Corneal disease is associated with an array of conditions that affect the transparent window at the front of the eye, the cornea. The cornea plays an important role in protecting the eye and helping to refract light.
Various symptoms may present when patients have corneal disease, including pain, blurred vision, sensitivity to light, redness, and tearing.1
Common corneal diseases
Diseases affecting the cornea primarily fall into three categories:
- Keratitis: Involves inflammation, which can be infectious or noninfectious.
- Ectatic: Characterized by changes in corneal shape leading to thinning and bulging, commonly associated with conditions like keratoconus and sometimes arising as a complication of surgeries such as laser-assisted in situ keratomileusis (LASIK).
- Dystrophy: Any of the genetic disorders that cause abnormal deposits in the cornea, including Fuchs’ dystrophy, epithelial basement membrane dystrophy (EBMD), lattice corneal dystrophy, and granular corneal dystrophy. Some forms worsen over time and affect vision.
Other conditions affecting the cornea include bullous keratopathy, corneal abrasion, keratoconjunctivitis, pterygium, and herpetic eye disease, alongside rare conditions like iridocorneal endothelial syndrome.2,3
Many of these conditions often do not require invasive procedures and are treated with eye drops, ointments, and contact lenses, along with possible laser procedures. However, some of these conditions can progress or fail medical therapy; this usually necessitates corneal transplantation.
Conditions requiring corneal transplantation
Conditions that may require corneal transplantation include keratoconus, Fuchs’ dystrophy, refractory corneal ulcers, corneal scarring, secondary corneal edema, corneal tears, and damage from previous eye surgery.4
There are three main types of keratoplasty procedures:
- Penetrating keratoplasty (PK, full-thickness)
- Endothelial keratoplasty (Descemet stripping endothelial keratoplasty [DSEK]/Descemet membrane endothelial keratoplasty [DMEK])
- Deep anterior lamellar keratoplasty (DALK, partial thickness corneal transplant)
During a PK, the surgeon removes a full-thickness section of the cornea and replaces it with a donor cornea. This is in contrast to endothelial keratoplasty (DSEK, DMEK) or DALK, where the surgeon removes and replaces only a specific layer of the cornea.2
History of corneal transplantation with pros and cons
Corneal transplants were first established in 1813. However, they were not performed until 1886 by Von Hipple, when he replaced a human cornea with a rabbit cornea. Eduard Zirm documented the first successful corneal transplant in 1905.5 Over the years, various improvements have been made in corneal transplants with improved surgical techniques and technology.
There has been a transition from full-thickness transplants to increasing numbers of lamellar transplants in recent years. Darlington and colleagues conducted a review spanning from 1980 to 2004, revealing that over 95% of corneal tissues were utilized for PK, with primary indications including pseudophakic bullous keratopathy (PBK), keratoconus, Fuchs’ endothelial corneal dystrophy (FECD), and failed grafts.6
Röck et al. investigated surgical procedure evolution, noting a doubling in corneal transplant rates over two 6-year periods, with a notable increase in DMEK from 2008 to 2016, signifying a shift from full-thickness keratoplasties towards lamellar procedures.7
Subsequent studies by Zhang et al., Le et al., Zare et al., and Park et al. corroborated this trend toward lamellar keratoplasty, particularly DSAEK and DALK, as preferred methods due to their efficacy and decreasing reliance on PK.8,9,10,11
Risk factors for corneal transplantation
Overall, all these procedures come with similar risk factors post-operatively, which include wound dehiscence, endophthalmitis, choroidal hemorrhage, elevated eye pressure, cataracts, swelling of the cornea, and retinal detachment.12 One of the major concerns following keratoplasty is corneal transplant rejection.
Graft rejection refers to the host's immune response against the transplanted corneal tissue, distinct from non-immune mediated failures like primary donor failure, which is characterized by persistent corneal edema post-surgery due to donor graft deficiencies or surgical factors.13 Guilbert et al. found an average time to rejection of 19.8 ± 20.4 months among 299 patients, with 49% progressing to graft failure.14
The differences in complication risk vary based on the procedure. Penetrating keratoplasty has a higher risk of complications due to removing a full-thickness cornea section. This procedure is also associated with an increased healing time of about 1 year as the cornea heals and the wound smooths out; there is also usually a need for suture removal in order to adjust for post-operative astigmatism.
Additionally, full-thickness keratoplasty comes with an increased risk of graft rejection in comparison with endothelial keratoplasty and DALK.13 DSAEK, DMEK, and DALK have less risk for transplant rejection due to less tissue graft use. In addition, healing time is usually less (weeks to months post-surgery).4
Overview of keratoprosthesis with recent research
One of the newer advancements in corneal transplant is keratoprosthesis. This is using a prosthetic cornea instead of a donor cornea during full-thickness keratoplasty.
There are three primary synthetic corneas on the market:
- Boston Keratoprosthesis (“KPro,” Massachusetts Eye & Ear Infirmary, Boston, MA)
- AlphaCor (Addition Technology Inc., Des Plaines, IL)
- Osteo-onto keratoprosthesis, also known as the “OOKP”
The OOKP is recommended for cases of bilateral blindness resulting from severe, end-stage ocular surface diseases—provided there is preserved retinal and optic nerve function. At the same time, the Boston Type I Keratoprosthesis is suitable for eyes with sufficient tear film and a functional blink mechanism.15
Boston Type I Keratoprosthesis
Of the three being used, the most common one utilized in the US is the Boston Type I Keratoprosthesis, which is composed of a clear plastic optic and back plate surrounding a corneal graft, secured with a titanium locking ring.
Figure 1 shows a post-operative slit-lamp image of the Boston Type I Keratoprosthesis device.16
Figure 1: Courtesy of Santos et al.
The procedure entails partial-thickness trephination of the host cornea, followed by full-thickness corneal resection and attachment of the keratoprosthesis using sutures. The Boston Type I Keratoprosthesis is primarily considered for patients with multiple failed PKs or severe ocular surface diseases like limbal stem cell failure due to conditions such as Stevens-Johnson syndrome, ocular cicatricial pemphigoid, aniridia, or chemical injury.16
Other indications include ocular cicatricial pemphigoid (OCP), various autoimmune diseases, ocular burns, and conditions with poor prognosis with traditional PK. Some surgeons now consider the Boston Type I Keratoprosthesis a primary treatment option for repeat graft failure and aniridia and, in a smaller subset, herpetic keratitis and pediatric corneal opacities.17
The Boston Type II Keratoprosthesis, featuring a longer optic extending through the upper eyelid, is reserved for the most severe cases of cicatrizing ocular surface diseases.16
Considerations and contraindications of Boston Keratoprosthesis
The decision to pursue keratoprosthesis (KPro) surgery should be carefully considered in patients who may benefit from traditional keratoplasty. Contraindications include patients with ocular co-morbidities, such as end-stage glaucoma, retinal pathology, or phthisis, particularly if they have impaired pre-operative vision or lack light perception.
While KPro surgery was historically limited to those with bilateral blindness, having good vision in the other eye is no longer a strict contraindication. It is important to note that patients must be able and willing to adhere to post-operative follow-up and preventative care after undergoing KPro surgery.18
Keratoprosthesis is often indicated following the previous failure of the donor cornea. A study performed by Akpek et al. looked at the short-term outcomes of repeated PK compared to those of Boston Type I Keratoprosthesis.
Investigators found post-operatively, 35% of PK eyes and 45% of KPro eyes achieved best-corrected visual acuity (BCVA) of 20/70, and the 2-year cumulative rate of graft failure was significantly higher for PK eyes (hazard ratio [HR]=3.23; 95% confidence interval [CI], 1.12–9.28; P=.03).
Rates of retinal detachment, endophthalmitis, and glaucoma were similar between groups (P=0.60 for all).19 These results indicate the potential for improved success of corneal transplants utilizing keratoprosthesis.
Additional studies have evaluated the effectiveness of the KPro in recent years. A survey by Zerbe et al. looked at 141 surgical procedures performed at 17 different surgical sites and found that 57% had BCVA ≥20/200 and 19% had BCVA ≥20/40. There was a retention rate of 95%, with an average follow-up of 8.5 months.
Post-operative complications included retroprosthetic membrane (RPM) in 25%, elevated intraocular pressure (IOP) in 15%, and sterile vitritis in 5% of eyes. No cases of infectious endophthalmitis were reported.20 These results highlight KPro as an effective treatment plan for those with indications for keratoprosthesis.
Alternative synthetic corneal transplants
Looking at the other available options for synthetic corneal transplants, AlphaCor and osteo-odonto keratoprosthesis have had similar outcomes to those witnessed with Boston Type I.
A study performed by Jirásková et al. showed the survival rate of the device at 1, 2, and 3 years was 87%, 58%, and 42%, respectively. An additional study performed by Hicks et al. demonstrated post-operative BCVA ranged from Light Perception (LP) to 20/30 with limited post-operative complications.21,22
In a retrospective study looking at the outcomes of OOKP, investigators found a survival rate of 80% at a 20-year time point, along with 60% of the patients achieving a vision of more than 20/60.23 Studies have also looked at the use of the Boston Type 1 and 2 compared to the OOKP. These devices are difficult to compare as the OOKP is meant for later-stage disease while Boston Type I is for less complicated diseases with good tear film.
Boston Type II was created for later-stage disease; however, when compared with OOKP, higher rates of tissue melting and aqueous leak occurred in Type I and 2. In addition, 20% of the Boston Type II and 33% of the Boston Type I KPros required explantation and replacement with an additional KPro or a tectonic corneal graft. However, comparable visual acuity results of 20/40 or better were achieved by Boston Type 1 and 2 and OOKP in patients with Stevens-Johnson syndrome.24
Post-operative complications of keratoprosthesis
The complications following surgery are similar regardless of the type of synthetic cornea used. The main complications include RPM, elevated IOP/glaucoma, and infectious endophthalmitis (IE); however, the most concerning is corneal melting or sterile keratolysis.
A cumulative review of case series that reported corneal melting indicated that with increased follow-up time, there was a higher percent chance of corneal melting, as shown with an average follow-up duration under 1 year of 1.7%. At the same time, follow-ups for 1 to 2 months and 1 to 2 years had a 7% and 11% chance, respectively, of corneal melting.
Management of corneal melting varies based on the severity of the melting seen. With minor cases requiring conservative management and severe having to replace the prosthesis completely.25
The future of keratoprosthesis
The field of corneal transplantation continues to grow, with new technology being invented yearly. Researchers in Melbourne, Australia, are currently working to create an endothelial transplant with the potential to produce multiple synthetic corneas using a single donor tissue.26
They aim to grow cells on hydrogel and make as many as 30 synthetic grafts from one donor tissue. This research would help reduce the shortage of corneas worldwide.26 Additionally, Precise Bio is creating a 3D-printed synthetic cornea with a similar goal.27
Cultivated autologous limbal epithelial cells (CALECs)
Researchers at Massachusetts Eye and Ear have also been investigating using stem cells to create cultivated autologous limbal epithelial cells (CALEC). During corneal transplants, the central cornea is replaced.
However, there may still be stem cell deficits. Investigators are working to utilize CALEC to help overcome this potential problem in transplants. They have shown feasibility and efficacy in the first stages of clinical trials and are currently in the second stage.28,29
Bioengineered porcine construct, double crosslinked (BPCDX)
Additionally, investigators are looking at treatments utilizing naturally derived cell-free implants. Researchers have developed a novel cell-free engineered corneal tissue called bioengineered porcine construct, double crosslinked (BPCDX), along with a minimally invasive surgical technique for its implantation.30
In a pilot study conducted in India and Iran, BPCDX was implanted via an intrastromal pocket in 20 individuals with advanced keratoconus. No adverse events were reported over a 24-month follow-up period.30
Significant improvements were observed in corneal thickness, maximum keratometry, and visual acuity. Notably, all initially blind participants with a logMAR BCVA ≥1.30 and contact lens intolerant achieved a substantial improvement in vision, with restored tolerance to contact lens wear.
This study is currently in phase 2 clinical trials, which suggests that BPCDX could be a promising alternative to traditional cornea transplantation, offering potentially safer and more accessible treatment options for vision restoration.30
Crosslinker-free collagen-based artificial corneas
Another group has also utilized collagen-based artificial corneas. They have developed a non-toxic, crosslinker-free cornea, as cross-linkers are often cytotoxic and need to be removed prior to application in humans.31 The investigators noted that crosslinkers often render the tissue weak and susceptible to degradation, therefore creating collagen-based artificial corneas without crosslinkers improves stability.
Researchers have devised a novel strategy for collagen free of crosslinkers, using a pyrene-conjugated dipeptide amphiphile (PyKC) without modifying the functional groups of collagen. This approach avoids cytotoxic effects associated with traditional crosslinkers and results in optically transparent, mechanically stable collagen implants (Coll-PyKC) capable of blocking UV light and supporting corneal cell growth and function.
Coll-PyKC implants also demonstrate anti-inflammatory properties and can inhibit the propagation of human adenovirus. This crosslinker-free method holds promise for corneal repair and regeneration and potential applications in other damaged organs.31
Artificial endothelial layer
A group in Israel has developed an artificial endothelial layer that can be utilized as an alternative to DMEK surgery for chronic corneal edema.32 The EndoArt is an adaptable artificial endothelial layer, just 50 micrometers thick, designed to conform to the posterior curvature of the cornea. Its primary role is to serve as a barrier to fluids within the posterior stroma, effectively replacing the damaged endothelium.
A study of two patients, performed in 2021, showed patient 1 experienced a reduction in central corneal thickness (CCT) from 730μm pre-operatively to 593μm at Day 1 post-operatively, while patient 2 saw a decrease from 761μm pre-operatively to 487μm during the same interval.32
Despite both patients encountering lamella dislocation, their satisfaction levels remained high, and they reported an overall improvement in visual clarity. Following a repositioning procedure, CCT was promptly restored, and at the 17-month follow-up, it remained stable at 526μm for patient 1 and 457μm for patient 2.32
These results show that EndoArt leads to rapid corneal deturgescence and can be a possible alternative to DMEK.
In conclusion
Corneal disease affects many individuals in the United States and throughout the world. With the use of corneal donor transplantation and synthetic corneal transplants, ophthalmologists can continue to help provide personally tailored treatment options for their patients.
The growth within the field of corneal transplantation will continue throughout the years, and it is essential to understand the available options and continue utilizing what works best for your practice and patients.
