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种植体都是成功的，但每个种植体期刊和国际会议都有关于种植体失败的论文和演讲。植入物失效的一个常见症状是纤维包裹，其通常由植入物缺乏初始稳定性引起。临床标准规定，必须取出不稳定的植入物，如果有足够的骨量，则进行更换。然而，几乎不能保证下一次植入尝试将是成功的，因为最初失败的潜在病因往往是不理解的。当然是生物力学的 影响种植体在骨中稳定性的因素。为了研究这一问题领域，我们在小鼠上颌骨中开发了一种新的、可重复的体内模型，以严格检验我们的假设，即过度的应变驱动种植体周围细胞沿着成纤维细胞而不是成骨细胞谱系分化。在同一模型中，我们还建议测试两种临床相关策略，以防止并可能扭转失败的纤维包裹的复杂问题 植入在AIM 1中，我们将测试种植体周围应变如何影响界面细胞增殖、血管生成和成骨分化。我们已经从我们先前在小鼠体内的工作中改编了一个微型体内加载装置，以创建一个新的小鼠模型，该模型具有以下几个独特的特征：1）通过将上颌种植体放入超大孔中，产生纤维包裹，导致完全种植体不稳定; 2）该模型允许我们稳定该植入物（使用微型刚性I型梁粘合到相邻牙齿），以测试稳定性是否促进种植体周围间隙的成骨愈合;和3）使用设计成在垂直方向上刚性但在水平方向上刚性较小的I形梁，我们可以施加已知的水平载荷以使梁及其附接的植入物偏转已知的量，从而产生受控的植入物微动和界面应变。总的来说，这些实验将使我们能够解开种植体不稳定性，界面应变和骨整合之间的关键关系。 AIM 2询问是否可以挽救纤维组织包裹（松散）的植入物。答案在于植入物周围的细胞是否被不可逆地指定为成纤维细胞，或者它们的命运是否 是可以改变的一系列的测试将检查纳米纹理植入物是否可以防止成纤维细胞的增殖和分化，最终导致纤维包裹。第二系列测试将在放置时将促成骨生物信号Wnt 3引入种植体床中，随后使用Wnt“报告物”沿着细胞增殖和成骨程序的诱导来测定种植体周围空间中的Wnt响应性。总的来说，结果将为改善骨支撑不足或次优成骨愈合患者的骨整合提供科学依据。