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Update/Review

Wound healing after photorefractive keratectomy

Fagerholm, Per MD, PhDa,*

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Journal of Cataract & Refractive Surgery: March 2000 - Volume 26 - Issue 3 - p 432-447
doi: 10.1016/S0886-3350(99)00436-8
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Abstract

The outcome of photorefractive keratectomy (PRK) is closely related to the wound-healing response. The refractive results, as well as other aspects of quality of vision, depend on it.

In PRK, an excimer laser is the radiation source.1–4 Currently, a wavelength of 193 nm is used. The laser beam is delivered to the eye through a series of mirrors and lenses and finally to the cornea. From 0.2 to 0.3 μm of corneal stroma is ablated with each pulse. Approximately 0.07 μm of the adjacent tissue is affected.5–9

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 laser beam delivery system and the number of laser pulses administered are monitored by an algorithm. Laser beam quality, delivery system, pulse frequency, and algorithms have been the focus during the rapid development of this surgical instrument. New aiming devices and eye tracking have been developed to avoid dependence on patients' ability to fixate their eyes on a target during surgery.

Various types of epithelial ablation are used: manual with a blade or a rotating brush, manual after alcohol administration, or epithelial laser ablation. Cooling the cornea before and after surgery is also done. It is clear that varying the surgical technique influences the wound-healing response. The question is, how much of the variation in results can be attributed to imperfect surgical technique and how much to the healing response?

Pharmacological agents have been used to control the remaining variations in the wound-healing response. Corticosteroids had been used extensively as a postoperative treatment, but their use has diminished as the surgical technique has changed from steep ablations with a small diameter to flat large-diameter treatments.

As knowledge and understanding of corneal wound-healing increases, other types of treatment will emerge. Better selection of suitable PRK patients will probably result.

Wound healing of all body parts follows a similar pattern with local variations. Wound healing in the skin provides the standard description of the discernible phases: (1) inflammation—early, polymorphonuclear leukocyte invasion; late, monocyte invasion; (2) granular tissue formation and re-epithelialization; (3) new matrix formation and remodeling of the matrix; (4) wound contraction; (5) collagen accumulation and normalization of the number of cells in the scar.

All these wound-healing phases occur in the cornea, but not to the same extent. One reason is the lack of vessels in the cornea. There are also differences between a surface-parallel and an incisional wound.

This review will discuss the normal corneal wound-healing response and related it to developments in the surgical technique as well as the clinical problems that can occur after PRK.

Clinical Problems in PRK

Accuracy

Accuracy is the primary problem in PRK, and it is also the key to its success. The aim of all development is to improve the surgical outcome. Such improvements over the years have made PRK possible in patients with higher levels of myopia.10–12

Correction of astigmatism and hyperopia has also been added to the indications for PRK. In myopic eyes, most unsatisfactory results are regressions toward myopia. A small fraction of eyes end up with hyperopia. In general, the latter causes more patient dissatisfaction, especially in those who are presbyopic or close to being so. Accuracy is also a problem in astigmatic and hyperopic correction.

Wound healing cannot be blamed for all variations in PRK's outcome. Preoperative refraction also contributes to the result. In addition, the laser manufacturing company may adjust the algorithm so that the mean result is slightly undercorrected or the astigmatism reduced.

Nonetheless, it is clear that wound healing is an important contributor to the variations in outcome. Patients have been divided into normal responders, aggressive responders, and nonresponders.13 In myopic corrections, aggressive responders end up myopic and the nonresponders, hyperopic. Few factors explain a tendency to regress. One is the hormonal influences of oral contraceptives and another is pregnancy.14,15

Heredity may contribute to excessive healing or a nonresponsiveness. In general, if 1 eye regresses, the other eye is prone to do so.14 It is, however, more challenging to explain the opposite. Photorefractive keratectomy is performed in adults in whom the myopia has stabilized.16 Little is known about how the young cornea reacts to PRK. Environmental factors such as minitrauma or ultraviolet light exposure may explain why only 1 eyes regresses.

Ultraviolet light has been shown experimentally to induce renewed healing after PRK.17,18 Trauma to an eye that has had PRK can probably initiate a wound-healing response, causing haze and regression.19

Details of the surgical technique, such as drying of the stroma between epithelial debridement and stromal ablation, may increase the ablation per pulse. This shifts the outcome to the hyperopic side.

Irregular Healing and Decentration

The cornea constitutes about 65% of the refractive power of the eye and has high-quality refractive properties. Most of the refraction occurs in the interphase between air and the tear film.

The cornea must be restored to its original refractive quality after PRK; however, this does not occur in all cases. Best corrected visual acuity (BCVA) sometimes worsens.20 Computerized corneal videokeratography may show a decentered treatment area.21–23 Healing can also be irregular (Figure 1). 24

Figure 1.
Figure 1.:
(Fagerholm) Six months after PRK for –6.00 diopters of myopia, the patient reported blurred vision. Uncorrected 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 debridement 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.

In my experience, it is difficult to clinically separate irregular healing from a decentered ablation by corneal topography alone. I always manually debride the wound as a first step.25 Then, I can see whether the original treatment was well centered. The surgical correction principle for decentered treatment areas should be the same as that for irregular healing, and much hope is placed on computer-topography-assisted phototherapeutic programs being developed by several excimer laser manufacturers.26

Recurrent Erosions

Postoperatively, some patients report symptoms similar to those of recurrent erosions, even though they do not have a real wound. Their eyes feel gritty and dry in the morning. At times, epithelial defects can be identified. These problems usually subside during the first year.27,28 Epithelial defects are rarely found.

Haze

Haze is normally associated with wound healing after PRK.29 With modern techniques, significant haze rarely occurs in eyes with low myopia after PRK. It can, however, be a major problem in eyes treated for high myopia. Persistent haze also occurs in patients who have PRK after radial keratotomy or after previous PRK in eyes with scarred or grafted corneas.

The Initial Wound

The energy distribution in the laser beam, the type of delivery system, and the algorithm determine how the wound looks immediately after ablation. The ablation imprint in the stromal surface was very evident with early iris-diaphragm delivery systems. The stepwise opening left concentric rings in the stroma.30 The epithelial coverage helped even the surface to create a smooth optical working surface. When these eyes had surgery years later, the concentric rings could still be identified after manual epithelial debridement.31

Bowman's layer is always ablated to bare stroma, even in eyes with very low myopia. Improvements have aimed at creating an even stromal surface to minimize the wound-healing reaction,32 facilitate wound healing, and optimize the optical quality of the refractive corneal surface.

One example of this was to allow the iris diaphragm to open several times during surgery (multizone treatment) and even more times for more myopic ablation (multizone, multipass).33 Similar effects have been sought with the flying-spot treatment and by modifying the scanning-mode ablation.34 Involuntary eye movements always occur during the ablation. These involuntary 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 beam may create an uneven ablation.36

In high resolution, the newly ablated stromal surface will appear very even, covered with an ultrathin homogenous membrane of unknown composition.5 Epithelial cells will migrate on this surface to cover the wound.

Pain

Pain from corneal injury is the consequence of excitation of corneal nerve terminals by a noxious stimulus or by locally released inflammatory substances. The latter prostaglandins, neuropeptides, biogenic amines, and kinins can also sensitize the nerves by decreasing the threshold for excitation.

Postoperative pain is a primary drawback of PRK.37 The corneal nerves are ablated,38 and inflammatory factors inducing pain are released, among them prostaglandins such as prostaglandin-2 (PGE2). The prostaglandins are found first in the cornea39 and then in the aqueous humor.40 They break down the blood–aqueous barrier (BAB), and flare can be recorded41 as a sign of keratouveitis.

The initial pain lasts 12 to 24 hours and is followed by irritation and tearing until epithelial coverage is complete after 48 to 72 hours. Photophobia is present until epithelial coverage is complete and then subsides rapidly.

Pain therapy is aimed locally or centrally. Local anesthetic agents and nonsteroidal anti-inflammatory agents (NSAIDs) can stop pain if given topically.42 Nonsteroidal anti-inflammatory drugs act as local anesthetic agents and can also prevent the release of prostaglandins.43 Topical diclofenac or other NSAIDs combined with a resorbable contact lens has been 1 treatment of choice. Topical diclofenac given postoperatively efficiently blocks the release of PGE2 in rabbits.40 This drug, however, slows epithelial closure,43 and when combined with a contact lens, necessitates checkups until epithelial closure because the risk of infection appears to be greater.

Long-term use of topical local anesthetic agents has been considered hazardous.44 The fear of short-term use is probably overrated, and they could probably be given as an adjunct in specific cases.45

Epithelial Healing

The epithelial covering of the ablated area is an early and important step in wound healing. When coverage is complete, the barrier against infection is restored; irritation, tearing, and photophobia stop; injection subsides; and vision returns. This process takes 48 to 72 hours. Epithelial healing is not really complete until permanent anchoring is restored, which requires about 6 weeks. The epithelial healing can be divided into a latent phase, lasting about 8 hours, followed by a linear healing phase of migration and proliferation, and finally the establishment of permanent cell attachments (adhesion).46

During the first hours after injury, the wound area is constant or slightly larger because of retraction of the wound edge and gathering of cells in that area.47 During the latent phase, the epithelial cells prepare to migrate onto the wound surface.48 The hemidesmosomal attachments between the basal cells and the basement membrane disappear 50 to 70 μm from the wound edge and are significantly reduced up to 200 μm from the edge.47 The cells become more round, but desmosomal attachments do not disappear completely.48

Superficial cells are desquamated, leading to a thinner epithelium at the wound edge.49,50 Two or 3 cell layers develop at the wound margin, with a single layer at the leading edge. The cells synthesize structural proteins, and actin filaments are assembled in the basal region of the migrating cells.

During the latent phase, the concentration of fibronectin, fibrinogen, and fibrin on the wound surface increases.49,51 Tenascin is also found at the surface at this early stage.52 Migration of epithelial cells onto the wound surface begins the linear healing phase.

Interleukins are present in the wound and regulate the healing process. The wound surface is also important in this regulation via integrins, which are cell surface receptors.53

Transforming growth factor-beta (TGF-β) stimulates migration and suppresses proliferation of corneal epithelial cells.54–56 Fibronectin at the surface via integrins also stimulates migration.57

Other interleukins are produced locally, present via the tear film, or are produced by leukocytes. Hepatocyte growth factor (HGF) produced by keratocytes is present in tears after PRK and is thought to stimulate both migration and proliferation of the epithelium and to inhibit differentiation.58–60 Synthesis of HGF is increased by platelet-derived growth factor (PDGF),61 also present in tears after PRK.62 Platelet-derived growth factor also enhances extracellular matrix (ECM) production and remodeling.63,64 Tumor necrosis factor-alpha stimulates fibronectin-induced epithelial cell migration.54 Tumor necrosis factor-β and PDGF act as chemoattractants for neutrophils and macrophages,65–67 probably by increasing the synthesis of interleukin-8 (IL-8) or granulocyte-macrophage colony-stimulating factor.62,68,69

Epidermal growth factor (EGF) also illustrates the complexity of the regulatory mechanisms of the epithelial healing process. Epidermal growth factor is present in tears.70–73 A 1998 study found that the individual response of EGF concentration in tears varies a great deal and that a high concentration increases the risk of a deviating refractive outcome.74 The number of EGF receptors on the epithelial cell increased 10-fold in rabbit corneas after keratectomy.75 Epidermal growth factor stimulates DNA synthesis as well as epithelial cell proliferation and differentiation.57,76–78 Keratinocyte growth factor is secreted by keratocytes and stimulates epithelial cell proliferation at the site of the receptor.79,80

Interleukin-6 has been detected in tear fluid samples after PRK. Interleukin-6 stimulates collagen, especially collagen I synthesis. It also reduces matrix metalloprotease (MMP) in vitro, in this case MMP-2. Interleukin-6 is also known to cause uveitis in animals after intracameral injection.81 Many details regarding interleukin regulation of wound healing remain to be clarified. The contribution of each interleukin and of the substrate in the epithelial wound-healing response is not clear.

The formation of lamellopodia and filopodia marks the beginning of the migration phase of epithelial healing. The actin filaments are considered to make the cells move.49 In addition to migration, the cells can also increase their volume or surface and cover a large area. During the first 24 hours, there is no cell division in the epithelium close to the wound. In the limbal area, however, early proliferative activity spreads to engage the entire epithelium.82 After wound closure, when the epithelium consists of 1 to 2 cell layers, basal cells proliferate to restore normal thickness. Small-diameter laser treatment is associated with increased epithelial thickness, while expanding the treatment diameter makes the epithelium heal to a normal thickness.83 Focal contacts are formed between the migrating cell and the wound surface substrate. These are first established by lamellopodia and filopodia. These adhesion plaques connect the surface substrate via the cell membrane to the intracellular cytoskeletal fibers.84,85

Fibrin and fibronectin stimulate epithelial cells to release plasminogen activator. The formed plasmin lyses the cell to substrate adhesions, allowing the cells to move forward and form new adhesions. These repeated events stop when the epithelial wound is closed.52 Imbalance in this system in mice leads to defective corneal healing.86 Tenascin is considered to promote migration over the wound surface.87,88 In PRK, the basement membrane is ablated. The advancing cell front produces a new basement membrane. New hemidesmosomes are then established from the periphery to the center of the cornea 4 to 6 weeks after PRK in the rabbit cornea.89,90 Symptoms such as foreign-body sensation, watering, and tenderness on rubbing the eye are sometimes encountered after PRK. These symptoms have been attributed to epithelial adhesion problems. Epithelial breakdown after PRK has been reported to occur in about 3% of eyes.27,28

Inflammatory Cells

Inflammation starts when the wound occurs. Prostaglandin-2 is present in the cornea after fewer then 24 hours39 and subsequently in the aqueous,40 where the BAB has broken down.41,91 The injured corneal cells produce vasoactive mediators and chemotactic factors. These cause local vessels to dilate and the vascular endothelium to express selectin. Polymorphonuclear leukocytes (PMNs) circulating in the blood thereby roll on the cell wall and migrate out of the vessel.92,93 The cells enter the limbal area and tears and then invade the corneal wound. After PRK, PMNs appear to invade the wound mainly via the tears.94 Mononuclear leukocytes reach the wound via the same route a few days later.

The leukocytes clean the wound from debris and bacteria. The monocytes can be transformed into macrophages.95 The leukocytes furthermore produce interleukins. After PRK epithelial closure, the leukocytes disappear. This means that PMNs, by timing and number, influence wound healing, possibly by local production of TGF-β, which in turn may influence epithelial migration and keratocytes. Polymorphonuclear leukocytes 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 corneal epithelial wound heals slower.94 This suggests that the sum of the interleukins, among them TGF-β, thought to be produced by PMNs, stimulates epithelial cell proliferation.

Stromal Healing

In the stroma, underlying the ablated surface, the keratocytes disappear to a depth of about 50 to 200 μm.96–99 The cell death occurs by apoptosis or programmed cell death. Injury-related release of interleukin-1 and the Fas ligand100 from the epithelium mediates keratocyte apoptosis. This type of cell death induces minimal local damage to surrounding cells. The extent of apoptosis disappearance is related to the type of epithelial removal, and transepithelial PRK is associated with comparatively low levels of central corneal apoptosis (Figure 2). 101,102

Figure 2.
Figure 2.:
(Fagerholm) Graphic presentation of how keratocytes disappear under the wound after PRK. The volume is then populated by activated keratocytes. These subsequently normalize in size and number.

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 These activated keratocytes have been associated with increased collagen deposition after PRK.104,105 It has been suggested that the extent of apoptosis is an important determinant of corneal wound healing.106

Other surgical variations in removing the epithelium (e.g., use of a brush or alcohol) have been suggested to improve the outcome after PRK, as has cooling the cornea preoperatively.107–111

The healing reaction between the epithelium and the superficial stroma continues after epithelial coverage. These events eventually decide the refractive outcome.

When a small-diameter treatment is used, a thick epithelium sometimes contributes to a myopic outcome.112 With enlargement of the treatment zone, epithelial 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 ablation profile is used, the outcome depends on the healing 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 hypertrophic 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 subepithelial 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 microscopic level (Figure 3). Newly formed hyaluronan,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 subsequently takes on the light-microscopic appearance of normal stroma.117

Figure 3.
Figure 3.:
(Fagerholm) Microradiogram of a freeze-sectioned, freeze-dried rabbit cornea that had PRK of –5.00 D and 4.5 mm in diameter. Four weeks after surgery, a dark zone (z) is found under the epithelium (e) (A). The dark areas indicate high water content. The stroma is brighter as the higher dry mass absorbs the x-rays (B). The zone that contains hyaluronan is subsequently organized by invading keratocytes that produce collagen and regular glucose aminoglycans.

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 determine the reactive outcome.

The disappearance and return of stromal keratocytes can be followed using the confocal microscope. The activated keratocytes scatter light and are more evident102; as they reappear in the wound area, they may contribute to haze.

The formation of the subepithelial volume and its subsequent consolidation corresponds to the granulation tissue formation, the production of new matrix, and the remodeling of this matrix in the skin wound.

The contraction phase of the new matrix seen in corneal incisional wounds122 seems to be an abortive phenomenon in PRK wounds. It has not been documented clinically to my knowledge. The contraction phase is accomplished by activated keratocytes or fibroblasts containing myocontractile elements, myofibroblasts. The contraction phase is modulated by a secreted protein that is acidic and rich in cysteine (SPARC).123 After PRK, the SPARC protein is expressed at the basal aspect of the recently healed epithelium during the first week after surgery in rabbits.124

Myofibroblasts have been associated with solid haze or scar formation. This resistant, dense haze is sometimes seen in eyes with high myopia after PRK. It is also thought to occur when corneas with pre-existing scars are treated with phototherapeutic keratectomy or a PRK retreatment of radial keratectomy. The myofibroblasts may already exist in these scars.

It has been shown that TGF-β initiates the activation of keratocytes into myofibroblasts.125 Therefore, neutralizing antibodies against TGF-β have been used to reduce haze formation in rabbits after PRK.125,126 Mannos 6-phosphate, a competitor for receptor binding with TGF-β, has been evaluated for the same purpose.127

Large-diameter ablation profiles are expected to heal with little or no new stromal haze formation. With this in mind, the historical division of patients into nonresponders, normal healers, and aggressive responders13 can now be reduced to normal and aggressive responders. A hyperopic outcome is likely to be caused by an erroneous refraction, at least in eyes with low myopia. Aggressive responders are still found in all grades of preoperative myopia. A high concentration of EGF in tears preoperatively may thus be a way to identify the aggressive responders.74

If new stroma is formed under the epithelium, it will develop from a high-water-content zone to a solid tissue containing activated keratocytes and all the collagen components and ECM components that exist in the normal stroma. The new stroma will not contain the regularly arranged collagen-containing lamella.128 However, the stroma will be clear, although some collagen fibril irregularity will remain. The increased density of activated keratocytes in the wound area will eventually, probably by apoptosis, return to normal density.

Matrix metalloproteinases are active in remodeling the scar after corneal injuries. Their action is balanced by tissue inhibitor metalloproteinases (TIMPs), which may guard against excessive ECM breakdown. Samples taken at reoperation from corneal wounds 20 or 30 months after PRK expressed mRNA for TIMP1 but not MMP-2 or -9.129 Both MMP-2 and -9 were, however, expressed in the epithelium of the rat cornea after PRK. In the rabbit cornea, a synthetic inhibitor of matrix metalloproteases was shown to delay epithelial healing.130 Matrix metalloprotease (gelatinase B) expression was found upregulated in both the epithelium and the stroma after PRK.131,132 A synthetic inhibitor of metalloproteinases has been found to reduce corneal haze after PRK in rabbits as well as the synthesis of type II collagen.133

Role of Postoperative Steroids

Steroids are known to delay wound healing in the cornea. They reduce wound infiltration of leukocytes134 and limit the subepithelial deposition of collagen and ECM135,136 including hyaluronan.115 Epithelial and keratocyte migration and proliferation are also suppressed.

In prospective clinical trials, the influence of steroids on refractive results is significant. However, after cessation of the drug, the difference often diminishes or disappears.

Steroids are able to suppress the movement and reparative efforts of activated keratocytes and, typically, haze formation is shifted until 1 or 2 months after the topical steroids are stopped.29,137 This means that some regression can occur after cessation of the drug and that stable refractive results cannot be counted on until a few month after steroids have been stopped.

The development toward large-diameter flat-profile treatments has made postoperative steroids unnecessary in eyes with up to –5.00 diopters (D) of myopia. In eyes with higher myopia, the steep type of treatment required necessitates steroids138 or the choice of another technique such as laser in situ keratomileusis (LASIK).

When evaluating studies on the possible effect of steroids, it is important to remember that the drug exists in various forms. The degree of potency and penetrability varies greatly.

Corneal Nerves

The corneal nerves are ablated when PRK is performed. As soon as 7 days after surgery, generating nerve fibers can be identified in both the human and rabbit cornea.139

The morphology of the regenerating corneal nerves, which is not restored to normal,140 can be studied with the confocal microscope. Corneal sensitivity is decreased in the operated area about 1 month after PRK.39,141,142 Ablation depth and degree of haze will influence the recovery of sensation, which is usually restored after 1 to 3 months.39 The clinical data on recovery of sensitization correlate well with histologic findings.140,143

It is well known that denervation somewhat impairs corneal wound healing. However, the influence of corneal nerve damage on corneal wound healing after PRK is not understood. This is different in LASIK,144 after which the morphology of the regenerating nerves are closer to normal.

After PRK, calcitonin gene-related peptide is released in excess from damaged nerves as assessed in tears. The substance may promote wound healing. It is also a potent vasodilator.145,146

Late Regression

Late regression is a reactivation of the wound-healing process after PRK. It is a rare phenomenon that seems to occur more often after small-diameter laser treatment. Typically, the treatment is initially successful and the cornea is clear. Over a few days, visual acuity worsens and the eye becomes myopic (–1.00 to –3.00 D). Best corrected visual acuity also drops several lines because of intense haze in the treated area.147

Topical steroids in the form of dexamethasone 0.1% given 3 to 5 times a day usually result in rapid improvement, especially if given soon after the beginning of the regression. If the eye responds to steroids after 2 to 3 weeks, slowly tapering the steroids helps resolve the thick haze. My impression is that late regression occurs after sun exposure when skiing or sailing. Experimentally, it has been possible to provoke a healing reaction in PRK-treated rabbits by exposure to ultraviolet light.17,18 Regression can also be provoked by pregnancy15 and trauma.19 Clinically, late regression can occur up to 2 years after the initial surgery. It should not be confused with postponed haze formation and regression, which occur 1 or 2 months after the postoperative steroids have been tapered.

Haze

The haze phenomenon30 has interested surgeons and researchers perhaps more than deserved. Haze is clearly seen at the slitlamp but only rarely experienced by the patient. The phenomenon has, however, been a driving force in finding out what happens in the wound.

Haze is a normal companion to corneal wound healing and usually subsides after 1 to 2 years.29,148 With small-diameter treatment or in high myopia, the haze can persist. One debate has been whether haze should be regarded as a scar or something else, a passing phenomenon on the way to a clear cornea. It can be both.

The source of haze, or light scattering in the wound, has been attributed to the interface between the epithelium and stroma or from the keratocytes in the stroma underlying the wound.

Confocal microscopy has contributed to the knowledge about haze. To some extent, it has been possible to separate the contribution of subepithelial deposits from that of keratocytes.149 In the subepithelial zone, several substances are produced such as glycosaminoglycans,150,151 fibronectin, laminin, type III collagen,152 keratin sulfate, and hyaluronic acid.114,115 This zone may scatter light because of an irregular structure that does not possess the refractive properties of the normal cornea stroma. The subepithelial interface also accumulates a large amount of water that co-localizes with the hyaluronan.114 The sharp demarcations of these zones creates sharp shifts in refractive index in these areas, causing light scattering. The resolution of the technique used to assess water content in the cornea is slightly lower than that of light microscopy. If the shifts in refractive index reach between lamellae, it would further induce light scattering by disturbing the structure.

Keratocytes disappear in the stroma under the wound after PRK.111 However, they rapidly repopulate the area and significantly increase in volume.159 They also increase their reflectivity,102,153,154 which contributes to light scattering in the area. The keratocytes repopulate the wound area to a much greater density than in the normal corneal stroma.29 The density then decreases to normal levels after about 6 months. The altered keratocytes are, to various extents, changed into myofibroblasts that deposit collagen and in the skin wound cause wound contraction. The action of these myofibroblasts is thought to cause the type of dense haze that is more or less persistent and that could be defined as scar tissue.

Interleukins are active in attracting human keratocytes. In a collagen gel model and using a Boyden blind-well chemotaxis chamber PDFG+BB, EGE, TSF-α, IGF-I and TFG-β increased keratocyte chemotaxis.155,156

Role of PRK in Refractive Surgery

Photorefractive keratectomy is an attractive refractive surgery technique. The procedure is fast and easy to perform. For the technique to maintain or improve its position in refractive surgery, the drawbacks must be addressed. These drawbacks do not seem insurmountable. The long time to obtain stability in the healing process is worrisome, as is the possibility of provoking renewed healing reactions 1 to 2 years after surgery.

It should be possible to identify aggressive responders before surgery. To be successful in higher myopia, pharmacological means to control wound healing are needed. Several possibilities have been described including antibodies to TFG-β,120,122 mannos 6-phosphate,123 and synthetic inhibitors of MMPs.123,130

Interferons can inhibit many aspects of the fibrotic response of fibroblasts including chemotaxis,157 proliferation,158 and collagen production.159 Interferon-alpha 2 inhibits fibroblast glycosaminoglycan production and increases collagenase production.160 Interferon-alpha 2 applied topically reduces the corneal haze in rabbits after PRK.161

Mitomycin-C as an adjunct to topical steroid therapy reduces the new production of collagen in rabbit corneas after PRK compared to the use of steroids alone. In another study of rabbits, mitomycin reduced scar tissue but not haze.162 Topical application of basic fibroblasts growth factor reduces the amount of haze in rabbits.163

Highly reactive free radicals are liberated during PRK. Intraoperative applications of antioxidants in rabbits have been tried to evaluate the effect on wound healing. Both dimethylsulfoxide and superoxid dismultase were applied, reducing the degree and extent of postoperative haze in the treated groups.164

There are many ways to influence wound healing to reduce its harmful consequences. The ideal way is to select patients before surgical intervention to a suitable technique. Improvements in the surgical technique have aimed at creating as little reactivity in the cornea as possible. The stromal ablation performed at the time of surgery should reflect, via the epithelium, the new permanent refractive surface. Stopping corneal reactivity to surgery in all patients may seem difficult in view of the extremely complicated wound-healing mechanisms. However, fewer than 10 years ago, steroids were the only option; since then, knowledge has grown exponentially.

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