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

项目摘要/摘要： 在临床上，大型骨缺损的治疗具有挑战性，通常需要植骨。自然嫁接 选择包括自体移植和同种异体移植；然而，这些替代组织的供应有限且困难。 以匹配复杂骨缺损处的尺寸不规则。组织工程(TE)的研究进展 合成移植物已成为克服天然移植物局限性的关键；然而，缺乏支架 制造方法和低效的骨诱导剂阻碍了传统的 TE构造。因此，克服这些限制的先进合成移植物的设计将 极大地影响了临床大段骨缺损的治疗。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 用于治疗特定患者的骨缺损症。这项提议的目标是发展TE建设 使用包括合成聚合物和天然聚合物的混合材料方法进行骨再生 3D打印结构，与骨诱导microRNA的持续释放相结合。高级TE 这项研究的构建将把可3D打印的FDA批准的聚合物与可调节的生物降解相结合 使用天然聚合物涂层来维持骨诱导microRNA的释放。中心假说 这项工作的一项工作是从聚合物涂层3D打印中持续释放骨诱导microRNA 构建物将通过延长再生信号来增强合成移植物的成骨能力 最大限度地促进骨骼再生。为了验证这一假设，我们将表征从聚合物中释放的microRNA- 涂层3D打印构建体(AIM 1)，评估microRNA释放诱导的体外成骨分化 来自聚合物涂层构建物(目标2)，并评估聚合物涂层的骨再生潜力 掺入microRNA的3D打印构建体(目标3)。总而言之，这些数据具有阐明机制 从聚合物涂层3D打印支架中可以优化哪种microRNA释放以维持释放 骨诱导信号，最大限度地促进骨骼再生。这些成果将推动 合成TE构造，包括骨传导和诱导特性，将有效地促进 骨再生，从而显著影响具有挑战性的、特定于患者的骨的临床治疗 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.