Novel technology for manipulation of fluids on a microscopic scale has the potential to revolutionise drug delivery. Professor Jaap den Toonder of Philips Research Europe outlines a European project that aims to make the prospect a reality
Microfluidics is the science and technology of manipulating and analysing fluid flow in structures of sub-millimetre dimensions. The availability of microfluidics technology is essential for the development of advanced products in a variety of application areas, the most important of which is the biomedical field. In this area, significant trends are emerging in which micro-fluidics technology plays an essential role and one example is controlled drug delivery.
In this application, a drug delivery system is either implanted in the human body, or attached to the skin, and medicine is released in a controlled way into the body. Depending on the disease treated, the release rate may be fast or slow, and continual or periodic. The exact control of the dosing of drug is critical for treatment effectiveness but also for preventing overdose. The system needs to be small, and the drugs are often applied in liquid form, in very small quantities. Micro-fluidics is, then, essential in actively controlling the release.
Another example of a biomedical application are biosensors. The purpose of a biosensor system is to analyze biological fluids like blood, urine, saliva etc., and to detect certain biological substances such as DNA or specific proteins or enzymes, with the aim to diagnose the possible presence or the level of disease. An essential feature of biosensors is the small size of the systems. What is usually envisioned is a credit-card size bio-chip containing a system of microscopic channels and flow chambers through which a small amount of fluid is transported, in which required chemical reactions take place, and in which the detection is being carried out, see Figure 1.
The detection can be carried out according to different physical principles: electrical, magnetic, or optical for example. A biochemical assay needs to be designed to achieve this, for example by labelling the biomolecules being sought with magnetic beads and detecting them with a magnetic probe.
Many biochemical operations are necessary to complete this assay, and all these must be carried out on the biochip. The microfluidics is essential , not only for transport of the fluid needed, but also for local mixing (for example in micro-reaction chambers), valving, or specific flow pattern generation (for example near the detection site), are desired.
Many (industrial) research groups are studying ways of micro-fluidic manipulation. Often these are based on downscaling of existing flow devices, such as pumps, valves, or mixers. Others use techniques based on physical principles that are advantageous at small scales, such as surface tension, surface energy patterning, or electro-osmosis. These techniques have various limitations: some are still relatively large, hampering true integration in a microfluidic device, whereas for most it is impossible to achieve local manipulation of the fluid or the generation of complex fluid patterns. The latter would be advantageous for example in many biosensor applications.
The, recently started, European research project ARTIC deals with a completely novel method of fluid manipulation technology in microfluidics systems, inspired by nature - namely by the mechanisms found in ciliates. This approach enables effective local fluid manipulation, and the possibility to generate complex flow patterns.
One particular microfluidics manipulation process "designed" by nature is that due to a covering of oscillating cilia over the external surface of micro-organisms. A cilium can be viewed as a small hair or flexible rod (in protozoa: typical length 10 µm and diameter smaller than 100 nm) attached to the surface (see Figure 2). The cilia move back and forth collectively in a particular concerted manner, and are in this way quite effective in generating flow: the swimming speed of Paramecium, for example, can be more than 1 mm/s. Apart from propelling micro-organisms, other functions of cilia are in cleansing of gills, feeding, excretion, and in reproduction. The human trachea, for instance, is covered with cilia that transport mucus upwards and out of the lungs. Cilia are also used to produce feeding currents by sessile organisms, covered with cilia, and that are attached to a rigid substrate by a lengthy stalk. The combined action of the cilia movement with the periodic lengthening and shortening of the stalk induces a chaotic vortex. This results in a chaotic filtration of the surrounding fluid.
The aim of the ARTIC project is to develop artificial cilia, on the basis of polymer microactuators, that can be integrated in microfluidic systems, and that can be used for fluid manipulation, in particular pumping. The movement of the artificial cilia can be actively controlled, preferably using a magnetic field or an electrical field. To achieve this, the project team will start by studying the natural cilia in terms of underlying mechanisms, energy consumption, and effectiveness. The knowledge obtained will be translated into advanced mechanical, electro-magnetic, and fluid flow models that will be used to generate optimum designs and specifications for the artificial cilia to be made. Based on these specifications, (composite) materials will be synthesized that can be used as a basis to fabricate the artificial cilia.
To validate the effectiveness of fluid manipulation using artificial cilia, the team will design and set up a basic experiment.
The final test will consist of fluid flow characterisation in an elementary micro-fluidic device containing the micro-actuators or artificial cilia, as conceptually sketched in figure 3. It consists of a microfluidic channel device in which the artificial cilia are integrated. By magnetically or electrically actuating the artificial cilia, fluid flow should be generated. The flow will be characterised using special flow velocity measurement techniques.
The aim is to create a liquid pumping effect with typical flow rates in the order of 10 pl/min to 1µl/min, which is a suitable range required by biosensor-applications. The liquid has a viscosity around 10-6 m2/s (water-like, suitable for many biological fluids), and the micro-channel has a typical cross-section of (100x100) µm2 and a length in the order of 1 cm.
The project consortium reflects the range of activities that are required to reach the goals of the project. Philips Research and Applied Technologies (The Netherlands) is project co-ordinator and brings the application and the technology knowhow. The Centre for Biomimetics and Natural Technologies, University of Bath (UK), will look at the biological ciliated systems and study underlying mechanisms, energy consumption and effectiveness. This knowledge serves as an inspiration and a reference for the technical, artificial cilia processes and technology.
A team of modelling groups will develop and use models to simulate the magneto-mechanical or electro-mechanical deformation behaviour of the artificial cilia and the fluid-cilia interaction, in order to extract design rules for the materials, geometries, and driving mechanisms to be developed: The University of Groningen (The Netherlands) for mechanical modelling, Polytechnic University of Bucharest (Romania) for magnetic modelling and design, and Eindhoven University of Technology (The Netherlands) for fluid flow modelling.
The synthesis of tailor-made polymer-based electromagnetic materials, as well as the microstructuring into cilia-geometries will be carried out by the University of Freiburg - IMTEK (Germany) and Liquids Research Ltd (UK).
The micro-channel device manufacturing and integration of the artificial cilia is the task of Philips Research and Applied Technologies. The microfluidic flow characterisation, finally, will be carried out by Delft University of Technology (The Netherlands).
Artic started in December 2006, and will run for four years. The project is partly funded under the European Sixth Framework NMP Programme and partly by the project members.