Review For reprint orders, please contact: reprints@futuremedicine.com Corneal epithelium tissue engineering: recent advances in regeneration and replacement of corneal surface Hamed Nosrati 1 , Zahra Abpeikar 1 , Zahra Gholami Mahmoudian 2 , Mahdi Zafari 3 , Jafar Majidi 4 , Akram Alizadeh 5 , Lida Moradi 6,7 & Shiva Asadpour* ,1,4 1 Department of Tissue Engineering & Applied Cell Sciences, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran 2 Department of Anatomical Sciences, Medical School, Kermanshah University of Medical Sciences, Kermanshah, Iran 3 Department of Bacteriology, Pasteur Institute of Iran, Tehran, Iran 4 Cellular & Molecular Research Center, Basic Health Science Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran 5 Department of Tissue Engineering & Applied Cell Sciences, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran 6 The Ronald O Perelman Department of Dermatology, New York University, School of Medicine, New York, NY 10016, USA 7 Department of Cell Biology, New York University, School of Medicine, New York, NY, 10016 USA *Author for correspondence: Tel.: +98 38 3333 5652-4; shiva.asadpour2020@gmail.com Currently, many corneal diseases are treated by corneal transplantation, artifcial corneal implantation or, in severe cases, keratoprosthesis. Owing to the shortage of cornea donors and the risks involved with ar- tifcial corneal implants, such as infection transmission, researchers continually seek new approaches for corneal regeneration. Corneal tissue engineering is a promising approach that has attracted much atten- tion from researchers and is focused on regenerative strategies using various biomaterials in combination with different cell types. These constructs should have the ability to mimic the native tissue microen- vironment and present suitable optical, mechanical and biological properties. In this article, we review studies that have focused on the current clinical techniques for corneal replacement. We also describe tissue-engineering and cell-based approaches for corneal regeneration. First draft submitted: 25 April 2019; Accepted for publication: 29 September 2020; Published online: 10 November 2020 Keywords: 3D scaffolds • corneal regeneration • ocular surface • stem cells • tissue engineering The cornea is made up of three distinct layers, including the epithelium (anterior and the outermost layer of the cornea), stroma (posterior to the epithelium) and endothelium (the innermost layer). These layers are separated by the Bowman layer and Descemet membrane (Figure 1) [1]. The corneal epithelium is a transparent tissue with a high potential for regeneration. The nonkeratinized cell layers form the epithelium of the cornea, which is approximately 50 μm thick, making up approximately 10% of the cornea’s thickness [2]. During development, the surface ectoderm layer forms the stratified squamous epithelium of cornea at approximately 5–6 weeks’ gestation. The corneal epithelium acts as a barrier against chemicals, water and microbes. The life span of the cornea’s epithelial cells is approximately 7–10 days, undergoing involution, desquamation and apoptosis [3]. The basement membrane (BM) of the corneal epithelium is a highly specialized extracellular matrix (ECM) that is located between the basal epithelial cells and the stroma. The BM anchors the epithelial cells to the stroma and provides scaffolding for migration, differentiation and maintenance of the differentiated epithelial phenotype during embryonic development. The BM plays an important role in homeostasis and wound healing as a barrier for the penetration of cytokines such as TGF-β1 and KGF from the epithelium to the stroma, and possibly from the stroma to the epithelium, respectively [4]. Previous studies have proven that stem cells from the sclerocorneal limbus area are the main cell source for the healing and regeneration of the corneal epithelium after injury (Figure 1) [5]. The limbal epithelium is a transitional zone between the cornea and conjunctiva with a thickness of approximately 10–12 cell layers. In addition, the Regen. Med. (Epub ahead of print) ISSN 1746-0751 10.2217/rme-2019-0055 C  2020 Future Medicine Ltd