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Bone plates are used to treat bone fractures by stabilizing the fracture site and allowing treatments to take place. Mechanical properties of the applied bone plate determine the stability of the fracture site and affect the endochondral ossification process and the healing performance. In recent years, biodegradable bone plates have been used in demand for the elimination of a second surgery to remove the plate. The degradation of these plates into the body environment is commonly accompanied by alterations in the mechanical properties of the bone plate and a shift in the healing performance of the bone. In the present study, the effects of using biodegradable plates with various elastic moduli and degradation patterns, including linear and nonlinear, on the healing process are investigated. A three-dimensional finite element model of the radius bone along with a mechano-regulation theory was used to study the healing performance. Two mechanical stimuli of octahedral shear strain and interstitial fluid flow are considered as the propelling factors of healing. The results of this study indicated that increasing the bone plate's initial elastic modulus accelerates the healing process. However, by increasing the initial Young's modulus of the plate more than 100 GPa, no noticeable alteration is observed. The degradation time period of the plate was seen to be directly related to the speed of the healing process. It is shown, however, that by increasing the degradation time period to more than 8 weeks, the healing performance remains almost unchanged. The results of this work showed that the application of plates with a high enough initial elastic modulus and degradation period can prevent the healing process from decelerating. [ABSTRACT FROM AUTHOR]

The coated porous section of stem surface is initially filled with callus that undergoes osseointegration process, which develops a bond between stem and bone, lessens the micromotions and transfers stresses to the bone, proximally. This phenomenon attributes to primary and secondary stabilities of the stems that exhibit trade-off the stem stiffness. This study attempts to ascertain the influence of stem stiffness on peri-prosthetic bone formation and stress shielding when in silico models of solid CoCr alloy and Ti alloy stems, and porous Ti stems (53.8 GPa and 31.5 GPa Young's moduli) were implanted. A tissue differentiation predictive mechanoregulation algorithm was employed to estimate the evolutionary bond between bone and stem interfaces with 0.5-mm- and 1-mm-thick calluses. The results revealed that the high stiffness stems yielded higher stress shielding and lower micromotions than that of low stiffness stems. Contrarily, bone formation around solid Ti alloy stem and porous Ti 53.8 GPa stem was augmented in 0.5-mm- and 1-mm-thick calluses, respectively. All designs of stems exhibited different rates of bone formation, diverse initial micromotions and stress shielding; however, long-term bone formation was coherent with different stress shielding. Therefore, contemplating the secondary stability of the stems, low stiffness stem (Ti 53.8 GPa) gave superior biomechanical performance than that of high stiffness stems. [ABSTRACT FROM AUTHOR]

While it is well established that an adequate blood supply is critical to successful bone regeneration, it remains poorly understood how progenitor cell fate is affected by the altered conditions present in fractures with disrupted vasculature. In this study, computational models were used to explore how angiogenic impairment impacts oxygen availability within a fracture callus and hence regulates mesenchymal stem cell (MSC) differentiation and bone regeneration. Tissue differentiation was predicted using a previously developed algorithm which assumed that MSC fate is governed by oxygen tension and substrate stiffness. This model was updated based on the hypothesis that cell death, chondrocyte hypertrophy and endochondral ossification are regulated by oxygen availability. To test this, the updated model was used to simulate the time course of normal fracture healing, where it successfully predicted the observed quantity and spatial distribution of bone and cartilage at 10 and 20 days post-fracture (dpf). It also predicted the ratio of cartilage which had become hypertrophic at 10 dpf. Following this, three models of fracture healing with increasing levels of angiogenic impairment were developed. Under mild impairment, the model predicted experimentally observed reductions in hypertrophic cartilage at 10 dpf as well as the persistence of cartilage at 20 dpf. Models of more severe impairment predicted apoptosis and the development of fibrous tissue. These results provide insight into how factors specific to an ischemic callus regulate tissue regeneration and provide support for the hypothesis that chondrocyte hypertrophy and endochondral ossification during tissue regeneration are inhibited by low oxygen. [ABSTRACT FROM AUTHOR]

Fixation of uncemented implant is influenced by peri-prosthetic bone ingrowth, which is dependent on the mechanical environment of the implant-bone structure. The objective of the study is to gain an insight into the tissue differentiation around an acetabular component. A mapping framework has been developed to simulate appropriate mechanical environment in the three-dimensional microscale model, implement the mechanoregulatory tissue differentiation algorithm and subsequently assess spatial distribution of bone ingrowth around an acetabular component, quantitatively. The FE model of implanted pelvis subjected to eight static load cases during a normal walking cycle was first solved. Thereafter, a mapping algorithm has been employed to include the variations in implant-bone relative displacement and host bone material properties from the macroscale FE model of implanted pelvis to the microscale FE model of the beaded implant-bone interface. The evolutionary tissue differentiation was observed in each of the 13 microscale models corresponding to 13 acetabular regions. The total implant-bone relative displacements, averaged over each region of the acetabulum, were found to vary between 10 and 60 $$\upmu \hbox {m}$$ . Both the linear elastic and biphasic poroelastic models predicted similar mechanoregulatory peri-prosthetic tissue differentiation. Considerable variations in bone ingrowth (13-88 %), interdigitation depth (0.2-0.82 mm) and average tissue Young's modulus (970-3430 MPa) were predicted around the acetabular cup. A progressive increase in the average Young's modulus, interdigitation depth and decrease in average radial strains of newly formed tissue layer were also observed. This scheme can be extended to investigate tissue differentiation for different surface texture designs on the implants. [ABSTRACT FROM AUTHOR]

Uncovering the mechanisms of the sensitivity of bone healing to mechanical factors is critical for understanding the basic biology and mechanobiology of the skeleton, as well as for enhancing clinical treatment of bone injuries. This study refined an experimental method of measuring the strain microenvironment at the site of a bone injury during bone healing. This method used a rat model in which a well-controlled bending motion was applied to an osteotomy to induce the formation of pseudarthrosis that is composed of a range of skeletal tissues, including woven bone, cartilage, fibrocartilage, fibrous tissue, and clot tissue. The goal of this study was to identify both the features of the strain microenvironment associated with formation of these different tissues and the expression of proteins frequently implicated in sensing and transducing mechanical cues. By pairing the strain measurements with histological analyses that identified the regions in which each tissue type formed, we found that formation of the different tissue types occurs in distinct strain microenvironments and that the type of tissue formed is correlated most strongly to the local magnitudes of extensional and shear strains. Weaker correlations were found for dilatation. Immunohistochemical analyses of focal adhesion kinase and rho family proteins RhoA and CDC42 revealed differences within the cartilaginous tissues in the calluses from the pseudarthrosis model as compared to fracture calluses undergoing normal endochondral bone repair. These findings suggest the involvement of these proteins in the way by which mechanical stimuli modulate the process of cartilage formation during bone healing. [ABSTRACT FROM AUTHOR]

Iterative computational models have been used to investigate the regulation of bone fracture healing by local mechanical conditions. Although their predictions replicate some mechanical responses and histological features, they do not typically reproduce the predominantly radial hard callus growth pattern observed in larger mammals. We hypothesised that this discrepancy results from an artefact of the models' initial geometry. Using axisymmetric finite element models, we demonstrated that pre-defining a field of soft tissue in which callus may develop introduces high deviatoric strains in the periosteal region adjacent to the fracture. These bone-inhibiting strains are not present when the initial soft tissue is confined to a thin periosteal layer. As observed in previous healing models, tissue differentiation algorithms regulated by deviatoric strain predicted hard callus forming remotely and growing towards the fracture. While dilatational strain regulation allowed early bone formation closer to the fracture, hard callus still formed initially over a broad area, rather than expanding over time. Modelling callus growth from a thin periosteal layer successfully predicted the initiation of hard callus growth close to the fracture site. However, these models were still susceptible to elevated deviatoric strains in the soft tissues at the edge of the hard callus. Our study highlights the importance of the initial soft tissue geometry used for finite element models of fracture healing. If this cannot be defined accurately, alternative mechanisms for the prediction of early callus development should be investigated. [ABSTRACT FROM AUTHOR]

During secondary bone healing, different tissue types are formed within the fracture callus depending on the local mechanical and biological environment. Our aim was to understand the temporal succession of these tissue patterns for a normal bone healing progression by means of a basic mechanobiological model. The experimental data stemmed from an extensive, previously published animal experiment on sheep with a 3 mm tibial osteotomy. Using recent experimental data, the development of the hard callus was modelled as a porous material with increasing stiffness and decreasing porosity. A basic phenomenological model was employed with a small number of simulation parameters, which allowed comprehensive parameter studies. The model distinguished between the formation of new bone via endochondral and intramembranous ossification. To evaluate the outcome of the computer simulations, the tissue images of the simulations were compared with experimentally derived tissue images for a normal healing progression in sheep. Parameter studies of the threshold values for the regulation of tissue formation were performed, and the source of the biological stimulation (comprising e.g. stem cells) was varied. It was found that the formation of the hard callus could be reproduced in silico for a wide range of threshold values. However, the bridging of the fracture gap by cartilage on the periosteal side was observed only (i) for a rather specific choice of the threshold values for tissue differentiation and (ii) when assuming a strong source of biological stimulation at the periosteum. [ABSTRACT FROM AUTHOR]

The control of the mechanical stimuli transmitted to the cells is critical for the design of functional scaffolds for tissue engineering. The objective of this study was to investigate the dynamics of the mechanical stimuli transmitted to the cells during tissue differentiation in an irregular morphology scaffold under compressive load and perfusion flow. A calcium phosphate-based glass porous scaffold was used. The solid phase and the fluid flow within the pores were modeled as linear elastic solid material and Newtonian fluid, respectively. In the fluid model, different levels of viscosity were used to simulate tissue differentiation. Compressive strain of 0.5% and fluid flow with constant inlet velocity of 10 μm/s or constant inlet pressure of 3 Pa were applied. Octahedral shear strain and fluid shear stress were used as mechano-regulatory stimuli. For constant inlet velocity, stimuli equivalent to bone were predicted in 80% of pore volume for the case of low tissue viscosity. For the cases of high viscosity, fluctuations between stimuli equivalent to tissue formation and cell death were predicted due to the increase in the fluid shear stress when tissue started to fill pores. When constant pressure was applied, stimuli equivalent to bone were predicted in 62% of pore volume when low tissue viscosity was used and 42% when high tissue viscosity was used. This study predicted critical variations of fluid shear stress when cells differentiated. If these variations are not controlled in vitro, they can impede the formation of new matured tissue. [ABSTRACT FROM AUTHOR]

computational model of mechanoregulation is proposed to predict bone tissue formation stimulated mechanically by overall dynamical compression within a porous polymeric scaffold rendered by micro-CT. Dynamic compressions of 0.5–5% at 0.0025–0.025 s were simulated. A force-controlled dynamic compression was also performed by imposing a ramp of force from 1 to 70 N. The model predicts homogeneous mature bone tissue formation under strain levels of 0.5–1% at strain rates of 0.0025–0.005 s. Under higher levels of strain and strain rates, the scaffold shows heterogeneous mechanical behaviour which leads to the formation of a heterogeneous tissue with a mixture of mature bone and fibrous tissue. A fibrous tissue layer was also predicted under the force-controlled dynamic compression, although the same force magnitude was found promoting only mature bone during a strain-controlled compression. The model shows that the mechanical stimulation of bone tissue formation within a porous scaffold closely depends on the loading history and on the mechanical behaviour of the scaffold at local and global scales. [ABSTRACT FROM AUTHOR]

A number of mechano-regulation theories have been proposed that relate the differentiation pathway of mesenchymal stem cells (MSCs) to their local biomechanical environment. During spontaneous repair processes in skeletal tissues, the organisation of the extracellular matrix is a key determinant of its mechanical fitness. In this paper, we extend the mechano-regulation theory proposed by Prendergast et al. (J Biomech 30(6):539–548, 1997) to include the role of the mechanical environment on the collagen architecture in regenerating soft tissues. A large strain anisotropic poroelastic material model is used in a simulation of tissue differentiation in a fracture subject to cyclic bending (Cullinane et al. in J Orthop Res 20(3):579–586, 2002). The model predicts non-union with cartilage and fibrous tissue formation in the defect. Predicted collagen fibre angles, as determined by the principal decomposition of strain- and stress-type tensors, are similar to the architecture seen in native articular cartilage and neoarthroses induced by bending of mid-femoral defects in rats. Both stress and strain-based remodelling stimuli successfully predicted the general patterns of collagen fibre organisation observed in vivo. This provides further evidence that collagen organisation during tissue differentiation is determined by the mechanical environment. It is envisioned that such predictive models can play a key role in optimising MSC-based skeletal repair therapies where recapitulation of the normal tissue architecture is critical to successful repair. [ABSTRACT FROM AUTHOR]

Abstract  Mechanical cues are known to regulate tissue differentiation during skeletal healing. Quantitative characterization of this mechano-regulatory effect has great therapeutic potential. This study tested an existing theory that shear strain and interstitial fluid flow govern skeletal tissue differentiation by applying this theory to a scenario in which a bending motion applied to a healing transverse osteotomy results in cartilage, rather than bone, formation. A 3-D finite element mesh was created from micro-computed tomography images of a bending-stimulated callus and was used to estimate the mechanical conditions present in the callus during the mechanical stimulation. Predictions regarding the patterns of tissues—cartilage, fibrous tissue, and bone—that formed were made based on the distributions of fluid velocity and octahedral shear strain. These predictions were compared to histological sections obtained from a previous study. The mechano-regulation theory correctly predicted formation of large volumes of cartilage within the osteotomy gap and many, though not all patterns of tissue formation observed throughout the callus. The results support the concept that interstitial fluid velocity and tissue shear strain are key mec- hanical stimuli for the differentiation of skeletal tissues. [ABSTRACT FROM AUTHOR]