Mechanobiology at Healing Bone-Implant Interfaces

愈合骨-植入物界面的力学生物学

• 批准号: 8003486
• 负责人: John Beyer Brunski
• 金额: $ 21.04万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8003486
• 关键词: Affect; Beds; Biochemical; Biological; Biomechanics; Cell Differentiation process; Cells; Cellular Assay; Cilia; DNA; Dental Implants; Environment; Event; Failure; Foundations; Genes; Genetic; Healed; Health; Implant; Integrins; Knowledge; Lead; Life; Measures; Mechanics; Molecular; Motion; Oral; Orthopedics; Osseointegration; Osteoblasts; Osteogenesis; Outcome; Phase; Problem Solving; Process; Published Comment; Role; Shapes; Signal Transduction; Stimulus; Surface; Testing; Texture; Time; Tissues; Transgenic Mice; Variant; Weight-Bearing state; Work; base; bone; bone healing; cell behavior; comparative; design; digital imaging; fetal; healing; implantable device; in vivo; insight; interfacial; maxillofacial; molecular scale; mouse model; nano; nanoscale; public health relevance; research study; response; skeletal; skeletal tissue

DESCRIPTION (provided by applicant): Immediate implant loading produces micromotion at the bone-implant interface, which can lead to fibrous or fibrocartilaginous encapsulation and implant failure. While mechanical conditions such as these appear to influence healing of skeletal tissues, there is only an incomplete understanding of the key physical factors and underlying mechanisms that influence cell fate decisions at the bone-implant interface. As a result, there is a limited scientific basis for the design of load-bearing implants for use in skeletal tissues. Our working hypothesis is that deformation in healing tissue as defined by principal strain magnitude, spatial extent, and related factors regulates cell fate decisions at the bone-implant interface. The proposed work will test this hypothesis in a mouse model using a miniature implant device that permits control and quantification of the biomechanical environment (i.e., the strain state) of the healing bone-implant interface, and which allows us to measure the cellular response to different mechanical stimuli using molecular, cellular, and genetic approaches. Aim 1 will examine how variations in strain magnitude, spatial extent, and number of strain cycles per day influence mechanobiology at the healing bone-implant interface. Our miniature device and implant design allows us to create situations where either principal compressive strain is the dominant type of strain, or principal tensile strain is the dominant type of strain. Strain will be measured using micro-CT and digital image correlation then correlated, in time and space, with the in vivo cellular response. Together, these experimental results will allow us to identify regimes of "safe", "dangerous", or "stimulatory" principal tensile or compressive strain. Aim 2 will explore how cells at a healing interface detect and decipher physical stimuli such as strain. Primary cilia are implicated in fetal bone mechanotransduction; we hypothesize that primary cilia are required for implant mechanotransduction. We will test this hypothesis by conditionally inactivating an essential component of the primary cilium molecular machinery, Kif3a, and measuring how this alters response to strain state and healing of the bone-implant interface. Aim 3 will test whether biomechanical strain operates at multiscale levels (macro, micro, and nano) to influence cell differentiation at implant interfaces. We hypothesize that an implant's surface texture (roughness) can influence local strain fields at the same size scale, e.g., microns. This will be tested by subjecting implants with differing surface textures to micromotions that are of the same size as the roughness. Overall, this project will contribute scientific insight that can guide design decisions with skeletal implants. PUBLIC HEALTH RELEVANCE: Loosening and failure of load-bearing bone implants remain a major health problem. In order to help solve this problem, this project is trying to understand why certain mechanical conditions at the bone-implant interface are dangerous to the healing processes, while others are safe and sometimes even beneficial to healing. Our work focuses on the role of deformation of healing tissues; the ways that living cells sense that deformation; and the ways that an implant's overall shape as well as its surface roughness can be better designed to take advantage of this knowledge.

描述（由申请人提供）：立即植入物加载在骨植入术界面处产生微功能，这会导致纤维或纤维状质的封装和植入物衰竭。诸如此类的机械条件似乎会影响骨骼组织的愈合，但对关键的物理因素和潜在机制只有不完全理解，这些机制影响了骨 - 植入物界面处的细胞命运决策。结果，设计承重植入物用于骨骼组织的科学基础有限。我们的工作假设是，由主应变幅度，空间范围和相关因素定义的愈合组织中的变形可调节骨植入术界面处的细胞命运决策。所提出的工作将使用微型植入剂装置在小鼠模型中检验这一假设，该设备允许对愈合骨植入术界面的生物力学环境（即应变状态）进行控制和定量，这使我们能够使用分子，细胞和遗传方法来测量细胞对不同机械刺激的反应。 AIM 1将检查应变幅度，空间范围和每天应变周期数量的变化如何影响愈合骨植入物界面上的机械生物学。我们的微型装置和植入物设计使我们能够创建主体压缩应变是主要类型的菌株类型，或者主拉伸应变是主要的菌株类型。应变将使用Micro-CT和数字图像相关性测量，然后在时间和空间中与体内细胞反应相关。这些实验结果一起将使我们能够确定“安全”，“危险”或“刺激性”主拉伸或压缩应变的制度。 AIM 2将探索愈合界面的细胞如何检测和破译物理刺激（例如应变）。原发性纤毛与胎儿的骨骼机械转导有关；我们假设原发性纤毛是植入物机械转导所必需的。我们将通过有条件地灭活原代纤毛分子机械（KIF3A）的重要组成部分，并测量这种假设的响应如何改变对菌株状态的反应和骨发生植物界面的愈合。 AIM 3将测试生物力学应变是否在多尺度水平（宏观，微观和纳米）上运行以影响植入物界面的细胞分化。我们假设植入物的表面纹理（粗糙度）可以在相同尺寸尺度（例如微米）上影响局部应变场。这将通过对具有不同表面纹理的植入物进行与粗糙度相同的微功能进行测试。总体而言，该项目将有助于科学见解，以指导使用骨骼植入物的设计决策。 公共卫生相关性：放松和承重骨植入物的失败仍然是一个主要的健康问题。为了帮助解决这个问题，该项目正在尝试了解为什么骨植入物界面处的某些机械条件对康复过程有危险，而其他项目则是安全的，有时甚至对治愈的有益。我们的工作着重于愈合组织变形的作用。活细胞感觉变形的方式；植入物的整体形状及其表面粗糙度的方式可以更好地设计以利用这一知识。