In 1964, Dr. Ignacio Barraquer introduced the concept of intrastromal lenticular implantation. However, it was not until the development of femtosecond laser technology that this procedure became feasible. Dr. Theo Seiler later developed the Lenticular Intrastromal Keratoplasty (LIKE) technique, which involves the creation of a standard laser-assisted in situ keratomileusis (LASIK) flap, reflecting it to expose the stromal bed, and then inserting a prepared lenticule of a desired refractive power onto the bed. The flap is then returned to its proper position over the lenticule. A modification to this procedure is small-incision Lenticule Intrastromal Keratoplasty (sLIKE), which creates a stromal pocket using a femtosecond laser, through which the preshaped lenticule is inserted and centered via one or two small incisions. This procedure has been successfully used to correct hyperopia and restore corneal integrity.
Femtosecond lasers produce focused near-infrared pulses of energy that cause a photoionization reaction, vaporizing localized small volumes of tissue. This results in the formation of water vapor and carbon dioxide cavitation bubbles along a cleavage plane. Over time, femtosecond laser technology has become more precise, with current models producing more-focused pulses with minimal collateral tissue damage. This technology has been implemented in various ocular procedures, including the creation of LASIK flaps, laser-assisted cataract surgery, lamellar keratoplasty, laser-assisted penetrating keratoplasty, tunnel creation for intracorneal ring segments (ICRS), and laser-based corneal astigmatic surgery [4]. The SMILE procedure is a more recent application of this technology, utilizing a femtosecond laser to create an intrastromal refractive lenticule that is removed by the surgeon via small incisions created by the same laser.
As an alternative refractive procedure to LASIK or photorefractive keratectomy (PRK), the SMILE procedure has gained popularity internationally since its launch in 2011. Lenticules produced in the SMILE procedure have traditionally been discarded as waste, but there is increasing interest in utilizing this tissue elsewhere. These lenticules are created either with a positive meniscus shape (thickness increasing from the periphery to the center) to correct myopia, or with a negative meniscus shape (thickness increasing from the center to the periphery) to correct hyperopia. LIKE utilizes this tissue as an organic intrastromal implant to correct hyperopia or restore corneal integrity by increasing stromal volume.
Safety of donor tissue is a top priority. Corneal donor screening processes involve a detailed medical and social history, including cause of death, circumstances of death, medications, infectious disease, IV drug use history, and past ocular and surgical history to carefully minimize risk of infection and rejection. The cornea is then evaluated by slit-lamp examination, pachymetry, and endothelial cell density measurement. The donor’s blood is also tested for abnormally high glucose levels, and an infectious disease workup is completed, including HIV testing (anti-HIV-1 and anti-HIV-2), hepatitis B and C testing (HBsAg, anti-HBc IgG and IgM, and/or NAT for HBV and anti-HCV or NAT for HCV), and syphilis testing (e.g., VDRL, RPR, Treponema pallidum particle agglutination assay) [5]. Living or deceased lenticule donors should be screened in a similar manner prior to lenticule use, except for endothelial cell count, which is not necessary with a purely stromal graft.
Lenticules for use in LIKE procedures must be stored properly before usage. The choice of storage method depends on how long after harvesting the lenticules will be implanted. Organ culture is the preferred method for lenticules that will be used within 24 h of harvesting, with tissue mediums often containing antibiotics and/or antifungals. Hypothermia is used for lenticules that will be used within 24 h to 2 weeks of harvesting. Lenticules can be stored in solutions such as phosphate-buffered solution (PBS) or optisol between 2 and 8 °C. Dehydration can also be used for both preparation for cryopreservation and short-term storage of lenticules, while cryopreservation is the chosen method for long-term storage of lenticules, ensuring structural integrity for up to 10 years [7,8,9,10,11].
When using cryopreservation, lenticules are generally stored in liquid nitrogen at temperatures between −80 and −196 °C, and they can be stored in solutions that contain a cryopreservant such as dimethylsulfoxide (DMSO) or in tissue or dehydration mediums such as Dulbecco’s modified Eagle’s medium (DMEM), serum-free medium (SFM), silica gel, or glycerol [8, 9, 11]. Cryopreserving previously dehydrated lenticules is the most effective and economical form of long-term storage, and studies indicate that cryopreserved lenticules maintain their collagen structure and cellular viability with no significant difference in wound healing compared with fresh lenticules [6,7,8, 11].
In conjunction, dehydrated lenticules maintain their biological and biomechanical properties, maintain corneal transparency, and show no difference in stiffness when compared with lenticules not dehydrated [8, 9]. Agents that facilitate dehydration include silica gel, glycerol, or polyethylene glycol [12,13,14]. The only disadvantage to dehydrating lenticules is that they showed reduced thickness when dehydrated, which persisted after rehydration [9]. However, the antimicrobial properties of dehydrating agents such as glycerol provide more potent long-term preservation, and therefore, the benefits of dehydrating lenticules prior to cryopreserving them often outweigh the potential loss in lenticular thickness [7]. Studies indicate that cryopreservation maintains the collagen structure and cellular viability of the lenticule and that there is no significant difference in wound healing between fresh and cryopreserved lenticules [6, 8, 11]. Another study revealed that keratocytes and nerve fibers slowly integrated into the lenticular architecture, successfully combining cryopreserved lenticules within the host stroma [6].
Decellularization, while not a storage or preservation technique, may be used to prepare lenticules prior to storage or implantation. Decellularization maintains the extracellular integrity of tissues while removing any cells or antigens that may stimulate an immune response. The process is accomplished using various detergents and enzymes that can lyse cells, such as sodium dodecyl sulfate (SDS). This technique is used to prepare xenogeneic lenticules for refractive implantation, a topic discussed later in this paper [8].
While most studies have used fresh lenticules that were either immediately transplanted or stored for less than 24 h prior to implantation, the possibility of eye banks storing SMILE-acquired lenticules for future use could expand treatment options and change the field of refractive surgery. The protocols for the preservation and storage of corneal tissue may not directly translate to the storage and preservation of lenticules, but establishing a standard protocol for their preparation and storage is essential for safety and should be explored in future studies.
Table 1 (storage and preservation table) documents data from 34 case studies (291 eyes) and case series among our sources [12, 15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46]. Studies that utilized fresh lenticules, hypothermic lenticules, or cryopreserved lenticules were listed, and additional sources were used to link the storage temperature, storage duration, and storage solutions or mediums used for each method.
Table 1 Storage and preservation methods detailing which method each study utilized, preferred storage temperature, duration of storage, and solution/media lenticules were stored in for each methodFull size table
The first case utilizing an extracted lenticule obtained via SMILE involved implantation to correct high hyperopia. This allogeneic transplant was published in Nepal by Pradhan et al., in 2013 and was referred to as endokeratophakia. At 1 year postoperatively, the patient had a spherical equivalent refraction reduction of 5.25 D, central corneal thickness (CCT) increase of 121 mm, and clear lenticule [4]. This successful first case in utilizing allogeneic lenticules opened opportunities for further use in patients worldwide.
The next set of studies occurred in 2020. Five patients underwent a lenticule transplant via either transepithelial phototherapeutic keratectomy (PTK-EP), in two patients and four eyes, or femtosecond laser-assisted lenticule intrastromal keratoplasty (LIKE), in three patients and six eyes. In PRK-EP, the myopic SMILE-obtained lenticule was placed on top of the stromal bed after removing the epithelium, whereas in LIKE, a flap was made, and the lenticule was placed on the stromal bed. Compared with corrected distance visual acuity (CDVA), 6/10 eyes had equal or better uncorrected distance visual acuity (UDVA). Postoperative spherical equivalent reached on target ± 0.5 D for 9/10 eyes [16]. In the USA, the first lenticule implantation via LIKE (lenticule obtained from a cadaver and stored in optisol for 6 days prior to implantation) was achieved by Moshirfar et al. in 2020, where the patient went from +6.00 D hyperopia to −1.25 D at 1 week and planar at 6 months postoperatively [6]. A prospective case series of 14 eyes and 9 patients with hyperopia (ranging from +3.00 to +8.00 D) showed encouraging transplantation results with a follow-up of 2 years. The lenticules, obtained from myopic SMILE donors, were implanted into a pocket made by a femtosecond laser, and showed improved spherical equivalent at 2 years postoperatively [12].
Lenticules can be utilized in eyes with more than simple hyperopia [13]. A retrospective study investigated 15 patients with hyperopia and astigmatism, who underwent SMILE to correct astigmatism and then utilized a donor lenticule, as an inlay to treat the hyperopia with a maximum follow-up of 1 year, showing eight eyes (42.1%) gaining at least one-line CDVA [35]. Another study showed enhancement after a primary allogenic refractive lenticule implantation with a positive meniscus lenticule, with improved UDVA and manifest refraction post-LIKE [14]. In moderate to high cases of hyperopia, a case-controlled study in 2022 showed sLIKE (lenticules obtained from myopic SMILE) having greater visual and refractive outcomes compared with femtosecond LASIK in 20 right eyes of 20 patients and 22 right eyes of 22 patients, respectively [36].
Thus far, we have described the use of allogeneic transplants in correcting hyperopia with or without astigmatism. There are limited studies published covering autogenic transplants, where patients have myopia and hyperopia in separate eyes. The earliest study was published in 2015 by the Zhou group that aimed to look at ten eyes from five patients where the myopic eye was treated with SMILE and the retrieved lenticule was implanted in the other eye [18]. The same group conducted a prospective study of ten patients with the same study design to establish a predictive formula for the refraction of autologous lenticule implantation. They discovered that, owing to tissue deturgescence, the refractive power of the lenticule decreased after implantation. To correct this, they derived a formula to achieve the desired correction post lenticular implantation A lenticule with a refractive power 1.2 times higher than the estimated power is required. The equation is as follows: LAC (D) = 1.22 LRP (D) (LAC = lenticule implantation achieved correction, LRP = lenticule refractive power, both measured in diopters). Li et al. state that autologous lenticule implantation could provide a reliable method of correcting hyperopia [19]. While previous studies confirmed the functional visual results, the Li et al. 2018 group aimed to understand what happens at the tissue level of integration. They used in vivo confocal microscopy to study the regeneration of the nerve fibers into the lenticule after implantation and demonstrated their return to normal morphology. The results were based on five patients [20].
Figure 2 highlights visual outcomes analyzed from 54 eyes pulled from 10 studies of either allogeneic or autogenic lenticule implantation for the treatment of hyperopia or hyperopia and astigmatism. Preoperative manifest refraction, vertex, and CDVA along with postoperative manifest refraction, vertex, UDVA, and CDVA values were documented [12,13,14,15,16,17,18,19,20,21]. Some manifest refraction values were converted from positive cylinder to negative cylinder. The graphs show variability in accuracy in the spherical equivalent of refraction and a trend towards undercorrection, with most patients experiencing residual hyperopia after lenticular implantation. Visual acuity outcomes were not ideal, with only 60% of patients with 20/40 or better UDVA, only 19% with 20/20 or better UDVA, and 10% losing one line of CDVA postoperatively. The figure also illustrates that there was an overall improvement in astigmatism post lenticule implantation and results were particularly effective in studies that specifically shaped lenticules with the intention of correcting astigmatism. Most recent follow-up values were used for each eye, ranging from 1 month to 2 years postoperatively. The average postoperative follow-up time was 13.8 ± 7.6 months. The safety (postop CDVA/preop CDVA) and efficacy (postop UDVA/preop CDVA) indices were calculated from relevant data, yielding a safety index of 1.16 ± 0.37, calculated from 29 eyes from seven studies [5, 6, 8,9,10, 12, 13], and an efficacy index of 0.95 ± 0.31, calculated from 28 eyes from six studies [13, 14, 16,17,18, 20] These values show that, despite variable visual outcomes, the safety and efficacy were sufficient for studies that reported all pre- and postoperative visual acuity data. However, these values may not be representative of all outcomes, as several studies did not report all pre- and postoperative visual acuity values. Owing to differences in the data reported in each study, not all graphs reported all 54 eyes.
Fig. 2Nine standard graphs for reporting refractive surgery, showing both the visual and refractive outcomes for 55 eyes from 11 studies treating hyperopia or hyperopia and astigmatism with intrastromal implantation of lenticules. UDVA uncorrected distance visual acuity, CDVA corrected distance visual acuity, D diopters, Postop postoperative, Preop preoperative, SEQ spherical equivalent refraction, TIA target-induced astigmatism, SIA surgically induced astigmatism. Note, graphs vii and ix show astigmatism results for all eyes with relevant data, whereas graphs x and xi show astigmatism results for only those studies with an explicit aim of correcting astigmatism
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A study published in 2020 reported the longest clinical history and postoperative course of a myopic cornea lenticule implanted via epikeratoplasty. A myopic epikeratoplasty lenticule from a commercial source was implanted and removed 30 years later owing to cataract formation. This 30-year-old case supports the long-term clarity and resilience of such allogeneic implants for innovative corneal refractive surgeries. Through the 30-year period, the patient initially had −16 D spherical equivalent, which after implant, became 20/30–40 vision, which regressed to < 20/50, improving with spectacles. However, 14 years after surgery, the patient underwent PRK with stable vision for the next 15 years [47].
A study by Jacob et al. published in 2017 describes a novel surgical technique, PrEsbyopic Allogenic Refractive Lenticule (PEARL), for the treatment of presbyopia using lenticules obtained from SMILE. In this procedure, SMILE lenticules were shaped into small disks (61.5 ± 3.32 mm thick) and implanted intrastromally to increase the central radius of curvature of the cornea and make it hyperprolate. This functioned in modifying the optical properties of the eye and improving near visual acuity. All eyes had an improvement in visual acuity of three to five lines, with maintenance of uncorrected distance visual acuity (20/20). All patients reported no need for glasses at near, intermediate, or distance vision, and there were no complications related to lenticular implantation at 6 months postoperatively. One of the limitations of this study was the short follow-up period such that long-term complications (i.e., corneal haze) were not documented. This procedure could replace the use of synthetic implants that have an increased risk of corneal necrosis and melt owing to the potential inability of nutrients to pass through the synthetic implant. The use of allogenic tissue also increases bioavailability and decreases the risk of inflammation while maintaining the ability to be removed or adjusted [37].
Despite the growing interest in refractive procedures for the correction of presbyopia and the apparent success of this procedure, there have been no more documented studies using the PEARL method specifically in literature. However, Allotex (Boston, MA) is undergoing clinical trials testing a similar method in locations including France, Ireland, Turkey, the UK, Austria, Switzerland, Belgium, and Slovakia. Presbyopic patients between 41 and 65 years old qualify for an intrastromal lenticular implantation in their nondominant eye if they have a manifest refractive spherical equivalent between −0.75 and 1.0 D and a refractive cylinder of less than 0.75 D, do not wear glasses for distance vision, and do not need an additional 1.75–3.50 D to read. Sheets of corneal tissue are created using a microcryotome. Disks are then cut out of the sheets using a biopsy punch. After this, corneal blanks are sterilized and femtosecond laser-sculpted into small, circular disks that are on average 2.0–3.5 mm in diameter and 15–25 microns thick. The lenticules are then placed into the recipient’s stroma via a flap formed by a femtosecond laser [48].
Lenticular implantation has been successfully utilized in the correction of various forms of corneal ectasia. Management typically initially involves various forms of contact lenses (rigid gas permeable, custom soft, hybrid lenses, and “piggyback” lenses) and progresses to ICRS implantation or collagen crosslinking (CXL). In severe cases, penetrating keratoplasty (PKP) is often employed. ICRS implantation induces spherical correction and corneal flattening in the short term but may result in regression over time [4] and cannot be used for advanced, progressive keratoconus [49]. Recent approaches have involved combination therapy with the insertion of ICRS with subsequent CXL, and CXL combined with excimer laser ablation procedures [5, 50]. This section will highlight the utility of implanted corneal lenticules in primary and secondary ectasia.
Keratoconus is a form of primary ectasia and numerous studies support the use of lenticules as an advantageous treatment plan. The first study involving LIKE with human keratoconic eyes was published in 2006 by Tan et al. from the Shiley Eye Center at the University of California San Diego [51]. In this study, one eye in each of four patients received intrastromal lenticules cut from donor cadaver corneas. Though the sample size was small and the follow-up only extended 6 months, the results were promising with an improved mean UDVA of one line, improved mean binocular distance corrected visual acuity (BCVA) of four lines, and 100% of eyes with BCVA between 20/50 and 20/80 at 6 months postoperatively. This study demonstrated that lenticules could be a viable option in patients with keratoconus.
In 2015, Ganesh and Brar attempted a study with six eyes of six patients with keratoconus in which the patients received collagen CXL simultaneously with the implantation of a donut-shaped stromal lenticule. Lenticules were obtained from ReLEx SMILE procedures treating myopia. They reported a mean increase in CCT of 18.3 ± 7.3, no loss of lines in CDVA, no haze, and no infection at 6 months postoperatively [22]. In 2018, Almodin et al. described the case of a 12-year-old male with advanced keratoconus with an extremely thin cornea who was treated with the implantation of a cadaveric corneal lenticule (290 mm thick, 6.0 mm diameter) that had been subjected to collagen CXL. The procedure aimed to increase the corneal thickness and flatten the cornea to a satisfactory point to postpone the need for corneal transplantation until adulthood. The treatment achieved its desired objectives by thickening the cornea (245 μm to 639 μm) and flattening the cornea 12 months postoperatively. This resulted in a 6.57-D decrease in astigmatism and improved BCVA (20/400 to 20/30) at 1 year postoperatively [23].
In a study published in October 2021, Jafarinasab et al. performed lenticule implantation (lenticules acquired from cadaver donors) simultaneously with CXL in five patients, with three implanted lenticules receiving excimer laser keratomileusis to correct for the recipient’s estimated refractive error. Three patients gained between one and five lines of vision, one showed no improvement in vision, and one lost three lines of vision. Corneal thickness was increased in all patients. The two patients who did not receive laser-treated lenticules experienced an increase in average keratometry values postoperatively. The study found no significant difference in patient satisfaction regarding visual acuity with the laser-treated versus non-laser-modified lenticules. Despite improvement in corneal thickness, three patients received deep anterior lamellar keratoplasty (DALK) 3–6 months postoperatively owing to dissatisfaction with visual outcomes, while two opted to wait for a refractive procedure until they could receive topography-guided custom laser ablation later [24].
In 2021, a larger study of 15 eyes of patients with advanced keratoconus also described promising results with cadaveric donors and negative-meniscus-shaped lenticules implanted intrastromally. They found improved visual acuity, increased central corneal thickness (65 ± 28 μm), decreased corneal steepness (improvement of mean Sim-K by 2.2 D), and improved apical epithelial thickness (43 to 50 μm) at 6 months postoperatively with no complications aside from mild edema that resolved after 1 month postoperatively [25].
A study in 2018 by Mastropasqua et al. described the use of lenticule implantation for advanced keratoconus. Negative-meniscus-shaped lenticules obtained from cadaver donors were implanted within the stroma of the recipient eyes, with 80% of patients showing improvement in UDVA between one and three lines, 90% showing improvement in CDVA, an average anterior mean curvature decrease of 3 mm, an increase in CCT in all eyes (406 ± 43 mm to 453 ± 39 mm), and normalized keratocyte morphology by 6 months postoperatively [26]. Another study from 2020 by Mastropasqua et al. investigated the outcomes of intrastromal lenticular implantation for advanced keratoconus. In this study, hyperopic lenticules obtained from an eye bank were used and evaluated at 12 months postoperatively for any changes in corneal or lenticule structure. The procedures were successful with no signs of inflammation, normal subbasal nerve density (preop 13 ± 3 to 12 ± 2 12 months postop), and stable endothelial and keratocyte density by 6 months postoperatively [27]. All these studies indicate the safe and effective use of disk-shaped intrastromal lenticules for the treatment of keratoconus.
Another application for lenticular implantation in the treatment of keratoconus is corneal allogeneic intrastromal ring segments (CAIRS). These ring segments are lenticules shaped into semicircular rings that can be placed into channels dissected in the recipient corneal stroma and function to flatten, stiffen, and stabilize the cornea and alter corneal curvature for the treatment of keratoconus. They have also been shown to improve visual acuity and decrease the likelihood of progression in keratoconus patients. CAIRS surgery has been successful using both femtosecond laser and manual dissection to create the intrastromal channel for ring insertion [28]. While femtosecond laser dissection allows for greater precision, which has specific advantages, successful manual dissection is important as femtosecond technology is often unavailable or unaffordable globally [29]. Owing to difficulty in visualization during surgery, trypan blue stain is often used to dye the donor corneal segments to better differentiate donor and recipient corneal tissue and ensure proper placement of the allogeneic intrastromal rings. Additionally, trypan blue stain is temporary and nontoxic when applied to human corneal tissue [52].
CAIRS is an alternative to synthetic intrastromal ring segments, which are currently used for the treatment of keratoconus. Synthetic ICRS must be implanted deep into the cornea to prevent erosion and extrusion and have an increased risk of complications; however, allogeneic stromal rings can be inserted at a mid-stromal depth, which reduces the risk of these complications. Jacob et al. discuss clinical outcomes of patients with keratoconus treated with CAIRS combined with corneal crosslinking. CAIRS segments were prepared from donor corneas. The donor epithelium was removed using dry sponges, the center marked, and Descemet’s membrane stripped. A circular trephine with an inner and outer blade was centered and used to cut a full-thickness allogeneic ring segment, which was subsequently bisected. The procedures were successful, with CAIRS implanted at mid-stromal depth (average depth of 314.4 ± 61 mm). There was an average improvement of 2.79 ± 2.65 lines in UDVA and average 1.29 ± 1.33 lines of improvement in CDVA at an average of 11.58 ± 3.6 months postoperatively. At 6–18 months postoperatively, the intrastromal rings were centered with no extrusion, necrosis, erosion, or melt. While allogenic tissue rings have greater influence on the anterior corneal curvature in the treatment of keratoconus, a disadvantage of allogenic intrastromal rings is the risk of rejection; however, this did not occur in any cases in this study [28].
Necklace-shaped lenticules can be used to modify lenticular geometry and improve treatment outcomes for keratoconus patients. A study by Doroodgar et al. describes the use of necklace-shaped lenticules, along with ring-shaped lenticules, for the treatment of keratoconus. All lenticules were obtained from SMILE performed on myopic eyes. Necklace lenticules are modified half rings, with a greater inferior radius of curvature compared with superior and greater central thickness. Necklace lenticules were placed beneath the pupil, while ring lenticules were placed above the pupil. Whether a specific patient was treated with only a necklace lenticule or both necklace and ring lenticules was determined by the location of the cone (centered or not), superior–inferior asymmetry, and mean keratometry value. This approach allowed for maximal improvement in central corneal thickness and corneal curvature. There was one or more lines of improvement in CDVA in 45% of patients, a 110 ± 11 µm average increase in central corneal thickness, and a 1.54 D change in refractive power at 6 months postoperatively. This study indicated that lenticular implantation for the treatment of advanced keratoconus may bring the cornea closer to normal than other methods of treatment [30].
Post-LASIK keratectasia is a form of secondary corneal ectasia. Lenticular implantation as a treatment for post-LASIK ectasia was first studied in China in 2017 with three patients who had developed progressive post-LASIK ectasia and had central corneal thickness < 400 μm. The donor lenticules were harvested from patients undergoing SMILE earlier that day. At the end of 1 year, the average central corneal thickness was 446.67 ± 41.63 μm, compared with 360 μm preoperatively, and all the grafts were clear with no evidence of immune rejection or other complications [32]. An additional study in 2018 involved the treatment of a patient who had developed myopia, astigmatism, and decreased CCT (20 mm) 10 years after LASIK. The procedure was performed with a lenticule received from a hyperopic SMILE patient. His BCVA improved to 20/40 postoperatively versus 20/60 preoperatively, corneal flat values decreased by 6.20 D, corneal steep values decreased by 5.90 D, and corneal thickness increased by 49 mm by 10 months postoperatively. This study demonstrated that allogeneic lenticule implantation could be a viable solution for severe post-LASIK ectasia, resulting in improved visual potential and a decreased refractive error [33].
Another case report from 2018 reported results from the first post-LASIK ectasia patient treated with lenticule addition and subsequent CXL, 4 months later. The lenticule was obtained from a myopic SMILE procedure on the same day. His UDVA improved from 20/200 to 20/125, BCVA improved from 20/63 to 20/40, CCT increased by 73 mm, K1 increased by 2.1 D, K2 increased by 4.5 D, and Kmax increased by 7.8 D by 30 months postoperatively. Corneal power and astigmatism did increase after lenticular implantation, but the authors hypothesize that this was due to the refractive error of the implanted lenticule (−2.75 DC, DC = diopters cylinder). This study was significant because it demonstrated 5 years of stability of the implanted lenticule, with no evidence of immunogenic rejection or regression of visual acuity in a patient with post-LASIK ectasia [34].
A recent study in 2020 examined the morphological changes to the cornea and the implanted lenticule via in vivo confocal microscopy after 3 years of follow-up in eight eyes that had received lenticular implantation for the treatment of post-LASIK ectasia. Cryopreserved lenticules, obtained from SMILE procedures, were implanted in recipient eyes. Patients were followed for 3–36 months, with improved clinical findings mirroring earlier studies. In vivo confocal microscopic examination revealed that activated keratocytes were detected in all eyes near the lenticule at postoperative month 6, indicating wound contraction and remodeling. At 1 year postoperatively, irregular keratocytes were detectable in the implanted lenticules, and one case had detectable nerve fibers in the implanted lenticule at 2 years. In an eye evaluated at postoperative years 1, 2, and 3, examination demonstrated increased keratocyte number and normalized keratocyte morphology within the first 3 years. There were also hyperreflective microdots on both the anterior and posterior lenticular surfaces that decreased in number over time, although they were still present by postoperative year 3 [6]. These findings demonstrate that, over time, keratocyte number and morphology gradually recover in the lenticule as recipient keratocytes migrate into the stroma, with possible regeneration of the subbasal nerve plexus occurring at the lenticule interfaces.
Pellucid marginal corneal degeneration (PMD) is another cause of primary corneal ectasia. There has been one case study documenting the use of intrastromal lenticular implantation in patients with PMD. This patient received both an intrastromal allogenic lenticular implant and a 359° ICRS to correct his ametropia and corneal thinning. The lenticular implant, obtained from myopic SMILE, was folded in half and placed in an inferior stromal pocket to improve the area of corneal thinning from 485 μm preoperatively to 624 μm at 3 months. As a result of the combined procedure, his UCVA improved by 0.48 decimals, BCVA improved by 0.3 decimals, and his astigmatism decreased by 4.5 D by 3 months postoperatively [31].
Lenticular implantation has also been successful at treating various unique ocular disorders. Possible additional applications of lenticular implantation are described below. One application for lenticular implantation is in the treatment of post-LASIK complications, with studies implicating its efficacy in treating severe post-LASIK hyperopia and astigmatism and in the treatment of an incomplete flap following a LASIK procedure [21, 38, 39]. All procedures were successful with improved visual outcomes, increased CCT, and reduction in astigmatism. Lenticules can also be used as grafts for the treatment of various corneal pathologies. Lenticules obtained from SMILE procedures have been used as patch grafts to successfully treat limbal dermoid, Mooren’s ulcer, Ahmed valve tube exposure, and bullous keratopathy. In each case, the lenticules were used to restore damaged tissue and resulted in improvement or maintenance of visual acuity and smooth the anterior curvature of the cornea [33,34,35,36]. Lenticules have been implanted intrastromally to treat central corneal ulcer and recurrent intrastromal corneal cyst. They functioned to replace damaged tissue that was removed and successfully treated the pathologies with improved visual acuity postoperatively [44, 53]. Figure 3 illustrates the possible applications of lenticular implantation mentioned and which type of lenticule is utilized for each indication.
Fig. 3Illustration of each type of lenticule discussed in this paper and what it would look like implanted in a human eye from a coronal and sagittal view
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A case series by Matthews et al. describes the clinical outcomes using gamma-irradiated corneal lenticules in both emergency and elective procedures of partial- or full-thickness keratoplasty for the treatment of noninflammatory corneal conditions, infectious keratitis, and corneal melt. Gamma irradiation was used to reduce the potential for allogeneic sensitization and potentially decrease the likelihood of keratolysis by collagenases, benefits particularly advantageous for patients with autoimmune conditions. Patients with noninflammatory corneal conditions received either DALK or automated lamellar keratoplasty (ALK) using lenticules or a standard Boston type 1 keratoprosthesis. At 1 year postoperatively, all grafts of DALK and ALK were intact, had epithelialized, and remained optically clear, with all but one having a visual acuity between 20/20 and 20/40. The patients who received Boston type 1 keratoprosthesis developed endophthalmitis 4–7 months after surgery. Patients with infectious keratitis received emergency patch grafting until optical or tectonic keratoplasty could be performed. Some grafts epithelialized and remained intact until optical keratoplasty was possible, while others had recurrent infectious keratitis and required tectonic keratoplasty. Patients with corneal melt underwent lamellar patch graft with the associated complication of recurrent corneal melt. As this study indicates, corneal lenticules may be used as reasonable alternatives for emergent procedures and may be better first-line treatments for procedures that do not need the donor endothelial layer (i.e., ALK) [45].
A study by Yang et al. also describes the use of lenticules as patch grafts for tectonic keratoplasty. In this study, SMILE-obtained lenticules were placed on the surface of the cornea to treat corneal ulcers and perforation. Any necrotic tissue on the surface of the cornea was removed, and the lenticule was placed over the lesion; lenticules were shaped to match the lesion, and sometimes more than one lenticule was used. The procedures were successful with improved BCVA in 54.5% of eyes and maintained in 40.9% of eyes, an increase in mean CCT (358.6 ± 186.7 μm preop to 440.00 ± 189.23 μm postop), restored the integrity of the globes, no graft rejection, and no corneal perforation at 6 months postoperatively. This study further supports the use of lenticules as a replacement for partial keratoplasty and can help address donor corneal shortages [46].
Clinical studies have also described the use of xenogeneic lenticules as a human cornea donor alternative, showing success using decellularized porcine lenticules for the treatment of severe keratoconus and post-LASIK ectasia. The lenticules were prepared by clearing all donor cells and cross-linking collagen fibrils via UV sterilization. The purified lenticules were then placed into mid-stromal pockets dissected in the recipient eye using femtosecond lasers. At 6 months postoperatively, all patients had improved visual acuity, increased mean central corneal thickness (389.43 ± 45.41 to 429.33 ± 63.20 μm), and increased mean corneal resistance factor (5.67 to 8.42). Since the porcine tissue does not integrate into host corneal tissue, there is a risk of ectasia progression beneath the implants. Corneal cross-linking was proposed to stabilize the cornea and prevent this complication. There is a risk of graft rejection with this procedure, but this did not occur in any patients in this study [54].
Another study aimed to create lenticules in vitro that could be used for transplantation in humans. This study used porcine corneal lenticules that were decellularized and air-dried in sheets. They were then layered between sheets of human corneal stromal cells enclosed in collagen I hydrogel. The corneal substitutes were highly transparent, easy to handle, and successfully integrated into human stromal tissue in an ex vivo ALK. This study highlights the potential uses for xenogeneic lenticules in the creation of corneal substitutes for use in ophthalmic procedures and would help address the donor cornea shortage [55].
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