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

11.1 Introduction

11.1.1 Historical note

Most people are surprised to learn that contact lenses were invented over 120 years ago – on 1 February, 1889, to be precise. On this day a 25-year-old medical student named August Müller (1864–1949) submitted the results of his final year project, entitled ‘Brillengläser und Hornhautlinsen’ (‘spectacle lenses and cornea-lenses’), to the University of Kiel in Germany (Pearson and Efron, 1989). As can be seen from Fig. 11.1, Müller wore spectacles to correct high myopia. In what must have been perceived as a bold and perhaps dangerous experiment, Müller fitted himself with large, thick glass contact lenses (known as ‘haptic’ lenses); however, he was only able to wear them for half an hour, and provided the following graphic description of his experience (Pearson and Efron, 1989):

Gradually, about a quarter of an hour after insertion, a sensation of pressure and burning appeared, which could not be localised exactly. After a further quarter of an hour, the sensation became so agonising that I had to remove

11.1 August Müller (here aged 66 years), the first person to fit contact lenses for the correction of myopia.

the lenses. Upon their removal, the violent pain immediately stopped and a short while after I could use the eyes again.

Müller was so disappointed with the results of his experiments that he gave up the idea of becoming an eye specialist and went on to practise as an orthopaedic surgeon.

This pioneering work signalled the beginning of the battle to develop contact lenses that could be worn comfortably and continually for many hours. As it turned out, Müller was entirely correct in ascribing the failure of his own lens- wearing experiments to ‘... a disturbance of nourishment of corneal tissue’.

Unlike all other tissues in the body, the cornea does not contain blood vessels (so that it can remain optically transparent); therefore, in order to respire normally, it must obtain oxygen directly from, and eliminate carbon dioxide directly to, the atmosphere. Although he did not know it at the time, Müller’s haptic lenses prevented this necessary exchange of respiratory gases.

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Up until 1938, all contact lenses were made of glass. Although glass is impermeable to oxygen, clinicians managed to circumvent this problem to some extent by introducing fenestrations (small holes) in the lens periphery to facilitate a limited tear exchange (and consequent gaseous exchange). After 1938, contact lenses began to be manufactured in clear plastic (Perspex

– poly(methyl methacrylate) or PMMA). PMMA had the advantages of being lighter and more durable (less likely to shatter), and it was easier to manufacture lenses using lathing and moulding technology. However, PMMA is also impermeable to oxygen, and strategies still had to be employed to facilitate corneal oxygenation during lens wear, such as the introduction of fenestrations and fitting smaller ‘corneal lenses’ that moved around on the cornea during blinking and enhanced tear and gaseous exchange beneath the lens.

Possibly the greatest understatement that can be found in the literature pertaining to contact lens development is the final sentence of a paper entitled ‘Hydrophilic gels for biological use’, published in Nature on January 9, 1960, by Wichterle and Lim (1960), which reads: ‘Promising results have also been obtained in experiments in other cases, for example, in manufacturing contact lenses, arteries, etc.’ This is the only mention in that paper, and the first mention in the scientific literature, of the possibility of manufacturing contact lenses from hydrophilic materials.

Initialattempts by Wichterle to produce softlenses from poly(2-hydroxyethyl methacrylate) (PHEMA), and manufactured using cast moulding, met with limited success. Unable to attract support from the Institute of Macromolecular Research in Czechoslovakia (now The Czech Republic) where he worked, and indeed discouraged by his superiors, Wichterle was forced to conduct further secret experiments in his own home. Working with a children’s mechanical construction kit, Wichterle developed the spin-casting technique and eventually managed to persuade his peers to conduct further trials at the Institute. He claims to have produced ‘the first suitable contact lenses’ in late 1961 (Wichterle, 1978), which presumably approximates to the first occasion when a soft lens was actually worn on a human eye. The patent to develop soft contact lenses was subsequently acquired by Bausch & Lomb in the USA, who introduced soft lenses commercially into the world market in 1972.

Lenses manufactured from PHEMA were an immediate market success, primarily by virtue of their superior comfort and enhanced biocompatibility.

However, clinical experience and laboratory studies indicated that the poor physiological response of the anterior eye during wear of the early thick

PHEMA lenses could be improved by making soft lenses more permeable to oxygen – specifically, by making them thinner and of a higher water content.

11.1.2 Physiological considerations

If a contact lens blocks off the normal oxygen supply, the corneal epithelium will become hypoxic and will begin to respire anaerobically. This leads to a build-up of lactic acid, which diffuses into the corneal stroma, creating an osmotic force that draws in water (Klyce, 1981). The cornea then develops oedema and becomes less transparent, and the eye becomes uncomfortable.

Carbon dioxide that is prevented by a contact lens from escaping from the corneal surface dissolves in the tears forming carbonic acid (Efron and Ang, 1990). The resulting acidosis compromises the physiological integrity of the cornea to a small extent, but the effects of hypoxia are far more critical. Other adverse hypoxic effects of contact lenses can include epithelial microcysts, epithelial thinning, stromal neovascularization, long-term stromal thinning, corneal warpage and endothelial polymegethism and pleomorphism (Efron,

2004).

The solution to the problem of hypoxia is to design contact lenses that maximize corneal oxygenation during lens wear. During the last quarter of the twentieth century, the majority of contact lenses fitted were made of soft hydrophilic materials. These lenses are fitted in such a way that they completely cover the cornea; therefore, the only option for preventing hypoxia is to use soft materials that are permeable to oxygen.

The ease with which oxygen can diffuse through a contact lens (defined by the term ‘oxygen transmissibility’, or Dk/t) is a function of the oxygen permeability (Dk) of the hydrogel material from which the lens is made and the thickness of the lens (a more complete definition of these terms is provided later in this chapter). A thinner lens provides less resistance to oxygen flow; however, nothing much can be done about lens thickness, because a lens must have a certain thickness profile to achieve the desired optical power for vision correction. Furthermore, if a lens is made too thin, it will fall apart. This leaves material Dk as the only variable. Hydrogel materials have water contents ranging from 35% to 75%. The higher the water content, the greater is the Dk – but higher water content materials tend to be more fragile.

During the waking hours, the cornea receives enough oxygen to avoid excessive oedema. There is a small but significant minority of patients who need or desire to sleep in lenses, but it is here that we encounter another problem that is best expressed as a paradox: even if it was possible to make an extremely thin contact lens out of 100% water, this would still not be sufficient to prevent corneal oedema during sleep. Slightly increased levels of corneal oedema are not dangerous in the short term (Efron, 2004); indeed, even in non-lens-wearers the cornea experiences low levels of oedema during sleep. Nevertheless, many changes can be observed in the cornea in association with chronic low level hypoxia and oedema, such as epithelial

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weakening, limbal vascular ingrowth, endothelial polymegethism and stromal thinning (Efron, 2004).

Perhaps the most critical of these chronic changes is a structural and metabolic weakening of the corneal epithelium. An intact epithelium provides a vital defence against invasion by potentially pathogenic microorganisms, which could either enter the eye by chance or,­ in a lens wearer, via contaminated fingers and/or contact lens storage solutions (Fleiszig, 2006).

The introduction of disposable lenses in the 1980s largely solved problems relating to the build-up of lens deposits; however, because the disposable lenses introduced at that time were still made of hydrogel materials, their capacity to minimize hypoxic effects such as oedema were just the same as non-disposable lenses.

As mentioned above, most lens wearers choose to sleep in contact lenses

(a practice known clinically as ‘extended wear’) because of the increased convenience; however, this introduces a greater physiological challenge to the eye than conventional daily ‘open-eye’ lens wear. During sleep, the atmosphere is replaced by the closed eyelid. Under these conditions, oxygen is derived from the capillary plexus of the palpebral conjunctiva – the vascularized tissue that lines the posterior surface of the eyelid. The oxygen tension in these vessels is 55 mmHg, which is about one-third of the oxygen tension in the atmosphere (about 155 mmHg at standard temperature and pressure at sea level) (Efron and Carney, 1979).

11.1.3 Silicone elastomer contact lenses

It had long been known in the contact lens industry that the physiological problems caused by conventional hydrogel lenses could potentially be overcome by making contact lenses from silicone rubber, which forms a unique category among contact lens materials. Silicone rubber is an optically transparent elastomer that has an extremely high permeability to oxygen and carbon dioxide and therefore provides minimal interference to corneal respiration; however, it is difficult to manufacture and its surface is hydrophobic and must be treated to allow comfortable wear. There was some patent activity in respect of attempts to manufacture clinically viable lenses from this material in the mid 1960s to early 1970s, and Mandell (1988) claims to have personally observed ten patients who were wearing such lenses in 1965, noting very poor clinical results.

A silicone elastomer contact lens is a ‘soft lens’ in terms of its physical behaviour and lenses are fabricated from this material in the form of a soft lens. Unlike all other soft lens materials, silicone elastomer does not contain water and in this respect is analogous to a hard lens material. The considerable difficulties involved in enhancing surface wettability severely limited the clinical application of this lens, and an alternative approach was required.

11.2 Silicone hydrogel contact lenses

11.2.1 Background

The allure of a contact lens made from a material with a phenomenally high oxygen performance never escaped the contact lens industry. The development of such a lens would be critical to solving the hypoxic lens-related problems outlined above. Polymer scientists in the contact lens industry had long recognized that many of the problems associated with silicone elastomers for contact lens fabrication could be theoretically overcome by creating a silicone–hydrogel hybrid.

The patent literature shows that combining silicone with conventional hydrogel monomers has been a goal for polymer scientists since the late 1970s. The greatest obstacle to this approach, however, is that silicone is hydrophobic and poorly miscible with hydrophilic monomers, resulting in opaque, phase-separated materials. In order to solve this problem, two main approaches have been utilized (Tighe 2004). The first approach involves the insertion of polar groups into the section of a siloxymethacrylate monomer known as tris(trimethylsiloxy)methacryloxy propylsilane (TRIS), at the point of the arrow in Fig. 11.2, in order to aid its miscibility with hydrophilic monomers (Tanaka et al., 1979; Künzler & Ozark, 1994). The second approach is that of utilizing macromers. Macromers are large monomers formed by preassembly of structural units that are designed to bestow particular properties on the final polymer (Tighe, 2004).

11.2 Molecular structure of key components of silicone-based contact lens materials. PDMS, polydimethylsiloxane; TRIS, tris (trimethylsiloxy) methacryloxy propylysilane; TPVC, tris(trimethylsiloxysilyl) propylvinyl carbamate.

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11.2.2 Market introduction

The first two silicone hydrogels were launched in the late 1990s – the balafilcon A lens (Bausch & Lomb) and the lotrafilcon A lens (CIBA Vision). Both were licensed for 30 days of continuous wear. The balafilcon A lens has an equilibrium water content (EWC) of 36% and a Dk/t of 110 barrer/cm (at –3.00D). The balafilcon A material is formulated by copolymerizing a carbamate-substituted TRIS-based material known as tris(trimethyl siloxysilyl) propylvinyl carbamate (TPVC) (Fig. 11.2) with

N-vinylpyrrolidone (NVP).

The lotrafilcon A lens has an EWC of 24% and a Dk/t of 175 barrer/ cm (at –3.00D). Tighe (2004) describes the lens as being a fluoroether macromer copolymerized with TRIS and DMA (N,N-dimethyl acrylamide) in the presence of a diluent. Its biphasic (two-channel) structure means that oxygen and water permeability channels are not reliant on each other. The silicone-containing phase allows passage of oxygen while the water phase primarily allows the lens to move.

Both of these lenses would be unsuitable for wear without further treatment due to the fact that the resultant material surfaces are very hydrophobic. In order to overcome this problem, both lenses are surface-treated using gas plasma techniques. High energy gases or gas mixtures (the plasma) are used to modify the lens surface properties without changing the bulk properties.

The result for the balafilcon lens is that surface wettability is gained via plasma oxidation, which produces glassy silicate islands on the lens surface (Maldonado-Codina et al., 2004a; Maldonado-Codina and Efron, 2005).

The lotrafilcon lens is coated with a dense 25-nm-thick coating. Both resultant surfaces have low molecular mobility, which minimizes the migration of hydrophobic silicone groups to the surface. However, despite these surface modifications, wettability problems with these lenses have been reported

(Maldonado-Codina and Morgan, 2007). It is generally accepted that these lenses have inferior wettability compared with conventional hydrogels; this occurs as a result of the hydrophobic interaction of silicone with the tear film.

Another important difference between these materials and conventional hydrogels is the fact that they have significantly greater elastic moduli, i.e. they are ‘stiffer’. Such mechanical characteristics mean that the lenses are easy to handle but they have also been implicated in the aetiology of a number of clinical complications (Dumbleton, 2003). These include higher incidences of superficial epithelial arcuate lesions, mucin balls and localized contact lens papillary conjunctivitis, especially with continuous wear of these lenses (Skotnitsky et al., 2002). The stiffness of the material may contribute to the mechanical irritation of the lens rubbing against the conjunctiva of the upper eyelid, producing a localized response.

The design of the lens, and in particular the edges, may have an impact on ocular compatibility. It has also been suggested that the design of the lens edge in conjunction with the mechanical properties of silicone hydrogel lenses may be responsible for increased conjunctival staining and conjunctival epithelial flaps observed with these lenses (Loftstrom & Kruse, 2005). A knife-point edge or chisel-shaped edge may cause more conjunctival staining and flap formation than a round edge by ‘carving’ into the conjunctival tissue. It has been proposed that certain edge designs incorporating localized increases in posterior edge lift, reduced peripheral thickness or peripheral channels may reduce the pressure on the conjunctiva (Weidemann and Lakkis, 2005).

11.2.3 ‘Second-generation’ lenses

In an attempt to improve on the problems encountered with the early silicone hydrogels, manufacturers have engaged in a programme of research aimed at manufacturing silicone hydrogel lenses with improved mechanical and surface characteristics. This has resulted in the gradual emergence of ‘secondgeneration’ silicone hydrogel lenses such as galyfilcon A, senofilcon A, narafilcon A, enfilcon A, comfilcon A and Clariti. Table 11.1 compares the properties of all the silicone hydrogel lenses currently on the market.

The main advantage of these second-generation silicone hydrogels, compared with the early silicone hydrogels, is that they have increased water contents and reduced moduli, and they do not need to be surface treated. The mechanical and surface properties can be thought of as being ‘in between’ those of conventional hydrogels and the early silicone hydrogels. Recent clinical work indicates that there may be a lower incidence of contact lens- induced papillary conjunctivitis with these lenses (Maldonado-Codina et al., 2004b).

Some of the lenses in Table 11.1 are based on materials containing

TRIS-like components. The Johnson & Johnson products – galyfilcon A, senofilcon A and narafilcon A – are based on Tanaka’s original patent (Tanaka et al., 1979), following its expiration after 25 years, ­using a modified

TRIS molecule, a silicone macromer and hydrophilic monomers such as 2-hydroxyethyl methacrylate and N,N-dimethylacrylamide. Alcohol is used as a solvent to aid the miscibility of these ingredients and is then extracted following polymerization. High molecular weight poly(N-vinylpyrrolidone) (PVP) is the internal wetting agent (‘Hydraclear’) used in these lenses, which is entangled and therefore ‘entrapped’ within the lens matrix. It is this that allows the lenses to be manufactured without requiring a surface treatment (Maiden et al., 2002; McCabe et al., 2004). The PVP essentially works by shielding the silicone from the tear film at the lens interface.

The CooperVision products – comfilcon A and enfilcon A – are not based on TRIS chemistry. They are composed solely of silicon-containing macromers

Table 11.1 Properties of currently available silicone hydrogel contact lenses

aUnited States Adopted Name.

bManufacturer-reported values.

Abbreviations: PVP, polyvinyl pyrrolidone, MPDMS: monofunctional polydimethylsiloxane; DMA, N,N-dimethylacrylamide; HEMA, hydroxyethyl methacrylate; EGDMA, ethyleneglycol dimethacrylate; TEGDMA, tetraethyleneglycol dimethacrylate; TRIS, trimethyl siloxysilyl; NVP, N-vinyl pyrrolidone, TPVC, tris-(trimethyl siloxysilyl) propylvinyl carbamate; NCVE, N-carboxyvinyl ester; PBVC, poly(dimethylsiloxy) di(silylbutanol) bis(vinyl carbamate); VMA, N-vinyl-N-methylacetamide; IBM, isobornyl methacrylate; TAIC, 1,3,5-triallyl-1,3,5-triazine-2,4,6(1H,3H,5H)-trione; M3U, bis(methacryloyloxyethyl iminocarboxy ethyloxypropyl)-poly(dimethylsiloxane)-poly(trifluoropropylmethylsiloxane)-poly(methoxy- poly[ethyleneglycol] propylmethylsiloxane); FM0411M, methacryloyloxyethyl iminocarboxyethyloxypropyl-poly(dimethylsiloxy)- butyldimethylsilane; HOB, 2-hydroxybutyl methacrylate; SIMA, siloxanyl methacrylate; SIA, siloxanyl acrylate.

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