Functionalized Nanofibrous Scaffold for Endogenous Bone Regeneration

用于内源性骨再生的功能化纳米纤维支架

• 批准号: 9770013
• 负责人: Hongli Sun
• 金额: $ 12.91万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9770013
• 关键词: Address; Adverse effects; Anatomy; Angiogenic Factor; Architecture; Attention; Autologous; BMP2 gene; BMP7 gene; Binding; Biocompatible Materials; Biomimetics; Bone Injury; Bone Marrow; Bone Morphogenetic Proteins; Bone Regeneration; Bone Tissue; Bone Transplantation; Cell Culture Techniques; Cells; Cephalic; Chemicals; Clinical; Collagen; Complex; Congenital Abnormality; Data; Defect; Deferoxamine; Dental; Disadvantaged; Dose; Drug Delivery Systems; Excision; FDA approved; Gelatin; Goals; Gold; Growth Factor; Harvest; Hormones; Hypoxia; Immobilization; In Situ; In Vitro; Infection; Injections; Injury; Knowledge; Longevity; Measures; Mediating; Medical; Mesenchymal Stem Cells; Modeling; Morbidity - disease rate; Mus; Nanosphere; Orthopedics; Osteitis; Osteogenesis; Peptides; Phase; Physiological; Play; Proteins; Reporting; Research; Risk; Role; Safety; Signal Pathway; Signal Transduction; Site; Stem cell transplant; Stem cells; Techniques; Therapeutic; Therapeutic Uses; Time; Tissue Engineering; Translations; Transplantation; Trauma; Vascular Endothelial Growth Factors; Work; aged; angiogenesis; base; bone; bone healing; bone morphogenetic protein 2; clinical practice; cost; crosslink; cytotoxicity; dosage; improved; innovation; nanofiber; neovascularization; novel; novel therapeutics; osteogenic; osteoprogenitor cell; pathogen; recruit; repaired; scaffold; stem; stem cell therapy; success; tissue regeneration; transmission process; tumor; tumorigenesis

PROJECT SUMMARY Repair of large bone defects remains a significant clinical challenge. While autologous bone graft is still considered the gold standard for most applications, it is limited by morbidity at the donor site and challenges associated with preparing anatomically-shaped grafts from harvested bone. Bone tissue engineering is considered a promising alternative, with two of the most widely-studied tissue engineering approaches being biomaterials-mediated exogenous stem/progenitor cells transplantation (e.g., bone marrow mesenchymal stem cells, BMSCs) and growth factors/hormones delivery (e.g., bone morphogenetic protein, BMPs). These approaches, BMPs in particular, have received widespread attention for their potential therapeutic use as stimulators of bone repair. FDA-approved BMP2 and BMP7, used successfully in the treatment of bone repair, recruits and induces endogenous stem/progenitor cells for osteogenic differentiation. BMP-based therapy, however, has been significantly impeded in clinical practice due to several critical barriers: high dose, high costs, and serious side effects. Accordingly, we aim to: (1) develop a novel 3D nanofibrous (NF) scaffold that can modulate both endogenous BMP and angiogenic signals; and (2) promote bone repair by a functionalized scaffold in a critical-size mouse cranial defect model. Our central hypothesis is that, without the addition of any exogenous cells or growth factors, biomimetic gelatin NF scaffold can improve in situ endogenous bone regeneration. Functionalization of essential components for bone formation will be accomplished via: (1) BMP binding peptide (BBP) for selectively capturing and stimulating endogenous BMPs from osseous injury sites to induce local bone formation; and (2) desferrioxamine (DFO) for mimicking temporary hypoxia, thereby triggering angiogenesis/neovascularization/osteogenesis and reparative cell recruitment. Our previous work demonstrates that a 3D porous, biodegradable NF scaffold is advantageous in tissue regeneration. Additional osteogenic signals (e.g., BMPs/osteoprogenitors), however, are still required and must be supplemented in NF scaffold for bone regeneration. In Aim 1, we will immobilize BBP and DFO to NF scaffold by chemical crosslinking and nanosphere incorporation, respectively. The bioactive functions of modified scaffolds will be studied by measuring BMP-2 binding, and BMP-2/VEGF expression using an in vitro cell culture model. In Aim 2, we will investigate the contributions of immobilized BBP and DFO (alone and synergistically) to bone formation and angiogenesis, using a critical-size mouse cranial defect model. This work will advance knowledge and therapeutic translation by exploring the use of the BBP peptide/DFO immobilized biomaterials for challenged bone repair.

项目总结 修复较大的骨缺损仍然是一个巨大的临床挑战。而自体骨移植 仍然被认为是大多数应用的黄金标准，但它受到捐赠者发病率的限制 与从采集的骨准备解剖形状的移植物相关的位置和挑战。 骨组织工程被认为是一种有前途的替代方案，其中两种研究最广泛 组织工程方法是生物材料介导的外源性干细胞/祖细胞 移植(例如，骨髓间充质干细胞)和生长 因子/激素传递(如骨形态发生蛋白，BMPs)。这些方法，BMP 特别是，由于它们作为刺激物的潜在治疗用途而受到广泛关注 骨修复术。FDA批准的BMP2和BMP7，成功地用于骨修复的治疗， 招募和诱导内源性干细胞/祖细胞进行成骨分化。基于BMP的 然而，由于几个关键障碍，治疗在临床实践中受到了严重阻碍： 剂量大，费用高，副作用严重。因此，我们的目标是：(1)开发一种新颖的3D 可调节内源性BMP和血管生成信号的纳米纤维(NF)支架； (2)功能化支架促进临界大小小鼠颅骨缺损模型的骨修复。 我们的中心假设是，在没有任何外源细胞或生长因子的情况下， 仿生明胶-核因子支架可促进原位内源性骨再生。 骨形成的基本成分的功能化将通过：(1)骨形成蛋白 选择性捕获和刺激骨组织内源性BMPs的结合肽 损伤部位诱导局部骨形成；和(2)去铁胺(DFO)模拟 暂时缺氧，从而触发血管生成/新生血管/成骨 修复性细胞募集。我们之前的工作表明，一种3D多孔性、可生物降解的核因子 支架材料具有良好的组织再生能力。附加的成骨信号(例如， BMPS/骨祖细胞)仍然是必需的，并且必须在NF支架中进行补充 骨骼再生。在目标1中，我们将通过化学方法将BBP和DFO固定到纳滤膜支架上 分别为交联剂和纳米球掺杂剂。改良剂的生物活性 将通过测量BMP-2结合和BMP-2/血管内皮生长因子的表达来研究支架 体外细胞培养模型。在目标2中，我们将调查固定化BBP和 DFO(单独和协同)对骨形成和血管生成的作用，使用临界大小的小鼠 颅骨缺损模型。这项工作将通过探索来促进知识和治疗性翻译 BBP肽/DFO固定化生物材料在挑战性骨修复中的应用。