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

项目总结/摘要 唇腭裂是第二常见的先天性畸形，每600人中就有一例 全球出生。由于严重缺乏局部组织，广泛的疤痕是术后常见的并发症。 唇裂对患者上颌骨的生长发育有重要影响， 存在寻求有效的颅面组织再生方法在早期CLP修订。可惜 目前可用的动物模型的缺点阻碍了它们正确地模仿人类CLP 发展，特别是CLP修订结果评估。例如，在子宫内先天诱导 模型需要大量的技术专长，并涉及多种胎儿畸形，增加子宫内 胎儿死亡和流产，以及裂隙严重程度的巨大变化。与此同时，只有狗和猴子被用来 作为代表年轻患者CLP状况的药物诱导模型。不仅价格昂贵， 这些模型几乎不用于基于细胞的再生方法， 应用于允许异构细胞的使用，这可能会导致数据解释中的一个复杂的论点。 此外，没有已发表的外科小动物模型在青春期前伴随缺陷发展， 因此早期唇裂修复对颅面生长发育的影响尚未完全阐明。 为了克服这些问题，在当前的R 03提案中，我们打算在年轻的 啮齿类动物1）模仿在CLP患者中观察到的颅面生长变形，2）评估 唇裂修复术后瘢痕对颅面生长发育的影响; 3）建立一个简便、规范的 一种在动物中建立一致的缺损大小的方法，这将有利于进一步探索 CLP管理中的再生策略。在常用的小实验动物中，大鼠是 对于基于骨量和结构进行涉及骨骼的基础研究非常有用 测量，因此代表了可靠和负担得起的替代大型动物。值得注意的是， 大鼠的生长模式已被深入记录，并与人类的生长模式相关，使大鼠变得更加 与其他小动物相比，其在代表人类CLP发展方面更有利。因此，在AIM 1中，单边 将在大鼠中手术产生具有或不具有临界尺寸牙槽缺损的唇裂，所述大鼠的年龄代表 0.5岁的人，而裂缝对他们的颅面生长的影响将在此期间进行跟踪 在目标2中，将在CLP大鼠中应用早期唇裂修复一周 观察唇裂术后早期修复对颅面发育的影响。 总体而言，本研究旨在为探索和无偏见地评价新的 CLP治疗的再生策略。如果成功，它将为改善患者的生活质量铺平道路， 尤其是正在成长的孩子，他们会受到疤痕引起的副作用的影响。

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.