Corneal wound healing

Pharmaceutical modulation of the healing process

Photorefractive keratectomy (PRK) and laser in situ keratomileusis (LASIK) are currently the most popular forms of laser based vision correction available. The outcome of surgery is based on the corneal wound healing response that follows. Due to the invasive nature of the techniques, the delicate wound healing process in some patients is disrupted. This leads to complications after surgery such as corneal haze, leading to changes in visual performance. Pharmaceutical modulation of this process is currently being investigated to achieve better results in wound healing following surgery. 

Introduction

Vision correction is usually carried out using glasses or contact lenses. As time has passed over the years and technical advances have improved, laser based vision rectification has developed and is now quite a popular method of myopia and hyperopia correction. Vision improvement is based on altering the shape of the cornea to allow rays of light to focus correctly on the retina. Optical measures such as laser eye surgery enable this repair to be permanent. PRK and LASIK have thus shown to be currently the most popular methods of surgery. The drawbacks are however, the complications which result following surgery due to the problems associated with the wound healing process after surgery. Pharmaceutical modulation of this wound healing response has been applied to correct any complications which may arise following surgery.

PRK and LASIK Surgery

Photorefractive keratectomy (PRK) and laser in situ keratomileusis (LASIK) are excimer laser based surgical procedures involved in the correction of vision, caused by refractive errors in the cornea (Barnes et al, 2004). PRK uses surface ablation, whereas LASIK involves excimer ablation carried out underneath a lamellar flap of corneal tissue, this allows the Bowman’s layer and epithelium to be preserved, resulting in refractive stability, minimal pain, and rapid visual recovery. For these reasons LASIK is preferred over PRK (Dastjerdi et al, 2002).

In 1983 the first use of the excimer laser for making cuts on the cornea was established, thus suggesting the use of the laser for corneal refractive surgery to correct errors in corneal curvature. PRK was first developed, involving the use of the laser to ablate the corneal surface in a controlled manner, and in turn correct the corneal error. Good results were discovered when it came to the correcting of low or moderate grade myopia (short sightedness), however, the procedure was found to have a number of drawbacks, the most significant being the development of haze in the central cornea, regression of its effect, and delayed wound healing (Bansal et al, 2002). Due to the continuing problems connected with PRK, LASIK development then followed.

The PRK technique involves the removal of corneal epithelium through mechanical means by using a blade or a spatula, or chemically using alcohol or topical anaesthetic agents, or by photoablative de-epithelialization using the excimer laser. Ablation of the central cornea using the excimer laser is computer controlled, so as to achieve the required steepening or flattening of the cornea. Following this the epithelium grows over the cornea to cover the defect in a few days. Stromal wound healing takes place over a period of a few months which delays the stabilisation of the end result of refraction (Bansal et al, 2002).

In contrast to PRK, LASIK involves ablation of the midstroma of the cornea, in contrast to the surface, which occurs during PRK, after raising a flap of superficial stroma. This surgical technique involves firstly, the lifting of a flap consisting of the epithelium, Bowman’s membrane and anterior stroma using a microkeratome, this is a devise which can cut at a precise depth. Ablating the stromal bed in the same manner as in PRK occurs next, after which the flap is carefully repositioned back onto the corneal surface. The flap sticks to the stromal bed because of the suction force that is created by a corneal endothelial pump. The outcome in terms of refractive recovery is better than that of PRK due to the little amount of stromal healing that needs to occur following the LASIK procedure (Bansal et al, 2002).

The laser that is used for both types of surgical procedures PRK and LASIK is termed the Excimer laser. The laser contains a gas mixture known as a lasting medium, which consists of a mixture of three gases: an inert gas (argon, krypton or xenon), a halide gas (fluoride, chloride or bromide) and a buffer gas (helium or neon). The buffer gas is important in the mediation of the transfer of energy. When the molecules of these gases are exposed to high powered electrical discharge they become excited and combine to form a rare gas-halide molecule. This rare molecule in turn can emit laser energy at different wavelengths and ultraviolet wavelengths can also be generated by the laser. This however, depends on the on the gas mixture used within the laser. The laser is applied to different areas of the cornea depending on what type of corrective surgery is required. For the correction of myopia, the laser beams are delivered in such a manner, that the central part of cornea gets more ablation than the periphery, which in turn enables the cornea to flatten. In contrast, for hyperopia (long-sightedness), lasers steepen the cornea through ablation of the periphery more than the centre. The lasers may also be applied for the correction of astigmatism, whereby ablation is carried out at one meridian, this alters the amount of stromal tissue removed and the area of tissue ablated, leading to a desired amount of refractive change (Bansal et al, 2002).

Corneal Wound Healing

The cornea is a tough and transparent membrane (figure 1), it forms a part of the outer wall of the eye, and it functions as an optical element and a protective barrier for the contents of the eye. A delicate balance between cellular proliferation, differentiation, motility and apoptosis provides eye integrity, homeostasis and is important for wound healing. The corneal epithelium, stroma and endothelium, as well as the adjacent tear layer and nerves, all provide growth factors to maintain corneal function and contribute to the maintenance of surface smoothness (Wilson et al, 2001; Klenkler et al, 2004).

Successful vision requires the cornea to remain transparent and along with the ocular lens to correctly reflect light onto the retina. Therefore the epithelial layer needs to undergo continuous renewal to maintain corneal transparency, also maintenance of the endothelial fluid transport activity is required to maintain stromal thinness. Secondly, the corneal epithelium forms a smooth refractive surface through its interaction with the tear film and it forms a protective tight junctional barrier which prevents a decrease in the fluid transport out from the stroma, as well as preventing pathogens from entering the eye. To maintain such a function, epithelial cells are specialized to form tight adherences between each other and to the basal lamellae (Lu et al, 2001).

Injury to the cornea disrupts the dynamic and accurate homeostasis developed by the different cell types in the cornea. The wounding of the corneal epithelial surface, leads to a breakdown of the epithelial junctional integrity due to the loss of part of the epithelial layer during damage. The loss of these cells causes a malfunction in cell membrane permeability and selectivity, which cannot be restored until after epithelial cells have migrated from the periphery during the healing process. Loss of epithelial integrity also leads to the cornea interior becoming susceptible to infection by invasive pathogens. (Lu et al, 2001)

Figure 1: Cross section of human cornea at 160X (Mathur, 2005)


Wounding of the cornea in turn, leads to a complex cascade of processes which finally lead to healing of the wound and restoration of vision. These processes are mediated through the interaction of various cell types, including epithelial cells, keratocytes of the stroma, corneal nerves, lachrymal glands, tear film, and cells of the immune system, which are involved in cellular proliferation, migration, differentiation, apoptosis and intercellular communication. These processes restore the structure and function of the cornea in most situations (Wilson et al, 2001; Klenkler et al, 2004). The complex cascade is also regulated by numerous cytokines, other factors and their receptors, it also involves the participation of major matrix components such as collagens and proteoglycans. Of the 19 known collagen types, the adult mammalian cornea expresses at least 10 of them (Zieske, 2001).

This cascade of healing can be separated into continuous phases, involving the movement of superficial cells to cover the wounded surface, cell proliferation, and stratification for the redevelopment of multi-cellular layers of cells. However, before the onset of the healing cascade there is a lag phase during which the cells change their metabolic status, also during the lag phase a large amount of cellular reorganization and protein synthesis occurs (Lu et al 2001). Healing of the epithelium may be divided into three parts, part one involves epithelial wound repair, whereby epithelial cells flatten and migrate as an intact sheet to cover the wound. Part two involves the division of cells distal to the wound in order to repopulate the cells lost, cell stratification and differentiation of epithelial cells also occurs. In the final part, hemidesmosomes are formed as well as the synthesis and reassembly of the extracellular matrix. It has also been identified that a variety of other matrix components are synthesized and deposited in response to wounding such as fibronectin, forming a “provisional matrix” before the start of part one of repair (Zieske, 2001).

Stromal wound healing also occurs in phases. Firstly, keratocytes next to the area of epithelial damage undergo apoptosis, this cell death thereby initiates the entire wound healing response. Next, the keratocytes immediately neighbouring the area of apoptosis proliferate to repopulate the wound area. In this second phase, keratocytes transform into fibroblasts and move to the wounded area, these cells synthesise and deposit matrix proteins at the migration site. In the final phase, fibroblasts are transformed into myofibroblasts, which are involved in contracting the wound. This may take up to a month to occur, after which stromal remodelling occurs (Zieske, 2001).

 

Figure 2: The processes involved in wound healing of the cornea (Klenkler et al, 2004).


The complex cascade of wound healing is dependent on the production of numerous factors which regulate the process (Figure 2). Within a few minutes following wound development the first response of the corneal cells is the secretion of cytokines such as interleukin 1 (IL-1) and tissue necrosis factor a (TNF-a), also known as ‘‘master
regulators’’ of the response, by the wounded epithelial cells, which leads to stromal cell apoptosis (Wilson, 2001). Following this, keratocytes proliferation begins within 12-24 hours and continues for several days, approximately 7 days post injury, these cells then produce elevated levels of factors such as, keratinocyte growth factor (KGF), epithelial growth factor (EGF) and hepatocyte growth factor (HGF) which stimulate epithelial cell proliferation as well as cause detached epithelial cells to migrate to the wound. It has been demonstrated that keratocytes apoptosis and necrosis also continue for at least a week after the initial wound formation. Also, a few days following the induction of apoptosis, apoptosis, necrosis, and mitosis wind down and a quiescent state is restored (Wilson, 2001).

Expression of platelet derived growth factor (PDGF) from the epithelial basement membrane also occurs to promote movement of fibroblasts to the wounded site. The corneal epithelial cells also release tissue plasminogen activator onto the surface of the eye, resulting in the production of plasmin which is thought to activate TGF-b, which in turn induces proliferation and migration of corneal stromal fibroblasts. The epithelial cells can also communicate with the fibroblasts, this positively affects epithelial tissue recovery through the production of further growth factors. These events occur very quickly, within hours of onset of injury to re-establish barrier function over the wound. The production and release of PDGF and TGF-b from the epithelium into the stroma, and an increased presence in tears also enables the stimulation of stromal cell proliferation. The presence of TGF-b found in the later stages of stromal healing, inhibits HGF and KGF expression, this stops excess epithelial cell proliferation (Klenkler et al, 2004).

Eight hours following injury, a provisional fibronectin matrix (composed of actin filaments and focal contacts) is synthesised and accumulates at the site of the wound. Corneal epithelial cells proliferate at the injury site and also produce factors which promote cell to cell adhesion. Once confluence of cells is developed, they are then promoted to differentiate forming a stratified epithelium. Following the development of this epithelium the fibronectin matrix disappears and the normal basement membrane composition of collagen and laminin is replaced (Klenkler et al, 2004). Remodelling of the collagen matrix of the stroma also occurs in order to eliminate scar tissue, after which the epithelium returns to a normal thickness (Wilson, 2001).

Beginning 12-24 hr following injury, an influx of inflammatory cells into the cornea from the limbal blood vessels occurs. This occurs following the activation of the different growth factors which bind to receptors on keratocytes, which in turn stimulate production of factors chemotactic to inflammatory cells. Immune cells which eliminate debris and microbes that may breach the injured surface and gain entry to the corneal stroma thus move to the site of the wound, they also release PDGF enabling the mediation of the healing process (Wilson, 2001).

After the injury has been established and healing processes have occurred, in the weeks and months after this process the cornea then returns to a normal state, inflammatory and myofibroblast and fibroblast cells are eliminated through apoptosis and the stroma is restored. The expression of growth factor receptors and proteins also return to the levels they were before wound development. The stromal re-modelling process can possibly carry on for years and result in the removal, at least in part of the stromal scars. Some studies have indicated that apoptosis of some stromal cells can also still be detected at a very low rate approximately three months after the initial injury (Wilson, 2001).

The Wound Healing Response Following PRK and LASIK
The complex wound healing cascade, as described, is activated during refractive surgery, such as PRK and LASIK. The refractive results, as well as other aspects of quality of vision, depend on the wound healing response following PRK and LASIK to be as close to the normal cascade as possible (Fagerholm, 1999). However, complications leading to changes in ocular surface and laminar structure from the norm, in turn leading to changes in the scattering optics of the eye and finally visual disturbances, do occur following surgery. This is due to a number of reasons, which may all be traced back to defects in the healing process following surgery, such as, variable stromal remodelling, epithelial hyperplasia and regression and haze. This also leads to variation in the clinical outcome of surgery in different patients as well as differences in the outcome of the two procedures. The main reason for the differences in wound healing following PRK and LASIK may be attributable to the difference in the procedures. In LASIK the epithelium is preserved, whereas in PRK, lasers are passed through the epithelium causing damage to it (Wilson et al, 2001). 

The first stage in the normal wound healing process is the apoptosis of keratocytes, triggered by damage to the cornea. The response seen following epithelial injury during PRK and LASIK represents the triggering of this wound healing process. With regards to PRK, this process occurs straight away underneath the epithelium, in LASIK however, apoptosis of keratocytes occurs at the interface further away from the epithelium, which may lead to epithelial hyperplasia (Wilson et al, 2001). Also in LASIK performed with a thin flap, keratocyte apoptosis appears to occur closer to the surface of the cornea, which leads to wound healing processes occurring nearer to the epithelium similarly to PRK (Kuo, 2004). The subsequent processes in the cascade also occur at different sites for both procedures. Therefore in PRK, the production of cytokines by the myofibroblast cells, as well as initiation of epithelial cell differentiation and other stages in wound healing all occur in closeness to the overlying epithelium (Wilson et al, 2001). This leads to differences in wound healing depending on which procedure is used, as well as the efficiency of the healing process. The grade of myopia and hyperopia also contributes to how much ablation is needed and so how much damage is done, leading to differences in the healing response. Higher levels of keratocyte apoptosis, keratocytes proliferation, and myofibroblast transformation are found in patients with higher grade myopia or hyperopia following surgery (Mohan et al, 2003). 

Alterations to the apoptosis process after injury during PRK and LASIK, in contrast to normal wound healing, have been shown to cause clinical differences, regression and haze in patients as well as other complications. These alterations were found to be attributable to diminished keratocyte apoptosis (Bilgihan, 2002). One study showed that, marked keratocyte apoptosis extending to 50-75 micrometres of corneal depth occurs in PRK with the cells uniformly affected near the anterior stromal surface, however, apoptosis after LASIK shows a different distribution and is found at the edge of the microkeratome cut (Bansal et al, 2002). Also a significantly greater number of apoptotic keratocytes, proliferating keratocytes, and myofibroblasts were seen in the PRK corneas, compared to the LASIK corneas (Mohan 2003).

As wound healing resumes, stromal cells are replenished through mitosis and migration of remaining keratocytes, some of which are activated and are transformed into myofibroblasts. In PRK, findings show that this simple process is defective and stromal hyperplasia occurs, which can lead to sub-epithelial haze. Also it has been found that gaping wounds and wounds that remove the basement membrane result in the production of more myofibroblasts than wounds that do not get to the basement membrane (Kuo 2004). With regard to this phase in the wound healing process, it appears also that the total number of proliferative cells after surgery were much greater for eyes undergoing PRK for high myopia, compared to that eyes undergoing LASIK. This may be due to the fact that, in the larger wound a higher level of epithelial stromal interactions occur leading to more myofibroblasts (Mohan et al, 2003).

Following both forms of surgery another change in the regular pattern of healing has been observed, hypercellularity of keratocytes occurs in the anterior area of the cornea and persists for six months to one year. These cells show intense metabolic activity, they synthesize new collagen and extra cellular matrix, they produce increased amounts of KGF and HGF that modulate epithelial functions leading to epithelial hyperplasia. The presence of the abnormal extracellular matrix and the disturbed arrangement of fibrils seems to continue for up to a year. Eventually the stroma returns to a normal pattern of components. However, type III collagen may remain elevated by 18 months following surgery leading to post operative haze (Bansal, 2002). Photorefractive keratectomy and laser in situ keratomileusis can also induce or exacerbate dry eye after surgery (Ang et al, 2001).

A number of alterations occur in the normal healing response of the cornea following LASIK surgery, they differ from those induced by PRK due to the mechanism of surgery. However, serious complications after LASIK are infrequent and damage to the retina is rare, also as the sheet of epithelium is cut and lifted before laser surgery, the epithelial layer is not disturbed following the procedure diminishing the need for stromal remodelling (Arevalo et al, 2004). However, at the area where the microkeratome cuts through the epithelium to enter the stroma, hyperplasic epithelial plug forms whereby, the epithelium remains flat in the centre but becomes 8-10 layers thick at the edge of the ablated area. After around five months the plugs do get smaller. Although, this could in turn lead to epithelial ingrowth across the stromal interface and if extensive, it may lead to melting of the corneal flap. Haze could also develop if there is a deposition of basement membrane components at the site of the ingrowth. Bending of the corneal flap may cause microfractures or microfoldings in the Bowman’s layer of the cornea. It has been noted that quick wound healing and minimal tissue proliferation do occur after LASIK, due to the lifting of the epithelium (Bansal, 2002).

LASIK surgery also involves infiltration of the laser deep into the cornea, this may lead to a great number of collagen fibrils being damaged, which may thus have an effect on corneal biomechanics (Baldwin et al, 2002). Retinal tears and damage to the vitreous and
retina from the pulsed energy applied to the cornea may also occur but are found to be rare (Arevalo et al, 2004).

The biggest changes in contrast to normal wound healing occur at the wound edge, fine fibres have been demonstrated along the incision, activated keratocytes have also only been found at the wound margins, disorganized extracellular matrix may be deposited around the plug nine months after surgery, these events lead to scarring occurring at the edges of the epithelial plug. However, no activated keratocytes have been found past 3 months after LASIK. These effects have been shown to clear six months beyond surgery (Bansal, 2002). Epithelial trauma induced by the use of the microkeratome may lead to chemokine production by the keratocytes, in turn inducing an inflammatory response which may lead to abrasions in the cornea, these appear to disappear 6-8 months following surgery (Wilson et al, 2003). Epithelial damage of the corneal flap may also occur after LASIK due to severe dehydration or mechanical injury, this may cause excessive wound healing, which may lead to LASIK haze (Nakamura et al, 2005).

After PRK surgery, similarly to LASIK, a number of changes to the normal corneal wound healing process occur, more so with regards to PRK. This may be due to ablation of the cornea through the epithelial surface, which leads to damage of both the epithelium and the stromal layer. Immediately after surgery, a pseudomembrane of epithelial cells is laid down over the surface of ablation, this leads to the disappearance of keratocytes under this membrane, which in turn reduces the number of keratocytes in the anterior stroma. This imbalance of cells in the cornea leads to changes in the refractive optics of the eye, causing visual disturbances (Bansal et al, 2002).

After PRK surgery, epithelium wound healing takes a period of months to complete, however a thin temporary epithelial layer does cover the wound in approximately three to five days. As normal healing progresses it may become exaggerated, the epithelium thickens and may become hyperplastic. The deeper the ablation at the site, the more there is a likelihood of this occurring, this leads to a reversion in the flattening of the cornea, changing its shape and laminar structure (Fagerholm et al, 2000).

The basement membrane also heals following surgery, it regenerates over a period of six weeks, and however, regeneration may lead to focal discontinuation and duplication. Unlike during LASIK, with PKR the Bowman’s layer is also damaged after surgery. It may be partially or completely removed depending on the depth of ablation, however, it does not appear to regenerate completely. This response is responsible for corneal scarring in the area where the layer was removed. Wound healing of the stroma carries on for a number of months to years, as normal healing continues alterations begin to take place in keratocytes, this leads to disorganisation of the anterior stroma and deposition of newly synthesised material, such as collagen (Bansal et al, 2002). It appears that minimal repair and replacement of stromal tissue is needed following surgery to reduce the negative effects that may be caused by excessive healing. This also will result in an encouraging refractive outcome and improvements in vision. The problems arise when in some patients healing becomes prolonged and inappropriately precipitated (Baldwin et al, 2002). 

It has been suggested that hyperplasia and stromal remodelling after PRK are modulated through cytokine-mediated communication between the wound healing cells of the stroma and the overlying epithelium and it is possible that these interactions would be more pronounced in corneas that have undergone PRK, where these interacting cells are in immediate proximity to one another. Less remodelling and hyperplasia occur after LASIK as the overlying epithelium is separated from the stroma being treated (Tanaka et al, 2000).

One of the most common complaints following PKR is the appearance of corneal haze. The development of haze reduces visual function and the onset been reported to vary from between 2 days to 2 months. Haze intensity appears to peak for one to six months and resolves at the most after 18 months following surgery. It is caused by epithelial surface irregularity, which is associated with epithelial closure and presence of tear film debris. There is also an increase in the number and activity of keratocytes with altered morphology, which act as foci for scattering of light, leading to visual disturbances. Patients with haze also show clumping of the collagen lamellae of the anterior stroma, the normal pattern of which was not maintained (Bansal 2002). Following healing after PRK histopathological studies show the presence of a number of substances in the sub-epithelial area. Factors such as, glycosaminoglycans, fibronectin, laminin, type III collagen, keratin sulphate, and hyaluronic acid, fibronectin, laminin, and proteoglycans have been found which make up the stromal extracellular matrix. The presence of the molecules in an incorrect irregular structure cause an alteration in the normal scattering of light, thus the refractive properties in the normal corneal stroma are not present. This effect is exacerbated by the disappearance of keratocytes underneath the wound and an increase in their reflectivity, which causes changes in light scattering. These cells also change into myofibroblasts, the degree of the stromal haze detected has been shown to correlate with the number of these cells and the amount of new extracellular matrix generated (Baldwin et al, 2002; Nakamura et al, 2005).

Due to the alterations in the normal wound healing process after both PRK and LASIK, which lead to changes in the normal structure of the corneal surface as well as the laminar structure, which in turn lead to visual disturbances, a number of complications have been identified. Examples include, “glare, halos, difficulty with night driving, ghosting, and shadows,” refractive errors or irregular astigmatism related to a decentred ablation and deeper myopic and/or astigmatic ablations (Jabbur et al, 2004). One study showed that the most common complications after refractive surgery in general, were overcorrection (30.4%), irregular astigmatism (29.8%), dry eyes complication (63.6%), followed by irregular astigmatism (29.8%), glare (26.1%), difficulty with night driving (40.9%) and overcorrection (31.8%) and corneal haze (16.7%). In the 22 eyes that had PRK corneal haze was the most common complaint (Jabbur et al, 2004).

Different patient heal in different ways, a number of patients undergo normal wound healing following surgery and do not experience any complications, some experience complications which fade over time. It has been postulated that a number of factors determine the effect of PRK or LASIK on a patient. Successful visual performance following surgery depends on how the corneal wound heals after photoablation, there is a great variability in healing of the wound in different eyes (Bansal et al, 2002). Heredity may contribute to excessive healing or non-responsiveness as it has been noted that if 1 eye regresses, the other eye is prone to do so. Another factor is trauma to an eye that has had PRK could probably initiate another wound healing response, leading to haze and regression (Fagerholm, 2000). One study showed differences in stromal cell apoptosis, keratocyte proliferation, and the numbers of myofibroblasts at a given time point in a given surgical group. They theorised that the factors which affect wound healing in different patients include, localization of the wound healing response in the cornea, biological variability in the healing response between individuals and the variation in surgical procedures (Mohan 2003).

Pharmaceutical Modulation of Corneal Wound Healing
The main goal of treatment of patients with different pharmaceutical agents is to control the wound healing response through application of agents to the eye before surgery. The agents would in turn minimise but not eliminate the response, as most of the complications following surgery are due to an excessive wound healing response. For example if an agent was applied minimising the initial apoptosis of keratocytes the rest of the response would also be attenuated. However, due to the complexity of the response this simple solution may not be sufficient (Wilson et al, 2001). It has been noted that the topical application of vitamin E immediately after surgery can prevent keratocyte apoptosis, this has only been used in animal studies so far (Bilgihan et al, 2001).

The main agents in use for the maintenance of the wound healing response are topical corticosteroids. They are used after refractive surgery as they inhibit activated keratocytes, decreasing their cellular activity and collagen synthesis. They have been shown to reduce haze and regression in patients but their effect is limited to the duration of their use (Bansal 2001; Baldwin, 2002).

The manipulation of wound healing through attenuation of growth factors appears to hold some promise. For example the use of neutralizing antibodies specific to a growth factor could prevent its binding to the receptor sites of target cells. This method has been used a number of investigators to block the effect of TGF-b, in the development of decreased stromal haze use (Baldwin, 2002; Saika, 2004). Another option being studied is the use of cytokine receptor blockers, such as mannose-6-phosphate which acts through competition with TGF-b at its receptor site. Preliminary trials with the use of this agent have shown preservation of the normal architecture of the eye and the absence of haze. Application of agents for the inhibition of post signalling processes also holds some promise. Studies have shown that application of growth factors topically to the eye does lead to attenuation of the healing response. For example enhanced epithelial wound healing was shown in a number of studies following topical use of EGF and FGF, HGF has also been implied in wound healing attenuation (Bansal 2001; Baldwin, 2002; Carrington et al, 2005).

Cytotoxic agents like mitomycin C agents have also been used to reduce keratocyte activity after PRK, their safety was doubtful but further studies have shown that it is a safe and successful method in preventing recurrence of sub-epithelial fibrosis after surgery (Majmudar, 2000; Bansal, 2001). A very recent study has indicated the success of the use of this agent, whereby, topical application of 0.02% mitomycin C was shown to reduce haze formation in highly myopic eyes undergoing PRK (Gambato, 2004). Topical application of amino acids have also been tried, results suggest that there is an improvement in re-epithelialisation when an increase of serum and tear film amino acids is obtained through oral administration (Vinciguerra et al, 2002).

Recently Reviglio et al, 2003, suggested the use of Fluoroquinolone (antibacterial) eye drops on the re-modelling of the corneal extracellular matrix by increasing expression of matrix metalloproteinase in the cornea, which degrade interstitial corneal collagens. Fluoroquinolone was found to induce the expression of MMP-1, MMP-2, MMP-8 and MMP-9. This appears promising however further work is required on the use of this agent.

Studies have also shown the success in application of steroids and NSAID’s in the reduction of inflammation following refractive surgery, due to their influence on the arachidonic acid inflammatory pathway in the cornea. Steroid application showed attenuation of the early inflammatory, which led to decreasing haze and myopic regression, especially in high myopic patients. Patients who received NSAID treatment in the first days after PRK, showed a significant difference in haze amount after 12 months (Vetrugno et al, 2001).

Conclusion

Laser refractive is now the most common technique in the correction of myopia and hyperopia. PRK and LASIK are mostly applied in vision correction. In a number of patients having surgery vision correction is successful and complications are small and resolve quickly. However, a number of patients also suffer form a range of complications following surgery. PRK appears to result in far more complications than LASIK, this is primarily due to the fact that the laser causes damage to the epithelial layer as well as the stroma of the cornea. With LASIK surgery the epithelium is preserved in the form of a flap, thus damage is minimal and focussed around the incision where the flap was generated. The normal wound healing process is a complex cascade of processes involving regulation by cytokines. Damage to the cornea following surgery initiates the wound healing process however, due to the intensity of the damage in some patients, the wound healing processes are intensified as well as irregular. This in turn leads to both short term and long term damage to the corneal surface and the laminar structure, which causes changes in refractive optics and visual disturbances. Due to the occurrence of these complications efforts are being made in the use of pharmaceutical agents to modulate the healing process. Numerous attempts have been effective, for example the use of corticosteroids or cytotoxic agents to reduce keratocyte activity. However, further work is required to develop agents which show no side effects and that are very efficient in the modulation of wound healing. Methods to reduce apoptosis, such as use of caspase inhibitors are currently being developed. Further developments in the field of laser refractive surgery are required, leading to success in the vision correction industry. The development of Laser sub-epithelial keratomileusis (LASEK) is a relatively recent technique which combines the advantages of PRK and LASIK (Dastjerdi et al, 2002; Barnes et al, 2004).

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