Evaluating the role of immunomodulation in synergizing BMP-induced bone repair

评估免疫调节在协同 BMP 诱导的骨修复中的作用

• 批准号: 10728000
• 负责人: Julianne Leigh Holloway
• 金额: $ 35.2万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10728000
• 关键词: Address; BMP2 gene; Behavior; Bone Morphogenetic Proteins; Bone Regeneration; Bone Tissue; Bone remodeling; Cell physiology; Cells; Cellular Metabolic Process; Cephalic; Citric Acid Cycle; Clinic; Clinical; Coculture Techniques; Complex; Data; Defect; Dendritic Cells; Disease; Dose; Equilibrium; Gene Expression; Glycolysis; Hyaluronic Acid; Hydrogels; Immune; In Vitro; Inflammatory; Kinetics; Macrophage; Matrix Metalloproteinases; Mediating; Metabolism; Minerals; Modeling; Mus; Osteoblasts; Osteoclasts; Osteogenesis; Patients; Peptide Hydrolases; Phenotype; Polymers; Process; Proliferating; Rattus; Recovery; Research; Research Personnel; Role; Signal Transduction; Techniques; Testing; Therapeutic; Therapeutic Effect; Time; Tissue Engineering; Tissues; Trauma; Work; alpha ketoglutarate; bone healing; bone repair; cell behavior; cost; design; immunoregulation; improved; in vivo; in vivo Model; innovation; mesenchymal stromal cell; metabolomics; migration; novel; osteogenic; particle; patient variability; prevent; repair model; repaired; side effect; skeletal; small molecule

Project Summary The use of bone morphogenetic proteins (BMPs) shows promise as therapeutics for improving bone repair; however, high supraphysiological concentrations required for the desired osteoinductive effect, costs, and patient variability have prevented the full advantages of BMP-based therapeutics from being realized. Thus, there is a clinical need to develop new bone tissue engineering approaches that promote osteogenesis at lower BMP doses and prevent adverse side effects. Healthy bone formation and remodeling requires a delicate balance between skeletal (e.g. osteoblasts) and immune (e.g. osteoclasts, macrophages, etc.) cells, which is often overlooked when developing new bone regeneration therapeutics. To address these limitations, we propose the use of immunomodulatory microparticles to enhance BMP-induced bone repair. Proteolytically- degradable hyaluronic acid hydrogels will be used to co-deliver BMP2 and immunomodulatory microparticles via cell-mediated hydrogel degradation. For the immunomodulatory microparticles, we have designed novel poly(alpha-ketoglutarate) microparticles (paKG MPs), which sustainably release alpha-ketoglutarate (aKG) upon hydrolytic degradation. aKG is known to regulate both osteoblast and osteoclast behavior. Furthermore, paKG MPs are highly tunable, enabling precise control over aKG release kinetics. In this project, the ability of paKG MPs to enhance BMP-induced osteogenesis will be investigated in vitro and in vivo. We hypothesize sustained aKG delivery will enable control over the balance between osteoblast and osteoclast signaling, leading to increased osteogenesis and bone formation. The proposed work will be accomplished through the following aims: (1) Develop hyaluronic acid hydrogels with combined, sustained delivery of BMP2 and aKG; and (2) Evaluate the effect of aKG on a) in vitro cell behavior and b) in vivo bone repair. A range of microparticle concentrations will be tested to optimize aKG delivery. In vitro cell behavior will be evaluated via viability, proliferation, metabolomics, differentiation (i.e. osteoblast and osteoclast markers), and mineral formation and resorption. In vivo bone repair will be assessed using a critical-sized cranial defect rat model.

项目摘要 骨形态发生蛋白（BMP）的使用显示出作为改善骨修复的治疗剂的前景; 然而，期望的骨诱导作用所需的高超生理浓度、成本和 患者的可变性阻碍了基于BMP的治疗的全部优点的实现。因此，在本发明中， 临床上需要开发新的骨组织工程方法， 降低BMP剂量并防止不良副作用。健康的骨骼形成和重塑需要一个微妙的 骨骼（如成骨细胞）和免疫（如破骨细胞、巨噬细胞等）之间的平衡细胞， 在开发新的骨再生疗法时经常被忽视。为了克服这些局限性，我们 提出使用免疫调节微粒来增强BMP诱导的骨修复。蛋白水解- 可降解的透明质酸水凝胶将用于共同递送BMP 2和免疫调节微粒 通过细胞介导的水凝胶降解。对于免疫调节微粒，我们设计了新颖的 聚（α-酮戊二酸）微粒（paKG MP），可持续释放α-酮戊二酸（aKG） 水解降解。已知aKG调节成骨细胞和破骨细胞的行为。此外，委员会认为， paKG MP是高度可调的，使得能够精确控制aKG释放动力学。在这个项目中， 将在体外和体内研究paKG MP增强BMP诱导的骨生成。我们假设 持续的aKG递送将能够控制成骨细胞和破骨细胞信号传导之间的平衡， 导致骨生成和骨形成增加。拟议的工作将通过 （1）开发具有BMP 2和aKG组合、持续递送的透明质酸水凝胶; 和（2）评估aKG对a）体外细胞行为和B）体内骨修复的影响。一系列 将测试微粒浓度以优化aKG递送。体外细胞行为将通过 活力、增殖、代谢组学、分化（即成骨细胞和破骨细胞标志物）和矿物质 形成和再吸收。将使用临界尺寸的颅骨缺损大鼠模型评估体内骨修复。