Allogeneic tissue engineering

Corneal transplant alternative shows promise in initial clinical trial.

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Photo of Cheryl Guttman Krader

A fibrin-agarose-based anterior lamellar corneal substitute is a feasible and safe treatment for severe trophic corneal ulcer or its sequelae, and preliminary data also show some encouraging signals of efficacy, reported researchers at the annual meeting of the Association for Research and Vision in Ophthalmology (ARVO), in 
Vancouver, Canada. A phase IIA clinical trial finished the follow-up of the 
first five patients who received the fibrin-agarose-based substitute, enrolled at different centres in Spain. Now, a comparative study is under way that is randomising patients 2:1 to receive the bioengineered corneal substitute or an amniotic membrane transplant, reported Miguel González-Andrades MD, MSc, PhD. “Treatment for corneal blindness today is similar as in 1905, when the first human penetrating keratoplasty was performed. However, there is a lack of corneal donors, a lack of corneal transplantation readiness and inability to successfully perform the transplantation in certain severe cases for which the procedure has a poor prognosis. It is in this context that more than 10 years ago, we set out to develop a corneal substitute,” explained Dr González-Andrades, Maimonides Biomedical Research Institute of Córdoba and Reina Sofia University Hospital, Córdoba, Spain. Dr González-Andrades worked on the development of the bioengineered implant during his Ophthalmology residency and PhD training in the Tissue Engineering Group of the University of Granada, Granada, Spain. The bioengineered graft material is manufactured at the GMP facility of the Cell Production & Tissue Engineering Unit at the University Hospital Complex of Granada. It is prepared by co-culturing allogeneic human corneal epithelial cells on top of a fibrin-agarose scaffold and allogeneic human corneal fibroblasts within the scaffold. The clinical trial is promoted and coordinated by the Andalusian Network of the Design and Translation for Advanced Therapies. The implantation procedure involves removal of the damaged tissue after partial trephining of the recipient cornea. The stromal substitute is sutured into place with 10-0 nylon. Eligibility criteria for the clinical trial required that patients have stage 3 Mackie corneal ulcers not responding to conventional medical treatment or sequelae from a previous stage 3 Mackie corneal ulcer, such as stromal fibrosis or corneal thinning, that had no effective therapeutic alternative. Stromal involvement not reaching the Descemet membrane was another inclusion criteria. Dr González-Andrades said that the five patients enrolled in the first phase all had mild-to-moderate limbal stem cell deficiency, corneal fibrosis, light perception visual acuity and retinal and/or optic nerve disease. Safety evaluation is the main focus of the study. 
Therefore, the five patients were sequentially enrolled at an interval of at least 45 days, and the trial protocol incorporated strict stopping rules that considered various adverse events and complications. “There were no corneal infections, graft-related inflammation, rejections or detachments,” reported Dr González-Andrades. There was good integration of the transplanted tissue in all eyes. The scaffold degrades after a few months, and in vivo confocal microscopy imaging performed after it disappeared identified stratified metaplastic epithelium in all cases and keratocytes in the stroma in some eyes. Clinical evaluation was performed using the Sotozono Eye Complications Grading System. Dr González-Andrades reported that the mean total score was significantly improved from baseline at three, six, 12 and 24 months. Component scores showed all patients had improvements in superficial punctate keratopathy and conjunctival hyperaemia, and some patients showed improvements in corneal epithelial defect, neovascularisation, opacification and keratinisation. The study also evaluated corneal and conjunctival staining using the SICCA ocular staining score. The results showed a global improvement during follow-up with a benefit that was statistically significant at 24 months. Assessments of lacrimal gland and tear function using a Schirmer test and tear break-up time showed no change. Subjective data were collected via a questionnaire, and the patients’ responses showed improvement in symptoms, particularly pain. In addition, all patients said that they would be willing to repeat the transplantation procedure. Dr González-Andrades noted that the severity of the initially enrolled cases preclude using visual acuity to assess efficacy. “Visual acuity improved in two patients, and hopefully we will be better able to evaluate change in visual acuity in future phases of the study,” he said. Miguel González-Andrades: mgandrades@gmail.com
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