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: 10391345
• 负责人: Hongli Sun
• 金额: $ 34.78万
• 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/10391345
• 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; bone repair; 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; translational applications

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.

项目总结 支架介导的外源细胞移植和生长因子/激素传递 两种被广泛研究的传统自体移植物的替代方案，即“黄金标准”。为 然而，治疗翻译这两种方法都遇到了各种障碍，包括安全性 担忧。与使用外源细胞/蛋白质相比，促进组织的策略 利用内源性细胞/信号原位再生更耐人寻味。尽管如此， 与衰老(铁蓄积和慢性炎症)相关的组织变化 骨骼再生和修复，特别是在老年人群中。新出现的证据表明 低氧诱导因子-1α(HIF-1α)信号通路是再生的中心驱动力 和血管生成。发现还显示由铁络合剂持续激活HIF-1α(例如， 去铁胺(deferoxine，DFO)是一种很有前途的提高老年人再生能力的策略 缺氧诱导因子-1α明显受铁水平升高抑制的骨骼。《太阳报》的前期工作 实验室发现，另一种小分子非那米显示出很强的抗炎能力。 此外，它还通过靶向BMP信号在促进骨形成方面发挥强大的作用。一个 局部和持续的药物输送系统和仿生支架对于 这些有前景的小分子药物的成功翻译应用。首要目标 这项研究的目的是开发一种创新的翻译组织工程策略，以提高 通过恢复内源性信号和修复细胞来再生老化的大片骨。我们的 中心假说是新型生物仿生3D纳米纤维(NF)支架介导的双重- 释放小分子DFO和非那米可促进临界大小的骨缺损修复 通过局部衰老的小鼠：(1)清除与衰老有关的有害因素，即过度 铁和炎性细胞因子；(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，并招募 原位修复细胞(例如，间充质干细胞、内皮细胞)，用于原发病灶的骨再生 非承重性骨缺损处。在目标1中，我们将开发新型的、仿生的3D NF支架， 使用我们的创新技术--热诱导纳米纤维自凝聚(TISA)。在AIM 2、我们将DFO和非那米的双释放系统从三维纳米支架发展到 在体外调节衰老细胞的血管生成和成骨。在目标3中，我们将调查 从支架局部和控制释放DFO和非那米米对临界值的贡献 老年小鼠颅骨缺损的大小修复。这个项目的成功将建立一种新颖的 通过促进内源性组织再生来挑战骨修复的策略。