Chapter 2. Literature Survey

Transcription

1 Chapter 2 Literature Survey

2 CHAPTER 2 LITERATURE SURVEY 2.0 INTRODUCTION Optical plastics have already become popular and most preferred materials to replace conventional inorganic materials (mostly glass) for different applications, especially for biomedical applications. The use of optical plastics for ophthalmic applications like contact lenses and intraocular lenses has been the subject of interest for material scientists all over the world [1-2]. Optical applications, as the term suggests, means all those applications where the laws and rules of optics are exploited for a given purpose. It encompasses all those devices used for the purpose as also all the materials employed to fabricate those devices. In order to develop a particular device, taking advantage of the principles of optics, it is essential therefore, to first understand the basic requirements for which the device is to be designed. Once that is done, the next most important step involves the development of the materials (also referred as optical materials) for the purpose. This is completely in line with the adage that for success of a novel device, it is utmost imminent to design an innovative material full of novelty. In other words, unless there are materials available to deliver the desired performance, the new devices cannot be introduced. This is an evolutionary exercise where one event follows the other in a continuous manner. By the time a new device is introduced, it runs the risk of getting obsolete within a short period because of the pace at which science and technology has been improving with time. Thus, the need for novel materials with improved properties is always in existence. In the area of optical applications, it is perhaps more challenging because many of the devices are also being used for biomedical applications. For biomedical applications, especially for implants, the choice of materials that can be chosen for the purpose is quite limited and hence, the challenge for the material scientists is even tougher. 24

3 The optical devices take advantage of basic optical phenomena such as reflection, refraction, transmission, dispersion, etc. Depending upon the applications, the devices are designed to cover the possible ranges of each parameter. Accordingly, the optical materials are to be designed. The basic properties to be maneuvered while designing optical materials for ophthalmic applications can be listed as: (i) Refractive index, (ii) Abbe number, (iii) Transmittance, (iv) Hardness, (v) Water absorption (vi) Elongation, (vii) Gel content (viii) Swelling behavior, etc. It must be noted that the most basic criteria for selection of optical materials are its clarity and refractive index. After this, the other properties are checked to ascertain the suitability of materials. Of course, the preference is given to low density materials. For implants, the bio-compatibility of materials becomes the most essential criteria. The present chapter deals with the complete survey of literature on the subject of optical plastics for biomedical applications. It aims to bring out the development on various aspects of development of contact lens and intraocular lens materials for optical applications as available in the literature. Based on this literature survey, an attempt has been made to list out the gap areas while describing the developments leading to the emergence of novel biocompatible materials. The whole subject of literature survey is covered here with the following outline: (a) Polyacrylates for optical applications (b) (c) (d) (e) (f) (g) (h) (i) Contact lenses Problems associated with contact lenses Intraocular lenses Problems associated with intraocular lenses Biocompatibility of intraocular lenses Path forward Challenge Objectives of the present work 25

4 2.1 POLYACRYLATES FOR OPTICAL APPLICATIONS Polyacrylates form an important class of materials which are used in all major optical applications such as contact lenses, intraocular lenses and spectacle lenses. Poly (methyl methacrylate) (PMMA) and poly (2-hydroxyethyl methacrylate) (phema) are two polymers, which have been commercially exploited for optical applications to a great extent. The material modification for having new improved polyacrylate based optical plastics can be achieved by modifying either the structure or the chemistry of the polyacrylates with suitable functional groups. The scope of the applications of polyacrylates can be widened, by suitable modifications, to take care of the drawbacks. One of the ways by which the improvement is possible is by incorporation of additives containing halogen atoms, aromatic rings and heavy metals in the monomer for improving the refractive index, hardness and thermal stability of polyacrylates. Incorporation of suitable biocompatibilizers for desired results has been considered as novel idea, in this regard. It has been reported that the surface modification of acrylates using some biomolecules bring tremendous improvements in the overall biocompatibility of polymers. Incorporation of biocompatibilizers into polyacrylates leads to positive results and helps in reducing the incidence of medical complications and makes the lenses more durable. Biomolecules which are present in the body like heparin (present in blood as an anticoagulant), hyaluronic acid (present in joints, dermis and aqueous humor of eye for lubrication), collagen (present in connective tissues) and the similar materials like chitosan and their derivatives can help in improving the biocompatibility of the acrylates when used for material modification. The idea behind the use of these biomolecules as biocompatibilizers is the approach to incorporate the biomimetic properties in acrylates, so that the body will consider it as its own part and the responses shown for a foreign material inside the body can be reduced. 26

5 Acrylates thus, exhibit properties suitable for use as optical material. But several drawbacks limit their application e.g. biocompatibility of intraocular lens materials. Thus, a need arises for modifying the acrylates to be used as materials for optical applications. However, not much work has been carried out on the modification of acrylates for optical applications [3-4]. Due to several favorable characteristics of acrylates, it would be meaningful if they can be modified to take care of the drawbacks. Thus, a novel methodology needs to be designed to overcome this gap. Let us discuss the key applications where polyacrylates play a major role. 2.2 CONTACT LENSES One of the major areas of application where acrylates are considered as key candidates are contact lenses. They are thin lenses fitted over the cornea of the eye to correct vision for cosmetic and therapeutic reasons. The first contact lenses were made up of glass, which caused eye irritation, and were not wearable for extended periods of time. But when lenses made from polymethyl methacrylate (PMMA or Perspex / Plexiglass) were introduced, they became much more convenient [5-8]. These polymethyl methacrylate (PMMA) lenses are commonly referred to as hard lenses. However, polymethyl methacrylate (PMMA) lenses have their own side effects i.e. no oxygen is transmitted through the lens to the cornea, which can cause a number of adverse clinical events. In the late 1970s, and through the 1980s and 1990s, improved rigid materials which were oxygen-permeable, were developed. Collectively, these polymers are referred to as rigid gas permeable or 'RGP' materials or lenses [9]. The advantage of hard lenses is that, due to their non-porous nature, they do not absorb chemicals or fumes and hence are safe to use in harsh environments Available Materials for Contact Lenses The principal breakthrough in soft lenses made by Otto Wichterle led to the launch of the first soft (hydrogel) lenses [10] in some countries in the 1960s 27

6 and the approval of the 'Soflens' material (polymacon) by the United States FDA in Soft lenses are comfortable, while rigid lenses require a period of adaptation before full comfort is achieved. The polymers from which soft lenses are manufactured improved primarily in terms of increasing the oxygen permeability by varying the ingredients making up the polymers [11]. The advances in material chemistry has affected both surface and bulk characteristics of contact lenses and given a basic understanding of the way in which a material behaves [12]. The basic raw materials used for the purpose of designing contact lenses fall under two basic chemistries viz. acrylic and silicones. a) Acrylics Amongst the acrylic materials, esters of acrylic acid play a major role in making materials for contact lenses. Poly hydroxyethyl methacrylate (phema) is regarded as an excellent hydrophilic polymer used for the purpose of making contact lenses. Poly hydroxylethyl methacrylate (phema), with a water content of 38%, appeared to be reasonably biocompatible and used even today in a variety of biomedical fields such as blood-contacting implants, artificial organs, drug delivery devices and for making intraocular lenses (IOL). When used as a contact lens material, various cross-linking agents are typically incorporated into poly hydroxylethyl methacrylate to enhance its strength. Specific polymerization and co-polymerization further improve water swelling properties. Methacrylic acid (MAA) is a hydrophilic monomer which is commonly used to increase water content resulting in improved oxygen permeability of the material. Currently, more than 150 different types of soft contact lenses are available, most of which are still based on poly hydroxyethyl methacrylate [13]. b) Silicones Another biocompatible material used for preparing contact lenses is silicon. Pure silicone is highly gas permeable, but due to its hydrophobic character siliconebased contact lenses are poorly wettable [14]. To combine the benefits of high 28

7 oxygen permeability of siloxane groups with the hydrophilic poly hydroxyethyl methacrylate, silicone hydrogel materials were developed and became commercially available in 1999 [15-16]. Today, eight silicon hydrogel materials are commercially available, with oxygen permeability ranging from 86 to 175x10-9 Dk/t. Typical components of silicone hydrogel contact lenses are DMA (N,N-dimethylacrylamide), PDMS (polydimethylsiloxane), TPVC (tris- (trimethylsiloxysilyl) propylvinyl carbamate), TRIS (trimethylsiloxy silane), PVP (polyvinyl pyrrolidone) and siloxane macromers [13]. Most silicone hydrogel lens materials require surface modification to overcome the hydrophobic nature of the silicone component. Balafilcon A, lotrafilcon A, lotrafilcon B and asmofilcon A are modified using different plasma treatments [13,17] where reactive gas plasma transforms the hydrophobic siloxane components on the surface of the lenses into hydrophilic silicate compounds (glassy islands) [13,18]. 2.3 PROBLEMS ASSOCIATED WITH CONTACT LENSES Early Complications Corneal Responses to Contact Lens Wear The healthy cornea is a vascular organ, which receives the required oxygen transferred to the cornea through tears. However, during the use of poly hydroxyethyl methacrylate based contact lenses, oxygen supply is immediately reduced by the presence of the lens, and the transfer of oxygen through the lens is limited by its water phase. If the oxygen transport is insufficient, the cornea may exhibit a variety of hypoxic complications. The only way to improve the oxygen permeability for poly hydroxyethyl methacrylate based materials is to increase the percentage of water, which is solely responsible for oxygen transport in this group of materials Late Complications During use of Contact Lens Use of contact lens impacts ocular physiology in a number of ways, including modifications in tear film composition [19-21], changes in function and structure 29

8 of the cornea and production of various inflammatory conditions [22,23,24]. These changes can potentially result in new ocular disorders [23-25, 26] Hypoxia Poly hydroxylethyl methacrylate based lens materials reduce the oxygen supply to the cornea and increase the corneal carbon dioxide level [27,28]. Hypoxia related effects seen in the epithelium layer include suppression of cell proliferation rates, production of microcysts and epithelial thinning [29]. In the stroma, a decrease in ph [61] increase in edema formation [31] and overall thinning [29] have been reported Inflammatory Complications/Infections The development of inflammatory complications during contact lens wear typically starts with redness, dryness, ocular discomfort, etc. [22, 32]. Contact lens induced acute red eye (CLARE) is related to increased levels of (typically) gram negative bacteria on the ocular surface and the contact lens. This often causes marked conjunctivitis injections [23, 33]. If the cornea becomes infected with pathogenic organisms, it is termed microbial keratitis Mechanical Complications Corneal deformation during lens wear has primarily been described with rigid lenses, and less often with poly hydroxyethyl methacrylate based materials [34, 35]. The first generation of silicon hydrogel lenses however, showed signs of corneal reshaping due to the higher rigidity of these materials [36]. Corneal erosions of the epithelium layer caused by a trauma or foreign body have been seen with all types of contact lenses [24] Giant Papillary Conjunctivitis Giant papillary conjunctivitis (GPC) is an inflammatory condition of the upper conjunctiva and, if caused due to contact lens, it is described as contact [37] lens-associated papillary conjunctivitis (CLPC) [38]. CLPC has been reported 30

9 with all kinds of lens materials, however, higher incidence rates have been observed with soft contact lenses, including silicone hydrogels, particularly if worn on an extended wear schedule [39, 40]. Typical symptoms of this condition are ocular discomfort, including itching, excessive lens movement, increased lens deposition and blurred vision, which finally lead to lens intolerance [33]. 2.4 INTRAOCULAR LENSES An intraocular lens (IOL) is implanted in the eye, usually replacing the existing crystalline lens, because it has been clouded over by a cataract, or as a form of refractive surgery to change the eye's optical power e.g. in the treatment of presbyopia (diminished ability to focus on near objects), phakic (implantable) treatment of myopia (nearsightedness) [41] and for phakic treatment for hyperopia (Farsightedness) [42]. It usually consists of a small plastic lens with plastic side struts, called haptic and optic to hold the lens in place within the capsular bag inside the eye. The first intraocular lens (IOL) was implanted in England in the early 1950s and the United States FDA approval for use of intraocular lens implants occurred in Prior to that time, patients who had cataract surgery without intraocular lenses (IOLs) required either thick glasses that resulted in significant magnification and distortion of vision or contact lenses that were associated with the wear-and-tear of daily application and removal. Intraocular lens (IOL) implantation has been a tremendous advancement which enabled restoration of nearly normal vision and greatly reduced problems associated with thick cataract spectacles and contact lenses [43]. In order to understand the behavior of intraocular lenses (IOLs), let us first understand the materials used for the development of intraocular lenses (IOLs) Materials for Intraocular Lenses Polymethylmethacrylate (PMMA) was the first plastic material to be used successfully for preparing intraocular lenses [44]. British ophthalmologist Sir 31

10 Harold Ridley observed that Royal Air Force pilots who sustained eye injuries during World War II involving polymethyl methacrylate (PMMA) wind shield material did not show any rejection or foreign body reaction. In polymethyl methacrylate (PMMA), the individual chains are inflexible and the chains are tightly packed together, the glassy properties are manifested. Deducing that the transparent material was inert and useful for implantation in the eye, Ridley designed and implanted the first intraocular lens in a human eye. Advances in technology have brought about the use of silicon and acrylic, both of which are soft, foldable and inert materials. A variety of different flexible polymers have been used for contact lenses and Intraocular lenses (IOLs). They fall into three categories: silicones, hydrophobic acrylics, and hydrophilic acrylics (or hydrogels). The flexibility of each of these materials is based on three factors in the polymer's structure: flexibility of the molecular chain, interchain flexibility and flexibility as the result of the presence of other materials. Let us discuss each of these materials one by-one in detail Silicones Silicones are chemically known as polysiloxanes. They possess a siliconeoxygen molecular backbone, which imparts mechanical flexibility to the material. The first silicone material used in the manufacture of intraocular lenses (IOLs) was polydimethylsiloxane, having a refractive index of This was termed as first-generation silicone. Poly (dimethyl diphenyl siloxane) is a later second-generation silicone intraocular lenses (IOL) material in use today. It has a higher refractive index of 1.46, resulting in thinner intraocular lenses (IOL) optics. Silicones derive their flexibility from a) their chain structure, which links silicon and oxygen in a very flexible bond, and b) an intermolecular structure, which is highly cross-linked. Substitutional modifications along the chain can be made to modify material properties, most notably flexibility and refractive index. These are the only non-hydrocarbon polymers in general use and were developed primarily because of their ease of fabrication and thermal stability. 32

11 They incite little inflammatory reaction and are used in scleral buckling (ophthalmological procedure) implant materials, heart valves, stents, and other surgical devices. Major manufacturers of silicone materials include, Santa Ana, California; STARR Surgical; and Bausch and Lomb Acrylics Acrylic is defined as any compound derived from acrylic acid. In general terms, it is used to apply to any type of plastic, for example, acrylic resin used by artists. The PMMA of Ridley's first implant was designated as an acrylic material. With the introduction of the AcrySof intraocular lens (IOL), the term acrylic was expanded to define a new type of foldable intraocular lens (IOL) optic material, which had come into existence, as opposed to the other foldable material of the time, silicone. The two adjectives hydrophobic and hydrophilic, which modify the term acrylic as it pertains to intraocular lens (IOL) chemistry, are based on the wet ability or more accurately the contact angle measurement of the material. (a) Polymethyl Methacrylate Due to their low price, polymethyl methacrylate (PMMA) based intraocular lenses (IOLs) are viable option for cataract surgery in developing countries where manual expression techniques (i.e. extracapsular cataract extraction) where large incision sizes are used. Polymethyl methacrylate (PMMA) based intraocular lenses (IOLs) with sharp optic edges result in relatively low posterior capsule opacification (PCO) rates [45-46]. Heparin surface modified polymethyl methacrylate (PMMA) intraocular lenses (IOLs) have been used in uveitis patients (inflammation of middle layer of eye) with good results. Currently, polymethyl methacrylate (PMMA) based intraocular lenses (IOLs) are used for sulcus placement and sulcus-suture techniques due to their high overall rigidity, resulting in good centration and resistance to tilt. Anterior chamber and iris-fixation intraocular lenses (IOLs) are also made of 33

12 polymethyl methacrylate (PMMA) [47] and are not associated with uveal inflammatory reaction. (b) Hydrophilic Acrylates Hydrophilic acrylic polymers for intraocular lenses (IOLs) consist of hydrophilic cross-linked polymers and water. They are insoluble in water but have the ability to swell like sponge in water and retain a significant amount of water in their structure while not dissolving. Their equilibrium water content depends on their composition and dictates their bulk and surface properties. The currently available hydrophilic acrylic lenses are manufactured from copolymers of acrylates with water content ranging from 18% to 38% (by wt.). One exception is represented by a lens manufactured in Brazil (Acqua, Mediphacos, Belo Horizonte, MG, Brazil), which has a water content of 73.5% (by wt). This expandable lens, based on the concept of the full-sized lens [48-49], was inserted in the dry state and attained its final dimension of the original crystalline lens within the capsular bag after hydration and expansion. Three hydrophilic lenses are presently available in the United States. The Bausch and Lomb Hydroview IOL (18% water), the IOL tech MemoryLens (La Rochelle, France) (20% water) hydrophilic acrylic designs, and the Collamer material (34% water) (STAAR Surgical), used for manufacture of phakic PC- IOLs or the phakic intraocular contact lens (ICL). The Collamer material is composed of a proprietary copolymer of hydrophilic acrylic material and porcine collagen, with a water content of 34% [50]. The Rayner C-flex IOL (Rayner) (26% water) design is presently under Food and Drug Administration (FDA) investigation in the United States. Clinical and laboratory studies as well as preliminary results of the FDA study have shown excellent results with low rates of posterior capsule opacification (PCO). [50] Major manufacturers of hydrophilic acrylics include Rayner Intraocular Lenses Ltd., Brighton Hove, East Sussex, England (C-Flex IOL, formerly Centerflex); Bausch and Lomb, Rochester, New York (Hydroview); STAAR Surgical (Collamer IOL); IOL tech (Memory Lens); and a wide variety of European lenses 34

13 that are not available in the United States [51]. These lenses are cut in a dehydrated state and then hydrated and stored in solution. The water content varies widely between IOLs and can be as high as 38%. In the past, hydrophilic acrylic intraocular lenses (IOLs) have not gained popularity due to several early reports of calcification and opacification [52-59]. But it was studied that hydrophilic acrylics offer physical, biological and optical qualities like less dysphotopsia (Seeing false images after cataract surgery) [60-62], Good biocompatibility [63], good optical clarity [64], resistance to damage during insertion, less susceptibility to bio-contamination [65] that make them suitable for use in intraocular lenses (IOLs). If their hydrophilicity can be optimized, they are a promising material for biocompatible intraocular lenses (IOLs). Keeping this in mind, people had tried the approach of copolymerization using different monomers [66]. (c) Hydrophobic Acrylates Flexible hydrophobic acrylic polymers are nearly identical to the glassy polymethyl methacrylate (PMMA) used for intraocular lenses (IOLs) for many years. However, substitutional changes to the units used to fabricate the chains, the use of two different units in a controlled composition, and control of the intrachain structure provide the desired flexibility of these acrylic materials. Hydrophobic acrylic lenses have very low water content, usually less than 2%. Major manufacturers of hydrophobic acrylic materials include Alcon Laboratories (AcrySof), AMO (Sensar) and Hoya (AF Series; Hoya, Japan) (Table 2.1)[50]. Foldable hydrophobic acrylate is currently the most commonly used material [67]. These polymers of acrylates are foldable at room temperature and have very low water content, high refractive indices and usually a strong plastic memory. These characteristics also make the material suitable for the haptics of one-piece, openloop intraocular lenses (IOLs). Hydrophobic acrylate unfolds in a controlled fashion and has been shown to have good uveal and excellent capsular biocompatibility. 35

14 Table 2.1: Examples of Intraocular Lens Materials Lens type Material Refractive index Water content Property PMMA MMA 1.49 <1% Rigid PMMA with HSM MMA 1.49 <1% Rigid Alcon Acrylsof PEA/PEMA 1.55 <1% Foldable Allergan Clariflex EA/EMA/TFEMA 1.47 <1% Foldable ORC MemoryLens HEMA/MMA % Foldable Storz Hydroview HEXMA/HEMA % Foldable Alcon HydroSof HEMA % Foldable Chiron C10UB PDMS 1.41 <1% Foldable Adatomed 90D PDMS 1.41 <1% Foldable Staar AA-4203 PDMS 1.41 <1% Foldable Allergan SI-18NGB/SI-26NB PDMS 1.41 <1% Foldable Iolab Soflex PDMDPS 1.43/1.46 <1% Foldable Domilens Silens PDMDPS 1.43/1.46 <1% Foldable Pharmacia Cee ON 920 PDMDPS 1.43/1.46 <1% Foldable Allergan SI-30NB/SI-40NB PDMDPS 1.43/1.46 <1% Foldable PMMA: poly(methyl methacrylate); MMA: methyl methacrylate; PEA: 2-phenethyl acrylate; PEMA: 2- phenethyl methacrylate; EA: ethylacrylate; EMA: ethyl methacrylate; TFEMA: 2,2,2-trifluoroethyl methacrylate; HEXMA: 6-hydroxyethyl methacrylate; HEMA: 2-hydroxyethyl methacrylate ; PDMS: poly(dimethylsiloxane); PDMDMS: poly(dimethyldiphenylsiloxane). Hydrophobic acrylic intraocular lenses (IOLs) are usually conditioned in their dry state before implantation, and the sudden change in environment (e.g., in the average temperature and humidity) after insertion in the eye results in the appearance of glistening [68]. Gregori et al [69] showed that glistenings were induced by temperature changes that led to condensation of excessive water in the micro-voids of the bulk material on cooling. Tognetto et al [70] found that this opacification happens because of scattering due to local changes in the refractive index between the intraocular lenses (IOL) material and the vacuoles. Heating the intraocular lenses (IOL) promotes the formation of glistening; however, they become visible only after the temperature is lowered. Intraocular 36

15 lenses with high levels of glistening strongly scatter light; they have been shown to significantly reduce spectral transmittance, reduce resolving power (modulation transfer function), reduce contrast sensitivity, and increase glare sensitivity [71]. In some extreme cases, in addition to scattering of light and causing intraocular lens (IOL) opacification (whitening) [72], glistenings lead to intraocular lenses (IOL) explantation [73] also Light Filters Two classes of UV-absorbing chromophores are used in general for the manufacture of intraocular lenses (IOLs) namely, benzotriazole and benzophenone. Recent concerns over the potential damage to the posterior segment of the eye arising from UV radiation following removal of the natural crystalline lens has encouraged companies to include UV absorbing chromophores [74] in intraocular lens (IOL) materials. These chromophores are generally derivatives of benzotriazole [75], which absorb UV radiation below 400nm and are either physically blended or chemically incorporated into the intraocular lenses (IOLs) material. Dr. Patrick H. Benz of Benz Research and Development created the first intraocular lens (IOL) material to incorporate UV-A blocking and violet light filtering chromophore that exist naturally in the human crystalline lens. This breakthrough material provides the exact chromophore the human retina has already specified for light protection through millions of years of evolution. Intraocular lenses are not only used for cataract treatment but are being used also in several types of refractive eye surgery. More recently, intraocular lenses (IOLs) that filter both UV and short wavelength visible violet and blue light have been introduced. A yellow chromophore is incorporated into the intraocular lens (IOL) optic, which represents an attempt to more accurately mimic the light transmission characteristics of the normal crystalline lens. 37

16 Haptic Materials Four materials are used at present for the manufacture of the haptic component (loops) of three-piece intraocular lenses: polymethyl methacrylate (PMMA), polypropylene (Prolene), polyamide (Elastamide), and polyvinylidene fluoride (PVDF) [76]. In the selection of a material for intraocular lenses especially foldable intraocular lenses, criteria that are important are glass transition temperature and elongation. It is preferred to use polymers having a glass transition temperatures below normal body temperature and no greater than normal room temperature, so that the lenses can be folded or rolled conveniently at room temperature. Another important property of intraocular lenses is their mechanical strength. The lenses must exhibit sufficient strength to allow them to be folded without fracturing. This indicates that an IOL optic made of the material generally will not crack, tear or split when folded [77-78]. 2.5 PROBLEMS ASSOCIATED WITH INTRAOCULAR LENSES Early Complications Endophthalmitis Endophthalmitis is associated inflammation of eye. The incidence of endophthalmitis in lens implantation surgery is comparable to that in routine cataract operation. Use of irrigating fluid, drugs, viscoelastic material and the intraocular lens (IOL) itself may be the source of exogenous infection Late Complications In addition to the complications of any intraocular operation the following are some of the specific complications of intraocular lens (IOL) implantation surgery [79-83] Uveitis Mild to moderate uveitis may result from lens implantation surgery. This can either be due to surgical trauma or in response to retained lens material, which 38

17 can lead to violent inflammatory reaction in some eyes. Uveitis may result in deposit on the surface of the implant and an anterior vitreous membrane Cystoid Macular Edema (CME) Cystoid macular edema is a clinical condition of the eye represented as the inflammatory responses in the macula reason of eye, usually occurs between 1 and 4 months of surgery, but can also occur years later. Whether it is due to the influence of an intraocular lens or the presence of an intact posterior capsule still remains speculative. A fluorescein angiographic study conducted by a group [84] has revealed a lower incidence of angiografic proven cystoid macular edema in the extracapsular cataract extraction with an implant and intact posterior capsule than the intracapsular extraction with or without implant. However, the distortion of visual acuity is not significant in most of the cases of angiographic proven cystoid macular edema. This is a more frequent complication following secondary intraocular lens (IOL) implantation, in which vitreous disturbance plays a major role Secondary Membranes This occurs more frequently after a planned extracapsular extraction, in which an excess of unevaluated lens material may migrate into the pupillary space. With the implant in-situ, the passage of this material into the anterior chamber retards the process of absorption. The slowing of absorption encourages dense secondary cataracts that occasionally vascularize forming secondary membranes. 2.6 BIOCOMPATIBILITY OF INTRAOCULAR LENSES In spite of the fact that the experience of using polymethyl methacrylate (PMMA) for intraocular lens (IOL) for more than 50 years has satisfactory demonstrate that these lenses are relatively inert, they cannot be called as perfectly biocompatible. It is well documented in the literature that a significant disadvantage inherent to polymethyl methacrylate (PMMA) intraocular lenses (IOLs) resides in the fact that even brief, non-traumatic contact between 39

18 corneal endothelium and polymethyl methacrylate (PMMA) surface results in extensive damage to the endothelium [85]. Posterior capsule opacification is another major problem noticed commonly with available intraocular lens (IOL) that occurs because of the localized release of different cytokins, including transforming growth factor beta and fibroblast growth factors [86]. The implantation of intraocular lenses (IOLs) following cataract surgery also induces a foreign body reaction of the intraocular lens (IOL) and a lens epithelial cell reaction [87]. Materials having the lowest contact angle are found to be more biocompatible [88], although biomolecules such as heparin modified surface show lowest contact angle but still some fibrous reaction and posterior capsule opacification was observed with these lenses [89]. In heparin surface modified intraocular lenses (IOLs), heparin surface defects after YAG laser treatment was observed due to which decreased heparin effect in-vivo could be possible [90]. After selecting the best biomaterials and after modifying the surface of the IOL, biocompatibility is improved but still lower grade of inflammatory cell adhesion, anterior capsule opacification (ACO) [91] and other problems associated with intraocular lenses (IOLs) was found. Various agents have been used in conjunction with scleral buckles in the treatment of retinal detachment. These agents are injected into the eye to provide an intravitreal tamponade. Silicone oil is most commonly used material, for this purpose but silicon oil emulsification and adherence in the eye results in poor biocompatibility [92-93]. Intraocular lenses (IOL) made from polymethyl methacrylate (PMMA) are found to damage the corneal endothelium and produce lower level of inflammatory response in terms of cellular adhesion and foreign body responses. These problems are not observed with foldable acrylates. A recent meta analysis of posterior capsule opacification (PCO) with these materials showed that hydrophilic acrylic lenses are slightly more prone to posterior capsule opacification (PCO) than hydrophobic acrylic or silicon 40

19 lenses [94]. This may be due to the high water content being more conducive to lens epithelial cell (LEC) in growth. Another reason may be that the optic edges of intraocular lenses (IOLs) in this group are never as sharp as with hydrophobic materials [95]. As a result, the bend of the capsule at the optic edge is less sharp and a less effective barrier to regenerating lens epithelial cells (LECs). Hydrophilic acrylic materials show good uveal biocompatibility with less flare and fewer cells on the intraocular lens (IOL) optic surface, but poorer capsular biocompatibility than hydrophobic materials. The poorer capsular biocompatibility manifests clinically as stronger tendency for lens epithelial cells (LEC) growth onto the intraocular lens (IOL) optic surface and especially as higher rates of posterior capsule opacification (PCO). One major problem with previous hydrophilic acrylic lens designs, primarily the hydroview IOL (Bausch and Lomb, Rochester, New York) and the Aquasense IOL (Ophthalmic Innovations International Inc.; now Aaren Scientific, Ontario, Canada), was opacification of the optic material due to calcification[96][97]. Patients with these opacified lenses required subsequent explantation due to poor optical quality. One advantage of the hydrophobic material group is their good uveal and excellent capsular biocompatibility. One drawback of this material group has been intralenticular changes. Small water inclusions in the optic material, called glistenings, can occur in hydrophobic materials; this has predominantly been seen with the AcrySof (Alcon Laboratories, Inc, Forth Worth, Texas) material [98]. Over time, the glistening can increase. As all hydrophobic acrylic lenses are not manufactured from the same materials or using the same processes. Therefore, each lens exhibits different characteristics, including refractive index, water content, and tendency for glistening formation [99,100]. Aromatic hydrophobic acrylates are material of choice for intraocular lenses due to their high refractive index. When used for intraocular lens (IOL) fabrication, these aromatic groups can result in water ingress [101]; its 41

20 subsequent accommodation may lead to the formation of glistening bodies (i.e. vacuoles) within the body of the intraocular lens (IOL) Approaches to Improve Biocompatibility It was found that by using the existing polyacrylates and also the comonomers of different polyacrylates the desired level of biocompatibility was still an issue to think on. Therefore different approaches were tried so that the biocompatibility level of intraocular lenses can be improved. The efforts were tried by considering the: Chemical Composition In this approach the material of construction of intraocular lens was kept in mind. It was found that the type of the material of construction of the optical plastics were the most important predictive factor for the formation of inflammatory deposits [102]. This shows that the biocompatibility can be achieved by changing the chemical composition or by incorporating suitable biocompatible monomers during the manufacturing process of optical plastics. Using this approach antimicrobial materials were tried. Another method involves the copolymerization by the thermo pressure extension method [103]. Other approach that have been investigated to reduce posterior capsule opacification (PCO) include the modification of the intraocular lens (IOL) surface with anti-metabolites. This approach was found to be effective in invitro models but there are some concerns over the effects of these antimetabolites on other ocular tissues. It was studied that hydrophilicity of the intraocular lens (IOL) materials prevents the attachment of the cells and the softness of the intraocular lenses (IOLs) reduced the damage against Nd: YAG laser photo disruption. The hydrophilicity of the intraocular lenses (IOLs) is also responsible for the decreased simulation of granulocytes and reduced corneal endothelial damage [104], thus the improvement of hydrophilicity and softness of intraocular lens (IOL) is also one of the ways to improve biocompatibility. 42

21 From this point of view, hydrophilic Hydroxyethyl methacrylate (HEMA) monomer based polymers are useful in the manufacture of optical plastic materials with minimized risk for glistening. Comparison of various lenses evaluate that the lenses made up of hydrophilic monomers show significantly less posterior capsule opacification than those with silicon or heparin surface modified intraocular lens (IOL) with a round-edged design [105]. A further small increase in the hydrophilicity of these materials can prevent the opacification of the lenses. By making lens surface hydrophilic using certain polysaccharides, the potential for silicon oil adsorption on intraocular lenses (IOLs) can also be significantly reduced [106]. Incorporation of certain biochemicals which are already present in the biological system can be tried e.g. polyurethanes, polyolefines, vinyl polymers, acrylic polymers, polyamides, polyesters, polysiloxanes etc. can be rendered biocompatible by including with the polymeric material hyaluronic acid as a salt [107], which in general is characterized by notable viscosity, slipperiness, and ability to reduce friction. This is the basis of its presence in bodies of humans and animals [108]. In another approach to improve biocompatibility, reactive and hydrophilic polymers are used to form covalent chemical linkages with the surface of intraocular lenses (IOLs). The preferred reactive, hydrophilic polymers have complementary chemical functionalities to that of the functional groups contained in the polymeric material of the intraocular lens (IOL). Such a complementary chemical functionality enables a chemical reaction between the functional groups of the polymeric material of the intraocular lens (IOL) and the reactive, hydrophilic polymer to form covalent chemical linkages. Such surface modification of an intraocular lens (IOL) implant reduces or eliminates silicon oil adsorption upon subsequent exposure, reduces or eliminates surface calcification, reduces or eliminates lens epithelial cell surface growth and/or reduces friction upon passage through an inserter for implantation [109]. 43

22 A biocompatibilizing process is also known which involves radical polymerization using ethylenically unsaturated monomers; A polymer having pendant zwitterionic groups bearing a center of permanent positive charge and other pendant groups that are capable of binding the polymer to a surface is used. Such coatings bind to the surface with good adhesion and are not removable in the environment in which the coated surfaces are used. Zwitterionic groups are known to mimic the structure of the head groups of phospholipids in cells; it is thought that the presence of such groups at a surface renders the surface biocompatible. [110] In another similar approach to improve biocompatibility radical polymerization of ethylenically unsaturated zwitterionic monomer containing a sulpho-betain zwitterionic group and a radical polymerizable ethylenically unsaturated comonomer containing a hydrophobic group is selected [111]. The co-polymerization of biocompatible monomers with monomers containing pendant amino groups has also shown promising results, Dimethyl Acrylate (DMA) is one such monomer, which shows most cell adhesion. Dimethyl acrylate (DMA) showed exceptional affinity for endothelial cells over platelets, which is a desirable property for blood contacting surfaces since one desires low thrombogenicity but a propensity for endothelialization [112] Chemical Modification Another approach for improving the biocompatibility is by chemically modification was tried by peoples. In one study fluorination was done as one way to improve the biocompatibility, using this approach it was found that fluorinated polymethyl methacrylate (PMMA) are more stable than polymethyl methacrylate (PMMA) and the biocompatibility tests show that they are as biocompatible as polymethyl methacrylate (PMMA). In the search for getting more biocompatible polymers, transparent polyamides were studied, which did not give superior results. Surfaces can be chemically modified using plasma technology to introduce reactive groups onto the surface of polymer materials in a fast and effective 44

23 manner. Elan et al described a treatment with oxygen plasma followed by the application of 3-glycidoxypropyltrimethoxy silane and the surfaces thus treated are used for the formation of covalent bonds with polysaccharides [ ]. However, the total number of reactions, which involve functional groups immobilized on a surface and large molecules, such as polysaccharides, is seriously limited by the effect commonly known as steric hindrance. The large size of the polysaccharide molecule prevents or impedes contact between reactive groups so that the probability of an effective reaction taking place is reduced. Under a similar approach, there are methods for modifying the surface of a material by forming activated sites by exposing the surface to Glow Discharge Plasma (GDP)[115] such as Radio Frequency Glow Discharge Plasma (RF- GDP) or microwave glow discharge plasma (GDP) of sufficient power for a time required to activate and/or excite the surface of the material and optionally, subsequently exposing the surface to air or oxygen to form peroxy or hydroperoxy groups or other chemically reactive atomic or molecular species on the surface. This surface is exposed to a solution of an ethylene unsaturated monomer or mixtures and polymerization is induced using gamma-or electron beam-irradiation. Covalent bonding to the active surface species by irradiating the surface with gamma or electron beam radiation is done [116]. Introduction of functional groups onto the surface of a polymeric material can be done by treatment with methanol plasma, followed by placing the material in contact with an epihydrochlorin solution which, guarantees the presence of groups, suited to react with polysaccharides [117]. One way to introduce amino groups onto the surface of polymer substrates is by the use of ammonia plasma. The amino groups are then reacted with hyaluronic acid or other polysaccharides by the use of a condensing agent [118]. One more method for this purpose involves the treatment of polymeric materials with reactive solutions, so as to introduce negative electrostatic charges onto the surface itself. This treated surface is placed in contact with an aqueous solution of polyethylene imine (PEI) a polymer characterized by the presence of amino 45

24 groups and a positive electrostatic charge. The interaction between the different charges binds polyethylene imine (PEI) to the modified surface, to produce a surface rich in amino groups. Heparin and other polysaccharides can be bound to the aminated surface after treatment with nitrite solutions [119]. The reaction between polyethylene imine (PEI) and any aldehyde groups present or introduced on the polysaccharide is however used to bind the polysaccharide in various conformations to the surface of the object. Typically, the reaction between carboxyl groups of the polysaccharide and amino groups of the surface is promoted by ethylene dimethyl amino propyl carbodiimide (EDC) [120][121]. Moreover, unlike other polysaccharides, hyaluronic acid is only slightly sensitive to partial oxidation reactions, which allows reactive aldehyde-type groups to be introduced on the polysaccharide. Keeping in view the benefits of heparin, lots of work has been done using the heparin. Towards the further advancement of this approach, there is one method for making improved heparinized biomaterial. In this approach heparinized surface [ ] is provided with an adsorbed protein, which may be activated by the immobilized heparin to block the coagulation of fibrinogen by thrombin. Several plasma proteins are known to inhibit the activity of thrombin and other serine proteases. Out of these antithrombin III (AT-III) [124] is the preferred adsorbed protein since it may be activated by heparin to inhibit thrombin and also because it inhibits other serine protease of the coagulation pathway such as IXa, XIa, Xa and XII. This can be achieved by the incubation of the heparinized surface in a HEPES buffer solution [125] for a few minutes followed by rinsing the surface to remove non bonded antithrombin [126] Surface Modification Mostly the bio-incompatibility issues starts on the surface of an optical plastic material as it was in immediate contact with the biological environment. Therefore surface modification of contact lense and intraocular lens material 46

25 can improve their biocompatibility e.g. polymethyl methacrylate (PMMA), which was the material used in the first contact and intraocular lens (IOL) material, dating back to 1949 is still, considered the gold standard by some cataract surgeon s [127]. Since it is extremely difficult to avoid any contact between implant surfaces and endothelium during surgical procedures and especially to other sensitive ocular tissues during implant life, i.e., the iris, ciliary sulcus etc, efforts have been undertaken to modify the polymethyl methacrylate (PMMA) ocular implant surfaces to reduce the tendency to adhere to and damage corneal endothelium. Ocular implant surfaces have been coated with various hydrophilic polymer solutions or temporary soluble coatings such as methylcellulose, polyvinylpyrrolidone, etc., to reduce the degree of adhesion between the implant surfaces and tissue cells [128]. While offering some temporary protection, these methods have not proven entirely satisfactory since such coatings complicate surgery, do not adhere adequately to the implant surfaces, become dislodged or deteriorate after implantation, dissolve away rapidly during or soon after surgery or may produce adverse post-operative complications. Moreover, it is difficult to control the thickness and uniformity of such coatings. Yalon et al has reported attempts to produce protective coatings on polymethyl methacrylate (PMMA) implant surfaces by gamma irradiation induced polymerization of vinylpyrrolidone [129]. Their efforts were not altogether successful, however, since their methods also presented problems in controlling the optical and tissue protective qualities of the coatings. The resulting coatings were also of poor quality and non-uniform mechanical stability. Certain process conditions and parameters that produce thin hydrophilic gamma or electron beam irradiation induced polymerized and chemically grafted coatings of N-vinylpyrrolidone (NVP) polymer, copolymerized N-vinylpyrollidone (NVP) and 2-hydroxyethyl methacrylate (HEMA) and their copolymers with ionic co-monomers on the surfaces of ocular implants constructed of materials including polymethyl methacrylate (PMMA) are known. These coatings increase the hydrophilicity of the implant surface and minimize adhesion between the surface and sensitive ocular 47

26 tissues [130]. They are thin, uniform, durable and less subject to removal, degradation or deterioration during or following surgery. Goldberg et al have invented an advanced method for modifying the surface of a material adapted for contact with tissue to impart biofunctional properties to the surface [131]. The method comprises exposing the surface to a solution of an ethylenically unsaturated monomer and a biofunctional agent and irradiating the surface with gamma or electron beam to thereby form on the surface a graft polymerized coating having physically entrapped or chemically bonded molecules of the biofunctional agent which imparts biofunctional properties to the surface. A method for making non-thrombogenic surfaces was disclosed where the surfaces were treated with a cationic surface-active agent as an intermediate layer and a conventional anticoagulant such as heparin as the top layer [ ]. Some papers describe the use of an intermediate layer between the substrate and the hyaluronic acid (HA) coating [134]. This intermediate layer physically adheres to the substrate and contains chemical groups which are suitable for the formation of a bond with the chemical groups of heparin / hyaluronic acid. As the intermediate layer is only physically attached to the substrate surface, which might not be very strong and stable, there is a risk of heparin or similar molecules becoming detached thereby reducing the effectiveness of the surface. The surface of a polymeric object is treated with reactive solutions, so as to introduce negative charges onto the surface itself. The surface thus treated is placed in contact with an aqueous solution of polyethylene imine (PEI), a polymer characterized by the presence of amino groups and a positive charge [135]. The interaction between the different charges binds polyethylene imine (PEI) to the modified surface, to produce a surface rich in amino groups. Heparin and other polysaccharides are then bound to the aminated surface after treatment with nitrite solutions [136]. Although this process effectively solves the problem of introduction of reactive groups on the surface of the material, it is not so effective 48