Search

Growth alterations have been described in patients operated on for oral clefts. The purpose of this work was to analyze the craniofacial and palate morphology and dimensions of young adults operated on for oral clefts in early childhood in Spain. Eighty-three patients from eight different hospitals were divided into four groups based on their type of cleft: cleft lip (CL, n = 6), unilateral cleft lip and palate (UCLP, n = 37), bilateral cleft lip and palate (BCLP, n = 16), and cleft palate only (CPO, n = 24). A control group was formed of 71 individuals. Three-dimensional (3D) digital models were obtained from all groups with an intraoral scanner, together with cephalometries and frontal, lateral, and submental facial photographs. Measurements were obtained and analyzed statistically. Our results showed craniofacial alterations in the BCLP, UCLP, and CPO groups with an influence on the palate, maxilla, and mandible and a direct impact on facial appearance. This effect was more severe in the BCLP group. Measurements in the CL group were similar to those in the control group. Cleft characteristics and cleft type seem to be the main determining factors of long-term craniofacial growth alterations in these patients. Prospective research is needed to clearly delineate the effects of different treatments on the craniofacial appearance of adult cleft patients., (© 2022. The Author(s).)

Background: Cleft palate (CP) constitutes the most frequently seen orofacial cleft and is often associated with low folate status. Folate plays an essential role in the human body as a major coenzyme in one-carbon metabolism, including DNA synthesis, repair, and methylation. Whether the administration of isolated folic acid (FA) supplements prevents the CP caused by genetic mutations is unknown, as is its effect on the mechanisms leading to palate fusion., Methods: FA was administered to females from two different strains of transforming growth factor β 3 heterozygous mice. Null mutant progeny of these mice exhibit CP in 100% of cases of varying severity. We measured cleft length, height of palatal shelf adhesion, and the number of proliferating mesenchymal cells. Immunohistochemistry was also carried for collagen IV, laminin, fibronectin, cytokeratin-17, and EGF., Results: FA supplementation significantly reduced CP severity and improved palatal shelf adhesion in both strains both in vivo and in vitro. Medial edge epithelium proliferation increased, and its differentiation was normalized as indicated by the presence and disposition of collagen IV, laminin, fibronectin, and cytokeratin-17., Conclusions: A maternal FA supplementation reduces the CP appearance by improving the mechanisms leading to palatal shelf adhesion.

We have recently presented the Old Spanish Pointer dog, with a 15-20% spontaneous congenital cleft palate rate, as a unique experimental model of this disease. This study aimed to describe the cleft palate of these dogs for surgical research purposes and to determine whether congenital cleft palate influences maxillofacial growth. Seven newborn Old Spanish Pointer dogs of both sexes, comprising a cleft palate group (n = 4) and a normal palate group (n = 3), were fed using the same technique. Macroscopic photographs and plaster casts from the palate, lateral radiographs and computer tomograms of the skull were taken sequentially over 41 weeks, starting at week 5. The cleft morphology, the size and the tissue characteristics in these dogs resembled the human cleft better than current available animal models. During growth, the cleft width varies. Most of the transverse and longitudinal measures of the palate were statistically lower in the cleft palate group. The cleft palate group showed hypoplasia of the naso-maxillary complex. This model of congenital cleft palate seems suitable for surgical research purposes. A reduced maxillofacial pre- and post-natal development is associated to the congenital cleft palate in the Old Spanish Pointer dog., (Copyright © 2013 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

The cleft palate presented by transforming growth factor-β3 (Tgf-β3) null mutant mice is caused by altered palatal shelf adhesion, cell proliferation, epithelial-to-mesenchymal transformation and cell death. The expression of epidermal growth factor (EGF), transforming growth factor-β1 (Tgf-β1) and muscle segment homeobox-1 (Msx-1) is modified in the palates of these knockout mice, and the cell proliferation defect is caused by the change in EGF expression. In this study, we aimed to determine whether this change in EGF expression has any effect on the other mechanisms altered in Tgf-β3 knockout mouse palates. We tested the effect of inhibiting EGF activity in vitro in the knockout palates via the addition of Tyrphostin AG 1478. We also investigated possible interactions between EGF, Tgf-β1 and Msx-1 in Tgf-β3 null mouse palate cultures. The results show that the inhibition of EGF activity in Tgf-β3 null mouse palate cultures improves palatal shelf adhesion and fusion, with a particular effect on cell death, and restores the normal distribution pattern of Msx-1 in the palatal mesenchyme. Inhibition of TGF-β1 does not affect either EGF or Msx-1 expression., (© 2014 S. Karger AG, Basel.)

Background: Raising mucoperiosteal flaps in traditional palatoplasty impairs mid-facial growth. Hyaluronic acid-based hydrogels have been successfully tested for minimally invasive craniofacial bone generation in vivo as carriers of bone morphogenetic protein-2 (BMP-2). We aimed to develop a novel flapless technique for cleft palate repair by injecting a BMP-2 containing hydrogel., Material and Methods: Dog pups with congenital cleft palate were either non-treated (n=4) or treated with two-flap palatoplasty (n=6) or with the proposed injection/adhesion technique (n=5). The experimental approach was to inject a hyaluronic acid-based hydrogel containing hydroxyapatite and BMP-2 subperiosteally at the cleft palate margins of pups aged six weeks. At week ten, a thin strip of the medial edge mucosa was removed and the margins were closed directly. Occlusal photographs and computed tomography (CT) scans were obtained up to week 20., Results: Four weeks after the gel injection the cleft palate margins had reached the midline and engineered bone had enlarged the palatal bones. Removal of the medial edge mucosa and suturing allowed complete closure of the cleft. Compared to traditional palatoplasty, the injection/adhesion technique was easier, and the post-surgical recovery was faster. CT on week 20 revealed some overlapping or "bending" of palatal shelves in the two-flap repair group, which was not observed in the experimental nor control groups., Conclusion: A minimally invasive technique for cleft palate repair upon injectable scaffolds in a dog model of congenital cleft palate is feasible. Results suggest better growth of palatal bones. This represents an attractive clinical alternative to traditional palatoplasty for cleft palate patients., (Copyright © 2013 Elsevier Inc. All rights reserved.)

In humans, cleft palate (CP) is one of the most common malformations. Although surgeons use palatoplasty to close CP defects in children, its consequences for subsequent facial growth have prompted investigations into other novel surgical alternatives. The animal models of CP used to evaluate new surgical treatments are frequently obtained by creating surgically induced clefts in adult dogs. This procedure has been ethically criticized due to its severity and questionable value as an animal model for human CP. Dogs born with a congenital CP would be much better for this purpose, provided they developed CP at a sufficient rate and could be fed. Up until now, feeding these pups carried the risk of aspiration pneumonia, while impeding normal suckling and chewing, and thus compromising orofacial growth. We developed a technique for feeding dog pups with CP from birth to the time of surgery using two old Spanish pointer dog pups bearing a complete CP. This dog strain develops CP in 15-20% of the offspring spontaneously. Custom-made feeding teats and palatal prostheses adapted to the pups' palates were made from thermoplastic plates. This feeding technique allowed lactation, eating and drinking in the pups with CP, with only sporadic rhinitis. To determine whether the use of this palatal prosthesis interferes with palatal growth, the palates of three littermate German shorthaired pointer pups without CP, either wearing or not wearing (controls) the prosthesis, were measured. The results showed that the permanent use of this prosthesis does not impede palatal growth in the pups.

Folic acid (FA) is essential for numerous bodily functions. Its decrease during pregnancy has been associated with an increased risk of congenital malformations in the progeny. The relationship between FA deficiency and the appearance of cleft palate (CP) is controversial, and little information exists on a possible effect of FA on palate development. We investigated the effect of a 2-8 weeks' induced FA deficiency in female mice on the development of CP in their progeny as well as the mechanisms leading to palatal fusion, i.e. cell proliferation, cell death, and palatal-shelf adhesion and fusion. We showed that an 8 weeks' maternal FA deficiency caused complete CP in the fetuses although a 2 weeks' maternal FA deficiency was enough to alter all the mechanisms analyzed. Since transforming growth factor-β(3) (TGF-β(3)) is crucial for palatal fusion and since most of the mechanisms impaired by FA deficiency were also observed in the palates of Tgf-β(3)null mutant mice, we investigated the presence of TGF-β(3) mRNA, its protein and phospho-SMAD2 in FA-deficient (FAD) mouse palates. Our results evidenced a large reduction in Tgf-β(3) expression in palates of embryos of dams fed an FAD diet for 8 weeks; Tgf-β(3) expression was less reduced in palates of embryos of dams fed an FAD diet for 2 weeks. Addition of TGF-β(3) to palatal-shelf cultures of embryos of dams fed an FAD diet for 2 weeks normalized all the altered mechanisms. Thus, an insufficient folate status may be a risk factor for the development of CP in mice, and exogenous TGF-β(3) compensates this deficit in vitro., (Copyright © 2011 S. Karger AG, Basel.)

Folic acid (FA) is essential for numerous bodily functions. Its decrease during pregnancy has been associated with an increased risk of congenital malformations in the progeny. The relationship between FA deficiency and the appearance of cleft palate (CP) is controversial, and little information exists on a possible effect of FA on palate development. We investigated the effect of a 2-8 weeks' induced FA deficiency in female mice on the development of CP in their progeny as well as the mechanisms leading to palatal fusion, i.e. cell proliferation, cell death, and palatal-shelf adhesion and fusion. We showed that an 8 weeks' maternal FA deficiency caused complete CP in the fetuses although a 2 weeks' maternal FA deficiency was enough to alter all the mechanisms analyzed. Since transforming growth factor-β3 (TGF-β3) is crucial for palatal fusion and since most of the mechanisms impaired by FA deficiency were also observed in the palates of Tgf-β3null mutant mice, we investigated the presence of TGF-β3 mRNA, its protein and phospho-SMAD2 in FA-deficient (FAD) mouse palates. Our results evidenced a large reduction in Tgf-β3 expression in palates of embryos of dams fed an FAD diet for 8 weeks; Tgf-β3 expression was less reduced in palates of embryos of dams fed an FAD diet for 2 weeks. Addition of TGF-β3 to palatal-shelf cultures of embryos of dams fed an FAD diet for 2 weeks normalized all the altered mechanisms. Thus, an insufficient folate status may be a risk factor for the development of CP in mice, and exogenous TGF-β3 compensates this deficit in vitro. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Although palatal shelf adhesion is a crucial event during palate development, little work has been carried out to determine which molecules are responsible for this process. Furthermore, whether altered palatal shelf adhesion causes the cleft palate presented by Tgf-β3 null mutant mice has not yet been clarified. Here, we study the presence/distribution of some extracellular matrix and cell adhesion molecules at the time of the contact of palatal shelves in both wild-type and Tgf-β3 null mutant palates of two strains of mice (C57/BL/6J (C57), and MF1) that develop cleft palates of different severity. We have performed immunohistochemistry with antibodies against collagens IV and IX, laminin, fibronectin, the α5- and β1-integrins, and ICAM-1; in situ hybridization with a Nectin-1 riboprobe; and palatal shelf cultures treated or untreated with TGF-β3 or neutralizing antibodies against fibronectin or the α5-integrin. Our results show the location of these molecules in the wild-type mouse medial edge epithelium (MEE) of both strains at the time of the contact of palatal shelves; the heavier (C57) and milder (MF1) alteration of their presence in the Tgf-β3 null mutants; the importance of TGF-β3 to restore their normal pattern of expression; and the crucial role of fibronectin and the α5-integrin in palatal shelf adhesion. We thus provide insight into the molecular bases of this important process and the cleft palate presented by Tgf-β3 null mutant mice. [ABSTRACT FROM AUTHOR]

Background: Palatoplasty has the undesired side effect of impaired mid-facial growth. To avoid this problem, we propose an alternative to palatoplasty. We hypothesize that if BMP-2 is injected together with a carrier into the periosteum of the cleft palate borders, border volume will increase and connective tissue cells will be activated to produce extra bone. Once these borders supported by bone reach the midline, extraction of their covering epithelia with trypsin will permit adhesion of the underlying tissues. We investigated in vitro the ability of cleft palate connective tissue cells to produce extra bone in the presence of BMP-2 and the possibility of using trypsin to remove the epithelium covering the cleft palate borders without impairing the underlying tissues’ ability to adhere. Materials and methods: We used the cleft palate presented by tgf-β3 null mice and small fragments of human cleft palate mucoperiosteum as models. Immunolabeling BMP-2-treated or untreated cultures with TUNEL and anti-osteocalcin or PCNA antibodies was performed. The epithelium of the cleft palate borders was removed with a trypsin solution, and the de-epithelialized tissues were cultured in apposition. Results: BMP-2 induces differentiation toward bone on cleft palate connective tissue cells without producing cell death or proliferation. Trypsin removal of the cleft palate margins’ epithelium does not impair the underlying tissues’ adhesion. Conclusion: It is possible to generate extra bone at the cleft palate margins and to chemically eliminate their covering epithelia without damaging the underlying tissues, which allows further investigation in vivo of this new approach for cleft palate closure. [Copyright &y& Elsevier]