Midfacial growth and surgically induced growth arrest

Background: Patients with isolated cleft palates exhibit normal growth potential but surgical intervention often results in midfacial hypoplasia. Why surgical repair causes this is not well understood. We identified a region that appeared to function as a growth center and tested whether surgical disruption of this site had an effect on midfacial growth.

Methods: C57BL/6, Axin2^LacZ/+, Gli1^LacZ/+, and Ptc1^LacZ/+ mice strains were used. Embryos were examined at multiple time points, and surgeries were performed on postnatal day 7 to mimic early surgical intervention where a 1mm biopsy was made in the central region of the hard palate with removal of mucoperiosteum. Mice (N=6 for each time point) were sacrificed at multiple time points. Three-dimensional reconstructions of the palate, histomorphometric measurements, immunohistochemical analyses, finite element modeling, and quantitative RT-PCR were employed to follow both the development and the healing process.

Results: We demonstrated that during development the palatal processes of the maxillary bones are capped by two cartilage growth plates separated by a fibrous interzone. Mediolateral expansion occurs at these sites and critically contributes to growth of the midface. Hedgehog/Wnt signaling at these sites predates the formation of the midpalatal suture complex and finite element modeling suggests that strain within the suture complex, generating by suckling, is an important regulator of growth. Surgical intervention impacts growth as well, resulting in a disruption of the growth plates that manifest as a lower level of cell proliferation, a significant increase in apoptosis, and a significant reduction in osteogenic gene expression that result in truncated growth of the palatal processes.

Discussion: The midpalatal suture complex develops through a unique combination of endochondral and intramembranous ossification and the structure of the growth plates is established during embryonic development through the coordinated action of Hedgehog and Wnt signals. Finite element modeling indicates that forces generated by suckling are sufficient to “lock in” the fate of the cells that comprise the suture complex.  Furthermore, we demonstrate that the act of raising a flap, here mimicked by denuding the mucoperiosteum, is sufficient to cause significant destruction to the palatal suture complex, leading to restricted mediolateral growth. These data strongly suggest that disruption of suture complexes, which have intrinsic growth potential, is the basis for midfacial growth arrest associated with palatal reconstruction.