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.

骨移植物在各种临床环境中用于帮助骨修复和再生。近年来，美国 美国以及世界其他国家对功能性骨的需求越来越高 移植物这包括美国军方和VA医疗保健系统，其中对骨移植物的需求很高 替代品，以修复关键尺寸的骨缺损，骨折不愈合，骨科重建事件， 战场创伤目前的修复过程使用患者自己的骨组织在重建过程中收获 手术然而，自体移植物供体部位的可用组织量有限， 通常需要场地。虽然从尸体来源获得的同种异体移植物消除了对二次移植的需要， 手术部位，并具有骨传导的优势，但它们与宿主排斥反应的风险有关 和加速移植物再吸收。自体骨移植和同种异体骨移植技术的缺点促使了 生物工程移植材料的开发。作为探索的一部分，我们开发了基于磷灰石的骨支架， 通过VA SPiRE Grant（#1 I21 RX 003328 - 01 A1）。我们的数据显示，在12周内， 氟磷灰石支架完全充满了活的新骨组织，证明了这些骨组织的有效性。 再生骨组织的支架。为了进一步开发这种新型材料用于临床应用， “自体移植样”骨支架修复临界尺寸的缺损，我们建议将我们的支架与基质 血管部分细胞作为成骨细胞来源。因此，假设氟磷灰石（FA） 植入患者自身干细胞的支架，包含在基质血管部分（SVF）中 从自体脂肪组织中提取的新的骨组织将能够在一个特定的时间内产生新的骨组织。 在非承重临界尺寸缺损模型和 承重断裂模型将以三个具体目标来检验这一假设。具体目标1将 确定修复大鼠模型中骨缺损所需的SVF细胞的最佳数量。具体目标2将 研究有和没有SVF的FA支架的成骨潜力和骨再生的时间过程， 在绵羊髂骨模型中的临界尺寸骨缺损中。基于mRNA的技术将用于突出 骨再生的机制差异作为后一项时程研究的次要结局。最后， 具体目标3将研究FA支架（含和/或不含SVF）在绵羊体重- 负重胫骨骨折模型。将有和没有SVF的FA与临床金标准，自体移植物， 以及FDA批准的羟基磷灰石支架。预期这种SVF和SVF的组合治疗是有效的。 FA支架将为临床骨修复提供“现成”支架材料的潜在来源， 再生和改善健康和生活质量的大量军事人员，退伍军人， 和需要骨骼重建的平民