Mechanisms Mediating Osseointegration of 3D Printed Titanium Constructs

3D 打印钛结构的骨整合调节机制

• 批准号: 10333283
• 负责人: Barbara D. Boyan
• 金额: $ 56.67万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-07 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10333283
• 关键词: 3-Dimensional; 3D Print; Address; Adult; Affect; Alloys; Animal Model; Animals; Autologous; Biological; Biological Products; Biomimetic Materials; Biomimetics; Bone Matrix; Bone Morphogenetic Proteins; Bone Transplantation; Bone remodeling; Cell Line; Cell Lineage; Cells; Cellular biology; Cephalic; Characteristics; Chemicals; Chemistry; Clinical; Clinical Research; Coagulation Process; Complex; Coupling; Cues; Dental; Dental Inlays; Dentistry; Dentures; Disease; Distal; Effectiveness; Endothelial Cells; Engineering; Environment; Estrogens; Event; Experimental Pathology; Family; Female; Femur; Fibrin; Generations; Geometry; Goals; Human; Image; Immature Bone; Immune; Implant; Implant-Supported Dental Prosthesis; Implantation procedure; In Vitro; Inflammation; Integrins; Intervention; Left; Mature Bone; Mechanics; Mediating; Medical; Mesenchymal Stem Cells; Metabolic Bone Diseases; Metals; Methods; Minerals; Modeling; Modification; Molecular Biology; Morphology; Nanostructures; Operative Surgical Procedures; Orthopedics; Oryctolagus cuniculus; Osseointegration; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Polystyrenes; Process; Production; Proliferating; Property; Protocols documentation; Quality of life; Rattus; Reaction; Regulation; Reproducibility; Research; Risk; Semaphorins; Sex Differences; Shapes; Signal Transduction; Site; Surface; Surface Properties; Technology; Testing; Texture; Time; Tissues; Titanium; Tooth structure; Trauma; Variant; Vertebral column; Vision; WNT Signaling Pathway; Weight-Bearing state; Work; aged; aging population; bone; bone health; bone loss; cortical bone; design; experience; functional restoration; hydrophilicity; improved; in vivo; macrophage; male; mandibular nerve; materials science; monocyte; nanoscale; novel; osteoblast differentiation; osteogenic; osteoprogenitor cell; physical property; planar cell polarity; preclinical study; recruit; response; side effect; skills; stem cells; success; tissue culture; tissue regeneration; tissue repair; vasculogenesis; 3-Dimensional; 3D Print; Address; Adult; Affect; Alloys; Animal Model; Animals; Autologous; Biological; Biological Products; Biomimetic Materials; Biomimetics; Bone Matrix; Bone Morphogenetic Proteins; Bone Transplantation; Bone remodeling; Cell Line; Cell Lineage; Cells; Cellular biology; Cephalic; Characteristics; Chemicals; Chemistry; Clinical; Clinical Research; Coagulation Process; Complex; Coupling; Cues; Dental; Dental Inlays; Dentistry; Dentures; Disease; Distal; Effectiveness; Endothelial Cells; Engineering; Environment; Estrogens; Event; Experimental Pathology; Family; Female; Femur; Fibrin; Generations; Geometry; Goals; Human; Image; Immature Bone; Immune; Implant; Implant-Supported Dental Prosthesis; Implantation procedure; In Vitro; Inflammation; Integrins; Intervention; Left; Mature Bone; Mechanics; Mediating; Medical; Mesenchymal Stem Cells; Metabolic Bone Diseases; Metals; Methods; Minerals; Modeling; Modification; Molecular Biology; Morphology; Nanostructures; Operative Surgical Procedures; Orthopedics; Oryctolagus cuniculus; Osseointegration; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Polystyrenes; Process; Production; Proliferating; Property; Protocols documentation; Quality of life; Rattus; Reaction; Regulation; Reproducibility; Research; Risk; Semaphorins; Sex Differences; Shapes; Signal Transduction; Site; Surface; Surface Properties; Technology; Testing; Texture; Time; Tissues; Titanium; Tooth structure; Trauma; Variant; Vertebral column; Vision; WNT Signaling Pathway; Weight-Bearing state; Work; aged; aging population; bone; bone health; bone loss; cortical bone; design; experience; functional restoration; hydrophilicity; improved; in vivo; macrophage; male; mandibular nerve; materials science; monocyte; nanoscale; novel; osteoblast differentiation; osteogenic; osteoprogenitor cell; physical property; planar cell polarity; preclinical study; recruit; response; side effect; skills; stem cells; success; tissue culture; tissue regeneration; tissue repair; vasculogenesis

This proposal addresses the growing clinical need in dentistry and orthopaedics for materials that enable rapid osseointegration and earlier loading times for implants in bone that has been compromised by trauma or disease. 38 million US adults will have no natural teeth by 2020. Implant-supported dentures significantly improve quality of life in comparison to removable dentures, but many denture patients experience considerable bone loss, risking exposing the mandibular nerve during surgery and limiting implant placement. The aging population has an increased need for technologies that provide predictable implant osseointegration in orthopaedic sites (e.g. spine). Medical treatment for metabolic bone diseases like osteoporosis improve implant success, but many patients are not treated with these drugs. Osteoinductive agents like BMPs can improve clinical outcomes, but these technologies are expensive, can have negative side effects, and for some applications are contra-indicated. Our goal is to exploit the physical surface properties of dental and orthopaedic implants to generate new bone in patients lacking sufficient supporting bone without relying on pharmacologic interventions. Our work has shown that the microscale and nanoscale properties of 2D titanium (Ti) and Ti-alloy surfaces are sufficient to drive osteoblast differentiation of multipotent mesenchymal stem cells (MSCs) in vitro and increase the rate of new bone formation in vivo in animals and patients, improving osseointegration and implant stability. Additive manufacturing (AM) makes it possible to design-patient specific implants, but the complex geometries that are needed make modifications to interior surfaces of 3D constructs difficult to achieve. To overcome this technology limitation, we will develop our novel magnesio(calcio)thermic [M(C)T] process for generating osteogenic nanostructure on both exterior and interior surfaces of 3D AM- derived Ti-6Al-4V implants. We will: (1) Determine the mechanism(s) of the M(C)T process controlling the surface nanostructure and use this understanding to tailor nanoscale surface features for enhanced osteoblast differentiation on AM-derived 3D implants; (2) Determine the mechanisms that mediate the differential effects of surface design features on planar cell polarity and MSC commitment to an osteoblast lineage fate (i.e., obligatory change in shape from flattened MSCs, which can migrate, adhere to the implant, and proliferate, to columnar secretory osteoblasts, which synthesize and mineralize bone matrix); and (3) Assess how changes in surface design impact bone formation and remodeling in vitro by understanding how MSCs modulate osteoclast activity and in vivo using aged male and female rats to assess any sex differences, estrogen- deficient rats as a model of compromised bone health, and rabbit femurs as a model of function under load- bearing conditions. Our studies take advantage of the investigative team's skills in cell and molecular biology, experimental pathology, material science, non-destructive testing and mechanical engineering.

该提案解决了牙科和骨科对材料的日益增长的临床需求 因创伤或 疾病。到2020年，3800万美国成年人将没有天然牙齿。 与可移动的义齿相比，改善生活质量，但许多义齿患者经历 大量骨质流失，有可能在手术和限制植入物放置过程中暴露下颌神经。 老龄化人口对提供可预测植入物骨整合的技术的需求越来越大 在骨科部位（例如脊柱）。骨质疏松症（例如骨质疏松症）的代谢骨疾病的医学治疗 植入物的成功，但许多患者未接受这些药物治疗。 BMP等骨诱导剂可以 改善临床结果，但是这些技术很昂贵，可能会产生负面影响，对于某些技术 申请是相互指示的。我们的目标是利用牙齿的物理表面特性和 骨科植入物可在缺乏足够支撑骨的患者中产生新的骨头 药理学干预措施。我们的工作表明2D钛的微观和纳米级特性 （Ti）和Ti-Aloy表面足以驱动多能间质干细胞的成骨细胞分化 （MSC）体外并增加动物和患者体内新骨形成的速率，改善 骨整合和植入物稳定性。增材制造（AM）使设计与特定特定的特定于 植入物，但是需要对3D构建体的内部表面进行修改的复杂几何形状 难以实现。为了克服这一技术限制，我们将开发新的Magnesio（Calcio）热液 [M（c）t]在3D AM-的外部和内部表面上产生成骨的过程 派生的TI-6AL-4V植入物。我们将：（1）确定控制M（c）t过程的机制 表面纳米结构并利用这种理解来量身定制纳米级表面特征，以增强成骨细胞 AM衍生的3D植入物的分化； （2）确定介导差异效应的机制 平面细胞极性上的表面设计特征和对成骨细胞血统命运的MSC承诺（即 从扁平的MSC进行的强制性变化，该MSC可以迁移，粘附到植入物，并扩散到 柱状分泌成骨细胞，合成并矿化骨基质）； （3）评估如何变化 表面设计通过了解MSC调制如何调节，影响骨形成和重塑体外重塑 破骨细胞活性和体内使用老年男性和雌性大鼠评估任何性别差异，雌激素 - 不足的大鼠是骨骼健康的模型，而兔股骨作为负载下的功能模型 轴承条件。我们的研究利用了调查小组在细胞和分子生物学方面的技能， 实验病理学，材料科学，非破坏性测试和机械工程。