Current Animal Models of Cleft Lip and/or Palate: A Narrative Review

Cleft lip with or without cleft palate (CL/P) is one of the most common congenital craniofacial anomalies worldwide and presents significant functional, esthetic, and psychosocial challenges. Despite advances in multidisciplinary care and surgical reconstruction, complications such as impaired wound healing, scar formation, and growth disturbances warrant the development of novel regenerative and surgical strategies, which heavily rely on animal models at the pre-clinical stage. For the current narrative review, the literature search was performed by combining cleft phenotype terms with modeling-approach terms in six databases and was supplemented by manual review of reference lists from full-text articles. The included articles were summarized based on cleft type and the methods for cleft induction (chemically induced, genetically engineered, and surgically created). Particularly, chemical teratogens such as retinoic acid, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), corticosteroids, and 6-aminonicotinamide have been widely used to induce cleft phenotypes and elucidate environmental influences on palatogenesis, whereas genetic models have clarified the roles of key molecules and signaling pathways, including Sonic hedgehog (SHH), bone morphogenetic protein (BMP), and transforming growth factor-β (TGF-β), in the development of lip and palate. Meanwhile, the surgical models have focused on the alveolar cleft in skeletally mature animals for evaluating novel grafting materials. By comparing the strengths and limitations of existing models, this review highlights opportunities for improving experimental design and translational relevance in future cleft research. Overall, despite a wide range of CL/P animal models available, few replicate clinically relevant defect anatomy and the postnatal craniofacial deformation observed in CL/P patients, underscoring the need for the development of new models.