Physiological Loading-Induced Interstitial Fluid Dynamics in Osteon of Osteogenesis Imperfecta Bone.

Osteogenesis imperfecta (OI), also known as "brittle bone disease," is a genetic bone disorder. OI bones experience frequent fractures. Surgical procedures are usually followed by clinicians in the management of OI. It has been observed physical activity is equally beneficial in reducing OI bone fractures in both children and adults as mechanical stimulation improves bone mass and strength. Loading-induced mechanical strain and interstitial fluid flow stimulate bone remodeling activities. Several studies have characterized strain environment in OI bones, whereas very few studies attempted to characterize the interstitial fluid flow. OI significantly affects bone micro-architecture. Thus, this study anticipates that canalicular fluid flow reduces in OI bone in comparison to the healthy bone in response to physiological loading due to altered poromechanical properties. This work attempts to understand the canalicular fluid distribution in single osteon models of OI and healthy bone. A poromechanical model of osteon is developed to compute pore-pressure and interstitial fluid flow as a function of gait loading pattern reported for OI and healthy subjects. Fluid distribution patterns are compared at different time-points of the stance phase of the gait cycle. It is observed that fluid flow significantly reduces in OI bone. Additionally, flow is more static than dynamic in OI osteon in comparison to healthy subjects. This work attempts to identify the plausible explanation behind the diminished mechanotransduction capability of OI bone. This work may further be extended for designing better biomechanical therapies to enhance the fluid flow in order to improve osteogenic activities in OI bone.

Canalicular fluid flow induced by loading waveforms: A comparative analysis.

Dynamic loading on the bone is beneficial in prevention and cure of bone loss as it encourages osteogenesis (i.e., new bone formation). Loading parameters such as strain magnitude, frequency, cycles, and strain rate (depending on loading waveform) affect the new bone formation. In-vivo studies suggested an optimal and osteogenic range of strain magnitude, frequency, and cycles to elicit the maximum new bone response. Still, there is no consensus on the selection of loading waveform. Animal studies on bone adaptation considered sinusoidal, and non-sinusoidal (e.g., trapezoidal, sawtooth, and triangular) loading waveforms according to physiological loadings (e.g., walking, running, and jumping etc.) without considering the relative effect of these waveforms on the loading-induced mechanical environment. The present study attempts to bridge this gap. Accordingly, this work hypothesizes that bone being a biphasic material (solid and fluid phases) experiences the same strain distribution for the different loading waves of the same amplitude, however, other components of the mechanical environment such as pore-pressure and interstitial fluid motion regulating the bone adaptation may differ. An in-vivo cantilever bending study is selected to substantiate the hypothesis. A poroelastic model is used to estimate the pore pressure and fluid motion developed in mouse tibia subjected to the: (i) trapezoidal, (ii) sawtooth, and (iii) triangular bending waves. Furthermore, poroelastic response of pore-pressure and fluid motion induced by these loading waveforms are compared and analyzed. This work also investigates how bone loss associated alterations in the microstructural environment of cortical bone affect the canalicular fluid motion induced by these waveforms. Overall results may be useful in designing optimal biomechanical interventions such as physical exercises to improve the bone health.

In silico modeling of bone adaptation to rest-inserted loading: Strain energy density versus fluid flow as stimulus.

In vivo studies suggest that cyclic and low-magnitude loading can be useful over pharmaceutical drugs in normalizing bone loss as it encourages osteogenesis (i.e. new bone formation) at the sites of elevated strain magnitude. In silico models assumed normal strain or strain energy density (SED) as the stimulus to predict loading-induced osteogenesis, however, these models may have limited success in fitting the in vivo new bone formation at several instances. For example, rest-inserted cyclic loading amplifies the new bone formation as compared to continuous-cyclic loading even though similar strain magnitude were induced in both the cases. It is also believed that loading-induced interstitial fluid flow can also be a potential stimulus of osteogenesis. The present study hypothesizes that fluid motion as osteogenic stimulus may explain the afore-mentioned anomalies. Accordingly, this work studies osteogenesis as functions of SED and canalicular fluid motion using an in silico model. Therefore, the new bone formation is considered roughly proportional to stimuli above their osteogenic thresholds. This model attempts to simulate in vivo new bone formation noticed in rest-inserted cantilever loading studies. The model's prediction of site-specific new bone formation improves when fluid flow is considered as the stimulus. It is also noticed that fluid motion as the stimulus closely fits the new bone formation for another in vivo study where the effects of aging on osteogenesis were examined. These attempts to establish fluid flow as a potential osteogenic stimulus can be useful in the prediction of site-specific new bone formation. The findings will ultimately be useful in designing biomechanical interventions such as prophylactic exercises to cure bone loss.

Computer modelling of electro-osmotically augmented three-layered microvascular peristaltic blood flow.

A theoretical study is presented here for the electro-osmosis modulated peristaltic three-layered capillary flow of viscous fluids with different viscosities in the layers. The layers considered here are the core layer, the intermediate layer and the peripheral layer. The analysis has been carried out under a number of physical restrictions viz. Debye-Hückel linearization (i.e. wall zeta potential ≤25mV) is assumed sufficiently small, thin electric double layer limit (i.e. the peripheral layer is much thicker than the electric double layer thickness), low Reynolds number and large wavelength approximations. A non-dimensional analysis is used to linearize the boundary value problem. Fluid-fluid interfaces, peristaltic pumping characteristics, and trapping phenomenon are simulated. Present study also evaluates the responses of interface, pressure rise, time-averaged volume flow rate, maximum pressure rise, and the influence of Helmholtz-Smoluchowski velocity on the mechanical efficiency (with two different cases of the viscosity of fluids between the intermediate and the peripheral layer). Trapping phenomenon along with bolus dynamics evolution with thin EDL effects are analyzed. The findings of this study may ultimately be useful to control the microvascular flow during the fractionation of blood into plasma (in the peripheral layer), buffy coat (intermediate layer) and erythrocytes (core layer). This work may also contributes in electrophoresis, hematology, electrohydrodynamic therapy and, design and development of biomimetic electro-osmotic pumps.

Computation of physiological loading induced interstitial fluid motion in muscle standardized femur: Healthy vs. osteoporotic bone.

BACKGROUND AND OBJECTIVES: Physiological loading-induced mechanical environments regulate bone modeling and remodeling. Thus, loading-induced normal strain is typically considered a stimulus to osteogenesis. However, several studies noticed new bone formation near the sites of minimal normal strain, e.g., the neutral axis of bending in long bones, which raises a question on how bone mass is maintained near these sites. Secondary mechanical components such as shear strain and interstitial fluid flow also stimulate bone cells and regulate bone mass. However, the osteogenic potential of these components is not well established. Accordingly, the present study estimates the distribution of physiological muscle loading-induced mechanical environments such as normal strain, shear strain, pore pressure, and interstitial fluid flow in long bones. METHODS: A poroelastic finite element muscle standardized femur (MuscleSF) model is developed to compute the distribution of the mechanical environment as a function of bone porosities associated with osteoporotic and disuse bone loss. RESULTS: The results indicate the presence of higher shear strain and interstitial fluid motion near the minimal strain sites, i.e., the neutral axis of bending of femoral cross-sections. This suggests that secondary stimuli may maintain the bone mass at these locations. Pore pressure and interstitial fluid motion reduce with the increased porosity associated with bone disorders, possibly resulting in diminished skeletal mechano-sensitivity to exogenous loading. CONCLUSIONS: These outcomes present a better understanding of mechanical environment-mediated regulation of site-specific bone mass, which can be beneficial in developing prophylactic exercise to prevent bone loss in osteoporosis and muscle disuse.

Computational modeling for osteogenic potential assessment of physical exercises based on loading-induced mechanobiological environments in cortical bone remodeling.

Osteoporosis and disuse can cause bone loss which reduces the weight-bearing strength of long bones. Physical exercise or mechanical loading prevents bone loss as it promotes bone modeling through osteogenesis, i.e., new bone formation. Several studies have observed distinct bone remodeling responses to physical exercises; nevertheless, the underlying mechanism behind such responses is not well established. Loading-induced pore-pressure and fluid motion act as mechanobiological stimuli to bone cells namely osteocytes which further initiate osteoactivities. The shape of loading waveforms also affects the poromechanical environment of bone. Accordingly, the present study hypothesizes that loading waveforms associated with physiological exercises may expose the bone to different mechanobiological stimuli resulting in distinct bone remodeling. A poromechanical finite element model is developed to compute pore-pressure and interstitial fluid velocity in femoral cortical bone tissue (healthy and osteoporotic) subjected to loading waveforms of three physiological exercises namely walking, running, and jumping. The model also computes the mechanobiological stimulus as a function of fluid velocity. The outcomes indicate that pore-pressure and fluid velocity decrease significantly in osteoporotic bone tissue in comparison with healthy tissue. Jumping and running both improve pore-pressure and fluid velocity in healthy and osteoporotic tissues, whereas running significantly enhances mechanobiological stimulus in both the tissues which indicates a possible explanation for distinct bone remodeling to different physical exercises. The present work also suggests that running may be recommended as a potential biomechanical therapeutic to prevent bone loss. Overall, the present work contributes to the area of orthopedic research to develop effective designs of prophylactic exercises to improve bone health.

Modeling cortical bone adaptation using strain gradients.

Cyclic and low-magnitude loading promotes osteogenesis (i.e. new bone formation). Normal strain, strain energy density and fatigue damage accumulation are typically considered as osteogenic stimuli in computer models to predict site-specific new bone formation. These models however had limited success in explaining osteogenesis near the sites of minimal normal strain, for example, neutral axis of bending. Other stimuli such as fluid motion or strain gradient also stimulate bone formation. In silico studies modeled the new bone formation as a function of fluid motion, however, computation of fluid motion involves complex mathematical calculations. Strain gradients drive fluid flow and thus can also be established as the stimulus. Osteogenic potential of strain gradients is however not well established. The present study establishes strain gradients as osteogenic stimuli. Bending-induced strain gradients are computed at cortical bone cross-sections reported in animal loading in vivo studies. Correlation analysis between strain gradients and site of osteogenesis is analyzed. In silico model is also developed to test the osteogenic potential of strain gradients. The model closely predicts in vivo new bone distribution as a function of strain gradients. The outcome establishes strain gradient as computationally easy and robust stimuli to predict site-specific osteogenesis. The present study may be useful in the development of biomechanical approaches to mitigate bone loss.

Anatomical variations in cortical bone surface permeability: Tibia versus femur.

Cortical bone surfaces (periosteal and endosteal) exhibit differential (re)modelling response to mechanical loading. This poses a serious challenge in establishing an in silico model to predict site-specific new bone formation as a function of mechanical stimulus. In this regard, mechanical loading-induced fluid motion in lacunar-canalicular system (LCS) is assumed osteogenic. Micro-architectural properties, especially permeability regulate canalicular fluid motion within the bone. The knowledge of these properties is required to compute flow distribution. Along the same line, it is possible that cortical surfaces may experience differential fluid distribution due to anatomical variations in microarchitectural properties which may induce distinct new bone response at cortical surfaces. Nevertheless, these properties are not well reported for cortical surfaces in the literature. Accordingly, the present study aims to measure microarchitectural properties especially permeability at different anatomical locations (medial, lateral, anterior, and posterior) of periosteal and endosteal surfaces using nanoindentation. A standard poroelastic optimization technique was used to estimate permeability, shear modulus, and Poisson's ratio. The properties are also compared for two weight-bearing bones i.e. tibia and femur. Endosteal surface was found more permeable as compared to the periosteal surface. Tibial endosteal surface had shown greater permeability values at most of the anatomical locations as compared to femoral endosteal surface. The outcomes may be used to precisely predict site-specific osteogenesis in cortical bone as a function of canalicular flow distribution. This work may ultimately be beneficial in designing the loading parameters to stimulate desired new bone response for the prevention and the cure of bone loss.

Signalling molecule transport analysis in lacunar-canalicular system.

Mechanical loading-induced fluid flow in lacunar-canalicular space (LCS) of bone excites osteocyte cells to release signalling molecules which initiate osteo-activities. Theoretical models considered canaliculi as a uniform and symmetrical space/channel in bone. However, experimental studies reported that canalicular walls are irregular and curvy resulting in inhomogeneous fluid motion which may influence the molecular transport. Therefore, a new mathematical model of LCS with curvy canalicular walls is developed to characterize cantilever bending-induced canalicular flow behaviour in terms of pore-pressure, fluid velocity, and streamlines. The model also analyses the mobility of signalling molecules involved in bone mechanotransduction as a function of loading frequency and permeability of LCS. Inhomogeneous flow is observed at higher loading frequency which amplifies mechanotransduction; nevertheless, it also promotes trapping of signalling molecules. The effects of shape and size of signalling molecules on transport behaviour are also studied. Trivially, signalling molecules larger in size and weight move slower as compared to molecules small in size and weight which validates the findings of the present study. The outcomes will ultimately be useful in designing better biomechanical exercise in combination with pharmaceutical agents to improve the bone health.

Establishing the relationship between loading parameters and bone adaptation.

Cyclic and low-magnitude loading is considered effective in arresting the bone loss as it promotes osteogenesis (i.e. new bone formation) at the sites of elevated normal strain magnitude. In silico models assumed normal strain as the stimulus to predict the sites of new bone formation. These models, however, may fail to fit the amount of newly formed bone. Loading parameters such as strain, frequency, and loading cycle decide the amount of new bone formation. The models did not incorporate this information. In fact, there is no unifying relationship to quantify the amount of new bone formation as a function of loading parameters. Therefore, the present work aims to establish an empirical relationship between loading parameters and a new bone formation parameter i.e. mineral apposition rate (MAR). A neural network model is used to serve the purpose. Loading parameters are supplied as input, whereas, MAR served as output. The model is trained and tested with experimental data. The model establishes an empirical relationship to estimate MAR as a function of loading parameters. The model's predictions of MAR align with in vivo experimental results. The model's response is analyzed which indicates that the bone adaptation characteristics are successfully captured in the relationship. The relationship established may be incorporated further to improve qualitative and quantitative prediction capabilities of computer models. These findings can be extended in future to design and develop effective biomechanical strategies such as prophylactic exercise to cure bone loss.

Computer modelling of bone's adaptation: the role of normal strain, shear strain and fluid flow.

Bone loss is a serious health problem. In vivo studies have found that mechanical stimulation may inhibit bone loss as elevated strain in bone induces osteogenesis, i.e. new bone formation. However, the exact relationship between mechanical environment and osteogenesis is less clear. Normal strain is considered as a prime stimulus of osteogenic activity; however, there are some instances in the literature where osteogenesis is observed in the vicinity of minimal normal strain, specifically near the neutral axis of bending in long bones. It suggests that osteogenesis may also be induced by other or secondary components of mechanical environment such as shear strain or canalicular fluid flow. As it is evident from the literature, shear strain and fluid flow can be potent stimuli of osteogenesis. This study presents a computational model to investigate the roles of these stimuli in bone adaptation. The model assumes that bone formation rate is roughly proportional to the normal, shear and fluid shear strain energy density above their osteogenic thresholds. In vivo osteogenesis due to cyclic cantilever bending of a murine tibia has been simulated. The model predicts results close to experimental findings when normal strain, and shear strain or fluid shear were combined. This study also gives a new perspective on the relation between osteogenic potential of micro-level fluid shear and that of macro-level bending shear. Attempts to establish such relations among the components of mechanical environment and corresponding osteogenesis may ultimately aid in the development of effective approaches to mitigating bone loss.