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Up Front | May 2002

New Techniques in Ocular Surface Reconstruction

Corneal stem cell transplantation is a new, technically challenging procedure for ocular surface reconstruction.

The ocular surface is composed of the corneal and conjunctival epithelium and the precorneal tear film. These three components must all maintain normal structure and function in order to preserve clear vision and ocular comfort. The corneal epithelium is arranged in an orderly fashion to provide a smooth ocular surface and clear vision. The conjunctival epithelium supports a healthy ocular surface by producing the aqueous and mucin components of the tear film. In order to support the corneal and conjunctival epithelium and to provide a smooth refractive surface for the eye, the tear film must maintain the correct composition of lipid, mucin, and aqueous.

The corneal and conjunctival epithelium are derived from stem cells. The conjunctival stem cells are located in the conjunctival fornices. As conjunctival epithelial cells turn over, new cells, created by the stem cells grow out from the fornices to cover the conjunctival surfaces. Corneal stem cells are located at the deep basal layers of the corneoscleral limbus.1 They reside between the palisades of Vogt in the interpalisade rete ridges, and their function is to replace cells that have died or those that have been lost through injury. These cells are capable of error-free proliferation, self-maintenance, a long life span, and the ability to produce a large progeny of highly differentiated, functional epithelial cells.

Primary stem cell deficiency occurs in aniridia due to incomplete differentiation of the corneoscleral limbus. Secondary stem cell loss may occur from external factors that injure or destroy the cells. Stem cell damage occurs with chemical or thermal injuries or ultraviolet radiation. Other causes of damage include Stevens-Johnson syndrome, ocular cicatricial pemphigoid, prolonged contact lens wear, corneal intraepithelial neoplasia, and surgical trauma, especially glaucoma surgeries with antimetabolites. The result of this stem cell loss is often corneal blindness that cannot be helped by transplant alone. This loss of vision due to the corneal surface may occur even when the remainder of the eye has normal visual potential.

The clinical manifestations of stem cell failure lead to a disrupted ocular surface (Figure 1). Without the normal barrier of limbal stem cells, conjunctival epithelium invades the cornea leading to a condition of irregular corneal cells called conjunctivalization. This irregular, unstable surface causes a degradation of visual acuity that leads to corneal epithelial irregularities, recurrent epithelial defects, corneal vascularization, corneal scarring, and possibly corneal melting. Slit lamp signs include a dull and irregular corneal surface, blunting of the normal architecture of the palisades of Vogt, and swirling patterns of conjunctival cells extending onto the cornea from the limbus that exhibit late fluorescein-stippled staining due to their increased permeability.

The treatment regimen involves removing the offending stimulus, such as contact lenses. If permanent damage to the stem cells has occurred, surgical therapy is necessary. Unfortunately, corneal transplantation in these patients is unsuccessful unless a normal ocular surface can be created. Partial stem cell loss can be managed by debridement of the abnormal cells with the hope that enough normal stem cells remain to replenish the damaged corneal surface. Severe stem cell loss must be managed with stem cell replacement.

Replacement can be via autografts of stem cells from the fellow healthy eye or via donor stem cell allografts. Although autografts are the most successful therapy, it is uncommon to find a healthy limbus in the fellow eye. Allografts are stem cells from a living-related relative2 or from a cadaver. The stem cells must be delivered to the diseased eye via a carrier. They can be brought to the recipient by way of donor conjunctiva or donor limbus.3 Most commonly, stem cells are transplanted from cadaveric limbal grafts called keratolimbal allografts (KLALs).

The KLAL procedure usually involves the harvesting of three partial-thickness crescentic lenticles of donor limbus from two cadaver eyes. This provides greater than 360º of limbal tissue to choose from for transplantation to the recipient limbus. After debriding all the abnormal corneal cells and pannus from the diseased eye, the surgeon carefully dissects these lenticles from the donor globe and sutures them to the recipient limbus (Figure 2). Patients whose ocular surface disease also involves extensive conjunctival scarring may benefit from replacing the diseased conjunctival stroma with a conjunctival transplant or an amniotic membrane transplant in addition to their stem cell transplants. The amniotic membrane tissue is placed under the stem cell grafts in order to provide a substrate for the growth of the new limbal cells. The surgeon places the donor conjunctiva over the areas where the scarred conjunctiva was excised.

Systemic immunosuppression is essential for the long-term suppression of graft rejection and therefore for the ultimate survival of the grafts. Multiple regimens have been used to prolong the life of the transplanted cells. The immunosuppressive drugs used include prednisone, cyclosporine A, mycophenolate mofetil, and most recently tacrolimus. These medications must be used for 1 to 2 years, if not for a lifetime. Careful monitoring for proper drug levels and systemic toxicity is often aided with the help of a consulting internist, rheumatologist, or oncologist.

Although these new procedures for ocular surface reconstruction are technically challenging and may only offer a 50 to 60% chance of success, any hope that can be provided for these patients is welcome. Future improvements may include the harvesting of normal stem cells from a normal limbal area, growing and amplifying these stem cells in a cell culture, and transplanting them to the diseased eye.4 This can provide an ample number of cells and possibly cells with a minimal chance of rejection if harvested from the patient's own eye.

Jonathan B. Rubenstein, MD, is Associate Professor of Ophthalmology and Director of Refractive Surgery at Rush Medical College in Chicago, Illinois. He may be reached at (312) 942-2734; Jonathan_Rubenstein@rush.edu
1. Dua HS, Azuara-Blanco A: Limbal stem cells of the corneal epithelium. Surv Ophthalmol 44:415-25, 2000
2. Tsubota K, Shimmura S, Shinozaki N, et al: Clinical application of living-related conjunctival-limbal allograft. Am J Ophthalmol 133:134-135, 2002
3. Daya SM, Ilari FA: Living related conjunctival limbal allograft for the treatment of stem cell deficiency. Ophthalmology 108:126-133, 2001
4. Tsai RJ, Li LM, Chen JK: Reconstruction of damaged corneas by transplantation of autologous limbal epithelial cells. N Engl J Med 343:136-138, 2000
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