Perfusion applied to a 3D model of bone metastasis results in uniformly dispersed mechanical stimuli

Abstract

Breast cancer most frequently metastasizes to the skeleton. Bone metastatic cancer is incurable and induces wide-spread bone osteolysis, resulting in significant patient morbidity and mortality. Mechanical cues in the skeleton are an important microenvironmental parameter that modulate tumor formation, osteolysis, and tumor cell-bone cell signaling, but which mechanical signals are the most beneficial and the corresponding molecular mechanisms are unknown. We focused on interstitial fluid flow based on its well-known role in bone remodeling and in primary breast cancer. We created a full-scale, microCT-based computational model of a 3D model of bone metastasis undergoing applied perfusion to predict the internal mechanical environment during in vitro experimentation. Applied perfusion resulted in uniformly dispersed, heterogeneous fluid velocities, and wall shear stresses throughout the scaffold's interior. The distributions of fluid velocity and wall shear stress did not change within model sub-domains of varying diameter and location. Additionally, the magnitude of these stimuli is within the range of anabolic mechanical signals in the skeleton, verifying that our 3D model reflects previous in vivo studies using anabolic mechanical loading in the context of bone metastasis. Our results indicate that local populations of cells throughout the scaffold would experience similar mechanical microenvironments.

Strategy for achieving standardized bone models

“…Scaffold architectural features and the ability to accurately control them play a central role in achieving an exploitable mechanical environment (Choi, Zhang, & Xia, ). We find essential to note that randomness often seems to be mistaken for homogeneity (Liu et al, ; Maes et al, ; Qian, Yuan, Zhimin, & Anchun, ). Conventional scaffold manufacturing methods (e.g., particle leaching and fiber meshing) can create only structures with high variability in shape and size within their macroporous network, resulting in “uniformly dispersed” shear stresses and fluid velocities within the scaffolds at best (Liu et al, ).…”

“…In Liu, Han, Hedrick, Modarres‐Sadeghi, and Lynch (), computational fluid dynamics (CFD) are adequately used to confirm that distributions of shear stress and fluid velocity remain constant in various subvolumes of salt‐leached PLG‐HA bone‐mimicking scaffolds. Nevertheless, the calculated shear stress values are distributed from 0.01 to 2,200 mPa, and the fluid velocity ranges from 0 to 4,260 µm/s.…”

“…(a) Wall shear stress map at the transverse cut plane (50%) in an 8‐mm diameter salt‐leached scaffold (pore size 315–400 µm, porosity 55%) for a 12 ml/min flowrate, calculated with HPMF (from Vetsch et al, ). (b) Wall shear stress map at the transverse cut plane (50%) in an 8 mm diameter salt‐leached scaffold (pore size 250–425 µm, porosity 80%) for a 0.3 ml/min flowrate, calculated with finite element analysis based on CFD using the actual scaffold geometry (from Liu et al, )…”

“…Boschetti et al present conflicting values of Darcy scale velocity and average velocity inside the scaffold, strongly impacting the correlation with CFD predicted shear stresses depending on the value used (Figure b). In addition, depending on the study, different viscosity values are declared for similar culture media, from 0.78 (Bacabac et al, ) to 1.45 (Cruel et al, ; Liu et al, ; Olivares, Marshal, Planell, & Lacroix, ; Zhao, Vaughan, & McNamara, ), creating a strong bias in calculated shear stress values for both CFD analysis and the simplified mathematical approach.…”

Numerical accuracy comparison of two boundary conditions commonly used to approximate shear stress distributions in tissue engineering scaffolds cultured under flow perfusion

“…The latter is the more realistic approach since it is based on the actual microscopic pore structures, which are typically obtained via a 3D scanning technique such as micro‐computed tomography (μCT). Yet, due to the computationally intensive nature of the scaffold reconstructions resulting from such high‐resolution imaging, researchers are forced to resort to implementing approximations . For example, rectangular “representative volume elements” (RVE) are cut from whole scaffolds and implemented in conjunction with various boundary conditions along the artificially created periphery.…”