Roundup of advances in B-Kpro research

Grappling with the complications of keratoprostheses.

By Borja Salvador-Culla, MD and Paraskevi Evi Kolovou, MD

For 225 years, researchers have been trying to develop an effective, complication-free keratoprosthesis for patients with severely opacified corneas.

They’ve yet to reach their goal. Complications, especially glaucoma, continue to be problematic.

Three major products dominate the market. They are:

1. The osteo-odonto-keratoprosthesis (OOKP)^1,2

2. The Boston keratoprosthesis (B-Kpro)^3,4,5

3. The so-called MICOF (Moscow Eye Microsurgery Complex in Russia).⁶

Of these keratoprosthesis devices, the B-Kpro (Figure 1A) is by far the most widely used; more than 10,000 units have been implanted worldwide. Approved by the FDA 22 years ago, the B-Kpro, in design and use, has undergone major changes. These changes are: the patient’s daily use of antibiotic prophylaxis to prevent endophthalmitis;⁷ the surgeon’s introduction of holes in the back plate so the corneal graft receives better nutrition⁸ and, most recently, the substitution of poly(methyl methacrylate) (PMMA) with titanium for the back plate (Figure 1B), to inhibit formation of retroprosthetic membranes.⁹ Similarly, by using an oversized titanium back plate, the surgeon can clamp the host-graft wound 10 (Figure 2), further reducing the formation of retroprosthetic membranes, which appear to originate in the host-graft junction.¹¹

Figure 1.
A) Schematic of the B-Kpro. The donor cornea is sandwiched between the front and the back plates.
B) B-Kpro with a PMMA back plate (bottom) and a titanium back plate (top).

Figure 2. Anterior segment OCT image of the graft-host junction in a patient implanted with an oversized back plate. The oversized backplate effectively clamps the graft-host junction without adverse effects to the angle anatomy or wound healing. This may be one strategy to provide better wound apposition, prevent retroprosthetic membrane formation, and reduce the likelihood of angle closure from iris synechiae to the wound.

COMPLICATIONS

Four categories

The primary postoperative complications are divided into four categories:

• infection

• chronic inflammation, especially in autoimmune diseases

• glaucoma

• tissue necrosis (corneal melt).

INFECTIONS AND ENDOPHTHALMITIS

Preventive drugs

The rates of infections and endophthalmitis have been brought under reasonable control in the last decade. For patients in this non-autoimmune category, one drop of polymyxin B Sulfate/Trimethoprim (Polytrim, Allergan) every day is effective in preventing endophthalmitis.¹²

INFLAMMATION

Detection

Although the consequences of chronic pre- and postoperative inflammation are substantial, its signs are subtle and hard to detect. To address this issue, our group recently developed a miniaturized model of the Boston keratoprosthesis (m-Kpro) for use in rodent models to study the levels of inflammatory cytokines.¹³

The preliminary results in mice are encouraging.

Preventive drug delivery

In parallel, Joseph B. Ciolino, MD, is developing a new contact lens drug delivery device that can deliver medication (e.g., antibiotics or antifungals) to the eye at a constant rate for a month.^14,15 The next step is to fine-tune this use of antibiotics and antifungals or both, which should reduce infections in B-Kpro patients.

GLAUCOMA

Monitoring progression

Glaucoma is the most common complication after B-Kpro implantation. A recent study showed that in one cohort, 66% of 106 patients presented with glaucoma before B-Kpro implantation, and sometimes they only were diagnosed after the opaque cornea had been replaced by the clear B-Kpro.

Moreover, in the patients who did not have glaucoma before surgery, 26% developed glaucoma de novo after surgery. More interestingly, the patients who had glaucoma surgery (mostly shunts) exhibited significantly slower progression of disc cupping than did those without such surgery.¹⁶

Drug delivery

After these revealing results, we are now recommending a combined B-Kpro and glaucoma shunt implantation in patients with known glaucoma or who are at high risk to develop glaucoma.

Even with glaucoma shunts, long-term control of IOP remains a challenge. This is why our group is addressing this problem from three lines of investigation.

In one investigation, a new shunt based on ferrofluidic principles is being developed with both an opening pressure and true closing pressure. The initial results in animals are promising, with good tolerance and retention.¹⁷

In another approach, the previously mentioned drug-eluting soft contact lens can be loaded with latanoprost.¹⁸

Initial studies in rabbits show therapeutic levels of latanoprost of up to a month in the animals’ anterior chambers with good retention of the contact lens. This new contact lens drug delivery device might improve the outcome in patients who are not compliant with glaucoma drops.

Wireless IOP Transducers

Lastly, research has focused on developing new tools to measure the IOP in B-Kpro patients. Because of the rigidity of both the front plate and the back plate of the B-Kpro, Goldman tonometry cannot be performed and finger palpation, a crude and inexact method, presently remains the only viable option. An experimental wireless IOP transducer (WIT), developed in Germany, can be implanted into the ciliary sulcus following extracapsular cataract extraction and “in the bag” IOL implantation. An external reader unit that emits radio waves can measure IOP. Recent studies show clinical outcomes for 18 months in a patient implanted with a WIT, with good tolerance.¹⁹ The IOP was successfully measured at every visit for the study’s duration, which allowed starting glaucoma treatment early after an increase in the IOP was detected. Further clinical trials are underway.

TISSUE NECROSIS

Titanium coating

The last group of complications includes those secondary to tissue necrosis and corneal melt. These events usually start around the stem of the B-Kpro and create a space for infectious microorganisms and tissue debris to enter into the eye. To combat this, our team is exploring the possibility of using different materials to coat the PMMA stem and increase the adherence to the donor cornea; titanium is our best candidate. In a study conducted in rabbits, we’ve shown good corneal tissue adherence to the stem when a titanium sleeve is inserted around the PMMA. These initial results, currently in submission, have lead to clinical studies that are already underway.

OTHER MATTERS

Clinical

Other lines of investigation have focused on several other issues. For instance, we’ve shown the risk of light-induced retinal damage from the operating microscope during B-Kpro implantation should be very low.²⁰

Another team is exploring the use of new carriers for the B-Kpro, including xenografts and gamma-irradiated corneas.¹⁰

One study has demonstrated an increased resistance to keratolysis in donor corneas after UV-crosslinking treatment (Figure 3), which may improve outcomes in patients with a tendency to corneal melt, such as those with certain autoimmune diseases.²¹ In these patients, it has previously been found that TNF-α inhibitors, such as infliximab (Remicade, Janssen Biotech) can reduce the tissue melt around the B-Kpro.²²

Figure 3. Resistance of ex vivo donor human corneas to collagenase degradation. All UV crosslinked corneas were found to be more resistant to collagenolytic degradation than control (* p<0.05), with a statistically significant linear relationship to the duration of crosslinking up to 30 minutes of treatment (dashed line, R2 = 0.98, p<0.05). [n=4 per group]

Cosmesis

Cosmesis of the device can be a problem. The metallic silver appearance of the new titanium back plate (Figure 4A, page 43) makes it less socially acceptable to some patients. Tinted contact lenses can help.²³ Another approach is coloring the titanium back plate with an inert and biocompatible titanium oxide layer, resulting in a brown or blue back plate.²⁴ (Figures 4B and 4C, page 43).

Figure 4. Close captions of the titanium back plates before oxidization
A) normal color, and after oxidization
B) brown color and
C) blue color.

Improving outcomes

The modifications in the design of the B-Kpro in the last decade have lead to better outcomes and long-term retention of the device. Nonetheless, the ultimate goal of developing an inexpensive, effective and long-term safe device will require considerable improvements. OM

References:

About the Authors
	Borja Salvador-Culla, MD is a clinical research fellow at Massachusetts Eye and Ear Infirmary.
	Paraskevi Evi Kolovou, MD is a senior research fellow at Massachusetts Eye and Ear Infirmary.
	Disclosure: Drs. Culla and Kolovou have no interests to disclose.