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

mechanical properties. This point is illustrated by comparing the strength of synthetic hydrogels such as PHEMA with that of natural composite hydrophilic gels, such as articular cartilage, intervertebral disc and the cornea. Cartilage has a modulus and tensile strength more than ten times greater than that of PHEMA, despite having double the water content (around 80%). Illustrative data are included in Table 19.1.

In summary, the elastic behaviour and rigidity of hydrogels are closely governed by monomer structure and effective crosslink density, which includes not only covalent crosslinks but also ionic, polar and steric interchain forces. To achieve good strength, network perfection, rather than the chain rotational behaviour of individual segments alone is a key factor. By use of modified monomer combinations and crosslinking agents and reducing impurity levels, high-EWC copolymer networks with improved stability and elasticity can be prepared. The currently available commercial high-water- content lenses illustrate this attention to detail and are vastly superior in strength to the first generation of fragile gels of similar water content based on HEMA–NVP. As a general rule of thumb, however, it is still true to say that increased water content reduces durability, particularly resistance to tearing, and this still presents a major limitation to the widespread use of hydrogels in more demanding applications. The logical biomimetic approach is to try to use nature’s composite tissue structures as models, and the logical way to approach this is with interpenetrant technology, described in Section 19.4.

It is important to examine the way in which increases in EWC influence mechanical properties – progressively and linearly or resembling either oxygen permeability on the one hand or surface properties on the other. Figure 19.9

Table 19.1 Mechanical properties under tension (modulus, Emod; tensile strength, Ts; and elongation at break, Eb) of hydrogel interpenetrating networks and reference materials based on: cellulose acetate butyrate (CAB), polyurethane (PU), tetrahydrofurfuryl methacrylate (Thfma), N,N-dimethyl acrylamide (NNDMA), acryloyl morpholine (AMO), N-vinyl pyrrolidone (NVP) and methyl methacrylate MMA).

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19.4.1 Semi-interpenetrating polymer networks

In the past two decades there has been a growing interest in applying polymer blend, composite technology, and interpenetrating network technology to hydrogels, principally because of the enhanced mechanical properties that these systems often possess. Expectation exists that this approach may enable the design of synthetic hydrogels that mimic some aspects of the behaviour of biological composites. There is sometimes confusion about the precise distinction between blends and composites when applied to polymers. Blends have been defined as ‘a mix of components which are inseparable and indistinguishable’ in contrast to the definition of composites as ‘a material made of constituents which remain recognizable’. Problems arise, however, when trying to apply these terms on a molecular level. Interpenetrating polymer networks (IPNs) have been more specifically defined as a combination of two polymers, each in network form, at least one of which has been synthesised and/or crosslinked in the presence of the other. Varying methods are used to synthesise IPNs and this, in turn, determines the class of IPN produced. These methods may be described as follows.

1.Monomer I is polymerised and crosslinked to give a polymer which is then swollen with monomer II plus its own crosslinker and initiator. Polymerisation of monomer II in situ produces a sequential IPN.

2.If only one polymer in the system is crosslinked, the network formed is called a semi-IPN (SIPN). With sequential polymerisation four such semi-IPNs may be produced.

3.Simultaneous polymerisation, of a solution of both monomers with their crosslinkers and initiators, by two different, non-interfering methods produces a simultaneous-IPN or SIN.

Although these materials are known as IPNs, it is only if there is total mutual solubility that full intermolecular interpenetration occurs. In most IPNs there is, therefore, some phase separation but this may be reduced by chain entanglement between the polymers. IPNs have been used in a wide range of applications and several reviews are available describing both these applications and the fundamental theory of IPNs (Frisch et al., 1981; Sperling, 1981; Klempner and Berkowski, 1987).

Hydrogel IPNs usually consist of a linear reinforcing polymer and an entwined crosslinked hydrogel copolymer. A similar principle describes the function of collagen, which reinforces the hydrophilic matrix of natural hydrogels such as articular cartilage. This technology allows hydrogels to be synthesised that have water contents similar to conventional hydrogels but which are mechanically tougher and stronger. Using this approach several examples of semi-interpenetrating hydrogel polymer networks (SIPNs) have been prepared in which preformed polymers are dissolved in hydrophilic

monomer and crosslinking agent mixtures, which are subsequently polymerised. In this way a synthetic hydrogel network is formed around a primary polymer chain with the primary polymer modifying the behaviour of the hydrogel.

The most obviously beneficial effects of interpenetration techniques used in this way relate to mechanical behaviour, but water binding, surface and optical properties are also affected. Optical properties are most strongly influenced by compatibility phenomena, which occur at two levels. The initial solubility of the ‘filler’ polymer and matrix monomer governs the first essential step in SIPN formation. This dissolution process can be assisted by use of non-reactive solvents that are subsequently removed but this has no beneficial effect on the compatibility of matrix polymer and ‘filler’ polymer in the dehydrated state. In hydrogel-based IPNs, additional and separate compatibility considerations in the hydrated state are involved because of the necessary presence of water as the essential third component. Translucence in the hydrated systems is generally a result of preferential water clustering around the more hydrophilic moieties creating a degree of phase segregation of hydrophobic blocks. Although high-water-content, optically clear SIPNs have considerable potential utility in ocular applications, translucent or opaque materials are of potential value both in non-ophthalmic biomaterials such as wound dressings and synthetic articular cartilage and in ocular implants and devices that do not demand optical clarity (Corkhill and Tighe, 1990, 1992; Corkhill et al., 1993).

Table 19.1 illustrates the use of interpenetrating network technology with two different types of interpenetrant in the synthesis of both translucent and optically clear systems exhibiting a range of mechanical properties. The properties of typical conventional homogeneous hydrogels are shown for comparison, together with articular cartilage. The marked effect that SIPN formation has in increasing initial modulus and tensile strength at the expense of elasticity is of considerable interest, since these are the characteristic ways in which biological composite hydrogels differ from their homogeneous synthetic counterparts.

Practical use has been made of hydrogel IPN technology in two quite different types of ocular device: the hydrogel keratoprosthesis (Chirila, 2001) and the contact lens (Hu et al., 2000; Maiden et al., 2002; Broad, 2008). Whereas the purpose of the IPN in the keratoprosthesis is to promote mechanical integration, the contact lens applications quoted have a different purpose. They make use of the observation that surface properties of SIPN materials are influenced by the nature of the interpenetrant. It was pointed out at the beginning of this section that interpretation of the molecular nature of polymer composites is difficult, but it appears that the materials described by Hu’s and Maiden’s groups are conventional SIPNs in which poly(ethylene glycol) and poly(N-vinylpyrrolidone), respectively, are used to enhance the hydrophilicity of the contact lens surface. The materials described by Broad,

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however, appear to involve sequential IPNs formed in situ from NVP for the same ultimate purpose. Commercial silicone hydrogel contact lenses that make use of the different technologies described in Maiden’s and Broad’s patents are described in Chapter 12.

19.4.2 Macroporous hydrogels

The versatility of hydrogel polymers and their numerous potential applications in the field of biomedicine stem from the extensive range of hydrophilic monomers available for their formation and from the ability to control the extent and nature of water binding within the polymer matrices. One feature of the materials is that in homogeneous hydrogels the transport properties are limited by effective mean pore, or mesh, diameters within the polymer. Although this feature may be employed to advantage in the design of permselective membranes, it limits the utilisation of hydrogels for the transport of high molecular weight species. This limitation is of prime importance in the design of hydrogels for use as sorbents in haemoperfusion and in macromolecular drug-delivery systems. An additional aspect of the application of hydrogels in bodily repair and regeneration is their use in implants requiring cellular integration, such as articular cartilage repair and keratoprosthesis.

Three different approaches to the preparation of macroporous hydrogels illustrate the fact that both pore size and detailed morphology can be manipulated in response to the requirements of different applications. These approaches are:

∑freeze–thaw polymerisation;

∑incorporation of water-extractable porosigens;

∑phase-separation polymerisation.

The first two of these methods of increasing the effective pore size of polymers involve polymerising monomers around a crystalline matrix that is subsequently dispersed or dissolved to leave an interconnected­ meshwork.

The significance of the freeze–thaw technique for hydrophilic monomers lies in the fact that aqueous systems can be induced to form ice-based crystalline matrices by rapid cooling of homogeneous solutions of these monomers. Crosslinking monomers are necessary to control the integrity of the resultant macroporous polymers and the solubility of the non-aqueous components must be maintained during cooling to avoid phase separation before ice crystal formation. The formation of macroporous hydrophilic matrices by the freeze–thaw technique consists, in principle, of freezing a monomer/ crosslinker/solvent mixture on to a cold plate, or by dropping the mixture into a cold non-solvent, to create a system that consists of a solid monomer matrix around and between solvent crystals. This monomer matrix is then

519 hydrogels of properties Physicochemical

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polymerised by photopolymerisation, utilising a water-soluble photocatalyst, such as uranyl nitrate. After polymerization, the aqueous solvent is removed by thawing and a macroporous polymer results. The principle can be employed to prepare membranes or particulates with morphologies based on interconnected pores with diameters in the range 1–20 μm (Krauch and Sanner, 1968; Haldon and Lee, 1972; Skelly and Tighe, 1979; Murphy et al., 1992; Oxley et al., 1993).

Polymerisation around pre-formed porosigens, although less elegant than freeze–thaw polymerisation, does allow a wider range of hydrogel compositions, including IPNs, to be prepared in macroporous form. Additionally, hydrogels with larger pores and asymmetric pore distributions can be prepared. These features are illustrated in Fig. 19.10.

The most dramatic success in the practical use of macroporous hydrogel technology in ophthalmic applications is found in phase separation technology and its application to the AlphaCor™ keratoprosthesis. The principle of phase-separation polymerisation lies in the selection of a solvent in which the monomer system but not the resultant polymer is soluble. Above a particular concentration of, in this case, water, phase-separation develops during polymerisation (Chirila et al., 1993; Chirila, 2001).

19.4.3 Silicone hydrogels

Macroporosity provides a means of overcoming the limitations imposed by the presence of the polymer structure on transport through the aqueous phase of the hydrogel. Silicone hydrogels seek to make use of the polymer to enhance transport through the gel. The principle is simple: since silicone rubber has an oxygen permeability at least ten times greater that that of water, why not make use of that in preparing ‘super-permeable’ hydrogels? As is often the case, the principle is simple but translating it into practice is not. The last decade has seen the principle harnessed so successfully that it now forms the basis of a multi-billion dollar industry – the silicone hydrogel contact lens. This is such a large and important subject that it requires separate treatment, and is discussed in Chapter 12.

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