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

Water content (%)

However, the SI unit for pressure is the pascal (Pa). Because the unit mmHg is now becoming obsolete internationally, it is being advocated that the closest accepted metric unit of pressure – 100 Pa, or hectopascal (hPa) – should replace mmHg (ISO, 2006a). The new units are referred to as ‘Dk units’ in this latest British and International Standard. When hPa is used, Dk and Dk/t values are quoted as below:

(Dk) in ‘Dk units’ = 10–11 (cm2 ∞ mlO2)/(s ∞ ml ∞ hPa) (Dk/t) in ‘Dk/t units’ = 10–9 (cm ∞ mlO2)/(s ∞ ml ∞ hPa)

The difficulty here is that converting from the traditional barrer or Fatt units to ISO units involves multiplying Dk or Dk/t by the constant 0.75. Thus, for example, a lens quoted with a traditional Dk/t of 40 units will have a revised ISO Dk/t of 30 units. It is understandable that such a ‘downsizing’ will be resisted by contact lens manufacturers, because higher numeric

Dk/t values are perceived clinically as being ‘superior’ when evaluating the oxygen performance of contact lenses with Dk values less than 35 barrer. Since virtually all of the relevant literature still uses non-SI units for citing

Dk and Dk/t values, ‘barrer’ units will be cited in this chapter.

11.3.2 Measurements on silicone hydrogel lenses

Although the manufacturers of silicone hydrogel contact lenses have published values of Dk relating to their products, the precise methodology used in determining these values is not readily available. A number of authors have therefore sought to derive independent estimates of the Dk of commercially available products. Three methods have been described for the measurement of contact lens Dk (Brennan et al., 1987). The polarographic (or ‘Fatt’) method (ISO 9913-1 Part 1 (ISO, 1996a)) involves placing a contact lens on a polarographic oxygen sensor and measuring the rate at which oxygen passes through the material from the atmosphere to the sensor electrodes. In the coulometric technique (ISO 9913-1 Part 2 (ISO, 1996b), an oxygen-free carrier gas passes over one side of the lens and transfers oxygen that has passed through it to an electrolytic fuel cell where a quantitative decomposition occurs. The gas-to-gas, or ‘volumetric’, method (Mizutani et al., 1992) involves mounting a lens material specimen between two fixed-volume chambers, one of which is pressurized with 100% oxygen up to several atmospheres greater than the second chamber. Oxygen passing through the lens in response to this pressure gradient is detected as a pressure increase in the second chamber. Most Dk data reported in the ophthalmic literature have been conducted using the polarographic or coulometric techniques.

Here we shall review the work of six groups of researchers (Alvord et al., 1998; Morgan et al., 2001; Compan et al., 2002; Young and Benjamin,

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2003; Efron et al., 2007; Chhabra et al., 2007) who have so far published estimates of the Dk of commercially available silicone hydrogel contact lenses. The two silicone hydrogel lenses that were introduced into the market in 1998 – lotrafilcon A and balafilcon A – were the only lenses on the market until 2003, at which time other products began to appear. Thus, the earlier studies of Alvod et al. (1998), Morgan et al. (2001), Compan et al. (2002) and Young and Benjamin (2003) only considered one or both of these lenses.

All of the authors of these studies have noted that the high Dk of silicone hydrogels places these materials outside the applicability of both the polarographic ISO standard and coulometric ISO draft standards for contact lens Dk determination, which were designed for measuring the oxygen performance of low-Dk conventional hydrogels. As such, various adaptations and refinements to existing methodology have had to be adopted to make these determinations.

Determinations pre-2004

The Dk of lotrafilcon A lenses was determined by Alvord et al. (1998) and Morgan et al. (2001). Alvord et al. (1998) adapted the standard coulometric method. Lenses with a thickness (t) ranging from 30 μm to over 300 μm were measured in a liquid-to-gas and a gas-to-gas configuration in an effort to combine features of the ISO standards to yield a valid measurement of the intrinsic material Dk. Different results were obtained, which depended upon factors such as whether or not a water overlay was used, whether liquid-to-gas or gas-to-gas procedures were adopted and stirring speed (Table 11.2).

Morgan et al. (2001) modified equipment for both polarographic and coulometric methods that included front surface masking to eliminate the

‘edge effect’. They used these two techniques to measure the Dk of lotrafilcon

A (Table 11.2). The coulometric technique yielded typical standard errors of <10%. They concluded that the coulometric method is preferable for the measurement of contact lens materials with Dk > 70 barrer.

Compan et al. (2002) and Young and Benjamin (2003) measured the Dk of lotrafilcon A and balafilcon A. Whereas Compan et al. (2002) used the so-called ‘stacking procedure’ (see below for a complete description of this technique), Young and Benjamin (2003) used conventional polarographic methodology to measure lenses of various power and thus differing thickness profiles. This is in essence a variation on the stacking technique, in that it is an alternative strategy for measuring oxygen flow through differing thicknesses of the same material (Table 11.2).

Table 11.2 Published estimates of silicone hydrogel contact lens oxygen permeability (barrer)

aNo error estimates given.

bError given as mean ± standard error.

cError given as: +SEM, 3.79; –SEM, 3.62.

dError estimates not defined.

eError given as 95% confidence interval (CI): 103.6–120.3.

fError given as 95% CI: 90.5–116.7.

gError given as 95% CI: 165.1–188.7.

hError given as 95% CI: 177.5–205.0.

permeability oxygen superior for search the lenses: Contact

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Determinations post-2004

Efron et al. (2007) used a ‘stacking technique’ to measure the Dk of five silicone hydrogel contact lenses on the market at the time of their experiment. All lenses were 1.00D in power to ensure they were approximately parallel- sided (Weissman and Fatt, 1989). The lenses were obtained through normal commercial channels without reference to the fact that they were to be used for Dk measurement.

In general terms, Efron et al. (2007) adhered to the procedures for measuring

Dk as stipulated in ISO 9913-1.4 Prior to Dk measurement, lenses were removed from their blister packs, placed in glass vials containing phosphate buffered saline solution, and left overnight in a thermostatically controlled water bath at 35 ± 0.5 °C. A single lens was placed on a polarographic oxygen sensor (Rehder Development Company, California, USA) comprising a pair of electrodes (gold cathode and silver anode) and a solid state temperature sensor. This assembly was housed in a chamber maintained at 35 °C and was connected to an external polarographic amplifier. The electric current passing between the two electrodes was monitored on a digital display on the amplifier unit. The steady-state current was recorded once the current reading had stabilized, which was typically within 20 minutes of placing the lens on the polarographic oxygen sensor.

This process was repeated using separate stacks of 2, 3, 4, 5 and 6 lenses.

Different lenses were used to create each stack, so 21 lenses were used for each lens type. This stacking technique has the advantage of allowing finished lenses to be used (rather than using specially manufactured lenses) without influencing measurement values (Weissman and Fatt, 1989). In each case, the thickness of the single lens and that of each of the stacks of 2, 3,

4, 5 and 6 lenses was measured using an electromechanical gauge (Rehder

Development Company). The entire procedure was conducted twice. Typically, to acquire a full dataset for each lens type using the procedure

described above took about five working days. The order in which the lens types were measured was randomized and the investigator undertaking these procedures was masked with respect to the lens type under evaluation. Masking was achieved by removing the lenses from the blister packs in which they were supplied and placing them in coded glass vials containing 0.9% phosphate-buffered saline.

The Dk/t for each lens stack was calculated by multiplying the mean of the current in microamperes by 2.854 ∞ 10–9. This value is based on Faraday’s constant, the partial pressure of oxygen in the atmosphere and the surface area of the electrode used in this work. A correction was made for the edge effect by using formulae given in the ISO standard. The values for the inverse of the calculated Dk/t (i.e. resistance) were plotted graphically against stack thickness; the inverse of the gradient of the line of best fit through the data

points for this graph represents the Dk of the lens material. This process eliminates error due to the boundary effect.

Chhabra et al. (2007) described a novel polarographic apparatus that requires only a single soft contact lens to ascertain oxygen permeabilities of high-Dk lenses. Unlike the stacking technique, the apparatus they described requires only a single-lens thickness. This is accomplished by minimizing (or completely eliminating) edge effects, boundary-layer resistances and lens desiccation in the polarographic apparatus. By taking these effects into account, Chhabra et al. (2007) were able to obtain reliable Dk estimates of six silicone hydrogel lenses. These authors claimed that their single-lens device provides a reliable, efficient and economical method for measuring

Dk of silicone hydrogel lenses.

The results of all of the studies described above, and the Dk values claimed by the manufacturers, are summarized in Table 11.2. Taking lotrafilcon A – the only lens measured by all authors – it can be seen that Dk estimates vary from 140 to 190.2 barrer. Five authors measured the Dk of balafilcon A, and results varied between 76 and 111 barrer. Given that (a) the stated error of measurement cited by all authors is considerably less than these ranges, and

(b) the commercially supplied materials used by all authors were essentially identical, it would appear that the discrepancies in mean values between authors are largely a result of the different methodologies adopted. Indeed, various ingenious but different strategies were employed by the different authors so as to adapt their protocols to be suitable for measuring lenses of much higher Dk values than stipulated by ISO 9913-1.

The Dk values of three silicone hydrogel lenses were determined by both Efron et al. (2007) and Chhabra et al. (2007). Whereas these authors were in reasonable agreement for estimates of galyfilcon A (75 and 72 barrer, respectively) and senofilcon A (107 and 100 barrer, respectively), the values they reported for lotrafilcon B were discrepant (81 and 120 barrer, respectively).

Practitioners who fit contact lenses generally rely upon the specifications provided by the manufacturer, for the simple reason that such information is readily accessible. It seems that, with few exceptions, the values cited by the manufacturers are generally lower than those reported by independent studies. Putting these discrepancies aside, it is clear that silicone hydrogel lenses, with Dk values above 60 barrer, have a far superior oxygen performance than was previously available with conventional hydrogel lenses, which all had Dk values less than 35 barrer.

The relation between contact lens Dk and water content is shown in

Fig. 11.4 for both conventional and silicone hydrogel lenses. Whereas Dk increases with increasing water content for conventional hydrogel lenses, the opposite is true for silicone hydrogel lenses.

The good fit of the data regression curve for conventional hydrogel lenses

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is attributed to hydrogels being considered as a single family of polymers. On the other hand, the different silicone hydrogel materials can be considered as being derived from different families of polymers, which is why the fit to the regression line is less accurate. Nevertheless, for silicone hydrogel materials, the principle is clear: since water is essentially a barrier to oxygen permeability, the less water present, the greater is the capacity for oxygen to flow through the material. The challenge for polymer chemists and clinicians is to find the right balance of material properties, whereby the silicone content is not so high as to compromise lens wettability and comfort, but not too low as to compromise oxygen performance.

11.3.3 Limitations of polarographic methodology

International standard ISO 9913-1 stipulates that Dk can be determined by measuring the current in a polarographic oxygen sensor when lens samples of various thickness are placed upon the sensor, as long as (a) the test samples have parallel or near-parallel anterior and posterior surfaces, (b) the thickest lens sample does not exceed 0.40 mm and (c) the resultant Dk is less than 100 barrer. As explained above, researchers have found it necessary to adapt the polarographic technique in different ways to measure the Dk of silicone hydrogel lenses, and in all cases ISO 9913-1 has been technically violated.

Compan et al. (2002) and Young and Benjamin (2003) used powered lenses of non-uniform thickness. Morgan et al. (2001) described four exceptions to the procedures described in ISO 9913-1 that they implemented when measuring Dk, and suggested that their modified technique could be used to measure soft lenses with Dk values up to 150 barrer. These authors criticized

ISO 9913-1, stating that it ‘... did not contain sufficient, appropriate detail to unambiguously implement … [the procedures described therein]’. Chhabra et al. (2007) used an apparently effective but non-ISO-sanctioned method for eliminating edge and boundary effects.

Instead of using lens samples of different thickness as prescribed by ISO 9913-1, Efron et al. (2007) used stacks of one to six parallel-sided lenses, all

–1.00D, according to the methodology described by Weissman and Fatt (1989).

Note 7 of ISO 9913-1 incorrectly states: ‘The near parallel condition would correspond to dioptric powers within the range +0.50 to –0.50’; however, Weissman and Fatt (1989) have demonstrated that the best approximation to parallel-sided soft lenses is achieved by using lenses of –1.00D.

The thickest stack of six silicone hydrogel lenses measured by Efron et al. (2007) reached 0.53 mm for lotrafilcon A. In addition, the resultant Dk values exceeded 100 barrer for two of the five silicone hydrogel lenses tested. Notwithstanding these technical violations of ISO 9913-1, Efron et al. (2007) demonstrated that, using stacks of up to six lenses, when applying

the polarographic methodology to the measurement of the Dk of silicone hydrogel contact lens materials, results in robust data acquisition. Indeed, when plotting resistance (t/Dk) versus stack thickness (t), an r2 value of greater than 0.98 was obtained for all five silicone hydrogel lenses tested, and the 95% confidence limits of all Dk estimates were within 8% to 20% of the mean.

This stacking methodology has been previously validated by Weissman and Fatt (1989); however, a possible disadvantage of the stacking technique is the potential for additional fine layers of saline to form between the lenses in the stack, cumulatively adding to the resistance to oxygen flow as the stack become larger. This results in a potential underestimation of the true Dk value. Efron et al. (2007) demonstrated that, as more lenses are stacked on each other, the thickness of the stacks tends to be greater than that which would be expected based upon the individual lens thicknesses that comprise the stacks. This discrepancy, which occurred for all lens types assessed in their work, is probably due to non-perfect alignment of the lens surfaces, and gaps between stacked lenses filling with saline.

The results of these various authors indicate that polarographic methodology can be used for measuring the Dk of silicone hydrogel lenses, with suitable modifications to the procedures laid out in ISO 9913-1. There is a clear need for ISO 9913-1 to be updated so as to accommodate the measurement of contact lenses with Dk values in excess of 100 barrer, by adopting one or more of the novel modifications as outlined above.

11.4Corneal oxygen availability with silicone hydrogel lenses

11.4.1 Oxygen flux

Clinicians are interested in the performance of contact lenses with respect to their impact on the physiology of the ocular surface. As such, they need to consider the amount of oxygen which reaches the ocular surface during lens wear, that is defined as the ‘oxygen flux’. Oxygen flux indicates the volume of oxygen that reaches a unit area of the corneal surface in unit time. In a number of ways, therefore, this is a more important clinical parameter than Dk, which is a laboratory measure that takes no account of ocular conditions.

For the range of Dk values offered by conventional hydrogels, there is an approximately linear relationship between Dk and corneal oxygen flux. Figure 11.5 presents the relationship between oxygen flux and transmissibility for open-eye and closed-eye conditions, for lenses of various thickness, using a mathematical model proposed by Brennan (2001). It is evident that, for conventional hydrogel lenses, increases in Dk afford similar proportional

Oxygen flux (μl cm–2 h–1)

Dk

changes in flux. As such, for conventional hydrogels, presenting values of

Dk for contact lenses is reasonably informative in terms of understanding the amount of oxygen that reaches the ocular surface.

At higher levels of oxygen performance, however, it is clear that there is a system of ‘diminishing returns’. That is, as measured contact lens Dk rises, the increase in the amount of oxygen that is delivered to the cornea reduces in magnitude. On this basis, it would seem that the use of Dk values in the era of silicone hydrogels is not appropriate. Corneal oxygen flux is a strong contender for replacing these parameters, although Brennan (2005), and more recently Chhabra et al. (2008) and Larrea and Büchler (2009), have argued for a more sophisticated and physiology-based approach which considers the amount of oxygen that is actually consumed by the cornea.

An important clinical ramification of flux theory as applied to contact lenses is that all silicone hydrogel lenses currently on the market are essentially equivalent in terms of corneal oxygen supply. This argument certainly applies to central corneal oxygenation. Alvord et al. (2007) have suggested that, for high minus-powered contact lenses, which are necessarily thicker in the lens periphery, oxygen flux can be significantly reduced in the peripheral cornea if silicone hydrogel lenses of lower Dk are fitted. This interpretation has been disputed by Brennan (2008), who argues that the minimum Dk required to fully oxygenate the peripheral cornea is only 30 barrer – not 125 barrer as suggested by the Alvord model.