Abstract
Understanding how bone marrow multipotent stromal cells (MSCs) contribute to new bone formation and remodeling in vivo is of principal importance for informing the development of effective bone tissue engineering strategies in vitro. However, the precise in situ stimuli that MSCs experience have not been fully established. The shear stress generated within the bone marrow of physiologically loaded samples has never been determined, but could be playing an important role in the generation of sufficient stimulus for MSCs to undergo osteogenic differentiation. In this study fluid structure interaction (FSI) computational models were used in conjunction with a bioreactor which physiologically compresses explanted trabecular bone samples to determine whether MSCs can be directly stimulated by mechanical cues within the bone marrow. Experimentally loaded samples were found to have greater osteogenic activity, as verified by bone histomorphometry, compared to control static samples. FSI models demonstrated a linear relationship between increasing shear stress and decreasing bone volume. The FSI models demonstrated that bone strain, not marrow shear stress, was likely the overall driving mechanical signal for new bone formation during compression. However, the shear stress generated in the models is within the range of values which has been shown previously to generate an osteogenic response in MSCs.
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References
Arnsdorf, E. J., P. Tummala, R. Y. Kwon, and C. R. Jacobs. Mechanically induced osteogenic differentiation–the role of RhoA, ROCKII and cytoskeletal dynamics. J. Cell Sci. 122:546–553, 2009.
Bakker, A. D., M. Joldersma, J. Klein-Nulend, and E. H. Burger. Interactive effects of PTH and mechanical stress on nitric oxide and PGE2 production by primary mouse osteoblastic cells. Am. J. Physiol. Endocrinol. Metab. 285:E608–E613, 2003.
Birmingham, E., J. A. Grogan, G. L. Niebur, L. M. McNamara, and P. E. McHugh. Computational modelling of the mechanics of trabecular bone and marrow using fluid structure interaction techniques. Ann. Biomed. Eng. 41:814–826, 2013.
Birmingham, E., T. C. Kreipke, E. B. Dolan, T. R. Coughlin, P. Owens, L. M. McNamara, G. L. Niebur, and P. E. McHugh. Mechanical stimulation of bone marrow in situ induces bone formation in trabecular explants. Ann. Biomed. Eng. 2014. doi:10.1007/s10439-014-1135-0.
Birmingham, E., G. L. Niebur, P. E. McHugh, G. Shaw, F. P. Barry, and L. M. McNamara. Osteogenic differentiation of mesenchymal stem cells is regulated by osteocyte and osteoblast cells in a simplified bone niche. Eur. Cell Mater. 23:13–27, 2012.
Bonewald, L. F. Osteocytes as dynamic multifunctional cells. Ann. N. Y. Acad. Sci. 1116:281–290, 2007.
Bryant, J. D., T. David, P. H. Gaskell, S. King, and G. Lond. Rheology of bovine bone marrow. Proc. Inst. Mech. Eng. H 203:71–75, 1989.
Burr, D. B., C. Milgrom, D. Fyhrie, M. Forwood, M. Nyska, A. Finestone, S. Hoshaw, E. Saiag, and A. Simkin. In vivo measurement of human tibial strains during vigorous activity. Bone 18:405–410, 1996.
Carter, D. R., D. P. Fyhrie, and R. T. Whalen. Trabecular bone density and loading history: regulation of connective tissue biology by mechanical energy. J. Biomech. 20:785–794, 1987.
Cartmell, S. H., B. D. Porter, A. J. García, and R. E. Guldberg. Effects of medium perfusion rate on cell-seeded three-dimensional bone constructs in vitro. Tissue Eng. 9:1197–1203, 2003.
Case, N., B. Sen, J. A. Thomas, M. Styner, Z. Xie, C. R. Jacobs, and J. Rubin. Steady and oscillatory fluid flows produce a similar osteogenic phenotype. Calcif. Tissue Int. 88:189–197, 2011.
Chen, J. C., and C. R. Jacobs. Mechanically induced osteogenic lineage commitment of stem cells. Stem Cell Res. Ther. 4:107, 2013.
Coughlin, T. R., and G. L. Niebur. Fluid shear stress in trabecular bone marrow due to low-magnitude high-frequency vibration. J. Biomech. 45:2222–2229, 2012.
David, V., A. Guignandon, A. Martin, L. Malaval, M.-H. Lafage-Proust, A. Rattner, V. Mann, B. Noble, D. B. Jones, and L. Vico. Ex vivo bone formation in bovine trabecular bone cultured in a dynamic 3D bioreactor is enhanced by compressive mechanical strain. Tissue Eng. A 14:117–126, 2008.
Davies, C. M., D. B. Jones, M. J. Stoddart, K. Koller, E. Smith, C. W. Archer, and R. G. Richards. Mechanically loaded ex vivo bone culture system “Zetos”: systems and culture preparation. Eur. Cell Mater. 11:57–75, 2006; (discussion 75, 2006).
Dickerson, D. A., E. A. Sander, and E. A. Nauman. Modeling the mechanical consequences of vibratory loading in the vertebral body: microscale effects. Biomech. Model. Mechanobiol. 7:191–202, 2008.
Endres, S., M. Kratz, S. Wunsch, and D. B. Jones. Zetos: a culture loading system for trabecular bone. Investigation of different loading signal intensities on bovine bone cylinders. J. Musculoskelet. Neuronal Interact. 9:173–183, 2009.
Fritton, S. P., K. J. McLeod, and C. T. Rubin. Quantifying the strain history of bone: spatial uniformity and self-similarity of low-magnitude strains. J. Biomech. 33:317–325, 2000.
Frost, H. M. Bone, “mass” and the “mechanostat”: a proposal. Anat. Rec. 219:1–9, 1987.
Garman, R., G. Gaudette, L.-R. Donahue, C. Rubin, and S. Judex. Low-level accelerations applied in the absence of weight bearing can enhance trabecular bone formation. J. Orthop. Res. 25:732–740, 2007.
Govey, P. M., A. E. Loiselle, and H. J. Donahue. Biophysical regulation of stem cell differentiation. Curr. Osteoporos. Rep. 11:83–91, 2013.
Gurkan, U. A., and O. Akkus. The mechanical environment of bone marrow: a review. Ann. Biomed. Eng. 36:1978–1991, 2008.
Huiskes, R., R. Ruimerman, G. H. van Lenthe, and J. D. Janssen. Effects of mechanical forces on maintenance and adaptation of form in trabecular bone. Nature 405:704–706, 2000.
Jones, D. B., E. Broeckmann, T. Pohl, and E. L. Smith. Development of a mechanical testing and loading system for trabecular bone studies for long term culture. Eur. Cell Mater. 5:48–59, 2003; (discussion 59–60, 2003).
Kajimura, D., R. Paone, J. J. Mann, and G. Karsenty. Foxo1 regulates Dbh expression and the activity of the sympathetic nervous system in vivo. Mol. Metab. 3:770–777, 2014.
Keaveny, T. M., E. F. Morgan, G. L. Niebur, and O. C. Yeh. Biomechanics of trabecular bone. Annu. Rev. Biomed. Eng. 3:307–333, 2001.
Lambers, F. M., K. Koch, G. Kuhn, D. Ruffoni, C. Weigt, F. A. Schulte, and R. Müller. Trabecular bone adapts to long-term cyclic loading by increasing stiffness and normalization of dynamic morphometric rates. Bone. doi:10.1016/j.bone.2013.04.016.
Lukas, C., D. Ruffoni, F. M. Lambers, F. A. Schulte, G. Kuhn, P. Kollmannsberger, R. Weinkamer, and R. Müller. Mineralization kinetics in murine trabecular bone quantified by time-lapsed in vivo micro-computed tomography. Bone 56:55–60, 2013.
Mann, V., C. Huber, G. Kogianni, D. Jones, and B. Noble. The influence of mechanical stimulation on osteocyte apoptosis and bone viability in human trabecular bone. J. Musculoskelet. Neuronal Interact. 6:408–417, 2006.
Metzger, T. A., T. C. Kreipke, T. J. Vaughan, L. McNamara, and G. L. Niebur. The in situ mechanics of trabecular bone marrow: the potential for mechanobiological response. J. Biomech. Eng. 2014. doi:10.1115/1.4028985.
Mohsin, S., F. J. O’Brien, and T. C. Lee. Microcracks in compact bone: a three-dimensional view. J. Anat. 209:119–124, 2006.
Mosley, J. R. Osteoporosis and bone functional adaptation: mechanobiological regulation of bone architecture in growing and adult bone, a review. J. Rehabil. Res. Dev. 37:189–199, 2000.
Nauman, E. A., R. L. Satcher, T. M. Keaveny, B. P. Halloran, and D. D. Bikle. Osteoblasts respond to pulsatile fluid flow with short-term increases in PGE2 but no change in mineralization. J. Appl. Physiol. 90:1849–1854, 2001.
Parfitt, A. M., M. K. Drezner, F. H. Glorieux, J. A. Kanis, H. Malluche, P. J. Meunier, S. M. Ott, and R. R. Recker. Bone histomorphometry: standardization of nomenclature, symbols, and units: report of the asbmr histomorphometry nomenclature committee. J. Bone Miner. Res. 2:595–610, 1987.
DS SIMULIA. Abaqus 6.12 theory manual. Providence, RI: DS SIMULIA Corp., 2012.
Qin, Y.-X., and H. Lam. Intramedullary pressure and matrix strain induced by oscillatory skeletal muscle stimulation and its potential in adaptation. J. Biomech. 42:140–145, 2009.
Qin, Y. X., H. Lam, S. Ferreri, and C. Rubin. Dynamic skeletal muscle stimulation and its potential in bone adaptation. J. Musculoskelet. Neuronal Interact. 10:12–24, 2010.
Recker, R. R., D. B. Kimmel, A. M. Parfitt, K. M. Davies, N. Keshawarz, and S. Hinders. Static and tetracycline-based bone histomorphometric data from 34 normal postmenopausal females. J. Bone Miner. Res. 3:133–144, 1988.
Sandino, C., J. A. Planell, and D. Lacroix. A finite element study of mechanical stimuli in scaffolds for bone tissue engineering. J. Biomech. 41:1005–1014, 2008.
Schaffler, M. B., W.-Y. Cheung, R. Majeska, and O. Kennedy. Osteocytes: master orchestrators of bone. Calcif. Tissue Int. 2013. doi:10.1007/s00223-013-9790-y.
Schulte, F. A., A. Zwahlen, F. M. Lambers, G. Kuhn, D. Ruffoni, D. Betts, D. J. Webster, and R. Müller. Strain-adaptive in silico modeling of bone adaptation—a computer simulation validated by in vivo micro-computed tomography data. Bone 52:485–492, 2013.
Vaughan, T. J., M. Voisin, G. L. Niebur, and L. M. McNamara. Multiscale modeling of trabecular bone marrow: understanding the micromechanical environment of mesenchymal stem cells during osteoporosis. J. Biomech. Eng. 2015. doi:10.1115/1.4028986.
Verbruggen, S. W., T. J. Vaughan, and L. M. McNamara. Strain amplification in bone mechanobiology: a computational investigation of the in vivo mechanics of osteocytes. J. R. Soc. Interface 9:2735–2744, 2012.
Vivanco, J., S. Garcia, H. L. Ploeg, G. Alvarez, D. Cullen, and E. L. Smith. Apparent elastic modulus of ex vivo trabecular bovine bone increases with dynamic loading. Proc. Inst. Mech. Eng. H 227:904–912, 2013.
Webster, D., E. Wasserman, M. Ehrbar, F. Weber, I. Bab, and R. Müller. Mechanical loading of mouse caudal vertebrae increases trabecular and cortical bone mass-dependence on dose and genotype. Biomech. Model. Mechanobiol. 9:737–747, 2010.
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The authors would like to acknowledge funding from the Irish Research Council, under the EMBARK program, U.S. National Science Foundation grant CMMI 1100207, Science Foundation Ireland under the Short Term Travel Fellowship and the ORS under the Collaborative Exchange Award.
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Associate Editor Sean S. Kohles oversaw the review of this article.
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Birmingham, E., Niebur, G.L., McNamara, L.M. et al. An Experimental and Computational Investigation of Bone Formation in Mechanically Loaded Trabecular Bone Explants. Ann Biomed Eng 44, 1191–1203 (2016). https://doi.org/10.1007/s10439-015-1378-4
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DOI: https://doi.org/10.1007/s10439-015-1378-4