Amniotic Membrane Derived Matrix for Large Bone Defect Repair

用于修复大骨缺损的羊膜衍生基质

• 批准号: 10019872
• 负责人: Brendan A. Harley
• 金额: $ 24.58万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-07 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10019872
• 关键词: 3-Dimensional; Acute; Address; Allogenic; Allografting; Animals; Autologous; Biocompatible Materials; Bone Injury; Bone Regeneration; Bone Transplantation; Cell Differentiation process; Cells; Characteristics; Chronic; Cicatrix; Clinical; Collagen; Complex; Defect; Dose; Evolution; Excision; Family suidae; Funding; GAG Gene; Geometry; Goals; Gold; Growth Factor; Human; Immune response; In Situ; Inflammatory; Inflammatory Response; Injury; Kinetics; Libraries; Mandible; Mediating; Membrane; Mesenchymal Stem Cells; Minerals; Modeling; Molecular; Natural regeneration; Oryctolagus cuniculus; Osteogenesis; Patients; Phenotype; Placenta; Process; Property; Proteins; Rattus; Receptor Activation; Regenerative Medicine; Science; Severities; Signal Pathway; Signal Transduction; Site; Soft Tissue Injuries; Source; Speed; Stem cells; Structure; Techniques; Technology; Tissue Engineering; Tissues; Trauma; aged; base; bone; bone morphogenetic protein receptors; clinically relevant; craniomaxillofacial; defined contribution; design; healing; immunoregulation; implantation; improved; in vivo; in vivo regeneration; inflammatory milieu; innovation; insight; macrophage; mechanotransduction; novel; novel therapeutics; osteogenic; recruit; regenerative; repaired; response; scaffold; soft tissue; tissue repair; tumor; wound

ABSTRACT Craniomaxillofacial (CMF) defects present unique, unmet challenges to the field of tissue engineering. Typically large in size and characterized by significant loss of hard- and soft-tissue, severe CMF defects are prevalent after acute (tumor resection, trauma) and chronic (degenerative, infectious) injuries. We are developing a collagen-based biomaterial to increase the quality and speed of bone regeneration as the essential first step for creating advanced biomaterials for complex CMF defects. Autologous bone transplantation remains the current gold-standard to repair structural CMF defects. However, limited access to autologous bone, concerns with secondary wound site creation, the destructive impact of post-injury inflammatory processes, and the irregular geometry of CMF defects motivate our efforts. Our long-term goal is to demonstrate a biomaterial that actively instructs, rather than passively supports, osteogenic differentiation and new bone formation using a patient's own mesenchymal stem cells (MSCs). However, while MSCs show promise for aiding healing, inflammatory signals within the wound can significantly reduce their efficacy. Our immediate objective is to demonstrate the innovative use of allogeneic tissue sources to create regeneration- inducing biomaterials that address two critical hurdles: [1] promoting MSC-osteogenesis; and [2] altering the kinetics of the M1-to-M2 macrophage transition through biomaterial design to further improve regeneration. We have recently developed a mineralized collagen scaffold with significant potential for regenerative repair of bone that can promote MSC osteogenesis in the absence of traditional growth factor supplements. Here we will integrate matrix proteins derived from the amniotic membrane (AM), the innermost layer of the placenta known to have significant immunomodulatory and anti-scarring properties, with this mineralized collagen scaffold to create a bioactive composite. We hypothesize the mineralized CG-AM composite will enhance MSC osteogenesis via endogenous BMPR activation and promote M2-like macrophage phenotype in response to inflammatory challenge. In Aim 1 we will dissect the contribution of AM matrix on osteogenic differentiation and inflammatory response within a mineralized collagen scaffold. In Aim 2 we will define the quality and kinetics of CG-AM composite induced mandible bone regeneration. While decellularized AM has shown promise as a stand-alone product for soft tissue repair, its significance as a bioactive component in 3D biomaterials has not been extensively investigated. We employ a systematic means to incorporate AM-matrix into the CG biomaterial to create a mineralized CG-AM composite, and then will define the contribution of the composite on MSC osteogenic differentiation, macrophage activity, and mandible regeneration in a clinically relevant porcine mandible defect model. Results derived here will significantly aid our ongoing efforts to design shelf-stable biomaterials that can be used clinically to regenerate large craniomaxillofacial defects.

摘要 颅颌面部（CMF）缺损是组织工程领域面临的独特挑战。 严重的CMF缺损通常尺寸较大，其特征是硬组织和软组织的显著损失， 在急性（肿瘤切除、创伤）和慢性（变性、感染）损伤后普遍存在。我们 开发一种基于胶原蛋白的生物材料，以提高骨再生的质量和速度， 为复杂CMF缺陷创建先进生物材料的重要第一步。自体骨 移植仍然是目前修复结构性CMF缺陷的金标准。然而，有限的机会， 自体骨，与继发性伤口部位创建有关，损伤后的破坏性影响 炎症过程和CMF缺陷的不规则几何形状激发了我们的努力。我们的长期目标是 证明生物材料主动指导而不是被动支持成骨分化 以及使用患者自身的间充质干细胞（MSC）形成新骨。然而，尽管MSC显示 虽然有望帮助愈合，但伤口内的炎症信号可显著降低其功效。我们 近期目标是展示同种异体组织来源的创新用途，以创造再生- 诱导生物材料解决两个关键障碍：[1]促进MSC成骨;[2]改变 通过生物材料设计进一步改善再生的M1至M2巨噬细胞转变动力学。我们 最近开发了一种矿化胶原支架，具有再生修复的巨大潜力， 在没有传统生长因子补充剂的情况下可以促进MSC成骨的骨。这里我们 将整合来自羊膜（胎盘最内层）的基质蛋白 已知具有显著的免疫调节和抗瘢痕形成特性， 支架来制造生物活性复合材料。我们假设矿化的CG-AM复合物将增强MSC 通过内源性BMPR激活促进成骨，并促进M2样巨噬细胞表型， 炎症性挑战在目标1中，我们将剖析AM基质对成骨分化的贡献， 矿化胶原支架内的炎症反应。在目标2中，我们将定义 CG-AM复合物诱导下颌骨再生。虽然脱细胞AM已显示出作为一种 作为软组织修复的独立产品，其作为3D生物材料中的生物活性成分的重要性尚未得到证实。 进行了广泛的调查。我们采用了一种系统的方法，将AM矩阵纳入CG 生物材料，以创建一个矿化CG-AM复合材料，然后将定义的复合材料的贡献， 临床相关猪的MSC成骨分化、巨噬细胞活性和下颌骨再生 下颌骨缺损模型这里得出的结果将大大有助于我们正在进行的努力，设计货架稳定 生物材料，可用于临床再生大的颅颌面缺损。