Biomimetics for craniofacial regeneration

颅面再生仿生学

• 批准号: 10005905
• 负责人: Laurie K. McCauley
• 金额: $ 37.05万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005905
• 关键词: Affect; Aging; Anabolic Agents; Animal Model; Apoptosis; Apoptotic; Biodegradable microsphere; Biological; Biological Assay; Biomimetics; Bone Regeneration; CCL2 gene; Calcium; Caliber; Calvaria; Cell Death; Cell Transplantation; Cells; Chronic Disease; Complex; Cues; Data; Defect; Dependence; Development; Disease; Drug Delivery Systems; Eating; Engineering; Event; Extracellular Matrix; Funding; Gene Proteins; Goals; Growth Factor; Homing; Immune; In Vitro; Individual; Knockout Mice; Ligands; Mediating; Mediator of activation protein; Mesenchymal; Mesenchymal Stem Cells; Microspheres; Minerals; Minor; Modality; Modeling; Mus; Natural regeneration; Osteoblasts; Osteogenesis; PTH gene; Pain; Pathway interactions; Phagocytes; Phagocytosis; Physiology; Procedures; Process; Production; Property; Quality of life; Regenerative Medicine; Regenerative response; Resolution; Role; Serine; Signal Transduction; Site; Societies; Structure; Surface; Systemic disease; Technology; Therapeutic; Tissue Engineering; Tissues; Tomatoes; Tooth Extraction; Translating; Translations; Trauma; Work; aging population; base; bone; bone healing; cell motility; chemokine; clinical application; clinical translation; clinically relevant; cost; craniofacial; craniofacial bone; density; design; functional restoration; healing; immune function; implantation; improved; in vivo; in vivo Model; in vivo regeneration; macrophage; macrophage-derived chemokine; migration; mimicry; nanofiber; novel; novel strategies; novel therapeutics; osteoclastogenesis; osteogenic; protein expression; receptor; reconstruction; recruit; regenerative; repaired; response; scaffold; skeletal; stem; stem cells; therapy outcome; uptake; wound; wound healing

Abstract In young healthy individuals minor insults to bone heal with minimal compromise. In an aging population, in chronic disease, and with large reconstructive needs, the process often fails leaving compromised form and function. Work in the previous project period as well as work from others has identified actions of the anabolic agent parathyroid hormone (PTH) to drive osteoclastogenesis and localization of macrophages on the endosteal surface. Such osteal macrophages are essential for normal osseous healing where they act to increase bone formation through various mechanisms. A vital function of macrophages is in the clearance of dead and dying cells, a process termed efferocytosis. Upon efferocytosis, macrophages produce factors which facilitate resolution and regeneration. Based on findings of cellular actions of calcium and drug delivery modalities in the previous funding period, the project team proposes a new strategy for bone regeneration. Biomimicry based on developing calcium loaded biodegradable microspheres with surface signals that macrophages recognize as dying cells triggers efferocytosis and the secretion of factors to evoke wound healing. The overall hypothesis of this proposal is that apoptotic cell mimicry enhances bone regeneration via macrophage efferocytosis. Three aims will dissect the mechanisms involved, optimize microsphere properties, and translate to clinically relevant models that will move this novel approach forward. Specifically, aim one will utilize apoptotic mimicry microspheres to elucidate the role of the macrophage derived chemokine CCL2 in mesenchymal stem cell (MSC) migration and osteogenesis. Aim two will develop optimal apoptosis-mimicry microspheres to drive MSC migration by modulating the size, composition, and surface signals. Aim three will determine the osseous regenerative capacity of calcium loaded apoptotic cell mimicry microspheres using a clinically relevant animal model. At the completion of this project, a new strategy that does not require cell transplantation but builds upon the innate capacity of macrophages to regenerate bone will be mechanistically validated, characterized and optimized for translation to a clinical application.

抽象的 在年轻的健康个体中，小小的侮辱以最小的折衷损害骨骼愈合。衰老 人口，在慢性疾病中以及有巨大的重建需求，这一过程常常失败 留下折衷的形式和功能。在上一个项目期间工作以及工作 来自其他人确定了合成代谢剂甲状旁腺激素（PTH）的行动 巨噬细胞在内膜表面的破骨细胞生成和巨噬细胞的定位。这样的骨 巨噬细胞对于正常的骨愈合至关重要，它们作用于增加骨骼 通过各种机制形成。巨噬细胞的重要功能是清除 死亡和垂死的细胞，这是一种称为肿瘤的过程。经吞噬作用，巨噬细胞 产生促进分辨率和再生的因素。基于细胞的发现 钙和药物输送方式在上一个资金期间，项目团队 提出了一种新的骨骼再生策略。基于发展钙的仿生 带有表面信号的可生物降解的微球，巨噬细胞识别为死亡 细胞会触发肿瘤病和引起伤口愈合的因素的分泌。总体 该提议的假设是凋亡细胞模仿通过 巨噬细胞肿瘤病。三个目标将剖析涉及的机制，优化 微球特性，并转化为临床相关模型，这些模型将移动这一新颖 向前迈进。具体而言，AIM ONE将利用凋亡模仿微球来阐明 巨噬细胞衍生的趋化因子CCL2在间充质干细胞中的作用（MSC） 迁移和成骨。目标两个将发展最佳的凋亡模拟微球到 通过调节大小，组成和表面信号来驱动MSC迁移。目标三 确定钙负载凋亡细胞模仿的骨再生能力 使用临床相关的动物模型的微球。该项目完成后，一个新的 不需要细胞移植的策略，而是基于天生的能力 巨噬细胞将通过机械验证，表征和优化。 用于翻译为临床应用。