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laboratory science
Blue light-absorbing intraocular lens and retinal
pigment epithelium protection in vitro
Janet R. Sparrow, PhD, Ashley S. Miller, Jilin Zhou, MD
Purpose: To compare the Alcon AcrySof威 Natural (SN60AT) and AcrySof
(SA60AT), the AMO Sensar威 (AR40e) and ClariFlex威, and the Pfizer CeeOn威 Edge
911A intraocular lenses (IOLs) as to their ability to protect retinal pigment epithelial (RPE) cells from light damage mediated by the lipofuscin fluorophore A2E.
Setting: Department of Ophthalmology, Columbia University, New York, New
York, USA.
Methods: Cultured human RPE cells (ARPE-19 cell line) that had accumulated
A2E were exposed to blue (430 nm ⫾ 30), green (550 ⫾ 10 nm), or white (390 to
750 nm) light with and without an IOL in the light path.
Results: The blue light-absorbing AcrySof Natural IOL was associated with significant reduction (78% to 82%; P⬍.01) in the death of A2E-laden RPE that were
exposed to blue, white, and green light. The decrease in the incidence of cell
death was greater in magnitude than would be expected from the amount of light
that was absorbed by the IOL. The considerably smaller declines in cell death observed with the AcrySof, Sensar, ClariFlex, and CeeOn Edge IOLs were likely due
to nonspecific reductions in light transmittance.
Conclusions: By absorbing blue light, the AcrySof Natural IOL shields RPE cells
that have accumulated the aging lipofuscin fluorophore A2E from the damaging effects of light. A long-term population-based clinical trial would determine whether
a blue light-absorbing IOL can reduce the risk for or progression of age-related
macular degeneration.
J Cataract Refract Surg 2004; 30:873–878  2004 ASCRS and ESCRS
T
he design of intraocular lenses (IOLs) should be
based on the properties of the human ocular lens,
especially in the transmission properties of the IOL.
Notably, the human crystalline lens absorbs most ultraviolet light between 300 nm and 400 nm.1 Thus, to
provide the same protection to the retina afforded by
the natural lens, the use of ultraviolet light-absorbing
IOLs became the standard of practice once these lenses
were developed.2–8 However, the transmission properties
of most IOLs are not comparable to those of the natural
Accepted for publication January 27, 2004.
Reprint requests to Janet R. Sparrow, PhD, Department of Ophthalmology, Columbia University, 630 West 128th Street, New York, New
York 10032, USA. email: [email protected].
 2004 ASCRS and ESCRS
Published by Elsevier Inc.
human lens, since the latter yellows with age while IOLs
in current use are colorless.2,9–13 The color change in the
natural lens is likely attributable to oxidation products of
tryptophan (n-formyl-kynurenine) and to glycosylation
of lens proteins.14 It results in a progressive increase
in absorbance within the blue range of the visible
spectrum.2,9
Filtering the shorter wavelengths of the visible spectrum is particularly significant because it is also this
portion of the spectrum that produces photochemical
damage to the retinal pigment epithelium (RPE).15–17
It is now generally accepted that at least 1 of the intracellular chromophores responsible for the blue light sensitivity of RPE cells18,19 is the lipofuscin constituent
A2E.20–22 This fluorophore is unique to RPE cells and
0886-3350/04/$–see front matter
doi:10.1016/j.jcrs.2004.01.031
LABORATORY SCIENCE: BLUE LIGHT-ABSORBING IOL
has been shown to accumulate in human RPE cells
throughout the lifetime of an individual, with levels
being highest in the aged eye.21 Thus, replacement of
a senile cataractous crystalline lens with a colorless IOL
may leave the RPE vulnerable at an age when its content
of blue light sensitive A2E is already high.
The RPE fluorophore A2E is maximally excited
by light in the blue region of the spectrum.18 When
irradiated, A2E generates singlet oxygen that proceeds to
add to carbon–carbon double bonds of A2E to generate
highly reactive epoxides (A2E-epoxides) along the sidearms of the molecule.23, 24 The cellular injury induced by
the illumination of A2E-laden RPE includes oxidative
DNA base changes,25,26 and it is likely that as electrophiles that can readily react with many cellular molecules, A2E-epoxides may account for much of the
cellular damage accrued.25 The photochemical events
provoked by the irradiation of A2E-laden RPE ultimately result in the initiation of a cell death program.
The sensitivity to blue light conferred by the lipofuscin
fluorophore A2E may explain why atrophic age-related
macular degeneration (AMD) has been linked to both
RPE lipofuscin27–33 and cumulative light exposure.34
Moreover, the loss of RPE cells in atrophic AMD is a
critical event as it leads to photoreceptor cell degeneration.
Given that the attenuation of blue light afforded
by the yellowed senescent lens may defend lipofuscinfilled RPE cells against blue light damage, we are interested in efforts being made to develop IOLs that
replicate the transmission characteristics of the aging
crystalline lens. In this study, we constructed a cell
culture system that allowed us to compare several IOLs
as to their ability to protect A2E-laden RPE from blue
light damage. In this cell culture system, A2E accumulates in the lysosomal compartment of a human RPE
cell line, as it does in RPE of the eye.35 Moreover, the
levels of A2E are comparable to the level occurring in
vivo.18,35 This model also allows us to study RPE cells
with and without intracellular deposits of A2E.
Materials and Methods
The IOLs studied were the Alcon AcrySof威 Natural
(SN60AT) (acrylic, 20.0 diopters [D], 6.0 mm optic diameter) and AcrySof (SA60AT) (acrylic, 20.0 D, 6.0 mm optic
diameter); the AMO ClariFlex威 (CLRFLXB) (silicone,
20.0 D, 6.0 mm optic diameter) and Sensar威 (AR40e)
(acrylic, 20.0 D, 6.0 mm optic diameter); and the Pharmacia
874
CeeOn威 Edge (911A) (silicone, 20.0 D, 6.0 mm optic
diameter).
A2E Accumulation in Culture
Human RPE cells (ARPE-19, American Type Culture
Collection), which are devoid of endogenous A2E,35 were
grown in 8-well, plastic chamber slides (Laboratory-Tek,
Nunc), as described.35 Once confluent, the cells were allowed
to accumulate synthesized A2E21 from a 20 ␮M concentration
added to the medium. With this protocol, A2E accumulates
in the lysosomal compartment of the cells to levels that are
comparable to amounts present in vivo.18,35
Illumination and Placement of the IOL
Immediately before illumination, the culture medium
was replaced with phosphate-buffered saline containing calcium, magnesium, and glucose. For quantitative measurements of light-induced cell death, the cells were exposed to
blue light (430 nm ⫾ 30 [SD], 8 mW/cm2), green light
(550 ⫾ 10 nm, 8 mW/cm2), or white light (246 mW/cm2)
over a 0.8 mm ⫻ 8.5 mm field. The light was delivered
from a tungsten halogen source for 20 minutes, and power
was measured with a Newport optical power meter (model
840). The spectral range of the lamp was 390 to 750 nm,
with a lower output at the shorter wavelengths.
The IOL to be tested was applied to the undersurface
of the culture well, where it remained attached, unaided. It
was centered over the light path.
To obtain a visual representation of IOL protection,
1.0 mm diameter disks were cut from the center of the IOL
using a trephine blade (Katena Products, Inc.). The IOL
disks were positioned on the undersurface of the well, which
was then irradiated (430 ⫾ 30 nm, 16 mW/cm2) from below.
Detection of Nonviable Cells
The nuclei of dead RPE cells were labeled with a membrane impermeant dye (Dead Red, Molecular Probes), and
the nuclei of all cells with 4⬘,6⬘-diamino-2-phenylindole
(DAPI), as reported.25,26 Blue light-illuminated A2E-containing RPE labeled in this way are undergoing an apoptotic
form of cell death.36 Digital images (5 fields per illumination
zone) were obtained using a Zeiss Axioplan II microscope
with Axiocam camera and KS400 image processing software.
Subsequently, Dead Red and DAPI-stained nuclei were
counted. Dead cells were quantified as a percentage of the
total number of cells in a field. Means are based on 3
experiments.
Statistical analysis was by an analysis of variance followed
by the Newman-Keul multiple comparison test (Prism,
GraphPad Software). A P value of 0.05 or less was considered significant.
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LABORATORY SCIENCE: BLUE LIGHT-ABSORBING IOL
Figure 1. (Sparrow) Quantitation of nonviable RPE cells after A2E
accumulation and blue light illumination (430 nm) with and without
an IOL placed in the light path. The percentage of nonviable cells
was determined by labeling all nuclei with DAPI and the nuclei of
nonviable cells with a membrane-impermeable dye. The data were
normalized to the percentage of nonviable cells in the absence of an
IOL. Values are mean ⫾ SEM.
Figure 2. (Sparrow) A blue light-absorbing IOL protects A2Eladen RPE from cell death due to 430 nm irradiation. The nuclei of
nonviable RPE were labeled with a membrane impermeable dye (left),
and all nuclei were stained with DAPI (right). The left and right panels
are corresponding fields of illuminated A2E-laden RPE. In the absence
of an IOL in the light path (top), the entire field is covered with nonviable
cells. Placement of a blue light-absorbing IOL (1.0 mm diameter disk;
AcrySof Natural) in the light path reduced the number of nonviable
cells in a circular zone corresponding to the area covered by the IOL
(bottom, dotted circle).
Results
Using a fluorescence assay that labels the nuclei of
nonviable cells, it was observed that illuminated RPE
that did not contain A2E (no A2E, no IOL) remained
viable, while blue light-illuminated (430 nm peak with
a bandwidth of 60 nm, 8 mW/cm2) RPE that had
previously accumulated A2E underwent marked cell
death. In the present experiments, 41.1% ⫾ 4.1% (3
experiments) of the A2E-laden cells in a field of illumination became nonviable after blue light exposure in
the absence of an IOL (Figure 1). When the yellowtinted AcrySof Natural IOL was placed in the center
of the light path, transmission of the 430 nm light
was reduced by approximately 50% and cell death was
reduced by 80% (P⬍.001) compared to irradiation in
the absence of an IOL (Figure 1). When the AcrySof,
Sensar, ClariFlex, or CeeOn Edge IOLs were in place,
the frequency of nonviable cells was not different
(P⬎.05) than cell death in the absence of an IOL. The
modest but consistent declines in cell death that were
detected with these IOLs (Figure 1) were undoubtedly
due to the small reductions in light transmission (⬃5%)
that were measured.
The ability of the AcrySof Natural IOL to attenuate
blue light-mediated cell death was evident when fields
of irradiated cells were imaged. In the absence of an IOL,
the nuclei of nonviable cells were uniformly distributed
across the illuminated field (Figure 2). Conversely,
placement of the blue light-absorbing AcrySof Natural
IOL (a 1.0 mm disk) within the light path spared a
circular zone of cells, the diameter of this area corresponding to the diameter of the IOL disc. Within this sector,
all nuclei were labeled with DAPI but labeled nuclei
of nonviable cells were only occasionally observed.
With the use of wide-band white light (390 to
750 nm; 246 mW/cm2) that included all wavelengths
toward which A2E exhibits sensitivity, the death of
A2E-laden RPE reached a frequency of 35% (35.4% ⫾
2.7% of the cells in an illumination zone; 3 experiments). In the presence of the blue light-absorbing AcrySof Natural IOL, cell death from white light was
reduced by 82% (P⬍.001) compared to that without
an IOL (Figure 3). In comparison, the AcrySof IOL
diminished the incidence of nonviable cells by 22%
(P⬍.05); with the Sensar, ClariFlex, and CeeOn Edge
IOLs, cell death was decreased by 37% to 39% (P⬍
.01). Again, the decreases observed with the colorless
IOLs were likely related to the reductions in spectral
transmittance associated with all IOLs.
When compared with blue and white light, green
light (550 ⫾ 20 nm) delivered at an intensity that was
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LABORATORY SCIENCE: BLUE LIGHT-ABSORBING IOL
Figure 3. (Sparrow) Quantitation of nonviable cells after white light
Figure 4. (Sparrow) Quantitation of nonviable cells after green light
(390 to 750 nm) illumination of A2E-laden RPE with and without the
indicated IOL placed in the light path. The percentage of nonviable
cells was normalized to values obtained in the absence of an IOL.
Values are mean ⫾ SEM.
illumination (550 nm) of A2E-laden RPE with and without the indicated
IOL placed in the light path. Values for percentage of nonviable cells
were normalized to values obtained in the absence of an IOL. Means ⫾
SEM are presented.
the same as that of the blue light (8 mW/cm2) induced
the death of only a small number of A2E-laden RPE
cells (2.9% ⫾ 0.6%; 3 experiments). With green light
irradiation, all IOLs reduced the death of RPE that had
accumulated A2E (Figure 4). With the AcrySof Natural,
the number of nonviable cells was decreased by 78%
(P⬍.01) compared to cell death without an IOL; while
cell death declined by 33% with the AcrySof (P⬎.05)
and by 52% to 57% (P⬍.05) with the Sensar, ClariFlex,
and CeeOn Edge IOLs.
with the other IOLs were probably due to IOL-associated nonspecific decreases (5% to 10%) in light transmission that have been reported.2,7,8,37
The AcrySof Natural IOL did not completely abolish cell death in this model. However, this is not surprising since by design, this IOL does not block all blue
light. Rather, the yellow tint of the lens is intended to
confer a spectral transmission similar to that of the
crystalline lens of an adult.1 That A2E-containing RPE
are less sensitive than to green light is to be expected:
A2E has an excitation maximum of approximately
430 nm with the emission elicited at 550 nm being less
than 5% of that elicited at 430 nm.18
Ham et al.15 were the first investigators to demonstrate that retinal injury from wavelengths that peak
around 425 nm is initiated by photochemical processes
in the RPE. The action spectrum of this damage corresponds to the absorption spectrum of the aging fluorophore A2E,18 and there is now an abundance of
experimental evidence that A2E is a sensitizing molecule
that can mediate light injury to RPE, leading to RPE
atrophy.18,23,25,26,36 Since lipofuscin fluorophores, including A2E, accumulate with age, the natural yellowing
of the aging human lens is fortunate as it may dampen
the damaging potential of short wavelength blue light.
For some time, it has been postulated that cumulative photochemical damage from lifetime exposures to
light are a cause of AMD,38 although the results of
Discussion
The study shows that by absorbing predominantly
in the blue region of the spectrum, the AcrySof Natural
IOL shields RPE cells that have accumulated the lipofuscin fluorophore A2E from the damaging effects of light.
The protection afforded by the AcrySof Natural IOL
was pronounced for wide-band white light just as it
was for narrow-band blue light. The reduction in cell
death afforded by this blue light-filtering IOL was
greater in magnitude than would be expected from the
decline in transmitted blue light. That a reduction in
blue light transmission of approximately 50% resulted
in an 80% decline in cell death probably occurred because blue light levels were brought below the threshold
for lethal damage for a significant proportion of the
cells. Small but consistent declines in cell death observed
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epidemiological studies are inconclusive.39,40 Nevertheless, it is of interest that the Chesapeake Bay Waterman
Study reported an association between the incidence of
advanced AMD and blue light exposure during the 20year period that preceded the study.34 Other reports
suggest a relationship between the incidence of AMD
and cataract extraction. For instance, the National
Health and Nutrition Survey observed 3087 patients
between 1970 and 1974 and reports that aphakic subjects had an increased risk for developing AMD.41 In
a study of 47 patients who presented with bilateral
drusen and pigmentary changes, choroidal neovascularization was observed in 19.1% of the eyes that had had
cataract extraction with implantation of a colorless IOL
compared with an incidence of 4.3% in the fellow
phakic eyes.42 The Beaver Dam Study comprised 4926
patients from 1988 to 1990 and found a positive association between cataract extraction and clinical indications
of early AMD.43 Indeed, both the 5-year and 10-year
follow-up studies confirm that eyes that had had cataract
surgery before baseline evaluation were more likely to
exhibit progression of AMD.44,45 Nevertheless, similar
associations were not reported by the Age-Related Eye
Disease Study (DF Martin, ARVO abstract 1907,
2002).
Circumstances that lead to damage in the aging RPE
cell are considered as a prelude to the photoreceptor
cell degeneration that characterizes the visual impairment
associated with AMD. We speculate that a yellow-tinted
IOL that simulates the adult natural lens and protects
lipofuscin-containing RPE from blue light damage may
reduce the risk for or progression of AMD. This concept
warrants evaluation by a long-term population-based
clinical study.
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From the Department of Ophthalmology, Columbia University, New
York, New York 10032, USA.
None of the authors has a financial or proprietary interest in any
product mentioned.
Presented at the XXI Congress of the European Society of Cataract and
Refractive Surgeons, Munich, Germany, September 2003.
Supported by grants from Alcon Laboratories, Ft. Worth, Texas; the
National Eye Institute (EY 12951), Bethesda, Maryland; and by unrestricted funds from Research to Prevent Blindness, New York, New
York, USA.
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