Orchestrating Bone Regeneration on Multiple Scales

在多个尺度上协调骨再生

基本信息

批准号：
7777855
负责人：
PETER X MA
金额：
$ 35.72万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-03-01 至 2012-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7777855
关键词：
Achievement Adhesions Angiogenic Factor Animals Architecture Area BMP7 gene Biological Biological Factors Bone Marrow Bone Morphogenetic Proteins Bone Regeneration Bone Tissue Caliber Cell-Matrix Junction Cells Collagen Computer-Aided Design Computer-Assisted Manufacturing Cues Defect Deposition Electrostatics Engineering Environment Fiber Fibroblast Growth Factor 2 Fracture Goals Growth Factor In Vitro Laboratories Lesion Marrow Measures Medical Imaging Modality Modeling Modification Molecular Morphology Mus Nanosphere Natural regeneration Nutrient Operative Surgical Procedures Osteogenesis Outcome Patients Phase Process Rattus Research Personnel Scanning Shapes Signal Transduction Signaling Molecule Solutions Stem cells Stromal Cells Structure Surface Techniques Testing Thick Time Tissue Engineering Tissues United States Vascularization angiogenesis base bone clinical application clinically relevant design extracellular in vitro Assay in vivo nano nanofiber nanometer nanopore nanoscale neovascularization novel osteogenic programs regenerative regenerative agent regenerative therapy release factor repaired scaffold self assembly success tissue regeneration

项目摘要

DESCRIPTION (provided by applicant): Bone fractures and defects result in more than 1.3 million surgical procedures each year in the United States. With current therapies, these fractures and defects can be restored to some degree, but far from an ideal solution. Although regenerative agents such as bone morphogenetic proteins (BMPs) have been shown to enhance bone formation when delivered to bone lesions in animal studies, results remain unpredictable for clinical applications. It is likely that the lack of an appropriate 3D scaffold that mimics the natural extracellular environment and supports bone regeneration is detrimental. It is also likely that inappropriate growth factor delivery (time, quantity, localization) confound the achievement of robust success. It is also likely that BMP alone is not sufficient but that additional factors and progenitor cells may be required in order to promote maximal bone regeneration. In addition, angiogenesis in parallel to tissue regeneration is critical to maintaining long-term viability and sustained function of regenerated tissues. Based on these analyses, we hypothesize that predictable and clinically relevant bone regeneration can be achieved by coordinating the biological activities (cells and regulating molecules) with structural cues (scaffold structures). We therefore propose a patient-specific, multi-scaled nano-fibrous scaffold for the delivery of bone marrow stromal cells (MSC) and multiple regenerative factors to engineer vascularized bone. The specific aims are: SA 1. Design "patient-specific" scaffolds with multi-scaled structures for bone regeneration. SA 2. Formulate NS to individually tune BMP? and bFGF release profiles in multi-scaled scaffolds in vitro; and determine the effects of scaffold structure, bFGF and BMP7 temporal release profiles on osteogenesis and angiogenesis in a mouse ectopic model. SA 3. Confirm that the multi-scaled and factor-releasing scaffolds (selected from Aims 1&2) afford a superior environment for vascularized bone regeneration in a rat critical defect model.

描述（由申请人提供）：美国每年因骨折和缺损而进行的外科手术超过 130 万例。通过目前的治疗方法，这些骨折和缺陷可以在一定程度上得到恢复，但远非理想的解决方案。尽管在动物研究中，骨形态发生蛋白 (BMP) 等再生剂已被证明可以增强骨形成，但临床应用的结果仍然不可预测。缺乏模拟自然细胞外环境并支持骨再生的适当 3D 支架可能是有害的。不适当的生长因子传递（时间、数量、定位）也可能会阻碍取得强劲成功。单独的 BMP 也可能是不够的，可能需要额外的因子和祖细胞才能促进最大限度的骨再生。此外，与组织再生并行的血管生成对于维持再生组织的长期活力和持续功能至关重要。基于这些分析，我们假设通过协调生物活动（细胞和调节分子）与结构线索（支架结构）可以实现可预测且临床相关的骨再生。因此，我们提出了一种针对患者的多尺度纳米纤维支架，用于输送骨髓基质细胞（MSC）和多种再生因子来工程化血管化骨。具体目标是： SA 1.设计具有多尺度结构的“患者特异性”支架，用于骨再生。 SA 2.制定NS来单独调整BMP？和 bFGF 在体外多尺度支架中的释放曲线；并确定支架结构、bFGF 和 BMP7 时间释放曲线对小鼠异位模型中骨生成和血管生成的影响。 SA 3. 确认多尺度和因子释放支架（选自目标 1 和 2）为大鼠严重缺损模型中的血管化骨再生提供了优越的环境。