Date of Award

Spring 1-1-2017

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Mechanical Engineering

First Advisor

Virginia L. Ferguson

Second Advisor

R. D. Carpenter

Third Advisor

Karen B. King

Fourth Advisor

Rong Long

Fifth Advisor

Corey Neu

Abstract

Chronic kidney disease (CKD) is associated with a clinically-observed increase in bone fragility, yet the specific changes to fracture resistance-determining bone quality are not understood. CKD disrupts systemic mineral homeostasis and alters bone turnover. Thus, it was hypothesized that CKD deleteriously affects tissue-scale material properties. In Aim 1, mice with surgically-induced moderate CKD had diminished tissue-scale material properties, including mineral content and nanoindentation modulus, in bone formed during CKD compared with sham mice. Heterogeneity of microscale bone material was also altered with CKD. Next, CKD occurs most often in the elderly, yet geriatric patients with CKD have higher fracture risk than age-matched individuals without CKD. Aging reduces bone quality and may affect the behavior of osteocytes, the most prevalent type of bone cell. Osteocytes are essential for maintaining bone quality, but age-related changes to osteocytes, including lacunar morphologies, are not known. We hypothesized that osteocyte lacunae would have different morphologies with increasing age in mouse cortical bone. In Aim 2, we found that osteocytes become smaller, more spherical, and sparser with advancing age. Additionally, a convenient and inexpensive method to visualize and analyze 3D osteocyte lacunar geometries from confocal laser scanning microscopy depth stacks was presented. In Aim 3, it was hypothesized that aging and CKD together reduce bone material quality for mice with moderate CKD across the hierarchical organization of the bone tissue composite. We found that aging and CKD diminish bone material properties, including mineral and collagen matrix, from the microscale to the whole bone. Additionally, CKD reduced microscale material heterogeneity. Lastly, in Aim 4, it was hypothesized that fracture toughness depends on microscale material heterogeneity. In a rat model of exercise and obesity, fracture toughness of the femur was significantly influenced by the heterogeneity of nanoindentation modulus for lamellar bone. The relationship between fracture toughness and standard deviation of modulus had a negative quadratic form, implying that too-low or too-high variability in mechanical properties is deleterious to bone toughness. The collected work reported here provides insights into how bone material quality is diminished in CKD as well as how these changes may alter bone fracture resistance.

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