Reducing Corneal Graft Rejection on a Very Small Scale

Corneal transplantation is the most commonly performed solid tissue transplant procedure in the world, with about 100,000 being performed each year (1). But 10 percent of those transplants end in graft rejection, and this is largely due to poor patient adherence with postoperative corticosteroid eyedrop treatment regimens. This is an unacceptable situation, especially as it’s estimated that there are as many as 10 million people worldwide with corneal blindness, who cannot receive transplants because of a shortage of donor tissue. On the other hand, it’s also understandable: many patients receiving corneal transplants are elderly, many different drugs are required in the immediate postoperative period, with frequent dosing schedules of q1h and q2h, and some – like corticosteroids – need to be applied according to this regimen for a period of one year – or longer. With steroids, it’s a function of ocular pharmacokinetics (PK) and pharmacodynamics (PD); they’re poorly absorbed and rapidly cleared from the eye, so therapeutic steroid concentrations don’t last long, hence their need for be frequent application. Subconjunctival injection of corticosteroids at the time of surgery is often employed, but again, PK/PD works against the patient – the injection produces a short spike of steroid levels (which can be associated with an increased rate of ocular side-effects), which is followed by a rapid clearance of the molecule.

In an effort to limit graft rejection because of these issues, specialists in ophthalmology and nanomedicine at The Johns Hopkins University School of Medicine (Baltimore, MD, USA) have worked to develop a biodegradable, subconjunctivally-injected sustained release formulation of dexamethasone (2).

“Corneal grafts are not easy to come by, and a lot of testing and time goes into ensuring the safe use of a graft for cornea transplant,” explained one of the study’s authors, Qingguo Xu. (3) “This is why we want to do a better job at making sure corneal transplants don’t end up in rejection, and our study illustrates a potentially better way.”

The nanoparticles, which are composed of poly(lactic-co-glycolic acid) and contain dexamethasone sodium phosphate (DSP), are 200 nm in diameter, or slightly thicker than a strand of human hair. When administered to 20 rats that had undergone corneal transplantation, the nanoparticles provided sustained levels of DSP over seven days and, given weekly, prevented corneal graft rejection in all animals for the full length of the nine-week study. Control treatment groups that received weekly injections of placebo nanoparticles or “free” (topically administered) DSP showed graft rejection in less than four weeks, accompanied by severe corneal edema, opacity and neovascularization. The fact that this nanoparticle delivery system shows 100 percent efficacy in preventing rat corneal graft rejection in this study means that it may one day translate into similar results for human patients.