December 2017

REFRACTIVE

Is it the age of allogenics?


by Liz Hillman EyeWorld Staff Writer

New procedures using allogenic tissue for refractive correction

The idea of using allogenic—human donor—tissue for refractive surgery goes back to Jose Barraquer, MD, who published his idea of epikeratophakia in 1949.1 Even in the 1980s when there was a resurgence of interest in putting a donor cornea on an aphakic patient’s own cornea with promising results, it did not go mainstream.2 This was most likely due to the success of laser refractive surgery. As David Muller, PhD, Boston, put it, the surgical technique and technology at the time were not refined enough to maximize outcomes or open up the possibility for other refractive procedures.
“The problem that plagued it all through the 1980s is that there was no real metrology to measure tissue thickness and tissue size. There was also no good mechanical way … to cut the tissue with the precision needed to get a good refractive result,” Dr. Muller said.
Fast forward to present day and Dr. Muller said we not only have accurate metrology for the precise measure of tiny tissues, but we have 20-plus years of laser development and experience accurately reshaping corneas.
The availability of corneal tissue—either from donors or from tissue removed during other refractive procedures—and the benefit of biocompatibility makes allogenic tissue implants—allografts—an attractive option for refractive procedures like correction of hyperopia or presbyopia and even has applications for keratoconus.

Allogenic vs. synthetic

Dr. Muller, well-known in the ophthalmic innovation space for his work with the excimer laser and Summit Technology (acquired by Alcon, Fort Worth, Texas, in 2000) and later Avedro (Waltham, Massachusetts), in 2014 founded Allotex (Zurich, Switzerland, and Boston), a company working on bring allogenic inlays and onlays for correction of presbyopia to the market.
There are already several surgical presbyopia-correcting procedures available in the U.S. Options that have received FDA approval include multifocal, trifocal, and extended depth of focus IOLs and two intracorneal inlays (KAMRA, AcuFocus, Irvine, California, and Raindrop, Revision Optics, Lake Forest, California); more are in development or are approved elsewhere. And there is monovision LASIK.
Dr. Muller said presbyopia almost always affects patients well before they develop a cataract and might be a candidate for a premium IOL, and currently approved intracorneal inlays, which target this pre-cataract market, are foreign bodies in the eye. They are, however, designed with nutrient and oxygen diffusion in mind.
Corneal allografts, in contrast to synthetic materials, are 100% neutral “Once you put this allogenic material in the cornea, it’s repopulated by the patient’s own keratocytes, and it becomes part of the cornea,” Dr. Muller said.
Anne Negrin, MD, a practicing ophthalmologist and TV medical contributor in the greater New York area, said that while she hasn’t personally used synthetic inlays, she understands that foreign body complications could occur.
“These inlays aren’t real corneal tissue, and they tend to behave as though they have a mind of their own, making refractive results less than optimal or simply not stable,” Dr. Negrin said.
From a donor cornea standpoint, Dr. Muller said that the U.S. has an ample supply of corneas, and surgeons performing corneal transplants are mostly interested in endothelial cells, while corneal allografts for refractive purposes can use other parts of the cornea.
“We don’t take away any corneas that can be used for transplants … no one’s vision is prejudiced because we took a cornea,” he said. What’s more, he said the amount of donor corneas that can be accepted is expanded for this purpose as age, endothelial cell quality, and the like are less of an issue because “we’re using the heart of the stroma for our process.”
Others aren’t using donor corneas, per se, for allografts but are using the lenticules from small incision lenticule extraction (SMILE).
Echoing similar thoughts to Dr. Muller’s, Dr. Negrin said she thinks the main reason why human corneal donor tissue was not used for refractive correction was due to the need to find reliable, reproducible methods to get donor corneas to recipients who truly needed them in an expeditious manner. Since the days of Barraquer and keratophakia, that hurdle has been cleared, so now “it’s time to look to using donor corneal tissue for more advanced refractive procedures,” Dr. Negrin said.

From SMILE to PEARL and beyond

The lenticule removed in SMILE procedures, which might otherwise be discarded, is being used by some to provide hyperopic or presbyopic treatments and may even have applications for keratoconus patients.
Pradhan et al. in 2013 described endokeratophakia where the lenticule from a myopic SMILE procedure was implanted in another patient to correct hyperopia.3 Earlier this year, Soosan Jacob, MD, Dr. Agarwal’s Eye Hospital, Chennai, India,
published a preliminary study involving four emmetropic presbyopic patients who underwent the new PrEsbyopic Allogenic Refractive Lenticule (PEARL) inlay procedure.4
This procedure involves taking a SMILE lenticule of a specified thickness and cutting it with a trephine to 1 mm in diameter. The button lenticule is then implanted into a femtosecond laser-created pocket centered over the pupil in the presbyopic patient’s non-dominant eye. The study found the procedure to be safe and effective with all four patients reporting good uncorrected vision at near, intermediate, and distance.
“Overall, we found very good results for the patients,” Dr. Jacob said, adding that they’ve since also performed myopic SMILE on patients and then used their own lenticule for autogenic PEARL.
In addition to PEARL, Dr. Jacob at the 2017 ASCRS•ASOA Symposium & Congress described a new technique using linear stromal tissue segments similar to Intacs (Addition Technology, Lombard, Illinois) to create corneal allogenic intrastromal ring segments (CAIRS). As with synthetic intracorneal inlays, the same complications can be associated with synthetic intrastromal ring segments.
“I thought, why not use allogenic segments made from donor cornea?” Dr. Jacob said, explaining that she uses a double-bladed trephine to punch out a full-thickness, circular segment of corneal tissue from donor cornea and then cuts it in two, implanting them on either side as she would Intacs segments in a keratoconus patient. She has also used CAIRS as a single, almost fully circular, 330-degree segment. She has found that like Intacs, the allogenic segments result in good regularization of the corneal topography while also correcting some myopic refraction and improving uncorrected and spectacle-corrected distance visual acuity. It also spreads out biomechanical forces by flattening the cornea. For patients still at risk for keratoconus progression, she will perform CAIRS and then crosslink.
“When you use allogenic tissue, the complications with synthetic materials are done away with, and therefore, a huge advantage is that you could use this in patients with corneas of any thickness unlike Intacs or other artificial segments where the cornea needs to have a certain minimum thickness in the zone of implantation,” she said.
As for the preservation aspect of corneal lenticules for later use in procedures like these, Ganesh et al. described a technique of cryopreservation in 2014 that seems to provide safe long-term storage.5

From an inlay to an onlay

Allotex is still in a research and engineering phase, with Dr. Muller saying they expect to start multicenter clinical trials in Europe in the first quarter of 2018.
“We haven’t focused on clinicals because we know it’s going to work. There’s too much data out there to show it works,” he said, citing published safety and/or efficacy research for epikeratophakia, intracorneal inlays, and corneal allografts, including the positive outcomes of Dr. Jacob’s PEARL technique.
“The key feature is with respect to safety, the jury is in. It’s hard to dispute 60+ years and hundreds of publications that show that human allograft tissue works fine for creating [corneal] shapes,” Dr. Muller said. “If you look at the more limited but compelling data that properly shaped human tissue gives a properly shaped result … you look at what we’re doing, what the Allotex team has done in the past, you make a pretty compelling case that we’re going to do it again.”
While the Allotex procedure could mimic other intracorneal inlay procedures where a thin femtosecond flap is made, the allograft centered over the pupil, and the flap smoothed back down, Dr. Muller said they’re moving toward a less invasive onlay procedure. A small divot of the patient’s corneal epithelium would be removed and the thin allograft lenticule would be placed on top of Bowman’s membrane, tucked a bit under the epithelium, and within 6–8 hours, the epithelium would cover back over it.
“Now you have a procedure where you didn’t do any surgery, just a little corneal insult,” he said. “If I want to take it out, I don’t have to do anything except reach in with forceps. We know of one doctor who was able to slide it out at the slit lamp with the patient not knowing it came out. It’s a completely different offering to the patient.”
In addition to technology and surgical techniques coming of age to make corneal allografts more feasible than before, Dr. Muller said sterilization and storage methods by Lions VisionGift Vision Research Laboratory has created an economical way to store sterile, ready-to-use tissue at room temperature without the need for reconstitution.
Dr. Muller said Allotex is refining the process engineering to take a cornea and make 150 of these button allografts out of it. At this point, Dr. Muller said he envisions stock amounts of the button lenticules of about 3 mm in diameter and 25 µm in central thickness being stored by physicians offering this procedure.
Dr. Muller said this donor tissue can be used to make lenticules of about 5.5 mm in diameter with a central thickness of 50 to 100 µm for treatment of hyperopia. Custom lenticules could also be fashioned for patients with astigmatism.
PEARL works, Dr. Muller said, because you’re taking a clinical laser on a clinical eye to remove a set amount of tissue and then taking a piece of that lenticule and putting it on another eye. To develop a laser system and process that allows you to take bits and pieces of a donor cornea, accurately measure and shape them, requires “millions of dollars worth of engineering to turn it from a cool idea into a real product.”
The challenge with inlays and onlays—both allogenic and synthetic—remains patient neuroadaptation. “In a sense, it’s a modified monovision,” Dr. Muller said. “What patient population tolerates this? We don’t know that number.”
However, the beauty of these inlays—and the synthetic variety—is their removability.
“It becomes the holy grail, a semi-permanent contact lens that can be removed if you don’t like it or removed and replaced if the refraction changes. I think that’s the key message,” Dr. Muller said.
“Just because refractive error/wearing corrective lenses is looked upon as a ‘nuisance’ and non-medical condition doesn’t mean we cannot strive to develop and offer better techniques in correcting it,” Dr. Negrin said. “I am all for using donor corneal tissue for this purpose provided there is no scarcity of donor tissue, and we are able to reliably provide the service.”

References

1. Ratner BD, et al. Biomaterials Science, Third Edition: An Introduction to Materials in Medicine. Academic Press. 2012 Dec 31;931.
2. McDonald MB, et al. The nationwide study of epikeratophakia for myopia. Am J Ophthalmol. 1987;103:375–83.
3. Pradhan KR, et al. Femtosecond laser-assisted keyhole endokeratophakia: correction of hyperopia by implantation of an allogenic lenticule obtained by SMILE from a myopic donor. J Refract Surg. 2013;29:777–82.
4. Jacob S, et al. Preliminary evidence of successful near vision enhancement with a new technique: PrEsbyopic Allogenic Refractive Lenticule (PEARL) corneal inlay using a SMILE lenticule. J Refract Surg. 2017;33:224–29.
5. Ganesh S, et al. Cryopreservation of extracted corneal lenticules after small incision lenticule extraction for potential use in human subjects. Cornea. 2014;33:1355–62.

Editors’ note: Dr. Muller has financial interests with Allotex. Dr. Jacob has financial interests with instruments she uses to perform CAIRS. Dr. Negrin has no financial interests related to her comments.

Contact information

Jacob
: dr_soosanj@hotmail.com
Muller: info@allotex.com
Negrin: asnreis@gmail.com

Is it the age of allogenics? Is it the age of allogenics?
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