The prevalence of myopia has increased worldwide over the last 50 years. Its incidence in the United States and Europe is now almost twice that 50 years ago, and it is even more prevalent in East Asia. Spectacles and contact lenses remain the most common means of vision correction, but the permanent correction of refractive errors, by refractive surgery, has emerged as an attractive alternative. However, such surgery is an invasive procedure that may compromise corneal structure, and post-surgical complications have been reported. We propose a novel, non-invasive approach to permanent vision correction based on a different mode of laser–cornea interaction. Our approach induces the formation of a low-density plasma that produces reactive oxygen species, which react with the surrounding proteins, forming crosslinks and triggering spatially resolved changes in mechanical properties. We show that the proposed method changes the refractive power of the eye, and confirm its safety and stability. Laser-driven crosslinking of molecules at the cornea offers a non-invasive alternative to surgical correction of the refractive power of the eye.

Femtosecond laser crosslinking of the cornea for non-invasive vision correction

Transparent ocular tissues, such as the cornea and crystalline lens, can be ablated or dissected using short-pulse lasers. In refractive and cataract surgeries, the cornea, lens, and lens capsule can be cut by producing dielectric breakdown in the focus of a near-infrared (IR) femtosecond laser, which results in explosive vaporization of the interstitial water, causing mechanical rupture of the surrounding tissue. Here, we compare the texture of edges of lens capsule cut by femtosecond lasers with IR and ultraviolet (UV) wavelengths and explore differences in interactions of these lasers with biological molecules. Scanning electron microscopy indicates that a 400-nm laser is capable of producing very smooth cut edges compared to 800 or 1030 nm at a similar focusing angle. Using gel electrophoresis and liquid chromatography/mass spectrometry, we observe laser-induced nonlinear breakdown of proteins and polypeptides by 400-nm femtosecond pulses above and below the dielectric breakdown threshold. On the other hand, 800-nm femtosecond lasers do not produce significant dissociation even above the threshold of dielectric breakdown. However, despite this additional interaction of UV femtosecond laser with proteins, we determine that efficient cutting requires plasma-mediated bubble formation and that remarkably smooth edges are the result of reduced thresholds and smaller focal volume.

https://www.spiedigitallibrary.org/journals/journal-of-biomedical-optics/volume-20/issue-12/125004/Finesse-of-transparent-tissue-cutting-by-ultrafast-lasers-at-various/10.1117/1.JBO.20.12.125004.pdf

Finesse of transparent tissue cutting by ultrafast lasers at various wavelengths.

A new paradigm for strengthening of corneal tissue as well as permanent correction of refractive errors has been proposed. Ultrafast laser irradiation is confined to the levels below optical breakdown such that tissue damage is avoided while creating an ionization field responsible for subsequent photochemical modification of the stroma. The concept was assed using newly developed platform for precise application of a near-IR femtosecond laser irradiation to the cornea in in-vitro experiments. Targeted irradiation with tightly focused ultrafast laser pulses allows spatially resolved crosslinking in the interior of the porcine cornea in the absence of photosensitizers. The formation of intra- or interstromal covalent bonds in collagen matrix locally increases lamellar density. Due to high resolution, treatment is spatially resolved and therefore can be tailored to either enhance structure of corneal stroma or adjust corneal curvature towards correcting refractive errors. As the induced modification is primarily driven by nonlinear absorption, the treatment is essentially wavelength independent, and as such potentially less harmful than current method of choice, joint application of UVA light irradiation in conjunction with riboflavin. Potential applicability of a near-IR femtosecond laser for biomechanical stabilization of cornea and non-invasive refractive eye corrections is discussed.

A new paradigm for use of ultrafast lasers in ophthalmology for enhancement of corneal mechanical properties and permanent correction of refractive errors

The presently disclosed subject matter provides techniques for inducing collagen cross-linking in human tissue, such as cartilage or cornea, without using a photosensitizer (e.g., riboflavin), by inducing ionization of the water contained in the tissue to produce free radicals that induce chemical cross-linking in the human tissue. In an embodiment, a femtosecond laser operates at sufficiently low laser pulse energy to avoid optical breakdown of tissue. In an embodiment, the femtosecond laser operates in the infrared frequency range.

Laser induced collagen crosslinking in tissue

Myopia and keratoconus have become common corneal diseases that threaten the quality of human vision, and keratoconus is one of the most common indications for corneal transplantation worldwide. Collagen crosslinking (CXL) using riboflavin and ultraviolet A (UVA) light is an effective approach for treating ophthalmic disorders and has been shown clinically not only to arrest further progression of keratoconus but also to improve refractive power for cornea. However, CXL surgery irradiated by UVA has various potential risks such as surface damage and endothelial cell damage. Here, near‐infrared femtosecond laser‐based two‐photon CXL was first applied to ex vivo human corneal stroma, operating at low photon energy with high precision and stability. After two‐photon CXL, the corneal stiffness can be enhanced by 300% without significantly reducing corneal transparency. These findings illustrate the optimized direction that depositing high pulses energy in corneal focal volume (not exceeding damage threshold), and pave the way to 3D CXL of in vivo human cornea with higher safety, precision, and efficacy.

Two‐photon collagen crosslinking in ex vivo human corneal lenticules induced by near‐infrared femtosecond laser

Collagen cross-linking in cornea has the capability of enhancing its mechanical properties and thereby providing an alternative treatment for eye diseases such as keratoconus. Currently, riboflavin assisted UVA light irradiation is a method of choice for cross-link induction in eyes. However, ultrafast pulsed laser interactions may be a powerful alternative enabling in-depth treatment while simultaneously diminishing harmful side effects such as, keratocyte apoptosis. In this study, femtosecond laser is utilized for treatment of bovine cornea slices. It is hypothesized that nonlinear absorption of femtosecond laser pulses plays a major role in the maturation of immature cross-links and the promotion of their growth. Targeted irradiation with tightly focused laser pulses allows for the absence of a photosensitizing agent. Inflation test was conducted on half treated porcine cornea to identify the changes of mechanical properties due to laser treatment. Raman spectroscopy was utilized to study subtle changes in the chemical composition of treated cornea. The effects of treatment are analyzed by observing shifts in Amide I and Amide III bands, which suggest deformation of the collagen structure in cornea due to presence of newly formed cross-links.

Femtosecond laser collagen cross-linking without traditional photosensitizers

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Femtosecond laser collagen cross-linking without traditional photosensitizers