Molecular structure, mechanical behavior and failure mechanism of the C-terminal cross-link domain in type I collagen

Uzel, Sebastien G. M.; Buehler, Markus J.

doi:10.1016/j.jmbbm.2010.07.003

Cited by 90 publications

(76 citation statements)

References 33 publications

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“…These act to degrade the structural integrity of the fibrils by stiffening them to restrict fibrillar sliding ¶ (plasticity) and consequently degrade the ductility, strength, and intrinsic toughness of the bone. Further, our results are consistent with computational models of fibril deformation (28,29,33), which predict an inhibition of fibrillar sliding with cross-linking, and with experiments (22) showing a reduced toughness in bone glycated in vitro.…”

Section: Discussionsupporting

confidence: 89%

“…Within the fibrils, sliding at the HA/ collagen interface (27), intermolecular cross-linking (16,28,29), and sacrificial bonding (3) constrain molecular stretching and provide the basis for the increased apparent strength of the collagen molecules without catastrophic failure of either component. The molecular behavior of the protein and mineral phases (fibrillar sliding) within a fibril enables a large regime of dissipative deformation once plastic yielding begins in mineralized tissues (4,30,31) and other biological materials (32).…”

Section: Discussionmentioning

confidence: 99%

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Age-related changes in the plasticity and toughness of human cortical bone at multiple length scales

Zimmermann

Schaible

Bale

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

342

315

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The structure of human cortical bone evolves over multiple length scales from its basic constituents of collagen and hydroxyapatite at the nanoscale to osteonal structures at near-millimeter dimensions, which all provide the basis for its mechanical properties. To resist fracture, bone’s toughness is derived intrinsically through plasticity (e.g., fibrillar sliding) at structural scales typically below a micrometer and extrinsically (i.e., during crack growth) through mechanisms (e.g., crack deflection/bridging) generated at larger structural scales. Biological factors such as aging lead to a markedly increased fracture risk, which is often associated with an age-related loss in bone mass ( bone quantity ). However, we find that age-related structural changes can significantly degrade the fracture resistance ( bone quality ) over multiple length scales. Using in situ small-angle X-ray scattering and wide-angle X-ray diffraction to characterize submicrometer structural changes and synchrotron X-ray computed tomography and in situ fracture-toughness measurements in the scanning electron microscope to characterize effects at micrometer scales, we show how these age-related structural changes at differing size scales degrade both the intrinsic and extrinsic toughness of bone. Specifically, we attribute the loss in toughness to increased nonenzymatic collagen cross-linking, which suppresses plasticity at nanoscale dimensions, and to an increased osteonal density, which limits the potency of crack-bridging mechanisms at micrometer scales. The link between these processes is that the increased stiffness of the cross-linked collagen requires energy to be absorbed by “plastic” deformation at higher structural levels, which occurs by the process of microcracking.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Age-related changes in the plasticity and toughness of human cortical bone at multiple length scales

Zimmermann

Schaible

Bale

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

342

315

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“…Despite these limitations, as confirmed in Table 1 the model properly captures the mechanical behavior seen in experiments, likely because the above listed constraints do not affect the behavior at relatively small deformation, below 20-30% strain. Indeed, the effects of cross-links between molecules and intermolecular sliding have been shown to dominate the properties primarily at larger deformation [64]. A microfibril model that explicitly considers multiple molecules poses no fundamental challenge; however, it would be rather challenging from a computational point of view.…”

Section: Resultsmentioning

confidence: 99%

Hierarchical Structure and Nanomechanics of Collagen Microfibrils from the Atomistic Scale Up

Gautieri

Vesentini²,

Redaelli³

et al. 2011

Nano Lett.

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596

488

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Abstract:Collagen constitutes one third of the human proteome, providing mechanical stability, elasticity and strength to connective tissues. Collagen is also the dominating material in the extracellular matrix (ECM) and is thus crucial for cell differentiation, growth and pathology. However, fundamental questions remain with respect to the origin of the unique mechanical properties of collagenous tissues, and in particular its stiffness, extensibility and nonlinear mechanical response. By using x-ray diffraction data of a collagen fibril reported by Orgel et al.(Proceedings of the National Academy of Sciences USA, 2006) in combination with protein structure identification methods, here we present an experimentally validated model of the nanomechanics of a collagen microfibril that incorporates the full biochemical details of the amino acid sequence of the constituting molecules. We report the analysis of its mechanical properties under different levels of stress and solvent conditions, using a full-atomistic force field including explicit water solvent. Mechanical testing of hydrated collagen microfibrils yields a Young's modulus of ≈300 MPa at small and ≈1.2 GPa at larger deformation in excess of 10% strain, in excellent agreement with experimental data. Dehydrated, dry collagen microfibrils show a significantly increased Young's modulus of ≈1.8 to 2.25 GPa (or ≈6.75 times the modulus in the wet state) owing to a much tighter molecular packing, in good agreement with experimental measurements (where an increase of the modulus by ≈9 times was found). Our model demonstrates that the unique mechanical properties of collagen microfibrils can be explained based on their hierarchical structure, where deformation is mediated through mechanisms that operate at different hierarchical levels. Key mechanisms involve straightening of initially disordered and helically twisted molecules at small strains, followed by axial stretching of molecules, and eventual molecular uncoiling at extreme deformation. These mechanisms explain the striking difference of the modulus of collagen fibrils compared with single molecules, which is found in the range of 4.8±2 GPa or ≈10-20 times greater. These findings corroborate the notion that collagen tissue properties are highly scale dependent and nonlinear elastic, an issue that must be considered in the development of models that describe the interaction of cells with collagen in the extracellular matrix. A key impact the atomistic model of collagen microfibril mechanics reported here is that it enables the bottom-up elucidation of structure-property relationships in the broader class of collagen materials such as tendon or bone, including studies in the context of genetic disease where the incorporation of biochemical, genetic details in material models of connective tissue is essential.

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“…The essential functional role of crosslinking in collagen fibril stability and whole tissue integrity, however, is clearly demonstrated in the severely compromised connective tissues of animals subjected to dietary inhibition of lysyl oxidase, which results in collagen fibrils and tendons with reduced strength 8,9 . The importance of crosslinks to fibril integrity has been indicated theoretically 17 and demonstrated experimentally 9,18 by balancing molecular slip and stretch under load. The importance of crosslinking in preventing molecular slippage and resultant fibrillar damage can also be inferred from the decreased thermal stability of tendons that is known to take place after sub-maximal tissue overload 19 .…”

Section: The Good: Enzyme Mediated Collagen Cros-slinkingmentioning

confidence: 98%

The role of collagen crosslinks in ageing and diabetes - the good, the bad, and the ugly

Snedeker¹

2014

MLTJ

114

112

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SummaryThe non-enzymatic reaction of proteins with glucose (glycation) is a topic of rapidly growing importance in human health and medicine. There is increasing evidence that this reaction plays a central role in ageing and disease of connective tissues. Of particular interest are changes in type-I collagens, long-lived proteins that form the mechanical backbone of connective tissues in nearly every human organ. Despite considerable correlative evidence relating extracellular matrix (ECM) glycation to disease, little is known of how ECM modification by glucose impacts matrix mechanics and damage, cell-matrix interactions, and matrix turnover during aging. More daunting is to understand how these factors interact to cumulatively affect local repair of matrix damage, progression of tissue disease, or systemic health and longevity. This focused review will summarize what is currently known regarding collagen glycation as a potential driver of connective tissue disease. We concentrate attention on tendon as an affected connective tissue with large clinical relevance, and as a tissue that can serve as a useful model tissue for investigation into glycation as a potentially critical player in tissue fibrosis related to ageing and diabetes.

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Molecular structure, mechanical behavior and failure mechanism of the C-terminal cross-link domain in type I collagen

Cited by 90 publications

References 33 publications

Age-related changes in the plasticity and toughness of human cortical bone at multiple length scales

Age-related changes in the plasticity and toughness of human cortical bone at multiple length scales

Hierarchical Structure and Nanomechanics of Collagen Microfibrils from the Atomistic Scale Up

The role of collagen crosslinks in ageing and diabetes - the good, the bad, and the ugly

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