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

19.4 Equilibrium water contents of copolymers of HEMA–MMA and HEMA–NVP.

19.5 Comparison of equilibrium water contents and freezing water contents of HEMA–MMA copolymers.

30:70 (wt:wt) of the N—CO— monomer with HEMA. It is important to note that this is not a universally applicable ‘hydrophilicity series’ because intramolecular hydrogen bonding competes with water binding in hydrogel polymers and the balance of these two effects varies with particular monomer pairs. Nonetheless, inspection of the monomer structures shows a similar balance of polar and steric effects to that seen with the hydroxyalkyl acrylates.

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19.6Equilibrium water contents of 70:30 (wt:wt) copolymers of

HEMA and monomers containing the N—C— group.

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The closeness of the nitrogen atom to the polymer backbone in the N-vinyl amides (NVP, NMVA and NVA) gives somewhat lower EWCs – for a given level of hydrophobic methyl or methylene substitution – than in the substituted acrylamides (AMO, NNDMA). Differences in reactivity ratios of the two families in copolymerisation provide useful versatility in influencing sequence distribution in hydrogels of similar water content.

The nitrogen-containing monomers represent the most widely used family of neutral hydrophilic monomers employed in the preparation of hydrogels that have EWCs greater than that of HEMA. Anionic monomers, such as sulphonates and carboxylates, are much more hydrophilic but are extremely susceptible to variations (e.g. pH, osmolarity) in their aqueous environment.

For that reason, their greater hydrophilicity is more difficult to exploit in applications where dimensional stability is important. The one monomer of this group that has found significant use in the contact lens field, particularly in disposable lenses, is methacrylic acid. Although the unionised carboxyl group is only modestly hydrophilic, at physiological pH the monomer exists in the form of the carboxylate anion. The level of hydrophilicity that this brings to hydrogels is illustrated by the fact that the range of EWCs shown (Fig. 19.6) by the incorporation into HEMA copolymers of 30 wt% of the nitrogen-containing monomers is achieved with only 3–4% by weight of methacrylic acid.

19.3Effect of hydrogel water content on properties

hydrogels. The central importance of transport phenomena, particularly oxygen permeability, to the contact lens field (see Chapter 12) led to the establishment of sound experimental methodologies. Standardisation of techniques for measurement of surface and mechanical properties of hydrogels in a reproducible and unambiguous manner has been more difficult to achieve.

This is in part becouse of the inherent properties that the materials possess, but to a large extent is related to the difficulties associated with the loss of water from the gel, when held in a non-aqueous environment. A variety of techniques has been used to probe the surface properties of hydrogels including sessile drop methods, inverted droplet techniques, the Wilhelmy plate method and predictive methods. All these methods have previously been described in detail and the many problems associated with the surface analysis of hydrogels have also been discussed. A similar level of attention has been paid to methodologies for the measurement of mechanical properties and useful summaries and descriptions of novel techniques have been presented (Yang et al., 2007; Ahearne et al., 2008; Lee et al., 2008).

19.3.1 Surface properties

Surface and interfacial properties are extremely important in the general biomaterials field and no less so in the area of ophthalmic biomaterials. One key aspect of this subject is the question of surface energy and, in order to deal with this, some definitions and concepts need to be addressed, starting with surface energy and surface tension. Surface tension has the dimension of force per unit length (mN/m), which is equivalent to the older erg/cm2 unit (i.e. energy per unit area). The term surface tension is synonymous with surface energy – which is a more useful descriptor since it applies equally to both solids and liquids. In surface chemistry the total surface energy (gt) of a covalently bonded liquid or solid is commonly and conveniently separated into polar (gp) and dispersive (gd) components. These are treated additively, i.e. gt = gd + gp. It is useful to summarise briefly the molecular implications as they relate to the particular features of hydrogels and biological interfaces. In covalently bonded molecules there are two weaker forms of intermolecular attractions – dispersion forces and dipole–dipole attractions. In addition, we have hydrogen bonding which is a stronger and much more specific form of intermolecular force. In surface energy considerations dipole–dipole and related forces taken together with hydrogen bonding are drawn together under the heading of ‘polar forces’ and are designated gp.

Dispersion forces are also known as van der Waals dispersion forces or London forces (named after Fritz London who first suggested how they might arise). The origin of van der Waals dispersion forces lies in temporary fluctuating dipoles. These arise because electrons are mobile, and are repeatedly asymmetrically located in a molecule. This constant mobility of

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the electrons in the molecule causes rapidly fluctuating dipoles. This sets up an induced dipole in adjacent molecules. The polarities continue to fluctuate synchronously in adjacent molecules so that attraction is maintained. As the number of electrons and the area over which they operate increases, so does the magnitude of the dispersion forces. Longer linear molecules can develop bigger temporary dipoles and can also pack more closely, as the contribution of rotational freedom at chain ends diminishes. As a result, dispersion forces (and the surface energies arising from them) increase as molecular weight increases – thus surface energy increases with molecular weight.

It is important to realise that all molecules experience dispersion forces. Dipole–dipole interactions are not an alternative to dispersion forces – they occur in addition to dispersion forces. Additionally, and perhaps surprisingly, dipole–dipole attractions (as distinct from hydrogen bonding) are fairly minor compared with dispersion forces. The consequence is that the additional effect of any dipolar contribution in polymers is usually relatively small. The increase in the dispersion forces as chain length increases from low molecular weight monomers and oligomers to polymers more than outweighs the usually insignificant contribution of dipole–dipole interactions.

The uniquely hydrogen-bonded structure of water and its ubiquitous presence in biological systems alter these considerations, however. Water has a total surface energy (or surface tension) of 72.8 mN/m. Of this total, the dispersive component is unexceptional (21.8 mN/m) and of similar magnitude to that of many covalently bonded liquids, whereas the polar component makes by far the dominant contribution (51.0 mN/m).

The significance of the magnitude of polar and dispersive components of surface energy becomes clearer when we consider the interfacial tension or interfacial energy between two phases. For the interface to be stable, the interfacial tension should be low. If there is an imbalance, a thermodynamic driving force will exist tending to reduce it. For a synthetic material in a biological environment, deposition processes usually achieve this. The interfacial tension (g1,2) between a solid (phase 1) and a liquid (phase 2) can be described in terms of the polar (gp) and dispersive (gd) components of surface energy of the two phases:

It can be seen by inspection that, for the interfacial tension to reach zero, the polar and dispersive components on both sides of the interface must match. Similarly, if a solid substrate has a polar component of zero, the interfacial tension between water and that substrate is going to be significant. Oils, fats and waxes, for example, have polar components that are very small and as a result show interfacial tensions with water of around 50 mN/m.

Hydrogels, as might be expected, show very low interfacial tensions with water but, in order to understand interfacial behaviour and the

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biological fluids such as blood and tears contain naturally occurring surface active molecules whose size generally precludes them from entering the hydrogel matrix. The consequence of the presence of these surface active species is that biological fluids show surface tensions appreciably lower than that of water (typically around 50 mN/m or below), which is achieved solely by reduction in the polar component. The consequence is that polar component values fall to around the level of the dispersive component (c. 20–25 mN/m), which is both lower than that of water and, initially at least, lower than that of the water-swollen matrix. This presents a paradox that will become increasingly apparent. In order to match both the polar and the dispersive component of tears, the EWC of the hydrogel would need to be reduced to a level such that water would make virtually no contribution to the desired transport and mechanical properties.

It is apparent that the types of synthetic hydrogels under consideration here do not suffer deficiencies in terms of inherent wettability, provided that they are fully hydrated. Two further factors influence their behaviour in the anterior eye, however. The first is the fact that the anterior surface of the lens will progressively lose water, especially in adverse environmental conditions. The second is that the polymer chains are able to rotate rapidly in response to a changed interface. In contact with aqueous fluids the hydrophilic groups rotate to the surface, whereas in contact with more hydrophobic interfaces, such as air or lipids during tear film break-up, the hydrophilic groups ‘bury’ themselves within the gel and a more hydrophobic surface is exposed. Chain rotation is a dynamic process, whereas evaporative water loss is a progressive process. Molecular processes such as protein deposition and denaturation are well able to respond to the dynamic processes, which is why the eye presents such a challenging environment. The progressive dehydration has a more influential effect on the gross surface properties of the hydrogel and is part of the complex process that produces end of day discomfort for many hydrogel contact lens wearers.

19.3.2 Transport properties

Oxygen permeability

The transport of the gas through a polymer membrane is expressed in the following terms:

In this expression, P is the permeability coefficient for a given combination of polymer and permeant (i.e. gas), D is the diffusion coefficient of the gas through the polymer, and S is the solubility of the gas in the polymer. Much of the standardisation work on oxygen permeability measurements with hydrogels has been related to contact lens materials and was carried

out by Irving Fatt, who chose to use the alternative term k to represent gas solubility (e.g. Weissman and Fatt, 1991). For this reason, the contact lens literature favours the use of the term Dk, whereas in membrane science, DS or more commonly, simply P is used. Thus Dk (or P) is the permeability coefficient for a given material, whereas DK/t or P/t refers specifically to the permeability (transmissibility) of a sample (such as a contact lens) of that material of a given thickness, t. The symbol L is also used to represent lens thickness, hence the term Dk/L is also found in the hydrogel literature.

In order to determine the permeability coefficient (P or Dk) of a material at a given temperature, it is necessary to measure the rate (volume per unit time) at which the chosen gas passes through a sample of membrane of given dimensions (area and thickness) for a given gas pressure. The units of Dk take these variables into account and are quite complex. It is common therefore to quote the value in barrers (1 barrer = 1 ∞ 10–11cm3O2 (STP) cm/s cm2 mmHg).

Since the oxygen passing through a contact lens is consumed by the cornea, it is apparent that, in principle, it should be possible to balance this consumption requirement with the oxygen flux through a contact lens of given dimensions and given conditions, and to define the required lens behaviour in terms of a permeability (Dk value). It is important to recognise, however, that the measured and quoted Dk values for contact lenses will only serve as a guide to their relative ability to deliver oxygen to the cornea. It is a very good guide, but not a precise indication. The question is much more critical in the case of extended (overnight) wear. For this reason it is important to identify carefully between the factors that affect the oxygen permeability of conventional hydrogels and to examine the principles involved in the development of so-called silicone hydrogels. This is the substance of Chapter 12, whereas this chapter will deal solely with factors affecting the permeability of homogeneous hydrogels.

In order to understand the permeability of hydrogel polymers, we have to look separately at the two terms that are involved: D and k, diffusion and solubility. While the diffusion term is related to the mobility of the polymer chains and the ease with which the oxygen molecule can meander through them, the solubility term is governed by the amount of oxygen that the material can dissolve. Incorporating water into a glassy polymer that resembles PMMA not only increases the ease of diffusion but also provides a medium that very effectively 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 and progressively increases the ease of diffusion. Because of this combined effect, 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 around 100 barrers.

Dk (barrers)

60

Dk (25∞C)

Dk (34∞C)

50

40

30

20

10

0

for a series of hydrogel membranes and commercial lenses as a function of water content. The figure contains data measured at both 25 °C and 34 °C.

Comparison of Fig. 19.8 with Figs. 19.7 and 19.5 illustrates the constraining factor in hydrogel design already referred to. Whereas the polar component of surface energy rises dramatically as water is introduced into the hydrogel, oxygen permeability – and indeed the permeability of all water-borne species

– rises only as freezing water becomes available. This latter fact has been well recognised by various workers and is indeed an important element of the design of reverse osmosis (salt rejection) membranes that allow molecular passage of water but not that of hydrated ions (Yasuda and Lamaze, 1971; Frommer and Lancet, 1972; Pedley and Tighe, 1979; Uragami et al., 1984; Hamilton et al., 1988; Murphy et al., 1988; McConville et al., 2002).

Permeation models and polymer–solute interaction

In addition to work on ionic inorganic species, the first two decades following

Wichterle’s disclosures saw a range of studies into the fundamental nature of permeation through hydrogels of a range of additional species including steroids, sugars and water itself (Yasuda et al., 1972; Zentner et al., 1979; Kim et al., 1980; Wisniewski and Kim, 1980). Because an understanding of the transport processes involved, and thus an ability to influence permeability and permselectivity, is important in applications such as reverse osmosis, kidney dialysis, sensors and drug delivery, there have been many attempts to rationalise available data in the form of a universally applicable transport model. Most of these seek to link permeability or diffusivity to the overall amount of water in the gel matrix. The free-volume model proposed by Yasuda is, perhaps, the one that has been most successful. This model applies to homogeneous water-swollen polymer matrices, where it is assumed that there is neither macroscopic phase separation of the polymer and non-polymer components nor any heterogeneity in these components. The free-volume model takes a partly thermodynamic, partly statistical approach in which the transported species is associated only with the water phase, with its diffusion being dependent upon the probability of it being located next to a suitable hole that is both unobstructed and large enough to accept the permeant. In the free-volume model the flux from high to low concentrations reflects the fact that fewer holes are occupied in the less concentrated regions and the penetrant has a higher probability of jumping to an unoccupied hole in the low concentration regions. The model predicts a linear relationship between ln P and 1/H, where P is the permeability coefficient in the hydrogel and

H is the degree of hydration. It also predicts that permeability decreases exponentially with increasing solute size and that the permselectivity of solutes increases as the degree of membrane hydration decreases. Other models have explored the applicability of the linear relationship between

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1/H and the logarithm of P or D, which gives the best fit for some sets of experimental data. More sophisticated models relate diffusion coefficient to an array of factors, including the degree of swelling, the radius of the solute, the number averaged molecular weight between crosslinks and function related to the mesh size, taking into account the effects of barriers such as those due to crosslinks and entanglements (Yasuda et al., 1968, 1969; Kojima et al., 1984; Peppas and Moynihan, 1985; Moynihan et al., 1986; Amsden, 1998; Hamilton et al., 1988; Murphy et al., 1988).

It is clear that the transport of small, water-soluble molecules through hydrogels with moderate to high EWCs is relatively well understood and predictable. The range of applications previously mentioned includes those in which permselectivity and controlled release characteristics are required. Here the chemical composition of the polymer, its water content, and the nature of the solute to be transported interact together to enable transport behaviour to be manipulated in such a way that a degree of specificity and control is achieved. In some applications it is desirable to circumvent the overriding influence of water content on the transport process. Two examples are silicone hydrogels, dealt with in Chapter 12, and macroporous hydrogels, which are described in Section 19.4.

19.3.3 Mechanical properties

In its dehydrated state, PHEMA (and indeed most other hydrogel-forming polymers) is hard and brittle. In this, it resembles PMMA. When swollen in water, however, it becomes soft and rubber-like with a very low tear and tensile strength. This lack of mechanical strength can have a profound effect on the usefulness of hydrogels as biomaterials. Even with a supported structure such as a contact lens, the lack of durability had a marked effect on the lifetime of the lens, which caused significant problems before the advent of disposability and frequent replacement. Although the water content has a marked effect on mechanical strength within a given family of materials, the chemical structure of the polymer also plays a large part.

This is not surprising, since mechanical properties are markedly influenced by chain rotation and even at an EWC of 50% the interchain distance is little more than 0.5 nm. By choosing co-monomers with bulky substituents (both cyclohexyl methacrylate and tetrahydrofurfuryl methacrylate have been used in this way) the energy barrier to rotation of the hydrogel polymer backbone can be raised considerably. In consequence, it is not difficult to increase the initial modulus – or stiffness – of a hydrogel. This approach does, however, reduce elasticity and achievable elongation of the hydrogel under tension. Increasing stiffness and reducing elasticity in this way often increases brittle failure and leads to a net reduction in tensile strength. It is generally true that homogeneous hydrogels compete poorly with natural tissue in terms of