Evaluation of the Clinical Usefulness of a Bioartificial Urethral Substitute Generated by Tissue Engineering in Laboratory Rabbits: Protocol for an In Vivo Study

BACKGROUND Surgical management of diseases compromising the integrity of the human urethra remains a major clinical challenge, and congenital conditions, such as hypospadias and epispadias, and acquired diseases, such as trauma, tumors, and strictures, are difficult to treat, highlighting the need for novel regenerative approaches capable of restoring urethral architecture and function. Recent advances in tissue engineering have allowed the generation of bioartificial tissues, including several models of artificial urethra generated with different types of cells and biomaterials. Although potentially useful, these models cannot reproduce the multilayered native human urethra structure. One biomaterial showing excellent biocompatibility for use in tissue engineering is fibrin-agarose hydrogel, which has been used with promising results in patients with severe alterations of the cornea, skin, and oral mucosa, suggesting its potential use for multilayered urethral substitutes. OBJECTIVE This study aims to evaluate the biosafety and efficacy of a multilayered artificial urethra generated by tissue engineering using fibrin-agarose biomaterials in laboratory rabbits to determine its clinical potential as an advanced therapy medicinal product. METHODS Five study groups will be established, including a positive control group of rabbits with a native (ie, normal) urethra, a negative control group of rabbits in which the ventral side of the urethra will be surgically sectioned and left unrepaired, a gold standard group in which the ventral side of the urethra will be surgically sectioned and repaired with an oral mucosa autograft, an acellular group in which the urethral defect will be repaired using an acellular multilayered fibrin-agarose biomaterial, and a cellular group of rabbits in which a multilayered cellular bioartificial urethra will be used to repair the urethral defect. The cellular group will allow us to assess the usefulness of a biomimetic urethral substitute generated by tissue engineering, as demonstrated in previously published models of bioartificial tissues, whereas the acellular group will allow us to determine whether the effects observed for the artificial urethra are attributable to the biomaterial itself, which could act as a physical barrier, or to the action of the cells. In all cases, animals will be observed for 3 months, and variables related to biosafety, functionality, and the histological structure of the urethral grafts will be determined. RESULTS This study was approved by the ethics committee for animal research (Junta de Andalucía; 17/12/2024/178) on December 20, 2024. The in vivo study began in February 2025 and is expected to be completed by December 2026. The study was funded in January 2023, and data collection is expected to be completed by December 2026. The results are expected to be published in 2026 and 2027. CONCLUSIONS The present preclinical study will contribute to determining the potential usefulness of these bioartificial tissues as novel advanced therapy medicinal products for clinical use. INTERNATIONAL REGISTERED REPORT DERR1-10.2196/93091