Microfluidics and, more generally, Lab-on-a-chip (LoC) systems have broadly been used to develop analytical tools for pharmaceutical, life science, and diagnostics (1). To date, LoC has shown outstanding performance and integration level to develop complex laboratory procedures at the microscale while requiring minute amounts of sample varying in the μL-pL range (2–6). Despite such extremely promising features, currently, microfluidics has only very seldomly reached commercial exploitation besides niche applications. The reason behind this weak economic impact can arguably be attributed to the chip-to-world interconnection (CWI) between the LoC and the peripherals (tubes, pumps, valves, etc.) (7–10). Even though this need was already identified in 2003 by Lie et al. (11–13), to date it is still an unsolved engineering need. Conceptually speaking, a robust CWI should (1) be biocompatible and chemically inert, (2) have zero or minimal dead volume, (3) be easy to plug, (4) be removable and reusable, (5) be reliable at operational pressures, (6) be made using simple and low-cost techniques, and (7) be fully compatible with commercial tubing and fittings (2).

Currently, one of the gold standards for CWI is the Luer slip connector due to easy handling and compatibility with medical and laboratory instruments, such as needles, syringes, and cannulas (3, 14, 15). The reason being is the ability to withstand fluidic pressures >2 bar without leakages, but equally important is to be automatable with a simple actuation movement and relative low force and being of multiple uses (2, 16). Despite such outstanding properties, Luer connectors have also severe drawbacks, mainly related to their size, since they have relatively large dead volumes, and require a significant footprint to assure leak-free. This approach goes against dense packaging or multiplexing (17, 18). Furthermore, as most prototyping techniques are not compatible for Luer manufacturing, researchers have sought for alternatives to Luer, such as a barb or direct connection without interfaces (19). The common industrial approach is then to develop highly specific connectors compatible only with their respective peripherals. Thus, a universal, reliable CWI is yet to be presented, hampering the overall applicability of LoC for large-scale applications.

Steps toward monolithic integration of Luer connectors with LoC have been done by taking advantage of the huge development of 3D printing. This technology offers flexibility, design freedom, and rapid prototype manufacturing providing good solutions for small fabrication volumes (20–23). The introduction of this highly versatile technology has allowed the prototyping of arbitrary complex LoC with a broad range of materials. Specifically related to 3D printing of polymers, their outstanding properties in terms of lightweight, low cost, optical transparency, and in some cases chemical resistances are unmatchable by other materials (24–26). Still, 3D printing is a serial process that lacks the required throughput to be considered as a mass-production technology. Even though there has been some progress related to multi-nozzle/parallel printing, it still can be considered as a technology only suitable for small batches, and other technologies, such as injection molding, are preferred since it is reported to be the cheapest and fastest approach for massive fabrication of LoC (16, 27, 28).

In this work, we aim to visualize this need from a different perspective. While keeping the full compatibility with injection molding, seven different Luer slip male connectors and five different Luer slip female connectors have been designed aiming toward the reduction of the aforementioned drawbacks while assuring their compatibility (whenever possible). To complete the study of the different approaches for tube-to-chip connection, the analysis of the useful life of the connector has been performed to define the number of cycles between 0 and 2 bar that the connectors can withstand before leakage.

The proposed designs are based on the ISO 80369-7 (29) norm which defines the main parameters of the standard Luer connectors as shown in Figure 1. The male connector is described in Figure 1A, where α is the cone angle, Ød is the external diameter in the extreme of the male cone at 0.750 mm, e is the length of the cone, Øf is the internal diameter, Øg is the external diameter in the extreme of the male cone at 7.500 mm, and r is the extreme exterior cone radius. The female connector is described in Figure 1B, where Ø_D is the external diameter in the extreme of the female cone at 0.750 mm, E is the depth of the cone, Ø_G is the external diameter in the extreme of the female cone at 7.500 mm, Ø_J is the external diameter of the female connector, and R is the radius on the entrance of the female cone.

The working principle in Luer Slip connectors is based on the fitting between the external face of the male connector and the internal face of the female connector. The holding is performed by friction on both surfaces. Therefore, the height and inner diameters that affect the friction area as well as the dead volume will be the most critical parameters for the correct functioning of the connectors.

Considering those parameters as critical, Table 1 shows the new parameters proposed for both male and female designed connectors. Male 1 and Female 1 are the standard Luer connectors, which are considered the gold standards in this work. All dimensions have been downscaled to the half in Male 2 and three-fourths in Male 3. Minimization of the friction area between male and female connectors has been done by independently studying the different key regions of the Luer. Specifically, the connector height has been reduced to half and three-fourth in Male 4 and 5, while keeping the rest of the parameters unaltered. In Male 6 and Male 7, the inner diameter has been decreased to half and three-fourths, respectively, focusing on the reduction of dead volumes. In all cases, female connectors have been designed to pair with the corresponding male connectors. The compatibility between connectors is also summarized in Table 1.

Focusing toward standardization, a dedicated test bench has been built and is presented in Figure 2 and described in more detail in the Supplementary Material. The platform is composed of an aluminum base that holds for placing all the components in the correct position with fine alignment and distances. Thereby, the chip containing different male Luer slip connectors is placed on one side of the test bench. On the opposite side, a pneumatic actuator (CJP2B10-20D, SMC) can provide actuation forces larger than 55 N with response time (ON/OFF) in the millisecond range. In the resting position of the actuator, the connector is at a distance smaller than the maximum path of the actuator, so that when extended, both male and female connectors under study are interlocked. Switching off the pneumatic actuator assures returning to the initial position, allowing unloading of the measured pair.

The actuation force is dependent on the input pressure; therefore, it can be modulated using a pressure regulator as observed in the schematic setup of the test bench, in Figure 3A. The obtained forces from applied pressure values provided by the datasheet are summarized in Table 2.

When the female connector reaches the male connector, the perfusion of the liquid starts. The fluid is driven with a required fluidic pressure from the reservoir using the pressure pump Fluigent MFCS™-EZ. The tubing led the fluid to the female connector and once it matches the male connector, the fluid comes out through the outlet and is stored in a reservoir. The circuit has been connected to the connector using a commercial PEEK Threaded fitting for tube connections. Figure 3B shows the image of the complete experimental setup (see Supplementary Information for details).

In this work, seven variations of the Luer slip male connectors and five variations of Luer slip female connectors have been designed, manufactured, and characterized to elucidate the strategies toward decreasing the footprint while retaining its performance. The main goal is the path to upscaling a reliable CWI in the LoC application.

Using a specifically designed and developed test bench, a minimum closure force required to hold on 2.0 bar fluidic pressure has been analyzed in which the downscaled connectors show the best compromise between the dead volume and closing force demanding 31.5 ± 0.4 N (M2) and 15.8 ± 0.4 N (M3). For the required closing force, a useful life analysis of the connectors has been performed by applying 100 closing cycles for each possible connector combination. Most of the compatible connectors withstand 100 cycles before leakage, except for the cases in which the friction area has been reduced (M4).

The study shows that the proportional downscaling of all dimensions in the standard Luer Slip connector allows the reduction of dead volumes without compromising the functionality of the connector. Furthermore, size reduction permits dense packaging or multiplexing in LoC devices and massive manufacturing of them using injection molding.

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding authors.

LE, UA, PG, and AS contributed to the design and manufacturing of the connectors. UA prepared the CAD designs and the organization of the setup. LE performed the experiments and wrote the first draft of the manuscript. JV-V contributed to assessment during revisions. AZ, LF, and JV-V contributed with the founding and resources. AL contributed with the supervision and project administration. All authors contributed to manuscript revision, read, and approved the submitted version.

The authors are grateful for the financial support from the Basque Country Government within the frame of the project BIKAINTEK 2018 (48-AF-W2-2018-00006).

LE, UA, PG, AS, LF, and AL were employed by microLIQUID S.L. LE and AZ were employed by Leartiker S. Coop. JV-V were employed by UPV/EHU and BC Materials. LE is a student of UPV/EHU.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.