Methods for promoting healing of corneal resurfacing wounds

Details Methods for promoting healing of corneal resurfacing wounds Methods for promoting healing of corneal resurfacing wounds

1999-10-19

2003-04-01

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Web, sheet or filament bases; compositions of bandages; or...

C424S444000, C424S445000, C424S427000

Reexamination Certificate

active

06541028

ABSTRACT:

FIELD OF THE INVENTION
The invention involves methods of using sheets of cultured epithelial cells to promote healing of corneal resurfacing wounds.
BACKGROUND OF THE INVENTION
Treatment of refraction defects such as spherical ametropias (myopia and hypermetropia) and cylindrical ametropias (astigmatism) has progressed in recent years beyond application of prosthetic devices designed to correct the defects, including eyeglasses and contact lenses. Surgical procedures are now commonly performed to achieve a measure of permanence in the correction of refraction defects. For example, radial keratotomy (RK) is a surgical procedure which corrects the shape of the eye by placing radial incisions in the periphery of the eye to change the curvature of the cornea. More recent advances include the treatment known as photorefractive keratectomy (PRK). In PRK, a laser is used to reshape the surface of the cornea by ablating a portion of the outer layers of the cornea. The preferred laser for PRK is the excimer laser which emits radiation with a wavelength of 193 nm. At this wavelength, photoablation results without thermal damage to deeper cells. PRK differs from RK and other surgical procedures by not altering the inner layers of the cornea (corneal endothelium); in PRK, only the outer layers of cells of the cornea are removed. On the other hand, in other laser procedures such as laser in situ keratomileusis (LASIK), ablation of stromal tissue is performed.
One of the difficulties which accompanies laser corneal resurfacing and LASIK procedures is the often painful post-treatment period. Most, if not all, patients suffer very intense pain during the first postoperative day. Many patients experience pain for several days after the completion of the PRK procedure.
Other postoperative symptoms of PRK and LASIK include photophobia, corneal opacity (haze) and corneal scarring. The typical recovery time for the regrowth of the corneal epithelium (reepithelialization) following PRK or LASIK is about 7 to 10 days. The degree of scarring has been reported to be a function of the time required for reepithelialization of the corneal surface (Wu et al., Arch. Ophthalmol. 109:1426-1432, 1991). Wu et al. also reported that residual stromal haze and scarring prevented significant improvement of vision in certain patients.
Present treatments for adverse effects associated with PRK rely on the administration of drugs. For example, Robertson et al. (U.S. Pat. No. 5,401,510) disclose the topical administration of non-steroidal antiinflammatory drugs such as ketorolac and diclofenac to the eye after PRK. While effective in the management of the intense pain associated with PRK, these non-steroidal drugs may slow epithelialization of the corneal laser wound. Robertson et al. also disclose the administration of wound healing modulators to the eye after PRK for the reduction of corneal haze. Such modulators are formulated as solutions, suspensions, emulsions, gels or delivered via use of a solid matrix such as a collagen shield or contact lens. The wound healing modulators are administered to enhance wound healing, prevent improper collagen repair, prevent improper epithelial cell coverage of the cornea and prevent inflammation. Robertson does not disclose the use of epithelial cells for promotion of wound healing.
The drawbacks of the prior art procedures include the side effects of topical anti-inflammatory drugs administered for pain management, the need to change corneal dressings, and the need to reapply healing and anti-pain agents to the cornea, all of which can exacerbate pain and expose the corneal resurfacing wound to biological and non-biological contaminants.
Thus, there is a need for a treatment of laser corneal resurfacing wound sites that will promote faster healing of the wound, lessen pain and reduce the possibility of lasting complications associated with the healing process, such as corneal scarring and haze. Additionally, there is a need for a treatment which need not be changed while the corneal resurfacing wound heals.
Sheets of cultivated human epithelial cells have been used as a replacement for skin and as a biological wound dressing. The culture of epithelial cells was pioneered in 1975 by Dr. Howard Green, which discovery served as the basis for both autograft and allograft wound healing technology. The first therapeutic product made from cultivated human epithelial cells was an autograft, where a patient's cells were cultured and returned to the same patient. The cells establish themselves at the wound site permanently. This technology has been used successfully to treat skin burns and other epidermal lesions such as ulcers.
The allograft technology involves treating a patient with cultured cells from tissue of a diferent individual. Such cells do not establish themselves permanently, but instead can be applied as a biological dressing for wounds, including partial thickness burns and healing of split-thickness autograft donor sites (see, e.g., EP 0 296 475, Cancedda et al.; PCT/US91/03582, Tubo et al.) Commercial allografts are not known to the inventors.
SUMMARY OF THE INVENTION
The present invention provides methods for promoting healing of corneal wounds, especially those wounds which result from laser surgery to alter refraction by the eye. The methods promote faster healing of corneal resurfacing wounds relative to prior art methods of healing such wounds. The methods are believed to reduce pain associated with corneal resurfacing wounds. The methods also are believed to reduce complications associated with the healing process, such as corneal scarring and haze. The methods involve the application of sheets of cultured epithelial cells to the cornea of a subject in need of such treatment.
According to one aspect of the invention, a method for promoting healing of a corneal wound is provided. The method involves applying a sheet of cultured epithelial cells to the wound of a patient in need of such treatment. Preferably, the sheet substantially covers the wound. The corneal wound, in preferred embodiments, is a laser resurfacing wound.
In certain embodiments, the sheet of cultured epithelial cells is a preserved sheet. The preserved sheet of cultured epithelial cells can be dried. If the preserved sheet of cells exists in a dry state, then it can be applied to the wound after rehydration or applied directly to the wound without prior rehydration, the dried cells rehydrating at the wound site.
In other embodiments, the sheet of cultured epithelial cells is disposed on a substratum. The cells can be attached to a substratum such as hyaluronic acid, collagen, fibrin glue, synthetic products and the like. The substratum can provide structural support to the sheet of cells during the step of applying the sheet to the wound.
In yet other embodiments, the sheet of cultured epithelial cells is disposed on a backing. The backing can provide, inler alia, structural support to the sheet of cells during the step of applying the sheet to the wound. Preferably, the backing is a contact lens or is a substrate configured like a contact lens. The method optionally provides for covering the applied sheet of cultured epithelial cells with a dressing.
In still other embodiments, the cultured epithelial cells are attached to a substratum or mixed with a gel. Preferably, the substratum is selected from the group consisting of microbeads, hyaluronic acid, collagen, fibrin glue and polymers.
In certain embodiments, the laser corneal resurfacing wound results from a laser eye surgical procedure selected from the group consisting of PRK and LASIK.
According to another aspect of the invention, a corneal wound healing device is provided. The device includes a substrate having an arcuate shape which conforms to the shape of an eye, such as the shape and dimensions of a contact lens, defining an inner concave surface. Cultured epithelial cells are attached to the inner concave surface of the substrate. In preferred embodiments the cultured epithelial cells are attached as a sheet. This device then may

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