Theranostic‐guided corneal cross‐linking: Preclinical evidence on a new treatment paradigm for keratoconus

Abstract

Theranostics is an emerging therapeutic paradigm of personalized medicine; the term refers to the simultaneous integration of therapy and diagnostics. In this work, theranostic‐guided corneal cross‐linking was performed on 10 human sclero‐corneal tissues. The samples were soaked with 0.22% riboflavin formulation and underwent 9 minutes UV‐A irradiance at 10 mW/cm2 using theranostic device, which provided both a measure of corneal riboflavin concentration and a theranostic score estimating treatment efficacy in real time. A three‐element viscoelastic model was developed to fit the deformation response of the cornea to air‐puff excitation of dynamic tonometry and to calculate the mean corneal stiffness parameter before and after treatment. Significant correlation was found between the theranostic score and the increase in mean corneal stiffness (R = 0.80; P < .001). Accuracy and precision of the theranostic score in predicting the induced corneal tissue stiffening were both 90%. The riboflavin concentration prior to starting the UV‐A photo‐therapy phase was the most important variable to allow corneal cross‐linking to be effective. Theranostic UV‐A light mediated imaging and therapy enables the operator to adopt a precise approach for achieving highly predictable biomechanical strengthening on individual corneas.

Predicting corneal cross-linking treatment efficacy with real-time assessment of corneal riboflavin concentration

“…The results from the epi-off protocol were in strict agreement with previous work, thus confirming the theranostic-guided CXL procedure reproducibility. 17 In addition, they were in agreement with previous reports showing, in the 3 to 10 mW/cm 2 range of power densities for 5.4 J/cm 2 energy dose, that UV-A light-mediated photodegradation of riboflavin in the corneal stroma is only energy-dependent in accordance with the Bunsen-Roscoe law and that the transepithelial irradiation with 10 mW/cm 2 for 9 minutes is effective in photodegrading intrastromal riboflavin as the conventional direct stromal irradiation by 3 mW/cm 2 for 30 minutes. 11,[14][15][16][29][30][31] This evidence could not be extrapolated for UV-A power density or energy dose higher than 10 mW/cm 2 or 5.4 J/cm 2 , respectively.…”

“…34 The k c parameter represents the resistance to deformation under load and is a strain-dependent value that changes with strain (or corneal deformation). 17 It has been previously validated through analysis of several corneal conditions, including response to CXL treatment. 17,24,25,28,39,40 The authors have shown that during the air-puff event, due to the high loading magnitude (greater than 45 mm Hg) and fast rate (shorter than 20 milliseconds), the cornea is not able to undergo any viscous deformation; for this reason, a pure elastic material model, as performed in this study, could be selected for biomechanical modeling of cornea in dynamic tonometry tests because neglecting a corneal viscoelastic behavior has been shown not to significantly affect the results of the study.…”

“…The amount of riboflavin into the corneal stroma before UV-A light irradiation has been confirmed to be the main variable leading to effective CXL. [11][12][13][14][15][16][17][18]30,31 Providing personalized patient care through the noninvasive measurement of corneal riboflavin during treatment could be advantageous to minimize the occurrence of crosslinking failure. 6,9 The theranostic-guided CXL approach is currently object of an ongoing randomized clinical trial (NCT05457647), whose aim is to validate the predictive ability of the theranostic score for treating patients with progressive keratoconus with either epi-off or epi-on treatment protocols.…”

“…Full description of the medical device operation sequence was provided in previous reports (Figure 1). 15–18…”

“…Full description of the medical device operation sequence was provided in previous reports (Figure 1). [15][16][17][18] The sclerocorneal tissues were randomly stratified to receive either CXL treatment with the cornea de-epithelialized (epi-off, n = 8) or with the epithelium intact (epi-on, n = 12). Baseline data for each subgroup are summarized in Table 1.…”