WO2004074694A1

WO2004074694A1 - Improvements in and relating to circuits

Info

Publication number: WO2004074694A1
Application number: PCT/GB2004/000491
Authority: WO
Inventors: Ian Paul Wilkes
Original assignee: Synthese A Grande Vitesse Limited
Priority date: 2003-02-22
Filing date: 2004-02-09
Publication date: 2004-09-02
Also published as: GB0304082D0

Abstract

The invention relates to a flow circuit comprising at least one flow channel in which is located a flow control means, wherein the physical state of the flow control means is alterable by application of an external stimulus, such that in use, the flow of a material through the circuit can be controlled. The invention further provides a method of controlling flow of a material through a flow circuit having at least one flow channel, the method comprising the steps of (a) locating a flow control means within at least a portion of a flow channel, the flow control means comprising a physical state which is alterable by application of an external stimulus; and (b) applying an external stimulus to or in the region of at least a portion of the flow control means, such that the physical state of the flow control means is altered to alter the flow of the material in the region of said portion of the flow control means.

Description

IMPROVEMENTS IN AMD RELATING TO CIRCUITS

Field of the Invention

5 This invention relates to fluidic circuits and methods of controlling flow of material in a fluidic circuit.

Background to the Invention

.0 It is known to provide fluidic circuit boards in which channels of electrically conductive, semi-conductive and insulating material are etched into a suitable substrate, and around which a fluidic circuit may flow. The channels generally comprise relatively thin open channels which are

L5 closed off by layers of substrate superposed on the channels .

The channels may include valves or gates which may be opened or closed in order to block off or activate certain 0 channels within the circuit board to allow electrical flow through those channels. The mechanical or electrical gates or valves are prone to malfunction such that they may be stuck in an open or closed position, thereby preventing electrical flow through a channel or circuit, 5 or effecting continuous flow through a channel or circuit when it is not desired to do so. In such cases, the circuit board generally has to be removed from the appliance in which it is mounted, and if it is possible, repaired; or alternatively if it cannot be repaired, 0 discarded. Repair of the valve/gate can be costly and time consuming, and if the circuit board has to be discarded, this can incur considerable costs in replacing the discarded circuit board. It would therefore be advantageous to provide an fluidic circuit board in which the channels of the circuit can be blocked and unblocked as desired by a user, in any desired position, rather than in discrete positions where valves and or gates are located, and in which the means to block and unblock the channels in any desired position are removable or alterable.

In other technical fields, such as combinatorial chemical syntheses or biochemical synthesis, analysis and prototyping, common methods of achieving said syntheses, analyses and prototyping generally involve providing an array of building blocks such as polystyrene beads, or supports, on which are anchored starting reagents and/or starting reactive functional groups. During use of these substrates, chemical compounds may be built up by sequential addition of chemical or biochemical reagents to the starting reagents and or functional groups, such that complex chemicals or biochemicals are synthesised. For example, one known method of combinatorial chemical synthesis involves providing an array of polystyrene beads on which different starting functional groups are provided on different sets of beads. During a first round of synthesis, a first reagent is reacted with each of the beads, such that each set of beads will produce a different chemical compound. The beads are then analysed and each compound on the beads recorded in a library database, before a second reagent is reacted with each or some of the sets of beads to provide sets of compounds of additional complexity. The analysis and recordal of each of the compounds is continued, followed by further syntheses and recordal of the resultant compounds, until desired. In this way, a large library of chemical compounds may be built up and recorded. Disadvantages in these methods of combinatorial syntheses include the need to remove synthesised compounds from beads when a desired compound has been synthesised, such as when a particular compound is subsequently required to be reacted with compounds on other beads . Furthermore, after each round of synthesis, sets of beads must be moved from the array in order to prevent them from undergoing chemical reaction with the next chemical reactant added to the array. Augmented procedures have been developed which allow automatic removal of individual, and sets of, beads from combinatorial arrays, but these necessitate the use of complex electronic and mechanical devices which can very easily malfunction and increase the cost of combinatorial synthesis.

It would therefore be advantageous to provide a device which would allow combinatorial synthesis to take place in which reactants may flow through a circuit, and be diverted to various channels in a circuit to be individually combined with further reactants, and in which the resultant synthesized compounds may be easily removed via outlets in the circuit, or fed back into the circuit for further synthesis. In order to provide such a device, it would be advantageous to include a means to control flow of material, such as reactants and solvents, through the fluidic circuit in a way in which the flow control means are not permanent fixtures within the channels of the fluidic device, and in which the flow control means may be added in situ, in order to create varied channel flow configurations as and when required. It is an aim of preferred embodiments of the invention to remove or mitigate at least one problem of the prior art, whether expressly disclosed herein above or not .

Summary of the Invention

According to a first aspect of the present invention there is provided a flow circuit comprising at least one flow channel in which is located a flow control means, wherein the physical state of the flow control means is alterable by application of an external stimulus. In this way, in use, the flow of a material through the circuit can be controlled by the flow control means.

The flow channel may be linear or branched.

Preferably the circuit comprises a plurality of flow channels. Suitably at least two flow channels are in fluid communication, and all of the channels may be in fluid communication with each other. Each flow channel preferably comprises a fluid inlet and a fluid outlet . The fluid inlet and fluid outlet may be one and the same. An outlet of a channel may be in fluid communication with an inlet of another channel .

The flow channel may comprise a main channel body, and transverse to the main channel body, one or more branch channels. Suitably the main channel body comprises an inlet at one end thereof and an outlet at the other end thereof, and each branch channel comprises an inlet, and/or outlet at the free end thereof. A branch channel of one flow channel may be connected to a branch channel or main channel body of a second flow channel, such that the two flow channels are in fluid communication.

When the main channel body comprises a plurality of branch channels, each branch channel may extend from the main channel body substantially parallel to another branch channel or may extend at a different angle to another branch channel .

The or each flow channel may comprise a hollow member. Suitably the hollow member comprises a bore running therethrough. Preferably the bore has a circular cross- section, an oval cross-section, a quadrilateral cross- section, or an elliptical cross-section.

Suitably, the bore of the flow channel has a minimum diameter or width of at least 0.005μm (microns), preferably at least 0.0075μm, and more preferably at least O.Olμ .

Suitably the bore of the flow channel has a maximum diameter or width of no more than 2000μm, preferably no more than 1500μm, more preferably no more than 1200μm, and most preferably no more than lOOOμm.

The flow channels may be constructed from any suitable materials. Materials particularly suitable for use in flow channels include metals (including alloys) , plastics material, glass and glass composite materials, quartz, carbon fibre materials, silicon, silicone polymers, polymer resins, ceramic materials such as aluminates, silicates and composites thereof, for example, and any mixture thereof . Suitable metals include gold, iron, zinc and aluminium for example, and alloys thereof.

Suitable plastics materials include polypropylene, polyethylene, acrylics, acrylates and acrylamides, and mixtures or copolymers thereof for example .

The flow circuit may comprise a plurality of channel layers arranged to be superposed, where each channel layer comprises one or more flow channels as described above. Suitably each layer is in fluid communication with at least one other layer, preferably at least one adjacent layer, more preferably each adjacent layer, and most preferably all the layers in the flow circuit.

Each layer may be in fluid communication with an adjacent layer by way of one or more branch channels arranged to interconnect with a channel in each of the adjacent layers.

Preferably the flow circuit is arranged to form a continuous loop. Suitably the flow circuit comprises at least one primary inlet, arranged to allow input of material into the loop of the circuit, and preferably further comprises at least one primary outlet, arranged to allow withdrawal of material from the loop of the circui .

Each layer of the flow circuit may comprise its own separate primary inlet and/or primary outlet. There may be at least one inlet for input of the flow control means, and at least one separate inlet for input of other material .

The flow control means preferably comprises a means alterable between a first physical state and a second physical state, by application of the external stimulus.

Suitably the flow control means is alterable between a first phase, as the first physical state, and a second phase, as the second physical state. Preferably the first phase is solid and the second phase is liquid.

Preferably alteration of the physical state of the flow control means is controllable by application of variable quantities of the external stimulus, such that a user may alter the physical state of the flow control means to any desired degree between the first and second physical states .

Thus a user may control the physical state of a flow control means between a first solid physical state and a second liquid physical state, such that the physical state may be any desired viscosity of the liquid state, a liquid crystal state or semi-solid state for example, by application of variable quantities of the external stimulus .

The flow control means may be present in one or more discrete fixed areas of the flow circuit. Alternatively the flow control means may be transportable around the flow circuit. The flow control means may comprise liquid at the temperature and pressure at which the circuit is normally operated, arranged to flow round the circuit, and alterable between the liquid state and a solid state by application of the external stimulus. The external stimulus may be applied to one or more discrete portions of the flow control means such that only those portions to which the stimulus is applied undergo a change in the physical state.

Thus in the case of a flow control means which is liquid at the normal circuit operating temperatures and pressures, and which is present substantially through the whole circuit, an external stimulus may be applied to a discrete area of the circuit in order to alter the physical state of the liquid in that area to a solid state, so as to block the areas of the channel in which the control means has solidified

In the case of a flow control means which is solid at the normal circuit operating temperatures and pressures, an external stimulus may be applied to the solid control means to alter the physical state to a liquid thus unblock the channel in which the control means is present.

Suitably the liquid flow control means is a solvent, able to dissolve material desired to flow round the circuit, and which may be altered between the liquid state and solid state by application of the external stimulus.

Suitably the solid flow control means is a solvent when altered to the liquid state. Suitably alteration of the flow control means between the first and second physical states is reversible, preferably by cessation of application of the external stimulus.

Preferred as flow control means are chemical compounds or compositions which undergo an alteration in their physical state upon application of electromagnetic radiation and /or heat . Particularly preferred are flow control means which are solid at the normal operating temperature of the flow circuit and which are altered to a liquid state upon application of electromagnetic radiation and/or heat.

In alternative embodiments of the invention, the flow control means may comprise means, the physical state of which is alterable by application of ultra-violet radiation, cross-linking agents, chemical curing agents, pressure, pH change of the flow control means or material flowing through the circuit, or combinations thereof.

In preferred embodiments of the invention, the flow control means has a physical state which is alterable by application of heat. Suitably the fluidity of the flow control is alterable in a given material by the direct or indirect application of heat. Alternatively the physical state of the flow control means may be altered between solid and liquid, or vice versa, by the direct or indirect application of heat or withdrawal of heat from the flow control .

Particularly preferred as control means are chemical compounds or compositions which undergo an alteration to their physical state upon exposure to electromagnetic radiation, the electromagnetic radiation being converted to heat, either directly (which is preferred) or by a chemical reaction undergone by a component of the compound or composition. Preferably the chemical compounds or compositions undergo a change in their physical state upon exposure to radiation having a wavelength predominantly or entirely exceeding 500m, more preferably 600m, still more preferably 700mm, and most preferably 800mm. Suitably the change is physical state is altered by exposure to radiation the wavelength of which is predominantly or entirely below 1900nm, more preferably below 1400nm, still more preferably below 1200nm and most preferably below 1150nm, especially below llOOnm. The electromagnetic radiation could for example be infra-red or visible radiation, but is preferably infra-red radiation. In order to increase the sensitivity of the flow control means to heat the flow control means may include a radiation absorbing compound, capable of absorbing incident radiation and converting it to heat, hereinafter called a ^radiation absorbing compound" . Suitably the radiation absorbing compound is capable of absorbing radiation, the wavelength thereof is infra-red or visible, and converting it to heat. Suitable radiation absorbing compounds include pigments and dyes, for example .

In preferred embodiments the radiation absorbing compound absorbs infra-red radiation, for example 1064 nm radiation from a Nd-YAG laser. However, other materials which absorb other wavelength radiation e.g. 488 nm radiation from an Ar-ion laser source, may be used with the radiation being converted to heat. The radiation absorbing compound is preferably a pigment, which is a black body or broad band absorber. It may be carbon such as carbon black or graphite. It may be a commercially available pigment such as Heliogen Green (RTM) as supplied by BASF or Nigrosine Base NG1 as supplied by NH Laboratories Inc or Milori Blue (C.I. Pigment Blue 27) as supplied by Aldrich.

The radiation absorbing compound may alternatively be an infra-red absorbing dye able to absorb the radiation selected for imaging and convert it to heat, and whose absorption spectrum is significant at the wavelength output of the laser which is (in preferred embodiments) to be used in the method of the present invention.

Pigments are generally insoluble in the compositions and so comprise particles therein. Generally they are broad band absorbers, preferably able efficiently to absorb electromagnetic radiation and convert it to heat over a range of wavelengths exceeding 200 nm, preferably exceeding 400 nm. Generally they are not decomposed by the radiation. Generally they have no or insignificant effect on the solubility of the unheated composition, in the developer. In contrast dyes are generally soluble in the compositions. Generally they are narrow band absorbers, typically able efficiently to absorb electromagnetic radiation and convert it to heat only over a range of wavelengths typically not exceeding 100 nm, and so have to be selected having regard to the wavelength of the radiation which is to be used for imaging.

Suitable compounds and compositions preferred as flow control means include aprotic solvents, such as dimethyl sulphoxide (DMSO) , water, carbon dioxide and organic solvents having melting points substantially below 40°C. Examples of suitable flow control means include waxes comprising hydrocarbons, and oxa-, amide, amine and/or thio derivatives thereof; N-methylpyrrolidene and ring heterocycles based upon amides; polymers such as gelatin, agaroses, acrylates, polyethers, poly alcohols, polya ides, acrylamides, for example; fats, including cholesterol, esters, diesters and triesters; non-ionic liquids and salts; metals, alloys, including germanium, tin/lead and gallium, or alloys thereof; and water.

According to a second aspect of the present invention there is provided a method of controlling flow of a material through a flow circuit having at least one flow channel, the method comprising the steps of:

(a) locating a flow control means within at least a portion of a flow channel, the flow control means comprising a physical state which is alterable by application of an external stimulus; and

(b) applying an external stimulus to or in the region of at least a portion of the flow control means, such that the physical state of the flow control means is altered to alter the flow of the material in the region of said portion of the flow control means .

Preferably the flow circuit, the or each flow channel and the or each flow control means is as described for the first aspect of the invention. Preferably the flow control means comprises a means which undergoes an alteration of its physical state upon application, directly or indirectly to heat such as by heat absorption of radiation followed by conversion to heat, or by direct application of heat, for example.

Step (a) may comprise adding a slug dose of a flow control means to the flow circuit . Alternatively step (a) may comprise substantially filling the flow circuit with a flow control means, the flow control means being preferably arranged to act as a solvent, in the liquid state, for other material to be inputted into the circuit.

The method may comprise inputting chemical reagents into the flow circuit and performing one or more chemical reactions with the or each flow channel of the circuit .

The chemical reactions may comprise chemical syntheses, nucleic acid syntheses, protein syntheses, chemical and biochemical analysis, combinatorial chemistry syntheses, inorganic chemical analyses and the like for example. The chemical reaction or reactions may include single reactions, multiple reactions or cyclic (i.e. repetitive loop) reactions. The method may comprise constructing one or more libraries of chemical or biochemical compounds via the chemical reactions.

The chemical reagents may be inputted before, during and/or after steps (a) and/or (b) of the method. Thus some reagents may be added to the circuit before step (a) and allowed to flow round the circuit, optionally undergoing chemical reactions, before the flow control means is added to the circuit. Alternatively the flow control means may be located in the desired portion of the circuit and the physical state of the flow control means altered to block said portion, before one or more chemical reagents are added to the circuit. In this way chemical reagents may be prevented from flowing to defined portions of the circuit, which may contain other chemical reactants, until the flow control means is exposed to an external stimulus in order to reverse the physical state change and unblock the circuit portion. In this way selective reactions of chemical reagents added to the circuit may be achieved.

According to a third aspect of the present invention there is provided a method of the second aspect of the invention performed using a flow circuit of the first aspect of the invention.

Brief Description of the Drawings

For a better understanding of the invention and to show how embodiments of the same may be put into effect, the various aspects of the invention will now be described by way of example with reference to the accompanying drawings in which:

Figure 1 illustrates a topological view of a flow circuit of the invention;

Figure 2A illustrates a perspective view of the boxed portion of the flow circuit of Figure 1, as shown by the box comprising dotted lines of Figure 1;

Figure 2B illustrates an end view of the channel portion shown in Figure 2A; Figure 2C illustrates the channel portion of Figure 2A in which a plug of flow control means has been inserted into the channel portion;

Figure 2D illustrates the channel portion of Figure 2C in which the physical state of the plug of flow control means has been altered in order to effect alteration of flow of reactants within the channel portion;

Figure 2E illustrates the channel portion of Figure 2A in which a plug of flow control means has been inserted into a different channel of the channel portion;

Figure 3A illustrates the channel portion of Figure 2A in which two plugs of flow control means have been inserted into separate channels;

Figure 3B illustrates the channel portion shown in Figure 2A in which two plugs of flow control means have been inserted into separate channels; and

Figure 3C illustrates the channel portion of Figure 2A in which a plug of flow control means has been inserted into a channel .

We refer firstly to Figure 1 which shows the topology of a flow circuit 2 of the invention. The topological flow circuit 2 includes a plurality of straight lines which illustrate flow channels 3 of the flow circuit 2. At the end of some of the flow channels 3 are inlet and outlet apertures 20 and injection inlets 22. We refer now to Figure 2A which corresponds to a perspective view of a portion of the flow circuit 2 defined by the dotted line box A in Figure 1. The portion of the flow circuit 2 comprises a first flow channel 4 and a second flow channel 6 connected via a branch channel 8 perpendicular to the first 4 and second 6 flow channels. The first flow channel 4 includes a first end 10 and a second end 12 , and the second flow channel 6 includes a corresponding first end 14 and second end 16.

Use of the flow circuit 2 of the invention will now be described with reference to Figures 1 and 2C to 2E. The flow circuit 2 is initially cooled to approximately 12°C, and maintained at that temperature by any suitable means known to those skilled in the art. The flow circuit 2 is also operated such that flow of material around the circuit can be controlled by varying the pressure and the direction of flow within any of the channels 3 or any desired portion thereof using any suitable pump or vacuum means.

We turn now to Figures 2A to Figure 2E to describe how channels may be selectively blocked by a flow control means 18 in the form of a slug of dimethysulphoxide (DMSO) . As shown in Figure 2C, a slug of DMSO 18 is injected into the circuit 2 at an desired injection point 22. As the circuit is kept at 12°C the DMSO slug 18 solidifies to create a solid slug. The slug 18 is then exposed to infra-red radiation by impingement of an infra- red laser beam, which heats the slug 18 to liquefy it. The liquefied slug 18 is then drawn round (transported) the circuit using a vacuum pump connected to the circuit 2 (not shown) . As the liquefied slug 18 is transported round the circuit 2, the infra-red laser beam is arranged to track the slug 18 so that it remains in the liquid state throughout the manipulation to the desired area, while it is transported around the flow circuit 2 and manipulated to enter the channel portion 4 via the upstream end 10. As the DMSO plug 18 reaches the junction between channel portion 4 and branching channel 8, the infra-red laser is turned off such that no further heat is generated in the slug 18. As the IR beam is stopped the slug 18 then cools down to the operating temperature

(12°C) of the circuit and solidifies, in order to block that channel. The plug of DMSO 18 blocks the channel portion 4 before the junction between the channel and branch channel 8, at the junction, and down stream of the branch channel 8, and also is manipulated to partially enter branch channel 8, as shown in Figure 2C. Thus, the solid plug of DMSO blocks entrance to the branch channel 8 from the upstream portion of channel 4, and blocks channel 4 in a direction downstream of the plug 18 towards the downstream outlet 12. In use, in this example, chemical reactants A, B, and C are incorporated into the flow circuit 2. Chemical reactant C is manipulated by manipulation of the flow of a solvent such that it is present in the downstream portion 12 of the first channel 4. Chemical reactants A and B are manipulated to enter, the first channel 4 and second channel 6 respectively, via the upstream ends 10 and 14 of their respective channels. Chemical reactant A is prevented from travelling further down the first channel 4 by the DMSO plug 18 which blocks entrance to the branch channel 8 and the downstream end 12 of the first channel 4. Chemical reactant B is prevented from entering the first channel 4 through the branch channel 8, again due to the channel blockage caused by the DMSO plug 18. Chemical reactant B therefore travels through the second channel 6 from the first end 14 to the second end 16.

We turn now to Figure 2D. In order to allow chemical reactants A and B to react to synthesize a new compound, the DMSO plug 18 is manipulated such that the region of the DMSO slug 18 is manipulated so that it's physical state is changed from solid to liquid. As shown in Figure 2D, the slug of DMSO is heated above it's melting point of approximately 18.5°C in the regions within the branch channel 8, the junction between the first channel 4 and branch channel 8 and the region upstream of said junction, such that the only remaining slug of DMSO 18 is downstream of the junction between branch channel 8 and the first channel 4. This provides the effect of unblocking branch channel 8 such that reactant A may move through the upstream portion of the first channel 4 and through branch channel 8, but is prevented from moving further down into to the downstream portion of the first channel 4 by the remaining slug of DMSO 18. As the chemical reactant A flows through the branch channel 8 it comes into contact with chemical reactant B in the second channel 6 and at the junction of branch channel 8 and the second channel 6 and reacts to form a new chemical substance AB, which is arranged to flow to the downstream portion of the second channel 6, into a further section of the flow circuit 2.

Alternatively, if it is desired to react chemical reactant A with chemical reactant C in the downstream portion 12 of the first channel 4, then the DMSO 18 as shown in Figure 2C is selectively melted as shown in Figure 2E such that only a plug of DMSO 18 remains in branch channel 8. Thus chemical reactant A may be arranged to flow entirely through the first channel 4 to react with chemical reactant C in the downstream portion 12 of the first channel 4 to create a new chemical AC . Reactant B in the second channel 6 cannot flow into the first channel 4 due to blockage of the branch channel 8 with the remaining DMSO plug 18, and thus flows entirely through the second channel 6 through the downstream portion 16. Thus by altering the physical state of the DMSO plug 18 between solid and liquid in various configurations, differing chemical reactions may take place between chemical reactants A, B and C in the first and second channels 4 and 6 in order to create new chemicals AB and AC.

We refer now to Figures 3A to 3C, to illustrate use of the flow circuit 2 of the invention to synthesize new chemicals from four chemical reactants A, B, C and D located in the first channel portion 4 and second channel portion 6 of the channel portion shown in Figures 2A and B.

We refer first to Figure 3A which illustrates the channel portion of Figure 2A in which a DMSO plug 18 has been manipulated into the first channel 4 downstream of the junction between said channel and branch channel 8, in order to block movement of material through the upstream portion 10 of the first channel 4 to the downstream portion 12. A second plug 18 of DMSO has been manipulated to block the second channel 6 downstream of the junction between the second channel 6 and the branch channel 8. Chemical reactant C has been arranged to be located in the downstream portion 12 of the first channel 4. Chemical reactant D has been arranged to be located in the downstream portion 16 of the second channel 6. Thus as chemical reactant A is arranged to flow into the upstream portion 10 of the first channel 4 and chemical reactant B is arranged to flow into the upstream portion 14 of second channel 6 chemical reactants A and B both flow into the branch channel 8 via their respective junctions, and react to form chemical intermediate AB. Once chemical intermediate AB has been formed, the DMSO plugs 18' and 18" may be removed by heating the first and second channels 4 and 6 in the location where the plugs 18' and 18" are situated, in order to change the physical state from solid to liquid, and unblock the channels 4 and 6. When the DMSO plugs 18' and 18" have been removed, the chemical intermediate AB may flow simultaneously to the downstream portion 12 of the first channel 4 and the downstream portion 16 of the second channel 6, to react with chemical reactant CD in their respective channels. Thus two chemicals, ABC and ABD will be formed in the first channel 4 and second channel 6 respectively, which chemicals may then flow out of the channels 4 and 6 into other parts of the flow circuit 2.

In an alternative embodiment, as shown in Figure 3C, if it is desired to produce chemical compounds AC and BD, a plug of DMSO 18 may be arranged to be located within branch channel 8 such that if chemical reactants A and B are arranged to flow into the first channel 4 and second channel 6 respectively, they will flow to the downstream portions 12 and 16 respectively in order to react with chemical reactants C and D in order to produce chemicals AC and BD. The plug of DMSO 18 within the branch channel 8 prevents chemical reactant A from entering second channel 6 and prevents chemical reactant B from entering the first channel 4.

Thus, as shown by the preceding embodiments, it is possible to create libraries of many different chemicals, and chemical intermediates by simply adjusting the flow of chemical reactants around the flow circuit 2 in order to force desired chemical reactants to react with other desired chemical reactants in particular portions of the flow circuit 2. The embodiments described herein above utilise DMSO as a flow control means due to it's physical characteristic of having the melting point approximately 18.5°C. Thus it is easy to run the circuit at temperatures less than 18.5°C in order to solidify the DMSO to block desired channels, and then to heat up the DMSO at desired locations in order to melt the DMSO and unblock the desired channels. Heating may be achieved by the contact of a desired channel with a heated body such as a heated stylus, but may be achieved with exposure to incident electromagnetic radiation such as infra red radiation which acts to heat up the DMSO within the channel whether radiation is directed. The DMSO (or any other heat-affected flow control means) may include an infra red absorbing compound which absorbs infra red radiation and converts the radiation to heat. Suitable infra red absorbing compounds include dyes and pigments, which also act as indicator means so that plugs of DMSO may easily be located by a user using necessary equipment such as a spectrophotometer which can locate the DMSO by analysing the absorption transmission spectrum of the dye or pigment mixed with the DMSO. Thus, it is possible to monitor passage of the DMSO through the flow circuit, in order to pinpoint where the DMSO is, and allow a user to selectively solidify or melt the DMSO as and when required. There may also be separate indicator means present within the flow control means, such as magnetic marker materials, IR absorbing materials, UV absorbing materials, coloured marker materials, and the like, so that a user may view transport and manipulation through the circuit by a corresponding detecting means for the indication means.

In other embodiments of the flow circuit of the invention and methods of the invention, various flow control means may be utilised which undergo a change in physical state due to pressure, pH change within the flow control means or flow channels, differing wavelengths of electromagnetic radiation such as ultra violet radiation, microwave or gamma rays, or polymerisation using cross-linking agents or chemical curing agents. It is preferred that the flow control means has the characteristic of being able to reverse the change in physical state, either by cessation of the external stimulus, or by application of a second external stimulus.

The flow circuit 2 may be incorporated into a loop system such that any chemicals synthesized within the circuit 2 are transported back to an inlet/outlet 20 in order to undergo further chemical reactions within the flow circuit 2. At least one of the inlet/outlets may be connected to a holding area in which to hold chemicals synthesized within the flow circuit 2 , and the holding area may comprise a plurality of compartments in which differing chemicals may be selectively deposited. The injection ports 22 may be arranged such that differing starting chemical reactants, intermediates or chemicals already synthesized within the flow circuit 2 may be injected into different injection ports 22.

In alternative embodiments of the invention the flow circuit 2 may be part of a circuit chip (not shown) in which a plurality of layers of flow circuit 2 are arranged to superpose on each other and are connected by connection channels. Thus, a number of chemical reactions may be performed in one layer, and the resultant synthesized chemicals may be transported through the connection channels to a second layer to undergo one or more further chemical reactions. Chemicals synthesized in any of the layers may be transported via the connection channels to any other layer to give a larger number of possibilities of chemical synthesis .

The embodiments described herein above have related to chemical synthesis, but biochemical synthesis are equally applicable, wherein, for example, nucleic acids may be synthesized from ademine, guanine, cytosine, thymine/uracil, in differing configurations by appropriate manipulation of flow control means within appropriate channels .

The flow circuit 2 of the invention may also be applied to electrical circuits, in which flow of electrons may be altered by blockage of channels comprising electrolyte in order to push electrons around the circuit in varying configurations .

Obviously for each application, differing flow control means may be need in order to prevent reaction of the flow control means of any of the chemical reactants. In this sense for chemical reactions and nucleic acid syntheses DMSO is a very useful flow control means, as it may act as a solvent without reacting with the reactants. In certain embodiments, the entire circuit may be filed with the flow control means such as DMSO, and arranged to work with the DMSO or flow control means in the liquid state, and cooled at desired portions in desired channels in order to solidify the flow control means at those areas in order to block the channels until it is desired to unblock the channels.

Attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.

All of the features disclosed in this specification (including any accompanying claims, abstract and drawings) , and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive.

Each feature disclosed in this specification (including any accompanying claims, abstract and drawings) may be replaced by alternative features serving the same, equivalent or similar purpose, unless expressly stated otherwise. Thus, unless expressly stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features. The invention is not restricted to the details of the foregoing embodiment (s) . The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings) , or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

Claims

1. A flow circuit comprising at least one flow channel in which is located a flow control means, wherein the physical state of the flow control means is alterable by application of an external stimulus.

2. A flow circuit as claimed in Claim 1, comprising a plurality of flow channels.

3. A flow circuit as claimed in Claim 1 or 2, wherein all of the channels are in fluid communication.

4. A flow circuit as claimed in any one of Claims 1 to 3 , wherein each flow channel comprises a fluid inlet and a fluid outlet.

5. A flow circuit as claimed in Claim 4, wherein the fluid inlet and fluid outlet are one and the same.

6. A flow circuit as claimed in Claim 4 or 5, wherein the outlet of a channel is in fluid communication with an inlet of another channel .

7. A flow circuit as claimed in any preceding claim, wherein the flow channel comprises a main channel body, and transverse to the main channel body, one or more branch channels.

8. A flow circuit as claimed in Claim 7, wherein a branch channel of one flow channel is connected to a branch channel or main channel body of a second flow channel .

9. A flow circuit as claimed in any preceding claim, wherein the or each flow channel comprises a hollow member.

10. A flow circuit as claimed in Claim 9, wherein the hollow member comprises a bore running therethrough.

11. A flow circuit as claimed in Claim 10, wherein the bore of the flow channel has a diameter or width of between 0.005μm and 2000μm.

12. A flow circuit as claimed in any preceding claim, wherein the flow channel or flow channels comprise metal, plastics material, glass or glass composite materials, quartz, carbon fibre materials, silicon, silicone polymers, polymer resins, ceramic materials or any mixture thereof .

13. A flow circuit as claimed in any preceding claim, comprising a plurality of channel layers arranged to be superposed, wherein each channel layer comprises one or more flow channels.

14. A flow circuit as claimed in Claim 13, wherein each layer is in fluid communication with at least one other layer.

15. A flow circuit as claimed in Claim 13 or 14, wherein each layer is in fluid communication with an adjacent layer by way of one or more branch channels arranged to interconnect with a channel in each of the adjacent layers .

16. A flow circuit as claimed in any preceding claim, arranged to form a continuous loop.

17. A flow circuit as claimed in any preceding claim, wherein the flow circuit comprises at least one primary inlet, arranged to allow input of material into the loop of the circuit .

18. A flow circuit as claimed in Claim 16 or 17, comprising at least one primary outlet, arranged to allow withdrawal of material from the loop of the circuit .

19. A flow circuit as claimed in any one of Claims 16 to 18, wherein each layer of the flow circuit comprises its own separate primary inlet and/or primary outlet .

20. A flow circuit as claimed in any one of Claims 16 to 19, comprising at least one inlet for input of the flow control means, and at least one separate inlet for input of other material .

21. A flow circuit as claimed in any preceding claim, wherein the flow control means comprises a means alterable between a first physical state and a second physical state, by application of the external stimulus .

22. A flow circuit as claimed in Claim 21, wherein the flow control means is alterable between a first phase, as the first physical state, and a second phase, as the second physical state.

23. A flow circuit as claimed in Claim 22, wherein the first phase is solid and the second phase is liquid.

24. A flow circuit as claimed in any one of Claims 21 to 23, wherein alteration of the physical state of the flow control means is controllable by application of variable quantities of the external stimulus, such that a user may alter the physical state of the flow control means to any desired degree between the first and second physical states .

25. A flow circuit as claimed in any preceding claim, wherein the flow control means is present in one or more discrete areas of the flow circuit.

26. A flow circuit as claimed in any one of Claims 1 to 24, wherein the flow control means is transportable around the flow circuit .

27. A flow circuit as claimed in any preceding claim, wherein the flow control means may comprise liquid at the temperature and pressure at which the circuit is normally operated, arranged to flow round the circuit, and alterable between the liquid state and a solid state by application of the external stimulus.

28. A flow circuit as claimed in any one of Claims 21 to

27, wherein the external stimulus is applied to one or more discrete portions of the flow control means such that only those portions to which the stimulus is applied undergo a change in physical state.

29. A flow circuit as claimed in any preceding claims, wherein the flow control means is a solvent, able to dissolve material desired to flow round the circuit, and which is alterable between the liquid state and solid state by application of the external stimulus.

30. A flow circuit as claimed in any one of Claims 21 to 29, wherein alteration of the flow control means between the first and second physical states is reversible.

31. A flow circuit as claimed in Claim 30, wherein reversible alteration is effected by cessation of application of the external stimulus.

32. A flow circuit as claimed in any preceding claim, wherein the flow control means is a chemical compound or composition which undergoes an alteration in its physical state upon application of electromagnetic radiation and/or heat.

33. A flow circuit as claimed in Claim 32, wherein the flow control means is a solid at the normal operating temperature of the flow circuit and which is altered to a liquid state upon application of electromagnetic radiation and/or heat.

3 . A flow circuit as claimed in any one of Claims 1 to 31, wherein the flow control means comprises means, the physical state of which is alterable by application of ultra-violet radiation, cross-linking agent, chemical curing agent, pressure, pH change of the flow control means or material flowing through the circuit, or combinations thereof.

35. A flow circuit as claimed in any preceding claim, wherein the flow control means is a chemical compound or composition which undergoes an alteration to its physical state upon exposure to electromagnetic radiation, the electromagnetic radiation being converted to heat, either directly or by a chemical reaction undergone by a component of the compound or composition.

36. A flow circuit as claimed in Claim 35, wherein the flow control means includes a radiation absorbing compound, capable of absorbing incident radiation and converting it to heat.

37. A flow circuit as claimed in any preceding claim, wherein the flow control means is selected from the group consisting of an aprotic solvent, water, carbon dioxide, an organic solvent having a melting point substantially below 40°C, or combinations thereof.

38. A method of controlling flow of a material through a flow circuit having at least one flow channel, the method comprising the steps of:

39. A method as claimed in Claim 38, wherein the flow circuit, the or each flow channel and the or each flow control means is as described in any one of Claims 1 to 37.

40. A method as claimed in Claim 38 to 39, wherein step (a) comprises adding a slug dose of a flow control means to the flow circuit .

41. A method as claimed in Claim 38 to 39, wherein step (a) comprises substantially filling the flow circuit with a flow control means .

42. A method as claimed in any one of Claims 38 to 41, wherein the method comprises inputting chemical reagents into the flow circuit and performing one or more chemical reactions on one or more of the chemical reagents within the circuit.

43. A method as claimed in Claim 43, wherein the chemical reactions comprise chemical syntheses, nucleic acid syntheses, protein syntheses, chemical and biochemical analysis or any mixture thereof .

44. A method as claimed in Claim 42 or 43, wherein the chemical reagent or reagents is or are inputted before, during and/or after steps (a) and/or (b) of the method.

45. A method as claimed in Claim 42 or 43, wherein the flow control means is located in a desired portion of the circuit and the physical state of the flow control means is altered to block said portion, before one or more chemical reagents is or are added to the circuit .

46. A method as claimed in any one of Claims 38 to 45, using a flow circuit of any one of Claims 1 to 37.

47. A flow circuit substantially as described herein, with reference to the accompanying drawings .

48. A method substantially as described herein, with reference to the accompanying drawings .