Rejuvenating aged bone regeneration by innovative nanomaterials-mediated drug delivery

项目摘要 支架介导的外源性细胞移植和生长因子/激素的递送是 两种被广泛研究的传统自体移植物的替代品，即“金标准”。“为 然而，这两种方法的治疗转化都遇到了各种障碍， 性问题与使用外源性细胞/蛋白质相比，促进组织生长的策略 通过原位利用内源性细胞/信号的再生更有趣。尽管如此， 与衰老（铁积累和慢性炎症）挑战相关的组织变化 骨再生和修复，特别是在老年人群中。新出现的证据表明 缺氧诱导因子-1 α（HIF-1α）信号通路是再生的中心驱动力， 和血管生成。研究结果还显示，铁螯合剂（例如， 去铁胺（Deferoxamine，DFO）是一种很有前途的提高老年人再生能力的策略 骨中HIF-1α明显受到铁水平升高的抑制。太阳的初步工作 实验室发现，另一种小分子，非那灭，显示出强烈的抗炎能力， 除了通过靶向BMP信号传导在促进骨形成中发挥强有力的作用之外。一 局部持续给药系统和生物模拟支架对于 这些有前途的小分子药物的成功转化应用。首要目标 这项研究的目的是开发一种创新的转化组织工程策略， 通过再生内源性信号和修复细胞来再生老化的大骨。我们 中心假设是，新的生物模拟3D纳米纤维（NF）支架介导的双- 释放小分子DFO和非那米，可以改善临界大小的骨缺损修复， 老年小鼠通过局部：（1）清除有害的年龄相关因子，即，过度 铁和炎性细胞因子;和（2）激活HIF 1 α和BMP信号通路，从而 促进内源性血管生成因子和成骨因子的产生， 修复细胞（例如，MSC，内皮细胞）原位，用于主要关注的骨再生 非承重性骨缺损在目标1中，我们将开发新型的仿生3D NF支架， 使用我们的创新技术热诱导自附聚（TISA）。在Aim中 2、将DFO和非那敏的双释放系统从三维纳米支架发展到 调节体外老化细胞中的血管生成和骨生成。在目标3中，我们将研究 DFO和非那米从支架中的局部和控制释放对关键- 大小的颅骨缺损修复。这个项目的成功将建立一个新的 通过改善内源性组织再生进行挑战性骨修复的策略。

PROJECT SUMMARY Scaffold-mediated exogenous cells transplantation and growth factors/hormones delivery are two widely-studied alternatives to conventional autologous grafts, the "gold standard." For therapeutic translation, however, both approaches encounter various barriers, including safety concerns. Compared to use of exogenous cells/proteins, strategies that promote tissue regeneration by leveraging endogenous cells/signals in situ are more intriguing. Nonetheless, changes in tissue associated with aging (iron accumulation and chronic inflammation) challenge bone regeneration and repair, particularly in older populations. Emerging evidence suggests that the hypoxia-induced factor-1α (HIF-1α) signaling pathway is a central driver of regeneration and angiogenesis. Findings also show sustained activation of HIF-1α by an iron chelator (e.g., Deferoxamine, DFO) is a promising strategy to improve the capacity of regeneration in aged bones where HIF-1α is markedly inhibited by elevated iron levels. Preliminary work by the Sun lab has found that another small molecule, phenamil, shows strong anti-inflammatory ability in addition to playing a powerful role in promoting bone formation by targeting BMP signaling. A locally and sustained drug delivery system and a bio-mimicking scaffold are critical for successful translational application of these promising small molecular drugs. The primary goal of this study is to develop an innovative translational tissue engineering strategy to improve aged large bone regeneration by rejuvenating endogenous signals and reparative cells. Our central hypothesis is that novel bio-mimicking 3D nanofibrous (NF) scaffold-mediated dual- release of small molecules, DFO and phenamil, can improve critical-sized bone defect repair in aged mice through locally: (1) scavenging for detrimental aged-related factors, i.e., excessive iron and inflammatory cytokines; and (2) activating HIF1α and BMP signaling pathways, thereby promoting production of endogenous angiogenic and osteogenic factors, and recruitment of reparative cells (e.g., MSCs, endothelial cells) in situ, for bone regeneration with a primary focus on non-load-bearing bone defects. In Aim 1, we will develop novel, biomimetic 3D NF scaffolds, using our innovative technique of thermally induced nanofiber self-agglomeration (TISA). In Aim 2, we will develop the dual-release system of DFO and phenamil from a 3D NF scaffold to modulate both angiogenesis and osteogenesis in aged cells in vitro. In Aim 3, we will investigate the contribution of local and controlled release of DFO and phenamil from scaffolds for critical- sized cranial bone defect repair in aged mice. The success of this project will establish a novel strategy for challenged bone repair by improving endogenous tissue regeneration.