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3D Pancreatic Tissue Modeling in vitro: Advances and Prospects

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Abstract

The pancreas is a relatively small organ, but it has structural and functional complexity that makes it difficult to understand underlying disease mechanisms and determine effective treatments. Thus, there is a great need for more effective tools to study pancreatic disease, and breakthroughs in various fields have contributed to development of in vitro tissue models to understand the pathophysiological conditions of pancreatic disease. Here, we provide an overview of three major parts of the strategies in pancreatic tissue modeling. The advent of stem cell technology enables large-scale production of cells, which can represent individual patients’ information. The biomaterials provide cells with a three-dimensional (3D) geometry to mimic the nature of cell—matrix contacts. With the benefits of 3D culture systems, decellularized extracellular matrix materials have been introduced as a promising tool for providing tissue-specific niches to cells. In addition, several biofabrication strategies allow modeling of structural complexities including cell deposition and neighboring environment, as compared to standard embedding cells in matrix. Integration of these strategies can overcome the current challenges to each approach and guide the path towards the next generation of 3D pancreatic tissue modeling for translational medicine.

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References

  1. Ellis, C., Ramzy, A. & Kieffer, T.J. Regenerative medicine and cell-based approaches to restore pancreatic function. Nat. Rev. Gastroenterol. Hepatol.14, 612–628 (2017).

    CAS  PubMed  Google Scholar 

  2. Caicedo, A. Paracrine and autocrine interactions in the human islet: more than meets the eye. Semin. Cell Dev. Biol.24 11–21 (2013).

    CAS  PubMed  Google Scholar 

  3. Bakhti, M., Böttcher, A. & Lickert, H. Modelling the endocrine pancreas in health and disease. Nat. Rev. Endocrinol.15, 155–171 (2019).

    CAS  PubMed  Google Scholar 

  4. Rask-Madsen, C. & Kahn, C.R. Tissue—specific insulin signaling, metabolic syndrome, and cardiovascular disease. Arterioscler., Thromb., Vasc. Biol.32, 2052–2059 (2012).

    CAS  Google Scholar 

  5. Latres, E., Finan, D.A., Greenstein, J.L., Kowalski, A. & Kieffer, T.J. Navigating two roads to glucose normalization in diabetes: automated insulin delivery devices and cell therapy. Cell Metab.29, 545–563 (2019).

    CAS  PubMed  Google Scholar 

  6. Roden, M. & Shulman, G.I. The integrative biology of type 2 diabetes. Nature576, 51–60 (2019).

    CAS  PubMed  Google Scholar 

  7. Kleeff, J., Korc, M., Apte, M., La Vecchia, C., Johnson, C.D., Biankin, A.V., Neale, R.E., Tempero, M., Tuveson, D.A. & Hruban, R.H. Pancreatic cancer. Nat. Rev. Dis. Primers2, 16022 (2016).

    PubMed  Google Scholar 

  8. Laurent, J., Blin, G., Chatelain, F., Vanneaux, V., Fuchs, A., Larghero, J. & Thery, M. Convergence of microengineering and cellular self-organization towards functional tissue manufacturing. Nat. Biomed. Eng.1, 939–956 (2017).

    CAS  PubMed  Google Scholar 

  9. Rossi, G., Manfrin, A. & Lutolf, M.P. Progress and potential in organoid research. Nat. Rev. Genet.19, 671–687 (2018).

    CAS  PubMed  Google Scholar 

  10. Pagliuca, F.W., Jeffrey R.M., Gürtler, M., Segel, M., Van Dervort, A., Ryu, J.H., Peterson, Q.P., Greiner, D. & Melton, D.A. Generation of Functional Human Pancreatic β Cells In Vitro. Cell159, 428–439 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Rezania, A., Bruin, J.E., Arora, P., Rubin, A., Batushansky, I., Asadi, A., O’Dwyer, S., Quiskamp, N., Mojibian, M., Albrecht, T., Yang, Y.H.C., Johnson, J.D. & Kieffer, T.J. Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells. Nat. Biotechnol.32, 1121–1133 (2014).

    CAS  PubMed  Google Scholar 

  12. Kieffer, T.J., Woltjen, K., Osafune, K., Yabe, D. & Inagaki, N. Beta-cell replacement strategies for diabetes. J. Diabetes Invest.9, 457–463 (2018).

    Google Scholar 

  13. Millman, J.R., Xie, C., Van Dervort, A., Gürtler, M., Pagliuca, F.W. & Melton, D.A. Generation of stem cell-derived β-cells from patients with type 1 diabetes. Nat. Commun.7, 11463 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Bruin, J.E., Rezania, A. & Kieffer, T.J. Replacing and safeguarding pancreatic β cells for diabetes. Sci. Transl. Med.7, 316ps323–316ps323 (2015).

    Google Scholar 

  15. Takahashi, Y., Sekine, K., Kin, T., Takebe, T. & Taniguchi, H. Self-condensation culture enables vascularization of tissue fragments for efficient therapeutic transplantation. Cell Rep.23, 1620–1629 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Driehuis, E., van Hoeck, A., Moore, K., Kolders, S., Francies, H.E., Gulersonmez, M.C., Stigter, E.C.A., Burgering, B., Geurts, V., Gracanin, A., Bounova, G., Morsink, F.H., Vries, R., Boj, S., van Es, J., Offerhaus, G.J.A., Kranenburg, O., Garnett, M.J., Wessels, L., Cuppen, E., Brosens, L.A.A. & Clevers, H. Pancreatic cancer organoids recapitulate disease and allow personalized drug screening. Proc. Natl. Acad. Sci.116, 26580 (2019).

    CAS  PubMed Central  Google Scholar 

  17. Balak, J.R., Juksar, J., Carlotti, F., Nigro, A.L. & de Koning, E.J. Organoids from the Human Fetal and Adult Pancreas. Curr. Diabetes Rep.19, 160 (2019).

    CAS  Google Scholar 

  18. Tao, T., Wang, Y., Chen, W., Li, Z., Su, W., Guo, Y., Deng, P. & Qin, J. Engineering human islet organoids from iPSCs using an organ-on-chip platform. Lab Chip19, 948–958 (2019).

    CAS  PubMed  Google Scholar 

  19. Drost, J. & Clevers, H. Organoids in cancer research. Nat. Rev. Cancer18, 407–418 (2018).

    CAS  PubMed  Google Scholar 

  20. Kratochvil, M.J., Seymour, A.J., Li, T.L., Paşca, S.P., Kuo, C.J. & Heilshorn, S.C. Engineered materials for organoid systems. Nat. Rev. Mater.4, 606–622 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Daoud, J.T., Petropavlovskaia, M.S., Patapas, J.M., Degrandpré, C.E., DiRaddo, R.W., Rosenberg, L. & Tabrizian, M. Long-term in vitro human pancreatic islet culture using three-dimensional microfabricated scaffolds. Biomaterials32, 1536–1542 (2011).

    CAS  PubMed  Google Scholar 

  22. Han, W., Singh, N.K., Kim, J.J., Kim, H., Kim, B.S., Park, J.Y., Jang, J. & Cho, D.-W. Directed differential behaviors of multipotent adult stem cells from decellularized tissue/organ extracellular matrix bio-inks. Biomaterials224, 119496 (2019).

    CAS  PubMed  Google Scholar 

  23. Kim, J., Shim, I.K., Hwang, D.G., Lee, Y.N., Kim, M., Kim, H., Kim, S.-W., Lee, S., Kim, S.C. & Cho, D.-W. 3D cell printing of islet-laden pancreatic tissue-derived extracellular matrix bioink constructs for enhancing pancreatic functions. J. Mater. Chem. B7, 1773–1781 (2019).

    CAS  PubMed  Google Scholar 

  24. Kim, J., Kim, M., Hwang, D.G., Shim, I.K., Kim, S. C. & Jang, J. Pancreatic Tissue-Derived Extracellular Matrix Bioink for Printing 3D Cell-Laden Pancreatic Tissue Constructs. J. Visualized Exp.154, e60434 (2019).

    Google Scholar 

  25. Takebe, T., Zhang, B. & Radisic, M. Synergistic engineering: organoids meet organs-on-a-chip. Cell Stem Cell21, 297–300 (2017).

    CAS  PubMed  Google Scholar 

  26. Jun, Y., Lee, J., Choi, S., Yang, J.H., Sander, M., Chung, S. & Lee, S.-H. In vivo—mimicking micro-fluidic perfusion culture of pancreatic islet spheroids. Sci. Adv.5, eaax4520 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Sipos, B., Kojima, M., Tiemann, K., Klapper, W., Kruse, M.-L., Kalthoff, H., Schniewind, B., Tepel, J., Weich, H., Kerjaschki, D. & Klöppel, G. Lymphatic spread of ductal pancreatic adenocarcinoma is independent of lymphangiogenesis. J. Pathol.207, 301–312 (2005).

    CAS  PubMed  Google Scholar 

  28. Lenggenhager, D., Amrutkar, M., Sántha, P., Aasrum, M., Löhr, J.-M., Gladhaug, P.I. & Verbeke, S.C. Commonly Used Pancreatic Stellate Cell Cultures Differ Phenotypically and in Their Interactions with Pancreatic Cancer Cells. Cells DOI https://doi.org/10.3390/cells8010023 (2019).

  29. Adams, G.G., Uddin, A., Vives-Pi, M. & Pujol-Borrell, R. Characterisation of the NES2Y cell line and its use in the production of human glucose- responsive insulin producing (hGRIP) cell lines by cell-cell fusion. Islets1, 117–123 (2009).

    PubMed  Google Scholar 

  30. McCluskey, J.T., Hamid, M., Guo-Parke, H., McClenaghan, N.H., Gomis, R. & Flatt, P.R. Development and functional characterization of insulin-releasing human pancreatic beta cell lines produced by electrofusion. J. Biol. Chem.286, 21982–21992 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Narushima, M., Kobayashi, N., Okitsu, T., Tanaka, Y., Li, S.-A., Chen, Y., Miki, A., Tanaka, K., Nakaji, S., Takei, K., Gutierrez, A.S., Rivas-Carrillo, J.D., Navarro-Álvarez, N., Jun, H.-S., Westerman, K.A., Noguchi, H., Lakey, J.R.T., Leboulch, P., Tanaka, N. & Yoon, J.-W. A human β-cell line for transplantation therapy to control type 1 diabetes. Nat. Biotechnol.23, 1274–1282 (2005).

    CAS  PubMed  Google Scholar 

  32. Ravassard, P., Hazhouz, Y., Pechberty, S., Bricout-Neveu, E., Armanet, M., Czernichow, P. & Scharfmann, R. A genetically engineered human pancreatic β cell line exhibiting glucose-inducible insulin secretion. J. Clin. Invest.121, 3589–3597 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Baroni, M.G., Cavallo, M.G., Mark, M., Monetini, L., Stoehrer, B. & Pozzilli, P. Beta-cell gene expression and functional characterisation of the human insulinoma cell line CM. J. Endocrinol.161, 59–68 (1999).

    CAS  PubMed  Google Scholar 

  34. Soldevila, G., Buscema, M., Marini, V., Sutton, R., James, R.F.L., Bloom, S.R., Robertson, R.P., Mirakian, R., Pujol-Borrell, R. & Bottazzo, G.F. Transfection with SV40 gene of human pancreatic endocrine cells. J. Autoimmun.4, 381–396 (1991).

    CAS  PubMed  Google Scholar 

  35. Serebriiskii, I., Castelló-Cros, R., Lamb, A., Golemis, E.A. & Cukierman, E. Fibroblast-derived 3D matrix differentially regulates the growth and drug-responsiveness of human cancer cells. Matrix Biol.27, 573–585 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Lightfoot, Y.L., Chen, J. & Mathews, C.E. Immunemediated β-cell death in type 1 diabetes: lessons from human β-cell lines. Eur. J. Clin. Invest.42, 1244–1251 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Baker, L.A., Tiriac, H., Clevers, H. & Tuveson, D.A. Modeling Pancreatic Cancer with Organoids. Trends Cancer2, 176–190 (2016).

    PubMed  PubMed Central  Google Scholar 

  38. Gunton, J.E., Kulkarni, R.N., Yim, S., Okada, T., Hawthorne, W.J., Tseng, Y.-H., Roberson, R.S., Ricordi, C., O’Connell, P.J., Gonzalez, F.J. & Kahn, C.R. Loss of ARNT/HIF1β Mediates Altered Gene Expression and Pancreatic-Islet Dysfunction in Human Type 2 Diabetes. Cell122, 337–349 (2005).

    CAS  PubMed  Google Scholar 

  39. Benam, K.H., Dauth, S., Hassell, B., Herland, A., Jain, A., Jang, K.-J., Karalis, K., Kim, H.J., MacQueen, L., Mahmoodian, R., Musah, S., Torisawa, Y.-S., Meer, A.D.v.d., Villenave, R., Yadid, M., Parker, K.K. & Ingber, D.E. Engineered In Vitro Disease Models. Annu. Rev. Pathol.10, 195–262 (2015).

    CAS  PubMed  Google Scholar 

  40. McCall, Michael D., Toso, C., Baetge, Emmanuel E. & Shapiro, A.M.J. Are stem cells a cure for diabetes? Clin. Sci.118, 87–97 (2009).

    Google Scholar 

  41. Domínguez-Bendala, J., Inverardi, L. & Ricordi, C. Stem cell-derived islet cells for transplantation. Curr. Opin. Organ Transplant.16, 76–82 (2011).

    PubMed  PubMed Central  Google Scholar 

  42. Shahjalal, H.M., Abdal Dayem, A., Lim, K.M., Jeon, T.-i. & Cho, S.-G. Generation of pancreatic β cells for treatment of diabetes: advances and challenges. Stem Cell Res. Ther.9, 355 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Sayed, N., Liu, C. & Wu, J.C. Translation of Human-Induced Pluripotent Stem Cells: From Clinical Trial in a Dish to Precision Medicine. J. Am. Coll. Cardiol.67, 2161–2176 (2016).

    PubMed  PubMed Central  Google Scholar 

  44. Wan, J., Huang, Y., Zhou, P., Guo, Y., Wu, C., Zhu, S., Wang, Y., Wang, L., Lu, Y. & Wang, Z. Culture of iPSCs derived pancreatic β-like cells in vitro using decellularized pancreatic scaffolds: a preliminary trial. Biomed Res. Int.2017, 4276928 (2017).

    PubMed  PubMed Central  Google Scholar 

  45. Shahjalal, H.M., Shiraki, N., Sakano, D., Kikawa, K., Ogaki, S., Baba, H., Kume, K. & Kume, S. Generation of insulin- producing β-like cells from human iPS cells in a defined and completely xeno-free culture system. J. Mol. Cell Biol. (Oxford, U. K.)6, 394–408 (2014).

    CAS  Google Scholar 

  46. Yabe, S.G., Fukuda, S., Takeda, F., Nashiro, K., Shimoda, M. & Okochi, H. Efficient generation of functional pancreatic β-cells from human induced pluripotent stem cells. J. Diabetes9, 168–179 (2017).

    CAS  PubMed  Google Scholar 

  47. Yabe, S.G., Fukuda, S., Nishida, J., Takeda, F., Nashiro, K. & Okochi, H. Induction of functional islet-like cells from human iPS cells by suspension culture. Regenerative Therapy10, 69–76 (2019).

    PubMed  PubMed Central  Google Scholar 

  48. Hosokawa, Y., Toyoda, T., Fukui, K., Baden, M.Y., Funato, M., Kondo, Y., Sudo, T., Iwahashi, H., Kishida, M., Okada, C., Watanabe, A., Asaka, I., Osafune, K., Imagawa, A. & Shimomura, I. Insulin-producing cells derived from ‘induced pluripotent stem cells’ of patients with fulminant type 1 diabetes: Vulnerability to cytokine insults and increased expression of apoptosis-related genes. J. Diabetes Invest.9, 481–493 (2018).

    CAS  Google Scholar 

  49. Boj, S.F., Hwang, C.-I., Baker, L.A., Chio, I.I.C., Engle, D.D., Corbo, V., Jager, M., Ponz-Sarvise, M., Tiriac, H., Spector, M.S., Gracanin, A., Oni, T., Yu, K.H., van Boxtel, R., Huch, M., Rivera, K.D., Wilson, J.P., Feigin, M.E., Öhlund, D., Handly-Santana, A., Ardito-Abraham, C.M., Ludwig, M., Elyada, E., Alagesan, B., Biffi, G., Yordanov, G.N., Delcuze, B., Creighton, B., Wright, K., Park, Y., Morsink, F.H. M., Molenaar, I.Q., Rinkes, I.H.B., Cuppen, E., Hao, Y., Jin, Y., Nijman, I.J., Iacobuzio-Donahue, C., Leach, S.D., Pappin, D.J., Hammell, M., Klimstra, D.S., Basturk, O., Hruban, R.H., Offerhaus, G.J., Vries, R.G.J., Clevers, H. & Tuveson, D.A. Organoid Models of Human and Mouse Ductal Pancreatic Cancer. Cell160, 324–338 (2015).

    CAS  PubMed  Google Scholar 

  50. Balboa, D., Saarimäki-Vire, J. & Otonkoski, T. Concise Review: Human Pluripotent Stem Cells for the Modeling of Pancreatic β-Cell Pathology. Stem Cells37, 33–41 (2019).

    PubMed  Google Scholar 

  51. Clevers, H. & Tuveson, D.A. Organoid Models for Cancer Research. Annu. Rev. Cancer Biol.3, 223–234 (2019).

    Google Scholar 

  52. Kim, J., Hoffman, J.P., Alpaugh, R.K., Rhim, A.D., Reichert, M., Stanger, B.Z., Furth, E.E., Sepulveda, A.R., Yuan, C.-X., Won, K.-J., Donahue, G., Sands, J., Gumbs, A.A. & Zaret, K.S. An iPSC Line from Human Pancreatic Ductal Adenocarcinoma Undergoes Early to Invasive Stages of Pancreatic Cancer Progression. Cell Rep.3, 2088–2099 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Huang, L., Holtzinger, A., Jagan, I., BeGora, M., Lohse, I., Ngai, N., Nostro, C., Wang, R., Muthuswamy, L.B., Crawford, H.C., Arrowsmith, C., Kalloger, S.E., Renouf, D.J., Connor, A.A., Cleary, S., Schaeffer, D.F., Roehrl, M., Tsao, M.-S., Gallinger, S., Keller, G. & Muthuswamy, S.K. Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell— and patient-derived tumor organoids. Nat. Med.21, 1364–1371 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Takebe, T., Enomura, M., Yoshizawa, E., Kimura, M., Koike, H., Ueno, Y., Matsuzaki, T., Yamazaki, T., Toyohara, T., Osafune, K., Nakauchi, H., Yoshikawa, Hiroshi Y. & Taniguchi, H. Vascularized and Complex Organ Buds from Diverse Tissues via Mesenchymal Cell- Driven Condensation. Cell Stem Cell16, 556–565 (2015).

    CAS  PubMed  Google Scholar 

  55. Lebreton, F., Lavallard, V., Bellofatto, K., Bonnet, R., Wassmer, C.H., Perez, L., Kalandadze, V., Follenzi, A., Boulvain, M., Kerr-Conte, J., Goodman, D.J., Bosco, D., Berney, T. & Berishvili, E. Insulin-producing organoids engineered from islet and amniotic epithelial cells to treat diabetes. Nat. Commun.10, 4491 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. von Ahrens, D., Bhagat, T.D., Nagrath, D., Maitra, A. & Verma, A. The role of stromal cancer-associated fibroblasts in pancreatic cancer. J. Hematol. Oncol.10, 76 (2017).

    PubMed  PubMed Central  Google Scholar 

  57. Liu, T., Han, C., Wang, S., Fang, P., Ma, Z., Xu, L. & Yin, R. Cancer-associated fibroblasts: an emerging target of anti-cancer immunotherapy. J. Hematol. Oncol.12, 86 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Öhlund, D., Handly-Santana, A., Biffi, G., Elyada, E., Almeida, A.S., Ponz-Sarvise, M., Corbo, V., Oni, T.E., Hearn, S.A., Lee, E.J., Chio, I.I.C., Hwang, C.-I., Tiriac, H., Baker, L.A., Engle, D.D., Feig, C., Kultti, A., Egeblad, M., Fearon, D.T., Crawford, J.M., Clevers, H., Park, Y. & Tuveson, D.A. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J. Exp. Med.214, 579–596 (2017).

    PubMed  PubMed Central  Google Scholar 

  59. Chan, B.P. & Leong, K.W. Scaffolding in tissue engineering: general approaches and tissue-specific considerations. Eur. Spine J.17, 467–479 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Jang, J. 3D Bioprinting and In Vitro Cardiovascular Tissue Modeling. Bioengineering (Basel)4, 71 (2017).

    Google Scholar 

  61. Bochenek, M.A., Veiseh, O., Vegas, A.J., McGarrigle, J.J., Qi, M., Marchese, E., Omami, M., Doloff, J.C., Mendoza-Elias, J., Nourmohammadzadeh, M., Khan, A., Yeh, C.-C., Xing, Y., Isa, D., Ghani, S., Li, J., Landry, C., Bader, A.R., Olejnik, K., Chen, M., Hollister-Lock, J., Wang, Y., Greiner, D.L., Weir, G.C., Strand, B.L., Rokstad, A.M.A., Lacik, I., Langer, R., Anderson, D.G. & Oberholzer, J. Alginate encapsulation as long-term immune protection of allogeneic pancreatic islet cells transplanted into the omental bursa of macaques. Nat. Biomed. Eng.2, 810–821 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Kumar, N., Joisher, H. & Ganguly, A. Polymeric Scaffolds for Pancreatic Tissue Engineering: A Review. Rev. Diabet. Stud.14, 334–353 (2018).

    PubMed  PubMed Central  Google Scholar 

  63. Ma, F., Tremmel, D.M., Li, Z., Lietz, C.B., Sackett, S.D., Odorico, J.S. & Li, L. In depth quantification of extracellular matrix proteins from human pancreas. J. Proteome Res.18, 3156–3165 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Sackett, S.D., Tremmel, D.M., Ma, F., Feeney, A.K., Maguire, R.M., Brown, M.E., Zhou, Y., Li, X., O’Brien, C., Li, L., Burlingham, W.J. & Odorico, J.S. Extracellular matrix scaffold and hydrogel derived from decellularized and delipidized human pancreas. Sci. Rep.8, 10452 (2018).

    PubMed  PubMed Central  Google Scholar 

  65. Llacua, L.A., Faas, M.M. & de Vos, P. Extracellular matrix molecules and their potential contribution to the function of transplanted pancreatic islets. Diabetologia61, 1261–1272 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Otonkoski, T., Banerjee, M., Korsgren, O., Thornell, L.E. & Virtanen, I. Unique basement membrane structure of human pancreatic islets: implications for β-cell growth and differentiation. Diabetes, Obes. Metab.10, 119–127 (2008).

    Google Scholar 

  67. Jiang, F.-X. & Harrison, L.C. Laminin-1 and epidermal growth factor family members co-stimulate fetal pancreas cell proliferation and colony formation. Differentiation73, 45–49 (2005).

    CAS  PubMed  Google Scholar 

  68. Daoud, J., Petropavlovskaia, M., Rosenberg, L. & Tabrizian, M. The effect of extracellular matrix components on the preservation of human islet function in vitro. Biomaterials31, 1676–1682 (2010).

    CAS  PubMed  Google Scholar 

  69. Lin, H.-Y., Tsai, C.-C., Chen, L.-L., Chiou, S.-H., Wang, Y.-J. & Hung, S.-C. Fibronectin and laminin promote differentiation of human mesenchymal stem cells into insulin producing cells through activating Akt and ERK. J. Biomed. Sci.17, 56 (2010).

    PubMed  PubMed Central  Google Scholar 

  70. Jalili, R.B., Moeen Rezakhanlou, A., Hosseini-Tabatabaei, A., Ao, Z., Warnock, G.L. & Ghahary, A. Fibroblast populated collagen matrix promotes islet survival and reduces the number of islets required for diabetes reversal. J. Cell. Physiol.226, 1813–1819 (2011).

    CAS  PubMed  Google Scholar 

  71. Llacua, L.A., Hoek, A., de Haan, B.J. & de Vos, P. Collagen type VI interaction improves human islet survival in immunoisolating microcapsules for treatment of diabetes. Islets10, 60–68 (2018).

    PubMed  PubMed Central  Google Scholar 

  72. Rubiano, A., Delitto, D., Han, S., Gerber, M., Galitz, C., Trevino, J., Thomas, R.M., Hughes, S.J. & Simmons, C.S. Viscoelastic properties of human pancreatic tumors and in vitro constructs to mimic mechanical properties. Acta Biomater.67, 331–340 (2018).

    PubMed  Google Scholar 

  73. Cramer, G.M., Jones, D.P., El-Hamidi, H. & Celli, J.P. ECM Composition and Rheology Regulate Growth, Motility, and Response to Photodynamic Therapy in 3D Models of Pancreatic Ductal Adenocarcinoma. Mol. Cancer Res.15, 15 (2017).

    CAS  PubMed  Google Scholar 

  74. Jee, J.H., Lee, D.H., Ko, J., Hahn, S., Jeong, S.Y., Kim, H.K., Park, E., Choi, S.Y., Jeong, S., Lee, J.W., Cho, H.-J., Kwon, M.-S. & Yoo, J. Development of Collagen-Based 3D Matrix for Gastrointestinal Tract-Derived Organoid Culture. Stem Cells Int.2019, 8472712 (2019).

    PubMed  PubMed Central  Google Scholar 

  75. Pati, F., Jang, J., Ha, D.-H., Won Kim, S., Rhie, J.-W., Shim, J.-H., Kim, D.-H. & Cho, D.-W. Printing three-dimensional tissue analogues with decellularized extracellular matrix bioink. Nat. Commun.5, 3935 (2014).

    CAS  PubMed  Google Scholar 

  76. Jang, J., Kim, T.G., Kim, B.S., Kim, S.-W., Kwon, S.-M. & Cho, D.-W. Tailoring mechanical properties of decellularized extracellular matrix bioink by vitamin B2-induced photo-crosslinking. Acta Biomater.33, 88–95 (2016).

    CAS  PubMed  Google Scholar 

  77. Jang, J., Park, H.-J., Kim, S.-W., Kim, H., Park, J.Y., Na, S.J., Kim, H.J., Park, M.N., Choi, S.H., Park, S.H., Kim, S.W., Kwon, S.-M., Kim, P.-J. & Cho, D.-W. 3D printed complex tissue construct using stem cell-laden decellularized extracellular matrix bioinks for cardiac repair. Biomaterials112, 264–274 (2017).

    CAS  PubMed  Google Scholar 

  78. Jiang, K., Chaimov, D., Patel, S.N., Liang, J.P., Wiggins, S.C., Samojlik, M.M., Rubiano, A., Simmons, C.S. & Stabler, C.L. 3-D physiomimetic extracellular matrix hydrogels provide a supportive microenvironment for rodent and human islet culture. Biomaterials198, 37–48 (2019).

    CAS  PubMed  Google Scholar 

  79. Giobbe, G.G., Crowley, C., Luni, C., Campinoti, S., Khedr, M., Kretzschmar, K., De Santis, M.M., Zambaiti, E., Michielin, F., Meran, L., Hu, Q., van Son, G., Urbani, L., Manfredi, A., Giomo, M., Eaton, S., Cacchiarelli, D., Li, V.S.W., Clevers, H., Bonfanti, P., Elvassore, N. & De Coppi, P. Extracellular matrix hydrogel derived from decellularized tissues enables endodermal organoid culture. Nat. Commun.10, 5658 (2019).

    PubMed  PubMed Central  Google Scholar 

  80. Sung, J.H., Koo, J. & Shuler, M.L. Mimicking the Human Physiology with Microphysiological Systems (MPS). BioChip J., 1–12 (2019).

  81. Zhang, B., Korolj, A., Lai, B.F.L. & Radisic, M. Advances in organ-on-a-chip engineering. Nat. Rev. Mater.3, 257–278 (2018).

    Google Scholar 

  82. Bauer, S., Huldt, C.W., Kanebratt, K.P., Durieux, I., Gunne, D., Andersson, S., Ewart, L., Haynes, W.G., Maschmeyer, I. & Winter, A. Functional coupling of human pancreatic islets and liver spheroids on-a-chip: Towards a novel human ex vivo type 2 diabetes model. Sci. Rep.7, 14620 (2017).

    PubMed  PubMed Central  Google Scholar 

  83. Choi, Y.-J., Jun, Y.-J., Kim, D.Y., Yi, H.-G., Chae, S.-H., Kang, J., Lee, J., Gao, G., Kong, J.-S. & Jang, J. A 3D cell printed muscle construct with tissue-derived bioink for the treatment of volumetric muscle loss. Biomaterials206, 160–169 (2019).

    CAS  PubMed  Google Scholar 

  84. Liu, X., Carter, S.-S.D., Renes, M.J., Kim, J., Rojas-Canales, D.M., Penko, D., Angus, C., Beirne, S., Drogemuller, C.J., Yue, Z., Coates, P.T. & Wallace, G.G. Development of a Coaxial 3D Printing Platform for Biofabrication of Implantable Islet- Containing Constructs. Adv. Healthcare Mater.8, 1801181 (2019).

    Google Scholar 

  85. Gao, G., Kim, B.S., Jang, J. & Cho, D.-W. Recent strategies in extrusion-based three-dimensional cell printing toward organ biofabrication. ACS Biomater. Sci. Eng.5, 1150–1169 (2019).

    CAS  PubMed  Google Scholar 

  86. Jang, J., Yi, H.-G. & Cho, D.-W. 3D printed tissue models: present and future. ACS Biomater. Sci. Eng.2, 1722–1731 (2016).

    CAS  PubMed  Google Scholar 

  87. Glieberman, A.L., Pope, B.D., Zimmerman, J.F., Liu, Q., Ferrier, J.P., Kenty, J.H., Schrell, A.M., Mukhitov, N., Shores, K.L. & Tepole, A.B. Synchronized stimulation and continuous insulin sensing in a microfluidic human Islet on a Chip designed for scalable manufacturing. Lab Chip19, 2993–3010 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Polacheck, W.J., Li, R., Uzel, S.G. & Kamm, R.D. Microfluidic platforms for mechanobiology. Lab Chip13, 2252–2267 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Lee, S.H., Hong, S., Song, J., Cho, B., Han, E.J., Kondapavulur, S., Kim, D. & Lee, L.P. Microphysiological analysis platform of pancreatic islet β-cell spheroids. Adv. Healthcare Mater.7, 1701111 (2018).

    Google Scholar 

  90. Yi, H.-G., Jeong, Y.H., Kim, Y., Choi, Y.-J., Moon, H.E., Park, S.H., Kang, K.S., Bae, M., Jang, J. & Youn, H. A bioprinted human-glioblastoma- on-a-chip for the identification of patient-specific responses to chemoradiotherapy. Nat. Biomed. Eng.3, 509–519 (2019).

    CAS  PubMed  Google Scholar 

  91. Lee, J.B., Park, J.S., Shin, Y.M., Lee, D.H., Yoon, J.K., Kim, D.H., Ko, U.H., Kim, Y., Bae, S.H. & Sung, H.J. Implantable Vascularized Liver Chip for Cross-Validation of Disease Treatment with Animal Model. Adv. Funct. Mater.29, 1900075 (2019).

    Google Scholar 

  92. Nguyen, D.-H.T., Lee, E., Alimperti, S., Norgard, R.J., Wong, A., Lee, J.J.-K., Eyckmans, J., Stanger, B.Z. & Chen, C.S. A biomimetic pancreatic cancer on-chip reveals endothelial ablation via ALK7 signaling. Sci. Adv.5, eaav6789 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Gioeli, D., Snow, C.J., Simmers, M.B., Hoang, S.A., Figler, R.A., Allende, J.A., Roller, D.G., Parsons, J.T., Wulfkuhle, J.D. & Petricoin, E.F. Development of a multicellular pancreatic tumor microenvironment system using patient-derived tumor cells. Lab Chip19, 1193–1204 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Marchioli, G., van Gurp, L., Van Krieken, P., Stamatialis, D., Engelse, M., Van Blitterswijk, C., Karperien, M., de Koning, E., Alblas, J. & Moroni, L. Fabrication of three-dimensional bioplotted hydrogel scaffolds for islets of Langerhans transplantation. Biofabrication7, 025009 (2015).

    CAS  PubMed  Google Scholar 

  95. Gao, G., Lee, J.H., Jang, J., Lee, D.H., Kong, J.S., Kim, B.S., Choi, Y.J., Jang, W.B., Hong, Y.J. & Kwon, S.M. Tissue engineered bio-blood-vessels constructed using a tissue-specific bioink and 3D coaxial cell printing technique: a novel therapy for ischemic disease. Adv. Funct. Mater.27, 1700798 (2017).

    Google Scholar 

  96. Das, S., Kim, S.-W., Choi, Y.-J., Lee, S., Lee, S.-H., Kong, J.-S., Park, H.-J., Cho, D.-W. & Jang, J. Decellularized extracellular matrix bioinks and the external stimuli to enhance cardiac tissue development in vitro. Acta Biomater. (2019).

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Acknowledgements

This journal was supported by the Bio & Medical Technology Development program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (2017M3A9C6032 067) and “ICT Consilience Creative Program” (IITP-2019-2011-1-00783) supervised by the IITP (Institute for Information & communications Technology Planning & Evaluation).

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Kim, M., Hwang, D.G. & Jang, J. 3D Pancreatic Tissue Modeling in vitro: Advances and Prospects. BioChip J 14, 84–99 (2020). https://doi.org/10.1007/s13206-020-4108-4

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