Review

Microtechnology applied to stem cells research and development

Juan Pablo Acevedo

*Author for correspondence: Tel.: +56 2 26181447;

E-mail Address: jpacevedo@uandes.cl

Laboratory of Nano-Regenerative Medicine, Faculty of Medicine, Universidad de Los Andes, Santiago, Chile

Cells for Cells, Santiago, Chile

Search for more papers by this author

Ioannis Angelopoulos

Laboratory of Nano-Regenerative Medicine, Faculty of Medicine, Universidad de Los Andes, Santiago, Chile

Cells for Cells, Santiago, Chile

Search for more papers by this author

Danny van Noort

Facultad de Ingeniería y Ciencias Aplicadas Universidad de los Andes, Santiago, Chile

Biotechnology, IFM, Linköping University, Sweden

Search for more papers by this author

Maroun Khoury

Laboratory of Nano-Regenerative Medicine, Faculty of Medicine, Universidad de Los Andes, Santiago, Chile

Cells for Cells, Santiago, Chile

Consorcio Regenero, Santiago, Chile

Search for more papers by this author

Published Online:20 Mar 2018https://doi.org/10.2217/rme-2017-0123

View article

Abstract

Microfabrication and microfluidics contribute to the research of cellular functions of cells and their interaction with their environment. Previously, it has been shown that microfluidics can contribute to the isolation, selection, characterization and migration of cells. This review aims to provide stem cell researchers with a toolkit of microtechnology (mT) instruments for elucidating complex stem cells functions which are challenging to decipher with traditional assays and animal models. These microdevices are able to investigate about the differentiation and niche interaction, stem cells transcriptomics, therapeutic functions and the capture of their secreted microvesicles. In conclusion, microtechnology will allow a more realistic assessment of stem cells properties, driving and accelerating the translation of regenerative medicine approaches to the clinic.

Keywords:

Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

1 Breslauer DN, Lee PJ, Lee LP. Microfluidics-based systems biology. Mol. Biosyst. 2(2), 97–112 (2006).Crossref, Medline, CAS, Google Scholar
2 Lee PJ, Hung PJ, Lee LP. An artificial liver sinusoid with a microfluidic endothelial-like barrier for primary hepatocyte culture. Biotechnol. Bioeng. 97(5), 1340–1346 (2007).Crossref, Medline, CAS, Google Scholar
3 Pampaloni F, Reynaud EG, Stelzer EH. The third dimension bridges the gap between cell culture and live tissue. Nat. Rev. Mol. Cell Biol. 8(10), 839–845 (2007).Crossref, Medline, CAS, Google Scholar
4 Toh YC, Zhang C, Zhang J et al. A novel 3D mammalian cell perfusion-culture system in microfluidic channels. Lab Chip 7(3), 302–309 (2007).Crossref, Medline, CAS, Google Scholar
5 Ong SM, Zhang C, Toh YC et al. A gel-free 3D microfluidic cell culture system. Biomaterials 29(22), 3237–3244 (2008).Crossref, Medline, CAS, Google Scholar
6 Abbott A. Cell culture: biology's new dimension. Nature 424(6951), 870–872 (2003).Crossref, Medline, CAS, Google Scholar
7 Kunz-Schughart LA, Freyer JP, Hofstaedter F, Ebner R. The use of 3D cultures for high-throughput screening: the multicellular spheroid model. J. Biomol. Screen. 9(4), 273–285 (2004).Crossref, Medline, CAS, Google Scholar
8 Johnson JI, Decker S, Zaharevitz D et al. Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials. Br. J. Cancer 84(10), 1424–1431 (2001).Crossref, Medline, CAS, Google Scholar
9 Vogel V, Sheetz MP. Cell fate regulation by coupling mechanical cycles to biochemical signaling pathways. Curr. Opin. Cell Biol. 21(1), 38–46 (2009).Crossref, Medline, CAS, Google Scholar
10 Yim EK, Sheetz MP. Force-dependent cell signaling in stem cell differentiation. Stem Cell. Res. Ther. 3(5), 41 (2012).Crossref, Medline, CAS, Google Scholar
11 Whitesides GM. The origins and the future of microfluidics. Nature 442(7101), 368–373 (2006).Crossref, Medline, CAS, Google Scholar
12 Wen Y, Zhang X, Yang ST. Microplate-reader compatible perfusion microbioreactor array for modular tissue culture and cytotoxicity assays. Biotechnol. Prog. 26(4), 1135–1144 (2010).Medline, CAS, Google Scholar
13 Ankam S, Teo BK, Kukumberg M, Yim EK. High throughput screening to investigate the interaction of stem cells with their extracellular microenvironment. Organogenesis 9(3), 128–142 (2013).Crossref, Medline, Google Scholar
14 Melin J, Quake SR. Microfluidic large-scale integration: the evolution of design rules for biological automation. Annu. Rev. Biophys. Biomol. Struct. 36, 213–231 (2007). • A review on the development of microfluidic large-scale integration and the applications to the field of biology.Crossref, Medline, CAS, Google Scholar
15 Walker GM, Zeringue HC, Beebe DJ. Microenvironment design considerations for cellular scale studies. Lab Chip 4(2), 91–97 (2004).Crossref, Medline, CAS, Google Scholar
16 Korin N, Bransky A, Dinnar U, Levenberg S. A parametric study of human fibroblasts culture in a microchannel bioreactor. Lab Chip 7(5), 611–617 (2007).Crossref, Medline, CAS, Google Scholar
17 Kim L, Vahey MD, Lee HY, Voldman J. Microfluidic arrays for logarithmically perfused embryonic stem cell culture. Lab Chip 6(3), 394–406 (2006).Crossref, Medline, CAS, Google Scholar
18 Zhang MY, Lee PJ, Hung PJ, Johnson T, Lee LP, Mofrad MR. Microfluidic environment for high density hepatocyte culture. Biomed. Microdevices 10(1), 117–121 (2008).Crossref, Medline, Google Scholar
19 Park J, Berthiaume F, Toner M, Yarmush ML, Tilles AW. Microfabricated grooved substrates as platforms for bioartificial liver reactors. Biotechnol. Bioeng. 90(5), 632–644 (2005).Crossref, Medline, CAS, Google Scholar
20 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. 29(11), 947–955 (2001).Crossref, Medline, CAS, Google Scholar
21 Anderson JR, Chiu DT, Jackman RJ et al. Fabrication of topologically complex three-dimensional microfluidic systems in PDMS by rapid prototyping. Anal. Chem. 72(14), 3158–3164 (2000).Crossref, Medline, CAS, Google Scholar
22 Mcdonald JC, Duffy DC, Anderson JR et al. Fabrication of microfluidic systems in poly(dimethylsiloxane). Electrophoresis 21(1), 27–40 (2000).Crossref, Medline, CAS, Google Scholar
23 Zhang Z, Boccazzi P, Choi HG, Perozziello G, Sinskey AJ, Jensen KF. Microchemostat-microbial continuous culture in a polymer-based, instrumented microbioreactor. Lab Chip 6(7), 906–913 (2006).Crossref, Medline, CAS, Google Scholar
24 Schober A, Augspurger C, Fernekorn U et al. Microfluidics and biosensors as tools for NanoBioSystems research with applications in the ‘Life Science’. Mater. Sci. Eng. B 169(1–3), 174–181 (2010).Crossref, CAS, Google Scholar
25 Grist SM, Chrostowski L, Cheung KC. Optical oxygen sensors for applications in microfluidic cell culture. Sensors Basel 10(10), 9286–9316 (2010).Crossref, Medline, CAS, Google Scholar
26 Lee S, Ibey BL, Coté GL, Pishko MV. Measurement of pH and dissolved oxygen within cell culture media using a hydrogel microarray sensor. Sensors Actuators B: Chem. 128(2), 388–398 (2008).Crossref, CAS, Google Scholar
27 Wan Y, Kim YT, Li N et al. Surface-immobilized aptamers for cancer cell isolation and microscopic cytology. Cancer Res. 70(22), 9371–9380 (2010).Crossref, Medline, CAS, Google Scholar
28 Karabacak NM, Spuhler PS, Fachin F et al. Microfluidic, marker-free isolation of circulating tumor cells from blood samples. Nat. Protoc. 9(3), 694–710 (2014). • A procedure for separating circulating tumor cells from blood samples by using tumor antigen-independent microfluidic circulating tumor cell-iChip technology.Crossref, Medline, CAS, Google Scholar
29 Wang S, Qu X, Zhao RC. Clinical applications of mesenchymal stem cells. J. Hematol. Oncol. 5(1), 19 (2012).Crossref, Medline, Google Scholar
30 Wei F, Wang T, Liu J, Du Y, Ma A. The subpopulation of mesenchymal stem cells that differentiate toward cardiomyocytes is cardiac progenitor cells. Exp. Cell Res. 317(18), 2661–2670 (2011).Crossref, Medline, CAS, Google Scholar
31 Ahmed O, Abdellah H, Elsayed M, Abdelgawad M, Mousa NA, El-Badri N. Tissue dissociation miniaturized platform for uterine stem cell isolation and culture. Presented at: 2014 Cairo International Biomedical Engineering Conference (CIBEC). Giza, Egypt, 11–13 December 2014.Crossref, Google Scholar
32 Lin CH, Lee DC, Chang HC, Chiu IM, Hsu CH. Single-cell enzyme-free dissociation of neurospheres using a microfluidic chip. Anal. Chem. 85(24), 11920–11928 (2013). • A microfluidic device that uses flow and microstructures to dissociate neurospheres.Crossref, Medline, CAS, Google Scholar
33 Lee WC, Shi H, Poon Z et al. Multivariate biophysical markers predictive of mesenchymal stromal cell multipotency. Proc. Natl Acad. Sci. USA 111(42), 8 (2014).Crossref, Google Scholar
34 Prieto JL, Lu J, Nourse JL, Flanagan LA, Lee AP. Frequency discretization in dielectrophoretic assisted cell sorting arrays to isolate neural cells. Lab Chip 12(12), 2182–2189 (2012).Crossref, Medline, CAS, Google Scholar
35 Lee WC, Bhagat AA, Huang S, Van Vliet KJ, Han J, Lim CT. High-throughput cell cycle synchronization using inertial forces in spiral microchannels. Lab Chip 11(7), 1359–1367 (2011). • A spiral microfluidic device for cell cycle syn-chronization, using the combined effects of inertial forces and Dean drag force.Crossref, Medline, CAS, Google Scholar
36 Green JV, Radisic M, Murthy SK. Deterministic lateral displacement as a means to enrich large cells for tissue engineering. Anal. Chem. 81(21), 9178–9182 (2009).Crossref, Medline, CAS, Google Scholar
37 Liu Z, Zhang W, Huang F et al. High throughput capture of circulating tumor cells using an integrated microfluidic system. Biosens. Bioelectron. 47, 113–119 (2013).Crossref, Medline, CAS, Google Scholar
38 Karnik R, Hong S, Zhang H et al. Nanomechanical control of cell rolling in two dimensions through surface patterning of receptors. Nano Lett. 8(4), 1153–1158 (2008).Crossref, Medline, CAS, Google Scholar
39 Greenberg AW, Hammer DA. Cell separation mediated by differential rolling adhesion. Biotechnol. Bioeng. 73(2), 111–124 (2001).Crossref, Medline, CAS, Google Scholar
40 Mahara A, Yamaoka T. Continuous separation of cells of high osteoblastic differentiation potential from mesenchymal stem cells on an antibody-immobilized column. Biomaterials 31(14), 4231–4237 (2010).Crossref, Medline, CAS, Google Scholar
41 Choi S, Levy O, Coelho MB, Cabral JM, Karp JM, Karnik R. A cell rolling cytometer reveals the correlation between mesenchymal stem cell dynamic adhesion and differentiation state. Lab Chip 14(1), 161–166 (2014). • A microfluidic device (cell rolling cytometer) that allows the quantification of cell-surface adhesion dynamics.Crossref, Medline, CAS, Google Scholar
42 Kavanagh DP, Durant LE, Crosby HA et al. Haematopoietic stem cell recruitment to injured murine liver sinusoids depends on (alpha)4(beta)1 integrin/VCAM-1 interactions. Gut 59(1), 79–87 (2010).Crossref, Medline, CAS, Google Scholar
43 Jones DL, Wagers AJ. No place like home: anatomy and function of the stem cell niche. Nat. Rev. Mol. Cell Biol. 9(1), 11–21 (2008).Crossref, Medline, CAS, Google Scholar
44 Choi NW, Cabodi M, Held B, Gleghorn JP, Bonassar LJ, Stroock AD. Microfluidic scaffolds for tissue engineering. Nat. Mater. 6(11), 908–915 (2007).Crossref, Medline, CAS, Google Scholar
45 Yang K, Han S, Shin Y et al. A microfluidic array for quantitative analysis of human neural stem cell self-renewal and differentiation in three-dimensional hypoxic microenvironment. Biomaterials 34(28), 6607–6614 (2013).Crossref, Medline, CAS, Google Scholar
46 Mahadik BP, Wheeler TD, Skertich LJ, Kenis PJ, Harley BA. Microfluidic generation of gradient hydrogels to modulate hematopoietic stem cell culture environment. Adv. Healthc. Mater. 3(3), 449–458 (2014).Crossref, Medline, CAS, Google Scholar
47 Allazetta S, Hausherr TC, Lutolf MP. Microfluidic synthesis of cell-type-specific artificial extracellular matrix hydrogels. Biomacromolecules 14(4), 1122–1131 (2013).Crossref, Medline, CAS, Google Scholar
48 Carrion B, Huang CP, Ghajar CM et al. Recreating the perivascular niche ex vivo using a microfluidic approach. Biotechnol. Bioeng. 107(6), 1020–1028 (2010).Crossref, Medline, CAS, Google Scholar
49 Lane SW, Williams DA, Watt FM. Modulating the stem cell niche for tissue regeneration. Nat. Biotechnol. 32(8), 795–803 (2014).Crossref, Medline, CAS, Google Scholar
50 Chung BG, Flanagan LA, Rhee SW et al. Human neural stem cell growth and differentiation in a gradient-generating microfluidic device. Lab Chip 5(4), 401–406 (2005).Crossref, Medline, CAS, Google Scholar
51 Toh YC, Lim TC, Tai D, Xiao G, Van Noort D, Yu H. A microfluidic 3D hepatocyte chip for drug toxicity testing. Lab Chip 9(14), 2026–2035 (2009).Crossref, Medline, CAS, Google Scholar
52 Wang G, Mccain ML, Yang L et al. Modeling the mitochondrial cardiomyopathy of Barth syndrome with induced pluripotent stem cell and heart-on-chip technologies. Nat. Med. 20(6), 616–623 (2014).Crossref, Medline, CAS, Google Scholar
53 Mathur A, Loskill P, Shao K et al. Human iPSC-based cardiac microphysiological system for drug screening applications. Sci. Rep. 5, 8883 (2015).Crossref, Medline, CAS, Google Scholar
54 Wang B, Jedlicka S, Cheng X. Maintenance and neuronal cell differentiation of neural stem cells C17.2 correlated to medium availability sets design criteria in microfluidic systems. PLoS ONE 9(10), e109815 (2014).Crossref, Medline, Google Scholar
55 Ankam S, Suryana M, Chan LY et al. Substrate topography and size determine the fate of human embryonic stem cells to neuronal or glial lineage. Acta Biomater. 9(1), 4535–4545 (2013).Crossref, Medline, CAS, Google Scholar
56 Chang YJ, Tsai CJ, Tseng FG, Chen TJ, Wang TW. Micropatterned stretching system for the investigation of mechanical tension on neural stem cells behavior. Nanomedicine 9(3), 345–355 (2013).Crossref, Medline, CAS, Google Scholar
57 Lopacinska JM, Emneus J, Dufva M. Poly(dimethylsiloxane) (PDMS) affects gene expression in PC12 cells differentiating into neuronal-like cells. PLoS ONE 8(1), 3 (2013).Crossref, Google Scholar
58 Jang K, Sato K, Igawa K, Chung UI, Kitamori T. Development of an osteoblast-based 3D continuous-perfusion microfluidic system for drug screening. Anal. Bioanal. Chem. 390(3), 825–832 (2008).Crossref, Medline, CAS, Google Scholar
59 Cohen DE, Melton D. Turning straw into gold: directing cell fate for regenerative medicine. Nat. Rev. Genet. 12(4), 243–252 (2011).Crossref, Medline, CAS, Google Scholar
60 Kaltz N, Ringe J, Holzwarth C et al. Novel markers of mesenchymal stem cells defined by genome-wide gene expression analysis of stromal cells from different sources. Exp. Cell Res. 316(16), 2609–2617 (2010).Crossref, Medline, CAS, Google Scholar
61 Zhao W, Phinney DG, Bonnet D, Dominici M, Krampera M. Mesenchymal stem cell biodistribution, migration, and homing in vivo. Stem Cells Int. 2014, 292109 (2014).Crossref, Medline, Google Scholar
62 Zhong JF, Chen Y, Marcus JS et al. A microfluidic processor for gene expression profiling of single human embryonic stem cells. Lab Chip 8(1), 68–74 (2008).Crossref, Medline, CAS, Google Scholar
63 Dalerba P, Kalisky T, Sahoo D et al. Single-cell dissection of transcriptional heterogeneity in human colon tumors. Nat. Biotechnol. 29(12), 1120–1127 (2011).Crossref, Medline, CAS, Google Scholar
64 Kiss MM, Ortoleva-Donnelly L, Beer NR et al. High-throughput quantitative polymerase chain reaction in picoliter droplets. Anal. Chem. 80(23), 8975–8981 (2008).Crossref, Medline, CAS, Google Scholar
65 Yamamura S, Kishi H, Tokimitsu Y et al. Single-cell microarray for analyzing cellular response. Anal. Chem. 77(24), 8050–8056 (2005).Crossref, Medline, CAS, Google Scholar
66 Moeller HC, Mian MK, Shrivastava S, Chung BG, Khademhosseini A. A microwell array system for stem cell culture. Biomaterials 29(6), 752–763 (2008).Crossref, Medline, CAS, Google Scholar
67 Dimov IK, Lu R, Lee EP et al. Discriminating cellular heterogeneity using microwell-based RNA cytometry. Nat. Commun. 5, 3451 (2014). •• A system to determine cellular heterogeneity.Crossref, Medline, Google Scholar
68 White AK, Vaninsberghe M, Petriv OI et al. High-throughput microfluidic single-cell RT-qPCR. Proc. Natl Acad. Sci. USA 108(34), 13999–14004 (2011).Crossref, Medline, CAS, Google Scholar
69 Streets AM, Zhang X, Cao C et al. Microfluidic single-cell whole-transcriptome sequencing. Proc. Natl Acad. Sci. USA 111(19), 7048–7053 (2014). •• A microfluidic device for single-cell whole transcriptome.Crossref, Medline, CAS, Google Scholar
70 Yeo RW, Lai RC, Zhang B et al. Mesenchymal stem cell: an efficient mass producer of exosomes for drug delivery. Adv. Drug Deliv. Rev. 65(3), 336–341 (2013).Crossref, Medline, CAS, Google Scholar
71 Alcayaga-Miranda F, Gonzalez PL, Lopez-Verrilli A et al. Prostate tumor-induced angiogenesis is blocked by exosomes derived from menstrual stem cells through the inhibition of reactive oxygen species. Oncotarget 7(28), 44462–44477 (2016).Crossref, Medline, Google Scholar
72 Alcayaga-Miranda F, Varas-Godoy M, Khoury M. Harnessing the angiogenic potential of stem cell-derived exosomes for vascular regeneration. Stem Cells Int. 2016, 3409169 (2016).Crossref, Medline, CAS, Google Scholar
73 Properzi F, Logozzi M, Fais S. Exosomes: the future of biomarkers in medicine. Biomark. Med. 7(5), 769–778 (2013).Link, CAS, Google Scholar
74 Chen C, Skog J, Hsu CH et al. Microfluidic isolation and transcriptome analysis of serum microvesicles. Lab Chip 10(4), 505–511 (2010).Crossref, Medline, CAS, Google Scholar
75 Yoon J, Jo W, Jeong D, Kim J, Jeong H, Park J. Generation of nanovesicles with sliced cellular membrane fragments for exogenous material delivery. Biomaterials 59, 12–20 (2015).Crossref, Medline, CAS, Google Scholar
76 Ajani JA, Song S, Hochster HS, Steinberg IB. Cancer stem cells: the promise and the potential. Semin. Oncol. 42(1), 21 (2015).Google Scholar
77 Islam F, Qiao B, Smith RA, Gopalan V, Lam AK. Cancer stem cell: fundamental experimental pathological concepts and updates. Exp. Mol. Pathol. 98(2), 184–191 (2015).Crossref, Medline, CAS, Google Scholar
78 Zhang W, Kai K, Choi DS et al. Microfluidics separation reveals the stem-cell-like deformability of tumor-initiating cells. Proc. Natl Acad. Sci. USA 109(46), 18707–18712 (2012). •• A microfluidic system to enhance physically deformable cells by mechanical manipulation with artificial microbarriers.Crossref, Medline, CAS, Google Scholar
79 Nagrath S, Sequist LV, Maheswaran S et al. Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature 450(7173), 1235–1239 (2007).Crossref, Medline, CAS, Google Scholar
80 Kim TH, Yoon HJ, Stella P, Nagrath S. Cascaded spiral microfluidic device for deterministic and high purity continuous separation of circulating tumor cells. Biomicrofluidics 8(6), 064117 (2014).Crossref, Medline, Google Scholar
81 Li P, Mao Z, Peng Z et al. Acoustic separation of circulating tumor cells. Proc. Natl Acad. Sci. USA 112(16), 4970–4975 (2015).Crossref, Medline, CAS, Google Scholar
82 Autebert J, Coudert B, Champ J et al. High purity microfluidic sorting and analysis of circulating tumor cells: towards routine mutation detection. Lab Chip 15(9), 2090–2101 (2015).Crossref, Medline, CAS, Google Scholar
83 Jeon JS, Bersini S, Gilardi M et al. Human 3D vascularized organotypic microfluidic assays to study breast cancer cell extravasation. Proc. Natl Acad. Sci. USA 112(1), 214–219 (2015). •• A microfluidic device to examine breast cancer cell extravasation into bone and muscle.Crossref, Medline, CAS, Google Scholar
84 Agastin S, Giang UB, Geng Y, Delouise LA, King MR. Continuously perfused microbubble array for 3D tumor spheroid model. Biomicrofluidics 5(2), 3 (2011).Crossref, Google Scholar
85 Galipeau J. The mesenchymal stromal cells dilemma--does a negative phase III trial of random donor mesenchymal stromal cells in steroid-resistant graft-versus-host disease represent a death knell or a bump in the road? Cytotherapy 15(1), 2–8 (2013).Crossref, Medline, Google Scholar
86 Von Bahr L, Sundberg B, Lonnies L et al. Long-term complications, immunologic effects, and role of passage for outcome in mesenchymal stromal cell therapy. Biol. Blood Marrow Transplant. 18(4), 557–564 (2012).Crossref, Medline, Google Scholar
87 Boroujeni ME, Gowda P, Johnson J, Rao J, Saremy S. The proliferation and differentiation capacity of bone marrow derived - human mesenchymal stem cells in early and late doubling. Asian J. Biochem. 7(1), 27–36 (2012).Crossref, CAS, Google Scholar
88 Rosland GV, Svendsen A, Torsvik A et al. Long-term cultures of bone marrow-derived human mesenchymal stem cells frequently undergo spontaneous malignant transformation. Cancer Res. 69(13), 5331–5339 (2009).Crossref, Medline, CAS, Google Scholar
89 Titmarsh DM, Tan CL, Glass NR, Nurcombe V, Cooper-White JJ, Cool SM. Microfluidic screening reveals heparan sulfate enhances human mesenchymal stem cell growth by modulating fibroblast growth factor-2 transport. Stem Cells Transl. Med. 6(4), 1178–1190 (2017).Crossref, Medline, CAS, Google Scholar
90 Kwon T, Prentice H, Oliveira J et al. Microfluidic cell retention device for perfusion of mammalian suspension culture. Sci. Rep. 7(1), 6703 (2017).Crossref, Medline, Google Scholar
91 Occhetta P, Centola M, Tonnarelli B, Redaelli A, Martin I, Rasponi M. High-throughput microfluidic platform for 3D cultures of mesenchymal stem cells, towards engineering developmental processes. Sci. Rep. 5, 10288 (2015).Crossref, Medline, CAS, Google Scholar
92 Siltanen C, Yaghoobi M, Haque A et al. Microfluidic fabrication of bioactive microgels for rapid formation and enhanced differentiation of stem cell spheroids. Acta Biomater. 34, 125–132 (2016).Crossref, Medline, CAS, Google Scholar
93 Uzel SG, Amadi OC, Pearl TM, Lee RT, So PT, Kamm RD. Simultaneous or sequential orthogonal gradient formation in a 3D cell culture microfluidic platform. Small 12(5), 612–622 (2016).Crossref, Medline, CAS, Google Scholar
94 Nava MM, Piuma A, Figliuzzi M et al. Two-photon polymerized “nichoid” substrates maintain function of pluripotent stem cells when expanded under feeder-free conditions. Stem Cell. Res. Ther. 7(1), 132 (2016).Crossref, Medline, Google Scholar
95 Ricci D, Nava MM, Zandrini T, Cerullo G, Raimondi MT, Osellame R. Scaling-up techniques for the nanofabrication of cell culture substrates via two-photon polymerization for industrial-scale expansion of stem cells. Materials 10(1), pii:E66 (2017).Crossref, Medline, Google Scholar
96 Orford KW, Scadden DT. Deconstructing stem cell self-renewal: genetic insights into cell-cycle regulation. Nat. Rev. Genet. 9(2), 115–128 (2008).Crossref, Medline, CAS, Google Scholar
97 Bravery CA, Carmen J, Fong T et al. Potency assay development for cellular therapy products: an ISCT review of the requirements and experiences in the industry. Cytotherapy 15(1), 9–19 (2013).Crossref, Medline, Google Scholar
98 Ginis I, Grinblat B, Shirvan MH. Evaluation of bone marrow-derived mesenchymal stem cells after cryopreservation and hypothermic storage in clinically safe medium. Tissue Eng. Part C Methods 18(6), 453–463 (2012).Crossref, Medline, CAS, Google Scholar
99 Francois M, Copland IB, Yuan S, Romieu-Mourez R, Waller EK, Galipeau J. Cryopreserved mesenchymal stromal cells display impaired immunosuppressive properties as a result of heat-shock response and impaired interferon-gamma licensing. Cytotherapy 14(2), 147–152 (2012).Crossref, Medline, CAS, Google Scholar
100 Bissoyi A, Bit A, Singh BK, Singh AK, Patra PK. Enhanced cryopreservation of MSCs in microfluidic bioreactor by regulated shear flow. Sci. Rep. 6, 35416 (2016).Crossref, Medline, CAS, Google Scholar
101 Song YS, Moon S, Hulli L, Hasan SK, Kayaalp E, Demirci U. Microfluidics for cryopreservation. Lab Chip 9(13), 1874–1881 (2009).Crossref, Medline, CAS, Google Scholar
102 Shin Y, Han S, Jeon JS et al. Microfluidic assay for simultaneous culture of multiple cell types on surfaces or within hydrogels. Nat. Protoc. 7(7), 1247–1259 (2012).Crossref, Medline, CAS, Google Scholar
103 Bobrie A, Colombo M, Krumeich S, Raposo G, Thery C. Diverse subpopulations of vesicles secreted by different intracellular mechanisms are present in exosome preparations obtained by differential ultracentrifugation. J. Extracell. Vesicles 16(1), doi:10.3402/jev.v1i0.18397 (2012).Crossref, Google Scholar
104 Jeppesen DK, Hvam ML, Primdahl-Bengtson B et al. Comparative analysis of discrete exosome fractions obtained by differential centrifugation. J. Extracell. Vesicles 3, 25011 (2014).Crossref, Medline, Google Scholar

Vol. 13, No. 2

Metrics

Downloaded 143 times

History

Received 22 August 2017

Accepted 5 January 2018

Published online 20 March 2018

Published in print March 2018

Information

Keywords

Author's contributions

JP Acevedo, I Angelopoulos, D van Noort and M Khoury contributed equally to this review study. The final manuscript was read and approved by all authors.

Financial & competing interests disclosure

This work was supported by the Chilean Ministry of Economy with its CORFO grant 3IDL2–18745 and the PMI fund UAN1301 granted by the Chilean Ministry of Education. M Khoury is the chief scientific officer of Cells for Cells and REGENERO. JP Acevedo received stipends from Cells for Cells. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

PDF download