Longitudinal monitoring of bone fracture healing using diffuse optical and correlation tomography

项目摘要 在每年经历骨折的1500万美国人中，有超过10%的人患有受损的骨骼。 治愈愈合受损的发生率高，导致患者生活质量差，总护理费用高， tients。为了促进骨折愈合，正在开发各种基于再生医学的方法，但 由于目前成像技术的限制，它们的发展速度很慢。例如，vasculariza- 骨愈合的关键步骤是使用需要处死/破坏动物的终点方法进行评估， 导致受试者之间的高度可变性、时间和成本。我们的目标是建立扩散光学层析成像 (DOT)和相关断层扫描（DCT）作为监测血管化的非侵入性纵向研究工具 并预测骨折愈合。DOT和DCT，3D深部组织血流动力学成像技术，是理想的， 由于低成本和使用非电离光而需要频繁的纵向监测。此外，DOT和DCT是 易于在临床前和临床应用之间扩展。总之，这些方法报告了多个微血管- 眼部参数：用DOT测量总血红蛋白浓度和血氧饱和度，用DCT测量血流。我们 假设DOT和DCT提供了局部血容量、氧合和血流准确定量， 骨和周围的软组织，其可以作为骨愈合质量的替代标记。三 目的1：构建骨折治疗的预测模型 使用动物骨折模型的有效性，目的2：直接比较DOT和DCT与组织形态计量学， 荧光微球技术和动态增强磁共振成像在小鼠体内的应用 骨折模型，目标3：构建跖骨近端骨折不愈合的临床预测模型 基于DOT和DCT测量。成功地完成这些目标将导致在以下方面的巨大进步 再生医学和肌肉骨骼研究，提供全面和创新的非侵入性 纵向监测工具。此外，本文的工作为DOT的临床翻译奠定了基础， 通过与传统血管化评估技术的直接比较进行骨血管监测 以及通过构建骨折愈合受损的临床预测模型。

PROJECT SUMMARY More than 10% of the 15 million Americans who experience skeletal fractures each year suffer from impaired healing. The large incidence of impaired healing results in poor quality of life and high total cost of care for pa- tients. To enhance fracture healing, various regenerative medicine based approaches are being developed, but their development rates are slow due to the limitations of current imaging techniques. For example, vasculariza- tion, a key step in bone healing, is assessed using endpoint methods requiring sacrifice/destruction of animals, leading to high inter-subject variability, time and cost. Our objective is to establish diffuse optical tomography (DOT) and correlation tomography (DCT) as non-invasive, longitudinal research tools to monitor vascularization and predict bone fracture healing. DOT and DCT, 3D deep-tissue hemodynamic imaging techniques, are ideal for frequent longitudinal monitoring due to low cost and the use of non-ionizing light. In addition, DOT and DCT are easily scalable between preclinical and clinical applications. Together, these methods report multiple microvas- cular parameters: total hemoglobin concentration and oxygen saturation with DOT and blood flow with DCT. We hypothesize that DOT and DCT provide accurate quantification of regional blood volume, oxygenation and flow in bone and surrounding soft tissues, which can serve as surrogate markers for the quality of bone healing. Three specific aims are designed to test the hypotheses: Aim 1: Construct a prediction model for bone fracture treatment efficacy using an animal bone fracture model, Aim 2: Directly compare DOT and DCT with histomorphometry, fluorescent microsphere technique and dynamic-contrast-enhanced magnetic resonance imaging in a murine fracture model, Aim 3: Construct clinical prediction model for nonunions in proximal fifth metatarsal fractures based on DOT and DCT measurements. Successful completion of these aims will result in great advances in regenerative medicine and musculoskeletal research by providing a comprehensive and innovative non-invasive longitudinal monitoring tool. In addition, the proposed work lays the foundation for clinical translation of DOT and DCT for bone vascular monitoring by direct comparison with traditional vascularization assessment techniques and by constructing a clinical prediction model for impaired healing in fractures.