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

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19.1Introduction

The treatment presented here deals with the physicochemical aspects of structure-property relationships in hydrogels and aims to indicate what is achievable in terms of those properties that are particularly important in ophthalmic applications, dealing with both advantages and limitations. The chapter outlines the principles involved in the formation of those forms of hydrogels, such as interpenetrating networks and macroporous materials, in which the properties are not so centrally dominated by the equilibrium water content as is the case with homogeneous hydrogels. The question of so-called silicone hydrogels is touched upon, but is dealt with in more detail in Chapter 12. It is inevitable that homogeneous hydrogels will assume a position of central importance in any treatment that deals with those properties of hydrogels that are of relevance in ophthalmic applications­. In this context it is important to show that poly(2-hydroxyethyl methacrylate) or PHEMA is only one material in a synthetically diverse field, and to appreciate the possibilities and limitations in the design of hydrogels that possess appropriate properties for a given application.

The special position that hydrogels occupy in the biomedical field can be illustrated by comparing their properties with more established biomaterials and with natural tissue. The feature that characterises non-hydrogel polymers such

as polyethylene, polypropylene, silicone rubber and poly(vinyl chloride) – all of which have important biomaterials applications – is their relative hydrophobicity. Even the more polar materials, such as poly(methyl methacrylate) (PMMA) and poly(ethylene terephthalate), have polar components of surface energy that are much lower in magnitude than the dispersive, or non-polar, component of the polymer; in contrast to water which has a surface energy dominated by its polar component. The behaviour of water at the surfaces of these relatively non-polar polymers is necessarily dominated by hydrophobic interactions and this is a feature that contributes to their success in the biomedical fields for which they were developed. In contrast, the cell surface is greatly influenced by more hydrophilic groups such as oligosaccharide units, and the wide variety of soft tissue interfaces in the body interact with water in a quite different way from conventional synthetic hydrophobic polymers.

It is this aspect of behaviour that sets the class of polymeric materials known collectively as hydrogels apart from conventional synthetic polymers.

There is no precise and limiting definition of the term hydrogel, and problems always arise when attempts are made to apply such definitions to the range of materials that may be encompassed by the term. Perhaps the most useful description that may be given is that hydrogels are water-swollen polymer networks, of either natural or synthetic origin. Of these, it is the crosslinked, covalently bonded, synthetic hydrogels whose biomedical use has grown most dramatically in recent years, including composite structures involving both natural and synthetic hydrophilic materials. This aspect points to the central problem in the design of polymeric biomaterials. Whereas the biological structure to be replaced, or with which an interface is required, is invariably structurally complex, the historic tendency has been to choose biomaterials from a range of simple homogeneous­ synthetic polymers. As a result, the single synthetic material is required to produce a combination of surface and mechanical properties that is achieved by a combination of elements in the natural host. The obvious requirement for the development of more effective synthetic biologically compatible composites can only be achieved by reaching a better understanding of the behaviour of homogeneous hydrogels in biological environments, and by optimising their synthetic versatility. This chapter is not a review of current hydrogel literature, which is extremely extensive; it aims, rather, to summarise the well-established physicochemical principles that provide the necessary basis for the optimisation of hydrogel design for specific applications.

19.2Water in hydrogels: effects of monomer structure

The vast majority of work in this field can be traced back to the pioneering work of Otto Wichterle, who was not only the ‘father’ of hydrogels, but

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also an early advocate of the principles of biomimesis. He recognised quite clearly the importance of attempting to match mechanical properties of the host tissue, allow diffusion of metabolites and achieve a compatible interface with biological fluids. In order to achieve these ends he attempted to harness water as a component of the biomaterial and together with his coworker Drahoslav Lim he demonstrated the usefulness, for biological applications, of lightly crosslinked polymers of 2-hydroxyethyl methacrylate (usually referred to simply as HEMA) (Wichterle and Lim, 1960). The great advantages of this material over most other hydrophilic gels (such as the synthetic acrylamide gels that have been known for many years) are its stability to varying conditions of pH, temperature and osmolarity, such as are commonly encountered in biomedical use. The foundations of the subject were laid in a range of reviews, edited symposia and reference works (Wichterle, 1971; Andrade, 1976; Peppas, 1986, 1987a, 1987b).

Hydrogels are normally prepared by free radical addition polymerisation of unsaturated monomers that contain functional groups capable of interacting with water. The single most commonly used monomer is still HEMA – which is a tribute to the enduring nature of Wicherle’s work. Indeed, one of the problems associated with the development of hydrogels for biomedical applications has been the assumption, by those unfamiliar with the synthetic versatility of this class of materials, that the properties attainable with hydrogel devices are limited to those associated with lightly crosslinked, homogeneous, polymers of HEMA. Because of the central position occupied by HEMA, both as a monomer and polymer, it is convenient to use this as a starting point in developing a consideration of structure–property relationships in hydrogels. When HEMA is polymerised in the absence of water, it is glassy and similar in many ways to PMMA. The difference between PHEMA and PMMA becomes quite apparent, however, when the materials are immersed in water. Whereas PMMA is relatively little affected by water, PHEMA absorbs some two-thirds of its own weight to form an elastic gel that contains around 40% by weight of water and is remarkably stable to changes in its aqueous environment.

The amount of water held by the hydrogel is described by the equilibrium water content (EWC):

EWC = (weight of water in the gel/total weight of hydrated gel) ∞ 100% [19.1]

The EWC is undoubtedly the single most important property of a hydrogel because this, in turn, influences several other properties. The water in a hydrogel acts as:

∑a transport medium for dissolved species;

∑a surface energy ‘bridge’ between the hydrogel and the external environment;

∑a plasticiser, giving the material flexibility;

∑a lubricant, influencing the coefficient of friction.

The underlying role of water in acting as a plasticiser, a transport medium in the polymer matrix for dissolved species (such as oxygen) and a ‘bridge’ between the very different surface energies of synthetic polymers and body fluids, is responsible for the unique position that hydrogels occupy in the field of biomaterials. Thus, the permeability­ of the membranes, their mechanical properties, their surface properties and resultant behaviour at biological interfaces are all a direct consequence of the amount and nature of water held in this way.

The EWCs of hydrogels are governed by a range of factors. These include the nature of the hydrophilic monomer used in preparing the gel, the nature and density of the crosslinking agent (the most common crosslinking agent being ethylene glycol dimethacrylate) and external factors such as the temperature, osmolarity (and nature of the constituent ions) and pH of the hydrating medium. Although PHEMA is relatively stable to these external factors, this is not the case for hydrogels derived from other hydrophilic monomers; especially responsive to these factors are hydrogels that contain anionic or cationic monomers.

There is a great deal of evidence that has been accumulated to suggest that water in polymers can exist at any one time in more than one state and that these states of water in the hydrogel will also affect its properties. Various descriptions have been applied to the nature of water held in the hydrogel network, although these are not usually regarded as thermodynamically stable states. Rather, the water present in a polymer network can be envisaged to exist in a continuum of states between two extremes. These are, water strongly associated with the polymer network through hydrogen bonding, and water with a much greater degree of mobility, unaffected by the polymeric environment. Several techniques, such as differential scanning calorimetry (DSC) and nuclear magnetic resonance (NMR) have been applied to the study of water binding in natural and synthetic polymers and the ratio of the various states of water obtained will depend on the experimental technique used. The technique used to study water binding in hydrogels has to some extent determined both the number of states into which the water is classified and the terms used to describe those states. When water binding is studied by DSC, it is convenient and unambiguous to refer directly to the experimentally determined states (i.e. non-freezing and freezing water) rather than to imply any particular molecular interpretation. The properties of a hydrogel are therefore strongly influenced both by the EWC of the hydrogel and by the ratio of freezing to non-freezing water. This difference becomes less important as the EWC of the hydrogel rises but, as will become apparent, it affects behaviour quite markedly at values of EWC below that

the monomers decrease in the order: dhpma > HEA > HPA > HEMA > HPMA. As expected, the additional steric hindrance of the α-methyl group on the methacrylate polymer backbone means that the homopolymers of HEA and HPA are more hydrophilic, respectively, than those of HEMA and HPMA, respectively Similarly, the EWCs of the homopolymers derived from HPA and HPMA are more hydrophobic than those derived from HEA and HEMA, respectively, because of the extra CH2 group in the side chain. It is interesting to compare the isomeric monomers HPA and HEMA. The higher water content of the homopolymer (and copolymers) derived from HPA compared with those based on HEMA illustrates that a greater reduction in water content is obtained by inserting the methylene group on to the backbone, than introducing it in the side chain. This principle applies extensively in hydrogel copolymer systems.

A great deal of interest in the field of synthetics has focused on the synthesis of hydrogels that have higher EWCs than those attainable by hydroxyalkyl acrylates alone. One of the major driving forces has been the desire to produce contact lens materials with higher oxygen permeability than that achievable with PHEMA. In the 30 years following Wichterle’s original disclosure, well over 100 patent specifications described conventional

(non-silicone-containing) hydrogel copolymers for contact lens uses, many of them claiming oxygen permeabilities of a sufficiently high level for extended wear. The validity of this claim is considered in Chapter 12. The hydrogel chemistry disclosed in these patent specifications and the compositions currently used in commercial contact lens materials have been previously reviewed (Tighe, 1987, 2007).

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19.2.2 Vinyl amides and substituted acrylamides

One of the most widely used methods of producing hydrogels with enhanced water contents for contact lens use depends upon the incorporation of N-vinylpyrrolidone (NVP). The structures of this and other nitrogen-containing monomers are shown in Fig. 19.3.

The range of EWCs obtained by copolymerising HEMA with both the more hydrophilic monomer NVP and with methyl methacrylate (MMA), which has no independent hydrophilic characteristics, is exemplified in Fig. 19.4. This figure illustrates a general principle that is applicable to other monomers that are either more, or less, hydrophilic than HEMA. This provides an effective way of preparing copolymers of any desired water content from approaching zero to greater than 80%. The 60:40 NVP–HEMA copolymer, which is seen to have an EWC in excess of 70%, is still commonly used as a material for the manufacture of so-called high-water-content conventional hydrogel contact lenses.

Two further figures serve to extend these points and conclude this section.

Figure 19.5 shows how the EWC of the HEMA–MMA copolymers contained in Fig. 19.4 relates to the experimentally determined freezing water content. This illustrates the point previously made that water binding effects of this type become more markedly differentiated at lower water contents. The relevance of this effect to hydrogel behaviour will become apparent when the relationships between EWC and surface, mechanical and transport properties are discussed in the next section.

Figure 19.6 shows how variations in the structure of monomers that contain the hydrophilic —N—CO— grouping influence the EWCs of HEMA copolymers. The series shown in Fig. 19.6 is based on monomer ratios of

19.3 Structures of nitrogen-containing monomers: N, N-dimethyl acrylamide (NNDMA), acryloyl morpholine (AMO), N-vinyl pyrrolidone (NVP), N-methyl vinyl acetamide (NMVA) and N-vinyl acetamide (NVA).