Abstract Organ-on-a-chip is an emerging in vitro biological model with great prospects in biomedical researches. However, its development is often limited by the cumbersome and expensive fabrication process. Recently, researchers have adopted 3D printing technology into the fabrication and therefore made this process simpler and less expensive. Besides, this strategy also increased the complexity of chip structure and allowed the one-step fabrication. 3D printing technology has strongly promoted organ-on-a-chip related researches and contributed to its wide application. This paper reviewed the research status of 3D printing technology in the fabrication of organ-on-a-chip, including the development background of organ-on-a-chip, limitations of traditional fabrication methods, the technical classification and biomedical applications of 3D printing technology.Five 3D printing methods were listed based on different forming principles, and their characteristics and applications in chip fabrication were compared as well. Besides, the applications of 3D printing technology in the construction of liver, kidney, blood vessel, heart and other organs-on-chips were also discussed. Finally, we concluded with our thoughts on the challenges and future perspectives of this technology.
Liu Yan,Yang Qingzhen,Chen Xiaoming, et al. Fabrication of Organ-on-a-Chip by 3D Printing Technology[J]. Chinese Journal of Biomedical Engineering, 2020, 39(1): 97-108.
[1] Occhetta P, Isu G, Lemme M, et al. A three-dimensional in vitro dynamic micro-tissue model of cardiac scar formation[J]. Integrative Biology, 2018, 10(3):174-183.
[2] Mazio C, Casale C, Imparato G, et al. Recapitulating spatiotemporal tumor heterogeneity in vitro through engineered breast cancer microtissues[J]. Acta Biomaterialia, 2018, 73:236-249.
[3] Verheijen M, Schrooders Y, Gmuender H, et al. Bringing in vitro analysis closer to in vivo: Studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling[J]. Toxicology Letters, 2018, 294:184-192.
[4] Jang J, Yi HG, Cho DW. 3D printed tissue models: Present and future[J]. ACS Biomaterials Science & Engineering, 2016, 2(10), 1722-1731.
[5] Yi HG, Lee H, Cho DW. 3D Printing of organs-on-chips[J]. Bioengineering, 2017, 4(1):e10
[6] Huh D, Kim HJ, Fraser JP, et al. Microfabrication of human organs-on-chips[J]. Nature Protocols, 2013, 8:2135-2157
[7] Bein A, Shin W, Jalili-Firoozinezhad S, et al. Microfluidic organ-on-a-chip models of human intestine[J]. Cellular and Molecular Gastroenterology and Hepatology, 2018, 5(4):659-668.
[8] Seder I, Kim DM, Hwang SH, et al. Microfluidic chip with movable layers for the manipulation of biochemicals[J]. Lab on a Chip, 2018, 18(13):1867-1874
[9] Bhatia SN, Ingber DE. Microfluidic organs-on-chips[J]. Nature Biotechnology, 2014, 32(8):760-772.
[10] Shin JS, Oh SY, Park H, et al. Laser cutting of steel plates up to 100 mm in thickness with a 6-kW fiber laser for application to dismantling of nuclear facilities[J]. Optics & Lasers in Engineering, 2018, 100:98-104.
[11] Martynova L, Locascio LE, Gaitan M, et al. Fabrication of plastic microfluid channels by imprinting methods[J]. Analytical Chemistry, 1997, 69(23):4783-4789.
[12] Wang Jilei, Wang Xiaogong, He Yaning. Fabrication of fluorescent surface relief patterns using AIE polymer through a soft lithographic approach[J]. Journal of Polymer Science Part B: Polymer Physics, 2016, 54, 1838-1845.
[13] Yashiro M, Tsushima H, Ohta T, et al. Excimer laser gas usage reduction technology for semiconductor manufacturing[C]// SPIE Advanced Lithography. San Jose: SPIE, 2017: e10147.
[14] Amin N, Thies W, Amarasinghe S. Computer-aided design for microfluidic chips based on multilayer soft lithography[C]// IEEE International Conference on Computer Design. Lake Tahoe: IEEE, 2009: 2-9.
[15] Madic′ M, Antucheviciene J, Radovanovic′ M, et al. Determination of laser cutting process conditions using the preference selection index method[J]. Optics & Laser Technology, 2017, 89:214-220.
[16] Werb ZJC. ECM and cell surface proteolysis: Regulating cellular ecology[J]. Cell, 1997, 91(4):439-442.
[17] Wang Bo, Li Wuwei, Dean D, et al. Enhanced hepatogenic differentiation of bone marrow derived mesenchymal stem cells on liver ECM hydrogel[J]. Journal of Biomedical Materials Research Part A, 2017, 106(3):829-838
[18] Yang Qingzhen, Lian Qin, Xu Feng. Perspective: Fabrication of integrated organ-on-a-chip via bioprinting[J]. Biomicrofluidics, 2017, 11(3):e031301.
[19] Cui Shaoyan, Liu Yaoping, Wang Wei, et al. A microfluidic chip for highly efficient cell capturing and pairing[J]. Biomicrofluidics, 2011, 5(3):e032003
[20] Yi WDT, Panda B, Paul SC, et al. 3D printing trends in building and construction industry: A review[J]. Virtual & Physical Prototyping, 2017, 12(3):1-16.
[21] Liu Jie, Dong Guanping, Fan Yanbin. Personalized ring design and rapid manufacturing based on reverse engineering and 3D printing[J]. Applied Mechanics and Materials, 2016, 851:599-602.
[22] 成思源,周小东,杨雪荣,等. 基于数字化逆向建模的3D打印实验教学 [J].实验技术与管理, 2015, 32(1):30-33.
[23] Joshi SC, Sheikh AA, Prototyping P. 3D printing in aerospace and its long-term sustainability[J]. Virtual and Physical Prototyping, 2015, 10(4):175-185.
[24] Hockaday LA, Kang KH, Colangelo NW, et al. Rapid 3D printing of anatomically accurate and mechanically heterogeneous aortic valve hydrogel scaffolds[J]. Rapid 3D printing of anatomically accurate and mechanically heterogeneous aortic valve hydrogel scaffolds[J]. Biofabrication, 2012, 4(3):e035005.
[25] Grix T, Ruppelt A, Thomas A, et al. Bioprinting perfusion-enabled liver equivalents for advanced organ-on-a-chip applications[J]. Genes, 2018, 9(4):e176.
[26] Moya A, Ortegaribera M, Guimerà X, et al. Online oxygen monitoring using integrated inkjet-printed sensors in a liver-on-a-chip system[J]. Lab on a Chip, 2018, 18(14):2023-2035.
[27] Lee SJ, Lee HJ, Kim SY, et al. In situ gold nanoparticle growth on polydopamine-coated 3D-printed scaffolds improves osteogenic differentiation for bone tissue engineering applications: in vitro and in vivo studies[J]. Nanoscale, 2018, 10(33):15447-15453.
[28] He Yong, Qiu Jinjiang, Fu Jianzhong, et al. Printing 3D microfluidic chips with a 3D sugar printer[J]. Microfluidics and Nanofluidics, 2015, 19(2): 447-456.
[29] Nguyen DG, Funk J, Robbins JB, et al. Bioprinted 3D primary liver tissues allow assessment of organ-level response to clinical drug induced toxicity in vitro[J]. PLoS ONE, 2016, 11(7):e0158674.
[30] King SM, Presnell SC, Nguyen DG. Abstract 2034: Development of 3D bioprinted human breast cancer for in vitro drug screening[J]. AACR Annual Meeting, 2014, 74:e2034.
[31] Kang Donggu, Ahn G, Kim D, et al. Pre-set extrusion bioprinting for multiscale heterogeneous tissue structure fabrication[J]. Biofabrication, 2018, 10(3):e035008.
[32] Therriault D, White SR, Lewis JA. Chaotic mixing in three-dimensional microvascular networks fabricated by direct-write assembly[J]. Nature Materials, 2003, 2(4):265-271.
[33] Rutz AL, Hyland KE, Jakus AE, et al. A multimaterial bioink method for 3D printing tunable, cell-compatible hydrogels[J]. Advanced Materials, 2015, 27(9):1607-1614.
[34] Lind JU, Busbee TA, Valentine AD, et al. Instrumented cardiac microphysiological devices via multimaterial three-dimensional printing[J]. Nature Materials, 2017, 16(3):303-308.
[35] Lee H, Cho DW. One-step fabrication of an organ-on-a-chip with spatial heterogeneity using a 3D bioprinting technology[J]. Lab on a Chip, 2016, 16(14):2618-2625.
[36] Dehurtevent M, Robberecht L, Hornez JC, et al. Stereolithography: A new method for processing dental ceramics by additive computer-aided manufacturing[J]. Dental Materials, 2017, 33(5):477-485.
[37] Hribar KC, Finlay D, Ma X, et al. Nonlinear 3D projection printing of concave hydrogel microstructures for long-term multicellular spheroid and embryoid body culture[J]. Lab on a Chip, 2015, 15(11):2412-2418.
[38] Yi Lu, Mapili G, Suhali G, et al. A digital micro-mirror device-based system for the microfabrication of complex, spatially patterned tissue engineering scaffolds[J]. Journal of Biomedical Materials Research Part A, 2010, 77A(2):396-405.
[39] Tumbleston JR, Shirvanyants D, Ermoshkin N, et al. Additive manufacturing. Continuous liquid interface production of 3D objects[J]. Science, 2015, 347(6228):1349-1352.
[40] Lin Xuancheng, Liu Huagang. Continuous liquid interface production 3D printing technology and its application in fabrication of architecture models[J]. Acta Optica Sinica, 2016, 36(8):e0816002.
[41] Au AK, Lee W, Folch A. Mail-order microfluidics: evaluation of stereolithography for the production of microfluidic devices[J]. Lab on a Chip, 2014, 14(7):1294-1301.
[42] Urrios A, Parra-Cabrera C, Bhattacharjee N, et al. 3D-printing of transparent bio-microfluidic devices in PEG-DA[J]. Lab on a Chip, 2016, 16(12):2287-2294.
[43] Grix T, Ruppelt A, Thomas A, et al. Bioprinting perfusion-enabled liver equivalents for advanced organ-on-a-chip applications[J]. Genes, 2018, 9(4):e176.
[44] Heo DN, Lee SJ, Timsina R, et al. Development of 3D printable conductive hydrogel with crystallized PEDOT:PSS for neural tissue engineering[J]. Materials Science and Engineering C, 2019, 99:582-590.
[45] Giustina GD, Gandin A, Brigo L, et al. Polysaccharide hydrogels for multiscale 3D printing of pullulan scaffolds[J]. Materials & Design, 2019, 165:e107566.
[46] Gong Hua, Beauchamp M, Perry S, et al. Optical approach to resin formulation for 3D printed microfluidics[J]. Royal Society of Chemistry, 2015, 5(129):106621-106632.
[47] Salentijn GI, Oomen PE, Grajewski M, et al. Fused deposition modeling 3D printing for (bio)analytical device fabrication: Procedures, materials, and applications[J]. Analytical Chemistry, 2017, 89(13):7053-7061.
[48] Morgan AJ, Hidalgo SJ, Jamieson WD, et al. Simple and versatile 3D printed microfluidics using fused filament fabrication[J]. PLoS ONE, 2016, 11(4):e0152023.
[49] Kuo CC, Mao Ruicheng. Development of a precision surface polishing system for parts fabricated by fused deposition modeling[J]. Advanced Manufacturing Processes, 2016, 31(8), 1113-1118.
[50] Kador K, Grogan P, Erik W, et al. Control of retinal ganglion cell positioning and neurite growth: combining 3D Printing with radial electrospun scaffolds[J]. Tissue Engineering Part A, 2016, 22(3-4):286-294.
[51] Christensen K, Xu Chen, Chai W, et al. Freeform inkjet printing of cellular structures with bifurcations[J]. Biotechnology & Bioengineering, 2015, 112(5):1047-1055.
[52] Cheng E, Yu Haoran, Ahmadi A, et al. Investigation of the hydrodynamic response of cells in drop on demand piezoelectric inkjet nozzles[J]. Biofabrication, 2016, 8(1):e015008.
[53] Das S, Pati F, Choi YJ, et al. Bioprintable, cell-laden silk fibroin-gelatin hydrogel supporting multilineage differentiation of stem cells for fabrication of three-dimensional tissue constructs[J]. Acta Biomaterialia, 2015, 11:233-246.
[54] Malda J, Visser J, Melchels FP, et al. 25th anniversary article: Engineering hydrogels for biofabrication[J]. Advanced Materials, 2013, 25(36):5011-5028.
[55] Pepper ME, Parzel CA, Burg T, et al. Design and implementation of a two-dimensional inkjet bioprinter[C]// International Conference of the IEEE Engineering in Medicine & Biology Society. Minneapolis: IEEE, 2009: 6001-6005.
[56] Matsusaki M, Sakaue K, Kadowaki K, et al. Three-dimensional human tissue chips fabricated by rapid and automatic inkjet cell printing[J]. Advanced Healthcare Marerials, 2013, 2(4):534-539.
[57] Moya A, Ortega-Ribera M, Guimerà X, et al. Online oxygen monitoring using integrated inkjet-printed sensors in a liver-on-a-chip system[J]. Lab on a Chip, 2018, 18(14):2023-2035.
[58] Bonyár A, Sántha H, Ring B, et al. 3D rapid prototyping technology (RPT) as a powerful tool in microfluidic development[J]. Procedia Engineering, 2010, 5:291-294.
[59] Zheng Sijia, Zlatin M, Selvaganapathy PR, et al. Multiple modulus silicone elastomers using 3D extrusion printing of low viscosity inks[J]. Additive Manufacturing, 2018, 24:86-92.
[60] Tweed CD, Wills GH, Crook AM, et al. Liver toxicity associated with tuberculosis chemotherapy in the REMoxTB study[J]. BMC Medicine, 2018, 16(1):e46.
[61] Yu Shua, Liu Fangfang, Wang Chen, et al. Role of oxidative stress in liver toxicity induced by nickel oxide nanoparticles in rats[J]. Molecular Medicine Reports, 2018, 17(2):3133-3139.
[62] Bhise NS, Manoharan V, Massa S, et al. A liver-on-a-chip platform with bioprinted hepatic spheroids[J]. Biofabrication, 2016, 8(1):e014101.
[63] Bertassoni LE, Cardoso JC, Manoharan V, et al. Direct-write bioprinting of cell-laden methacrylated gelatin hydrogels[J]. Biofabrication, 2014, 6(2):e024105.
[64] Illa X, Vila S, Yeste J, et al. A Novel Modular Bioreactor to In Vitro Study the Hepatic Sinusoid[J]. PLoS ONE, 2014, 9(11):e111864.
[65] Ho CT, Lin RZ, Chang Wenyu, et al. Rapid heterogeneous liver-cell on-chip patterning via the enhanced field-induced dielectrophoresis trap[J]. Lab on a Chip, 2006, 6(6):724-734.
[66] Hegde M, Jindal R, Bhushan A, et al. Dynamic interplay of flow and collagen stabilizes primary hepatocytes culture in a microfluidic platform[J]. Lab on a Chip, 2014, 14(12):2033-2039.
[67] Lee D, Levin A, Kiess M, et al. Chronic kidney damage in the adult Fontan population[J]. International Journal of Cardiology, 2018, 257:62-66.
[68] Enoc MG, Utiel FJB, Ángeles MA, et al. Kidney damage due to the use of anabolic androgenic steroides and practice of bodybuilding[J]. Nefrologia Publicacion, 2018, 38(1):101-103.
[69] Homan KA, Kolesky DB, Skylar-Scott MA, et al. Bioprinting of 3D convoluted renal proximal tubules on perfusable chips[J]. Scientific Reports, 2016, 6(1):e34845.
[70] Huang HC, Chang YJ, Chen WC, et al. Enhancement of renal epithelial cell functions through microfluidic-based coculture with adipose-derived stem cells[J]. Tissue Engineering Part A,2013, 19(17-18):2024-2034.
[71] Zhou Mengying, Ma Huipeng, Lin Hongli, et al. Induction of epithelial-to-mesenchymal transition in proximal tubular epithelial cells on microfluidic devices[J]. Biomaterials,2014, 35(5):1390-1401.
[72] Frohlich EM, Zhang Xin,Charest JL. The use of controlled surface topography and flow-induced shear stress to influence renal epithelial cell function[J]. Integrative Biology, 2012, 4(1):75-83.
[73] Sochol RD, Gupta NR, Bonventre JV. A role for 3D printing in kidney-on-a-chip platforms[J]. Current Transplantation Reports, 2016, 3(1):82-92.
[74] Cochrane A, Albers HJ, Passier R, et al. Advanced in vitro models of vascular biology: Human induced pluripotent stem cells and organ-on-chip technology[J]. Advanced Drug Delivary Reviews. 2019, 140:68-77.
[75] Raven JA. Evolution and palaeophysiology of the vascular system and other means of long-distance transport[J]. Philosophical Transactions of the Royal Society of London, 2018, 373(1739):e20160497.
[76] Chiara G. The primo vascular system as a possible exosomal route across the body: Implications for tumor proliferation and metastasis[J]. Journal of Acupuncture and Meridian Studies, 2019, 12(1):25-28.
[77] Miller JS, Stevens KR, Yang MT, et al. Rapid casting of patterned vascular networks for perfusable engineered three-dimensional tissues[J]. Nature Materials, 2012, 11(9):768-774.
[78] Kolesky DB, Homan KA, Skylar-Scott MA, et al. Three-dimensional bioprinting of thick vascularized tissues[J]. Proceedings of the National Academy of Sciences, 2016, 113(12):3179-3184.
[79] Massa S, Sakr MA, Seo J, et al. Bioprinted 3D vascularized tissue model for drug toxicity analysis[J]. Biomaterials, 2014, 35(28):8092-8102.
[80] Mayourian J, Ceholski DK, Gorski P, et al. Exosomal microRNA-21-5p mediates mesenchymal stem cell paracrine effects on human cardiac tissue contractility[J]. Circulation Research, 2018, 2(7):933-944.
[81] Wang Zhan, Lee S J, Cheng Hengjie, et al. 3D bioprinted functional and contractile cardiac tissue constructs[J]. Acta Biomaterialia, 2018, 70:48-56.
[82] Zhang YS, Arneri A, Bersini S, et al. Bioprinting 3D microfibrous scaffolds for engineering endothelialized myocardium and heart-on-a-chip[J]. Biomaterials, 2016, 110:45-59.
[83] Ash C. From stomach ache to depression[J]. Science, 2017, 357(6349):366-368.
[84] Yoon SW, Webby RJ, Webster RG, et al. Evolution and ecology of influenza A viruses[J]. Current Topics in Microbiology and Immunology, 2014, 385:359-375.
[85] Skardal A, Murphy SV, Devarasetty M, et al. Multi-tissue interactions in an integrated three-tissue organ-on-a-chip platform[J]. Scientific Reports, 2017, 7(1):e8837.
[86] Urrios A, Parra-Cabrera C, Bhattacharjee N, et al. 3D-printing of transparent bio-microfluidic devices in PEG-DA[J]. Lab on a Chip, 2016, 16(12):2287-2294.
[87] Xu Tao, Zhao Weixin, Zhu Jianming, et al. Complex heterogeneous tissue constructs containing multiple cell types prepared by inkjet printing technology[J]. Biomaterials, 2013, 34(1):130-139.
[88] Chang CC, Boland E, Williams S, et al, Direct-write bioprinting three-dimensional biohybrid systems for future regenerative therapies[J]. Journal of Biomedical Materials Research Part B Applied Biomaterials, 2011, 98B(1):160-170.
[89] Faurie J, Baudet M, Porée J, et al. Coupling myocardium and vortex dynamics in diverging-wave echocardiography[J]. IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control, 2019,66(3):425-432.
[90] Bavrina AP, Monich VA, Malinovskaya SL, et al. Influence of low-intensive red light on the myocardium in experimental asphyxia[J]. Bulletin of Experimental Biology and Medicine, 2018, 165(3):322-324.
[91] Kai D, Prabhakaran MP, Jin G, et al. Guided orientation of cardiomyocytes on electrospun aligned nanofibers for cardiac tissue engineering[J]. Journal of Biomedical Materials Research Part B Applied Biomaterials, 2011, 98B(2):379-386.
[92] Lane JD, Montaigne D, Tinker A. Tissue-level cardiac electrophysiology studied in murine myocardium using a microelectrode array: Autonomic and thermal modulation[J]. The Journal of Membrane Biology, 2017, 250(5):471-481.
[93] Lee H, Kim DS, Ha SG, et al. A pumpless multi-organ-on-a-chip (MOC) combined with a pharmacokinetic-pharmacodynamic (PK-PD) model[J]. Biotechnology and Bioengineering, 2016, 114(2):432-443.
[94] Satoh T, Sugiura S, Shin K, et al. A multi-throughput multi-organ-on-a-chip system on a plate formatted pneumatic pressure-driven medium circulation platform[J]. Lab on a Chip, 2017, 18(1):115-125.
[95] Xue Weimin, Liu Xiaoli, Ma Heping, et al. AMF responsive DOX-loaded magnetic microspheres: Transmembrane drug release mechanism and multimodality postsurgical treatment of breast cancer[J]. Journal of Materials Chemistry B, 2018, 6, 2289-2303.
[96] Zhang YS. Modular multi-organ-on-chips platform with physicochemical sensor integration[C]//IEEE 60th International Midwest Symposium on Circuits and Systems. Boston: IEEE, 2017: 80-83.
