AccScience Publishing / IJB / Volume 11 / Issue 6 / DOI: 10.36922/IJB025320314
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REVIEW ARTICLE

3D bioprinting–microfluidics technology: Pioneering advances in tumor microenvironment modeling, cancer treatment optimization, and diagnostic biomarker discovery

Wang Wang1† Zhicheng Zhang1† Yang Yu1† Yikang Wang1† Kai Ni1*
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1 Department of Urology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
†These authors contributed equally to this work.
IJB 2025, 11(6), 23–50; https://doi.org/10.36922/IJB025320314
Received: 6 August 2025 | Accepted: 12 September 2025 | Published online: 17 September 2025
(This article belongs to the Special Issue 3D-Printed Biomedical Devices)
© 2025 by the Author(s).. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
Abstract

Conventional tumor models have historically failed to fully recapitulate the intricate pathophysiological complexity and dynamic microenvironment of human malignancies, significantly limiting their translational potential. The recent convergence of microfluidic technology and 3D bioprinting has ushered in a paradigm shift in oncology research, enabling more physiologically relevant models. This review provides a comprehensive analysis of the limitations inherent in traditional tumor modeling platforms and elaborates on the fundamental principles underlying microfluidics and additive manufacturing. It systematically explores the integrated applications of 3D-bioprinting–microfluidics systems across three core domains: engineering pathomimetic tumor models, advancing therapeutic screening platforms, and developing high-sensitivity diagnostic tools. This interdisciplinary synergy allows for unprecedented spatiotemporal control over the tumor microenvironment, precise biochemical gradient formation, and seamless integration of functional biosensors. The review further discusses persistent challenges—such as material biocompatibility, fabrication scalability, and the need for standardized validation—and proposes future directions—including the development of multiorgan-on-chip systems, stimuli-responsive biomaterials, and artificial intelligence-enhanced analytical frameworks. The continued integration of 3D bioprinting and microfluidics holds transformative potential for accelerating precision oncology and improving clinical outcomes.  

Graphical abstract
Keywords
3D printing
Cancer treatment optimization
Diagnostic biomarker discovery
Microfluidic technology
Tumor microenvironment model
Funding
This work was supported by the National Natural Science Foundation of China (grant number: 82103260 to K.N.); the Shanghai Rising-Star Program (grant number: 22QA1407100 to K.N.); the Excellent Youth Cultivation Program of Shanghai Sixth People’s Hospital (grant number: ynyq202204 to K.N.); and the Fundamental Research Funds for the Shanghai Sixth People’s Hospital (grant number: X-2490 to K.N.).
Conflict of interest
The authors declare no conflict of interest.
References
  1. Day CP, Merlino G, Van Dyke T. Preclinical mouse cancer models: a maze of opportunities and challenges. Cell. 2015;163(1):39-53. doi: 10.1016/j.cell.2015.08.068
  2. Kim JW, Ho WJ, Wu BM. The role of the 3D environment in hypoxia-induced drug and apoptosis resistance. Anticancer Res. 2011;31(10):3237-3245.
  3. Loessner D, Stok KS, Lutolf MP, Hutmacher DW, Clements JA, Rizzi SC. Bioengineered 3D platform to explore cell– ECM interactions and drug resistance of epithelial ovarian cancer cells. Biomaterials. 2010;31(32):8494-8506. doi: 10.1016/j.biomaterials.2010.07.064
  4. Katt ME, Placone AL, Wong AD, Xu ZS, Searson PC. In vitro tumor models: advantages, disadvantages, variables, and selecting the right platform. Front Bioeng Biotechnol. 2016;4:12. doi: 10.3389/fbioe.2016.00012
  5. Trujillo-de Santiago G, Flores-Garza BG, Tavares-Negrete JA, et al. The tumor-on-chip: recent advances in the development of microfluidic systems to recapitulate the physiology of solid tumors. Materials. 2019;12(18):2945. doi: 10.3390/ma12182945
  6. Winters IP, Murray CW, Winslow MM. Towards quantitative and multiplexed in vivo functional cancer genomics. Nat Rev Genet. 2018;19(12):741-755. doi: 10.1038/s41576-018-0053-7
  7. Yoshida GJ. Applications of patient-derived tumor xenograft models and tumor organoids. J Hematol Oncol. 2020; 13(1):4. doi: 10.1186/s13045-019-0829-z
  8. Abdolahi S, Ghazvinian Z, Muhammadnejad S, Saleh M, Asadzadeh Aghdaei H, Baghaei K. Patient-derived xenograft (PDX) models, applications and challenges in cancer research. J Transl Med. 2022;20(1):206. doi: 10.1186/s12967-022-03405-8
  9. James Kirkpatrick C, Fuchs S, Iris Hermanns M, Peters K, Unger RE. Cell culture models of higher complexity in tissue engineering and regenerative medicine. Biomaterials. 2007;28(34):5193-5198. doi: 10.1016/j.biomaterials.2007.08.012
  10. Nolan J, Pearce OMT, Screen HRC, Knight MM, Verbruggen SW. Organ-on-a-chip and microfluidic platforms for oncology in the UK. Cancers. 2023;15(3):635. doi: 10.3390/cancers15030635
  11. Li Z, Li Q, Zhou C, et al. Organoid-on-a-chip: current challenges, trends, and future scope toward medicine. Biomicrofluidics. 2023;17(5):51505. doi: 10.1063/5.0171350
  12. Drost J, Clevers H. Organoids in cancer research. Nat Rev Cancer. 2018;18(7):407-418. doi: 10.1038/s41568-018-0007-6
  13. Xu R, Zhou X, Wang S, Trinkle C. Tumor organoid models in precision medicine and investigating cancer-stromal interactions. Pharmacol Ther. 2021;218:107668. doi: 10.1016/j.pharmthera.2020.107668
  14. Quintard C, Tubbs E, Jonsson G, et al. A microfluidic platform integrating functional vascularized organoids-on-chip. Nat Commun. 2024;15(1):1452. doi: 10.1038/s41467-024-45710-4
  15. Yu F, Hunziker W, Choudhury D. Engineering microfluidic organoid-on-a-chip platforms. Micromachines. 2019;10(3):165. doi: 10.3390/mi10030165
  16. Zhang J, Tavakoli H, Ma L, Li X, Han L, Li X. Immunotherapy discovery on tumor organoid-on-a-chip platforms that recapitulate the tumor microenvironment. Adv Drug Deliv Rev. 2022;187:114365. doi: 10.1016/j.addr.2022.114365
  17. Li C, Holman JB, Shi Z, Qiu B, Ding W. On-chip modeling of tumor evolution: advances, challenges and opportunities. Mater Today Bio. 2023;21:100724. doi: 10.1016/j.mtbio.2023.100724
  18. Shirure VS, Hughes CCW, George SC. Engineering vascularized organoid-on-a-chip models. Annu Rev Biomed Eng. 2021;23:141-167. doi: 10.1146/annurev-bioeng-090120-094330
  19. Zou Z, Lin Z, Wu C, et al. Micro-engineered organoid-on-a-chip based on mesenchymal stromal cells to predict immunotherapy responses of HCC patients. Adv Sci (Weinh). 2023;10(27):e2302640. doi: 10.1002/advs.202302640
  20. Du Y, Wang YR, Bao QY, et al. Personalized vascularized tumor organoid-on-a-chip for tumor metastasis and therapeutic targeting assessment. Adv Mater. 2025;37(6):e2412815. doi: 10.1002/adma.202412815
  21. Ayuso JM, Rehman S, Virumbrales-Munoz M, et al. Microfluidic tumor-on-a-chip model to evaluate the role of tumor environmental stress on NK cell exhaustion. Sci Adv. 2021;7(8):eabc2331. doi: 10.1126/sciadv.abc2331
  22. Gil JF, Moura CS, Silverio V, Gonçalves G, Santos HA. Cancer models on chip: paving the way to large-scale trial applications. Adv Mater. 2023;35(35):e2300692. doi: 10.1002/adma.202300692
  23. Ju M, Jin Z, Yu X, et al. Gastric cancer models developed via GelMA 3D bioprinting accurately mimic cancer hallmarks, tumor microenvironment features, and drug responses. Small. 2025;21(8):e2409321. doi: 10.1002/smll.202409321
  24. R N, Aggarwal A, Sravani AB, Mallya P, Lewis S. Organ-on-a-chip: an emerging research platform. Organogenesis. 2023;19(1):2278236. doi: 10.1080/15476278.2023.2278236
  25. Ko J, Park D, Lee S, Gumuscu B, Jeon NL. Engineering organ-on-a-chip to accelerate translational research. Micromachines. 2022;13(8):1200. doi: 10.3390/mi13081200
  26. Kimura H, Sakai Y, Fujii T. Organ/body-on-a-chip based on microfluidic technology for drug discovery. Drug Metab Pharmacokinet. 2018;33(1):43-48. doi: 10.1016/j.dmpk.2017.11.003
  27. Mehta G, Hsiao AY, Ingram M, Luker GD, Takayama S. Opportunities and challenges for use of tumor spheroids as models to test drug delivery and efficacy. J Control Release. 2012;164(2):192-204. doi: 10.1016/j.jconrel.2012.04.045
  28. El Harane S, Zidi B, El Harane N, Krause KH, Matthes T, Preynat-Seauve O. Cancer spheroids and organoids as novel tools for research and therapy: state of the art and challenges to guide precision medicine. Cells. 2023;12(7):1001. doi: 10.3390/cells12071001
  29. Li W, Zhou Z, Zhou X, et al. 3D biomimetic models to reconstitute tumor microenvironment In vitro: spheroids, organoids, and tumor-on-a-chip. Adv Healthc Mater. 2023;12(18):e2202609. doi: 10.1002/adhm.202202609
  30. Mehta V, Vilikkathala Sudhakaran S, Nellore V, Madduri S, Rath SN. 3D stem-like spheroids-on-a-chip for personalized combinatorial drug testing in oral cancer. J Nanobiotechnology. 2024;22(1):344. doi: 10.1186/s12951-024-02625-y
  31. Nayak P, Bentivoglio V, Varani M, Signore A. Three-dimensional in vitro tumor spheroid models for evaluation of anticancer therapy: recent updates. Cancers. 2023;15(19):4846. doi: 10.3390/cancers15194846
  32. Torisawa YS, Takagi A, Shiku H, Yasukawa T, Matsue T. A multicellular spheroid-based drug sensitivity test by scanning electrochemical microscopy. Oncol Rep. 2005;13(6):1107-1112. doi: 10.3892/or.13.6.1107
  33. Kelm JM, Fussenegger M. Microscale tissue engineering using gravity-enforced cell assembly. Trends Biotechnol. 2004;22(4):195-202. doi: 10.1016/j.tibtech.2004.02.002
  34. Banerjee D, Singh YP, Datta P, et al. Strategies for 3D bioprinting of spheroids: a comprehensive review. Biomaterials. 2022;291:121881. doi: 10.1016/j.biomaterials.2022.121881
  35. O’Neill PF, Ben Azouz A, Vázquez M, et al. Advances in three-dimensional rapid prototyping of microfluidic devices for biological applications. Biomicrofluidics. 2014;8(5): 52112. doi: 10.1063/1.4898632
  36. Gallegos-Martínez S, Choy-Buentello D, Pérez-Álvarez KA, et al. A 3D-printed tumor-on-chip: user-friendly platform for the culture of breast cancer spheroids and the evaluation of anti-cancer drugs. Biofabrication. 2024;16(4). doi: 10.1088/1758-5090/ad5765
  37. Auricchio F. The magic world of 3D printing. In: 2017 IEEE MTT-S International Microwave Workshop Series on Advanced Materials and Processes for RF and Thz Applications (IMWS-AMP). 2017:1-1. doi: 10.1109/IMWS-AMP.2017.8247328
  38. Dong T, Hu J, Dong Y, et al. Advanced biomedical and electronic dual-function skin patch created through microfluidic-regulated 3D bioprinting. Bioact Mater. 2024;40:261-274. doi: 10.1016/j.bioactmat.2024.06.015
  39. Joseph A, Rajendran A, Karthikeyan A, Nair BG. Implantable microfluidic device: an epoch of technology. Curr Pharm Des. 2022;28(9):679-689. doi: 10.2174/1381612827666210825114403
  40. Whitesides GM. The origins and the future of microfluidics. Nature. 2006;442(7101):368-373. doi: 10.1038/nature05058
  41. Sackmann EK, Fulton AL, Beebe DJ. The present and future role of microfluidics in biomedical research. Nature. 2014;507(7491):181-189. doi: 10.1038/nature13118
  42. Tien J, Dance YW. Microfluidic biomaterials. Adv Healthc Mater. 2021;10(4):e2001028. doi: 10.1002/adhm.202001028
  43. Bischel LL, Lee SH, Beebe DJ. A practical method for patterning lumens through ECM hydrogels via viscous finger patterning. J Lab Autom. 2012;17(2):96. doi: 10.1177/2211068211426694
  44. Zhang AP, Qu X, Soman P, et al. Rapid fabrication of complex 3D extracellular microenvironments by dynamic optical projection stereolithography. Adv Mater. 2012;24(31):4266-4270. doi: 10.1002/adma.201202024
  45. Wu W, DeConinck A, Lewis JA. Omnidirectional printing of 3D microvascular networks. Adv Mater. 2011;23(24):H178-183. doi: 10.1002/adma.201004625
  46. Gong L, Cretella A, Lin Y. Microfluidic systems for particle capture and release: a review. Biosens Bioelectron. 2023;236:115426. doi: 10.1016/j.bios.2023.115426
  47. Gharib G, Bütün İ, Muganlı Z, et al. Biomedical applications of microfluidic devices: a review. Biosensors. 2022;12(11):1023. doi: 10.3390/bios12111023
  48. Waheed S, Cabot JM, Macdonald NP, et al. 3D printed microfluidic devices: enablers and barriers. Lab Chip. 2016;16(11):1993-2013. doi: 10.1039/c6lc00284f
  49. Zhang N, Wang Z, Zhao Z, et al. 3D printing of micro-nano devices and their applications. Microsyst Nanoeng. 2025;11(1):35. doi: 10.1038/s41378-024-00812-3
  50. Logunov L, Ulesov A, Khramenkova V, et al. 3D and inkjet printing by colored mie-resonant silicon nanoparticles produced by laser ablation in liquid. Nanomaterials. 2023;13(6):965. doi: 10.3390/nano13060965
  51. Sagot M, Derkenne T, Giunchi P, et al. Functionality integration in stereolithography 3D printed microfluidics using a “print-pause-print” strategy. Lab Chip. 2024;24(14):3508-3520. doi: 10.1039/D4LC00147H
  52. Su R, Wang F, McAlpine MC. 3D printed microfluidics: advances in strategies, integration, and applications. Lab Chip. 2023;23(5):1279-1299. doi: 10.1039/D2LC01177H
  53. Groll J, Burdick JA, Cho DW, et al. A definition of bioinks and their distinction from biomaterial inks. Biofabrication. 2018;11(1):13001. doi: 10.1088/1758-5090/aaec52
  54. Coates IA, Pan W, Saccone MA, et al. High-resolution stereolithography: negative spaces enabled by control of fluid mechanics. Proc Natl Acad Sci U S A. 2024;121(37):e2405382121. doi: 10.1073/pnas.2405382121
  55. Randhawa A, Dutta SD, Ganguly K, Patel DK, Patil TV, Lim KT. Recent advances in 3D printing of photocurable polymers: types, mechanism, and tissue engineering application. Macromol Biosci. 2023;23(1):e2200278. doi: 10.1002/mabi.202200278
  56. Shahrubudin N, Koshy P, Alipal J, Kadir MHA, Lee TC. Challenges of 3D printing technology for manufacturing biomedical products: a case study of Malaysian manufacturing firms. Heliyon. 2020;6(4):e03734. doi: 10.1016/j.heliyon.2020.e03734
  57. Naderi A, Bhattacharjee N, Folch A. Digital manufacturing for microfluidics. Annu Rev Biomed Eng. 2019;21:325-364. doi: 10.1146/annurev-bioeng-092618-020341
  58. Karamzadeh V, Sohrabi-Kashani A, Shen M, Juncker D. Digital manufacturing of functional ready-to-use microfluidic systems. Adv Mater. 2023;35(47):2303867. doi: 10.1002/adma.202303867
  59. Shafique H, Karamzadeh V, Kim G, et al. High-resolution low-cost LCD 3D printing for microfluidics and organ-on-a-chip devices. Lab Chip. 2024;24(10):2774-2790. doi: 10.1039/D3LC01125A
  60. Steinberg E, Friedman R, Goldstein Y, et al. A fully 3D-printed versatile tumor-on-a-chip allows multi-drug screening and correlation with clinical outcomes for personalized medicine. Commun Biol. 2023;6(1):1-14. doi: 10.1038/s42003-023-05531-5
  61. Ong LJY, Islam A, DasGupta R, Iyer NG, Leo HL, Toh YC. A 3D printed microfluidic perfusion device for multicellular spheroid cultures. Biofabrication. 2017;9(4):045005. doi: 10.1088/1758-5090/aa8858
  62. Chen J, Liu CY, Wang X, et al. 3D printed microfluidic devices for circulating tumor cells (CTCs) isolation. Biosens Bioelectron. 2020;150:111900. doi: 10.1016/j.bios.2019.111900
  63. Wang S, Chen X, Han X, et al. A review of 3D printing technology in pharmaceutics: technology and applications, now and future. Pharmaceutics. 2023;15(2):416. doi: 10.3390/pharmaceutics15020416
  64. Han C, Zhang R, He X, et al. A digital manufactured microfluidic platform for flexible construction of 3D co-culture tumor model with spatiotemporal resolution. Biofabrication. 2024;17(1). doi: 10.1088/1758-5090/ad9636
  65. Moghimi N, Hosseini SA, Dalan AB, Mohammadrezaei D, Goldman A, Kohandel M. Controlled tumor heterogeneity in a co-culture system by 3D bio-printed tumor-on-chip model. Sci Rep. 2023;13:13648. doi: 10.1038/s41598-023-40680-x
  66. Schuster B, Junkin M, Kashaf SS, et al. Automated microfluidic platform for dynamic and combinatorial drug screening of tumor organoids. Nat Commun. 2020;11(1):5271. doi: 10.1038/s41467-020-19058-4
  67. Prince E, Kheiri S, Wang Y, et al. Microfluidic arrays of breast tumor spheroids for drug screening and personalized cancer therapies. Adv Healthc Mater. 2022;11(1):e2101085. doi: 10.1002/adhm.202101085
  68. Ayuso JM, Gong MM, Skala MC, Harari PM, Beebe DJ. Human tumor-lymphatic microfluidic model reveals differential conditioning of lymphatic vessels by breast cancer cells. Adv Healthc Mater. 2020;9(3):1900925. doi: 10.1002/adhm.201900925
  69. Mehta P, Rahman Z, Ten Dijke P, Boukany PE. Microfluidics meets 3D cancer cell migration. Trends Cancer. 2022;8(8):683-697. doi: 10.1016/j.trecan.2022.03.006
  70. Morshed A, Dutta P. Hypoxic behavior in cells under controlled microfluidic environment. Biochim Biophys Acta Gen Subj. 2017;1861(4):759-771. doi: 10.1016/j.bbagen.2017.01.017
  71. Ao Z, Cai H, Wu Z, et al. Evaluation of cancer immunotherapy using mini-tumor chips. Theranostics. 2022;12(8):3628-3636. doi: 10.7150/thno.71761
  72. Ruzycka M, Cimpan MR, Rios-Mondragon I, Grudzinski IP. Microfluidics for studying metastatic patterns of lung cancer. J Nanobiotechnology. 2019;17(1):71. doi: 10.1186/s12951-019-0492-0
  73. Behroodi E, Latifi H, Bagheri Z, Ermis E, Roshani S, Salehi Moghaddam M. A combined 3D printing/ CNC micro-milling method to fabricate a large-scale microfluidic device with the small size 3D architectures: an application for tumor spheroid production. Sci Rep. 2020; 10(1):22171. doi: 10.1038/s41598-020-79015-5
  74. Silvani G, Bradbury P, Basirun C, et al. Testing 3D printed biological platform for advancing simulated microgravity and space mechanobiology research. NPJ Microgravity. 2022;8(1):19. doi: 10.1038/s41526-022-00207-6
  75. Jubelin C, Muñoz-Garcia J, Griscom L, et al. Three-dimensional in vitro culture models in oncology research. Cell Biosci. 2022;12(1):155. doi: 10.1186/s13578-022-00887-3
  76. Vitale S, Calapà F, Colonna F, et al. Advancements in 3D in vitro models for colorectal cancer. Adv Sci. 2024;11(32):2405084. doi: 10.1002/advs.202405084
  77. Yi HG. Introduction to bioprinting of in vitro cancer models. Essays Biochem. 2021;65(3):603-610. doi: 10.1042/EBC20200104
  78. Yang R, Zhan M, Shen S, et al. Microfluidic synthesis of carrier-free full-active metal-phenolic nanocapsules for tumor chemo-chemodynamic-immune therapy. Adv Funct Mater. 2025;35(11):2417070. doi: 10.1002/adfm.202417070
  79. Sontheimer-Phelps A, Hassell BA, Ingber DE. Modelling cancer in microfluidic human organs-on-chips. Nat Rev Cancer. 2019;19(2):65-81. doi: 10.1038/s41568-018-0104-6
  80. Yang R, Ouyang Z, Guo H, et al. Microfluidic synthesis of intelligent nanoclusters of ultrasmall iron oxide nanoparticles with improved tumor microenvironment regulation for dynamic MR imaging-guided tumor photothermo-chemo-chemodynamic therapy. Nano Today. 2022; 46:101615. doi: 10.1016/j.nantod.2022.101615
  81. Oh HJ, Kim J, Kim H, Choi N, Chung S. Microfluidic reconstitution of tumor microenvironment for nanomedical applications. Adv Healthc Mater. 2021;10(9): 2002122. doi: 10.1002/adhm.202002122
  82. Lim W, Park S. A microfluidic spheroid culture device with a concentration gradient generator for high-throughput screening of drug efficacy. Molecules. 2018;23(12):3355. doi: 10.3390/molecules23123355
  83. Komar ZM, van Gent DC, Chakrabarty S. Establishing a microfluidic tumor slice culture platform to study drug response. Curr Protoc. 2023;3(3):e693. doi: 10.1002/cpz1.693
  84. Du Z, Mi S, Yi X, Xu Y, Sun W. Microfluidic system for modelling 3D tumour invasion into surrounding stroma and drug screening. Biofabrication. 2018;10(3):034102. doi: 10.1088/1758-5090/aac70c
  85. Pavesi A, Tan AT, Chen MB, Adriani G, Bertoletti A, Kamm RD. Using microfluidics to investigate tumor cell extravasation and T-cell immunotherapies. In: 2015 37th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC). 2015: 1853-1856. doi: 10.1109/EMBC.2015.7318742
  86. Sano E, Deguchi S, Matsuoka N, et al. Generation of tetrafluoroethylene-propylene elastomer-based microfluidic devices for drug toxicity and metabolism studies. ACS Omega. 2021;6(38):24859-24865. doi: 10.1021/acsomega.1c03719
  87. Rahimifard M, Bagheri Z, Hadjighassem M, et al. Investigation of anti-cancer effects of new pyrazino[1,2-a] benzimidazole derivatives on human glioblastoma cells through 2D in vitro model and 3D-printed microfluidic device. Life Sci. 2022;302:120505. doi: 10.1016/j.lfs.2022.120505
  88. Li Y, Zhang T, Pang Y, Li L, Chen ZN, Sun W. 3D bioprinting of hepatoma cells and application with microfluidics for pharmacodynamic test of Metuzumab. Biofabrication. 2019;11(3):034102. doi: 10.1088/1758-5090/ab256c
  89. Moroni L, Boland T, Burdick JA, et al. Biofabrication: a guide to technology and terminology. Trends Biotechnol. 2018;36(4):384-402. doi: 10.1016/j.tibtech.2017.10.015
  90. Benien P, Swami A. 3D tumor models: history, advances and future perspectives. Future Oncol. 2014;10(7): 1311-1327. doi: 10.2217/fon.13.274
  91. Jaiswal C, Dey S, Prasad J, Gupta R, Agarwala M, Mandal BB. 3D bioprinted microfluidic based osteosarcoma-on-a chip model as a physiomimetic pre-clinical drug testing platform for anti-cancer drugs. Biomaterials. 2025;320:123267. doi: 10.1016/j.biomaterials.2025.123267
  92. Xie H, Appelt JW, Jenkins RW. Going with the flow: modeling the tumor microenvironment using microfluidic technology. Cancers. 2021;13(23):6052. doi: 10.3390/cancers13236052
  93. Gunti S, Hoke ATK, Vu KP, London NR. Organoid and spheroid tumor models: techniques and applications. Cancers. 2021;13(4):874. doi: 10.3390/cancers13040874
  94. Swartz MA, Iida N, Roberts EW, et al. Tumor microenvironment complexity: emerging roles in cancer therapy. Cancer Res. 2012;72(10):2473-2480. doi: 10.1158/0008-5472.CAN-12-0122
  95. Han J, Jeong HJ, Choi J, et al. Bioprinted patient-derived organoid arrays capture intrinsic and extrinsic tumor features for advanced personalized medicine. Adv Sci (Weinh). 2025;12(20):e2407871. doi: 10.1002/advs.202407871
  96. Xu K, Huang Y, Wu M, Yin J, Wei P. 3D bioprinting of multi-cellular tumor microenvironment for prostate cancer metastasis. Biofabrication. 2023;15(3). doi: 10.1088/1758-5090/acd960
  97. Xiong Q, Liu T, Ying Y, et al. Establishment of bladder cancer spheroids and cultured in microfluidic platform for predicting drug response. Bioeng Transl Med. 2024;9(2):e10624. doi: 10.1002/btm2.10624
  98. Skubal M, Larney BM, Phung NB, et al. Vascularized tumor on a microfluidic chip to study mechanisms promoting tumor neovascularization and vascular targeted therapies. Theranostics. 2025;15(3):766-783. doi: 10.7150/thno.95334
  99. G P, Singh M, Gupta PK, Shukla R. Synergy of microfluidics and nanomaterials: a revolutionary approach for cancer management. ACS Appl Bio Mater. 2025;8(4):2716-2734. doi: 10.1021/acsabm.5c00123
  100. Goel HL, Mercurio AM. VEGF targets the tumour cell. Nat Rev Cancer. 2013;13(12):871-882. doi: 10.1038/nrc3627
  101. Abdalla AME, Xiao L, Ullah MW, Yu M, Ouyang C, Yang G. Current challenges of cancer anti-angiogenic therapy and the promise of nanotherapeutics. Theranostics. 2018;8(2):533-548. doi: 10.7150/thno.21674
  102. Chen X, Qian H, Qiao H, et al. Tumor-adhesive and pH-degradable microgels by microfluidics and photo-cross-linking for efficient antiangiogenesis and enhanced cancer chemotherapy. Biomacromolecules. 2020;21(3):1285-1294. doi: 10.1021/acs.biomac.0c00049
  103. Huang K, He Y, Zhu Z, et al. Small, traceable, endosome-disrupting, and bioresponsive click nanogels fabricated via microfluidics for CD44-targeted cytoplasmic delivery of therapeutic proteins. ACS Appl Mater Interfaces. 2019;11(25):22171-22180. doi: 10.1021/acsami.9b05827
  104. Arduino I, Di Fonte R, Sommonte F, et al. Fabrication of biomimetic hybrid liposomes via microfluidic technology: homotypic targeting and antitumor efficacy studies in glioma cells. Int J Nanomedicine. 2024;19:13217-13233. doi: 10.2147/IJN.S489872
  105. Wei W, Sun J, Guo XY, et al. Microfluidic-based holonomic constraints of siRNA in the kernel of lipid/polymer hybrid nanoassemblies for improving stable and safe in vivo delivery. ACS Appl Mater Interfaces. 2020;12(13):14839-14854. doi: 10.1021/acsami.9b22781
  106. Balachandran YL, Li X, Jiang X. Integrated microfluidic synthesis of aptamer functionalized biozeolitic imidazolate framework (BioZIF-8) targeting lymph node and tumor. Nano Lett. 2021;21(3):1335-1344. doi: 10.1021/acs.nanolett.0c04053
  107. Yan J, Xu X, Zhou J, et al. Fabrication of a pH/redox-triggered mesoporous silica-based nanoparticle with microfluidics for anticancer drugs doxorubicin and paclitaxel codelivery. ACS Appl Bio Mater. 2020;3(2):1216-1225. doi: 10.1021/acsabm.9b01111
  108. Han X, Zhang G, Wu X, et al. Microfluidics-enabled fluorinated assembly of EGCG-ligands-siTOX nanoparticles for synergetic tumor cells and exhausted t cells regulation in cancer immunotherapy. J Nanobiotechnology. 2024;22(1):90. doi: 10.1186/s12951-024-02328-4
  109. Zhang Q, Wang X, Kuang G, Yu Y, Zhao Y. Photopolymerized 3D printing scaffolds with Pt(IV) prodrug initiator for postsurgical tumor treatment. Research (Wash DC). 2022;2022:9784510. doi: 10.34133/2022/9784510
  110. Li J, Zhu T, Jiang Y, Zhang Q, Zu Y, Shen X. Microfluidic printed 3D bioactive scaffolds for postoperative treatment of gastric cancer. Mater Today Bio. 2024;24:100911. doi: 10.1016/j.mtbio.2023.100911
  111. Xu Y, Zhu S, Xia C, et al. Liquid biopsy-based multi-cancer early detection: an exploration road from evidence to implementation. Sci Bull. 2025;70(17):2852-2867. doi: 10.1016/j.scib.2025.06.030
  112. Sun H, Yao X, Jiao Y, et al. DNA remnants in red blood cells enable early detection of cancer. Cell Res. 2025;35(8): 568-587. doi: 10.1038/s41422-025-01122-7
  113. Abusara OH, Agha ASAA, Bardaweel SK. Advancements and innovations in liquid biopsy through microfluidic technology for cancer diagnosis. Analyst. 2025;150(9):1711-1725. doi: 10.1039/d5an00105f
  114. Xie Y, Xu X, Wang J, Lin J, Ren Y, Wu A. Latest advances and perspectives of liquid biopsy for cancer diagnostics driven by microfluidic on-chip assays. Lab Chip. 2023;23(13):2922-2941. doi: 10.1039/d2lc00837h
  115. Marassi V, Giordani S, Placci A, et al. Emerging microfluidic tools for simultaneous exosomes and cargo biosensing in liquid biopsy: new integrated miniaturized FFF-assisted approach for colon cancer diagnosis. Sensors. 2023;23(23):9432. doi: 10.3390/s23239432
  116. Asleh K, Dery V, Taylor C, Davey M, Djeungoue-Petga MA, Ouellette RJ. Extracellular vesicle-based liquid biopsy biomarkers and their application in precision immuno-oncology. Biomark Res. 2023;11(1):99. doi: 10.1186/s40364-023-00540-2
  117. Hou Y, Lin J, Yao H, Wu Z, Lin Y, Lin JM. Linking metastatic behavior and metabolic heterogeneity of circulating tumor cells at single-cell level using an integrative microfluidic system. Adv Sci (Weinh). 2025;12(14):e2413978. doi: 10.1002/advs.202413978
  118. Sollier E, Go DE, Che J, et al. Size-selective collection of circulating tumor cells using Vortex technology. Lab Chip. 2013;14(1):63-77. doi: 10.1039/C3LC50689D
  119. Fachin F, Spuhler P, Martel-Foley JM, et al. Monolithic chip for high-throughput blood cell depletion to sort rare circulating tumor cells. Sci Rep. 2017;7(1):10936. doi: 10.1038/s41598-017-11119-x
  120. Stiefel J, Freese C, Sriram A, et al. Characterization of a novel microfluidic platform for the isolation of rare single cells to enable CTC analysis from head and neck squamous cell carcinoma patients. Eng Life Sci. 2022; 22(5):391-406. doi: 10.1002/elsc.202100133
  121. Tan SJ, Yobas L, Lee GYH, Ong CN, Lim CT. Microdevice for the isolation and enumeration of cancer cells from blood. Biomed Microdevices. 2009;11(4):883-892. doi: 10.1007/s10544-009-9305-9
  122. Wang S, Liu K, Liu J, et al. Highly efficient capture of circulating tumor cells using nanostructured silicon substrates with integrated chaotic micromixers. Angew Chem Int Ed Engl. 2011;50(13):3084-3088. doi: 10.1002/anie.201005853
  123. Wang S, Wang H, Jiao J, et al. Three-dimensional nanostructured substrates toward efficient capture of circulating tumor cells. Angew Chem Int Ed Engl. 2009;48(47):8970-8973. doi: 10.1002/anie.200901668
  124. Cohen EN, Jayachandran G, Hardy MR, Venkata Subramanian AM, Meng X, Reuben JM. Antigen-agnostic microfluidics-based circulating tumor cell enrichment and downstream molecular characterization. PLoS One. 2020;15(10):e0241123. doi: 10.1371/journal.pone.0241123
  125. Leitão TP, Corredeira P, Kucharczak S, et al. Clinical validation of a size-based microfluidic device for circulating tumor cell isolation and analysis in renal cell carcinoma. Int J Mol Sci. 2023;24(9):8404. doi: 10.3390/ijms24098404
  126. Law KS, Huang CE, Chen SW. Detection of circulating tumor cell-related markers in gynecologic cancer using microfluidic devices: a pilot study. Int J Mol Sci. 2023;24(3):2300. doi: 10.3390/ijms24032300
  127. Ayuso JM, Virumbrales-Muñoz M, Lang JM, Beebe DJ. A role for microfluidic systems in precision medicine. Nat Commun. 2022;13:3086. doi: 10.1038/s41467-022-30384-7
  128. Xu J, Wan R, Cai Y, et al. Circulating tumor DNA-based stratification strategy for chemotherapy plus PD-1 inhibitor in advanced non-small-cell lung cancer. Cancer Cell. 2024;42(9):1598-1613.e4. doi: 10.1016/j.ccell.2024.08.013
  129. Jamshidi A, Liu MC, Klein EA, et al. Evaluation of cell-free DNA approaches for multi-cancer early detection. Cancer Cell. 2022;40(12):1537-1549.e12. doi: 10.1016/j.ccell.2022.10.022
  130. Pantel K, Alix-Panabières C. Liquid biopsy and minimal residual disease — latest advances and implications for cure. Nat Rev Clin Oncol. 2019;16(7): 409-424. doi: 10.1038/s41571-019-0187-3
  131. Chen H, Zhou Q. Detecting liquid remnants of solid tumors treated with curative intent: circulating tumor DNA as a biomarker of minimal residual disease (review). Oncol Rep. 2023;49(5):1-13. doi: 10.3892/or.2023.8543
  132. Gauri S, Ahmad MR. ctDNA detection in microfluidic platform: a promising biomarker for personalized cancer chemotherapy. J Sens. 2020;2020(1):8353674. doi: 10.1155/2020/8353674
  133. Wan JCM, Massie C, Garcia-Corbacho J, et al. Liquid biopsies come of age: towards implementation of circulating tumour DNA. Nat Rev Cancer. 2017;17(4):223-238. doi: 10.1038/nrc.2017.7
  134. Pekin D, Skhiri Y, Baret JC, et al. Quantitative and sensitive detection of rare mutations using droplet-based microfluidics. Lab Chip. 2011;11(13):2156-2166. doi: 10.1039/C1LC20128J
  135. He M, Crow J, Roth M, Zeng Y, Godwin AK. Integrated immunoisolation and protein analysis of circulating exosomes using microfluidic technology. Lab Chip. 2014;14(19):3773-3780. doi: 10.1039/C4LC00662C
  136. Das J, Ivanov I, Sargent EH, Kelley SO. DNA clutch probes for circulating tumor DNA analysis. J Am Chem Soc. 2016;138(34):11009-11016. doi: 10.1021/jacs.6b05679
  137. Im YR, Tsui DWY, Diaz LA, Wan JCM. Next-generation liquid biopsies: embracing data science in oncology. Trends Cancer. 2021;7(4):283-292. doi: 10.1016/j.trecan.2020.11.001
  138. Simpson RJ, Lim JW, Moritz RL, Mathivanan S. Exosomes: proteomic insights and diagnostic potential. Expert Rev Proteomics. 2009;6(3):267-283. doi: 10.1586/epr.09.17
  139. Wang Y, Wang S, Li L, Zou Y, Liu B, Fang X. Microfluidics-based molecular profiling of tumor-derived exosomes for liquid biopsy. View. 2023;4(2):20220048. doi: 10.1002/VIW.20220048
  140. Reátegui E, van der Vos KE, Lai CP, et al. Engineered nanointerfaces for microfluidic isolation and molecular profiling of tumor-specific extracellular vesicles. Nat Commun. 2018;9(1):175. doi: 10.1038/s41467-017-02261-1
  141. Dorayappan KDP, Gardner ML, Hisey CL, et al. A microfluidic chip enables isolation of exosomes and establishment of their protein profiles and associated signaling pathways in ovarian cancer. Cancer Res. 2019;79(13):3503-3513. doi: 10.1158/0008-5472.CAN-18-3538
  142. Barbosa AI, Reis NM. A critical insight into the development pipeline of microfluidic immunoassay devices for the sensitive quantitation of protein biomarkers at the point of care. Analyst. 2017;142(6):858-882. doi: 10.1039/C6AN02445A
  143. Emde B, Niehaus K, Tickenbrock L. Evaluation of 3D-printed microfluidic structures for use in AML-specific biomarker detection of PML::RARA. Int J Mol Sci. 2025; 26(2):497. doi: 10.3390/ijms26020497
  144. Sharafeldin M, Chen T, Ozkaya GU, et al. Detecting cancer metastasis and accompanying protein biomarkers at single cell levels using a 3D-printed microfluidic immunoarray. Biosens Bioelectron. 2021;171:112681. doi: 10.1016/j.bios.2020.112681
  145. Chen C, Ran B, Liu B, et al. Development of a novel microfluidic biosensing platform integrating micropillar array electrode and acoustic microstreaming techniques. Biosens Bioelectron. 2023;223:114703. doi: 10.1016/j.bios.2022.114703
  146. Lee D, Tran HQ, Sharma NS, et al. 3D-printed microfluidic platform for creating porous nanofibrous microspheres to regulate cell response and enhance tissue regeneration. Small. 2025:e2502033. doi: 10.1002/smll.202502033
  147. Nielsen AV, Beauchamp MJ, Nordin GP, Woolley AT. 3D printed microfluidics. Annu Rev Anal Chem (Palo Alto Calif). 2020;13(1):45-65. doi: 10.1146/annurev-anchem-091619-102649
  148. Barbosa F, Coutinho P, Ribeiro MP, Moreira AF, Lourenço LM, Miguel SP. Advancements and challenges in SLA-based microfluidic devices for organ-on-chip applications. Mater Des. 2025;256:114254. doi: 10.1016/j.matdes.2025.114254
  149. Lui YS, Sow WT, Tan LP, Wu Y, Lai Y, Li H. 4D printing and stimuli-responsive materials in biomedical aspects. Acta Biomater. 2019;92:19-36. doi: 10.1016/j.actbio.2019.05.005
  150. Loo JFC, Ho AHP, Turner APF, Mak WC. Integrated printed microfluidic biosensors. Trends Biotechnol. 2019;37(10):1104-1120. doi: 10.1016/j.tibtech.2019.03.009
  151. Ding A, Tang F, Alsberg E. 4D printing: a comprehensive review of technologies, materials, stimuli, design, and emerging applications. Chem Rev. 2025;125(7):3663-3771. doi: 10.1021/acs.chemrev.4c00070
  152. Zhang C, Cai D, Liao P, et al. 4D printing of shape-memory polymeric scaffolds for adaptive biomedical implantation. Acta Biomater. 2021;122:101-110. doi: 10.1016/j.actbio.2020.12.042
  153. Gara DK, Gujjala R, Prasad PS, Madaboosi N, Ojha S. 4D bioprinting: a review on smart bio-adaptable technology to print stimuli-responsive materials. Prog Addit Manuf. 2024;10:4375-4417. doi: 10.1007/s40964-024-00876-7
  154. Kalogeropoulou M, Diaz-Payno PJ, Mirzaali MJ, van Osch GJVM, Fratila-Apachitei LE, Zadpoor AA. 4D printed shape-shifting biomaterials for tissue engineering and regenerative medicine applications. Biofabrication. 2024;16(2):22002. doi: 10.1088/1758-5090/ad1e6f
  155. Maidin S, Wee KJ, Sharum MA, Rajendran TK, Ali LM, Ismail S. A review on 4d additive manufacturing the applications, smart materials & effect of various stimuli on 4d printed objects. J Teknol Sci Eng. 2023;85(5): 63-71. doi: 10.11113/jurnalteknologi.v85.19889
  156. Lai J, Wang M. Developments of additive manufacturing and 5D printing in tissue engineering. J Mater Res. 2023;38(21):4692-4725. doi: 10.1557/s43578-023-01193-5
  157. Cheng YJ, Wu TH, Tseng YS, Chen WF. Development of hybrid 3D printing approach for fabrication of high-strength hydroxyapatite bioscaffold using FDM and DLP techniques. Biofabrication. 2024;16(2). doi: 10.1088/1758-5090/ad1b20
  158. Han X, Saiding Q, Cai X, et al. Intelligent vascularized 3D/4D/5D/6D-printed tissue scaffolds. Nano Micro Lett. 2023;15(1):239. doi: 10.1007/s40820-023-01187-2
  159. Peng S, Yan Y, Ogino K, Ma G, Xia Y. Spatiotemporal coordination of antigen presentation and co-stimulatory signal for enhanced anti-tumor vaccination. J Control Release. 2024;374:312-324. doi: 10.1016/j.jconrel.2024.08.025
  160. Boussommier-Calleja A, Li R, Chen MB, Wong SC, Kamm RD. Microfluidics: a new tool for modeling cancer-immune interactions. Trends Cancer. 2016;2(1):6-19. doi: 10.1016/j.trecan.2015.12.003
  161. Kolesky DB, Homan KA, Skylar-Scott MA, Lewis JA. Three-dimensional bioprinting of thick vascularized tissues. Proc Natl Acad Sci U S A. 2016;113(12):3179-3184. doi: 10.1073/pnas.1521342113
  162. Zielke C, Pan CW, Gutierrez Ramirez AJ, et al. Microfluidic platform for the isolation of cancer-cell subpopulations based on single-cell glycolysis. Anal Chem. 2020;92(10):6949-6957. doi: 10.1021/acs.analchem.9b05738
  163. Wang M, Xiao Y, Lin L, Zhu X, Du L, Shi X. A microfluidic chip integrated with hyaluronic acid-functionalized electrospun chitosan nanofibers for specific capture and nondestructive release of CD44-overexpressing circulating tumor cells. Bioconjug Chem. 2018;29(4):1081-1090. doi: 10.1021/acs.bioconjchem.7b00747

 

 



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International Journal of Bioprinting, Electronic ISSN: 2424-8002 Print ISSN: 2424-7723, Published by AccScience Publishing