Orchestrating Bone Regeneration on Multiple Scales

描述（由申请人提供）：在美国，骨折和骨缺损每年导致超过130万例外科手术。通过目前的治疗，这些骨折和缺损可以在一定程度上恢复，但远不是理想的解决方案。尽管在动物研究中，骨形态发生蛋白（BMP）等再生剂在递送至骨病变时已显示出增强骨形成，但临床应用的结果仍不可预测。很可能缺乏模拟天然细胞外环境并支持骨再生的适当3D支架是有害的。也有可能是不适当的生长因子输送（时间，数量，本地化）混淆了稳健成功的实现。也有可能单独的BMP是不够的，但为了促进最大的骨再生，可能需要额外的因子和祖细胞。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，我们假设可预测的和临床相关的骨再生可以通过协调生物活性（细胞和调节分子）与结构线索（支架结构）来实现。因此，我们提出了一种患者特异性的，多尺度的纳米纤维支架，用于骨髓基质细胞（MSC）和多种再生因子的输送，以工程化血管化骨。具体目标是：SA 1。为骨再生设计具有多尺度结构的“患者特异性”支架。SA 2.制定NS单独调整BMP？和bFGF的释放曲线在体外多尺度支架;并确定支架结构，bFGF和BMP 7的时间释放曲线对骨生成和血管生成在小鼠异位模型的影响。SA 3.确认多尺度和因子释放支架（选自目标1和2）为大鼠临界缺损模型中的血管化骨再生提供了上级环境。

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.