David Muller

Photochemical Kinetics of Corneal Cross-Linking with Riboflavin

PURPOSEnTo model the photochemical kinetics of corneal cross-linking with riboflavin (Rf) and confirm the model through measured oxygen concentration experiments under varying energy input conditions by UV-A irradiance and temperature modulation in ex vivo porcine cornea.nnnMETHODSnA theoretical model was developed to describe the corneal cross-linking photochemical kinetics of Rf. After instillation with drops of Rf solution in distilled water, de-epithelialized porcine corneas were exposed to 365-nm ultraviolet light (UV-A) under varying irradiance and temperature. Oxygen concentration in the cornea at a known depth was monitored during UV-A illumination with a dissolved oxygen fiberoptic microsensor. Data from the oxygen experiments were used to confirm the model.nnnRESULTSnOn the basis of the known chemical reactions and diffusion rates of Rf and oxygen into the cornea, the authors developed a theoretical model consistent with corneal oxygen consumption experimental results during UV-A irradiation under different conditions. Oxygen concentration in the cornea is modulated by UV-A irradiance and temperature and quickly decreased at the beginning of UV-A exposure. The time-dependence of both Type-I and Type-II photochemical mechanisms in corneal cross-linking with Rf are discussed.nnnCONCLUSIONSnUsing a chemical kinetics modeling approach, the authors developed a simple model that is in agreement with their experimental results on oxygen consumption in the cornea during corneal cross-linking with Rf. It is suggested that the main photochemical kinetics mechanism is the direct interaction between Rf triplets and reactive groups of corneal proteins, which leads to the cross-linking of the proteins mainly through radical reactions.

Advanced corneal cross-linking system with fluorescence dosimetry.

Purpose. This paper describes an advanced system that combines corneal cross-linking with riboflavin with fluorescence dosimetry, the ability to measure riboflavin diffusion within the cornea both before and during UVA treatment. Methods and Results. A corneal cross-linking system utilizing a digital micromirror device (DMD) was assembled and used to measure diffusion coefficients of 0.1% riboflavin in 20% dextran in porcine eyes. A value of (3.3 ± 0.2) × 10−7u2009cm2/s was obtained for the stroma. Diffusion coefficients for the transepithelial formulation of 0.1% riboflavin in 0.44% saline and 0.02% BAK were also measured to be 4.7 ± 0.3 × 10−8u2009cm2/s for epithelium only and (4.6 ± 0.4) × 10−7u2009cm2/s for stroma only. Riboflavin consumption during a UVA treatment was also demonstrated. Conclusion. A new advanced corneal cross-linking system with fluorescence dosimetry of riboflavin has been demonstrated. It is hoped that this method may play a significant role in determining the underlying mechanisms of corneal cross-linking and assist with the development of additional riboflavin formulations. Moreover, dosimetry may prove valuable in providing a method to account for the biological differences between individuals, potentially informing cornea-specific UVA treatment doses in real time.

Photorefractive keratectomy (PRK) at 193 nm using an erodible mask: new developments and clinical progress

This paper reports on our progress using an erodible mask to perform photorefractive keratectomy (PRK) for the correction of myopic astigmatism. We describe modifications to the mask, the mask eye cup and the surgical microscope aimed at simplifying the procedure and improving the ergonomics of the hardware. We report the clinical results of the post-op exam for 20 patients who have undergone PRK for myopic astigmatism under a Phase IIA study. The results compare favorably with an earlier Phase IIA study for performing PRK with a computer-controlled iris. Most important, the clinical data show the absence of any significant corneal haze and no significant decrease in spectacle corrected visual acuity. Although more long term follow-up is needed, the preliminary results support the safety and effectiveness of using an erodible mask to perform PRK for myopic astigmatism.

Current Concepts and Future Developments of Corneal Cross-Linking

The introduction of corneal cross-linking (CXL) has changed the landscape of treatment and management of keratoconus and ectasia after refractive surgery. Previously, treatment options provided only temporary visual rehabilitation without limiting disease progression. Keratoconus and ectasia resulted in significant vision-related reduction in quality of life and a substantial lifetime economic burden, with up to 20% of keratoconus cases resulting in eventual corneal transplantation [1]. CXL was introduced as the first therapeutic option for keratoconus aimed at stiffening the cornea in order to treat the underlying stromal instability. From the time that the first reports of the clinical application of cross-linking in the cornea were published in 2003 [2], CXL has rapidly been adopted as a standard therapy for treatment of progressive keratoconus in much of the world [3–5]. n nThe potential for early intervention with corneal cross-linking before visual function has been compromised has resulted in a shift in the way we think about corneal biomechanics and has reawakened interest in the early diagnosis of ectasia. In this issue, J. Steinberg et al. report two new parameters to detect biomechanical changes in the keratoconic cornea after CXL using in vivo corneal visualization Scheimpflug technology. Research in the area of corneal biomechanics has the potential to enable earlier diagnosis of patients in need of CXL and better analysis of the effects of the procedure. n nWhile many questions remain unanswered, the understanding of the photochemical mechanisms that result in the formation of cross-links in the cornea has grown exponentially in the last decade. Improved scientific understanding of the mechanisms of CXL has driven clinical research aimed at optimizing CXL for better efficiency and efficacy [6]. In this issue, A. C. da Paz et al. present a critical review of known and as yet undetermined effects of CXL on corneal structure, biomechanics, and functional aspects. J. Antoun et al. examine patient characteristics that contribute to cross-linking failure to stabilize keratometry and examine the effect of repeat treatments on eyes that have continued to progress after primary CXL. n nThe remaining contributions to the special issue explore modifications to the conventional protocol that incorporate new technology, such as transepithelial riboflavin formulations designed to improve patient comfort (S. Taneri et al.) and higher irradiance and pulsed UVA delivery aimed at improving procedure speed and photon efficiency (C. Mazzotta et al.). CXL combination procedures targeted at maximizing visual outcomes through the addition of simultaneous intracorneal ring implantation (P. Studeny et al.) or subsequent phakic toric implantable collamer lens insertion (R. Antonios et al.) are also discussed. n nTogether, the papers in this special issue describe the next generation of corneal cross-linking. The contributors explore the potential to maximize CXL efficacy, provide equivalent or greater treatment effect in shorter total treatment times, reduce patient discomfort and speed visual recovery, and offer both stabilization and functional visual improvement through CXL combination procedures. n n nSuphi Taneri n nElias Jarade n nJohn A. Kanellopoulos n nDavid Muller