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

评价唇裂修复疤痕对颅面生长发育影响的小动物模型

• 批准号: 10642519
• 负责人: CHENSHUANG LI
• 金额: $ 32.5万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10642519
• 关键词: 3-Dimensional; 5 year old; Affect; Age; Age Months; Alveolar; Anatomy; Animal Experiments; Animal Model; Animals; Basic Science; Birth; Bone Transplantation; Bone structure; Canis familiaris; Cells; Cicatrix; Cleft Lip; Cleft lip with or without cleft palate; Clinical; Complication; Congenital Abnormality; Data; Data Analyses; Defect; Development; Disadvantaged; Excision; Fetal Death; Foundations; Future; Growth; Growth and Development function; Human; Hypertrophic Cicatrix; Immunosuppression; Impairment; Incidence; Individual; Left; Lip structure; Maxilla; Measurement; Measures; Methods; Modeling; Monkeys; Mus; Natural regeneration; Operative Surgical Procedures; Oral; Orthodontic; Outcome; Outcome Assessment; Patients; Pattern; Performance; Pharmacology; Physiology; Postoperative Period; Procedures; Proteins; Puberty; Publications; Publishing; Quality of life; Rattus; Rodent; Severities; Skeleton; Speech; Sprague-Dawley Rats; Standardization; Surgeon; Surgical Models; Surgical sutures; Technical Expertise; Techniques; Tissue Engineering; Tissues; Variant; abortion; alveolar bone; alveolar cleft; bone mass; cleft lip and palate; clinically relevant; craniofacial; craniofacial development; craniofacial structure; craniofacial tissue; fetal; fibromodulin; improved; in utero; malformation; mechanical load; model development; novel; operation; orthognathic; palate repair; prevent; regenerative approach; repaired; side effect; skeletal maturation; social; soft tissue; treatment strategy; two-dimensional; wound

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.

项目摘要/摘要 唇裂（CLP）是第二常见的先天性畸形，每600中影响一个 全球出生。由于局部组织的严重缺乏，广泛的疤痕是一个常见的并发症 早期修复唇裂，这会影响患者的上颌生长和发育，而迫切需要 在早期CLP修订中寻求有效的颅面组织再生方法的存在。不幸的是， 当前可用的动物模型的缺点是正确模仿人类CLP的障碍 开发，特别是CLP修订结果评估。例如，在子宫内诱导的 模型需要巨大的技术专长，并且与多种胎儿畸形有关，宫内增加 胎儿死亡和堕胎，以及裂口严重程度的巨大变化。同时，仅使用狗和猴子 作为代表年轻患者CLP状况的手术诱导模型。不仅很昂贵，而且 这些模型几乎不用于基于细胞的再生方法，因为免疫抑制必须是 应用于允许异质细胞使用情况，这可能导致数据解释中的复杂论证。 此外，没有发表的手术小动物模型伴随着青春期前的缺陷发育， 因此，尚未完全阐明早期裂口修复对颅面生长和发育的影响。 为了征服这些问题，在当前的R03提案中，我们打算在Young中建立一个新颖的CLP模型 啮齿动物至1）模仿CLP患者观察到的颅面生长变形，2）评估 裂口唇修复因颅面生长和发育而造成疤痕，3）建立一个简单而标准化的 在动物之间创造一致的缺陷大小的方法，这将有助于进一步探索 CLP管理中的再生策略。在常用的小型实验动物中，大鼠是 对于基于骨骼和结构的骨骼进行基础研究非常有用 测量，因此代表了大型动物的可靠且负担得起的替代品。值得注意的是，颅面 大鼠的生长模式已被深深的文献记载并与人类的相关性，使大鼠更多 与其他小动物相比，代表人类CLP的发展有利。因此，在AIM 1中，单方面 在代表年龄的大鼠中，将通过手术产生有或没有关键尺寸肺泡缺陷的裂口唇。 0.5岁的人，而裂口对颅面生长的影响将在此期间进行跟踪 代表整个人类青春期；在AIM 2中，将在CLP大鼠中进行早期裂口修复 在产生缺陷之后，以评估早期唇部修订对颅面发育的影响。 总体而言，这项研究旨在为探索和公正评估新的结果奠定基础 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， 尤其是成长中的人，患有疤痕引起的副作用。