An Evaluation of Serum Based Indices to Assess Fracture Healing

评估骨折愈合的血清指标

• 批准号: 9032090
• 负责人: Louis Charles Gerstenfeld
• 金额: $ 18.02万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9032090
• 关键词: Aging; Antibodies; Biological; Biological Assay; Biological Markers; Biological Process; Biomechanics; Bone callus; Bone remodeling; Cartilage; Characteristics; Clinical; Clinical Trials; Complication; Correlation Studies; Development; Diagnosis; Diagnostic; Enzyme-Linked Immunosorbent Assay; Evaluation; Failure; Fracture; Fracture Healing; Healed; Healthcare; Human; Impaired wound healing; Inflammatory Response; Injury; Mass Spectrum Analysis; Measurement; Measures; Medicine; Methods; Mus; Operative Surgical Procedures; Organ; Osteogenesis; Osteoporosis; Outcome; Pain-Free; Patient Outcomes Assessments; Patients; Proteins; Proteome; Proteomics; Relative (related person); Roentgen Rays; Secondary to; Serum; Serum Markers; Serum Proteins; Set protein; Spectrophotometry; Structure; Surveys; Technology; Testing; Therapeutic Intervention; Tibial Fractures; Time; Tissues; Translations; United States; Variant; Weight-Bearing state; Work; aptamer; base; bone; bone healing; cartilage development; contrast enhanced; cost; design; healing; improved; indexing; long bone; mineralization; novel; prognostic; protein expression; repaired; response to injury; skeletal tissue; tool

ABSTRACT Fractures are the most common large-organ, traumatic injuries in humans, and osteoporosis-related fractures are the fastest growing health care problem of aging. While fracture repair after surgery is usually optimal, up to 10% percent of the estimated ~8 to 10 million fractures that occur annually in the United States show delayed or impaired healing (Praemer et al., 1992). Currently, radiographic assessment, with reduction in healing complication and validated patient reported outcomes of regain of pain free weight bearing and function are the primary diagnostic tools to assess the progression of fracture healing. However none of these current assessments either define underlying biological processes that are related to the progression of fracture healing or are they prognostic for delayed healing or non-unions. Thus, there is an immense and immediate need to identify objective quantifiable biological markers: 1) that relate to the underlying biological processes of skeletal tissue healing: 2) that are indicative of the progression of skeletal tissue healing:3) that would be prognostic of deficiencies in skeletal tissue healing. The development of such an assay would be an immense benefit to: 1) be informative to the underlying causes for delayed and failed healing: 2) use in clinical trials that assess the efficacy of biological or pharmacological therapies that promote bone healing and: 3) identify those patients that would benefit from biological or pharmacological therapeutic interventions to promote bone healing. Our hypothesis is that there will be a combination of serum markers that can be used to define the biological progression of fracture healing and that we will be able to relate one or more of these markers to structural, functional and clinical characteristics that define the progression of healing. Two specific aims are proposed. Aim 1 will identify those proteins in the serum proteome that show changed levels of expression across the time course of fracture healing relative to unfractured bone. In this aim, two approaches will be used: a mass spectrometry approach and a more targeted novel aptamer-based multiplexed proteomic technology. This aim is will identify and provide preliminary quantification of a subset of proteins that can be related to various biological processes that define the temporal progression of fracture healing. In Aim 2, we will test a subset of these proteins for their statistical correlation to the development and resorption of cartilage, development and remodeling of bone and callus tissue structure mineralization as determined by both cartilage contrast enhanced and standard µCT. We will test for statistical correlation of specific protein expression to specific biomechanical functions (stiffness, strength, work to failure). Finally, we will test how callus structure, function measurements and specific protein markers correlate to current clinically used Radiographic Union Score for Tibial (RUST) fracture healing (Whelan et al., 2010) that is used to assess the progression of human long bone healing. If successful this study will identify a set of proteins that can be used in a human trial to test for their diagnostic efficacy to follow fracture healing and their prognostic efficacy for delayed or failed healing.

抽象的 骨折是人类中最常见的大器官，创伤性损伤和骨质疏松相关的骨折 是增长最快的医疗保健问题。虽然手术后的断裂修复通常是最佳的，但 每年在美国发生的估计约8至1000万骨折的10％ 延迟或受损的愈合（Praemer等，1992）。目前，射线照相评估，减少 康复并发症和经过验证的患者报告了剩余的无痛体重轴承的结果 功能是评估断裂愈合进展的主要诊断工具。但是这些都不 当前的评估要么定义与基本的生物学过程相关的生物学过程 骨折愈合，或者是预后延迟治愈或非工会的预后。那是一个巨大的 立即需要确定客观可量化的生物学标记：1）与潜在的生物学有关的 骨骼组织愈合的过程：2）指示骨骼组织愈合的进展：3） 将是骨骼组织愈合缺陷的预后。这种测定的开发将是 巨大的好处：1）对延迟和失败的愈合的根本原因有用：2）用于临床 评估促进骨骼愈合的生物或药物疗法的有效性的试验：3） 确定那些将受益于生物或药物治疗干预措施的患者 促进骨骼愈合。我们的假设是，将有多种血清标记的组合 定义骨折愈合的生物学进展，我们将能够将其中一个或多个联系起来 定义愈合进展的结构，功能和临床特征的标记。两个具体 提出了目标。 AIM 1将识别血清蛋白质组中的那些蛋白质，显示出变化的水平 裂缝愈合相对于未分裂的骨骼的时间过程中的表达。在这个目标中，两种方法 将使用：质谱法和更具针对性的基于apatamer的多重蛋白质组学 技术。这个目标是识别并提供可以是蛋白质子集的初步量化 与定义断裂愈合暂时进展的各种生物过程有关。在AIM 2中，我们 将测试这些蛋白质的子集与软骨的开发和分辨率的统计相关性， 通过两种软骨确定的骨骼和愈伤组织结构矿化的开发和重塑 对比度增强和标准µCT。我们将测试特定蛋白表达与 特定的生物力学功能（刚度，强度，工作到失败）。最后，我们将测试愈伤组织的结构如何 功能测量和特异性蛋白质标记物与当前使用的射线照相联合相关 胫骨（Rust）骨折愈合的分数（Whelan等，2010），用于评估人的进展 长骨愈合。如果成功，本研究将识别一组可以在人类试验中使用的蛋白质 为了使他们的诊断效率跟随骨折愈合及其预后效率，以延迟或失败。