Better insight of cornea ushers in new generation of corneal refractive surgery

A superficial flap for sub-Bowman’s keratomileusis enhances healing and postoperative corneal stability, experts say.

New research on corneal biomechanics and wound healing is yielding innovations that may help refractive surgeons improve wound stability and minimize haze, according to three researchers.

Conventional surface ablation offers biomechanical stability but causes pain and haze. Intrastromal ablation causes neither pain nor haze but may result in long-term biomechanical instability, the experts said. They described emerging strategies to mitigate those drawbacks.

John Marshall, PhD, FRCPath, of King’s College and St. Thomas’ Hospital, London, delivered a keynote lecture on research findings and potential clinical applications during Refractive Subspecialty Day preceding the American Academy of Ophthalmology meeting.

In subsequent interviews with Ocular Surgery News, Dr. Marshall’s fellows, Nathaniel E. Knox Cartwright, MRCOphth, and Romesh Angunawela, MD, MRCOphth, discussed their findings on incision design and biochemically targeted healing control.

Sub-Bowman’s keratomileusis (SBK) epitomizes the “fourth generation” of corneal refractive surgery, Dr. Marshall said in his presentation.

The preceding generations were early PRK, LASIK, and LASEK and epi-LASIK, Dr. Marshall said.

Each technique has limitations, but SBK offers the best combination of biomechanical stability and rapid healing, Dr. Marshall said. Refractive surgery will “return to the surface” as SBK becomes the refractive surgical method of choice, he said.

“You can do deep incisional surgery, which is unstable, no haze, no pain,” Dr. Marshall said. “In the case of surface procedures, we want to control wound healing, and in the case of LASIK, we want to control biomechanics. Hence, the suggestion of SBK or a very superficial flap.”

In PRK, damage to the epithelium and stroma produced haze. LASIK was found to damage the stroma but not the epithelium. LASEK focused on the corneal surface with an epithelial flap, Dr. Marshall said.

“The third generation was an attempt to go back to the surface by using the technique of LASEK or lifting an epithelial flap,” he said. “Interestingly, what this did was delay the wound-healing process.”

SBK is enabled by femtosecond laser technology that can be used to create innovative incision designs, Dr. Marshall said.

‘Best of both worlds’

Currently, refractive surgery is a compromise between surface ablation, which can result in haze, and LASIK, which can cause long-term biomechanical instability, refractive regression and sometimes ectasia, Dr. Knox Cartwright told OSN in a telephone interview.

“The ideal would be to find a procedure that would combine the best of both worlds, so you would have a rapid, pain-free visual rehabilitation but also have postoperative biomechanical stability,” Dr. Knox Cartwright said. “With the femtosecond laser, it’s now possible to cut accurately and precisely very shallow intrastromal flaps.”

The precision afforded by the femtosecond laser enables surgeons to cut shallow flaps. The sub-Bowman’s flap is typically 90 µm below the surface, while the conventional LASIK flap is 140 µm to 160 µm, Dr. Knox Cartwright said.

He cited a randomized, prospective study in which OSN Refractive Surgery Section Editor Daniel S. Durrie, MD, and Section Member Stephen G. Slade, MD, compared ethanol- assisted surface ablation in one eye and SBK in the other eye on 100 eyes of 50 patients. They used SBK flaps thinner than 100 µm.

At 1 month after surgery, 50% of PRK eyes saw 20/20 compared with 90% of SBK eyes, they reported. By 6 months postop, the results were statistically even.

“It looks as if SBK may be a procedure that can combine the best of both worlds,” Dr. Knox Cartwright said.

SBK involves a relatively short learning curve for surgeons who are comfortable with femtosecond laser technology, he said.

“For people who use the femtosecond laser, it’s really no more difficult to create the shallow flap,” Dr. Knox Cartwright said. “It’s not a great shift in technique. It’s just a change in settings and a simple way to improve outcomes for the better.”

Corneal stability and healing

A shallow incision and superficial flap in the anterior stroma may maintain the cornea’s strength and structural integrity, Dr. Knox Cartwright said.

“The structure of the anterior third of the cornea is different to that in the posterior two-thirds of the corneal stroma,” he said. “In the anterior third, fibers are more densely packed and more densely interwoven than they are in the posterior two-thirds.”

The cohesive tensile strength of the anterior third of the cornea is about twice that of the posterior two-thirds, Dr. Knox Cartwright said. In clinical practice, any incision in the anterior stroma may adversely affect structural strength.

“It’s really important to minimize the biomechanical impact of surgery, to try and keep the maximum depth of the incision as shallow as possible,” Dr. Knox Cartwright said. “Any weakening caused by the surgery is permanent.”

The ideal incision is oblique and slopes outward, with a narrower epithelial diameter than stromal diameter, which increases strain less than a conventional vertical or parallel-sided flap, Dr. Knox Cartwright said.

“We think the reason for this is, firstly, that such a flap is physically held in place and is far more resistant to dislocation,” he said. “As the intraocular pressure increases, it actually gets held more securely because it’s pressed strongly in place.”

Secondly, the sloping interface creates a larger area of contact between the edges to promote healing without any angles where strain would concentrate.

“It is what engineers call a scarf joint, which is known to be the strongest way to join composite materials,” Dr. Knox Cartwright said.

“It’s stable, and because it reduces the strength of the cornea minimally, it should remain stable as well as surface procedures,” Dr. Marshall said at the AAO meeting. “We’re going to make it better, I think, by actually changing the edge angle of the flap. The more oblique you make the flap, the stronger the flap is postoperatively.”

Cytokine release creates haze

Damaged epithelial cells release cytokines, proteins or peptides that serve as biological signaling compounds, which cause haze, Dr. Knox Cartwright said.

“Haze is a consequence of simultaneous stromal and epithelial injury,” he said. “With sub-Bowman’s keratomileusis, there’s no epithelial injury, so you don’t get the cytokine release that might cause haze development. It’s a way of performing LASIK, while nonetheless maintaining the biomechanical advantages of surface ablation.”

Dr. Marshall recalled repeated attempts to eliminate haze with steroids and nonsteroidal agents.

“The real problem with haze was an ongoing problem,” he said. “We tried attacking it with steroids and nonsteroidal anti-inflammatories, but there are always going to be patients in which haze is going to be a problem.”

Dr. Marshall and colleagues used a human tissue culture model to assess the limitations of conventional PRK, LASIK and LASEK at 4 to 6 weeks after surgery. He said most research to date has been limited to rabbit or monkey corneas.

Early results showed that, in LASEK, keratocyte repopulation of the surgical site was delayed about 4 days. Haze was linked to cytokine release from living but damaged epithelial cells, Dr. Marshall said.

“LASEK or epi-LASIK has problems,” he said.

Lifting the epithelium ruptures the hemidesmosomes on the basal border of the basal epithelial cells, leaving intact but damaged cells, Dr. Marshall said.

“The net result is they will release cytokines and you may generate haze,” he said.

The ideal approach would be to kill the epithelial cells when lifting them; the dead epithelial cells would act as a bandage contact lens, Dr. Marshall said.

“When you look at the time sequence in this model, you see that the cells within the flap play no role in true wound healing and are displaced by epithelial cells growing in from the edge and then throwing them off the surface,” he said.

Targeted wound healing

In an e-mail interview with OSN, Dr. Angunawela discussed his research of mannose-6-phosphate (M6P), a macromolecular sugar derived from aloe vera, to prevent postoperative scarring and haze.

“From the clinical perspective, successful treatment with M6P could reduce haze postoperatively,” Dr. Angunawela said. “Crucially, as M6P is derived from aloe vera, it is a nontoxic modulator of wound healing, and specifically with regard to SBK, it is likely to be applicable in drop form and diffuse sufficiently across the epithelium.”

M6P inhibits the TGF-beta 1 and 2 cytokine, a key factor in the transformation of passive keratocytes into haze-forming myofibroblasts, Dr. Angunawela said.

Dr. Angunawela has also performed research on targeted drug delivery, in which an aptamer, a molecular courier, delivers a secondary drug to a targeted cell type.

“A targeted therapeutic approach is likely to be more effective than current therapeutic modalities while avoiding the secondary effects of agents such as topical steroids, which can cause glaucoma and cataract,” Dr. Angunawela said. “Aptamers are also nontoxic and cheaper to produce than similar agents such as antibodies, and as they are cell-specific, the active drug would be required in a much lower quantity to be effective.”

Also, attaching a fluorescent molecule to a cell-specific aptamer would enable a surgeon to perform objective slit lamp analysis and manage wound healing and haze, Dr. Angunawela said.

“Our research has focused on aptamers as a novel method for cell-targeted drug delivery and M6P as an effective anti-TGF-beta agent,” Dr. Angunawela said. “The two could theoretically be combined, although both projects have been carried out independently.”

Targeted wound control, which Dr. Marshall termed “pharmaceutically modulated PRK,” has a great future, Dr. Angunawela said.

For more information:

• John Marshall, PhD, FRCPath, Nathaniel E. Knox Cartwright, MRCOphth, and Romesh Angunawela, MD, MRCOphth, can be reached at Department of Ophthalmology, King’s College, London, Rayne Institute, St. Thomas’ Hospital, London SE1 7EH, UK. Dr. Marshall can be reached at 44-20-7188-4296; fax: 44-20-7401-9062; e-mail: marshall-eye@kcl.ac.uk. Dr. Knox Cartwright can be reached at 44-20-7971-056-028; fax: 44-20-7401-9062; e-mail: n.knoxcartwright@googlemail.com. Dr. Angunawela can be reached at 44-20-7188-4296; fax: 44-20-7401-9062; e-mail: romeshi@hotmail.com.

• Matt Hasson is an OSN Staff Writer who covers all aspects of ophthalmology. He focuses on regulatory, legislative and practice management topics.
• Lauren Wolkoff, Executive Editor of OSN U.S. Edition, also contributed to this report.