Towards Microsurgical Correction of Cleft Lip Ex Utero via Restoration of Craniofacial Developmental Programs.

Background: Cleft Lip with or without Palate (CL/P) is present in approximately 1 in 500-700 live births, representing the most common congenital craniofacial anomaly. Previously, we developed a unique murine model with compound Pbx deficiency that exhibits fully penetrant CL/P. To investigate the possibility of tissue repair at an early gestational stage, we designed a minimally invasive surgical approach suitable for intrauterine repair using Wnt9b-soaked collagen microspheres to restore craniofacial developmental programs for cleft correction. Methods: Collagen microspheres with diameters ranging from 20-50 microns were fabricated to serve as a delivery vehicle for Wnt9b. At gestational day 11.5, wild type and Pbx-deficient murine embryos were isolated. Microspheres soaked in murine purified Wnt9b protein were microsurgically implanted at the midface [lambda] junction. Embryos were cultured in a 37[degrees]C modified Whole Embryo Culture (WEC) system. Results: Targeted release of Wnt9b resulted in augmented Wnt expression at the [lambda] junction. Microsurgical implantation of Wnt9b-soaked microspheres resulted in cleft correction in 27.1% of the Pbx-deficient embryos. The difference in the ratio of the areas of clefting between implanted and non-implanted embryos was significant (p

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