Rejuvenating aged bone regeneration by innovative nanomaterials-mediated drug delivery

通过创新纳米材料介导的药物输送使衰老的骨再生恢复活力

• 批准号: 10194462
• 负责人: Hongli Sun
• 金额: $ 35.16万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10194462
• 关键词: 3-Dimensional; Address; Adult; Aging; Anti-Inflammatory Agents; Autologous; Autologous Transplantation; Biomimetics; Bone Diseases; Bone Matrix; Bone Morphogenetic Proteins; Bone Regeneration; Bone Tissue; Bone Transplantation; Cell Transplantation; Cells; Cephalic; Chitosan; Chronic; Cost of Illness; Defect; Deferoxamine; Drug Delivery Systems; Elasticity; Elderly; Electrospinning; Endothelial Cells; Engineering; Female; Fibrinogen; Goals; Gold; Growth Factor; HA coating; HIF1A gene; Healthcare; Hormones; Human; Hypoxia; Immobilization; In Situ; In Vitro; Inflammation; Inflammatory; Iron; Iron Chelating Agents; Irregular Bone; Knowledge; Mediating; Medical; Mesenchymal Stem Cells; Modeling; Modernization; Molecular; Mus; Natural regeneration; Older Population; Osteogenesis; Patients; Pharmaceutical Preparations; Play; Polymers; Population; Prevalence; Production; Proteins; Regenerative Medicine; Regenerative capacity; Research; Role; Safety; Signal Pathway; Signal Transduction; Signaling Protein; Somatotropin; Stem cell transplant; Structure; System; Techniques; The Sun; Therapeutic; Tissue Engineering; Tissues; Translations; Transplantation; Work; age related; aged; aging population; angiogenesis; bone; bone aging; cell age; cell growth; chemical conjugate; chemical property; clinically relevant; combinatorial; controlled release; cost; cytokine; effectiveness evaluation; human stem cells; improved; innovation; local drug delivery; male; mechanical properties; nanofiber; nanomaterials; new therapeutic target; next generation; novel; novel strategies; osteoblast differentiation; osteogenic; phenylamil; recruit; repaired; restoration; scaffold; small molecule; stem; success; tissue regeneration

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.

项目概要 支架介导的外源细胞移植和生长因子/激素递送是 传统自体移植物的两种广泛研究的替代品，即“黄金标准”。 然而，治疗性翻译这两种方法都会遇到各种障碍，包括安全性 与使用外源细胞/蛋白质相比，促进组织的策略。 通过利用内源性细胞/信号进行原位再生更有趣。 与衰老相关的组织变化（铁积累和慢性炎症）挑战 新的证据表明，骨骼再生和修复，尤其是老年人群。 缺氧诱导因子 1α (HIF-1α) 信号通路是再生的核心驱动因素 研究结果还显示铁螯合剂（例如， 去铁胺（Deferoxamine，DFO）是一种有前景的提高老年人再生能力的策略 太阳的铁水平升高会显着抑制 HIF-1α 的骨骼。 实验室发现另一种小分子 phenamil 具有很强的抗炎能力 除了通过靶向 BMP A 信号传导在促进骨形成方面发挥强大作用外。 局部持续的药物输送系统和仿生支架对于 这些有前途的小分子药物的成功转化应用是首要目标。 这项研究的目的是开发一种创新的转化组织工程策略来改善 通过恢复内源性信号和修复细胞来促进老化的大骨再生。 中心假设是新型仿生 3D 纳米纤维 (NF) 支架介导的双 小分子 DFO 和 phenamil 的释放可以改善临界大小的骨缺损修复 衰老小鼠通过局部：（1）清除与衰老相关的痛苦因素，即过度的 铁和炎症细胞因子；(2) 激活 HIF1α 和 BMP 信号通路，从而 促进内源性血管生成和成骨因子的产生，以及招募 原位修复细胞（例如间充质干细胞、内皮细胞），主要用于骨再生 在目标 1 中，我们将开发新型仿生 3D NF 支架， 使用我们的热诱导纳米纤维自团聚 (TISA) 创新技术。 2、我们将开发DFO和phenamil的双重释放系统，从3D NF支架到 在目标 3 中，我们将研究在体外调节衰老细胞的血管生成和骨生成。 DFO 和 phenamil 从支架中局部和受控释放的贡献对于关键- 该项目的成功将建立一种新颖的老年小鼠颅骨缺损修复方法。 通过改善内源性组织再生来修复受挑战的骨的策略。