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

of all blindness (Resnikoff et al., 2004). As a result, cataract formation is a substantial economic and public health burden.

2.4Cataract surgery and intraocular lens materials

Treatment of cataracts by extraction of the natural opacified lens and implantation of a polymeric IOL is currently the most common ophthalmic procedure, with approximately 6 million surgeries performed worldwide each year (Werner, 2007). Over the past 50 years, the route of surgical implantation and the nature of the materials implanted have evolved greatly. The observation by Harold Ridley that both glass and acrylic, under certain conditions, appeared to be inert within body tissues (Apple and Sims, 1996), coupled with their optical qualities and the fact that these materials were relatively inexpensive and easy to fashion into shapes, has led to the development of the materials currently used today. An appropriate biological host response to the implanted lens material is critical for maintenance of IOL transparency and visual acuity, particularly as IOLs are progressively being implanted in earlier stages of life (Werner, 2008). Developments in lens materials and designs have resulted in marked improvements in this respect.

IOL materials in current clinical use are grouped into two major categories: acrylic and silicone. Among the acrylics, the most commonly used material for

IOLs since their development in 1949 is poly(methyl methacrylate) (PMMA), a rigid polymer that is well established, particularly in developing countries, owing to its cheapness and long-term reliability (Yuan, 2003). Newer, foldable lenses are now preferentially used as they require smaller incisions for implant insertion. These are made from either hydrophobic or hydrophilic (i.e. hydrogel) acrylic materials such as poly(2-hydroxyethyl methacrylate), and vary in refractive index, mechanical properties and water content based on the copolymer composition (Werner, 2008). Foldable silicone-based IOLs are also highly elastic, oxygen permeable and chemically stable, and their lower refractive index (~1.41 compared with ~1.47) results in reduced glare compared with acrylic versions (Yao et al., 2006). Because they fill the entire lens capsule, the need for fixation of these lenses by polymeric haptic loops is avoided and the implant more closely mimics the natural lens (Hettlich 1991; et al., Werner, 2008). In addition to differences in refractive index, the major differentiating property between foldable acrylic and silicone IOL materials is the glass transition temperature which leads to differences in unfolding time between the different materials.

2.5Biological responses to intraocular lens materials

Upon extraction of an opacified lens and implantation of an IOL in the remaining lens capsular bag, a breakdown of the blood–aqueous barrier

20 Biomaterials and regenerative medicine in ophthalmology

(BAB) occurs with immediate release of proteins and cells into the anterior eye chamber. Numerous biological interactions to the foreign IOL material ensue; these initially include nonspecific protein deposition and complement activation, and subsequent inflammation, foreign-body response, and cellular adhesion, transformation, migration and proliferation (Yuan, 2003; Werner, 2008). Several different aspects of the host response must be assessed for an IOL material, including both capsular biocompatibility (the relationship of the IOL with the epithelial cells remaining in the lens capsule) and uveal biocompatibility (the inflammatory foreign-body reaction upon contact with the vascularized tissue of the iris, ciliary body and choroid) (Amon, 2001;

Werner, 2008). The biocompatibility of a specific material in both of these respects is the subject of significant recent research, and depends on the nature of the cell–material interaction as dictated in turn by the underlying material surface properties and chemical structure.

2.5.1Capsular biocompatibility

In most cases, the IOL comes only into direct contact with the capsular bag tissue, and resulting complications may include development of opacities in the anterior (ACO) or posterior (PCO) capsule, and capsular contraction. PCO remains the most significant late postoperative problem following cataract surgery. Because the capsule membrane is an integral part of the lens structure, it remains a platform for cellular adhesion and migration after surgery. Residual lens epithelial cells (LECs) under the anterior capsule can migrate along the posterior capsule, and upon aggregation into multilayer islets and transformation into mesenchymal cells in a process known as EMT (epithelial to mesenchymal transition), result in opacification of the central region behind the IOL and ultimately reduced vision (Yuen et al., 2006). These LECs aggregates swell and excrete extracellular matrix components including cytokines and matrix metalloproteinases which further induce proliferation and transformation of the LECs. The transformed cells become more fibroblastic and contractile in phenotype, leading to contraction and wrinkling of the capsule and to eventual decentring of the IOL (Yuen et al., 2006). While PCO is typically treated by opening the opacified capsule with a neodymium: yttrium–aluminium–garnet

(Nd:YAG) laser, risks associated with this procedure include IOL damage, intraocular pressure elevation, cystoid macular oedema and retinal detachment; additionally, such laser technology is not readily available in the developing world (Yuen et al., 2006; Cheng et al., 2007).

2.5.2Uveal biocompatibility

An IOL material may additionally invoke an inflammatory reaction upon implantation. As a result of surgical trauma causing disruption of the BAB,

and in some instances direct contact of the IOL with vascularized uveal tissue, the IOL is exposed to an influx of proteins and inflammatory cells (Amon,

2001). Following initial adsorption of proteins to the surface, monocytes, macrophages and small fibroblast-like cells may then adhere through this protein layer and, upon activation, secrete cytokines to further intensify the course of the inflammation. These cells later fuse into epithelioid and foreign-body giant cells, resulting in chronic inflammation or deposition of an acellular proteinaceous membrane that is commonly detected up to 1 year after surgery (Amon, 2001; Werner, 2008). It has been suggested that PCO itself may be a late form of postoperative inflammation, as inflammatory mediators derived after BAB damage or synthesized by macrophages can also stimulate LEC proliferation and migration (Tognetto et al., 2003b; Yuen et al., 2006). Inflammation may result in decreased contrast sensitivity in the patient, damage to the corneal endothelial layer and other implications that are not yet understood (Werner et al., 1999; Yamakawa et al., 2003).

2.5.3Lens design and material effects

While some degree of inflammation and foreign-body reaction occurs in all eyes following IOL implantation, the severity is dependent on the lens design and material factors such as surface chemistry, stability and mechanical properties. In a study by Yamakawa and coworkers, adhesion of inflammatory cells to PMMA IOLs decreased with increasing polishing time and smoothness of the IOL, possibly owing to reduced adsorption of cell-adhesive matrix proteins on smoother surfaces (Yamakawa et al., 2003). Hydrophobic acrylic IOLs with intermediate values of wettability, such as PMMA, are generally associated with stronger uveal cell adhesion and growth compared with other materials (Werner et al., 1999; Tognetto et al., 2003a); however the increased inflammation caused by PMMA IOLs versus other types has been shown in some but not all studies (Ozdal et al., 2005). High small-cell counts and membranous deposition have also been detected on silicone IOLs (Ozdal et al., 2005; Yao et al., 2006).

Similarly, changes in surgical technique and the design of IOLs have been instrumental in reducing PCO rates although no clinicalor material- based factor has eliminated this complication all together. In particular, the use of a square rather than a rounded edge is thought to act as a barrier to the ingrowth of LECs migrating from the lens equator along the posterior capsule, an effect that is observed among different IOL materials (Wejde et al., 2003; Cheng et al., 2007). The effect of the IOL material itself on

PCO development is less clear, although this has been demonstrated to be significant in various clinical studies. It is noted that the effect of IOL design, surgical technique and patient-related factors is often difficult to separate

22 Biomaterials and regenerative medicine in ophthalmology

from that of the material alone in these studies, and a combination of these factors probably dictates the overall outcome (Heatley et al., 2005).

It was observed (Wedje et al., 2003) that less PCO formation occurred after 2 years on hydrophobic acrylic versus silicone IOLs. However, other studies (Findl et al., 2005; Hayashi and Hayashi, 2007) have shown that both silicone and hydrophobic acrylic IOLs had low rates of PCO when a square-edge design was introduced. Heatley et al. measured significantly lower PCO levels in hydrophobic versus hydrophilic acrylic lenses (Heatley et al., 2005). In a meta-analysis of 23 clinical trials (Cheng et al., 2007), it was determined that silicone and hydrophobic acrylic IOLs were more effective in preventing PCO than both PMMA and hydrogel IOLs.

The reasons for these differing responses to the various IOL material types is not fully understood, and may be a result of differences in protein and subsequent cell adhesion following implantation. According to the

‘sandwich theory’ proposed by Linnola, faster and stronger adhesion of the IOL material to the capsular bag, either directly or through a uniform monolayer of LECs, will prevent further LEC growth between the IOL surface and capsule implicated in PCO (Linnola et al., 2000a; Linnola et al., 2003). As such, adsorption of certain extracellular matrix proteins including fibronectin and vitronectin, which are present in plasma or synthesized by

LECs themselves, can mediate the subsequent adhesion of the LEC and/or the collagenous lens capsule to the IOL material and may result in reduced

PCO rates. Hydrophobic materials may be more conducive to such protein and cell binding, although the high incidence of PCO on both hydrophobic silicone and hydrophilic hydrogel IOLs indicates that a simple correlation between polymer wettability and biocompatibility does not exist (Linnola et al., 2003; Okajima et al., 2006). Higher levels of fibronectin and associated lens capsular adhesion were measured on hydrophobic versus hydrophilic acrylic, PMMA and silicone lens materials (Linnola et al., 2000a; Linnola et al., 2000b; Linnola et al., 2003), in accordance with the lower PCO rates observed clinically (Wejde et al., 2003). Vitronectin, which was detected on hydrophobic acrylic IOLs may also play a role in enhancing IOL–capsular bag adhesion or healing after implantation (Linnola et al., 2000a; Linnola et al., 2000b). Conversely, collagen type IV is a constituent of fibrotic PCO tissue, and higher amounts of this protein were detected on silicone, hydrophilic acrylic and other hydrogel IOLs which were less stimulatory to cell growth and adhesion (Linnola et al., 2000a; Linnola et al., 2003).

2.5.4Surface modification for reducing complications

the interactions of the lens surface with the cellular membranes of macrophages (Tognetto et al., 2003a). The mobile surface structure of heparin-surface- modified (HSM) IOLs appears normal to the host immunological system, thus preventing a foreign-body reaction against the IOL (Werner et al., 1999).

HSM-PMMA IOLs showed reduced spreading and growth of fibroblasts and inflammatory cells versus those made of conventional PMMA (Larsson et al., 1989; Werner et al., 1999); they were, however, less biocompatible than hydrophobic AcrySof (Alcon, Inc.) and silicone IOLs in terms of inflammatory cell adhesion, ACO and PCO (Tognetto et al., 2003a; Wejde et al., 2003). Work continues into the use of heparin coatings to prevent cell adhesion and reduce inflammation (Schroeder et al., 2008). Binding of Teflon, carbon and titanium to render PMMA IOLs more hydrophobic was also found to reduce inflammation in several studies; however, results in humans have yet to be demonstrated (Werner et al., 1999; Yuan, 2003; Yuan et al., 2004).

Silicone IOLs have been modified by grafting of MPC, resulting in decreased adhesion of macrophages as well as LECs (Yao et al., 2006).

Surface modification of IOL materials has also been investigated as a way of controlling LEC growth and adhesion to inhibit PCO development.

Formation of a uniform, morphologically correct layer of LECs on the IOL surface may simulate normal optics of the human lens and adherence of the capsule according to the sandwich theory (Linnola et al., 2003). The hydrophilicity or hydrophobicity of the material can affect, and in extreme cases inhibit, LEC adhesion and maintenance of normal cellular phenotype (El Khadali et al., 2002). Yuen et al. showed that plasma treatment of IOLs increased their hydrophilicity and enhanced LEC adhesion and maintenance of normal epithelial morphology, when compared with untreated surfaces where a fibroblastic appearance was observed that could potentially promote PCO (Yuen et al., 2006). Silicone IOLs, which due to their extreme hydrophobicity do not adhere to the lens capsule tissue, were modified with oxygen plasma to increase cell spreading (Hettlich et al., 1991). Plasma treatment may also contribute to the low PCO rates observed clinically in

AcrySof hydrophobic IOLs (Matsushima et al., 2006). It was demonstrated that UV/ozone treatment, which may be less damaging to the polymer surface than plasma modification, was more effective in increasing surface wettability, and fibronectin and LEC adhesion on hydrophobic acrylic IOLs, while inhibiting LEC proliferation and PCO formation in a rabbit model (Matsushima et al., 2006). An alternative approach for reducing PCO is the complete prevention of protein and subsequent cell adhesion to the IOL surface. Hydrogel IOLs were coated with poly(ethylene glycol) (PEG), which is well known to sterically inhibit the attraction of proteins and cells to surfaces, and protein deposition and LEC adhesion were reduced in vitro (Bozukova et al., 2007). Modification of silicone IOLs with poly(2- methacryloyloxyethyl phosphorylcholine) (MPC), a biomimetic component

24 Biomaterials and regenerative medicine in ophthalmology

of the cell membrane, increased hydrophilicity and inhibited LECs and fibrosis (Yao et al., 2006); however, similar experiments with hydrophobic acrylic IOLs indicated that migration of LECs toward the posterior capsule may in fact be stimulated by such MPC treatment (Okajima et al., 2006). Changing the chemical composition of PMMA, poly(HEMA-co-MMA) and silicone by introduction of sulfonate and carboxylate groups resulted in decreased LEC and fibroblast growth compared with the unmodified polymers, probably as a result of a conformational change in adsorbed fibronectin and vitronectin leading to altered intracellular signalling in the attached cells (Latz et al., 2000; El Khadali et al., 2002; Evans et al., 2004; Yammine et al., 2005).

2.5.5Drug-releasing IOLs for mitigating complications

IOLs that deliver drugs that hinder LEC proliferation or reduce inflammation may have potential for reducing complications. While a choice of potent drugs is currently available, there are other limitations to designing drugreleasing IOL materials. Most importantly, the loaded material has to maintain transparency above the 1.382 refractive index limit (Lloyd et al., 2001). The material should also remain foldable and easily manipulated, to avoid other surgical complications, especially in paediatric patients (Rowe et al., 2004).

IOL materials, particularly acrylics and hydrogels, have been examined for the release of antibiotics, anti-inflammatory drugs and other molecules that have the potential to decrease complications such as PCO. For example,

IOLs containing a drug-delivery system releasing the steroid dexamethasone or other similar molecules have been tested in rabbit eyes, and may further prevent inflammation following cataract surgery (Kleinmann et al., 2006a; Kleinmann et al., 2006b; Siqueira et al., 2006). However, these studies have not advanced to human trials. Hydrogels releasing such drugs as diclofenac sodium, tranilast, mitomycin C, colchicines, ethylene diamine tetraacetic acid and 5-fluorouracil were tested in vitro (Matsushima et al., 2005), and may present an alternative route for management of PCO.

Coating of IOL materials with degradable polymeric drug-delivery systems has also been used to facilitate the delivery of drugs from these materials. This method avoids direct modification of the IOL material, and therefore does not interfere with optical properties. Release duration can be modulated by coating thickness. The first report of an IOL-associated controlled drug release system came from Tetz and coworkers in 1996 (Tetz et al., 1996), who used poly(dl-lactide) containing the drugs daunorubicin and indomethacin for prevention of PCO. In parallel, Nishi et al. used a similar degradable drug-delivery system for indomethacin, designed to be implanted as a disk sandwiched with the IOL (Nishi et al., 1996). Both

26 Biomaterials and regenerative medicine in ophthalmology

2.6Multifocal intraocular lenses

Since most currently available lens materials cannot accommodate for vision, IOL recipients must wear corrective lenses to provide them with near vision. Recently, IOLs capable of providing patients with multiple focal points have begun to debut all over the world (Lane et al., 2006). The Helmholtz theory of accommodation, the most accepted theory for the mechanism of accommodation of the native lens, states that vision is accommodated by the lens through the contraction and relaxation of the ciliary muscle. For near vision, the muscles contract and effectively reduce the tension on the zonule fibres and allowing the lens to become thicker, increasing the optical power of the lens. Conversely, for distance vision the ciliary muscles relax, thereby increasing the tension on the zonule fibres and decreasing the thickness and optical power of the lens.

Current multifocal IOLs provide multiple focal distances to the patient independent of ciliary body function and capsular mechanics. Once the lens is securely placed within the capsular bag, the function of these lenses will not change or deteriorate. Multifocal lenses can be designed to take advantage of many innovations in IOL technology that have led to improved outcomes (Lane et al., 2006). Currently, there are two FDA-approved multifocal IOLs on the market: the ReZoom lens and the ReStor lens.

2.6.1ReZoom lens

The ReZoom lens is a clear, foldable IOL made from a high-refractive-index acrylic material (Lane et al., 2006). The second-generation refractive multifocal

IOL, the first generation being the Array IOL, distributes light over five optic zones so that each lens has a distance-dominant central zone for distance vision under bright-light conditions when the pupil is constricted. In the refractive profile, the odd zones (1, 3 and 5) are adjusted for far vision and the even zones (2 and 4) are adjusted for near vision. Therefore, the optical behaviour of the IOL depends on the pupil’s size. With a small pupil, light energy is sent to distance vision, but as the pupil size increases, the IOL sends light energy simultaneously to both near and distant focal points.

2.6.2ReStor lens

The ReStor IOL is designed to provide quality near to distance vision by combining ‘apodized’ diffractive and refractive technologies. Apodization is defined as the gradual tapering of diffractive steps from the centre of the lens towards the outside edge to create a smooth transition of light between the distance, intermediate and near focal points (Ortiz et al., 2008). On the ReStor IOL, the centre of the lens surface consists of an apodized

diffractive optic with a 3.6 mm diameter for focusing light from near and distant objects. Conversely, the outer ring of the ReStor IOL surrounds the apodized diffractive region and is dedicated to focusing light for distance vision. Therefore, unlike the ReZoom lens, this IOL effectively restores near and distance vision regardless of pupil size. In bright light situations where the pupils are constricted, the lens sends light simultaneously to both near and distant focal points. In low light situations where the pupils are dilated, the apodized diffractive lens sends a greater amount of light to distance vision to minimize visual disturbances.

2.7Accommodating intraocular lenses

Over the last several decades researchers have focused on developing a biocompatible material that is soft enough to be capable of providing truly accommodative vision. There are currently three IOLs on the market that are generally accepted as being able to provide accommodative vision: the BioComFold Ring-haptic IOL, the 1CU Accommodative IOL and the AT45 Crystalens.

2.7.1BioComFold ring-haptic intraocular lens

Introduced in 1996, this IOL was the first artificial accommodating IOL on the market (Menapace et al., 2007). The IOL itself is constructed of a single piece of a foldable hydrophilic acrylic material with an optic size of 5.8 mm. The lens features three rigid haptics that are angled to the anterior, which is opposite to the features of most current designs. The accommodative mechanism of this lens relies on the sphincter-like ciliary muscle circumferentially compressing the haptics of the lens, which results in the forward motion of the optic and an increase in the refractive power when focusing on near objects. Similarly, there is an associated backward motion upon relaxation which is inherent in the optic owing to its elasticity.

2.7.21CU accommodative intraocular lens

The 1CU was first introduced on the market in 2001 and features another single-piece optic 5.5 mm in size. Like the ring-haptic IOL, the 1CU is made of a foldable hydrophilic acrylic material. The main difference between the two lies in the four delicate broad-based haptics used by the 1CU, which compress upon zonular relaxation and which move the lens forward to accommodate vision for near objects. This IOL then relies on the assumption that the capsular bag retains sufficient residual elasticity to provide backwards motion to the lens.

28 Biomaterials and regenerative medicine in ophthalmology

2.7.3AT-45 Crystalens intraocular lens

The AT-45 Crystalens is a multipiece silicone accommodating IOL which initially received US Food and Drug Administration (FDA) approval in November 2003 to correct aphakia (Cumming et al., 2006). The lens was then approved again in August 2004 to correct presbyopia following cataract extraction and to provide near, intermediate and distance vision without spectacles. Specifically, the AT-45 Crystalens is a biconvex lens with a 4.5 mm optic and flexible hinged-plate haptics that permit the forward movement of the optic during accommodation (Cumming et al., 2006). The lens design incorporates grooves across the plates adjacent to the lens optic that allow for forward and backward movement of plate-haptic lenses against the vitreous face. The mechanism of accommodation is based on the working assumption of mass redistribution presumed by Coleman (Coleman and Fish, 2001), who suggested that the contraction of the ciliary muscle causes it to bulge into the incompressible vitreous body, which reacts by dislodging the anteriorly located capsule and IOL. This would then push the lens forward and increase power while accommodating for near vision.

2.8Lens refilling

Although these multifocal IOLs are generally accepted to provide accommodative vision to patients, some researchers believe that the best way to design a solution to the problem of cataracts is to develop an artificial lens that more closely mimics the natural mechanism of accommodation of the eye. It was demonstrated that the ciliary muscle retains its function through to 80 years of age (Strenk et al., 1999). Therefore, injectable materials that function as artificial lenses and which use the natural mechanism of accommodation are theoretically possible. Current work is aimed at the development of softer materials that can be stretched and compressed by the ciliary muscles of the eye through a technique known as lens refilling.

Lens refilling has been shown to be a potentially valuable alternative treatment option to the direct injection of a foldable, accommodating IOL.

The technique was first explored as an IOL replacement therapy by Kessler in 1964 (Kessler, 1964). Using some of the knowledge gained during this work, Haefliger and coworkers took up the concept under the name PhacoErsatz (Haefliger et al., 1987). In a study published in 1994, this group proved the efficacy of using lens refilling to restore visual accommodation in the senile primate eye (Haefliger and Parel, 1994). With this technique, the capsular bag was evacuated through a small capsular opening and refilled with a silicone-based elastic polymer capable of responding to changes in surface curvature according to varying zonular tension.

Hettlich and coworkers investigated the safety and efficacy of a monomer