Photorefractive Intrastromal Cross-Linking

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Assigned status Update Pending
 by Severin Pouly, M.D. on October 3, 2021.


Corneal collagen cross-linking (CXL) was FDA-approved for the treatment of keratoconus in April of 2016[1]and has since become routine for stabilizing corneal ectasia.[2] Post-CXL improvement in visual acuity as a result of corneal stiffening has been reported in the literature.[3] [4] [5] To achieve more pronounced refractive changes, higher fluence of UV light was used in the CXL procedure, thus creating photorefractive intrastromal cross-linking (PiXL).[1] PiXL is a refractive procedure. Achievability of predictable refractive changes and tolerability of this procedure have been confirmed.[6]

Objectives & Candidates

PiXL is appropriate for patients with low myopia or hyperopia as a second line to conventional refractive surgeries (i.e. LASIK, PRK, intraocular lens implant), and for patients who require correction of residual refractive error or refractive regression after conventional refractive surgeries.[7] PiXL is recommended for patients with corneal topography inappropriate for conventional refractive surgeries, i.e. forme fruste keratoconus, because corneal tissue ablation is unnecessary. PiXL has also been applied to presbyopia.[8]


PiXL is a high-fluence CXL administered in a customizable pattern and intensity in order to steepen or flatten the cornea through corneal strengthening.[6] The specific application of UV-A for each patient takes into account the refractive error and corneal topography.[7] The major components of the therapy are riboflavin injection and UV-A irradiation, and the procedure is followed by a course of topical antibiotics and corticosteroids. Details of the procedure and patient positioning are depicted in the figures below (Figures 1 and 2).

Figure 1: PiXL Procedure.[9]

Figure 2: PiXL Patient Positioning. [10]

Types of PiXL

Epithelium-On or Transepithelial: No debridement of corneal epithelium

  • Advantages:
    • Improved post-procedure comfort
    • Lower risk of corneal infection
  • Disadvantages:
    • Less stable result in hyperopic patients

Epithelium-Off: Debridement of corneal epithelium

  • Advantages:
    • More stable result in hyperopic patients
  • Disadvantages:
    • Higher risk of the following:
    • Corneal infection
    • Sub-epithelial haze
    • Sterile corneal infiltrates
    • Corneal scarring
    • Endothelial damage
    • Herpetic activation


None [11]


PiXL offers the potential for immediate improvement in visual acuity without pain or discomfort.[6] The adverse effect profile includes moderate to severe dry eyes.[7] No significant changes in endothelial cell counts or corneal clarity have been reported.[6] PiXL has shown sustained visual acuity results up to 12 months of follow-up.[7] In one study of myopic patients an average of 2.3D of visual acuity improvement occurred in the first post-procedural (epithelium-on) week, which regressed to 1.44D at 1 month and subsequently remained stable at the 6 month follow-up.[6] This is consistent with results from other studies, which cite a reduction of myopic refractive error with epithelium-on approach by -1.00 to -1.35D3 and 0.72+/-0.43D.[7] A study of PiXL in hyperopia has achieved a +0.85D hyperopic correction with an epithelium-on method.[2]


  1. 1.0 1.1 Editor, M. S. (2016, July 05). At Last, Cross-Linking Comes to U.S. Surgeons. Retrieved September 30, 2017, from
  2. 2.0 2.1 Kanellopoulous AJ, Asimellis G. Hyperopic correction: Clinical validation with epithelium-on and epithelium-off protocols, using variable fluence and topographically customized collagen Cross-linking. Clinical Ophthalmology. 2014;8:2425–2433.
  3. Ghanem RC, Santhiago MR, Berti T, Netto MV, Ghanem VC. Topographic, corneal wavefront, and refractive outcomes 2 years after collagen crosslinking for progressive keratoconus. Cornea. 2014;33(1):43–48.
  4. Arora R, Jain P, Goyal JL, Gupta D. Comparative Analysis of Refractive and Topographic Changes in Early and Advanced Keratoconic Eyes Undergoing Corneal Collagen Crosslinking. Cornea. 2013 Aug 22; Epub.
  5. Raiskup-Wolf F, Hoyer A, Spoerl E, Pillunat LE. Collagen crosslinking with riboflavin and ultraviolet-A light in keratoconus: long-term results. J Cataract Refract Surg. 2008;34(5):796–801.
  6. 6.0 6.1 6.2 6.3 6.4 Kanellopoulos, A. J. (2014). Novel myopic refractive correction with transepithelial very high-fluence collagen cross-linking applied in a customized pattern: early clinical results of a feasibility study. Clinical Ophthalmology (Auckland, N.Z.), 8, 697–702.
  7. 7.0 7.1 7.2 7.3 7.4 Lim, W. K., Soh, Z. D., Choi, H. K. Y., & Theng, J. T. S. (2017). Epithelium-on photorefractive intrastromal cross-linking (PiXL) for reduction of low myopia. Clinical Ophthalmology (Auckland, N.Z.), 11, 1205–1211.
  8. Kanellopoulos, A. J., & Asimellis, G. (2015). Presbyopic PiXL cross-linking. Current Ophthalmology Reports, 3(1), 1-8.
  9. Krader, C. G. (2016). Crosslinking showing potential for refractive correction.
  10. Say Hello To PiXL™ — The New Non-Invasive Vision Improvement Procedure. (n.d.). Retrieved September 30, 2017, from
  11. Healthegy Follow. (2016, May 13). OPHTHALMOLOGY INNOVATION SHOWCASE - Avedro. Retrieved September 30, 2017, from
  1. Nawaz S, Gupta S, Gogia V, Sasikala NK, Panda A. Trans-epithelial versus Conventional corneal collagen cross-linking: a randomized trial in keratoconus. Oman J Ophthalmol. 2015;8(1):9–13.
  2. Matthias Elling, PiXL for Myopia: Clinical results of a controlled prospective clinical trial. ESCRS; Athens: 2016.
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