The Evolution of Laser Therapy in Ophthalmology:

A Perspective on the Interactions Between Photons,

Patients, Physicians, and Physicists: The LXX Edward
Jackson Memorial Lecture
MARK S. BLUMENKRANZ
 PURPOSE:

To present the evolution of laser therapy in

modern ophthalmic practice.
 DESIGN: Review of published experimental and clinical
studies.
 METHODS: A review was undertaken of the work of
multiple investigators leading to the invention of the
laser, its biophysical effects on ocular tissues from which
it derives its name (light-amplified stimulation of emitted
radiation), and the development of various laser-based
devices and methods to treat common ophthalmologic disorders, with particular emphasis on new and emerging
retinal and anterior segment applications.
 RESULTS: Because the eye is optimized for the transmission of light and its transduction into neural signals,
lasers are particularly well suited for ophthalmic therapy.
This fact and the high demands for precision in therapy
have inspired the development of highly sophisticated
laser systems that have impacted the treatment of common diseases. These include diabetic retinopathy, agerelated macular degeneration, retinal venous occlusive
disease, retinopathy of prematurity, and optical aberrations including ametropia, cataract, and glaucoma, among
others. Recent developments in scanning laser systems,
including image-guided systems with eye tracking, realtime feedback, and ultra-short pulse durations, have
enabled increased selectivity, precision, and safety in
ocular therapy. However, improved outcomes have been
associated with increased cost of medical care, and attention to and optimization of their cost effectiveness will
continue to be required in the future.
 CONCLUSIONS: The invention and evolution of modern ophthalmic lasers have enhanced therapeutic options
and can serve as a heuristic model for better understanding the process of innovation, including the societal
benefits and also unintended consequences, including
increased costs. (Am J Ophthalmol 2014;158:1225.
2014 by Elsevier Inc. All rights reserved.)
Accepted for publication Mar 23, 2014.
From the Department of Ophthalmology, Byers Eye Institute, Stanford
University, Palo Alto, California.
Inquiries to Mark S. Blumenkranz, Department of Ophthalmology,
Byers Eye Institute, Stanford University, 2452 Watson Court, Palo Alto,
CA 94303; e-mail: mark.blumenkranz@stanford.edu

12

2014 BY

T IS A GREAT HONOR TO DELIVER THE 70TH JACKSON

Memorial Lecture and I thank the American Journal

of Ophthalmology and the American Academy of
Ophthalmology for selecting me to do so.
In this lecture, I discuss the invention and evolution of
the ophthalmic laser over the past 5 decades. I have
treated the subject not simply as a chronological listing
of key milestones that have occurred over a series of decades, but rather as a narrative story about people and
ideas that contributed to this process. The resulting
manuscript necessarily entails a personal perspective on
the field because it is drawn not only from review of the
published literature and my own work in this area, but
also from familiarity and professional interactions with
many of the cited principals in this area over that time
period.
I initially relate the early history and general principles
of lasertissue interactions as they relate to ophthalmology because they are important to understanding
how lasers work and how the field evolved to the point
it stands today. I then specifically focus on what I judge
to be the key emerging trends that are likely to become
increasingly important in the future. These include the
introduction of scanning, short pulse durations, and
image-guided systems. These advances have facilitated
much greater precision in the dose, localization, and
selectivity of laser energy delivery, as well as in automation of treatment.15
Finally, there is much to be learned from studying
ophthalmic laser evolution about the various aspects of
medical device innovation and competition, and its impact
on clinical trial design, practice patterns, and medical economics. I will attempt to touch upon these, albeit briefly. I
trust that Dr Jackson, were he alive today, would have
judged this a topic worthy of inclusion in this distinguished
series.

THE EARLY HISTORY OF LASER

BECAUSE THE EYE IS OPTIMIZED FOR THE TRANSMISSION

of light and its transduction into neural signals, it is not

surprising that lasers are particularly well suited for

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ophthalmic therapy. The word laser itself is an acronym for

a sequence of physical processes: Light Amplification by
Stimulated Emission of Radiation. The prospect of stimulated emission of radiation was first predicted by Einstein
in 1917,6 but it was another 40 years before this theoretical
construct was converted into a practical device.3,7 Townes
at Columbia in the late 1940s with a number of
collaborators, including his postdoctoral fellow and future
brother-in-law Arthur Schawlow, developed a microwave
amplification chamber.8,9 During that time period, 2
Russian physicists, Alexander Prokhorov and Nicolai
Basov, working apparently independently, described how
a molecular beam of alkali halide directed through a
resonating cavity might also result in a microwave
oscillator.10 Townes and Schawlow, having since relocated
to the Bell Labs, continued their research in amplification
of increasingly shorter wavelengths in the infrared and
visible spectrum, ultimately culminating in their seminal
publication of 1958 on infrared and optical masers.3 For
their efforts, Townes was jointly awarded the 1964 Nobel
Prize in Physics with Prokhorov and Basov, and Schawlow
separately in 1981.8 In 1960 Maiman at Hughes Aircraft in
California produced a functioning laser for the first time
with ruby red light output of approximately 694 nm
wavelength.7
The field of ophthalmic lasers evolved very quickly from
that point. The technique of retinal light photocoagulation
had been first pioneered 10 years earlier starting with solar
coagulation by Meyer-Schwickerath in the late 1940s, and
then with his work on the Xenon Arc photocoagulator in
the late 1950s. The precision and selectivity of Xenon
Arc coagulation, however, was limited by the fact that
the light was polychromatic, the footprint of the device
was large, spots were required to be very large, and the ergonomics and focusing system were difficult.4 As a result,
although it was widely recognized that retinal light photocoagulation was promising, it remained an unwieldy and
difficult technique to incorporate into clinical practice.
After their invention it was soon apparent that lasers represented a better approach to light creation than xenon flash
lamps, and they were rapidly embraced.
In 1961, Zaret and associates applied the pulsed ruby
laser to produce lesions in the rabbit retina.11 Javan,
Bennet, and Herriot described the first gas lasers that
same year.12 By 1963, Kapany, Peppers, Zweng, and Flocks
had expanded the field of laser retinal coagulation and
demonstrated a nonlinear relationship between incident
energy and burn size, and the tendency for the creation
of thermomechanical effects including bubbles and retinal
hemorrhage with higher energies.13,14 Additional studies
with both solid-state and gas lasers soon followed by
Campbell, LEsperance and colleagues,15,16 Beetham and
Aiello,17 and Little, Zweng and LEsperence laying out
the general principles of laser retinal photocoagulation.

VOL. 158, NO. 1

This included the development of a more ergonomic and

precise slit-lamp delivery apparatus with articulating arm,
and some of the early indications for treatment including
treatment of retinal tears, diabetic retinopathy, and ocular
tumors.18,19
Ironically, although the first laser constructed by
Maiman was a small solid-state prototype, the first lasers
that enjoyed widespread ophthalmic adoption and commercial success were argon gas tube lasers because it was
felt by many at that time that the blue-green emission spectrum of argon was better suited to the direct treatment of
vascular tissues in the eye, compared with the synthetic
ruby red laser light output. (H. Christian Zweng, personal
communication, 1977). Gas lasers were bulkier and more
difficult to operate and maintain because of the need for
water cooling and fragility of gas tubes, and it was more
than a decade later that more portable and economical
semiconductor lasers currently in use were introduced.2023

PRINCIPLES OF LASER LIGHT EMISSION

LIGHT IS COMPOSED OF INDIVIDUAL PACKETS OF ENERGY

called photons. For stimulated emission to occur more

frequently than absorption and hence result in light amplification, the optical material should have more photons in
an excited state than in a lower state. Such population
inversion can be achieved using an excitation source, or
pump, such as a flash lamp or electrical source that
imparts the energy to achieve population inversion into
the cavity. In that cavity, emitted light circulates between
2 mirrors on either side, with a fraction of the photons
escaping through an aperture in 1 of the 2 mirrors, which
is semi-reflective, to form the laser beam. The light trapped
inside the cavity stimulates emission of new photons from
the excited laser material with the same wavelength, direction, and phase, thereby forming a coherent laser beam, as
illustrated in Figure 1. This beam can then be directly
emitted into space, focused with an appropriate lens system, transmitted by a fiber-optic cable or some combination of the above to achieve the desired effects.2

LASERTISSUE INTERACTIONS
INTERACTIONS OF LIGHT WITH BIOLOGICAL TISSUES

depend on its wavelength, pulse duration, and irradiance

(amount of power per unit area, W/cm2). With sufficiently
high photon energy, light can induce photochemical reactions. Light absorption by the tissue can also result in heating, which may lead to thermal denaturation. At higher
temperatures, and especially with shorter pulses, tissue
can be rapidly vaporized, which can result in mechanical

THE EVOLUTION OF LASER THERAPY IN OPHTHALMOLOGY

13

FIGURE 1. (Top) Diagram of a typical laser, including the lasing medium, resonant optical cavity, and pump. (Bottom) Diagram of
photon emission from an atom in excited (upper) state, stimulated by the passing photon.

disruption or tissue ejection. Very short pulses with high

peak irradiance can ionize materials, enabling precise
dissection of tissue. These types of interactions are
described below in more detail.1,2
 PHOTOCHEMICAL INTERACTIONS:

Light-induced chemical reactions are typically not associated with a meaningful change in tissue temperature. Such interactions are
typically mediated by exogenously administered agents,
such as verteporfin.24 Photochemical interactions are the
basis for retinal photodynamic therapy in age-related macular degeneration, or cross-linking of corneal collagen
with riboflavin to treat keratoconus.25 To avoid heating,
therapeutic photochemical interactions are typically
performed at very low irradiances (<1 W/cm2) and with
long exposurestens of seconds or minutes.2426

 PHOTOTHERMAL INTERACTIONS:

Depending on the
temperature rise and duration of exposure, different tissue
effects may occur, including metabolic alterations, necrosis,
and vaporization.2633 The absorption coefficient of biologic
tissue chromophores strongly depends on the laser
wavelength. Major chromophores of ocular tissues include
water, proteins, melanin, blood, and macular pigments.
The extent of tissue damage can be quantified by the
Arrhenius integral V, which describes the changes in
temperature in time and space in biologic tissue in
response to the application of laser energy. This
relationship reflects the rate at which different individual
proteins with important structural and regulatory functions
in a cell are affected in response to laser treatment.
Denaturation of cellular proteins varies as an exponential

14

function of temperature and a linear function of the laser

pulse duration; the Arrhenius integral mathematically
describes this relationship. The parameters necessary to
create lesions of differing effect in biologic tissue of defined
composition can be chosen based on the predicted
decline in the concentration of different critical protein
molecular components of the cell necessary for normal
structure and function.26,34,35 This may range from visually
imperceptible events such as induced cytokine expression
without obvious structural change to frank apoptosis,
necrosis, or vaporization of cells, depending on the amount
and temporal profile of energy applied.812 Clinical
examples of this are illustrated in the subsequent section
on new approaches.32,33,3639
Retinal Photocoagulation. Retinal photocoagulation typically involves application of pulses with durations ranging
from 10 to 200 ms, and transient hyperthermia by tens of degrees Celsius above body temperature. Various lasers have
been used in the past, including ruby (694 nm), argon
(488, 514 nm), and krypton (647 nm). Currently the most
common lasers in photocoagulation are green frequencydoubled neodymiumyttrium-aluminum-garnet (Nd:YAG)
(532 nm) and yellow semiconductor lasers (577 nm). The
laser energy is absorbed primarily by melanin in the retinal
pigment epithelium (RPE) and choroid, and by
hemoglobin. Heat generated by light absorption in the
RPE and choroid diffuses into the retina and causes
coagulation of the photoreceptors and, sometimes, of the
inner retina. During 100 ms applications, the heat diffuses
up to 200 mm, thus smoothing the edge and extending
the coagulated zone beyond the boundaries of the laser

AMERICAN JOURNAL OF OPHTHALMOLOGY

JULY 2014

remodeling. RPE migration and proliferation restore continuity of the RPE monolayer within 1 week compared with fullthickness damage with longer-duration pulses of 100 ms.
The damage zone in the photoreceptor layer is initially filled
with glia. Over time, the photoreceptors from the adjacent
retina shift into the damage zone, thereby reducing its
size. With sufficiently small lesions (below 200 mm), and
no damage to the inner retinal layers, photoreceptors can
completely refill the damage zone and rewire to local bipolar
cells over time,27 thereby restoring retinal structure and function (Bottom right) and avoiding the extensive glial scarring
and neuronal loss associated with longer-duration retinal
burns (Figure 3, Top right). These effects can be modulated
with the concomitant administration of pharmacologic agents
such as steroids.29,36,37
 PHOTOMECHANICAL INTERACTIONS:

FIGURE 2. Acute lesion diameters for 132 mm aerial beam size

in rabbit retina as a function of pulse duration (Top) and power
(Bottom). Note linear relationship between power and burn size
and nonlinear relationship between pulse duration and burn
size. Figures modified from ref [30].

spot, termed thermal blooming. Heat diffusion using

shorter pulses and smaller spot sizes can be limited to the
RPE and photoreceptor layers, thereby avoiding or
minimizing inner retinal damage. The diameter of the
acute retinal lesion increases logarithmically with
increasing pulse duration (Figure 2, Top) and linearly with
increasing laser power (Figure 2, Bottom).
The threshold power required for the creation of a retinal
lesion increases with decreasing pulse duration. A relatively modest power increase is required to produce comparable lesion grades going from 100 ms to 10 ms, whereas a
much steeper increase is seen for durations under 10 ms.
At 2 ms or less it is not consistently possible to reproducibly
create a visible lesion of moderate grade without rupturing
the retina, and therefore shorter pulse durations in this
range or lower should never be used to create visible
lesions, although they can be used safely when the desired
treatment endpoints are sub-visible.
When only the outer layers of the retina are acutely
damaged with shorter pulse durations (Figure 3, Bottom left)
compared with the full-thickness burns seen acutely with
longer durations (Figure 3, Top left), the retina shows considerable capacity for renewal through regeneration and
VOL. 158, NO. 1

Photoablation and
Photodisruption. Photomechanical interactions are at the
heart of laser in situ keratomileusis (LASIK) and other
types of corneal refractive surgery. Precise corneal photoablation is achieved using nanosecond pulses of ArF excimer
laser as a result of the limited 200 nm penetration depth of
193 nm radiation in the cornea and very short pulse durations (w10 ns) enabling extremely precise ablation, with a
very narrow zone of residual tissue damage (<0.2 mm) at
the edges of the ablation zone. Both photoablation and
photodisruption occur when laser absorption results in
the tissue temperature exceeding the vaporization
threshold. Expanding and collapsing vapor bubbles
following explosive vaporization can rupture nearby tissue
or eject tissue fragments from the exposed surface.39,40
Vaporization temperature ranges between 100 and 305 C.
To avoid heat diffusion away from the laser absorption
zone during the pulse, energy needs to be applied using
relatively short pulse durationsin the range of
microseconds to nanoseconds rather than milliseconds.41
Dielectric Breakdown. At extremely high irradiances
(1081011 W/cm2), which can be achieved in a tightly
focused short-pulsed (ns-fs) laser beam, the electric field
is so high that even transparent material can be
ionized.40 This mechanism, called dielectric breakdown,
allows for a highly localized deposition of energy at the
focal point of the laser beam. The development of plasma
and associated absorption of the laser energy in the focal
spot lead to explosive vaporization of the liquid medium,
accompanied by tissue rupture.
Plasma-mediated lasertissue interactions are applied to
fragmentation of an opacified posterior lens capsule with
nanosecond Nd:YAG lasers. At shorter pulse durations
(1 ps to 100 fs) and much lower energies, this process is
applied to intrastromal cutting for refractive surgery.41,42
This approach has also been tested in the dissection of
epiretinal membranes using a tightly focused beam.43
Despite the very low energy required for this process, its
applicability in the posterior pole is limited owing to the

THE EVOLUTION OF LASER THERAPY IN OPHTHALMOLOGY

15

FIGURE 3. Histology of rabbit retina after laser photocoagulation with 132 mm aerial size light to moderate clinical grade (Top
row, right and left) and barely visible clinical grade (Bottom row, right and left). Left column represents acute appearance (1 hour
after treatment), and the right column shows the appearance after healing at 4 months post treatment. Note pyknosis of outer nuclear
layer in both specimens acutely (Left column) but relative sparing of the inner nuclear, ganglion cell, and nerve fiber layers in barely
visible lesion specimens acutely (Bottom left) compared with light to moderate specimens, which show full-thickness coagulative
necrosis acutely (Top left). Four months later there has been relative restoration of all layers of the retina, including the photoreceptors, in the barely visible burns (Bottom right), whereas the light to moderate specimen shows evidence of a glial scar replacing most of
the retina in that region, including the ganglion cells and both inner and outer nuclear layers as well as the photoreceptors (Top right).
(Hematoxylin-eosin preparation. Yellow bar approximate width of lesion, black bar equals 50 mm.)

difficulty in axial differentiation between the epiretinal

membranes and the retina located very close behind
them. Recently, this process has been applied to anterior
capsulotomy and fragmentation of the crystalline lens during cataract surgery.4446

MAJOR CLINICAL INDICATIONS FOR

OPHTHALMIC LASER THERAPY
 VITREORETINAL DISEASES:

Laser has been a mainstay

for the treatment of a large number of vitreoretinal diseases
in the years since its introduction. The major conditions
include diabetic retinopathy, age-related macular degeneration, retinal venous occlusive disease, retinal breaks and
detachment, ophthalmic tumors, and miscellaneous other
retinal and choroidal vascular conditions including central
serous choroidopathy, sickle cell retinopathy, and retinopathy of prematurity; these are well covered in many prior
publications.2 The Diabetic Retinopathy Study (DRS)
and Early Treatment of Diabetic Retinopathy Study
(ETDRS) were pivotal events in the history of clinical
research, as 2 of the first large extramural multicenter trials
supported by the National Institutes of Health to assess the
safety and efficacy of new technologies. At the time, laser
was still a somewhat controversial therapy prior to the
16

release of the study results. A long-term benefit of these

studies was their contribution to establishing the large
federally sponsored prospective multicenter randomized
trial as the gold standard for evaluation of new forms of
ophthalmic therapy.22,47 Focal and grid laser today, either
alone or in combination with pharmacologic agents
including ranabizumab, bevacizumab, and intravitreal
steroids, still play an important role in the control of
macular edema for a large number of patients, including
those with more focal disease and leakage or those not
responsive to pharmacologic agents alone as well as
selected cases of macular edema associated with retinal
vein occlusion.4850
One of the great remaining mysteries of retinal photocoagulation is the precise mechanism by which panretinal
photocoagulation (PRP) works to cause regression of
retinal and iris neovascularization, and the effect of grid
photocoagulation on diffuse capillary leakage in diabetic
retinopathy and retinal venous occlusive disease. Most theories that have been advanced center around reducing
expression of vascular endothelial growth factor (VEGF).
However, the way in which laser accomplishes this remains
unknown, and may involve upstream effects including
facilitation of transport of nutrients, including oxygen, to
the retina from the choroid; transport of by-products of
metabolism out of the retina; overall reduction of retinal
metabolic load by decreasing the total number of

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photoreceptors; or reduced sequestration of proangiogenic

cytokines in the photoreceptors.2,51 There may be a
secondary, although not fully understood, benefit
from less damaging treatment of the retina whereby
this treatment promotes secretion of cytokines that
downregulate angiogenesis and capillary permeability.
Possible cytokines involved in this pathway include heat
shock protein and alpha-crystallins, as well as other complexes, and they may impact gene expression that ultimately affects inflammation and hyperpermeability in the
retina.34,35,5254
 CATARACT AND REFRACTIVE DISORDERS:

Q-switched
Nd:YAG lasers were first introduced by Aron-Rosa and
associates55 and Fankhauser39 to noninvasively perform
posterior capsulotomy following cataract surgery. New
photomechanical lasers for corneal applications were subsequently introduced, beginning with the introduction of the
argon fluoride excimer laser, which was capable of producing smooth surface ablation of tissue with extremely higher
radiances and ultrashort focused pulses in the range of nanoseconds to femtoseconds.41,56,57 Further refinements in
excimer laserassisted corneal refractive surgery included
the technique of laser-assisted LASIK,41,58 a technique
that has largely replaced photorefractive keratectomy
owing to fewer effects on the corneal epithelium. This
procedure is typically now performed with the use of an
intrastromal femtosecond laser, rather than the
mechanical microkeratome originally described, for
cutting of the corneal flap.42 Photodisruptive lasers have
also been explored as a means to improve the elasticity of
the aging lens to counteract presbyopia, although none
have yet been proven effective or commercialized.59

RECENT INNOVATIONS IN OCULAR

LASER THERAPY
 THE IMPACT OF SCANNERS:

The availability of scanning

galvanometers has had an important impact on the creation of sophisticated medical laser delivery systems, capable
of increased efficacy, precision, and safety. Initially both
retinal and anterior segment lasers employed single pulses,
or trains of pulses, which limited the area of tissue that
could be treated and also the ability to easily differentiate
treated from untreated regions within that area, depending
on the clinical need and availability of visible endpoints.
In the case of excimer refractive lasers, the first Food &
Drug Administration (FDA)-approved laser employed the
method of broad beam ablation, which limited the physicians ability to easily treat patients with astigmatism, or
other higher-order optical aberrations, with customized
ablations. This limitation was resolved with the introduction
of scanning excimer lasers that were capable of treating relatively larger areas of the cornea by rapidly moving the beam

VOL. 158, NO. 1

using a computerized system that determined the area and

depth of ablation and could be individualized based on preoperative measurements.57,60
In the case of retinal lasers, the decision to use scanners
was initially driven by our interest in reducing treatment
times for patients undergoing diabetic retinopathy management but ultimately resulted in a number of other unanticipated benefits.61 In order to use a scanner, it was necessary
to shorten each individual pulse duration from the DRS and
ETDRS standard of 100200 ms.22,47 We chose 1030 ms
pulse durations as a new standard in order to ensure that
an array of multiple burns could be placed precisely where
intended and not be influenced by ocular movements
that typically occur with time durations in excess of
200 ms.61 Although the original intent was to insure that
these shorter-duration pulses resulted in lesions histologically comparable to longer-duration burns, we soon recognized that the use of shorter pulse durations resulted in a
greater ability to predict the precise depth of impacted,
including impacted tissue minimizing the amount of collateral damage.
The shorter-pulse-duration burns appeared more uniform and smaller than lesions induced by traditional longer
pulse durations.26,28,30,61 While it had been previously
shown that laser pulse durations in the range of
nanoseconds to microseconds were capable of limiting
the damage to the pigment epithelium,3133 for subvisible burns, this same precise effect on selective layers
of the retina had not been well characterized for visible
burns. Additionally, the clinical utility and acceptance of
this type of sub-visible therapy by clinicians had been
limited by the inability to reliably judge where to place
spots relative to other earlier sub-visible burns during treatment sessions. With the introduction of scanners, many of
the limitations of single spot lasers, whether small or broad
beam, were resolved and new opportunities presented.
These included a more complete examination of the role
of laser systems with short (tens of milliseconds) as well
as ultra-short (microseconds) pulse duration and new
methods of photocoagulation.
 SHORT-PULSE-DURATION AND REDUCED-FLUENCE
SYSTEMS: Choices in the treatment parameters of pulse

duration, power, wavelength, and aerial spot size have a

predictable impact on the intensity, depth, and ultimate
size of coagulative lesions, as correctly predicted by the
Arrhenius model described above.2830,35 These impacts
have served as the basis for the development of a new
generation of commercial retinal lasers, including those
that function in both the millisecond and microsecond
domain with and without scanning and image-guidance
capability. Pattern scanning lasers with typical pulse
durations in the range of 1030 ms produce burns primarily confined to the pigment epithelium, photoreceptors,
and outer retina. As a result, secondary complications,
including visual field defects associated with ganglion cell

THE EVOLUTION OF LASER THERAPY IN OPHTHALMOLOGY

17

loss and nerve fiber layer defects, as well as pain from

choroidal heating, occur less frequently.6164
Further reduction in the pulse durations to below 50 ms
enables selective photodisruption by explosive vaporization
of the melanosomes in the RPE, sometimes termed selective
retinal therapy (SRT).3133,65,66 Since heat does not escape
from the melanosomes during microsecond pulses, there is
sparing of photoreceptors and Bruch membrane. In a few
days RPE cells from adjacent areas migrate into the
damage zone and fill the defects, thereby restoring the RPE
monolayer, so it can again support the metabolic needs of
the photoreceptors that remain viable above the treated
zone. While the lesions may not be visible at the time of
application, they may be either subsequently delineated by
the passage of time and atrophic scar formation or
demonstrated acutely by enhanced imaging techniques,
including both retinal fluoroscein angiography and optical
coherence tomography (OCT) examination.35
An alternative approach to the use of individual pulses is
the application of patterns of relatively short pulse durations, in the range of single milliseconds, which can be
applied stepwise as a semiautomated grid. With this technique, the patterns of sub-visible burns can be outlined
by slightly more intense marker burns delineating the
boundaries of the treated area.35 This pattern scanning
approach to treatment can use laser settings that create
structural damage to selected layers, such as photoreceptors
or just the RPE, or less energetic nondamaging hyperthermia in which the only effects are thought to be metabolic,
as evidenced by the lack of structural changes in histologic
and contrast imaging studies.35,53
The laser energy can be optimized in accordance with
the Arrhenius integral model, to select a threshold power
and pulse duration necessary to create a sub-visible non
structurally damaging tissue effect owing to the lower tissue
temperatures produced. As has been shown in prior laboratory studies, the peak tissue temperature needed to stimulate expression of heat shock protein 70, a naturally
occurring ubiquitous cytokine that inhibits inappropriate
protein aggregation, inflammation, and apoptosis, is 49 C.
At that temperature point, no structural damage is seen
in photocoagulated tissues in experimental models,
compared with the 62 C temperature that typically results
in cell death.34,35,53 With this approach 200 mm spots may
be placed at 30% of the energy needed to produce a barely
visible burn using green or yellow laser light and a grid
pattern with 0.25 beam diameters spot spacing covering
the area of abnormal retina where there is accumulation
of subretinal or intraretinal fluid. Although initial
clinical experience with this approach is still limited, it
appears that a number of patients treated with this
regimen may show clinically significant benefits,
including resolution of intraretinal and subretinal fluid
and improvement in visual acuity in cases of diabetic
macular edema, central serous chorioretinopathy, and
branch retinal vein occlusion35 (Figure 4). As of yet there
18

have been no published large randomized multicenter trials

employing this approach, although the initial experience
has been sufficiently promising that planning efforts are
underway to undertake such trials. Such randomized studies
are required to confirm the utility of this approach to larger
groups of patients.
Yet another variation, to date only used in preclinical
studies, is the use of a pattern scanning laser programmed
with specialized software to deliver continuous lines
rather than individual spots. Continuous laser line scanning with velocity on the order of 10 m/s and spot sizes
of 100 mm results in approximately 10-ms exposures
(beam dwell time) for any irradiated point on the retina
along the line scanned. With such short exposures the
effects can be limited solely to the pigment epithelium,
sparing both the underlying choroid and the overlying
photoreceptors36 (Figure 5). This approach may prove
to be an alternative to SRT in treatment of macular diseases. Preclinical studies have indicated that even when
there is occasional damage to photoreceptors along the
narrow lines of scanning, migration and rewiring of photoreceptors to bipolar cells restore the normal retinal
structure.27
Selective destruction of RPE using line scanning laser can
be used to downregulate protein secretion resulting from
therapeutic transfection of the RPE in a highly precise and
reproducible way; this has been recently demonstrated using
a fluorescent reporter protein.67 This represents an intriguing
opportunity to fine-tune gene therapy by selectively
decreasing expression of transgenes such as those coding
for anti-angiogenic proteins, when necessary. This has the
additional potential benefit of not requiring surgical intervention and avoiding heavier laser-induced structural damage to the neural retina overlaying the transfected RPE.
 THE IMPACT OF ADVANCED IMAGING SYSTEMS COMBINED WITH SHORT-PULSE-DURATION AND SCANNING
TECHNOLOGY:

New Retinal Applications. Advanced retinal laser photocoagulation systems enabled with digital angiographic capture capability and software-driven treatment planning
modules based on imaging information, both coupled to
short-pulse-duration scanners and eye tracking, have made
precise, fully automated retinal photocoagula-tion possible.
Initial results with such a system, which has recently
received FDA and Conformite Europeenne clearance,
suggests that it is possible to achieve excellent precision
and reproducibility of the placement of retinal burns
compared with conventional methods.68,69 Additional
refinements in this form of technology include the ability
to noninvasively assess the temperature using a photoacoustic element embedded within a corneal contact lens
in experimental systems.70 This approach could provide for
real-time automated modulation of the intensity of retinal
burns placed by automated systems. Photo-acoustic or
OCT-guided approaches could theoretically enable even

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tion to reduced lateral dimensions as described by diameter,

shorter-pulse, lighter-intensity burns also have a concomitant reduction in damage to the inner and middle retinal
layers that is likely associated with differential therapeutic
effects and collateral damage as well.2830 The availability
of anti-VEGF agents with the ability to cause temporary
involution of residual retinal neovascularization, combined
with short-pulse-duration therapy, allows the opportunity
for more precise titration of short-pulse laser therapy to
optimize the risk-benefit ratio in patients with retinal diseases such as macular edema, while minimizing the potential complications and cost of both conventional lasers and
antiangiogenic drugs.

FIGURE 4. Optical coherence tomography (OCT) images from

a patient with diabetic macular edema (DME) refractory to conventional ETDRS focal and modified grid photocoagulation
9 months earlier in the left eye. (Top) OCT remove thickness
map scan appearance immediately following sub-visible treatment with 768 200-mm spots in grid pattern with 0.25 burn
diameter spacing and 30% of energy required for barely visible
burn threshold of 110 mW. (Middle) Appearance 10 weeks
following treatment with significant reduction in edema and central macular thickness from baseline. (Bottom) OCT appearance 8 months following treatment, with complete resolution
of DME and no further interval treatment. (Images courtesy
of Daniel Lavinsky.)

higher degrees of safety and precision with automated

methods, particularly in patients with regional differences
in the amount of intraretinal fluid or choroidal pigment
that make laser uptake variable from lesion to lesion.
As might be expected, several caveats are in order with
the transition from conventional DRS and ETDRS photocoagulation parameters to shorter pulse durations and scanning systems. In one nonconsecutive nonrandomized
series, the observation was made that patients undergoing
PRP with short-pulse-duration pattern scanning appeared
to have more incomplete regression of diabetic retinal
neovascularization than patients undergoing conventional
longer-pulse-duration PRP.71 Calculations performed
based on the lesion diameter of shorter-pulse-duration laser
burns indicate that to maintain the same total treated
area as in 1000 standard burns (100 ms, moderate) with a
400-mm beam, a greater number of 20-ms lesions are
required, ranging from 1464 to 1979 for moderate and light
intensities, respectively.72 It should be noted that in addiVOL. 158, NO. 1

New Cataract Applications. The combination of advanced

forms of image guidance and ultra-short pulse durations has
also enabled a different approach to be employed in
cataract surgery, overcoming many of the limitations of
earlier attempts with erbium-YAG laser handpieces.
Femtosecond pulses of near-infrared wavelengths can be
noninvasively introduced into the eye, passing through
transparent tissue with appropriate optical focusing
systems. A number of such systems have been introduced
into clinical practice in the United States and elsewhere,
including systems by LensX/Alcon, LensAR, Bausch and
Lomb, and Optimedica/AMO, as of the time of this
writing. All of these are reported to have irradiance
specifications well within published and recalculated
ranges for retinal safety.44,45,73 We reported one such early
3-dimensional (3-D) scanning femtosecond laser that
has approximate parameters of 1.03 mm wavelength,
400 fs pulse duration, up to 10 uJ pulse energy, and a
1280 kHz repetition rate optically combined with
long-range spectral-domain OCT (<11 mm depth resolution, >12 mm image depth) as well as near-infrared video
imaging.44 With this and other systems, it has been shown
in initial clinical series to be possible to treat the cornea
and the lens, including both nucleus and capsule, with a
high degree of spatial and temporal confinement, limiting
diffusion and collateral damage7476 (Figure 6). It is also
possible to use the advanced imaging capabilities of such a
system to accurately map out the 3-D anatomy of the
anterior segment preoperatively and intraoperatively and
facilitate highly accurate determination of key landmarks.
These include the optical and geometric center of the eye
as well as pupil, sulcus, and capsule location for the
purpose of choice and positioning of intraocular lenses.
This technology also makes possible the creation of complex user-specified patterns of capsulotomy with the scanning laser technology. While not fully developed into
clinical practice as of the time of writing of this manuscript,
this capability should enable the development of a new generation of intraocular lenses that depend upon more
accurate placement within the eye. These include cut
capsular edge as well as in-the-bag and sulcus fixation as a
means of employing more advanced optics.76 This may

THE EVOLUTION OF LASER THERAPY IN OPHTHALMOLOGY

19

FIGURE 5. Appearance of the linear pattern of retinal pigment epithelial (RPE) loss 1 day after line scanning laser treatment as seen
by scanning electron microscopy (Top left and Top right for lower and higher magnification, respectively). (Yellow bar equals 200 and
50 mm, respectively, Top left and Top right.) RPE cells in the pattern are missing, and Bruch membrane is clearly seen. (Bottom)
Scanning electron microscopy of the RPE layer 7 days after treatment. Note complete restoration of the continuity of the RPE monolayer through the combination of sliding from adjacent areas of hyperplasia (Bottom left) and appearance of rosette-like cluster of
RPE with smaller cells centrally in higher-power view (Bottom right).

facilitate the implantation of lenses with dynamic accommodation capability, multifocality, and toric alignment.
These systems also facilitate the creation of optimized
multiplanar corneal incisions for intraocular instrument entry as well as astigmatism control. Some existing commercial systems also have software capabilities that facilitate
lamellar and full-thickness keratoplasty with performance
enhancements over previous laser-assisted techniques.77
Initial studies confirm that it is possible to safely, very
precisely, and reproducibly create perfectly circular
capsular openings noninvasively that greatly surpass the
ability of surgeons using the manual technique of continuous curvilinear capsulorrhexis7880 (Figure 7). Laboratory
studies in porcine eyes confirm that laser capsulorrhexis is
more accurate than manual capsulorrhexis, with average
deviation from the intended diameter of the resected
capsule of 29 mm compared with 337 mm for the manual
technique and mean deviations from circularity of 6% vs
20%, respectively.78
Early clinical studies indicated that reductions in phacoemulsification ultrasonic energy in the range of 40%50%
could be achieved in eyes that were pretreated with
femtosecond lasers.44,45 More recent reports from some
centers suggest that reduction in energy in excess of
95% can be achieved, in the majority of eyes, with greater
experience with this technique using presegmentation
20

and nuclear cutting with the laser prior to the

introduction of the phacoemulsification handpiece75,80
(Figures 6 and 7). Preclinical studies also suggest that
capsular edge strength and stretching are improved relative
to manual techniques.78,79 Subsequent clinical studies with
these units have confirmed the safety and precision of
laser-assisted femtosecond cataract surgery.80 Refinements
have continued to occur, including the development of
improved docking interface systems between the eye and
the laser using water baths and soft-gel interfaces, which
reduce both the corneal distortion and beam aberrations
and also intraocular pressure increases associated with rigid
curved applanation plates.81
 ECONOMIC IMPACTS OF LASER TECHNOLOGY INNOVATION: As of the time of this writing, there have been no

unique CPT codes established in the United States to cover

the higher practice costs associated with purchase of automated and semiautomated retinal lasers with and without image guidance compared with less expensive
conventional systems; however, practice efficiencies
related to shortened treatment times and single-visit treatment regimens for PRP have been suggested.63,64
The high purchase prices of the new cataract femtosecond laser systems at the present time, as well as
incremental per-use charges, have also impacted the

AMERICAN JOURNAL OF OPHTHALMOLOGY

JULY 2014

FIGURE 6. Lens nucleus fragmentation pattern produced in a patients eye by Catalys femtosecond laser. Intraoperative view via the
infrared imaging system of the laser during laser procedure (Left) and prior to mechanical component of surgery. Intraoperative view
with surgical microscope prior to removal of the crystalline lens with microfluidic handpiece (Right).

FIGURE 7. Typical examples of the capsule disc extracted after laser capsulotomy (Top left) and manual capsulorrhexis (Top right).
Staining of capsules with toluidine blue in flat mounts unmagnified. Appearance of the capsule edge (arrows) after intraocular lens
(IOL) implantation following laser capsulotomy (Bottom left) and manual capsulorrhexis (Bottom right). Note circularity and centration of laser capsulotomy relative to pupil and IOL in laser-treated eye (Left, Top and Bottom) compared with irregularity in manual
specimen (Right, Top and Bottom).

affordability of the procedure for physicians and patients.

The incremental cost of femtosecond laserassisted cataract surgery is not currently covered by most insurance
carriers in the United States.
To date, there has been no comprehensive cost effectiveness analysis published on this technology to guide public
policy or individual patient decision making. This technology may over time be shown to be associated with further
improvements in relatively infrequent complication rates
such as capsular tears, dislocated lens fragments, or late
VOL. 158, NO. 1

lens decentration from irregular capsular contraction, but

greater clinical experience, longer-term follow-up, and
larger patient cohorts will be required to answer that question. Similarly, measurement of potential short- and longterm benefits of laser-assisted cataract surgery, including
increased postoperative patient comfort, reduced endothelial cell loss and thermal damage to the cornea, and potential optical benefits when compared with manual ultrasonic
surgery, will require more experience and well-controlled
clinical trials with appropriate quality-of-life metrics.

THE EVOLUTION OF LASER THERAPY IN OPHTHALMOLOGY

21

In other nonmedical industries, including computers,

telecommunications, media, transportation, and energy, it
has been observed that initially disruptive technologies
that have ultimately resulted in significant improvements
in performance and cost are oftentimes more expensive
and initially inferior to established methods, at least in their
early stages of development.82,83 With the passage of time
and increased understanding gained from experience,
these initially nonoptimized designs and inefficiencies in
manufacturing or delivery may be reduced or eliminated
along with significant second- and third-generation
enhancements to the fundamental technology, enabling
improvements in both price and performance that make
the technology affordable and attractive.
With the development of new styles of intraocular lenses
and surgical tools that are optimized for eyes undergoing
femtosecond laser pretreatment, further benefits may be
realized, including better intraoperative environment control, improved centration of multifocal lenses, enhanced
rotational stability and positioning of toric intraocular
lenses, and possibly the achievement of true dynamic accommodation by changes in shape or location enabled by
customized capsular fixation.
Finally, in keeping with the adage that while failure is an
orphan, success has many fathers, the history of the laser,
which has had so many positive disruptive impacts on
modern-day life, continues to be written and rewritten.
To a significant extent, because of the economic impacts
it has had on so many industries, authorship of the intellectual property surrounding the laser has proven to be a highly
contentious issue, dating back to the original conception by
Townes and his colleagues at Columbia and the Bell Labs in
the late 1950s and continuing until the present time with
litigation on the invention of the method for performing

LASIK and the ways in which royalty-bearing licenses

might be enforced.60,84 These issues have had an
important impact on the organization and economic
development of the ophthalmic laser industry, particularly
in the early years following the introduction of new types
of lasers and laser-based procedures. No fewer than 3 books
have been written presenting a variety of different viewpoints as to who invented the laser and when, and who
won and lost the battles of both intellectual property ownership and academic distinction.8,85,86

SUMMARY
THE DEVELOPMENT OF OPHTHALMIC LASERS HAS RESULTED

in contributions to the improvement of ocular health as

well as the facilitation of biomedical research into the
causes and treatment of blinding diseases. Study of the
continuing evolution of ophthalmic lasers has also led to
useful insights into the economic and societal impact of
advanced technology development on the delivery and
cost of medical care.
Despite advances in the understanding of basic ophthalmic disease processes, including the use of modern biopharmaceuticals, lasers continue to play an important role
in the armamentarium of the modern ophthalmologist.
While we do not yet have sufficient clinical experience to
definitively answer questions of incremental cost effectiveness for the very newest and most advanced image-guided
short-pulse-duration retinal and anterior segment laser systems, if history is any guide, they are likely to occupy an
important niche in the ophthalmic care of the future.

THE AUTHOR HAS COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST.
Mark Blumenkranz has board membership on the following: Optimedica, Avalanche Biotechnologies, Oculeve, Vantage Surgical, Digisight, Presbia,
and Peak Surgical. This work was supported in part by an unrestricted gift by the Horngren Family Fund. Mark Blumenkranz, as sole author, is responsible
for all aspects of preparation of this manuscript.

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Biosketch
Mark S. Blumenkranz, MD, MMS, is the HJ Smead Professor and Chairman of the Department of Ophthalmology and the
Founding Director of the Byers Eye Institute at Stanford University. His interests have centered on Retinal Surgery and
Pharmacology. Dr Blumenkranz has served on the Editorial Boards of the American Journal of Ophthalmology, Retina,
Ophthalmology, and Graefe1s Archives for Ophthalmology and is a past recipient of the Heed Award, the Rosenthal
Award, the Academy Lifetime Achievement Award, the Alcon Research Institute Award, and the Gertrude Pyron
Award. Dr Blumenkranz is a past President of the American University Professors of Ophthalmology (AUPO), the
Retina Society and the Macula Society.

25.e1

AMERICAN JOURNAL OF OPHTHALMOLOGY

JULY 2014