Biomechanics of Ophthalmic Crosslinking

Abstract

Crosslinking involves the formation of bonds between polymer chains, such as proteins. In biological tissues, these bonds tend to stiffen the tissue, making it more resistant to mechanical degradation and deformation. In ophthalmology, the crosslinking phenomenon is being increasingly harnessed and explored as a treatment strategy for treating corneal ectasias, keratitis, degenerative myopia, and glaucoma. This review surveys the multitude of exogenous crosslinking strategies reported in the literature, both “light” (involving light energy) and “dark” (involving non-photic chemical processes), and explores their mechanisms, cytotoxicity, and stage of translational development. The spectrum of ophthalmic applications described in the literature is then discussed, with particular attention to proposed therapeutic mechanisms in the cornea and sclera. The mechanical effects of crosslinking are then discussed in the context of their proposed site and scale of action. Biomechanical characterization of the crosslinking effect is needed to more thoroughly address knowledge gaps in this area, and a review of reported methods for biomechanical characterization is presented with an attempt to assess the sensitivity of each method to crosslinking-mediated changes using data from the experimental and clinical literature. Biomechanical measurement methods differ in spatial resolution, mechanical sensitivity, suitability for detecting crosslinking subtypes, and translational readiness and are central to the effort to understand the mechanistic link between crosslinking methods and clinical outcomes of candidate therapies. Data on differences in the biomechanical effect of different crosslinking protocols and their correspondence to clinical outcomes are reviewed, and strategies for leveraging measurement advances predicting clinical outcomes of crosslinking procedures are discussed. Advancing the understanding of ophthalmic crosslinking, its biomechanical underpinnings, and its applications supports the development of next-generation crosslinking procedures that optimize therapeutic effect while reducing complications.

Repeatability of a Scheimpflug tonometer to measure biomechanical parameters before and after myopic refractive surgery

“…3,4 The efficacy of corneal crosslinking, which can be conducted to improve corneal biomechanical properties, can also be assessed through this approach. 5 As a result, such measurements are generally valued by clinicians and are gradually becoming more frequently used.…”

Glaucoma and biomechanics

“…Because scleral stiffness influences the transmission of mechanical load to the ONH, there has been interest in stiffening the sclera as a possible therapy in glaucoma [104–107,108 ▪ ]. Computational and laboratory studies suggest that stiffening the peripapillary sclera would have therapeutic benefit [66,92,109] by reinforcing the region around the soft, delicate ONH, therefore reducing the IOP-linked biomechanical insult delivered to this tissue.…”

Collagen cross-linking as monotherapy in experimentally induced corneal abscess in rabbits

“…CXL has also emerged as a new line of management for corneal infections through improved collagen resistance and bactericidal effect due to intercalation between DNA and RNA causing nucleic acid damage when exposed to UV that eventually leads to rapid elimination of the infecting microorganism and reducing inflammation [ 3 – 5 ]. Experimental evidence suggests that riboflavin and UVA photochemical cross-linking increases the corneas' resistance to collagenase, trypsin, and pepsin and interferes with the toxic enzymatic digestion, which causes the corneal melting by proteases and prevents further thinning of the cornea [ 6 , 7 ].…”