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.

近年来，骨移植被用于各种临床环境以帮助骨修复和再生。 各州以及世界其他国家对功能性骨的需求日益增长 这包括美国军队和退伍军人管理局医疗系统，这些系统对骨移植的需求很高。 修复临界尺寸骨缺损、骨折不愈合和骨科重建事件的替代品 目前的修复过程使用的是患者在重建过程中采集的自己的骨组织。 然而，自体移植供体部位的可用组织数量有限，并且需要进行二次手术。 通常需要场地，而从尸体来源收获的同种异体移植物消除了二次的需要。 手术部位并具有骨传导的优势，但它们与宿主排斥的风险相关 自体移植和同种异体移植骨技术的缺点促使移植物吸收加速。 开发生物工程移植材料作为这一探索的一部分，我们开发了基于磷灰石的骨支架。 通过 VA SPiRE 补助金 (# 1I21RX003328-01A1) 我们的数据显示，在 12 周内，毛孔内的情况发生了变化。 氟磷灰石支架完全充满了可行的新骨组织，证明了这些材料的功效 进一步开发这种新型材料作为临床应用。 “自体移植样”骨支架用于修复临界尺寸的缺损，我们建议将我们的支架与基质相结合 血管部分细胞作为成骨细胞来源因此，捕获了氟磷灰石（FA）。 植入患者自身干细胞的支架，包含在基质血管部分（SVF）内 从自体脂肪组织中提取的，将有能力以一定的速度生成新的骨组织 在非负重临界尺寸缺损模型和非承重临界尺寸缺损模型中，其水平与自体移植骨相当 负重骨折模型将通过三个具体目标进行检验。 具体目标 2 将确定修复大鼠模型中骨缺损所需的 SVF 细胞的最佳数量。 研究有或没有 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，将使用基于 mRNA 的技术来突出显示骨缺损。 最后，骨再生的机制差异作为后一个时间过程研究的次要结果。 具体目标 3 将研究 FA 支架（有和/或没有 SVF）在绵羊体重中的功效 带有和不带有 SVF 的轴承胫骨骨折模型将与临床金标准、自体移植物、 以及 FDA 批准的羟基磷灰石支架有望实现 SVF 和这种联合治疗。 FA 支架将为临床骨修复和骨修复提供潜在的“现成”支架材料来源。 恢复并改善大量军事人员、退伍军人、 以及需要骨骼重建的平民。