| 1. |
- Notermans, Thomas, et al.
(författare)
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A numerical framework for mechano-regulated tendon healing-Simulation of early regeneration of the Achilles tendon
- 2021
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Ingår i: PLoS Computational Biology. - : Public Library of Science (PLoS). - 1553-7358. ; 17:2, s. 1008636-1008636
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Tidskriftsartikel (refereegranskat)abstract
- Mechano-regulation during tendon healing, i.e. the relationship between mechanical stimuli and cellular response, has received more attention recently. However, the basic mechanobiological mechanisms governing tendon healing after a rupture are still not well-understood. Literature has reported spatial and temporal variations in the healing of ruptured tendon tissue. In this study, we explored a computational modeling approach to describe tendon healing. In particular, a novel 3D mechano-regulatory framework was developed to investigate spatio-temporal evolution of collagen content and orientation, and temporal evolution of tendon stiffness during early tendon healing. Based on an extensive literature search, two possible relationships were proposed to connect levels of mechanical stimuli to collagen production. Since literature remains unclear on strain-dependent collagen production at high levels of strain, the two investigated production laws explored the presence or absence of collagen production upon non-physiologically high levels of strain (>15%). Implementation in a finite element framework, pointed to large spatial variations in strain magnitudes within the callus tissue, which resulted in predictions of distinct spatial distributions of collagen over time. The simulations showed that the magnitude of strain was highest in the tendon core along the central axis, and decreased towards the outer periphery. Consequently, decreased levels of collagen production for high levels of tensile strain were shown to accurately predict the experimentally observed delayed collagen production in the tendon core. In addition, our healing framework predicted evolution of collagen orientation towards alignment with the tendon axis and the overall predicted tendon stiffness agreed well with experimental data. In this study, we explored the capability of a numerical model to describe spatial and temporal variations in tendon healing and we identified that understanding mechano-regulated collagen production can play a key role in explaining heterogeneities observed during tendon healing.
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| 2. |
- Notermans, Thomas
(författare)
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Computational modeling of mechanobiology in intact and healing rat Achilles tendon
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)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.
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| 3. |
- Notermans, Thomas, et al.
(författare)
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Predicting the effect of reduced load level and cell infiltration on spatio-temporal Achilles tendon healing
- 2021
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Ingår i: Journal of Biomechanics. - : Elsevier BV. - 0021-9290.
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Tidskriftsartikel (refereegranskat)abstract
- Mechanobiology plays an important role in tendon healing. However, the relationship between mechanical loading and spatial and temporal evolution of tendon properties during healing is not well understood. This study builds on a recently presented mechanoregulatory computational framework that couples mechanobiological tendon healing to tissue production and collagen orientation. In this study, we investigated how different magnitudes of mechanical stimulation (principal strain) affect the spatio-temporal evolution of tissue production and the temporal evolution of elastic and viscoelastic mechanical parameters. Specifically, we examined the effect of cell infiltration (mimicking migration and proliferation) in the callus on the resulting tissue production by modeling production to depend on local cell density. The model predictions were carefully compared with experimental data from Achilles tendons in rats, at 1, 2 and 4 weeks of healing. In the experiments, the rat tendons had been subjected to free cage activity or reduced load levels through intramuscular botox injections. The simulations that included cell infiltration and strain-regulated collagen production predicted spatio-temporal tissue distributions and mechanical properties similarly to that observed experimentally. In addition, lack of matrix-producing cells in the tendon core during early healing may result in reduced collagen content, regardless of the daily load level. This framework is the first to computationally investigate mechanobiological mechanisms underlying spatial and temporal variations during tendon healing for various magnitudes of loading. This framework will allow further characterization of biomechanical, biological, or mechanobiological processes underlying tendon healing.
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| 4. |
- Notermans, Thomas, et al.
(författare)
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Tendon mechanobiology in small animal experiments during post-transection healing
- 2021
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Ingår i: European Cells and Materials. - Switzerland : AO Research Institute Davos. - 1473-2262. ; 42, s. 375-391
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Tidskriftsartikel (refereegranskat)abstract
- Ruptures to tendons are common and costly, and no clinical consensus exists on the appropriate treatment and rehabilitation regimen to promote their healing as well as full recovery of functionality. Although mechanobiology is known to play an important role in tendon regeneration, the understanding of how mechano-regulated processes affect tendon healing needs further clarification. Many small-animal studies, particularly in rats and mice, have characterized the progression of healing in terms of geometrical, structural, compositional, mechanical, and cellular properties. Some of the properties are also studied under different mechanical loading regimens. The focus of this review is to summarize and generalize the information in the literature regarding spatial and temporal differentiation of tendon properties during rodent tendon healing following full-tendon transection, as well as how this is affected by altered in vivo loading regimens.
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