Otolaryngologists have it easy. They can instruct their patients not to stick anything in their ear that is smaller than their elbow. Not only is it sound medical advice, it has a fairly high rate of compliance. Eye-care professionals (ECPs) who fit contact lenses have a more difficult hill to climb because we purposely put materials in our patients’ eyes, which would be impossible without products that are biocompatible.
What is biocompatibility?
Biocompatibility is the degree to which a synthetic material impacts the human body.1,2 ‘Degree’ is an important qualifier because a material can have an impact on its intended environment—that is, 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 two examples of synthetic materials that work with the eye to help restore or improve visual acuity. In eye care, the key is for a product to have a tolerable impact on the eye while maintaining an effective result.
There is no single test for biocompatibility; a series of tests is 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) that 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, sensitisation, 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 and electrical resistance.5
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 (for example, manufacturing, packaging and 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
Figure 1. Efron Grading Scales for contact lens complications27
Biocompatibility is important to contact lens wearers
There are several reasons why contact lens products, both lenses and solutions, require a certain level of biocompatibility. The primary reason is that these materials come into direct contact with the ocular tissue and therefore, there is the possibility that they 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 oedema.12
If the disinfection efficacy of a contact lens solution (multipurpose solutions [MPS] and hydrogen peroxide) is too weak, then bacterial colonisation may occur on the lens or lens case, potentially leading to proliferation once the contaminated lens is placed on the eye. If efficacy 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. Although 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.
Figure 2. Punctate pattern
Image: Dr Adrian Bruce, Australian College of Optometry
Keep up with the literature
New products continue to enter the market and it is the responsibility of all optometrists to stay current on how these additions impact treatment options for patients, in terms of both 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 as there could be issues with the study’s design or conclusions. The debate surrounding corneal staining is a good example of why this is important.
Corneal staining: an issue of biocompatibility?
Corneal staining is a complex issue. Little is known for certain about it and yet it can be a very polarising topic. Is it proof that some contact lens solutions may have an adverse impact on the corneal epithelium? Does it mean something less severe or perhaps nothing at all?
The cornerstone of the corneal staining debate is undoubtedly the Andrasko Grid, which captures the level of corneal fluorescence with fluorescein staining at two hours with various MPS and lens combinations.13,14 The degree of fluorescence has been implied by some to be indicative of certain MPS—most prominently PHMB-based solutions—having adverse effects on the corneal epithelium. Do the results shown on this grid reflect a lack of biocompatibility? The short answer is ‘no’. Dillehay and colleagues (2007) questioned whether the data had any clinical relevance due to weaknesses of the study design behind the formation of the grid, such as:15
- Lack of statistical testing
- Too small a sample size for assessment of product differences
- Overrepresentation of staining as a result of only using measurements from the worst eye
- Pre-cycling of lens cases, which is inconsistent with product instructions and industry standards for evaluating efficacy
- Resampling of patients, non-masking, and non-randomisation across the entire study design.
In addition to statistical deficiencies, the study also fails to incorporate some key facts about how fluorescein, contact lenses and MPS interact with one another. We shall examine two of them.
- All soft contact lenses take up MPS during the soaking, releasing it when the lens is placed on the eye.16,17 The release time varies depending on the material and the MPS preservative, but PQ-1 is released more quickly than PHMB, with peak release points at about 30 minutes vs one to three hours, respectively.16-21
- Fluorescein, the agent used to measure the integrity of corneal epithelial cells, has different levels of attraction to PHMB vs PQ-1. Fluorescein binds with PHMB 10 to 50 times more strongly, depending on temperature, than it does with PQ-1.21
Figure 3. Central staining
Image: Dr Adrian Bruce, Australian College of Optometry
What do release times and fluorescein/preservative attraction levels have to do with the results of the Andrasko grid? Everything.
By measuring corneal staining at the arbitrary time point of two hours, the results are skewed against PHMB. If this grid showed the results of corneal staining at 30 minutes, it is likely that the staining associated with MPS containing PQ-1 would be higher and those using PHMB would be lower. Does that mean that PQ-1 lacks biocompatibility? No, it simply means that at 30 minutes the level of PQ-1 released into the tear film is most likely to be at its highest. If you were to examine the corneal staining at eight hours, you would probably find that most of it had dissipated, regardless of the MPS preservative used.
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 two 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 non-pathologic processes such as desquamation (the shedding or peeling of epithelial cells).22-26
Corneal staining can have a multitude of aetiologies, including solution-induced corneal staining and preservative-associated transient hyperfluorescence, which makes it difficult to determine if it is pathological in nature with fluorescein testing alone.
Figure 4. Central staining revealing fine superficial punctate keratitis
Image: Dr Adrian Bruce, Australian College of Optometry
Determine the threat level of corneal staining to your patient
Non-pathological corneal staining is generally a condition requiring nothing more from the optometrist than vigilance and most patients will be asymptomatic; however, if symptomatic, then a change in lens or lens care may be necessary.
There are six types of clinically important corneal staining in contact lens wearers: mechanical, exposure, metabolic, toxic, inflammatory and infections.27-29 How can the optometrist 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 for determining the threat level to your patient:
- If at the initial observation of staining, the patient is exhibiting signs or symptoms (for example: redness, oedema or infiltrates) associated with pathological conditions (for example: inflammation, infection or 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 (Figure 1), 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 two hours have passed. If at this later time 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 in the first bullet.
Biocompatibility is the degree to which a product can be used safely and effectively with the human body. 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 per cent compliant with product guidelines. That is the reason optometrists 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 exactly what 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, optometrists need to take the lead in detecting and managing this issue.
Optometrists need to keep as current as possible as the 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.
The Andrasko Grid, while also part of the literature, has unfortunately had the opposite effect. The grid and the subsequent articles based on its conclusions have instilled confusion and uncertainty into treatment patterns that optometrists have in the past found to be clinically successful. It may also have influenced optometrists to change to a lens/solution combination associated with less staining by the grid (thus greater perceived biocompatibility) in patients already following a successful regimen.
As additional research becomes available, optometrists should take their clinical experiences into consideration and should evaluate the merits of the data on their own and not rely solely on 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 elbow, 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?
- Williams DF. The Williams Dictionary of Biomaterials. Liverpool, UK; Liverpool University Press; 1999.
- US 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/GuidanceComplianceRegulatory Information/Guidances/Blood/ucm062958.pdf. Accessed July 3, 2013.
- 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.
- 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.
- 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; 35: 4: 163-170.
- Onuki Y, Bhardwaj U, Papadimitrakopoulos F et al. A review of the biocompatibility of implantable devices: current challenges to overcome foreign body response. J Diabetes Sci Technol 2008 ; 2: 6: 1003-1015.
- Pacific BioLabs. Assessing Biocompatibility: A Guide for Medical Device Manufacturers. Available at: http://www.pacificbiolabs.com/biocomp_download_confirm.asp. Accessed July 3, 2013.
- Kaslow CM, Reindel WT, Merchea MM, Bateman KM, Barr JT. Tear cytokine response to multipurpose solutions for contact lenses. Clin Ophthalmol 2013; 7: 1291-1302.
- Wilson SE, Netto M, Ambrosio R Jr. Corneal cells: chatty in development, homeostasis, wound healing, and disease. Am J Ophthalmol 2003; 136: 3: 530-536.
- 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; 64: Suppl 88: S84-S93.
- Bratlie KM, Dang TT, Lyle S et al. Rapid biocompatibility analysis of materials via in vivo fluorescence imaging of mouse models. PLoS One 2010; 5: e10032.
- 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.
- Andrasko Corneal Staining Grid. Available at: www.StainingGrid.com. Accessed May 10, 2013.
- Andrasko G, Ryen KA. A series of evaluations of MPS and silicone hydrogel lens combinations. Rev Cornea Contact Lens 2007; Mar: 36-42.
- 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.
- Dassanayake NL, Garofalo R, Carey R et al. Correlating biocide uptake and release profiles with corneal staining and subjective symptoms. Invest Ophthalmol Vis Sci 2005; 46: e-abstract 915.
- Powell CH, Lally JM, Hoong LD et al. Lipophilic versus hydrodynamic modes of uptake and release by contact lenses of active entities used in multipurpose solutions. Cont Lens Anterior Eye 2010; 33: 1: 9-18.
- Garofalo RJ, Dassanayake N, Carey C et al. Corneal staining and subjective symptoms with multipurpose solutions as a function of time. Eye Contact Lens 2005; 31: 4: 166-174.
- Kislan T. An evaluation of corneal staining with 2 multipurpose solutions. Optometry 2008; 79: 6: 330. Poster 69.
- Willcox MD, Phillips B, Ozkan J et al. Interactions of lens care with silicone hydrogel lenses and effect on comfort. Optom Vis Sci 2010; 87: 11: 839-846.
- Bright PV, Merchea MM, Kraut ND et al. A preservative-and-fluorescein interaction model for benign multipurpose solution—associated transient corneal hyperfluorescence. Cornea 2012; 31: 12: 1480-1488.
- 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; 52: 5: 2127-2135.
- Feenstra RP, Tseng SC. Comparison of fluorescein and rose Bengal staining. Ophthalmology 1992; 99: 4: 605-617.
- 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: e-abstract 100959.
- 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; 94: 4: 406-409.
- Wilson G, Ren H, Laurent J. Corneal epithelial fluorescein staining. J Am Optom Assoc 1995; 66: 7: 435-441.
- Efron N. Contact Lens Complications, 3rd ed. Edinburgh, UK: Elsevier/Saunders; 2012.
- Steinemann TL, Ehlers W, Suchecki JK. Contact lens-related complication. In: Yanoff M, Duker JS, eds. Ophthalmology, 3rd ed. St Louis, MO: Mosby Inc; 2008.
- Sowka JW, Gurwood AS, Kabat AG. Keratitis sicca/dry eye syndrome. In: Handbook of Ocular Disease Management, 5th ed [book on the Internet]: Review of Optometry, 2004. Available from: http://cms.revoptom.com/handbook/sect3a.htm.