Fibrin Networks Support Recurring Mechanical Loads by Adapting their Structure across Multiple Scales

Abstract

Tissues and cells sustain recurring mechanical loads that span a wide range of loading amplitudes and timescales as a consequence of exposure to blood flow, muscle activity, and external impact. Both tissues and cells derive their mechanical strength from fibrous protein scaffolds, which typically have a complex hierarchical structure. In this study, we focus on a prototypical hierarchical biomaterial, fibrin, which is one of the most resilient naturally occurring biopolymers and forms the structural scaffold of blood clots. We show how fibrous networks composed of fibrin utilize irreversible changes in their hierarchical structure at different scales to maintain reversible stress stiffening up to large strains. To trace the origin of this paradoxical resilience, we systematically tuned the microstructural parameters of fibrin and used a combination of optical tweezers and fluorescence microscopy to measure the interactions of single fibrin fibers for the first time, to our knowledge. We demonstrate that fibrin networks adapt to moderate strains by remodeling at the network scale through the spontaneous formation of new bonds between fibers, whereas they adapt to high strains by plastic remodeling of the fibers themselves. This multiscale adaptation mechanism endows fibrin gels with the remarkable ability to sustain recurring loads due to shear flows and wound stretching. Our findings therefore reveal a microscopic mechanism by which tissues and cells can balance elastic nonlinearity and plasticity, and thus can provide microstructural insights into cell-driven remodeling of tissues.

Programming the mechanics of cohesive fiber networks by compression

“…Cyclic shear loading has been shown to cause reinforcement for a number of biopolymer systems [14][15][16][17] , al-though softening can occur as well 18,19 . The physical principles responsible for these varied inelastic responses are still not fully understood, although possible mechanisms include bond breaking and reformation between fibers 13,19,20 and within fibers 18 .…”

“…The mechanisms of mechanical reinforcement are generally thought to originate from cellular activity, involving strain-dependent fiber degradation and synthesis 10,11 . However, recent studies suggest that biopolymer networks are inherently adaptive themselves, since they are held together by weak transient bonds 12,13 . Cyclic shear loading has been shown to cause reinforcement for a number of biopolymer systems [14][15][16][17] , al-though softening can occur as well 18,19 .…”

The Inelastic Hierarchy: Multiscale Biomechanics of Weak Bonds

“…Both exhibit stress stiffening, inelastic hysteresis, cyclic shakedown, and the Mullins effect. Kurniawan et al (1) can now show more quantitatively how much of this rheological phenomenology is due to inelastic stretching of individual fibers and how much is due to an inelastic reworking of the network architecture.…”

“…These scaffolds are the essential ingredients of natural blood clots as well as some biomimetic two-component glues employed in plastic surgery. Kurniawan et al (1) systematically tuned the microstructural parameters of fibrin and used a combination of optical tweezers and fluorescence microscopy to measure, for the first time, the sticky mutual interactions of single fibrin fibers. Thereby, they could identify fiber stickiness as the molecular mechanism making the nonlinear elastic response of deformed and undeformed fibrin networks indistinguishable, although the sample partially breaks and never returns to the original state when deformed.…”

Fibrin network adaptation to cell-generated forces

“…Rheology is used to measure the viscoelastic properties of fibrin networks using different rheological techniques (Ferry et al 1997;Jansen et al 2013;Kurniawan et al 2016;Piechocka et al 2016). Ferry et al (1997) were the first to study the linear viscoelastic behavior of fibrin clots using torsional rheometry (Ferry et al 1997).…”