Solute Transport in the Bone Lacunar-Canalicular System

骨腔隙-小管系统中的溶质运输

• 批准号: 7914149
• 负责人: LIYUN WANG
• 金额: --
• 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 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7914149
• 关键词: Affect; Anesthesia procedures; Animals; Arthritis; Biological; Blood Pressure; Blood Vessels; Blood flow; Bone Matrix; Cells; Computer Simulation; 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; Radial; Regimen; Relative (related person); Research; Rest; Signaling Molecule; Solutions; Stimulus; System; Testing; Time; Tissue Engineering; Tissues; Tracer; Venous; ankle joint; aqueous; base; bone; bone health; bone imaging; bone quality; cytokine; design; fluid flow; fluorescence imaging; imaging modality; in vivo; insight; interstitial; intravenous injection; novel strategies; pressure; scaffold; 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）：骨细胞是骨骼中数量最多的细胞，对于骨骼健康和骨骼质量至关重要。它们对于骨骼感知和适应机械刺激以及重塑受损组织至关重要。由于骨细胞完全包裹在矿化骨基质中，它们的生存和功能完全依赖于溶质（代谢物、生长因子、细胞因子和其他信号分子）通过腔隙-小管系统（LCS）的运输。尽管在描绘骨骼中的运输途径方面取得了进展，但人们对体内生物分子往返于骨细胞的机制知之甚少。这反映出缺乏在活体动物的实时条件下研究这些问题的方法。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，可以原位实时测量骨 LCS 中的溶质运动（Wang 等，2005。Proc Natl Acad Sci 102 ：11911）。我们建议将这种新颖的方法与数学/计算模型相结合，以充分表征骨骼中的扩散和对流。为了检验机械载荷引起的对流是 LCS 中大分子移动的主要机制这一假设，我们将首先量化死后骨骼中各种尺寸溶质的基线扩散传输。随后将在活体动物中测量由血压和机械负荷驱动的对流运输。这些研究将描述骨细胞活力和骨力传导所必需的运输机制，并为其他生物和工程系统（例如组织工程支架）中的质量运输提供新的见解。关于分子如何在骨骼内移动的详细知识将有助于定义分子参数，例如新药的流体动力学半径和半衰期，以便它们可以有效地输送到骨骼中以治疗骨质疏松症和关节炎等疾病。我们的具体目标是： 1) 确定溶质在骨 LCS 中的扩散如何取决于溶质的分子量； 2) 确定血管压力如何影响骨LCS中的溶质转运； 3) 确定机械负载如何影响骨 LCS 中的溶质运输。