Issue: July 2021
Source: Healio Interviews
Disclosures: Brar and Jacob report no relevant financial disclosures. Krueger reports he is a consultant for Alcon Laboratories, Bausch + Lomb and Johnson & Johnson Vision. Mastropasqua reports no relevant financial disclosures. Price reports he is a consultant for Gebauer and Alcon Laboratories.
July 21, 2021
11 min read

Reuse of SMILE lenticules presents opportunities and obstacles

Issue: July 2021
Source: Healio Interviews
Disclosures: Brar and Jacob report no relevant financial disclosures. Krueger reports he is a consultant for Alcon Laboratories, Bausch + Lomb and Johnson & Johnson Vision. Mastropasqua reports no relevant financial disclosures. Price reports he is a consultant for Gebauer and Alcon Laboratories.
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The lenticules extracted during SMILE procedures can be potentially reused in many ways. They are integer, neatly cut discs from young, healthy corneas suitable for biomedical research, tissue repair and tissue-addition procedures.

Several ophthalmologists have creatively developed techniques to use the lenticules, but regulatory and organizational challenges hinder their use in Western countries.

Soosan Jacob, MS, FRCS, DNB
According to Soosan Jacob, MS, FRCS, DNB, throwing away SMILE lenticules is a “huge waste of tissue and a huge loss of opportunities.”

Source: Soosan Jacob, MS, FRCS, DNB

“Some of these techniques could potentially be game changers, and indications cover a broad enough area to make it worth trying to implement SMILE lenticule reuse. We have an efficient system with eye banks for corneal transplantation, but we need a regulatory and organizational framework figured out for lenticules,” Ronald R. Krueger, MD, said.

In India, SMILE lenticules are used in multiple areas of corneal and refractive surgery in some of the nation’s best hospitals.

“It is an extremely useful resource with so many potential applications. If you think that, to date, more than 3 million SMILE procedures have been performed worldwide, and the annual rate is constantly growing, throwing away those lenticules is a huge waste of tissue and a huge loss of opportunities,” Soosan Jacob, MS, FRCS, DNB, said.

PEARL for presbyopia

A few years ago, Jacob developed the presbyopic allogenic refractive lenticule (PEARL) technique. SMILE lenticules previously stored and punched centrally to create a 1-mm disc of tissue were implanted into a femtosecond laser-created pocket to achieve a hyperprolate corneal shape for increased depth of focus in the nondominant eye.

“In our studies, there was an improvement in near vision between three and five lines and an improvement in reading speed. Since the inlay was only 1 mm in size, the decrease in distance vision in the operated eye was low,” Jacob said.

As compared with synthetic corneal inlays, allogenic tissue allows better integration into the cornea and unhindered flow of oxygen and nutrients, thus preventing the risk for corneal necrosis and melt. Theoretically, however, there is a small risk of stromal rejection with allogenic grafts, which may be of concern with a graft placed on the visual axis.

An autologous variation of this technique has been used by Jacob to address incipient presbyopia in patients undergoing SMILE refractive surgery for 2 D to 3 D of myopia at around 40 years of age.

“We cut the patient’s own SMILE lenticule and reimplant it into the stromal pocket during the same sitting. This autogenic procedure is easy and effective for these patients who have started to need reading glasses. It has no risk of rejection and adds just a little time to an ongoing surgery, though candidates with these characteristics are only a few,” Jacob said.

Sealing, resurfacing

There are other interesting ways to use SMILE lenticules that have become part of Jacob’s armamentarium and were reported in peer-reviewed publications. One of them is to seal intraoperative perforations that occur as a complication of deep anterior lamellar keratoplasty.

“A patient was referred to me 1 month after manual pre-Descemetic DALK for persistent corneal edema and counting finger vision. What we encountered was two large macroperforations, which led to a postoperative leak, double anterior chamber formation and an edematous graft,” Jacob said.

After a failed attempt to seal the perforations with fibrin glue and sutures, a SMILE lenticule was applied and secured with fibrin glue, providing a complete leakproof seal. The patient eventually recovered 20/30 corrected distance visual acuity.

A second good use of lenticules is for corneal resurfacing and interface tattooing after excision of limbal dermoids, congenital benign fleshy choristomas that grow on the limbus and may cause ocular surface disturbances, astigmatism and cosmetic concerns for the patient.

“I dissect the dermoid and carefully apply corneal tattoo powder to harmonize the excision area with the color of the iris, carefully following the circular shape marked near the limbus. Then I spread out the SMILE lenticule and fix it with a minimum amount of fibrin glue, trimming it so that it lies completely within the margins of the dissection,” Jacob said.

Both the refractive and cosmetic effects are excellent, she said.

SLAK for keratoconus

Keratoconus is one of the most promising areas for SMILE lenticule reuse. The stromal lenticule addition keratoplasty (SLAK) technique, developed by Leonardo Mastropasqua, MD, and Mario Nubile, MD, uses implanted lenticules to reshape and stabilize the cornea in eyes with progressive ectasia or keratoconus.

“To comply with Italian and European regulations, we use eye bank tissue specially cut for this purpose from donor corneas with the same technique that we use for SMILE surgery. But the actual SMILE lenticules could potentially be used if the legislation changes, and this is desirable for the future,” Mastropasqua said. In theory, the use of “decellularized” and cryopreserved lenticules could further improve the biocompatibility of living donor stromal tissues.

The lenticules for SLAK are thinner in the center and thicker in the periphery, just like a hyperopic SMILE lenticule, to provide a thickening, flattening effect, similar to the arc-shortening effect achieved with intrastromal corneal ring segments. The procedure can be combined with the use of contact lenses when needed and with corneal cross-linking (CXL).

“Corneal reshaping enhances tolerance to contact lenses, and the thickness increase makes CXL safe in corneas that would be otherwise too thin for the procedure,” Mastropasqua said.

Clinical studies have shown significant improvement in topographic indexes, irregular astigmatism, myopic refraction, and both uncorrected and best corrected visual acuity. In 2019, an international SLAK study group was established, including university centers in the United Kingdom, France, Spain, Singapore and Denmark as well as the University of Chieti in Italy.

FILI for hyperopia, keratoconus, post-SMILE ectasia

FILI, short for femtosecond intrastromal lenticule implantation, is a tissue addition technique developed by the group of Sri Ganesh, MS, and Sheetal Brar, MS, to treat hyperopia as well as keratoconus and post-SMILE ectasia.

“We indicate this procedure for hyperopia between +3 D and +10 D. We select donor lenticules that match the refractive error but with a slightly higher power. For example, to correct +4 D, we usually select a donor lenticule of –4.5 D. However, patients who have very high hyperopia, greater than +6 D, may get undercorrected due to posterior curvature changes, and we always explain that they might need enhancement in future. We have described a novel method of enhancement for these eyes called Bowman’s membrane relaxation, which is currently under review for publication,” Brar said.

As for keratoconus and post-SMILE ectasia, only mild to moderately advanced cases are selected, with spherical equivalent within 3 D and centrally located cones. The lenticule is cut into a doughnut shape and placed around the cone as a filler, providing a strengthening support and a relative flattening effect that improves aberrations and visual quality. In both these conditions, the tissue addition is combined with pocket cross-linking to prevent further progression of the ectasia.

The 6-month clinical outcomes of FILI for all these conditions have been published. All patients in the hyperopia series (32 eyes) had postop spherical equivalent refraction within ±1.5 D, and patients with keratoconus (nine eyes) and SMILE ectasia (five eyes) were within ±2 D.

“Apart from two eyes in the hyperopia series, which had suspected stromal rejection, no other eye in either of the groups developed any long-term complications. In this patient who had stromal rejection, cryopreserved lenticules were used. Impurities in the tissue may have been the cause of rejection, but also the improper use of postoperative steroid drops,” Brar said.

LIKE for hyperopia

LASIK and intrastromal keratoplasty (LIKE) is another technique in which a 7-mm to 8-mm stromal lenticule with a predefined profile and power is implanted under a large LASIK flap.

“Once vision has stabilized, approximately 2 to 3 months later, LASIK enhancement with the Contoura topography-guided technology (Alcon) is performed on the donor tissue to fine-tune vision,” OSN Cornea/External Disease Board Member Francis W. Price Jr., MD, said.

This technique is used to correct hyperopia between +3 D and +9 D and has not led to any loss in best corrected vision, which is unusual with larger hyperopic corrections as there is image minification. According to Price, it is a better procedure than LASIK or PRK in young hyperopes and should be more stable and long-lasting.

Francis W. Price Jr., MD
Francis W. Price Jr.

The lenticule is precut in the eye bank with a special microkeratome (Gebauer) and includes the anterior portion of the cornea with an intact Bowman’s layer. Price has doubts whether reusing SMILE lenticules for these refractive procedures would be a good idea.

“You would have to test the patients, as we do for donor tissue with blood samples and medical history, and ask for their consent to transplant their tissue on someone else. Also, in the LIKE procedure, we use the tissue from the front of the cornea, and it would be harder to use tissue from the mid-stroma because the cornea gets softer the further back you go in the eye,” he said.

Keep on storage for future evaluation

In 2019, Rohit Shetty, MD, and co-authors published the results of an analysis of molecular markers performed on SMILE lenticules of a patient who developed ectasia 3 years after the refractive procedure.

Ronald R. Krueger, MD
Ronald R. Krueger

“Having kept the SMILE lenticules on storage gave us this opportunity. We found that the eye that had ectasia had reduced expression of collagen type I alpha 1 (COL1A1) and lysyl oxidase (LOX), a natural cross-linking agent, as compared with the SMILE lenticules of five control eyes,” study co-author Krueger said.

This would be yet another way to reuse lenticules for scientific and diagnostic purposes.

“If a patient has a problem later, we can figure things out,” he said.

Preserving and storing lenticules

Infection and rejection are two potential risks in the reuse of lenticules. No consensus has yet been reached on the best methods to provide safe lenticules that maintain integrity and clarity and do not trigger tissue reactions, and various options are under investigation.

Decellularization could potentially increase the safety of lenticule transplantation without compromising the efficacy, according to Mastropasqua.

“Cells are removed so that only the collagen fibrils architecture of the lenticule remains, with no trace of the donor’s DNA. The risk of rejection is down to zero because there are no cellular antigens,” he said.

The group of Jodhbir Mehta, MD, PhD, in Singapore, has been researching methods for decellularization of corneal lenticules for several years. They found that treatment with 0.1% sodium dodecyl sulfate (SDS) followed by extensive washes was the most efficient protocol, superior to other methods in preserving the extracellular matrix content. Transparency and light transmittance of the natural lenticules were maintained. Preclinical studies showed that the decellularized lenticules supported corneal stromal fibroblast growth and exhibited long-term biocompatibility with no risk of rejection.

“We are refining decellularization techniques for our SLAK lenticules, and results so far are encouraging. Decellularized lenticules could be cryopreserved in bio banks and made available for the various methods of intrastromal surgery,” Mastropasqua said.

Anhydrous glycerol preservation at –78°C is an ideal method for reducing antigens without damaging the structure and function of lenticules, according to a study carried out at the University of Beijing, China.

Yanfeng Shang, MD, and co-authors investigated the pathogenicity and immunogenicity of 132 SMILE lenticules, one-third fresh, one-third preserved in –78°C anhydrous glycerol, and one-third decellularized by using 0.1% SDS. The fresh lenticules were all negative for HSV-1, HSV-2, bacteria, fungi and Acanthamoeba, but HLA-I A/B/C were detected on the cell surface. Antigens were equally reduced by glycerol cryopreservation and SDS decellularization, but the ultrastructure of the collagen fibers and the optical and mechanical properties of the lenticules were significantly damaged by SDS.

“Thus, we can infer that –78°C anhydrous glycerol preservation can not only achieve the effect of reducing antigens by 0.1% SDS, but can also avoid its damage to the normal collagen fiber structure and the optical and mechanical properties of the corneal stromal lenticules,” the authors wrote, while fresh lenticules have a low infection risk but still carry some risk of rejection.

“It is good to see that there are studies assessing the safety, potential risks and best practices for preserving and reusing SMILE lenticules,” Krueger said.

“Glycerol was the best because it gets rid of keratocytes, but studies are needed on how it affects refraction,” Price said.

He said that the risk of rejection is, however, low.

“We have seen that rejection rate is really low with DMEK, and the endothelium is no more important for immunological recognition than the stroma is. I believe that, probably, the patient’s own keratocytes eventually replace the donor’s keratocytes,” he said.

Using fresh lenticules

At Dr. Agarwal’s Eye Hospital, fresh lenticules are always available due to the high volume of SMILE surgery performed, and they are safe if adequate protocols are used, according to Jacob.

“We routinely screen patients with serology before SMILE, whether we are planning to reuse them or not, so we have tissue readily available every day for procedures where the refractive power of the lenticule is not important. We also preserve specific powered lenticules in Optisol for a few days if required, but for many indications, we don’t need to do this because we have fresh tissue every day,” she said.

Brar said that they used to cryopreserve lenticules until they found some impurities that looked like thin bluish fibers probably acquired during the transfer and processing of the tissue. They tried to investigate the source of these fibers, changed the processing solution and added additional steps of washing but still were unable to completely eliminate them. To avoid the risk of tissue reaction, they shifted to the use of fresh lenticules.

“Currently, whenever we have patients with high hyperopia or keratoconus who may benefit from tissue addition using SMILE lenticules, we look for suitable donors, get the informed consent and screen them for any viral transmissible diseases. If the reports are negative, we plan both the donor SMILE surgery and the recipient FILI surgery on the same day in the same OR,” she said.

As soon as the lenticule is extracted, it is transferred into balanced salt solution at room temperature, and the recipient surgery is performed, typically within 1 hour of the donor surgery. If for any reason the recipient surgery does not take place on the same day, the tissue can be safety kept in balanced salt solution for up to 48 hours in refrigerator at 4°C.

“No patient has developed rejection, reaction or infection with the use of fresh lenticules so far. Probably, if the lenticules are pretreated with UV radiation, they may be even more suitable for implantation, as UV radiation is also known to cause keratocyte apoptosis. However, we have neither any data nor personal experience to support this idea,” Brar said.

Refractive eye banking

Refractive eye banking could be the new frontier in which refractive and corneal surgery interact, according to Krueger.

“I presented this idea in my Barraquer Lecture at the AAO already some years ago. Refractive surgery is expanding into more tissue addition procedures, and refractive is an area where eye banks could grow. Eversight, which is a large network of eye banks in the USA, got interested in this project and now has facilities for cutting corneal tissues with customized refractive power,” he said.

Eye banks would ensure quality and safety of tissue and would facilitate the development of a regulatory framework for the reuse of lenticules from living donors, Mastropasqua said.

“One of the goals of the SLAK study group is the creation of a European biobank for the procurement, processing, preservation, storage and distribution of tissue donated by refractive surgery patients. Tissue donation rates vary widely across Europe, and the reuse of corneal tissue from living donors would create a new opportunity to overcome the shortages of donors in some areas,” he said. “It would also give new impulse to tissue additional procedures that hold promise and deserve a more prominent role in our armamentarium.”

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