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What’s new in ophthalmic surgery
WHAT’S NEW IN SURGERY
What’s New in Ophthalmic Surgery Michael A Lemp, MD, FACS “What’s New in Surgery” evolves from the contributions of leaders in each of the fields of surgery. In every instance the author has been designated by the appropriate Council from the American College of Surgeons’ Advisory Councils for the Surgical Specialties. This feature is now presented in issues of the Journal throughout the year.
In this report I will focus on an area of great interest, activity, and potential: reconstruction of the ocular surface using amniotic membrane, limbal stem cell transplantation, or both. The ocular surface is comprised of the cornea and conjunctiva. This tissue, which forms a contiguous outer lining of the eye, serves several purposes, including optical (the cornea provides a clear, curved optical surface and is the major refracting element in the eye), and protective (defense mechanisms protecting against infection, dessication, and injury are centered in the epithelial lining of the ocular surface).1 These epithelial defense mechanisms are integrated with several adnexal structures: lids, lashes, and lacrimal glands by a neurosensory pathway that is responsive to insult to the ocular surface. An intact sensory and motor pathway linking the ocular surface with the central nervous system and effector structures is essential for the maintenance and repair of the ocular surface.2 The cornea and conjunctiva are supplied with a dense network of nerve fibers; they reach their greatest density in the central cornea. The nerve endings contain fibers that respond to temperature, pressure, and pain. When there is damage to the cornea or conjunctiva from infection, toxins, chemicals, physical injury, or inflammatory disease, signals from these nerve endings elicit a response in the lids (blinking) and lacrimal glands (cytokines are secreted in the tears, which stimulate cellular proliferation and movement to reestablish an intact surface). When this neurally mediated response is damaged, healing is delayed or prevented, leading to persistent epithe-
lial defects with subsequent ulceration and, in severe cases, perforation of the cornea.3 Conventional treatment of ocular surface lesions include immobilization of the upper lid by patching or suturing to remove the abrasive action of the eyelid. Also bandage soft contact lenses are used to minimize abrasion from the movement of the upper lid. Despite these measures, in many cases of disease and injury, healing is delayed or prevented, leading to scarring with loss of vision, perforation with risk of loss of the eye, or both.4 This is particularly true in cases in which nervous innervation to the ocular surface has been compromised; eg, denervation from neurologic lesions, surgery, or inflammation. In this context, attention has been directed to novel ways to reconstruct the ocular surface. The use of surgical adhesives, grafts from other tissues such as peritoneum, fascia, or cadaveric cornea or sclera have met with mixed success. Attention has recently focused on the use of amniotic membrane to facilitate healing and reconstruct the surface. The first recorded use of placental tissue to treat ocular surface problems was in 1940.5 A few scattered reports of subsequent use to treat caustic burns of the eye followed in the 1940s.6,7 This modality was not reported again until 1995 when Kim and Tseng8 reported using preserved human amnion to cover epithelial defects in a rabbit model of ocular surface stem cell deficiency. Since then there has been a considerable number of papers detailing surgical techniques and clinical results in treating a variety of healing problems of the ocular surface.9-11 Conditions treated include: pterygium, after conjunctival excision of large lesions; lysis of symblephara; scleral melts; persistent corneal epithelial defects; chemical burns; bullous keratopathy; band keratopathy; StevensJohnson syndrome; corneal perforations; ulcers; acute
Received June 27, 2002; Accepted June 27, 2002. From the Departments of Ophthalmology, Georgetown University and George Washington University, Washington, DC. Correspondence address: Michael A Lemp, MD, FACS, 4000 Cathedral Ave NW, Apartment 828B, Washington DC 20016.
© 2002 by the American College of Surgeons Published by Elsevier Science Inc.
361
ISSN 1072-7515/02/$21.00 PII S1072-7515(02)01318-2
362
Lemp
What’s New in Ophthalmic Surgery
toxic epidermal necrolysis; neurotrophic keratitis; and stem cell deficiency. The putative mechanisms of action of amniotic membrane include promotion of the growth of epithelial cells over the basement membrane surface of the graft,12 exclusion of inflammatory cells from its stromal surface,13 suppression of transforming growth factor (TGF)- signaling system and myofibroblast differentiation of normal fibroblasts reducing scarring,14 promotion of nongoblet cell epithelial proliferation, and goblet cell differentiation over conjunctival epithelial defects.15,16 So amniotic membrane use tends to facilitate reepithelialization and reduces inflammation, vascularization, and scarring. The membrane is replaced by new basement membrane over a period of weeks to months. Amniotic membrane transplantation has become a new modality for use as a temporary patch and as a reconstructive graft in destructive lesions of the cornea and conjunctiva. Results have been encouraging, but as a recent paper pointed out, there is a need for wellcontrolled clinical studies with positive controls in determining the relative clinical use in treating nonhealing lesions of the ocular surface.17 One condition in which amniotic membrane grafts are not successful is total stem cell deficiency.18 About 30 years ago, attention was first called to the limbal area; ie, the narrow rim of superficial tissue marking the border between the cornea and conjunctiva as the primary source of progenitor stem cells.19 These slow-cycling, long-lived cells give rise to a rapidly proliferating group of transiently amplifying cells that ultimately give rise to fully differentiated corneal epithelium. Similar areas of stem cells in the conjunctiva have been identified.20 The limbal area surrounding the cornea is critical in maintaining the integrity of the corneal surface, and a deficiency in or damage to this area results in serious problems. Examples of conditions in which there is a stem cell deficiency are listed in Table 1.21 Involvement of the limbal stem cells can be partial or total. In varying degrees, these conditions deprive the cornea of its normal complement of fully differentiated corneal epithelial cells with their unique structure (avascular), biochemistry, and genetic characteristics. Clinically, the epithelium resembles the conjunctiva in its vascularity and irregular thickness. Attempts to restore clarity to the cornea by transplantation of donor cornea are typically unsuccessful because of postoperative healing problems,
J Am Coll Surg
Table 1. Limbal Stem Cell Deficiency Primary limbal stem cell deficiency Aniridia Multiple endocrine deficiency Erythrokeratodermia Secondary limbal stem cell deficiency Chemical burns Thermal burns Irradiation Contact lens Iatrogenic limbal deficiency Multiple limbal surgeries Inflammation Stevens-Johnson syndrome Cicatricial pemphigoid Bacterial keratitis (From: Kruse FE. Classification of ocular surface disease. In: Holland EJ, Mannis MJ, eds. Ocular surface disease. New York: Springer;2001, with permission.)
overgrowth of vascularized conjunctival epithelium with loss of clarity, or both. The first ocular surface transplantation procedure, conjunctival transplantation for monocular chemical burns, was described in 1977.22 This preceded recognition of the critical role of limbal stem cells and resulted in translucent conjunctival epithelium covering the cornea. In 1989 the first specific limbal stem cell transplant for severe ocular surface disease was reported.23 In this procedure, the fellow eye served as the donor. Because of concern for damage to the fellow eye and the need to develop treatment for bilateral cases of ocular surface disease, attention shifted to cadaveric donors. In the mid 1990s, several techniques were described in which varying amounts of peripheral corneal and conjunctival tissue encompassing limbal stem cells from cadaveric donors were used.24-26 Results were encouraging, although only gradually did information emerge on the extent of donor transplantation necessary to achieve consistently good results. It is now recognized that there must be contiguous donor implantation in areas of stem cell deficiency to preclude vascular ingrowth with loss of corneal clarity. Recent advances have centered on means to enhance the amount and supply of donor material for transplantation.27,28 In this regard, tissue culture of human corneal epithelial cells on a suitable substrate for transplantation has been developed. More recently, use of amniotic membrane as a substrate for augmentation of corneal
Vol. 195, No. 3, September 2002
epithelial cell growth before transplantation has been described.29 This, then, represents the state of the surgical art. Results for reconstruction of a stable ocular surface with major improvement in vision have been impressive. Further refinements will, undoubtedly, be forthcoming—an exciting and gratifying chapter in the advancement of surgical science. REFERENCES 1. Nishida T. Cornea. In: Cornea. Vol. 1. Krachmer J, Mannis M, Holland E, eds. St. Louis: Mosby;1997. 2. Stern ME, Beuerman RW, Fox RI, et al. The pathology of dry eye and interaction between ocular surface and lacrimal glands. Cornea 1998;17:584–589. 3. Mackie IA. Role of the corneal nerves in destructive disease of the cornea. Trans Ophthalmol Soc UK 1978;93:343–349. 4. Pfister RR. Clinical measures to promote epithelial healing. Acta Ophthalmol (Suppl) 1992;230:314–317. 5. deRotth A. Plastic repair of conjunctival defects with fetal membrane. Arch Ophthalmol 1940;23:522–525. 6. Lavery FS. Lime burn of conjunctiva and cornea treated with amnioplastic graft. Trans Ophthalmol Soc UK 1946;66:668. 7. Sorsby A, Symons HM. Amniotic membrane grafts in caustic burns of the eye (burns of the second degree). Br J Ophthalmol 1946;30:337–345. 8. Kim JC, Tseng SCG. Transplantation of preserved human amniotic membrane for surface reconstruction in severely damaged rabbit cornea. Cornea 1995;14:473–484. 9. Dua HS, Azuara-Blanco A. Amniotic membrane transplantation. Br J Ophthalmol 1999;14:748–752. 10. Shimzaki J, Yang HY, Tsubota K. Amniotic membrane transplantation for ocular surface reconstruction in patients with chemical and thermal burns. Ophthalmology 1997;104:2068– 2076. 11. Lethko E, Stechschulte SV, Kenyon KR, et al. Amniotic membrane inlay and overlay grafting for corneal epithelial defects and stromal ulcers. Arch Ophthalmol 2001;119:659–663. 12. Guo M, Grinnell F. Basement membrane and human epithelial differentiation in vitro. J Invest Dermatol 1989;93:372–378.
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What’s New in Ophthalmic Surgery
363
13. Shimmura S, Shimazaki J, Ohashi Y, et al. Antiinflammatory effects of amniotic membrane transplantation in ocular surface disorders. Cornea 2001;20:408–413. 14. Tseng SCG, Li D-Q, Ma X. Suppression of transforming growth factor isoforms, TGF- II, and myofibroblast differentiation in cultured human corneal and limbal fibroblasts by amniotic membrane matrix. J Cell Physiol 1999;179:325–335. 15. Miller D, Tseng SCG. Conjunctival epithelial differentiation on amniotic membrane. Invest Ophthalmol Vis Sci 1999;40:878– 886. 16. Praghasawat P, Tseng SCG. Impression cytology study of epithelial phenotype of ocular surface reconstructed by preserved amniotic membrane. Arch Ophthalmol 1997;115:1360–1367. 17. Baum J. Amniotic membrane transplantation. Why is it effective? Cornea 2002;21:339–341. 18. Tseng SCG, Tsubota K. Amniotic membrane transplantation for ocular surface reconstruction. In: Holland EJ, Mannis MJ, eds. Ocular surface disease. New York: Springer;2001. 19. Davanger M, Evensen A. Role of the pericorneal papillary structure in renewal of corneal epithelium. Nature 1971;229:560– 561. 20. Dua HS, Azuaro-Blanco A. Limbal stem cells of the corneal epithelium. Surv Ophthalmol 2000;44:415–425. 21. Kruse FE. Classification of ocular surface disease. In: Holland EJ, Mannis MJ, eds. Ocular surface disease. New York: Springer; 2001. 22. Thoft RA. Conjunctival transplantation. Arch Ophthalmol 1997;95:1425–1427. 23. Kenyon KR, Tseng SCG. Limbal autograft transplantation for ocular surface disorders. Ophthalmology 1989;96:709–723. 24. Tsai RJF, Tseng SCG. Human allograft limbal transplantation for corneal surface reconstruction. Cornea 1994;13:389–400. 25. Tsubota K, Toda I, Saito H, et al. Reconstruction of the corneal epithelium by limbal allograft transplantation for severe ocular surface disorders. Ophthalmology 1995;102:1486–1495. 26. Holland EJ. Epithelial transplantation for the management of severe ocular surface disease. Trans Amer Ophthalmol Soc 1996; 94:677–743. 27. Tsai RJF, Li L-M, Chen J-K. Reconstruction of damaged corneas by transplantation of autologous limbal epithelial cells. N Engl J Med 2000;343:86–93. 28. Schwab IR. Cultured corneal epithelium for ocular surface disease. Trans Amer Ophthalmol Soc 1999;97:891–986. 29. Schwab IR, Reyes M, Isseroff RR. Successful transplantation of bioengineered tissue replacements in patients with ocular surface disease. Cornea 2000;19:421–426.
What’s New in Ophthalmic Surgery Michael A Lemp, MD, FACS “What’s New in Surgery” evolves from the contributions of leaders in each of the fields of surgery. In every instance the author has been designated by the appropriate Council from the American College of Surgeons’ Advisory Councils for the Surgical Specialties. This feature is now presented in issues of the Journal throughout the year.
In this report I will focus on an area of great interest, activity, and potential: reconstruction of the ocular surface using amniotic membrane, limbal stem cell transplantation, or both. The ocular surface is comprised of the cornea and conjunctiva. This tissue, which forms a contiguous outer lining of the eye, serves several purposes, including optical (the cornea provides a clear, curved optical surface and is the major refracting element in the eye), and protective (defense mechanisms protecting against infection, dessication, and injury are centered in the epithelial lining of the ocular surface).1 These epithelial defense mechanisms are integrated with several adnexal structures: lids, lashes, and lacrimal glands by a neurosensory pathway that is responsive to insult to the ocular surface. An intact sensory and motor pathway linking the ocular surface with the central nervous system and effector structures is essential for the maintenance and repair of the ocular surface.2 The cornea and conjunctiva are supplied with a dense network of nerve fibers; they reach their greatest density in the central cornea. The nerve endings contain fibers that respond to temperature, pressure, and pain. When there is damage to the cornea or conjunctiva from infection, toxins, chemicals, physical injury, or inflammatory disease, signals from these nerve endings elicit a response in the lids (blinking) and lacrimal glands (cytokines are secreted in the tears, which stimulate cellular proliferation and movement to reestablish an intact surface). When this neurally mediated response is damaged, healing is delayed or prevented, leading to persistent epithe-
lial defects with subsequent ulceration and, in severe cases, perforation of the cornea.3 Conventional treatment of ocular surface lesions include immobilization of the upper lid by patching or suturing to remove the abrasive action of the eyelid. Also bandage soft contact lenses are used to minimize abrasion from the movement of the upper lid. Despite these measures, in many cases of disease and injury, healing is delayed or prevented, leading to scarring with loss of vision, perforation with risk of loss of the eye, or both.4 This is particularly true in cases in which nervous innervation to the ocular surface has been compromised; eg, denervation from neurologic lesions, surgery, or inflammation. In this context, attention has been directed to novel ways to reconstruct the ocular surface. The use of surgical adhesives, grafts from other tissues such as peritoneum, fascia, or cadaveric cornea or sclera have met with mixed success. Attention has recently focused on the use of amniotic membrane to facilitate healing and reconstruct the surface. The first recorded use of placental tissue to treat ocular surface problems was in 1940.5 A few scattered reports of subsequent use to treat caustic burns of the eye followed in the 1940s.6,7 This modality was not reported again until 1995 when Kim and Tseng8 reported using preserved human amnion to cover epithelial defects in a rabbit model of ocular surface stem cell deficiency. Since then there has been a considerable number of papers detailing surgical techniques and clinical results in treating a variety of healing problems of the ocular surface.9-11 Conditions treated include: pterygium, after conjunctival excision of large lesions; lysis of symblephara; scleral melts; persistent corneal epithelial defects; chemical burns; bullous keratopathy; band keratopathy; StevensJohnson syndrome; corneal perforations; ulcers; acute
Received June 27, 2002; Accepted June 27, 2002. From the Departments of Ophthalmology, Georgetown University and George Washington University, Washington, DC. Correspondence address: Michael A Lemp, MD, FACS, 4000 Cathedral Ave NW, Apartment 828B, Washington DC 20016.
© 2002 by the American College of Surgeons Published by Elsevier Science Inc.
361
ISSN 1072-7515/02/$21.00 PII S1072-7515(02)01318-2
362
Lemp
What’s New in Ophthalmic Surgery
toxic epidermal necrolysis; neurotrophic keratitis; and stem cell deficiency. The putative mechanisms of action of amniotic membrane include promotion of the growth of epithelial cells over the basement membrane surface of the graft,12 exclusion of inflammatory cells from its stromal surface,13 suppression of transforming growth factor (TGF)- signaling system and myofibroblast differentiation of normal fibroblasts reducing scarring,14 promotion of nongoblet cell epithelial proliferation, and goblet cell differentiation over conjunctival epithelial defects.15,16 So amniotic membrane use tends to facilitate reepithelialization and reduces inflammation, vascularization, and scarring. The membrane is replaced by new basement membrane over a period of weeks to months. Amniotic membrane transplantation has become a new modality for use as a temporary patch and as a reconstructive graft in destructive lesions of the cornea and conjunctiva. Results have been encouraging, but as a recent paper pointed out, there is a need for wellcontrolled clinical studies with positive controls in determining the relative clinical use in treating nonhealing lesions of the ocular surface.17 One condition in which amniotic membrane grafts are not successful is total stem cell deficiency.18 About 30 years ago, attention was first called to the limbal area; ie, the narrow rim of superficial tissue marking the border between the cornea and conjunctiva as the primary source of progenitor stem cells.19 These slow-cycling, long-lived cells give rise to a rapidly proliferating group of transiently amplifying cells that ultimately give rise to fully differentiated corneal epithelium. Similar areas of stem cells in the conjunctiva have been identified.20 The limbal area surrounding the cornea is critical in maintaining the integrity of the corneal surface, and a deficiency in or damage to this area results in serious problems. Examples of conditions in which there is a stem cell deficiency are listed in Table 1.21 Involvement of the limbal stem cells can be partial or total. In varying degrees, these conditions deprive the cornea of its normal complement of fully differentiated corneal epithelial cells with their unique structure (avascular), biochemistry, and genetic characteristics. Clinically, the epithelium resembles the conjunctiva in its vascularity and irregular thickness. Attempts to restore clarity to the cornea by transplantation of donor cornea are typically unsuccessful because of postoperative healing problems,
J Am Coll Surg
Table 1. Limbal Stem Cell Deficiency Primary limbal stem cell deficiency Aniridia Multiple endocrine deficiency Erythrokeratodermia Secondary limbal stem cell deficiency Chemical burns Thermal burns Irradiation Contact lens Iatrogenic limbal deficiency Multiple limbal surgeries Inflammation Stevens-Johnson syndrome Cicatricial pemphigoid Bacterial keratitis (From: Kruse FE. Classification of ocular surface disease. In: Holland EJ, Mannis MJ, eds. Ocular surface disease. New York: Springer;2001, with permission.)
overgrowth of vascularized conjunctival epithelium with loss of clarity, or both. The first ocular surface transplantation procedure, conjunctival transplantation for monocular chemical burns, was described in 1977.22 This preceded recognition of the critical role of limbal stem cells and resulted in translucent conjunctival epithelium covering the cornea. In 1989 the first specific limbal stem cell transplant for severe ocular surface disease was reported.23 In this procedure, the fellow eye served as the donor. Because of concern for damage to the fellow eye and the need to develop treatment for bilateral cases of ocular surface disease, attention shifted to cadaveric donors. In the mid 1990s, several techniques were described in which varying amounts of peripheral corneal and conjunctival tissue encompassing limbal stem cells from cadaveric donors were used.24-26 Results were encouraging, although only gradually did information emerge on the extent of donor transplantation necessary to achieve consistently good results. It is now recognized that there must be contiguous donor implantation in areas of stem cell deficiency to preclude vascular ingrowth with loss of corneal clarity. Recent advances have centered on means to enhance the amount and supply of donor material for transplantation.27,28 In this regard, tissue culture of human corneal epithelial cells on a suitable substrate for transplantation has been developed. More recently, use of amniotic membrane as a substrate for augmentation of corneal
Vol. 195, No. 3, September 2002
epithelial cell growth before transplantation has been described.29 This, then, represents the state of the surgical art. Results for reconstruction of a stable ocular surface with major improvement in vision have been impressive. Further refinements will, undoubtedly, be forthcoming—an exciting and gratifying chapter in the advancement of surgical science. REFERENCES 1. Nishida T. Cornea. In: Cornea. Vol. 1. Krachmer J, Mannis M, Holland E, eds. St. Louis: Mosby;1997. 2. Stern ME, Beuerman RW, Fox RI, et al. The pathology of dry eye and interaction between ocular surface and lacrimal glands. Cornea 1998;17:584–589. 3. Mackie IA. Role of the corneal nerves in destructive disease of the cornea. Trans Ophthalmol Soc UK 1978;93:343–349. 4. Pfister RR. Clinical measures to promote epithelial healing. Acta Ophthalmol (Suppl) 1992;230:314–317. 5. deRotth A. Plastic repair of conjunctival defects with fetal membrane. Arch Ophthalmol 1940;23:522–525. 6. Lavery FS. Lime burn of conjunctiva and cornea treated with amnioplastic graft. Trans Ophthalmol Soc UK 1946;66:668. 7. Sorsby A, Symons HM. Amniotic membrane grafts in caustic burns of the eye (burns of the second degree). Br J Ophthalmol 1946;30:337–345. 8. Kim JC, Tseng SCG. Transplantation of preserved human amniotic membrane for surface reconstruction in severely damaged rabbit cornea. Cornea 1995;14:473–484. 9. Dua HS, Azuara-Blanco A. Amniotic membrane transplantation. Br J Ophthalmol 1999;14:748–752. 10. Shimzaki J, Yang HY, Tsubota K. Amniotic membrane transplantation for ocular surface reconstruction in patients with chemical and thermal burns. Ophthalmology 1997;104:2068– 2076. 11. Lethko E, Stechschulte SV, Kenyon KR, et al. Amniotic membrane inlay and overlay grafting for corneal epithelial defects and stromal ulcers. Arch Ophthalmol 2001;119:659–663. 12. Guo M, Grinnell F. Basement membrane and human epithelial differentiation in vitro. J Invest Dermatol 1989;93:372–378.
Lemp
What’s New in Ophthalmic Surgery
363
13. Shimmura S, Shimazaki J, Ohashi Y, et al. Antiinflammatory effects of amniotic membrane transplantation in ocular surface disorders. Cornea 2001;20:408–413. 14. Tseng SCG, Li D-Q, Ma X. Suppression of transforming growth factor isoforms, TGF- II, and myofibroblast differentiation in cultured human corneal and limbal fibroblasts by amniotic membrane matrix. J Cell Physiol 1999;179:325–335. 15. Miller D, Tseng SCG. Conjunctival epithelial differentiation on amniotic membrane. Invest Ophthalmol Vis Sci 1999;40:878– 886. 16. Praghasawat P, Tseng SCG. Impression cytology study of epithelial phenotype of ocular surface reconstructed by preserved amniotic membrane. Arch Ophthalmol 1997;115:1360–1367. 17. Baum J. Amniotic membrane transplantation. Why is it effective? Cornea 2002;21:339–341. 18. Tseng SCG, Tsubota K. Amniotic membrane transplantation for ocular surface reconstruction. In: Holland EJ, Mannis MJ, eds. Ocular surface disease. New York: Springer;2001. 19. Davanger M, Evensen A. Role of the pericorneal papillary structure in renewal of corneal epithelium. Nature 1971;229:560– 561. 20. Dua HS, Azuaro-Blanco A. Limbal stem cells of the corneal epithelium. Surv Ophthalmol 2000;44:415–425. 21. Kruse FE. Classification of ocular surface disease. In: Holland EJ, Mannis MJ, eds. Ocular surface disease. New York: Springer; 2001. 22. Thoft RA. Conjunctival transplantation. Arch Ophthalmol 1997;95:1425–1427. 23. Kenyon KR, Tseng SCG. Limbal autograft transplantation for ocular surface disorders. Ophthalmology 1989;96:709–723. 24. Tsai RJF, Tseng SCG. Human allograft limbal transplantation for corneal surface reconstruction. Cornea 1994;13:389–400. 25. Tsubota K, Toda I, Saito H, et al. Reconstruction of the corneal epithelium by limbal allograft transplantation for severe ocular surface disorders. Ophthalmology 1995;102:1486–1495. 26. Holland EJ. Epithelial transplantation for the management of severe ocular surface disease. Trans Amer Ophthalmol Soc 1996; 94:677–743. 27. Tsai RJF, Li L-M, Chen J-K. Reconstruction of damaged corneas by transplantation of autologous limbal epithelial cells. N Engl J Med 2000;343:86–93. 28. Schwab IR. Cultured corneal epithelium for ocular surface disease. Trans Amer Ophthalmol Soc 1999;97:891–986. 29. Schwab IR, Reyes M, Isseroff RR. Successful transplantation of bioengineered tissue replacements in patients with ocular surface disease. Cornea 2000;19:421–426.