Biotechnology and Bioprocess Engineering

, Volume 12, Issue 1, pp 48–53 | Cite as

Bone tissue engineering using marrow stromal cells

  • Inho Jo
  • Jung Min Lee
  • Hwal Suh
  • Hyongbum Kim


Bone tissue defects cause a significant socioeconomic problem, and bone is the most frequently transplanted tissue beside blood. Autografting is considered the gold standard treatment for bone defects, but its utility is limited due to donor site morbidity. Hence much research has focused on bone tissue engineering as a promising alternative method for repair of bone defects. Marrow stromal cells (MSCs) are considered to be potential cell sources for bone tissue engineering. In bone tissue engineering using MSCs, bone is formed through intramembranous and endochondral ossification in response to osteogenic inducers. Angiogenesis is a complex process mediated by multiple growth factors and is crucial for bone regeneration. Vascular endothelial growth factor plays important roles in bone tissue regeneration by promoting the migration and differentiation of osteoblasts, and by inducing angiogenesis. Scaffold materials used for bone tissue engineering include natural components of bone, such as calcium phosphate and collagen I, and biodegradable polymers such as poly(lactide-coglycolide) However, ideal scaffolds for bone tissue engineering have yet to be found. Bone tissue engineering has been successfully used to treat bone defects in several human clinical trials to regenerate bone defects. Through investigation of MSC biology and the development of novel scaffolds, we will be able to develop advanced bone tissue engineering techniques in the future.


marrow stromal cells tissue engineering bone scaffolds angiogenesis vascular endothelial growth factor 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Rose, F. R. and R. O. Oreffo (2002) Bone tissue engineering: hope vs hype.Biochem. Biophys. Res. Commun. 292 1–7.CrossRefGoogle Scholar
  2. 2.
    Bauer, T. W. and G. F. Muschler (2000) Bone graft materials. An overview of the basic science.Clin. Orthop. Relat. Res. 371: 10–27.CrossRefGoogle Scholar
  3. 3.
    Xu, H. H. and C. G. Simon, Jr. (2005) Fast setting calcium phosphate-chitosan scaffold: mechanical properties and biocompatibility.Biomaterials 26: 1337–1348.CrossRefGoogle Scholar
  4. 4.
    Derubeis, A. R. and R. Cancedda (2004) Bone marrow stromal cells (BMSCs) in bone engineering: limitations and recent advances.Ann. Biomed. Eng. 32: 160–165.CrossRefGoogle Scholar
  5. 5.
    Caplan, A. I. and S. P. Bruder (2001) Mesenchymal stem cells: building blocks for molecular medicine in the 21st century.Trends Mol. Med. 7: 259–264.CrossRefGoogle Scholar
  6. 6.
    Petite, H., V. Viateau, W. Bensaid, A. Meunier, C. de Pollak, M. Bourguignon, K. Oudina, L. Sedel, and G. Guillemin (2000) Tissue-engineered bone regenerationNat. Biotechnol. 18: 959–963.CrossRefGoogle Scholar
  7. 7.
    Shang, Q., Z. Wang, W. Liu, Y. Shi, L. Cui, and Y. Cao (2001) Tissue-engineered bone repair of sheep cranial defects with autologous bone marrow stromal cells.J. Craniofac. Surg. 12: 586–593: discussion 594–595.CrossRefGoogle Scholar
  8. 8.
    Kim, H., H. Suh, S. A. Jo, H. W. Kim, J. M. Lee, E. H. Kim, Y. Reinwald, S. H. Park, B. H. Min, and I. Jo (2005)In vivo bone formation by human marrow stromal cells in biodegradable scaffolds that release dexamethasone and ascorbate-2-phosphate.Biochem. Biophys. Res. Commun. 332: 1053–1060.CrossRefGoogle Scholar
  9. 9.
    Friedenstein, A. J., K. V. Petrakova, A. I. Kurolesova, and G. P. Frolova (1968) Heterotopic of bone marrow Analysis of precursor cells for osteogenic and hematopoietic tissues.Transplantation 6: 230–247.CrossRefGoogle Scholar
  10. 10.
    Friedenstein, A. J., J. F. Gorskaja, and N. N. Kulagina (1976) Fibroblast precursors in normal and irradiated mouse hematopoietic organs.Exp. Hematol. 4: 267–274.Google Scholar
  11. 11.
    Pittenger, M. F., A. M. Mackay, S. C. Beck, R. K. Jaiswal, R. Douglas, J. D. Mosca, M. A. Moorman, D. W. Simonetti, S. Craig, and D. R. Marshak (1999) Multilineage potential of adult human mesenchymal stem cells.Science 284: 143–147.CrossRefGoogle Scholar
  12. 12.
    Kuznetsov, S. A., P. H. Krebsbach, K. Satomura, J. Kerr, M. Riminucci, D. Benayahu, and P. G. Robey (1997) Single-colony derived strains of human marrow stromal fibroblasts form bone after transplantationin vivo.J. Bone Miner. Res. 12: 1335–1347.CrossRefGoogle Scholar
  13. 13.
    Muraglia, A., R. Cancedda, and R. Quarto (2000) Clonal mesenchymal progenitors from human bone marrow differentiatein vitro according to a hierarchical model.J. Cell Sci. 113 (Pt 7): 1161–1166.Google Scholar
  14. 14.
    Gregory, C. A., J. Ylostalo, and D. J. Prockop (2005) Adult bone marrow stem/progenitor cells (MSCs) are preconditioned by microenvironmental “niches” in culture: a two-stage hypothesis for regulation of MSC fate.Sci. STKE 2005: pe37.CrossRefGoogle Scholar
  15. 15.
    Digirolamo, C. M., D. Stokes, D. Colter, D. G. Phinney, R. Class, and D. J. Prockop (1999) Propagation and senescence of human marrow stromal cells in culture: a simple colony-forming assay identifies samples with the greatest potential to propagate and differentiate.Br. J. Haematol. 107: 275–281.CrossRefGoogle Scholar
  16. 16.
    Shi, S., S. Gronthos, S. Chen, A. Reddi, C. M. Counter, P. G. Robey, and C. Y. Wang (2002) Bone formation by human postnatal bone marrow stromal stem cells is enhanced by telomerase expression.Nat. Biotechnol. 20: 587–591.CrossRefGoogle Scholar
  17. 17.
    Simonsen, J. L., C. Rosada, N. Serakinci, J. Justesen, K. Stenderup, S. L. Rattan, T. G. Jensen, and M. Kassem (2002) Telomcrase expression extends the proliferative life-span and maintains the osteogenic potential of human bone marrow stromal cells.Nat. Biotechnol. 20: 592–596.CrossRefGoogle Scholar
  18. 18.
    Gronthos, S., S. Chen, C. Y. Wang, P. G. Robey, and S. Shi (2003) Telomerase accelerates osteogenesis of bone marrow stromal stem cells by upregulation of CBFA1, osterix, and osteocalcin.J. Bone Miner. Res. 18: 716–722.CrossRefGoogle Scholar
  19. 19.
    Sekiya, I., B. L. Larson, J. R. Smith, R. Pochampally, J. G. Cui, and D. J. Prockop (2002) Expansion of human adult stem cells from bone marrow stroma: conditions that maximize the yields of early progenitors and evaluate their quality.Stem Cells 20: 530–541.CrossRefGoogle Scholar
  20. 20.
    Colter, D. C., I. Sekiya, and D. J. Prockop (2001) Identification of a subpopulation of rapidly self-renewing and multipotential adult stem cells in colonies of human marrow stromal cells.Proc. Natl. Acad. Sci. USA 98: 7841–7845.CrossRefGoogle Scholar
  21. 21.
    Colter, D. C., R. Class, C. M. DiGirolamo, and D. J. Prockop (2000) Rapid expansion of recycling stem cells in cultures of plastic-adherent cells from human bone marrow.Proc. Natl. Acad Sci. USA 97: 3213–3218.CrossRefGoogle Scholar
  22. 22.
    Kim, H., J. H. Lee, and H. Suh (2003) Interaction of mesenchymal stem cells and osteoblasts forin vitro osteogenesis.Yonsci Med. J. 44: 187–197.Google Scholar
  23. 23.
    Kim, H., H. W. Kim, and H. Suh (2003) Sustained release of ascorbate-2-phosphate and dexamethasone from porous PLGA scaffolds for bone tissue engineering using mesenchy mal stem cells.Biomaterials 24: 4671–4679.CrossRefGoogle Scholar
  24. 24.
    Jorgensen, N. R., Z. Henriksen, O. H. Sorensen, and R. Civitelli (2004) Dexamethasone, BMP-2, and 1,25-dihydroxyvitamin D enhance a more differentiated osteoblast phenotype; validation of anin vitro model for human bone marrow-derived primary osteoblasts.Steroids 69: 219–226.CrossRefGoogle Scholar
  25. 25.
    Cheng, S. L., J. W. Yang, L. Rifas, S. F. Zhang, and L. V. Avioli (1994) Differentiation of human bone marrow osteogenic stromal cellsin vitro: induction of the osteoblast phenotype by dexamethasone.Endocrinology 134: 277–286.CrossRefGoogle Scholar
  26. 26.
    Huang, W., B. Carlsen, I. Wulur, G. Rudkin, K. Ishida, B. Wu, D. T. Yamaguchi, and T. A. Miller (2004) BMP-2 exerts differential effects on differentiation of rabbit bone marrow stromal cells grown in two-dimensional and three-dimensional systems and is required forin vitro bone formation in a PLGA scaffold.Exp. Cell Res. 299: 325–334.CrossRefGoogle Scholar
  27. 27.
    Bruder, S. P., K. H. Kraus, V. M. Goldberg, and S. Kadiyala (1998) The effect of implants loaded with autologous mesenchymal stem cells on the healing of canine segmental bone defects.J. Bone Joint Surg. Am. 80: 985–996.Google Scholar
  28. 28.
    Noel, D., D. Gazit, C. Bouquet, F. Apparailly, C. Bony, P. Plence, V. Millet, G. Turgeman, M. Perricaudet, J. Sany, and C. Jorgensen (2004) Short-term BMP-2 expression is sufficient forin vivo osteochondral differentiation of mesenchymal stem cells.Stem Cells 22: 74–85.CrossRefGoogle Scholar
  29. 29.
    Diefenderfer, D. L., A. M. Osyczka, G. C. Reilly, and P. S. Leboy (2003) BMP responsiveness in human mesenchymal stem cells.Connect. Tissue Res. 44 Suppl 1: 305–311.CrossRefGoogle Scholar
  30. 30.
    Osyczka, A. M., D. L. Diefenderfer, G. Bhargave, and P. S. Leboy (2004) Different effects of BMP-2 on marrow stromal cells from human and rat bone.Cells Tissues Organs 176: 109–119.CrossRefGoogle Scholar
  31. 31.
    Kronenberg, H. M. (2003) Developmental regulation of the growth plate.Nature 423: 332–336.CrossRefGoogle Scholar
  32. 32.
    Chung, U. I., H. Kawaguchi, T. Takato, and K. Nakamura (2004) Distinct osteogenic mechanisms of bones of distinct origins.J. Orthop. Sci. 9: 410–414.CrossRefGoogle Scholar
  33. 33.
    Choi, I. H., C. Y. Chung, T. J. Cho, and W. J. Yoo (2002) Angiogenesis and mineralization during distraction osteogenesis.J. Kor. Med. Sci. 17: 435–447.Google Scholar
  34. 34.
    Einhorn, T. A. (2005) The science of fracture healing.J. Orthop. Trauma 19 Suppl: S4-S6.CrossRefGoogle Scholar
  35. 35.
    Thompson, Z., T. Miclau, D. Hu, and J. A. Helms (2002) A model for intramembranous ossification during fracture healing.J. Orthop. Res. 20: 1091–1098.CrossRefGoogle Scholar
  36. 36.
    Sampath, T. K., J. C. Maliakal, P. V. Hauschka, W. K. Jones, H. Sasak, R. F. Tucker, K. H. White, J. E. Coughlin, M. M. Tucker, R. H. Panget al. (1992) Recombinant human osteogenic protein-1 (hOP-1) induces new bone formationin vivo with a specific activity comparable with natural bovine osteogenic protein and stimulates osteoblast proliferation and differentiationin vitro.J. Biol. Chem. 267: 20352–20362.Google Scholar
  37. 37.
    Chen, Y., K. M. Cheung, H. F. Kung, J. C. Leong, W. W. Lu, and K. D. Luk (2002)In vivo new bone formation by direct transfer of adenoviral-mediated bone morphogenetic protein-4 gene.Biochem. Biophys. Res. Commun. 298: 121–127.CrossRefGoogle Scholar
  38. 38.
    Simmons, C. A., E. Alsberg, S. Hsiong, W. J. Kim, and D. J. Mooney (2004) Dual growth factor delivery and controlled scaffold degradation enhancein vivo bone formation by transplanted bone marrow stromal cells.Bone 35: 562–569.CrossRefGoogle Scholar
  39. 39.
    Sekiya, I., B. L. Larson, J. T. Vuoristo, R. L. Reger, and D. J. Prockop (2005) Comparison of effect of BMP-2.-4 and-6 onin vitro cartilage formation of human adult stem cells from bone marrow stroma.Cell Tissue Res. 320: 269–276.CrossRefGoogle Scholar
  40. 40.
    Johnstone, B., T. M. Hering, A. I. Caplan, V. M. Goldberg, and J. U. Yoo (1998)In vitro chondrogenesis of bone marrow-derived mesenchymal progenitor cells.Exp. Cell Res. 238: 265–272.CrossRefGoogle Scholar
  41. 41.
    Jaiswal, N., S. E. Haynesworth, A. I. Caplan, and S. P. Bruder (1997) Osteogenic differentiation of purified, culture-expanded human mesenchymal stem cellsin vitro.J. Cell. Biochem. 64: 295–312.CrossRefGoogle Scholar
  42. 42.
    Schacke, H., W. D. Docke, and K. Asadullah (2002) Mechanisms involved in the side effects of glucocorticoids.Pharmacol. Ther. 96: 23–43.CrossRefGoogle Scholar
  43. 43.
    Attisano, L. and J. L. Wrana (2002) Signal transduction by the TGF-beta superfamily.Science 296: 1646–1647.CrossRefGoogle Scholar
  44. 44.
    Childs, S. G. (2005) Osteonecrosis: death of bone cells.Orthop. Nurs. 24: 295–301; quiz 302–303.Google Scholar
  45. 45.
    Hausman, M. R., M. B. Schaffler, and R. I. Majeska (2001) Prevention of fracture healing in rats by an inhibitor of angiogenesis.Bone 29: 560–564.CrossRefGoogle Scholar
  46. 46.
    Fang, T. D., A. Salim, W. Xia, R. P. Nacamuli, S. Guccione, H. M. Song, R. A. Carano, E. H. Filvaroff, M. D. Bednarski, A. J. Giaccia, and M. T. Longaker (2005) Angiogenesis is required for successful bone induction during distraction osteogenesis.J. Bone Miner. Res. 20: 1114–1124.CrossRefGoogle Scholar
  47. 47.
    Maes, C., P. Carmeliet, K. Moermans, I. Stockmans, N. Smets, D. Collen, R. Bouillon, and G. Carmeliet (2002) Impaired angiogenesis and endochondral bone formation in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188.Mech. Dev. 111: 61–73.CrossRefGoogle Scholar
  48. 48.
    Gerber, H. P. and N. Ferrara (2000) Angiogenesis and bone growth.Trends Cardiovasc. Med. 10: 223–228.CrossRefGoogle Scholar
  49. 49.
    Risau, W. (1997) Mechanisms of angiogenesis.Nature 386: 671–674.CrossRefGoogle Scholar
  50. 50.
    Yancopoulos, G. D., S. Davis, N. W. Gale, J. S. Rudge, S. J. Wiegand, and J. Holash (2000) Vascular-specific growth factors and blood vessel formation.Nature 407: 242–248.CrossRefGoogle Scholar
  51. 51.
    Polverini, P. J. (2002) Antiogenesis in health and disease: insights into basic mechanisms and therapeutic opportunities.J. Dent. Educ. 66: 962–975.Google Scholar
  52. 52.
    Street, J., M. Bao, L. deGuzman, S. Bunting, F. V. Peale, Jr., N. Ferrara, H. Steinmetz, J. Hoeffel, J. L. Cleland, A. Daugherty, N. van Bruggen, H. P. Redmond, R. A. Carano, and E. H. Filvaroff (2002) Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover.Proc. Natl. Acad. Sci. USA 99: 9656–9661.CrossRefGoogle Scholar
  53. 53.
    Huang, Y. C., D. Kaigler, K. G. Rice, P. H. Krebsbach, and D. J. Mooney (2005) Combined angiogenic and osteogenic factor delivery enhances bone marrow stromal cell-driven bone regeneration.J. Bone Miner. Res. 20: 848–857.CrossRefGoogle Scholar
  54. 54.
    Kaigler, D., Z. Wang, K. Horger, D. J. Mooney, and P. H. Krebsbach (2006) VEGF scaffolds enhance angiogenesis and bone regeneration in irradiated osseous defects.J. Bone Miner. Res. 21: 735–744.CrossRefGoogle Scholar
  55. 55.
    Leach, J. K., D. Kaigler, Z. Wang, P. H. Krebsbach, and D. J. Mooney (2006) Coating of VEGF-releasing scaffolds with bioactive glass for angiogenesis and bone regeneration.Biomaterials 27: 3249–3255.CrossRefGoogle Scholar
  56. 56.
    Kaigler, D., P. H. Krebsbach, P. J. Polverini, and D. J. Mooney (2003) Role of vascular endothelial growth factor in bone marrow stromal cell modulation of endothelial cells.Tissue Eng. 9: 95–103.CrossRefGoogle Scholar
  57. 57.
    Mayr-Wohlfart, U., J. Waltenberger, H. Hausser, S. Kessler, K. P. Gunther, C. Dehio, W. Puhl, and R. E. Brenner (2002) Vascular endothelial growth factor stimulates chemotactic migration of primary human osteoblasts.Bone 30: 472–477.CrossRefGoogle Scholar
  58. 58.
    Zelzer, E., W. McLean, Y. S. Ng, N. Fukai, A. M. Reginato, S. Lovejoy, P. A. D'Amore, and B. R. Olsen (2002) Skeletal defects in VEGF (120/120) mice reveal multiple roles for VEGF in skeletogenesis.Development 129: 1893–1904.Google Scholar
  59. 59.
    Bouletreau, P. J., S. M. Warren, J. A. Spector, Z. M. Peled, R. P. Gerrets, J. A. Greenwald, and M. T. Longaker (2002) Hypoxia and VEGF up-regulate BMP-2 mRNA and protein expression in microvascular endothelial cells: implications for fracture healing.Plast. Reconstr. Surg. 109: 2384–2397.CrossRefGoogle Scholar
  60. 60.
    El-Ghannam, A. (2005) Bone reconstruction: from bioceramics to tissue engineering.Expert Rev. Med. Devices 2: 87–101.CrossRefGoogle Scholar
  61. 61.
    Whang, K., D. C. Tsai, E. K. Nam, M. Aitken, S. M. Sprague, P. K. Patel, and K. E. Healy (1998) Ectopic bone formation via rhBMP-2 delivery from porous bioabsorbable polymer scaffolds.J. Biomed. Mater. Res. 42: 491–499.CrossRefGoogle Scholar
  62. 62.
    Hsiong, S. X. and D. J. Mooney (2006) Regeneration of vascularized bone.Periodontol. 2000 41: 109–122.CrossRefGoogle Scholar
  63. 63.
    Kotoh, H., T. Kitakoji, H. Tsuchiya, H. Mitsuyama, H. Nakamura, M. Katoh, and N. Ishiguro (2004) Transplantation of marrow-derived mesenchymal stem cells and platelet-rich plasma during distraction osteogenesis: a preliminary result of three cases.Bone 35: 892–898.CrossRefGoogle Scholar
  64. 64.
    Schimming, R. and R. Schmelzeisen (2004) Tissue-engineered bone for maxillary sinus augmentation.J. Oral Maxillofac. Surg. 62: 724–729.CrossRefGoogle Scholar
  65. 65.
    Vacanti, C. A., L. J. Bonassar, M. P. Vacanti, and J. Shufflebarger (2001) Replacement of an avulsed phalanx with tissue-engineered bone.N. Engl. J. Med. 344: 1511–1514.CrossRefGoogle Scholar

Copyright information

© The Korean Society for Biotechnology and Bioengineering 2007

Authors and Affiliations

  • Inho Jo
    • 1
  • Jung Min Lee
    • 1
  • Hwal Suh
    • 2
    • 3
  • Hyongbum Kim
    • 1
  1. 1.Center for Biomedical SciencesNational Institute of HealthSeoulKorea
  2. 2.Department of Medical EngineeringYonsei University College of MedicineSeoulKorea
  3. 3.National BK21 Project Team of Nanobiomaterials for Cell-based ImplantsYonsei UniversitySeoulKorea

Personalised recommendations