Computational modeling of mechanobiology in intact and healing rat Achilles tendon

Abstract: Tendons fulfill an important musculoskeletal function by enabling energy-efficient force transmission between muscles and bones. The tendon is a collagen-rich connective tissue that adapts to mechanical loading through mechanobiological processes. The tendon contains a hierarchical collagen fiber structure that displays complex mechanical behaviour by storing and dissipating energy. Current understanding of how tendon properties adapt to short and long-term mechanical loading is limited, but is key to prevent tendon disease and design optimal rehabilitation protocols after tendon rupture. Recently, an increasing amount of small animal experiments have investigated how intact and healing tendons adapt in vivo upon different mechanical loading regimens. Yet, limited numerical models have investigated tendon mechanobiology; even though existing modeling tools from other research fields are available and the amount of experimental data for validation is growing. The aim of this thesis was to investigate the mechanobiology of intact and healing tendon by utilizing and developing advanced numerical models. First, a 3D finite element framework was used to determine the constitutive viscoelastic material properties of intact healthy tendons in rats. The material properties were fitted to experimental data from rats that were subjected to two loading regimens, i.e. free cage activity (full loading) and reduced loading, for five weeks. The resulting material properties showed strong differences in both elastic and damping properties of the collagen between the rats that were subjected to full or reduced loading. Using this material model, a finite element mechanobiological healing framework for Achilles tendons was developed. The adaptive healing model investigated how principal strain and cell infiltration can govern tissue regeneration. The tendon model was stimulated with different levels of external loading, mimicking physiological and sub-physiological load levels explored in animal experiments. Model predictions of the spatio-temporal evolution of tissue distribution, collagen alignment and mechanical properties (stiffness, creep behaviour and strain levels) were validated by comparison with experimental measurements from rat Achilles tendon throughout the first four weeks of spontaneous healing after rupture. Interestingly, both strain-dependent and cell density-dependent tissue production were identified as possible explanations for decreased tissue production in the tendon core during healing. The healing framework was expanded to predict formation of different tissue types during healing. According to established tissue differentiation frameworks in bone fracture healing, different mechanobiological factors were explored to regulate the formation of different tissue types, i.e. tendon-, cartilage-, fat- and bone-like tissue. This framework is the first to reproduce experimental observations of these tissues. It provides several potential mechanisms of mechanobiological regulation of the formation of different tissue types during tendon healing. In summary, this thesis investigated mechanobiology in intact and healing tendon. An adaptive framework was developed that enabled the prediction of heterogeneous tissue distribution, organization, differentiation, and evolution of mechanical function during tendon healing. The spatial distribution of mechanical stimuli, particularly strain, but also biological stimuli such as cells and oxygen, were identified as potential mechanisms to regulate tendon healing by influencing formation of different tissue types, tissue alignment and the recovery of mechanical properties. Further development and thorough characterization of these models could expand our understanding of mechanobiological, biomechanical or biological processes in intact, diseased or healing tendons. Ultimately, these models could help designing optimal loading regimens to prevent chronic tendon disease or stimulate tendon healing after rupture.