Although the first successful documented human corneal transplant dates back to just over 100 years ago¹, it became one of the most widespread and reliable transplants. It seems appropriate to look back to highlight significant milestones in the rich evolution of keratoplasty and pay tribute to the many colleagues who with their inspiration and talent conceived the idea and made it happen despite painful failures, laying the foundations of what has been become one of the success stories of the twentieth century and a triumph of perseverance and dedication².

EARLY HISTORY OF KERATOPLASTY

The idea of exchanging the cornea

Although it had been suggested since antiquity - some references would go back to ancient Egypt around the year 2000 BC³ - the idea of completely restoring an opaque cornea was a product of the late eighteenth century. It was a Frenchman, Pellier de Quengsyⁱ (Figure 1), who in 1789 proposed the replacement of an altered cornea for the first time. He suggested fixing a thin crystal disk in a silver ring sutured to the sclera⁴, which represents the first idea that exists about a keratoprosthesis, although he never carried it out⁵. In fact, few practical advances were made to achieve that dream until the 19th century, when the pioneering surgeons carried out extensive research on cornea transplantation, both in animals and humans.

The first experiences

There is controversy about who was the first to think about replacing opacified corneas with living tissue⁶. Although the original idea of the corneal graft belongs to the German surgeon Himlyⁱⁱ, the success has been generally attributed to his pupil Reisingerⁱⁱⁱ, who began experimenting with rabbit corneal transplants in 1818⁷. He coined the term "keratoplasty" in 1824 and suggested the possibility of transferring corneal tissue from an animal to replace the damaged human cornea⁸. The majority of its results were, however, failures due to endophthalmitis or graft opacification.

The next milestone in the history of corneal transplantation was carried out in the Egyptian desert around Cairo in 1837, when Bigger - a Dublin surgeon, a captive of the Bedouins of the Sahara - successfully performed a corneal homograft on a gazelle that was his pet, blinded by a corneal wound^2,7. Later he experimented with rabbits and reported his findings. In 1844, before the introduction of anesthesia and asepsis, the New York ophthalmologist Richard Sharp Kissam (1808-1861), inspired by Bigger's experiences, changed the opaque cornea of the only functional eye of a young Irishman using a pig of 6 months as a donor. The patient's vision improved, but the cornea became opaque in two weeks⁹.

The first keratoplasties in humans

It was not until 1866 in Germany, when von Hippel^iv (Figure 2), using iodoform as an antiseptic, performed the first successful keratoplasty in a human¹⁰. He grafted the full-thickness cornea of a rabbit into the lamellar bed of a young patient. Thus, he initiated a new era in cornea transplantation, characterized by advances in its surgical technique. von Hippel focused his efforts on lamellar keratoplasty (LK), since he believed that corneal transparency depended mainly on the integrity of the endothelium and Descemet's membrane.

One of his main contributions was the invention in 1891 of the circular clockwork trephines (Figure 3), which quickly replaced the scalpels and the cork borers. The idea had previously been suggested but never attempted by Erasmus Darwin (Charles Darwin's grandfather) at the end of the 18th century¹¹. In this way, the trephine became the main instrument of modern corneal surgery, allowing a safer corneal incision and avoiding lesions of the iris, lens and vitreous to a large extent.

The first attempt to use human corneas as a donor - of fetal origin - is attributed to Sellerbeck in 1878. Although the idea that living tissue should come from an individual of the same species was already formulated at the end of the 19th century, the insistence of Von Hippel against it may have delayed the evolution of keratoplasty for decades, until it was accepted way into the 20th century. Because full-thickness corneal transplantation produced many complications, such as infection and leakage of aqueous humor, until the early twentieth century, LK was the standard technique for the few keratoplasties performed each year¹².

The success of penetrating keratoplasty

After many decades of errors and unsuccessful trials, the first penetrating keratoplasty (PK) that remained transparent in humans is attributed to the Viennese Eduard Konrad Zirm (1863-1944), on December 7, 1905 in a small town called Olomouc, Moravia – nowadays the Czech Republic¹ –. The patient was an unfortunate farmer who had burned his eyes with lime and presented with a vision of counting fingers. Zirm performed penetrating grafts on both eyes using the corneas of an 11-year-old boy who had been blinded by trauma, which he had enucleated just before the transplant. The graft of the left eye remained transparent and achieved a visual acuity of 0.17 (Figure 4).

From his experience, Zirm established the fundamental principles of keratoplasty: the careful selection of cases and the exclusive use for the grafting of a young and healthy human cornea, of adequate anesthesia and asepsis, of von Hippel's trephine and of superimposed sutures, protect the graft with gauze moistened with saline and avoid any contact of the antiseptic with the cornea. Except for changes of a technical nature, these principles have remained in force until now^2,7.

THE DEVELOPMENT OF KERATOPLASTY IN THE 20^TH CENTURY

Although Zirm identified several of the key concepts of PK, it took almost 50 years and the effort and dedication of a number of great personalities in the matter, to transform those methods into the modern techniques of corneal transplantation. In the first decades of the last century there was important research regarding the shape of the graft, the size and the suture techniques. The systematic work on animals by Galo Leoz Ortín in Madrid¹³ and those of clinical pioneers such as Magitot in Paris¹⁴ and Elschnig^v in Prague, who emphasized the value of the small diameter penetrating graft and the superimposed sutures¹⁵, stand out. In 1930, Sir Thomas Tudor^vi, in Cardiff, exhibited a series of successful rabbit grafts, followed by surprising results in humans⁷.

The normalization of penetrating keratoplasty

The next big step was the demonstration, by the Russian ophthalmologist Vladimir Filatov (1875-1956) (Figure 5), that the corneal tissue could be collected and used post mortem. During the 1930s he established a large clinic in Odessa and, on a series of 842 corneal transplants from cadavers, concluded that PK was superior to LK¹⁶. Thanks to this extensive experience, he described most of the main complications and technical problems associated with the PK and devised a series of surgical instruments and innovations that have greatly contributed to advances in corneal graft surgery¹⁷.

However, no name has had such a large influence on modern keratoplasty as the Spanish ophthalmologist Ramón Castroviejo^vii. In 1931, as a fellow of the Mayo Clinic, he perfected the techniques of PK¹⁸. In 1941, in the city of New York, he developed the square-shaped graft (Figure 6), with the use of superimposed sutures, and designed numerous instruments that facilitated the realization of PK¹⁹. The organization in 1944 of the first eye bank, by his friend and collaborator Richard Townley Paton (1901-1984)²⁰, allowed an easier obtaining of corneas. In a few years, New York became the world reference center for keratoplasty²¹. The square PK of Castroviejo continued to be popular until the 1950s, when the improvement of instrumentation along with the demand for aesthetically better results gave way again to the circular format. He also invented the electrokeratome or "keratoplastotome", a mechanized instrument to obtain lamellar cuts (video 1.3.2).

Keratoplasty and the progress of microsurgery

The way in which keratoplasty is practiced today, depends to a great extent on a series of advances, in what from the mid of the 20th century would come to be called microsurgery. The introduction of the surgical microscope led to the development of new instruments and new techniques. One of those that supposed a change of paradigm, was the substitution of the superimposed sutures by the ones "border to border", either independent or continuous. These were introduced in 1949 in Barcelona by José I. Barraquer (1916-1998)²², later considered the founder of refractive keratoplasty. His father, Ignacio Barraquer (1884-1965) had performed the first cornea transplant in Spain in 1940²³, and it was his brother Joaquín (1927-2016) who in 1962 created the first eye bank in continental Europe (Figure 7) (videos 1.3.3 to 1.3.5). José Barraquer already devised at that time, techniques to obtain stepped grafts "in mushroom" or "top hat" shapes (videos 1.3.6 and 1.3.7), as well as the carving of lamellar grafts by freezing the tissue and using a miniaturized lathe (video 1.3.8), a technique that he called "keratorheusis", and advocated the later ones of keratomileusis and keratophakia.

In addition to advances in microsurgery techniques, in instrumentation and suture materials, the second half of the last century is characterized by the progress of pharmacology, with the introduction of antibiotics, corticosteroids and immunosuppressants, viscoelastics, etc., as well as a greater knowledge of corneal immunobiology. All this made keratoplasty one of the most performed transplant surgeries in the world. The list of other relevant contributors to the art and science of keratoplasty in this period is stellar: Arruga, Forstot, Maumenee, Kaufman, Sourdille and Franceschetti, among others².

The crucial role of the eye banks

As PK matured and became an increasingly common procedure, the demand for corneas increased. For its part, LK was also popularized, especially by the French school of Louis Paufique and Jacques Charleux in Lyon²⁴. All this led to the creation of eye banks, from the aforementioned by Paton in New York and Barraquer in Barcelona, to the one established in London in 1952 by Sir Benjamin Rycroft⁷, and the development of new and more efficient forms of corneal preservation.

In the 1970s, the McCarey-Kaufman medium was introduced²⁵, the first capable of preserving the viability of an isolated cornea at 4 °C for one week, while Doughman et al. later applied hot tissue culture techniques to extend conservation beyond one month²⁶. The cultivation and storage of corneas long term made possible better logistics and safety, facilitating checking the viability and sterility of the tissue and ascertaining its histocompatibility, as well as the exchange between centers²⁷.

Towards the 21st century and beyond

Corneal transplantation has evolved in a remarkable way in the last decades. Although PK represented the "gold standard" of this surgery for more than a century, the selective substitution of corneal components has emerged as an unstoppable tendency in its different modalities of anterior and posterior LK. The historical development of these will be the subject of other chapters throughout this book. Keratoplasty in the 21st century is presented as a field full of vitality and new and fascinating perspectives. The dream of Pellier de Quengsy has given way to a reality that surpasses it, but we still do not know how far it will lead us.