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: 10045736
• 负责人: Hongli Sun
• 金额: $ 36.48万
• 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/10045736
• 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; Effectiveness; 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; 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; 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.

项目摘要 脚手架介导的外源细胞移植和生长因子/激素的传递是 传统自体移植物的两个广泛研究的替代品，即“金标准”。为了 但是，治疗翻译的翻译方法都遇到了各种障碍，包括安全 关注。与使用外源细胞/蛋白质的使用相比，促进组织的策略 通过利用内源细胞/信号原位再生更有趣。尽管如此， 与衰老相关的组织变化（铁积累和慢性炎症）挑战 骨骼再生和修复，特别是在较老的人群中。新兴证据表明 缺氧诱导的因子-1α（HIF-1α）信号通路是再生的中心驱动力 和血管生成。发现还显示了铁螯合剂对HIF-1α的持续激活（例如， DFO）是提高老年再生能力的有前途的策略 铁水平升高明显抑制了HIF-1α的骨骼。阳光下的初步工作 实验室发现，另一个小分子empamil在 除了通过靶向BMP信号传导来促进骨形成中发挥强大的作用。一个 本地和持续的药物输送系统和生物模仿脚手架对于 这些承诺小分子药物的成功翻译应用。主要目标 这项研究的是制定一种创新的翻译组织工程策略 通过恢复内源信号和修复细胞来使大骨再生老化。我们的 中心假设是新型的生物模仿3D纳米纤维（NF）支架介导的双重 - 释放小分子，DFO和Phenamil，可以改善关键尺寸的骨缺损修复 通过局部衰老的小鼠：（1）清除有害老年相关因素，即 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，并募集 原位的修复细胞（例如MSC，内皮细胞），用于骨再生，主要焦点 在非负载骨缺损上。在AIM 1中，我们将开发出新颖的仿生3D NF脚手架， 使用我们的热诱导纳米纤维自我组合（TISA）的创新技术。目标 2，我们将开发DFO和Phanamil的双重释放系统从3D NF支架到 在体外调节老化细胞的血管生成和成骨。在AIM 3中，我们将调查 局部和受控释放DFO和苯胺从脚手架中的贡献 - 关键 - 老年小鼠大小的颅骨缺损修复。该项目的成功将建立小说 通过改善内源性组织再生来挑战骨修复的策略。