Organ-on-a-chip platforms for drug screening and tissue engineering

Biomedical Engineering: Frontier Research and Converging Technologies

Volumn 9, Issue , 2015, Pages 209-233

  Wang, Zongjie ^a   Samanipour, Roya ^a   Kim, Keekyoung ^a  

^a UNIVERSITY OF BRITISH COLUMBIA   (Canada)

Author keywords

Cellular microenvironment; Drug screening and delivery; Microfluidics system; Organ on a chip; Tissue engineering

Indexed keywords

CELL CULTURE; CONTROLLED DRUG DELIVERY; DIAGNOSIS; HISTOLOGY; TARGETED DRUG DELIVERY; TISSUE;

CELLULAR MICROENVIRONMENT; CONVENTIONAL SYSTEMS; DRUG SCREENING; DYNAMIC INTERACTION; MICROFABRICATED DEVICES; MICROFLUIDICS SYSTEMS; NANOFLUIDIC TECHNOLOGIES; ORGAN-ON-A-CHIP;

TISSUE ENGINEERING;

EID: 84956807101     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1007/978-3-319-21813-7_10     Document Type: Chapter

References (92)

1. Tonkens, R.: An overview of the drug development process. Physician Exec. 31, 48-52 (2005)
2. Djulbegovic, B., Hozo, I., Ioannidis, J.P.A.: Improving the drug development process:more not less randomized trials. JAMA 311, 355-356 (2014). doi:10.1001/jama.2013.283742
3. Bhise, N.S., Shmueli, R.B., Sunshine, J.C., Tzeng, S.Y., Green, J.J.: Drug delivery strategies for therapeutic angiogenesis and antiangiogenesis. Expert Opin Drug Deliv. 8, 485-504 (2011). doi:10.1517/17425247.2011.558082
4. Baharvand, H., Hashemi, S.M., Kazemi Ashtiani, S., Farrokhi, A.: Differentiation of human embryonic stem cells into hepatocytes in 2D and 3D culture systems in vitro. Int. J. Dev. Biol. 50, 645-652 (2006). doi:10.1387/ijdb.052072hb
5. Tibbitt, M.W., Anseth, K.S.: Hydrogels as extracellular matrix mimics for 3D cell culture. Biotechnol. Bioeng. 103, 655-663 (2009). doi:10.1002/bit.22361
6. Bhise, N.S., Gray, R.S., Sunshine, J.C., Htet, S., Ewald, A.J., Green, J.J.: The relationship between terminal functionalization and molecular weight of a gene delivery polymer and transfection efficacy in mammary epithelial 2-D cultures and 3-D organotypic cultures. Biomaterials 31, 8088-8096 (2010). doi:10.1016/j.biomaterials.2010.07.023
7. Tung, Y.-C., Hsiao, A.Y., Allen, S.G., Torisawa, Y., Ho, M., Takayama, S.: High-throughput 3D spheroid culture and drug testing using a 384 hanging drop array. Analyst 136, 473-478 (2011). doi:10.1039/c0an00609b
8. Wilkening, S., Stahl, F., Bader, A.: Comparison of primary human hepatocytes and hepatoma cell line HepG2 with regard to their biotransformation properties. Drug Metab. Dispos. 31, 1035-1042 (2003). doi:10.1124/dmd.31.8.1035
9. Karp, J.M., Yeh, J., Eng, G., Fukuda, J., Blumling, J., Suh, K.-Y., Cheng, J., Mahdavi, A., Borenstein, J., Langer, R., Khademhosseini, A.: Controlling size, shape and homogeneity of embryoid bodies using poly(ethylene glycol) microwells. Lab. Chip. 7, 786-794 (2007). doi:10.1039/b705085m
10. Patel, N.G., Zhang, G.: Stacked stem cell sheets enhance cell-matrix interactions. Organogenesis 10, 170-176 (2014). doi:10.4161/org.28990
11. Karp, J.M., Yeh, J., Eng, G., Fukuda, J., Blumling, J., Suh, K.-Y., Cheng, J., Mahdavi, A., Borenstein, J., Langer, R., Khademhosseini, A.: Controlling size, shape and homogeneity of embryoid bodies using poly(ethylene glycol) microwells. Lab. Chip. 7, 786-794 (2007). doi:10.1039/b705085m
12. Papenburg, B.J., Liu, J., Higuera, G.A., Barradas, A.M.C., de Boer, J., van Blitterswijk, C.A., Wessling, M., Stamatialis, D.: Development and analysis of multi-layer scaffolds for tissue engineering. Biomaterials 30, 6228-6239 (2009). doi:10.1016/j.biomaterials.2009.07.057
13. Patel, N.G., Zhang, G.: Stacked stem cell sheets enhance cell-matrix interactions. Organogenesis 10, 170-176 (2014). doi:10.4161/org.28990
14. Douville, N.J., Zamankhan, P., Tung, Y.-C., Li, R., Vaughan, B.L., Tai, C.-F., White, J., Christensen, P.J., Grotberg, J.B., Takayama, S.: Combination of fluid and solid mechanical stresses contribute to cell death and detachment in a microfluidic alveolar model. Lab. Chip. 11, 609-619 (2011). doi:10.1039/c0lc00251h
15. Huh, D., Matthews, B.D., Mammoto, A., Montoya-Zavala, M., Hsin, H.Y., Ingber, D.E.: Reconstituting organ-level lung functions on a chip. Science 328, 1662-1668 (2010). doi:10.1126/science.1188302
16. Mahto, S.K., Yoon, T.H., Rhee, S.W.: A new perspective on in vitro assessment method for evaluating quantum dot toxicity by using microfluidics technology. Biomicrofluidics 4, 1-9 (2010). doi:10.1063/1.3486610
17. Cho, E.C., Zhang, Q., Xia, Y.: The effect of sedimentation and diffusion on cellular uptake of gold nanoparticles. Nat. Nanotechnol. 6, 385-391 (2011). doi:10.1038/nnano.2011.58
18. Stirland, D.L., Nichols, J.W., Miura, S., Bae, Y.H.: Mind the gap: a survey of how cancer drug carriers are susceptible to the gap between research and practice. J. Control Release 172, 1045-1064 (2013). doi:10.1016/j.jconrel.2013.09.026
19. Lammers, T., Kiessling, F., Hennink, W.E., Storm, G.: Drug targeting to tumors: principles, pitfalls and (pre-) clinical progress. J. Control Release 161, 175-187 (2012). doi:10.1016/j.jconrel.2011.09.063
20. Bhise, N.S., Ribas, J., Manoharan, V., Zhang, Y.S., Polini, A., Massa, S., Dokmeci, M.R., Khademhosseini, A.: Organ-on-a-chip platforms for studying drug delivery systems. J. Control Release 190, 82-93 (2014). doi:10.1016/j.jconrel.2014.05.004
21. U.S.Food and Drug Administration: Guidance for industry safety testing of drug guidance for industry safety testing of drug metabolites (2008)
22. Fröde, T.S., Medeiros, Y.S.: Animal models to test drugs with potential antidiabetic activity. J. Ethnopharmacol. 115, 173-183 (2008). doi:10.1016/j.jep.2007.10.038
23. Moraes, C., Mehta, G., Lesher-Perez, S.C., Takayama, S.: Organs-on-a-chip: a focus on compartmentalized microdevices. Ann. Biomed Eng. 40, 1211-1227 (2012). doi:10.1007/s10439-011-0455-6
24. Zimmerlin, L., Donnenberg, A.D., Rubin, J.P., Basse, P., Landreneau, R.J., Donnenberg, V.S.: Regenerative therapy and cancer: in vitro and in vivo studies of the interaction between adipose-derived stem cells and breast cancer cells from clinical isolates. Tissue Eng. Part A 17, 93-106 (2011). doi:10.1089/ten.TEA.2010.0248
25. Duffy, D.C., McDonald, J.C., Schueller, O.J., Whitesides, G.M.: Rapid prototyping of microfluidic systems in Poly(dimethylsiloxane). Anal. Chem. 70, 4974-4984 (1998). doi:10.1021/ac980656z
26. Leclerc, E., Furukawa, K.S., Miyata, F., Sakai, Y., Ushida, T., Fujii, T.: Fabrication of microstructures in photosensitive biodegradable polymers for tissue engineering applications. Biomaterials 25, 4683-4690 (2004). doi:10.1016/j.biomaterials.2003.10.060
27. Huh, D., Torisawa, Y., Hamilton, G.A., Kim, H.J., Ingber, D.E.: Microengineered physiological biomimicry: organs-on-chips. Lab. Chip. 12, 2156-2164 (2012). doi:10.1039/c2lc40089h
28. Kwak, B., Ozcelikkale, A., Shin, C.S., Park, K., Han, B.: Simulation of complex transport of nanoparticles around a tumor using tumor-microenvironment-on-chip. J. Control Release 194, 157-167 (2014). doi:10.1016/j.jconrel.2014.08.027
29. Lee, P.J., Hung, P.J., Lee, L.P.: An artificial liver sinusoid with a microfluidic endothelial- like barrier for primary hepatocyte culture. Biotechnol. Bioeng. 97, 1340-1346 (2007). doi:10.1002/bit.21360
30. Jang, K.-J., Mehr, A.P., Hamilton, G.A., McPartlin, L.A., Chung, S., Suh, K.-Y., Ingber, D.E.: Human kidney proximal tubule-on-a-chip for drug transport and nephrotoxicity assessment. Integr. Biol. (Camb) 5, 1119-1129 (2013). doi:10.1039/c3ib40049b
31. Huh, D., Hamilton, G.A., Ingber, D.E.: From 3D cell culture to organs-on-chips. Trends Cell Biol. 21, 745-754 (2011). doi:10.1016/j.tcb.2011.09.005
32. Ghaemmaghami, A.M., Hancock, M.J., Harrington, H., Kaji, H., Khademhosseini, A.: Biomimetic tissues on a chip for drug discovery. Drug Discov. Today 17, 173-181 (2012). doi:10.1016/j.drudis.2011.10.029
33. Jiang, B., Zheng, W., Zhang, W., Jiang, X.: Organs on microfluidic chips: A mini review. Sci. China Chem. 57, 356-364 (2013). doi:10.1007/s11426-013-4971-0
34. Therriault, D., White, S.R., Lewis, J.A.: Chaotic mixing in three-dimensional microvascular networks fabricated by direct-write assembly. Nat. Mater 2, 265-271 (2003). doi:10.1038/nmat863
35. Bernard, A., Renault, J.P., Michel, B., Bosshard, H.R., Delamarche, E.: Microcontact printing of proteins. Adv. Mater. 12, 1067-1070 (2000). doi:10.1002/1521-4095(200007)12:14<1067:Aid-Adma1067>3.0.Co;2-M
36. Lee, H., Chung, M., Jeon, N.L.: Microvasculature: An essential component for organon- chip systems. MRS Bull 39, 51-59 (2014). doi:10.1557/mrs.2013.286
37. Gates, B.D., Xu, Q., Stewart, M., Ryan, D., Willson, C.G., Whitesides, G.M.: New approaches to nanofabrication: Molding, printing, and other techniques. Chem. Rev. 105, 1171-1196 (2005). doi:10.1021/cr030076o
38. Rolland, J.P., Van Dam, R.M., Schorzman, D.A., Quake, S.R., DeSimone, J.M.: Solvent-resistant photocurable "Liquid Teflon" for microfluidic device fabrication. J. Am. Chem. Soc. 126, 2322-2323 (2004). doi:10.1021/ja031657y
39. Rolland, J.P., Hagberg, E.C., Denison, G.M., Carter, K.R., De Simone, J.M.: Highresolution soft lithography: Enabling materials for nanotechnologies. Angew. Chemie. - Int. Ed. 43, 5796-5799 (2004). doi:10.1002/anie.200461122
40. Berthier, E., Young, E.W.K., Beebe, D.: Engineers are from PDMS-land, Biologists are from Polystyrenia. Lab. Chip. 12, 1224-1237 (2012). doi:10.1039/c2lc20982a
41. Bhatia, S.N., Ingber, D.E.: Microfluidic organs-on-chips. Nat. Biotechnol. 32, 760-772 (2014). doi:10.1038/nbt.2989
42. Prentice-Mott, H.V., Chang, C.-H., Mahadevan, L., Mitchison, T.J., Irimia, D., Shah, J.V.: Biased migration of confined neutrophil-like cells in asymmetric hydraulic environments. Proc. Natl. Acad. Sci. USA 110, 21006-21011 (2013). doi:10.1073/pnas.1317441110
43. Radisic, M., Deen, W., Langer, R., Vunjak-Novakovic, G.: Mathematical model of oxygen distribution in engineered cardiac tissue with parallel channel array perfused with culture medium containing oxygen carriers. Am. J. Physiol. Heart Circ. Physiol. 288, H1278-H1289 (2005). doi:10.1152/ajpheart.00787.2004
44. Cimetta, E., Cannizzaro, C., James, R., Biechele, T., Moon, R.T., Elvassore, N., Vunjak-Novakovic, G.: Microfluidic device generating stable concentration gradients for long term cell culture: application to Wnt3a regulation of β-catenin signaling. Lab. Chip. 10, 3277-3283 (2010). doi:10.1039/c0lc00033g
45. Zhao, L., Wang, Z., Fan, S., Meng, Q., Li, B., Shao, S., Wang, Q.: Chemotherapy resistance research of lung cancer based on micro-fluidic chip system with flow medium. Biomed. Microdevices 12, 325-332 (2010). doi:10.1007/s10544-009-9388-3
46. Huang, C.-W., Cheng, J.-Y., Yen, M.-H., Young, T.-H.: Electrotaxis of lung cancer cells in a multiple-electric-field chip. Biosens Bioelectron 24, 3510-3516 (2009). doi:10.1016/j.bios.2009.05.001
47. Xu, Z., Gao, Y., Hao, Y., Li, E., Wang, Y., Zhang, J., Wang, W., Gao, Z., Wang, Q.: Application of a microfluidic chip-based 3D co-culture to test drug sensitivity for individualized treatment of lung cancer. Biomaterials 34, 4109-4117 (2013). doi:10.1016/j.biomaterials.2013.02.045
48. Hou, H.-S., Tsai, H.-F., Chiu, H.-T., Cheng, J.-Y.: Simultaneous chemical and electrical stimulation on lung cancer cells using a multichannel-dual-electric-field chip. Biomicrofluidics 8, 052007 (2014). doi:10.1063/1.4896296
49. Huang, T., Jia, C.-P., Jun-Yang, Sun W.-J., Wang, W.-T., Zhang, H.-L., Cong, H., Jing, F.-X., Mao, H.-J., Jin, Q.-H., Zhang, Z., Chen, Y.-J., Li, G., Mao, G.-X., Zhao, J.-L.: Highly sensitive enumeration of circulating tumor cells in lung cancer patients using a size-based filtration microfluidic chip. Biosens Bioelectron 51, 213-218 (2014). doi:10.1016/j.bios.2013.07.044
50. Long, C., Finch, C., Esch, M., Anderson, W., Shuler, M., Hickman, J.: Design optimization of liquid-phase flow patterns for microfabricated lung on a chip. Ann. Biomed. Eng. 40, 1255-1267 (2012). doi:10.1007/s10439-012-0513-8
51. Shin, S.R., Jung, S.M., Zalabany, M., Kim, K., Zorlutuna, P., Kim, S.B., Nikkhah, M., Khabiry, M., Azize, M., Kong, J., Wan, K.T., Palacios, T., Dokmeci, M.R., Bae, H., Tang, X., Khademhosseini, A.: Carbon-nanotube-embedded hydrogel sheets for engineering cardiac constructs and bioactuators. ACS Nano 7, 2369-2380 (2013). doi:10.1021/nn305559j
52. Grosberg, A., Alford, P.W., McCain, M.L., Parker, K.K.: Ensembles of engineered cardiac tissues for physiological and pharmacological study: heart on a chip. Lab. Chip. 11, 4165-4173 (2011). doi:10.1039/c1lc20557a
53. Chiu, L.L.Y., Montgomery, M., Liang, Y., Liu, H., Radisic, M.: Perfusable branching microvessel bed for vascularization of engineered tissues. Proc. Natl. Acad. Sci. USA 109, E3414-E3423 (2012). doi:10.1073/pnas.1210580109
54. Werdich, A.A., Lima, E.A., Ivanov, B., Ges, I., Anderson, M.E., Wikswo, J.P., Baudenbacher, F.J.: A microfluidic device to confine a single cardiac myocyte in a sub-nanoliter volume on planar microelectrodes for extracellular potential recordings. Lab. Chip. 4, 357-362 (2004). doi:10.1039/b315648f
55. Cheng, W., Klauke, N., Sedgwick, H., Smith, G.L., Cooper, J.M.: Metabolic monitoring of the electrically stimulated single heart cell within a microfluidic platform. Lab. Chip. 6, 1424-1431 (2006). doi:10.1039/b608202e
56. Ohashi, K., Yokoyama, T., Yamato, M., Kuge, H., Kanehiro, H., Tsutsumi, M., Amanuma, T., Iwata, H., Yang, J., Okano, T., Nakajima, Y.: Engineering functional two- and three-dimensional liver systems in vivo using hepatic tissue sheets. Nat. Med. 13, 880-885 (2007). doi:10.1038/nm1576
57. Lee, S.-A., No, D.Y., Kang, E., Ju, J., Kim, D.-S., Lee, S.-H.: Spheroid-based three-dimensional liver-on-a-chip to investigate hepatocyte-hepatic stellate cell interactions and flow effects. Lab. Chip. 13, 3529-3537 (2013). doi:10.1039/c3lc50197c
58. Domansky, K., Inman, W., Serdy, J., Dash, A., Lim, M.H.M., Griffith, L.G.: Perfused multiwell plate for 3D liver tissue engineering. Lab. Chip. 10, 51-58 (2010). doi:10.1039/b913221j
59. Toh, Y.-C., Lim, T.C., Tai, D., Xiao, G., van Noort, D., Yu, H.: A microfluidic 3D hepatocyte chip for drug toxicity testing. Lab. Chip. 9, 2026-2035 (2009). doi:10.1039/b900912d
60. Toh, Y.-C., Zhang, C., Zhang, J., Khong, Y.M., Chang, S., Samper, V.D., van Noort, D., Hutmacher, D.W., Yu, H.: A novel 3D mammalian cell perfusion-culture system in microfluidic channels. Lab. Chip. 7, 302-309 (2007). doi:10.1039/b614872g
61. Goral, V.N., Hsieh, Y.-C., Petzold, O.N., Clark, J.S., Yuen, P.K., Faris, R.A.: Perfusion-based microfluidic device for three-dimensional dynamic primary human hepatocyte cell culture in the absence of biological or synthetic matrices or coagulants. Lab. Chip. 10, 3380-3386 (2010). doi:10.1039/c0lc00135j
62. Lee, J., Kim, S.H., Kim, Y.C., Choi, I., Sung, J.H.: Fabrication and characterization of microfluidic liver-on-a-chip using microsomal enzymes. Enzyme. Microb. Technol. 53, 159-164 (2013). doi:10.1016/j.enzmictec.2013.02.015
63. Srigunapalan, S., Lam, C., Wheeler, A.R., Simmons, C.A.: A microfluidic membrane device to mimic critical components of the vascular microenvironment. Biomicrofluidics 5, 13409 (2011). doi:10.1063/1.3530598
64. Zheng, W., Jiang, B., Wang, D., Zhang, W., Wang, Z., Jiang, X.: A microfluidic flowstretch chip for investigating blood vessel biomechanics. Lab. Chip. 12, 3441-3450 (2012). doi:10.1039/c2lc40173h
65. Yeon, J.H., Ryu, H.R., Chung, M., Hu, Q.P., Jeon, N.L.: In vitro formation and characterization of a perfusable three-dimensional tubular capillary network in microfluidic devices. Lab. Chip. 12, 2815 (2012). doi:10.1039/c2lc40131b
66. Kim, S., Lee, H., Chung, M., Jeon, N.L.: Engineering of functional, perfusable 3D microvascular networks on a chip. Lab. Chip. 13, 1489-1500 (2013). doi:10.1039/c3lc41320a
67. Kusunose, J., Zhang, H., Gagnon, M.K.J., Pan, T., Simon, S.I., Ferrara, K.W.: Microfluidic system for facilitated quantification of nanoparticle accumulation to cells under laminar flow. Ann. Biomed. Eng. 41, 89-99 (2013). doi:10.1007/s10439-012-0634-0
68. Korin, N., Kanapathipillai, M., Matthews, B.D., Crescente, M., Brill, A., Mammoto, T., Ghosh, K., Jurek, S., Bencherif, S.A., Bhatta, D., Coskun, A.U., Feldman, C.L., Wagner, D.D., Ingber, D.E.: Shear-activated nanotherapeutics for drug targeting to obstructed blood vessels. Science 337, 738-742 (2012). doi:10.1126/science.1217815
69. Kim, D., Finkenstaedt-Quinn, S., Hurley, K.R., Buchman, J.T., Haynes, C.L.: On-chip evaluation of platelet adhesion and aggregation upon exposure to mesoporous silica nanoparticles. Analyst 139, 906-913 (2014). doi:10.1039/c3an01679j
70. Rosano, J.M., Tousi, N., Scott, R.C., Krynska, B., Rizzo, V., Prabhakarpandian, B., Pant, K., Sundaram, S., Kiani, M.F.: A physiologically realistic in vitro model of microvascular networks. Biomed. Microdevices 11, 1051-1057 (2009). doi:10.1007/s10544-009-9322-8
71. Namdee, K., Thompson, A.J., Charoenphol, P., Eniola-Adefeso, O.: Margination propensity of vascular-targeted spheres from blood flow in a microfluidic model of human microvessels. Langmuir 29, 2530-2535 (2013). doi:10.1021/la304746p
72. Samuel, S.P., Jain, N., O'Dowd, F., Paul, T., Kashanin, D., Gerard, V.A., Gun'ko, Y.K., Prina-Mello, A., Volkov, Y.: Multifactorial determinants that govern nanoparticle uptake by human endothelial cells under flow. Int. J. Nanomedicine 7, 2943-2956 (2012). doi:10.2147/IJN.S30624
73. Lamberti, G., Tang, Y., Prabhakarpandian, B., Wang, Y., Pant, K., Kiani, M.F., Wang, B.: Adhesive interaction of functionalized particles and endothelium in idealized microvascular networks. Microvasc. Res. 89, 107-114 (2013). doi:10.1016/j.mvr.2013.03.007
74. Tesfamariam, B., DeFelice, A.F.: Endothelial injury in the initiation and progression of vascular disorders. Vascul. Pharmacol. 46, 229-237 (2007). doi:10.1016/j.vph.2006.11.005
75. Li, Y.-S.J., Haga, J.H., Chien, S.: Molecular basis of the effects of shear stress on vascular endothelial cells. J. Biomech. 38, 1949-1971 (2005). doi:10.1016/j.jbiomech.2004.09.030
76. Zervantonakis, I.K., Kothapalli, C.R., Chung, S., Sudo, R., Kamm, R.D.: Microfluidic devices for studying heterotypic cell-cell interactions and tissue specimen cultures under controlled microenvironments. Biomicrofluidics 5, 13406 (2011). doi:10.1063/1.3553237
77. Hyun, K.-A., Lee, T.Y., Jung, H.-I.: Negative enrichment of circulating tumor cells using a geometrically activated surface interaction chip. Anal. Chem. 85, 4439-4445 (2013). doi:10.1021/ac3037766
78. Li, P., Stratton, Z.S., Dao, M., Ritz, J., Huang, T.J.: Probing circulating tumor cells in microfluidics. Lab. Chip. 13, 602-609 (2013). doi:10.1039/c2lc90148j
79. Yamamura, S., Yatsushiro, S., Abe, K., Baba, Y., Kataoka, M.: Development of a cell microarray chip for detection of circulating tumor cells. J. Phys. Conf. Ser. 352, 012041 (2012). doi:10.1088/1742-6596/352/1/012041
80. Alshareef, M., Metrakos, N., Juarez Perez, E., Azer, F., Yang, F., Yang, X., Wang, G.:Separation of tumor cells with dielectrophoresis-based microfluidic chip. Biomicrofluidics 7, 11803 (2013). doi:10.1063/1.4774312
81. Sun, D., Lu, J., Chen, Z., Yu, Y., Li, Y.: A novel three-dimensional microfluidic platform for on chip multicellular tumor spheroid formation and culture. Microfluid Nanofluidics 17, 831-842 (2014). doi:10.1007/s10404-014-1373-3
82. Elliott, N.T., Yuan, F.: A microfluidic system for investigation of extravascular transport and cellular uptake of drugs in tumors. Biotechnol. Bioeng. 109, 1326-1335 (2012). doi:10.1002/bit.24397
83. Tan, J., Shah, S., Thomas, A., Ou-Yang, H.D., Liu, Y.: The influence of size, shape and vessel geometry on nanoparticle distribution. Microfluid Nanofluidics 14, 77-87 (2013). doi:10.1007/s10404-012-1024-5
84. Vidi, P.-A., Maleki, T., Ochoa, M., Wang, L., Clark, S.M., Leary, J.F., Lelièvre, S.A.:Disease-on-a-chip: mimicry of tumor growth in mammary ducts. Lab. Chip. 14, 172-177 (2014). doi:10.1039/c3lc50819f
85. Duque-Muñoz, L., Aguirre-Echeverry, C.A., Castellanos-Domínguez, G.: EEG rhythm analysis using stochastic relevance. IFMBE Proc. 41, 658-661 (2014). doi:10.1007/978-3-319-00846-2
86. Rigat-Brugarolas, L.G., Elizalde-Torrent, A., Bernabeu, M., De Niz, M., Martin-Jaular, L., Fernandez-Becerra, C., Homs-Corbera, A., Samitier, J., del Portillo, H.A.: A functional microengineered model of the human splenon-on-a-chip. Lab. Chip. 14, 1715-1724 (2014). doi:10.1039/c3lc51449h
87. Grafton, M.M.G., Wang, L., Vidi, P.-A., Leary, J., Lelièvre, S.A.: Breast on-a-chip:mimicry of the channeling system of the breast for development of theranostics. Integr. Biol. (Camb) 3, 451-459 (2011). doi:10.1039/c0ib00132e
88. Yang, X., Mironov, V., Wang, Q.: Modeling fusion of cellular aggregates in biofabrication using phase field theories. J. Theor. Biol. 303, 110-118 (2012). doi:10.1016/j.jtbi.2012.03.003
89. Yang, X., Sun, Y., Wang, Q.: A phase field approach for multicellular aggregate fusion in biofabrication. J. Biomech. Eng. 135, 71005 (2013). doi:10.1115/1.4024139
90. Thomas, G.L., Mironov, V., Nagy-Mehez, A., Mombach, J.C.M.: Dynamics of cell aggregates fusion: Experiments and simulations. Phys. A Stat. Mech. its Appl. 395, 247-254 (2014). doi:10.1016/j.physa.2013.10.037
91. Ki, C.S., Lin, T.-Y., Korc, M., Lin, C.-C.: Thiol-ene hydrogels as desmoplasiamimetic matrices for modeling pancreatic cancer cell growth, invasion, and drug resistance. Biomaterials 35, 9668-9677 (2014). doi:10.1016/j.biomaterials.2014.08.014
92. Abdulla, T, Imms, RA, Schleich, J-M, Summers, R: Towards multiscale systems modeling of endocardial to mesenchymal transition. In: Conf Proc. Annu Int Conf IEEE Eng Med Biol Soc IEEE Eng Med Biol Soc Annu Conf 2011, pp. 449-52 (2011). doi:10.1109/IEMBS.2011.6090062