Palatogenesis: engineering, pathways and pathologies

Abstract

Cleft palate represents the second most common birth defect and carries substantial physiologic and social challenges for affected patients, as they often require multiple surgical interventions during their lifetime. A number of genes have been identified to be associated with the cleft palate phenotype, but etiology in the majority of cases remains elusive. In order to better understand cleft palate and both surgical and potential tissue engineering approaches for repair, we have performed an in-depth literature review into cleft palate development in humans and mice, as well as into molecular pathways underlying these pathologic developments. We summarize the multitude of pathways underlying cleft palate development, with the transforming growth factor beta superfamily being the most commonly studied. Furthermore, while the majority of cleft palate studies are performed using a mouse model, studies focusing on tissue engineering have also focused heavily on mouse models. A paucity of human randomized controlled studies exists for cleft palate repair, and so far, tissue engineering approaches are limited. In this review, we discuss the development of the palate, explain the basic science behind normal and pathologic palate development in humans as well as mouse models and elaborate on how these studies may lead to future advances in palatal tissue engineering and cleft palate treatments.

Figure 1

Human palatal development. (A) Week six of human palatal development, with the secondary palate shown vertically on each side of the tongue and a gap between the secondary palate, nasal septum and primary palate. (B) After descent of the tongue, the secondary palatal shelves elevate and orient horizontally, allowing them to come in contact and begin fusing. (C) Fusion of the primary and secondary palate and the nasal septum separating the oropharynx from the nasopharynx. Figure modified from Dixon et al.

Figure 2

Correlation between human and mouse palates. (A) Normal human upper lip, hard palate and soft palate. (B) Normal mouse upper lip, hard palate and soft palate. (C) Cleft of the secondary palate in human patient. (D) Clefting of secondary palate in transgenic mouse.

Figure 3

Palate cultures. (A) Schematic of palate culture using 6-well plate and insert with 0.4 µM pores allowing cytokines but not cells to pass through. (B) Schematic of paired palatal shelves in palate culture. (C) H&E stain of palatal fusion after 72 h of 2 palatal shelves in culture while in contact with each other.

Figure 4

Von Langenbeck palatal repair. (A) Secondary cleft palate palate with dotted red lines demonstrating incisions. (B) Mucuoperiosteal flap elevation with orange demonstrating opening of the incisions. (C) Midline nasal closure of the defect with the nasal layer in orange. (D) Closure of the midline incision with the oral mucosa over the nasal layer closure.