A brief history of corneal transplantation: From ancient to modern.

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 17(th) and 18(th) centuries, true scientific and surgical experimentation in this field did not begin until the 19(th) 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 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.

Introduction

Contemporary corneal transplantation techniques are the result of a culmination of ideas, experimentation, and perseverance 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 some of the pivotal events in the development of corneal transplantation.

Table 1

Considering the evolution and progress of corneal transplantation in terms of seven major epochs

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 (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 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.

Table 2

Major landmarks in the evolution of corneal transplantation 1800-2000

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, 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 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.[1718]

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,[2021] the recognition of the immunological phenomenon of corneal graft rejection by Paufique et al.,[22] and later Maumenee;[23] and the increasing availability of antibiotics in the 1940s and corticosteroids in the 1950s.[12425] 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.

Figure 1

Dr. Eduard Zirm, the first to perform a successful penetrating keratoplasty (1905) in his operating theatre

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 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].[2930] He popularized the use of direct sutures, and was innovative in surgical instrumentation. Several modern instruments bear his name.

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

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]

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)

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 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.[343536373839] 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

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.