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

The additional feature is the incorporation of poly(N-vinylpyrrolidone) (PVP) to enable an adequate degree of lens wettability to be achieved without subsequent surface treatment. The PVP is referred to as ‘HydraClear™’ technology and is sometimes described as functioning as an internal wetting agent (McCabe et al., 2004).

Galyfilcon A was launched as a precursor to an extended wear version, senofilcon A, which has the name Acuvue Oasys. This material is based on the same chemistry, but has a water content of 38% and a Dk of 103 barrers. These second-generation silicone hydrogels are formulated quite differently from the first generation, as indicated by the much lower modulus of Acuvue Oasys in comparison to PureVision, which has a similar water content. The other marked difference is the absence of a coating, as PVP is serving to provide a wettable lubricious surface. In this general time frame,

CIBA Vision launched a higher water content (33%) and lower Dk (110 barrers) version of Night & Day. This material (lotrafilcon B) was initially launched as O2 Optix and subsequently renamed Air Optix. The marked difference in modulus of the CIBA Vision and Bausch & Lomb materials approach on the one hand and the Vistakon formulation on the other is clear from Table 12.3. The most recent development in the Vistakon portfolio is Acuvue TruEye (narafilcon A). Although this combines a water content of 54% with a Dk of 100 barrers (Dk/t = 117), it is currently sold as a daily disposable material suggesting that reformulation to achieve improvements in process technology have been the main driver. In 2008/2009 CibaVision introduced ‘Aqua’ versions of both Air Optix and Night & Day. These changes involve a surface modification step brought about by introducing an N-vinylpyrrolidone-co-N,N-dimethylaminoethyl methacrylate copolymer (commercially available as Copolymer 845, ISP Corporation) to the lens packing solution before the final autoclaving step. The intention is to increase initial comfort. Although no characterisation data are available as yet, it is interesting that this is effectively a means of producing a PVP surface.

The next silicone hydrogel lens to appear was the CooperVision Biofinity (comfilcon A). It combines a water content of 48% (marginally higher than

Acuvue Advance) with an oxgen permeability of 128 barrers and a modulus intermediate between that of Air Optix and Acuvue Advance. A subsequent daily wear variant, Avaira (enfilcon A) has a similar water content (46%) coupled with a Dk of 100 barrers. The comfilcon material was immediately interesting for two reasons. The first was the absence of either surface treatment or an internal wetting agent. The second was the fact that the oxygen permeability is, on the basis of existing materials, unexpectedly high for its water content – as inspection of Table 12.1 shows. This is not, in principle, a completely unexpected development. The oxygen permeabilities of gas permeable materials vary over a wide range, indicating that the structure of the non-aqueous part of a silicone hydrogel will, equally, be capable of

330 Biomaterials and regenerative medicine in ophthalmology

influencing the achievable oxygen permeability at a given water content.

Similarly, the oxygen permeability of silicone rubber is appreciably higher than that of TRIS, indicating that replacing TRIS by more extensive linear sequences of siloxy material would lead to increased oxygen permeability. Examination of the relevant patent (Iwata et al., 2006) indicates that this strategy has been used.

The technology underpinning the comfilcon material originates in a Japanese patent filed in December 2000 by the Asahikasei Aime Co.,

Ltd. Asahikasei Aime Company entered into an agreement with Ocular

Sciences who subsequently became part of CooperVision leading to Iwata’s 2006 patent. There are two interesting disclosures, which give a clue as to the reasons for the departure of comfilcon from the previous ‘mould’ in which silicone hydrogels had been developed. The first is the fact that the conventional ‘TRIS’ monomer and its derivatives are not used. Instead, the patent claims that two siloxy macromers of different sizes, one of which is only monofunctionalised (contains only one polymerisable double bond), when used together produce advantageously high oxygen permeabilities. The second is the use of vinyl amides as hydrophilic monomers. Whereas these monomers are well known (indeed NVP is a vinyl amide), the specific advantages of N-methyl-N-vinyl acetamide, which is a central component in the Iwata patent, have not been previously harnessed in silicone hydrogels. The patent contains other subtleties which, taken together, appear to have enhanced the compatibility of the silicone moieties with the hydrophilic domains and produced a very useful addition to the silicone hydrogel product portfolio.

The most recent silicone hydrogel to emerge is the only material produced by a UK company. The patent (Broad, 2008) has interesting features of novelty and ingenuity in this intensely competitive area. The essence of the patent is the production of a silicone hydrogel with a wettable surface without use of coating or added internal wetting agent. This aspect of the invention is achieved by incorporating sufficient NVP to ensure that the product contains a significant proportion of PVP homopolymer. This might be regarded as a sequential semi-interpenetrating network, which enables

PVP to exert a similar surface influence to that encountered in patents that use preformed polymer in their formulation. The other element of novelty lies in the use of a siloxy monomer with a linear pendant polysiloxane chain

– essentially a monofunctional macromer, which is used in conjunction with 3-methacryloxypropyl tris(trimethylsiloxy) silane. This, together with the use of hydrophilic monomer in addition to N-vinyl pyrrolidone enables an optically clear product to be obtained. The currently available lens (Clariti) based on this technology is a daily wear lens with a water content of 58%, a Dk of

60 barrers and a modulus equivalent to that of PHEMA.

12.8Conclusions

12.8.1 Extended wear contact lenses: candidate materials

The criteria for successful extended wear, considered against the achievable properties of candidate materials, have led to the conclusion that, of the four families that have been examined for this type of contact lens, only three can meet current clinical requirements for oxygen transmissibility. Conventional hydrogels have many attractive features and from a theoretical standpoint it would be possible to meet the transmissibility requirements with ultra-thin (<50 μm), high water content (>75%) lenses. The practicalities of manufacturing an adequately durable lens to meet these constraints represents a considerable, but perhaps not insuperable, challenge. The combined approach of increasing water content and reducing lens thickness has received a considerable amount of attention in the past and has demonstrated that even if manufacturing and handling problems did not exist, there is a more major obstacle: lens dehydration. The proposed mechanisms and clinical consequences are beyond the scope of this discussion; suffice to say this has not proved to be a viable route to successful extended lens wear.

Each of the remaining candidate materials – silicone rubber, RGPs and silicone hydrogels – has attractions. Tables 12.2 and 12.3 summarise the oxygen transmissibilites of available examples of these materials and, in terms of oxygen transmissibilies alone, no single class would be excluded. The broad requirements discussed in Section 12.1, taken together with the clinical observations reported in Section 12.4, indicate that there is little or no prospect of success for a mass-market RGP or silicone rubber extended wear contact lens. Silicone hydrogels, in contrast, have developed into a wide-ranging family of materials as the information assembled in Table 12.3 shows.

12.8.2Comparative properties of conventional and silicone-modified hydrogel materials

Until the mid 1990s the three paradigm properties against which the potential success of new contact lens materials was judged were wettability, mechanical behaviour and oxygen permeability. There were clearly other more or less obvious considerations – such as optical clarity, cost, processibility, toxicity and deposit resistance – but in terms of measurable physical properties that could be used (on the basis of acquired clinical experience) to predict minimum acceptable baseline performance of a material, reliance was inevitably placed upon measurement by appropriate methods of its wetting properties, oxygen permeability and mechanical properties. As a general observation, it can be said that the properties of silicone hydrogels are in many ways similar to those of conventional hydrogels. The earlier sections of this chapter have raised questions, however, as to the adequacy of the

Water content, permeability and mechanical properties

As a general rule of thumb, the most significant effect of increasing water content in silicone hydrogels is a decrease in both oxygen permeability and stiffness. The extensive CIBA 1996 patent (Section 12.6) proposed an additional type of permeability measurement, which is linked to lens movement on the eye – aqueous and ionic permeability. The patent, which underpins CIBA’s

Night & Day material, not only describes the preparation of biphasic materials with high oxygen permeability, it also defines minimum levels of ion or water permeation that are sufficient to enable silicone hydrogel lenses to move adequately on the eye. These levels of permeability correspond approximately to values independently measured for PHEMA. Because of this, the relevance of this property increases as water contents of silicone hydrogels fall markedly below that of PHEMA – especially since the elastomeric ‘grab’ of the materials also increases with decreasing water contents.

Although achievement of a threshold level of ion permeability was relevant in terms of the polymer design of Focus Night & Day and perhaps Air Optix, which have water contents significantly below that of PHEMA, the passage of time has made it less relevant to the development of new materials. The move to higher water contents and lower moduli, enabled by moves away from TRIS and its variants to longer siloxane sequences, has ensured that the materials produced have adequate ionic permeabilities as a consequence of their inherent water content. Nonetheless the teaching in the patent, and its translation to practice, has provided valuable information. The practical benefits of the biphasic approach appear to be primarily in the achievement of higher oxygen permeabilities while maintaining ion transport at the level achieved by conventional hydrogels. Now that there is such a wide range of available silicone hydrogels, the relative perceived importance of higher oxygen permeability, at a cost of compromise in other properties, will be demonstrated by practitioner and patient preference.

The relative oxygen permeabilities of the nine materials shown in

Table 12.3 can be seen by inspection to show a general downward trend with increasing water content. Significantly, the permeabilities of the last four materials to be introduced all lie above the ‘TRIS’ line shown in Fig. 12.6. The primary advantage of materials with higher water contents is the consequent reduction in stiffness, and this is more important with silicone-containing than with conventional hydrogels. This is because the silicone content conveys

elements of elastomeric behaviour, which becomes more apparent as silicone increases and water decreases. One aspect of this behaviour is that the stiffness changes as the rate of deformation increases – the faster the deformation, the stiffer the material appears to be. The deformational movement of the eyelid is rapid, whereas the deformation produced by handling a material is slow. There has been no need with conventional materials to employ sophisticated testing techniques but with silicone hydrogels the separate assessment of the viscous and elastic components gives important information. It does seem clear that the effect of these mechanical property characteristics, together with the contribution of silicone segments to the wetting behaviour – particularly the high hysteresis – was in significant part responsible for the clinical complications, such as SEALS (superior epithelial arctuate lesions), corneal erosions and CLPC (contact lens-induced papillary conjunctivitis), that were associated with the early years of silicone hydrogel use. The first generation of silicone hydrogels provided a clinical spearhead and brought a wealth of experimental data to the study of contact lens behaviour (Sweeney, 2004). The fact that the subsequent silicone hydrogels moved to higher water contents reflects two things. The first is that clinical research and opinion suggests that less stiff materials would be likely to produce better clinical outcomes. The second is that laboratory evaluation demonstrated that the aim of producing silicone hydrogels with mechanical properties more closely resembling those of conventional hydrogels entailed reduction of the high-frequency elastomeric behaviour described above. This, in turn, is much easier to eliminate as percentage water contents rise above the mid 30s.

Surface properties and spoilation

The most obvious measure of surface properties is wettability. There are several ways of measuring wettability, but perhaps the most generally valuable for contact lens materials is the dynamic contact angle technique in which a sample of material is repeatedly and cyclically immersed in, and removed from, a test solution (usually saline or water). The reason that this technique is so valuable is that it reflects the breaking and reformation of the tear film. Hydrogels undergo relatively rapid backbone rotation at an air interface with hydrophilic groups clustered into the gel and presenting hydrophobic groups externally. When covered by the tear film, the polar water-loving groups surround the hydrophobic polymer backbone. When the tear film breaks and leaves the surface of the hydrogel exposed to air or to a deposited lipid layer (both of which are relatively hydrophobic), the structure is more dominated by the relatively hydrophobic polymer backbone. The consequence of this change in the surface structure is that the intrinsic wettability of the polymer changes. This change is very effectively reflected in the change in contact angle as an aqueous layer advances over, and then

334 Biomaterials and regenerative medicine in ophthalmology

recedes from, the surface. The advancing angle is designated as qA, the receding contact angle is designated as qR and the difference between them (the so-called contact angle hysteresis) is designated as qH.

There is a range of values of qA, qR and qH that have been found to correspond to minimum levels of clinical acceptability, and although values of around 70°, 20° and 50°, respectively, appear to be desirable for conventional hydrogels, materials showing lower wettabilities (i.e. higher values of qA and qR) perform reasonably well. It must be emphasised that wettability of unworn lenses as determined by dynamic contact angle is a necessary, but not sufficient, criterion for success. It is important that the material should retain its wettability (a) after spoilation by tear components, and (b) under load in friction studies.

For both conventional and silicone hydrogels, values of the receding contact angle generally lie between 25° and 45° with silicone hydrogels at the upper end of the range. The major difference between conventional and silicone hydrogels lies in the advancing contact angle, however. The advancing angle for silicone hydrogels is often around 100°, depending upon the time of exposure to air in the dipping cycle. A typical value for conventional hydrogels measured under the same conditions would be around 70°. All the currently available silicone hydrogels have wettabilities that are inferior to the best conventional hydrogels. This is not very marked until the materials are exposed to air – under these conditions that advancing contact angle rises sharply with time of exposure. The clinical consequence is that, as the front surface of the lens begins to dehydrate, it becomes very hydrophobic and consequently accumulates lipid deposits. This will be patient dependent and will be affected by a combination of tear break-up time and inter-blink period as well as tear lipid profile.

It is important to note that variations in individual tear chemistries frequently override differences between one material and another. There are, however, some useful generalisations to be made. The general tendency of hydrogels to undergo chain rotation, which is responsible for the differences in advancing contact angles of silicone hydrogels and conventional hydrogels, occurs much more readily in siloxane sequences than in carbon–carbon sequences. This has been discussed in Section 12.4. Additionally, silicones are hydrophobic, low surface energy materials. As a consequence, lipid accumulation is vastly greater on silicone hydrogel than on a conventional hydrogel surface. In contrast, protein accumulation on silicone hydrogels is very modest. For this reason, overall patterns of spoilation are quite different between the two classes of lens. Having commented that Focus Night & Day has the lowest water content and the highest modulus of the silicone hydrogels, it is important to indicate also that, because of the plasma coating on the lens, there is less opportunity for silicone group ‘dynamics’ at the surface. As a consequence, it has much more modest contact angle hysteresis and shows lower levels of surface lipid accumulation than the generality of silicone hydrogel lenses.

Biotribology and friction

Biotribology is concerned with lubrication, friction and wear at biological interfaces. The study of the biotribology of other body sites provides a sound basis for understanding the behaviour of the lens-wearing eye. The lubrication of the normal eye involves both aqueous and non-aqueous species (proteins, mucins, lipids, etc.) and mechanisms that are common to other body sites, such as articulating joints and lung alveoli. The contact lens influences these lubrication mechanisms, and when lubrication breaks down complications inevitably follow. In the in vivo situation, lid movement over the lens surface induces both movement of the lens on the cornea and transfer of shear forces to the ocular surface. Different contact lens materials show frictional differences, especially at start-up, but the presence and nature of the hydrodynamic lubricating layer are the single most important factors.

Because the retention of a liquid (hydrodynamic) layer is vital to the normal lens lubrication mechanism, it is clear that lens wettability is a necessary but not sufficient surface property criterion. Whereas measurement of advancing and receding contact angles provides information on the stability of the intrinsic wettability of the surface layer, measurement of the coefficient of friction under eyelid load gives an indication of the stability of the wetting layer during the blink. For conventional hydrogel lenses it has been demonstrated that, when this wetting layer (e.g. the tear film) is intact, the frictional behaviour of lenses is very similar. General observations about silicone hydrogels reflect the same behaviour but with differences of degree. The frictional coefficients of the silicone hydrogels with an intact lubrication layer are lower than those of most conventional hydrogels. This is a consequence of the techniques (internal wetting agent, etc.) that have been used to maintain the wettability of the lens. In contrast, changes of lubricating liquid and break-up of the lubricating layer cause appreciably greater increases in friction; a consequence of the inherent hydrophobicity and elastomeric character of the siloxy sequences.

It is clear that there is still some considerable margin for improvement in the surface properties of silicone hydrogel contact lenses. On the other hand, it must be emphasised that tremendous strides have already been made with this exciting group of materials. The properties of all the silicone hydrogel lenses described here are clinically acceptable and no one material is universally preferred. It is likely that perceived differences are driven as much by the patient as by the material. The problem of lipid deposition reflects this, because patient-to-patient variation in lipid levels is so marked and the propensity for lipid deposition is probably the single most undesirable feature of silicone hydrogels. Nonetheless, the development of silicone hydrogel extended wear lenses has been one of the major success stories in the history of the contact lens.

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12.9References

Bambury R E and Seelye D (1991), ‘Vinyl carbonate and vinyl carbamate contact lens material monomers’, US Patent 5070215.

Bambury R E and Seelye D (1997), ‘Vinyl carbonate and vinyl carbamate contact lens material monomers’, US Patent 5610252.

Broad R A (2008), to Sauflon CL Ltd, ‘Contact Lens’, WO/2008/061992.

Cleaver C S (1976), ‘Contact lens having an optimum combination of properties’, US Patent 3950315.

Efron N and Brennan N A (1987), ‘In search of the oxygen requirement of the cornea’, Contax, 1(6), 5–11.

Gaylord N G (1974), to Polycon Lab Inc., ‘Oxygen-permeable contact lens composition methods and article of manufacture’, US Patent 3, 808, 178.

Gaylord N G (1978), to Syntex USA Inc., ‘Methods of correcting visual defects: compositions and articles of manufacture useful therein’, US Patent 4, 120, 570.

Harvey T B (1985) Hydrophilic siloxane monomers and dimmers for contact lens materials and contact lenses fabricated therefrom US Patent 4,711,943.

Holden B and Mertz G (1984), ‘Critical oxygen levels to avoid corneal edema for daily and extended wear contact lenses’, Invest Ophthalmol Vis Sci, 25, 1161–1167.

Iwata J, Hoki T, Ikawa S and Back A (2006) Silicone hydrogel contact lens US Patent Application Number 11/213437.

Kunzler J and Ozark R (1994), ‘Fluorosilicone hydrogels’, US Patent 5321108. Lopez-Alemany A, Compan V and Refojo M F (2002), ‘Porous structure of Purevision

versus Focus Night&Day and conventional hydrogel contact lenses’, J Biomed Mater Res (Appl Biomat), 63, 319–325.

McCabe K, Molock F, Azaam A, Steffen R B, Vanderlaan D G and Young K A (2004), to Johnson & Johnson Vision Care Inc., ‘Biomedical devices containing internal wetting agents’, US Patent 6822016.

Nicholson P, Baron R, Chabrecek P et al. (1996), to CIBA Vision, ‘Extended wear ophthalmic lens’, WO 96/31792.

Robertson J R, Su K C, Goldenberg M S and Mueller K F (1991), ‘Wettable, flexible, oxygen permeable contact lens containing block copolymer polysiloxane–polyoxyalkylene backbone units and use thereof’, US Patent 5070169.

Sweeney D, Ed. (2004), Silicone Hydrogels (2nd Edition), Butterworth-Heineman, Oxford, UK.

Tanaka K, Takahashi K, Kanada M and Toshikawa T (1979), to Toyo contact Lens Co. Ltd, Japan, ‘Methyl di(trimethylsiloxy)silylpropyl glycerol methacrylate’, US Patent 4 139 548.

Tighe B J (1989), ‘Contact lens materials’, chapter 3 in Contact lenses practice (3rd edition), Phillips A J and Stone J, Eds, Butterworths, London, pp. 72–124.

Tighe, B J (2000), Silicone hydrogel materials – how do they work? Chapter 1 in Silicone Hydrogels: the rebirth of continuous wear, Ed D Sweeney. Butterworth–Heineman,

(pp 1-21).

Tighe, B J (2004), Silicone hydrogel materials – structure, properties and behaviour Chapter 1 in Silicone Hydrogels (2nd Edition), Ed D Sweeney. Butterworth–Heineman, (pp 1-27).

13

Designing hydrogels as vitreous substitutes in ophthalmic surgery

K. E. Swindle-Reilly and N. Ravi, Washington University in St Louis, USA

Abstract: In this chapter, the optimization of the design of vitreous substitutes will be discussed. First, a review will explain the structure and function of the vitreous humor and the need for a better vitreous substitute. The approach taken in this work will be to develop a biomimetic vitreous substitute. As a result, the next section will discuss the biomechanics of the natural vitreous humor and the development of an animal model for the ideal vitreous substitute. Mixture design is used to screen candidates rapidly for use as in situ-forming polymeric hydrogel vitreous substitutes. Statistical experimental design is used to determine the effects of the crosslinker content, hydrophobic substitution, and polymer concentration in the hydrogel on the optomechanical properties. In addition, the equilibrium swelling properties are characterized and the osmotic pressure exerted by the hydrogel is calculated to determine whether or not these hydrogels could tamponade the retina via exertion of a slight osmotic pressure as vitreous substitutes.

Key words: vitreous substitutes, vitreous humor, in situ-forming hydrogel.

13.1Introduction

For years, vitreous substitute research dealt primarily with looking for a biocompatible fluid capable of approximating the retina to the posterior of the eye. This has led to the development of several short-term vitreous substitutes. However, they are not appropriate for long-term or permanent vitreous substitution because of migration from the eye, toxic reactions, and other unsuitable properties (Chirila et al., 1998; Giordano and Refojo, 1998).

It would be more appropriate to design a vitreous substitute that mimics the physical and mechanical properties of the natural vitreous humor. Porcine, bovine, and human vitreous are natural hydrogels that have been tested by rheological methods to determine their viscoelastic properties, and the results have been recently summarized (Swindle and Ravi, 2007). It has been determined that the vitreous behaves as a viscoelastic solid with higher elasticity than viscosity.

Accordingly, the focus of recent vitreous substitute research has been on polymeric hydrogels. Hydrogels are hydrophilic polymers that form a gel network when crosslinked and are capable of absorbing several times their weight in water. The result is typically a clear viscoelastic gel that strongly

340 Biomaterials and regenerative medicine in ophthalmology

resembles the natural vitreous humor. Hydrogels are more favorable vitreous substitutes because they are clear, tend to be biocompatible, and can act as a viscoelastic damper much like the natural vitreous (Chirila et al., 1998). Additionally, hydrogels exhibit controllable swelling in aqueous solution, which enables the substitute to push the retina into place by exerting osmotic pressure while swelling (Brannon-Peppas and Peppas, 1990).

The main problem with preformed polymeric hydrogels as vitreous substitutes is that they irreversibly shear upon injection into the eye during vitrectomy. This irreversible destruction of the network causes the hydrogels to lose some of their elasticity and become more fluid-like and viscous. Additionally, shearing of the hydrogels through injection breaks the crosslinks in the gels, potentially decreasing biocompatibility as a result of the uncrosslinked polymer chains infiltrating the posterior segment and causing irritation and variation in swelling pressure (Hong et al., 1996; Vijayasekaran et al., 1996; Chirila and Hong, 1998).

This problem has been addressed by our process of in situ regelation. Our group has achieved regelation in situ with disulfide chemical crosslinks, which are found in natural biopolymers such as proteins. These disulfide crosslinks form when the thiol-containing polymer comes into contact with oxygen. There are other methods of in situ gel formation such as thermally reversible gels and ionic gels (Suri and Banerjee, 2006). However, the formation of chemical crosslinks is preferable because it improves biocompatibility, increases retention in the eye, and mimics the natural vitreous.

The vitreous humor is an avascular network occupying the majority of the volume of the eye. The vitreous fills the space between the retina and the lens, allows for clear passage of light, holds the retina in place, and dampens eye movements. A schematic of the eye is shown in Fig. 13.1. It is known that the vitreous is a natural hydrogel composed of 99% water and a framework of collagen and hyaluronic acid. Even in a normal eye the vitreous undergoes syneresis or degradation. The collections of collagen fibers are frequently referred to as ‘floaters’, which may interfere with vision. Liquefaction of the gel structure can cause degeneration or detachment of the vitreous. Retinal detachment occurs when the neurosensory retinal segments separate from the retinal pigment epithelium. A number of vision-threatening phenomena, such as macular holes, retinal detachments, and vitreous hemorrhage, are associated with this transition (Los et al., 2003).

The vitreous humor undergoes liqueifaction or transformation from a formed gel to a phase-separated fluid with advancing age, and in some cases it causes retinal detachments that can lead to blindness. The vitreous is removed during some surgical procedures and replaced with a vitreous substitute. No permanent vitreous substitutes are currently available, and the use of silicone oil as a vitreous substitute accelerates the formation of cataracts (Federman and Schubert, 1998).