Predicting the formation of different tissue types during Achilles tendon healing using mechanoregulated and oxygen-regulated frameworks.

During Achilles tendon healing in rodents, besides the expected tendon tissue, also cartilage-, bone- and fat-like tissue features have been observed during the first twenty weeks of healing. Several studies have hypothesized that mechanical loading may play a key role in the formation of different tissue types during healing. We recently developed a computational mechanobiological framework to predict tendon tissue production, organization and mechanical properties during tendon healing. In the current study, we aimed to explore possible mechanobiological related mechanisms underlying formation of other tissue types than tendon tissue during tendon healing. To achieve this, we further developed our recent framework to predict formation of different tissue types, based on mechanobiological models established in other fields, which have earlier not been applied to study tendon healing. We explored a wide range of biophysical stimuli, i.e., principal strain, hydrostatic stress, pore pressure, octahedral shear strain, fluid flow, angiogenesis and oxygen concentration, that may promote the formation of different tissue types. The numerical framework predicted spatiotemporal formation of tendon-, cartilage-, bone- and to a lesser degree fat-like tissue throughout the first twenty weeks of healing, similar to recent experimental reports. Specific features of experimental data were captured by different biophysical stimuli. Our modeling approach showed that mechanobiology may play a role in governing the formation of different tissue types that have been experimentally observed during tendon healing. This study provides a numerical tool that can contribute to a better understanding of tendon mechanobiology during healing. Developing these tools can ultimately lead to development of better rehabilitation regimens that stimulate tendon healing and prevent unwanted formation of cartilage-, fat- and bone-like tissues.