Biomechanical and microstructural evaluation of newly formed bone following static/dynamic bone growth modulation in an immature animal model.

背景：无融合医疗器械是儿童脊柱畸形最有前途的治疗方法之一，因为它们能够防止脊柱关节融合术和重复/分阶段手术，就像目前的内固定治疗一样。它们是基于骨生长的机械调节，即力可以调节骨生长速率的过程。为了矫正畸形，这些植入物通过局部增加椎体生长板（骨生长的地方）上的压应力来限制脊柱弯曲凸度上的单侧骨生长。到目前为止，实验研究主要集中在静态和/或动态压缩对生长板的影响上，而生长调节对生长板下方出现的“新形成骨”质量的影响，既没有在其微结构方面也没有在其生物力学方面进行表征。随着对这些无融合植入物的兴趣和发展迅速增加，确定这些装置传递的载荷参数将影响新形成骨的质量以进一步指导其设计用于治疗儿童骨骼畸形变得非常重要。目的和方法：本项目包括两个主要研究目标：(1)表征体内静态和动态生长调节对新形成小梁骨的生物学和微观结构的影响；（II）评估体内静态与动态生长调节对新生小梁骨生物力学性能的影响。作为先前生长板力学生物学工作的逻辑延伸，我们将使用大鼠尾巴模型研究精细控制的静态或循环载荷对新形成骨的影响。静态或动态压缩将使用我们在大鼠尾部植入的空气驱动装置来加载第七尾椎。体内监测新形成的骨微结构将使用微ct成像来评估典型的骨小梁和皮质参数。基于提取的微ct几何和力学数据的有限元方法将被开发并用于非破坏性地估计新形成骨的力学性能。新形成骨的组成和生物学也将使用成骨标志物的免疫组织化学/染色技术以及评估骨生长速度的标记技术来表征。统计分析将允许比较静态/动态生长调节对新形成骨的微观结构、组成和生物力学质量的影响。新颖性和预期意义：目前治疗脊柱畸形，如脊柱侧凸，涉及侵入性手术内固定和椎体融合。脊柱无融合技术的最新进展，通过局部机械调节骨生长，在治疗这些进行性脊柱畸形方面显示出很大的希望。与传统手术相比，它们具有更低的手术风险和并发症，并能保持脊柱生长、脊柱运动和功能。很明显，更好地了解骨生长调节的相关因素对于指导和改进新型无融合技术的设计至关重要，这种技术可以或多或少地限制传输静态或动态载荷。然而，目前尚不清楚什么样的加载参数对骨生长调节有效且无损伤。所提出的研究项目将产生的知识将对设计用于儿童骨骼畸形的新型无融合植入物具有重要价值，不仅适用于脊柱，也适用于下肢/上肢畸形。

CONTEXT: Fusionless medical devices are one of the most promising treatments of pediatric spinal deformities due to their capacity to prevent spinal arthrodesis and repetitive/staged surgeries as in current instrumentation treatments. They are based on the mechanical modulation of bone growth, a process by which forces can modulate bone growth rate. To correct the deformities, these implants restrict unilateral bone growth on the convexity of the spinal curvature by locally increasing compressive stress over vertebral growth plates, where bone growth occurs. Up to now, experimental studies have mainly focused on the effects of static and/or dynamic compression on the growth plates, while the impact of growth modulation on the quality of « newly formed bone », emerging below the growth plate, has not been characterized neither in its microarchitecture nor its biomechanics. With rapidly increasing interest and developments in these fusionless implants, it becomes very important to identify which loading parameters transferred by these devices will impact on the quality of newly formed bone to further guide their design for the treatment of pediatric skeletal deformities. OBJECTIVES AND METHODOLOGY: This program comprises two main research objectives: (I) to characterize the effects of in vivo static vs dynamic growth modulation on the biology and microstructure of newly formed trabecular bone; (II) to evaluate the effects of in vivo static vs dynamic growth modulation on the biomechanical properties of newly formed trabecular bone. As a logical extension of previous work on growth plate mechanobiology, the effects of finely controlled static or cyclic loads on newly formed bone will be investigated using our rat tail model. Static or dynamic compression will be applied using our air-driven device implanted on the rat tail to load the 7th caudal vertebra. In vivo monitoring of newly formed bone microarchitecture will be done using micro-CT imaging to evaluate typical trabecular and cortical parameters. A finite element approach, based on extracted micro-CT geometrical and mechanical data, will be developed and used to non-destructively estimate the mechanical properties of the newly formed bone. The composition and biology of newly formed bone will also be characterized using immunohistochemistry/staining techniques for osteogenesis markers as well as labeling techniques to evaluate bone growth rates. Statistical analyses will allow comparing the impacts of static/dynamic growth modulation on the quality of newly formed bone in terms of microstructure, composition and biomechanics. NOVELTY AND EXPECTED SIGNIFICANCE: Current treatments of spinal deformities, such as scoliosis, involve invasive surgical instrumentation and vertebral fusion. Recent advances in fusionless techniques of the spine, by means of local mechanical modulation of bone growth, have shown great promise in the treatment of these progressive spinal deformities. They present less surgical risks and complications than the traditional surgery and preserve spinal growth, spinal motion and function. It is clear that a better understanding of the factors involved in bone growth modulation are essential to guide and improve the design of novel fusionless techniques, which could be designed more or less constrained to transmit either static or dynamic loads. However, it still is not clear at the moment what loading parameters would be efficient and non-damaging for bone growth modulation. The knowledge that will result from the proposed research program will be of great value for the design of novel fusionless implants for pediatric skeletal deformities, not only in the spine but also in the lower/upper limb deformities.