Evaluation of Pressure Stable Chip-to-Tube Fittings Enabling High

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Evaluation of Pressure Stable Chip-to-Tube Fittings Enabling High-Speed Chip-HPLC with Mass Spectrometric Detection Carsten Lotter, Josef J. Heiland, Volkmar Stein, Michael Klimkait, Marco Queisser, and Detlev Belder Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.6b01907 • Publication Date (Web): 09 Jul 2016 Downloaded from http://pubs.acs.org on July 10, 2016

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Analytical Chemistry

Evaluation of Pressure Stable Chip-to-Tube Fittings Enabling HighSpeed Chip-HPLC with Mass Spectrometric Detection Carsten Lottera, Josef J. Heilanda, Volkmar Steinb, Michael Klimkaita, Marco Queisserc and Detlev Beldera* a) Institute of Analytical Chemistry, University of Leipzig, Linnéstraße 3, 04103 Leipzig, Germany b) Fraunhofer ICT-IMM, Carl-Zeiss-Str. 18-20, 55129 Mainz, Germany c) Fraunhofer IZM, Gustav-Meyer-Allee 25, 13355 Berlin, Germany ABSTRACT: Appropriate chip-to-tube interfacing is an enabling technology for high-pressure and by that high-speed liquid chromatography on chip. For this purpose various approaches, to connect pressure resistant glass chips with HPLC pumps working at pressures of up to 500 bar, were examined. Three side-port and one top-port connection approach were evaluated with regard to pressure stability and extra column band broadening. A clamp based top-port approach enabled chip-HPLC-MS analysis of herbicides at the highest pressure and speed.

High-performance liquid chromatography (HPLC) is nowadays the most powerful and widespread separation technique in analytical laboratories. Especially with the winning combination of mass spectrometric detection, it became an irreplaceable tool for chemical analysis. Since the first introduction in 19901, the miniaturization of HPLC in the context of lab-on-achip2 applications is an active field of research. The current state of microfluidic chip-HPLC has been reviewed extensively.3–6 The advantages miniaturization has to offer are a low sample and solvent consumption, greatly reduced void volumes, as well as the seamless integration of further functionalities.7 Especially the minimal extra column volumes predestine the chip technology as a tool for high-speed chromatography. In HPLC, as in chip-LC, the obtainable analysis speed is associated with the back pressure of the system. This is especially true when high-performance particulate column material is utilized as packed stationary phase. In the context of microfluidic chips the technical demands with regard to pressure stability and robustness are rather high. A key aspect to realize high-speed chip chromatography is accordingly the world-to-chip interface. While a lot of possible connection techniques are described in literature, most of them do not provide the necessary pressure stability. There are very few reports from academia on high-quality chip-based LC separations with particulate columns at pressures in excess of 100 bar, presumably exactly for this reason. It has however recently been shown by instrument companies that the challenges of pressure driven chip-LC can be solved. Eksigent (now SCIEX) reports a maximal system pressure of 275 bar for their glass chip docking station, while Waters provides ceramic LC-MS chips for operating pressures of up to 690 bar. Both systems use an off-chip injection and do not elaborate on the fluidic interfacing. Agilent developed a laminated polyimide LC-MS chip with integrated trap column which is sand-

wiched in a 6-port valve for fluidic connection. They recommend a maximum system pressure of 150 bar. A recent review by Temiz et al.8 describes the progress in chip interfacing over the last decades from an academic point of view. The interfaces can be grouped into different categories. A very straightforward approach is to insert a connection tubing or needle directly into a receiving port of the microchip. The sealing is then achieved either by compression of the soft chip material,9–12 integration of gaskets into the receiving port,13–15 the use of micro fabricated holding structures16,17 or via threaded needles.18 However, these interfaces are only suitable for very low pressure applications. Somewhat higher pressures can be realized via the use of a gasket to seal a connection tubing versus the flat chip surface. Most approaches use either elastomeric sealing layers19–21 or micro o-rings.22,23 A noteworthy example was demonstrated by Chambers et al.24 who used a PTFE ferrule to connect a capillary to a glass chip via a threaded clamp. They reported a pressure stability of up to 100 bar and utilized it for on-chip hyphenation of LC with CE-MS. Furthermore, full body clamp-on chip holders which completely enclose polymeric chips were reported by Wouters et al.25 to be suitable for system pressures of up to 250 bar. A similar system was later utilized for the investigation of comprehensive spatial two-dimensional chip-LC in polymer devices at about 20 bar.26 Other interesting setups report on the simultaneous realization of various connections in the lower pressure range of up to 6 bar.27,28 The most common approach for high-pressure stable but permanent connections is the use of adhesives. The utilization of epoxy glue to implement capillaries into ridged chips was demonstrated to withstand pressures of up to 690 bar29 and was later utilized for pillar array chip-LC at working pressures of up to 350 bar.30 Mats et al.31 recently integrated capillaries into COC chips for chip-LC-MS by hot embossing and thermal bonding and reported a pressure stability of up to 100 bar.

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Jensen’s group32 reported a solder-based approach to connect chip-based micro reactors at up to 200 bar. While these connections resist very high pressures, they are not interchangeable, elaborate and the utilized adhesives may foul the microfluidic device. Recently Gupta et al.33 reported on metal 3D printing to implement standard ports for the fluidic connection of an on-chip column with a pressure stability of 120 bar. The current contribution focuses on the evaluation of different interface technologies to enable high-speed HPLC-MS with microfluidic glass chips.34 For this purpose we developed and systematically evaluated several approaches for highpressure chip-to-tube interfacing.

EXPERIMENTAL SECTION Chemicals and Materials. Analytical standard grade fenuron, cyanazine, tebuthiuron, fluometuron, diuron, siduron and metolachlor, thiourea (99%), 1,3-butanediol diacrylate (98%), 3-(trimethoxysilyl)propyl methacrylate (98%), 2,2-dimethoxy2-phenylacetophenone (99%) and LC-MS grade formic acid (98%) were acquired from Sigma-Aldrich GmbH (Taufkirchen, Germany). The solvents methanol (gradient grade), chloroform (p.a.) and n-heptane (p.a.) were purchased from VWR International LLC (Radnor, USA). A Smart2Pure purifying system (TKA GmbH, Niederelbert, Germany) delivered ultrapure water (18.2 MΩcm). Microchip Design and Fabrication. The HPLC microchips were produced by iX-factory (Dortmund, Germany) according to our specifications via common photolithography, wetetching and fusion bonding. They are made up of two 1.1 mm thick borosilicate (BOROFLOAT® 33) glass slides and measure 10 mm · 45 mm. The utilized chip layout and manufacturing details for the particulate column and electrospray emitter were described previously.34 The chip features a 35 mm long column channel, which is slurry packed with particulate stationary phase material via a packing channel, which is thereafter sealed via laser assisted photo polymerization. The particles are retained via the keystone effect. A cross at the column head functions as an on-chip flow splitter and sample injector. Two platinum electrodes and an optional sheath flow channel facilitate the electrical connection to apply the electrospray potential for MS coupling. For that purpose, a ground and hydrophobized monolithic electrospray emitter without the sheath channel function was implemented, as described previously.34 The chips have powder blasted access holes in the top side. The microfluidic design allows to remove these access holes by cutting the chip lengthwise. This results in a fully functional HPLC-chip but with open channels at the side face of the chip, as shown in Figure 1. Instrumentation and Operation. The chip-HPLC-MS instrumentation is based on a previously developed setup.34 It consists of three piston pumps (1200 Cap and Nano Pump, 1260 Iso Pump, bypassed electronic flow sensor, Agilent Technologies Inc., Santa Clara, USA), a 6-port and a 10-port valve (100 µm bore, VICI AG, Schenkon, Switzerland). Polyetheretherketone (PEEK) capillaries (360 µm OD, 50 or 75 µm ID, VICI AG, Schenkon, Switzerland) were used for interconnection. For high speed HPLC-MS separations the microchip was connected via developed microfluidic clamps, which utilize perfluoro-elastomeric (FFKM) ferrules and headless 6-32

Figure 1. Utilized chips for top-port and side-port chip-to-tube connection approaches. For the side-port approaches, the chip is cut open lengthwise. An enlarged side view is shown on the bottom with a SEM image of the opening.

PEEK screws (N-123-04 and N-123H, IDEX Cop., Lake Forest, USA). For the investigated side-port connection approaches elastomeric flat bottom ferrules (FFKM, N-123-03, IDEX) and micro O-rings (0.5 x 0.3 mm, ethylene propylene diene rubber, Alwin Höfert KG, Ammersbek, Germany) were used. A Q-TOF mass spectrometer (6520 Q-TOF, Agilent Technologies Inc., Santa Clara, USA) was utilized in TOF-only mode for all measurements. For ESI-MS coupling the chip was held at ground potential via implemented electrodes and positioned at a distance of about 2 mm in front of the MS orifice, which was set to 3000 V. The MS was operated with 5 L·min-1 drying gas at 300 °C and 100-1000 m/z mass range. The standard acquisition rate was 4 spectra per second, high-speed separations were performed at 16 spectra per second. A schematic drawing of the setup is shown in Figure 1. Compared to our previous setup34 it was further developed by the addition of a pressure sensor (DURATEC Analysentechnik GmbH, Hockenheim, Germany) to monitor the pressure shortly after the on-chip cross in elution mode. Sample injection is realized on-chip by directed flow steering utilizing external valves. This allows to void-volume-free direct a defined portion of the sample flow to the column via the injection cross, as described previously.35

RESULTS AND DISCUSSION A key aspect for the realization of high speed and high pressure chip-HPLC-MS turned out to be the fluidic world-to-chip interface connecting the chip to HPLC-pumps. For this purpose we designed different chip-to-tube interfaces and evaluated them for their applicability in a respective chip-LC setup. Key characteristics in this context are the pressure resistance, the dead volume and the ease of operation. A connection of microfluidic glass chips to tubing can be realized either via access holes in the top chip-layer or versus the front side with open channels ending there. With a side-port approach it is in principal easier to avoid dead volumes associated with common and rather large conical access holes. In the current study we developed and compared three side-port approaches with a further developed top-port clamp interface.34,35


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For the side-port approach we utilized microfluidic chips which were cut open in a way that the channels end at the chip side. Exemplary pictures of a chip with powder blasted access holes and a chip after cutting, along with a scanning electron microscopic (SEM) image of the tiny channel opening are shown in Figure 1. Three different approaches were examined to connect these channel openings with a width of 90 µm and a depth of 40 µm to HPLC-tubing. An essential aspect of the investigations was the high-pressure stability which was examined in respective experiments. To this end the chip was connected to an HPLC-pump while surplus channels were sealed with glue. The flow of the HPLC-pump was then increased stepwise, while the pressure within the chip was monitored with an additional sensor, as described in Figure S-1 in the supporting information. The first examined side-port approach was to simply mount common HPLC tubing at the blunt side of the chip. In order to improve the sealing of the utilized 1/16 in. PEEK tubing it was engraved by laser ablation, generating a cavity to house a micro O-ring (0.5 x 0.3 mm).23 Via an attached metal ferrule the tubing was then pressed versus the flat chip surface. A schematic drawing of this interface is shown in Figure 2a and a photograph in Figure 2e. With this setup we achieved a pressure stability of up to 180 bar. The respective data are shown in Figure S-2 in the supporting information. As the integration of micro O-rings at the opening of PEEKtubing is a rather elaborate process, we evaluated the use of common elastomeric flat bottom ferrules, to directly press capillary tubing against the chip side. As this does not rely on laser engravement it works with various capillary materials including fused silica as shown in Figure 2b and g. This more basic approach worked quite well, but with a lower pressure stability of about 100 bar (see Figure S-2b). A challenge for both side-port techniques was the exact positioning of the tubing at the tiny on-chip channel openings. For this purpose we designed a metal housing for the chip with predefined threaded holes to align the tubing with the channel openings, as shown in Figure 2f. In daily practice, however, the exact and reproducible alignment remained difficult. This problem can be circumvented by directly fusing a glass capillary to the channel opening by laser welding. For this purpose both joining partners are aligned to each other and brought in contact under defined mechanical tension. With the aid of a CO2-laser the fused-silica capillary was directly fused to the glass surface of the chip. This results in a seamless glass-to-glass connection and a corresponding void-volumefree channel to capillary transition, as documented in the photograph in Figure 2h. A more detailed description of this process can be found in Figure S-3 in the supporting information. If the channel dimensions (90 µm x 40 µm) and the inner diameter of the capillary (75µm) match well, dead volumes can be completely avoided, as shown in the microscopic image of the junction in Figure 3b. Although the glass chip with the fused capillary appeared mechanically fragile the connection proofed to withstand pressures of about 90 bar. After we studied the pressure stability of the different chipto-tube interfaces we evaluated the dead volumes and the induced peak broadening in another set of experiments. To this end the microfluidic chip was connected to a fused silica capillary (ID: 75 µm) via the respective interface and flushed with

Figure 2. Illustration of the developed world-to-chip interfaces. a) 1/16 in. PEEK tubing with embedded micro O-ring seal. b) Capillary with elastomeric flat bottom ferrule. e-g) Photograph of the interfaces and the utilized housing. c) Laser welded fused silica capillary. h) Close-up picture of fused capillary, additionally recoated and stabilized by glue. d) Top-port connection clamp in exploded view drawing. i) Picture of three mounted clamps.

10 µL·min-1 methanol with 0.1% formic acid. Via a nanoinjection valve 5 nL of a 7-amino-4-methylcoumarin solution were injected. The peak broadening was determined by comparing the sample plug widths within the fused silica capillary shortly before the interface and on the microfluidic chip directly after the interface. A schematic illustration of the utilized setup is shown in Figure S-4 in the supporting information. The band broadening was calculated as the difference of the averaged full width at half maximum (FWHM) of the detected peaks before and after the interface. The reported band broadening was corrected for the diffusive broadening along the fused silica capillary between the detection point and the microchip. Representative signals of the detected peaks before and after the interface, along with the calculated band broadening from triplicate runs are shown in Figure 3. A significant peak broadening is only evident for the clamp interface, as expected due to the considerable dead volume. The on-tube sealing with embedded micro O-rings could not be investigated in the same manner, because of the opaque nature of PEEK tubing. These studies reveal that the side-port ap-



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proaches exhibit excellent performance with regard to dead volumes, as interface induced peak broadening is

Figure 3 Band broadening studies. Diagrams of the detected peaks before and after the chip-to-tube interfaces and calculated band broadening with the standard deviation of three consecutive repetitions. The inserts in b) and c) show microscopic images of the chip-to-tube transitions.

Table 1 Chip-to-tube interface characteristics

minimized or even absent. A summary of the findings concerning peak broadening and pressure resistance is given in Table 1. As most works in the literature report solely on the working pressure readout of the HPLC-pump, rather than that of a pressure sensor close to the interface, we added these values in brackets as well for a better comparability. While the side-port connections showed an excellent performance with regard to dead volume and peak broadening the pressure stability appeared to be insufficient for the intended realization of high-speed separations with packed columns on a chip. As consequence we further developed and investigated a top-port connection approach using removable connection clamps which previously proofed to withstand pressures of up to 200 bar.34 Within these a capillary is pressed via an elastomeric ferrule into a powder blasted connection port of the microchip. With an optimized design utilizing a 6-32 PEEK screw, pressing on a special metal insert with an angled hole to house the ferrule we achieved an improved pressure stability of at least 360 bar. Technical details on the setup and a plot of 3 repetitive pressure measurements can be found in Figure S-1 and Figure S-2 in the supporting information. The experiments revealed that the pressure resistance was not limited by the chip interface but by the pressure stability of the utilized PEEK capillaries. To circumvent this issue we tried fused silica capillaries instead, but the fixation of the capillaries turned out to be challenging, as they slipped out of the ferrules at pressures of about 340 bar. While the pressure stability of this improved clamp outperforms the three side-port approaches the dead volume is significantly higher. This is induced by the powder blasted connection holes, which have an opening of about 1100 µm and taper off to about 400 µm. The ferrule is pressed into the connection hole to about half its depth, guiding the capillary to the bottom of the chip hole, as shown in the insert of Figure 3c. This leaves an estimated dead volume of about 60 nL. These studies revealed the clamp approach as the method of choice for the intended highpressure and high-speed chip-HPLC-MS application, due to the highest pressure stability and ease of use in daily practice. The higher dead volumes and respective peak broadening as documented in Figure 3c were found to be uncritical as we use an on-chip injection method, as described previously.34,35 After this successful development of an advanced highpressure chip-HPLC-MS system it was applied to realize highspeed chip-HPLC-MS separations. In a proof of concept study we chose the isocratic separation of the herbicides fenuron and fluometuron as model application. For this purpose the elution


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pump was operated at a maximum of 400 bar which generated an effective pressure of about 230 bar at the injection cross. This resulted in a chip-HPLC separation of the compounds in less than 6 s, as shown in Figure 4. This demonstrates the potential of the presented approach to enable HPLC-MS with so far unsurpassed analysis speed. Such high-speed separations are of great interest not only for high throughput screening 36 or multidimensional separations as documented by the recent literature, reporting in part even faster LC separations with optical detection.37–41

Figure 4. Ultrafast separation of the herbicides fenuron and fluometuron via chip-HPLC-MS (TIC). Column: ProntoSIL C18 SH, 3 µm, 35 mm. Elution: MeOH/H2O (80/20 vol%) with 0.1% formic acid at 10 mm·s-1 and 230 bar.

CONCLUSIONS Pressure resistant chip-to-tube interfacing with a low dead volume is an enabling technology for chip-based high-speed HPLC-MS. While side-port approaches show minimal dead volumes, top-port interfacing allows to work at highest pump pressures of 500 bar. While the high-pressure stable and reusable top-port clamps were the method of choice in this study, the side-port approaches are very appealing for applications where lowest dead volumes are needed such as in off-chip injection or off-chip detection strategies.

ASSOCIATED CONTENT Supporting Information As noted within the article. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author * Tel.: +49 341 97 – 36091; E-mail: [email protected]

ACKNOWLEDGMENT We thank the Deutsche Forschungsgemeinschaft and the Arbeitsgemeinschaft industrieller Forschungsvereinigungen for funding.

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Evaluation of Pressure Stable Chip-to-Tube Fittings Enabling High

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