Veva De Groot Dokter in de genees-, heel-, en verloskunde

(1)

Prevention of

POSTERIOR CAPSULE OPACIFICATION by new surgical techniques and

a new intraocular lens design

Veva De Groot

Dokter in de genees-, heel-, en verloskunde

Proefschrift voorgelegd tot het behalen van de academische graad van Doctor in de Medische Wetenschappen aan de Universiteit Antwerpen

Promotor: Prof. Dr. M.J. Tassignon

Co-promotor: Prof. G.F.J.M. Vrensen September 2005

UNIVERSITEIT ANTWERPEN

F

ACULTEIT

G

ENEESKUNDE

(2)

MEMBERS OF THE JURY

Prof. M.J. Tassignon, Promotor

Department of Ophthalmology University Hospital Antwerp

Prof. G.F.J.M. Vrensen, Copromotor Department of Ophthalmology

Leiden University Medical Center, The Netherlands

Prof. P. Van de Heyning, President of the jury Department of Otorhinolaringiology University Hospital Antwerp

Prof. Van Marck, Dean of the Faculty of Medicine Department of Pathology

University Hospital Antwerp

Prof. G. Duncan

Department of Biomedicine

School of Biological Sciences, University of East Anglia, Norwich, U.K.

Prof. A. Galand

Department of Ophthalmology University Hospital Liège

Prof. G. Hubens

Department of Abdominal Surgery University Hospital Antwerp

Prof . S. Peeters

Laboratorium of Medical Elektronica University Antwerp

(3)

DANKWOORD

Velen hebben bijgedragen aan het tot stand komen van dit proefschrift. Enkele van hen wil ik met name noemen en bedanken voor hun hulp en inzet.

Allereerst gaat mijn dank uit naar mijn promotor en huidig diensthoofd Prof Marie- José Tassignon. Zij introduceerde me in 1992 in de intraoculaire chirurgie en niet lang daarna in wetenschappelijk onderzoek aangaande intraoculaire lenzen. Zij was de drijvende kracht achter deze thesis. Haar gedrevenheid stimuleerde me de klini- sche activiteit te combineren met het schrijven van een thesis. Haar drang te ver- nieuwen en grenzen te verleggen, bleek een onuitputtelijke bron van nieuwe ideeën en projecten.

Een belangrijke bijdrage voor deze thesis kwam van mijn copromotor Prof. Gijs Vren- sen. Na een voordracht over het secundair sluiten van de posterieure capsulorhexis in Montpellier sprak hij me aan, beaamde dat het een zeer interessant onderwerp was en overtuigde me dit in vitro verder uit te diepen. Met veel enthousiasme en kritische zin heeft hij meegeholpen aan de histopathologische interpretatie van het materiaal. Zijn opbouwende kritiek en onze vele leerrijke discussies vormen mee de basis voor dit werk.

Bijzondere dank ben ik verschuldigd aan Rudi Leysen, medisch-oogheelkundig foto- graaf, voor het deskundig fotograferen van ontelbare ogen van zowel patiënten als konijnen. Hij tekende met toewijding alle originele illustratieve schemata van dit werk en leverde didactische foto’s voor voordrachten en publicaties.

Veel dank ben ik verschuldigd aan Ben Willekens, voor de hulp bij het in vitro deel van het onderzoek in het Internationaal Oogheelkundig Instituut te Amsterdam. Hij zorgde voor de continuïteit tijdens de weken durende in vitro culturen, hij gaf me heel wat praktische vaardigheden mee in het labo en zorgde voor haarﬁjne coupes en prachtige plaatjes. Een bekroning van zijn werk was een artistieke bewerking van één van onze elektronenmicroscopische foto’s die de coverpagina haalde van IOVS, het meest gerenommeerde tijdschrift in de oogheelkundige research. Deze foto is tevens de cover van dit proefschrift. Alle medewerkers van de Corneabank van Amsterdam wil ik bedanken voor het leveren van de humane preparaten.

Ook Prof. Jaap Van Best van de Rijksuniversiteit Leiden, wil ik bedanken voor de analyse van het ﬂuorofotometrisch onderzoek.

(4)

Tenslotte gaat mijn dank uit naar mijn familie. Allereerst mijn ouders, voor hun on- voorwaardelijk steun en zorgen tijdens mijn studies en de geregelde opvang van de kinderen in de periode nadien. In het bijzonder mijn zeer lieve echtgenoot Johan, zijn enthousiasme en geduld betekenden voor mij een grote steun. Eens kunnen overleggen of iemand kunnen roepen als de computer het weer begeeft, is goud waard. En uiteraard onze twee kapoentjes, Eline en Anneleen, 10 en 8 jaar oud, die voorzichtig bleven vragen of mijn thesis nu bijna af was.

Juli 2005.

(5)

VII. IN VITRO STUDY ON THE CLOSURE OF POSTERIOR CAPSULORHEXIS

IN THE HUMAN EYE 83

VII.1. Abstract 83

VII.2. Introduction 84

VII.3. Materials and methods 85

VII.4. Results 87

VII.4.1. Microscopic Observations 87

VII.4.2. Quantitative Results 92

VII.5. Discussion 93

VII.6. Conclusion 95

VII.7. Acknowledgments 95

VII.8. References 95

VIII. BAG-IN-THE-LENS IMPLANTATION OF INTRAOCULAR LENSES 97

VIII.1. Abstract 97

VIII.2. Introduction 98

VIII.3. Patients and Methods 99

VIII.3.1. The IOL Design 99

VIII.3.2. In Vitro Data 100

VIII.3.3. First In Vivo Implantations 101

VIII.4. Results 102

VIII.4.1. In Vitro 102

VIII.4.2. In Vivo 103

VIII.5. Discussion 104

VIII.6. References 106

IX. EFFECT OF BAG-IN-THE-LENS IMPLANTATION ON POSTERIOR

CAPSULE OPACIFICATION IN HUMAN DONOR EYES AND RABBIT EYES 109

IX.1. Abstract 109

IX.2. Introduction 110

IX.3. Materials and Methods 111

IX.3.1. Bag-in-the-lens Design and Principle of Action 111 IX.3.2. In Vitro Implantation in Human Donor Eyes 112 IX.3.3. In Vivo Implantation in Rabbit Eyes 113

IX.4. Results 114

IX.4.1. In Vitro Study in Human Donor Eyes 114

IX.4.2. In Vivo Study in Rabbits 115

IV. SECONDARY CLOSURE OF POSTERIOR CONTINUOUS CURVILINEAR

CAPSULORHEXIS 53

IV.1 Abstract 53

IV.2 Introduction 53

IV.3 Subjects and methods 54

IV.4 Results 56

IV.5 Discussion 58

IV.6 Conclusion 59

IV.7 References 59

V. LACK OF FLUOROPHOTOMETRIC EVIDENCE OF AQUEOUS-VITREOUS

BARRIER DISRUPTION AFTER POSTERIOR CAPSULORHEXIS 61

V.1. Abstract 61

V.2. Introduction 62

V.3. Patients and methods 63

V.3.1. Surgical Technique 64

V.3.2. Fluorophotometry 64

V.3.3. Diffusion Coefﬁcient 66

V.4. Results 68

V.5. Discussion 70

V.6. Conclusion 72

V.7. References 72

VI. SECONDARY CLOSURE OF THE POSTERIOR CURVILINEAR CAPSULORHEXIS IN NORMAL EYES AND EYES AT RISK FOR

POSTOPERATIVE INFLAMMATION 75

VI.1 Abstract 75

VI.2 Introduction 76

VI.3 Patients and methods 76

VI.4 Results 79

VI.5 Discussion 80

VI.6 Conclusion 81

VI.7 References 81

(6)

ABBREVIATIONS

α-SMA alpha smooth muscle actin

ACCC anterior continuous circular capsulorhexis A-cells LECs lining the anterior capsule

E-cells LECs lining the equator of the capsular bag ECCE extra capsular cataract extraction

FBGCs foreign body giant cells

ICCE intra capsular cataract extraction IOL intraocular lens

LEC lens epithelial cell

Nd:YAG neodymium:yttrium-aluminum-garnet PAS periodic acid shift

PCCC posterior continuous circular capsulorhexis PCO posterior capsule opaciﬁcation

PMMA polymethylmethacrylate TGF-b transforming growth factor beta

IX.5. Discussion 117

IX.6. References 118

X. ONE YEAR FOLLOW-UP OF THE BAG-IN-LENS IMPLANTATION IN 60 EYES 121

X.1 Abstract 121

X.2 Introduction 122

X.3 Materials and Methods 123

X.3.1. The bag-in-the-lens design 123

X.3.2. Implantation technique 124

X.4 Patients 125

X.5 Results 126

X.6 Discussion 129

X.7 References 130

XI. SUMMARY AND GENERAL DISCUSSION 133

XII. SAMENVATTING 141

List of publications 147

Appendix: United States Patent 6,027,531 149

Abstract 149

Claims 149

Description 151

(7)

Chapter I Chapter I _I Chapter I Chapter I _I

Chapter I POSTERIOR CAPSULE OPACIFICATION

I.1. INTRODUCTION

From a clinical point of view cataract can be defi ned as any opacifi cation and discoloration of the human eye lens causing impairment of vision (Fig. 1). Cataract is the world’s major cause of blindness especially due to its prevalence in underdeveloped countries. A large number of etiological factors for cataract have been identifi ed, of which ageing is the most common. Extra capsular cataract extraction (ECCE) is nowadays the standard surgical intervention to treat cataract. During this surgical procedure the content of the natural lens is removed through an anterior capsulorhexis leaving the remaining capsular bag empty. Since the eighties the removal of the lens content is performed by phacoemulsifi cation, which has become the standard procedure (Fig. 2). An artifi cial intraocular lens (IOL) with appropriate refractive power is placed in the empty capsular bag (Fig. 3). Nowadays cataract surgery is mainly performed on an ambulatory basis. Cataract surgery is currently, apart from dental treatments, the most frequently performed surgical procedure in the world. In 2003 about 76,000 patients underwent a cataract extraction in Belgium on a total population of 10.5 million inhabitants: which means roughly one ECCE per 150 inhabitants.

The total annual cost for the Belgian Social Security is in the range of 28,000,000 €.

Fig. 1. Slit-lamp image of an adult eye with cataract. Fig. 2. This 3/4 cross section view shows the phacoemulsiﬁ cation probe (P) removing the lens nucleus (N). The anterior rhexis is indicated by an arrow. (from Boyd 1995)

(8)

Chapter I Posterior capsule opaciﬁcation

I.1.1 Deﬁnition and history

PCO, also referred to as secondary or after-cataract, can clinically be defined as those changes of the posterior capsule leading to loss of vision, necessitating a second surgical intervention to restore vision. The term posterior capsule opacification is in fact a misnomer, as it is not the capsule itself that becomes opaque, but opacifica- tions are caused by proliferation of lens epithelial cells (LECs) on the internal face of the capsular bag.

Indeed, PCO is caused by the LECs, left in the capsular bag after cataract surgery, proliferating and migrating towards the central part of the posterior capsule (Fig. 4) (Apple et al., 1992; Kappelhof and Vrensen, 1992; Marcantonio et al., 1999). When the number of LECs accumulating on the posterior capsule exceeds a certain level, they will cause impairment of vision by direct blocking and forward scattering of the incoming light. In addition, mechanical forces resulting from the contraction of LECs may cause wrinkles and folds in the posterior capsule with traction-induced IOL decentration as a result, explaining patient’s subjective complaints of visual distortions and glare.

Clinically two different types of PCO can be distinguished: one in which fibrosis of the proliferating and migrating LECs predominates (fibrotic type) and one in which the formation of Elschnig’s pearls predominates (pearl type). The fibrotic type is seen as a whitish to gray discoloration of the initial transparent capsule (Fig. 5 A);

the pearl type is characterized by clusters of swollen LEC-endings lying on the posterior capsule (fig. 5 B). The fibrotic type tends to appear somewhat earlier postoperatively (about 6 months) than the pearl type (after several years), but the fibrotic type causes less visual impairment.

PCO has been observed as early as the ﬁrst extracapsular cataract extractions (ECCE) had been introduced in ophthalmology. Ridley already reported on the occurrence of PCO after having performed his ﬁrst IOL implantations in 1950 (Apple and Ridley, 1999; Apple et al., 1999).

I.1.2 Symptoms

It may take between 1 to 5 years for PCO to develop. Visual symptoms may vary widely and are usually proportional to the extensiveness of ﬁbrosis and wrinkling and the density of Elschnig’s pearls. However some patients presenting severe PCO, as documented by slitlamp examination, may have few or no visual complaints, while other patients having minimal PCO may complain badly (Nishi O. and Nishi K., 1999).

The occurrence of PCO is rather disappointing for most patients. After having the beneﬁt of an almost perfectly restored vision following cataract surgery, they experience again progressive decrease in vision due to PCO. This progressive decrease in Comparable prevalences and costs are

given for other European Union countries and the USA.

While ECCE is a highly effective procedure with a low initial complication rate, the medium and long-term outcome is less promising because of the occurrence of posterior capsule opaciﬁcation (PCO) some months to some years after surgery. PCO leaded in the nineties to severe loss of vision in about one quarter of the treated patients (Schaumberg et al., 1998) who needed further help by surgical Nd:YAG laser capsulotomy. Because of the high prevalence of PCO and as a consequence the high cost, its prevention has attracted great attention of ophthalmologists and eye researchers over the last decade. In this chapter the histopathology of PCO, as well as the epidemiology, the physiopathology, the diagnosis and current treatment options will be summarized.

This will provide a link to the experimental studies of this thesis: the evaluation of new surgical techniques and a new IOL design to prevent the occurrence of PCO after cataract surgery.

Fig. 3. Capsular bag after cataract extraction and implantation of the IOL.

Fig. 4.

Top: Schematic drawing of an IOL in the capsular bag immediately after the surgery. Residues of the monolayer of LECs cover the anterior capsule and the equator.

Bottom: The same capsular bag several months later. LECs have migrated on the posterior capsule and formed a mono- or multilayer behind the IOL optic. In addition, LECs are growing on the anterior surface of the IOL and even on the outside of the anterior capsule. In a later stage, a ring of Soemmerring may form at the equator of the capsular bag. (from Wormstone IM, 2002)

(9)

Chapter I Posterior capsule opaciﬁ cation It is generally accepted that PCO needs treatment as soon as vision gets worse.

However, no consistent criteria have been forwarded to defi ne when PCO is clinically signifi cant and should be treated (Clark, 2000). Some reports on the incidence of PCO even do not mention the criteria used to defi ne PCO, as for instance slit-lamp characteristics or loss in visual acuity or both (Goarnisson et al., 1999; Krishna et al., 1998). Sundelin and Sjöstrand (1999) defi ned PCO as clinically signifi cant when the following criteria were fulfi lled: (1) reduction in visual acuity by two lines compared to the best-corrected visual acuity in the early postoperative period, (2) morphological signs of PCO seen against the red refl ex by ophthalmoscopy, (3) morphological signs of PCO visible within the central area of the pupil at slit-lamp examination and (4) patients complaining of glare, reduced vision, or both. In case the patient presented ocular co morbidity impairing visual acuity, all criteria have to be fulfi lled except the fi rst one.

Several ophthalmoscopic or slit-lamp based devices for measuring the density, exten- sion and progression of PCO have been developed lately. However, these methods are time consuming and expensive since they need speciﬁ c cameras and software.

Furthermore, no single method has been accepted as the golden standard so far.

Clinical assessment of PCO remains for this reason still the most commonly used in the literature. As the prevention of PCO and not the assessment of PCO is the main subject of the thesis, the advantages and disadvantages of the different methods to assess PCO will not be discussed in detail.

I.1.4 Epidemiology

During the last decade, PCO, as the most common complication after ECCE and IOL implantation, shows a tendency to decrease in incidence.

Through the 1980s and early 1990s the number of eyes needing Nd:YAG laser capsulotomy for the treatment of PCO was as high as 50 % after one year (early PCO rate) (Apple et al., 1992). At that time, the importance of cortical and cellular clean up during surgery was not yet fully understood and the IOLs used were manufactured of a rigid biomaterial (polymethylmethacrylate = PMMA).

The data of the late 1990s show that by improving surgical techniques and by using new IOL designs and new foldable biomaterials, the incidence of PCO steadily decreased to about one quarter of the patients. In a meta-analysis of 49 published studies performed in the mid-1990s, the overall Nd:YAG rate was 11.8 % at 1 year after surgery, 20.7 % after 3 years, and 28.4 % after 5 years (Schaumberg et al., 1998).

Similar ﬁ ndings came out of a large post-mortem study conducted from 1988 to 2000, visual acuity is the most common ﬁ nding after cataract surgery though haze, glare,

reduced contrast sensitivity, and sometimes astigmatism and monocular diplopia may occur as well (Phelps-Brown and Bron, 1996).

I.1.3 Diagnosis

PCO can be suspected when patients complain of discomfort in vision for the last months or years following cataract surgery. Sometimes, it is diagnosed by chance at a routine visit while measuring the patient’s visual acuity of each eye separately.

PCO can be easily diagnosed at the slit-lamp: Elschnig’s pearls are best seen by retro illumination while ﬁ brosis is best seen by direct illumination (Fig. 5).

Detection of PCO may be problematic in elderly patients because of their poor insight in the possible cause of their failing vision. Since they already had cataract surgery, they believe that this second deterioration of vision is due to ageing, conditions they perceive as inevitable and not treatable, and therefore they do not consult the ophthalmologist.

Fig. 5.

A. Photograph taken with lateral illumination demonstrating posterior capsule ﬁ brosis.

B. Anterior segment photograph under retroillumination showing Elschnig’s pearls on the posterior capsule.

C. Fibrosis on the posterior capsule inducing wrinkles, in lateral (top) and retroilumination (bottom).

A

B C

(10)

Chapter I Posterior capsule opaciﬁcation Financial considerations

PCO is a serious ﬁnancial burden for the health care budgets in the developed countries. In 2003 about 22,000 Nd:YAG laser treatments were performed in Belgium with an estimated cost of 1,500,000 €. At European level a total expenditure of 116,351,000 € for PCO treatment can be estimated based on extrapolation of the numbers of inhabitants per country. For the United States, annual expenses for treatment of PCO are estimated at 250,000,000 $ and it was concluded that “PCO remains the second most expensive surgical cost of the US Medicare System after the cataract surgery itself” (Apple et al., 2001, Apple et al., 2000).

Developing world problem

In the developing world, the occurrence of PCO is a very serious drawback for the use of the ECCE/IOL procedure to treat cataract on a large scale. In these countries no sufﬁcient ﬁnances, adequate equipment or surgical expertise is readily available to treat PCO. Therefore older techniques without risk of PCO but with higher morbidity for the eye are often preferred such as intracapsular cataract extraction (ICCE) where the lens capsule is removed together with the lens, often not followed by an IOL implantation. This technique will result in a high hypermetropia for which glasses are necessary.

I.2. PATHOGENESIS OF PCO

There is overwhelming evidence that PCO is caused by proliferation, migration and transformation of lens epithelial cells (LECs) still present in the capsular bag after ECCE. PCO happens to take two morphological forms or a mixture of both: (1) clusters of Elschnig’s pearls and (2) ﬁbrotic transformation of LECs covering the posterior capsule (ﬁbrotic plaques).

A basic knowledge of the embryology and normal structure of the crystalline lens is necessary for a better understanding of the pathogenesis of PCO.

I.2.1 Embryology of the lens (Lance Olson 1991)

In an early embryological stage (3.2 mm) the optic pits protruding from the neuro- ectoderm of the forebrain start to form the optic vesicles (Fig. 6). The optic vesicles are approaching the surface ectoderm, which is beginning to thicken and to form the lens plate. Shortly thereafter the lens plate and also the optic vesicle starts to invaginate. At the end of the fourth week of gestation (7.0 mm), the primary where the rate of Nd:YAG laser capsulotomy in pseudophakic eyes was analysed

(Schmidbauer et al., 2001). The authors studied 6,425 eyes with posterior chamber IOLs: 5,316 eyes had a rigid type of IOL and 1,109 eyes a foldable. In this study 32.3 % of the eyes with a rigid lens had received Nd:YAG capsulotomy, compared to 15.3% of the eyes with foldable lenses.

The most recent important improvement in IOL design was the square optic edge, which decreased Nd:YAG rates to 14.6 % after 5 years (Davison 2004).

In children PCO is much more prevalent. In this group of patients, PCO rates reach percentages as high as 83 % (Vasavada et al., 2004).

I.1.5 Reasons to combat PCO

Prevention of PCO is medically as well as economically justiﬁed.

Ophthalmological aspects

The current most common treatment for PCO is a central posterior capsulotomy performed with the Nd:YAG laser. This treatment removes the central opaciﬁcation of the posterior capsule and restores vision. However, in about 5 % of the cases the laser treatment causes a number of serious ocular complications. These complications include damage to or luxation of the IOL, intraocular pressure elevation, cystoid macular edema due to disruption of the internal ocular barriers and ﬁnally retinal detachment (Apple et al., 1992; Holweger and Marefat, 1997; Javitt et al., 1992; Newland et al., 1999). All these complications can be treated, though not always successfully.

In children presenting high PCO rates, Nd:YAG laser capsulotomy can only be done under general anesthesia. This increases dramatically the ocular and general co-morbidity in this group of patients with life long drawbacks.

Refractive purposes

In recent days, lens extraction is increasingly used for refractive purposes, aiming at the correction of visual acuity for distant and near vision by implanting IOLs attempting to restore accommodation. A low PCO rate is mandatory in these cases not only for the preservation of ocular transparency, but also for the stability of the IOL within the capsular bag. Capsular contraction and subsequent IOL decentration will seriously impair visual outcome of these accommodative IOLs (Gayton et al., 2000;

Wemer, Apple et al., 2000). Furthermore, when refractive lens exchange (clear lens extraction) and IOL implantation is used in high myopic eyes, PCO is highly unde- sired because it is known from the literature that these patients present a higher risk for retinal detachment after Nd:YAG laser treatment.

(11)

Chapter I Posterior capsule opacification the equator elongate simultaneously between the previous fiber layer and the anterior LECs anteriorly and the capsule posteriorly. In this way distinct shells of secondary lens fibers are formed, mutually interdigitated by ball-and-socket junctions and edge protrusions. Moreover the separate shells are also mutually interconnected by ball-and-socket junctions and edge protrusions. In addition the fibers of opposite sides interdigitate and form anteriorly and posteriorly the so-called suture lines.

This type of growth pattern leads to a stable network of shells made up of individual interconnected fibers, which have a minimal intercellular space and which are not sliding along each other. This is important for a homogenous refractive index over the whole lens and for the flexing of the lens as a whole during accommodation. Af- ter elongation and differentiation to fiber cells with an unprecedented high protein (crystalline) content (35–40 %), the secondary fibers also start to loose their cell organelles and nuclei in the same manner as described for the primary lens fibers.

Because of the absence of organelles, light scattering within the pupillary space is minimal and only due to the short-range order of the crystallins. The original basal lamina of the ectodermal cells is becoming thicker, due to the secretion of mainly collagen IV by the anterior LECs and the posterior elongating ﬁbers. Since both have a different ability to synthesize collagen, the thickness of the later lens capsule varies: it is thickest anteriorly and thinnest in the posterior pole.

The formation, growth and differentiation of the shells of secondary lens ﬁbers is going on throughout life, increasing the anterior-posterior thickness of the lens throughout life from approximately 3 to 5 mm and the equatorial diameter up to the 3rd decade from approximately 6.5 to10 mm.

For more details see for instance Phelps-Brown and Bron (1996), Kappelhof et al.

(1987) and Vrensen et al. (1991).

I.2.2 Structure of the normal adult lens

The lens is a unique transparent, biconvex intraocular structure able to change its shape during accommodation.

Along its whole circumference the lens is suspended from the ciliary body by ﬁne zonula ﬁbers, which are radially inserted in its pre-equatorial, equatorial and post- equatorial capsule (Fig. 7). This so-called suspensory ligament transmits the force of the ciliary muscle to the lens thus enabling accommodation. The lens is bordered posteriorly by the vitreous and anteriorly by the iris and the aqueous humour. It is not innervated and has no blood supply after the regression of the tunica vasculosa lentis starting at the 4th month of fetal life. The lens, especially the outer cortex with its proliferating and differentiating LECs, is a metabolically active organ and its transparency strongly depends on proper nourishment. Because of its avascularity optic vesicle has fully invagi-

nated and forms the double- layered optic cup.

The outer layer will form the retinal and ciliary body pigment epithelium, and the anterior pigment epithelium of the iris;

the inner layer will form the sensory retina and the posterior pigment epithelium of the iris. The invaginating surface ectoderm, or lens pit, almost completely ﬁlls the invaginated optic cup. Initially the lens pit is still in contact with the surface ectoderm but soon thereafter it is pinched off, and form the lens vesicle.

It is important to realize that during this process of lens in- vagination the future LECs are inverted, which means that the apical side of the original surface ectodermal cells is directed toward the lumen of the vesicle, while their basal lamina is viewing outward. This basement membrane evolves into the lens capsule. At the same time mesodermal cells have invaded the space between the lens vesicle and the optic cup, forming the hyaloid artery, the tunica vasculosa lentis and in later life the vitreous body. Nourishment for the rapidly developing lens is provided by the hyaloid artery and the tunica vasculosa lentis, which regress from the 4th to the 7th month of gestation.

The first stage in the differentiation of the lens is the elongation of the posterior LECs, untill their apex contacts the apex of the anterior cuboidal LECs, completely obliterating the lens cavity. These elongated cells are primary lens fibers and remain unchanged throughout life as the embryonic nucleus. After synthesis of the full complement of lens specific proteins: the α, β and γ crystallins, the cell organelles and nuclei of these primary lens fibers are broken down in a process reminiscent of apoptosis except that it leaves the fibers intact (Vrensen et al., 1991).

Germinative cells at the pre-equatorial region, are starting to undergo mitotic divi- sion and to form the meridional rows of LECs. Cohorts of meridional cells all around

Fig. 6. Development of the embryonic nucleus from the 5th to the 7th week of gestation. (from Olson L. 1991)

(12)

Chapter I Posterior capsule opaciﬁ cation Anterior cells

Anterior cells (A-cells) form a single cell layer on the inner face of the anterior capsule. Under physiological conditions A-cells are relatively quiescent with minimal mitotic activity. Post-mortem histological studies of human capsular bags have shown a stable single layer of A-cells on the inner surface of the anterior capsule even years after cataract surgery, suggesting a strong tendency to maintain their original shape and mitotic properties (Marcantonio et al., 2000). Rakic et al. (1997) have shown in short term cultured whole mount specimens of human capsules that the mitotic proliferation of LECs is largely restricted to the equatorial zone and that the anterior rhexis zone does not show mitotic activity.

However, recent studies have shown that after severe (ultraviolet) injury of the lens, A-cells are able to proliferate and restore the anterior monolayer of LECs within a relatively short time (Michael et al., 2000; Yamada et al., 2001).

Equatorial cells

Equatorial cells (E-cells) are found in the equatorial region, all around the lens periphery. This population of LECs is mitotically active throughout life and can be considered as stem cells. Their mitotic activity is moderate. One of the daughter cells remains in the equatorial region and starts new cycles of mitosis. The other daughter cell goes to a pool of cells, which forms the so-called meridional row of LECs. These meridional cells ﬁ nally differentiate to lens ﬁ ber cells.

I.2.3 Impact of surgery on LECs

Extracapsular cataract extraction is classically performed using the phacoemulsifi cation technique (Fig. 2). The anterior capsule is opened by means of an anterior circular continuous capsulorhexis (ACCC), resulting in a strong elastic free border, which prevents zipping of the anterior capsule towards the equator, where the zonular fi bers will prevent further zipping to the posterior capsule. The lens nucleus is emulsifi ed by ultrasonic waves and the cortex is aspirated. LECs lining the remaining part of the anterior capsule (A-cells) can be aspirated to a large extent. It is technically impossible however, to remove the LECs at the equator of the bag (E-cells). They will remain in the bag together with the newly implanted intraocular lens. There is no doubt that LECs will suffer from the cataract surgery. They will not only be injured mechanically by the instruments but also by the circulating nuclear fragments, the irrigation solu- tions and their osmotic effect. In vitro studies demonstrated that these injured LECs recover from this surgical trauma within 24 hours by proliferating and covering the posterior and anterior capsule completely within one week (Wormstone et al., 1997).

This outgrowth of LECs can be interpreted as a wound healing response.

the lens depends for its supply of nutrients and oxygen on the surrounding aqueous and vitreous, which are also responsible for the removal of waste products. Insults occurring to the lens, whether of metabolic, chemical or mechanical nature, or due to irradiation, trauma, disease or just ageing may induce opaciﬁ cation of some len- ticular elements, and will result in a so-called “cataract”.

The lens has a central nucleus, surrounded by the cortex consisting of the postna- tally formed cortical ﬁ bers (Fig. 8) (Phelps-Brown and Bron, 1996). Also on account of the arrangement of the suture lines the central nucleus can be subdivided in an embryonic, a fetal and a juvenile nucleus (Kuszak et al., 1984). Related to the so- called zones of discontinuity the cortex can be subdivided in a deep and a superﬁ cial

cortex. The lens capsule is a true, PAS- positive basement membrane, a secreto- ry product of the lens epithelium. It is the thickest basement membrane in the body (3–10 µm).

LECs are forming a monolayer lining the inner surface of the anterior capsule up to the equator (Fig. 8). Under physiological conditions, LECs do not grow towards the posterior capsule. Their migration is stopped by the presence of the posteriorly growing lens ﬁ ber cones.

Although all LECs originate from a single cell line, dividing these into two different functional groups is useful for the better understanding of their role in pathological processes:

Fig. 8. Schematic illustration showing components of an adult crystalline lens. Note the area of active mitosis of the LECs in the equatorial region.

The postmitotic LECs start to elongate and differenti- ate, and form the equatorial lens bow of nucleated lens ﬁ bers. (from Apple et al. 1992)

Fig. 7.

A. Anatomy of the human eye showing the lens and its zonulae attached to the ciliary body.

B. Zonula ﬁ bers from the ciliary processus to the lens capsule. (from Hogan MJ et al. 1971)

A B

(13)

Chapter I Posterior capsule opaciﬁ cation promoting ﬁ brotic PCO (Apple et al., 1992). In normal circumstances, the contribution of A-cells to classic PCO is however limited.

Changes in the E-cells

The E-cells at the equator of the capsular bag will induce PCO, either of the ﬁ brotic or of the pearl type. In vitro studies of whole-mount capsular bag models where the lens material has been removed, demonstrated that the germinative cells of the pre- equatorial zone are able to proliferate and migrate along the posterior capsule (Rakic et al., 1997). Proliferation and migration of LECs in the natural human lens is a very rare condition that is only found as a response to chronic uveitis or some medica- tion. This behaviour can be considered as a healing response after surgical trauma.

In vitro as well as in vivo the proliferating E-cells form a lens bow-like structure at the capsule equator, and differentiate to lens fi bers. This leads to the formation of the Soemmering’s ring, which is donut-shaped and composed of newly formed fi b- bers. In fact, it is an attempt of the LECs to repair the removed lens by attempting to make new lens fi bers.

Soemmering’s ring was initially described after ocular trauma with disruption of the anterior lens capsule resulting in spontaneous resorption of the lens material with time and allowing the anterior and posterior capsules to stick to each other. But in between both capsule blades the E-cells start to become active and to form a new lens (Fig. 9). A Soemmering’s ring is formed in virtually all eyes after an extracapsular cataract extraction. (Werner et al., 2000; Apple et al., 2001). Rakic et al. (1997) demonstrated that the presence of newly formed lens ﬁ bers decreases the mitotic activity of the E-cells, reducing the risk for PCO. This inhibition might be responsible for slowing down or even stopping LEC migration after cataract surgery in 60 to 80 % of the patients, which will never develop PCO.

E-cells growing on the posterior capsule can cause two types of PCO:

– When E-cells differentiate to lens ﬁ bers, forming the ring of Soemmering, some do escape into the space behind the IOL where they tend to form large bal- loon-like (Wedl) cells that do not express a-SMA (Kuroska et al., 1996). When these cells cluster together they form the so-called Elschnig’s pearls. Evidence in favour of this suggestion can be found in the studies of Kappelhof and Vrensen (1992).

– They can cause the fi brous form of PCO by undergoing fi brous metaplasia, characterized by the expression of α-SMA. These metaplastic cells further produce extracellular material as basement membrane fragments, proteoglycans and collagen fi brils. Because of their contractile elements (α-SMA) they can induce wrinkling of the posterior capsule (Fig. 5 C), leading to visual disturbances and IOL displacement (tilting or dislocation). LECs have a tendency to spread along these folds.

Fig. 9.

A. Drawing of an empty capsular bag some time after cataract extraction, showing a Soemmering’s ring at the periphery between the anterior and posterior capsules.

B. Post-mortem images of a Soemmering’s ring: (Vrensen GFJM)

- left : anterior segment potograph after removal of cornea, limbus and iris, showing an IOL with the lower haptic in the capsular bag and the upper haptic in the sulcus and with a posterior capsulotomy.

- right : isolated capsular bag stained with aldehyde and osmium, demonstrating a large Soemmering’s ring and LEC growth on the posterior capsule. O: optic, H: haptic, AR: anterior rhexis, PC: posterior capsule, RS:

ring of Soemmering.

B A

Soon after surgery a number of changes do occur in the A- or E-cells (Bertelmann and Kojetinsky, 2001):

Changes in the A-cells

A-cells that are not removed become almost immediately opaque after surgery, probably as a result of the swelling induced by the surgical trauma. The primary type of response of the A-cells is proliferation and metaplasia into fi brous tissue, also termed pseudofi brous metaplasia in situ by Font and Brownstein (1974). Their fi bro- muscular differentiation is expressed by a positive staining for α-smooth muscle actin (α-SMA), an isoform of actin normally restricted to smooth muscle cells (Mc- Donell et al., 1983 and 1985; Saxby et al., 1998; Marcantonio et al., 2000). They cause anterior capsular opacifi cation and in extreme cases even a contraction of the anterior capsule, a so-called capsular contraction syndrome. When the anterior rhexis size is larger than the optic of the IOL, the A-cells come in contact with the posterior capsule, giving them the possibility to proliferate on that substrate

(14)

Chapter I Posterior capsule opaciﬁcation proliferation and migration of these LECs (Duncan, 1998). Moreover, Wormstone et al. (1997) have shown on in vitro organ culture of LECs on lens capsules that exo- genous growth factors are not needed for LECs to proliferate.

Removal of the lens content

Removal of the lens content might in itself induce PCO without the participation of cytokines or local growth factors. Rakic et al. (1997) showed that direct contact with lens ﬁbers inhibits the mitotic activity of LECs. After cataract extraction this inhibition will of course stop immediately.

In addition, the older concept of “no space, no cell growth” (Born and Ryan, 1990), stating that LECs stop proliferating as soon as the available space is ﬁlled up, might be another reason why the LECs start to proliferate after lens extraction.

I.3. PCO PREVENTION

Based on the crucial role of the LECs in the development of PCO, two major strategies have been pursued to prevent PCO: (1) surgical efforts to minimize the number LECs left in the capsular bag after surgery and (2) non-surgical efforts to stop the remaining LECs from proliferating and migrating into the visual axis. These strategies have been used in different types of preventive therapies as overviewed below.

I.3.1 Surgical methods to prevent PCO

The progress in surgical techniques has been ongoing the last two decades, reducing PCO rates from about 50 % to about 16 % 4 years postoperatively (Davison, 2004).

Although all steps of the cataract procedure are important to minimize complications, three surgery-related factors and three IOL-related factors stand out as particularly important regarding the prevention or at least the delay of PCO development.

Surgery-Related Factors

1. Improved Clean up by Hydrodissection

An important and underestimated act during ECCE is the hydrodissection of the capsule from the lens cortex, also called cortical cleaving hydrodissection (Peng et al., 2000; Fine, 1992; Faust, 1984; Assia et al., 1992; Gimbel, 1994). During the hydro-dissection procedure a ﬂow of ﬂuid is injected through the anterior capsule opening towards the posterior capsule to separate capsule and lens cortex.

I.2.4 Triggers for LEC proliferation and migration

It is not yet very clear which are the factors triggering the LEC proliferation and migration after ECCE. Disruption of the blood aqueous barrier during and after surgery, thereby activating the release of inﬂammatory mediators such as cytokines and the presence of local growth factors are believed to be stimulating factors.

Cytokines

Cytokines have been identified as important elements in the development of PCO in different studies. Transforming growth factor-β (TGF-β) and basic fibroblast growth factor (bFGF) seem to play major roles. TGF-β inhibits epithelial cell proliferation, while high levels of bFGF stimulates mitosis of LECs. In addition, TGF-β stimulates metaplastic transformation of LECs and the production of extracellular matrix components like collagen. It was shown that the concentration of TGF-β reaches a minimum level immediately after cataract surgery, suggesting a predominant effect of bFGF during this period. After returning to normal levels 2 weeks after surgery, ris- ing levels of TGF-β may provoke further PCO changes like myofibroblastic differentiation, extracellular matrix formation, and attachment of LECs to the posterior capsule (Meacock et al., 2000). TGF-β-producing cells could be detected on the surface of explanted intraocular lenses (IOLs) (Saika et al., 2000).

Changes in cytokine patterns following cataract surgery have been attributed to changes in the blood-aqueous barrier (Meacock et al., 2000). This probably explains why underlying diseases related to changes in the blood-aqueous barrier, like uveitis, are associated with higher rates of PCO (Krishna et al., 1998; Dana et al., 1997). On the other hand, inconsistent information exists about the PCO rate of patients with diabetes mellitus, who more likely present disturbances in the blood-aqueous barrier.

In some studies a higher rate was found (Ionides et al., 1994), in others a lower rate of PCO (Knorz et al., 1991; Kuchle et al., 1997; Zaczek and Zetterstrom, 1999).

Clinical studies suggest that patients with diabetes and uveitis are more likely to develop ﬁbrotic changes than pearls. Pseudo-exfoliation and retinitis pigmentosa are associated with a higher rate of PCO (Kuchle et al., 1997; Auffarth et al., 1997).

As mentioned before, the most important factor inﬂuencing the rate of PCO is the patient’s age (children having PCO rates up to 83%, Vasavada et al, 2004).

The interpretation of PCO formation as a wound-healing response, involving inﬂam- mation-associated cytokines like interleukin 1 and 6, brought attempts to inhibit PCO by application of non-steroid antiphlogistic drugs like diclofenac. However, such treatment failed to be effective under in vivo conditions (Tetz et al., 1996).

Endogenous growth factors

Endogenous growth factors, including hepatocyte factor and ﬁbroblast growth factor, have been found to be produced by the LECs and are known to be able to promote

(15)

Chapter I Posterior capsule opaciﬁcation foldable IOLs the number of secure in-the-bag ﬁxations has risen to more than 90 % (Ram et al., 1999 I). Only in cases of peroperative complications, e.g. a large capsular tear, implantation of the IOL in the capsular bag might not be possible, and must be implanted in the ciliary sulcus or in the anterior chamber.

The most obvious advantage of in-the-bag fixation is the accomplishment of good optic centration and sequestration of the IOL from adjacent uveal tissues, which is less obvious in sulcus or anterior chamber fixation. An optimal fixation of the IOL in the bag will help reducing PCO, an aspect that is often underestimated (Ram et al., 1999 I and II; Peng et al., 2000; Apple et al., 1985). The in-the-bag fixation reduces PCO by enhancing the IOL-optic barrier effect, which reaches its optimal effect when the lens optic is fully in-the-bag and has direct contact with the posterior capsule (Peng et al., 2000). If one or both haptics are not carefully placed in the bag, a potential space is created, allowing LECs to grow posteriorly toward the visual axis.

3. Anterior circular continuous capsulorhexis

The importance of the anterior circular continuous capsulorhexis (ACCC), with a diameter slightly smaller than the diameter of the IOL optic has been advocated by several authors in order to reduce PCO (Wren et al. 2005) (Fig. 10). In this way a tight ﬁt between the anterior edge of the capsule and the anterior surface of the IOL optic is possible. The IOL optic will remain sequestered within the capsular bag from the surrounding aqueous humour. This may help to protect the capsule from potentially deleterious factors present in the aqueous humour, e.g.

macromolecules and inﬂammatory mediators (Peng et al., 2000; Ravalico et al., 1996).

Eyes that have an anterior rhexis larger than the implant or a rhexis that is partly on and partly off the optic, develop wrinkling of the posterior capsule within a few weeks after the operation (Spalton, 1999; Hollick et al., 1999; Wren et al., 2005; Wejde et al., 2004). A possible explanation is that in case of a large rhexis the anterior LECs will have direct contact with the posterior capsule on which they can migrate. These cells will differentiate fast into myoﬁbroblasts and produce wrinkling. If the capsular ﬂaps are separated by the optic, the access of the LECs to the posterior capsule is certainly limited in the early postoperative period.

IOL-Related factors

The amount of PCO varies considerably with the IOL design and the biomaterial of which it is manufactured.

Different factors have been found to be important in this respect and are summarized below.

After freeing and rotating the lens nucleus, the removal of the remaining cortex is very easy to perform. Until fairly recently, many surgeons had a rather fa- talistic expectation about removal of LECs after phacoemulsiﬁcation. This was partly justiﬁed, because it is impossible to ensure their complete removal. How- ever, reducing the number of remaining LECs at the time of surgery may delay PCO formation, especially in round-edged IOLs (Sacu et al., 2004a and 2004b).

With a special aspiration probe (mono or bimanual) attempt are made to aspirate the LECs from the anterior capsule and the equator. This surgical manoeuvre is difﬁcult to perform accurately because the equator of the bag is not visible.

Another commonly used technique is to polish the lens capsule manually with a blunt, rough cannula.

2. In-the-bag ﬁxation

The hallmark of cataract surgery is to consistently secure the IOL in-the-bag (Figs. 3 and 10) (Ram et al., 1999 I and II; Peng et al., 2000; Apple et al., 1985).

In-the-bag fixation (Ram et al., 1999 I) reached a limit of approximately 60 % using the non-phaco-emulsification ECCE technique, that means large-incision extracapsular surgery with can-opener anterior capsulotomy and rigid IOL implantation (Schmidbauer et al., 2001). Nowadays using phacoemulsification and

Fig. 10. A front view of an IOL implanted in a capsular bag, with the anterior rhexis covering the optic of the IOL.

(16)

2. Edge of the IOL optic

Recently it has been shown that IOLs having a square, truncated edge develop less PCO compared to IOLs with a round, tapered edge (Hansen et al., 1988; Hara et al., 1991; Nishi O. and Nishi K., 1999; Nagata and Watanabe, 1996). In bags implanted with an IOL with round optic edge, LECs can easily grow behind the optic. A truncated square-edged optic on the contrary will create a sharp bend in the posterior capsule and LECs will experience a sharp demarcation of the available space (Fig. 12) (Peng et al., 2000; Masket, 2000). This mechanical blockage will only work if the optic is in close contact with the posterior capsule. The idea behind this design is that as soon as the capsular bag becomes ﬁbrotic, the anterior and posterior capsules will fuse and the sharp impression of the edge will be enhanced at the level of the posterior capsule.

The beneﬁcial effect of a sharp square-edge optic design to form a mechanical barrier for the LECs was ﬁrst reported by Nishi and colleagues (Nishi et al., 1999).

They introduced the AcrySof lens with a sharp edge, which showed a lower incidence of PCO in human eyes. In clinical studies comparing two silicone lenses, one with a sharp optic edge versus one with a round optic edge, a signiﬁcantly lower PCO rate was found in the group with the sharp optic edge (Kruger et al., 2000; Buehl et al., 2004). In a clinicopathological study, Apple conﬁrmed this phenomenon (Apple et al., 1998; Peng et al., 2000). In bags with squared, truncated optic edges they often observed an abrupt block of LECs at the peripheral edge of the optic. However, the best results using these square-edged IOLs still show a cumulative Nd:YAG laser capsulotomy rate of 13.3 to 16.0 % after 6 years of implantation (Davison, 2004).

A disadvantage of the square, truncated edge is the possible occurrence of clinical visual aberrations as e.g. glare, halos, and crescents. Subtle changes in manufacturing can help to alleviate these complications.

The capsular bending ring introduced by Nishi et al. (1998) seems to reduce PCO based on the same mechanism.

3. Biocompatibility of IOL

There is ample evidence that apart from the size and shape of the IOL as described above, the chemical composition of the IOL plays a role in the proliferation, 1. Maximal contact between IOL and the posterior capsule

Clinical and experimental evidence revealed the importance of the relationship between the IOL optic and the posterior capsule in providing a barrier to the migration of LECs into the visual axis (Apple et al., 1992). By promoting a ﬁrm contact between the IOL and the capsule, the LECs have no space to proliferate, the so called the “no space, no cells” concept (Sterling and Wood, 1986; Davis and Hill, 1989). This can be obtained by different approaches.

First, creating a radial force through the IOL haptics stretches the equator of the capsular bag and the posterior capsule, thereby improving the contact between the back of IOL optic and the posterior capsule (Hansen et al., 1988) (Fig. 11).

The haptics have thus to be long enough as to stretch the bag circumferentially but not too large in order not to create folds in the posterior capsule along which the LECs are able to migrate. Different haptic designs have been tested.

Lenses with a J- or C-loop more often produce folds in the posterior capsule, especially when the IOL has a much larger total diameter than the diameter of the capsular bag. This problem was less pronounced in IOLs with circular haptics as they more equally stretch the posterior capsule. A capsular tension ring can also be used for this purpose. This ring is made of PMMA and is put in the capsular bag before implanting the IOL. It will exert radial tension on the posterior capsule over approximately 360°.

Second, posterior angulation of the IOL can be achieved by a slight posterior vaulting of the optic with respect to the haptics. This way the IOL optic is lo- cated in a more posterior position and provides an additional pressure against the posterior capsule (Fig. 11) (Apple et al., 1992; Hansen et al., 1988; Nagata et al., 1998). However, in case of capsule contraction, the IOL will undergo an even more posterior displacement causing a hyperopic shift.

Third, a posterior convex optic provides an additional improvement of better contact with the posterior capsule. Almost all IOLs have a convex posterior surface (Fig. 11).

Fourth, the adhesiveness of the IOL material to the posterior capsule can have an important inﬂuence. The relative stickiness of the IOL optic biomaterial helps to produce an adhesion between the capsule and IOL optic (Nagata et al., 1998;

Linnola, 1997; Linnola et al., 2000 I and II; Oshika et al., 1998).

Fig. 12. Optic design demonstrating the barrier effect of a biconvex IOL with a square truncated edge. The posterior capsule is bended around the truncated edge, causing abrupt blockage of LEC migration.

Fig. 11. Schematic drawing of an IOL in a capsular bag, showing the apposition of the central posterior face of the optic against the posterior capsule, thanks to the biconvex optic with posterior angulation of the IOL.

(17)

• Capsular biocompatibility

In ophthalmic literature biocompatibility is deﬁned as the reaction of LECs and capsule to IOL material. It is generally seen as the ability to inhibit proliferation and migration of LECs and so to lower the chance for PCO (Schmidbauer, 2001; Apple et al., 2000; Wemer et al., 2000; Hollick et al., 1998; Ram, 1999 II).

The incidence and intensity of anterior and posterior capsular opaciﬁcation are thus parameters of capsular biocompatibility or bio-incompatibility.

Acryl and silicone are the most frequently used materials at present. During the last years many studies have shown that acrylic polymers have a superior biocompatibility and have a low incidence of anterior capsule opaciﬁcation (Werner et al., 2000), Soemmering’s ring formation (Ram, 1999 II) and more importantly PCO (Apple et al., 2000). Care should be taken with studies, comparing two variables (the acrylic IOL was the ﬁrst to have a sharp optic edge) at the same time, since the contribution of each variable to the prevention of PCO will remain uncertain (Oner et al., 2000; Auffarth et al. 2004). When silicone lenses with a sharp optic edge became available, they also showed a decrease in PCO rate (Findl et al. 2005, Sundelin et al. 2005).

Moreover surface properties, like hydrophobic versus hydrophilic, are important parameters in capsular biocompatibility. The effect on PCO of the same material but with different afﬁnity to water can differ dramatically, e.g. hydrophobic and hydrophylic acrylics (Heatley et al, 2005; Auffarth et al., 2004).

– Hydrophobic materials (silicone and hydrophobic acrylic lenses) induce more fibrous transformation of the LECs. Why exactly these LECs start to differentiate into fibroblast-like cells, producing a-SMA instead of F-actin (Marcantonio et al., 2000), is not known. Because the degree of surgical trauma is comparable in all studies, and many types of IOLs have a good apposition between the IOL and the posterior capsule, the IOL biomaterial seems to play an important role. LECs proliferating between the anterior capsule and the IOL surface undergo fibrous metaplasia, leading to opacification of the anterior capsule and thickening of the capsulorhexis rim (Abela-Formanek et al., 2002). Ante- rior capsule opacification is an important parameter for IOL biocompatibility, but does not influence visual acuity, except that it may play a role in the final centration of the lens within the capsular bag. Hydrophobic lenses also show more fibrosis of the posterior capsule and less Elschnig’s pearls.

– Hydrophilic materials (hydrophilic acrylic lenses) support LEC proliferation better, with less or no metaplasia, resulting in less opaciﬁcation of the anterior capsulorhexis rim and less ﬁbrosis of the posterior capsule, but more Elschnig’s pearls. Since hydrophobic materials have less vision impairing PCO, they are considered to have a better capsular biocompatibility than hydrophilic acrylic materials (Abela-Formanek et al., 2002).

migration, differentiation and ﬁbrotic transition of LECs and thus may inﬂuence the extent and severity of PCO.

Besides this healing process of the LECs, cataract surgery also induces a cellular response. In this respect we have to make a distinction between the short- term migration of monocytes, macrophages from the uveal vessel walls into the aqueous induced by the surgical trauma itself and the long-lasting foreign-body reaction to the IOL, characterized by the transformation of macrophages into epitheloid cells and foreign-body giant cells (FBGCs). IOL material and surface properties are also of relevance for the adherence of these white blood cells.

Since the IOL can cause a speciﬁc foreign body response at the level of the uvea and ﬁbrotic and pearl response at the level of the capsule, two different types of reactions can be distinguished: the uveal and the capsular reaction (Amon, 2001).

• Uveal biocompatibility

Because of surgical trauma the blood-aqueous barrier will be disrupted and monocytes and macrophages will migrate from the uveal vessel walls into the aqueous.

They may adhere to the anterior IOL surface and the density of these cells thus reﬂects the biocompatibility of the IOL material for these cells. Monocytes transform into small round cells, and macrophages into epitheloid cells and foreign- body giant cells (FBGCs).

The small round cells reﬂect mainly the early postoperative reaction to the surgical trauma (Abela-Formanek et al., 2002). Small round cells are usually present in the ﬁrst few days and weeks after surgery. Abela-Formanek et al. (2002) found a higher incidence of these cells in second-generation silicone, compared to hydrophobic acrylic lenses and to hydrophilic acrylic lenses. There is also evidence that more small round cells are present on PMMA lenses in the early postoperative weeks. This may indicate that the surfaces of silicone and PMMA lenses form a better substrate for the adherence of these small round cells than the acrylic lenses i.e. are more bio-compatible.

Epithelioid cells and FBGCs are formed by the differentiation and fusion of macrophages. They reflect the lasting non-specific immunological foreign-body reac- tion. If in situ a foreign-body reaction persists, FBGCs and epithelioid cells will start to accumulate on the IOL surface. (The differences between the two cell types are the size and number of nuclei in the cells.) They are usually found in eyes with a prolonged inflammatory reaction and are therefore an indicator of the uveal bio-incompatibility of IOL materials. The results of Abela-Formanek et al. (2002) suggest that hydrophobic acrylic lenses have a higher density of FBGCs than hydrophilic acrylic, silicone and PMMA lenses. This means that the hydrophobic acrylic lenses more easily induce a foreign-body reaction and thus can be considered to be less uveal biocompatible.

(18)

Chapter I Posterior capsule opaciﬁcation nology aiming at restoring accommodation based partially on the anterior movement of the capsule-IOL complex during the reﬂex of accommodation.

In summary, the ideal biomaterial should not induce a foreign-body reaction of the uvea, and should therefore be biocompatible for the uvea and the anterior chamber.

On the other hand, the material should inhibit LECs’ proliferation, and should there- fore be bio-incompatible for the LECs so that the outgrowth of LECs on its natural substrate (the capsule) and the surface of the IOL is inhibited or not enhanced. In view of this, the search for the “ideal” IOL biomaterial is intrinsically confronted with a conﬂicting demand. If we would have found a material that is bio-incompatible for LECs, there is a good chance that it is also bio-incompatible for other elements of the anterior segment and will induce a foreign-body reaction and may even have an indirect effect on the corneal endothelium and the ciliary body.

Many questions remain unanswered. The perfect biomaterial still has to be found.

The overall impact of IOL biocompatibility in the pathogenesis of PCO is multifacto- rial and depends on the combination of IOL material and design. Early PCO by fibrosis, which is associated with less visual discomfort, may be efficacious in protecting against the vision disturbing pearl formation, developing later in time and which can be blocked by the barrier effect of the sharp optic edge. Additionally, different IOL types made of the same material (hydrophobic acrylic) showed significant differences in anterior capsular reaction (Abela-Formanek et al., 2002; Tognetto et al., 2002) probably because they exhibit other surface characteristics or because the material is not completely identical. “Acryl” is not one specific chemical entity, but a collective noun for materials with acrylic properties. Likewise, not all silicone lenses are made of the same silicone (Chang, 2000).

I.3.2 Non-surgical strategies for PCO inhibition

A variety of non-surgical strategies for the prevention of PCO have been evaluated.

The possible approaches are based on the four classical steps leading to PCO due to the presence of LECs remaining after cataract extraction: (1) adhesion of the remaining LECs to the capsule, (2) proliferation, (3) migration and (4) differentiation to ﬁbrotic cells. The concern with these strategies is not only to obtain LEC death but also to restrict the damage to the LECs only. For this reason few have ever made it from in vivo laboratory studies to human trials. In addition, since the agent is mostly applied intraoperatively, it must be able to kill all the LECs within a few minutes.

1. Antimetabolites

Antimetabolites have been effectively used in inhibiting LEC proliferation and dif- ferentiation in vitro and in reducing PCO in experimental settings, but their clinical Comparing uveal compatibility and capsular compatibility Abela-Formanek (2002

A + B) showed that hydrophilic acrylic material had good uveal but bad capsular biocompatibility and hydrophobic acrylic material had lower uveal but better capsular biocompatibility, which does sound strange. On the other hand, Hollick and co-authors (1999) found that LEC proliferation is associated with reduced inﬂammatory cell reaction, and concluded that if an IOL is too biocompatible, it may incite LEC growth on its surface.

According to the definition of biocompatibility (“biocompatibility is the capability of a prosthesis implanted in the body to exist in harmony with tissue without causing deleterious changes”, Int. Dictionary), the term biocompatibility in ophthalmic literature is associated with the least amount of PCO (Amon, 2001). Since the fibrotic type of PCO produces less visual disturbances than the pearl type, IOLs inducing fibrosis present less PCO and are considered in the literature to have a better “biocompatibility” than pearl-inducing IOLs. This terminology is a little controversial with the theoretical definition of biocompatibility, since pearl formation indicates that the LECs did not transform into another cell type, which should be considered as a more biocompatible behaviour. Pearl formation is also the behaviour seen in the absence of any implant. We question whether the word biocompatibility has been used in the correct way. In our opinion, materials inducing fibrosis are less

“biocompatible”, since bio-compatibility should be inversely related to altering the original nature of cells.

An excellent example of a biocompatible material is PMMA. Based on observations during World War II that methacrylate splinters of aircraft windows did not induce inﬂammatory reactions in the anterior eye segment of pilots, Ridley successfully introduced PMMA IOLs (cfr. Apple, 1999). Since PMMA is not toxic and does not induce a foreignbody reaction, it is biocompatible with the uvea. It is also common knowledge that PMMA, coated or uncoated, is a good substrate for in vitro culture of numerous cell types. Thus PMMA is very biocompatible for LEC growth. This explains why after modern cataract surgery, the incidence of PCO remains considerable with PMMA lenses.

Biocompatibility can be deﬁned as the ability of a particular substrate to allow unre- strained growth and differentiation of cells. For the capsule this means that a truly biocompatible IOL will not inhibit the normal outgrowth of LECs on the capsular bag.

With respect to PCO we just want the opposite, namely a bio-incompatible IOL, which is able to inhibit the growth and differentiation of the remaining LECs. Our conclusion is that IOLs inducing a ﬁbrotic type of PCO have in fact a bad bio-compatibility.

We further advocate that an important drawback of the so-called bio-compatibility- related ﬁbrotic type of PCO causing less visual disturbances, will result in reduced ﬂexibility of the capsular bag, which is an important drawback for the modern tech-