The Fetal Cleft Palate: III. Ultrastructural and Functional Analysis of Palatal Development following In Utero Repair of the Congenital Model

Abstract

The role of fetal surgery in the management of congenital anomalies and intrauterine abnormalities is appropriately restricted on the basis of feasibility and risk-to-benefit analyses of intrauterine intervention. Recently, the authors demonstrated that in utero cleft palate repair of the congenital caprine model is technically feasible and results in scarless healing of the mucoperiosteum and velum, with subsequent development of a potentially functional bilaminar palate with distinct oral and nasal mucosal layers, following single-layer repair of the fetal mucoperiosteal flaps. A slight indentation at the site of repair was the only remaining evidence of a cleft. At 6 months of age, normal palatal architecture, including that of mucosal, muscular, and glandular elements, was seen grossly and histologically. The present work investigated the ultrastructural and functional aspects of the palate following in utero cleft repair to determine what benefits might be derived from fetal intervention. Six goats pregnant with twins were gavaged twice daily for 10 days (gestational days 32 to 41; term, 145 days) with dry, ground Nicotiana glauca plant delivering between 2.4 and 14 mg/kg per day of anabasine, doses that were adjusted in response to mater-nal toxicity. At 85 days' gestation, six fetuses underwent in utero palatoplasty using a modified von Langenbeck technique with elevation of bilateral mucoperiosteal flaps and lateral relaxing incisions. A single-layer repair of the mucoperiosteal flaps was performed using interrupted 6-0 Vicryl sutures. Six fetuses remained as unrepaired clefted controls. Six months after in utero palatoplasty, each group of goats underwent nasoendoscopy to evaluate palatal function; two unclefted 6-month-old goats served as controls. Subsequently, soft palate muscle was harvested from each of the goats and was evaluated by light and electron microscopy. Velar muscle was also harvested from the unclefted control goats and was similarly studied. Nasoendoscopy demonstrated functional palates capable of dynamic velopharyngeal closure following in utero cleft repair; this motion was similar to that observed in unclefted animals. Unrepaired clefted goats did not demonstrate any evidence of velar motion or velopharyngeal closure. Soft palate muscle from this group demonstrated evidence of myofibril degeneration, atrophy, and loss compared with unclefted control velar muscle. Ultrastructural changes included sarcomere "scalloping, " partial Z-line degeneration and loss, and progressive I-band degeneration and loss. Repaired clefted soft palate muscle was remarkably similar to unclefted control muscle. Significantly less myofibril, Z-line, and I-band degeneration and loss were observed with minimal evidence of sarcomere scalloping. In utero cleft palate repair results in a functional soft palate with restoration of ultrastructural architecture of the velum. These findings were attributed to reconstitution of the velar muscular sling, which is disrupted during the clefting process and remains abnor...

Strategies to Improve Regeneration of the Soft Palate Muscles After Cleft Palate Repair

“…Therefore, the selection of an appropriate animal model for the study of the regeneration of the soft palate muscles is highly important. The use of an existing congenital cleft palate model in the goat 51,[54][55][56] is not feasible due to the high costs that limits group size. Cleft palate models in knockout mice are generally limited to embryological studies due to high mortality after birth, and lack of reproducibility of the induced clefts.…”

Contractile Properties of Single Permeabilized Muscle Fibers from Congenital Cleft Palates and Normal Palates of Spanish Goats

“…In the congenital cleft palate model, Weinzweig et al observed degeneration of myofibrils and Z-bands. 8 We hypothesize that intrinsic differences in the levator veli palatini muscle alter the functional state of the muscles and that those differences may play a more crucial role in the differential outcomes following surgery than the surgical procedure itself.…”

Ultrasound prenatal diagnosis of a lateral facial cleft (Tessier number 7)

“…The same authors showed that the intrauterine lysis of these forces (sutures) was able to prevent the abnormal growth of the facial commissure9. More recently, it was demonstrated that in‐utero cleft repair is technically possible in a goat model10, 11.…”