To understand the future of keratoprostheses it is necessary to start from the current situation. Today, the two most widely used types of keratoprostheses are the osteo-odonto-keratoprosthesis (OOKP) – with more than 50 years of experience – and the Boston keratoprosthesis (B-Kpro) – with more than 12,000 units implanted until March 2015. To these can be added the MICOF in Russia, as well as the emerging designs: Alphacor, KeraKlear and Miro Cornea (see chapter 8.2). Of this last group, the first one started with strength, but its use has stalled due to the limited results; the last two show promising results, although with a short follow-up time.

ADVANCES AND RESEARCH IN BOSTON KERATOPROSTHESIS

The aspects related to the application of the B-Kpro have been exposed in section 8.4 of this work. In recent years, advances in the design and management of B-Kpro have multiplied, stimulated above all by the need to reduce the rate of postoperative complications. These can be grouped into four categories: infection, chronic inflammation, glaucoma and corneal necrosis or keratolysis.

Prevention of infection and chronic inflammation

The rate of infections and endophthalmitis has been reduced exponentially in the last decade thanks to the daily prophylactic use of broad spectrum antibiotics. So, a daily drop of polymyxin sulphate B/trimethoprim (Polytrim^®) has been shown to be very effective in the prevention of endophthalmitis in patients with non-autoimmune pathologies – the majority of patients with B-Kpro¹ –. The usefulness of periodic cleaning of the surface of the prosthesis with antiseptics such as 5% povidone iodine has also been observed.

Even in the absence of infection, one of the biggest problems associated with B-Kpro is a state of chronic inflammation of variable degree. In its severe form it can lead to keratolysis, but a low level is possibly the main cause of retroprosthetic membranes, one of its most frequent complications. These tend to originate in the graft-receptor junction² and therefore would be due to an excessive scarring response. To improve the access of the aqueous humor and the nutrition of the corneal tissue, holes were incorporated in the posterior plate, and more recently its PMMA material has been replaced by titanium³. It has been shown that using a titanium plate somewhat larger than the graft strengthens its apposition with the recipient cornea, which would reduce the formation of retroprosthetic membranes⁴.

In order to facilitate research in this area, our group at the Massachusetts Eye and Ear Infirmary (MEEI) has developed a miniaturized design or m-Kpro (Figure 1) that can be implanted in rodents. With it, it has been possible to assess the inflammatory response by determining the levels of cytokines or other markers⁵, and to demonstrate that inhibitors of tumor necrosis factor alpha (TNF-α) such as infliximab decrease inflammation in a model after chemical burn⁶.

Reducing low-grade chronic inflammation would also have beneficial effects on the rate of other complications such as optic neuropathy, epiretinal membrane or retinal detachment. On the other hand, the light from the surgical microscope during surgery of B-Kpro does not seem to suppose a substantial risk of retinal damage⁷. All this does not diminish the importance of closely monitoring these patients, since the signs of chronic inflammation are often subtle, while their consequences can be disastrous.

Glaucoma prevention

One of the postoperative complications that limits mostly the final visual outcomes is glaucoma. In a cohort of 106 eyes of 87 patients with B-Kpro type 1 followed for a mean of 3.3 ± 1.0 years, 66% had preoperative glaucoma⁸. Due to the inability to visualize the optic disc previously, this diagnosis could only be corroborated after surgery. Of the patients without previous signs of glaucoma, 75% developed it de novo. Due to the difficulty in measuring intraocular pressure (IOP) – only by finger palpation – and to obtain reliable visual fields – only in 59% in this series – the main parameter of follow-up is the papillary excavation, which was <0.8 in 31% of the eyes, often in the presence of a pallor that suspects other mechanisms of neuropathy in addition to the elevation of IOP. 65% of cases with B-Kpro and glaucoma were operated on at some point and only 30% did not show progression⁸. Those who received a valvular implant showed a significantly slower progression (of the excavation) than those without an associated glaucoma surgery.

Based on these results, the MEEI group recommends implanting a valvular device along with B-Kpro in all patients with confirmed diagnosis or glaucoma risk factors. Among the available valvular implants, Ahmed's seems to provide better initial control of IOP. Even so, the prevention of glaucoma in the long term continues to represent a great challenge that we are trying to address through three lines of research. In the first place, we developed a new valve based on ferrofluid nanoparticles, which allows to establish not only an opening pressure but also a true closing pressure⁹. Both values ​​can be customized depending on the desired target IOP. Initial results in animals have shown good tolerance and retention of the implant (Figure 2), and a design with certain modifications is in the last experimental phase prior to clinical trials in humans.

A second line comprises the development of contact lenses as a reservoir for continuous drug release. Studies with latanoprost in animals (Figure 3A) have shown good tolerance and in vivo retention of the lens, with therapeutic levels in the anterior chamber maintained for a period of one month¹⁰. This is currently in the evaluation phase of efficacy in animals, prior to clinical trials in humans. We hope that this lens will be especially useful in patients who are not very compliant with the treatment. The next step includes the use of other drugs, such as antibiotics, antifungals or corticosteroids, the latter also at the stage of animal experimentation (Figure 3B)¹¹.

The third line of research in glaucoma focuses on the development of new devices to measure IOP. Our group collaborates with a German engineering team that has developed a wireless IOP-meter called WIT (Wireless Intraocular Transducer)¹². With an external diameter of 11.3 mm, an internal diameter of 7.0 mm and a thickness of 0.9 mm, the WIT is designed to be implanted in the iridocapsular space (sulcus) of a pseudophakic eye. The IOP is measured externally thanks to a radio wave reader that serves as a charger for the device. Melki's group successfully implanted a WIT in a human eye, which provided repeated and reliable measurements of IOP for 18 months and, after detecting an elevation of the same, allowed immediate initiation of the hypotensive treatment¹³.

Prevention of keratolysis

Corneal tissue necrosis or keratolysis usually begins around the optical cylinder of the B-Kpro. This creates a space between the corneal graft and the implant that can facilitate the entry of microorganisms and tissue debris into the eye (Figure 4). To prevent it, we investigated the possible use of materials such as titanium to improve the adhesion of the prosthesis to the donor tissue. In an ongoing study, we observed that by introducing a titanium ring around the optic stem, the graft tends to remain strongly adhered (Figure 5), which became more evident when the surface of the titanium was rough¹⁴.

We have also explored possible alternatives to donor corneal tissue, such as corneas of animal origin or human corneas previously irradiated with gamma rays¹⁵. The preliminary results of the photodynamic crosslinking of the cornea that supports B-Kpro, through a standard Dresden’s protocol of riboflavin and UVA, indicate that it may improve the anatomical retention by increasing the resistance to keratolysis, especially in patients with autoimmune pathology¹⁶.

Improvement of the aesthetic appearance

Despite being situations of extreme commitment to vision and few alternatives, the appearance of the eye carrying a keratoprosthesis may constitute an aesthetic problem for some patients or their environment. In the case of the B-Kpro, the PMMA model gives rise to a whitish coloration that simulates a pale iris around a dark pupil, but the titanium plate makes this more apparent by its metallic shine and contrast with the holes (Figure 6). To improve the cosmetics, colored contact lenses are effective (Figure 7), although their use is limited by the not always easy tolerance and by its cost¹⁷.

There is the possibility of coloring the titanium plate in a biocompatible way by ionic anodization, without the need to introduce colorants¹⁸. This results in different tones between brown and blue, depending only on the thickness of the applied titanium oxide layer (Figure 8). Thus, an appearance more similar to that of the contralateral eye can be obtained.

ADVANCES AND PERSPECTIVES IN KERATOPROSTHESES OF AUTOLOGOUS SUPPORT

The idea of ​​using a tooth as a support for a keratoprosthesis, proposed by Benedetto Strampelli more than half a century ago, was received with disbelief among the ophthalmologists of the time. However, the persistence of Strampelli and other pioneers, together with the good results, made the OOKP the reference keratoprosthesis for decades. Aspects related to the current application of the OOKP are discussed in section 8.3 of this work.

OOKP presents complications in common with other keratoprostheses such as glaucoma or vitreous-retinal type. Some of them are reduced with modifications that have then been applied in a standard way to other models, such as lens extraction, iris and anterior vitrectomy, advocated by the Falcinelli group together with the replacement of labial mucosa by buccal mucosa¹⁹. Others, such as retroprosthetic membranes and keratolysis, occur less frequently than with B-Kpro.

The most specific drawbacks of the OOKP are found in (a) the complexity of the technique, which initially required 3 surgical phases separated by months, (b) the non-availability in edentulous patients of the adequate tissue, as well as the problems derived from its extraction, and (c) the marked limitation in the visual field. The first has been reduced by bringing together in one the first two stages of the preparation of the recipient with mucosal graft and the prosthesis. To solve the second, Falcinelli proposes using the tooth of a relative¹⁹. Temprano introduced the osteokeratoprosthesis (OKP), which uses a hard bone disc taken from the patient's tibia as support (chapter 8.3.2), with anatomical and visual results comparable to those of OOKP²⁰ (Figure 9). The third has stimulated the development of new designs of the optical cylinder to obtain a wide-angle effect²¹. A less frequent complication, such as the growth of the mucosa over the optic, which sometimes requires repeated resections, can be avoided with the use of mitomycin C²².

Different cements have also been evaluated to join the optics with the dentine, although the usual "acrylic for bone" is the one that gave the greatest resistance followed closely by the universal resin²³. Finally, new materials have been sought to replace the osteo-dentary tissue, such as the hydroxyapatite of coral origin, first proposed by León and Barraquer²⁴ or various synthetic materials of the ceramic type, bioactive crystal²⁵ or metals such as titanium²⁶. Although all of them can be cemented to optics, none replaces the key function – sometimes forgotten – that makes the humble alveolus-dental ligament: the physiological union of the "mineral" part of the prosthesis (dentine etc.) with the autologous bone tissue, for now the only one able to heal with the surrounding living tissues.

WHAT DOES THE FUTURE HOLD?

Keratoprostheses offer the possibility of replacing the pathological cornea with a perfect optic, without the possibility of opacification and with unlimited availability. The advances collected here are only a small sample of the moment of boiling in which this field is located. Current designs are aimed at improving results by using more biocompatible materials that allow greater integration with the recipient tissue and provide the patient with good long-term maintained vision. However, postoperative complications remain the great enemy to beat. In short, the ideal keratoprosthesis is yet to be discovered, although every day we are closer to achieving this.