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

permeant (e.g. oxygen) molecule can meander through them, the solubility term is governed by the amount of oxygen that the material can dissolve at a given ambient partial pressure. Thus k is a partition coefficient. Values of Dk are conveniently quoted in barrers, where 1 barrer = 10–11 cm3O2 (STP) cm/s cm2 mmHg.

Thus Dk (or P) is the permeability coefficient for a given material, and the transmissibility of a sample of a given thickness t (such as a contact lens) of that material becomes Dk/t. Since lenses are around 0.1 mm thick, the values of contact lens transmissibility are usually quoted with units of 10–9 (cm ∞ mlO2)/(s ml mmHg), which keeps them numerically similar to Dk values.

Chapter 19 shows that incorporation of water into a glassy polymer not only increases the ease of diffusion, but also provides a medium that dissolves oxygen. Not surprisingly, then, the more water that the polymer contains, the greater amount of oxygen that it will dissolve and the higher the resultant permeability. Additionally, the water acts as a plasticiser, as described in the same chapter, and progressively increases the ease of diffusion. There is, however, a limitation imposed by water as a transport medium. The product of diffusion and solubility (i.e. permeability or Dk) in a conventional hydrogel will always be significantly below the value for water itself, which at 34 °C is no more than 100 barrers. Given the fragility of high-EWC hydrogels, especially if lens thickness is reduced in order to increase Dk/t, there is no possibility of meeting the Holden and Mertz criterion with conventional hydrogel contact lenses. The story of contact lens material development has been driven by attempts to increase both D and k while maintaining levels of surface and mechanical properties appropriate to successful lens wear.

Several types of material have been used in contact lens production, some more successfully that others. The most significant, in approximate order of availability, are:

∑glass;

∑poly(methyl methacrylate) (PMMA);

∑conventional hydrogels;

∑silicone rubber;

∑rigid gas permeable lenses (RGPs);

∑silicone hydrogels.

Of these, all except glass and PMMA have been used in extended wear lenses. Currently, silicone hydrogels are growing dramatically in importance, RGPs have a very limited market appeal and silicone rubber has minimal use except in a medical setting. Each material has, however, contributed to the existence and current success of silicone hydrogels. In order to understand the emergence and unrivalled position of silicone hydrogels, it is necessary to examine some preliminary data.

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The solubility of oxygen in water is relatively low – less than 5 ml oxygen/ ml water at 25 °C and atmospheric pressure. Workers in various fields have sought inert liquids of similar physical properties, for example, boiling point, in which to carry out oxygen-mediated processes more effectively. Typical silicone oils having molecular weights around 350 show oxygen solubilities of around 100 ml/100 ml silicone oil at 25 °C. Silicones are not the only organic compounds with high oxygen dissolution capabilities that have been harnessed in the contact lens field. Fluorocarbons show similar, although less marked, dissolution advantages over water; perfluoro-n-heptane, which also has a molecular weight of around 350 and a boiling point of 115 °C, shows an oxygen solubility of around 45 ml/100 ml fluorocarbon at 25 °C. Fluorine and silicon are complementary, rather than competitive elements in polymer design. Fluorine can replace hydrogen directly in many organic compounds but can not form chains. Silicon, on the other hand, can form chains with oxygen (the silicones) and can replace carbon in certain situations. Figure 12.1 illustrates this point and provides the basis for an interesting comparison of relative oxygen permeability values of structures incorporating fluorine and silicon. As Fig. 12.1 shows, poly(hexafluoroisopropyl methacrylate) has a Dk value around 100 times greater than that of PMMA. Poly(dimethyl siloxane), better known in the form of silicone rubber, has a Dk value at least 1000 times greater than that of PMMA. Not surprisingly, these properties have not gone unexploited in the contact lens field.

There is one unusual feature about the development of silicon-based

(and to a much lesser extent, fluorine-based) polymers as biomaterials.

There has been a growing tendency in recent years to exploit the principles of biomimesis in biomaterials development. This was certainly the case in both Wichterle’s original work, and much of the subsequent innovation and development in the field of hydrogels. It is useful to put these organofluorine and organosilicon compounds into perspective and to speculate why the body has no need of structures with similarly high oxygen permeability.

The number of chemical elements exceeds 100 but the vast majority (over 95%) of living matter is made up of only 4 (carbon, nitrogen, oxygen and hydrogen). There is no biomimetic driving force to exploit silicon or fluorine, or even analogous structures on which the polymers contained in

Fig. 12.1 might be loosely based. When it comes to the historic development of materials based on natural resources, the story is rather different. The four most abundant elements on Earth are oxygen, iron, silicon and magnesium – fluorine joins the list at 17th. Historically, materials science was driven by commonly available inorganic raw materials such as metals and ceramics. It is only since the field of biomaterials has developed that materials science has turned to the structure and function of the human body for inspiration. In this respect silicon is something of an anomaly. Its role in the formation of glass gave it an important position in civilisation because of the unique

12.1 Fluorine-containing and silicon-containing polymers and their relative oxygen permeabilities. MMA, methyl methacrylate; TFEMA, trifluoroethyl methacrylate; HFIPMA, hexafluoroisopropyl methacrylate; TRIS, tris(trimethyl- siloxy)-γ-methacryloxy-propylsilane; silicone rubber, poly(dimethyl siloxane). Oxygen permeability increases in the order: polyMMA < polyTFEMA < polyHFIPMA < polyTRIS < silicone rubber. Relative magnitude of increase c. 0.5, 25, 40, 300, 1000, respectively.

lenses contact wear Extended

12.2 Characteristics of the Si—O—Si and C—C—C backbones.

in the mid 1960s and were found clinically to have little deleterious effect on corneal respiration. The problems of maintaining adequate surface properties, which were initially encountered in its routine clinical use, have never been fully overcome, despite a great deal of effort. The exceedingly hydrophobic nature of silicone elastomers resulted in poor lens wetting and rapid lipid deposition, which inevitably limited the use of these lenses. The uniquely high oxygen permeability, coupled with the resistance to tearing and general durability of the lens, led to its use in paediatric aphakia, where most of its applications still lie. Perhaps the best known silicone elastomer lens is Silsoft (Bausch & Lomb), which obtained US

Food and Drug Administration (FDA) approval in 1984 as a 30-day extended wear lens for aphakia.

In retrospect, following many years of materials development and the study of the relationship between surface properties and mechanical properties, the behaviour of siliconerubberfitsaclearpattern.Elastomers,suchassiliconerubber,areinmany ways intermediate between thermoplastics (such as PMMA) and hydrogels (such as polyhydroxyethyl methacrylate (PHEMA)). Thus, they possess to a degree the toughness associated with the former group of materials and the softness of the latter and in this sense they are ideal candidates for contact lens usage. Unfortunately, however, they all possess the same inherent disadvantage. The molecular features required for true elastic behaviour invariably produce polymers with hydrophobic surfaces. All polymers in this group, not only the silicone-based materials, require some form of surface modification to render them sufficiently hydrophilic for use as contact lenses, but because of the ease of chain rotation consequent upon their elastomeric characteristics, the surfaces slowly revert to their untreated state. This problem is made worse by the virtually instantaneous (dynamic) elastic recovery of the materials, which causes them to ‘grab’ the cornea after being deformed by the blink. This in turn displaces the posterior tear film and leads to lens binding.

Despite the attempts to harness almost every available elastomeric material, as witnessed by the patent literature, no true elastomer has been successfully used

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as a commercial contact lens material. Current understanding of silicone hydrogel behaviour suggests a link between adherence to the ocular surface and inadequate fluid and ion transport. This indicates the fundamental difficulty in achieving reasonable lens movement with silicone elastomers, which coupled with the exceedingly hydrophobic nature which results in poor wetting and rapid lipid deposition, has led to very limited use of these lenses. The uniquely high oxygen permeabilityofthesilicon–oxygenbackbonehas,however,beenharnessedintwo distinct types of contact lens material: the so-called rigid gas permeable (RGP) materials and the silicone hydrogels.

Once the need for a contact lens material with higher oxygen permeability than PMMA was established, a wide-ranging search began. A detailed account of the sequence of patents and products is given elsewhere (Tighe, 1989). If the principles of the separate contribution of diffusion and solubility to oxygen permeability are accepted, the logic of combining the ease of preparation of acrylics and the oxygen permeability of silicone rubber is inescapable. The siloxymethacrylates that form the basis of both current gas permeable and silicone hydrogel technology achieve this aim in a well-recognised, but nevertheless quite ingenious, way. The most widely used example is the siloxymethacrylate monomer tris(trimethylsiloxy)-γ- methacryloxy-propylsilane (Fig. 12.1), commonly referred to as TRIS. In essence, it consists of individual segments of silicone rubber structure assembled as pendant groupsontoamodifiedmethylmethacrylatemolecule.Thismajoradvancewasone aspect of the work of Norman Gaylord, which paved the way for the subsequent developmentofRGPcontactlensmaterials.AnotherimportantaspectofGaylord’s work was the recognition of the value of incorporating fluoroalkyl methacrylates as comonomers, principally to enhance oxygen permeability (Gaylord, 1974, 1978).

The concept of a fluorine-containing contact lens was not entirely new, as the description of the advantages of contact lenses prepared from perfluoroalkylethyl methacrylates can be found in a series of DuPont patents (e.g. Cleaver, 1976). Whereas earlier descriptions of the advantages of fluorine incorporation went unexploited, however, Gaylord’s patents led rapidly to commercial products. The underlying reason is that the fluoromethacrylates, on their own, do not produce a clinically significant balance of advantages over PMMA, whereas the gain in oxygen permeability of the siloxymethacrylates over conventional methacrylates is dramatic. The particular benefit of the fluorinated methacrylates comes when they are used to partially replace methyl methacrylate (as a comonomer) in copolymers with TRIS. The balance of the three components (fluoro methacrylate, methyl methacrylate and TRIS) is adjusted to optimise oxygen permeability, hardness

(which influences processability) and wettability. Although Gaylord’s patents markedthebeginningoftheinventivethread,severalotherworkersmadesignificant contributions to the development of lenses with advantages in clinical practice by identifying ways of optimising the balance of oxygen permeability, wettability and mechanical behaviour (Tighe, 1989). These led to the current commercially

available high-Dk RGPs, which have Dk values above 100 barrers. They adequately meet the Holden and Mertz criterion and give excellent clinical outcomes with no significant adverse responses (Sweeney, 2004). There are, then, two distinct types of lens material that meet criteria for extended wear lenses, silicone rubber and RGPs. The properties of current commercial examples, together with those of PMMA for comparison, are summarised in Table 12.2.

Despite the fact that the Holden and Mertz criteria are exceeded by both these high-Dk material types, they have not given rise to successful high-volume cosmetic lenses. This is an illustration of the importance of addressing all the properties highlighted in Section 12.1 if successful lens performance is to be achieved. The materials in Table 12.2 have different shortcomings. Silicone elastomers suffer from poor wettability and high lipid deposition, which in turn cause problems with the lens adhering to the eye and subsequent adverse effects. The fact that lenses are not easy to manufacture in comfortable designs with good edge profiles adds to lens discomfort. RGP contact lens materials also have high Dk values, which undisputedly meet the corneal needs for oxygen. Although they have excellent tear flow behind the lens and produce no significant level of adverse responses, their popularity is poor with both practitioners and patients. Patients find them inherentlyuncomfortableandmanypractitionersexperiencedifficultyinfittingthe lenses, especially when compared with the current generation of single basecurve soft lenses.

12.5The need for water: emergence of silicone hydrogels

The underlying concept that led to the development of the class of materials that have come to be called ‘silicone hydrogels’ follows logically from the description of the effect of water in conventional hydrogels. Since water

Table 12.2 Properties of silicone rubber and RGP contact lenses

B&L = Bausch & Lomb.

12.4 Structural variants of TRIS monomer described in the patents of, from left to right, Gaylord (1974), Tanaka et al. (1979) and Harvey (1985).

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CH3

(where n = 3–44, m = 25–40 and total molecular weight = 2000–10 000) Siloxy-based polyether macromer

(where n = 5–100, but especially 14–28, and m = 10–30) Siloxy-based polyfluoroether macromer

12.5 Examples of siloxy macromers (Nicholson et al., 1996).

the siloxane chain alternating, for instance, with hydrophilic segments of poly(ethylene glycol);

∑the use of monomers other than HEMA, for example, monomers that contain the —N—CO— linkage (Fig. 12.3).

Two of these approaches have been at the heart of the development of successful silicone hydrogels over the last decade. The earliest patent to propose and exemplify a more hydrophilic version of TRIS was granted to the

Toyo Contact Lens Company in 1979, with Kyoichi Tanaka as the principal inventor (Tanaka et al., 1979). His solution to the problem involves inserting a hydroxyl group into the pendant propyl linkage – simple in concept but less simple to achieve in practice. The fact that another 20 years elapsed before the widespread launch of silicone hydrogel contact lenses illustrates the point that the problems are more complex than might have been initially assumed. This conclusion is further supported by the fact that additional approaches have been regularly described in the patent literature of the 1980s and 1990s, but it was not until the mid 1990s, however, that patents explicitly addressed the question of lens movement – which has proved to be a critical and contentious issue.

The second approach is the development of macromer technology. Macromers are large monomers formed by pre-assembly of structural units that are designed to bestow particular properties on the final polymer. This can be illustrated by a 1991 CIBA patent entitled ‘Wettable, flexible, oxygen permeable contact lens containing block copolymer polysiloxane–polyoxyalkylene backbone units and use thereof’, with Robertson, Su, Goldenberg and Mueller as the named inventors (Robertson et al., 1991). The title describes very well the nature of the invention. The principle involved is the construction of a macromer that contains, typically, hydrophilic polyethylene oxide segments