Fluoridated scaffolds for the treatment of critical-size bone defects

用于治疗临界尺寸骨缺损的氟化支架

• 批准号: 10633345
• 负责人: Jayant Prasad Agarwal
• 金额: --
• 依托单位: VA SALT LAKE CITY HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10633345
• 关键词: Acceleration; Adipose tissue; Allografting; American; Animals; Apatites; Autologous; Autologous Transplantation; Autopsy; Biocompatible Materials; Biomedical Engineering; Blood Vessels; Bone Regeneration; Bone Substitutes; Bone Tissue; Bone Transplantation; Cadaver; Cell Fraction; Cells; Clinical; Combined Modality Therapy; Country; Data; Defect; Dental; Development; Diameter; Distal; Evaluation; FDA approved; Family suidae; Fatty acid glycerol esters; Female; Femur; Fracture; Generations; Grant; Growth Factor; Harvest; Health; Healthcare Systems; Human; Hydroxyapatites; Implant; In Vitro; Intramedullary Nailing; Knowledge; Left; Measures; Mechanics; Messenger RNA; Military Personnel; Modeling; Natural regeneration; Operative Surgical Procedures; Orthopedics; Osteogenesis; Outcome Measure; Patients; Phosphoproteins; Process; Publishing; Quality of life; Rattus; Reconstructive Surgical Procedures; Resources; Risk; Sheep; Signal Transduction; Site; Skeleton; Source; Stainless Steel; Surface; Techniques; Testing; Tibial Fractures; Time; Tissue Harvesting; Tissues; Trauma; United States; Veterans; Water fluoridation; Weight-Bearing state; X-Ray Computed Tomography; adipose derived stem cell; allogenic bone transplantation; aspirate; bone; bone engineering; bone reconstruction; bone repair; bone scaffold; calcium phosphate; cell type; clinical application; clinical material; cost; density; design; efficacy testing; experience; fluorapatite; ilium; improved; in vivo; male; microCT; novel; osteoblast differentiation; osteogenic; porcine model; primary outcome; reconstruction; repaired; scaffold; secondary outcome; skeletal; stem cell population; stem cells; substantia spongiosa; tibia; transcriptome sequencing

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.

骨移植物用于各种临床环境中，以帮助骨修复和再生。近年来，联合 各州以及全球其他国家都经历了对功能骨骼的需求越来越高 移植物。这包括美国军方和VA医疗保健系统，对骨移植的需求很高 替代临界大小的骨缺损，裂缝非工会和骨科重建事件 战场创伤。当前的维修过程使用重建期间收获的患者自身的骨组织 外科手术。但是，自体移植供体部位的可用组织量和次级手术量受到限制 通常需要站点。而从尸体来源收获的同种异体移植消除了对次级的需求 手术部位，具有破骨的优势，它们与宿主排斥的风险有关 并加速移植分辨率。自体移植和同种异体骨技术的弊端已促使 生物工程移植物材料的开发。作为此任务的一部分，我们开发了基于磷灰石的骨支架 通过VA Spire赠款（＃1I21RX003328-01A1）。我们的数据表明，在12周内， 氟磷灰石支架完全充满了可行的新骨组织，证明了这些效率 再生骨组织中的脚手架。为了进一步开发这种新颖的材料作为临床应用 “自体移植”骨支架，用于修复临界尺寸缺陷，我们建议将脚手架与基质结合 血管分数细胞作为成骨细胞源。那就是假设氟磷灰石（FA） 脚手架与患者自身的干细胞播种，其中包含在基质血管分数（SVF）中 从自体脂肪组织中提取的，将具有在A处产生新的骨组织的能力 在非重量轴承临界大小缺陷模型和A中，与自体移植骨的水平相当 承重断裂模型。该假设将以三个特定目的进行检验。具体目标1将 确定在大鼠模型中修复骨缺损所需的最佳SVF细胞数量。具体目标2将 研究有或没有SVF的FA支架骨再生的成骨潜力和时间顺序 在绵羊ilium模型中的临界尺寸骨缺损中。基于mRNA的技术将用于突出显示 在以后的时间课程中，骨再生的机理差异是次要结果。最后， 特定的目标3将在绵羊重量中调查使用和/或没有SVF的FA支架的效率 - 轴承骨折模型。具有和不带SVF的FA将与临床黄金标准，自体移植进行比较 以及FDA批准的羟基磷灰石支架。预计这种SVF和 FA脚手架将为临床骨修复和 再生并改善大量军人，退伍军人的健康和生活质量， 和需要骨骼重建的平民。