Plastic Surgery Research Council
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PSRC 60th Annual Meeting
Program and Abstracts

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Microsurgical Intervention of Cleft Lip Ex Utero by Reactivation of Craniofacial Developmental Programs
Wilmina N. Landford, B.A., Elisabetta Ferretti, Ph.D, Ope Asanbe, M.D., Peipei Zhang, M.B.B.S, Ph.D, James Hart, D.V.M., Licia Selleri, M.D., Jason A. Spector, M.D., FACS.
Weill Cornell Medical College, New York, NY, USA.

PURPOSE:
Cleft lip/palate (CLP) affects 1 in 500-700 live births, representing the most common congenital craniofacial anomaly. Pbx homeoproteins have been linked to normal midfacial morphogenesis through the activation of transcriptional regulators Wnt9-Wnt3, which control localized apoptotic programs at the embryonic lambdoidal (λ) junction. Previously, we developed a unique compound Pbx-deficient murine model with fully penetrant CLP and demonstrated genetic rescue strategies to reconstitute Wnt signaling and correct midface clefting. We now seek to restore Wnt-mediated craniofacial developmental programs in our Pbx-deficient embryonic murine model using microsurgical intervention ex utero.
METHODS:
A modified Whole Embryo Culture (WEC) technique will be used to culture mouse embryos ex utero. Briefly, wildtype and Pbx compound mutant mouse embryos will be dissected out of the uterus, the yolk sac and amnion pierced open, and the embryos cultured at 37°C. At gestational days 9.5 and 11, collagen microspheres soaked in murine purified Wnt9b (or Wnt3) protein will be microsurgically implanted into the midfacial λ junction of wildtype and Pbx compound mutant embryos. Correction of CLP will be assessed by gross morphology, histology, and evaluation of the restoration of apoptotic programs. Furthermore, titration assays will be conducted to optimize the dose of Wnt by assessing protein content and release kinetics as well as its range of action in the embryonic face with regard to space and time. In vitro studies will be done to determine optimal formulations of collagen microspheres.
RESULTS:
In our previous studies, Pbx-deficient mice with fully penetrant CLP in which Wnt1 is mis-expressed in superficial cephalic ectoderm cells, showed full correction of the cleft lip phenotype after genetic rescue by reactivation of Wnt signaling at the lambdoidal junction. We hypothesize that microsurgical delivery of Wnt proteins to the midfacial λ junction of Pbx mutant mouse embryos with CLP will restore localized cellular apoptosis, reactivate craniofacial developmental programs, and ultimately correct CLP.
CONCLUSION:
The microsurgical correction of CLP via a collagen microsphere-based protein delivery system is a promising and innovative strategy that could lead to prenatal surgical correction of CLP in humans. We aim to provide an alternative strategy for cleft lip repair using protein-loaded collagen microspheres applicable for tissue engineering.


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