Mechanobiology at Healing Bone-Implant Interfaces

愈合骨-植入物界面的力学生物学

• 批准号: 7037636
• 负责人: John Beyer Brunski
• 金额: $ 46.46万
• 依托单位: RENSSELAER POLYTECHNIC INSTITUTE
• 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 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7037636
• 关键词: X ray; angiogenesis; biomarker; bone; bone development; bone regeneration; cartilage development; cell differentiation; digital imaging; extracellular matrix; immunocytochemistry; implant; in situ hybridization; laboratory mouse; mechanical stress

DESCRIPTION (provided by applicant): Immediately loaded orthopaedic and oral implants can undergo interfacial micromotion and fail by forming interfacial fibrous or cartilaginous tissue rather than bone. While in this instance and others it is evident that mechanical conditions affect healing of skeletal tissue ("mechanobiology"), specific factors influencing cell fate decisions, and mechanisms by which cells interpret and respond to changes in mechanical environment, remain unclear. This gap in understanding restricts design of conventional as well as new tissue-engineered implants. However, recent insights from fracture healing and other healing situations suggests the hypothesis that extracellular matrix remodeling and angiogenesis are central in bone healing around implants, and that tissue deformation (strain) during early implant loading affects these processes, and, in turn, cell differentiation at interfaces. To test this idea, this project will measure spatial/temporal expression of key molecular makers of angiogenesis, bone, and cartilage formation at: 1) healing sites without implants: and 2) healing interfaces where biomechanical strain conditions are varied. The project will use a novel model of the bone-implant interface in mouse tibiae, which allows experimental control of biomaterial and biomechanical factors. Also, the project will use wild-type (wt) and NEMP9-null mice (MMP9-/-), since the latter lack a key matrix metalloproteinase (MMP9, gelatinase B) involved in angiogenesis. The project will integrate data from in situ hybridization, ultrastructural analyses, immunocytochemistry and biomechanical tests to examine mechanobiology of interfacial healing. Aim 1 will test if matrix remodeling and angiogenesis are prerequisites for osteoblast (OB) differentiation in holes without implants; the aim will develop a "molecular map" of expression of markers of angiogenesis, bone and cartilage formation during healing of empty drill holes (diam. 0.2, 0.4 and 1.0 ram) at 3, 9 and 27 days in wt and MMP9-/- mice. Aim 2 will test if matrix remodeling and angiogenesis are essential for differentiation of mesenchymal cells into OBs in unstrained bone-implant gaps. Using wt and MMP9-/- mice, we will develop molecular maps of healing at 0, 3, 9 and 27 days at: (1) a bone-implant gap interface (BIGI) around stabilized polylactide (PLA) pins in oversized holes; and (2) a direct bone-implant interface (DBII), having a mix of direct bone-implant contact and gaps around stabilized PLA screws. Aim 3 will control implant micromotion in its implant bed, in response to a defined load immediately post-implantation, to test whether specific strain conditions in interfacial gaps inhibit matrix remodeling, angiogenesis and differentiation of mesenchymal cells into OBs. A miniaturized rmcromotion device will be used to create implant stability vs. cyclic axial implant micromotion (100-200 (m) of pins and screws in a BIGI during healing. Interfaces will be analyzed biologically as in Aims 1-2, and interfacial strain fields will be measured directly by digital image correlation based on micro-CT images of whole bone-implant specimens.

描述（由申请人提供）： 立即加载的骨科和口腔植入物可以通过形成界面纤维或软骨组织而不是骨骼而失败。尽管在这种情况下和其他情况下，很明显，机械条件会影响骨骼组织的愈合（“机械生物学”），但影响细胞命运决策的特定因素以及细胞来解释和响应机械环境变化的机制，尚不清楚。理解的差距限制了常规以及新的组织工程植入物的设计。然而，裂缝愈合和其他愈合情况的最新见解表明，植入物周围的骨骼愈合中的细胞外基质重塑和血管生成至关重要，并且早期植入物期间的组织变形（应变）会影响这些过程，而这些过程又影响了这些过程，而又一次，接口处的细胞分化。为了测试这一想法，该项目将测量以下位置血管生成，骨和软骨形成的关键分子制造商的空间/时间表达：1）没有植入物的愈合位点：和2）愈合生物力学应变条件的愈合接口。该项目将使用小鼠胫骨中的骨植入物界面的新型模型，该模型允许对生物材料和生物力学因子的实验控制。此外，该项目将使用野生型（WT）和NEMP9-NULL小鼠（MMP9 - / - ），因为后者缺乏参与血管生成的关键基质金属蛋白酶（MMP9，明胶酶B）。该项目将整合原位杂交，超微结构分析，免疫细胞化学和生物力学测试的数据，以检查界面愈合的机械生物学。 AIM 1将测试基质重塑和血管生成是否是无植入物孔中成骨细胞（OB）分化的先决条件；在WT和MMP9 - / - 小鼠中，在3、9和27天，在3、9和27天的空钻孔（直径0.2、0.4和1.0 RAM）愈合过程中，在空孔孔（直径0.2、0.4和1.0 RAM）愈合过程中，该目标将形成一个“分子图”。 AIM 2将测试基质重塑和血管生成是否对于在未培养的骨植入植物间隙中分化为obs的obs是否至关重要。使用WT和MMP9 - / - 小鼠，我们将在0、3、9和27天以稳定孔（PLA）围绕超大孔中的稳定聚乳化药物（PLA）销周在0、3、9和27天的愈合分子图； （2）直接的骨植入界面（DBII），与稳定的PLA螺钉围绕稳定的PLA螺钉的混合物混合在一起。 AIM 3将控制植入物床中的植入物微功能，以响应于植入后立即定义的载荷，以测试界面间隙中特定的应变条件是否抑制了基质细胞的基质重塑，血管生成和分化中质细胞的菌株。将使用微型的RMCROMOTION装置来创建植入物稳定性与循环轴向植入物微功能（100-200（m）在愈合过程中，大型的销钉和螺钉中的销钉和螺钉。将在生物学上分析界面，例如AIMS 1-2中的界面，以及基于数字图像相关的数字图像相关图像，将在AIMS 1-2和界面应力场中直接测量界面。