Research Papers

Multiscale Modeling of Trabecular Bone Marrow: Understanding the Micromechanical Environment of Mesenchymal Stem Cells During Osteoporosis

[+] Author and Article Information
T. J. Vaughan, M. Voisin

Biomechanics Research Centre (BMEC),
Biomedical Engineering,
National University of Ireland,
Galway, Ireland

G. L. Niebur

Department of Aerospace
and Mechanical Engineering,
University of Notre Dame,
Notre Dame, IN 46556

L. M. McNamara

Biomechanics Research Centre (BMEC),
Biomedical Engineering,
National University of Ireland,
Galway, Ireland
e-mail: Laoise.McNamara@nuigalway.ie

1Corresponding author.

Manuscript received June 1, 2014; final manuscript received October 16, 2014; accepted manuscript posted November 5, 2014; published online December 10, 2014. Assoc. Editor: Ara Nazarian.

J Biomech Eng 137(1), 011003 (Jan 01, 2015) Paper No: BIO-14-1240; doi: 10.1115/1.4028986 History: Received June 01, 2014; Revised October 16, 2014; Accepted November 05, 2014; Online December 10, 2014

Mechanical loading directs the differentiation of mesenchymal stem cells (MSCs) in vitro and it has been hypothesized that the mechanical environment plays a role in directing the cellular fate of MSCs in vivo. However, the complex multicellular composition of trabecular bone marrow means that the precise nature of mechanical stimulation that MSCs experience in their native environment is not fully understood. In this study, we developed a multiscale model that discretely represents the cellular constituents of trabecular bone marrow and applied this model to characterize mechanical stimulation of MCSs in vivo. We predicted that cell-level strains in certain locations of the trabecular marrow microenvironment were greater in magnitude (maximum ε12 = ∼24,000 με) than levels that have been found to result in osteogenic differentiation of MSCs in vitro (>8000 με), which may indicate that the native mechanical environment of MSCs could direct cellular fate in vivo. The results also showed that cell–cell adhesions could play an important role in mediating mechanical stimulation within the MSC population in vivo. The model was applied to investigate how changes that occur during osteoporosis affected mechanical stimulation in the cellular microenvironment of trabecular bone marrow. Specifically, a reduced bone volume (BV) resulted in an overall increase in bone deformation, leading to greater cell-level mechanical stimulation in trabecular bone marrow (maximum ε12 = ∼48,000 με). An increased marrow adipocyte content resulted in slightly lower levels of stimulation within the adjacent cell population due to a shielding effect caused by the more compliant behavior of adipocytes (maximum ε12 = ∼41,000 με). Despite this reduction, stimulation levels in trabecular bone marrow during osteoporosis remained much higher than those predicted to occur under healthy conditions. It was found that compensatory mechanobiological responses that occur during osteoporosis, such as increased trabecular stiffness and axial alignment of trabeculae, would be effective in returning MSC stimulation in trabecular marrow to normal levels. These results have provided novel insight into the mechanical stimulation of the trabecular marrow MSC population in both healthy and osteoporotic bone, and could inform the design three-dimensional (3D) in vitro bioreactor strategies techniques, which seek to emulate physiological conditions.

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Fig. 1

H&E stained sections showing cellular microenvironment of trabecular bone marrow. Samples imaged are from female Wistar rats; (a) healthy (SHAM) control (total age 10 months) and (b) 34 weeks post OVX (total age 18 months).

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Fig. 2

Multiscale modeling framework used to characterize the mechanical environment of trabecular bone marrow depicting (a) the tissue-level trabecular unit cell (BV/TV = 22%) consisting of trabecular bone and surrounding bone marrow (b) trabecular unit cell with submodel L1 boundaries, North and West, identified and FE mesh and (c) cellular submodel that discretely represents the cellular components of bone marrow, where zoom-box shows the level of discretisation in the FE mesh.

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Fig. 4

(a) Distribution of minimum principal strain in trabecular unit cell of healthy bone (BV/TV = 30.4%) under simulated physiological loading conditions, (b) volume average distribution of shear strain from cellular submodels; contour plots of shear strain in cellular submodels for healthy (AVF = 30%) conditions in Regions, (c) L1, (d) L2, and (e) L3 and for osteoporotic conditions (AVF = 60%) in Regions (f) L1, (g) L2, and (h) L3.

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Fig. 5

(a) Volume average distribution of shear strain from cellular submodels comparing the effect of adhesion; contour plots of shear strain in the cellular submodels for (b) adhered cellular distribution, and (c) nonadhered cellular distribution.

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Fig. 6

(a) Distribution of minimum principal strain in trabecular unit cell of osteoporotic bone (BV/TV = 22%) under simulated physiological loading conditions, (b) volume average distribution of shear strain from cellular submodels; contour plots of shear strain in cellular submodels for healthy (AVF = 30%) conditions in Regions, (c) L1, (d) L2, and (e) L3 and for osteoporotic conditions (AVF = 60%) in Regions (f) L1 (g) L2, and (h) L3.

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Fig. 7

(a) Distribution of minimum principal strain in trabecular unit cell of osteoporotic bone (BV/TV = 22%) with increased tissue stiffness; (b) volume average distribution of shear strain from cellular submodels; contour plots of shear strain in cellular submodels for osteoporotic (AVF = 60%) marrow in Region L1 for a tissue stiffness of (c) 1.5 E and (d) 2 E

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Fig. 8

Proposed sequence of events affecting MSC stimulation in trabecular bone marrow during osteoporosis; (i) the initial resorption phase results in a reduced trabecular microarchitecture, with newly created voids being filled by fat cells resulting in an increased adipocyte content in the marrow; (ii) while the increased adipocyte content reduces mechanical loading in the marrow, the reduced trabecular microarchitecture has the opposite effect and dominates mechanical loading in the marrow, resulting in a net increase in MSC stimulation; (iii) this this causes a mechanobiological response, increasing trabecular stiffness, thickness and axial alignment, which in turn causes a reduction in mechanical loading of the marrow, returning stimulation of MSCs to normal levels.



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