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  • Review Article
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Synthetic alternatives to Matrigel

Nature Reviews Materials volume 5, pages 539–551 (2020)Cite this article

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Abstract

Matrigel, a basement-membrane matrix extracted from Engelbreth–Holm–Swarm mouse sarcomas, has been used for more than four decades for a myriad of cell-culture applications. However, Matrigel is limited in its applicability to cellular biology, therapeutic-cell manufacturing and drug discovery, owing to its complex, ill-defined and variable composition. Variations in the mechanical and biochemical properties within a single batch of Matrigel — and between batches — have led to uncertainty in cell-culture experiments and a lack of reproducibility. Moreover, Matrigel is not conducive to physical or biochemical manipulation, making it difficult to fine-tune the matrix to promote intended cell behaviours and achieve specific biological outcomes. Recent advances in synthetic scaffolds have led to the development of xenogenic-free, chemically defined, highly tunable and reproducible alternatives. In this Review, we assess the applications of Matrigel in cell culture, regenerative medicine and organoid assembly, detailing the limitations of Matrigel and highlighting synthetic-scaffold alternatives that have shown equivalent or superior results. Additionally, we discuss the hurdles that are limiting a full transition from Matrigel to synthetic scaffolds and provide a brief perspective on the future directions of synthetic scaffolds for cell-culture applications.

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Fig. 1: Comparison of Matrigel and synthetic scaffolds.
Fig. 2: Advantages of synthetic scaffolds over Matrigel for cell culture, tissue engineering and organoid formation.
Fig. 3: Comparison of Matrigel and synthetic scaffolds for stem-cell differentiation and tissue engineering.
Fig. 4: Comparison of Matrigel and synthetic scaffolds for organoid assembly and preclinical tissue models.

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References

  1. Orkin, R. W. et al. A murine tumor producing a matrix of basement membrane. J. Exp. Med. 145, 204–220 (1977).

    CAS  Google Scholar 

  2. LeBleu, V. S., Macdonald, B. & Kalluri, R. Structure and function of basement membranes. Exp. Biol. Med. 232, 1121–1129 (2007).

    CAS  Google Scholar 

  3. Kubota, Y., Kleinman, H. K., Martin, G. R. & Lawley, T. J. Role of laminin and basement membrane in the morphological differentiation of human endothelial cells into capillary-like structures. J. Cell Biol. 107, 1589–1598 (1988).

    CAS  Google Scholar 

  4. Kleinman, H. K. et al. Basement membrane complexes with biological activity. Biochemistry 25, 312–318 (1986). This paper investigates the protein composition and biological activity of the basement-membrane extract from EHS mouse chondrosarcomas; this extract was later developed and commercialized as Matrigel.

    CAS  Google Scholar 

  5. Kleinman, H. K. & Martin, G. R. Matrigel: basement membrane matrix with biological activity. Semin. Cancer Biol. 15, 378–386 (2005).

    CAS  Google Scholar 

  6. Corning Incorporated Life Sciences. Corning Matrigel matrix. Frequently asked questions (Corning, 2019).

  7. Hughes, C. S., Postovit, L. M. & Lajoie, G. A. Matrigel: a complex protein mixture required for optimal growth of cell culture. Proteomics 10, 1886–1890 (2010). A full proteomic analysis of Matrigel and GFR Matrigel, reporting their complex, ill-defined and variable composition.

    CAS  Google Scholar 

  8. Timpl, R. et al. Laminin — a glycoprotein from basement membranes. J. Biol. Chem. 254, 9933–9937 (1979).

    CAS  Google Scholar 

  9. Terranova, V. P., Aumailley, M., Sultan, L. H., Martin, G. R. & Kleinman, H. K. Regulation of cell attachment and cell number by fibronectin and laminin. J. Cell. Physiol. 127, 473–479 (1986).

    CAS  Google Scholar 

  10. Miyazaki, T. et al. Recombinant human laminin isoforms can support the undifferentiated growth of human embryonic stem cells. Biochem. Biophys. Res. Commun. 375, 27–32 (2008).

    CAS  Google Scholar 

  11. Ponce, M. L. et al. Identification of endothelial cell binding sites on the laminin γ1 chain. Circ. Res. 84, 688–694 (1999).

    CAS  Google Scholar 

  12. Wang, K., Ji, L. & Hua, Z. Functional peptides from laminin-1 improve the cell adhesion capacity of recombinant mussel adhesive protein. Protein Pept. Lett. 24, 348–352 (2017).

    Google Scholar 

  13. Heaton, M. B. & Swanson, D. J. The influence of laminin on the initial differentiation of cultured neural tube neurons. J. Neurosci. Res. 19, 212–218 (1988).

    CAS  Google Scholar 

  14. Farrukh, A. et al. Bifunctional hydrogels containing the laminin motif IKVAV promote neurogenesis. Stem Cell Rep. 9, 1432–1440 (2017).

    CAS  Google Scholar 

  15. Ali, S., Saik, J. E., Gould, D. J., Dickinson, M. E. & West, J. L. Immobilization of cell-adhesive laminin peptides in degradable PEGDA hydrogels influences endothelial cell tubulogenesis. BioResearch Open Access 2, 241–249 (2013).

    CAS  Google Scholar 

  16. Engbring, J. A. & Kleinman, H. K. The basement membrane matrix in malignancy. J. Pathol. 200, 465–470 (2003).

    CAS  Google Scholar 

  17. Kikkawa, Y. et al. Laminin-111-derived peptides and cancer. Cell Adh. Migr. 7, 150–159 (2013).

    Google Scholar 

  18. Vukicevic, S. 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. 202, 1–8 (1992). This study identifies multiple active growth factors in Matrigel and suggests caution when interpreting cellular activity when cultured on Matrigel.

    CAS  Google Scholar 

  19. Talbot, N. C. & Caperna, T. J. Proteome array identification of bioactive soluble proteins/peptides in Matrigel: relevance to stem cell responses. Cytotechnology 67, 873–883 (2015).

    CAS  Google Scholar 

  20. Gillette, K. M., Forbes, K. & Sehgal, I. Detection of matrix metalloproteinases (MMP), tissue inhibitor of metalloproteinase-2, urokinase and plasminogen activator inhibitor-1 within Matrigel and growth factor-reduced Matrigel basement membrane. Tumori 89, 421–425 (2003).

    CAS  Google Scholar 

  21. Xu, C. et al. Feeder-free growth of undifferentiated human embryonic stem cells. Nat. Biotechnol. 19, 971–974 (2001).

    CAS  Google Scholar 

  22. Qian, L. & Saltzman, W. M. Improving the expansion and neuronal differentiation of mesenchymal stem cells through culture surface modification. Biomaterials 25, 1331–1337 (2004).

    CAS  Google Scholar 

  23. Lee, S.-W. et al. Optimization of Matrigel-based culture for expansion of neural stem cells. Anim. Cell Syst. 19, 175–180 (2015).

    CAS  Google Scholar 

  24. Laflamme, M. A. et al. Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts. Nat. Biotechnol. 25, 1015–1024 (2007).

    CAS  Google Scholar 

  25. Ponce, M. L. Tube formation: an in vitro Matrigel angiogenesis assay. Methods Mol. Biol. 467, 183–188 (2009).

    CAS  Google Scholar 

  26. Ponce, M. L. In vitro Matrigel angiogenesis assays. Methods Mol. Med. 46, 205–209 (2001).

    CAS  Google Scholar 

  27. Mondrinos, M. J. et al. Engineering three-dimensional pulmonary tissue constructs. Tissue Eng. 12, 717–728 (2006).

    CAS  Google Scholar 

  28. Li, Z. & Guan, J. Hydrogels for cardiac tissue engineering. Polymers 3, 740–761 (2011).

    CAS  Google Scholar 

  29. Lancaster, M. A. & Knoblich, J. A. Organogenesis in a dish: modeling development and disease using organoid technologies. Science 345, 1247125 (2014).

    Google Scholar 

  30. Lancaster, M. A. et al. Cerebral organoids model human brain development and microcephaly. Nature 501, 373–379 (2013).

    CAS  Google Scholar 

  31. Benton, G., Kleinman, H. K., George, J. & Arnaoutova, I. Multiple uses of basement membrane-like matrix (BME/Matrigel) in vitro and in vivo with cancer cells. Int. J. Cancer 128, 1751–1757 (2011).

    CAS  Google Scholar 

  32. Cruz-Acuña, R. & García, A. J. Synthetic hydrogels mimicking basement membrane matrices to promote cell-matrix interactions. Matrix Biol. 57–58, 324–333 (2017).

    Google Scholar 

  33. Polykandriotis, E., Arkudas, A., Horch, R. E., Kneser, U. & Mitchell, G. To Matrigel or not to Matrigel. Am. J. Pathol. 172, 1441–1442 (2008).

    Google Scholar 

  34. Kohen, N. T., Little, L. E. & Healy, K. E. Characterization of Matrigel interfaces during defined human embryonic stem cell culture. Biointerphases 4, 69–79 (2009).

    Google Scholar 

  35. Soofi, S. S., Last, J. A., Liliensiek, S. J., Nealey, P. F. & Murphy, C. J. The elastic modulus of Matrigel as determined by atomic force microscopy. J. Struct. Biol. 167, 216–219 (2009).

    CAS  Google Scholar 

  36. Dirami, G. et al. Identification of transferrin and inhibin-like proteins in Matrigel. In Vitro Cell. Dev. Biol. Anim. 31, 409–411 (1995).

    CAS  Google Scholar 

  37. Hansen, K. C. et al. An in-solution ultrasonication-assisted digestion method for improved extracellular matrix proteome coverage. Mol. Cell. Proteom. 8, 1648–1657 (2009).

    CAS  Google Scholar 

  38. Zaman, M. H. et al. Migration of tumor cells in 3D matrices is governed by matrix stiffness along with cell-matrix adhesion and proteolysis. Proc. Natl Acad. Sci. USA 103, 10889–10894 (2006).

    CAS  Google Scholar 

  39. Semler, E. J., Ranucci, C. S. & Moghe, P. V. Mechanochemical manipulation of hepatocyte aggregation can selectively induce or repress liver-specific function. Biotechnol. Bioeng. 69, 359–369 (2000).

    CAS  Google Scholar 

  40. Kane, K. I. W. et al. Determination of the rheological properties of Matrigel for optimum seeding conditions in microfluidic cell cultures. AIP Adv. 8, 125332 (2018).

    Google Scholar 

  41. Alcaraz, J. et al. Laminin and biomimetic extracellular elasticity enhance functional differentiation in mammary epithelia. EMBO J. 27, 2829–2838 (2008).

    CAS  Google Scholar 

  42. Reed, J., Walczak, W. J., Petzold, O. N. & Gimzewski, J. K. In situ mechanical interferometry of Matrigel films. Langmuir 25, 36–39 (2009).

    CAS  Google Scholar 

  43. Peterson, N. C. From bench to cageside: risk assessment for rodent pathogen contamination of cells and biologics. ILAR J. 49, 310–315 (2008).

    CAS  Google Scholar 

  44. Liu, H. et al. Removal of lactate dehydrogenase-elevating virus from human-in-mouse breast tumor xenografts by cell-sorting. J. Virol. Methods 173, 266–270 (2011).

    CAS  Google Scholar 

  45. Ammann, C. G., Messer, R. J., Peterson, K. E. & Hasenkrug, K. J. Lactate dehydrogenase-elevating virus induces systemic lymphocyte activation via TLR7-dependent IFNα responses by plasmacytoid dendritic cells. PLoS One 4, e6105 (2009).

    Google Scholar 

  46. Riley, V. et al. The LDH virus: an interfering biological contaminant. Science 200, 124–126 (1978).

    CAS  Google Scholar 

  47. Caliari, S. R. & Burdick, J. A. A practical guide to hydrogels for cell culture. Nat. Methods 13, 405–414 (2016).

    CAS  Google Scholar 

  48. Li, X., Sun, Q., Li, Q., Kawazoe, N. & Chen, G. Functional hydrogels with tunable structures and properties for tissue engineering applications. Front. Chem. 6, 499 (2018).

    CAS  Google Scholar 

  49. Fischer, R. S., Myers, K. A., Gardel, M. L. & Waterman, C. M. Stiffness-controlled three-dimensional extracellular matrices for high-resolution imaging of cell behavior. Nat. Protoc. 7, 2056–2066 (2012).

    CAS  Google Scholar 

  50. Tse, J. R. & Engler, A. J. Preparation of hydrogel substrates with tunable mechanical properties. Curr. Protoc. Cell Biol. 47, 10.16.1–10.16.16 (2010).

    Google Scholar 

  51. Pelham, R. J. Jr. & Wang, Y.-l. Cell locomotion and focal adhesions are regulated by substrate flexibility. Proc. Natl Acad. Sci. USA 94, 13661–13665 (1997).

    CAS  Google Scholar 

  52. Zustiak, S. P. & Leach, J. B. Hydrolytically degradable poly(ethylene glycol) hydrogel scaffolds with tunable degradation and mechanical properties. Biomacromolecules 11, 1348–1357 (2010).

    CAS  Google Scholar 

  53. Krsko, P. & Libera, M. Biointeractive hydrogels. Mater. Today 8, 36–44 (2005).

    CAS  Google Scholar 

  54. Zhu, J. Bioactive modification of poly(ethylene glycol) hydrogels for tissue engineering. Biomaterials 31, 4639–4656 (2010).

    CAS  Google Scholar 

  55. Lin, C.-C. & Anseth, K. S. PEG hydrogels for the controlled release of biomolecules in regenerative medicine. Pharm. Res. 26, 631–643 (2009).

    CAS  Google Scholar 

  56. Tibbitt, M. W. & Anseth, K. S. Hydrogels as extracellular matrix mimics for 3D cell culture. Biotechnol. Bioeng. 103, 655–663 (2009).

    CAS  Google Scholar 

  57. Fairbanks, B. D. et al. A versatile synthetic extracellular matrix mimic via thiol-norbornene photopolymerization. Adv. Mater. 21, 5005–5010 (2009).

    CAS  Google Scholar 

  58. Bryant, S. & Anseth, K. in Scaffolding in Tissue Engineering (eds Ma, P. X. & Elisseeff, J.) 71–90 (CRC, 2005).

  59. Nguyen, K. T. & West, J. L. Photopolymerizable hydrogels for tissue engineering applications. Biomaterials 23, 4307–4314 (2002).

    CAS  Google Scholar 

  60. Nair, D. P. et al. The thiol-Michael addition click reaction: a powerful and widely used tool in materials chemistry. Chem. Mater. 26, 724–744 (2014).

    CAS  Google Scholar 

  61. Schense, J. C. & Hubbell, J. A. Cross-linking exogenous bifunctional peptides into fibrin gels with factor XIIIa. Bioconjug. Chem. 10, 75–81 (1999).

    CAS  Google Scholar 

  62. Ehrbar, M. et al. Biomolecular hydrogels formed and degraded via site-specific enzymatic reactions. Biomacromolecules 8, 3000–3007 (2007).

    CAS  Google Scholar 

  63. Bryant, S. J., Chowdhury, T. T., Lee, D. A., Bader, D. L. & Anseth, K. S. Crosslinking density influences chondrocyte metabolism in dynamically loaded photocrosslinked poly(ethylene glycol) hydrogels. Ann. Biomed. Eng. 32, 407–417 (2004).

    Google Scholar 

  64. Roberts, J. J. & Bryant, S. J. Comparison of photopolymerizable thiol-ene PEG and acrylate-based PEG hydrogels for cartilage development. Biomaterials 34, 9969–9979 (2013).

    CAS  Google Scholar 

  65. Burdick, J. A. & Anseth, K. S. Photoencapsulation of osteoblasts in injectable RGD-modified PEG hydrogels for bone tissue engineering. Biomaterials 23, 4315–4323 (2002).

    CAS  Google Scholar 

  66. Kharkar, P. M., Rehmann, M. S., Skeens, K. M., Maverakis, E. & Kloxin, A. M. Thiol–ene click hydrogels for therapeutic delivery. ACS Biomater. Sci. Eng. 2, 165–179 (2016).

    CAS  Google Scholar 

  67. Thomson, J. A. et al. Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147 (1998).

    CAS  Google Scholar 

  68. Avior, Y., Sagi, I. & Benvenisty, N. Pluripotent stem cells in disease modelling and drug discovery. Nat. Rev. Mol. Cell Biol. 17, 170–182 (2016).

    CAS  Google Scholar 

  69. Singh, V. K., Kalsan, M., Kumar, N., Saini, A. & Chandra, R. Induced pluripotent stem cells: applications in regenerative medicine, disease modeling, and drug discovery. Front. Cell Dev. Biol. 3, 2 (2015).

    Google Scholar 

  70. Shi, Y., Inoue, H., Wu, J. C. & Yamanaka, S. Induced pluripotent stem cell technology: a decade of progress. Nat. Rev. Drug. Discov. 16, 115–130 (2017).

    CAS  Google Scholar 

  71. Ortiz-Vitali, J. L. & Darabi, R. iPSCs as a platform for disease modeling, drug screening, and personalized therapy in muscular dystrophies. Cells 8, 20 (2019).

    CAS  Google Scholar 

  72. Hovatta, O. Derivation of human embryonic stem cell lines, towards clinical quality. Reprod. Fertil. Dev. 18, 823–828 (2006).

    Google Scholar 

  73. Qian, X., Villa-Diaz, L. G., Kumar, R., Lahann, J. & Krebsbach, P. H. Enhancement of the propagation of human embryonic stem cells by modifications in the gel architecture of PMEDSAH polymer coatings. Biomaterials 35, 9581–9590 (2014).

    CAS  Google Scholar 

  74. Nandivada, H. et al. Fabrication of synthetic polymer coatings and their use in feeder-free culture of human embryonic stem cells. Nat. Protoc. 6, 1037–1043 (2011).

    CAS  Google Scholar 

  75. Villa-Diaz, L. G. et al. Synthetic polymer coatings for long-term growth of human embryonic stem cells. Nat. Biotechnol. 28, 581–583 (2010). Along with reference 74, this was one of the first studies to develop a fully synthetic, chemically defined scaffold for long-term hESC culture and to directly compare the performance with that of Matrigel.

    CAS  Google Scholar 

  76. Brafman, D. A. et al. Long-term human pluripotent stem cell self-renewal on synthetic polymer surfaces. Biomaterials 31, 9135–9144 (2010).

    CAS  Google Scholar 

  77. Meng, Y. et al. Characterization of integrin engagement during defined human embryonic stem cell culture. FASEB J. 24, 1056–1065 (2009).

    Google Scholar 

  78. Rowland, T. J. et al. Roles of integrins in human induced pluripotent stem cell growth on Matrigel and vitronectin. Stem Cell Dev. 19, 1231–1240 (2010).

    CAS  Google Scholar 

  79. Mondal, G., Barui, S. & Chaudhuri, A. The relationship between the cyclic-RGDfK ligand and αvβ3 integrin receptor. Biomaterials 34, 6249–6260 (2013).

    CAS  Google Scholar 

  80. Lambshead, J. W. et al. Long-term maintenance of human pluripotent stem cells on cRGDfK-presenting synthetic surfaces. Sci. Rep. 8, 701 (2018).

    Google Scholar 

  81. Nguyen, E. H. et al. Versatile synthetic alternatives to Matrigel for vascular toxicity screening and stem cell expansion. Nat. Biomed. Eng. 1, 0096 (2017). This study uses a high-throughput screening method of synthetic scaffolds to determine a synthetic alternative to Matrigel, finding that matrix-induced effects caused by the biological function of Matrigel can affect toxicity screenings.

    CAS  Google Scholar 

  82. Hayman, E. G., Pierschbacher, M. D., Suzuki, S. & Ruoslahti, E. Vitronectin — a major cell attachment-promoting protein in fetal bovine serum. Exp. Cell Res. 160, 245–258 (1985).

    CAS  Google Scholar 

  83. Melkoumian, Z. et al. Synthetic peptide-acrylate surfaces for long-term self-renewal and cardiomyocyte differentiation of human embryonic stem cells. Nat. Biotechnol. 28, 606–610 (2010). An early report on tethering synthetic peptides to synthetic scaffolds that provides a direct comparison with Matrigel.

    CAS  Google Scholar 

  84. Deng, Y. et al. Long-term self-renewal of human pluripotent stem cells on peptide-decorated poly(OEGMA-co-HEMA) brushes under fully defined conditions. Acta Biomater. 9, 8840–8850 (2013).

    CAS  Google Scholar 

  85. Higuchi, A. et al. Long-term xeno-free culture of human pluripotent stem cells on hydrogels with optimal elasticity. Sci. Rep. 5, 18136 (2015).

    CAS  Google Scholar 

  86. Jin, S., Yao, H., Weber, J. L., Melkoumian, Z. K. & Ye, K. A synthetic, xeno-free peptide surface for expansion and directed differentiation of human induced pluripotent stem cells. PLoS One 7, e50880 (2012).

    CAS  Google Scholar 

  87. Yasuda, S. et al. Chemically defined and growth-factor-free culture system for the expansion and derivation of human pluripotent stem cells. Nat. Biomed. Eng. 2, 173–182 (2018).

    CAS  Google Scholar 

  88. Farach-Carson, M. C. & Carson, D. D. Perlecan — a multifunctional extracellular proteoglycan scaffold. Glycobiology 17, 897–905 (2007).

    CAS  Google Scholar 

  89. Furue, M. K. et al. Heparin promotes the growth of human embryonic stem cells in a defined serum-free medium. Proc. Natl Acad. Sci. USA 105, 13409–13414 (2008).

    CAS  Google Scholar 

  90. Spivak-Kroizman, T. et al. Heparin-induced oligomerization of FGF molecules is responsible for FGF receptor dimerization, activation, and cell proliferation. Cell 79, 1015–1024 (1994).

    CAS  Google Scholar 

  91. Vlodavsky, I., Miao, H. Q., Medalion, B., Danagher, P. & Ron, D. Involvement of heparan sulfate and related molecules in sequestration and growth promoting activity of fibroblast growth factor. Cancer Metastasis Rev. 15, 177–186 (1996).

    CAS  Google Scholar 

  92. Chang, C.-W. et al. Engineering cell–material interfaces for long-term expansion of human pluripotent stem cells. Biomaterials 34, 912–921 (2013).

    CAS  Google Scholar 

  93. Klim, J. R., Li, L., Wrighton, P. J., Piekarczyk, M. S. & Kiessling, L. L. A defined glycosaminoglycan-binding substratum for human pluripotent stem cells. Nat. Methods 7, 989–994 (2010).

    CAS  Google Scholar 

  94. Musah, S. et al. Glycosaminoglycan-binding hydrogels enable mechanical control of human pluripotent stem cell self-renewal. ACS Nano 6, 10168–10177 (2012).

    CAS  Google Scholar 

  95. Gerecht, S. et al. Hyaluronic acid hydrogel for controlled self-renewal and differentiation of human embryonic stem cells. Proc. Natl Acad. Sci. USA 104, 11298–11303 (2007).

    CAS  Google Scholar 

  96. Lei, Y. & Schaffer, D. V. A fully defined and scalable 3D culture system for human pluripotent stem cell expansion and differentiation. Proc. Natl Acad. Sci. USA 110, E5039–E5048 (2013).

    CAS  Google Scholar 

  97. Ovadia, E. M., Colby, D. W. & Kloxin, A. M. Designing well-defined photopolymerized synthetic matrices for three-dimensional culture and differentiation of induced pluripotent stem cells. Biomater. Sci. 6, 1358–1370 (2018).

    CAS  Google Scholar 

  98. Murphy, W. L., McDevitt, T. C. & Engler, A. J. Materials as stem cell regulators. Nat. Mater. 13, 547–557 (2014).

    CAS  Google Scholar 

  99. Folkman, J. & Moscona, A. Role of cell shape in growth control. Nature 273, 345–349 (1978).

    CAS  Google Scholar 

  100. Caiazzo, M. et al. Defined three-dimensional microenvironments boost induction of pluripotency. Nat. Mater. 15, 344–352 (2016).

    CAS  Google Scholar 

  101. Khalil, A. S., Xie, A. W. & Murphy, W. L. Context clues: the importance of stem cell–material interactions. ACS Chem. Biol. 9, 45–56 (2014).

    CAS  Google Scholar 

  102. Eve, D. J. The continued promise of stem cell therapy in regenerative medicine. Med. Sci. Monit. 17, RA292–RA305 (2011).

    Google Scholar 

  103. Helmy, K. Y., Patel, S. A., Silverio, K., Pliner, L. & Rameshwar, P. Stem cells and regenerative medicine: accomplishments to date and future promise. Ther. Deliv. 1, 693–705 (2010).

    Google Scholar 

  104. Hoffman, T., Khademhosseini, A. & Langer, R. Chasing the paradigm: clinical translation of 25 years of tissue engineering. Tissue Eng. Part A 25, 679–687 (2019).

    Google Scholar 

  105. Hwang, N. S., Varghese, S. & Elisseeff, J. Controlled differentiation of stem cells. Adv. Drug Deliv. Rev. 60, 199–214 (2008).

    CAS  Google Scholar 

  106. Burdick, J. A. & Vunjak-Novakovic, G. Engineered microenvironments for controlled stem cell differentiation. Tissue Eng. Part A 15, 205–219 (2009).

    CAS  Google Scholar 

  107. Lutolf, M. P., Gilbert, P. M. & Blau, H. M. Designing materials to direct stem-cell fate. Nature 462, 433–441 (2009).

    CAS  Google Scholar 

  108. Uriel, S. et al. Extraction and assembly of tissue-derived gels for cell culture and tissue engineering. Tissue Eng. Part C 15, 309–321 (2009).

    CAS  Google Scholar 

  109. Enemchukwu, N. O. et al. Synthetic matrices reveal contributions of ECM biophysical and biochemical properties to epithelial morphogenesis. J. Cell Biol. 212, 113–124 (2016).

    CAS  Google Scholar 

  110. Le, N. N. T., Zorn, S., Schmitt, S. K., Gopalan, P. & Murphy, W. L. Hydrogel arrays formed via differential wettability patterning enable combinatorial screening of stem cell behavior. Acta Biomater. 34, 93–103 (2016).

    CAS  Google Scholar 

  111. Koepsel, J. T., Brown, P. T., Loveland, S. G., Li, W.-J. & Murphy, W. L. Combinatorial screening of chemically defined human mesenchymal stem cell culture substrates. J. Mater. Chem. 22, 19474–19481 (2012).

    CAS  Google Scholar 

  112. Koutsopoulos, S. & Zhang, S. Long-term three-dimensional neural tissue cultures in functionalized self-assembling peptide hydrogels, Matrigel and Collagen I. Acta Biomater. 9, 5162–5169 (2013).

    CAS  Google Scholar 

  113. Zhang, J. et al. A genome-wide analysis of human pluripotent stem cell-derived endothelial cells in 2D or 3D culture. Stem Cell Rep. 8, 907–918 (2017).

    CAS  Google Scholar 

  114. Farhat, W. et al. Hydrogels for advanced stem cell therapies: a biomimetic materials approach for enhancing natural tissue function. IEEE Rev. Biomed. Eng. 12, 333–351 (2019).

    Google Scholar 

  115. Tsou, Y.-H., Khoneisser, J., Huang, P.-C. & Xu, X. Hydrogel as a bioactive material to regulate stem cell fate. Bioact. Mater. 1, 39–55 (2016).

    Google Scholar 

  116. Donnelly, H., Salmeron-Sanchez, M. & Dalby, M. J. Designing stem cell niches for differentiation and self-renewal. J. R. Soc. Interface 15, 20180388 (2018).

    Google Scholar 

  117. Vining, K. H. & Mooney, D. J. Mechanical forces direct stem cell behaviour in development and regeneration. Nat. Rev. Mol. Cell Biol. 18, 728–742 (2017).

    CAS  Google Scholar 

  118. Engler, A. J., Sen, S., Sweeney, H. L. & Discher, D. E. Matrix elasticity directs stem cell lineage specification. Cell 126, 677–689 (2006).

    CAS  Google Scholar 

  119. Slater, K., Partridge, J. & Nandivada, H. Tuning the elastic moduli of Corning Matrigel and collagen I 3D matrices by varying the protein concentration (Corning, 2018).

  120. Gobaa, S. et al. Artificial niche microarrays for probing single stem cell fate in high throughput. Nat. Methods 8, 949–955 (2011).

    CAS  Google Scholar 

  121. Rape, A. D., Zibinsky, M., Murthy, N. & Kumar, S. A synthetic hydrogel for the high-throughput study of cell–ECM interactions. Nat. Commun. 6, 8129 (2015).

    Google Scholar 

  122. Nemir, S. & West, J. L. Synthetic materials in the study of cell response to substrate rigidity. Ann. Biomed. Eng. 38, 2–20 (2010).

    Google Scholar 

  123. Sill, T. J. & von Recum, H. A. Electrospinning: applications in drug delivery and tissue engineering. Biomaterials 29, 1989–2006 (2008).

    CAS  Google Scholar 

  124. Xu, C., Inai, R., Kotaki, M. & Ramakrishna, S. Electrospun nanofiber fabrication as synthetic extracellular matrix and its potential for vascular tissue engineering. Tissue Eng. 10, 1160–1168 (2004).

    CAS  Google Scholar 

  125. Rashidi, H., Yang, J. & M. Shakesheff, K. Surface engineering of synthetic polymer materials for tissue engineering and regenerative medicine applications. Biomater. Sci. 2, 1318–1331 (2014).

    CAS  Google Scholar 

  126. Yim, E. K. F., Pang, S. W. & Leong, K. W. Synthetic nanostructures inducing differentiation of human mesenchymal stem cells into neuronal lineage. Exp. Cell Res. 313, 1820–1829 (2007).

    CAS  Google Scholar 

  127. Zhu, W. et al. 3D printing of functional biomaterials for tissue engineering. Curr. Opin. Biotechnol. 40, 103–112 (2016).

    CAS  Google Scholar 

  128. Yamazoe, T. et al. A synthetic nanofibrillar matrix promotes in vitro hepatic differentiation of embryonic stem cells and induced pluripotent stem cells. J. Cell Sci. 126, 5391–5399 (2013).

    CAS  Google Scholar 

  129. Franzin, C. et al. Single-cell PCR analysis of murine embryonic stem cells cultured on different substrates highlights heterogeneous expression of stem cell markers. Biol. Cell 105, 549–560 (2013).

    CAS  Google Scholar 

  130. Highet, A. R., Zhang, V. J., Heinemann, G. K. & Roberts, C. T. Use of Matrigel in culture affects cell phenotype and gene expression in the first trimester trophoblast cell line HTR8/SVneo. Placenta 33, 586–588 (2012).

    CAS  Google Scholar 

  131. Sampaziotis, F. et al. Directed differentiation of human induced pluripotent stem cells into functional cholangiocyte-like cells. Nat. Protoc. 12, 814–827 (2017).

    CAS  Google Scholar 

  132. Ranga, A. et al. Neural tube morphogenesis in synthetic 3D microenvironments. Proc. Natl Acad. Sci. USA 113, E6831–E6839 (2016).

    CAS  Google Scholar 

  133. Schneider, M. C. et al. Local heterogeneities improve matrix connectivity in degradable and photoclickable poly(ethylene glycol) hydrogels for applications in tissue engineering. ACS Biomater. Sci. Eng. 3, 2480–2492 (2017).

    CAS  Google Scholar 

  134. Chu, S. et al. Understanding the spatiotemporal degradation behavior of aggrecanase-sensitive poly(ethylene glycol) hydrogels for use in cartilage tissue engineering. Tissue Eng. Part A 23, 795–810 (2017).

    CAS  Google Scholar 

  135. Dolo, V. et al. Matrix-degrading proteinases are shed in membrane vesicles by ovarian cancer cells in vivo and in vitro. Clin. Exp. Metastasis 17, 131–140 (1999).

    CAS  Google Scholar 

  136. Balduyck, M. et al. Specific expression of matrix metalloproteinases 1, 3, 9 and 13 associated with invasiveness of breast cancer cells in vitro. Clin. Exp. Metastasis 18, 171–178 (2000).

    CAS  Google Scholar 

  137. Wong, A. P., Cortez, S. L. & Baricos, W. H. Role of plasmin and gelatinase in extracellular matrix degradation by cultured rat mesangial cells. Am. J. Physiol. 263, F1112–F1118 (1992).

    CAS  Google Scholar 

  138. Wolf, M. Influence of matrigel on biodistribution studies in cancer research. Pharmazie 63, 43–48 (2008).

    CAS  Google Scholar 

  139. Shen, D., Wen, R., Tuo, J., Bojanowski, C. M. & Chan, C.-C. Exacerbation of retinal degeneration and choroidal neovascularization induced by subretinal injection of Matrigel in CCL2/MCP-1-deficient mice. Ophthalmic Res. 38, 71–73 (2006).

    CAS  Google Scholar 

  140. Kano, M. R. et al. VEGF-A and FGF-2 synergistically promote neoangiogenesis through enhancement of endogenous PDGF-B-PDGFRbeta signaling. J. Cell Sci. 118, 3759–3768 (2005).

    CAS  Google Scholar 

  141. Lee, J. H. Injectable hydrogels delivering therapeutic agents for disease treatment and tissue engineering. Biomater. Res. 22, 27 (2018).

    Google Scholar 

  142. Yu, L. & Ding, J. Injectable hydrogels as unique biomedical materials. Chem. Soc. Rev. 37, 1473–1481 (2008).

    CAS  Google Scholar 

  143. Kretlow, J. D., Klouda, L. & Mikos, A. G. Injectable matrices and scaffolds for drug delivery in tissue engineering. Adv. Drug Deliv. Rev. 59, 263–273 (2007).

    CAS  Google Scholar 

  144. Pascual-Garrido, C. et al. Current and novel injectable hydrogels to treat focal chondral lesions: properties and applicability. J. Orthop. Res. 36, 64–75 (2018).

    CAS  Google Scholar 

  145. Kharkar, P. M., Kiick, K. L. & Kloxin, A. M. Designing degradable hydrogels for orthogonal control of cell microenvironments. Chem. Soc. Rev. 42, 7335–7372 (2013).

    CAS  Google Scholar 

  146. Han, W. M. et al. Synthetic matrix enhances transplanted satellite cell engraftment in dystrophic and aged skeletal muscle with comorbid trauma. Sci. Adv. 4, eaar4008 (2018).

    CAS  Google Scholar 

  147. Fernandes, S., Kuklok, S., McGonigle, J., Reinecke, H. & Murry, C. E. Synthetic matrices to serve as niches for muscle cell transplantation. Cells Tissues Organs 195, 48–59 (2012).

    CAS  Google Scholar 

  148. Nagahama, K. et al. Nanocomposite injectable gels capable of self-replenishing regenerative extracellular microenvironments for in vivo tissue engineering. Biomater. Sci. 6, 550–561 (2018).

    CAS  Google Scholar 

  149. Clevers, H. Modeling development and disease with organoids. Cell 165, 1586–1597 (2016).

    CAS  Google Scholar 

  150. Camp, J. G. et al. Human cerebral organoids recapitulate gene expression programs of fetal neocortex development. Proc. Natl Acad. Sci. USA 112, 15672–15677 (2015).

    CAS  Google Scholar 

  151. Murrow, L. M., Weber, R. J. & Gartner, Z. J. Dissecting the stem cell niche with organoid models: an engineering-based approach. Development 144, 998–1007 (2017).

    CAS  Google Scholar 

  152. Astashkina, A. I., Mann, B. K., Prestwich, G. D. & Grainger, D. W. A 3-D organoid kidney culture model engineered for high-throughput nephrotoxicity assays. Biomaterials 33, 4700–4711 (2012).

    CAS  Google Scholar 

  153. Takebe, T. et al. Vascularized and functional human liver from an iPSC-derived organ bud transplant. Nature 499, 481–484 (2013).

    CAS  Google Scholar 

  154. Eiraku, M. et al. Self-organizing optic-cup morphogenesis in three-dimensional culture. Nature 472, 51–56 (2011).

    CAS  Google Scholar 

  155. Dye, B. R. et al. In vitro generation of human pluripotent stem cell derived lung organoids. eLife 4, e05098 (2015).

    Google Scholar 

  156. Cruz-Acuña, R. et al. Synthetic hydrogels for human intestinal organoid generation and colonic wound repair. Nat. Cell Biol. 19, 1326–1335 (2017). The authors present a protocol to generate human intestinal and lung organoids using a fully synthetic, chemically defined PEG hydrogel scaffold.

    Google Scholar 

  157. Chua, C. W. et al. Single luminal epithelial progenitors can generate prostate organoids in culture. Nat. Cell Biol. 16, 951–961 (2014).

    CAS  Google Scholar 

  158. Ardalani, H. et al. 3-D culture and endothelial cells improve maturity of human pluripotent stem cell-derived hepatocytes. Acta Biomater. 95, 371–381 (2019).

    CAS  Google Scholar 

  159. Ramachandran, S. D. et al. In vitro generation of functional liver organoid-like structures using adult human cells. PLoS One 10, e0139345 (2015).

    Google Scholar 

  160. Spence, J. R. et al. Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro. Nature 470, 105–109 (2011).

    Google Scholar 

  161. Cruz-Acuña, R. et al. PEG-4MAL hydrogels for human organoid generation, culture, and in vivo delivery. Nat. Protoc. 13, 2102 (2018).

    Google Scholar 

  162. Gjorevski, N. et al. Designer matrices for intestinal stem cell and organoid culture. Nature 539, 560–564 (2016).

    CAS  Google Scholar 

  163. Gjorevski, N. & Lutolf, M. P. Synthesis and characterization of well-defined hydrogel matrices and their application to intestinal stem cell and organoid culture. Nat. Protoc. 12, 2263–2274 (2017).

    CAS  Google Scholar 

  164. Fatehullah, A., Tan, S. H. & Barker, N. Organoids as an in vitro model of human development and disease. Nat. Cell Biol. 18, 246–254 (2016).

    Google Scholar 

  165. Bray, L. J. et al. A three-dimensional ex vivo tri-culture model mimics cell-cell interactions between acute myeloid leukemia and the vascular niche. Haematologica 102, 1215–1226 (2017).

    CAS  Google Scholar 

  166. Papadimitriou, C. et al. 3D culture method for Alzheimer’s disease modeling reveals interleukin-4 rescues Aβ42-induced loss of human neural stem cell plasticity. Dev. Cell 46, 85–101.e8 (2018).

    CAS  Google Scholar 

  167. Nowak, M., Freudenberg, U., Tsurkan, M. V., Werner, C. & Levental, K. R. Modular GAG-matrices to promote mammary epithelial morphogenesis in vitro. Biomaterials 112, 20–30 (2017).

    CAS  Google Scholar 

  168. Weber, H. M., Tsurkan, M. V., Magno, V., Freudenberg, U. & Werner, C. Heparin-based hydrogels induce human renal tubulogenesis in vitro. Acta Biomater. 57, 59–69 (2017).

    CAS  Google Scholar 

  169. Livingston, M. K. et al. Evaluation of PEG-based hydrogel influence on estrogen-receptor-driven responses in MCF7 breast cancer cells. ACS Biomater. Sci. Eng. 5, 6089–6098 (2019).

    CAS  Google Scholar 

  170. Edmondson, R., Adcock, A. F. & Yang, L. Influence of matrices on 3D-cultured prostate cancer cells’ drug response and expression of drug-action associated proteins. PLoS One 11, e0158116 (2016).

    Google Scholar 

  171. Collier, J. H. & Segura, T. Evolving the use of peptides as biomaterials components. Biomaterials 32, 4198–4204 (2011).

    CAS  Google Scholar 

  172. Hosoyama, K., Lazurko, C., Muñoz, M., McTiernan, C. D. & Alarcon, E. I. Peptide-based functional biomaterials for soft-tissue repair. Front. Bioeng. Biotechnol. 7, 205 (2019).

    Google Scholar 

  173. Xie, A. W. & Murphy, W. L. Engineered biomaterials to mitigate growth factor cost in cell biomanufacturing. Curr. Opin. Biomed. Eng. 10, 1–10 (2019).

    Google Scholar 

  174. Heidariyan, Z. et al. Efficient and cost-effective generation of hepatocyte-like cells through microparticle-mediated delivery of growth factors in a 3D culture of human pluripotent stem cells. Biomaterials 159, 174–188 (2018).

    CAS  Google Scholar 

  175. Bratt-Leal, A. M., Nguyen, A. H., Hammersmith, K. A., Singh, A. & McDevitt, T. C. A microparticle approach to morphogen delivery within pluripotent stem cell aggregates. Biomaterials 34, 7227–7235 (2013).

    CAS  Google Scholar 

  176. Alberti, K. et al. Functional immobilization of signaling proteins enables control of stem cell fate. Nat. Methods 5, 645–650 (2008).

    CAS  Google Scholar 

  177. Platt, M. O. et al. Sustained epidermal growth factor receptor levels and activation by tethered ligand binding enhances osteogenic differentiation of multi-potent marrow stromal cells. J. Cell. Physiol. 221, 306–317 (2009).

    CAS  Google Scholar 

  178. Yu, X. et al. Nanostructured mineral coatings stabilize proteins for therapeutic delivery. Adv. Mater. 29, 1701255 (2017).

    Google Scholar 

  179. Khalil, A. S., Xie, A. W., Johnson, H. J. & Murphy, W. L. Sustained release and protein stabilization reduce the growth factor dosage required for human pluripotent stem cell expansion. Biomaterials 248, 120007 (2020).

    CAS  Google Scholar 

  180. Belair, D. G., Le, N. N. & Murphy, W. L. Design of growth factor sequestering biomaterials. Chem. Commun. 50, 15651–15668 (2014).

    CAS  Google Scholar 

  181. Belair, D. G. & Murphy, W. L. Specific VEGF sequestering to biomaterials: influence of serum stability. Acta Biomater. 9, 8823–8831 (2013).

    CAS  Google Scholar 

  182. Yan, H. J. et al. Synthetic design of growth factor sequestering extracellular matrix mimetic hydrogel for promoting in vivo bone formation. Biomaterials 161, 190–202 (2018).

    CAS  Google Scholar 

  183. Jha, A. K. et al. Enhanced survival and engraftment of transplanted stem cells using growth factor sequestering hydrogels. Biomaterials 47, 1–12 (2015).

    CAS  Google Scholar 

  184. Chen, K. G., Mallon, B. S., McKay, R. D. G. & Robey, P. G. Human pluripotent stem cell culture: considerations for maintenance, expansion, and therapeutics. Cell Stem Cell 14, 13–26 (2014).

    CAS  Google Scholar 

  185. Julavijitphong, S. et al. A xeno-free culture method that enhances Wharton’s jelly mesenchymal stromal cell culture efficiency over traditional animal serum-supplemented cultures. Cytotherapy 16, 683–691 (2014).

    CAS  Google Scholar 

  186. Thirumala, S., Goebel, W. S. & Woods, E. J. Manufacturing and banking of mesenchymal stem cells. Expert Opin. Biol. Ther. 13, 673–691 (2013).

    CAS  Google Scholar 

  187. Halme, D. G. & Kessler, D. A. FDA regulation of stem-cell-based therapies. N. Engl. J. Med. 355, 1730–1735 (2006).

    CAS  Google Scholar 

  188. Xiao, J., Yang, D., Li, Q., Tian, W. & Guo, W. The establishment of a chemically defined serum-free culture system for human dental pulp stem cells. Stem Cell Res. Ther. 9, 191 (2018).

    CAS  Google Scholar 

  189. Hirata, T. M. et al. Expression of multiple stem cell markers in dental pulp cells cultured in serum-free media. J. Endod. 36, 1139–1144 (2010).

    Google Scholar 

  190. Chen, G. et al. Chemically defined conditions for human iPSC derivation and culture. Nat. Methods 8, 424–429 (2011).

    CAS  Google Scholar 

  191. Beers, J. et al. A cost-effective and efficient reprogramming platform for large-scale production of integration-free human induced pluripotent stem cells in chemically defined culture. Sci. Rep. 5, 11319 (2015).

    CAS  Google Scholar 

  192. Xie, A. W. et al. Controlled self-assembly of stem cell aggregates instructs pluripotency and lineage bias. Sci. Rep. 7, 14070 (2017).

    Google Scholar 

  193. Leong, M. F. et al. Electrospun polystyrene scaffolds as a synthetic substrate for xeno-free expansion and differentiation of human induced pluripotent stem cells. Acta Biomater. 46, 266–277 (2016).

    CAS  Google Scholar 

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Acknowledgements

This research was funded by the US Environmental Protection Agency (STAR grant no. 83573701), the US National Institutes of Health (award nos. 1U01TR002383, R01HL093282 and 1R01NS109427) and the US National Science Foundation (award nos. EEC1648035 and DMR 170179). E.A.A. acknowledges funding by the US National Institutes of Health (T32HL110853).

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  1. Department of Surgery, University of Wisconsin, Madison, WI, USA

    Elizabeth A. Aisenbrey

  2. Department of Biomedical Engineering, University of Wisconsin, Madison, WI, USA

    William L. Murphy

  3. Department of Orthopedics and Rehabilitation, University of Wisconsin, Madison, WI, USA

    William L. Murphy

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  1. Elizabeth A. Aisenbrey
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W.L.M. is a co-founder and shareholder of Stem Pharm, Inc. E.A.A. declares no competing interests.

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Aisenbrey, E.A., Murphy, W.L. Synthetic alternatives to Matrigel. Nat Rev Mater 5, 539–551 (2020). https://doi.org/10.1038/s41578-020-0199-8

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