Hydroxyapatite for Keratoprosthesis Biointegration

According to the World Health Organization, corneal disease accounted for 8 million cases of blindness in 2009.1 Corneal allograft surgery is often successful in such cases, but in some patients and conditions the success rate is low. In a large outcome study, only 20% of regrafts remained clear for 5 years2; more recent reports have confirmed this trend.3,4 With repeated allograft failure, few treatments are available, and tissue-engineered corneas are not yet suitable for clinical use. Corneal prostheses (keratoprosthesis; KPro) are the only viable option for restoring sight. There are several KPros on the global market that vary in terms of indications, surgical complexity regarding placement, and outcomes. The primary material used in the optic axis of many devices is polymethylmethacrylate (PMMA) because of its transparency, high mechanical strength, ease of processing, and low cost. Firm bonding of any KPro to the surrounding cornea is clinically critical; it is the main challenge in the development of most keratoprostheses. For example, in the case of the Boston KPro, which is relatively simple to construct and implant and which continues to have improved outcomes and expanded indications thanks to design enhancements and optimized postoperative management,5,6 the poor adhesion of PMMA to the surrounding tissue creates opportunities for bacteria to enter the eye, resulting in infection, leakage of aqueous humor, and even extrusion of the implant.7,8 Hydroxyapatite (HAp) is a main component of bone and teeth and has been widely used for surface modification of bone implants9 because it can bind electrostatically with charged biological molecules.10,11 HAp induces a relatively limited inflammatory and foreign body response12 and supports the adhesion and growth of human keratocytes (corneal fibroblasts) better than glass, polytetrafluoroethylene, and polyhydroxymethacrylate in vitro.13 These properties make it a desirable material for use in a KPro. However, the poor mechanical properties of bulk HAp ceramics make them challenging to work with. Here we have developed or adapted a variety of related approaches to coating PMMA with HAp and assessed their effectiveness in enhancing integration with the cornea. HAp coating can be achieved through biomineralization using simulated body fluid (SBF).14–16 Deposition on PMMA can be enhanced by treatment with highly concentrated sodium hydroxide (NaOH), which produces negatively charged carboxyl groups on the surface.17 Coating with polydopamine, which can form on a wide range of surfaces,18 can also induce HAp deposition on various substrates in SBF.19 We have hypothesized that further coating the polydopamine-modified PMMA discs with 11-mercaptoundecanoic acid (11-MUA) would enhance apatite deposition. The carboxyl groups of 11-MUA can act as nucleation sites for Ca/P deposition.20 We have characterized these HAp-coated PMMAs in vitro, alone and in the presence of corneal fibroblasts. In addition to the cell-based experiments commonly performed in studies of biointegration, we have used a custom-made 3D printed device to determine whether coating with HAp improves the mechanical strength of the tissue interaction ex vivo. Finally, we studied the effect of coating with HAp on biocompatibility in vivo.