Corneal remodelling and topography following biological inlay implantation with combined crosslinking in a rabbit model

Abstract

Implantation of biological corneal inlays, derived from small incision lenticule extraction, may be a feasible method for surgical management of refractive and corneal diseases. However, the refractive outcome is dependent on stromal remodelling of both the inlay and recipient stroma. This study aimed to investigate the refractive changes and tissue responses following implantation of 2.5-mm biological inlays with or without corneal collagen crosslinking (CXL) in a rabbit model. Prior to implantation, rotational rheometry demonstrated an almost two-fold increase in corneal stiffness after CXL. After implantation, haze gradually subsided in the CXL-treated inlays (p = 0.001), whereas the untreated inlays preserved their clarity (p = 0.75). In-vivo confocal microscopy revealed reduced keratocyte cell count at the interface of the CXL inlays at week 8. Following initial steepening, regression was observed in anterior mean curvature from week 1 to 12, being most prominent for the non-CXL subgroups (non-CXL: −12.3 ± 2.6D vs CXL: −2.3 ± 4.4D at 90 μm depth, p = 0.03; non-CXL: −12.4 ± 8.0D vs CXL: −5.0 ± 4.0D at 120 μm depth, p = 0.22). Immunohistochemical analysis revealed comparable tissue responses in CXL and untreated subgroups. Our findings suggest that CXL of biological inlays may reduce the time before refractive stabilization, but longer postoperative steroid treatment is necessary in order to reduce postoperative haze.

Femtosecond laser-assisted stromal keratophakia for keratoconus: A systemic review and meta-analysis

“…Second, the question remains whether CXL is required and whether the CXL should be performed in the lenticule only or the entire cornea. In our study using a rabbit model, we showed that CXL of lenticules limited the flexibility of the lenticular stroma to natural tissue remodeling of the recipient corneas, which in turn, stabilized the refractive status of the corneas earlier and reduced the refractive regression over time [32]. This suggested that CXL is beneficial for the efficacy of the femtosecond laser-assisted keratophakia to prevent loss of effect from stromal remodeling and also endogenous tissue proteases.…”

“…However, the risk of persistent haze development induced by CXL in patients, typically with advanced keratoconus, has to be considered if one decides to cross-link the entire cornea [52]. Our model was one of presbyopic treatment [32], but when used in a keratoconic patient, the recipient cornea is also biomechanically weaker, hence, it would be advantageous to cross-link the complete cornea with the lenticule implanted. Third, the implantation depth plays a role in determining the refractive effects of the lenticule implantation.…”

“…In addition to the simplicity, the potential appeal of keratophakia procedure lies on its potentially better immunological advantage over DALK because the implanted lenticule is away from the limbal lymphatic vessels and is protected from the cytokines and immune cells in the tear fluid on the ocular surface and aqueous humor in the anterior chamber [29]. In addition, the tissue addition can structurally reinforce thin corneas in advanced keratoconus and permit correction of corneal refraction directly (without further invasive refractive surgery) or indirectly via post-keratophakia photorefractive keratectomy (PRK) or laser-assisted in situ keratomileusis (LASIK) [30][31][32]. In the current review, we discussed the clinical outcomes of the femtosecond laser-assisted stromal keratophakia in the treatment of keratoconus.…”

Recent developments in regenerative ophthalmology

“…Similarly, Yin et al studied a method for reconstruction and thickening of lenticules to meet clinical requirements (Yin et al, 2016). Damgaard et al suggested that prior corneal crosslinking (CXL) induction of SMILE-derived lenticules may reduce time to refractive stabilization, but it also requires longer postoperative steroid treatment (Damgaard et al, 2019). However, additional research is needed to confirm if the additional CXL step reduces the incidence of iatrogenic keratectasia (Lau et al, 2019).…”

Noninvasive detection of nanoscale structural changes in cornea associated with cross‐linking treatment

“…Another option for detecting ultrastructure in the cornea is histology, which requires the anatomy of the tissue and therefore only applicable for ex vivo tissue. Some other methodologies including X‐ray microscopy and confocal microscopy also have various limitations, such as harmfulness from radiation damage, small imaging area or shallow imaging depth, causing difficulties in clinical eye diagnostics.…”