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: 10543521
• 负责人: Barbara D. Boyan
• 金额: $ 58.33万
• 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 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10543521
• 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; Cultured Cells; Dental; Dental Inlays; Dentistry; Dentures; Disease; Distal; Effectiveness; Endothelial Cells; Engineering; Environment; Estrogen deficiency; 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; Macrophage; Mature Bone; Mechanics; Mediating; Medical; Mesenchymal Stem Cells; Metabolic Bone Diseases; Metals; Methods; Modeling; Modification; Molecular Biology; Morphology; Nanostructures; Operative Surgical Procedures; Orthopedics; Oryctolagus cuniculus; Osseointegration; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Physiologic calcification; Polystyrenes; Process; Production; Proliferating; Property; Protocols documentation; Quality of life; Rattus; Reaction; Regulation; Reproducibility; Research; Semaphorins; Sex Differences; Shapes; Signal Transduction; Site; Structure; Surface; Surface Properties; Technology; Testing; Texture; 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; fabrication; functional restoration; hydrophilicity; improved; in vivo; male; mandibular nerve; manufacture; materials science; migration; monocyte; nano; nanoscale; novel; osseointegrated implant; osteoblast differentiation; osteogenic; osteoprogenitor cell; pharmacologic; 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日益增长的临床需求，需要能够快速实现修复的材料。 因创伤或损伤而受损的骨中种植体的骨整合和早期加载时间 疾病。到 2020 年，3800 万美国成年人将没有天然牙齿。种植牙支持的假牙将显着减少 与活动假牙相比，可以提高生活质量，但许多假牙患者都经历过 大量骨质流失，手术期间存在暴露下颌神经并限制种植体植入的风险。 人口老龄化对提供可预测种植体骨整合的技术的需求不断增加 在骨科部位（例如脊柱）。骨质疏松症等代谢性骨病的药物治疗得到改善 植入成功，但许多患者没有接受这些药物治疗。 BMP 等骨诱导剂可以 改善临床结果，但这些技术价格昂贵，可能会产生负面影响，并且对于某些人来说 应用程序有禁忌。我们的目标是利用牙科和牙科材料的物理表面特性 骨科植入物可以为缺乏足够支撑骨的患者生成新骨，无需依赖 药物干预。我们的工作表明，二维钛的微米级和纳米级特性 (Ti) 和钛合金表面足以驱动多能间充质干细胞的成骨细胞分化 （间充质干细胞）体外并增加动物和患者体内新骨形成的速度，改善 骨整合和种植体稳定性。增材制造 (AM) 使得针对患者的特定设计成为可能 植入物，但所需的复杂几何形状需要对 3D 结构的内表面进行修改 很难实现。为了克服这一技术限制，我们将开发新型镁（钙）热 [M(C)T] 在 3D AM- 的外表面和内表面上生成成骨纳米结构的过程 衍生的 Ti-6Al-4V 植入物。我们将： (1) 确定 M(C)T 过程控制的机制 表面纳米结构，并利用这种理解来定制纳米级表面特征以增强成骨细胞 AM 衍生 3D 植入物的差异化； (2) 确定介导差异效应的机制 表面设计特征对平面细胞极性和 MSC 对成骨细胞谱系命运的承诺（即， 扁平 MSC 的形状必须发生变化，可以迁移、粘附到植入物上并增殖， 柱状分泌性成骨细胞，合成和矿化骨基质）； (3) 评估变化如何 通过了解 MSC 如何调节，表面设计影响体外骨形成和重塑 破骨细胞活性和体内使用老年雄性和雌性大鼠来评估任何性别差异，雌激素 缺陷大鼠作为骨骼健康受损的模型，兔股骨作为负荷下功能的模型 轴承条件。我们的研究利用了研究团队在细胞和分子生物学方面的技能， 实验病理学、材料科学、无损检测和机械工程。

项目成果

Acellular mineralized allogenic block bone graft does not remodel during the 10 weeks following concurrent implant placement in a rabbit femoral model.

• DOI: 10.1111/clr.13544
• 发表时间: 2020-01
• 期刊: Clinical oral implants research
• 影响因子: 4.3
• 作者: Cohen DJ;Scott KM;Kulkarni AN;Wayne JS;Boyan BD;Schwartz Z
• 通讯作者: Schwartz Z

The Biological Basis for Surface-dependent Regulation of Osteogenesis and Implant Osseointegration.

• DOI: 10.5435/jaaos-d-21-00523
• 发表时间: 2022-07-01
• 期刊: JOURNAL OF THE AMERICAN ACADEMY OF ORTHOPAEDIC SURGEONS
• 影响因子: 3.2
• 作者: Boyan, Barbara D.;Berger, Michael B.;Nelson, Fred R.;Donahue, Henry J.;Schwartz, Zvi
• 通讯作者: Schwartz, Zvi

Bisphosphonates inhibit surface-mediated osteogenesis.

• DOI: 10.1002/jbm.a.36944
• 发表时间: 2020-08-01
• 期刊: Journal of biomedical materials research. Part A
• 作者: Lotz EM;Lohmann CH;Boyan BD;Schwartz Z
• 通讯作者: Schwartz Z

Growth factors produced by bone marrow stromal cells on nanoroughened titanium-aluminum-vanadium surfaces program distal MSCs into osteoblasts via BMP2 signaling.

• DOI: 10.1002/jor.24869
• 发表时间: 2021-09
• 期刊: Journal of orthopaedic research : official publication of the Orthopaedic Research Society
• 作者: Berger MB;Bosh KB;Jacobs TW;Joshua Cohen D;Schwartz Z;Boyan BD
• 通讯作者: Boyan BD

Hot isostatic pressure treatment of 3D printed Ti6Al4V alters surface modifications and cellular response.

• DOI: 10.1002/jbm.b.34474
• 发表时间: 2020-05
• 期刊: Journal of biomedical materials research. Part B, Applied biomaterials
• 作者: Michael B Berger;Thomas W. Jacobs;B. Boyan;Z. Schwartz