Bioartificial human corneas generated by tissue engineering. A historical and technical review

Different types of bioartificial corneas have been generated by tissue engineering through combining cells, biomaterials, and bioactive molecules. Orthotypical corneal cells can be obtained from corneal biopsies, and include epithelial, stromal, and endothelial cells, whereas heterotypical cells are obtained from alternative cell sources with corneal differentiation potential, such as mesenchymal stem cells. In turn, two main types of biomaterials have been applied to corneal tissue engineering: those generated by the decellularization of natural tissues and biomaterials generated de novo using synthetic or natural biomaterials, especially collagen, fibrin, and agarose. Cells and biomaterials are combined with bioactive factors, inducing cell proliferation and differentiation. A review of previous studies revealed that most bioartificial corneas were not able to fulfill the complex requirements required for clinical translation, which include a thorough preclinical characterization, generation of the tissue as an advanced therapy medicinal product, a clinical research phase, and a final authorization by the European Medicines Agency or another competent regulatory agency. Most authorized products correspond to partial corneal substitutes consisting of one cell type associated or not with a scaffold, and only one product consisting of a human bioartificial cornea containing a fibrin-agarose scaffold and two corneal cell lineages (epithelial and stromal cells) called NANOULCOR was evaluated in patients in the context of an advanced therapy medicinal product. These findings confirm the existence of a bottleneck between basic and clinical research and suggest the need to implement novel clinical studies to develop new therapies that can improve the results of current corneal therapies.