Ординатура / Офтальмология / Английские материалы / Biomaterials and regenerative medicine in ophthalmology_Chirila_2010

11.4.2 Critical oxygen requirement

A vital question in understanding the issues relating to contact lens oxygen performance is the amount of oxygen that is required for normal corneal physiology. This has been addressed in many different ways historically. For open-eye (daily wear) conditions, the best known value is that of Holden and Mertz (1984), who suggested that a lens with Dk/t of 24.1 barrer/cm/would not induce corneal swelling during daily wear. At the time of the work, Dk values were not normally edge-corrected, and the edge-corrected equivalent Dk/t value is 21.8 barrers/cm (Table 11.3).

The situation for overnight wear is more complex. Holden and Mertz (1984) found that a lens with a transmissibility of 87 barrer/cm (73 barrer/cm if edge-corrected values are employed) would limit overnight corneal swelling to 4% – a value considered to be that of a non-lens wearer. Subsequent workers, using a variety of rationales, have reported thresholds up to 300 barrer/cm. Superficially, this seems to be a large range of values, which clearly must be in contradiction with each other. However, when these values are considered as flux measures, this difference is much reduced because of the relationship between oxygen flux and transmissibility.

Table 11.3 Estimates of critical oxygen transmissibility to avoid contact lensinduced corneal changes

PN, pyridine nucleotides; Fp, Flavoproteins; LDH, lactate dehydrogenase; MDH, malate dehydrogenase.

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11.5Conclusions

The century-long battle to develop contact lenses that allow sufficient levels of oxygen to reach the anterior ocular surface during contact lens wear for normal corneal metabolism is over. Silicone hydrogel lenses have been measured by numerous authors to have very high Dk levels – in excess of 60 barrer for all contact lenses on the market today. Considerations of anterior eye corneal oxygen flux has lead to the conclusion that there is essentially no difference in oxygen performance between current-generation silicone hydrogel lenses.

However, the search for the perfect contact lens is not over. Although the issue of lens-induced hypoxia has largely been solved, other issues remain. For example, silicone hydrogel materials have a higher modulus (greater stiffness) than conventional hydrogels, which possibly confers a greater mechanical effect on the cornea. This can result in reduced lens comfort and mechanically induced effects such as disruption to the corneal and conjunctival epithelial surface (Alba-Bueno et al., 2009; Sorbara et al., 2009) and corneal infiltrative responses (Efron et al., 2005; Szczotka-Flynn and Diaz, 2007). Silicone hydrogel contact lenses are still associated with a risk of microbial keratitis, albeit low (Efron et al., 2005; Stapleton et al., 2008), and strategies need to be developed to reduce the risk of lens-associated infection even further. No doubt attention will now turn away from the question of oxygen and will begin to focus more acutely on some of these unresolved issues, in search of the ‘perfect’ contact lens.

11.6References

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Ichijima H and Cavanagh H D (1994), ‘Effects of rigid lens extended wear on lactate dehydrogenase activity and isozymes in rabbit tears’, Cornea, 13(5), 429–434.

Ichijima H, Petroll W M, Jester J V, Ohashi J and Cavanagh HD (1992), ‘Effects of increasing Dk with rigid contact lens extended wear on rabbit corneal epithelium using confocal microscopy’, Cornea, 11(4), 282–287.

Imayasu M, Moriyama T, Ohashi J and Cavanagh HD (1993), ‘Effects of rigid gas permeable contact lens extended wear on rabbit cornea assessed by LDH activity, MDH activity, and albumin levels in tear fluid’, CLAO J, 19(153), 153–157.

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ISO (1996b), ISO International Standard 9913-1 ‘Optics and optical instrumentation – Contact lenses – Part 2: Determination of oxygen permeability and transmissibility by coulometric method’, Geneva, International Organization for Standardization.

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12.1Introduction

It is perhaps not immediately obvious that the use of polymers in contact lenses represents an excellent example of biomaterials design. The use of quite similar materials in joint replacement, heart valves, membrane oxygenators and haemodialysis membranes presents specific problems associated with, for example, their biocompatibility, strength and permeability that might seem to be absent in contact lenses. This is certainly not the case, however, and the general biomedical principle of designing the material to give a balance of properties appropriate to the particular environment is of prime importance. The situation is obviously less critical in the case of lenses intended for daily wear only, than for those intended for successive day and night periods, frequently referred to as extended wear. Nonetheless, properties very similar to those required for other biomedical applications are involved. Indeed, the research carried out into the use of hydrogels in contact lenses provides information on a range of materials that will assist future work on their use in other medical applications.

Thepropertiesthatarerelevanttothecontactlensfieldareimportantindifferent ways and to different extents. Some are essential to the successful performance of the lens in the eye; others affect convenience of handling, while a third group govern the behaviour of the lens during manufacture. The relative importance

of the various properties will further depend upon whether the lens is intended for daily wear or extended (overnight) wear. In addition, some properties such as refractive index and density vary by relatively small amounts within a given range of polymers, but will not greatly affect the potential usefulness of a material, whereas others have a critical and limiting effect on the ability of the lens to perform successfully.

In general terms, a lens for extended wear must be considered as an extension of the cornea. Thus, the lens must allow the cornea to respire normally, it must resist the deforming force of the eyelid and it must permit a continuous tear film to be maintained around the lens, while minimising the accumulation of deposits. These factors can be discussed in terms of oxygen permeability, rigidity modulus and surface properties. Some attempt must be made therefore to put quantitative limits on these very important properties, which are discussed in relation to hydrogel structure in Chapter 19. Once these fundamental requirements are met, there are properties controlling aspects of lens behaviour that relate to patient perception to consider. Perhaps the most important of these relates to long-term comfort and the maintenance of adequate lubrication of the lens throughout the day. This is the area of biotribology, reflected principally in the coefficient of friction between the lens and the eyelid, together with the changes in this property brought about by factors such as progressive lens dehydration and changes in the tear film. Since coefficientoffrictionissoaffectedbytheseenvironmentalchangesandisdifficult to measure accurately and reproducibly, it has only recently been recognised as an important measurable parameter in assessing materials properties.

It is always instructive to consider the nature and properties of any biological environment that is to be interfaced with a synthetic biomaterial. Making a synthetic material equivalent to the cornea presents formidable difficulties, since corneal surface and bulk properties are separately governed by the epithelium and stroma, and their natures are quite different. Such information is valuable, however, in providing a basis for understanding the way in which contact lens materials behave in the eye, particularly in extended wear. Appropriate data are summarised in Table 12.1. These lead on naturally to a more detailed consideration of achievable properties of available materials in relation to their structure. Although this discussion is primarily concerned with the behaviour of hydrogel contact lenses in relation to the factors discussed in Chapter 19, it extends naturally to

Table 12.1 Typical properties of the cornea and its environment

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other materials that can satisfy, in whole or part, the very demanding requirements of successful extended wear of contact lenses.

There are three important couplings of aspects of the anterior eye and physicochemical properties of the lens material:

∑cornea and transport properties;

∑eyelid and mechanical properties;

∑tears and surface properties.

The cornea is avascular when healthy and governs the oxygen permeability requirements of the material. The eyelid, which exerts a significant deforming force, governs the need for a balance between comfort and visual stability.

The tear film, which maintains ocular lubrication and defence, governs the wettability and (together with the eyelid) frictional requirements. These links, and the properties shown in Chapter 19, Table 19.1, need to be considered in the context of the more detailed stuctural aspects of the anterior eye discussed elsewhere in this volume. The cornea is a complex composite structure with a high epithelial turnover rate. The tear film is ‘structured’ with a thin superficial lipid layer that ‘breaks up’ at time intervals (which are very patient dependent) of approximately 10 seconds. The aqueous component of the tear film has a volume of some 7–10 μl and is replenished at a rate of around 1 μl per minute. Lipid turnover is appreciably slower.

Set in this context, the various aspects of contact lens design seem to face very considerable problems, for the simple reason that the contact lens is some ten times thicker than the tear film. This means that the problems associated with lens wettability and tear film stability are more severe than those in the non-lens-wearing eye. A stable tear film needs to exist on both anterior and posterior surfaces of the lens and adequate post-lens tear flow needs to be maintained in order to remove cellular debris and metabolic waste products. The necessary lens movement means that the mechanical property requirements are not the same as those of the cornea itself. One important consequence of the fact that the lens is so much thicker than the tear film is that the tear film break-up time is markedly reduced and the lipid layer is progressively deposited on the anterior surface of the lens. If the lens material has an affinity for lipids, these are immobilised and exposed to oxygen and light for very much longer periods than is the case in the normal eye, where lipid turnover minimises such problems. As well as these problems, which are common to both daily wear and extended wear lenses, extended wear faces additional problems – one of which is central to the discussion in this chapter: this is the need to allow the cornea to respire in a substantially undisturbed fashion in an environment where the partial pressure of oxygen is reduced from around 155 mm to some 55 mm.

12.2Oxygen: corneal requirements and the limitations of hydrogel permeability

The importance of oxygen to corneal metabolism and the physiological consequences of oxygen deprivation in this respect have long been recognised. A great deal of information has been published over the last 40 years as the quantitative aspects of the subject have been addressed with increasingly sophisticated techniques. Two questions have been addressed: how much oxygen is required to satisfy the requirements of the cornea, and how does that information convert to the required permeability of lens materials? The development of measurement techniques has been at the heart of the progress that has been made.

The oxygen requirement of the cornea has been expressed in various ways, including a direct figure for oxygen consumption (as shown in Table 12.1) and, alternatively, as the minimum partial pressure of oxygen required to maintain normal corneal metabolism. Such quantities are difficult to measure in such a manner that the techniques employed give unambiguous results and do not, in their use, influence corneal behaviour. Thus, the value accepted as the minimum partial pressure of oxygen required to prevent corneal oedema, which was 11–19 mmHg in 1970 had progressively risen to 23–37 mmHg by

1980. In the following decade, available techniques for measuring increases in corneal thickness increased in sensitivity. Experimental results show an approximately exponential decline in corneal thickness with increase in available oxygen, which makes it increasingly difficult to obtain an absolute correlation between the two values. In consequence, clinical assessments of the oxygen requirements at that time varied between 40 and 74 mmHg. A useful overview of these developments has been compiled by Efron and Brennan

(1987). Although these considerations may seem somewhat obscure, they are central to the design of materials for extended wear contact lenses.

The translation of corneal oxygen requirement to the thickness­ and oxygen permeability (P) of a material can be approached in various ways. The minimal partial pressure of oxygen (sometimes called oxygen tension) required at the anterior surface of the epithelium is assumed to be the minimum oxygen tension required behind a contact lens during bothopen and closed-eye conditions­. This value can then be inserted into a simple relationship, which enables the oxygen flux(F)acrosstheepithelialsurfaceunder a tight-fitting contact lens (i.e. assuming no leakage from the side) to be determined. As indicated above, in the 1970s a value of around 15 mmHg was considered to be appropriate, which produces a value for F of approx­imately 3.5 ∞ 10–6 1 cm–2 h–1. This is taken as a minimum but sufficient oxygen flux to maintain corneal transparency. The resultant value can then be used in equation [12.1], which relates the oxygen flux (F) to the permeability (P) and thickness­ (t) of a polymer membrane, and the pressure gradient across the membrane (dp). dp will be the difference between the