Advancing modular microfluidics: Stereolithographic 3D printing of reconfigurable connectors for bioanalytical applications
Traditional monolithic microfluidic devices are constrained by their inability to accommodate modifications to circuit elements, necessitating complete redesign and refabrication. To address these limitations, this study introduces modular microfluidic connectors fabricated via stereolithographic (SL) 3D printing. We designed and evaluated three distinct connector types—tessellated, sponge, and solid-walled—using tailored photoresins to enhance reusability, flexibility, and sealing performance. The tessellated connectors, printed with poly(ethylene glycol) diacrylate (PEGDA; Mw ~258) and incorporating an octet unit cell structure, reduced the rigidity of PEGDA prints, improving reusability under moderate conditions. The sponge connectors, fabricated from a PEGDA and 2-hydroxyethyl acrylate (2-HEA; Mw ~116) blend (2-HEA-co-PEGDA), exhibited greater flexibility; however, swelling in aqueous environments may limit their long-term utility. In contrast, the solid-walled connectors, produced with commercial Asiga Soft Resin, demonstrated superior reliability and adaptability, as validated in a reconfigurable concentration gradient generator with scalable output capabilities. Cytocompatibility tests confirmed that PEGDA-printed devices, following isopropanol and ultraviolet post-processing, are suitable for bioanalytical applications that do not require incubation. These findings establish SL 3D printing as a promising method for developing flexible, reconfigurable microfluidic platforms, with potential uses in material synthesis, chemical analysis, and point-of-care diagnostics. While challenges related to environmental durability persist, these advances lay the foundations for developing more robust and adaptable microfluidic systems with versatile applications.
1. Introduction
Over the past few decades, microfluidic technology has gained significant attention and achieved substantial advancement across various fields, including biomedical research, chemical analysis, point-of-care testing, and material synthesis. Microfluidics enables precise fluid control at the microscale, leading to reduced reagent consumption and enhanced experimental efficiency.1–3 However, despite its advantages, the widespread adoption and further development of microfluidic systems face considerable challenges. One major limitation stems from the prevalent design of microfluidic devices, in which all functional elements are integrated into a single chip. Monolithic microfluidic devices lack the flexibility to adapt to dynamic application scenarios because each chip is typically designed for a specific purpose. Additionally, as device structures become more complex, designing and fabricating these systems require specialized skills and expertise. The increasing number of functional units in each device also demands larger surface areas for micromachining, escalating manufacturing costs, and difficulty. A flexible, reconfigurable, and standardized microfluidic platform could address these challenges by simplifying the design and fabrication processes, thereby advancing microfluidic technology.4
To overcome these limitations, the concept of modular microfluidics has emerged. This approach involves the integration of discrete, interchangeable microfluidic modules that can be assembled and reconfigured as needed. Each module is designed, tested, and fabricated independently, improving system design efficiency and construction flexibility.5–7 For example, in a monolithic microfluidic chip, modifying a single functional part often requires redesigning and retesting the entire chip. In contrast, a modular system allows users to replace only the faulty module without needing to fabricate the entire system again, reducing manufacturing costs and easing maintenance. Moreover, modularity enhances adaptability, allowing users to quickly adapt and optimize microfluidic systems for specific applications, hence fostering innovation and expanding the scope of microfluidic technology. For instance, in point-of-care testing, where real-time adjustments to system configurations are often difficult to achieve in monolithic systems, this adaptability is particularly valuable. As a result, modular microfluidics offers a more practical, versatile, and field-deployable approach for a wide range of applications.8–13
Modular microfluidic systems consist of discrete functional modules, many of which incorporate complex 3D geometries to facilitate assembly. However, traditional manufacturing techniques, such as dry/wet etching and polydimethylsiloxane (PDMS) micromolding, are not well-suited for fabricating highly intricate chips. Consequently, digital manufacturing technologies provide an alternative approach for producing complex structures. Assisted by computer-aided design (CAD) and control, digital manufacturing facilitates a range of tasks, including 3D modeling, performance simulation, automated fabrication, rapid prototyping, and quality control. These technologies can be broadly categorized into additive manufacturing (also known as 3D printing) and subtractive manufacturing, each with distinct advantages and limitations that should be thoroughly considered before adoption.14
In recent years, 3D printing has gained significant traction for microfluidic fabrication due to its advantages in rapid design iteration, geometrical freedom, and low-cost prototyping. In addition to these performance advantages, fabrication cost is also an important consideration. Traditional microfabrication methods, such as soft lithography and micromilling, typically involve cleanroom facilities, photomasks, and manual bonding steps, leading to higher infrastructure and labor costs. In contrast, 3D printing enables rapid, one-step production of enclosed structures without post-alignment or additional sealing processes. Recent studies have demonstrated that additive manufacturing significantly reduces both fabrication time and labor requirements, resulting in lower overall device costs compared to traditional microfabrication.15 Based on our experience, the turnaround time from design to prototype can be less than 1 h, making 3D printing particularly attractive for low-volume production, iterative development, and rapid prototyping of customized microfluidic devices.
al incubation is not required.
1.Stone HA, Stroock AD, Ajdari A. Engineering flows in small devices: microfluidics toward a Lab-on-a-Chip. Annu Rev Fluid Mech. 2004;36(1):381-411.
doi: 10.1146/annurev.fluid.36.050802.122124
2.Tu TY, Shen YP, Lim SH, Wang YK. A facile method for generating a smooth and tubular vessel lumen using a viscous fingering pattern in a microfluidic device. Front Bioeng Biotechnol. 2022;10:877480.
doi: 10.3389/fbioe.2022.877480
3.Wang LC, Chang LC, Su GL, et al. Chemical structure and shape enhance mr imaging-guided X-ray therapy following marginative delivery. ACS Appl Mater Interfaces. 2022;14(11):13056-13069.
4.Whitesides GM. The origins and the future of microfluidics. Nature. 2006;442(7101):368-373.
doi: 10.1038/nature05058
5.Volpatti LR, Yetisen AK. Commercialization of microfluidic devices. Trends Biotechnol. 2014;32(7):347-350.
doi: 10.1016/j.tibtech.2014.04.010
6.Hsieh YF, Yang AS, Chen JW, et al. A Lego®-like swappable fluidic module for bio-chem applications. Sens Actuators B Chem. 2014;204:489-496.
doi: 10.1016/j.snb.2014.07.122
7.Vit FF, Nunes R, Wu YT, et al. A modular, reversible sealing, and reusable microfluidic device for drug screening. Anal Chim Acta. 2021;1185:339068.
doi: 10.1016/j.aca.2021.339068
8.Wu J, Fang H, Zhang J, Yan S. Modular microfluidics for life sciences. J Nanobiotechnology. 2023;21(1):85.
doi: 10.1186/s12951-023-01846-x
9.Yuen PK, Bliss JT, Thompson CC, Peterson RC. Multidimensional modular microfluidic system. Lab Chip. 2009;9(22):3303.
doi: 10.1039/b912295h
10.Bhargava KC, Thompson B, Malmstadt N. Discrete elements for 3D microfluidics. Proceedings of the National Academy of Sciences. 2014;111(42):15013-15018.
11.Lee KG, Park KJ, Seok S, et al. 3D printed modules for integrated microfluidic devices. RSC Adv. 2014;4(62):32876-32880.
doi: 10.1039/C4RA05072J
12.Tsuda S, Jaffery H, Doran D, et al. Customizable 3D printed ‘plug and play’ millifluidic devices for programmable fluidics. PLoS One. 2015;10(11):e0141640.
doi: 10.1371/journal.pone.0141640
13.Riche CT, Roberts EJ, Gupta M, Brutchey RL, Malmstadt N. Flow invariant droplet formation for stable parallel microreactors. Nat Commun. 2016;7(1):10780.
doi: 10.1038/ncomms10780
14.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
15.Duarte LC, Figueredo F, Chagas CLS, Cortón E, Coltro WKT. A review of the recent achievements and future trends on 3D printed microfluidic devices for bioanalytical applications. Anal Chim Acta. 2024;1299:342429.
doi: 10.1016/j.aca.2024.342429
16.Lai X, Yang M, Wu H, Li D. Modular microfluidics: current status and future prospects. Micromachines (Basel). 2022;13(8):1363.
doi: 10.3390/mi13081363
17.Bhattacharjee N, Urrios A, Kang S, Folch A. The upcoming 3D-printing revolution in microfluidics. Lab Chip. 2016;16(10):1720-1742.
doi: 10.1039/c6lc00163g
18.Nielsen AV, Beauchamp MJ, Nordin GP, Woolley AT. 3D printed microfluidics. Annu Rev Anal Chem. 2020;13(1):45-65.
doi: 10.1146/annurev-anchem-091619-102649
19.Ng WL, An J, Chua CK. Process, material, and regulatory considerations for 3D printed medical devices and tissue constructs. Engineering. 2024;36:146-166.
doi: 10.1016/j.eng.2024.01.028
20.Ong LJY, Ching T, Chong LH, et al. Self-aligning Tetris-Like (TILE) modular microfluidic platform for mimicking multiorgan interactions. Lab Chip. 2019;19(13):2178-2191.
doi: 10.1039/C9LC00160C
21.Owens CE, Hart AJ. High-precision modular microfluidics by micromilling of interlocking injection-molded blocks. Lab Chip. 2018;18(6):890-901.
doi: 10.1039/C7LC00951H
22.Anshori I, Lukito V, Adhawiyah R, et al. Versatile and lowcost fabrication of modular lock-and-key microfluidics for integrated connector mixer using a stereolithography 3D printing. Micromachines (Basel). 2022;13(8):1197.
doi: 10.3390/mi13081197
23.Chen X, Mo D, Gong M. 3D printed reconfigurable modular microfluidic system for generating gel microspheres. Micromachines (Basel). 2020;11(2):1-9.
doi: 10.3390/mi11020224
24.Urrios A, Parra-Cabrera C, Bhattacharjee N, et al. 3D-printing of transparent bio-microfluidic devices in PEG-DA. Lab Chip. 2016;16(12):2287-2294.
doi: 10.1039/c6lc00153j
25.Jiang Y, Wang Q. Highly-stretchable 3D-architected mechanical metamaterials. Sci Rep. 2016;6:34147.
doi: 10.1038/srep34147
26.Kim YT, Ahmadianyazdi A, Folch A. A ‘print–pause– print’ protocol for 3D printing microfluidics using multimaterial stereolithography. Nat Protoc. 2023;18(4): 1243-1259.
doi: 10.1038/s41596-022-00792-6
27.Ruiz C, Kadimisetty K, Yin K, Mauk MG, Zhao H, Liu C. Fabrication of hard–soft microfluidic devices using hybrid 3D printing. Micromachines (Basel). 2020;11(6):567.
doi: 10.3390/mi11060567
28.Venzac B, Deng S, Mahmoud Z, et al. PDMS curing inhibition on 3D-printed molds: why? Also, how to avoid it? Anal Chem. 2021;93(19):7180-7187.
doi: 10.1021/acs.analchem.0c04944
29.Ahmadianyazdi A, Miller IJ, Folch A. Tunable resins with PDMS-like elastic modulus for stereolithographic 3D-printing of multimaterial microfluidic actuators. Lab Chip. 2023;23(18):4019-4032.
doi: 10.1039/D3LC00529A
30.de Almeida Monteiro Melo Ferraz M, Nagashima JB, Venzac B, Le Gac S, Songsasen N. 3D printed mold leachates in PDMS microfluidic devices. Sci Rep. 2020;10:994.
doi: 10.1038/s41598-020-57816-y
31.Kreß S, Schaller-Ammann R, Feiel J, Priedl J, Kasper C, Egger D. 3D printing of cell culture devices: Assessment and prevention of the cytotoxicity of photopolymers for stereolithography. Materials. 2020;13(13):3011.
doi: 10.3390/ma13133011
32.Männel MJ, Fischer C, Thiele J. A non-cytotoxic resin for micro-stereolithography for cell cultures of HUVECs. Micromachines (Basel). 2020;11(3):246.
doi: 10.3390/mi11030246
33.Piironen K, Haapala M, Talman V, Järvinen P, Sikanen T. Cell adhesion and proliferation on common 3D printing materials used in stereolithography of microfluidic devices. Lab Chip. 2020;20(13):2372-2382.
doi: 10.1039/d0lc00114g
34.Kuo AP, Bhattacharjee N, Lee YS, Castro K, Kim YT, Folch A. High-precision stereolithography of biomicrofluidic devices. Adv Mater Technol. 2019;4(6):1800395.
35.Warr C, Valdoz JC, Bickham BP, et al. Biocompatible PEGDA resin for 3D printing. ACS Appl Bio Mater. 2020;3(4):2239-2244.
36.Lee YS, Bhattacharjee N, Folch A. 3D-printed Quakestyle microvalves and micropumps. Lab Chip. 2018;18(8):1207-1214.
doi: 10.1039/c8lc00001h
37.Saini RS, Vaddamanu SK, Dermawan D, Mosaddad SA, Heboyan A. Investigating the role of temperature and moisture on the degradation of 3D-printed polymethyl methacrylate dental materials through molecular dynamics simulations. Sci Rep. 2024;14(1):26079.
doi: 10.1038/s41598-024-77736-5
38.Banjo AD, Agrawal V, Auad ML, Celestine ADN. Moisture-induced changes in the mechanical behavior of 3D printed polymers. Composites Part C: Open Access. 2022;7: 100243.
doi: 10.1016/j.jcomc.2022.100243
39.Huang J, Chen Z, Wen C, Ling T, Chen Z. Thermally assisted 3D printing of bio-polymer with high solute loading with improved mechanical properties. Addit Manuf. 2022;59:103088.
doi: 10.1016/j.addma.2022.103088
40.Afshar A, Mihut D. Enhancing durability of 3D printed polymer structures by metallization. J Mater Sci Technol. 2020;53:185-191.