Vascularization of critical-sized craniomaxillofacial defects

临界尺寸颅颌面缺损的血管化

• 批准号: 10427079
• 负责人: Lobat Tayebi
• 金额: $ 36.26万
• 依托单位: MARQUETTE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-02 至 2024-09-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10427079
• 关键词: 3-Dimensional; 3D Print; Acetates; Alveolar; Animals; Area; Biological; Bioreactors; Blood; Blood Vessels; Bolus Infusion; Bone Regeneration; Cells; Cessation of life; Defect; Diagnostic radiologic examination; Drug Delivery Systems; Elements; Encapsulated; Environment; Equilibrium; Failure; Growth Factor; Histologic; Human; Human body; Hybrids; Hydrophobicity; Hydroxides; Immobilization; In Vitro; Injections; International; Legal patent; Lipids; Magnesium; Mandible; Mechanics; Messenger RNA; Methods; Micelles; Microfluidics; Modality; Modeling; New Zealand; Oryctolagus cuniculus; Osteogenesis; Oxygen; Penetration; Perfusion; Polymers; Polyvinyls; Preparation; Procedures; Process; Production; Property; Proteins; Quantitative Reverse Transcriptase PCR; Reaction; Reproducibility; Resolution; Safety; Sampling; Secure; Skeleton; Solid; Structure; Surface; Therapeutic; Time; Tissues; VEGFA gene; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factors; Vascularization; Western Blotting; alveolar bone; angiogenesis; base; blood vessel development; craniomaxillofacial; design; healing; in vivo; mechanical load; mechanical properties; microCT; neovascularization; novel; particle; prevent; release factor; scaffold; side effect; tumor; tumorigenic

Project Summary Lack of proper vascularization leads to the ultimate failure in treatment of critical-sized craniomaxillofacial defects. The large size of the defect obstructs penetration of blood components from the surrounding environment into the inner parts of the defect, and thus hinders vascularity. In such situations, vascular endothelial growth factor (VEGF) is the most effective factor that can reestablish the oxygen supply to tissues. While applying external VEGF is a key means for blood vessel formation in critical-sized defects, its slight uncontrolled administration is risky and can be tumorigenic. Thus, conventional methods cannot be used for encapsulation and delivery of VEGF. In this proposal, we will develop a new on-chip method for delivery of VEGF with precise and sustained release capabilities using a microfluidic platform. Our novel design allows making monodispersed particles in a highly controllable and reproducible manner, providing us with the ability to fine- tune the size, microstructure, loading capacity and release rate of particles, in addition to balancing the pH and maintaining the VEGF bioactivity. Release of VEGF must not be only controlled and sustained, but also highly localized in the region of the defect as moving the VEGF-loaded particles into unwanted areas is not favorable and can be risky. Thus, in another strategy, the VEGF-loaded particles will be immobilized onto a new 3D-printed scaffold specifically designed for critical-sized defects. The design of this novel scaffold (filed for patent) is inspired by reinforced concrete, in which reinforcing Rebars are embedded in the host material to enhance the mechanical properties of the scaffold (100-375 times improvement). In other words, it is a hybrid scaffold, made of two components: 1) Skeleton Rebars: non-porous and slowly-biodegradable constituent undertaking mechanical necessities of the scaffold, and 2) Host Component: porous and rapidly-biodegradable constituent undertaking biological necessities of the scaffold. Although the mechanical strength of Rebars is the property that makes the scaffold appropriate for critical-sized defects, another functionality of the Rebar, which is its slow degradability (6 months), makes the design a perfect choice for the VEGF delivery purpose. Rebars will provide us with the opportunity to immobilize VEGF-loaded particles on a solid surface and not let the particles move elsewhere. The immobilization process itself is a new method developed in our lab that can firmly attach these particles to the rebars of the scaffolds. The VEGF-loaded scaffold will undergo a detailed in vitro analysis and release adjustment inside a bioreactor, which can mimic the body condition. The VEGF release profiles will be adjusted to reach the target value (1.2 ng/ml per day per cm3 of scaffold), and the comprehensive in vitro analyses will evaluate the osteogenesis and angiogenesis characters of the construct. The optimized VEGF-loaded scaffold will undergo a detailed in vivo study using critical-sized alveolar bone defects in New Zealand white rabbits. The new bone formation and angiogenesis will be fully studied to assess the functionality of the VEGF-loaded scaffold in comparison with a VEGF-free scaffold, as well as defects treated with a current therapeutic modality.

项目摘要 缺乏适当的血管化会导致临界大小的颅颌面治疗的最终失败 缺陷。大尺寸的缺陷阻碍了血液成分从周围的渗透 环境进入缺陷的内部，因此阻碍了血管。在这种情况下，血管 内皮生长因子（VEGF）是可以重新建立组织氧气供应的最有效因素。 虽然应用外部VEGF是临界大小缺陷的血管形成的关键手段，但它的轻微 不受控制的给药是有风险的，可能是肿瘤的。因此，传统方法不能用于 VEGF的封装和交付。在此提案中，我们将开发一种新的芯片载体方法来交付VEGF 使用微流体平台具有精确和持续的释放功能。我们的小说设计允许制作 以高度可控制和可重复的方式单分散的颗粒，使我们有能力 除了平衡pH和pH和 保持VEGF生物活性。释放VEGF的释放不仅必须受到控制和维持，而是高度的 由于将VEGF负载的颗粒移动到不良区域时，位于缺陷区域不利 并且可能有风险。因此，在另一种策略中，载有VEGF的颗粒将被固定在新的3D打印上 专为关键大小缺陷而设计的脚手架。这个小说脚手架的设计（申请专利）是 受钢筋混凝土的启发，其中增强的钢筋嵌入到宿主材料中以增强 支架的机械性能（改善了100-375倍）。换句话说，这是一个混合脚手架，制作了 在两个组件中：1）骨架钢筋：非孔子和缓慢降解的成分企业 脚手架的机械必需品和2）主机组件：多孔和快速降解的成分 承担脚手架的生物必需品。虽然钢筋的机械强度是特性 这使得脚手架适合关键大小的缺陷，钢筋的另一个功能，这是它的慢速 降解性（6个月）使设计成为VEGF交付目的的理想选择。钢筋将提供 我们有机会将载有VEGF的颗粒固定在固体表面上而不让颗粒移动 别处。固定过程本身是我们实验室中开发的一种新方法，可以牢固地附加这些方法 粒子到脚手架的钢筋。负载VEGF的支架将进行详细的体外分析，并 在生物反应器中释放调整，该调整可以模仿身体状况。 VEGF发布配置文件将是 调整以达到目标值（每CM3每天1.2 ng/ml）和全面的体外分析 将评估构建体的成骨和血管生成特征。优化的负载VEGF的脚手架 将使用新西兰白兔子中的临界尺寸肺泡骨缺损进行详细的体内研究。这 将充分研究新的骨形成和血管生成，以评估VEGF负载支架的功能 与无VEGF的支架以及用当前治疗方式治疗的缺陷相比。

项目成果

Structural parameters of nanoparticles affecting their toxicity for biomedical applications: a review.

• DOI: 10.1007/s11051-023-05690-w
• 发表时间: 2023
• 期刊: JOURNAL OF NANOPARTICLE RESEARCH
• 影响因子: 2.5
• 作者: Abbasi, Reza;Shineh, Ghazal;Mobaraki, Mohammadmahdi;Doughty, Sarah;Tayebi, Lobat
• 通讯作者: Tayebi, Lobat