Biomimetics for craniofacial regeneration

摘要 对于年轻健康的人来说，轻微的侮辱会使骨骼愈合，并做出最小的妥协。在老龄化中 在人口、慢性病和有大量重建需求的情况下，这一过程经常失败 留下了妥协的形式和功能。在上一个项目期的工作和工作 从其他人那里发现了合成代谢剂甲状旁腺激素(PTH)驱动 破骨细胞的发生和巨噬细胞在骨内膜表面的定位。这样的骨头 巨噬细胞对正常的骨愈合是必不可少的，因为巨噬细胞的作用是增加骨骼 通过各种机制形成。巨噬细胞的一项重要功能是清除 死亡和濒临死亡的细胞，这一过程称为胞吐作用。吞噬时，巨噬细胞 产生促进分解和再生的因素。基于细胞的研究结果 上一个供资期间钙和药物输送方式的行动，项目组 提出了一种新的骨再生策略。基于开发钙的仿生学 负载表面信号的可生物降解微球，巨噬细胞可识别为死亡 细胞会触发吞噬和分泌因子，从而促进伤口愈合。整体而言 这一建议的假设是，凋亡细胞拟态通过 巨噬细胞泡沫化。三个目标将对所涉及的机制进行剖析、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 往前走。具体地说，Aim One将利用凋亡模拟微球来阐明 巨噬细胞源性趋化因子CCL2在间充质干细胞中的作用 迁移和成骨。目标二将开发最佳的细胞凋亡模拟微球以 通过调节MSC的大小、组成和表面信号来驱动MSC迁移。目标三意志 钙离子诱导的细胞凋亡拟态成骨能力的测定 使用临床相关动物模型的微球。在这个项目完成时，一个新的 不需要细胞移植，但建立在先天能力基础上的策略 用于再生骨的巨噬细胞将从机制上进行验证、表征和优化 用于转化为临床应用。

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.