Corneal Cross-Linking Technique

Updated: Jul 07, 2017
  • Author: Manolette R Roque, MD, MBA, FPAO; more...
  • Print

Approach Considerations

The procedure is usually done in a clean room, such as a refractive surgery suite. It may also be performed in a sterile room, like an operating theater. Preoperative medications are given in the peri-operative room. Facial and eyelash scrubs for antisepsis using an aseptic technique is completed. The patient is assisted into the operating suite and lies down supine on an operating table. Topical ophthalmic anesthesia, usually proparacaine, is given to the patient. Sterile drapes are placed to keep the eyelashes away from the operative field. A self-retaining bladed eyelid retractor is applied to keep the eyelid open during the entire procedure. BSS is used to wash debris from the conjunctiva. Ultrasonic pachymetry is performed on specific areas of the cornea.

Different techniques of collagen cross linking may be performed.

  • Standard Dresden Protocol (Epi-Off)
  • Transepithelial cross-linking
  • Pocket cross-linking
  • Contact Lens-assisted cross-linking
  • Accelerated cross-linking
  • Athens Protocol (PRK + CXL)
  • TG-PRK + CXL
  • CXL + ICRS
  • Lasik Xtra
  • CXL + mini assymetric radial keratotomy
  • Photorefractive Instrastromal corneal cross-linking

There are numerous different kinds of Riboflavin which are available for use:

  • Riboflavin with Dextran solution is applied to the cornea for 30 minutes.
  • Riboflavin with hydroxypropyl methylcellulose (HPMC) solution has better corneal penetration is applied to the cornea for 10 minutes.

At the end of the cross-linking procedure, a bandage contact lens is applied and removed after complete epithelialization. A topical treatment with artificial tears, steroids, and antibiotics is prescribed.



Standard cross-linking (CXL)

The standard protocol of corneal cross-linking is with epithelium removal. The corneal epithelial layer is removed to increase the penetration of riboflavin into the corneal stroma. Corneal collagen cross-linking involves a 30 minute application of riboflavin solution to the eye that is activated by illumination with UV-A light for approximately 30 or less minutes. The riboflavin causes new bonds to form across adjacent collagen strands in the stromal layer of the cornea, which recovers and preserves some of the cornea's mechanical strength. 

Dresden Protocol

Total treatment time = 60 minutes

Eight to 9 mm central epithelial debridement (Epi-Off technique) with a blunt metal spatula or a soft brush. Photosensitization with an isotonic 0.1% Riboflavin (vitamin B2) mixed with 20% dextran solution, usually for 30 minutes (pre-soak) before irradiation and then every 2 to 5 minutes during irradiation to maintain saturation of the cornea.

Hypotonic riboflavin is used in patients with thinnest pachymetry below 400 μm, with the cutoff level being 350 μm. Ultrasound pachymetry is repeatedly performed during the procedure, and hypotonic riboflavin is administered every 10 seconds during two minutes whenever pachymetry drops below 400 μm. This minimal corneal thickness is maintained throughout the procedure to avoid harmful endothelial side effects that would occur if oxygen radicals were created too deep. Uniform 365nm ultraviolet A (UVA) irradiation at 3 mW/cm2 for 30 minutes, accounting for a surface dose of 5.4 J/cm2. The light causes the riboflavin to fluoresce, leading to the formation of bonds between collagen molecules (collagen crosslinking). The masking of the limbus and/or the treatment zone diameter is carefully selected to protect the limbal stem cells from the toxic effects of oxygen radicals generated by the procedure.



Transepithelial cross-linking (TCXL)

Transepithelial cross-linking technique is also known as epithelium-on (Epi-On) cross-linking technique. The epithelium is left intact in this technique, and a special formalution of riboflavin, supplemented with epithelial penetration enhancers trishydroxymethyl aminomethane and sodium EDTA, is used to allow adequate corneal stroma penetration.


Pocket cross-linking (PCXL)

This is usually performed in conjunction with intrastromal corneal ring segment insertion procedures. The instrastromal corneal pocket is directly injected with riboflavin.


Contact lens-assisted collagen cross-linking (CACXL)

This is performed for patients with corneal stromal thickness between 350 µm to 400 µm after epithelial removal. In this method a pre-corneal riboflavin film, a riboflavin-soaked UV barrier-free soft contact lens (90 microns thick) of negligible power and a pre-contact lens riboflavin film are used to decrease UV irradiance to safe levels at the level of the endothelium.


Accelerated cross-linking

Total treatment time = 14 minutes or less

Accelerated cross-linking: a higher irradiance was delivered to reduce exposure time (i.e., 9 mW/cm2 for 10 minutes or 30 mW/cm2 for 4 minutes instead of 3 mW/cm2 for 30 minutes).

Eight to 9 mm central epithelial debridement (Epi-Off technique) with a blunt metal spatula or a soft brush. Photosensitization with 0.1% Riboflavin (vitamin B2) mixed with saline and HPMC solution, usually for 10 minutes (pre-soak) before irradiation and then every 2 to 5 minutes during irradiation to maintain saturation of the cornea.

  1. Riboflavin (vitamin B2) drops are applied to the cornea (10 minute riboflavin pre-soak)
  2. The cornea is exposed to ultra violet light (4 minute irradiation with 30mW/cm2365nm UVA)
  3. The light causes the riboflavin to fluoresce, leading to the formation of bonds between collagen molecules or collagen cross-linking2

Combined with other refractive eye procedures

Corneal cross-linking may be combined with:

See the list below:

  • photorefractive keratectomy (PRK) | Athens Protocol
  • Topography-guided PRK
  • LASIK | Lasik Xtra
  • intrastromal corneal ring segments
  • mini assymetric radial keratotomy

Athens Protocol

The management of keratoconus and post-LASIK ectasia by means of combined, same-day, topography-guided partial PRK and collagen cross-linking. The steps are listed below:

See the list below:

  • 6.5 mm phototherapeutic keratectomy to remove 50 μm of epithelium
  • topography-guided partial PRK
  • mitomycin C (0.025 for 20 seconds)
  • CXL procedure

Lasik Xtra

Corneal cross-linking performed in conjunction with LASIK, enhances corneal biomechanical integrity. This combined procedure neither lengthens the operative time of the LASIK procedure, nor does it increase patient discomfort. After the refractive correction has been made in a standard LASIK procedure, 0.22% Isotonic Riboflavin with saline is applied to the exposed stromal bed and the flap is replaced. UVA illumination at 45 mW/cm2 is then applied through the intact epithelium for little over a minute.


Photorefractive Intrastromal corneal cross-linking (PiXL)

Avedro's Photorefractive Intrastromal Cross-Linking (PixL™) procedure provides non-laser low refractive correction with Accelerated Cross-Linking alone, while eliminating the risk of weakening the corneal structure and integrity. PiXL both strengthens the cornea and restores its biomechanical stability, using precise, patterned topography-guided Accelerated Cross-Linking with programmable, customizable illumination patterns.

Low myopic patients, as well as post-cataract patients with low residual refractive errors, may benefit from this procedure.