Biomechanical Changes After Repeated Collagen Cross-Linking on Human Corneas Assessed In Vitro Using Scanning Acoustic Microscopy

Beshtawi, Ithar; Akhtar, Riaz; Hillarby, M. C.; O’Donnell, Clare; Zhao, Xu; Brahma, Arun; Carley, Fiona; Derby, Brian; Radhakrishnan, Hema

doi:10.1167/iovs.13-13042

Cited by 25 publications

(10 citation statements)

References 30 publications

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“…In order to test the hypothesis that C post and C consumption% were key factors to achieve effective outcome of corneal cross‐linking, we correlated these measurements with the induced stiffening effect on the anterior stroma of 10 eye bank donor tissues. After treatment, the Young's modulus of elasticity of the anterior stroma increased by 1.02 to 1.58 times in comparison with baseline measurements, which showed a fair agreement with previous studies . The increased biomechanical strengthening of the stroma was highly significantly correlated with the intrastromal concentration of riboflavin prior to UV‐A illumination of the cornea and the consumption of intrastromal riboflavin caused by UV‐A illumination of the cornea.…”

Section: Discussionsupporting

confidence: 86%

“…Confocal imaging could theoretically improve the UV‐A device's axial resolution and allow for analysis of intrastromal riboflavin at increasing depth of the cornea; on the other hand, the concentration of riboflavin has been shown to be almost constant up to 320 to 350 μm stromal depth (keratoconus corneas have in general stromal thickness thinner than 400 μm) and the effect of biomechanical strengthening has been measured to be mainly limited to the anterior 250 μm stromal depth . Therefore, increasing complexity in the system would not lead to a real advantage in the outcome measures.…”

Section: Discussionmentioning

confidence: 99%

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

Lombardo

Villari

Micali

et al. 2018

Journal of Biophotonics

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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.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

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

Lombardo

Villari

Micali

et al. 2018

Journal of Biophotonics

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“…Recently, scanning microscopy techniques have been used to evaluate the changes of the elastic properties of porcine and human corneas after riboflavin/UV-A cross-linking [ 15 – 17 ]. Dias et al [ 16 ] used micrometer-sized spherical indenters (59–74 μm diameter) and 10.4 N/m cantilever to probe the stroma at different depths.…”

Section: Discussionmentioning

confidence: 99%

“…Overall, the results from previous AFM studies have provided quantitative information on the depth-dependent profiles of the Young’s modulus, showing that the stiffening effect of corneal cross-linking is mainly limited to the anterior 220 μm stromal depth. Beshtawi et al [ 15 ] used scanning acoustic microscopy to explore the biomechanical changes induced by cross-linking in donor human corneas. The speed of sound in the anterior region between the cross-linked and control corneas was increased by a factor of 1.05, in fair accordance with this work.…”

Section: Discussionmentioning

confidence: 99%

Understanding of the Viscoelastic Response of the Human Corneal Stroma Induced by Riboflavin/UV-A Cross-Linking at the Nano Level

et al. 2015

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PurposeTo investigate the viscoelastic changes of the human cornea induced by riboflavin/UV-A cross-linking using Atomic Force Microscopy (AFM) at the nano level.MethodsSeven eye bank donor corneas were investigated, after gently removing the epithelium, using a commercial AFM in the force spectroscopy mode. Silicon cantilevers with tip radius of 10 nm and spring elastic constants between 26- and 86-N/m were used to probe the viscoelastic properties of the anterior stroma up to 3 µm indentation depth. Five specimens were tested before and after riboflavin/UV-A cross-linking; the other two specimens were chemically cross-linked using glutaraldehyde 2.5% solution and used as controls. The Young’s modulus (E) and the hysteresis (H) of the corneal stroma were quantified as a function of the application load and scan rate.ResultsThe Young’s modulus increased by a mean of 1.1-1.5 times after riboflavin/UV-A cross-linking (P<0.05). A higher increase of E, by a mean of 1.5-2.6 times, was found in chemically cross-linked specimens using glutaraldehyde 2.5% (P<0.05). The hysteresis decreased, by a mean of 0.9-1.5 times, in all specimens after riboflavin/UV-A cross-linking (P<0.05). A substantial decrease of H, ranging between 2.6 and 3.5 times with respect to baseline values, was observed in glutaraldehyde-treated corneas (P<0.05).ConclusionsThe present study provides the first evidence that riboflavin/UV-A cross-linking induces changes of the viscoelastic properties of the cornea at the scale of stromal molecular interactions.

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“…Interestingly, samples that were cross-linked two or three times failed to show an additive increase in speed of sound and stiffness when compared to samples that underwent CXL only once. 7 Several experimental differences make it hard to compare these results with our own observation. First, repetitive CXL was performed within 24 hours in an ex vivo tissue, which only allowed immediate and mid-term changes to occur after CXL, whereas in our case, 4 years passed between the two procedures, allowing for longterm changes.…”

Section: Discussionmentioning

confidence: 83%

Additive Effect of Repeated Corneal Collagen Cross-linking in Keratoconus

Hafezi¹,

Tabibian²,

Richoz³

2014

J Refract Surg

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PURPOSE: To report the long-term clinical outcome in a patient diagnosed as having bilateral progressive keratoconus who received a single corneal collagen cross-linking (CXL) treatment in the right eye and repeated CXL in the left eye. METHODS: Observational case report. Topographical changes were assessed by high-resolution Scheimpflug imaging. The right eye underwent a standard epithelium-off CXL procedure in February 2008, followed by the left eye 4 weeks later. In 2012, the left eye was treated with CXL for a second time. Irradiation was performed in all cases at a fluence of 5.4 J/cm 2 . Energy settings were 30 minutes @ 3 mW/cm 2 for the CXL procedures performed in 2008, and 10 minutes @ 9 mW/cm 2 for the second CXL procedure of the left eye that was performed in 2012. RESULTS: The right eye that underwent a single CXL procedure showed a flattening of keratometry values between 2008 and 2012, followed by stabilization. The left eye showed a similar flattening effect between 2008 and 2012, followed by another flattening effect after the second CXL procedure and accompanied by a distinct increase in corrected distance visual acuity. CONCLUSIONS: Following repeated CXL, the corneal stroma and endothelium remained inconspicuous, and postoperative haze and visibility of the stromal demarcation line was similar to what is usually observed after a single CXL procedure. Whether the additive flattening effect of the anterior surface observed in this single case goes along with an additive increase in biomechanical stiffness remains to be seen. [ J Refract Surg. 2014;30(10):716–718.]

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Biomechanical Changes After Repeated Collagen Cross-Linking on Human Corneas Assessed In Vitro Using Scanning Acoustic Microscopy

Abstract: A significant increase in speed of sound was found in all treated groups compared with the control group; however, the difference among the treated groups is not significant, suggesting no further cross-links are induced when collagen cross-linking treatment is repeated.

Cited by 25 publications

References 30 publications

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

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

Understanding of the Viscoelastic Response of the Human Corneal Stroma Induced by Riboflavin/UV-A Cross-Linking at the Nano Level

Additive Effect of Repeated Corneal Collagen Cross-linking in Keratoconus

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