Mineralized collagen composite to accelerate craniofacial bone regeneration

矿化胶原复合物加速颅面骨再生

• 批准号: 10606592
• 负责人: Brendan A. Harley
• 金额: $ 43.23万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-03 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10606592
• 关键词: Acceleration; Address; Affect; Anisotropy; Architecture; Autologous; Biocompatible Materials; Biological Process; Biophysics; Blood Vessels; Bone Injury; Bone Marrow; Bone Regeneration; Calvaria; Clinical; Collagen; Complex; Complication; Congenital Abnormality; Data; Defect; Deposition; Dose; Endothelial Cells; Failure; Family; Glycoproteins; Gold; Histologic; Implant; In Vitro; Invaded; Malignant Neoplasms; Mechanics; Mesenchymal Stem Cells; Methods; Modeling; Natural regeneration; Nature; Operative Surgical Procedures; Oryctolagus cuniculus; Osteoclasts; Osteogenesis; Performance; Phenotype; Polymers; Population; Porosity; Printing; Process; Production; Proliferating; Property; Receptor Signaling; Reconstructive Surgical Procedures; Research; Shapes; Signal Transduction; Structure; Technology; Time; Tissue Engineering; Trauma; Tumor necrosis factor receptor 11b; Vascular remodeling; Work; bone; bone morphogenetic protein receptors; collagen scaffold; cost; craniofacial; craniofacial bone; cranium; defined contribution; design; healing; improved; in vivo; in vivo regeneration; inhibitor; innovation; mechanical properties; mechanotransduction; millimeter; mineralization; morphogens; osteogenic; osteoprogenitor cell; pre-clinical; process improvement; prototype; reconstruction; recruit; regeneration potential; regenerative; regenerative therapy; repaired; sample fixation; scaffold; stem; stem cell expansion; stem cells; stroke therapy

ABSTRACT Defects in craniofacial bones of the skull occur congenitally, after high-energy impacts, and during the course of treatment for stroke and cancer. Autologous bone or alloplastic implants are the current gold-standards for surgical reconstruction. However, limited quantities and time-intensive intraoperative fitting of autologous bone, the non-regenerative nature of alloplastic implants, and surgical challenges that stem from irregular defect margins and the quality of the surrounding bone all contribute to poor healing and high complication rates. A biomaterial that could be shaped precisely and quickly like an alloplastic implant but that works in a regenerative fashion like autologous bone would be transformative for craniofacial reconstruction. The objective of this proposal is to potentiate regeneration of the structure, composition, and mechanical properties of craniofacial bone using an innovative scaffold-mesh composite biomaterial. We have generated extensive proof-of-principle data for a surgically-practical composite biomaterial for craniofacial bone regeneration. Our core technology is a porous mineralized collagen scaffold to expand MSCs in vivo. We have identified microstructural features of this material to activate mechanotransduction and BMP receptor signaling to accelerate MSC osteogenicity and secretion of osteoprotegerin (OPG), a soluble glycoprotein and endogenous inhibitor of osteoclast activity. As a result, this material increases osteogenicity and transiently inhibits osteoclast activity to accelerate regenerative healing of craniofacial bone defects osteogenic supplements or exogenously-seeded stem cells. We have independently developed a millimeter-scale polymeric mesh that can be integrated into the scaffold, à la rebar in concrete, to form a modular composite that can be shaped intraoperatively to conformally fit irregular defects. Excitingly, prototype scaffold-mesh composites generated using a mesh printed from an advanced Hyperelastic Bone® material increases MSC OPG secretion. These findings suggest the exciting possibility to co-optimize scaffold microstructural properties as well as the composition and architecture of the integrated polymer mesh to both passively aid surgical-practicality and actively accelerate regenerative healing. Our central hypothesis is that a multi-scale scaffold-mesh composite will accelerate MSC recruitment and retention, increase osteogenesis while inhibiting osteoclast activity, and facilitate vascular remodeling to improve regeneration. To do this we will first define the contribution of scaffold anisotropy on the recruitment and activity of osteoprogenitors and endothelial cells (Aim 1). We will establish topology parameters of a scalable mesh to aid surgical practicality and regenerative potential (Aim 2). Lastly, we will demonstrate in vivo efficacy of a scaffold-mesh composite in a confined calvarial defect model (Aim 3). Our unified effort to develop craniofacial regenerative technologies will generate significant preclinical data to support an FDA IDE application essential for accelerating this technology towards clinical use as a material-only regenerative therapy for craniofacial bone injuries.

抽象的 在高能撞击之后，颅骨颅骨的缺陷在先天性出现。 中风和癌症的治疗。自体骨或同种异体牙齿是当前的金标准 手术重建。但是，自体骨的数量有限和时间密集型术中拟合， 同种异体焦眼的非再生性质，以及源于不规则缺陷的手术挑战 边缘和周围骨骼的质量都导致愈合不良和高并发症发生率。一个 生物材料可以像同种异体植入物一样精确而迅速地形成，但可在再生中起作用 像自体骨一样的时尚将是颅面重建的变化。这个目的 建议是颅面的结构，组成和机械性能的潜在再生 使用创新的脚手架 - 现象复合生物材料的骨头。我们已经获得了广泛的原理证明 用于颅面骨再生的手术实行复合生物材料的数据。我们的核心技术是 多孔矿化胶原蛋白支架以在体内扩展MSC。我们已经确定了这一点的微观结构特征 激活机械转导和BMP受体信号的材料，以加速MSC成骨和 骨蛋白蛋白蛋白酶（OPG）的分泌，一种可溶性糖蛋白和破骨细胞活性的内源性抑制剂。作为 结果，该材料会增加成骨和瞬时抑制破骨细胞活性以加速再生 颅面骨缺损的愈合可造成成骨补充剂或外生物种子的干细胞。我们有 独立开发了一个毫米尺度的聚合物网，可以集成到脚手架中àlarebar 在混凝土中，形成一个模块化复合材料，可以在术中形成术中形状，以形成一个不规则的不规则缺陷。 令人兴奋的是，使用高级超弹性印刷的网格产生的原型支架网状复合材料 Bone®材料增加了MSC OPG分泌。这些发现表明了合作优化的令人兴奋的可能性 脚手架微观结构特性以及集成聚合物网的组成和结构 既可以被动地帮助手术实践性，又可以积极加速再生愈合。我们的中心假设是 多尺度的脚手架 - 网状复合材料将加速MSC募集和保留率，增加成骨的作用 同时抑制破骨细胞活性，并促进血管重塑以改善再生。为此，我们将 首先定义脚手架各向异性对破骨者和活性的贡献 内皮细胞（AIM 1）。我们将建立可扩展网格的拓扑参数，以帮助手术实践 和再生潜力（目标2）。最后，我们将演示脚手架复合材料的体内效率 狭窄的颅缺陷模型（AIM 3）。我们开发颅面再生技术的统一努力 将生成重要的临床前数据，以支持FDA IDE应用程序加速至关重要 用于临床用作颅骨骨损伤的仅材料再生疗法的技术。

项目成果

Amnion and chorion matrix maintain hMSC osteogenic response and enhance immunomodulatory and angiogenic potential in a mineralized collagen scaffold.

• DOI: 10.3389/fbioe.2022.1034701
• 发表时间: 2022
• 期刊: FRONTIERS IN BIOENGINEERING AND BIOTECHNOLOGY
• 影响因子: 5.7
• 作者: Kolliopoulos, Vasiliki;Dewey, Marley J.;Polanek, Maxwell;Xu, Hui;Harley, Brendan A. C.
• 通讯作者: Harley, Brendan A. C.

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• DOI: 10.1001/jama.2023.8232
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• 期刊: JAMA
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Modulating Temporospatial Phosphate Equilibrium by Nanoparticulate Mineralized Collagen Materials Induces Osteogenesis via PiT-1 and PiT-2.

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• DOI: 10.1002/adhm.202202750
• 发表时间: 2023
• 期刊: Advanced healthcare materials
• 影响因子: 10
• 作者: Ren,Xiaoyan;Zhou,Qi;Bedar,Meiwand;Foulad,David;Huang,KellyX;Dejam,Dillon;Dahan,NatalieJ;Kolliopoulos,Vasiliki;Harley,BrendanAC;Lee,JustineC
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Growing Pains: The Need for Engineered Platforms to Study Growth Plate Biology.

• DOI: 10.1002/adhm.202200471
• 发表时间: 2022-10
• 期刊: ADVANCED HEALTHCARE MATERIALS
• 影响因子: 10
• 作者: Tiffany, Aleczandria S.;Harley, Brendan A. C.
• 通讯作者: Harley, Brendan A. C.