A study protocol for a multicentre randomised clinical trial evaluating the safety and feasibility of a bioengineered human allogeneic nanostructured anterior cornea in patients with advanced corneal trophic ulcers refractory to conventional treatment

Abstract

IntroductionThere is a need to find alternatives to the use of human donor corneas in transplants because of the limited availability of donor organs, the incidence of graft complications, as well as the inability to successfully perform corneal transplant in patients presenting limbal deficiency, neo-vascularized or thin corneas, etc. We have designed a clinical trial to test a nanostructured fibrin-agarose corneal substitute combining allogeneic cells that mimics the anterior human native cornea in terms of optical, mechanical and biological behaviour.Methods and analysisThis is a phase I-II, randomised, controlled, open-label clinical trial, currently ongoing in ten Spanish hospitals, to evaluate the safety and feasibility, as well as clinical efficacy evidence, of this bioengineered human corneal substitute in adults with severe trophic corneal ulcers refractory to conventional treatment, or with sequelae of previous ulcers. In the initial phase of the trial (n=5), patients were sequentially recruited, with a safety period of 45 days, receiving the bioengineered corneal graft. In the second phase of the trial (currently ongoing), subjects are block randomised (2:1) to receive either the corneal graft (n=10), or amniotic membrane (n=5), as the control treatment. Adverse events, implant status, infection signs and induced neovascularization are evaluated as determinants of safety and feasibility of the bioengineered graft (main outcomes). Study endpoints are measured along a follow-up period of 24 months, including 27 post-implant assessment visits according to a decreasing frequency. Intention to treat, and per protocol, and safety analysis will be performed.Ethics and disseminationThe trial protocol received written approval by the corresponding Ethics Committee and the Spanish Regulatory Authority and is currently recruiting subjects. On completion of the trial, manuscripts with the results of phases I and II of the study will be published in a peer-reviewed journal.Trial registrationCT.gov identifier: NCT01765244 (Jan2013). EudraCT number: 2010-024290-40 (Dec2012).

Corneal Stromal Regeneration: Current Status and Future Therapeutic Potential

“…In a first clinical case, the compressed collagen matrix was used to fill the ulcerated defect region (as a corneal inlay) while a second identical matrix was used to cover the cornea as a bandage (onlay). 56 While the bandage onlay degraded within the first postoperative week, it facilitated coverage of the entire ulcerated region by recipient corneal epithelium, with the inlay portion remaining intact. During the following six month period, the inlay also degraded but with epithelium remaining intact without signs of inflammation or immune rejection.…”

In Vitro Generation of Novel Functionalized Biomaterials for Use in Oral and Dental Regenerative Medicine Applications

“…However, one of the limitations of the present study is the need of performing all quality control analyses required by national Medicines Agencies for clinical translation of advanced therapies medicinal products generated by tissue engineering, including biomechanical, biodegradation, porosity, vascularization, and biocompatibility characterization once grafted in vivo. The fact that the basic biomaterial used in the present work fulfilled all these requirements and is currently approved for clinical use [22,23] supports the future clinical usefulness of F-FAOM, but future in vivo analyses should determine the real potential of these novel functionalized tissues. Another limitation is the lack of long-term follow-up, as tissues were analyzed up to 3 weeks.…”

“…From a technical standpoint, we found that novel F-FAOM could be easily generated in the laboratory by combining small oral mucosa biopsies with fibrin-agarose biomaterials previously used in tissue engineering [17,18,20], without the need of establishing primary cell cultures previously. Nonfunctionalized fibrin-agarose biomaterials have previously shown adequate biomechanical properties [16] and very good in vivo biocompatibility in animal models [13,21], which allowed us to use these biomaterials in patients [22,23] with promising preliminary results. However, it is well known that previous non-functionalized bioartificial periodontal tissue models typically require several weeks of culture to obtain adequate numbers of stromal cells, followed by a maturation time of the bioartificial tissue of ~3 weeks once the tissue construct is generated [5].…”

Substitute therapy of the sclera. Identification of the patologies and methodologies in the University Hospital of Granada (2014-2019)

“…En los últimos años, el hidrogel de fibrina-agarosa se ha utilizado con éxito para generar modelos similares a tejidos con bioingeniería para aplicaciones clínicas (27)(28)(29). Después de estudios ex vivo y en estudios vivo-preclínicos, los modelos basados en fibrina agarosa de córnea y piel se elaboraron como productos médicos avanzados en condiciones GMP(Good manufacturing practices) para uso clínico (30). Estudios recientes demostraron la posibilidad de mejorar las propiedades estructurales, biomecánicas y biológicas de la fibrina agarosa mediante el uso de la técnica de nano-estructuración, el uso de agentes reticulantes químicos o la combinación de ambos (31,32).…”