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However, development of tubular full\u2010thickness substitutes is challenging. In this work, we have generated and evaluated ex vivo a novel full\u2010thickness human urethra substitute (FHUS) containing its three main layers: the urethral mucosa (UM), the spongy layer (SP), and the tunica albuginea (AL). Results first showed that the generation of a FHUS significantly improved the biomechanical properties of this artificial tissue as compared to the individual layers, although the resistance of the native urethra was not reached. At the structural level, we found that FHUS shared important histological similarities with the native urethra. Analysis of the individual layers showed that UM had a stratified epithelium that expressed several epithelial markers, including cytokeratins CK7 and CK14, uroplakin 1b, and the intercellular junction proteins desmoplakin, tight junction protein 1, and claudin. At the stromal level, UM tended to increase the presence of collagen fibers and versican with time. The SP layer displayed abundant CD31 and CD34\u2010positive blood vessels, but small amounts of collagen and proteoglycans. The AL layer showed scattered smooth muscle cells expressing \u03b1\u2010smooth muscle actin, smoothelin, and desmin cell markers, and contained low amounts of collagen and proteoglycans. Analysis of the basement membrane components collagen IV and laminin revealed their progressive development with time, especially collagen IV. These results confirm the possibility of developing a partially biomimetic full\u2010thickness substitute of human urethra that might have potential clinical usefulness for the clinical repair of severe urethral lesions.<\/jats:p>","DOI":"10.1002\/btm2.70049","type":"journal-article","created":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T08:46:13Z","timestamp":1758012373000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Generation and ex vivo characterization of a full\u2010thickness substitute of the human urethra by tissue engineering"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4755-7741","authenticated-orcid":false,"given":"David","family":"S\u00e1nchez\u2010Porras","sequence":"first","affiliation":[{"name":"Department of Histology, Tissue Engineering Group, School of Medicine University of Granada  Granada Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria ibs.GRANADA  Granada Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Etayo\u2010Escanilla","sequence":"additional","affiliation":[{"name":"Department of Histology, Tissue Engineering Group, School of Medicine University of Granada  Granada Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria ibs.GRANADA  Granada Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9\u2010Andr\u00e9s","family":"Moreno\u2010Delgado","sequence":"additional","affiliation":[{"name":"Division of Pediatric Surgery University Hospital Virgen de Las Nieves  Granada Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"del Mar Lozano\u2010Mart\u00ed","sequence":"additional","affiliation":[{"name":"Department of Histology, Tissue Engineering Group, School of Medicine University of Granada  Granada Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabiola","family":"Bermejo\u2010Casares","sequence":"additional","affiliation":[{"name":"Department of Histology, Tissue Engineering Group, School of Medicine University of Granada  Granada Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Alaminos","sequence":"additional","affiliation":[{"name":"Department of Histology, Tissue Engineering Group, School of Medicine University of Granada  Granada Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria ibs.GRANADA  Granada Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jes\u00fas","family":"Chato\u2010Astrain","sequence":"additional","affiliation":[{"name":"Department of Histology, Tissue Engineering Group, School of Medicine University of Granada  Granada Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria ibs.GRANADA  Granada Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Campos","sequence":"additional","affiliation":[{"name":"Department of Histology, Tissue Engineering Group, School of Medicine University of Granada  Granada Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria ibs.GRANADA  Granada Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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