Non‐invasive optical method for real‐time assessment of intracorneal riboflavin concentration and efficacy of corneal cross‐linking

Abstract

Keratoconus is the primary cause of corneal transplantation in young adults worldwide. Riboflavin/UV-A corneal cross-linking may effectively halt the progression of keratoconus if an adequate amount of riboflavin enriches the corneal stroma and is photo-oxidated by UV-A light for generating additional cross-linking bonds between stromal proteins and strengthening the biomechanics of the weakened cornea. Here we reported an UV-A theranostic prototype device for performing corneal cross-linking with the ability to assess corneal intrastromal concentration of riboflavin and to estimate treatment efficacy in real time. Seventeen human donor corneas were treated according to the conventional riboflavin/UV-A corneal cross-linking protocol. Ten of these tissues were probed with atomic force microscopy in order to correlate the intrastromal riboflavin concentration recorded during treatment with the increase in elastic modulus of the anterior corneal stroma. The intrastromal riboflavin concentration and its consumption during UV-A irradiation of the cornea were highly significantly correlated (R = 0.79; P = .03) with the treatment-induced stromal stiffening effect. The present study showed an ophthalmic device that provided an innovative, non-invasive, real-time monitoring solution for estimating corneal cross-linking treatment efficacy on a personalized basis.

Influencing Factors Relating the Demarcation Line Depth and Efficacy of Corneal Crosslinking

“…Kling et al) that oxygen-mediated type-II plays the critical role of CXL, Kamaev et al 8 kinetic model showed that CXL is predominated by type-I, while oxygen (or type-II) only plays a limited and transient role. Lin's 3-pathway model 9 showed mathematical details of the role of oxygen, supporting the claim of Kamaev et al 8 In addition, a recent clinical study of Lombardo et al 10 showed a simple-exponential kinetic of RF concentration also implied that, in ambient environment (with approximately 21% partial pressure of oxygen), nonoxygen-mediated type-I mechanism is predominant. 6.…”

The Role of Riboflavin Concentration and Oxygen in the Efficacy and Depth of Corneal Crosslinking

“…In contrast to the conventional belief that oxygen-mediated type-II plays the critical role of CXL, the kinetic model of Kamaev et al 6 showed that CXL is predominated by type-I, whereas oxygen (or type-II) plays only a limited and transient role. Lin's 3-pathway model 5,7 showed mathematical details of the role of oxygen, supporting the claim of Kamaev et al 6 Moreover, a recent clinical study of Lombardo et al 8 showed a simpleexponential temporal profile of Rf concentration that implied that, in ambient environment, non-oxygen-mediated type-I mechanism is predominant.…”

“…In contrast to type-II (S2), in which oxygen plays a transient but critical role, type-I (S1) does not require oxygen and it is the predominant pathway of CXL efficacy. [4][5][6][7][8] At steady-state (with btX>>1), S1 follows a nonlinear scaling law 4 that S1 is proportional to (FC 0 /I 0 ) 0.5 exp(0.5Az), or S1a[C 0 ] 0.5 (for z ¼ 0) and stronger dependence of S1a[C 0 exp(Az)] 0.5 (for z > 0), because A is also proportional to C 0 . For example, on corneal surface (or z ¼ 0), when C 0 is doubled (from 0.1% to 0.2%), S1 increases by a factor of 1.43.…”

Advances in the diagnosis and treatment of keratoconus

“…Techniques that were used in a laboratory environment included spectrophotometry, high-performance liquid chromatography, confocal fluorescence microscopy, and two-photon optical microscopy, all of which involve some degree of invasiveness and are not readily translatable into a clinical setting. [55][56][57][58] To fill in this lacuna, Lombardo and colleagues 59 have recently developed a noninvasive optical method for real-time assessment of intrastromal riboflavin concentration which has the potential to be useful in delivering personalized C-CXL treatments.…”