WO2002016046A1

WO2002016046A1 - Moving liquid into and along micro-fluidic channels

Info

Publication number: WO2002016046A1
Application number: PCT/GB2001/003528
Authority: WO
Inventors: Ruth Elizabeth Harper; Linda Jane Mccausland; George Richard Morgan; John Patrick Perkins; Paul Nicholas Smith; John William Stairmand; John Andrew George Temple; Simon Dennis Roe; Andrew Robert Lewin; William David Griffiths; James Alexander Purvis
Original assignee: Accentus Plc
Priority date: 2000-08-18
Filing date: 2001-08-06
Publication date: 2002-02-28
Also published as: GB0020487D0; AU2001276517A1

Abstract

Liquid is introduced into a channel (12), of cross sectional dimension of the order of 10 microns to 100 microns, of a micro-fluidic device by creating electrically charged aerosol droplets, of diameter of the order of 1 or 2 microns, at the entrance to the channel (12). The aerosol droplets are encouraged to move along the channel (12) by application of electric voltages to a series of electrodes positioned along the length of the channel (12). Ultrasonic vibration of a conical structure (15) is the preferred method of forming the aerosol droplets.

Description

Moving Liquid into and along Micro-Fluidic Channels

The invention relates to a method and apparatus for moving liquid into and along micro- fluidic channels and application of the method and apparatus for moving liquid along micro-fluidic channels to drug delivery.

Micro-fluidic ^'devices^' comprise intercommunicating channels and reaction chambers on a small-scale (sub- millilitre, micro-litre and nano-litre 'Scale, in channels below su -millimetre transverse dimension and typically of micron size transverse dimension). These devices have been manufactured using micro-machining techniques and the techniques of electronic integrated circuit manufacture and are sometimes referred to as a "lab on a chip" .

Such micro-fluidic devices have applications in home diagnostics, drug discovery and preparation, highly parallel analysis, micro-total analysis systems, manufacturing avoiding scale-up issues, and rapid prototyping of chemical and biological reactions. Micro- fluidic devices also have potential applications in drug delivery. Conventional propellant -based systems of drug delivery involving dry powders have a number of drawbacks . Thus , there is a requirement for environmentally-friendly propellants, the drug may not be effective when inhaled as it may remain'"in the throat region of the patient rather than be deposited into the lung, the propellant may decrease the biological activity of the drug and some pharmaceutical materials are unstable when converted 'to a dry powder or unstable as they contain a radioactive isotope and for which conversion to a dry form is not desired. Hence there are requirements for improved drug delivery. Causing liquid to enter the channels of micro- fluidic devices, controlling the volume and controlling the flow within the channels presents problems. Use of electrical charging of liquid droplets has been described with reference to the transport of fluids . For example WO 00/50880 (Isis Innovation) mixes two liquid components to form a sample for mass spectrometry. Liquids are pumped along microchannels to a mixing chamber, ejected from a capillary tube as droplets with a size of around 100 micrometres after which the liquid droplets are electrically charged and directed to a sampling cone of a mass spectrometer. However in WO 00/50800 electrically charged liquid droplets are not directed 'to travel along micro-fluidic channels. US 5,453,163 (Yan) describes a method of packing a capillary column with an internal diameter of from less than 10 micrometres to about 500 micrometres with aluminium oxide based particles around 3 micrometres. One end of the capillary tube is immersed in a slurry of packing material, here aluminium oxide and the other end of the tube is connected to a buffer solution. Application of a voltage between the ends of the capilary tube allows the tube to be packed uniformly with aluminium oxide packing material. Electrokiήetic and electroosmotic flow allow the charged solid particles of packing material to fill the tube, However US

5,453,163 does not describe the formation of electrically charged aerosol droplets and their transport along micro- fluidic channels.

It is an object of the present invention to address these problems and to provide a relatively inexpensive method and apparatus for moving controlled volumes of liquid into and in micro- fluid channels. The invention provides, in one of its aspects, a method of moving liquid into and/or along a micro-fluidic channel comprising forming the liquid into electrically charged aerosol droplets at or close to an entrance to the channel, 'the size of the droplets being small compared with the transverse dimensions of the channel , and providing an electric field in the channel so as to encourage flow of the charged aerosol droplets into the channel .

Preferably, the electric field in the channel is such as to both encourage droplet flow into the channel and movement of aerosol droplets along the channel .

By pulsing the electric field, it is possible to propel pulses of aerosol droplet flow into and along the micro-fluidic channels.

The invention provides, in another of its aspects, an apparatus for moving liquid into and/or along a micro- fluidic channel comprising a device for converting the liquid into aerosol droplets the size, of which is small compared with the transverse dimensions of the channel , the device being positioned to form the droplets at or close to an entrance to the channel, means for imparting an electric charge to the droplets, and at least one control electrode in or adjacent to the channel such that, in use, aerosol droplets are cause ^~t^~ϋ move into and/or along the channel by application of electric potential to the control electrode. The invention provides in another of its aspects an apparatus for moving liquid into and/or along a microfluidic channel for _.application in the delivery of a drug in aerosol form for inhalation purposes. The device ^'for converting .the liquid into aerosol droplets may comprise a pressurised spray nozzle, the outlet of which is positioned at the entrance to the channel .

Preferably, the device for converting the liquid into aerosol droplets comprises a surface along which liquid can flow and which tapers to a point located at or close to the entrance to the channel , and means for imparting ultrasonic vibrations to the surface.

Conveniently, the means for imparting electric charge comprise an electrode at or close to the point at which aerosol droplets are formed.

By droplets the size of which is small compared with the transverse dimensions of the channel , we mean droplets of diameter which is typically not greater than about 1/lOth of the smallest transverse dimension of the channel. However, for some applications it is ^'desirable to have droplets of much smaller diameter, for example down to droplet sizes of the order of 0.1 micron in diameter.

A specific apparatus and method embodying the invention will now be described by way of example and r with reference to the drawings filed herewith, in which:

Figure 1 is a sectional view from above of part of a micro- fluidic device,

Figure 2 is a section on the line 2-2 in Figure 1; and Figure 3 is a graphical representation of an example of a pattern of voltages to be applied to electrodes of the device.

Referring- to Figure 1, a partly cut away portion of a micro-fluidic device 11 is shown. A micro-fluidic channel 12 is formed in the device and leads from a side surface of the device to a further part of the device which may comprise a sensor or, as represented by dashed lines, a reactor chamber 13. The channel 12 may have any shape in cross -section but may typically be of rectangular, square, or circular cross -section. Depending upon the design and application, the typical transverse dimensions of the channel 12 are of the order of 10 microns to 100 microns. A typical length of the channel 12 from the side surface_. of the device to the sensor or reactor chamber 13 is a few millimetres up to a typical maximum of 1 cm.

Secured in fluid tight sealing engagement with the side of the device 11, and so as to be in communication with the channel 12, is a macroscopic supply channel in the form of a tube 14, which is square in cross -section and of diagonal diameter typically of the order of 1 millimetre. Mounted within the tube 14 is a cone structure 15 having diagonal arms 16 (see Figure 2) by which the structure is affixed to the tube 14 with the conical portion centrally located and the^~point 17 of the cone projecting just into the entrance to the micro- fluidic channel 12. Depending upon the application and the required aerosol droplet size (see below) the cone angle of this conical ^• structure 15 may be between 10 degrees and 80 degrees. In use, the cone structure 15 'is vibrated at ultrasonic frequency. This is achieved by fabricating the cone itself from piezoelectric material or positioning a piezoelectric plate (not shown) in contact with the cone structure 15 and providing electrical connection (not shown) to the piezoelectric material. In this way, a standard well-known form of ultrasonic driver can be connected to provide ultrasonic vibration of the conical structure 15.

Flow passages 18 (see Figure 2) between the conical structure 15 and the walls of the tube 14 provide a path for liquid in .the tube 14 to flow on to the outer surface of the conical structure 15 and, when ultrasonic vibration is applied to the latter, be broken up into aerosol droplets 19 at the entrance to the micro-fluidic channel 12. The size of aerosol droplets formed in this way depends upon the radius at the point of the conical structure 15 and the frequency of vibration.

Formed in the structure of the micro-fluidic device is a series of pairs of electrodes extending one on each side of the micro-fluidic channel 12. The first pair of electrodes, marked C, are positioned at the entrance to the channel 12 and serve to induce electrical charge on the aerosol droplets 19 as these are formed. Figure 1 shows 'two further pairs of electrodes of the series marked Fl and' F2 but there may be 10 or-more pairs of such electrodes along the length of the channel 12^'. Typical dimensions of the electrodes will be of the order of 10 microns to 100 microns in width spaced apart at 10 micron to 100 micron intervals .

In use, when ultrasonic vibration is applied to the conical structure 15 and liquid pumped into the tube 14, and a voltage (which may be positive or negative) applied to electrode pair C, electrically charged aerosol droplets are formed at the entrance to the channel 12. By stopping the ultrasonic vibration, formation of aerosol droplets ceases and, thus, movement of the liquid into the channel 12 can be stopped. This enables the flow volume to be controlled.

The charged aerosol droplets 19. are encouraged to move along the channel 12 by appropriate voltages applied to the series of electrode pairs FI, F2 , etc. Figure 3 shows a pattern of voltages V against time t applied to the electrode pairs FI, F2, F3 appropriate for encouraging a pulsed sequence of charged aerosol droplets to move along the channel 12 into the sensor or reactor chamber 13.

Calculations indicate that liquid can be . introduced and moved in micro-fluidic channels in this way as an aerosol of 1-2 microns droplet size more effectively than by direct pressurised liquid flow. There will be some loss of aerosol droplets to the walls of the channel 12 but most of the aerosol droplets remain suspended in the channel making no contact with the walls. Aerosol droplets less than approximately 1 micron in diameter can be expected to travel for approximately 1 cm without touching the channel walls.

The rate of reactions in the microfluidic reaction chamber may be enhanced above the rates attainable with bulk liquid flows if the two or more materials to be mixed and which are to react together are in the 'form of aerosol droplets. When reactions take place in the microfluidic reaction chamber the droplet size may increase due to coalescence to an extent that liquid droplets settle out of the gas phase and form a bulk liquid. Under these conditions bulk liquid formed in the reaction chamber may be converted to droplets for drug delivery by use of a second micro-fluidic device combined with ultrasonic means for generation of droplets.

The invention is not restricted to the details of foregoing example. For instance, the conical structure 15 and associated tube 14 need not necessarily be symmetrical. Instead of a symmetrical three-dimensional structure these components may, for example, have a quasi-three-dimensional shape formed by etching techniques. In this way, for example, the cone could be formed from base material by undercutting but leaving a supporting rib.

The series of electrode pairs need not necessarily be equisized and equispaced as shown. There may be variations in size and spacing and this could lead to improved efficiency of movement of the aerosol droplets. For example, appropriate positioning of electrodes may assist in supporting the aerosol droplets against drift under the influence of gravity and thus enable movement over longer path lengths if required. Similarly, other patterns of time variation of applied voltage^'s from those shown in Figure 3 may be adopted and square wave or pulsed voltages may be more appropriate.

A single supply tube 14 and micro-fluidic channel 12 are shown, but it will be appreciated that a microfluidic device may have two or more such inputs and these may lead two or more liquid reagents into a single reaction chamber 13, a form of configuration required, for ^'example, for rapid chemical reaction prototyping. A single supply tube may also contain two or or more liquid components .

The control and effectiveness of ultrasonic vibration for producing aerosol droplets is preferred, but it may, for example, be replaced by a pressurised nozzle spray such as is used for scent bottles.

When the microfluidic device is used for drug delivery examples of components that can be mixed together include liposomes with DNA, vaccines with an adjuvant or stabiliser as well as enzymes for activating inert drugs to an activated form. Pharmaceutical material for use in microfluidic devices can be prepared by a process of cell lysis combines with a fluidic vortex mixer as described in EP 0 967 269 Al (AEA Technology) . In addition the microfluidic device may be customised for individual patients and deliver 'people specific' medicine where the amount of drug to be delivered may be related to the physiological characteristics of the patient such as breathing rate. Microfluidic devices of the type describe herein may also be used for applications other than drug delivery such as for propulsion systems in satellites and synthesis of ceramic powders .

Claims

1. A method of moving liquid into and/or along a microfluidic channel comprising forming the liquid into electrically charged aerosol droplets at or close to an entrance to the channel, the size- of the droplets being small compared with the transverse dimensions of the channel, and providing an electric field in the channel so as to encourage flow of the charged aerosol droplets into the channel .

2. A method as claimed in claim 1, wherein the electric field in the channel is such as to both encourage droplet flow into the channel and movement of aerosol droplets along the channel .

3. A method as claimed in claim 1 or claim 2 , wherein the electric field is pulsed.

4. Apparatus for moving liquid into and/or along a micro-fluidic channel comprising a device for converting the liquid into aerosol droplets the size of which is small compared with- the transverse dimensions of the channel, the device being positioned to form the droplets at or close to an entrance to the channel, means for imparting an electric charge to the droplets, and at least one control electrode in or adjacent to the channel such that, in use,, aerosol droplets are-caused to move into and/or along the channel by application of electric potential to the control electrode.

5. Apparatus as claimed in claimed 4, wherein the device for converting the liquid into aerosol droplets comprises a pressurised spray nozzle, the outlet of which is positioned at the entrance to the channel.

6. Apparatus as claimed in claim , wherein the device for converting the liquid into aerosol droplets comprises a surface along which liquid can flow and which tapers to a point located at or close to the entrance to the channel, and means for imparting ultrasonic vibrations to the surface.

7. Apparatus as claimed in any one .of claims 4 to 6 , wherein the means for imparting electric charge comprise an electrode at or close to the point at which aerosol droplets are formed.

8. Apparatus as claimed in any one of claims 4 to 7 , wherein the device for converting -liquid into aerosol droplets is such as to form droplets of diameter less than 1/lOth of the smallest transverse dimension of the channel .

9. Apparatus as claimed in claim 8 , wherein the device for converting liquid into aerosol droplets is such as to form droplets of diameter less than 1/lOOth of the smallest transverse dimension of the channel.

10. A method of moving liquid into and/or along a microfluidic channel substantially as hereinbefore described with reference to the drawings filed herewith.

11. Apparatus for moving liquid into and/or along a micro-fluidic channel substantially as -hereinbefore described with reference to, and illustrated in, the drawings filed herewith.