As a natural composite material, bone fragility is due to multiple factors at different hierarchical levels. Clinically, bone fragility fractures are associated directly with ultrastructural changes. Such ultrastructural changes could significantly affect bone nanomechanics and subsequently lead to increases in bone fragility fractures. During bone formation, collagen fibril network is first laid down by osteoblasts. Then, mineralization is initiated at the gap region of collagen fibrils and gradually extended into both intrafibrillar and extrafibrillar spaces. From biomechanics perspectives, intrafibrillar mineralization may play a pivotal role in stiffening the collagen fibrils and serving as an interlocking mechanism between the mineral and collagen phases. Previous evidence that loss of intrafibrillar mineralization is associated with significant decreases in stiffness and strength and increases in bone fragility in osteogenesis imperfecta patients shows. To explore the underlying mechanism, the effect of intrafibrillar mineralization on bone nanomechanics and its impact to bone fragility will be investigated in this study. The general hypothesis is that bone fragility is directly related to the degree of intrafibrillar mineralization. To test the hypothesi, two specific aims are proposed:
Aim 1 is to determine changes in the degree of intrafibrillar mineralization in bone samples from wild type, mild, and severe oim mice using advanced synchrotron X-ray scattering techniques. The working hypothesis for is that the degree of intrafibrillar mineralization decreases with the severity of osteogenesis imperfecta in oim mouse models.
Aim 2 is to determine the effect of intrafibrillar mineralization on the nanomechanics of bone and its impact to the bulk tissue fragility using the oim mouse models. Two hypotheses will be tested using the oim mouse models in Aim 2. One is that the pre-strain in the mineral phase decreases with diminishing degree of intrafibrillar mineralization, thus leading to a reduced tensile strength of bone, and the other is that The load sharing by the mineral phase increases as the degree of intrafibrillar mineralization diminishes, thus leading to the reduction in the elastic modulus, strength, and toughness of bone in oim mouse models. This study will be the first effort to tackle this very important while considerably challenging issue using a novel nanomechanics approaches. Upon completion of this study, we expect to elucidate the role of intrafibrillar mineralization in bone nanomechanics and its impact to the bulk tissue fragility. Ths understanding will give rise to a nanomechanics basis for studies on the underlying pathological mechanisms (e.g. osteogenesis imperfect) that cause the loss of intrafibrillar mineralization. In addition, the synchrotron X-ray scattering and nanomechanics methodologies proposed in this study will offer a useful evaluation tool for future development of effective therapeutic treatment on bone disorders associated with abnormal intrafibrillar mineralization.

Public Health Relevance

Upon completion of this study, we expect to elucidate the role of intrafibrillar mineralization in bone nanomechanics and its impact to the bulk tissue fragility. This understanding will give rise to a nanomechanics basis for studies on the underlying pathological mechanisms (e.g. osteogenesis imperfect) that cause the loss of intrafibrillar mineralization. In addition, the synchrotron X-ray scattering and nanomechanics methodologies proposed in this study will offer a useful evaluation tool for future development of effective therapeutic treatments on bone disorders associated with abnormal intrafibrillar mineralization.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AR065641-01
Application #
8621625
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Sharrock, William J
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Engineering (All Types)
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
City
San Antonio
State
TX
Country
United States
Zip Code
78249