Coupling osteoinductive factors to graft materials to promote osteoregeneration

将骨诱导因子与移植材料偶联以促进骨再生

• 批准号: 9110953
• 负责人: Susan L Bellis
• 金额: $ 36.75万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9110953
• 关键词: Address; Adverse effects; Allografting; Amino Acids; Animals; Autologous; BMP2 gene; Binding; Bone Cements; Bone Regeneration; Bone Transplantation; Calcium; Calcium Binding; Calvaria; Cataract; Cell Culture Techniques; Chemicals; Chronic; Clinical; Collagen; Complex; Coupled; Coupling; Defect; Development; Dose; Edema; Employee Strikes; Engineering; Fibrosis; Foreign Bodies; Foundations; Fracture; Goals; HA coating; Health; Immune; Immune response; Implant; Inflammation; Length; Malignant Neoplasms; Mandible; Medicine; Membrane; Mesenchymal Stem Cells; Methods; Modeling; Molecular; Monitor; Mutation; Operative Surgical Procedures; Organ Culture Techniques; Organ Transplantation; Osteogenesis; Pathway interactions; Patients; Peptides; Performance; Plague; Proteins; Rattus; Recombinants; Regenerative Medicine; Research; Signal Transduction; Site; Source; Stem cells; Surface; System; Therapeutic; Tissues; Translations; Transplanted tissue; Treatment outcome; Variant; Xenograft procedure; allogenic bone transplantation; angiogenesis; bone; bone healing; bone morphogenetic protein receptors; bone morphogenic protein; bone xenograft; calcification; clinical efficacy; cost; craniofacial; implant material; implantable device; improved; inhibitor/antagonist; innovation; insight; lipid biosynthesis; mimetics; new technology; novel; osteoblast differentiation; osteogenic; osteoinductive factor; osteoprogenitor cell; peptidomimetics; preclinical study; protein aminoacid sequence; receptor binding; recombinant peptide; reconstitution; regenerative; response; stem; subcutaneous; wound

DESCRIPTION (provided by applicant): Due to limitations associated with autografted bone, allograft, xenograft and alloplast materials are commonly used for bone grafting procedures. However these materials lack osteoinductivity. The proposed research aims to couple osteoinductive factors to the surface of these alternative graft sources in order to enhance osteoregeneration in sites of bone deficiency. Our group is utilizing a unique approach involving the addition of a calcium-binding amino acid domain, heptaglutamate (E7), to an osteoinductive peptide derived from BMP2. Preclinical studies show that graft materials coupled with the E7-modified BMP2 peptide (E7-BMP2pep) stimulated significantly greater new bone synthesis than uncoated materials in both a subcutaneous (ectopic) and mandibular defect model. Importantly, bone formation was comparable to, and in some cases greater than, that induced by graft coated with full-length rBMP2, and no side effects were noted for the E7-BMP2pep group. In contrast, animals implanted with rBMP2 developed chronic inflammation and cataracts. We hypothesize that the E7-BMP2pep is an effective, safe, and readily translatable agent that can be used to enhance the performance of a wide array of bone grafting materials including allograft, xenograft and alloplast. There are two major objectives of this proposal: (1) to comprehensively analyze host response to the E7- BMP2pep in order to advance the research toward translation (Aim 1); and (2) to elucidate the mechanism by which BMP2 mimetic peptides activate osteoprogenitor cells, with the broader goal of identifying a BMP2 derivative with maximal osteoinductive potential. AIM 1: Host response to E7-BMP2pep-coupled graft materials A mandibular defect model will be used to assess the effects of E7-BMP2pep coupled materials on immune and foreign body response, fibrosis, angiogenesis, quantity and quality of newly-formed bone, and implant integration. Dissemination of the peptides and rBMP2 away from the implant site will also be monitored. We hypothesize that E7-BMP2pep will remain tightly localized within the defect, promoting rapid and effective bone healing. AIM 2: Molecular characterization and engineering of BMP2 mimetics to enhance osteoinductive potential Using cell culture and calvarial organ culture systems, the mechanisms by which E7-modified BMP2 mimetic peptides regulate stem/progenitor cells will be elucidated. Additionally, BMP2 peptide variants with activating mutations will be developed, and in complementary studies, an E7 domain will be engineered onto full-length rBMP2 to improve coupling to carriers. These BMP variants will be evaluated for receptor binding activity and induction of cell signaling and osteoblastogenesis. Enhanced osteoinductivity of the variants will be confirmed by mandibular implant studies. The broad goal of Aim 2 is to identify the ideal BMP2 cargo molecule for E7- directed coupling to graft materials.

描述（由申请人提供）：由于与自体移植骨相关的限制，同种异体移植、异种移植和同种异体材料通常用于骨移植手术。然而这些材料缺乏骨诱导性。拟议的研究旨在将骨诱导因子耦合到这些替代移植物来源的表面，以增强骨缺乏部位的骨再生。我们的团队正在利用一种独特的方法，将钙结合氨基酸结构域七谷氨酸 (E7) 添加到源自 BMP2 的骨诱导肽中。临床前研究表明，在皮下（异位）和下颌缺损模型中，与 E7 修饰的 BMP2 肽 (E7-BMP2pep) 结合的移植材料比未涂层的材料显着刺激更多的新骨合成。重要的是，骨形成与涂有全长 rBMP2 的移植物诱导的骨形成相当，在某些情况下大于，并且 E7-BMP2pep 组没有注意到副作用。相比之下，植入 rBMP2 的动物出现了慢性炎症和白内障。我们假设 E7-BMP2pep 是一种有效、安全且易于翻译的试剂，可用于增强多种骨移植材料的性能，包括同种异体移植、异种移植和同种异体。该提案有两个主要目标：（1）全面分析宿主对E7-BMP2pep的反应，以推进翻译研究（目标1）； (2) 阐明 BMP2 模拟肽激活骨祖细胞的机制，更广泛的目标是鉴定具有最大骨诱导潜力的 BMP2 衍生物。目标 1：宿主对 E7-BMP2pep 偶联移植材料的反应 下颌缺损模型将用于评估 E7-BMP2pep 偶联材料对免疫和异物反应、纤维化、血管生成、新形成骨的数量和质量以及种植体整合的影响。还将监测肽和 rBMP2 远离植入部位的传播。我们假设 E7-BMP2pep 将紧密定位在缺损处，促进快速有效的骨愈合。目标 2：增强骨诱导潜力的 BMP2 模拟物的分子表征和工程利用细胞培养和颅骨器官培养系统，将阐明 E7 修饰的 BMP2 模拟肽调节干/祖细胞的机制。此外，将开发具有激活突变的 BMP2 肽变体，并且在补充研究中，E7 结构域将被设计到全长 rBMP2 上，以改善与载体的耦合。将评估这些 BMP 变体的受体结合活性以及细胞信号传导和成骨细胞生成的诱导。下颌种植体研究将证实变体增强的骨诱导性。目标 2 的总体目标是确定用于 E7 定向偶联至移植材料的理想 BMP2 货物分子。