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Predicted evolution of normalised osteoblast density under different loading regimes at Iterations 20, 40 and 60
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Mechanical stimulation, in the form of fluid perfusion or mechanical strain, enhances osteogenic differentiation and overall bone tissue formation by mesenchymal stems cells cultured in biomaterial scaffolds for tissue engineering applications. In silico techniques can be used to predict the mechanical environment within biomaterial scaffolds, and...
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Scaffolds are used in diverse tissue engineering applications as hosts for cell proliferation and extracellular matrix formation. One of the most used tissue engineering materials is collagen, which is well known to be a natural biomaterial, also frequently used as cell substrate, given its natural abundance and intrinsic biocompatibility. This stu...
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... In recent years, there has been an increasing trend toward using artificial intelligence and algorithms for solving medical issues, such as health care efficiency [13], health information services [14], medical image processing [15][16][17], and electrical signal processing [18], etc. Additionally, algorithms have been applied to predict tissue regeneration [19][20][21]. Multiple studies have revealed that tissue regeneration is mechano-driven [22]. ...
A mechano-regulation algorithm was developed to predict the fusion processes of A/O/X/T/PLIF based on finite element modeling and iterative evaluations of the mechanobiological activities of mesenchymal stem cells (MSCs) and their differentiated cells (osteoblasts, chondrocytes, and fibroblasts). Fusion occurred in the grafting region, and each differentiated cell type generated the corresponding tissue proportional to its concentration. The corresponding osteogenesis volume was calculated by multiplying the osteoblast concentration by the grafting volume. Results: TLIF and ALIF achieved markedly greater osteogenesis volumes than did PLIF and O/XLIF (5.46, 5.12, 4.26, and 3.15 cm 3 , respectively). Grafting volume and cage size were the main factors influencing the osteo-genesis outcome in patients treated with LIF. A large grafting volume allowed more osteoblasts (bone tissues) to be accommodated in the disc space. A small cage size reduced the cage/endplate ratio and therefore decreased the stiffness of the LIF. This led to a larger osteogenesis region to promote osteoblastic differentiation of MSCs and osteoblast proliferation (bone regeneration), which subsequently increased the bone fraction in the grafting space. Conclusion: TLIF and ALIF produced more favorable biomechanical environments for osteogenesis than did PLIF and O/XLIF. A small cage and a large grafting volume improve osteogenesis by facilitating osteogenesis-related cell activities driven by mechanical forces.
... The process of converting external mechanical forces into biochemical responses, known as mechanotransduction [5], includes the response of the osteocyte to the cell direct mechanical deformation/strain as a consequence of bone matrix strain [56], to shear stress due to load-induced fluid flow [57], to electric fields caused by stress-generated streaming potentials [58], and to hydrostatic pressure [59]. Recent mechano-regulatory in vitro and in silico bone tissue engineering experiments [60] point towards the determinant influence of low shear strain and fluid velocity in bone adaptive response and cell differentiation. Despite the mechanism of stimuli perception in osteocytes not being fully understood, both cell bodies (e.g., osteocytes plasma membrane disruptions) [61] and dendritic processes [62,63] have been proven to perceive mechanical forces applied to the bone. ...
Bone is an outstanding, well-designed composite. It is constituted by a multi-level structure wherein its properties and behavior are dependent on its composition and structural organization at different length scales. The combination of unique mechanical properties with adaptive and self-healing abilities makes bone an innovative model for the future design of synthetic biomimetic composites with improved performance in bone repair and regeneration. However, the relation between structure and properties in bone is very complex. In this review article, we intend to describe the hierarchical organization of bone on progressively greater scales and present the basic concepts that are fundamental to understanding the arrangement-based mechanical properties at each length scale and their influence on bone’s overall structural behavior. The need for a better understanding of bone’s intricate composite structure is also highlighted.
... The mathematical formulation associated to the octahedral shear strain and interstitial fluid flow leads to a biophysical stimulus driving the differentiation of mesenchymal stem cells into fibroblasts, chondrocytes and osteoblasts. The biological output of such mechanoregulatory theory is the amount of fibrous, cartilaginous and osseous tissue formed [130,135]. At the cellular level, the mechanical stimulation on individual cells seeded into a bone scaffold can be compared to the strains that bone cells experience in vivo, thus identifying the optimal perfusion and compression inducing osteogenic differentiation in a bone scaffold [136]. ...
Mechanical environment has a crucial role in our organism at the different levels, ranging from cells to tissues and our own organs. This regulatory role is especially relevant for bones, given their importance as load-transmitting elements that allow the movement of our body as well as the protection of vital organs from load impacts. Therefore bone, as living tissue, is continuously adapting its properties, shape and repairing itself, being the mechanical loads one of the main regulatory stimuli that modulate this adaptive behavior. Here we review some key results of bone mechanobiology from computational models, describing the effect that changes associated to the mechanical environment induce in bone response, implant design and scaffold-driven bone regeneration.
... [6,20] Similarly, structures optimized for increased fluid flow and surface area provide good computational results for fixation and ingrowth. [21,22] Bone remodeling appears to be its most effective when scaffold elastic tensor matches or is slightly higher than that of the host bone. [6] These studies demonstrate the theory of strain controlled bone remodeling, but this technology is yet to be demonstrated in an experimental human model. ...
Bone remodeling is mediated by several factors including strain. An increase in strain between 1 and 10% compared to homeostasis can trigger bone formation. We aim to create an orthopedic implant using clinically established imaging and manufacturing methods that induces this strain control in human bone. Titanium scaffolds were manufactured with multiaxial apparent modulus tailored to the mechanical properties of bone defined from computed tomography scans of cadaver human tibiae. Five bone cubes were tested with corresponding titanium scaffolds by loading under compression, which is similar to the implanted tibia loading condition. Bone strain was precisely controlled by varying the scaffold modulus, from 0-15% bone strain increase. This strain increase is the magnitude reported to invoke bone's positive remodeling. Axial modulus was closely matched between titanium scaffolds and bone, ranging from 48-728 MPa and 81-800 MPa respectively, whereby scaffold axial modulus was within 2% of nominal target values. Fine control of multiaxial moduli resulted in transverse modulus that matched bone well; ranging from 42-648 MPa and 47-585 MPa in scaffolds and bone respectively. The scaffold manufacturing material and method are already used in the orthopedic industry. This study has significant clinical implications as it enables the design of implants which positively harness bone's natural mechanoresponse and respect bone's mechanical anisotropy and heterogeneity.
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... Therefore, an in silico model could be used to determine the feasibility of medical devices. Computational modelling of bone healing has been extensively described in the literature (Perren and Rahn, 1980;Perren, 2002;Gómez-Benito et al., 2005;Borgiani et al., 2017;Zhao et al., 2018;Alierta et al., 2014) and numerical algorithms of Mg degradation have been developed recently (Gastaldi et al., 2011;Grogan et al., 2011). ...
Orthognathic surgery is performed to realign the jaws of a patient through several osteotomies. The state-of-the-art bone plates used to maintain the bone fragments in place are made of titanium. The presence of these non-degradable plates can have unwanted side effects on the long term (e.g. higher infection risk) if they are not removed. Using a biodegradable material such as magnesium may be a possible solution to this problem. However, biodegradation leads to a decrease of mechanical strength, therefore a time-dependent computational approach can help to evaluate the performance of such plates. In the present work, a computational framework has been developed to include biodegradation and bone healing algorithms in a finite element model. It includes bone plates and the mandible, which are submitted to masticatory loads during the early healing period (two months following the surgery). Two different bone plate designs with different stiffnesses have been tested. The stiff design exhibited good mechanical stability, with maximum Von Mises stress being less than 40% of the yield strength throughout the simulation. The flexible design shows high stresses when the bone healing has not started in the fracture gaps, indicating possible failure of the plate. However, this design leads to a higher bone healing quality after two months, as more cartilage is formed due to higher strains exerted in fracture gaps. We therefore conclude that in silico modelling can support tuning of the design parameters to ensure mechanical stability and while promoting bone healing.
... Matrix deformations and fluid flow occur together (Robling & Turner, 2009), thus delineating the individual roles of each signal in cancer cell mechanobiology studies is challenging. One approach is to apply perfusion and compression in combination and isolation, and several recent studies using this approach report that fluid flow-and compression-induced signals together enhance bone anabolism (Ramani-Mohan et al., 2018;Zhao et al., 2015Zhao et al., , 2018. For example, multiscale computational modeling of a hydrogel scaffold undergoing perfusion, compression, or both predicted that the combination of low magnitude (0.5% peak strain) compression and pore pressure (10 kPa) would induce more osteogenic differentiation and bone mass (Zhao et al., 2018), perhaps as a result of greater cell deformation . ...
... One approach is to apply perfusion and compression in combination and isolation, and several recent studies using this approach report that fluid flow-and compression-induced signals together enhance bone anabolism (Ramani-Mohan et al., 2018;Zhao et al., 2015Zhao et al., , 2018. For example, multiscale computational modeling of a hydrogel scaffold undergoing perfusion, compression, or both predicted that the combination of low magnitude (0.5% peak strain) compression and pore pressure (10 kPa) would induce more osteogenic differentiation and bone mass (Zhao et al., 2018), perhaps as a result of greater cell deformation . Furthermore, when computational approaches were combined with combinatorial experiments involving MSCs with an AP-1 (an intracellular strain sensor) luciferase reporter, applied compression resulted in the greatest cellular deformation and osteogenesis, suggesting physical strain is the main driver of bone anabolism rather than fluid flow alone (Ramani-Mohan et al., 2018). ...
... We previously determined the necessary inlet flow velocity to engender physiological and anabolic wall shear stresses (WSSs) in our bonemimetic scaffold (Liu et al., 2018) as well as determined an osteogenic level of dynamic compression that also impacted bone cell-tumor cell interactions (Lynch et al., 2016). Here, we extend our previous work to include simulations of multiple magnitudes as well as dynamic compression, and we anticipate that the combination of applied compression and perfusion will synergize to produce the greatest mechanical signals (Zhao et al., 2018). ...
Incurable breast cancer bone metastasis causes widespread bone loss, resulting in fragility, pain, increased fracture risk, and ultimately increased patient mortality. Increased mechanical signals in the skeleton are anabolic and protect against bone loss, and they may also do so during osteolytic bone metastasis. Skeletal mechanical signals include interdependent tissue deformations and interstitial fluid flow, but how metastatic tumor cells respond to each of these individual signals remains underinvestigated, a barrier to translation to the clinic. To delineate their respective roles, we report computed estimates of the internal mechanical field of a bone mimetic scaffold undergoing combinations of high and low compression and perfusion using multiphysics simulations. Simulations were conducted in advance of multimodal loading bioreactor experiments with bone metastatic breast cancer cells to ensure that mechanical stimuli occurring internally were physiological and anabolic. Our results show that mechanical stimuli throughout the scaffold were within the anabolic range of bone cells in all loading configurations, were homogenously distributed throughout, and that combined high magnitude compression and perfusion synergized to produce the largest wall shear stresses within the scaffold. These simulations, when combined with experiments, will shed light on how increased mechanical loading in the skeleton may confer anti‐tumorigenic effects during metastasis.
... While high porosities of~80% are regarded as optimal for the regeneration of new bone, cell ingrowth is also highly dependent on the degree of connectivity among the pores [220][221][222][223][224]. Additionally, recent studies are also indicating that interconnected pores are necessary to allow for the circulation of nutrients, waste and to promote the migration of cells to the center of the implant [225,226]. Thus, biomaterials scaffolds for BTE should exhibit both suitable pore sizes and porosity, as well as good interconnectivity among the pores [74,[227][228][229]. ...
Tissue engineering is a promising strategy to treat tissue and organ loss or damage caused by injury or disease. During the past two decades, mesenchymal stem cells (MSCs) have attracted a tremendous amount of interest in tissue engineering due to their multipotency and self-renewal ability. MSCs are also the most multipotent stem cells in the human adult body. However, the application of MSCs in tissue engineering is relatively limited because it is difficult to guide their differentiation toward a specific cell lineage by using traditional biochemical factors. Besides biochemical factors, the differentiation of MSCs also influenced by biophysical cues. To this end, much effort has been devoted to directing the cell lineage decisions of MSCs through adjusting the biophysical properties of biomaterials. The surface topography of the biomaterial-based scaffold can modulate the proliferation and differentiation of MSCs. Presently, the development of micro- and nano-fabrication techniques has made it possible to control the surface topography of the scaffold precisely. In this review, we highlight and discuss how the main topographical features (i.e., roughness, patterns, and porosity) are an efficient approach to control the fate of MSCs and the application of topography in tissue engineering.
... Matrix deformations and fluid flow occur together (Robling & Turner, 2009), thus delineating the individual roles of each signal in cancer cell mechanobiology studies is challenging. One approach is to apply perfusion and compression in combination and isolation, and several recent studies using this approach report that fluid flow-and compression-induced signals together enhance bone anabolism (Ramani-Mohan et al., 2018;Zhao et al., 2015Zhao et al., , 2018. For example, multiscale computational modeling of a hydrogel scaffold undergoing perfusion, compression, or both predicted that the combination of low magnitude (0.5% peak strain) compression and pore pressure (10 kPa) would induce more osteogenic differentiation and bone mass (Zhao et al., 2018), perhaps as a result of greater cell deformation . ...
... One approach is to apply perfusion and compression in combination and isolation, and several recent studies using this approach report that fluid flow-and compression-induced signals together enhance bone anabolism (Ramani-Mohan et al., 2018;Zhao et al., 2015Zhao et al., , 2018. For example, multiscale computational modeling of a hydrogel scaffold undergoing perfusion, compression, or both predicted that the combination of low magnitude (0.5% peak strain) compression and pore pressure (10 kPa) would induce more osteogenic differentiation and bone mass (Zhao et al., 2018), perhaps as a result of greater cell deformation . Furthermore, when computational approaches were combined with combinatorial experiments involving MSCs with an AP-1 (an intracellular strain sensor) luciferase reporter, applied compression resulted in the greatest cellular deformation and osteogenesis, suggesting physical strain is the main driver of bone anabolism rather than fluid flow alone (Ramani-Mohan et al., 2018). ...
... We previously determined the necessary inlet flow velocity to engender physiological and anabolic wall shear stresses (WSSs) in our bonemimetic scaffold (Liu et al., 2018) as well as determined an osteogenic level of dynamic compression that also impacted bone cell-tumor cell interactions (Lynch et al., 2016). Here, we extend our previous work to include simulations of multiple magnitudes as well as dynamic compression, and we anticipate that the combination of applied compression and perfusion will synergize to produce the greatest mechanical signals (Zhao et al., 2018). ...
... Thus, to determine the flow rate for the bioreactor, computational fluid dynamics (CFD) approaches have been used for calculating the fluidic environment within scaffolds with specific micro-structural geometries (Stops et al. 2010;Papantoniou et al. 2014;Zhao et al. 2018b). In many studies, the scaffolds were idealized with a regular geometry due to the limitations on real geometry meshing and high computational cost (Olivares et al. 2009;Ali and Sen 2018a;Melke et al. 2018;Zhao et al. 2018a). However, a recent study found that the WSS calculated based on idealized scaffolds had considerable differences from the one calculated based on a realistic scaffold geometry (Marin and Lacroix 2015). ...
Mechanical stimulation can regulate cellular behavior, e.g., differentiation, proliferation, matrix production and mineralization. To apply fluid-induced wall shear stress (WSS) on cells, perfusion bioreactors have been commonly used in tissue engineering experiments. The WSS on cells depends on the nature of the micro-fluidic environment within scaffolds under medium perfusion. Simulating the fluidic environment within scaffolds will be important for gaining a better insight into the actual mechanical stimulation on cells in a tissue engineering experiment. However, biomaterial scaffolds used in tissue engineering experiments typically have highly irregular pore geometries. This complexity in scaffold geometry implies high computational costs for simulating the precise fluidic environment within the scaffolds. In this study, we propose a low-computational cost and feasible technique for quantifying the micro-fluidic environment within the scaffolds, which have highly irregular pore geometries. This technique is based on a multiscale computational fluid dynamics approach. It is demonstrated that this approach can capture the WSS distribution in most regions within the scaffold. Importantly, the central process unit time needed to run the model is considerably low.
... Various modelling approaches carried out within the last decade are reported in the literature. [32][33][34][35] To evaluate the localized fluid shear stress distributions throughout the culture period from micro-tomography images, giving an indication of the effects of tissue growth on the flow-induced stress field, the authors deployed fluid dynamic simulations using a custom in-house lattice Boltzmann (LBM) program. 30 LBM easily handles complex geometries such as porous media. ...
... CFD approaches have shown promising results to estimate WSS distribution in idealized geometries and numerically reconstructed scaffold geometry from X-ray tomography. [33][34][35]55,56 To date, this strategy has been implemented with considerable success on single scaffold with a singlecell resolution without contrast agent. 28,29 This approach enables the assessment of cell proliferation (and mineralization) within the volume of 3D scaffolds. ...
By favoring cell proliferation and differentiation, perfusion bioreactors proved efficient at optimizing cell culture. The aim of this study was to quantify cell proliferation within a perfusion bioreactor and correlate it to the wall shear stress (WSS) distribution by combining 3‐D imaging and computational fluid dynamics simulations.NIH‐3T3 fibroblasts were cultured onto a scaffold model made of impermeable polyacetal spheres or Polydimethylsiloxane cubes. After 1, 2, and 3 weeks of culture, constructs were analyzed by micro‐computed tomography (μCT) and quantification of cell proliferation was assessed. After 3 weeks, the volume of cells was found four times higher in the stacking of spheres than in the stacking of cube.3D‐μCT reconstruction of bioreactors was used as input for the numerical simulations. Using a lattice‐Boltzmann method, we simulated the fluid flow within the bioreactors. We retrieved the WSS distribution (PDF) on the scaffolds surface at the beginning of cultivation and correlated this distribution to the local presence of cells after 3 weeks of cultivation. We found that the WSS distributions strongly differ between spheres and cubes even if the porosity and the specific wetted area of the stackings were very similar. The PDF is narrower and the mean WSS is lower for cubes (11 mPa) than for spheres (20 mPa). For the stacking of spheres, the relative occupancy of the surface sites by cells is maximal when WSS is greater than 20 mPa. For cubes, the relative occupancy is maximal when the WSS is lower than 10 mPa. The discrepancies between spheres and cubes are attributed to the more numerous sites in stacking of spheres that may induce 3‐D (multi‐layered) proliferation.
