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.

项目概要 大骨缺损的修复仍然是一个重大的临床挑战。虽然自体骨移植 仍然被认为是大多数应用的黄金标准，但它受到供体发病率的限制 与从收获的骨中制备解剖形状的移植物相关的地点和挑战。 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干/祖细胞 移植（例如骨髓间充质干细胞，BMSC）和生长 因子/激素传递（例如骨形态发生蛋白，BMP）。这些方法、BMP 特别是，因其作为刺激剂的潜在治疗用途而受到广泛关注 的骨修复。 FDA批准的BMP2和BMP7，成功用于骨修复治疗， 招募并诱导内源干/祖细胞进行成骨分化。基于BMP 然而，由于以下几个关键障碍，该疗法在临床实践中受到严重阻碍： 剂量大、成本高、副作用严重。因此，我们的目标是：（1）开发一种新颖的 3D 纳米纤维 (NF) 支架可以调节内源性 BMP 和血管生成信号；和 (2) 在临界尺寸的小鼠颅骨缺损模型中通过功能化支架促进骨修复。 我们的中心假设是，在不添加任何外源细胞或生长因子的情况下， 仿生明胶NF支架可以改善原位内源性骨再生。 骨形成必需成分的功能化将通过以下方式完成：(1) BMP 结合肽 (BBP)，用于选择性捕获和刺激骨中的内源性 BMP 损伤部位诱导局部骨形成； (2) 去铁胺 (DFO) 用于模仿 暂时缺氧，从而引发血管生成/新血管形成/成骨 修复性细胞募集。我们之前的工作表明，3D 多孔、可生物降解的 NF 支架有利于组织再生。额外的成骨信号（例如， 然而，BMP/骨祖细胞仍然是必需的，并且必须在 NF 支架中进行补充 骨再生。在目标 1 中，我们将通过化学方法将 BBP 和 DFO 固定到 NF 支架上 分别是交联和纳米球掺入。修饰后的生物活性功能 将通过使用 in 测量 BMP-2 结合和 BMP-2/VEGF 表达来研究支架 体外细胞培养模型。在目标 2 中，我们将研究固定化 BBP 和 使用临界尺寸的小鼠，DFO（单独和协同）促进骨形成和血管生成 颅骨缺损模型。这项工作将通过探索推进知识和治疗翻译 使用 BBP 肽/DFO 固定生物材料进行骨修复。