Bone Regeneration Induced by the Sustained Release of Osteoinductive microRNAs from 3D-printed Constructs

项目概要/摘要： 大面积骨缺损的治疗在临床上具有挑战性，通常需要植骨。自然嫁接 选择包括自体移植物和同种异体移植物;然而，这些替代组织的供应有限， 以匹配复杂骨缺损的尺寸不规则性。组织工程的发展 合成移植物对于克服天然移植物的局限性已变得至关重要;然而，缺乏支架 制造方法和低效的骨诱导剂阻碍了传统骨诱导剂的临床转化， TE结构。因此，克服这些限制的先进合成移植物的设计将 极大地影响了大面积骨缺损的临床治疗。这项拟议工作的长期目标是 开发具有骨传导和诱导特性的可生物降解的3D打印结构，用于临床应用 用于治疗患者特定的骨缺损。本提案的目的是开发一种TE结构 使用混合材料方法进行骨再生，该方法包括合成和天然聚合物， 3D打印的结构，结合持续释放的骨诱导microRNA。高级TE 这项研究的结构将结合联合收割机3D打印，FDA批准的聚合物与可调生物降解 速率与天然聚合物涂层，以维持骨诱导microRNA的释放。核心假设 这项工作的一个重要方面是，从聚合物涂层的3D打印材料中持续释放骨诱导微RNA， 构建体将通过延长再生信号传导来增强合成移植物的成骨能力， 最大化骨再生。为了验证这一假设，我们将描述聚合物中microRNA的释放， 包被的3D打印构建体（目的1），评估microRNA释放诱导的体外成骨分化 从聚合物涂层结构（目的2），并评价聚合物涂层的骨再生潜力 microRNA掺入的3D打印构建体（Aim 3）。总的来说，这些数据阐明了 从聚合物涂覆的3D打印支架中释放的microRNA可以被优化以维持 骨诱导信号和最大化骨再生。这些成果将推动 合成TE构建体包括骨传导和诱导性质， 骨再生，从而显著影响具有挑战性的患者特异性骨的临床治疗 缺陷

Project Summary/Abstract: Large bone defects are clincially challenging to treat and often necessitate bone grafting. Natural grafting options include autografts and allografts; however, these replacement tissues are limited in supply and difficult to match to the dimensional irregularities of complex bone defects. The development of tissue-engineered (TE) synthetic grafts has become essential to overcome the limitations of natural grafts; however, deficient scaffold fabrication methods and inefficient osteoinductive agents have prevented the clinical translation of traditional TE constructs. Therefore, the design of advanced synthetic grafts that overcome these limitations would greatly impact the clinical treatment of large bone defects. The long-term goal of this proposed work is to develop biodegradable, 3D-printed constructs with osteoconductive and inductive properties toward clinical use for the treatment of patient-specific bone defects. The objective of this proposal aims to develop a TE construct for bone regeneration using a hybrid materials approach that includes both synthetic and natural polymers in the 3D-printed structure, combined with the sustained release of osteoinductive microRNAs. Advanced TE constructs for this investigation will combine 3D-printable, FDA-approved polymers with tunable biodegradation rates with natural polymer coatings to sustain the release of osteoinductive microRNAs. The central hypothesis of this work is that the sustained release of osteoinductive microRNAs from polymer-coated 3D-printed constructs will enhance the osteogenic capabilities of synthetic grafts by prolonging regenerative signaling to maximize bone regeneration. To test this hypothesis, we will characterize microRNA release from polymer- coated 3D-printed constructs (Aim 1), assess in vitro osteogenic differentiation induced by microRNA release from polymer-coated constructs (Aim 2), and evaluate the bone regeneration potential of polymer-coated microRNA-incorporated 3D-printed constructs (Aim 3). Collectively, these data with elucidate mechanisms in which microRNA release from polymer-coated 3D-printed scaffolds can be optimized to sustain the release of osteoinductive signals and maximize bone regeneration. These results will advance the development of synthetic TE constructs to include both osteoconductive and inductive properties that will effectively promote bone regeneration, and thus significantly impact the clinical treatment of challenging, patient-specific bone defects.