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Research Papers

The In Situ Mechanics of Trabecular Bone Marrow: The Potential for Mechanobiological Response

[+] Author and Article Information
Thomas A. Metzger, Tyler C. Kreipke

Department of Aerospace
and Mechanical Engineering
and Bioengineering Graduate Program,
Tissue Mechanics Laboratory,
University of Notre Dame,
Notre Dame, IN 46556

Ted J. Vaughan, Laoise M. McNamara

Department of Biomedical Engineering,
National University of Ireland,
Galway, Ireland

Glen L. Niebur

Department of Aerospace
and Mechanical Engineering
and Bioengineering Graduate Program,
Tissue Mechanics Laboratory,
University of Notre Dame,
Notre Dame, IN 46556
e-mail: gniebur@nd.edu

1Corresponding author.

Manuscript received June 26, 2014; final manuscript received October 30, 2014; accepted manuscript posted November 5, 2014; published online December 10, 2014. Assoc. Editor: Blaine Christiansen.

J Biomech Eng 137(1), 011006 (Jan 01, 2015) Paper No: BIO-14-1295; doi: 10.1115/1.4028985 History: Received June 26, 2014; Revised October 30, 2014; Accepted November 05, 2014; Online December 10, 2014

Bone adapts to habitual loading through mechanobiological signaling. Osteocytes are the primary mechanical sensors in bone, upregulating osteogenic factors and downregulating osteoinhibitors, and recruiting osteoclasts to resorb bone in response to microdamage accumulation. However, most of the cell populations of the bone marrow niche, which are intimately involved with bone remodeling as the source of bone osteoblast and osteoclast progenitors, are also mechanosensitive. We hypothesized that the deformation of trabecular bone would impart mechanical stress within the entrapped bone marrow consistent with mechanostimulation of the constituent cells. Detailed fluid-structure interaction models of porcine femoral trabecular bone and bone marrow were created using tetrahedral finite element meshes. The marrow was allowed to flow freely within the bone pores, while the bone was compressed to 2000 or 3000 microstrain at the apparent level. Marrow properties were parametrically varied from a constant 400 mPa·s to a power-law rule exceeding 85 Pa·s. Deformation generated almost no shear stress or pressure in the marrow for the low viscosity fluid, but exceeded 5 Pa when the higher viscosity models were used. The shear stress was higher when the strain rate increased and in higher volume fraction bone. The results demonstrate that cells within the trabecular bone marrow could be mechanically stimulated by bone deformation, depending on deformation rate, bone porosity, and bone marrow properties. Since the marrow contains many mechanosensitive cells, changes in the stimulatory levels may explain the alterations in bone marrow morphology with aging and disease, which may in turn affect the trabecular bone mechanobiology and adaptation.

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References

Schaffler, M. B., Cheung, W. Y., Majeska, R., and Kennedy, O., 2014, “Osteocytes: Master Orchestrators of Bone,” Calcif. Tissue Int., 94(1), pp. 5–24. [CrossRef] [PubMed]
Bonewald, L. F., 2011, “The Amazing Osteocyte,” J. Bone Miner. Res., 26(2), pp. 229–238. [CrossRef] [PubMed]
Gurkan, U. A., and Akkus, O., 2008, “The Mechanical Environment of Bone Marrow: A Review,” Ann. Biomed. Eng., 36(12), pp. 1978–1991. [CrossRef] [PubMed]
Zhong, Z., and Akkus, O., 2011, “Effects of Age and Shear Rate on the Rheological Properties of Human Yellow Bone Marrow,” Biorheology, 48(2), pp. 89–97. [CrossRef] [PubMed]
Bryant, J. D., David, T., Gaskell, P. H., King, S., and Lond, G., 1989, “Rheology of Bovine Bone Marrow,” Proc. Inst. Mech. Eng., Part H, 203(2), pp. 71–75. [CrossRef]
Metzger, T. A., Shudick, J. M., Seekell, R., Zhu, Y., and Niebur, G. L., 2014, “Rheological Behavior of Fresh Bone Marrow and the Effects of Storage,” J. Mech. Behav. Biomed. Mater., 40(C), pp. 307–313. [CrossRef] [PubMed]
Rosen, C. J., and Bouxsein, M. L., 2006, “Mechanisms of Disease: Is Osteoporosis the Obesity of Bone?,” Nat. Clin. Pract. Rheumatol., 2(1), pp. 35–43. [CrossRef] [PubMed]
Devlin, M. J., and Rosen, C. J., “The Bone–Fat Interface: Basic and Clinical Implications of Marrow Adiposity,” Lancet Diabetes Endocrinol. [CrossRef]
Gimble, J. M., and Nuttall, M. E., 2012, “The Relationship Between Adipose Tissue and Bone Metabolism,” Clin. Biochem., 45(12), pp. 874–879. [CrossRef] [PubMed]
Kafka, V., 1993, “On Hydraulic Strengthening of Bones [Letter],” J. Biomech., 26(6), pp. 761–762. [CrossRef] [PubMed]
Bryant, J. D., 1988, “On the Mechanical Function of Marrow in Long Bones,” Eng. Med., 17(2), pp. 55–58. [CrossRef] [PubMed]
Bryant, J. D., 1983, “The Effect of Impact on the Marrow Pressure of Long Bones In Vitro,” J. Biomech., 16(8), pp. 659–665. [CrossRef] [PubMed]
Ochoa, J. A., Sanders, A. P., Kiesler, T. W., Heck, D. A., Toombs, J. P., Brandt, K. D., and Hillberry, B. M., 1997, “In Vitro Observations of Hydraulic Stiffening in the Canine Femoral Head,” ASME J. Biomech. Eng., 119(1), pp. 103–108. [CrossRef]
Ochoa, J. A., Sanders, A. P., Heck, D. A., and Hillberry, B. M., 1991, “Stiffening of the Femoral Head Due to Inter-Trabecular Fluid and Intraosseous Pressure,” ASME J. Biomech. Eng., 113(3), pp. 259–262. [CrossRef]
Pilcher, A., Wang, X., Kaltz, Z., Garrison, J. G., Niebur, G. L., Mason, J., Song, B., Cheng, M., and Chen, W., 2010, “High Strain Rate Testing of Bovine Trabecular Bone,” ASME J. Biomech. Eng., 132(8), p. 081012. [CrossRef]
Kasra, M., and Grynpas, M. D., 2007, “On Shear Properties of Trabecular Bone Under Torsional Loading: Effects of Bone Marrow and Strain Rate,” J. Biomech., 40(13), pp. 2898–2903. [CrossRef] [PubMed]
Carter, D. R., and Hayes, W. C., 1976, “Bone Compressive Strength: The Influence of Density and Strain Rate,” Science, 194(4270), pp. 1174–1176. [CrossRef] [PubMed]
Arramon, Y. P., and Cowin, S. C., 1997, “Hydraulic Stiffening of Cancellous Bone,” Forma, 12(3,4), pp. 209–221.
Whyne, C. M., Hu, S. S., and Lotz, J. C., 2001, “Parametric Finite Element Analysis of Vertebral Bodies Affected by Tumors,” J. Biomech., 34(10), pp. 1317–1324. [CrossRef] [PubMed]
Dickerson, D. A., Sander, E. A., and Nauman, E. A., 2008, “Modeling the Mechanical Consequences of Vibratory Loading in the Vertebral Body: Microscale Effects,” Biomech. Modell. Mechanobiol., 7(3), pp. 191–202. [CrossRef]
Coughlin, T. R., and Niebur, G. L., 2012, “Fluid Shear Stress in Trabecular Bone Marrow due to Low-Magnitude High-Frequency Vibration,” J. Biomech., 45(13), pp. 2222–2229. [CrossRef] [PubMed]
Grellier, M., Bareille, R., Bourget, C., and Amedee, J., 2009, “Responsiveness of Human Bone Marrow Stromal Cells to Shear Stress,” J. Tissue Eng. Regen. Med., 3(4), pp. 302–309. [CrossRef] [PubMed]
Miyanishi, K., Trindade, M. C., Lindsey, D. P., Beaupre, G. S., Carter, D. R., Goodman, S. B., Schurman, D. J., and Smith, R. L., 2006, “Dose- and Time-Dependent Effects of Cyclic Hydrostatic Pressure on Transforming Growth Factor-Beta3-Induced Chondrogenesis by Adult Human Mesenchymal Stem Cells In Vitro,” Tissue Eng., 12(8), pp. 2253–2262. [CrossRef] [PubMed]
Miyanishi, K., Trindade, M. C., Lindsey, D. P., Beaupre, G. S., Carter, D. R., Goodman, S. B., Schurman, D. J., and Smith, R. L., 2006, “Effects of Hydrostatic Pressure and Transforming Growth Factor-Beta 3 on Adult Human Mesenchymal Stem Cell Chondrogenesis In Vitro,” Tissue Eng., 12(6), pp. 1419–1428. [CrossRef] [PubMed]
Nagatomi, J., Arulanandam, B. P., Metzger, D. W., Meunier, A., and Bizios, R., 2003, “Cyclic Pressure Affects Osteoblast Functions Pertinent to Osteogenesis,” Ann. Biomed. Eng., 31(8), pp. 917–923. [CrossRef] [PubMed]
Nagatomi, J., Arulanandam, B. P., Metzger, D. W., Meunier, A., and Bizios, R., 2001, “Frequency- and Duration-Dependent Effects of Cyclic Pressure on Select Bone Cell Functions,” Tissue Eng., 7(6), pp. 717–728. [CrossRef] [PubMed]
Qin, Y. X., Kaplan, T., Saldanha, A., and Rubin, C., 2003, “Fluid Pressure Gradients, Arising From Oscillations in Intramedullary Pressure, Is Correlated With the Formation of Bone and Inhibition of Intracortical Porosity,” J. Biomech., 36(10), pp. 1427–1437. [CrossRef] [PubMed]
Rubin, J., Biskobing, D., Fan, X., Rubin, C., McLeod, K., and Taylor, W. R., 1997, “Pressure Regulates Osteoclast Formation and MCSF Expression in Marrow Culture,” J. Cell Physiol., 170(1), pp. 81–87. [CrossRef] [PubMed]
Nagatomi, J., Arulanandam, B. P., Metzger, D. W., Meunier, A., and Bizios, R., 2002, “Effects of Cyclic Pressure on Bone Marrow Cell Cultures,” ASME J. Biomech. Eng., 124(3), pp. 308–314. [CrossRef]
Birmingham, E., Grogan, J. A., Niebur, G. L., McNamara, L. M., and McHugh, P. E., 2013, “Computational Modelling of the Mechanics of Trabecular Bone and Marrow Using Fluid Structure Interaction Techniques,” Ann. Biomed. Eng., 41(4), pp. 814–826. [CrossRef] [PubMed]
Gurkan, U. A., Krueger, A., and Akkus, O., 2011, “Ossifying Bone Marrow Explant Culture as a Three-Dimensional Mechanoresponsive In Vitro Model of Osteogenesis,” Tissue Eng, Part A, 17(3–4), pp. 417–428. [CrossRef]
Gurkan, U. A., Gargac, J., and Akkus, O., 2010, “The Sequential Production Profiles of Growth Factors and Their Relations to Bone Volume in Ossifying Bone Marrow Explants,” Tissue Eng., Part A, 16(7), pp. 2295–2306. [CrossRef]
Birmingham, E. C., Kreipke, T. C., Dolan, E. B., Coughlin, T. R., Owens, P., McNamara, L. M., Niebur, G. L., and McHugh, P. E., 2014, “Mechanical Stimulation of Bone Marrow In Situ Induces Bone Formation in Trabecular Explants,” Ann. Biomed. Eng. [CrossRef]
Martin, R. B., and Zissimos, S. L., 1991, “Relationships Between Marrow Fat and Bone Turnover in Ovariectomized and Intact Rats,” Bone, 12(2), pp. 123–131. [CrossRef] [PubMed]
Yeung, D. K., Wong, S. Y., Griffith, J. F., and Lau, E. M., 2004, “Bone Marrow Diffusion in Osteoporosis: Evaluation With Quantitative MR Diffusion Imaging,” J. Magn. Reson. Imaging, 19(2), pp. 222–228. [CrossRef] [PubMed]
Griffith, J. F., Yeung, D. K., Tsang, P. H., Choi, K. C., Kwok, T. C., Ahuja, A. T., Leung, K. S., and Leung, P. C., 2008, “Compromised Bone Marrow Perfusion in Osteoporosis,” J. Bone Miner. Res., 23(7), pp. 1068–1075. [CrossRef] [PubMed]
Devlin, M. J., Cloutier, A. M., Thomas, N. A., Panus, D. A., Lotinun, S., Pinz, I., Baron, R., Rosen, C. J., and Bouxsein, M. L., 2010, “Caloric Restriction Leads to High Marrow Adiposity and Low Bone Mass in Growing Mice,” J. Bone Miner. Res., 25(9), pp. 2078–2088. [CrossRef] [PubMed]
Niebur, G. L., Feldstein, M. J., Yuen, J. C., Chen, T. J., and Keaveny, T. M., 2000, “High Resolution Finite Element Models With Tissue Strength Asymmetry Accurately Predict Failure of Trabecular Bone,” J. Biomech., 33(12), pp. 1575–1583. [CrossRef] [PubMed]
Bayraktar, H. H., and Keaveny, T. M., 2004, “Mechanisms of Uniformity of Yield Strains for Trabecular Bone,” J. Biomech., 37(11), pp. 1671–1678. [CrossRef] [PubMed]
Ochoa, J. A., Heck, D. A., Brandt, K. D., and Hillberry, B. M., 1991, “The Effect of Intertrabecular Fluid on Femoral Head Mechanics,” J. Rheumatol., 18(4), pp. 580–584. [PubMed]
Johnson, D. L., McAllister, T. N., and Frangos, J. A., 1996, “Fluid Flow Stimulates Rapid and Continuous Release of Nitric Oxide in Osteoblasts,” Am. J. Physiol., 271(1 Pt 1), pp. E205–E208. [PubMed]
McAllister, T. N., and Frangos, J. A., 1999, “Steady and Transient Fluid Shear Stress Stimulate NO Release in Osteoblasts Through Distinct Biochemical Pathways,” J. Bone Miner. Res., 14(6), pp. 930–936. [CrossRef] [PubMed]
McAllister, T. N., Du, T., and Frangos, J. A., 2000, “Fluid Shear Stress Stimulates Prostaglandin and Nitric Oxide Release in Bone Marrow-Derived Preosteoclast-Like Cells,” Biochem. Biophys. Res. Commun., 270(2), pp. 643–648. [CrossRef] [PubMed]
Castillo, A. B., and Jacobs, C. R., 2010, “Mesenchymal Stem Cell Mechanobiology,” Curr. Osteoporosis Rep., 8(2), pp. 98–104. [CrossRef]
Soves, C. P., Miller, J. D., Begun, D. L., Taichman, R. S., Hankenson, K. D., and Goldstein, S. A., 2014, “Megakaryocytes are Mechanically Responsive and Influence Osteoblast Proliferation and Differentiation,” Bone, 66(C), pp. 111–120. [CrossRef] [PubMed]
Liu, J., Zhao, Z., Li, J., Zou, L., Shuler, C., Zou, Y., Huang, X., Li, M., and Wang, J., 2009, “Hydrostatic Pressures Promote Initial Osteodifferentiation With ERK1/2 Not p38 MAPK Signaling Involved,” J. Cell. Biochem., 107(2), pp. 224–232. [CrossRef] [PubMed]
Liu, J., Zhao, Z., Zou, L., Li, J., Wang, F., Zhang, X., Chen, S., Zhi, M., and Wang, J., 2009, “Pressure-Loaded MSCs During Early Osteodifferentiation Promote Osteoclastogenesis by Increase of RANKL/OPG Ratio,” Ann. Biomed. Eng., 37(4), pp. 794–802. [CrossRef] [PubMed]
Frangos, J. A., McIntire, L. V., and Eskin, S. G., 1988, “Shear Stress Induced Stimulation of Mammalian Cell Metabolism,” Biotechnol. Bioeng., 32(8), pp. 1053–1060. [CrossRef] [PubMed]
Sen, B., Xie, Z., Case, N., Ma, M., Rubin, C., and Rubin, J., 2008, “Mechanical Strain Inhibits Adipogenesis in Mesenchymal Stem Cells by Stimulating a Durable Beta-Catenin Signal,” Endocrinology, 149(12), pp. 6065–6075. [CrossRef] [PubMed]
Govey, P. M., Loiselle, A. E., and Donahue, H. J., 2013, “Biophysical Regulation of Stem Cell Differentiation,” Curr. Osteoporosis Rep., 11(2), pp. 83–91. [CrossRef]
Harrigan, T. P., Jasty, M., Mann, R. W., and Harris, W. H., 1988, “Limitations of the Continuum Assumption in Cancellous Bone,” J. Biomech., 21(4), pp. 269–275. [CrossRef] [PubMed]
Bourne, B. C., and van der Meulen, M. C. H., 2004, “Finite Element Models Predict Cancellous Apparent Modulus When Tissue Modulus is Scaled From Specimen CT-Attenuation,” J. Biomech., 37(5), pp. 613–621. [CrossRef] [PubMed]
Jaasma, M. J., Bayraktar, H. H., Niebur, G. L., and Keaveny, T. M., 2002, “Biomechanical Effects of Intraspecimen Variations in Tissue Modulus for Trabecular Bone,” J. Biomech., 35(2), pp. 237–246. [CrossRef] [PubMed]
Cowin, S. C., 1999, “Bone poroelasticity,” J. Biomech., 32(3), pp. 217–238. [CrossRef] [PubMed]
Cook, D., Julias, M., and Nauman, E., 2014, “Biological Variability in Biomechanical Engineering Research: Significance and Meta-Analysis of Current Modeling Practices,” J. Biomech., 47(6), pp. 1241–1250. [CrossRef] [PubMed]
Yang, H., Butz, K. D., Duffy, D., Niebur, G. L., Nauman, E. A., and Main, R. P., 2014, “Characterization of Cancellous and Cortical Bone Strain in the In Vitro Mouse Tibial Loading Model Using MicroCT-Based Finite Element Analysis,” Bone, 66, pp. 131–139. [CrossRef] [PubMed]
Kohles, S. S., Roberts, J. B., Upton, M. L., Wilson, C. G., Bonassar, L. J., and Schlichting, A. L., 2001, “Direct Perfusion Measurements of Cancellous Bone Anisotropic Permeability,” J. Biomech., 34(9), pp. 1197–1202. [CrossRef] [PubMed]
Souzanchi, M. F., Cardoso, L., and Cowin, S. C., 2013, “Tortuosity and the Averaging of Microvelocity Fields in Poroelasticity,” ASME J. Appl. Mech., 80(2), p. 0209061. [CrossRef]
Downey, D. J., Simkin, P. A., and Taggart, R., 1988, “The Effect of Compressive Loading on Intraosseous Pressure in the Femoral Head In Vitro,” J. Bone Joint Surg., 70(6), pp. 871–877.
Mantila Roosa, S. M., Liu, Y., and Turner, C. H., 2011, “Gene Expression Patterns in Bone Following Mechanical Loading,” J. Bone Miner. Res., 26(1), pp. 100–112. [CrossRef] [PubMed]
Shin, J. W., Swift, J., Ivanovska, I., Spinler, K. R., Buxboim, A., and Discher, D. E., 2013, “Mechanobiology of Bone Marrow Stem Cells: From Myosin-II Forces to Compliance of Matrix and Nucleus in Cell Forms and Fates,” Differentiation, 86(3), pp. 77–86. [CrossRef] [PubMed]
Wu, M. H., Dimopoulos, G., Mantalaris, A., and Varley, J., 2004, “The Effect of Hyperosmotic Pressure on Antibody Production and Gene Expression in the GS-NS0 Cell Line,” Biotechnol. Appl. Biochem., 40(Pt 1), pp. 41–46. [CrossRef] [PubMed]
Di Maggio, N., Piccinini, E., Jaworski, M., Trumpp, A., Wendt, D. J., and Martin, I., 2011, “Toward Modeling the Bone Marrow Niche Using Scaffold-Based 3D Culture Systems,” Biomaterials, 32(2), pp. 321–329. [CrossRef] [PubMed]

Figures

Grahic Jump Location
Fig. 1

(a) Hematoxylin and eosin staining of freshly harvested trabecular bone marrow from a porcine vertebra. Matrix is stained light, and nuclei are dark spots. The marrow consists predominantly of cells (B = bone tissue). (b) Bone marrow is located within the pore space of trabecular bone, where it is subject to mechanical stress during bone deformation.

Grahic Jump Location
Fig. 2

(a) Conforming finite element meshes of a trabecular bone sample with bone marrow. (b) Displacement boundary conditions were applied to the superior surface of the trabecular bone. Confined compression conditions were applied to the bottom and sides. (c) The bone marrow had a zero pressure boundary condition at the bottom surface while the pressure and velocity were unconstrained on all other free surfaces. The interface between bone and marrow had no slip boundary conditions.

Grahic Jump Location
Fig. 3

The deformation of the bone induced shear stress within the marrow (a). A pressure gradient developed during loading due to the differential displacements of the bone and marrow (b), which resulted in fluid velocity on the order of 10 μm/s (c). The results displayed are at 0.1 s, using the power-law viscosity model.

Grahic Jump Location
Fig. 4

The mean shear stress (a) and pressure gradient (b) were calculated by volume averaging over the nodal finite element results at selected time points. An initial transient increase in both outputs was followed by a decrease as the bone deformation reached its maximum, and then increased as the bone reached its maximum strain rate. Only the compressive portion of the load cycle is displayed here.

Grahic Jump Location
Fig. 5

The spatial distribution of the marrow shear stress for the 1 Hz simulation to 3000 μ-strain at 0.5 s (maximum velocity). Marrow shear stress was highest at the bone–marrow interface, with stress dissipating toward the middle of the pores. Shear stress was below mechanostimulatory levels when the viscosity was assume to be 0.4 Pa·s (a). Shear stress increased when marrow was modeled at 85 Pa·s (b) and as a power-law material (c). However, the spatial distribution of shear stress and the velocity gradients were similar for all cases, indicating that viscous forces dominate the solution.

Grahic Jump Location
Fig. 6

The mean shear stress (a) and pressure gradient magnitude (b) were proportional to the maximum strain rate for all three marrow constitutive models

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Fig. 7

The pressure gradient (a), velocity gradient magnitude (b), and shear stress (c) calculated for the power law viscosity model increased proportionally with strain rate

Grahic Jump Location
Fig. 8

Distributions of shear stress in the two specimens at the peak shear rate demonstrate that increased trabecular bone density (BV/TV) increases the shear stress in the marrow, and subjects a larger fraction of the marrow to higher shear stress

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