Presbyopia has been treated with glasses, contact lenses, pharmacological treatments (i.e., constricting the pupil to achieve a pinhole effect and softening the lens proteins by acting on the disulfide bonds), and surgical options such as clear lens extraction with intraocular lens (IOL) placement, presbyopic laser refractive surgery, and alloplastic and allogenic corneal inlays (see “Presbyopia Facts,” below).

This article provides an overview of allogenic corneal inlays for the treatment of presbyopia, a discussion of what is currently available, and what’s in the pipeline.

Overview

Jose Barraquer, a Spanish ophthalmologist, often referred to as the “father of modern refractive surgery,” first used allografts in 1949 in a procedure called keratophakia. However, the use of imprecise cryolathed grafts and the lack of technology to create precise pockets in the recipient’s eye made this procedure far from perfect.

Today, corneal inlays are generally implanted in presbyopic emmetropic patients between the ages of 40 and 60, although the inlays may also be combined with laser-assisted in-situ keratomileusis (LASIK) in presbyopic eyes that have refractive errors.

The ideal patient for the procedure is, of course, one who understands that there is no perfect solution yet for presbyopia. Perfectionist patients, patients with visually demanding jobs, Type A personalities, and patients with dry eyes or autoimmune disorders, corneal abnormalities, irregular astigmatism, cataractous changes in their crystalline lens, etc., are not ideal candidates.

Allogenic inlays are easy to reverse and adjust, and in the procedures described, they have been reported to keep the overlying cornea healthy and decrease the risk for corneal necrosis and melt.^1,2 Additionally, allogenic tissue has great biocompatibility and integrates well into the cornea. The risk of clinically significant haze and corneal opacity is, therefore, significantly less (with none reported in the pilot studies).^1,2

Allogenic tissue also has the advantage of being capable of being placed as an “onlay” under the epithelium and over Bowman’s membrane, making it much easier to perform by potentially simply scraping the epithelium toward the sides, placing and centering the onlay over Bowman’s membrane, tucking the edges of the onlay under the epithelium, and placing a protective bandage contact lens. (Note: Onlays have not yet been performed in clinical trials, in the author’s knowledge.) Healing would be rapid, with the epithelium quickly growing over within a few hours. Onlays would also have the advantage of being more easily explantable and exchangeable when required, even as an in-office procedure.

Theoretically, there is a risk of stromal rejection with allogenic grafts; but in practice, this outcome has not been reported. The reasons are that the cornea is an immunologically privileged site, and corneal grafts are less susceptible to rejection compared to other sites of the body. The volume of tissue transferred as inlays, onlays, and segments (described below) is an extremely small antigenic load.¹

It is a well-established fact that deep anterior lamellar keratoplasty (DALK) is associated with a low risk of rejection, despite the transplantation of a large quantity of epithelium and a much larger volume of stroma. The transfer of a significantly smaller volume of pure stroma in allogenic presbyopic inlays would, therefore, be susceptible to a much lower risk. Lack of any epithelial or endothelial transfer further decreases antigenicity. Further, the small volume of transfer allows for the rapid repopulation of the inlay by the patient’s own keratocytes from all sides. Deantigenization by processing of the inlays is possible.

Finally, allogenic inlays are placed far from the limbus and are sutureless, preventing other risks such as corneal neovascularization and consequent increased risk of rejection. The safe use of allogenic implants has been shown for multiple indications, such as aphakia, hypermetropia, keratoconus, and others.^3-7

What Is Currently Available

Currently, the PEARL (PrEsbyopic Allogenic Refractive Lenticule) procedure is available. I described this procedure in 2015. The PEARL inlay is similar to the no-longer available Raindrop corneal inlay in that it is a shape-change inlay that alters the central radius of curvature by creating a hyperprolate corneal shape, which induces spherical aberrations. This results in an increased depth of focus.

For the procedure, tissue from a Small Incision Lenticule Extraction (SMILE), obtained from a healthy donor after appropriate tests and screening, was stored in Optisol GS (Bausch + Lomb)/Cornisol (Aurolab). The lenticule was then used to fashion a presbyopic corneal inlay. It was chosen because, at the time, it was the only allogenic tissue available with precise known thickness, refractive power, and other dimensions. In our pilot study, we used lenticules from approximately -2.50 D myopes, although this choice could be altered depending on the thickness attained.

A 1 mm trephine was used to punch out a small round inlay, which was ready for implantation with its right side facing up. It was implanted centered on the coaxially sighted light reflex marked on the nondominant eye’s cornea of a presbyopic patient inside a femtosecond laser-dissected pocket. This procedure was done by programming a LASIK flap to have a large hinge size and only a small side cut that was brought superiorly and to the side of the surgeon’s dominant hand to facilitate ease of implantation. Centration was confirmed again by postoperative topography. I have also used the PEARL technique as an autologous PEARL inlay using a SMILE lenticule extracted from a myopic presbyopic patient to implant within the same patient’s nondominant eye.

At the onset of presbyopia (typically age 40), many patients can still read small print by holding the material farther away. I implant PEARL in patients older than age 43, by which time most patients experience significant discomfort and inability to read small print. Ideally, the manifest refraction spherical equivalent should be between -0.75 D and +1.00 D with nil to low astigmatism (typically less than 0.75 DC) in the nondominant eye.

Uncorrected near and intermediate vision, as well as reading speed and ease of performing near tasks, is improved. Uncorrected distance visual acuity may be decreased slightly in the eye with the inlay in some patients.

The patient is comfortable binocularly for near, intermediate, and distance tasks with spectacle independence. Best-corrected distance and near visual acuity remains unaffected in the implanted eye. Just as the LASIK flap adheres soon after surgery, the lenticule adheres to the stroma on either side and remains in position within the pocket. Cosmetically, the inlay is not visible, unless looked for carefully at the slit lamp. We used slit-lamp imaging, anterior-segment OCT, and Orbscan to show a well-centered inlay and absence of inlay-induced complications, such as opacification, extrusion, vascularization, or infection.

In the Pipeline

The future of allogenic implants seems bright. To start, the TransForm (Allotex) corneal inlay is currently undergoing FDA clinical trials, with the early results promising with regard to safety, efficacy, and biocompatibility with uncorrected near vision improvement in all pilot study patients. A slight decrease in uncorrected distance visual acuity in four of 12 patients and a slight myopic shift to the refraction were reported, with best-corrected distance visual acuity remaining the same as preoperatively. The inlay is therefore placed in the nondominant eye for both distance and near vision binocularly.

The TransForm inlay is prepared from eye bank corneal tissue that is not of fresh transplant potential. The donor tissue is punched with a trephine into buttons of the desired diameter, each of which is then sliced along a lamellar plane into multiple tissue blanks. These blanks are then precisely shaped with an excimer laser, decellularized, packaged, stored in recombinant albumin solution, and sterilized with electron beam radiation. A single donor cornea can, thus, be used to create a large number of inlays. These presbyopic inlays are of 3 mm in diameter, 20 µm in thickness, target refractive add power of 2.5 D, and have a shelf life at room temperature of up to 24 months. The TransForm inlay, thus, essentially provides a precut sterile allograft corneal inlay that is ready to be inserted into the patient’s cornea. It can also be used for correction of hypermetropia. Despite the large size of inlay needed for this task, the allogenic nature of the inlay would not result in the increased risks seen with synthetic implants.

Second, CAIRS (corneal allogenic intrastromal ring segments) is a new technique in cases in which allogenic tissue is again used to advantage. Specifically, segments of de-epithelialized and de-endothelialized corneal stromal tissue are placed within femtosecond laser-dissected channels created in the midperipheral stroma of the cornea, somewhat similar to synthetic intracorneal ring segments (ICRS). This process results in cone flattening and centralization, regularization of corneal topography, sphere and cylinder decreases and improvement in uncorrected and best corrected visual acuity, while avoiding all of the complications associated with synthetic ICRS, such as melts, necrosis, extrusion, intrusion, migration etc.

CAIRS can be used in mild and severe cases, and it has even been used to avoid corneal transplantation in many advanced cases. Risks associated with possible rejection are again extremely low for the same reasons elaborated upon earlier. In addition, the midperipheral nature of the implantation keeps the visual axis clear at all times. Postoperative steroids are used in a tapering dose for only 6 weeks.

Raising Awareness

Allogenic presbyopic corneal inlays are shown to be easy, rapid, reversible, adjustable, safe, and effective, with good biocompatibility and biointegration. The challenges: to make the procedure more widely known, available, and accepted and to publish larger studies that contain longer-term data. Further research is bound to result in improved benefits for the patient. CP

References:

1. Jacob S, Kumar DA, Agarwal A, Agarwal A, Aravind R, Saijimol AI. 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(4):224-229.
2. Kılıç A, Tabakcı BN, Özbek M, Muller D, Mrochen M. Excimer laser shaped allograft corneal inlays for presbyopia: initial clinical results of a pilot study. J Clin Exp Ophthalmol. 2019;10(4):1-7.
3. Pradhan KR, Reinstein DZ, Carp GI, Archer TJ, Gobbe M, Gurung R. Femtosecond laser-assisted keyhole endokeratophakia: correction of hyperopia by implantation of awn allogeneic lenticule obtained by SMILE from a myopic donor. J Refract Surg. 2013;29(11):777-82.
4. Sun L, Yao P, Li M, Shen Y, Zhao J, Zhou X. The safety and predictability of implanting autologous lenticule obtained by SMILE for hyperopia. J Refract Surg. 2015;31(6):374-379.
5. Ganesh S, Brar S. Femtosecond intrastromal lenticular implantation combined with accelerated collagen cross-linking for the treatment of keratoconus-initial clinical result in 6 eyes. Cornea. 2015;34(10):1331-9.
6. Jacob S, Dhawan P, Tsatsos M, Agarwal A, Narasimhan S, Kumar A. Fibrin glue-assisted closure of macroperforation in predescemetic deep anterior lamellar keratoplasty with a donor obtained from small incision lenticule extraction. Cornea. 2019;38(6):775-779.
7. Jacob S, Narasimhan S, Agarwal A, Agarwal A, Ai S. Combined interface tattooing and fibrin glue-assisted sutureless corneal resurfacing with donor lenticule obtained from small-incision lenticule extraction for limbal dermoid. J Cataract Refract Surg. 2017;43(11):1371-1375.

 

DR. SOOSAN JACOB is director and chief of Dr. Agarwal’s Refractive and Cornea Foundation at Dr. Agarwal’s Eye Hospital, Chennai, India, and can be reached at dr_soosanj@hotmail.com. Dr. Jacob has a patent pending for special trephines, devices, and processes used to create these segments, as well as for the CAIRS segments and various types of shaped and processed corneal segments.