Review Article
A brief history of corneal transplantation: From ancient to modern Alexandra Z Crawford, Dipika V Patel, Charles NJ McGhee Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Sciences, University of Auckland,Auckland, New Zealand
This review highlights many of the fundamental concepts and events in the development of corneal transplantation – from ancient times to modern. Tales of eye, limb, and even heart transplantation appear in ancient and medieval texts; however, in the scientific sense, the original concepts of corneal surgery date back to the Greek physician Galen (130-200 AD). Although proposals to provide improved corneal clarity by surgical interventions, including keratoprostheses, were better developed by the 17th and 18th centuries, true scientific and surgical experimentation in this field did not begin until the 19th century. Indeed, the success of contemporary corneal transplantation is largely the result of a culmination of pivotal ideas, experimentation, and perseverance by inspired individuals over the last 200 years. Franz Reisinger initiated experimental animal corneal transplantation in 1818, coining the term “keratoplasty”. Subsequently, Wilhelmus Thorne created the term corneal transplant and 3 years later Samuel Bigger, 1837, reported successful corneal transplantation in a gazelle. The first recorded therapeutic corneal xenograft on a human was
Introduction Contemporary corneal transplantation techniques are the result of a culmination of ideas, experimentation, and perseverance Access this article online Quick Response Code: Website: www.ojoonline.org DOI: 10.4103/0974-620X.122289
reported shortly thereafter in 1838—unsurprisingly this was unsuccessful. Further progress in corneal transplantation was significantly hindered by limited understanding of antiseptic principles, anesthesiology, surgical technique, and immunology. There ensued an extremely prolonged period of debate and experimentation upon the utility of animal compared to human tissue, and lamellar versus penetrating keratoplasty. Indeed, the first successful human corneal transplant was not performed by Eduard Zirm until 1905. Since that first successful corneal transplant, innumerable ophthalmologists have contributed to the development and refinement of corneal transplantation aided by the development of surgical microscopes, refined suture materials, the development of eye banks, and the introduction of corticosteroids. Recent developments, including the replacement of selected corneal layers rather than full-thickness keratoplasty, have the potential to improve or transform corneal transplant surgery in the future. Keywords: Cornea, history, keratoplasty, transplantation
over centuries [Table 1].[1] The evolution of transplantation can be traced from ancient mythology, through early religious writings to the modern era. Each cell and organ-defined branch of transplantation also has its own unique history,[2] and the chronicles of corneal transplantation weave in and out of the main story of organ transplantation. The word “graft” is a metaphoric derivation of the Greek graphion meaning writing implement or stylus.[3] The metaphor was established in the late 15th century through the observation that two artificially united plant stems resembled a writing stylus. The original sense of the word refers to the insertion of a plant part into a living plant. However, the medical application of the word is a late 19th century development. This review article highlights
Copyright: 2013 Crawford AZ, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Correspondence: Prof. Charles NJ McGhee, Department of Ophthalmology, Private Bag 92019, University of Auckland, Auckland, New Zealand. E-mail: [email protected]
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Oman Journal of Ophthalmology, Vol. 6, No. 3, Supplement 2013
Crawford, et al.: A brief history of corneal transplantation
Table 1: Considering the evolution and progress of corneal transplantation in terms of seven major epochs Seven epochs of corneal transplantation Pre-1700 Effectively the corneal “Dark Ages” 1701-1800 Superficial keratectomy and early surgical proposals 1801-1845 The beginnings of keratoplasty and xenotransplantation 1846-1904 Trials and errors-tissue source, lamellar, and penetrating keratoplasty 1905-1946 Penetrating keratoplasty success and early advances 1947-1995 Refinement, understanding, and the golden age of penetrating keratoplasty 1995-2010 Radical reawakening of lamellar keratoplasty techniques
some of the pivotal events in the development of corneal transplantation.
Before Modern Times: Myth to Theory The ancient Greeks conceived of transplantation, albeit in the form of mythical monsters woven from the various parts of different animals. The most spectacular of these creatures was the chimaera; a fire breathing creature composed of the body and head of a lion, a dragon’s tail, and the head of a goat arising from the center of the spine. The earliest known literary reference to the chimaera appears in Homer’s Iliad.[4] However, the term chimaera has passed into modern transplantation nomenclature to denote an organism of diverse genetic constitution. Interestingly, the term chimaera has also come to mean a fantastical delusion.[3] The first description of human organ transplantation appears in ancient Chinese texts dating from the 4th century BC. The eminent Chinese surgeon, Tsin Yue-Jin is reported to have exchanged the hearts of two soldiers; one endowed with a strong will but a weak spirit and the other conversely afflicted. However, the original concept of corneal transplantation is attributed to the Greek physician Galen (130-200 AD) a few centuries later.[1] Generally considered the founder of experimental physiology, Galen proposed abrasio cor’naea (precursor of superficial keratectomy) as a means of restoring corneal transparency. However, there are no reports of Galen actually attempting this procedure.[5] The patron saints of physicians and surgeons, twin brothers Cosmas and Damian are credited with performing human transplantation in the 3rd century AD.[6] These early Christian martyrs were known as Aά (literally the silverless) as they practiced medicine without fee according to their beliefs. Their most famous exploit, popularly depicted in paintings, involved the transplantation of a leg from a recently deceased Ethiopian soldier to replace the ulcerated leg of an elderly parishioner. The divine prerogative of transplantation continued with the account of Saint Lucy (283-304 AD); the patron saint of ophthalmology. According to the legend, Saint Lucy plucked out her beautiful eyes in order to escape unwelcome attention from an undesirable suitor. Her virtue was rewarded with the restoration of her sight with a pair of even more beautiful eyes. The most famous Oman Journal of Ophthalmology, Vol. 6, No. 3, Supplement 2013
incarnation of Saint Lucy is in Dante’s Divine Comedy. Plagued himself by poor eyesight, it is thought that Dante may have viewed Saint Lucy as his personal patron saint.[7]
Theory to Practice In the 17th century, the alchemy from myth to theory began with the work of the Dutch microbiologist Antonie van Leeuwenhoek and his microscopic observations of the cornea. 1 The first description of a keratoprosthesis is attributed to the French surgeon Guillaume Pellier de Quengsy.[8] During the French Revolution in 1789, he published the first monograph dedicated to ophthalmology. In this work, he suggested that a transparent material could be used to replace an opaque cornea in order to restore vision. Erasmus Darwin (Grandfather of Charles) proposed the first trephine in 1796, and postulated that the cornea might heal by secondary intention to form a ‘transparent scar’.[9] “Could not a small piece of cornea be cut out by a kind of trephine, about the size of a thick bristle, or a small crow quill, and would it not heal with a transparent scar?” (Erasmus Darwin, Zoonomia, or the laws of organic life).[9] Progress in corneal transplantation was given impetus by an epidemic of blinding Egyptian ophthalmia (trachoma) which ravaged Europe early in the 19th century.[10] British and French soldiers engaged in the Egyptian campaigns of the Napoleonic wars (1789-1799) contracted the disease and subsequently introduced it into the ‘crowded tenements of Europe’ on their return from service. This disease was responsible for the establishment of ophthalmology as the first of the surgical subspecialties and provided the stimulus for the foundation of Moorfields Eye Hospital, London, in 1817.[10] Experimentation in corneal transplantation did not begin until the 19th century [Table 2].[1] In 1813, Karl Himley (1772-1837) was the first to suggest that transplanted corneas from other animals could be used to replace opaque animal corneas.[1] However, it was his student, Franz Reisinger (1768-1855), who initiated experimental animal corneal transplantation in 1818.[11] He coined the term keratoplasty and in 1824 suggested the use of animal tissue to replace human corneas. Reisinger performed his experiments on hundreds of rabbits and chickens, excising the host cornea with a cataract knife and suturing the graft in place. Unfortunately, his experiments met with failure. A contemporary of Reisginer, Johan Dieffenbach (1792-1847), also experienced repeated failures in replacing entire corneas in a variety of animal species. He later described the idea as ‘one of the most audacious fantasies’ and remarked that it ‘would be the highest reward of surgery if this operation succeeded’.[12] In 1837, dwindling hope in the feasibility of the procedure was revived by the Irish surgeon Samuel Bigger who published a report describing his successful attempts at keratoplasty.[13] Bigger was travelling near Cairo in 1935 when a local war broke out and he was abducted for ransom by Bedouins.[1] During his captivity, S13
Crawford, et al.: A brief history of corneal transplantation
Table 2: Major landmarks in the evolution of corneal transplantation 1800-2000 Major Landmarks in the evolution of corneal transplantation 1800-2000 1813 Karl Himley suggests transplantation of corneas between animals 1824 Franz Reisenger reports first penetrating grafts in animals and term “keratoplasty” 1834 Wilhelmus Thorne-creates the term “corneal transplantation” 1837 Samuel Bigger describes successful gazelle to gazelle penetrating transplant 1843 Himly claims he first described the penetrating keratoplasty (PKP) technique in 1813 1844 Edward Kissam performs unsuccessful pig to human xenografts in USA 1846 General anesthesia introduced in Massachusetts General Hospital, USA 1867 Joseph Lister introduces surgical asepsis concepts in Glasgow, Scotland 1867 Henry Power recommends human rather than animal tissue for transplantation 1888 Von Hippel develops circular trephine, promotes small xenografts, performs DALK in dog 1905 Eduard Zirm performs the first successful human corneal transplant 1914 Elschnig pioneers corneal transplantation-first to suggest use of cadaveric tissue 1930 Elschnig presents 20 year data-170 corneal transplants with 22% overall success 1931 Vladimir Filatov-popularizes use of cadaveric corneas performed >3,500 PKP in career 1932 Ramon Castroviejo-major contributions to popularizing PKP in USA and globally 1944 First Eye Bank established by Townley Paton and John McLean in New York 1947 First American Academy of Ophthalmology sponsored corneal transplant symposium 1951 Early use of corticosteroids in animal models of corneal transplant 1952 Stocker notes importance of the endothelium in corneal hydration 1953 Zeiss introduces the first commercially available operating microscope 1960 Mackensen and Harms (Tubingen) introduce ophthalmic nylon sutures 1963 Richard Troutman introduces nylon sutures to USA 1965 Pollack and Barraquer describe hinged flap posterior lamellar keratoplasty 1968 Ethicon develops 10/0 nylon suture specifically for keratoplasty 1980 Ten year success of PKP for keratoconus>90% 1984 Eduardo Archilla describes deep lamellar keratoplasty using injection of intrastromal air 1998 Gerrit Melles reports first human endothelial keratoplasty via the sclerolimbus 1999 Gerrit Melles describes a technique of deep anterior lamellar keratoplasty (DALK) 2000 Mark Terry performs first deep lamellar endothelial keratoplasty in the USA
having his surgical instruments with him, he performed the first reported successful penetrating allograft in animals on a pet gazelle blinded by extensive corneal scarring. In his report he noted: ‘The cornea was taken from another animal of the same species brought S14
in wounded but not quite dead; adhesion took place and 10 days after the operation, the animal gave unequivocal signs of vision, and the upper part of the transplanted cornea remained perfectly transparent’.[13] Unaware of the importance that Bigger had performed a within-species allograft (gazelle to gazelle), this achievement inspired New York based ophthalmologist Richard Kissam to perform the first recorded therapeutic corneal xenograft on a human in 1838.[14] The recipient was a young Irishman with perception of light visual acuity in his only functional eye. The donor was a 6-month-old pig. Kissam removed the opaque cornea with a Beer cataract knife and attached the graft with two sutures placed at 3 and 9 O’clock. These sutures were removed after 36 h. While there was ‘increased light perception’ in the immediate postoperative period, the cornea opacified within the first fortnight and was absorbed within the 1st month. For the remainder of the 19th century, the pioneers of corneal transplantation were divided between those who favored xenografts and those who favored allografts. However, neither side of the argument had the advantage of an immunologic understanding of transplantation. The German professor, Arthur von Hippel (1841-1916),[1] who developed a number of graft instruments including a clockwork trephine, advocated lamellar xenografts, whereas the English ophthalmologist Henry Power[15] favored allografts. Power believed that allografts had ‘better matched thicknesses’ and was also the first to really understand the importance of allografts in terms of failure. These eminent ophthalmologists also disagreed on the ideal form of corneal transplantation. Von Hippel promoted lamellar grafts as he believed that corneal transparency depended on the integrity of the endothelium and Descemet’s membrane. Power, however favored penetrating keratoplasty.
The Modern Era In the modern era, corneal transplantation was the forerunner in developments of human organ transplantation. Indeed, the first successful human corneal transplant was performed in 1905, and there was an interval of 49 years before the first successful solid organ (kidney) transplant;[16] an eon in the modern medical timeline. Like many achievements in medicine, progress in corneal transplantation was hindered by a lack of understanding of antiseptic principles, anesthesiology, surgical technique, and immunology.[17,18] Developments in the practical achievement of corneal transplantation are marked by the recognition and surmounting of these obstacles. Pivotal achievements include the development of anesthesia in the late 19th century, the publication of Lister’s principles of antiseptic surgery in 1867,[19] the pioneering work by Medawar and Billingham et al., in the field of immunology in the 1940s and 1950s,[20,21] the recognition of the immunological phenomenon of corneal graft rejection by Paufique et al.,[22] and Oman Journal of Ophthalmology, Vol. 6, No. 3, Supplement 2013
Crawford, et al.: A brief history of corneal transplantation later Maumenee;[23] and the increasing availability of antibiotics in the 1940s and corticosteroids in the 1950s.[1,24,25] The final ingredients were the introduction of nylon sutures by Ethicon specifically for keratoplasty in the 1960s and the introduction of surgical microscopes into ophthalmology the late 1960s and early 1970s. The year 1905 marked the first successful human allograft performed by Eduard Zirm (1887-1948) in Olmutz near Prague [Figure 1].[26] The recipient was a 45-year-old Alois Glogar; a farm laborer who had sustained severe bilateral alkali burns while cleaning out a chicken coop with lime 16 months earlier. The living donor was an 11-year-old boy whose eye had been blinded by a penetrating injury to the sclera. The donor eye was enucleated prior to transplantation and the one cornea was used to provide two 5 mm donor grafts. Although the graft in the right eye failed, the surviving graft in the left eye improved the patient’s visual acuity from counting fingers to 6/36 at 6 months. Zirm subsequently recommended the following points for successful corneal transplantation; exclusive use of human corneas (preferably from young and healthy donors), use of the von Hippel trephine, deep anesthesia, strict asepsis, overlay sutures, use of an AC maintainer, avoidance of touching tissue, and placement of the graft between moist gauze for protection prior to transplantation. Since the first successful corneal transplant, innumerable ophthalmologists have contributed to the development and refinement of corneal transplantation. Their collective achievements allowed improved surgical methodology, technology, and instrumentation; improved understanding of corneal biology; and better control of rejection through anti-inflammatory agents. Three of these deserve special mention. The Russian ophthalmologist Vladimir Filatov (1875-1956) first suggested the use of cadaver corneas ‘in the attempt to find a new source of transplant corneas if the serious difficulty of supply was to be
Figure 1: Dr. Eduard Zirm, the first to perform a successful penetrating keratoplasty (1905) in his operating theatre
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overcome’.[27] This idea was further developed by the American ophthalmologist Richard Paton who established the first eye bank in 1944.[28] Another notable ophthalmologist is the Spanish Ramon Castroviejo (1904-1989) who conducted detailed studies of graft technique in the United States [Figure 2].[29,30] He popularized the use of direct sutures, and was innovative in surgical instrumentation. Several modern instruments bear his name.
The Future The major limitations of modern day corneal transplantation surgery may be classified under the following headings; paucity of donor tissue, graft rejection and failure, and variable visual and tectonic outcomes. Evolution in the field of corneal transplantation is therefore targeted towards overcoming these obstacles. Recent developments with the potential to transform corneal transplant surgery include: A revival of anterior and posterior lamellar techniques [Figure 3], the artificial or bioengineered cornea, the manipulation of corneal endothelial cells as a substitute for transplantation, and the use of the surgical femtosecond laser.[31]
Lamellar keratoplasty Penetrating keratoplasty has traditionally been the treatment of choice for corneal opacification. In more recent years, there has been a renaissance of anterior and posterior lamellar techniques which selectively replace only the diseased layers of the cornea while retaining healthy layers.
Bioengineered cornea The artificial or bioengineered cornea represents the “holy grail” of corneal transplantation; simultaneously nullifying the dual obstacles of donor tissue availability and immunological incompatibility. Ideally, the bioengineered cornea[32] would begin as an acellular stromal scaffold with ex vivo colonization of host endothelial cells, keratocytes, and epithelium. The
Figure 2: Dr. Ramon Castroviejo (right) who was largely responsible for popularizing penetrating keratoplasty in the USA in 1930s and Dr. R. Townley Paton (left), performing one of the first corneal transplants in New York, 1937
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References 1. 2. 3. 4.
a
b
5.
6. 7.
c Figure 3: Three examples of contemporary corneal transplant surgery: (a) Deep anterior lamellar keratoplasty (DALK) with removal of host stroma down to Descemet’s membrane, (b) penetrating keratoplasty (PKP) with combination of interrupted (10-0) and continuous (11-0) sutures, and (c) Descemet’s stripping endothelial keratoplasty (DSEK) with the graft host interface visible in the periphery (arrow)
8. 9. 10. 11.
host cells would be modified to eliminate the original disease characteristics, thereby resulting in a disease-free bioengineered tissue which is genetically and therefore immunologically identical to the host. Mimics of corneal extracellular matrix have recently been used as an anterior lamellar corneal transplant.[33]
Manipulation of corneal endothelial cells Recent advances in the understanding of the cell-cycle activation pathways of endothelial cells in vitro have allowed progress in human corneal endothelial cell culture. The transplantation of cultured corneal endothelial cells has met with some success in experimental settings.[34-39] In future clinical practice, cultured endothelial cells may be implanted either as a monolayer or by injection into the anterior chamber.[31]
Ophthalmic femtosecond lasers Ophthalmic femtosecond lasers are capable of creating precise cuts in the cornea with minimum collateral damage to surrounding tissue, and are being used to perform accurate corneal trephination for donor and recipients. The high degree of accuracy offered by the femtosecond laser may translate into better visual and tectonic outcomes though there are insufficient data to support this conjecture at present.[31]
Conclusion
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From mythological and allegorical tales to reality, corneal transplantation is now established as the most common and indeed the most successful form of human transplantation. Corneal transplantation continues to evolve and emerging techniques offer the potential of a truly customized personal transplant material within a generation. S16
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Moffatt SL, Cartwright VA, Stumpf TH. Centennial review of corneal transplantation. Clin Experiment Ophthalmol 2005;33:642-57. Starzl TE. History of clinical transplantation. World J Surg 2000;24:759-82. Thompson DF. The Oxford modern English dictionary. 2nd ed. Oxford: Oxford University Press, 1996. Homer, Callan N, Mack MtE, Pope AWteoabP. The Illiad of Homer. ([Translated by] Alexander Pope.) Edited by Maynard Mack. Associate editors: Norman Callan [and others], etc: London: Methuen and Co.; New Haven: Yale University Press, 1967. Anastas CN, McGhee CN, Webber SK, Bryce IG. Corneal tattooing revisited: Excimer laser in the treatment of unsightly leucomata. Aust N Z J Ophthalmol 1995;23:227-30. Dewhurst J. Cosmas and Damian, patron saints of doctors. Lancet 1988;2:1479-80. Dante A, Raffel B, Carrigan HL. The divine comedy. Evanston, Ill.: Northwestern University Press, 2010. Pellier de Quengsy G. Précis ou cours d’opérations sur la chirurgie des yeux par M. G. Pellier de Quengsy, fils. Paris: Didot, 1789. Darwin E. Zoonomia, or, the laws of organic life. By Erasmus Darwin: Dublin: Printed for P. Byrne. Coster DJ. A century of corneal transplantation. Clin Experiment Ophthalmol 2005;33:557-8. Reisinger F. Die keratoplastik, ein versuch zur enweiterund der augenheilkunde. Bayerische Annalem 1824;1:207. Dieffenbach J. Beitrage zur Verpflanzung der Hornhaut. Festschr Ophthalmol (von Ammon) 1831;1:172-6. Bigger S. An inquiry into the possibility of transplanting the cornea with a view to relieving blindness. Dublin J Med Sci 1837;11:408-17. Kissam R. Ceratoplastics in man. NY J Med 1844;2:281-2. Power H. On transplantation of the cornea. IV International Congress of Ophthalmology 1873;IV: 172-6. Merrill JP, Murray JE, Harrison JH, Guild WR. Successful homotransplantation of the human kidney between identical twins. J Am Med Assoc 1956;160:277-82. Groth CG, Brent LB, Calne RY, Dausset JB, Good RA, Murray JE, et al. Historic landmarks in clinical transplantation: Conclusions from the consensus conference at the University of California, Los Angeles. World J Surg 2000;24:834-43. Calne R. The history and development of organ transplantation: Biology and rejection. Baillieres Clin Gastroenterol 1994;8:389-97. Lister J. On the Antiseptic Principle in the Practice of Surgery. Br Med J 1867;2:246-8. Medawar PB. Immunity to homologous grafted skin; the fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye. Br J Exp Pathol 1948;29:58-69. Billingham RE, Brent L, Medawar PB. The antigenic stimulus in transplantation immunity. Nature 1956;178:514-9. Paufique L, Sourdille G-P, Offret G, Paufique L. L. Paufique., G.-P. Sourdille., Guy Offret., Les Greffes de la cornée, kérato-plasties, rapport présenté à la Société française d’ophtalmologie le 23 mai 1948. Paris, Masson (Alençon, Impr. alençonnaise), 1948. Maumenee AE. The influence of donor-recipient sensitization on corneal grafts. Am J Ophthalmol 1951;34:142-52. Mannis MJ, Krachmer JH. Keratoplasty: A historical perspective. Surv Ophthalmol 1981;25:333-8. Forstot SL, Kaufman HE. Corneal transplantation. Annu Rev Med 1977;28:21-35. Zirm E. Eine erfolgreiche totale keratoplastik. Arch Ophthalmol 1906;64:580-93. Filatov V. Transplantation of the cornea from preserved cadavers’ eyes. Lancet 1937;1:1395-7. Paton D. The founder of the first eye bank: R. Townley Paton, MD. Refract Corneal Surg 1991;7:190-5.
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Castroviejo R. Keratoplasty. Am J Ophthalmol 1941;24:1-20. Polack FM. Ramon Castroviejo 1904-1987. Cornea 2000;19:593-602. Tan DT, Dart JK, Holland EJ, Kinoshita S. Corneal transplantation. Lancet 2012;379:1749-61. Griffith M, Osborne R, Munger R, Xiong X, Doillon CJ, Laycock NL, et al. Functional human corneal equivalents constructed from cell lines. Science 1999;286:2169-72. Fagerholm P, Lagali NS, Merrett K, Jackson WB, Munger R, Liu Y, et al. A biosynthetic alternative to human donor tissue for inducing corneal regeneration: 24-month follow-up of a phase 1 clinical study. Sci Transl Med 2010;2:46ra61. Yokoo S, Yamagami S, Yanagi Y, Uchida S, Mimura T, Usui T, et al. Human corneal endothelial cell precursors isolated by sphere-forming assay. Invest Ophthalmol Vis Sci 2005;46:1626-31. Sumide T, Nishida K, Yamato M, Ide T, Hayashida Y, Watanabe K, et al. Functional human corneal endothelial cell sheets harvested from temperature-responsive culture surfaces. FASEB J 2006;20:392-4.
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Ruberti JW, Zieske JD. Prelude to corneal tissue engineering-gaining control of collagen organization. Prog Retin Eye Res 2008;27:549-77. Peh GS, Beuerman RW, Colman A, Tan DT, Mehta JS. Human corneal endothelial cell expansion for corneal endothelium transplantation: an overview. Transplantation 2011;91:811-9. Okumura N, Ueno M, Koizumi N, Sakamoto Y, Hirata K, Hamuro J, et al. Enhancement on primate corneal endothelial cell survival in vitro by a ROCK inhibitor. Invest Ophthalmol Vis Sci 2009;50:3680-7. Mimura T, Yamagami S, Usui T, Ishii Y, Ono K, Yokoo S, et al. Long-term outcome of iron-endocytosing cultured corneal endothelial cell transplantation with magnetic attraction. Exp Eye Res 2005;80:149-57.
Cite this article as: Crawford AX, Patel DV, McGhee CN. A brief history of corneal transplantation: From ancient to modern. Oman J Ophthalmol 2013;6:S12-7. Source of Support: Nil, Conflict of Interest: None declared.
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A brief history of corneal transplantation: From ancient to modern Alexandra Z Crawford, Dipika V Patel, Charles NJ McGhee Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Sciences, University of Auckland,Auckland, New Zealand
This review highlights many of the fundamental concepts and events in the development of corneal transplantation – from ancient times to modern. Tales of eye, limb, and even heart transplantation appear in ancient and medieval texts; however, in the scientific sense, the original concepts of corneal surgery date back to the Greek physician Galen (130-200 AD). Although proposals to provide improved corneal clarity by surgical interventions, including keratoprostheses, were better developed by the 17th and 18th centuries, true scientific and surgical experimentation in this field did not begin until the 19th century. Indeed, the success of contemporary corneal transplantation is largely the result of a culmination of pivotal ideas, experimentation, and perseverance by inspired individuals over the last 200 years. Franz Reisinger initiated experimental animal corneal transplantation in 1818, coining the term “keratoplasty”. Subsequently, Wilhelmus Thorne created the term corneal transplant and 3 years later Samuel Bigger, 1837, reported successful corneal transplantation in a gazelle. The first recorded therapeutic corneal xenograft on a human was
Introduction Contemporary corneal transplantation techniques are the result of a culmination of ideas, experimentation, and perseverance Access this article online Quick Response Code: Website: www.ojoonline.org DOI: 10.4103/0974-620X.122289
reported shortly thereafter in 1838—unsurprisingly this was unsuccessful. Further progress in corneal transplantation was significantly hindered by limited understanding of antiseptic principles, anesthesiology, surgical technique, and immunology. There ensued an extremely prolonged period of debate and experimentation upon the utility of animal compared to human tissue, and lamellar versus penetrating keratoplasty. Indeed, the first successful human corneal transplant was not performed by Eduard Zirm until 1905. Since that first successful corneal transplant, innumerable ophthalmologists have contributed to the development and refinement of corneal transplantation aided by the development of surgical microscopes, refined suture materials, the development of eye banks, and the introduction of corticosteroids. Recent developments, including the replacement of selected corneal layers rather than full-thickness keratoplasty, have the potential to improve or transform corneal transplant surgery in the future. Keywords: Cornea, history, keratoplasty, transplantation
over centuries [Table 1].[1] The evolution of transplantation can be traced from ancient mythology, through early religious writings to the modern era. Each cell and organ-defined branch of transplantation also has its own unique history,[2] and the chronicles of corneal transplantation weave in and out of the main story of organ transplantation. The word “graft” is a metaphoric derivation of the Greek graphion meaning writing implement or stylus.[3] The metaphor was established in the late 15th century through the observation that two artificially united plant stems resembled a writing stylus. The original sense of the word refers to the insertion of a plant part into a living plant. However, the medical application of the word is a late 19th century development. This review article highlights
Copyright: 2013 Crawford AZ, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Correspondence: Prof. Charles NJ McGhee, Department of Ophthalmology, Private Bag 92019, University of Auckland, Auckland, New Zealand. E-mail: [email protected]
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Oman Journal of Ophthalmology, Vol. 6, No. 3, Supplement 2013
Crawford, et al.: A brief history of corneal transplantation
Table 1: Considering the evolution and progress of corneal transplantation in terms of seven major epochs Seven epochs of corneal transplantation Pre-1700 Effectively the corneal “Dark Ages” 1701-1800 Superficial keratectomy and early surgical proposals 1801-1845 The beginnings of keratoplasty and xenotransplantation 1846-1904 Trials and errors-tissue source, lamellar, and penetrating keratoplasty 1905-1946 Penetrating keratoplasty success and early advances 1947-1995 Refinement, understanding, and the golden age of penetrating keratoplasty 1995-2010 Radical reawakening of lamellar keratoplasty techniques
some of the pivotal events in the development of corneal transplantation.
Before Modern Times: Myth to Theory The ancient Greeks conceived of transplantation, albeit in the form of mythical monsters woven from the various parts of different animals. The most spectacular of these creatures was the chimaera; a fire breathing creature composed of the body and head of a lion, a dragon’s tail, and the head of a goat arising from the center of the spine. The earliest known literary reference to the chimaera appears in Homer’s Iliad.[4] However, the term chimaera has passed into modern transplantation nomenclature to denote an organism of diverse genetic constitution. Interestingly, the term chimaera has also come to mean a fantastical delusion.[3] The first description of human organ transplantation appears in ancient Chinese texts dating from the 4th century BC. The eminent Chinese surgeon, Tsin Yue-Jin is reported to have exchanged the hearts of two soldiers; one endowed with a strong will but a weak spirit and the other conversely afflicted. However, the original concept of corneal transplantation is attributed to the Greek physician Galen (130-200 AD) a few centuries later.[1] Generally considered the founder of experimental physiology, Galen proposed abrasio cor’naea (precursor of superficial keratectomy) as a means of restoring corneal transparency. However, there are no reports of Galen actually attempting this procedure.[5] The patron saints of physicians and surgeons, twin brothers Cosmas and Damian are credited with performing human transplantation in the 3rd century AD.[6] These early Christian martyrs were known as Aά (literally the silverless) as they practiced medicine without fee according to their beliefs. Their most famous exploit, popularly depicted in paintings, involved the transplantation of a leg from a recently deceased Ethiopian soldier to replace the ulcerated leg of an elderly parishioner. The divine prerogative of transplantation continued with the account of Saint Lucy (283-304 AD); the patron saint of ophthalmology. According to the legend, Saint Lucy plucked out her beautiful eyes in order to escape unwelcome attention from an undesirable suitor. Her virtue was rewarded with the restoration of her sight with a pair of even more beautiful eyes. The most famous Oman Journal of Ophthalmology, Vol. 6, No. 3, Supplement 2013
incarnation of Saint Lucy is in Dante’s Divine Comedy. Plagued himself by poor eyesight, it is thought that Dante may have viewed Saint Lucy as his personal patron saint.[7]
Theory to Practice In the 17th century, the alchemy from myth to theory began with the work of the Dutch microbiologist Antonie van Leeuwenhoek and his microscopic observations of the cornea. 1 The first description of a keratoprosthesis is attributed to the French surgeon Guillaume Pellier de Quengsy.[8] During the French Revolution in 1789, he published the first monograph dedicated to ophthalmology. In this work, he suggested that a transparent material could be used to replace an opaque cornea in order to restore vision. Erasmus Darwin (Grandfather of Charles) proposed the first trephine in 1796, and postulated that the cornea might heal by secondary intention to form a ‘transparent scar’.[9] “Could not a small piece of cornea be cut out by a kind of trephine, about the size of a thick bristle, or a small crow quill, and would it not heal with a transparent scar?” (Erasmus Darwin, Zoonomia, or the laws of organic life).[9] Progress in corneal transplantation was given impetus by an epidemic of blinding Egyptian ophthalmia (trachoma) which ravaged Europe early in the 19th century.[10] British and French soldiers engaged in the Egyptian campaigns of the Napoleonic wars (1789-1799) contracted the disease and subsequently introduced it into the ‘crowded tenements of Europe’ on their return from service. This disease was responsible for the establishment of ophthalmology as the first of the surgical subspecialties and provided the stimulus for the foundation of Moorfields Eye Hospital, London, in 1817.[10] Experimentation in corneal transplantation did not begin until the 19th century [Table 2].[1] In 1813, Karl Himley (1772-1837) was the first to suggest that transplanted corneas from other animals could be used to replace opaque animal corneas.[1] However, it was his student, Franz Reisinger (1768-1855), who initiated experimental animal corneal transplantation in 1818.[11] He coined the term keratoplasty and in 1824 suggested the use of animal tissue to replace human corneas. Reisinger performed his experiments on hundreds of rabbits and chickens, excising the host cornea with a cataract knife and suturing the graft in place. Unfortunately, his experiments met with failure. A contemporary of Reisginer, Johan Dieffenbach (1792-1847), also experienced repeated failures in replacing entire corneas in a variety of animal species. He later described the idea as ‘one of the most audacious fantasies’ and remarked that it ‘would be the highest reward of surgery if this operation succeeded’.[12] In 1837, dwindling hope in the feasibility of the procedure was revived by the Irish surgeon Samuel Bigger who published a report describing his successful attempts at keratoplasty.[13] Bigger was travelling near Cairo in 1935 when a local war broke out and he was abducted for ransom by Bedouins.[1] During his captivity, S13
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Table 2: Major landmarks in the evolution of corneal transplantation 1800-2000 Major Landmarks in the evolution of corneal transplantation 1800-2000 1813 Karl Himley suggests transplantation of corneas between animals 1824 Franz Reisenger reports first penetrating grafts in animals and term “keratoplasty” 1834 Wilhelmus Thorne-creates the term “corneal transplantation” 1837 Samuel Bigger describes successful gazelle to gazelle penetrating transplant 1843 Himly claims he first described the penetrating keratoplasty (PKP) technique in 1813 1844 Edward Kissam performs unsuccessful pig to human xenografts in USA 1846 General anesthesia introduced in Massachusetts General Hospital, USA 1867 Joseph Lister introduces surgical asepsis concepts in Glasgow, Scotland 1867 Henry Power recommends human rather than animal tissue for transplantation 1888 Von Hippel develops circular trephine, promotes small xenografts, performs DALK in dog 1905 Eduard Zirm performs the first successful human corneal transplant 1914 Elschnig pioneers corneal transplantation-first to suggest use of cadaveric tissue 1930 Elschnig presents 20 year data-170 corneal transplants with 22% overall success 1931 Vladimir Filatov-popularizes use of cadaveric corneas performed >3,500 PKP in career 1932 Ramon Castroviejo-major contributions to popularizing PKP in USA and globally 1944 First Eye Bank established by Townley Paton and John McLean in New York 1947 First American Academy of Ophthalmology sponsored corneal transplant symposium 1951 Early use of corticosteroids in animal models of corneal transplant 1952 Stocker notes importance of the endothelium in corneal hydration 1953 Zeiss introduces the first commercially available operating microscope 1960 Mackensen and Harms (Tubingen) introduce ophthalmic nylon sutures 1963 Richard Troutman introduces nylon sutures to USA 1965 Pollack and Barraquer describe hinged flap posterior lamellar keratoplasty 1968 Ethicon develops 10/0 nylon suture specifically for keratoplasty 1980 Ten year success of PKP for keratoconus>90% 1984 Eduardo Archilla describes deep lamellar keratoplasty using injection of intrastromal air 1998 Gerrit Melles reports first human endothelial keratoplasty via the sclerolimbus 1999 Gerrit Melles describes a technique of deep anterior lamellar keratoplasty (DALK) 2000 Mark Terry performs first deep lamellar endothelial keratoplasty in the USA
having his surgical instruments with him, he performed the first reported successful penetrating allograft in animals on a pet gazelle blinded by extensive corneal scarring. In his report he noted: ‘The cornea was taken from another animal of the same species brought S14
in wounded but not quite dead; adhesion took place and 10 days after the operation, the animal gave unequivocal signs of vision, and the upper part of the transplanted cornea remained perfectly transparent’.[13] Unaware of the importance that Bigger had performed a within-species allograft (gazelle to gazelle), this achievement inspired New York based ophthalmologist Richard Kissam to perform the first recorded therapeutic corneal xenograft on a human in 1838.[14] The recipient was a young Irishman with perception of light visual acuity in his only functional eye. The donor was a 6-month-old pig. Kissam removed the opaque cornea with a Beer cataract knife and attached the graft with two sutures placed at 3 and 9 O’clock. These sutures were removed after 36 h. While there was ‘increased light perception’ in the immediate postoperative period, the cornea opacified within the first fortnight and was absorbed within the 1st month. For the remainder of the 19th century, the pioneers of corneal transplantation were divided between those who favored xenografts and those who favored allografts. However, neither side of the argument had the advantage of an immunologic understanding of transplantation. The German professor, Arthur von Hippel (1841-1916),[1] who developed a number of graft instruments including a clockwork trephine, advocated lamellar xenografts, whereas the English ophthalmologist Henry Power[15] favored allografts. Power believed that allografts had ‘better matched thicknesses’ and was also the first to really understand the importance of allografts in terms of failure. These eminent ophthalmologists also disagreed on the ideal form of corneal transplantation. Von Hippel promoted lamellar grafts as he believed that corneal transparency depended on the integrity of the endothelium and Descemet’s membrane. Power, however favored penetrating keratoplasty.
The Modern Era In the modern era, corneal transplantation was the forerunner in developments of human organ transplantation. Indeed, the first successful human corneal transplant was performed in 1905, and there was an interval of 49 years before the first successful solid organ (kidney) transplant;[16] an eon in the modern medical timeline. Like many achievements in medicine, progress in corneal transplantation was hindered by a lack of understanding of antiseptic principles, anesthesiology, surgical technique, and immunology.[17,18] Developments in the practical achievement of corneal transplantation are marked by the recognition and surmounting of these obstacles. Pivotal achievements include the development of anesthesia in the late 19th century, the publication of Lister’s principles of antiseptic surgery in 1867,[19] the pioneering work by Medawar and Billingham et al., in the field of immunology in the 1940s and 1950s,[20,21] the recognition of the immunological phenomenon of corneal graft rejection by Paufique et al.,[22] and Oman Journal of Ophthalmology, Vol. 6, No. 3, Supplement 2013
Crawford, et al.: A brief history of corneal transplantation later Maumenee;[23] and the increasing availability of antibiotics in the 1940s and corticosteroids in the 1950s.[1,24,25] The final ingredients were the introduction of nylon sutures by Ethicon specifically for keratoplasty in the 1960s and the introduction of surgical microscopes into ophthalmology the late 1960s and early 1970s. The year 1905 marked the first successful human allograft performed by Eduard Zirm (1887-1948) in Olmutz near Prague [Figure 1].[26] The recipient was a 45-year-old Alois Glogar; a farm laborer who had sustained severe bilateral alkali burns while cleaning out a chicken coop with lime 16 months earlier. The living donor was an 11-year-old boy whose eye had been blinded by a penetrating injury to the sclera. The donor eye was enucleated prior to transplantation and the one cornea was used to provide two 5 mm donor grafts. Although the graft in the right eye failed, the surviving graft in the left eye improved the patient’s visual acuity from counting fingers to 6/36 at 6 months. Zirm subsequently recommended the following points for successful corneal transplantation; exclusive use of human corneas (preferably from young and healthy donors), use of the von Hippel trephine, deep anesthesia, strict asepsis, overlay sutures, use of an AC maintainer, avoidance of touching tissue, and placement of the graft between moist gauze for protection prior to transplantation. Since the first successful corneal transplant, innumerable ophthalmologists have contributed to the development and refinement of corneal transplantation. Their collective achievements allowed improved surgical methodology, technology, and instrumentation; improved understanding of corneal biology; and better control of rejection through anti-inflammatory agents. Three of these deserve special mention. The Russian ophthalmologist Vladimir Filatov (1875-1956) first suggested the use of cadaver corneas ‘in the attempt to find a new source of transplant corneas if the serious difficulty of supply was to be
Figure 1: Dr. Eduard Zirm, the first to perform a successful penetrating keratoplasty (1905) in his operating theatre
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overcome’.[27] This idea was further developed by the American ophthalmologist Richard Paton who established the first eye bank in 1944.[28] Another notable ophthalmologist is the Spanish Ramon Castroviejo (1904-1989) who conducted detailed studies of graft technique in the United States [Figure 2].[29,30] He popularized the use of direct sutures, and was innovative in surgical instrumentation. Several modern instruments bear his name.
The Future The major limitations of modern day corneal transplantation surgery may be classified under the following headings; paucity of donor tissue, graft rejection and failure, and variable visual and tectonic outcomes. Evolution in the field of corneal transplantation is therefore targeted towards overcoming these obstacles. Recent developments with the potential to transform corneal transplant surgery include: A revival of anterior and posterior lamellar techniques [Figure 3], the artificial or bioengineered cornea, the manipulation of corneal endothelial cells as a substitute for transplantation, and the use of the surgical femtosecond laser.[31]
Lamellar keratoplasty Penetrating keratoplasty has traditionally been the treatment of choice for corneal opacification. In more recent years, there has been a renaissance of anterior and posterior lamellar techniques which selectively replace only the diseased layers of the cornea while retaining healthy layers.
Bioengineered cornea The artificial or bioengineered cornea represents the “holy grail” of corneal transplantation; simultaneously nullifying the dual obstacles of donor tissue availability and immunological incompatibility. Ideally, the bioengineered cornea[32] would begin as an acellular stromal scaffold with ex vivo colonization of host endothelial cells, keratocytes, and epithelium. The
Figure 2: Dr. Ramon Castroviejo (right) who was largely responsible for popularizing penetrating keratoplasty in the USA in 1930s and Dr. R. Townley Paton (left), performing one of the first corneal transplants in New York, 1937
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References 1. 2. 3. 4.
a
b
5.
6. 7.
c Figure 3: Three examples of contemporary corneal transplant surgery: (a) Deep anterior lamellar keratoplasty (DALK) with removal of host stroma down to Descemet’s membrane, (b) penetrating keratoplasty (PKP) with combination of interrupted (10-0) and continuous (11-0) sutures, and (c) Descemet’s stripping endothelial keratoplasty (DSEK) with the graft host interface visible in the periphery (arrow)
8. 9. 10. 11.
host cells would be modified to eliminate the original disease characteristics, thereby resulting in a disease-free bioengineered tissue which is genetically and therefore immunologically identical to the host. Mimics of corneal extracellular matrix have recently been used as an anterior lamellar corneal transplant.[33]
Manipulation of corneal endothelial cells Recent advances in the understanding of the cell-cycle activation pathways of endothelial cells in vitro have allowed progress in human corneal endothelial cell culture. The transplantation of cultured corneal endothelial cells has met with some success in experimental settings.[34-39] In future clinical practice, cultured endothelial cells may be implanted either as a monolayer or by injection into the anterior chamber.[31]
Ophthalmic femtosecond lasers Ophthalmic femtosecond lasers are capable of creating precise cuts in the cornea with minimum collateral damage to surrounding tissue, and are being used to perform accurate corneal trephination for donor and recipients. The high degree of accuracy offered by the femtosecond laser may translate into better visual and tectonic outcomes though there are insufficient data to support this conjecture at present.[31]
Conclusion
12. 13. 14. 15. 16.
17.
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21. 22.
23. 24. 25.
From mythological and allegorical tales to reality, corneal transplantation is now established as the most common and indeed the most successful form of human transplantation. Corneal transplantation continues to evolve and emerging techniques offer the potential of a truly customized personal transplant material within a generation. S16
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Castroviejo R. Keratoplasty. Am J Ophthalmol 1941;24:1-20. Polack FM. Ramon Castroviejo 1904-1987. Cornea 2000;19:593-602. Tan DT, Dart JK, Holland EJ, Kinoshita S. Corneal transplantation. Lancet 2012;379:1749-61. Griffith M, Osborne R, Munger R, Xiong X, Doillon CJ, Laycock NL, et al. Functional human corneal equivalents constructed from cell lines. Science 1999;286:2169-72. Fagerholm P, Lagali NS, Merrett K, Jackson WB, Munger R, Liu Y, et al. A biosynthetic alternative to human donor tissue for inducing corneal regeneration: 24-month follow-up of a phase 1 clinical study. Sci Transl Med 2010;2:46ra61. Yokoo S, Yamagami S, Yanagi Y, Uchida S, Mimura T, Usui T, et al. Human corneal endothelial cell precursors isolated by sphere-forming assay. Invest Ophthalmol Vis Sci 2005;46:1626-31. Sumide T, Nishida K, Yamato M, Ide T, Hayashida Y, Watanabe K, et al. Functional human corneal endothelial cell sheets harvested from temperature-responsive culture surfaces. FASEB J 2006;20:392-4.
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Ruberti JW, Zieske JD. Prelude to corneal tissue engineering-gaining control of collagen organization. Prog Retin Eye Res 2008;27:549-77. Peh GS, Beuerman RW, Colman A, Tan DT, Mehta JS. Human corneal endothelial cell expansion for corneal endothelium transplantation: an overview. Transplantation 2011;91:811-9. Okumura N, Ueno M, Koizumi N, Sakamoto Y, Hirata K, Hamuro J, et al. Enhancement on primate corneal endothelial cell survival in vitro by a ROCK inhibitor. Invest Ophthalmol Vis Sci 2009;50:3680-7. Mimura T, Yamagami S, Usui T, Ishii Y, Ono K, Yokoo S, et al. Long-term outcome of iron-endocytosing cultured corneal endothelial cell transplantation with magnetic attraction. Exp Eye Res 2005;80:149-57.
Cite this article as: Crawford AX, Patel DV, McGhee CN. A brief history of corneal transplantation: From ancient to modern. Oman J Ophthalmol 2013;6:S12-7. Source of Support: Nil, Conflict of Interest: None declared.
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