An Evaluation of Serum Based Indices to Assess Fracture Healing

评估骨折愈合的血清指标

• 批准号: 9144317
• 负责人: Louis Charles Gerstenfeld
• 金额: $ 21.71万
• 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 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9144317
• 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; Mass Spectrum Analysis; Measurement; Measures; Medicine; Methods; Mus; Operative Surgical Procedures; Organ; Osteogenesis; Osteoporosis; Outcome; Pain-Free; Patient Outcomes Assessments; Patients; Proteins; Proteome; Proteomics; Roentgen Rays; Secondary to; Serum; Serum Markers; Serum Proteins; Set protein; Spectrophotometry; Structure; Surveys; Technology; Testing; Therapeutic Intervention; Tibial Fractures; Time; Tissues; Translations; Traumatic injury; 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 biomarkers; 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 骨折是人类最常见的大器官、外伤以及与骨质疏松症相关的骨折 是增长最快的老龄化医疗保健问题，而手术后的骨折修复通常是最佳的。 据估计，美国每年发生约 8 至 1000 万例骨折，其中 10% 愈合延迟或受损（Praemer 等人，1992）。目前，放射线评估减少了。 治愈并发症并经过验证的患者报告了恢复无痛负重的结果 功能是评估骨折愈合进展的主要诊断工具，但是这些都不是。 目前的评估要么定义与进展相关的潜在生物过程 骨折愈合还是延迟愈合或不愈合的预后因此，存在巨大的不确定性。 迫切需要确定客观的可量化生物标志物：1）与潜在的生物标志物相关 骨骼组织愈合的过程：2) 表明骨骼组织愈合的进展：3) 将是骨骼组织愈合缺陷的预后。这种检测的发展将是一种方法。 巨大的好处是：1）为延迟和失败愈合的根本原因提供信息：2）在临床中使用 评估促进骨愈合的生物或药物疗法的功效的试验以及：3) 确定那些将从生物或药物治疗干预中受益的患者 我们的假设是，将存在可用于促进骨愈合的血清标记物组合。 定义骨折愈合的生物学进展，并且我们将能够将其中的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物。 目标 1 将鉴定血清蛋白质组中显示变化水平的蛋白质。 相对于未骨折的骨折愈合时间过程中的表达 在此目的中，有两种方法。 将使用：质谱方法和更具针对性的新型基于适体的多重蛋白质组学 该技术的目标是识别并提供可用于蛋白质子集的初步定量。 与定义骨折愈合时间进展的各种生物过程相关。在目标 2 中，我们。 将测试这些蛋白质的子集与软骨发育和吸收的统计相关性， 由软骨决定的骨和骨痂组织结构矿化的发育和重塑 对比增强和标准 µCT 我们将测试特定蛋白质表达与的统计相关性。 特定的生物力学功能（刚度、强度、工作至极限）最后，我们将测试愈伤组织的结构， 功能测量和特定蛋白质标记与当前临床使用的放射线联合相关 胫骨 (RUST) 骨折愈合评分（Whelan 等人，2010），用于评估人类的进展情况 如果成功，这项研究将鉴定出一组可用于人体试验的蛋白质。 其对骨折愈合后的诊断功效以及对延迟或愈合失败的预后功效。