  Cross-links are considered to be a key component of collagen fibrils as they
can change the fibrillar behavior in various ways. Advanced-Glycation
Endproducts (AGEs), one particular type of cross-links, have been shown to
accumulate and impair the mechanical properties of collageneous tissues,
whereas enzymatic cross-links (ECLs) are known for stabilizing the structure of
the fibril. However, the reasons for whether a given type of cross-link
improves or impairs the material properties remain unknown. Here, we use
coarse-grained steered molecular models to evaluate the effect of AGEs and ECLs
cross-links content on the deformation and failure properties of collagen
fibrils. Our simulations show that the collagen fibrils stiffen at high strain
levels when the AGEs content exceeds a critical value. In addition, the
strength of the fibril increases with AGEs accumulation. By analyzing the
forces within the different types of cross-links (AGEs and ECLs) as well as
their failure, we demonstrate that a change of deformation mechanism is at the
origin of these observations. A high AGEs content reinforces force transfer
through AGEs cross-links rather than through friction between sliding
tropocollagen molecules. We show that this failure mechanism, which is
associated with lower energy dissipation, results in more abrupt failure of the
collagen fibril. Our results provide a direct and causal link between increased
AGEs content, inhibited intra-fibrillar sliding, increased stiffness, and
abrupt fibril fracture. Therefore, they explain the mechanical origin of bone
brittleness as commonly observed in elderly and diabetic populations. Our
findings contribute to a better understanding of the mechanisms underlying
impaired tissue behaviour due to elevated AGEs content and could enable
targeted measures regarding the reduction of specific collagen cross-linking
levels.
