Development and Persistence of Tissue-Level Musculoskeletal Deformity Following Brachial Plexus Birth Injury

臂丛神经出生损伤后组织水平肌肉骨骼畸形的发展和持续

• 批准号: 10585930
• 负责人: Jacqueline H Cole
• 金额: $ 31.29万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-10 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585930
• 关键词: Activities of Daily Living; Address; Affect; Articular Range of Motion; Automobile Driving; Biological; Birth; Birth trauma; Bone Development; Bone Growth; Bone structure; Brachial plexus structure; Categories; Child; Childhood Injury; Clinical; Complex; Computer Models; Computer Simulation; Consensus; Contracts; Contracture; Deformity; Denervation; Deposition; Development; Diameter; Engineering; Environment; FGF2 gene; Family; Forearm; Foundations; Future; Growth; Growth Factor; Growth and Development function; Impairment; Individual; Injury; Insulin-Like Growth Factor I; Joints; Knowledge; Limb structure; Location; Mechanics; Metabolism; Minerals; Modeling; Muscle; Muscle Development; Musculoskeletal; Natural regeneration; Neuromechanics; Operative Surgical Procedures; Orthopedic Surgery; Osteogenesis; Osteotomy; Outcome; Paralysed; Perinatal; Posture; Public Health; Quality of life; Radial; Rattus; Reporting; Research; Research Design; Rodent Model; Role; Shoulder; Signal Transduction; Stimulus; Structure; Surgical Disarticulation; Tissues; Traumatic injury; Weight-Bearing state; Work; arm; arm function; biomechanical engineering; bone; bone geometry; clinical decision-making; critical period; humerus; improved; innovation; joint loading; loss of function; mechanical load; multidisciplinary; muscular structure; negative affect; nerve damage; nerve injury; neural; neuromuscular; postnatal; postnatal period; preference; rapid growth; reduced muscle mass; scapula; skeletal; timeline

PROJECT SUMMARY Brachial plexus birth injury (BPBI) is a traumatic perinatal neuromuscular injury causing muscle paralysis and lifelong arm impairment. Muscle paralysis in these children also leads to bone and joint consequences, including deformed growth of the scapula and humerus. BPBI occurs during a critical period of rapid musculoskeletal growth, but the parallel postnatal interactions of muscle and bone that drive these persistent deformities are not understood. Clinical reports and preliminary work suggest that short, contracted muscles after injury can alter mechanical loading of the shoulder consistent with observed bone deformity at macro- and microstructural levels. Altered active limb function with reduced range of motion and load bearing is also present; disuse is known to alter tissue growth and maturation. Finally, nerve injury in other conditions also affects bone growth directly, and direct effects in the postnatal period are not clear. Identifying appropriate targets for future treatment requires understanding which factors associated with altered bone and muscle development are most critical for driving altered growth. Almost nothing is known about the timing and progression of changes in underlying bone and muscle structure or metabolism following nerve injury occurring at birth to provide a foundation for clinical decision-making. Our primary hypothesis is that the bone deformity following BPBI is driven primarily by the mechanical environment, derived from impaired longitudinal growth of paralyzed muscle and altered active functional loading beginning shortly after injury. We will apply our unique rodent and computational models of BPBI that probe the separate contributions of nerve injury and muscle contracture to perform complementary assessments of the relative contributions of nerve injury, passive muscle loading, and active functional loading following BPBI to bone deformity. We will do so using 1) previously validated rat neurectomy models of brachial plexus injury and our unique disarticulation model of altered loading and 2) an integrated computational model to determine which specific features of bone deformity following BPBI are driven primarily by each potential driver. This R01 project, conducted by a multidisciplinary team with expertise in orthopedic surgery and biomechanical engineering, has high potential to elucidate the role of denervation in the parallel development of bone and muscle that occurs postnatally. Our innovative study design permits us to isolate both direct neural effects and indirect effects from altered passive and active mechanical loading on bone development in a way that has not previously been possible. Ultimately, this work has the potential to shift current research and treatment paradigms from an isolated focus on muscle as a treatment target to an integrated muscle and bone approach based on driving factors of deformity and loss of function. We anticipate our results will provide new candidates for improved treatment of BPBI and other neuromuscular injuries.

项目概要 臂丛神经产伤 (BPBI) 是一种创伤性围产期神经肌肉损伤，导致肌肉麻痹和 终生手臂损伤。这些儿童的肌肉麻痹还会导致骨骼和关节后果，包括 肩胛骨和肱骨生长畸形。 BPBI 发生在肌肉骨骼快速发展的关键时期 生长，但驱动这些持续性畸形的肌肉和骨骼的出生后平行相互作用并不是 明白了。临床报告和初步工作表明，受伤后短而收缩的肌肉可以改变 肩部的机械负荷与宏观和微观结构水平上观察到的骨畸形一致。 还存在活动肢体功能改变，运动范围和承重范围缩小；众所周知，废弃 改变组织生长和成熟。最后，其他情况下的神经损伤也会直接影响骨骼生长，并且 对产后时期的直接影响尚不清楚。确定未来治疗的适当目标需要 了解哪些与骨骼和肌肉发育改变相关的因素对于驾驶最为关键 改变增长。关于底层骨骼变化的时间和进展几乎一无所知 出生时发生神经损伤后的肌肉结构或代谢，为临床提供基础 决策。我们的主要假设是 BPBI 后的骨畸形主要是由 机械环境，源自瘫痪肌肉的纵向生长受损和主动改变 受伤后不久开始功能负荷。我们将应用我们独特的啮齿动物和计算模型 BPBI 探究神经损伤和肌肉挛缩的单独贡献以执行互补 评估神经损伤、被动肌肉负荷和主动功能负荷的相对贡献 BPBI 后骨畸形。我们将使用 1) 先前验证的大鼠臂神经切除模型来做到这一点 神经丛损伤和我们独特的改变负荷的离断模型以及 2) 集成计算模型 确定 BPBI 后骨畸形的哪些具体特征主要由每种潜在因素驱动 司机。这个 R01 项目由具有骨科手术专业知识的多学科团队进行 生物力学工程，具有很大的潜力来阐明去神经支配在并行发展中的作用 出生后发生的骨骼和肌肉。我们的创新研究设计使我们能够分离直接神经 改变被动和主动机械负荷对骨骼发育的影响和间接影响 这在以前是不可能的。最终，这项工作有可能改变当前的研究和 治疗范式从孤立地关注肌肉作为治疗目标到整合肌肉和骨骼 基于畸形和功能丧失的驱动因素的方法。我们预计我们的结果将提供新的 改善 BPBI 和其他神经肌肉损伤治疗的候选者。