update/review

Wound healing after photorefractive

keratectomy
Per Fagerholm, MD, PhD

ABSTRACT
For more than 15 years, the excimer laser has been used as a surgical instrument on the
cornea. Photorefractive keratectomy (PRK) followed radial keratotomy as researchers
sought a more precise technique. In PRK, precision turned out to depend on surgical
technique as well as the wound-healing process, with the 2 factors interdependent. The
PRK technique has evolved toward a large diameter, flat ablation curvatures, and an even
surface. The role of such factors as cytokines and interleukins has become more clear in
the past 10 years. However, understanding the wound-healing process becomes more
complicated with increasing knowledge. Learning the contributing factors and performing
trials with new drugs and antibodies to modulate wound healing have shown positive
results on the experimental level. Patient selection based on the concentration of epidermal
growth factor in tears may be another way to increase PRK’s precision. The PRK technique
has taught much about wound healing. For the technique to be competitive, increased
precision, particularly in eyes with high myopia, is needed. Two other factors are impera-
tive: controlling postoperative pain and decreasing visual rehabilitation time. J Cataract
Refract Surg 2000; 26:432– 447 © 2000 ASCRS and ESCRS

T he outcome of photorefractive keratectomy (PRK)

is closely related to the wound-healing response.
The refractive results, as well as other aspects of quality
Various technical modalities are used to modify the
delivery system, such as an iris diaphragm in a circular
beam, a scanning-slit beam, or a flying-spot beam. The
of vision, depend on it. laser beam delivery system and the number of laser
In PRK, an excimer laser is the radiation source.1– 4 pulses administered are monitored by an algorithm. La-
Currently, a wavelength of 193 nm is used. The laser ser beam quality, delivery system, pulse frequency, and
beam is delivered to the eye through a series of mirrors algorithms have been the focus during the rapid devel-
and lenses and finally to the cornea. From 0.2 to 0.3 ␮m opment of this surgical instrument. New aiming devices
of corneal stroma is ablated with each pulse. Approxi- and eye tracking have been developed to avoid depen-
mately 0.07 ␮m of the adjacent tissue is affected.5–9 dence on patients’ ability to fixate their eyes on a target
during surgery.
Various types of epithelial ablation are used: manual
Accepted for publication November 8, 1999. with a blade or a rotating brush, manual after alcohol
From St. Eriks Eye Hospital, Karolinska Institutet, Stockholm, Sweden. administration, or epithelial laser ablation. Cooling the
Supported by the Swedish Medical Research Council, Kronprinsessan cornea before and after surgery is also done. It is clear
Margaretas Arbetsnämnd, Karolinska Institutet fonder. that varying the surgical technique influences the
Reprint requests to Per Fagerholm, MD, PhD, Professor, St. Eriks Eye wound-healing response. The question is, how much
Hospital, Polhemsgatan 50, SE 112 82 Stockholm, Sweden. of the variation in results can be attributed to imper-
© 2000 ASCRS and ESCRS 0886-3350/00/$–see front matter
Published by Elsevier Science Inc. PII S0886-3350(99)00436-8
 UPDATE/REVIEW: WOUND HEALING AFTER PRK

fect surgical technique and how much to the healing Wound healing cannot be blamed for all variations
response? in PRK’s outcome. Preoperative refraction also contrib-
Pharmacological agents have been used to con- utes to the result. In addition, the laser manufacturing
trol the remaining variations in the wound-healing company may adjust the algorithm so that the mean
response. Corticosteroids had been used extensively result is slightly undercorrected or the astigmatism
as a postoperative treatment, but their use has dimin- reduced.
ished as the surgical technique has changed from steep Nonetheless, it is clear that wound healing is an
ablations with a small diameter to flat large-diameter important contributor to the variations in outcome. Pa-
treatments. tients have been divided into normal responders, aggres-
As knowledge and understanding of corneal sive responders, and nonresponders.13 In myopic
wound-healing increases, other types of treatment will corrections, aggressive responders end up myopic and
emerge. Better selection of suitable PRK patients will the nonresponders, hyperopic. Few factors explain a ten-
probably result. dency to regress. One is the hormonal influences of oral
Wound healing of all body parts follows a similar contraceptives and another is pregnancy.14,15
pattern with local variations. Wound healing in the skin Heredity may contribute to excessive healing or a
provides the standard description of the discernible nonresponsiveness. In general, if 1 eye regresses, the
phases: (1) inflammation— early, polymorphonuclear other eye is prone to do so.14 It is, however, more chal-
leukocyte invasion; late, monocyte invasion; (2) granu- lenging to explain the opposite. Photorefractive keratec-
lar tissue formation and re-epithelialization; (3) new ma- tomy is performed in adults in whom the myopia has
trix formation and remodeling of the matrix; (4) wound stabilized.16 Little is known about how the young cor-
contraction; (5) collagen accumulation and normaliza- nea reacts to PRK. Environmental factors such as mini-
tion of the number of cells in the scar. trauma or ultraviolet light exposure may explain why
All these wound-healing phases occur in the cornea, only 1 eyes regresses.
but not to the same extent. One reason is the lack of Ultraviolet light has been shown experimentally to
vessels in the cornea. There are also differences between induce renewed healing after PRK.17,18 Trauma to an
a surface-parallel and an incisional wound. eye that has had PRK can probably initiate a wound-
This review will discuss the normal corneal wound- healing response, causing haze and regression.19
healing response and related it to developments in the Details of the surgical technique, such as drying of
surgical technique as well as the clinical problems that the stroma between epithelial debridement and stromal
can occur after PRK. ablation, may increase the ablation per pulse. This shifts
the outcome to the hyperopic side.

Clinical Problems in PRK Irregular Healing and Decentration

Accuracy The cornea constitutes about 65% of the refractive
Accuracy is the primary problem in PRK, and it is power of the eye and has high-quality refractive proper-
also the key to its success. The aim of all development is ties. Most of the refraction occurs in the interphase be-
to improve the surgical outcome. Such improvements tween air and the tear film.
over the years have made PRK possible in patients with The cornea must be restored to its original refractive
higher levels of myopia.10 –12 quality after PRK; however, this does not occur in all
Correction of astigmatism and hyperopia has also cases. Best corrected visual acuity (BCVA) sometimes
been added to the indications for PRK. In myopic eyes, worsens.20 Computerized corneal videokeratography
most unsatisfactory results are regressions toward myo- may show a decentered treatment area.21–23 Healing can
pia. A small fraction of eyes end up with hyperopia. In also be irregular (Figure 1).24
general, the latter causes more patient dissatisfaction, In my experience, it is difficult to clinically separate
especially in those who are presbyopic or close to being irregular healing from a decentered ablation by corneal
so. Accuracy is also a problem in astigmatic and hyper- topography alone. I always manually debride the wound
opic correction. as a first step.25 Then, I can see whether the original

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 UPDATE/REVIEW: WOUND HEALING AFTER PRK

Figure 1. (Fagerholm) Six months af-

ter PRK for – 6.00 diopters of myopia, the
patient reported blurred vision. Uncor-
rected visual acuity was 20/40 and
BCVA, 20/25 with – 6.00 sphere. Corneal
topography (EyeSys) irregularity explains
the eye’s bifocality (A). After manual de-
bridement of the wound area, renewed
healing produced a fairly even flattening
of the wound area (B). Final BCVA was
20/20 with – 0.75 sphere. This case is a
clear example of irregular healing.

treatment was well centered. The surgical correction they do not have a real wound. Their eyes feel gritty
principle for decentered treatment areas should be the and dry in the morning. At times, epithelial defects
same as that for irregular healing, and much hope is can be identified. These problems usually subside
placed on computer-topography-assisted photothera- during the first year.27,28 Epithelial defects are rarely
peutic programs being developed by several excimer la- found.
ser manufacturers.26
Haze
Recurrent Erosions Haze is normally associated with wound healing af-
Postoperatively, some patients report symptoms ter PRK.29 With modern techniques, significant haze
similar to those of recurrent erosions, even though rarely occurs in eyes with low myopia after PRK. It can,

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 UPDATE/REVIEW: WOUND HEALING AFTER PRK

however, be a major problem in eyes treated for high Postoperative pain is a primary drawback of PRK.37
myopia. Persistent haze also occurs in patients who have The corneal nerves are ablated,38 and inflammatory fac-
PRK after radial keratotomy or after previous PRK in tors inducing pain are released, among them prosta-
eyes with scarred or grafted corneas. glandins such as prostaglandin-2 (PGE2). The prosta-
glandins are found first in the cornea39 and then in the
The Initial Wound aqueous humor.40 They break down the blood–aqueous
barrier (BAB), and flare can be recorded41 as a sign of
The energy distribution in the laser beam, the type
keratouveitis.
of delivery system, and the algorithm determine how the
The initial pain lasts 12 to 24 hours and is followed
wound looks immediately after ablation. The ablation
by irritation and tearing until epithelial coverage is
imprint in the stromal surface was very evident with
complete after 48 to 72 hours. Photophobia is present
early iris-diaphragm delivery systems. The stepwise
until epithelial coverage is complete and then subsides
opening left concentric rings in the stroma.30 The epi-
rapidly.
thelial coverage helped even the surface to create a
Pain therapy is aimed locally or centrally. Local an-
smooth optical working surface. When these eyes had
esthetic agents and nonsteroidal anti-inflammatory
surgery years later, the concentric rings could still be
agents (NSAIDs) can stop pain if given topically.42
identified after manual epithelial debridement.31
Nonsteroidal anti-inflammatory drugs act as local anes-
Bowman’s layer is always ablated to bare stroma,
thetic agents and can also prevent the release of prosta-
even in eyes with very low myopia. Improvements have
glandins.43 Topical diclofenac or other NSAIDs
aimed at creating an even stromal surface to minimize
combined with a resorbable contact lens has been 1
the wound-healing reaction,32 facilitate wound healing,
treatment of choice. Topical diclofenac given postoper-
and optimize the optical quality of the refractive corneal
atively efficiently blocks the release of PGE2 in rabbits.40
surface.
This drug, however, slows epithelial closure,43 and when
One example of this was to allow the iris diaphragm
combined with a contact lens, necessitates checkups un-
to open several times during surgery (multizone treat-
til epithelial closure because the risk of infection appears
ment) and even more times for more myopic ablation
to be greater.
(multizone, multipass).33 Similar effects have been
Long-term use of topical local anesthetic agents has
sought with the flying-spot treatment and by modifying
been considered hazardous.44 The fear of short-term use
the scanning-mode ablation.34 Involuntary eye move-
is probably overrated, and they could probably be given
ments always occur during the ablation. These involun-
as an adjunct in specific cases.45
tary movements help smooth the ablated surface.35
The homogeneity of the laser beam, especially of
broad-beam lasers, must be monitored. Hot spots in a Epithelial Healing
beam may create an uneven ablation.36
The epithelial covering of the ablated area is an early
In high resolution, the newly ablated stromal sur-
and important step in wound healing. When coverage is
face will appear very even, covered with an ultrathin
complete, the barrier against infection is restored; irrita-
homogenous membrane of unknown composition.5 Ep-
tion, tearing, and photophobia stop; injection subsides;
ithelial cells will migrate on this surface to cover the
and vision returns. This process takes 48 to 72 hours.
wound.
Epithelial healing is not really complete until permanent
anchoring is restored, which requires about 6 weeks.
Pain The epithelial healing can be divided into a latent phase,
Pain from corneal injury is the consequence of ex- lasting about 8 hours, followed by a linear healing phase
citation of corneal nerve terminals by a noxious stimulus of migration and proliferation, and finally the establish-
or by locally released inflammatory substances. The lat- ment of permanent cell attachments (adhesion).46
ter prostaglandins, neuropeptides, biogenic amines, and During the first hours after injury, the wound area is
kinins can also sensitize the nerves by decreasing the constant or slightly larger because of retraction of the
threshold for excitation. wound edge and gathering of cells in that area.47 During

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the latent phase, the epithelial cells prepare to migrate deal and that a high concentration increases the risk of
onto the wound surface.48 The hemidesmosomal at- a deviating refractive outcome.74 The number of EGF
tachments between the basal cells and the basement receptors on the epithelial cell increased 10-fold in
membrane disappear 50 to 70 ␮m from the wound edge rabbit corneas after keratectomy.75 Epidermal growth
and are significantly reduced up to 200 ␮m from the factor stimulates DNA synthesis as well as epithelial
edge.47 The cells become more round, but desmosomal cell proliferation and differentiation.57,76 –78 Keratino-
attachments do not disappear completely.48 cyte growth factor is secreted by keratocytes and stimu-
Superficial cells are desquamated, leading to a thin- lates epithelial cell proliferation at the site of the
ner epithelium at the wound edge.49,50 Two or 3 cell receptor.79,80
layers develop at the wound margin, with a single layer at Interleukin-6 has been detected in tear fluid samples
the leading edge. The cells synthesize structural proteins, after PRK. Interleukin-6 stimulates collagen, especially
and actin filaments are assembled in the basal region of collagen I synthesis. It also reduces matrix metallopro-
the migrating cells. tease (MMP) in vitro, in this case MMP-2. Interleu-
During the latent phase, the concentration of fi- kin-6 is also known to cause uveitis in animals after
bronectin, fibrinogen, and fibrin on the wound surface intracameral injection.81 Many details regarding inter-
increases.49,51 Tenascin is also found at the surface at leukin regulation of wound healing remain to be clari-
this early stage.52 Migration of epithelial cells onto the fied. The contribution of each interleukin and of the
wound surface begins the linear healing phase. substrate in the epithelial wound-healing response is not
Interleukins are present in the wound and regulate clear.
the healing process. The wound surface is also important The formation of lamellopodia and filopodia marks
in this regulation via integrins, which are cell surface the beginning of the migration phase of epithelial heal-
receptors.53 ing. The actin filaments are considered to make the cells
Transforming growth factor-beta (TGF-␤) stimu- move.49 In addition to migration, the cells can also in-
lates migration and suppresses proliferation of corneal crease their volume or surface and cover a large area.
epithelial cells.54 –56 Fibronectin at the surface via inte- During the first 24 hours, there is no cell division in the
grins also stimulates migration.57 epithelium close to the wound. In the limbal area, how-
Other interleukins are produced locally, present via ever, early proliferative activity spreads to engage the
the tear film, or are produced by leukocytes. Hepatocyte entire epithelium.82 After wound closure, when the ep-
growth factor (HGF) produced by keratocytes is present ithelium consists of 1 to 2 cell layers, basal cells prolifer-
in tears after PRK and is thought to stimulate both mi- ate to restore normal thickness. Small-diameter laser
gration and proliferation of the epithelium and to in- treatment is associated with increased epithelial thick-
hibit differentiation.58 – 60 Synthesis of HGF is ness, while expanding the treatment diameter makes the
increased by platelet-derived growth factor (PDGF),61 epithelium heal to a normal thickness.83 Focal contacts
also present in tears after PRK.62 Platelet-derived are formed between the migrating cell and the wound
growth factor also enhances extracellular matrix (ECM) surface substrate. These are first established by lamel-
production and remodeling.63,64 Tumor necrosis fac- lopodia and filopodia. These adhesion plaques connect
tor-alpha stimulates fibronectin-induced epithelial cell the surface substrate via the cell membrane to the intra-
migration.54 Tumor necrosis factor-␤ and PDGF act as cellular cytoskeletal fibers.84,85
chemoattractants for neutrophils and macro- Fibrin and fibronectin stimulate epithelial cells to
phages,65– 67 probably by increasing the synthesis of in- release plasminogen activator. The formed plasmin lyses
terleukin-8 (IL-8) or granulocyte-macrophage colony- the cell to substrate adhesions, allowing the cells to move
stimulating factor.62,68,69 forward and form new adhesions. These repeated events
Epidermal growth factor (EGF) also illustrates the stop when the epithelial wound is closed.52 Imbalance in
complexity of the regulatory mechanisms of the epithe- this system in mice leads to defective corneal healing.86
lial healing process. Epidermal growth factor is present Tenascin is considered to promote migration over the
in tears.70 –73 A 1998 study found that the individual wound surface.87,88 In PRK, the basement membrane is
response of EGF concentration in tears varies a great ablated. The advancing cell front produces a new base-

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ment membrane. New hemidesmosomes are then estab- leukin-1 and the Fas ligand100 from the epithelium me-
lished from the periphery to the center of the cornea 4 to diates keratocyte apoptosis. This type of cell death
6 weeks after PRK in the rabbit cornea.89,90 Symptoms induces minimal local damage to surrounding cells. The
such as foreign-body sensation, watering, and tender- extent of apoptosis disappearance is related to the type of
ness on rubbing the eye are sometimes encountered after epithelial removal, and transepithelial PRK is associated
PRK. These symptoms have been attributed to epithelial with comparatively low levels of central corneal apopto-
adhesion problems. Epithelial breakdown after PRK has sis (Figure 2).101,102
been reported to occur in about 3% of eyes.27,28 The volume void of keratocytes is repopulated
within a few days after surgery, but the keratocytes now
contain abundant cell organelles and dark nuclei.103
Inflammatory Cells These activated keratocytes have been associated with
Inflammation starts when the wound occurs. Pros- increased collagen deposition after PRK.104,105 It has
taglandin-2 is present in the cornea after fewer then 24 been suggested that the extent of apoptosis is an impor-
hours39 and subsequently in the aqueous,40 where the tant determinant of corneal wound healing.106
BAB has broken down.41,91 The injured corneal cells Other surgical variations in removing the epithe-
produce vasoactive mediators and chemotactic factors. lium (e.g., use of a brush or alcohol) have been suggested
These cause local vessels to dilate and the vascular endo- to improve the outcome after PRK, as has cooling the
thelium to express selectin. Polymorphonuclear leuko- cornea preoperatively.107–111
cytes (PMNs) circulating in the blood thereby roll on The healing reaction between the epithelium and
the cell wall and migrate out of the vessel.92,93 The cells the superficial stroma continues after epithelial cover-
enter the limbal area and tears and then invade the cor- age. These events eventually decide the refractive
neal wound. After PRK, PMNs appear to invade the outcome.
wound mainly via the tears.94 Mononuclear leukocytes When a small-diameter treatment is used, a thick
reach the wound via the same route a few days later. epithelium sometimes contributes to a myopic out-
The leukocytes clean the wound from debris and
bacteria. The monocytes can be transformed into mac-
rophages.95 The leukocytes furthermore produce inter-
leukins. After PRK epithelial closure, the leukocytes
disappear. This means that PMNs, by timing and num-
ber, influence wound healing, possibly by local produc-
tion of TGF-␤, which in turn may influence epithelial
migration and keratocytes. Polymorphonuclear leuko-
cytes can be excluded from a corneal wound by blocking
selectin, the molecule that causes the cells to roll on and
adhere to the vascular endothelium before leaving the
vessel through diapedes. In the absence of PMNs, a cor-
neal epithelial wound heals slower.94 This suggests that
the sum of the interleukins, among them TGF-␤,
thought to be produced by PMNs, stimulates epithelial
cell proliferation.

Stromal Healing
In the stroma, underlying the ablated surface, the
Figure 2. (Fagerholm) Graphic presentation of how keratocytes
keratocytes disappear to a depth of about 50 to
disappear under the wound after PRK. The volume is then populated
200 ␮m.96 –99 The cell death occurs by apoptosis or by activated keratocytes. These subsequently normalize in size and
programmed cell death. Injury-related release of inter- number.

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 UPDATE/REVIEW: WOUND HEALING AFTER PRK

come.112 With enlargement of the treatment zone, epi-

thelial thickness becomes normal.83 The large diameter,
and thus the flat ablation profile, cause little wound-
healing reaction, and the refractive results in eyes with
low myopia are very good. Still, some patients express
high concentrations of EGF in their tears after PRK, and
the tendency for the correction to regress may be an
epithelial response.76
When a small-diameter treatment with a steep ab-
lation profile is used, the outcome depends on the heal-
ing reaction. This is expected as the refraction shows a
significant hyperopic shift soon after surgery.113 During
the following months, the average outcome is close to
emmetropia, a regression that depends on a wound-
healing reaction. Formation of new stroma and hyper-
trophic epithelium accomplishes the shift in the
refractive surface. A steep ablation curve is now needed
in eyes with higher myopia, in which regression is still a
quantitative problem.
The formation of new stroma after PRK follows a
specific pattern. Water is most prominent in the subep-
ithelial zone.114 The water content is much higher than
in normal corneal stroma. The zones or volumes of high
water content are sharply delineated at the light micro-
scopic level (Figure 3). Newly formed hyaluro-
nan,115,116 which is highly water binding, is strictly co-
localizing to the high-water-content zones.114 In
rabbits, this zone is then repopulated by keratocytes117
that alone or with the epithelium produce collagen types
I, III, IV, V, and VI, and proteoglycans.118 –120 The
initially disorganized collagen and cells are subsequently
organized. The subepithelial zone or volume subse-
quently takes on the light-microscopic appearance of
normal stroma.117
Formation of new stroma in the rabbit after PRK is
more evident when a steep ablation profile is used.121
The same type of reactivity can be provoked by creating
a very uneven ablation surface.117 A flat ablation surface
causes little wound-healing reactivity.122 Thereby, the
original stroma ablation surface and profile will deter-
Figure 3. (Fagerholm) Microradiogram of a freeze-sectioned,
mine the reactive outcome.
freeze-dried rabbit cornea that had PRK of –5.00 D and 4.5 mm
The disappearance and return of stromal kerato- in diameter. Four weeks after surgery, a dark zone (z) is found
cytes can be followed using the confocal microscope. under the epithelium (e) (A). The dark areas indicate high water con-
tent. The stroma is brighter as the higher dry mass absorbs the x-rays
The activated keratocytes scatter light and are more ev-
(B). The zone that contains hyaluronan is subsequently organized
ident102; as they reappear in the wound area, they may by invading keratocytes that produce collagen and regular glucose
contribute to haze. aminoglycans.

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The formation of the subepithelial volume and its gen fibril irregularity will remain. The increased density
subsequent consolidation corresponds to the granula- of activated keratocytes in the wound area will eventu-
tion tissue formation, the production of new matrix, and ally, probably by apoptosis, return to normal density.
the remodeling of this matrix in the skin wound. Matrix metalloproteinases are active in remodeling
The contraction phase of the new matrix seen in the scar after corneal injuries. Their action is balanced by
corneal incisional wounds122 seems to be an abortive tissue inhibitor metalloproteinases (TIMPs), which may
phenomenon in PRK wounds. It has not been docu- guard against excessive ECM breakdown. Samples taken
mented clinically to my knowledge. The contraction at reoperation from corneal wounds 20 or 30 months
phase is accomplished by activated keratocytes or fibro- after PRK expressed mRNA for TIMP1 but not MMP-2
blasts containing myocontractile elements, myofibro- or -9.129 Both MMP-2 and -9 were, however, expressed
blasts. The contraction phase is modulated by a secreted in the epithelium of the rat cornea after PRK. In the
protein that is acidic and rich in cysteine (SPARC).123 rabbit cornea, a synthetic inhibitor of matrix metallo-
After PRK, the SPARC protein is expressed at the basal proteases was shown to delay epithelial healing.130 Ma-
aspect of the recently healed epithelium during the first trix metalloprotease (gelatinase B) expression was found
week after surgery in rabbits.124 upregulated in both the epithelium and the stroma after
Myofibroblasts have been associated with solid haze PRK.131,132 A synthetic inhibitor of metalloproteinases
or scar formation. This resistant, dense haze is some- has been found to reduce corneal haze after PRK in
times seen in eyes with high myopia after PRK. It is also rabbits as well as the synthesis of type II collagen.133
thought to occur when corneas with pre-existing scars
are treated with phototherapeutic keratectomy or a PRK
retreatment of radial keratectomy. The myofibroblasts Role of Postoperative Steroids
may already exist in these scars.
Steroids are known to delay wound healing in the
It has been shown that TGF-␤ initiates the activa-
cornea. They reduce wound infiltration of leuko-
tion of keratocytes into myofibroblasts.125 Therefore,
cytes134 and limit the subepithelial deposition of
neutralizing antibodies against TGF-␤ have been used
collagen and ECM135,136 including hyaluronan.115 Ep-
to reduce haze formation in rabbits after PRK.125,126
Mannos 6-phosphate, a competitor for receptor bind- ithelial and keratocyte migration and proliferation are
ing with TGF-␤, has been evaluated for the same also suppressed.
purpose.127 In prospective clinical trials, the influence of ste-
Large-diameter ablation profiles are expected to heal roids on refractive results is significant. However, after
with little or no new stromal haze formation. With this cessation of the drug, the difference often diminishes or
in mind, the historical division of patients into nonre- disappears.
sponders, normal healers, and aggressive responders13 Steroids are able to suppress the movement and re-
can now be reduced to normal and aggressive respond- parative efforts of activated keratocytes and, typically,
ers. A hyperopic outcome is likely to be caused by an haze formation is shifted until 1 or 2 months after the
erroneous refraction, at least in eyes with low myopia. topical steroids are stopped.29,137 This means that some
Aggressive responders are still found in all grades of pre- regression can occur after cessation of the drug and that
operative myopia. A high concentration of EGF in tears stable refractive results cannot be counted on until a few
preoperatively may thus be a way to identify the aggres- month after steroids have been stopped.
sive responders.74 The development toward large-diameter flat-profile
If new stroma is formed under the epithelium, it will treatments has made postoperative steroids unnecessary
develop from a high-water-content zone to a solid tissue in eyes with up to –5.00 diopters (D) of myopia. In eyes
containing activated keratocytes and all the collagen with higher myopia, the steep type of treatment required
components and ECM components that exist in the necessitates steroids138 or the choice of another tech-
normal stroma. The new stroma will not contain the nique such as laser in situ keratomileusis (LASIK).
regularly arranged collagen-containing lamella.128 When evaluating studies on the possible effect of
However, the stroma will be clear, although some colla- steroids, it is important to remember that the drug exists

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 UPDATE/REVIEW: WOUND HEALING AFTER PRK

in various forms. The degree of potency and penetrabil- nancy15 and trauma.19 Clinically, late regression can
ity varies greatly. occur up to 2 years after the initial surgery. It should not
be confused with postponed haze formation and regres-
Corneal Nerves sion, which occur 1 or 2 months after the postoperative
steroids have been tapered.
The corneal nerves are ablated when PRK is per-
formed. As soon as 7 days after surgery, generating nerve
fibers can be identified in both the human and rabbit Haze
cornea.139
The haze phenomenon30 has interested surgeons
The morphology of the regenerating corneal nerves,
and researchers perhaps more than deserved. Haze is
which is not restored to normal,140 can be studied with
clearly seen at the slitlamp but only rarely experienced by
the confocal microscope. Corneal sensitivity is decreased
the patient. The phenomenon has, however, been a driv-
in the operated area about 1 month after PRK.39,141,142
ing force in finding out what happens in the wound.
Ablation depth and degree of haze will influence the
Haze is a normal companion to corneal wound heal-
recovery of sensation, which is usually restored after 1 to
ing and usually subsides after 1 to 2 years.29,148 With
3 months.39 The clinical data on recovery of sensitiza-
small-diameter treatment or in high myopia, the haze
tion correlate well with histologic findings.140,143
can persist. One debate has been whether haze should be
It is well known that denervation somewhat impairs
regarded as a scar or something else, a passing phenom-
corneal wound healing. However, the influence of cor-
enon on the way to a clear cornea. It can be both.
neal nerve damage on corneal wound healing after PRK
The source of haze, or light scattering in the wound,
is not understood. This is different in LASIK,144 after
has been attributed to the interface between the epithe-
which the morphology of the regenerating nerves are
lium and stroma or from the keratocytes in the stroma
closer to normal.
underlying the wound.
After PRK, calcitonin gene-related peptide is re-
Confocal microscopy has contributed to the knowl-
leased in excess from damaged nerves as assessed in tears.
edge about haze. To some extent, it has been possible to
The substance may promote wound healing. It is also a
separate the contribution of subepithelial deposits from
potent vasodilator.145,146
that of keratocytes.149 In the subepithelial zone, several
substances are produced such as glycosaminogly-
Late Regression cans,150,151 fibronectin, laminin, type III collagen,152
Late regression is a reactivation of the wound-heal- keratin sulfate, and hyaluronic acid.114,115 This zone
ing process after PRK. It is a rare phenomenon that may scatter light because of an irregular structure that
seems to occur more often after small-diameter laser does not possess the refractive properties of the normal
treatment. Typically, the treatment is initially successful cornea stroma. The subepithelial interface also accumu-
and the cornea is clear. Over a few days, visual acuity lates a large amount of water that co-localizes with the
worsens and the eye becomes myopic (–1.00 to –3.00 hyaluronan.114 The sharp demarcations of these zones
D). Best corrected visual acuity also drops several lines creates sharp shifts in refractive index in these areas,
because of intense haze in the treated area.147 causing light scattering. The resolution of the technique
Topical steroids in the form of dexamethasone used to assess water content in the cornea is slightly
0.1% given 3 to 5 times a day usually result in rapid lower than that of light microscopy. If the shifts in re-
improvement, especially if given soon after the begin- fractive index reach between lamellae, it would further
ning of the regression. If the eye responds to steroids induce light scattering by disturbing the structure.
after 2 to 3 weeks, slowly tapering the steroids helps Keratocytes disappear in the stroma under the
resolve the thick haze. My impression is that late regres- wound after PRK.111 However, they rapidly repopulate
sion occurs after sun exposure when skiing or sailing. the area and significantly increase in volume.159 They
Experimentally, it has been possible to provoke a healing also increase their reflectivity,102,153,154 which contrib-
reaction in PRK-treated rabbits by exposure to ultravi- utes to light scattering in the area. The keratocytes re-
olet light.17,18 Regression can also be provoked by preg- populate the wound area to a much greater density than

440 J CATARACT REFRACT SURG—VOL 26, MARCH 2000

 UPDATE/REVIEW: WOUND HEALING AFTER PRK

in the normal corneal stroma.29 The density then de- healing. Both dimethylsulfoxide and superoxid dismul-
creases to normal levels after about 6 months. The al- tase were applied, reducing the degree and extent of
tered keratocytes are, to various extents, changed into postoperative haze in the treated groups.164
myofibroblasts that deposit collagen and in the skin There are many ways to influence wound healing to
wound cause wound contraction. The action of these reduce its harmful consequences. The ideal way is to
myofibroblasts is thought to cause the type of dense haze select patients before surgical intervention to a suitable
that is more or less persistent and that could be defined technique. Improvements in the surgical technique have
as scar tissue. aimed at creating as little reactivity in the cornea as pos-
Interleukins are active in attracting human kera- sible. The stromal ablation performed at the time of
tocytes. In a collagen gel model and using a Boyden surgery should reflect, via the epithelium, the new per-
blind-well chemotaxis chamber PDFG⫹BB, EGE, manent refractive surface. Stopping corneal reactivity to
TSF-␣, IGF-I and TFG-␤ increased keratocyte surgery in all patients may seem difficult in view of the
chemotaxis.155,156 extremely complicated wound-healing mechanisms.
However, fewer than 10 years ago, steroids were the only
option; since then, knowledge has grown exponentially.
Role of PRK in Refractive Surgery
Photorefractive keratectomy is an attractive refrac-
tive surgery technique. The procedure is fast and easy to
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