Mechano-biology of bone regeneration
Final Report Abstract
Distraction osteogenesis (DO) is a procedure widely used for the correction of large bone defects. Unfortunately a high rate of complications is associated with this method. Numerical models that could be used to optimize callus distraction have been limited by insufficient in vivo data and have therefore required extensive assumptions regarding tissue behavior. Therefore, in order to create a better numerical model of distraction osteogenesis, it is necessary to both characterize the new tissue's viscoelasticity during distraction and determine the influence of strictly isolated stimulation in each loading mode (tension, compression, and shear) to account for potential differences in mechanical and histological response. To achieve these aims, a unique distraction and stimulation system was developed that allows the application of controlled mechanical movements to healing bone tissue without superimposed interfragmentary movements (IFM) as well as the measurement of the mechanical properties of the newly formed tissue at the tibiae of sheep in vivo. Animal and histological studies were performed to quantify the influence of isolated cyclic stimulation on tissue differentiation and revascularization during the maturation phase of DO. The analysis revealed that only intramembranous bone formation and no endochondral ossification could be seen in the healing zone independent of the magnitude of tissue strain or direction of IFM. The extremely stable distraction procedure employed in this study suppressed chondrocyte differentiation during stimulation with magnitudes that typically lead to endochondral ossification in the distraction and maturation phases. We hypothesize that pure tensile strain in the callus tissue during very stable distraction induces a strong osteogenic differentiation of mesenchymal stem cells and suppresses chondral differentiation. In these studies, it could be shown that a high, approximately equal vessel density results from both small and large amplitude cyclic compression. Tension and shear result in significantly lower vessel density. Additionally, the larger compressive stimulation led to significantly more bone formation than the small compressive stimulation and large tension or shear. The in vivo measurements of the time dependent tissue properties allowed, for the first time, the calculation of material properties under isolated and defined mechanical conditions. The average instantaneous modulus and the equilibrium modulus increased over the distraction phase. Significant differences in viscoelastic behavior during cyclic tension and cyclic compression in the post distraction phase are described. The newly determined viscoelastic Prony model had replaced the former elasto-viscoplastic Perzyna model in our numerical simulation. None of the models could however predict the new vascular growth and bone formation that was seen in the animal study. As an important outcome of this study, it became clear that none of the rules applied so far are sufficient to predict the bone formation. Further specific animal experiments have to be performed to define new tissue transformation rules for callus distraction processes. Nevertheless, the conclusion of this study for the clinical procedure is that a very stable fixation of the bone fragments during the distraction process triggers better vascularization of the post-distraction tissue and intramembranous bone formation without fibrocartilaginous tissue formation. Moderate instabilities during the post distraction process do not disturb the intramembranous bone formation but lead to lower bone formation rates than pure and more stimulatory compression movements.
Publications
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(2017) Novel systems for the application of isolated tensile, compressive, and shearing stimulation of distraction callus tissue. PLOS ONE 12(12):e0189432
Meyers N, Schülke J, Ignatius A, Claes L
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(2018) Evolution of callus tissue behavior during stable distraction osteogenesis, J Mechanical Behaviour Biomedical Materials, 85, 12-19
Meyers N, Schülke J, Ignatius A, Claes L
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(2018) Intramembranous bone formation after callus distraction is augmented by increasing axial compressive strain. PLOS ONE 13(4): e0195466
Schülke J, Meyers N, Reitmaier S, Klose S, Ignatius A, et al.
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(2018) Simulating lateral distraction osteogenesis. PLOS ONE 13(3): e0194500
Niemeyer F, Claes L, Ignatius A, Meyers N, Simon U
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(2018) The mode of interfragmentary movement affects bone formation and revascularization after callus distraction PLOS ONE 13(8): e0202702
Claes L, Schülke J, Meyers N, Reitmaier S, Klose S, Ignatius A
