Natural Variation in the Growth and Development of the ACL Complex

ACL 复合体生长和发育的自然变异

• 批准号: 9224458
• 负责人: Stephen Schlecht
• 金额: $ 9.18万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-21 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9224458
• 关键词: 15 year old; Address; Adolescent; Adult; Affect; Age; Anatomy; Anterior Cruciate Ligament; Applications Grants; Area; Athletic; Atomic Force Microscopy; Biological Markers; Biomedical Engineering; Child; Clinical; Complex; Development; Diagnostic; Elbow; Event; Exercise; Failure; Fatigue; Feedback; Frequencies; Future; Gene Targeting; Genotype; Goals; Growth; Growth Factor; Growth and Development function; High Pressure Liquid Chromatography; Human; Inbred Mouse; Individual; Individual Differences; Injury; Intervention; Lead; Ligaments; Location; Mechanics; Mentors; Methods; Modeling; Modulus; Morphology; Mus; Musculoskeletal; Musculoskeletal System; Organ; Outcome; Phase; Phenotype; Physical activity; Population; Predisposition; Prevalence; Prevention program; Process; Raman Spectrum Analysis; Research; Resistance; Risk; Risk Factors; Role; Rotator Cuff; Sports; Structure; Study models; System; Testing; Tissues; Training; Translating; United States; Variant; Vertebral column; Work; Youth; anterior cruciate ligament rupture; bone; emerging adult; foot; functional adaptation; high risk; in vivo; injury prevention; ligament injury; mechanical load; mechanical properties; mouse model; novel strategies; postnatal; prevent; response; trait

Identifying risk factors to prevent anterior cruciate ligament (ACL) injuries remains a major objective of musculoskeletal research. Athletic participation in the United States among children and adolescents has increased over the last three decades, resulting in a greater prevalence of ACL injuries. The frequency of ACL injuries among individuals under 15 years of age has risen 924% since 1994 despite the incorporation of injury prevention programs in youth sports. Further, 70% of ACL injuries occur while performing non-contact maneuvers (e.g. single foot landings, pivots). Yet, it remains unclear whether these injuries result from a single overload event or a fatigue failure wherein a period of intervention is available. Injuries are likely multifactorial and influenced by an individual's natural anatomical variation. Fatigue failure of the ACL via repetitive loading, combined with the natural variation in anatomical structure between individuals, has largely been overlooked as an explanatory mechanism for unanticipated ACL failures. We showed previously that ACL cross-sectional area (CSA) is a significant predictor of peak relative strain. However, injury risk between individuals is not easily delineated because of the large degree of variation in this trait. We hypothesize that the natural variation in ACL CSA is accompanied by coordinated changes in tissue-level mechanical properties and/or other gross anatomical features that together allow the `ACL-complex' (i.e. the ligament and its entheses) to be mechanically functional under routine loading conditions. We further hypothesize that this coordination, although effective in establishing the strength of the ACL-complex, may result in changes in tissue-level mechanical properties that deleteriously affect the fatigue resistance of the ACL-complex for certain individuals. We will test our hypotheses using a mouse model that mirrors the natural variation in ACL-complex traits among humans. At the completion of this work we will have an established mouse model for generating new hypotheses, along with a better understanding of how the ACL-complex develops postnatally and functionally adapts to mechanical loads. These outcomes are expected to guide interventions aimed at maximizing ACL strength while minimizing ACL rupture among children and adolescents, and to have a broad positive impact in other anatomically unique locations where ligamentous and tendinous injuries routinely occur (e.g. rotator cuff, elbow, spine) and are likely influenced by a similar complex adaptive system wherein multiple traits are coordinated to establish organ-level strength and stiffness.

识别风险因素以预防前交叉韧带（ACL）损伤仍然是 肌肉骨骼研究在美国，儿童和青少年参加体育运动的人数 在过去的三十年中增加，导致ACL损伤的患病率更高。ACL的频率 自1994年以来，15岁以下的个人受伤人数增加了924%， 预防青少年体育项目。此外，70%的ACL损伤发生在执行非接触式手术时， 机动（例如单脚着陆、旋转）。然而，目前还不清楚这些伤害是否是由单一的 过载事件或疲劳故障，其中干预时间段是可用的。受伤可能是多方面的 并受到个体自然解剖变异的影响。通过重复加载导致ACL疲劳失效， 再加上个体之间解剖结构的自然变异， 作为意外ACL故障的解释机制。我们之前指出，ACL横截面 面积（CSA）是峰值相对应变的重要预测因子。然而，个体之间的伤害风险并不 因为这种性状的变异程度很大，所以很容易描述。我们假设自然变异 在ACL中，CSA伴随着组织水平机械性能和/或其他总体 这些解剖特征共同允许“ACL复合体”（即韧带及其附着点） 在常规负载条件下机械功能正常。我们进一步假设，这种协调， 虽然在建立ACL复合物的强度方面有效，但可能导致组织水平的变化， 机械性能，不利地影响ACL复合物的抗疲劳性， 个体我们将使用反映ACL复合物自然变异的小鼠模型来测试我们的假设。 人类的特征在这项工作完成后，我们将有一个建立的小鼠模型，以产生 新的假设，沿着更好地理解ACL复合体如何在出生后发展， 在功能上适应机械负载。预计这些成果将指导旨在 最大限度地提高ACL强度，同时最大限度地减少儿童和青少年的ACL断裂， 在韧带和肌腱损伤经常发生的其他解剖学上独特的位置产生积极影响 (e.g.肩袖、肘、脊柱），并且可能受到类似的复杂适应系统的影响，其中多个 协调性状以建立器官水平的强度和刚度。