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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

基本信息

批准号：
10615065
负责人：
Hongli Sun
金额：
$ 35.11万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
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/10615065
关键词：
3-Dimensional Acceleration 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 Defect Deferoxamine Drug Delivery Systems Elasticity Elderly Electrospinning Endothelial Cells Engineering Female Goals Growth Factor HA coating HIF1A gene Healthcare Hormones Human Hypoxia Immobilization In Situ In Vitro Inflammation Inflammatory Iron Iron Chelation 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 Rejuvenation Research Role Safety Signal Pathway Signal Transduction Signaling Protein Somatotropin Stem cell transplant Structure System Techniques Tissue Engineering Tissues 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 regenerative therapy repaired restoration scaffold small molecule success tissue regeneration translational applications translational therapeutics

项目摘要

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”。“对于然而，治疗转化，这两种方法都遇到了各种障碍，包括安全性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。一局部和持续的药物递送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和非那明从支架中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。