Fluoridated scaffolds for the treatment of critical-size bone defects

骨移植被用于各种临床环境中，以帮助骨修复和再生。近年来，美国 美国以及世界各地的其他国家都经历了对功能性骨的日益增长的需求 嫁接。这包括美国军方和退伍军人管理局的医疗系统，那里对骨移植的需求很高 修复临界大小的骨缺损、骨折不愈合和矫形重建事件的替代品，以 战场创伤。目前的修复过程使用患者在重建过程中获得的自己的骨组织 做手术。然而，自体移植供体部位可用组织数量有限，二次手术。 站点通常是必需的。而从身体来源获得的同种异体移植物消除了对二次 手术部位具有骨传导的优势，它们与宿主排斥反应的风险有关。 并加速了移植物的吸收。自体和同种异体骨移植技术的缺点推动了 生物工程接枝材料的发展。作为这一探索的一部分，我们开发了磷灰石基骨支架 通过退伍军人事务部尖顶赠款(#1I21RX003328-01A1)。我们的数据显示，在12周内，皮肤内的毛孔 氟磷灰石支架完全充满了可存活的新骨组织，证明了这些材料的有效性 再生骨组织中的支架。为了进一步开发这种新型材料作为临床应用， “自体移植类”骨支架用于修复临界大小的缺损，我们建议将我们的支架与基质相结合。 血管碎片细胞作为成骨细胞来源。由此推测，氟磷灰石(FA) 植入患者自身干细胞的支架，包含在间质血管部分(SVF)中 从自体脂肪组织中提取的，将有能力在一次 与自体移植骨水平相当的非负重临界大小缺损区模型和 承重断裂模型。这一假设将通过三个具体目标进行检验。具体目标1将 确定修复大鼠骨缺损所需的SVF细胞的最佳数量。特定目标2将 观察支架材料的成骨潜能和骨再生的时程。 在绵羊髂骨模型的临界大小的骨缺损处。基于信使核糖核酸的技术将用于突出 在后一项时程研究中，次要结果是骨再生的机制差异。最后， 具体目标3将研究FA支架在有和/或没有SVF的情况下对绵羊体重的效果。 承重胫骨骨折模型。有无SVF的FA将与临床黄金标准--自体移植、 以及FDA批准的羟基磷灰石支架。预计这样的SVF和SVF的联合治疗 FA支架将为临床骨修复和骨修复提供潜在的“现成”支架材料 更新和改善相当数量的军事人员、退伍军人、 以及需要骨骼重建的平民。

Bone grafts are used in various clinical settings to aid bone repair and regeneration. In recent years, the United States, as well as other countries worldwide, have experienced an increasingly high demand for functional bone grafts. This includes the US military and the VA healthcare systems, where there is a high demand for bone graft substitutes to repair critical-size bone defects, fracture non-unions, and orthopedic reconstruction incidents to battlefield trauma. Current repair processes use the patient’s own bone tissue harvested during reconstructive surgery. However, autograft donor sites are limited in the amount of tissue available, and secondary surgical sites are usually required. While allografts harvested from cadaveric sources eliminate the need for secondary surgical sites and have the advantage of being osteoconductive, they are associated with the risk of host rejection and accelerated graft resorption. The downsides of autograft and allograft bone techniques have impelled the development of bioengineered graft materials. As part of this quest, we developed apatite-based bone scaffolds through a VA SPiRE Grant (# 1I21RX003328-01A1). Our data showed that, in 12-weeks, the pores within the fluorapatite scaffolds became completely filled with viable new bone tissue, demonstrating the efficacy of these scaffolds in regenerating bone tissues. To further develop this novel material for clinical applications as an “autograft-like” bone scaffold for the repair of critical-size defects, we propose combining our scaffold with stromal vascular fraction cells as an osteogenic cell source. Thus, it is hypothesized that fluorapatite (FA) scaffoldings seeded with patients’ own stem cells, contained within the stromal vascular fraction (SVF) that is extracted from autologous fat tissue, will have the ability to generate new osseous tissue at a level comparable to that of autograft bone in both a non-weight bearing critical-size defect model and a weight-bearing fracture model. This hypothesis will be tested with three specific aims. Specific Aim 1 will determine the optimal number of SVF cells needed for repairing bone defects in a rat model. Specific Aim 2 will investigate the osteogenic potential and time-course of bone regeneration of FA scaffolds, with and without SVF, in a critical size bone defect in a sheep ilium model. mRNA-based techniques will be used to highlight the mechanistic differences in bone regeneration as a secondary outcome in the latter time-course study. Finally, Specific Aim 3 will investigate the efficacy of the FA scaffolds, with and/or without SVF, in a sheep weight- bearing tibial fracture model. FA with and without SVF will be compared to the clinical gold standard, autograft, as well as FDA-approved hydroxyapatite scaffold. It is expected that such a combination treatment of SVF and FA scaffolds will provide a potential source of “off-the-shelf” scaffolding materials for clinical bone repair and regeneration and improve the health and quality of life for a significant number of military personnel, veterans, and civilians requiring skeletal reconstruction.