Dengyi Zhou

Eye transplantation has long been one of the most complex goals in medical science due to the intricate structure of the eye and its vital connections to the brain. While advances have been made in partial transplants like corneal grafts, the prospect of full eye transplantation has remained largely theoretical. However, recent developments, including the first whole eye transplant attempt in May 2023, have brought this ambitious goal closer to realisation. This article explores the current state of eye transplants, the advancements that have enabled recent breakthroughs, and the potential future of this field.

Corneal Transplants: The Current Gold Standard

Corneal transplantation or keratoplasty is the most commonly performed and also the most successful allogenic transplant worldwide (1). The first corneal transplant was performed by Zirm in 1905 (2). This procedure involves replacing a damaged cornea with a healthy donor cornea, which can restore or significantly improve vision for conditions like keratoconus or corneal scarring. The success rates are high, with one-year graft survival rate of around 90% and five-year survival rate of around 75% (3).

Traditionally, penetrating keratoplasty has been the standard technique, which involves the transplantation of all corneal layers. However, advancements in surgical methods have led to the development of targeted techniques such as Deep Anterior Lamellar Keratoplasty (DALK), Descemet’s Membrane Endothelial Keratoplasty (DMEK), and Descemet’s Stripping Automated Endothelial Keratoplasty (DSAEK). These newer approaches replace only the damaged layers of the cornea while preserving the healthy and functioning layers. Such innovations have improved recovery times and reduced the risk of rejection, further solidifying the reliability and effectiveness of corneal transplants in restoring vision (4).

Recent Breakthrough: The First Whole Eye Transplant Attempt

In November 2023, surgeons in New York achieved a groundbreaking milestone by performing the first-ever combined whole eye and face transplant for a 46-year old man who sustained catastrophic facial and ocular injuries from a high-voltage electrical accident (5). The procedure aimed to restore both functional and anatomical integrity after severe tissue loss, including damage to the left globe.

At one year post-transplant, the donor eye has demonstrated promising signs of viability: normal intraocular pressure, perfusion of retinal and choroidal vessels, persistence of some retinal architecture on optical coherence tomography (OCT), and minimal responses detected on electroretinography. Despite these encouraging findings, visual function remains at no light perception. The optic nerve exhibits pallor, and OCT shows significant retinal tissue loss, highlighting the challenges in achieving true visual restoration (5).

The primary obstacle lies in the regeneration and functional integration of the optic nerve, which contains over a million axons crucial for transmitting visual signals to the brain’s visual cortex (6). Current technology and biological understanding do not yet allow for the regeneration of severed axons or their reconnection to central visual pathways.

While the procedure represents an unprecedented step forward, it underscores the critical need for advances in neural regeneration and functional integration to make whole eye transplantation a viable solution for restoring vision in cases of severe ocular trauma or degenerative conditions.

Nerve Regeneration: The Key Challenge

For whole eye transplants to be successful, regenerating the optic nerve is essential. Current research into neural regeneration has shown promising results, especially in preclinical studies. For example, Lim et al. (7) used a combination of gene therapy, visual stimulation, and pharmacological agents to promote long-distance, target-specific regeneration of retinal ganglion cell axons in mice. These findings underscore the potential for developing therapies to restore optic nerve connectivity and visual function.

Neurotrophic factors—proteins that support neuronal growth and survival—are also being investigated as a means to encourage optic nerve regeneration. These factors have shown efficacy in promoting axonal regrowth in mouse models, although translating these findings to human applications presents considerable challenges (8). The complex structure and functional requirements of the human optic nerve, along with the need for precise integration with central visual pathways, highlight the importance of continued research and innovation in this field.

Emerging Technologies: Gene Editing and Stem Cell Therapy

Gene editing and stem cell therapy represent two of the most promising therapeutic strategies for retinal diseases and optic nerve regeneration. The CRISPR-Cas9 gene-editing tool has enabled precise modification of genes involved in ocular development and function (9). In preclinical animal models, gene editing has demonstrated potential in reversing hereditary forms of blindness, such as those caused by mutations in retinal dystrophy genes (9). However, significant work remains to validate the safety, efficacy, and long-term outcomes of CRISPR-based interventions in human clinical trials.

Stem cell therapy has also shown considerable promise, particularly in retinal diseases where retinal pigment epithelium (RPE) dysfunction is central to pathogenesis. Stem cells can be differentiated into RPE cells, which are critical for the maintenance of retinal health and function. Clinical trials involving stem cell-derived RPE cell transplantation have reported encouraging outcomes, especially in patients with age-related macular degeneration (AMD), a leading cause of irreversible blindness. These trials have demonstrated improved visual acuity and retinal function, offering hope for future treatments for AMD and other degenerative retinal diseases (10).

Artificial Vision: Retinal Implants and Prosthetics

While biological transplants have limits, artificial vision systems offer a promising alternative for certain types of blindness. Retinal implants, such as the Argus II, uses an electrode array to stimulate remaining viable inner retinal cells, providing patients with advanced retinal degeneration the ability to perceive basic visual information, such as light and shapes (11).

Recent advancements in retinal implants are focused on enhancing both resolution and longevity. Nanotechnology innovations have led to the development of high-resolution electrode arrays, which hold the potential to deliver more detailed visual information (12). Additionally, Maya-Vetencourt et al. (13) subretinally injected semiconducting polymer nanoparticles to rescue vision in a rat model of retinal dystrophy. These breakthroughs are paving the way for next-generation retinal prosthetics with enhanced functionality, potentially enabling users to recognise faces and navigate complex environments.

Ethical Considerations

The field of eye transplantation and vision restoration raises significant ethical concerns, particularly around the use of gene editing, stem cell-derived transplants, and whole-eye transplantation (6). These advancements introduce challenges related to accessibility, affordability, and equity in healthcare, as well as the allocation of donor eyes. Ethical considerations also extend to the psychological and emotional impact on recipients and donors’ families. Moreover, artificial vision systems must undergo rigorous testing to ensure their safety and little is known about their long-term side effects. Balancing innovation with ethical responsibility is essential for the sustainable development and equitable implementation of these transformative technologies.

Conclusion

While a fully functional eye transplant is not yet achievable, recent advancements, including the world’s first whole eye transplant attempt, have highlighted the potential of this field. Current corneal transplants continue to provide vision-restoring solutions, and innovations in optic nerve regeneration, gene editing, stem cell therapy, and artificial vision are rapidly pushing the boundaries. As technology advances, the prospect of restoring full vision through eye transplants or bioengineered solutions seems closer than ever, holding great promise for future generations.

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