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There are two main types of fluid in bone tissue, blood and interstitial fluid. The chemical composition of these fluids varies with time and location in bone. Blood arrives through the arterial system containing oxygen and other nutrients and the blood components depart via the venous system containing less oxygen and reduced nutrition. Within the bone, as within other tissues, substances pass from the blood through the arterial walls into the interstitial fluid. The movement of the interstitial fluid carries these substances to the cells within the bone and, at the same time, carries off the waste materials from the cells. Bone tissue would not live without these fluid movements. The development of a model for poroelastic materials with hierarchical pore space architecture for the description of blood flow and interstitial fluid flow in living bone tissue is reviewed. The model is applied to the problem of determining the exchange of pore fluid between the vascular porosity and the lacunar–canalicular porosity in bone tissue due to cyclic mechanical loading and blood pressure. These results are basic to the understanding of interstitial flow in bone tissue that, in turn, is basic to understanding of nutrient transport from the vasculature to the bone cells buried in the bone tissue and to the process of mechanotransduction by these cells.

This contribution reviews recent research performed to assess the porosity and permeability of bone tissue with the objective of understanding interstitial fluid movement. Bone tissue mechanotransduction is considered to occur due to the passage of interstitial pore fluid adjacent to dendritic cell structures in the lacunar–canalicular porosity. The movement of interstitial fluid is also necessary for the nutrition of osteocytes. This review will focus on four topics related to improved assessment of bone interstitial fluid flow. First, the advantages and limitations of imaging technologies to visualize bone porosities and architecture at several length scales are summarized. Second, recent efforts to measure the vascular porosity and lacunar–canalicular microarchitecture are discussed. Third, studies associated with the measurement and estimation of the fluid pressure and permeability in the vascular and lacunar–canalicular domains are summarized. Fourth, the development of recent models to represent the interchange of fluids between the bone porosities is described.

Background The porous structure in bone tissue is essential for maintaining the physiological functions and overall health of intraosseous cells. The lacunar-canalicular net (LCN), a microscopic porous structure within osteons, facilitates the transport of nutrients and signaling molecules through interstitial fluid flow. However, the transient behavior of fluid flow within these micro-pores under dynamic loading conditions remains insufficiently studied. Methods The study constructs a fluid-solid coupling model including the Haversian canal, canaliculi, lacunae, and interstitial fluid, to examine interstitial fluid flow behavior within the LCN under dynamic loading with varying frequencies and amplitudes. The relationship between changes of LCN pore volume and fluid velocity, and pressure is researched. Results The results demonstrate that increasing strain amplitude leads to significant changes of LCN pore volume within osteons. In a complete loading cycle, with the increase of compressive strain, the pore volume in the osteon gradually shrinks, and the pressure gradient in the LCN increases, which promotes the increase of interstitial fluid velocity. When the compressive strain reaches the peak value, the flow velocity also reaches the maximum. In the subsequent unloading process, the pore volume began to recover, the pressure gradient gradually decreased, the flow rate decreased accordingly, and finally returned to the steady state level. At a loading amplitude of 1000 µε, the pore volume within LCN decreases by 1.1‰. At load amplitudes of 1500 µε, 2000 µε, and 2500 µε, the pore volume decreases by 1.6‰, 2.2‰ and 2.7‰ respectively, and the average flow velocity at the center of the superficial lacuna is 1.36 times, 1.77 times, and 2.14 times that at 1000 µε, respectively. Additionally, at a loading amplitude of 1000 µε under three different loading frequencies, the average flow velocities at the center of the superficial bone lacuna are 0.60 μm/s, 1.04 μm/s, and 1.54 μm/s, respectively. This indicates that high-frequency and high-amplitude dynamic loading can promote more vigorous fluid flow and pressure fluctuations with changes in LCN pore volume. Conclusions Dynamic mechanical loading can significantly enhance the interstitial fluid flow in LCN by the changes of LCN pore volume. and dynamic loading promoted fluid flow in shallow lacunae significantly higher than that in deep lacunae. The relationship between changes of LCN pore volume and interstitial fluid flow behavior has implications for drug delivery and bone tissue engineering research.

Flow in a porous medium can be driven by the deformations of the boundaries of the porous domain. Such boundary deformations locally change the volume fraction accessible by the fluid, creating non-uniform porosity and permeability throughout the medium. In this work, we construct a deformation-driven porous medium transport model with spatially and temporally varying porosity and permeability that are dependent on the boundary deformations imposed on the medium. We use this model to study the transport of interstitial fluid along the basement membranes in the arterial walls of the brain. The basement membrane is modeled as a deforming annular porous channel with the compressible pore space filled with an incompressible, Newtonian fluid. The role of a forward propagating peristaltic heart pulse wave and a reverse smooth muscle contraction wave on the flow within the basement membranes is investigated. Our results identify combinations of wave amplitudes that can induce either forward or reverse transport along these transport pathways in the brain. The magnitude and direction of fluid transport predicted by our model can help in understanding the clearance of fluids and solutes along the Intramural Periarterial Drainage route and the pathology of cerebral amyloid angiopathy.

We report on results of experimental flow measurements inside a bone scaffold model, subjected to a uniform incoming flow (applied perfusion). Understanding the flow behavior inside a tissue engineered scaffold is essential for mechanistic studies of mechanobiology, particularly flow-sensitive bone cells. Nearly all existing studies that quantify interstitial flow inside engineered bone scaffolds have been based on numerical results, in part due to the difficulties associated with quantitative measurements and visualization of flow inside large, opaque bone or bone mimics. Thus, an experimental platform to complement and validate in silico studies is needed. Therefore, we developed a flow visualization method using Phase-Contrast Magnetic Resonance Imaging (PC-MRI) to measure flow velocities within a 3D-printed microCT-based rendering of a bone scaffold. We designed and built a non-magnetic recirculating water tunnel to apply uniform perfusion to the 3D-printed model and we measured flow distribution within the scaffold and compared these experimental results with CFD results. Both magnitude and distribution of flow velocities observed at different slices of the scaffold were in quantitative agreement numerically and experimentally. This experimental approach can be used to both validate numerical studies and provide insight into the flow behavior inside tissue-engineered scaffolds for a range of applications, including fundamental mechanobiology of healthy cells, and in the context of diseases, such as cancer.

The present study develops a numerical model, which is the most complex one, in comparison to previous research to investigate drug delivery accompanied by the anti-angiogenesis effect. This paper simulates intravascular blood flow and interstitial fluid flow using a dynamic model. The model accounts for the non-Newtonian behavior of blood and incorporates the adaptation of the diameter of a heterogeneous microvascular network derived from modeling the evolution of endothelial cells toward a circular tumor sprouting from two-parent vessels, with and without imposing the inhibitory effect of angiostatin on a modified discrete angiogenesis model. The average solute exposure and its uniformity in solid tumors of different sizes are studied by numerically solving the convection-diffusion equation. Three different methodologies are considered for simulating anti-angiogenesis: modifying the capillary network, updating the transport properties, and considering both microvasculature and transport properties modifications. It is shown that anti-angiogenic therapy decreases drug wash-out in the periphery of the tumor. Results show the decisive role of microvascular structure, particularly its distribution, and interstitial transport properties modifications induced via vascular normalization on the quality of drug delivery, such that it is improved by 39% in uniformity by the second approach in R = 0.2 cm.

Spinal cord injury (SCI) initiates a complex cascade of chemical and biophysical phenomena that result in tissue swelling, progressive neural degeneration, and formation of a fluid‐filled cavity. Previous studies show fluid pressure above the spinal cord (supraspinal) is elevated for at least 3 days after injury and contributes to a phase of damage called secondary injury. Currently, it is unknown how fluid forces within the spinal cord itself (interstitial) are affected by SCI and if they contribute to secondary injury. We find spinal interstitial pressure increases from −3 mmHg in the naive cord to a peak of 13 mmHg at 3 days post‐injury (DPI) but relatively normalizes to 2 mmHg by 7 DPI. A computational fluid dynamics model predicts interstitial flow velocities up to 0.9 μm/s at 3 DPI, returning to near baseline by 7 DPI. By quantifying vascular leakage of Evans Blue dye after a cervical hemi‐contusion in rats, we confirm an increase in dye infiltration at 3 DPI compared to 7 DPI, suggestive of higher fluid velocities at the time of peak fluid pressure. In vivo expression of the apoptosis marker caspase‐3 is strongly correlated with regions of interstitial flow at 3 DPI, and exogenously enhancing interstitial flow exacerbates tissue damage. In vitro, we show overnight exposure of neuronal cells to low pathological shear stress (0.1 dynes/cm2) significantly reduces cell count and neurite length. Collectively, these results indicate that interstitial fluid flow and shear stress may play a detrimental role in post‐traumatic neural degeneration.

Osteocytes play a critical role in bone mechanobiology, sensing and responding to mechanical loading through fluid flow within the lacunar-canalicular network (LCN). Experimental measurements of interstitial fluid flow in bone are difficult due to the embedded nature of osteocytes in the dense mineralized matrix. Therefore, accurate computer simulations of these processes are essential for understanding bone mechanobiology. Two computational approaches have mostly been used to characterize convective interstitial fluid flow in bone: poroelastic finite element (FE) models, which treat bone as a homogenized porous medium, and fluid–structure interaction (FSI) models, which incorporate explicit LCN microarchitecture. However, these approaches have predicted fluid velocities that differ by three to four orders of magnitude. Here, we investigate the reasons for this discrepancy and demonstrate how imposed pressure gradients influence the predicted fluid velocities. Using an FSI model of a single osteocyte embedded in the mineralized matrix, we show that when an imposed pore pressure gradient is smaller than that generated by bone matrix deformation under mechanical loading, the convective fluid velocities in the canaliculi reach ∼100 nm/s and scale with the applied strain. In contrast, applying higher pressure gradients decouples fluid flow from the solid bone matrix deformation, resulting in fluid velocities bigger than 100 μm/s that are insensitive to loading conditions. Future studies investigating the effect of load-induced convection flow on osteocyte mechanobiology should therefore apply small imposed pressure gradients to avoid overestimating interstitial flow and more realistically capture load-induced convective flow.

At the site of the tumor, myeloid derived suppressor cells (MDSCs) infiltrate and interact with elements of the tumor microenvironment in complex ways. Within the invading tumor, MDSCs are exposed to interstitial fluid flow (IFF) that exists within the chronic inflammatory tumor microenvironment at the tumor–lymphatic interface. As drivers of cell migration and invasion, the link between interstitial fluid flow, lymphatics, and MDSCs have not been clearly established. Here, we hypothesized that interstitial fluid flow and cells within the breast tumor microenvironment modulate migration of MDSCs. We developed a novel 3D model to mimic the breast tumor microenvironment and incorporated MDSCs harvested from 4T1-tumor bearing mice. Using live imaging, we found that sorted GR1+ splenocytes had reduced chemotactic index compared to the unsorted population, but their speed and displacement were similar. Using our adapted tissue culture insert assay, we show that interstitial fluid flow promotes MDSC invasion, regardless of absence or presence of tumor cells. Coordinating with lymphatic endothelial cells, interstitial fluid flow further enhanced invasion of MDSCs in the presence of 4T1 cells. We also show that VEGFR3 inhibition reduced both MDSC and 4T1 flow response. Together, these findings indicate a key role of interstitial fluid flow in MDSC migration as well as describe a tool to explore the immune microenvironment in breast cancer.

The effect of fluid flow on tissue adaptation was the focus of many research works during the last years. Moreover, the use of poroelasticity models to simulate and understand the interstitial flow movement has taken interest due to the possibility to include the fluid effect on mechanical simulations. In particular, shear stresses induced by bone canalicular fluid flow are suggested to be one of the mechanical stimulus controlling bone remodeling processes. Due to the high difficulty to measure canalicular fluid flow and shear stresses, computational poroelastic models can be used in order to estimate these parameters. In this work, a finite element dual porosity model based on Russian doll poroelasticity is developed. Two experiments with a turkey ulna and a human femur are simulated. Bone lacuno-canalicular fluid flow is computed and compared with the experimental results, focusing on the zones of bone remodeling and showing a relation between this flow and the bone formation process.