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.

摘要 在年轻的健康个体中，轻微的骨损伤以最小的损害愈合。在老龄化 在慢性疾病人群中，以及有大量重建需求的人群中， 留下受损的形式和功能。项目前期的工作以及 从其他人已经确定了行动的合成代谢剂甲状旁腺激素（PTH），以推动 破骨细胞生成和巨噬细胞在骨内膜表面的定位。这样的骨质 巨噬细胞对于正常的骨愈合是必不可少的，在那里它们起到增加骨的作用 通过各种机制形成。巨噬细胞的一个重要功能是清除 死亡和垂死的细胞，这一过程被称为红细胞增多症。在巨噬细胞增多时， 产生促进分解和再生的因子。根据细胞的发现， 在上一个供资期间，项目小组对钙和药物输送方式采取了行动， 提出了骨再生的新策略。基于钙的仿生学 装载有巨噬细胞识别死亡的表面信号的可生物降解的微球 细胞触发红细胞增多和因子的分泌以引起伤口愈合。整体 该建议的假设是凋亡细胞模拟通过以下途径增强骨再生： 巨噬细胞增多症三个目标将剖析所涉及的机制，优化 微球的性质，并转化为临床相关的模型，将推动这一新的 向前走。具体而言，目标一将利用凋亡模拟微球来阐明 巨噬细胞趋化因子CCL2在骨髓间充质干细胞中的作用 迁移和成骨。目的二是研制最佳的拟骨化微球， 通过调节大小、组成和表面信号驱动MSC迁移。目标三意志 测定钙负载凋亡细胞模拟物的骨再生能力 使用临床相关的动物模型制备微球。在这个项目完成后，一个新的 这一策略不需要细胞移植，但建立在先天的能力， 巨噬细胞再生骨的机制将得到验证，表征和优化 用于临床应用。