Vascularization of critical-sized craniomaxillofacial defects

临界尺寸颅颌面缺损的血管化

基本信息

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
项目类别：
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

项目摘要

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.

项目概要缺乏适当的血管化导致临界尺寸颅颌面骨治疗的最终失败缺陷。缺陷的大尺寸阻碍了周围血液成分的渗透环境进入缺损部位的内部，从而阻碍血管分布。在这种情况下，血管内皮生长因子（VEGF）是能够重建组织氧供应的最有效因子。虽然应用外部 VEGF 是在临界尺寸缺损处形成血管的关键手段，但其轻微不受控制的给药是有风险的，并且可能导致肿瘤。因此，传统方法无法用于 VEGF 的封装和递送。在本提案中，我们将开发一种新的片上 VEGF 递送方法使用微流体平台具有精确和持续释放的能力。我们新颖的设计使以高度可控和可重复的方式单分散颗粒，使我们能够精细除了平衡 pH 值和维持VEGF的生物活性。 VEGF 的释放不仅必须受到控制和持续，而且必须高度定位于缺损区域，因为将负载 VEGF 的颗粒移动到不需要的区域是不利的并且可能有风险。因此，在另一种策略中，负载 VEGF 的颗粒将被固定到新的 3D 打印载体上。专门为临界尺寸缺陷设计的支架。这种新型支架的设计（已申请专利）是受到钢筋混凝土的启发，其中钢筋嵌入主体材料中，以增强支架的机械性能（提高100-375倍）。换句话说，它是一个混合支架，由由两个组件组成： 1) 骨架钢筋：无孔且可缓慢生物降解的组成部分支架的机械需求，以及 2) 主体成分：多孔且可快速生物降解的成分承担支架的生物必需品。尽管钢筋的机械强度是其属性这使得脚手架适用于临界尺寸的缺陷，这是 Rebar 的另一个功能，即其缓慢可降解性（6 个月），使该设计成为 VEGF 递送目的的完美选择。钢筋将提供我们有机会将负载 VEGF 的颗粒固定在固体表面上并且不让颗粒移动别处。固定化过程本身是我们实验室开发的一种新方法，可以牢固地附着这些颗粒到脚手架的钢筋上。装载 VEGF 的支架将进行详细的体外分析并生物反应器内的释放调节可以模拟身体状况。 VEGF 释放曲线将是调整至目标值（1.2 ng/ml/天/cm3支架），并进行综合体外分析将评估构建体的成骨和血管生成特征。优化的 VEGF 负载支架将使用新西兰白兔的临界尺寸牙槽骨缺陷进行详细的体内研究。这将充分研究新骨形成和血管生成，以评估负载 VEGF 的支架的功能与无 VEGF 支架的比较，以及用当前治疗方式治疗的缺陷。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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