Small animal model for evaluating the impacts of cleft lip repairing scar on craniofacial growth and development

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PROJECT SUMMARY/ABSTRACT Cleft lip and palate (CLP) is the second most common congenital malformation, affecting one in every 600 births worldwide. Due to the significant lack of local tissue, extensive scarring is a common complication after early repair of the cleft lip that vitally impacts patients' maxilla growth and development, while an urgent need exists for seeking effective craniofacial tissue regenerative approaches in early CLP revision. Unfortunately, the disadvantages of the currently available animal models hurdle them from properly mimicking human CLP development, particularly the CLP revision outcome assessment. For instance, in utero congenitally induced models require immense technical expertise and relate to multiple fetal malformations, increased intrauterine fetal death and abortions, and large variation of the cleft severity. Meanwhile, only dogs and monkeys were used as surgical-induced models representing the CLP conditions in young patients. Not only being expensive, but these models are hardly used for cell-based regenerative approaches since immunosuppression has to be applied to permit heterogeneous cell usage, which may lead to an intricate argument in data interpretation. Moreover, no published surgical small animal models are accompanied by defect development before puberty, and thus the impact of early cleft lip repair on craniofacial growth and development has not been fully elucidated. To conquer these questions, in the current R03 proposal, we intend to establish a novel CLP model in young rodents to 1) mimic the craniofacial growth deformation observed in CLP patients, 2) evaluate the impacts of scarring from cleft lip repair on craniofacial growth and development, and 3) set up an easy and standardized approach to creating consistent defect size among animals, which will be beneficial for further exploring regenerative strategies in CLP management. Among the commonly used small experimental animals, rats are extremely useful for conducting basic research involving the skeleton based on the bone mass and structure measurements, and thus represent reliable and affordable alternatives to large animals. Notably, the craniofacial growth pattern of rats has been deeply documented and correlated to that of humans, making rats more advantageous for representing human CLP development than other small animals. Therefore, in AIM 1, unilateral cleft lip with or without a critical-sized alveolar defect will be generated surgically in rats at the age representing 0.5-year-old human, while the influence of the cleft on their craniofacial growth will be tracked through the period representing the entire human puberty; and in Aim 2, early cleft lip repair will be applied in CLP rats one week after the creation of the defects to assess the influence of early cleft lip revision on craniofacial development. Overall, this study aims to set up the foundation for exploring and unbiasedly evaluating the outcomes of new regenerative strategies for CLP treatment. If successful, it will pave the path to improve the life quality of patients, especially growing ones, who suffer from scarring-induced side effects.