Celia R. Hicks

Keratoprostheses: Advancing toward a true artificial cornea

Keratoprosthesis surgery is carried out in very few centers. Elaborate surgical techniques and high complication rates limit the application of currently available keratoprostheses (KPros). However, the clinical need for an alternative to donor tissue has sparked considerable research interest in the development of new KPros. This paper charts the evolution of KPros from the earliest devices to those currently used, describes their drawbacks and discusses the specifications of an ideal device. Recent research focuses upon the use of porous polymers as the skirt component of core-and-skirt KPros in order to obtain improved biological integration of the prosthetic material. Developments in biomaterials technology make a KPro analogous to a donor corneal button an increasingly realistic goal. However, two particular problems still need to be addressed. First, it must be demonstrated that secure long-term fixation that is able to withstand trauma is achievable in a full-thickness artificial cornea. Second, an ideal artificial cornea for a wet eye requires an epithelialized surface, and this has yet to be achieved.

Corneal replacement using a synthetic hydrogel cornea, AlphaCor: device, preliminary outcomes and complications.

AbstractPurpose Clinical assessment of outcome of corneal replacement with a synthetic cornea, AlphaCor™, in patients considered at too high risk for conventional penetrating keratoplasty with donor tissue to be successful, but excluding indications such as end-stage dry eye that might be suited to traditional prosthokeratoplasty.Methods All patients in the multicentre clinical trial were managed according to an approved protocol, with Ethics Committee approval in each centre. Preoperative visual acuity ranged from perception of light (PL) to 6/60 (20/200). Implantation was by means of an intralamellar technique, with a conjunctival flap in most cases. Tissues anterior to the optic were removed as a secondary procedure.Results Up to 30 November 2001, 40 AlphaCor™ devices had been implanted in 38 patients, of mean age 60 years. Follow-up ranged from 0.5 months to 3 years. There had been one extrusion (2.5%) and four cases (10%) where a device had been removed due to melt-related complications. All five of these cases received a donor corneal graft after the device was removed, with these grafts remaining anatomically satisfactory and epithelialised to date. Corneal melts in AlphaCor™ recipients were found to be strongly associated with a history of ocular herpes simplex infection. Two further devices (5%) were removed owing to reduced optic clarity after presumed drug-related deposition, and have been successfully replaced with second devices. Mean preoperative best-corrected visual acuity was hand movements. Visual acuities after surgery ranged from PL to 6/6−2 (20/20−2).Conclusions Early results suggest that the AlphaCor™, previously known as the Chirila keratoprosthesis (Chirila KPro), has a low incidence of the complications traditionally associated with keratoprostheses and can be effective in restoring vision in patients considered untreatable by conventional corneal transplantation. Importantly, the device can be replaced with a donor graft in the event of development of a significant complication. A history of ocular herpes simplex is a contraindication to AlphaCor™ implantation. Ongoing monitoring of clinical outcomes in all patients will allow the indications for AlphaCor™, as opposed to donor grafts, to be determined.

Development and clinical assessment of an artificial cornea

Keratoprosthesis research has been a gradual, rather fragmentary process with advances being made by isolated groups of researchers. This has arisen partly because of poor funding in the area; research groups which have achieved commercial support have often had constraints upon the full disclosure of their findings. Despite these difficulties there has been real progress over the last decade by several independent groups. This article concentrates upon our own development of a hydrogel core-and-skirt keratoprosthesis, the Chirila KPro, in order to illustrate the scientific and clinical problems common to keratoprosthesis research. Pilot data from a clinical trial is presented and the priorities for future research are discussed.

AlphaCor : Clinical outcomes

Purpose: To study the outcomes of AlphaCor implantation. Methods: The AlphaCor artificial cornea is indicated for corneal blindness not treatable by donor grafting. Prospective preoperative and follow-up data were collected. Data were evaluated using SPSS for statistical analysis of outcomes, trends, and associations. Results: This report includes data returned through February 28, 2006, for all 322 devices implanted, with mean follow-up in situ of 15.5 months and a maximum of 7.4 years. The probability of AlphaCor retention at 6 months and 1 and 2 years for protocol cases was 92%, 80%, and 62%, respectively, and off-label cases were at higher risk (P = 0.010), as were cases not prescribed medroxyprogesterone (MPG; P = 0.001). Currently, the most common complications were stromal melting, fibrous reclosure of the posterior lamellar opening, and white intraoptic deposits, with incidences in 2005 of 11.4%, 5.1%, and 2.6%, respectively. MPG seems to protect against melts, and eyes with a history of herpetic keratitis were not at increased risk. A history of glaucoma or the presence of tubes did not affect device retention. Complications culminated in loss of an eye in 1.3%. Mean preoperative visual acuity (VA) was hand movements. The VA achieved postoperatively (light perception to 20/20) was affected by previous pathology and postoperative course, with a mean improvement of 2 lines. Conclusion: AlphaCor provides a treatment option where a donor tissue graft would not succeed in severe corneal conditions, while being reversible to a donor graft in the event of complications for anatomic integrity. Surgical technique and adjunctive therapies are evolving with experience. Continued data collection is important for a fuller understanding of AlphaCors role.

The Chirila Keratoprosthesis: phase I human clinical trial

OBJECTIVE To undertake a preliminary safety and performance evaluation of an artificial cornea, the Chirila Keratoprosthesis, in human patients. DESIGN A prospective, interventional case series. PARTICIPANTS Fourteen consecutive patients with blindness of corneal origin not treatable by repeated standard penetrating keratoplasty. METHODS Keratoprostheses were manufactured and implanted. The patients, all with preoperative visual acuity of light perception to count fingers (CF), were followed clinically in adherence to a protocol. MAIN OUTCOME MEASURES Safety (keratoprosthesis retention, incidence of serious complications) and performance (visual acuity, comfort, appearance). RESULTS Ninety-three percent of keratoprostheses were retained to the date of reporting, up to 2.5 years. One keratoprosthesis (7%) was removed in a manner that restored the patients preoperative condition. All but one patient maintained their preoperative level of visual acuity or improved on it, with most achieving their estimated full potential visual acuity, (range, count fingers - 20/20). CONCLUSIONS This keratoprosthesis is acceptably safe and has demonstrated an ability to restore vision in cases in which alternative management would have had a poor prognosis. More extensive trials are warranted.

Cell viability and inflammatory response in hydrogel sponges implanted in the rabbit cornea

In the quest for the development of a functional keratoprosthesis, the biocompatibility of the porous skirt material in the Chirila keratoprosthesis (KPro) was investigated. The population of live and dead cells within, and the inflammatory response to, a tissue-integrating poly(2-hydroxyethyl methacrylate) (PHEMA) sponge were studied. Samples of the hydrogel sponge were implanted in rabbit corneas and explanted at predetermined time points up to 12 weeks. The explanted sponges were subjected to cell viability assay using two types of fluoroprobes, 5-chloromethylfluorescein diacetate and ethidium homodimer-1. A semiquantitative analysis was performed to assess the number of dead cells within the sponge and in the area of corneal stroma proximal to the sponge. Five rabbits were used for each end point (2, 4 and 12 weeks). To investigate the inflammatory response to the sponge, immunocytochemistry, using specific antibodies to rabbit macrophages, enzyme histochemistry of chloroacetate esterase (to detect neutrophils) and transmission electron microscopy (TEM) were also employed at 24 h, 2, 4 and 12 weeks after implantation. Four weeks after implantation, fewer viable cells were observed in the sponge when compared to the 2-week implant. However, the proportion of viable cells increased dramatically by 12 weeks. The proportion of nonviable cells decreased gradually with time; central sponge contained 34+/-11 % dead cells after 2 weeks, and 15+/-4.3% after 12 weeks. The staining of inflammatory cells demonstrated the presence of macrophages and neutrophils up to 12 weeks after implantation. TEM confirmed the presence of these cell types and others. including eosinophils and myofibroblasts, as well as blood capillaries. The presence of a significant number of viable cells at each time point and the uniform reduction of the nonviable cell proportion with time suggests that the sponge is a conducive environment supporting a prolific, viable cellular colonization. Dead cells observed in the first instance indicate a normal injury pattern. However, the presence of a small but significant proportion of invading inflammatory cells 12 weeks after implantation confirms a characteristic pattern of wound healing within the sponges.

Calcification of poly (2-hydroxyethyl methacrylate) hydrogel sponges implanted in the rabbit cornea: A 3-month study

Poly(2-hydroxyethyl methacrylate) (PHEMA) hydrogels have been used in the past as ocular implants. In a recent development, PHEMA sponges have shown suitable properties as materials for the peripheral component of an artificial cornea (keratoprosthesis). However, the propensity of PHEMA to calcify could threaten the long-term stability of the implanted devices. In an attempt to improve the understanding of the calcification mechanism, the dynamics, extent, and nature of calcified deposits within PHEMA sponges implanted in the cornea were investigated in this study, and the possible correlation between necrosis of cells and calcification was critically examined. Samples of a PHEMA sponge were implanted in rabbit corneas and explanted at predetermined time points (2, 4, and 12 weeks). The samples were examined by microscopy (light, transmission, scanning) and energy dispersive analysis of X-rays. Histological assessment and semiquantitative analysis of the amount of calcium deposited was performed using image analysis. An in vitro experiment was also performed by incubating sponge samples for 2 weeks in a solution of calcium and phosphate ions at a ratio similar to that in hydroxyapatite, in the absence of cells. Calcification was not seen in the 2- and 4-week explants, however, small deposits were detected in two of the 12-week explants, both within and on the sponges constituent polymer particles. The deposit volumes represented 0.094% and 0.21%, respectively, of the total sponge volumes. Calcium deposits were present in large amounts both within the constituent polymer particles and on the surface of the sponges incubated in the abiotic calcifying solution. Cooperative mechanisms are suggested for the calcification of PHEMA sponges in vivo. The initial event may occur at a molecular level, when plasma proteins are adsorbed onto the polymer surface and bound through chelation to the calcium ions present in the medium. After their natural degradation, these structures may act as nucleation sites for calcium phosphate crystallization. Concurrently, the calcium ions can diffuse into the hydrogel particles and then the spontaneous precipitation of calcium phosphate may be caused by supersaturation due to the lower content of water in polymer, an effect which is likely predominant in vitro. The second event is the recruitment of phagocytic cells to clear calcium debris. Degeneration of these cells may then form nucleation sites for secondary calcification.

Melting after keratoprosthesis implantation: the effects of medroxyprogesterone.

Purpose This study was conducted to evaluate the effect of topical medroxyprogesterone (MPG) following KPro implantation in human subjects in whom donor tissue grafts had been contraindicated by high risk of failure. Methods Outcomes of implantation of the Chirila KPro, now known as AlphaCor, were reviewed with respect to postoperative MPG therapy. Ten of 45 (22%) patients had received MPG for a period of 12 months, while 35/45 (78%) had not. MPG treatment was halted because the drug is not approved as an adjunctive treatment of KPro patients. The main outcome measures were the incidence and timing of corneal stromal melting and visual acuity. Results Of those untreated with MPG, 34% developed a melt (mean follow-up 9.7 months), whereas of those who received MPG, 60% developed a melt (mean follow-up 28.4 months). However, mean time to melt onset for untreated cases was 8.8 months, whereas mean time to melt onset for treated cases was 23.2 months. There is a statistically significant association between time to melt onset, where melts occurred, and MPG therapy (&khgr;2 = 0.001). In both groups, melts were strongly associated with a history of ocular HSV, which represented 17.1% of untreated and 20% of treated cases and is now considered a contraindication for AlphaCor. Preoperative visual acuities were in the range Perception Light (PL)-Count Fingers (CF) in all cases, whereas mean best postoperative best corrected visual acuity was 20/200 (range PL-20/30) in untreated cases and was 20/120 [range Hand Movements (HM)–20/30)] in MPG-treated cases. Conclusions Although MPG may not influence the underlying incidence of melt-related complications, which are likely to be associated with other risk factors especially HSV, it may have a protective effect with regard to melt onset and severity. Controlled studies would assist evaluation of its use in this indication.

AlphaCor™ cases : comparative outcomes

Purpose To describe clinical outcomes after a novel type of corneal surgery, implantation of an artificial cornea, AlphaCor™, and to evaluate outcomes in comparison with alternative keratoprostheses and high-risk grafts. Methods Case reports and data from a noncontrolled clinical trial and a literature review. Results The probability of AlphaCor retention to 1 year is 80%. Postoperative best corrected visual acuity ranges from Perception Light to 20/30. The most significant complications are stromal melts and optic depositions, for both of which the main risk factors have been identified. Complications can be managed without loss of the eye. Conclusion Results from the clinical trial period have helped to determine the indications and risk factors for AlphaCor surgery and to refine surgical techniques. Continued monitoring of outcomes as the series increases will allow a more accurate determination of comparative outcomes. The series provides preliminary evidence that AlphaCor may have a lower incidence of complications than traditional keratoprostheses and may prove to be preferable to a donor graft in high-risk cases.

Outcomes of implantation of an artificial cornea, AlphaCor: effects of prior ocular herpes simplex infection.

Purpose. To review outcomes of AlphaCor artificial cornea implantation in patients with and without a history of ocular herpes simplex virus (HSV) and to determine whether herpetic eye disease is an indication for AlphaCor surgery. Methods. Outcomes of the initial 40 implantations were reviewed and stratified by the presence of a history of ocular disease caused by HSV. Outcomes measures (complications, visual acuity gained) were compared. Results. Eight of the 40 AlphaCor implantations (20%) were in patients with a history of ocular HSV. Six of these eight patients (75%) developed melt-related complications after AlphaCor insertion. Half of the affected patients required removal of the AlphaCor and replacement with a donor corneal graft to restore ocular integrity. In comparison, only six of the 32 (18.8%) patients without HSV developed a melt after AlphaCor insertion. Patients with HSV with devices in situ exhibited a mean loss of 0.3 line of best-corrected visual acuity compared with the preoperative visual acuity, whereas patients without HSV exhibited a mean gain of 1.4 lines of best-corrected visual acuity. Conclusions. The extensive lamellar corneal surgery involved in AlphaCor implantation may precipitate reactivation of latent HSV such that reactivation and resultant inflammation reduce device biointegration and facilitate melting of corneal stromal tissue anterior to the device. Although there may be some benefit from systemic antiviral medication, the current series is not large enough to demonstrate such a benefit, and melting can occur despite medication. The statistically significant difference in outcomes between recipients of AlphaCor with and without HSV is evidence that a history of HSV should be an exclusion factor for AlphaCor surgery.