Solute Transport in the Bone Lacunar-Canalicular System

骨腔隙-小管系统中的溶质运输

• 批准号: 7380285
• 负责人: LIYUN WANG
• 金额: $ 29.07万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7380285
• 关键词: Affect; Anesthesia procedures; Animals; Arthritis; Biological; Blood Pressure; Blood Vessels; Blood flow; Bone Matrix; Cells; Computer Simulation; Condition; Convection; Custom; Devices; Diffusion; Disease; Drug Delivery Systems; Engineering; Ensure; Fluorescence Recovery After Photobleaching; Frequencies; Growth Factor; Half-Life; Image; In Situ; Intercellular Fluid; Knee; Knowledge; Life; Measurement; Measures; Mechanics; Methods; Modeling; Molecular; Molecular Weight; Morphologic artifacts; Motion; Movement; Mus; Osteocytes; Osteoporosis; Pathway interactions; Pharmaceutical Preparations; Relative (related person); Research; Rest; Signaling Molecule; Solutions; Stimulus; System; Testing; Time; Tissue Engineering; Tissues; Tracer; Treatment Protocols; Venous; ankle joint; aqueous; base; bone; bone health; bone imaging; bone quality; cytokine; design; fluid flow; fluorescence imaging; in vivo; insight; interstitial; intravenous injection; novel strategies; pressure; radius bone structure; scaffold; size; solute; tibia; Affect; Anesthesia procedures; Animals; Arthritis; Biological; Blood Pressure; Blood Vessels; Blood flow; Bone Matrix; Cells; Computer Simulation; Condition; Convection; Custom; Devices; Diffusion; Disease; Drug Delivery Systems; Engineering; Ensure; Fluorescence Recovery After Photobleaching; Frequencies; Growth Factor; Half-Life; Image; In Situ; Intercellular Fluid; Knee; Knowledge; Life; Measurement; Measures; Mechanics; Methods; Modeling; Molecular; Molecular Weight; Morphologic artifacts; Motion; Movement; Mus; Osteocytes; Osteoporosis; Pathway interactions; Pharmaceutical Preparations; Relative (related person); Research; Rest; Signaling Molecule; Solutions; Stimulus; System; Testing; Time; Tissue Engineering; Tissues; Tracer; Treatment Protocols; Venous; ankle joint; aqueous; base; bone; bone health; bone imaging; bone quality; cytokine; design; fluid flow; fluorescence imaging; in vivo; insight; interstitial; intravenous injection; novel strategies; pressure; radius bone structure; scaffold; size; solute; tibia

DESCRIPTION (provided by applicant): Osteocytes, the most numerous cells in bone, are critical for bone health and bone quality. They are essential for bone to sense and adapt to mechanical stimuli and to remodel damaged tissue. Since osteocytes are completely encased in mineralized bone matrix, their survival and function are entirely dependent on transport of solutes (metabolites, growth factors, cytokines, and other signaling molecules) through the lacunar-canalicular system (LCS). Despite advances in delineating transport pathways in bone, little is known about the mechanisms involved in moving biological molecules to and from osteocytes in vivo. This reflects a lack of methods available to study these questions under real-time conditions in living animals. To this end, we recently developed a new imaging method based on Fluorescence Recovery After Photobleaching (FRAP) that allows measurement of solute movement in the bone LCS in situ and in real-time (Wang et al.,2005. Proc Natl Acad Sci 102:11911). We propose to use this novel approach in combination with mathematical / computational modeling to fully characterize diffusion and convection in bone. To test the hypothesis that convection due to mechanical loading is the primary mechanism for moving large molecules in the LCS, we will first quantify the baseline diffusive transport of solutes of various sizes in post-mortem bones. Convective transport driven by blood pressure and mechanical loading will be subsequently measured in live animals. These studies will delineate the transport mechanisms that are essential for osteocyte viability and bone mechano-transduction, and provide new insights into mass transport in other biological and engineered systems (e.g., tissue engineering scaffolds). Detailed knowledge of how molecules move within bone will help define molecular parameters such as hydrodynamic radii and half-life times for new drugs so that they can be delivered effectively into bone to treat diseases such as osteoporosis and arthritis. Our specific aims are: 1) to determine how solute diffusion in the bone LCS depends on the solute's molecular weight; 2) to determine how solute transport in the bone LCS is affected by vascular pressure; 3) to determine how solute transport in the bone LCS is affected by mechanical loading.

描述（由申请人提供）：骨细胞是骨骼中最多的细胞，对骨骼健康和骨质质量至关重要。它们对于骨骼感测并适应机械刺激并重塑损坏的组织至关重要。由于骨细胞完全包裹在矿化骨基质中，因此它们的存活和功能完全取决于溶质（代谢物，生长因子，细胞因子和其他信号分子）通过lacunar-analicular-canicular-canicular System（LCS）的运输。尽管描述了骨骼中的传输途径的进步，但对移动生物分子往返于体内骨细胞的机制知之甚少。这反映了在活动物中实时条件下研究这些问题的缺乏方法。为此，我们最近开发了一种基于光漂白后荧光恢复（FRAP）的新成像方法，该方法允许在原位和实时实时测量骨LC中的溶质运动（Wang等，2005。ProcNatl Acad Sci 102：11911）。我们建议将这种新型方法与数学 /计算建模结合使用，以完全表征骨骼中的扩散和对流。为了测试假设，机械载荷引起的对流是在LCS中移动大分子的主要机制，我们将首先量化验尸骨骼中各种大小的溶质的基线扩散运输。随后将在活动物中测量由血压和机械负荷驱动的对流运输。这些研究将描述对于骨细胞生存能力和骨骼机械转导至关重要的运输机制，并为其他生物学和工程系统（例如组织工程支架）提供新的见解。详细了解分子如何在骨中移动将有助于定义分子参数，例如水动力半径和新药的半衰期时间，以便可以有效地将其输送到骨骼中，以治疗诸如骨质疏松症和关节炎等疾病。我们的具体目的是：1）确定骨LC中溶质扩散如何取决于溶质的分子量； 2）确定骨LC中的溶质转运如何受到血管压力的影响； 3）确定骨LC中的溶质转运如何受到机械负荷的影响。