Role of Microstructure in Nanomechanical Behavior of Bone Tissue

描述（由申请人提供）：组织微观结构在组织机械性能中的作用对于理解骨骼完整性的决定因素非常重要。该提案的目标是将骨组织成分与组织机械特性相关联，以进行治疗，从而导致骨基质成分发生明确的改变并改变整个骨骼强度，以测试以下假设：假设 1：骨矿物质密度降低或矿物质晶体尺寸增加会降低组织弹性模量和硬度。具体目标 1a：生长中的大鼠缺乏维生素 D 3 周和 4 周后，矿物质含量将会减少。治疗将通过全骨弯曲测试来确认。将表征组织弹性模量、成分和微观结构。组织成分和微观结构与股骨和腰椎的压痕模量和硬度相关。具体目标 1b：对生长中的大鼠进行 3 周和 4 周的氟化物处理将改变矿化，从而削弱整个骨骼结构并改变矿物质晶体尺寸。将如具体目标 1a 中那样对组织特性进行分析和关联。假设 2：代谢性酸中毒会产生基质变化，从而降低组织弹性模量。具体目标 2：绵羊代谢性酸中毒是人类骨质疏松症的临床前模型，会减少骨量并改变组织矿化。如具体目标 1 所示，将在此绵羊模型中分析和关联组织特性。此外，还将确定皮质样本的整体特性。包含微观结构细节的模型将用于关联跨长度尺度的行为。假设 3：双膦酸盐治疗增加组织弹性模量和硬度。具体目标 3：双磷酸盐治疗将用于克服具体目标 2 中代谢性酸中毒后的骨质疏松症。组织和整体特性将按照具体目标 2 进行分析和关联。我们将把骨组织的成分和微观结构与弹性行为联系起来，重点关注矿物质和胶原蛋白含量、晶体大小和胶原蛋白排列的作用。我们的方法将交叉关联以前未用于表征骨组织力学的几种微观技术。

DESCRIPTION (provided by applicant): The role of tissue microstructure in the tissue mechanical properties is important to understanding the determinants of skeletal integrity. The goal of this proposal is to correlate bone tissue composition with tissue mechanical properties for treatments that result in well-established alterations in bone matrix composition and altered whole bone strength to test the following hypotheses: Hypothesis 1: Reduced bone mineral density or increased mineral crystal size reduces tissue elastic modulus and hardness. Specific Aim 1a: Mineral content will be reduced by 3 and 4 weeks of vitamin D-deficiency in growing rats. The treatment will be confirmed with whole bone bending tests. Tissue elastic modulus, composition and microstructure will be characterized. Tissue composition and microstructure will be correlated with indentation moduli and hardness in the femur and lumbar vertebra. Specific Aim 1b: Altered mineralization will be produced by 3 and 4 weeks of fluoride treatment of growing rats to weaken whole bone structure and alter mineral crystal size. Tissue properties will be analyzed and correlated as in Specific Aim 1 a. Hypothesis 2: Metabolic acidosis produces matrix changes that reduce tissue elastic modulus. Specific Aim 2: Metabolic acidosis in sheep is a preclinical model of human osteoporosis that reduces bone mass and alters tissue mineralization. The tissue properties will be analyzed and correlated in this sheep model as in Specific Aim 1. Additionally, bulk properties will be determined for specimens from the cortex. Models incorporating microstructural detail will be used to relate the behavior across length scales. Hypothesis 3: Bisphosphonate treatment increases tissue elastic modulus and hardness. Specific Aim 3: Bisphosphonate treatment will be used to overcome osteoporosis following metabolic acidosis from Specific Aim 2. Tissue and bulk properties will be analyzed and correlated as in Specific Aim 2. We will relate composition and microstructure of bone tissue to the elastic behavior, focusing on the role of mineral and collagen content, crystal size and collagen alignment. Our approach will cross-correlate several microlevel techniques that have not been previously used to characterize bone tissue mechanics.