Mechanobiology at Healing Bone-Implant Interfaces

愈合骨-植入物界面的力学生物学

• 批准号: 8762070
• 负责人: Jill Helms A Helms
• 金额: $ 69.31万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8762070
• 关键词: Affect; Appearance; Area; Basic Science; Beds; Biological; Biological Assay; Biomechanics; Bite Force; Cell Proliferation; Cells; Chemicals; Clinical; Devices; Encapsulated; Environment; Etiology; Exhibits; Failure; Fibroblasts; Healed; Health; Implant; International; Journals; Lateral; Maxilla; Measures; Modeling; Modification; Mus; Oral; Osseointegration; Osteogenesis; Paper; Patients; Play; Reporter; Role; Series; Signal Transduction; Specific qualifier value; Surface; Symptoms; Testing; Therapeutic; Time; Tissues; Tooth structure; Weight-Bearing state; Work; angiogenesis; bone; bone healing; clinically relevant; design; healing; improved; in vivo; in vivo Model; interfacial; mouse model; nano; novel; osteogenic; prevent; programs; public health relevance; research study; response; symposium; tibia

DESCRIPTION (provided by applicant): While the vast majority of modern oral implants are successful, every implant journal and international conference has papers and presentations about implant failures. One common symptom of implant failure is fibrous encapsulation, which typically arises from a lack of primary stability of the implant. Clinical standards dictate that a unstable implant must be removed and, if sufficient bone stock remains, replaced. However, there is little guarantee that the next implant attempt will be successful because the underlying etiology of the initial failure is often not understood in the first place. Certainly biomechanical factors influence implant stability in bone. To examine this problem area, we have developed a novel, reproducible, in vivo model in the mouse maxilla to rigorously test our hypothesis that excessive strain drives peri-implant cells to differentiate along a fibroblastic rather than an osteoblastic lineage. In the same model we also propose to test two clinically relevant strategies to prevent -- and potentially reverse - the perplexing problem of fibrous encapsulation of a failed implant. In AIM 1 we will test how peri-implant strain affects interfacial cell proliferation, angiogenesis, and osteogenic differentiation. We have adapted a miniature in vivo loading device from our previous work in mice tibiae to create a new mouse model with several unique features: 1) Complete implant instability is caused by placing a maxillary implant into an oversized hole, creating fibrous encapsulation; 2) The model allows us to stabilize this implant (using a miniature rigid I-beam bonded to adjacent teeth) to test if stabilization promotes osteogenic healing in the peri-implant space; and 3) Using I-beams designed to be stiff in the vertical direction but less stiff in the horizontal direction, we can apply known horizontal loads o deflect the beam and its attached implant by known amounts, thereby creating controlled implant micromotion and interfacial strains. Collectively, these experiments will allow us to unravel critical relationships among implant instability, interfacial strain, and osseointegration. AIM 2 asks whether a fibrous-tissue-encapsulated (loose) implant can be rescued. The answer lies in whether peri-implant cells are irreversibly specified as fibroblasts, or whether their fate can be altered. One series of tests will examine whether nano-textured implants can prevent the proliferation and differentiation of fibroblasts that can culminate in fibrous encapsulation. A second series of tests will introduce a pro-osteogenic biological signal, Wnt3, into the implant bed at the time of placement, followed by assays for Wnt responsiveness in the peri-implant space using Wnt "reporter" along with cell proliferation and induction of the osteogenic program. Collectively, results will provide a scientific rationale for improving osseointegration in patient in which there is inadequate bone support or sub-optimal osteogenic healing.

描述（由申请人提供）：虽然绝大多数现代口腔植入物都是成功的，但每个植入物期刊和国际会议都有有关植入物失败的论文和演讲。植入物衰竭的一种常见症状是纤维封装，通常是由于植入物缺乏主要稳定性而产生的。临床标准规定必须去除不稳定的植入物，如果保留足够的骨库存，则更换。但是，几乎没有保证下一个植入物的尝试将是成功的，因为首先通常不了解初始失败的潜在病因。当然是生物力学 因素会影响骨骼中的植入物稳定性。为了检查这个问题区域，我们在小鼠上颌骨中开发了一种新颖的，可重现的体内模型，以严格测试我们的假设，即过量的应变驱动植入物细胞沿成纤维细胞而不是成骨细胞谱系区分。在同一模型中，我们还建议测试两种临床相关的策略，以防止（可能扭转）失败的纤维封装问题的困惑问题 注入。在AIM 1中，我们将测试植入物周围菌株如何影响界面细胞的增殖，血管生成和成骨分化。我们已经从以前在小鼠胫骨中的工作中改编了一个微型的体内装载设备，以创建具有几个独特功能的新鼠标模型：1）完全植入物不稳定性是由将上颌植入物放入超大孔中，创建纤维封装而引起的； 2）该模型允许我们稳定这种植入物（使用与邻近牙齿粘合到相邻牙齿的微型刚性I光束），以测试稳定是否促进了植入物周围空间中的成骨治疗； 3）使用设计为垂直方向僵硬但在水平方向上刚刚刚性的I梁，我们可以通过已知的量偏向梁及其附着的植入物，从而产生受控的植入物微电位和界面菌株。总的来说，这些实验将使我们能够在植入物不稳定性，界面菌株和骨整合中阐明关键关系。 AIM 2询问是否可以救出纤维组织包裹的（松散）植入物。答案在于植入物细胞是否不可逆转地指定为成纤维细胞，还是其命运是 可以改变。一系列测试将检查纳米纹理的植入物是否可以防止成纤维细胞的增殖和分化，而成纤维细胞可以在纤维封装中达到顶峰。第二个测试将在放置时将亲稳态的生物学信号Wnt3引入植入床，然后使用Wnt“报告者”以及细胞增殖和诱导的测定在植入植物周围空间中的Wnt响应性测定成骨程序。总体而言，结果将为改善骨骼支撑不足或亚最佳成骨愈合的患者的骨整合提供科学原理。