Multi-scale mechanics of collagen extracellular matrix

Abstract

Extracellular matrix (ECM) provides the principal avenue for mechanochemical communication between tissue and cells. ECM not only plays an important role in providing structural and biomechanical support, but also in regulating a series of cellular behaviors. However, the underlying mechanisms by which the ECM mechanics influence cell and tissue function remain to be elucidated, since this process span size scales from tissue to molecular level. Furthermore, ECM has a hierarchical 3D structure and the load distribution is highly dependent on the architecture and mechanical properties. In this thesis, the multiscale mechanics of collagen ECM was studied using both experimental and modeling approaches. Rheological and biaxial tensile testing were performed to study the macroscopic mechanical properties. A theoretical framework was developed to determine the continuous relaxation spectrum. Investigating the spectrum in terms of number of peaks, peak intensity and time constants sheds light on the main intrinsic properties of viscoelastic materials. Material parameters from continuous relaxation spectrum were used in finite element models to simulate the dynamic rheological measurements of collagen matrix. The microscopic mechanical properties were measured using Optical Magnetic Twisting Cytometry (OMTC). Ferromagnetic beads embedded in the matrix were used as mechanical probes. Our study on the macro- and micro-scopic mechanical properties of collage matrix suggested several interesting differences originated from the scales of measurements. In macroscopic measurements, the storage and shear modulus increase with collagen concentration. At microscopic scale, the apparent storage and loss modulus are less sensitive to changes in collagen concentration. However, the loss modulus is more affected by the local interstitial fluid environment, leading to an increase in viscosity, especially at higher frequencies. A novel experimental approach was established to study the multi-scale ECM mechanics that allows the measurements of local ECM mechanical properties with controlled tissue-level mechanical loading by integrating the OMTC and biaxial tensile tester. Multiphoton imaging reveals structural changes in the collagen network that involve gradual straightening and collagen fiber recruitment with tissue level mechanical loading. Our study shows there is a complex interplay among structural heterogeneity, collagen fiber orientation, and fiber engagement in determining the ECM local mechanical properties.