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.

这项建议满足了牙科和矫形外科对材料日益增长的临床需求，使快速 因创伤或创伤而受损的骨内植入物的骨整合和更早的加载时间 疾病。到2020年，3800万美国成年人将没有天然牙齿。种植体支持义齿显著 与可摘义齿相比，提高了生活质量，但许多义齿患者经历了 大量的骨丢失，在手术中有暴露下颌神经的风险，并限制种植体的放置。 老龄化人口对提供可预测的种植体骨结合的技术的需求增加 在骨科部位(如脊柱)。骨质疏松症等代谢性骨病的医疗治疗有所改善 植入成功，但许多患者没有用这些药物治疗。像BMPs这样的骨诱导剂可以 改善临床结果，但这些技术昂贵，可能有负面副作用，而且对一些人来说 申请是相反的。我们的目标是开发牙科和牙科的物理表面特性 骨科植入物在缺乏足够支持骨的患者中生成新骨而不依赖 药物干预。我们的工作表明，2D钛的微尺度和纳米尺度的性质 钛及钛合金表面足以促进多能间充质干细胞向成骨细胞分化 (MSCs)体外培养，提高动物和患者体内新骨形成率，改善 骨整合与种植体稳定性。加法制造(AM)使设计特定于患者的设计成为可能 植入物，但所需的复杂几何形状对3D构件的内表面进行修改 很难实现。为了克服这一技术限制，我们将开发我们的新型镁(钙)热敏材料 在3D AM内外表面生成成骨纳米结构的[M(C)T]方法 衍生的Ti-6Al-4V种植体。我们将：(1)确定M(C)T过程控制的机制(S) 表面纳米结构，并利用这一理解为增强的成骨细胞量身定制纳米尺度的表面特征 AM衍生3D种植体的差异性；(2)确定调节差异性效应的机制 平面细胞极性和MSC对成骨细胞谱系命运的承诺的表面设计特征(即， 从扁平的MSCs到平坦的MSCs的形状必须改变，它可以迁移、附着到植入物上并增殖到 柱状分泌型成骨细胞，它合成和矿化骨基质)；以及(3)评估 表面设计通过了解骨髓间充质干细胞如何调控在体外影响骨形成和重建 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- 轴承状况。我们的研究利用了调查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

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

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

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

Bone marrow stromal cells are sensitive to discrete surface alterations in build and post-build modifications of bioinspired Ti6Al4V 3D-printed in vitro testing constructs.

• DOI: 10.1002/jbm.b.35194
• 发表时间: 2022-11
• 期刊: Journal of biomedical materials research. Part B, Applied biomaterials
• 作者: Michael B Berger;D. Cohen;Kyle Snyder;John Sions;B. Boyan;Z. Schwartz