Integration of Biomaterials into 3D Stem Cell Microenvironments

  • Andres Bratt-Leal
  • Richard Carpenedo
  • Todd McDevitt
Chapter
Part of the Studies in Mechanobiology, Tissue Engineering and Biomaterials book series (SMTEB, volume 2)

Abstract

Stem cells receive physical and chemical cues capable of influencing their phenotype from inter-related elements of the microenvironment, such as cell–cell contacts, soluble molecule signals and physical interactions with the ECM. In contrast to conventional 2D culture systems, barriers to diffusion within 3D cultures limit the effectiveness of media manipulation as a method to direct cell behavior. Efforts to engineer stem cell microenvironments in 3D using biomaterials have generally been attempted by either scaffold seeding, cell encapsulation, or microcarrier/microparticle based approaches. These different methods have been applied not only for the propagation of pluri- and multipotent stem cells, but also to direct the differentiation of such stem cells into more differentiated phenotypes. This chapter discusses the unique benefits, as well as associated challenges of integrating biomaterials into 3D stem cell microenvironments.

References

  1. 1.
    Watt, F.M., Hogan, B.L.: Out of Eden: stem cells and their niches. Science 287(5457), 1427–1430 (2000)CrossRefGoogle Scholar
  2. 2.
    Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., Yamanaka, S.: Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131(5), 861–872 (2007)CrossRefGoogle Scholar
  3. 3.
    Yu, J., Vodyanik, M.A., Smuga-Otto, K., Antosiewicz-Bourget, J., Frane, J.L., Tian, S., Nie, J., Jonsdottir, G.A., Ruotti, V., Stewart, R., Slukvin, II, Thomson, J.A.: Induced pluripotent stem cell lines derived from human somatic cells. Science 318(5858), 1917–1920 (2007)CrossRefGoogle Scholar
  4. 4.
    Spradling, A., Drummond-Barbosa, D., Kai, T.: Stem cells find their niche. Nature 414(6859), 98–104 (2001)CrossRefGoogle Scholar
  5. 5.
    Thomson, J.A., Itskovitz-Eldor, J., Shapiro, S.S., Waknitz, M.A., Swiergiel, J.J., Marshall, V.S., Jones, J.M.: Embryonic stem cell lines derived from human blastocysts. Science 282(5391), 1145–1147 (1998)CrossRefGoogle Scholar
  6. 6.
    Amit, M., Carpenter, M.K., Inokuma, M.S., Chiu, C.P., Harris, C.P., Waknitz, M.A., Itskovitz-Eldor, J., Thomson, J.A.: Clonally derived human embryonic stem cell lines maintain pluripotency and proliferative potential for prolonged periods of culture. Dev. Biol. 227(2), 271–278 (2000)CrossRefGoogle Scholar
  7. 7.
    Smith, A.G., Heath, J.K., Donaldson, D.D., Wong, G.G., Moreau, J., Stahl, M., Rogers, D.: Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides. Nature 336(6200), 688–690 (1988)CrossRefGoogle Scholar
  8. 8.
    Williams, R.L., Hilton, D.J., Pease, S., Willson, T.A., Stewart, C.L., Gearing, D.P., Wagner, E.F., Metcalf, D., Nicola, N.A., Gough, N.M.: Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells. Nature 336(6200), 684–687 (1988)CrossRefGoogle Scholar
  9. 9.
    Xu, C., Inokuma, M.S., Denham, J., Golds, K., Kundu, P., Gold, J.D., Carpenter, M.K.: Feeder-free growth of undifferentiated human embryonic stem cells. Nat. Biotechnol. 19(10), 971–974 (2001)CrossRefGoogle Scholar
  10. 10.
    Martin, M.J., Muotri, A., Gage, F., Varki, A.: Human embryonic stem cells express an immunogenic nonhuman sialic acid. Nat. Med. 11(2), 228–232 (2005)CrossRefGoogle Scholar
  11. 11.
    Amit, M., Shariki, C., Margulets, V., Itskovitz-Eldor, J.: Feeder layer- and serum-free culture of human embryonic stem cells. Biol. Reprod. 70(3), 837–845 (2004)CrossRefGoogle Scholar
  12. 12.
    Doetschman, T.C., Eistetter, H., Katz, M., Schmidt, W., Kemler, R.: The in vitro development of blastocyst-derived embryonic stem cell lines: formation of visceral yolk sac, blood islands and myocardium. J. Embryol. Exp. Morphol. 87, 27–45 (1985)Google Scholar
  13. 13.
    Wada, T., Honda, M., Minami, I., Tooi, N., Amagai, Y., Nakatsuji, N., Aiba, K.: Highly efficient differentiation and enrichment of spinal motor neurons derived from human and monkey embryonic stem cells. PLoS One 4(8), e6722 (2009)CrossRefGoogle Scholar
  14. 14.
    Langer, R., Vacanti, J.P.: Tissue engineering. Science 260(5110), 920–926 (1993)CrossRefGoogle Scholar
  15. 15.
    Li, W.J., Tuli, R., Okafor, C., Derfoul, A., Danielson, K.G., Hall, D.J., Tuan, R.S.: A three-dimensional nanofibrous scaffold for cartilage tissue engineering using human mesenchymal stem cells. Biomaterials 26(6), 599–609 (2005)CrossRefGoogle Scholar
  16. 16.
    Li, W.J., Chiang, H., Kuo, T.F., Lee, H.S., Jiang, C.C., Tuan, R.S.: Evaluation of articular cartilage repair using biodegradable nanofibrous scaffolds in a swine model: a pilot study. J. Tissue Eng. Regen. Med. 3(1), 1–10 (2009)CrossRefMATHGoogle Scholar
  17. 17.
    Li, W.J., Tuli, R., Huang, X., Laquerriere, P., Tuan, R.S.: Multilineage differentiation of human mesenchymal stem cells in a three-dimensional nanofibrous scaffold. Biomaterials 26(25), 5158–5166 (2005)CrossRefGoogle Scholar
  18. 18.
    Yang, J., Cao, C., Wang, W., Tong, X., Shi, D., Wu, F., Zheng, Q., Guo, C., Pan, Z., Gao, C., Wang, J.: Proliferation and osteogenesis of immortalized bone marrow-derived mesenchymal stem cells in porous polylactic glycolic acid scaffolds under perfusion culture. J. Biomed. Mater. Res. A (2009)Google Scholar
  19. 19.
    Xin, X., Hussain, M., Mao, J.J.: Continuing differentiation of human mesenchymal stem cells and induced chondrogenic and osteogenic lineages in electrospun PLGA nanofiber scaffold. Biomaterials 28(2), 316–325 (2007)CrossRefGoogle Scholar
  20. 20.
    Park, K., Cho, K.J., Kim, J.J., Kim, I.H., Han, D.K.: Functional PLGA scaffolds for chondrogenesis of bone-marrow-derived mesenchymal stem cells. Macromol. Biosci. 9(3), 221–229 (2009)CrossRefGoogle Scholar
  21. 21.
    Tanaka, T., Hirose, M., Kotobuki, N., Tadokoro, M., Ohgushi, H., Fukuchi, T., Sato, J., Seto, K.: Bone augmentation by bone marrow mesenchymal stem cells cultured in three-dimensional biodegradable polymer scaffolds. J. Biomed. Mater. Res. A 91(2), 428–435 (2009)CrossRefGoogle Scholar
  22. 22.
    Stiehler, M., Bunger, C., Baatrup, A., Lind, M., Kassem, M., Mygind, T.: Effect of dynamic 3-D culture on proliferation, distribution, and osteogenic differentiation of human mesenchymal stem cells. J. Biomed. Mater. Res. A 89(1), 96–107 (2009)Google Scholar
  23. 23.
    Hofmann, S., Knecht, S., Langer, R., Kaplan, D.L., Vunjak-Novakovic, G., Merkle, H.P., Meinel, L.: Cartilage-like tissue engineering using silk scaffolds and mesenchymal stem cells. Tissue Eng. 12(10), 2729–2738 (2006)CrossRefGoogle Scholar
  24. 24.
    Meinel, L., Hofmann, S., Karageorgiou, V., Zichner, L., Langer, R., Kaplan, D., Vunjak-Novakovic, G.: Engineering cartilage-like tissue using human mesenchymal stem cells and silk protein scaffolds. Biotechnol. Bioeng. 88(3), 379–391 (2004)CrossRefGoogle Scholar
  25. 25.
    Meinel, L., Karageorgiou, V., Hofmann, S., Fajardo, R., Snyder, B., Li, C., Zichner, L., Langer, R., Vunjak-Novakovic, G., Kaplan, D.L.: Engineering bone-like tissue in vitro using human bone marrow stem cells and silk scaffolds. J. Biomed. Mater. Res. A 71(1), 25–34 (2004)CrossRefGoogle Scholar
  26. 26.
    Kim, H.J., Kim, U.J., Kim, H.S., Li, C., Wada, M., Leisk, G.G., Kaplan, D.L.: Bone tissue engineering with premineralized silk scaffolds. Bone 42(6), 1226–1234 (2008)CrossRefGoogle Scholar
  27. 27.
    Li, Y.J., Chung, E.H., Rodriguez, R.T., Firpo, M.T., Healy, K.E.: Hydrogels as artificial matrices for human embryonic stem cell self-renewal. J. Biomed. Mater. Res. A 79(1), 1–5 (2006)CrossRefGoogle Scholar
  28. 28.
    Nur, E.K.A., Ahmed, I., Kamal, J., Schindler, M., Meiners, S.: Three-dimensional nanofibrillar surfaces promote self-renewal in mouse embryonic stem cells. Stem Cells 24(2), 426–433 (2006)CrossRefGoogle Scholar
  29. 29.
    Levenberg, S., Huang, N.F., Lavik, E., Rogers, A.B., Itskovitz-Eldor, J., Langer, R.: Differentiation of human embryonic stem cells on three-dimensional polymer scaffolds. Proc. Natl Acad. Sci. USA 100(22), 12741–12746 (2003)CrossRefGoogle Scholar
  30. 30.
    Levenberg, S., Burdick, J.A., Kraehenbuehl, T., Langer, R.: Neurotrophin-induced differentiation of human embryonic stem cells on three-dimensional polymeric scaffolds. Tissue Eng. 11(3–4), 506–512 (2005)CrossRefGoogle Scholar
  31. 31.
    Liu, H., Roy, K.: Biomimetic three-dimensional cultures significantly increase hematopoietic differentiation efficacy of embryonic stem cells. Tissue Eng. 11(1–2), 319–330 (2005)CrossRefGoogle Scholar
  32. 32.
    Liu, H., Lin, J., Roy, K.: Effect of 3D scaffold and dynamic culture condition on the global gene expression profile of mouse embryonic stem cells. Biomaterials 27(36), 5978–5989 (2006)CrossRefGoogle Scholar
  33. 33.
    Gerecht-Nir, S., Cohen, S., Itskovitz-Eldor, J.: Bioreactor cultivation enhances the efficiency of human embryoid body (hEB) formation and differentiation. Biotechnol. Bioeng. 86(5), 493–502 (2004)CrossRefGoogle Scholar
  34. 34.
    Willerth, S.M., Arendas, K.J., Gottlieb, D.I., Sakiyama-Elbert, S.E.: Optimization of fibrin scaffolds for differentiation of murine embryonic stem cells into neural lineage cells. Biomaterials 27(36), 5990–6003 (2006)CrossRefGoogle Scholar
  35. 35.
    Liu, H., Collins, S.F., Suggs, L.J.: Three-dimensional culture for expansion and differentiation of mouse embryonic stem cells. Biomaterials 27(36), 6004–6014 (2006)CrossRefGoogle Scholar
  36. 36.
    Battista, S., Guarnieri, D., Borselli, C., Zeppetelli, S., Borzacchiello, A., Mayol, L., Gerbasio, D., Keene, D.R., Ambrosio, L., Netti, P.A.: The effect of matrix composition of 3D constructs on embryonic stem cell differentiation. Biomaterials 26(31), 6194–6207 (2005)CrossRefGoogle Scholar
  37. 37.
    Garreta, E., Genove, E., Borros, S., Semino, C.E.: Osteogenic differentiation of mouse embryonic stem cells and mouse embryonic fibroblasts in a three-dimensional self-assembling peptide scaffold. Tissue Eng. 12(8), 2215–2227 (2006)CrossRefGoogle Scholar
  38. 38.
    Karoubi, G., Ormiston, M.L., Stewart, D.J., Courtman, D.W.: Single-cell hydrogel encapsulation for enhanced survival of human marrow stromal cells. Biomaterials 30(29), 5445–5455 (2009)CrossRefGoogle Scholar
  39. 39.
    Dang, S.M., Gerecht-Nir, S., Chen, J., Itskovitz-Eldor, J., Zandstra, P.W.: Controlled, scalable embryonic stem cell differentiation culture. Stem Cells 22(3), 275–282 (2004)CrossRefGoogle Scholar
  40. 40.
    Markusen, J.F., Mason, C., Hull, D.A., Town, M.A., Tabor, A.B., Clements, M., Boshoff, C.H., Dunnill, P.: Behavior of adult human mesenchymal stem cells entrapped in alginate-GRGDY beads. Tissue Eng. 12(4), 821–830 (2006)CrossRefGoogle Scholar
  41. 41.
    Ma, H.L., Hung, S.C., Lin, S.Y., Chen, Y.L., Lo, W.H.: Chondrogenesis of human mesenchymal stem cells encapsulated in alginate beads. J. Biomed. Mater. Res. A 64(2), 273–281 (2003)CrossRefGoogle Scholar
  42. 42.
    Maguire, T., Novik, E., Schloss, R., Yarmush, M.: Alginate-PLL microencapsulation: effect on the differentiation of embryonic stem cells into hepatocytes. Biotechnol. Bioeng. 93(3), 581–591 (2006)CrossRefGoogle Scholar
  43. 43.
    Connelly, J.T., Garcia, A.J., Levenston, M.E.: Inhibition of in vitro chondrogenesis in RGD-modified three-dimensional alginate gels. Biomaterials 28(6), 1071–1083 (2007)CrossRefGoogle Scholar
  44. 44.
    Park, J.S., Woo, D.G., Yang, H.N., Lim, H.J., Park, K.M., Na, K., Park, K.H.: Chondrogenesis of human mesenchymal stem cells encapsulated in a hydrogel construct: neocartilage formation in animal models as both mice and rabbits. J. Biomed. Mater. Res. A 92(3), 988–996 (2010)Google Scholar
  45. 45.
    Nuttelman, C.R., Tripodi, M.C., Anseth, K.S.: In vitro osteogenic differentiation of human mesenchymal stem cells photoencapsulated in PEG hydrogels. J. Biomed. Mater. Res A 68(4), 773–782 (2004)CrossRefGoogle Scholar
  46. 46.
    Alhadlaq, A., Tang, M., Mao, J.J.: Engineered adipose tissue from human mesenchymal stem cells maintains predefined shape and dimension: implications in soft tissue augmentation and reconstruction. Tissue Eng. 11(3–4), 556–566 (2005)CrossRefGoogle Scholar
  47. 47.
    Hwang, N.S., Varghese, S., Zhang, Z., Elisseeff, J.: Chondrogenic differentiation of human embryonic stem cell-derived cells in arginine-glycine-aspartate-modified hydrogels. Tissue Eng. 12(9), 2695–2706 (2006)CrossRefGoogle Scholar
  48. 48.
    Temenoff, J.S., Park, H., Jabbari, E., Sheffield, T.L., LeBaron, R.G., Ambrose, C.G., Mikos, A.G.: In vitro osteogenic differentiation of marrow stromal cells encapsulated in biodegradable hydrogels. J. Biomed. Mater. Res. A 70(2), 235–244 (2004)CrossRefGoogle Scholar
  49. 49.
    Fok, E.Y., Zandstra, P.W.: Shear-controlled single-step mouse embryonic stem cell expansion and embryoid body-based differentiation. Stem Cells 23(9), 1333–1342 (2005)CrossRefGoogle Scholar
  50. 50.
    Ng, E.S., Davis, R.P., Azzola, L., Stanley, E.G., Elefanty, A.G.: Forced aggregation of defined numbers of human embryonic stem cells into embryoid bodies fosters robust, reproducible hematopoietic differentiation. Blood 106(5), 1601–1603 (2005)CrossRefGoogle Scholar
  51. 51.
    Bauwens, C.L., Peerani, R., Niebruegge, S., Woodhouse, K.A., Kumacheva, E., Husain, M., Zandstra, P.W.: Control of human embryonic stem cell colony and aggregate size heterogeneity influences differentiation trajectories. Stem Cells 26(9), 2300–2310 (2008)CrossRefGoogle Scholar
  52. 52.
    Kramer, J., Hegert, C., Guan, K., Wobus, A.M., Muller, P.K., Rohwedel, J.: Embryonic stem cell-derived chondrogenic differentiation in vitro: activation by BMP-2 and BMP-4. Mech. Dev. 92(2), 193–205 (2000)CrossRefGoogle Scholar
  53. 53.
    Gerecht, S., Brudick, J.A., Ferreira, L., Townsend, S.A., Langer, R., Vunjak-Novakovic, G.: Hyaluronic acid hydrogel for controlled self-renewal and differentiation of human embryonic stem cell. Proc. Natl Acad. Sci. USA 104(27), 11298–11303 (2007)CrossRefGoogle Scholar
  54. 54.
    Siti-Ismail, N., Bishop, A.E., Polak, J.M., Mantalaris, A.: The benefit of human embryonic stem cell encapsulation for prolonged feeder-free maintenance. Biomaterials 29(29), 3946–3952 (2008)CrossRefGoogle Scholar
  55. 55.
    Hwang, N.S., Varghese, S., Theprungsirikul, P., Canver, A., Elisseeff, J.: Enhanced chondrogenic differentiation of murine embryonic stem cells in hydrogels with glucosamine. Biomaterials 27(36), 6015–6023 (2006)CrossRefGoogle Scholar
  56. 56.
    Bauwens, C., Yin, T., Dang, S., Peerani, R., Zandstra, P.W.: Development of a perfusion fed bioreactor for embryonic stem cell-derived cardiomyocyte generation: oxygen-mediated enhancement of cardiomyocyte output. Biotechnol Bioeng. 90(4), 452–461 (2005)CrossRefGoogle Scholar
  57. 57.
    Chayosumrit, M., Tuch, B., Sidhu, K.: Alginate microcapsule for propagation and directed differentiation of hESCs to definitive endoderm. Biomaterials 31(3), 505–514 (2009)CrossRefGoogle Scholar
  58. 58.
    Benoit, D.S., Schwartz, M.P., Durney, A.R., Anseth, K.S.: Small functional groups for controlled differentiation of hydrogel-encapsulated human mesenchymal stem cells. Nat. Mater. 7(10), 816–823 (2008)CrossRefGoogle Scholar
  59. 59.
    Nie, Y., Bergendahl, V., Hei, D.J., Jones, J.M., Palecek, S.P.: Scalable culture and cryopreservation of human embryonic stem cells on microcarriers. Biotechnol. Prog. 25(1), 20–31 (2009)CrossRefGoogle Scholar
  60. 60.
    Fernandes, A.M., Marinho, P.A., Sartore, R.C., Paulsen, B.S., Mariante, R.M., Castilho, L.R., Rehen, S.K.: Successful scale-up of human embryonic stem cell production in a stirred microcarrier culture system. Braz. J. Med. Biol. Res. 42(6), 515–522 (2009)CrossRefGoogle Scholar
  61. 61.
    Lock, L.T., Tzanakakis, E.S.: Expansion and differentiation of human embryonic stem cells to endoderm progeny in a microcarrier stirred-suspension culture. Tissue Eng. Part A 15(8), 2051–2063 (2009)CrossRefGoogle Scholar
  62. 62.
    Fernandes, A.M., Fernandes, T.G., Diogo, M.M., da Silva, C.L., Henrique, D., Cabral, J.M.: Mouse embryonic stem cell expansion in a microcarrier-based stirred culture system. J. Biotechnol. 132(2), 227–236 (2007)CrossRefGoogle Scholar
  63. 63.
    Abranches, E., Bekman, E., Henrique, D., Cabral, J.M.: Expansion of mouse embryonic stem cells on microcarriers. Biotechnol. Bioeng. 96(6), 1211–1221 (2007)CrossRefGoogle Scholar
  64. 64.
    Frauenschuh, S., Reichmann, E., Ibold, Y., Goetz, P.M., Sittinger, M., Ringe, J.: A microcarrier-based cultivation system for expansion of primary mesenchymal stem cells. Biotechnol. Prog. 23(1), 187–193 (2007)CrossRefGoogle Scholar
  65. 65.
    Wang, C., Gong, Y., Zhong, Y., Yao, Y., Su, K., Wang, D.A.: The control of anchorage-dependent cell behavior within a hydrogel/microcarrier system in an osteogenic model. Biomaterials 30(12), 2259–2269 (2009)CrossRefGoogle Scholar
  66. 66.
    Bratt-Leal, A.M., Carpenedo, R.L., McDevitt, T.C.: Engineering the embryoid body microenvironment to direct embryonic stem cell differentiation. Biotechnol. Prog. 25(1), 43–51 (2009)CrossRefGoogle Scholar
  67. 67.
    Alberti, K., Davey, R.E., Onishi, K., George, S., Salchert, K., Seib, F.P., Bornhauser, M., Pompe, T., Nagy, A., Werner, C., Zandstra, P.W.: Functional immobilization of signaling proteins enables control of stem cell fate. Nat. Methods 5(7), 645–650 (2008)CrossRefGoogle Scholar
  68. 68.
    Beckstead, B.L., Santosa, D.M., Giachelli, C.M.: Mimicking cell–cell interactions at the biomaterial–cell interface for control of stem cell differentiation. J. Biomed. Mater. Res. A 79(1), 94–103 (2006)CrossRefGoogle Scholar
  69. 69.
    Jaklenec, A., Wan, E., Murray, M.E., Mathiowitz, E.: Novel scaffolds fabricated from protein-loaded microspheres for tissue engineering. Biomaterials 29(2), 185–192 (2008)CrossRefGoogle Scholar
  70. 70.
    Patel, Z.S., Yamamoto, M., Ueda, H., Tabata, Y., Mikos, A.G.: Biodegradable gelatin microparticles as delivery systems for the controlled release of bone morphogenetic protein-2. Acta Biomater. 4(5), 1126–1138 (2008)CrossRefGoogle Scholar
  71. 71.
    Mahoney, M.J., Saltzman, W.M.: Transplantation of brain cells assembled around a programmable synthetic microenvironment. Nat. Biotechnol. 19(10), 934–939 (2001)CrossRefGoogle Scholar
  72. 72.
    Carpenedo, R.L., Bratt-Leal, A.M., Marklein, R.A., Seaman, S.A., Bowen, N.J., McDonald, J.F., McDevitt, T.C.: Homogeneous and organized differentiation within embryoid bodies induced by microsphere-mediated delivery of small molecules. Biomaterials 30(13), 2507–2515 (2009)CrossRefGoogle Scholar
  73. 73.
    Ferreira, L., Squier, T., Park, H., Choe, H., Kohane, D.S., Langer, R.: Human embryoid bodies containing nano- and microparticulate delivery vehicles. Adv. Mater. 20(12), 2285–2291 (2008)CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  • Andres Bratt-Leal
    • 1
  • Richard Carpenedo
    • 1
  • Todd McDevitt
    • 1
  1. 1.Wallace H. Coulter Department of Biomedical EngineeringGeorgia Institute of TechnologyAtlantaUSA

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