CETONI Elements now supports precision scales!

Integration of a high-resolution precision balance in your application offers you precise information at every point in your process and thus additional security. With the help of our flexible laboratory automation software CETONI Elements You can now integrate precision scales into your process and use them for targeted control of your high-precision dosing, automation of processes or permanent process monitoring.

Simply install the latest QmixElements update and getting started!

The CETONI Elements software now supports the integration of laboratory balances via the balance plug-in. A device driver for Sartorius scales (Entris, ED, GK and GW scales) is already included with the release of the plugin. This means that you can easily integrate your existing Sartorius laboratory balance into the CETONI Elements software. Thus you not only extend your CETONI system with the possibility to weigh substances, substances or dosed liquids, but you can also synchronise or completely automate processes as you wish in interaction with other CETONI hardware and your own analysis.

CETONI Elements with two Nemesys syringe pumps and a scale

The configuration of the scale devices is carried out, as you are used to from the CETONI Elements software, via the device configurator. Simply create a new configuration or add the scale to an existing configuration and save it. After activating the configuration, the scale is available in the software.

Elements Device Configurator

In the software, the scale is then displayed as a normal analogue input channel in the list of I/O channels ❶. There you can see the current value at any time and tare the scale via the context menu of the channel. Like all other analogue channels, you can also record this channel in the graphic logger ❷ or in the CSV logger and use it to create control channels. Due to the real-time recording of the measured value in the graphic logger, dynamic weight changes, e.g. when dosing into a sample vessel, can be visualised and followed very well.

List of I/O channels with scale channel

The measuring channel of the scale can be read via the script system and taring of the scale is also possible via a script function. This allows the scale to be easily integrated into more complex analyses and automated processes.

Cell-on-Chip: More and more research fields aim to miniaturize and transfer cell cultures and complete assays to a lab-on-a-chip system. On the one hand, the reduced analysis areas mean that less sample is required, and on the other hand, it is possible to observe cell behaviour in real time. High-precision and pulsation-free dosing systems are the key to successful implementation of such lab-on-a-chip procedures. Our CETONI nemesys syringe pumps are used in numerous laboratories for the realization of microfluidic analyses.

We have therefore compiled 10 tips from which beginners and experienced researchers can benefit in their work.

1. The right chip material

The demands on the chip material for cell cultivation are high. The material should not only be biocompatible, but also have a high transmission property. For this reason, most of the work is based on the polymers PDMS (polydimethylsiloxane) or COC (cycloolefin copolymers). Nevertheless, PDMS also has some disadvantages due to its gas permeability and it is not resistant to chemicals, which means that COC or glass are becoming more and more important.

2. CO2-independent cell culture media

CO2-independent media are ready-to-use formulations which independently build up HEPES-(2-(4-(2-hydroxyethyl)-1-piperazinyl)-ethanesulfonic acid)- a buffer system, e.g. based on mono- and di-basic sodium phosphate and β-glycerophosphate. Therefore, the supply of CO2 is not necessary to maintain the buffer system.

3. Separated cell reservoirs

The use of cavities (lowered cell reservoirs) can both create a microclimate within the cell reservoir and protect the cells from shear stress, both of which are otherwise disadvantages of flow cell cultivation.

4. Coating favours cell adhesion

Many different wet chemical coating substances are known to promote cell adhesion. Collagen, gelatine or the substance mixture Matrigel® are most commonly used. Depending on the cell culture used, the suitability must be investigated on the basis of a time-dependent growth profile.

5. Exact control of the flow

A too high flow rate can not only prevent the adhesion of the cells, but can even detach them, both of which are a consequence of the shear stress that is too high in this case. A flow rate that is too low, on the other hand, would not mean a sufficient supply of nutrients for the cells. Ultimately, a compromise must be chosen in which the flow rate is adapted to the glucose consumption of the cells.

6. Constant temperatures

Miniaturized cell-based sensors allow the holistic statement on cell physiological processes in real time through incubator-independent observation. However, this requires the maintenance of 37 °C for the cultivation of human cells. In this respect, different approaches are taken when heating an incubator-independent system. Peltier elements, heating foils or slides, which have been provided with an ITO (Indium Tin Oxide) coating. The ITO coating offers an even temperature distribution and an excellent optical transparency for simultaneous light microscopic examinations of the cell culture.

7. Eliminating gas bubbles

In addition to the general aim of air-free filling of the system, the greatest challenge in microfluidics is to reduce remaining gas bubbles in the chip system. Very often media are degassed beforehand or so-called “bubble traps” (degasser) are used in the process. These not only represent an expense in terms of equipment and a potential risk of contamination, but also make pulsation-free conveying more difficult. Another approach makes use of Henry’s law, where the proportion of gas dissolved in a liquid is proportional to the pressure. In a figurative sense, the increase in pressure in the system favours the solubility of the smallest gas bubbles in the system, which thus lose their disturbing effect. This effect can be exploited by the correct placement of a back-pressure regulator (BPR), which provides a fluidic resistance and thus ensures the desired pressure increase depending on the set flow rate.

8. Continuous-flow

In order to expose cells to conditions as homogeneous as possible and to supply them continuously with nutrients, a continuous and low-pulsating flow is essential. Subsequent incubation with appropriate test substances allows meaningful and reproducible results to be generated afterwards.

9. Reduce the risk of contamination

A contaminated cell culture is a nightmare for every cell researcher. Especially in incubator-independent cell-on-chip research, the risk of contamination is correspondingly high and should be monitored particularly carefully. The use of special sterile filters before and after the chip system supports contamination-free cultivation. Special attention should of course be paid to the fluid connection technology and the conveyor system. Through the targeted use of disposable or autoclavable components such as syringes and valves, the modular nemesys syringe pumps are ideally suited for this purpose.

10. The cell seeding

The cell seeding process in the chip system is particularly critical because the uniform cell distribution has a decisive influence on the validity of the experiment. The introduction of the cells into a fully assembled microfluidic system requires either some fingertip sensitivity or constructive mechanisms that ensure an even cell distribution. The following methods for cell trapping can be distinguished: hydrodynamic, optical, magnetic, electrical or acoustic.

Nowadays, medical science needs to be more innovation-driven and personalized than ever. That’s why microfluidics play a critical role in researching new therapeutic approaches. CETONI has a clear mission: with innovative solutions, we not only empower our customers to be part of the development process, we even allow them to take charge.

Unlike conventional methods, individualized medicine focuses on humans instead of diseases. The primary goal is patient-oriented interventions without time loss or side effects. The establishment of in-vitro assays, as a first step toward authoritative effectiveness tests, has paved the way for developing personalized therapies in a way that is sensible and available to the masses.

Conventional processes are reaching their limits

Cell cultivation is usually done in standardized cell culture flasks in a regulated CO2 environment. The enclosed incubation unit maintains a constant temperature, high humidity and sterility. But there is a problem caused by spatial separation between cell cultures and the analysis unit, which makes it impossible to arrive at a holistic conclusion about the real-time physiological process inside the cells. Microfluidic systems, on the other hand, are perfectly suited to the simultaneous analysis of different test substances. Therefore, the development of an automated cell culture for the purpose of reducing costs and time-consuming tasks, as well as the real-time observation of cells, becomes very interesting, particularly with respect to developing personalized therapies.

After a short implementation phase, the miniaturization of laboratory processes, from standardized in-vitro assays in well designs to lab-on-a-chip systems, becomes extremely lucrative in terms of time and cost-savings. Due to the reduced analysis areas inside the chip, the required samples are very small. This technology offers new possibilities, particularly when it comes to cell cultivation. These systems can not only automate cell seeding and supply nutrients to the cell culture. They also allow for toxic stimulation of cells in real time. Since the cell culture areas are very small, only a small number of cells are needed, which can be analyzed in real time, while ensuring a controlled supply of cells through an automatic pump and supply system with a heating unit. In addition, the pump system allows for automated cultivation.

The syringe pump offers enormous advantages for microfluidic applications due to its volumetric delivery principle and minimized pulsation. However, it also has a major disadvantage compared to other pumps: the delivery naturally ends as soon as the syringe is empty. This is why the syringe pump is often used in applications where this is irrelevant because the process is paused from time to time and the syringe can be refilled, such as filling individual cavities during pipetting.

In many applications – especially in flow chemistry – an interruption would not be possible, as this would disturb the steady state that has already been set at the beginning of the process by the flow of eluents (chemicals that react with one another).

This problem can be solved by using two syringe pumps per dosing channel, working alternately. This means that when the first syringe is empty, the second syringe takes over the delivery, while a 3/2-way valve refills the first pump from a reservoir. The first syringe then resumes delivery and the second syringe is refilled.

In order not to generate hard impulses when switching the pumps, flatter acceleration and deceleration ramps (crossflow) must be used instead of abrupt stopping when switching from one pump to the other. For applications at higher pressures, however, this is not sufficient to avoid all pressure or flow rate impulses, since the entire mechanical-fluidic system (including the pump that is currently pumping) is pressurized, while the replenished pump – waiting to be used – is under atmospheric pressure. If you now connect this refilled pump to the application by switching the 3/2-way valve, a pressure compensation takes place, which results in a compensation stream. As a result, a certain volume flows from the pressurized application into the unpressurized pump. This reduces the flow rate in the application and, in the worst case, can even become negative for a short time. This must be avoided.

We solve this problem by increasing the pressure of the refilled pump to the same pressure as in the application before connecting it to the application. We achieve this by using two pressure sensors, several valves and an intelligent software implementation. The refilled pump is first run against closed valves and a pressure comparison is made between the two pumps. Based on the parameters defined by the user, the acceptance criterion is reached after a short time, which assumes that the pressure is equal and the valve can therefore be opened for the application.

Since both pressures are the same at the moment of switching on, there is no pressure compensation and therefore no volume compensation flow. The pressure and volume conditions in the application remain constant as desired. The result is a continuous pulsation-free flow (Conti Flow).

When Sir Alexander Fleming discovered penicillin in 1928, it was by coincidence, more than anything else. He had forgotten to take a bacterial culture from the lab and later notice that a fungus had grown on it. Apparently, this fungus was able to keep the bacteria in its environment at bay. Being a researcher, Fleming wanted to find out how the fungus managed to do this and extract the active substance it produced.

Penicillin made it possible to heal bacterial infections, often caused by minor wounds, that previously killed people in large numbers. But the discovery of penicillin and its first widespread application happened a long time ago. Over the years, other antibiotically active substances were found and used. Meanwhile, humanity has reached a point at which new agents are desperately needed, since various strains of bacteria have become resistant to antibiotics.

Fleming once commented his discovery by saying, “One sometimes finds, what one is not looking for.” Now, the time has come to actively look for such new agents, instead of hoping for their discovery. But where to begin? In the ground! A cubic centimeter of soil contains about a billion lifeforms. If one could cultivate and examine the various species, the chances of finding one or even several promising candidates would be pretty good. Applied to an agar plate (a petri dish with a culture medium), microorganisms multiply and form colonies. However, a small number of fast-growing species usually impede many of the slower species by suppressing their growth. This means that the slower-growing species never register. They do exist in soil, however, apparently because there they find habitats conducive to their growth. So, if you wanted to cultivate them, you would have to offer them those same habitats.

And this is where microfluidics come into play. The so-called segmented flow is one of the wonderful tools in the microfluidic toolbox. This flow is generated in micro-reactors featuring channels with a diameter of 100 to 200 µm. A polar liquid (water) is introduced to an intersection point of a nonpolar carrier flow (oil). Since the two liquids will not mix, individual water droplets will be torn away and join the oil flow. The droplet sizes are very defined and constant and they happen at defined intervals, while being separated from each other by the oil between them. Large amounts of these droplets can be created in a very short time. If the soil concentration in the water is correct, each droplet contains just one individual or very few organisms, existing in their own habitat, where they can procreate and form cultures. Arranged on a coil of narrow tubing, similar to beads on a pearl necklace, they can now be taken to an incubator offering the appropriate growing environment.

Generating such small, defined and segmented flows requires highly precise, pulsation-free and controllable pumps, such as the neMESYS 290N low-pressure pump made by CETONI. Thanks to its excellent dosing properties, substances, such as nutrients, can be dosed into the individual droplets. Also, it is possible to detect clouding and separate promising droplets. The CETONI Elements (QmixElements) software allows users to operate the system comfortably and intuitively. Maybe, this method will lead to a breakthrough one day. While it is the proverbial search for a needle in a haystack, microfluidic methods and high-quality equipment make it possible to miniaturize and automate this process.

In our #CETONIacademy section, we will start discussing the basics of micro-fluidics in regular intervals. The series starts with the term “pulsation-free”, because there is nothing more essential in micro-fluidics than a consistent flow of fluids.

So, what is “pulsation-free”?

The field of micro-fluidics is characterized by applications involving extremely small volumes of fluids in equally small cavities. Numerous applications, such as those found in flow-chemistry, require a steady, pulsation-free flow of fluids, to ensure continuous mixing ratios, even at very short time intervals. The creation and manipulation of compartmentalized flows in biochemical applications also demands such consistency.

In microfluidics, pulsations refer to oscillations of the actual flow rate, whereby the averaged flow rate can be absolutely correct. At extremely small flow rates, which often occur in micro-fluidic applications, pulsation can be strong, in relative terms, and have negative effects on small-scale processes. Even though mechanical components are incapable of delivering completely pulsation-free performance, pulsation can be reduced to such an extent that it can no longer be detected by existing measuring devices or ceases to have an influence on the application process at hand. This state is known as “pulsation-free”.

Driving a car around a corner – with your eyes closed

Syringe pumps allow the volumetric transport of fluids through displacement, using a piston of a defined size, which moves at a defined speed. In order to generate a constant flow rate with a syringe pump, the lateral movement of the piston has to be extremely consistent. In this respect, conventional syringe pumps are often lacking, since the resolution of their drive section is limited. In turn, this leads to pulsation. However, the resolution of the pump’s measuring elements (encoder) is critically important.

The piston’s lateral movement must be generated by a controlled drive system. Commonly, the rotation of an electric motor is converted into linear movement by way of a spindle drive. A position controller checks the actual position or the motor’s rotation angle in regular, small intervals, and compares it with the respective target position. The deviation between actual and target value determines the amount of control necessary for motor, effected by manipulating motor current. A position sensor with a small resolution leads to longer measuring intervals, particularly at slow speeds. Therefore, the controller receives information on the actual position of the piston at relatively long intervals, which complicates control corrections and leads to speed fluctuations.

The following example will make this clearer. Imagine a control circuit, which stipulates that the driver of a car has to drive a certain distance, but may only open his eyes every two seconds in order to check his position and make course corrections. If the experiment is conducted on a straight track at a speed of 20 km/h, it will work reasonably well. However, if the driver has to go around a corner, the likelihood of success is strongly diminished. The vehicle’s path will probably resemble the shape of a polygon, rather than that of a curve, because, when opening his eyes, the driver will be compelled to make strong corrections to his position in order to stay on track.

Maximum Resolution – Maximum Quality

Low sampling rates in syringe drives lead to constant corrections, effected by increasing or lowering motor current. This prevents a smooth and steady operation. Pulsations arise. At CETONI, we therefore rely on the highest quality components and equip our syringe pumps with drives offering a resolution in the sub-micrometer range. As a result, the pulsation of our drives is so low that it does not play a role in the currently established microfluidic processes. Therefore, neMESYS syringe pumps are suitable for microfluidic applications with the highest precision requirements.

Our innovative spirit and the continuing miniaturization of chemical processes drives us to keep developing our micro-fluidic systems, instead of resting on our laurels. That is the only way to fulfill our mission and enable top-level research and development.

Many applications require a continuous media supply independent from the syringe volume. For such cases we have created now a simple and effective solution of a compact valve unit as an ideal supplement to our neMESYS low and medium pressure modules. In combination with a novelty in the configuration dialog of the continuous flow mode in our QmixElements software, the pressure controlled switching, the continuous dosing can be realized easily and quickly. For this purpose, two syringe pumps equipped with this novel valve unit are optimally synchronized in the switching behaviour, whereby a smooth transition is achieved.

Product details

The compact combination of two separate 2/2-way valves and a pressure sensor (up to max. 10 bar) enables you to set up a continuous pumping procedure quick and conveniently – whether for our low-pressure or mid pressure syringe pumps.

The sophisticated valve unit combines two 2/2-way valves and one pressure sensor per module in one compact component. The less space consuming and compact design and practical arrangement allows quick and comfortable access to the fluidic interface (1/4”-28 UNF inlet/outlet).

On the input side, the selected syringe is screwed directly into the valve unit and is thus safely fixed on the module. The fluidic interface for application and reservoir are on the opposite side and are labeled with RES and APP. Visual user support during operation is guaranteed by the LEDs under the respective fluid connection which indicates the current switching position. PPS, FKM and Al2O3 are installed in the valve unit as wetted parts.

Indication of the valve switching position (application / reservoir) by LEDs
Indication of the valve switching position (application / reservoir) by LEDs

For the continuous operation, connect the two RES connections to your reservoir (yellow in the picture) and the APP connections of both pumps to your application (blue in the picture), for example via a T-piece. The valve unit has three fluidic connections with ¼”-28 UNF female thread.

The following overview illustrates how three previously separate products, two valves and one pressure sensor, are now compactly and clearly combined in one product.

Specification

• 3/4-way valve (10 bar max.)
• one integrated pressure sensor (20 bar)
• wetted parts: PPS, FKM, AI2O3
• for neMESYS Low and Mid Pressure Syringe Pumps

You can find detailed information and technical details about our new 3/4-way Contiflow Valve on our product page. We are happy to support you for the realisation of your individual set-up for continuous media supply.

With the new Python integration for the Qmix SDK you can develop small applications in the shortest time, automate certain dosing processes or realize your own analyses. The main advantage of Python is its ease of programming, which significantly reduces the time required to develop, debug and maintain the code. In the following example we show you how easy and fast you can implement an application with Python and the Qmix SDK.

Installation

To install, simply use the Qmix SDK installation package for Windows. The SDK will be installed in a folder of your choice.

Integration

To include the Qmix SDK in your Python script you have to add the path containing the Qmix SDK modules to the module search path. In order for Python to load the shared libraries (DLLs) of the SDK, you must then add the path containing the DLLs to the Windows search path. All details are also available in the online documentation.

import sys
import os
QMIXSDK_DIR = "C:/temp/QmixSDK-64bit_20180626"
sys.path.append(QMIXSDK_DIR + "/lib/python")
os.environ['PATH'] += os.pathsep + QMIXSDK_DIR

Now you can import the modules of the Qmix SDK Python integration.

from qmixsdk import qmixbus
from qmixsdk import qmixpump

The first Python application

Now you can start developing your first application. The following program shows a small example. First a bus object is created, initialized with the path to a device configuration and then the communication is started. Then we create a pump object and connect it to the first pump in the SDK – device index 0. As a test we print the name of the pump with the print function.

def main():
"""
A small example that shows how to use the Qmix SDK for Python
"""
bus = qmixbus.Bus()
bus.open("testconfig_qmixsdk", "")
bus.start()
pump = qmixpump.Pump()
pump.lookup_by_device_index(0)
print(pump.get_device_name())

In the next step we perform a reference run with the calibrate function to determine the zero position of the pump. Before the reference run, we clear any remaining errors (clear_fault) and enable the pump (enable). With the help of a timeout timer we wait until the calibration is finished.

pump.clear_fault()
pump.enable(True)
pump.calibrate()
timeout_timer = qmixbus.PollingTimer(10000)
result = timeout_timer.wait_until(pump.is_calibration_finished, True)
print(result)

The pump is now initialized and we can start dosing. For this we set the units for volume and flow rate to milliliter and milliliter per second. As a test we will output the unit for the flow with the print function. Then we configure the syringe to be used. We use a syringe with 1 mm inner diameter and 60 mm plunger stroke. In line 41 we start the aspiration (aspirate) of 0.02 ml with a flow rate of 0.004 ml/s. With a timeout timer we wait again until the dosage is finished.

pump.set_volume_unit(UnitPrefix.milli, VolumeUnit.litres)
pump.set_flow_unit(UnitPrefix.milli, VolumeUnit.litres, TimeUnit.per_second)
print(pump.get_flow_unit()
pump.set_syringe_param(1, 60)
print(pump.get_syringe_param())
print(pump.get_volume_max())
print(pump.get_flow_rate_max())
pump.aspirate(0.02, 0.004)
timeout_timer.set_period(10000)
result = timeout_timer.wait_until(pump.is_pumping, False)
print(result)

At the end of the program we stop the communication and call the close function of the bus object to release all resources again.

bus.stop()
bus.close()

We hope you got a small impression of how powerful and simple the Qmix SDK for Python is. You can download the Python example from this blog post here.