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Clinical implications of corneal hyperfluorescence


Otolaryngologists (ENTs) have it easy. They can instruct their patients not to stick anything in their ears that is smaller than their elbows, and not only is it sound medical advice, but it has a fairly high rate of compliance. Eyecare professionals (ECPs) who fit contact lenses, on the other hand, have a more difficult hill to climb because we purposely put materials in our patients’ eyes, an impossible feat without biocompatible products.

Otolaryngologists (ENTs) have it easy. They can instruct their patients not to stick anything in their ears that is smaller than their elbows, and not only is it sound medical advice, but it has a fairly high rate of compliance. Eyecare professionals (ECPs) who fit contact lenses, on the other hand, have a more difficult hill to climb because we purposely put materials in our patients’ eyes, an impossible feat without biocompatible products.

What is biocompatibility?

Biocompatibility is the degree to which a synthetic material affects the human body.1,2 “Degree” is an important qualifier because a material can have an impact on its intended environment (i.e., reasonable risk of adverse effects [both local and in the body as a whole]) and still have a level of biocompatibility.2 Synthetic materials are used to improve or restore function lost as a result of disease, tissue damage, or defective tissue.3 Contact lenses and accommodative lenses are 2 examples of synthetic materials that work with the eye to help restore or improve visual acuity. In eye care, the goal is for a product to have a tolerable impact on the eye while maintaining an effective result.

Evaluating biocompatibility

There is no single test for biocompatibility; a series of tests are required. Regulatory agencies such as the International Standards Organization (ISO) and the United States Food and Drug Administration (FDA) have established test protocols and minimum requirements that are specific to the duration and type of exposure (internal vs. external) the material will have with the body.4 ISO 10933 is one of the most widely used guidelines for evaluating biocompatibility. This protocol includes an extensive battery of tests for cytotoxicity, genotoxicity, sensitization, irritation, and systemic effects.3,4 Once extensive in vitro and in vivo trials are completed, clinical trials to test the efficacy and safety of these products are conducted on humans.4 In vitro assays may look at a number of indicators of biocompatibility, including:

• Overall cell health

• Membrane viability

• Apoptosis

• Barrier function,

• Tight junction integrity

• Electrical resistance5

Standard protocols such as ISO 10933 measure biocompatibility at the cellular and tissue levels and in the body as a whole,6 take into consideration individual materials of a product as well as the end product, and review the procedures involved in production (e.g., manufacturing, packaging, storage).7 The levels of clinical markers of cell injury and inflammation that develop, such as interleukin (IL)-1 and IL-6, and the presence of non-resident immune cells such as macrophages, mast cells, and neutrophils, help determine the biocompatibility level of a product.6,8,9 The higher the number of cell injury and inflammatory markers that are produced, the lower the level of biocompatibility.10,11










Biocompatibility and contact lens wear

There are several reasons why both contact lenses and solutions require a certain level of biocompatibility. The primary reason is that these materials come into direct contact with the ocular tissue. These products may directly and irreparably harm the eye and the patient’s vision. Lens materials with poor oxygen permeability can cause hypoxic symptoms, which contribute to the development of edema.12 If the disinfection efficacy of a contact lens solution (multi-purpose solutions [MPS] and hydrogen peroxide) is too weak, then bacterial colonization may occur on the lens or lens case, potentially leading to proliferation once the contaminated lens is placed on the eye; and if it is too strong, the solution may cause irritation or the refractive surface may be disrupted. By having international standards, practitioners and patients are assured that a product has a particular level of safety regardless of where it was manufactured.

While products are thoroughly tested, it is impossible to say conclusively that the product is safe for all patients due to patient variability and suboptimal levels of compliance with product use instructions. New products continue to enter the market, and it is the responsibility of all ECPs to stay current on how these additions affect treatment options for patients, both in terms of efficacy and safety. Medical association meetings are excellent sources of new study data. Journal publications, both print and online, are essential conduits of new information. Regardless of the medium for dissemination, data should always be reviewed with a critical eye because there could be concerns with the study’s design or conclusions. The debate surrounding corneal staining is a good example of why this is important.

The Andrasko Grid captures the level of corneal fluorescence with fluorescein staining at 2 hours with various MPS and lens combinations.13,14 The degree of fluorescence has been suggested to be indicative of certain MPS-most prominently PHMB-based solutions-having adverse effects on the corneal epithelium. But do the results shown on this grid reflect a lack of biocompatibility? The quick answer is “no.” Dillehay and colleagues questioned whether the data had any clinical relevance due to weaknesses (eg, lack of statistical testing, small sample size) of the study design upon which the grid is based.15

We all use fluorescein to measure the integrity of the corneal epithelium. However, in contact lens wearers, results should be interpreted with a great degree of caution. Because fluorescein has been shown to bind so strongly with PHMB molecules, it is possible that any transient hyperfluorescence observed may be the aggregation of these 2 types of molecules at the ocular surface. In addition, studies have suggested that corneal staining/hyperfluorescence may be the result of the ability of fluorescein to enter healthy cells or nonpathologic processes such as desquamation (the shedding or peeling of epithelial cells).16-20 Corneal staining can present in different ways (see Figure 1). It can also have a multitude of etiologies, including solution-induced corneal staining (SICS)21 and preservative-associated transient hyperfluorescence (PATH),21 which makes it difficult to determine if staining is pathological in nature with fluorescein testing alone.

Nonpathological corneal staining is generally a condition requiring nothing more from the ECP than vigilance because most patients will be asymptomatic. However, if the patient is symptomatic, then a change in lens or lens care may be necessary. There are 6 types of clinically important corneal staining in contact lens wearers:

• Mechanical

• Exposure

• Metabolic

• Toxic

• Inflammatory

• Infectious22-24

How can the ECP determine if the patient is at risk if fluorescein testing alone is not specific enough to determine if corneal staining is pathological? Here are some general guidelines that we use in our practices for determining the threat level to patients: 

• If at the initial observation of staining, the patient is exhibiting signs or symptoms (e.g., redness, edema, infiltrates) associated with pathological conditions (e.g., inflammation, infection, trauma), then a more detailed evaluation should be conducted that includes the patient’s medical history and the pattern/location of the fluorescence. Once a diagnosis has been made, the patient should be treated accordingly.

• If no signs or symptoms are observed, and the staining is Grade 2 or lower according to the Efron Grading Scale for Corneal Staining,22 then the staining is considered not to be clinically significant.

• If no signs or symptoms are observed, but the staining is greater than Grade 2, then the staining should be re-evaluated after more than 2 hours have passed. If at this later time point the staining is still present, but at Grade 2 or less, then the staining is not clinically significant. If it remains greater than Grade 2, then the patient needs to be re-evaluated as described previously.



ECPs must take the lead

All ophthalmic products approved for medical use have passed a battery of in vivo and in vitro standard tests that support their safety. Does this mean that a particular ophthalmic product has the same level of biocompatibility in all patients? No, but this is due to a combination of patient variability and the inability of all patients to be 100% compliant with product guidelines. That is why ECPs should choose the product that they feel will work most effectively and safely with each patient.

Corneal staining is a controversial topic; probably because the only things of which we can be certain are:

• It is there

• We do not know what, exactly, it represents (especially because it can also occur in non–contact lens–wearing patients)

• Additional research is needed

That is not to say that we know nothing. We know that there can be several different causes of corneal staining, and not all are pathological. Until corneal staining is fully explained, ECPs need to take the lead in detecting and managing it.

ECPs need to keep as current as possible as the ever expanding literature can educate and provide clarification, helping them to make informed decisions regarding treatment recommendations that reflect the greatest safety and efficacy benefits possible. As additional research becomes available, ECPs should take their clinical experiences into consideration and should evaluate the merits of the data on their own and not rely solely upon the conclusions of the study authors. This is especially true in cases where there is already a considerable amount of data in the literature demonstrating the safety of a product.

The biocompatibility of ophthalmic products reflects our knowledge of how the eye works and our ability to create materials that function in this sensitive environment. As our understanding increases and our diagnostic/manufacturing abilities become more sophisticated, we can expect to see products with increased safety and improved abilities. We will never be able to tell our patients not to put anything in their eye that is smaller than their elbows, but then why would we want to when there is so much that we can do to improve vision and safeguard the health of our patients’ eyes?ODT


Editorial support was provided by BioScience Communications through an unrestricted educational grant from Bausch + Lomb.


1. Williams DF. The Williams Dictionary of Biomaterials. Liverpool, UK; Liverpool University Press; 1999.

2. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Biologics Evaluation and Research. Guidance for FDA Reviewers: Premarket Notification Submissions for Transfer Sets (Excluding Sterile Connecting Devices). July 2001. Available at: http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/ucm062958.pdf. Accessed July 3, 2013.

3. Basu B, Nath S. Fundamentals of biomaterials and biocompatibility. In: Basu B, Katti DS, Kumar A, eds. Advanced Biomaterials: Fundamentals, Processing, and Applications. Hoboken, NJ: John Wiley & Sons Inc.; 2009:3-18.

4. Bumgardener JD, Vasquez-Lee M, Fulzele KS, et al. Biocompatibility testing. In: Wnek GE, Bowlin GL, eds. Encyclopedia of Biomaterials and Biomedical Engineering. 2nd ed. London, UK: Informa Healthcare; 2008.

5. Cavet ME, Harrington KL, VanDerMeid KR, et al. In vitro biocompatibility assessment of multipurpose contact lens solutions: effects on human corneal epithelial viability and barrier function. Cont Lens Anterior Eye. 2012 Aug;35(4):163-70.

6. Onuki Y, Bhardwaj U, Papadimitrakopoulos F, Burgess DJ. A review of the biocompatibility of implantable devices: current challenges to overcome foreign body response. J Diabetes Sci Technol. 2008 Nov;2(6):1003-15.

7. Pacific BioLabs. Assessing Biocompatibility: A Guide for Medical Device Manufacturers. Available at: http://www.pacificbiolabs.com/biocomp_download_confirm.asp. Accessed July 3, 2013.

8. Kaslow CM, Reindel WT, Merchea MM, et al. Tear cytokine response to multipurpose solutions for contact lenses. Clin Ophthalmol. 2013;7:1291-302.

9. Wilson SE, Netto M, Ambrosio R Jr. Corneal cells: chatty in development, homeostasis, wound healing, and disease. Am J Ophthalmol. 2003 Sep;136(3):530-6.

10. Mackenzie R, Holmes CJ, Jones S, et al. Clinical indices of in vivo biocompatibility: the role of ex vivo cell function studies and effluent markers in peritoneal dialysis patients. Kidney Int Suppl. 2003 Dec;64(88):S84-93.

11. Bratlie KM, Dang TT, Lyle S, et al. Rapid biocompatibility analysis of materials via in vivo fluorescence imaging of mouse models. PLoS One. 2010 Apr 6;5(4).

12. Holden B, Stretton S, Lazon de la Jara P, et al. The future of contact lenses: Dk really matters. Contact Lens Spectrum. February 1, 2006. Available at: http://www.clspectrum.com/articleviewer.aspx?articleid=12953. Accessed June 17, 2013.

13. Andrasko Corneal Staining Grid. Available at: www.StainingGrid.com. Accessed May 10, 2013.

14. Andrasko G, Ryen KA. A series of evaluations of MPS and silicone hydrogel lens combinations. Rev Cornea Contact Lens. 2007 Mar:36-42.

15. Dillehay SM, Long B, Cutter G. A statistical analysis of the staining grid. Contact Lens Spectrum. November 2007. Available at: http://www.clspectrum.com/article.aspx?article=101062. Accessed February 25, 2013.

16. Mokhtarzadeh M, Casey R, Glasgow BJ. Fluorescein punctate staining traced to superficial corneal epithelial cells by impression cytology and confocal microscopy. Invest Ophthalmol Vis Sci. 2011 Apr 5;52(5):2127-35.

17. Feenstra RP, Tseng SC. Comparison of fluorescein and rose Bengal staining. Ophthalmology. 1992 Apr;99(4):605-17.

18. Bakkar M, Maldonado-Codina C, Morgan PB, et al. Development of an in-vitro model of solution induced corneal staining. Optom Vis Sci. 2010;87.

19. Thinda S, Sikh PK, Hopp LM, et al. Polycarbonate membrane impression cytology: evidence for fluorescein staining in normal and dry eye corneas. Br J Ophthalmol. 2010 Apr;94(4):406-9.

20. Wilson G, Ren H, Laurent J. Corneal epithelial fluorescein staining. J Am Optom Assoc. 1995 Jul;66(7):435-41.

21. Efron N. Putting vital stains in context. Clin Exp Optom. 2013 Jul;96(4):400-21.

22. Efron N. Contact Lens Complications. 3rd ed. Edinburgh, UK: Elsevier/Saunders; 2012.

23. Steinemann TL, Ehlers W, Suchecki JK. Contact lens-related complication. In: Yanoff M, Duker JS, eds. Ophthalmology, 3rd edition. St. Louis, MO: Mosby Inc.; 2008.

24. Sowka JW, Gurwood AS, Kabat AG. Keratitis sicca/dry eye syndrome. In: Handbook of Ocular Disease Management, 5th edition [book on the Internet]: Review of Optometry. 2004. Available from: http://cms.revoptom.com/handbook/sect3a.htm. Accessed July 3, 2013. 

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