Multiscale regression modeling in mouse supraspinatus tendons reveals that dynamic processes act as mediators in structure–function relationships

Abstract

Recent advances in technology have allowed for the measurement of dynamic processes (re-alignment, crimp, deformation, sliding), but only a limited number of studies have investigated their relationship with mechanical properties. The overall objective of this study was to investigate the role of composition, structure, and the dynamic response to load in predicting tendon mechanical properties in a multi-level fashion mimicking native hierarchical collagen structure. Multiple linear regression models were investigated to determine the relationships between composition/structure, dynamic processes, and mechanical properties. Mediation was then used to determine if dynamic processes mediated structure-function relationships. Dynamic processes were strong predictors of mechanical properties. These predictions were location-dependent, with the insertion site utilizing all four dynamic responses and the midsubstance responding primarily with fibril deformation and sliding. In addition, dynamic processes were moderately predicted by composition and structure in a regionally-dependent manner. Finally, dynamic processes were partial mediators of the relationship between composition/structure and mechanical function, and results suggested that mediation is likely shared between multiple dynamic processes. In conclusion, the mechanical properties at the midsubstance of the tendon are controlled primarily by fibril structure and this region responds to load via fibril deformation and sliding. Conversely, the mechanical function at the insertion site is controlled by many other important parameters and the region responds to load via all four dynamic mechanisms. Overall, this study presents a strong foundation on which to design future experimental and modeling efforts in order to fully understand the complex structure-function relationships present in tendon.

Dynamic Loading and Tendon Healing Affect Multiscale Tendon Properties and ECM Stress Transmission

“…Sets of alignment maps (30 images) were taken during the quasi-static ramp and following frequency sweeps at 1% or 10% strain. With these data, we assessed the strain at which collagen fiber re-alignment occurred by determining the transition point of a bilinear fit using CSD versus strain data 61 .…”

Tendon exhibits complex poroelastic behavior at the nanoscale as revealed by high-frequency AFM-based rheology

“…Collagen molecules arrange in a staggered packing arrangement to form individual fibrils, which then bundle to form fibers, fascicles and eventually tendon proper. This collagen network is able to respond dynamically to load through a series of structural arrangements known as collagen re-alignment, uncrimping, sliding, and deformation (Connizzo et al, 2016, 2014b; Miller et al, 2012a; Szczesny and Elliott, 2014a). In addition, a number of other extracellular matrix components may be responsible for the mechanical response.…”

Strain Distribution of Intact Rat Rotator Cuff Tendon-to-Bone Attachments and Attachments With Defects

“…In addition, mineral accumulation and collagen fibril orientation has been shown, using modeling, as some of the key factors of the attachments' mechanical properties [4]. Multiscale regression modeling has also been used to probe how the composition, structure, and dynamic processes of tendon and the tendon-to-bone attachment establish their mechanical properties [16]. These studies utilized computation and regression modeling to explain how the intact structures prevent stress concentrations at the attachment and have motivated many experimental studies to define the structure-function relationships of the tendon-to-bone attachment [17][18][19].…”