Mechanisms Mediating Osseointegration of 3D Printed Titanium Constructs

该提案解决了牙科和骨科对材料日益增长的临床需求， 骨整合和植入物在骨中的早期加载时间已受到创伤或 疾病到2020年，美国将有3800万成年人没有天然牙齿。种植体支持的义齿显著 与可摘义齿相比，可摘义齿改善了生活质量，但许多义齿患者 大量的骨质流失，在手术过程中有暴露下颌神经的风险，并限制了种植体的放置。 人口老龄化对提供可预测种植体骨整合的技术的需求增加 骨科部位（例如脊柱）。骨质疏松症等代谢性骨病的药物治疗改善 植入成功，但许多患者没有用这些药物治疗。骨诱导剂如BMP可以 改善临床结果，但这些技术是昂贵的，可能有负面的副作用， 应用程序是禁忌。我们的目标是利用牙齿的物理表面特性， 骨科植入物，用于在缺乏足够支撑骨的患者中生成新骨， 药物干预。我们的工作表明，2D钛的微米级和纳米级性质 (Ti)钛合金表面足以驱动多能间充质干细胞的成骨细胞分化 在动物和患者中，在体外培养间充质干细胞（MSC）并增加体内新骨形成的速率， 骨整合和种植体稳定性。增材制造（AM）使设计患者特异性成为可能 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，我们将开发新的镁（钙）热 用于在3D AM的外表面和内表面上产生成骨纳米结构的[M（C）T]方法 衍生Ti-6Al-4V植入物。我们将：（1）确定M（C）T过程控制的机制。 表面纳米结构并使用这种理解来定制用于增强成骨细胞纳米级表面特征 （2）确定介导差异效应的机制 平面细胞极性和MSC向成骨细胞谱系命运的定向的表面设计特征（即， 从扁平的MSC的强制性形状变化，其可以迁移，粘附到植入物上并增殖， 柱状分泌成骨细胞，其合成和矿化骨基质）;和（3）评估 表面设计通过理解MSC如何调节体外骨形成和重塑 破骨细胞活性和体内使用老年雄性和雌性大鼠评估任何性别差异，雌激素- 缺陷大鼠作为受损骨健康的模型，兔股骨作为负荷下的功能模型- 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、无损检测和机械工程。

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.