of a matrix of sterile amniotic membrane.

Some cells from the other dishes are frozen and banked for possible later use.

On the matrix, the corneal cells grow into a layer 5 to 10 cells thick, forming a sturdy composite tissue that combines the elasticity and resilience of amniotic membrane with the biological properties of corneal tissue. This bioengineered composite tissue is then stitched onto the patient's eye, after the abnormal corneal tissue has been removed.

Amniotic membranes have been widely used in tissue engineering and corneal repair for many years. The membranes, which are acquired by donation from mothers after babies are born, make an ideal matrix because they do not trigger an immune reaction in the recipient.

The Taiwanese group reports using a slightly different approach from the technique developed at UC Davis. The Taiwanese group seeds harvested corneal stem cells directly onto an amniotic membrane, rather than first expanding the corneal cells laboratory dishes. Another difference is that the Taiwanese group so far has used its technique only in patients who have one healthy cornea; the group has not yet tried cells harvested from related donors.

"One potential advantage of our approach is that we can bank cells in the freezer for later use, so that if a transplant fails, or if we want to treat the other eye, we do not need to subject the patient or related donor to a repeat procedure to harvest additional stem cells," Dr. Schwab says.

Of the 14 patients treated at UC Davis, four received a transplant of composite tissue grown from cornea cells donated by a sibling or child, including Beebe, whose sister donated cells. All four of these patients experienced improved or restored eyesight, and none of the donors experienced complications.

The other 10 UC Davis patients, who each had one healthy cornea, received transplants of composite tissue cultivated from corneal stem cells harvested form their good eye. Of these 10 patients, six had a successful outcome.

The stem cells are harvested by corneal biopsy in a quick, painless procedure that poses minimal risk to the donor eye.

Dr. Schwab emphasized that the transplants remain investigational, and for now are appropriate only for patients with corneal problems that have not responded to more conventional therapies. More needs to be known about the transplants' long-term success and risks before the procedure can be considered as a first-line treatment, he says.

The number of patients who might benefit from corneal stem cell transplant in this country is relatively small. Only a few thousand people in the United States suffer diseases or injuries each year that cause devastating cornea damage leading to vision loss. The numbers are much greater in developing nations, however, where infectious diseases of the eye remain common.

But the technique may have exciting applications outside ophthalmology. Corneal tissue, like skin, is an example of epithelial tissue, or epithelium. In fact, more than 60 percent of the cell types in the human body are epithelial cells.

"We learned about skin, and used that knowledge to create biological skin replacements for burn victims," Dr. Isseroff says. "Now we have transplanted that knowledge to the eye. In the future, we hope to translate this knowledge to the lung, the gastrointestinal tract, the bladder and other epithelial tissues throughout the body."

"The really exciting thing is where this can take us," Dr. Schwab agreed. "Replacing diseased tissues and organs with bioengineered tissue is rapidly moving from the realm of science fiction to reality."

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The research on stem cell corneal transplants was funded by UC Davis Health System.