Intervertebral Disc Mechanics Measured by dualMRI In Vivo

项目摘要/摘要 这项建议的目的是翻译双磁共振成像，一种新的非侵入性测量椎间的方法。 椎间盘(IVD)生物力学，对人类。IVD变性是一种常见的骨科问题，困扰着数百万人 在美国的人们。IVD的病理生理学涉及一系列的退行性病变，破坏了正常 细胞外基质蛋白合成，增加炎性细胞因子和酶的表达。 IVD生物力学功能对退变敏感，内部三维模式改变 (3D)与髓核(NP)中的水分损失和蛋白多糖分解有关的菌株， 纤维环(AF)结构完整性丧失。幸运的是，退化的级联导致了 许多潜在的治疗靶点。在终末期治疗(如脊柱融合术)之前，许多可能的 IVD变性的生物治疗和管理策略包括干细胞和自体细胞 植入、基因治疗、预防性注射和IVD去神经。一种理想的疗法最终会 恢复IVD的生物力学功能，其特点是内部应变场揭示局部修复和 在损伤后愈合。目前还没有可用的活体方法来测量3D生物力学 在IVD的整个内部运作。为了开发一种非侵入性的成像生物标记物 追踪治疗后肌肉骨骼组织的生物力学功能，我们开发了双磁共振成像 (在外加载荷下的位移)，用于测量内部的机械应变 关节软骨和静脉畸形。我们现在准备实施双重磁共振成像，用于活体测量 健康和退行性腰椎静脉畸形志愿者的生物力学研究。我们将制定一项工作议定书， 人体在体双磁共振成像，包括定制机械加载方法和MRI脉冲 序列，这将很容易在未来的应用中扩展到更大规模的病理和临床研究。我们 将追求两个目标。在目标1中，我们将使用双重mri来测量人类椎间盘的三维图像。 紧张。在目标2中，我们将在活体内演示健康和异常IVD之间的菌株差异。如果 成功后，我们将为IVD的无创性和在体功能评估提供一种新的工具。这 工作将为肌肉骨骼、制药和胸外科社区提供(A)临床 以动物和人类早期变性为靶点的治疗药物疗效评估的诊断工具 试验，(B)从功能上评估新出现的生物疗法治疗和修复IVD的能力，(C) 描述人体体内IVD健康功能的基线数据，以及(D)平台技术，以获得更多 广泛研究体内承重组织(如半月板、韧带)的力学功能。

PROJECT SUMMARY / ABSTRACT The objective of this proposal is to translate dualMRI, a new noninvasive method of measuring intervertebral disc (IVD) biomechanics, to humans. IVD degeneration is a common orthopaedic problem, afflicting millions of people in the United States. The IVD pathophysiology involves a degenerative cascade that disrupts normal extracellular matrix protein synthesis and increases the expression of inflammatory cytokines and enzymes. IVD biomechanical function is sensitive to degeneration, with altered internal patterns of three dimensional (3D) strains related to the loss of water content and proteoglycan breakdown in the nucleus pulposus (NP), and loss of structural integrity of the annulus fibrosus (AF). Fortunately, the degenerative cascade gives rise to many potential therapeutic targets. Prior to end-stage treatment (e.g. spinal fusion), numerous possible biological therapies and management strategies for IVD degeneration include stem and autologous cell implantation, gene therapy, prophylactic injection, and IVD denervation. An ideal therapy would ultimately restore the biomechanical function of the IVD, characterized by internal strain fields that reveal local repair and healing following damage. There are currently no in vivo methods available to measure 3D biomechanical function throughout the interior of the IVD. In an effort to develop an imaging biomarker that noninvasively tracks the biomechanical functional of musculoskeletal tissues following therapy, we developed dualMRI (displacements under applied loading by MRI) for the measurement of mechanical strain in the interior of articular cartilage and IVDs. We are now poised to implement dualMRI for the in vivo measurement of biomechanics in volunteers with healthy and degenerated lumbar IVDs. We will establish a working protocol for in vivo dualMRI in human volunteers, including custom mechanical loading methods and MRI pulse sequences, which will readily expand to larger scale pathologic and clinical studies in future applications. We will pursue two Aims. In Aim 1, we will implement dualMRI to measure 3D patterns of human intervertebral disc strain. In Aim 2, we will demonstrate strain differences between healthy and abnormal IVDs in vivo. If successful, we will provide a new tool for the noninvasive and in vivo functional assessment of the IVD. This work will provide musculoskeletal, pharmaceutical, and othopaedic surgery communities with (a) a clinical diagnostic tool to evaluate efficacy of therapeutic agents to target early degeneration in animal and human trials, (b) the ability to functionally evaluate IVD healing and repair with emerging biological therapies, (c) baseline data describing the healthy function of human IVDs in vivo, and (d) a platform technology to more broadly study mechanical function of load-bearing tissues (e.g. meniscus, ligament) in vivo.