Corneal Replacement Device

What Is A Corneal Replacement Device?

A corneal replacement device, also known as an artificial cornea or keratoprosthesis (KPro), is a medical device used to replace a damaged, diseased, or distorted cornea to treat corneal opacity/blindness [1]. KPros are intended for patients with irreversible corneal blindness in whom repeat donor corneal transplants have failed or because other treatment options would be expected to fail. There are an estimated 12.7 million people worldwide waiting for corneal transplants; KPros are intended as an alternative option to help offset the low supply of donor corneas [2]. A corneal transplant involving an artificial cornea is called a prostho-keratoplasty.

What Is The Cornea?

The cornea is the transparent, dome-shaped front layer of the eye that is responsible for transmitting and refracting light into the eyes to allow for vision as well as regulating fluid pressure within the eye. There are three main layers of the cornea:

1. Epithelium: a thin multicellular epithelial tissue layer that acts as a barrier to protect the cornea against dust, bacteria, other particulates, and ultraviolet radiation. This layer is also responsible for absorbing oxygen and nutrients from tears and distributing these nutrients to the remainder of the cornea. Epithelial cells are constantly being produced with it taking about one week for the entire corneal epithelium to be replaced.
2. Stroma: a thick middle layer (constitutes about 90% of corneal thickness) composed primarily of extracellular matrix (ECM), regularly arranged collagen fibers, and interconnected keratocytes that provides the cornea with its strength and dome-shaped structure.
3. Endothelium: a simple squamous (cells are flat and scale-like) monolayer of mitochondria-rich cells that regulate the balance of fluid and solute in the cornea, keeping it thin and transparent.

Pathological Conditions

A clear and healthy cornea is required for vision, so when the cornea becomes damaged, diseased, or distorted, light is not able to be transmitted and refracted properly, causing blurred vision or blindness depending on the severity of the damage [3]. One way that vision can be compromised is if the cornea becomes cloudy; the cornea can become cloudy due to various reasons such as the epithelium layer being unable to constantly produce new cells, the ECM and collagen in the stroma becoming more randomly arranged, or the endothelium layer being unable to properly regulate fluid pressure.

According to the World Health Organization (WHO), corneal opacity is the 4th largest cause of blindness globally (5.1%) after cataracts (51%), glaucoma (12%), and age-related macular degeneration (AMD). Corneal opacity is a result of significant scarring or trauma of corneal tissue due to infectious and inflammatory eye diseases such as trachoma. A global estimate of 4.2 million people are afflicted with corneal opacity with an additional 2 million people afflicted with trachoma, which can lead to corneal opacity if not treated. Damage from corneal opacity is irreversible and the only currently available treatment is a surgical cornea transplant, also known as keratoplasty [4].

Treatment Options

There are several keratoplasty options varying from partial to full corneal thickness transplants as well as choosing between a corneal donor or artificial cornea. Current keratoplasty procedures include:

• Anterior Lamellar Keratoplasty (ALK): the surgeon selectively removes the front, scarred part of the cornea and replaces it with a matching area from a donor cornea. This procedure is less invasive and may or may not need sutures depending on the amount of cornea replaced.
• Deep Anterior Lamellar Keratoplasty (DALK): the surgeon removes the cornea down to Descemet’s membrane and is most useful for when only the endothelium layer functions normally.
• Descemet’s Membrane Endothelial Keratoplasty (DMEK): the surgeon removes the patient’s endothelium and descemet’s membrane and replaces them with donor tissue (~5% of inner corneal thickness).
• Descemet’s Stripping Endothelial Keratoplasty (DSEK): the surgeon removes the patient’s descemet’s membrane and replaces it with a partial thickness graft of a transplanted disc of posterior stroma, descemet, and endothelium (20% – 30% of inner corneal thickness).
• Penetrating Keratoplasty (PK): a full-thickness transplant in which the surgeon uses a trephine to make a full-thickness resection of the patient’s cornea and places a full-thickness corneal graft. Interrupted and/or running sutures are placed radially at equal tension to minimize postoperative astigmatism.

Any of these procedures can be done with a donor cornea, but artificial corneas can only be transplanted with a full-thickness removal of the existing cornea.

How Artificial Corneas Are Transplanted

The basic prostho-keratoplasty procedural steps are:

1. Mark the center of the patient’s cornea using a Sinskey hook and measure the cornea to determine the appropriate transplant size.
2. Trephine (circularly cut) the donor cornea to match the size of the patient’s cornea.
3. Assemble the keratoprosthesis by sandwiching the corneal graft between the front and back plates of the KPro device.
4. Trephinate the patient’s cornea to remove the entire thickness of the abnormal or diseased corneal tissue.
5. Create a hole in the trephinated groove or the corneal periphery and inject Healon or a similar substance into the anterior chamber to preserve anterior chamber depth and stability.
6. Insert the Kpro into the trephinated groove to replace the removed corneal tissue.
7. Secure the assembled KPro to the patient’s remaining corneal tissue using interrupted and/or running sutures.
8. Rotate the sutures to bury the knots.

Complications of Keratoprostheses

While the use of keratoprostheses has gained popularity due to advances in materials, designs, and surgical techniques, it remains a controversial topic among ophthalmologists and corneal specialists due to possible postoperative complications as well as the high level of care needed. The three most commonly reported postoperative complications include:

1. Elevated Intraocular Pressure (IOP)/Glaucoma: a disease that occurs when fluid (aqueous humour) builds up in the front part of the eye, resulting in increased eye pressure that damages the optic nerves [5]. Glaucoma is the largest threat to vision in KPro patients with a reported incidence preoperatively in KPro eyes of 60-76%; postoperative elevated IOP has been shown in 15-38% of KPro eyes. Many suspect that the cause of this is due to gradual closure of the anterior chamber angle, which determines the rate at which aqueous humour drains out of the eye, but the cause is not definite. Another complication is that IOP cannot be reliably measured once a KPro is implanted so it is recommended that existing glaucoma be treated/managed prior to keratoplasty. This complication is often managed in close consultation with glaucoma specialists and often requires filtration surgery with aqueous shunts and topical IOP-lowering agents [6].
2. Infectious Endophthalmitis (IE): a purulent inflammation of intraocular fluids (vitreous and aqueous) due to infection that often results in vision loss. Acute cases are caused by gram-positive/negative bacteria and are most often seen within 6 weeks postoperative; chronic cases that occur outside the 6-week period are commonly caused by slowly progressive infections such as Propionibacterium acnes or fungus. The incidence following penetrating trauma is 4-13% and can increase to as high as 30% after injuries in rural settings. Treatment depends on the severity of the infection and can include a vitrectomy, surgery to remove infectious debris from the eye, injection of antibiotics or antifungal agents directly inside the eye, or use of antibiotic eye drops [7].
3. Retroprosthetic Membrane (RPM): a situation in which keratocytes in the host cornea activate and form a membrane behind the KPro in the graft-host junction, blocking the visual axis. It is the most common postoperative complication with a reported incidence of 25-65% in clinical studies. To mitigate this issue, Dr. Colby of Massachusetts Eye and Ear Infirmary introduced the idea of using a back plate larger than the host opening and was successful in reducing the incidence of RPM to about 15% and with no wound healing issues [8]. To treat RPM, most cases can be treated with a single session YAG membranectomy [6].

Most Commonly Used Keratoprosthesis Worldwide

Artificial corneal transplants, for many people, offer a way of restoring vision following injury or disease related congenital forms of blindness. The Boston Keratoprosthesis (Boston KPro), developed by the Massachusetts Eye and Ear Infirmary (MEEI) and manufactured by J.G. Machine, is the most commonly used KPro in the world. The device was Food and Drug Administration (FDA) approved in 1992, and CE-marked in 2014, resulting in more than 12,000 devices implanted worldwide as of March 2015 [9].

Other KPros on the market or in development include the osteo-odonto-keratoprosthesis (OOKP), the CorNeat KPro by CorNeat Vision, and the GORE-TEX Eye by Gore.

Materials, Structure, and Properties

There are two model types of the Boston KPro, Types I and II, with the use of each depending on the severity of the damage on the patient’s ocular surface. Type I is used in non-scarred situations like graft failures, aniridia, trauma, post-infections, etc… whereas Type II is used in scarred situations and severe dry eye conditions like Stevens-Johnson’s syndrome, graft-versus-host disease, rheumatoid arthritis, etc…

The Boston KPro Type I has a collar button design in which there are two main parts: an anterior plate made of medical grade poly methyl methacrylate (PMMA) with UVA/UVB blocking with a central optical stem and a snap-on back plate made of titanium with 16 holes that relieve access of the corneal tissue to the aqueous humor. A donor cornea is designed to be sandwiched between the two plates – the structure is then treated like a standard graft and sutured into the patient’s eye. The Boston KPro Type II has the same design as the Type I, but features an anterior nub extension that emerges between the plate lids or through the upper lid. The Type I is shown below in Figure A and the Type II is shown below in Figure B.

The front plate is the primary functioning piece of the device and features a main optical surface 3.5-3.7mm in diameter with the whole front plate being 5mm in diameter. The optical surface is where all of the dioptric power of the KPro is machined in and the radius of curvature of this surface determines the power of the KPro. The optical surface on the front plate is polished manually on a revolving polisher using contact lens polishing liquid. The front plate has an extremely refined edge to provide a smooth blend between the PMMA and cornea; this interface is of utmost importance since this is where infections can enter the eye and is the most common site of initial corneal melt. To prepare the KPro for use, it is cleaned using sterilized water, dried with forced air, packaged, and then ETO sterilized.

PMMA, also known as acrylic, acrylic glass, or plexiglass, is a transparent thermoplastic that is light-weight and shatter resistant, ideal characteristics for an artificial corneal application. PMMA is also known to have a minimal inflammatory response, a contributing factor as to why MEEI chose PMMA for the design. Titanium was chosen due to its inertness [10].

Changes/Modifications In Design Over Time

The most important changes in the last decade have been:

• Implementing a daily dose of topical broad-spectrum antibiotic prophylaxis to reduce the rate of infectious keratitis and endophthalmitis.
• Drilling holes in the back plate to allow for better nutrition of donor cornea from the aqueous humor, thus reducing the rate of tissue melting.
• Substituting PMMA for titanium as the main component of the back plate to decrease the formation of RPM by using an enlarged back plate to clamp the donor host junction [11].

Studies and Assessments

According to Dr. Albert Cheung, the ideal patients for the KPro Type I device are those who are older and have failed multiple transplants. Patients with extreme scarring or inflammatory stem cell deficiency, like mucous membrane pemphigoid or johnson syndrome, are poor candidates, as well as those with severe dry eyes.

However, in its patient population, the KPro has shown promising results. Dr. Aldave and colleagues found that the KPro has provided pleasing visual improvements in most eyes with more than 50% of eyes in his study regaining and maintaining 20/20 corrected distance visual acuity each year through 8 years of follow up. Furthermore, the study also found that the frequency of postoperative complication decreased abundantly over the first 10 years after surgery. Furthermore, although 25% of implanted KPro’s were removed, over 90% of eyes that reached 5 years of follow-up retained keratoprosthesis at the final follow-up. This study included 74 KPro procedures performed on 55 patients with a mean follow up of 57-145 months. The most common indication for KPros implantation was corneal transplant failure (50%). 51.7% of eyes experienced postoperative retroprosthetic membrane formation [12].

Current Business Strategies

In the case of MEEI, they have made several revisions in their product design over the years to strike a balance between improving the Boston KPro and controlling the increasing costs of manufacturing, regulation, and marketing. MEEI’s latest product, the Boston Keratoprosthesis Type I Lucia Design, was approved by the FDA last year with an intent to “reduce manufacturing costs and simplify our inventory, while also providing an improved cosmetic appearance after implantation.” The product primarily follows the same design except for a few minor modifications: the titanium back plate diameter was changed to 7.75mm, halfway between the currently available 7mm and 8.5mm, to accommodate both adult and pediatric eyes with one device. They also changed the shape of the back plate holes from round to radial with a petaloid appearance as well as anodizing the back plate to better mimic a normal eye color for a more natural appearance [13].

Future Trends and Improvements

A lot of research and development on KPros is based around the idea of utilizing biomaterials, coatings, and/or scaffolds to improve mechanical properties and biointegration. Some current developments include:

• Liu et al. created a collagen-based KPro to improve biological adhesion between the KPro and the corneal stroma. Their studies have shown stromal cell ingrowth and nerve cell attachment. Adhering the two interfaces together lessens the chance for an infection and promotes better postoperative tissue healing.
• Karkhaneh et al. used an oxygen plasma treatment by attaching collagen onto polydimethylsiloxane (PDMS) to encourage epithelialization of the prosthesis.
• Wang et al. studied coating PMMA with hydroxyapatite to improve biointegration and reduce inflammation. As more materials and designs are studied, the efficacy of KPros is likely to improve, resulting in a lower chance of postoperative complications and an increase in product functioning [10].
• MEEI is trying to integrate a pressure sensor in the Boston KPro in order to monitor IOP in patients. The Boston Keratoprosthesis Laboratory successfully integrated a micro-optomechanical pressure sensor in the Boston KPro and was able to acquire pressure readings using broadband light interferometry. They implanted this iB-KPro in six rabbits and were able to obtain stable, accurate readings for over two years in vitro with minimal drift in IOP measurements (± 0.8mmHg). The readings gradually began to deviate from the true IOP due to dense RPM formation, but it is expected to perform better in humans [13].

References

[1] Cornea Research Foundation of America. (2017). “Artificial Cornea”. Retrieved from http://www.cornea.org/Learning-Center/Treatment-Options/Cornea-Transplants/Artificial-Cornea.aspx

[2] Islam, Mohammad Mirazul et al. (July 2019). “Finding an Optimal Substitute for Human Donor Corneas”. Retrieved from https://eye.hms.harvard.edu/files/eye/files/kpro_2019_newsletterfinalweb.pdf

[3] Cornea Research Foundation of America. (2017). “What is the Cornea?”. Retrieved from http://www.cornea.org/Learning-Center/How-the-Eye-Works.aspx

[4] World Health Organization. (2019). “Priority eye diseases”. Retrieved from https://www.who.int/blindness/causes/priority/en/index8.html

[5] Boyd, Kierstan and William Barry Lee. (28 August 2019). “What Is Glaucoma?”. Retrieved from https://www.aao.org/eye-health/diseases/what-is-glaucoma

[6] Klufas, Michael A. et al. (8 November 2019). “Boston Keratoprosthesis (KPro)”. Retrieved from https://eyewiki.aao.org/Boston_Keratoprosthesis_(KPro)

[7] Bakri, Sophie J. et al. (2016). “Endophthalmitis”. Retrieved from https://www.asrs.org/patients/retinal-diseases/29/endophthalmitis

[8] Lipuma, Lauren. (October 2014). “Current issues and solutions with the Boston keratoprosthesis”. Retrieved from https://www.eyeworld.org/article-current-issues-and-solutions-with-the-boston-keratoprosthesis

[9] John, Thomas. (6 July 2017). “Boston KPro: Current And Future Directions”. Retrieved from https://www.reviewofophthalmology.com/article/boston-kpro-current-and-future-directions

[10] Cortina, M. Soledad and Jose de la Cruz. (2015). Keratoprestheses and Artificial Corneas. Retrieved from https://doi-org.prox.lib.ncsu.edu/10.1007/978-3-642-55179-6

[11] Magazine, O. N.- E. W. (2018, February 8). EyeWorld. Retrieved from https://www.eyeworld.org/what-s-new-boston-keratoprosthesis

[12] Salvador-Culla, Borja, and Paraskevi E Kolovou. “Keratoprosthesis: A Review of Recent Advances in the Field.” Journal of Functional Biomaterials, MDPI, 19 May 2016, www.ncbi.nlm.nih.gov/pmc/articles/PMC4932470/.

[13] Hui, Pui-Chuen et al. (July 2019). “Integrating a Pressure Sensor in the Boston KPro”. Retrieved from https://eye.hms.harvard.edu/files/eye/files/kpro_2019_newsletterfinalweb.pdf

[Image 1] Cleveland Clinic. (14 February 2018). “Anatomy of the eye and layers of the cornea”. Retrieved from https://my.clevelandclinic.org/health/treatments/17714-cornea-transplant

[Image 2] Icahn School of Medicine at Mount Sinai. (n.d.). “Cloudy Cornea”. Retrieved from https://www.mountsinai.org/health-library/symptoms/cloudy-cornea

[Image 3] All About Vision. (n.d.). “Corneal Abrasion”. Retrieved from https://www.allaboutvision.com/conditions/corneal-abrasion.htm

[Image 4] Wikipedia. (24 November 2019). “Boston keratoprosthesis”. Retrieved from https://en.wikipedia.org/wiki/Boston_keratoprosthesis

[Image 5] Salvador-Culla, Borja, and Paraskevi E Kolovou. “Keratoprosthesis: A Review of Recent Advances in the Field.” Journal of Functional Biomaterials, MDPI, 19 May 2016, www.ncbi.nlm.nih.gov/pmc/articles/PMC4932470/.

[Image 6] Chronis, Nikos. “A POWERLESS OPTICAL MICROSENSOR FOR MONITORING INTRAOCULAR PRESSURE WITH KERATOPROSTHESES.” ResearchGate, June 2013, http://www.researchgate.net/publication/261228304_A_powerless_optical_microsensor_for_monitoring_intraocular_pressure_with_keratoprostheses.

[Video 1] YouTube. 2020. Boston Keratoprosthesis, Type I. [online] Available at: <https://www.youtube.com/watch?v=K9K7JSuTwqI&gt;

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