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  1. Article ; Online: The Role of Water Compartments in the Material Properties of Cortical Bone.

    Granke, Mathilde / Does, Mark D / Nyman, Jeffry S

    Calcified tissue international

    2015  Volume 97, Issue 3, Page(s) 292–307

    Abstract: Comprising ~20% of the volume, water is a key determinant of the mechanical behavior of cortical bone. It essentially exists in two general compartments: within pores and bound to the matrix. The amount of pore water-residing in the vascular-lacunar- ... ...

    Abstract Comprising ~20% of the volume, water is a key determinant of the mechanical behavior of cortical bone. It essentially exists in two general compartments: within pores and bound to the matrix. The amount of pore water-residing in the vascular-lacunar-canalicular space-primarily reflects intracortical porosity (i.e., open spaces within the matrix largely due to Haversian canals and resorption sites) and as such is inversely proportional to most mechanical properties of bone. Movement of water according to pressure gradients generated during dynamic loading likely confers hydraulic stiffening to the bone as well. Nonetheless, bound water is a primary contributor to the mechanical behavior of bone in that it is responsible for giving collagen the ability to confer ductility or plasticity to bone (i.e., allows deformation to continue once permanent damage begins to form in the matrix) and decreases with age along with fracture resistance. Thus, dehydration by air-drying or by solvents with less hydrogen bonding capacity causes bone to become brittle, but interestingly, it also increases stiffness and strength across the hierarchical levels of organization. Despite the importance of matrix hydration to fracture resistance, little is known about why bound water decreases with age in hydrated human bone. Using (1)H nuclear magnetic resonance (NMR), both bound and pore water concentrations in bone can be measured ex vivo because the proton relaxation times differ between the two water compartments, giving rise to two distinct signals. There are also emerging techniques to measure bound and pore water in vivo with magnetic resonance imaging (MRI). The NMR/MRI-derived bound water concentration is positively correlated with both the strength and toughness of hydrated bone and may become a useful clinical marker of fracture risk.
    MeSH term(s) Animals ; Bone and Bones/metabolism ; Fractures, Bone/metabolism ; Haversian System/metabolism ; Humans ; Porosity ; Tensile Strength/physiology ; Water/metabolism
    Chemical Substances Water (059QF0KO0R)
    Language English
    Publishing date 2015-09
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
    ZDB-ID 304266-2
    ISSN 1432-0827 ; 0944-0747 ; 0008-0594 ; 0171-967X
    ISSN (online) 1432-0827
    ISSN 0944-0747 ; 0008-0594 ; 0171-967X
    DOI 10.1007/s00223-015-9977-5
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  2. Article ; Online: Bone collagen network integrity and transverse fracture toughness of human cortical bone.

    Willett, Thomas L / Dapaah, Daniel Y / Uppuganti, Sasidhar / Granke, Mathilde / Nyman, Jeffry S

    Bone

    2018  Volume 120, Page(s) 187–193

    Abstract: Greater understanding of the determinants of skeletal fragility is highly sought due to the great burden that bone affecting diseases and fractures have on economies, societies and health care systems. Being a complex, hierarchical composite of collagen ... ...

    Abstract Greater understanding of the determinants of skeletal fragility is highly sought due to the great burden that bone affecting diseases and fractures have on economies, societies and health care systems. Being a complex, hierarchical composite of collagen type-I and non-stoichiometric substituted hydroxyapatite, bone derives toughness from its organic phase. In this study, we tested whether early observations that a strong correlation between bone collagen integrity measured by thermomechanical methods and work to fracture exist in a more general and heterogeneous sampling of the population. Neighboring uniform specimens from an established, highly characterized and previously published collection of human cortical bone samples (femur mid-shaft) were decalcified in EDTA. Fifty-four of the original 62 donors were included (26 male and 28 females; ages 21-101 years; aging, osteoporosis, diabetes and cancer). Following decalcification, bone collagen was tested using hydrothermal isometric tension (HIT) testing in order to measure the collagen's thermal stability (denaturation temperature, T
    MeSH term(s) Adult ; Aged ; Aged, 80 and over ; Bone and Bones/metabolism ; Collagen/metabolism ; Cortical Bone/pathology ; Female ; Fractures, Bone/pathology ; Humans ; Linear Models ; Male ; Middle Aged ; Young Adult
    Chemical Substances Collagen (9007-34-5)
    Language English
    Publishing date 2018-10-28
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 632515-4
    ISSN 1873-2763 ; 8756-3282
    ISSN (online) 1873-2763
    ISSN 8756-3282
    DOI 10.1016/j.bone.2018.10.024
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  3. Article ; Online: Manipulating the Amount and Structure of the Organic Matrix Affects the Water Compartments of Human Cortical Bone.

    Nyman, Jeffry S / Uppuganti, Sasidhar / Unal, Mustafa / Leverant, Calen J / Adabala, Saahit / Granke, Mathilde / Voziyan, Paul / Does, Mark D

    JBMR plus

    2019  Volume 3, Issue 6, Page(s) e10135

    Abstract: Being predictors of the mechanical properties of human cortical bone, bound and pore water measurements by magnetic resonance (MR) imaging are being developed for the clinical assessment of fracture risk. While pore water is a surrogate of cortical bone ... ...

    Abstract Being predictors of the mechanical properties of human cortical bone, bound and pore water measurements by magnetic resonance (MR) imaging are being developed for the clinical assessment of fracture risk. While pore water is a surrogate of cortical bone porosity, the determinants of bound water are unknown. Manipulation of organic matrix properties by oxidative deproteinization, thermal denaturation, or nonenzymatic glycation lowers bone toughness. Because bound water contributes to bone toughness, we hypothesized that each of these matrix manipulations affect bound water fraction (V
    Language English
    Publishing date 2019-01-28
    Publishing country England
    Document type Journal Article
    ISSN 2473-4039
    ISSN (online) 2473-4039
    DOI 10.1002/jbm4.10135
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  4. Article ; Online: Tissue-Level Mechanical Properties of Bone Contributing to Fracture Risk.

    Nyman, Jeffry S / Granke, Mathilde / Singleton, Robert C / Pharr, George M

    Current osteoporosis reports

    2016  Volume 14, Issue 4, Page(s) 138–150

    Abstract: Tissue-level mechanical properties characterize mechanical behavior independently of microscopic porosity. Specifically, quasi-static nanoindentation provides measurements of modulus (stiffness) and hardness (resistance to yielding) of tissue at the ... ...

    Abstract Tissue-level mechanical properties characterize mechanical behavior independently of microscopic porosity. Specifically, quasi-static nanoindentation provides measurements of modulus (stiffness) and hardness (resistance to yielding) of tissue at the length scale of the lamella, while dynamic nanoindentation assesses time-dependent behavior in the form of storage modulus (stiffness), loss modulus (dampening), and loss factor (ratio of the two). While these properties are useful in establishing how a gene, signaling pathway, or disease of interest affects bone tissue, they generally do not vary with aging after skeletal maturation or with osteoporosis. Heterogeneity in tissue-level mechanical properties or in compositional properties may contribute to fracture risk, but a consensus on whether the contribution is negative or positive has not emerged. In vivo indentation of bone tissue is now possible, and the mechanical resistance to microindentation has the potential for improving fracture risk assessment, though determinants are currently unknown.
    MeSH term(s) Biomechanical Phenomena ; Bone and Bones/diagnostic imaging ; Bone and Bones/metabolism ; Bone and Bones/physiopathology ; Elastic Modulus ; Fractures, Bone/epidemiology ; Fractures, Bone/metabolism ; Fractures, Bone/physiopathology ; Hardness ; Humans ; Risk ; Second Harmonic Generation Microscopy ; Spectroscopy, Fourier Transform Infrared ; Spectrum Analysis ; Spectrum Analysis, Raman
    Language English
    Publishing date 2016-06-04
    Publishing country United States
    Document type Journal Article ; Review ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2186581-4
    ISSN 1544-2241 ; 1544-1873
    ISSN (online) 1544-2241
    ISSN 1544-1873
    DOI 10.1007/s11914-016-0314-3
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  5. Article ; Online: Prevalent role of porosity and osteonal area over mineralization heterogeneity in the fracture toughness of human cortical bone.

    Granke, Mathilde / Makowski, Alexander J / Uppuganti, Sasidhar / Nyman, Jeffry S

    Journal of biomechanics

    2016  Volume 49, Issue 13, Page(s) 2748–2755

    Abstract: Changes in the distribution of bone mineralization occurring with aging, disease, or treatment have prompted concerns that alterations in mineralization heterogeneity may affect the fracture resistance of bone. Yet, so far, studies assessing bone from ... ...

    Abstract Changes in the distribution of bone mineralization occurring with aging, disease, or treatment have prompted concerns that alterations in mineralization heterogeneity may affect the fracture resistance of bone. Yet, so far, studies assessing bone from hip fracture cases and fracture-free women have not reached a consensus on how heterogeneity in tissue mineralization relates to skeletal fragility. Owing to the multifactorial nature of toughening mechanisms occurring in bone, we assessed the relative contribution of heterogeneity in mineralization to fracture resistance with respect to age, porosity, and area fraction of osteonal tissue. The latter parameters were extracted from quantitative backscattered electron imaging of human cortical bone sections following R-curve tests of single-edge notched beam specimens to determine fracture toughness properties. Microstructural heterogeneity was determined as the width of the mineral distribution (bulk) and as the sill of the variogram (local). In univariate analyses of measures from 62 human donors (21 to 101 years), local but not bulk heterogeneity as well as pore clustering negatively correlated with fracture toughness properties. With age as covariate, heterogeneity was a significant predictor of crack initiation, though local had a stronger negative contribution than bulk. When considering all potential covariates, age, cortical porosity and area fraction of osteons explained up to 50% of the variance in bone׳s crack initiation toughness. However, including heterogeneity in mineralization did not improve upon this prediction. The findings of the present work stress the necessity to account for porosity and microstructure when evaluating the potential of matrix-related features to affect skeletal fragility.
    MeSH term(s) Adult ; Aging/physiology ; Biomechanical Phenomena ; Calcification, Physiologic ; Female ; Fractures, Bone/physiopathology ; Haversian System/injuries ; Haversian System/physiology ; Haversian System/physiopathology ; Humans ; Male ; Middle Aged ; Porosity ; Young Adult
    Language English
    Publishing date 2016-06-15
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218076-5
    ISSN 1873-2380 ; 0021-9290
    ISSN (online) 1873-2380
    ISSN 0021-9290
    DOI 10.1016/j.jbiomech.2016.06.009
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  6. Article ; Online: The age-related decrease in material properties of BALB/c mouse long bones involves alterations to the extracellular matrix.

    Creecy, Amy / Uppuganti, Sasidhar / Girard, Madeline R / Schlunk, Siegfried G / Amah, Chidi / Granke, Mathilde / Unal, Mustafa / Does, Mark D / Nyman, Jeffry S

    Bone

    2019  Volume 130, Page(s) 115126

    Abstract: One possibility for the disproportionate increase in fracture risk with aging relative to the decrease in bone mass is an accumulation of changes to the bone matrix which deleteriously affect fracture resistance. In order to effectively develop new ... ...

    Abstract One possibility for the disproportionate increase in fracture risk with aging relative to the decrease in bone mass is an accumulation of changes to the bone matrix which deleteriously affect fracture resistance. In order to effectively develop new targets for osteoporosis, a preclinical model of the age-related loss in fracture resistance needs to be established beyond known age-related decreases in bone mineral density and bone volume fraction. To that end, we examined long bones of male and female BALB/c mice at 6-mo. and 20-mo. of age and assessed whether material and matrix properties of cortical bone significantly differed between the age groups. The second moment of area of the diaphysis (minimum and maximum principals for femur and radius, respectively) as measured by ex vivo micro-computed tomography (μCT) was higher at 20-mo. than at 6-mo. for both males and females, but ultimate moment as measured by three-point bending tests did not decrease with age. Cortical thickness was lower with age for males, but higher for old females. Partially accounting for differences in structure, material estimates of yield, ultimate stress, and toughness (left femur) were 12.6%, 11.1%, and 40.9% lower, respectively, with age for both sexes. The ability of the cortical bone to resist crack growth (right femur) was also 18.1% less for the old than for the young adult mice. These decreases in material properties were not due to changes in intracortical porosity as pore number decreased with age. Rather, age-related alterations in the matrix were observed for both sexes: enzymatic and non-enzymatic crosslinks by high performance liquid chromatography increased (femur), volume fraction of bound water by
    MeSH term(s) Animals ; Bone Density ; Bone and Bones/diagnostic imaging ; Extracellular Matrix ; Female ; Femur/diagnostic imaging ; Male ; Mice ; Mice, Inbred BALB C ; X-Ray Microtomography
    Language English
    Publishing date 2019-10-31
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 632515-4
    ISSN 1873-2763 ; 8756-3282
    ISSN (online) 1873-2763
    ISSN 8756-3282
    DOI 10.1016/j.bone.2019.115126
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  7. Article ; Online: Assessing glycation-mediated changes in human cortical bone with Raman spectroscopy.

    Unal, Mustafa / Uppuganti, Sasidhar / Leverant, Calen J / Creecy, Amy / Granke, Mathilde / Voziyan, Paul / Nyman, Jeffry S

    Journal of biophotonics

    2018  Volume 11, Issue 8, Page(s) e201700352

    Abstract: Establishing a non-destructive method for spatially assessing advanced glycation end-products (AGEs) is a potentially useful step toward investigating the mechanistic role of AGEs in bone quality. To test the hypothesis that the shape of the amide I in ... ...

    Abstract Establishing a non-destructive method for spatially assessing advanced glycation end-products (AGEs) is a potentially useful step toward investigating the mechanistic role of AGEs in bone quality. To test the hypothesis that the shape of the amide I in the Raman spectroscopy (RS) analysis of bone matrix changes upon AGE accumulation, we incubated paired cadaveric cortical bone in ribose or glucose solutions and in control solutions for 4 and 16 weeks, respectively, at 37°C. Acquiring 10 spectra per bone with a 20X objective and a 830 nm laser, RS was sensitive to AGE accumulation (confirmed by biochemical measurements of pentosidine and fluorescent AGEs). Hyp/Pro ratio increased upon glycation using either 0.1 M ribose, 0.5 M ribose or 0.5 M glucose. Glycation also decreased the amide I sub-peak ratios (cm
    MeSH term(s) Amides/chemistry ; Arginine/analogs & derivatives ; Arginine/chemistry ; Arginine/metabolism ; Cortical Bone/metabolism ; Female ; Glycation End Products, Advanced/chemistry ; Glycation End Products, Advanced/metabolism ; Glycosylation ; Humans ; Kinetics ; Lysine/analogs & derivatives ; Lysine/chemistry ; Lysine/metabolism ; Male ; Middle Aged ; Spectrum Analysis, Raman
    Chemical Substances Amides ; Glycation End Products, Advanced ; glucosepane (66K23JT22H) ; Arginine (94ZLA3W45F) ; pentosidine (BJ4I2X2CQJ) ; Lysine (K3Z4F929H6)
    Language English
    Publishing date 2018-05-06
    Publishing country Germany
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2390063-5
    ISSN 1864-0648 ; 1864-063X
    ISSN (online) 1864-0648
    ISSN 1864-063X
    DOI 10.1002/jbio.201700352
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  8. Article ; Online: MRI-derived bound and pore water concentrations as predictors of fracture resistance.

    Manhard, Mary Kate / Uppuganti, Sasidhar / Granke, Mathilde / Gochberg, Daniel F / Nyman, Jeffry S / Does, Mark D

    Bone

    2016  Volume 87, Page(s) 1–10

    Abstract: Accurately predicting fracture risk in the clinic is challenging because the determinants are multi-factorial. A common approach to fracture risk assessment is to combine X-ray-based imaging methods such as dual-energy X-ray absorptiometry (DXA) with an ... ...

    Abstract Accurately predicting fracture risk in the clinic is challenging because the determinants are multi-factorial. A common approach to fracture risk assessment is to combine X-ray-based imaging methods such as dual-energy X-ray absorptiometry (DXA) with an online Fracture Risk Assessment Tool (FRAX) that includes additional risk factors such as age, family history, and prior fracture incidents. This approach still does not adequately diagnose many individuals at risk, especially those with certain diseases like type 2 diabetes. As such, this study investigated bound water and pore water concentrations (Cbw and Cpw) from ultra-short echo time (UTE) magnetic resonance imaging (MRI) as new predictors of fracture risk. Ex vivo cadaveric arms were imaged with UTE MRI as well as with DXA and high-resolution micro-computed tomography (μCT), and imaging measures were compared to both whole-bone structural and material properties as determined by three-point bending tests of the distal-third radius. While DXA-derived areal bone mineral density (aBMD) and μCT-derived volumetric BMD correlated well with structural strength, they moderately correlated with the estimate material strength with gender being a significant covariate for aBMD. MRI-derived measures of Cbw and Cpw had a similar predictive ability of material strength as aBMD but did so independently of gender. In addition, Cbw was the only imaging parameter to significantly correlate with toughness, the energy dissipated during fracture. Notably, the strength of the correlations with the material properties of bone tended to be higher when a larger endosteal region was used to determine Cbw and Cpw. These results indicate that MRI measures of Cbw and Cpw have the ability to probe bone material properties independent of bone structure or subject gender. In particular, toughness is a property of fracture resistance that is not explained by X-ray based methods. Thus, these MRI-derived measures of Cbw and Cpw in cortical bone have the potential to be useful in clinical populations for evaluating fracture risk, especially involving diseases that affect material properties of the bone beyond its strength.
    Language English
    Publishing date 2016-06
    Publishing country United States
    Document type Journal Article
    ZDB-ID 632515-4
    ISSN 1873-2763 ; 8756-3282
    ISSN (online) 1873-2763
    ISSN 8756-3282
    DOI 10.1016/j.bone.2016.03.007
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  9. Article ; Online: Differences in sensitivity to microstructure between cyclic- and impact-based microindentation of human cortical bone.

    Uppuganti, Sasidhar / Granke, Mathilde / Manhard, Mary Kate / Does, Mark D / Perrien, Daniel S / Lee, Donald H / Nyman, Jeffry S

    Journal of orthopaedic research : official publication of the Orthopaedic Research Society

    2017  Volume 35, Issue 7, Page(s) 1442–1452

    Abstract: Unlike the known relationships between traditional mechanical properties and microstructural features of bone, the factors that influence the mechanical resistance of bone to cyclic reference point microindention (cRPI) and impact microindention (IMI) ... ...

    Abstract Unlike the known relationships between traditional mechanical properties and microstructural features of bone, the factors that influence the mechanical resistance of bone to cyclic reference point microindention (cRPI) and impact microindention (IMI) have yet to be identified. To determine whether cRPI and IMI properties depend on microstructure, we indented the tibia mid-shaft, the distal radius, and the proximal humerus from 10 elderly donors using the BioDent and OsteoProbe (neighboring sites). As the only output measure of IMI, bone material strength index (BMSi) was significantly different across all three anatomical sites being highest for the tibia mid-shaft and lowest for the proximal humerus. Total indentation distance (inverse of BMSi) was higher for the proximal humerus than for the tibia mid-shaft but was not different between other anatomical comparisons. As a possible explanation for the differences in BMSi, pore water, as determined by
    MeSH term(s) Aged ; Aged, 80 and over ; Cortical Bone/anatomy & histology ; Cortical Bone/physiology ; Female ; Humans ; Male ; Mechanical Phenomena
    Language English
    Publishing date 2017
    Publishing country United States
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 605542-4
    ISSN 1554-527X ; 0736-0266
    ISSN (online) 1554-527X
    ISSN 0736-0266
    DOI 10.1002/jor.23392
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  10. Article ; Online: Applying Full Spectrum Analysis to a Raman Spectroscopic Assessment of Fracture Toughness of Human Cortical Bone.

    Makowski, Alexander J / Granke, Mathilde / Ayala, Oscar D / Uppuganti, Sasidhar / Mahadevan-Jansen, Anita / Nyman, Jeffry S

    Applied spectroscopy

    2017  Volume 71, Issue 10, Page(s) 2385–2394

    Abstract: A decline in the inherent quality of bone tissue is a † Equal contributors contributor to the age-related increase in fracture risk. Although this is well-known, the important biochemical factors of bone quality have yet to be identified using Raman ... ...

    Abstract A decline in the inherent quality of bone tissue is a † Equal contributors contributor to the age-related increase in fracture risk. Although this is well-known, the important biochemical factors of bone quality have yet to be identified using Raman spectroscopy (RS), a nondestructive, inelastic light-scattering technique. To identify potential RS predictors of fracture risk, we applied principal component analysis (PCA) to 558 Raman spectra (370-1720 cm
    MeSH term(s) Adult ; Aged ; Aged, 80 and over ; Bone Density ; Collagen/chemistry ; Cortical Bone/chemistry ; Cortical Bone/physiology ; Female ; Fractures, Bone/physiopathology ; Humans ; Male ; Middle Aged ; Spectrum Analysis, Raman/methods ; Young Adult
    Chemical Substances Collagen (9007-34-5)
    Language English
    Publishing date 2017-07-14
    Publishing country United States
    Document type Journal Article
    ISSN 1943-3530
    ISSN (online) 1943-3530
    DOI 10.1177/0003702817718149
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