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http://dx.doi.org/10.1016/j.ajo.2014.03.013
LASERTISSUE INTERACTIONS
INTERACTIONS OF LIGHT WITH BIOLOGICAL TISSUES
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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.
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
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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:
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
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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.)
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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
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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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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
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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).
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SUMMARY
THE DEVELOPMENT OF OPHTHALMIC LASERS HAS RESULTED
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.
REFERENCES
1. Palanker DV, Blumenkranz MS, Marmor MF. Fifty years of
ophthalmic laser therapy. Arch Ophthalmol 2011;129(12):
16131619.
2. Palanker D, Blumenkranz MS. Retinal laser therapy: biophysical
basis and applications. Chapter 39. In: Ryan SJ, Schachat Ap,
Wilkinson CP, Hinton DR, Sadda SR, Wiedemann P, editors.
RETINA, vol. 3, 5th edition. St Louis, MO: Mosby Inc; 2012.
3. Schawlow AL, Townes CH. Infrared and optical masers.
Physical Review 1958;112(6):19401949.
4. Meyer-Schwickerath G. Koagulation der Netzhaut
mit Sonnenlicht. Ber Dtsch Ophthalmol Ges 1949;55:
256259.
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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.
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