Hepatic Tissue Engineering

  • Jing Shan
  • Kelly R. Stevens
  • Kartik Trehan
  • Gregory H. Underhill
  • Alice A. Chen
  • Sangeeta N. Bhatia
Part of the Molecular Pathology Library book series (MPLB, volume 5)


Liver tissue engineering aims to provide novel therapies for liver diseases and create effective tools for understanding fundamental aspects of liver biology and pathologic processes. Approaches range from bio-mimetic in vitro model systems of the liver to three-dimensional implantable constructs. Collectively, these cell-based approaches endeavor to replace or enhance organ transplantation, which is the current standard treatment for liver diseases in most clinical settings. However, the complexity of liver structure and function as well as the limited supply of human hepatocytes pose unique challenges for the field. This chapter reviews advances in the field of liver tissue engineering within the context of current therapies for liver diseases, and clinical alternatives such as cell transplantation strategies and extracorporeal bioartificial liver devices.


Human Hepatocyte Primary Hepatocyte PLGA Scaffold Spheroid Culture Hepatic Progenitor Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Funding provided by NIH R01-DK065152 and NIH R01-DK56966.


  1. 1.
    Kim WR, Brown RS, Terrault NA, El-Serag H. Burden of liver disease in the United States: summary of a workshop. Hepatology. 2002;36(1):227–42.PubMedGoogle Scholar
  2. 2.
    Brown KA. Liver transplantation. Curr Opin Gastroenterol. 2005;21(3):331–6.PubMedGoogle Scholar
  3. 3.
    Michalopoulos GK, DeFrances MC. Liver regeneration. Science. 1997;276(5309):60–6.PubMedGoogle Scholar
  4. 4.
    Harper AM, Edwards EB, Ellison MD. The OPTN waiting list, 1988–2000. Clin Transpl. 2001:73–85.Google Scholar
  5. 5.
    Allen JW, Hassanein T, Bhatia SN. Advances in bioartificial liver devices. Hepatology. 2001;34(3):447–55.PubMedGoogle Scholar
  6. 6.
    Strain AJ, Neuberger JM. A bioartificial liver – state of the art. Science. 2002;295(5557):1005–9.PubMedGoogle Scholar
  7. 7.
    Yarmush ML, Dunn JC, Tompkins RG. Assessment of artificial liver support technology. Cell Transplant. 1992;1(5):323–41.PubMedGoogle Scholar
  8. 8.
    Allen JW, Bhatia SN. Engineering liver therapies for the future. Tissue Eng. 2002;8(5):725–37.PubMedGoogle Scholar
  9. 9.
    Allen JW, Bhatia SN. Improving the next generation of bioartificial liver devices. Semin Cell Dev Biol. 2002;13(6):447–54.PubMedGoogle Scholar
  10. 10.
    Chan C, Berthiaume F, Nath BD, et al. Hepatic tissue engineering for adjunct and temporary liver support: critical technologies. Liver Transplant. 2004;10(11):1331–42.Google Scholar
  11. 11.
    Fisher RA, Strom SC. Human hepatocyte transplantation: worldwide results. Transplantation. 2006;82(4):441–9.PubMedGoogle Scholar
  12. 12.
    Rhim JA, Sandgren EP, Degen JL, et al. Replacement of diseased mouse-liver by hepatic cell transplantation. Science. 1994;263(5150):1149–52.PubMedGoogle Scholar
  13. 13.
    Fitzpatrick E, Mitry RR, Dhawan A. Human hepatocyte transplantation: state of the art. J Intern Med. 2009;266(4):339–57.PubMedGoogle Scholar
  14. 14.
    Gupta S, Chowdhury JR. Therapeutic potential of hepatocyte transplantation. Semin Cell Dev Biol. 2002;13(6):439–46.PubMedGoogle Scholar
  15. 15.
    Overturf K, AlDhalimy M, Ou CN, et al. Serial transplantation reveals the stem-cell-like regenerative potential of adult mouse hepatocytes. Am J Pathol. 1997;151(5):1273–80.PubMedGoogle Scholar
  16. 16.
    Sokhi RP, Rajvanshi P, Gupta S. Transplanted reporter cells help in defining onset of hepatocyte proliferation during the life of F344 rats. Am J Physiol Gastrointest Liver Physiol. 2000;279(3):G631–40.PubMedGoogle Scholar
  17. 17.
    Azuma H, Paulk N, Ranade A, et al. Robust expansion of human hepatocytes in Fah(−/−)/Rag2(−/−)/Il2rg(−/−) mice. Nat Biotechnol. 2007;25(8):903–10.PubMedGoogle Scholar
  18. 18.
    Fausto N. Liver regeneration and repair: hepatocytes, progenitor cells, and stem cells. Hepatology. 2004;39(6):1477–87.PubMedGoogle Scholar
  19. 19.
    Demetriou AA, Whiting J, Levenson SM, Chowdhury NR, et al. New method of hepatocyte transplantation and extracorporeal liver support. Ann Surg. 1986;204(3):259–71.PubMedGoogle Scholar
  20. 20.
    Kaihara S, Vacanti JP. Tissue engineering – toward new solutions for transplantation and reconstructive surgery. Arch Surg. 1999;134(11):1184–8.PubMedGoogle Scholar
  21. 21.
    Strain AJ. Ex vivo liver cell morphogenesis: one step nearer to the bioartificial liver? Hepatology. 1999;29(1):288–90.PubMedGoogle Scholar
  22. 22.
    Dunn JCY, Yarmush ML, Koebe HG, Tompkins RG. Hepatocyte function and extracellular-matrix geometry – long-term culture in a sandwich configuration. FASEB J. 1989;3(2):174–7.PubMedGoogle Scholar
  23. 23.
    Hewitt NJ, Lechon MJG, Houston JB, et al. Primary hepatocytes: current understanding of the regulation of metabolic enzymes and transporter proteins, and pharmaceutical practice for the use of hepatocytes in metabolism, enzyme induction, transporter, clearance, and hepatotoxicity studies. Drug Metab Rev. 2007;39(1):159–234.PubMedGoogle Scholar
  24. 24.
    Higgins GM, Anderson RM. Experimental pathology of liver: restoration of liver in white rat following partial surgical removal. Arch Pathol. 1931;12:186–202.Google Scholar
  25. 25.
    Stocker E, Wullstein HK, Brau G. Capacity of regeneration in liver epithelia of juvenile, repeated partially hepatectomized rats. Autoradiographic studies after continous infusion of 3H-thymidine. Virchows Arch B Cell Pathol. 1973;14:93.PubMedGoogle Scholar
  26. 26.
    Overturf K, AlDhalimy M, Tanguay R, et al. Hepatocytes corrected by gene therapy are selected in vivo in a murine model of hereditary tyrosinaemia type I. Nat Genet. 1996;12(3):266–73.PubMedGoogle Scholar
  27. 27.
    Grompe M, Overturf K, Al-Dhalimy M, Finegold M. Serial transplantation reveals stem cell like regenerative potential in parenchymal mouse hepatocytes. Hepatology. 1996;24(4 PART 2):256A.Google Scholar
  28. 28.
    Edwards AM, Michalopoulos GK. Conditions for growth of hepatocytes in culture. In: Berry MN, Edwards AM, editors. The hepatocyte review. Norwell: Kluwer Academic Publishers; 2000. p. 73–96.Google Scholar
  29. 29.
    Michalopoulos G, Cianciulli HD, Novotny AR, et al. Liver-regeneration studies with rat hepatocytes in primary culture. Cancer Res. 1982;42(11):4673–82.PubMedGoogle Scholar
  30. 30.
    Block GD, Locker J, Bowen WC, et al. Population expansion, clonal growth, and specific differentiation patterns in primary cultures of hepatocytes induced by HGF/SF, EGF and TGF alpha in a chemically defined (HGM) medium. J Cell Biol. 1996;132(6):1133–49.PubMedGoogle Scholar
  31. 31.
    Ismail T, Howl J, Wheatley M, et al. Growth of normal human hepatocytes in primary culture – effect of hormones and growth-factors on DNA-synthesis. Hepatology. 1991;14(6):1076–82.PubMedGoogle Scholar
  32. 32.
    Richman RA, Claus TH, Pilkis SJ, Friedman DL. Hormonal-stimulation of DNA-synthesis in primary cultures of adult rat hepatocytes. Proc Natl Acad Sci U S A. 1976;73(10):3589–93.PubMedGoogle Scholar
  33. 33.
    Mitaka T, Sattler CA, Sattler GL, et al. Multiple cell-cycles occur in rat hepatocytes cultured in the presence of nicotinamide and epidermal growth-factor. Hepatology. 1991;13(1):21–30.PubMedGoogle Scholar
  34. 34.
    Cable EE, Isom HC. Exposure of primary rat hepatocytes in long-term DMSO culture to selected transition metals induces hepatocyte proliferation and formation of duct-like structures. Hepatology. 1997;26(6):1444–57.PubMedGoogle Scholar
  35. 35.
    Uyama N, Shimahara Y, Kawada N, et al. Regulation of cultured rat hepatocyte proliferation by stellate cells. J Hepatol. 2002;36(5):590–9.PubMedGoogle Scholar
  36. 36.
    Mizuguchi T, Hui T, Palm K, et al. Enhanced proliferation and differentiation of rat hepatocytes cultured with bone marrow stromal cells. J Cell Physiol. 2001;189(1):106–19.PubMedGoogle Scholar
  37. 37.
    Cho CH, Berthiaume F, Tilles AW, Yarmush ML. A new technique for primary hepatocyte expansion in vitro. Biotechnol Bioeng. 2008;101(2):345–56.PubMedGoogle Scholar
  38. 38.
    Shimaoka S, Nakamura T, Ichihara A. Stimulation of growth of primary cultured adult-rat hepatocytes without growth-factors by coculture with nonparenchymal liver-cells. Exp Cell Res. 1987;172(1):228–42.PubMedGoogle Scholar
  39. 39.
    Clayton TA, Lindon JC, Cloarec O, et al. Pharmaco-metabonomic phenotyping and personalized drug treatment. Nature. 2006;440(7087):1073–7.PubMedGoogle Scholar
  40. 40.
    Nelson DR. Cytochrome P450 and the individuality of species. Arch Biochem Biophys. 1999;369(1):1–10.PubMedGoogle Scholar
  41. 41.
    Gibbs RA, Weinstock GM, Metzker ML, et al. Rat Genome Sequencing Project. Genome sequence of the Brown Norway rat yields insights into mammalian evolution. Nature. 2004;428(6982):493–521.PubMedGoogle Scholar
  42. 42.
    Kobayashi N, Fujiwara T, Westerman KA, et al. Prevention of acute liver failure in rats with reversibly immortalized human hepatocytes. Science. 2000;287(5456):1258–62.PubMedGoogle Scholar
  43. 43.
    Werner A, Duvar S, Muthing J, et al. Cultivation of immortalized human hepatocytes HepZ on macroporous CultiSpher G microcarriers. Biotechnol Bioeng. 2000;68(1):59–70.PubMedGoogle Scholar
  44. 44.
    Kono Y, Yang SY, Letarte M, Roberts EA. Establishment of a human hepatocyte line derived from primary culture in a collagen gel sandwich culture system. Exp Cell Res. 1995;221(2):478–85.PubMedGoogle Scholar
  45. 45.
    Kelly JH, Darlington GJ. Modulation of the liver specific phenotype in the human hepatoblastoma line HEP-G2. In Vitro Cell Dev Biol. 1989;25(2):217–22.PubMedGoogle Scholar
  46. 46.
    Jauregui HO. Cellular component of bioartificial liver support systems. Artif Organs. 1999;23(10):889–93.PubMedGoogle Scholar
  47. 47.
    Nyberg SL, Remmel RP, Mann HJ, et al. Primary hepatocytes outperform HEP G2 cells as the source of biotransformation functions in a bioartificial liver. Ann Surg. 1994;220(1):59–67.PubMedGoogle Scholar
  48. 48.
    Yanai N, Suzuki M, Obinata M. Hepatocyte cell-lines established from transgenic mice harboring temperature-sensitive simian virus-40 large T-antigen gene. Exp Cell Res. 1991;197(1):50–6.PubMedGoogle Scholar
  49. 49.
    Kobayashi N, Noguchi H, Fujiwara T, Tanaka N. Establishment of a reversibly immortalized human hepatocyte cell line by using Cre/LoxP site-specific recombination. Transplant Proc. 2000;32(5):1121–2.PubMedGoogle Scholar
  50. 50.
    Cai J, Ito M, Westerman KA, et al. Construction of a non-tumorigenic rat hepatocyte cell line for transplantation: reversal of hepatocyte immortalization by site-specific excision of the SV40 T antigen. J Hepatol. 2000;33(5):701–8.PubMedGoogle Scholar
  51. 51.
    Tateno C, Yoshizane Y, Saito N, et al. Near completely humanized liver in mice shows human-type metabolic responses to drugs. Am J Pathol. 2004;165(3):901–12.PubMedGoogle Scholar
  52. 52.
    Katoh M, Sawada T, Soeno Y, et al. In vivo drug metabolism model for human cytochrome P450 enzyme using chimeric mice with humanized liver. J Pharm Sci. 2007;96(2):428–37.PubMedGoogle Scholar
  53. 53.
    Turrini P, Sasso R, Germoni S, et al. Development of humanized mice for the study of hepatitis C virus infection. Transplant Proc. 2006;38(4):1181–4.PubMedGoogle Scholar
  54. 54.
    Meuleman P, Hesselgesser J, Paulson M, et al. Anti-CD81 antibodies can prevent a hepatitis c virus infection in vivo. Hepatology. 2008;48(6):1761–8.PubMedGoogle Scholar
  55. 55.
    Hamazaki T, Iiboshi Y, Oka M, et al. Hepatic maturation in differentiating embryonic stem cells in vitro. FEBS Lett. 2001;497(1):15–9.PubMedGoogle Scholar
  56. 56.
    Chinzei R, Tanaka Y, Shimizu-Saito K, et al. Embryoid-body cells derived from a mouse embryonic stem cell line show differentiation into functional hepatocytes. Hepatology. 2002;36(1):22–9.PubMedGoogle Scholar
  57. 57.
    Yamada T, Yoshikawa M, Kanda S, et al. In vitro differentiation of embryonic stem cells into hepatocyte-like cells identified by cellular uptake of indocyanine green. Stem Cells. 2002;20(2):146–54.PubMedGoogle Scholar
  58. 58.
    Cho CH, Parashurama N, Park EYH, et al. Homogeneous differentiation of hepatocyte-like cells from embryonic stem cells: applications for the treatment of liver failure. FASEB J. 2008;22(3):898–909.PubMedGoogle Scholar
  59. 59.
    Gouon-Evans V, Boussemart L, Gadue P, et al. BMP-4 is required for hepatic specification of mouse embryonic stem cell-derived definitive endoderm. Nat Biotechnol. 2006;24(11):1402–11.PubMedGoogle Scholar
  60. 60.
    Soto-Gutierrez A, Kobayashi N, Rivas-Carrillo JD, et al. Reversal of mouse hepatic failure using an implanted liver-assist device containing ES cell-derived hepatocytes. Nat Biotechnol. 2006;24(11):1412–9.PubMedGoogle Scholar
  61. 61.
    Wandzioch E, Zaret KS. Dynamic signaling network for the specification of embryonic pancreas and liver progenitors. Science. 2009;324(5935):1707–10.PubMedGoogle Scholar
  62. 62.
    Lemaigre F, Zaret KS. Liver development update: new embryo models, cell lineage control, and morphogenesis. Curr Opin Genet Dev. 2004;14(5):582–90.PubMedGoogle Scholar
  63. 63.
    Schmelzer E, Zhang L, Bruce A, et al. Human hepatic stem cells from fetal and postnatal donors. J Exp Med. 2007;204(8):1973–87.PubMedGoogle Scholar
  64. 64.
    Zhang LL, Theise N, Chua M, Reid LM. The stem cell niche of human livers: symmetry between development and regeneration. Hepatology. 2008;48(5):1598–607.PubMedGoogle Scholar
  65. 65.
    Oh SH, Hatch HM, Petersen BE. Hepatic oval ‘stem’ cell in liver regeneration. Semin Cell Dev Biol. 2002;13(6):405–9.PubMedGoogle Scholar
  66. 66.
    Sell S. The role of progenitor cells in repair of liver injury and in liver transplantation. Wound Repair Regen. 2001;9(6):467–82.PubMedGoogle Scholar
  67. 67.
    Strick-Marchand H, Weiss MC. Inducible differentiation and morphogenesis of bipotential liver cell lines from wild-type mouse embryos. Hepatology. 2002;36(4):794–804.PubMedGoogle Scholar
  68. 68.
    Strick-Marchand H, Morosan S, Charneau P, et al. Bipotential mouse embryonic liver stem cell lines contribute to liver regeneration and differentiate as bile ducts and hepatocytes. Proc Natl Acad Sci U S A. 2004;101(22):8360–5.PubMedGoogle Scholar
  69. 69.
    Duncan AW, Dorrell C, Grompe M. Stem cells and liver regeneration. Gastroenterology. 2009;137(2):466–81.PubMedGoogle Scholar
  70. 70.
    Schwartz RE, Reyes M, Koodie L, et al. Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells. J Clin Investig. 2002;109(10):1291–302.PubMedGoogle Scholar
  71. 71.
    Hong SH, Gang EJ, Jeong JA, et al. In vitro differentiation of human umbilical cord blood-derived mesenchymal stem cells’into hepatocyte-like cells. Biochem Biophys Res Commun. 2005;330(4):1153–61.PubMedGoogle Scholar
  72. 72.
    Ong SY, Dai H, Leong KW. Hepatic differentiation potential of commercially available human mesenchymal stem cells. Tissue Eng. 2006;12(12):3477–85.PubMedGoogle Scholar
  73. 73.
    Sato Y, Araki H, Kato J, et al. Human mesenchymal stem cells xenografted directly to rat liver are differentiated into human hepatocytes without fusion. Blood. 2005;106(2):756–63.PubMedGoogle Scholar
  74. 74.
    Aurich H, Sgodda M, Kaltwasser P, et al. Hepatocyte differentiation of mesenchymal stem cells from human adipose tissue in vitro promotes hepatic integration in vivo. Gut. 2009;58(4):570–81.PubMedGoogle Scholar
  75. 75.
    De Coppi P, Bartsch G, Siddiqui MM, et al. Isolation of amniotic stem cell lines with potential for therapy. Nat Biotechnol. 2007;25(1):100–6.PubMedGoogle Scholar
  76. 76.
    in ‘tAnker PS, Scherjon SA, Kleijburg-van der Keur C, et al. Amniotic fluid as a novel source of mesenchymal stem cells for therapeutic transplantation. Blood. 2003;102(4):1548–9.Google Scholar
  77. 77.
    Miki T, Lehmann T, Cai HB, et al. Stem cell characteristics of amniotic epithelial cells. Stem Cells. 2005;23(10):1549–59.PubMedGoogle Scholar
  78. 78.
    Miki T, Marongiu F, Ellis ECS, et al. Production of hepatocyte-like cells from human amnion. Methods Mol Biol. 2009;481:155–68.PubMedGoogle Scholar
  79. 79.
    Tsai MS, Lee JL, Chang YJ, Hwang SM. Isolation of human multipotent mesenchymal stem cells from second-trimester amniotic fluid using a novel two-stage culture protocol. Hum Reprod. 2004;19(6):1450–6.PubMedGoogle Scholar
  80. 80.
    Lowry WE, Richter L, Yachechko R, et al. Generation of human induced pluripotent stem cells from dermal fibroblasts. Proc Natl Acad Sci U S A. 2008;105(8):2883–8.PubMedGoogle Scholar
  81. 81.
    Park IH, Zhao R, West JA, et al. Reprogramming of human somatic cells to pluripotency with defined factors. Nature. 2008;451(7175):141–U1.PubMedGoogle Scholar
  82. 82.
    Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861–72.PubMedGoogle Scholar
  83. 83.
    Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76.PubMedGoogle Scholar
  84. 84.
    Yu JY, Vodyanik MA, Smuga-Otto K, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318(5858):1917–20.PubMedGoogle Scholar
  85. 85.
    Si-Tayeb K, Noto FK, Nagaoka M, et al. Highly efficient generation of human hepatic cells from induced pluripotent stem cells. Hepatology. 2010;51(1):297–305.PubMedGoogle Scholar
  86. 86.
    Song ZH, Cai J, Liu YX, et al. Efficient generation of hepatocyte-like cells from human induced pluripotent stem cells. Cell Res. 2009;19(11):1233–42.PubMedGoogle Scholar
  87. 87.
    Sullivan GJ, Hay DC, Park IH, et al. Generation of functional human hepatic endoderm from human induced pluripotent stem cells. Hepatology. 2010;51(1):329–35.PubMedGoogle Scholar
  88. 88.
    Zhou Q, Brown J, Kanarek A, et al. In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature. 2008;455(7213):627–U30.PubMedGoogle Scholar
  89. 89.
    Gebhardt R, Hengstler JG, Muller D, et al. New hepatocyte in vitro systems for drug metabolism: metabolic capacity and recommendations for application in basic research and drug development, standard operation procedures. Drug Metab Rev. 2003;35(2–3):145–213.PubMedGoogle Scholar
  90. 90.
    Guillouzo A. Liver cell models in in vitro toxicology. Environ Health Perspect. 1998;106:511–32.PubMedGoogle Scholar
  91. 91.
    Sivaraman A, Leach JK, Townsend S, et al. A microscale in vitro physiological model of the liver: predictive screens for drug metabolism and enzyme induction. Curr Drug Metab. 2005;6(6):569–91.PubMedGoogle Scholar
  92. 92.
    Khetani SR, Bhatia SN. Microscale culture of human liver cells for drug development. Nat Biotechnol. 2008;26(1):120–6.PubMedGoogle Scholar
  93. 93.
    Mooney DJ, Sano K, Kaufmann PM, et al. Long-term engraftment of hepatocytes transplanted on biodegradable polymer sponges. J Biomed Mater Res. 1997;37(3):413–20.PubMedGoogle Scholar
  94. 94.
    Underhill GH, Chen AA, Albrecht DR, Bhatia SN. Assessment of hepatocellular function within PEG hydrogels. Biomaterials. 2007;28(2):256–70.PubMedGoogle Scholar
  95. 95.
    Grosse-Siestrup C, Nagel S, Unger V, et al. The isolated perfused liver: a new model using autologous blood and porcine slaughterhouse organs. J Pharmacol Toxicol Meth. 2001;46(3):163–8.Google Scholar
  96. 96.
    Thohan S, Rosen GM. Liver slice technology as an in vitro model for metabolic and toxicity studies. Methods Mol Biol. 2002;196:291–303.PubMedGoogle Scholar
  97. 97.
    Donato MT, Jimenez N, Castell JV, Gomez-Lechon MJ. Fluorescence-based assays for screening nine cytochrome P450 (P450) activities in intact cells expressing individual human P450 enzymes. Drug Metab Dispos. 2004;32(7):699–706.PubMedGoogle Scholar
  98. 98.
    Venkatakrishnan K, von Moltke LL, Greenblatt DJ. Evaluation of Supermix (TM) as an in vitro model of human liver microsomal drug metabolism. Biopharm Drug Dispos. 2002;23(5):183–90.PubMedGoogle Scholar
  99. 99.
    Cederbaum AI, Wu DF, Mari M, Bai JX. CYP2E1-dependent toxicity and oxidative stress in HEPG2 cells. Free Radic Biol Med. 2001;31(12):1539–43.PubMedGoogle Scholar
  100. 100.
    Fukaya KI, Asahi S, Nagamori S, et al. Establishment of a human hepatocyte line (OUMS-29) having CYP 1A1 and 1A2 activities from fetal liver tissue by transfection of SV-10 LT. In Vitro Cell Dev Biol Anim. 2001;37(5):266–9.PubMedGoogle Scholar
  101. 101.
    Liu J, Pan J, Naik S, et al. Characterization and evaluation of detoxification functions of a nontumorigenic immortalized porcine hepatocyte cell line (HepLiu). Cell Transplant. 1999;8(3):219–32.PubMedGoogle Scholar
  102. 102.
    Mills JB, Rose KA, Sadagopan N, et al. Induction of drug metabolism enzymes and MDR1 using a novel human hepatocyte cell line. J Pharmacol Exp Ther. 2004;309(1):303–9.PubMedGoogle Scholar
  103. 103.
    Trubetskoy O, Marks B, Zielinski T, et al. A simultaneous assessment of CYP3A4 metabolism and induction in the DPX-2 cell line. AAPS J. 2005;7(1):E6–E13.PubMedGoogle Scholar
  104. 104.
    Griffith LG, Swartz MA. Capturing complex 3D tissue physiology in vitro. Nat Rev Mol Cell Biol. 2006;7(3):211–24.PubMedGoogle Scholar
  105. 105.
    Laishes BA, Williams GM. Conditions affecting primary-cell cultures of functional adult rat hepatocytes. 1. Effect of insulin. In Vitro. 1976;12(7):521–33.PubMedGoogle Scholar
  106. 106.
    Isom HC, Secott T, Georgoff I, et al. Maintenance of differentiated rat hepatocytes in primary culture. Proc Natl Acad Sci U S A. 1985;82(10):3252–6.PubMedGoogle Scholar
  107. 107.
    Miyazaki M, Handa Y, Oda M, et al. Long-term survival of functional hepatocytes from adult-rat in the presence of phenobarbital in primary culture. Exp Cell Res. 1985;159(1):176–90.PubMedGoogle Scholar
  108. 108.
    Enat R, Jefferson DM, Ruizopazo N, et al. Hepatocyte proliferation in vitro – its dependence on the use of serum-free hormonally defined medium and substrata of extracellular-matrix. Proc Natl Acad Sci U S A. 1984;81(5):1411–5.PubMedGoogle Scholar
  109. 109.
    Kidambi S, Yarmush RS, Novik E, et al. Oxygen-mediated enhancement of primary hepatocyte metabolism, functional polarization, gene expression, and drug clearance. Proc Natl Acad Sci U S A. 2009;106(37):15714–9.PubMedGoogle Scholar
  110. 110.
    Jindal R, Nahmias Y, Tilles AW, et al. Amino acid-mediated heterotypic interaction governs performance of a hepatic tissue model. FASEB J. 2009;23(7):2288–98.PubMedGoogle Scholar
  111. 111.
    LeCluyse EL, Bullock PL, Parkinson A. Strategies for restoration and maintenance of normal hepatic structure and function in long-term cultures of rat hepatocytes. Adv Drug Deliv Rev. 1996;22(1–2):133–86.Google Scholar
  112. 112.
    Lin P, Chan WCW, Badylak SF, Bhatia SN. Assessing porcine liver-derived biomatrix for hepatic tissue engineering. Tissue Eng. 2004;10(7–8):1046–53.PubMedGoogle Scholar
  113. 113.
    Flaim CJ, Chien S, Bhatia SN. An extracellular matrix microarray for probing cellular differentiation. Nat Meth. 2005;2(2):119–25.Google Scholar
  114. 114.
    LeCluyse EL, Audus KL, Hochman JH. Formation of extensive canalicular networks by rat hepatocytes cultured in collagen-sandwich configuration. Am J Physiol. 1994;266(6):C1764–74.PubMedGoogle Scholar
  115. 115.
    Richert L, Binda D, Hamilton G, et al. Evaluation of the effect of culture configuration on morphology, survival time, antioxidant status and metabolic capacities of cultured rat hepatocytes. Toxicol in Vitro. 2002;16(1):89–99.PubMedGoogle Scholar
  116. 116.
    Chen AA, Khetani SR, Lee S, et al. Modulation of hepatocyte phenotype in vitro via chemomechanical tuning of polyelectrolyte multilayers. Biomaterials. 2009;30(6):1113–20.PubMedGoogle Scholar
  117. 117.
    Janorkar AV, Rajagopalan P, Yarmush ML, Megeed Z. The use of elastin-like polypeptide-polyelectrolyte complexes to control hepatocyte morphology and function in vitro. Biomaterials. 2008;29(6):625–32.PubMedGoogle Scholar
  118. 118.
    Guguenguillouzo C, Clement B, Baffet G, et al. Maintenance and reversibility of active albumin secretion by adult-rat hepatocytes co-cultured with another liver epithelial-cell type. Exp Cell Res. 1983;143(1):47–54.Google Scholar
  119. 119.
    Bhatia SN, Balis UJ, Yarmush ML, Toner M. Effect of cell-cell interactions in preservation of cellular phenotype: cocultivation of hepatocytes and nonparenchymal cells. FASEB J. 1999;13(14):1883–900.PubMedGoogle Scholar
  120. 120.
    Hansen LK, Hsiao CC, Friend JR, et al. Enhanced morphology and function in hepatocyte spheroids: a model of tissue self-assembly. Tissue Eng. 1998;4(1):65–74.Google Scholar
  121. 121.
    Koide N, Sakaguchi K, Koide Y, et al. Formation of multicellular spheroids composed of adult-rat hepatocytes in dishes with positively charged surfaces and under other nonadherent environments. Exp Cell Res. 1990;186(2):227–35.PubMedGoogle Scholar
  122. 122.
    Peshwa MV, Wu FJ, Sharp HL, et al. Mechanistics of formation and ultrastructural evaluation of hepatocyte spheroids. In Vitro Cell Dev Biol Anim. 1996;32(4):197–203.PubMedGoogle Scholar
  123. 123.
    Wu FJ, Friend JR, Remmel RP, et al. Enhanced cytochrome P450IA1 activity of self-assembled rat hepatocyte spheroids. Cell Transplant. 1999;8(3):233–46.PubMedGoogle Scholar
  124. 124.
    Yagi K, Tsuda K, Serada M, et al. Rapid formation of multicellular spheroids of adult-rat hepatocytes by rotation culture and their immobilization within calcium alginate. Artif Organs. 1993;17(11):929–34.PubMedGoogle Scholar
  125. 125.
    Yuasa C, Tomita Y, Shono M, et al. Importance of cell-aggregation for expression of liver functions and regeneration demonstrated with primary cultured-hepatocytes. J Cell Physiol. 1993;156(3):522–30.PubMedGoogle Scholar
  126. 126.
    Landry J, Bernier D, Ouellet C, et al. Spheroidal aggregate culture of rat-liver cells – histotypic reorganization, biomatrix deposition and maintenance of functional activities. J Cell Biol. 1985;101(3):914–23.PubMedGoogle Scholar
  127. 127.
    Roberts RA, Soames AR. Hepatocyte spheroids – prolonged hepatocyte viability for in-vitro modeling of nongenotoxic carcinogenesis. Fundam Appl Toxicol. 1993;21(2):149–58.PubMedGoogle Scholar
  128. 128.
    Bissell DM, Arenson DM, Maher JJ, Roll FJ. Support of cultured-hepatocytes by a laminin-rich gel. Evidence for a functionally significant subendothelial matrix in normal rat-liver. J Clin Invest. 1987;79(3):801–12.PubMedGoogle Scholar
  129. 129.
    LeCluyse EL. Human hepatocyte culture systems for the in vitro evaluation of cytochrome P450 expression and regulation. Eur J Pharm Sci. 2001;13(4):343–68.PubMedGoogle Scholar
  130. 130.
    Vukicevic S, Kleinman HK, Luyten FP, et al. Identification of multiple active growth-factors in basement-membrane matrigel suggests caution in interpretation of cellular-activity related to extracellular-matrix components. Exp Cell Res. 1992;202(1):1–8.PubMedGoogle Scholar
  131. 131.
    Hsiao CC, Friend JR, Wu FJ, et al. Receding cytochrome P450 activity in disassembling hepatocyte spheroids. Tissue Eng. 1999;5(3):207–21.PubMedGoogle Scholar
  132. 132.
    Powers MJ, Domansky K, Kaazempur-Mofrad MR, et al. A microfabricated array bioreactor for perfused 3D liver culture. Biotechnol Bioeng. 2002;78(3):257–69.PubMedGoogle Scholar
  133. 133.
    Kojima R, Yoshimoto K, Takahashi E, et al. Spheroid array of fetal mouse liver cells constructed on a PEG-gel micropatterned surface: upregulation of hepatic functions by co-culture with nonparenchymal liver cells. Lab Chip. 2009;9(14):1991–3.PubMedGoogle Scholar
  134. 134.
    Brophy CM, Luebke-Wheeler JL, Amiot BP, et al. Rat hepatocyte spheroids formed by rocked technique maintain differentiated hepatocyte gene expression and function. Hepatology. 2009;49(2):578–86.PubMedGoogle Scholar
  135. 135.
    Chia SM, Leong KW, Li J, et al. Hepatocyte encapsulation for enhanced cellular functions. Tissue Eng. 2000;6(5):481–95.PubMedGoogle Scholar
  136. 136.
    Eschbach E, Chatterjee SS, Noldner M, et al. Microstructured scaffolds for liver tissue cultures of high cell density: morphological and biochemical characterization of tissue aggregates. J Cell Biochem. 2005;95(2):243–55.PubMedGoogle Scholar
  137. 137.
    Knedlitschek G, Schneider F, Gottwald E, et al. A tissue-like culture system using microstructures: influence of extracellular matrix material on cell adhesion and aggregation. J Biomech Eng. 1999;121(1):35–9.PubMedGoogle Scholar
  138. 138.
    Park JK, Lee DH. Bioartificial liver systems: current status and future perspective. J Biosci Bioeng. 2005;99(4):311–9.PubMedGoogle Scholar
  139. 139.
    Allen JW, Khetani SR, Bhatia SN. In vitro zonation and toxicity in a hepatocyte bioreactor. Toxicol Sci. 2005;84(1):110–9.PubMedGoogle Scholar
  140. 140.
    Domansky K, Inman W, Serdy J, et al. Perfused multiwell plate for 3D liver tissue engineering. Lab Chip. 2010;10(1):51–8.PubMedGoogle Scholar
  141. 141.
    Tilles AW, Baskaran H, Roy P, et al. Effects of oxygenation and flow on the viability and function of rat hepatocytes cocultured in a microchannel flat-plate bioreactor. Biotechnol Bioeng. 2001;73(5):379–89.PubMedGoogle Scholar
  142. 142.
    Park J, Berthiaume F, Toner M, et al. Microfabricated grooved substrates as platforms for bioartificial liver reactors. Biotechnol Bioeng. 2005;90(5):632–44.PubMedGoogle Scholar
  143. 143.
    Roy P, Baskaran H, Tilles AW, Yarmush ML, Toner M. Analysis of oxygen transport to hepatocytes in a flat-plate microchannel bioreactor. Ann Biomed Eng. 2001;29(11):947–55.PubMedGoogle Scholar
  144. 144.
    Park J, Li Y, Berthiaume F, et al. Radial flow hepatocyte bioreactor using stacked microfabricated grooved substrates. Biotechnol Bioeng. 2008;99(2):455–67.PubMedGoogle Scholar
  145. 145.
    Yates C, Shepard CR, Papworth G, et al. Novel three-dimensional organotypic liver bioreactor to directly visualize early events in metastatic progression. In: George FVW, George K, editors. Advances in cancer research. Academic Press; 2007. p. 225–246.Google Scholar
  146. 146.
    Gerlach JC. Development of a hybrid liver support system: a review. Int J Artif Organs. 1996;19(11):645–54.PubMedGoogle Scholar
  147. 147.
    Catapano G, Patzer JF, Gerlach JC. Transport advances in disposable bioreactors for liver tissue engineering. Adv Biochem Eng Biotechnol. 2010;115:117–43.PubMedGoogle Scholar
  148. 148.
    Macdonald JM, Wolfe SP, Gupta B, et al. Tissue engineering liver in a novel multi-coaxial hollow fiber bioreactor. Free Radic Biol Med. 2001;31:432.Google Scholar
  149. 149.
    Khetani SR, Bhatia SN. Engineering tissues for in vitro applications. Curr Opin Biotechnol. 2006;17:524–31.PubMedGoogle Scholar
  150. 150.
    Folch A, Toner M. Microengineering of cellular interactions. Annu Rev Biomed Eng. 2000;2:227–56.PubMedGoogle Scholar
  151. 151.
    Chen CS, Mrksich M, Huang S, et al. Geometric control of cell life and death. Science. 1997;276(5317):1425–8.PubMedGoogle Scholar
  152. 152.
    Singhvi R, Kumar A, Lopez GP, et al. Engineering cell-shape and function. Science. 1994;264(5159):696–8.PubMedGoogle Scholar
  153. 153.
    Lipshutz RJ, Fodor SPA, Gingeras TR, Lockhart DJ. High density synthetic oligonucleotide arrays. Nat Genet. 1999;21:20–4.PubMedGoogle Scholar
  154. 154.
    King KR, Wang S, Irimia D, Jayaraman A, et al. A high-throughput microfluidic real-time gene expression living cell array. Lab Chip. 2007;7(1):77–85.PubMedGoogle Scholar
  155. 155.
    Fukuda J, Sakai Y, Nakazawa K. Novel hepatocyte culture system developed using microfabrication and collagen/polyethylene glycol microcontact printing. Biomaterials. 2006;27(7):1061–70.PubMedGoogle Scholar
  156. 156.
    Ohashi K, Yokoyama T, Yamato M, et al. Engineering functional two- and three-dimensional liver systems in vivo using hepatic tissue sheets. Nat Med. 2007;13(7):880–5.PubMedGoogle Scholar
  157. 157.
    Chao P, Maguire T, Novik E, et al. Evaluation of a microfluidic based cell culture platform with primary human hepatocytes for the prediction of hepatic clearance in human. Biochem Pharmacol. 2009;78(6):625–32.PubMedGoogle Scholar
  158. 158.
    Hui EE, Bhatia SN. Micromechanical control of cell-cell interactions. Proc Natl Acad Sci U S A. 2007;104(14):5722–6.PubMedGoogle Scholar
  159. 159.
    Lohmann V, Korner F, Koch JO, et al. Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science. 1999;285(5424):110–3.PubMedGoogle Scholar
  160. 160.
    Kato T, Furusaka A, Miyamoto M, et al. Sequence analysis of hepatitis C virus isolated from a fulminant hepatitis patient. J Med Virol. 2001;64(3):334–9.PubMedGoogle Scholar
  161. 161.
    Lindenbach BD, Evans MJ, Syder AJ, et al. Complete replication of hepatitis C virus in cell culture. Science. 2005;309(5734):623–6.PubMedGoogle Scholar
  162. 162.
    Wakita T, Pietschmann T, Kato T, et al. Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nat Med. 2005;11(7):791–6.PubMedGoogle Scholar
  163. 163.
    Zhong J, Gastaminza P, Cheng GF, et al. Robust hepatitis C virus infection in vitro. Proc Natl Acad Sci U S A. 2005;102(26):9294–9.PubMedGoogle Scholar
  164. 164.
    Buck M. Direct infection and replication of naturally occurring hepatitis C virus genotypes 1, 2, 3 and 4 in normal human hepatocyte cultures. PLoS One. 2008;3(7):e2660.PubMedGoogle Scholar
  165. 165.
    Molina S, Castet V, Pichard-Garcia L, et al. Serum-derived hepatitis C virus infection of primary human hepatocytes is tetraspanin CD81 dependent. J Virol. 2008;82(1):569–74.PubMedGoogle Scholar
  166. 166.
    Ploss A, Khetani SR, Rice CM, Bhatia SN. Persistent hepatitis C virus infection in microscale primary human hepatocyte culture. Proc Natl Acad Sci U S A. 2010;107(7):3141–5.PubMedGoogle Scholar
  167. 167.
    Mazier D, Beaudoin RL, Mellouk S, et al. Complete development of hepatic stages of Plasmodium-falciparum invitro. Science. 1985;227(4685):440–2.PubMedGoogle Scholar
  168. 168.
    Mazier D, Landau I, Druilhe P, et al. Cultivation of the liver forms of Plasmodium-vivax in human hepatocytes. Nature. 1984;307(5949):367–9.PubMedGoogle Scholar
  169. 169.
    Yalaoui S, Huby T, Franetich JF, et al. Scavenger receptor BI boosts hepatocyte permissiveness to Plasmodium infection. Cell Host Microbe. 2008;4(3):283–92.PubMedGoogle Scholar
  170. 170.
    van Schaijk BCL, Janse CJ, van Gemert G-J, et al. Gene disruption of Plasmodium falciparum p52 results in attenuation of malaria liver stage development in cultured primary human hepatocytes. PLoS One. 2008;3(10):e3549.PubMedGoogle Scholar
  171. 171.
    Bates RC, Edwards NS, Yates JD. Spheroids and cell survival. Crit Rev Oncol Hematol. 2000;36(2–3):61–74.PubMedGoogle Scholar
  172. 172.
    Zahir N, Weaver VM. Death in the third dimension: apoptosis regulation and tissue architecture. Curr Opin Genet Dev. 2004;14(1):71–80.PubMedGoogle Scholar
  173. 173.
    Grossmann J. Molecular mechanisms of “detachment-induced apoptosis – Anoikis”. Apoptosis. 2002;7(3):247–60.PubMedGoogle Scholar
  174. 174.
    Demetriou AA, Whiting JF, Feldman D, et al. Replacement of liver function in rats by transplantation of microcarrier-attached hepatocytes. Science. 1986;233(4769):1190–2.PubMedGoogle Scholar
  175. 175.
    Kasai S, Sawa M, Nishida Y, et al. Cellulose microcarrier for high-density culture of hepatocytes. Transplant Proc. 1992;24(6):2933–4.PubMedGoogle Scholar
  176. 176.
    Kino Y, Sawa M, Kasai S, Mito M. Multiporous cellulose microcarrier for the development of a hybrid artificial liver using isolated hepatocytes. J Surg Res. 1998;79(1):71–6.PubMedGoogle Scholar
  177. 177.
    Kobayashi N, Okitsu T, Maruyama M, et al. Development of a cellulose-based microcarrier containing cellular adhesive peptides for a bioartificial liver. Transplant Proc. 2003;35(1):443–4.PubMedGoogle Scholar
  178. 178.
    Tao X, Shaolin L, Yaoting Y. Preparation and culture of hepatocyte on gelatin microcarriers. J Biomed Mater Res A. 2003;65(2):306–10.PubMedGoogle Scholar
  179. 179.
    Li K, Wang Y, Miao Z, et al. Chitosan/gelatin composite microcarrier for hepatocyte culture. Biotechnol Lett. 2004;26(11):879–83.PubMedGoogle Scholar
  180. 180.
    Dixit V, Darvasi R, Arthur M, et al. Restoration of liver function in Gunn rats without immunosuppression using transplanted microencapsulated hepatocytes. Hepatology. 1990;12(6):1342–9.PubMedGoogle Scholar
  181. 181.
    Zhao Y, Xu Y, Zhang B, et al. In vivo generation of thick, vascularized hepatic tissue from collagen hydrogel-based hepatic units. Tissue Eng Part C Methods. 2009.Google Scholar
  182. 182.
    Fan J, Shang Y, Yuan Y, Yang J. Preparation and characterization of chitosan/galactosylated hyaluronic acid scaffolds for primary hepatocytes culture. J Mater Sci Mater Med. 2010;21(1):319–27.PubMedGoogle Scholar
  183. 183.
    Semino CE, Merok JR, Crane GG, et al. Functional differentiation of hepatocyte-like spheroid structures from putative liver progenitor cells in three-dimensional peptide scaffolds. Differentiation. 2003;71(4–5):262–70.PubMedGoogle Scholar
  184. 184.
    Haque T, Chen H, Ouyang W, et al. In vitro study of alginate-chitosan microcapsules: an alternative to liver cell transplants for the treatment of liver failure. Biotechnol Lett. 2005;27(5):317–22.PubMedGoogle Scholar
  185. 185.
    Hirai S, Kasai S, Mito M. Encapsulated hepatocyte transplantation for the treatment of d-galactosamine-induced acute hepatic failure in rats. Eur Surg Res. 1993;25(4):193–202.PubMedGoogle Scholar
  186. 186.
    Maguire T, Novik E, Schloss R, Yarmush M. Alginate-PLL microencapsulation: effect on the differentiation of embryonic stem cells into hepatocytes. Biotechnol Bioeng. 2006;93(3):581–91.PubMedGoogle Scholar
  187. 187.
    Miura Y, Akimoto T, Kanazawa H, Yagi K. Synthesis and secretion of protein by hepatocytes entrapped within calcium alginate. Artif Organs. 1986;10(6):460–5.PubMedGoogle Scholar
  188. 188.
    Yoon JJ, Nam YS, Kim JH, Park TG. Surface immobilization of galactose onto aliphatic biodegradable polymers for hepatocyte culture. Biotechnol Bioeng. 2002;78(1):1–10.PubMedGoogle Scholar
  189. 189.
    Torok E, Pollok JM, Ma PX, et al. Hepatic tissue engineering on 3-dimensional biodegradable polymers within a pulsatile flow bioreactor. Dig Surg. 2001;18(3):196–203.PubMedGoogle Scholar
  190. 190.
    Pollok JM, Kluth D, Cusick RA, et al. Formation of spheroidal aggregates of hepatocytes on biodegradable polymers under continuous-flow bioreactor conditions. Eur J Pediatr Surg. 1998;8(4):195–9.PubMedGoogle Scholar
  191. 191.
    Mooney DJ, Park S, Kaufmann PM, et al. Biodegradable sponges for hepatocyte transplantation. J Biomed Mater Res. 1995;29(8):959–65.PubMedGoogle Scholar
  192. 192.
    Lee JS, Kim SH, Kim YJ, et al. Hepatocyte adhesion on a poly[N-p-vinylbenzyl-4-O-beta-d-galactopyranosyl-d-glucoamide]-coated poly(l-lactic acid) surface. Biomacromolecules. 2005;6(4):1906–11.PubMedGoogle Scholar
  193. 193.
    Kaufmann PM, Heimrath S, Kim BS, Mooney DJ. Highly porous polymer matrices as a three-dimensional culture system for hepatocytes. Cell Transplant. 1997;6(5):463–8.PubMedGoogle Scholar
  194. 194.
    Jiang J, Kojima N, Guo L, et al. Efficacy of engineered liver tissue based on poly-l-lactic acid scaffolds and fetal mouse liver cells cultured with oncostatin M, nicotinamide, and dimethyl sulfoxide. Tissue Eng. 2004;10(9–10):1577–86.PubMedGoogle Scholar
  195. 195.
    Hasirci V, Berthiaume F, Bondre SP, et al. Expression of liver-specific functions by rat hepatocytes seeded in treated poly(lactic-co-glycolic) acid biodegradable foams. Tissue Eng. 2001;7(4):385–94.PubMedGoogle Scholar
  196. 196.
    Fiegel HC, Havers J, Kneser U, et al. Influence of flow conditions and matrix coatings on growth and differentiation of three-dimensionally cultured rat hepatocytes. Tissue Eng. 2004;10(1–2):165–74.PubMedGoogle Scholar
  197. 197.
    Carlisle ES, Mariappan MR, Nelson KD, et al. Enhancing hepatocyte adhesion by pulsed plasma deposition and polyethylene glycol coupling. Tissue Eng. 2000;6(1):45–52.PubMedGoogle Scholar
  198. 198.
    Nam YS, Yoon JJ, Lee JG, Park TG. Adhesion behaviours of hepatocytes cultured onto biodegradable polymer surface modified by alkali hydrolysis process. J Biomater Sci Polym Ed. 1999;10(11):1145–58.PubMedGoogle Scholar
  199. 199.
    Houchin ML, Topp EM. Chemical degradation of peptides and proteins in PLGA: a review of reactions and mechanisms. J Pharm Sci. 2008;97(7):2395–404.PubMedGoogle Scholar
  200. 200.
    Freed LE, Vunjak-Novakovic G, Biron RJ, et al. Biodegradable polymer scaffolds for tissue engineering. Biotechnology. 1994;12(7):689–93.PubMedGoogle Scholar
  201. 201.
    Wang DA, Williams CG, Yang F, et al. Bioresponsive phosphoester hydrogels for bone tissue engineering. Tissue Eng. 2005;11(1–2):201–13.PubMedGoogle Scholar
  202. 202.
    Wang DA, Williams CG, Li Q, et al. Synthesis and characterization of a novel degradable phosphate-containing hydrogel. Biomaterials. 2003;24(22):3969–80.PubMedGoogle Scholar
  203. 203.
    Nuttelman CR, Tripodi MC, Anseth KS. Dexamethasone-functionalized gels induce osteogenic differentiation of encapsulated hMSCs. J Biomed Mater Res A. 2006;76(1):183–95.PubMedGoogle Scholar
  204. 204.
    Nuttelman CR, Tripodi MC, Anseth KS. Synthetic hydrogel niches that promote hMSC viability. Matrix Biol. 2005;24(3):208–18.PubMedGoogle Scholar
  205. 205.
    Nuttelman CR, Tripodi MC, Anseth KS. In vitro osteogenic differentiation of human mesenchymal stem cells photoencapsulated in PEG hydrogels. J Biomed Mater Res A. 2004;68(4):773–82.PubMedGoogle Scholar
  206. 206.
    Mahoney MJ, Anseth KS. Three-dimensional growth and function of neural tissue in degradable polyethylene glycol hydrogels. Biomaterials. 2006;27(10):2265–74.PubMedGoogle Scholar
  207. 207.
    Burdick JA, Mason MN, Hinman AD, et al. Delivery of osteoinductive growth factors from degradable PEG hydrogels influences osteoblast differentiation and mineralization. J Control Release. 2002;83(1):53–63.PubMedGoogle Scholar
  208. 208.
    Burdick JA, Anseth KS. Photoencapsulation of osteoblasts in injectable RGD-modified PEG hydrogels for bone tissue engineering. Biomaterials. 2002;23(22):4315–23.PubMedGoogle Scholar
  209. 209.
    Mann BK, Schmedlen RH, West JL. Tethered-TGF-beta increases extracellular matrix production of vascular smooth muscle cells. Biomaterials. 2001;22(5):439–44.PubMedGoogle Scholar
  210. 210.
    Mann BK, Gobin AS, Tsai AT, et al. Smooth muscle cell growth in photopolymerized hydrogels with cell adhesive and proteolytically degradable domains: synthetic ECM analogs for tissue engineering. Biomaterials. 2001;22(22):3045–51.PubMedGoogle Scholar
  211. 211.
    Raeber GP, Lutolf MP, Hubbell JA. Molecularly engineered PEG hydrogels: a novel model system for proteolytically mediated cell migration. Biophys J. 2005;89(2):1374–88.PubMedGoogle Scholar
  212. 212.
    Lutolf MP, Lauer-Fields JL, Schmoekel HG, et al. Synthetic matrix metalloproteinase-sensitive hydrogels for the conduction of tissue regeneration: engineering cell-invasion characteristics. Proc Natl Acad Sci U S A. 2003;100(9):5413–8.PubMedGoogle Scholar
  213. 213.
    Lee SH, Miller JS, Moon JJ, West JL. Proteolytically degradable hydrogels with a fluorogenic substrate for studies of cellular proteolytic activity and migration. Biotechnol Prog. 2005;21(6):1736–41.PubMedGoogle Scholar
  214. 214.
    Gobin AS, West JL. Effects of epidermal growth factor on fibroblast migration through biomimetic hydrogels. Biotechnol Prog. 2003;19(6):1781–5.PubMedGoogle Scholar
  215. 215.
    Riley SL, Dutt S, De La Torre R, et al. Formulation of PEG-based hydrogels affects tissue-engineered cartilage construct characteristics. J Mater Sci Mater Med. 2001;12(10–12):983–90.PubMedGoogle Scholar
  216. 216.
    Park Y, Lutolf MP, Hubbell JA, et al. Bovine primary chondrocyte culture in synthetic matrix metalloproteinase-sensitive poly(ethylene glycol)-based hydrogels as a scaffold for cartilage repair. Tissue Eng. 2004;10(3–4):515–22.PubMedGoogle Scholar
  217. 217.
    Martens PJ, Bryant SJ, Anseth KS. Tailoring the degradation of hydrogels formed from multivinyl poly(ethylene glycol) and poly(vinyl alcohol) macromers for cartilage tissue engineering. Biomacromolecules. 2003;4(2):283–92.PubMedGoogle Scholar
  218. 218.
    Bryant SJ, Chowdhury TT, Lee DA, et al. Crosslinking density influences chondrocyte metabolism in dynamically loaded photocrosslinked poly(ethylene glycol) hydrogels. Ann Biomed Eng. 2004;32(3):407–17.PubMedGoogle Scholar
  219. 219.
    Bryant SJ, Anseth KS, Lee DA, Bader DL. Crosslinking density influences the morphology of chondrocytes photoencapsulated in PEG hydrogels during the application of compressive strain. J Orthop Res. 2004;22(5):1143–9.PubMedGoogle Scholar
  220. 220.
    Drury JL, Mooney DJ. Hydrogels for tissue engineering: scaffold design variables and applications. Biomaterials. 2003;24(24):4337–51.PubMedGoogle Scholar
  221. 221.
    Peppas NA, Bures P, Leobandung W, Ichikawa H. Hydrogels in pharmaceutical formulations. Eur J Pharm Biopharm. 2000;50(1):27–46.PubMedGoogle Scholar
  222. 222.
    Liu Tsang V, Chen AA, Cho LM, et al. Fabrication of 3D hepatic tissues by additive photopatterning of cellular hydrogels. FASEB J. 2007;21(3):790–801.PubMedGoogle Scholar
  223. 223.
    Gutsche AT, Lo H, Zurlo J, et al. Engineering of a sugar-derivatized porous network for hepatocyte culture. Biomaterials. 1996;17(3):387–93.PubMedGoogle Scholar
  224. 224.
    Park TG. Perfusion culture of hepatocytes within galactose-derivatized biodegradable poly(lactide-co-glycolide) scaffolds prepared by gas foaming of effervescent salts. J Biomed Mater Res. 2002;59(1):127–35.PubMedGoogle Scholar
  225. 225.
    Chua KN, Lim WS, Zhang P, et al. Stable immobilization of rat hepatocyte spheroids on galactosylated nanofiber scaffold. Biomaterials. 2005;26(15):2537–47.PubMedGoogle Scholar
  226. 226.
    Karamuk E, Mayer J, Wintermantel E, Akaike T. Partially degradable film/fabric composites: textile scaffolds for liver cell culture. Artif Organs. 1999;23(9):881–4.PubMedGoogle Scholar
  227. 227.
    Mayer J, Karamuk E, Akaike T, Wintermantel E. Matrices for tissue engineering-scaffold structure for a bioartificial liver support system. J Control Release. 2000;64(1–3):81–90.PubMedGoogle Scholar
  228. 228.
    Hersel U, Dahmen C, Kessler H. RGD modified polymers: biomaterials for stimulated cell adhesion and beyond. Biomaterials. 2003;24(24):4385–415.PubMedGoogle Scholar
  229. 229.
    Seliktar D, Zisch AH, Lutolf MP, et al. MMP-2 sensitive. VEGF-bearing bioactive hydrogels for promotion of vascular healing. J Biomed Mater Res A. 2004;68(4):704–16.PubMedGoogle Scholar
  230. 230.
    Patel PN, Gobin AS, West JL, Patrick Jr CW. Poly(ethylene glycol) hydrogel system supports preadipocyte viability, adhesion, and proliferation. Tissue Eng. 2005;11(9–10):1498–505.PubMedGoogle Scholar
  231. 231.
    Davis KA, Burdick JA, Anseth KS. Photoinitiated crosslinked degradable copolymer networks for tissue engineering applications. Biomaterials. 2003;24(14):2485–95.PubMedGoogle Scholar
  232. 232.
    Anseth KS, Metters AT, Bryant SJ, et al. In situ forming degradable networks and their application in tissue engineering and drug delivery. J Control Release. 2002;78(1–3):199–209.PubMedGoogle Scholar
  233. 233.
    Martinez-Hernandez A, Amenta PS. The extracellular matrix in hepatic regeneration. FASEB J. 1995;9(14):1401–10.PubMedGoogle Scholar
  234. 234.
    Knittel T, Mehde M, Grundmann A, et al. Expression of matrix metalloproteinases and their inhibitors during hepatic tissue repair in the rat. Histochem Cell Biol. 2000;113(6):443–53.PubMedGoogle Scholar
  235. 235.
    Kim TH, Mars WM, Stolz DB, Michalopoulos GK. Expression and activation of pro-MMP-2 and pro-MMP-9 during rat liver regeneration. Hepatology. 2000;31(1):75–82.PubMedGoogle Scholar
  236. 236.
    Ranucci CS, Kumar A, Batra SP, Moghe PV. Control of hepatocyte function on collagen foams: sizing matrix pores toward selective induction of 2-D and 3-D cellular morphogenesis. Biomaterials. 2000;21(8):783–93.PubMedGoogle Scholar
  237. 237.
    Oates M, Chen R, Duncan M, Hunt JA. The angiogenic potential of three-dimensional open porous synthetic matrix materials. Biomaterials. 2007;28(25):3679–86.PubMedGoogle Scholar
  238. 238.
    Chung TW, Yang J, Akaike T, et al. Preparation of alginate/galactosylated chitosan scaffold for hepatocyte attachment. Biomaterials. 2002;23(14):2827–34.PubMedGoogle Scholar
  239. 239.
    Glicklis R, Shapiro L, Agbaria R, et al. Hepatocyte behavior within three-dimensional porous alginate scaffolds. Biotechnol Bioeng. 2000;67(3):344–53.PubMedGoogle Scholar
  240. 240.
    Elcin YM, Dixit V, Gitnick G. Hepatocyte attachment on biodegradable modified chitosan membranes: in vitro evaluation for the development of liver organoids. Artif Organs. 1998;22(10):837–46.PubMedGoogle Scholar
  241. 241.
    Dvir-Ginzberg M, Gamlieli-Bonshtein I, Agbaria R, Cohen S. Liver tissue engineering within alginate scaffolds: effects of cell-seeding density on hepatocyte viability, morphology, and function. Tissue Eng. 2003;9(4):757–66.PubMedGoogle Scholar
  242. 242.
    Li J, Pan J, Zhang L, Yu Y. Culture of hepatocytes on fructose-modified chitosan scaffolds. Biomaterials. 2003;24(13):2317–22.PubMedGoogle Scholar
  243. 243.
    Kawase M, Michibayashi N, Nakashima Y, et al. Application of glutaraldehyde-crosslinked chitosan as a scaffold for hepatocyte attachment. Biol Pharm Bull. 1997;20(6):708–10.PubMedGoogle Scholar
  244. 244.
    Yang J, Goto M, Ise H, et al. Galactosylated alginate as a scaffold for hepatocytes entrapment. Biomaterials. 2002;23(2):471–9.PubMedGoogle Scholar
  245. 245.
    Wang XH, Li DP, Wang WJ, et al. Crosslinked collagen/chitosan matrix for artificial livers. Biomaterials. 2003;24(19):3213–20.PubMedGoogle Scholar
  246. 246.
    Wang X, Yan Y, Xiong Z, et al. Preparation and evaluation of ammonia-treated collagen/chitosan matrices for liver tissue engineering. J Biomed Mater Res B Appl Biomater. 2005;75(1):91–8.PubMedGoogle Scholar
  247. 247.
    Wang X, Yan Y, Lin F, et al. Preparation and characterization of a collagen/chitosan/heparin matrix for an implantable bioartificial liver. J Biomater Sci Polym Ed. 2005;16(9):1063–80.PubMedGoogle Scholar
  248. 248.
    Suh H, Song MJ, Park YN. Behavior of isolated rat oval cells in porous collagen scaffold. Tissue Eng. 2003;9(3):411–20.PubMedGoogle Scholar
  249. 249.
    Seo SJ, Kim IY, Choi YJ, et al. Enhanced liver functions of hepatocytes cocultured with NIH 3T3 in the alginate/galactosylated chitosan scaffold. Biomaterials. 2006;27(8):1487–95.PubMedGoogle Scholar
  250. 250.
    Seo SJ, Choi YJ, Akaike T, et al. Alginate/galactosylated chitosan/heparin scaffold as a new synthetic extracellular matrix for hepatocytes. Tissue Eng. 2006;12(1):33–44.PubMedGoogle Scholar
  251. 251.
    Park IK, Yang J, Jeong HJ, et al. Galactosylated chitosan as a synthetic extracellular matrix for hepatocytes attachment. Biomaterials. 2003;24(13):2331–7.PubMedGoogle Scholar
  252. 252.
    Yannas IV, Burke JF, Gordon PL, et al. Design of an artificial skin. II. Control of chemical composition. J Biomed Mater Res. 1980;14(2):107–32.PubMedGoogle Scholar
  253. 253.
    Yannas IV, Burke JF. Design of an artificial skin. I. Basic design principles. J Biomed Mater Res. 1980;14(1):65–81.PubMedGoogle Scholar
  254. 254.
    Sumita Y, Honda MJ, Ohara T, et al. Performance of collagen sponge as a 3-D scaffold for tooth-tissue engineering. Biomaterials. 2006;27(17):3238–48.PubMedGoogle Scholar
  255. 255.
    Sugimoto S, Harada K, Shiotani T, et al. Hepatic organoid formation in collagen sponge of cells isolated from human liver tissues. Tissue Eng. 2005;11(3–4):626–33.PubMedGoogle Scholar
  256. 256.
    Nehrer S, Breinan HA, Ramappa A, et al. Matrix collagen type and pore size influence behaviour of seeded canine chondrocytes. Biomaterials. 1997;18(11):769–76.PubMedGoogle Scholar
  257. 257.
    Hosseinkhani H, Azzam T, Kobayashi H, et al. Combination of 3D tissue engineered scaffold and non-viral gene carrier enhance in vitro DNA expression of mesenchymal stem cells. Biomaterials. 2006;27(23):4269–78.PubMedGoogle Scholar
  258. 258.
    Dagalakis N, Flink J, Stasikelis P, et al. Design of an artificial skin. Part III. Control of pore structure. J Biomed Mater Res. 1980;14(4):511–28.PubMedGoogle Scholar
  259. 259.
    Yang TH, Miyoshi H, Ohshima N. Novel cell immobilization method utilizing centrifugal force to achieve high-density hepatocyte culture in porous scaffold. J Biomed Mater Res. 2001;55(3):379–86.PubMedGoogle Scholar
  260. 260.
    Lee KY, Peters MC, Anderson KW, Mooney DJ. Controlled growth factor release from synthetic extracellular matrices. Nature. 2000;408(6815):998–1000.PubMedGoogle Scholar
  261. 261.
    Badylak SF, Park K, Peppas N, et al. Marrow-derived cells populate scaffolds composed of xenogeneic extracellular matrix. Exp Hematol. 2001;29(11):1310–8.PubMedGoogle Scholar
  262. 262.
    Tsang VL, Bhatia SN. Three-dimensional tissue fabrication. Adv Drug Deliv Rev. 2004;56(11):1635–47.PubMedGoogle Scholar
  263. 263.
    Kim SS, Utsunomiya H, Koski JA, et al. Survival and function of hepatocytes on a novel three-dimensional synthetic biodegradable polymer scaffold with an intrinsic network of channels. Ann Surg. 1998;228(1):8–13.PubMedGoogle Scholar
  264. 264.
    Petronis S, Eckert KL, Gold J, Wintermantel E. Microstructuring ceramic scaffolds for hepatocyte cell culture. J Mater Sci Mater Med. 2001;12(6):523–8.PubMedGoogle Scholar
  265. 265.
    Ogawa K, Ochoa ER, Borenstein J, et al. The generation of functionally differentiated, three-dimensional hepatic tissue from two-dimensional sheets of progenitor small hepatocytes and nonparenchymal cells. Transplantation. 2004;77(12):1783–9.PubMedGoogle Scholar
  266. 266.
    Kaihara S, Borenstein J, Koka R, et al. Silicon micromachining to tissue engineer branched vascular channels for liver fabrication. Tissue Eng. 2000;6(2):105–17.PubMedGoogle Scholar
  267. 267.
    Vozzi G, Flaim C, Ahluwalia A, Bhatia S. Fabrication of PLGA scaffolds using soft lithography and microsyringe deposition. Biomaterials. 2003;24(14):2533–40.PubMedGoogle Scholar
  268. 268.
    Tan W, Desai TA. Layer-by-layer microfluidics for biomimetic three-dimensional structures. Biomaterials. 2004;25(7–8):1355–64.PubMedGoogle Scholar
  269. 269.
    Tan W, Desai TA. Microfluidic patterning of cells in extracellular matrix biopolymers: effects of channel size, cell type, and matrix composition on pattern integrity. Tissue Eng. 2003;9(2):255–67.PubMedGoogle Scholar
  270. 270.
    Wang X, Yan Y, Pan Y, et al. Generation of three-dimensional hepatocyte/gelatin structures with rapid prototyping system. Tissue Eng. 2006;12(1):83–90.PubMedGoogle Scholar
  271. 271.
    Hahn MS, Taite LJ, Moon JJ, et al. Photolithographic patterning of polyethylene glycol hydrogels. Biomaterials. 2006;27(12):2519–24.PubMedGoogle Scholar
  272. 272.
    Revzin A, Russell RJ, Yadavalli VK, et al. Fabrication of poly(ethylene glycol) hydrogel microstructures using photolithography. Langmuir. 2001;17(18):5440–7.PubMedGoogle Scholar
  273. 273.
    Beebe DJ, Moore JS, Bauer JM, et al. Functional hydrogel structures for autonomous flow control inside microfluidic channels. Nature. 2000;404(6778):588–90.PubMedGoogle Scholar
  274. 274.
    Albrecht DR, Underhill GH, Wassermann TB, et al. Probing the role of multicellular organization in three-dimensional microenvironments. Nat Methods. 2006;3(5):369–75.PubMedGoogle Scholar
  275. 275.
    Kloxin AM, Kasko AM, Salinas CN, Anseth KS. Photodegradable hydrogels for dynamic tuning of physical and chemical properties. Science. 2009;324(5923):59–63.PubMedGoogle Scholar
  276. 276.
    Itle LJ, Koh WG, Pishko MV. Hepatocyte viability and protein expression within hydrogel microstructures. Biotechnol Prog. 2005;21(3):926–32.PubMedGoogle Scholar
  277. 277.
    Powers MJ, Janigian DM, Wack KE, et al. Functional behavior of primary rat liver cells in a three-dimensional perfused microarray bioreactor. Tissue Eng. 2002;8(3):499–513.PubMedGoogle Scholar
  278. 278.
    Quek CH, Li J, Sun T, et al. Photo-crosslinkable microcapsules formed by polyelectrolyte copolymer and modified collagen for rat hepatocyte encapsulation. Biomaterials. 2004;25(17):3531–40.PubMedGoogle Scholar
  279. 279.
    Dawson L, Bateman-House AS, Mueller Agnew D, et al. Safety issues in cell-based intervention trials. Fertil Steril. 2003;80(5):1077–85.PubMedGoogle Scholar
  280. 280.
    Hill E, Boontheekul T, Mooney DJ. Regulating activation of transplanted cells controls tissue regeneration. Proc Natl Acad Sci U S A. 2006;103(8):2494–9.PubMedGoogle Scholar
  281. 281.
    Sands RW, Mooney DJ. Polymers to direct cell fate by controlling the microenvironment. Curr Opin Biotechnol. 2007;18(5):448–53.PubMedGoogle Scholar
  282. 282.
    Godier AF, Marolt D, Gerecht S, et al. Engineered microenvironments for human stem cells. Birth Defects Res C Embryo Today. 2008;84(4):335–47.PubMedGoogle Scholar
  283. 283.
    Hwa AJ, Fry RC, Sivaraman A, et al. Rat liver sinusoidal endothelial cells survive without exogenous VEGF in 3D perfused co-cultures with hepatocytes. FASEB J. 2007;21(10):2564–79.PubMedGoogle Scholar
  284. 284.
    Moghe PV, Coger RN, Toner M, Yarmush ML. Cell-cell interactions are essential for maintenance of hepatocyte function in collagen gel but not on matrigel. Biotechnol Bioeng. 1997;56(6):706–11.PubMedGoogle Scholar
  285. 285.
    Saito S, Sakagami K, Matsuno T, et al. Long-term survival and proliferation of spheroidal aggregate cultured hepatocytes transplanted into the rat spleen. Transplant Proc. 1992;24(4):1520–1.PubMedGoogle Scholar
  286. 286.
    Corlu A, Ilyin G, Cariou S, et al. The coculture: a system for studying the regulation of liver differentiation/proliferation activity and its control. Cell Biol Toxicol. 1997;13(4–5):235–42.PubMedGoogle Scholar
  287. 287.
    Harada K, Mitaka T, Miyamoto S, et al. Rapid formation of hepatic organoid in collagen sponge by rat small hepatocytes and hepatic nonparenchymal cells. J Hepatol. 2003;39(5):716–23.PubMedGoogle Scholar
  288. 288.
    Inamori M, Mizumoto H, Kajiwara T. An approach for formation of vascularized liver tissue by endothelial cell-covered hepatocyte spheroid integration. Tissue Eng A. 2009;15(8):2029–37.Google Scholar
  289. 289.
    Gu J, Shi X, Zhang Y, et al. Establishment of a three-dimensional co-culture system by porcine hepatocytes and bone marrow mesenchymal stem cells in vitro. Hepatol Res. 2009;39(4):398–407.PubMedGoogle Scholar
  290. 290.
    Abu-Absi SF, Hansen LK, Hu WS. Three-dimensional co-culture of hepatocytes and stellate cells. Cytotechnology. 2004;45(3):125–40.PubMedGoogle Scholar
  291. 291.
    Sudo R, Chung S, Zervantonakis IK, et al. Transport-mediated angiogenesis in 3D epithelial coculture. FASEB J. 2009;23(7):2155–64.PubMedGoogle Scholar
  292. 292.
    Kirouac DC, Zandstra PW. Understanding cellular networks to improve hematopoietic stem cell expansion cultures. Curr Opin Biotechnol. 2006;17(5):538–47.PubMedGoogle Scholar
  293. 293.
    Aldridge BB, Burke JM, Lauffenburger DA, Sorger PK. Physicochemical modelling of cell signalling pathways. Nat Cell Biol. 2006;8(11):1195–203.PubMedGoogle Scholar
  294. 294.
    Khetani SR, Chen AA, Ranscht B, Bhatia SN. T-cadherin modulates hepatocyte functions in vitro. FASEB J. 2008;22(11):3768–75.PubMedGoogle Scholar
  295. 295.
    van de Kerkhove MP, Hoekstra R, van Gulik TM, Chamuleau RA. Large animal models of fulminant hepatic failure in artificial and bioartificial liver support research. Biomaterials. 2004;25(9):1613–25.PubMedGoogle Scholar
  296. 296.
    Terblanche J, Hickman R. Animal models of fulminant hepatic failure. Dig Dis Sci. 1991;36(6):770–4.PubMedGoogle Scholar
  297. 297.
    Newsome PN, Plevris JN, Nelson LJ, Hayes PC. Animal models of fulminant hepatic failure: a critical evaluation. Liver Transpl. 2000;6(1):21–31.PubMedGoogle Scholar
  298. 298.
    Rahman TM, Hodgson HJ. Animal models of acute hepatic failure. Int J Exp Pathol. 2000;81(2):145–57.PubMedGoogle Scholar
  299. 299.
    Meuleman P, Leroux-Roels G. The human liver-uPA-SCID mouse: a model for the evaluation of antiviral compounds against HBV and HCV. Antiviral Res. 2008;80(3):231–8.PubMedGoogle Scholar
  300. 300.
    Grompe M, Lindstedt S, al-Dhalimy M, et al. Pharmacological correction of neonatal lethal hepatic dysfunction in a murine model of hereditary tyrosinaemia type I. Nat Genet. 1995;10(4):453–60.PubMedGoogle Scholar
  301. 301.
    Lindros KO, Cai YA, Penttila KE. Role of ethanol-inducible cytochrome P-450 IIE1 in carbon tetrachloride-induced damage to centrilobular hepatocytes from ethanol-treated rats. Hepatology. 1990;12(5):1092–7.PubMedGoogle Scholar
  302. 302.
    Anundi I, Lahteenmaki T, Rundgren M, et al. Zonation of acetaminophen metabolism and cytochrome P450 2E1-mediated toxicity studied in isolated periportal and perivenous hepatocytes. Biochem Pharmacol. 1993;45(6):1251–9.PubMedGoogle Scholar
  303. 303.
    Jirtle RL, Michalopoulos G. Effects of partial hepatectomy on transplanted hepatocytes. Cancer Res. 1982;42(8):3000–4.PubMedGoogle Scholar
  304. 304.
    Roger V, Balladur P, Honiger J, et al. Internal bioartificial liver with xenogeneic hepatocytes prevents death from acute liver failure: an experimental study. Ann Surg. 1998;228(1):1–7.PubMedGoogle Scholar
  305. 305.
    Enzan H, Himeno H, Hiroi M, et al. Development of hepatic sinusoidal structure with special reference to the Ito cells. Microsc Res Tech. 1997;39(4):336–49.PubMedGoogle Scholar
  306. 306.
    Lesman A, Habib M, Caspi O, et al. Transplantation of a tissue-engineered human vascularized cardiac muscle. Tissue Eng Part A. 2010;16(1):115–25.PubMedGoogle Scholar
  307. 307.
    Levenberg S, Rouwkema J, Macdonald M, et al. Engineering vascularized skeletal muscle tissue. Nat Biotechnol. 2005;23(7):879–84.PubMedGoogle Scholar
  308. 308.
    Stevens KR, Kreutziger KL, Dupras SK, et al. Physiological function and transplantation of scaffold-free and vascularized human cardiac muscle tissue. Proc Natl Acad Sci U S A. 2009;106(39):16568–73.PubMedGoogle Scholar
  309. 309.
    Smith MK, Riddle KW, Mooney DJ. Delivery of hepatotrophic factors fails to enhance longer-term survival of subcutaneously transplanted hepatocytes. Tissue Eng. 2006;12(2):235–44.PubMedGoogle Scholar
  310. 310.
    Smith MK, Peters MC, Richardson TP, et al. Locally enhanced angiogenesis promotes transplanted cell survival. Tissue Eng. 2004;10(1–2):63–71.PubMedGoogle Scholar
  311. 311.
    Lee H, Cusick RA, Browne F, et al. Local delivery of basic fibroblast growth factor increases both angiogenesis and engraftment of hepatocytes in tissue-engineered polymer devices. Transplantation. 2002;73(10):1589–93.PubMedGoogle Scholar
  312. 312.
    Richardson TP, Peters MC, Ennett AB, Mooney DJ. Polymeric system for dual growth factor delivery. Nat Biotechnol. 2001;19(11):1029–34.PubMedGoogle Scholar
  313. 313.
    Kedem A, Perets A, Gamlieli-Bonshtein I, et al. Vascular endothelial growth factor-releasing scaffolds enhance vascularization and engraftment of hepatocytes transplanted on liver lobes. Tissue Eng. 2005;11(5–6):715–22.PubMedGoogle Scholar
  314. 314.
    Sudo R, Mitaka T, Ikeda M, Tanishita K. Reconstruction of 3D stacked-up structures by rat small hepatocytes on microporous membranes. FASEB J. 2005;19(12):1695–7.PubMedGoogle Scholar
  315. 315.
    Ishida Y, Smith S, Wallace L, et al. Ductular morphogenesis and functional polarization of normal human biliary epithelial cells in three-dimensional culture. J Hepatol. 2001;35(1):2–9.PubMedGoogle Scholar
  316. 316.
    Auth MK, Joplin RE, Okamoto M, et al. Morphogenesis of primary human biliary epithelial cells: induction in high-density culture or by coculture with autologous human hepatocytes. Hepatology. 2001;33(3):519–29.PubMedGoogle Scholar
  317. 317.
    Miyazawa M, Torii T, Toshimitsu Y, et al. A tissue-engineered artificial bile duct grown to resemble the native bile duct. Am J Transplant. 2005;5(6):1541–7.PubMedGoogle Scholar
  318. 318.
    Vemuri MC, Schimmel T, Colls P, et al. Derivation of human embryonic stem cells in xeno-free conditions. Methods Mol Biol. 2007;407:1–10.PubMedGoogle Scholar
  319. 319.
    Peiffer I, Barbet R, Hatzfeld A, et al. Optimization of physiological xenofree molecularly defined media and matrices to maintain human embryonic stem cell pluripotency. Methods Mol Biol. 2010;584:97–108.PubMedGoogle Scholar
  320. 320.
    Odorico JS, Kaufman DS, Thomson JA. Multilineage differentiation from human embryonic stem cell lines. Stem Cells. 2001;19(3):193–204.PubMedGoogle Scholar
  321. 321.
    Racanelli V, Rehermann B. The liver as an immunological organ. Hepatology. 2006;43(2 Suppl 1):S54–62.PubMedGoogle Scholar
  322. 322.
    Starzl TE, Lakkis FG. The unfinished legacy of liver transplantation: emphasis on immunology. Hepatology. 2006;43(2 Suppl 1):S151–63.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Jing Shan
  • Kelly R. Stevens
  • Kartik Trehan
  • Gregory H. Underhill
  • Alice A. Chen
  • Sangeeta N. Bhatia
    • 1
  1. 1.M.I.T.CambridgeUSA

Personalised recommendations