Load-Driven Bone Lengthening

描述（由申请人提供）： 本项目的长期目标是了解负荷驱动骨延长的机制。虽然牵张成骨是有效的治疗肢体长度不等的患者，这种侵入性的程序偶尔会产生的问题，如过早巩固，延迟愈合，感染。为了研究一种负荷驱动的无创治疗的可能性，我们将重点放在膝关节负荷上 一种联合装载方式。在这个R 03项目中，我们解决了一系列问题：（1）膝关节负荷是否会增加生长板中软骨细胞的增殖并延长股骨远端和胫骨近端的增殖和肥大区？(2)延长效果取决于年龄吗？(3)向生长板内注射胰岛素生长因子-2（IGF-2）是否能增强负荷效应？我们假设：（a）在适当的负荷条件下施加于膝关节的侧向负荷可以通过刺激生长板中的软骨细胞的增殖来延长股骨和胫骨;（B）负荷驱动的骨延长的功效在年轻人中比在老年人中更强;以及（c）通过在生长板中注射IGF-1可以增强在老年人中的延长效果。为了检验上述假设，提出了三个具体的目标，使用C57 BL/6小鼠的后肢作为模型系统。“在不同机械条件下负荷驱动骨延长的评价“不同年龄小鼠的负荷效果比较“在有和没有膝关节负荷的情况下将IGF-2局部施用到生长板中的效果。我们将使用定制的压电机械加载器，并使用不同的成像方式进行骨组织形态计量学和基因表达分析。这项研究有望为肢体长度不等患者的非侵入性物理治疗做出贡献。目前，侵入性外科手术（牵引成骨）通常用于延长长骨。然而，该手术存在一系列潜在风险，如过早固结、延迟愈合、骨感染、关节僵硬和新形成骨断裂。拟议的R 03项目将有助于研究非侵入性物理疗法治疗肢体长度不等患者的可能性。

DESCRIPTION (provided by applicant): The long-term objective of the proposed project is to understand the mechanism of load-driven bone lengthening. Although distraction osteogenesis is effective to treat the patients with limb length discrepancy, this invasive procedure occasionally generates problems such as premature consolidation, delayed union, and infection. In order to investigate a possibility of load-driven non-invasive therapy, we will focus on knee loading a form of joint loading modalities. In this R03 project, we address a set of questions: (1) Does knee loading enhance proliferation of chondrocytes in the growth plate and lengthen the proliferative and hypertrophic zones in the distal femur and the proximal tibia? (2) Is the lengthening effect dependent on ages? (3) Does injection of insulin growth factor-2 (IGF-2) into the growth plate enhance the loading effects? We hypothesize: (a) Lateral loads, applied to the knee with appropriate loading conditions, can lengthen both the femur and the tibia through stimulating proliferation of chondrocytes in the growth plate; (b) Efficacy of load-driven bone lengthening is stronger in the youth than the elderly; and (c) The lengthening effect can be augmented in the elderly by injecting IGF-1 in the growth plate. In order to examine the above hypotheses, three specific aims are proposed using a hindlimb of C57BL/6 mice as a model system. " Evaluation of load-driven bone lengthening under varying mechanical conditions " Comparison of the loading effects among mice with varying ages " Effects of local administration of IGF-2 into the growth plate with and without knee loading. We will use a custom-made piezoelectric mechanical loader, and conduct bone histomorphometric and gene expression analyses using varying imaging modalities. The proposed study is expected to contribute to developing a non-invasive physical therapy for treatment of patients with limb length discrepancy. PROJECT NARRATIVE Currently the invasive surgical procedure (distraction osteogenesis) is commonly employed to lengthen long bones. However, this procedure presents a series of potential risks such as premature consolidation, delayed union, bone infection, joint stiffness, and fracture of newly formed bone. The proposed R03 project will contribute to examining a possibility of non-invasive physical therapy for treatment of patients with limb length discrepancy.