METHOD FOR PRODUCING A HEATABLE AND REFRIGERABLE ELEMENT FOR A SYSTEM HANDLING SMALL QUANTITIES OF LIQUID, AND AN ELEMENT MANUFACTURED BY THE METHOD

Abstract: The invention relates to a method for producing a heatable and refrigerable element (12) for a system handling small amounts of liquid and to an element manufactured by the method. The element comprises flow channels (11) and one or more liquid spaces (8) communicating with them, the channels being provided with valves (10) connected to a refrigerator (25) and a heater (18), for blocking the channels by freezing the liquid in them. The element (12) is produced by using a removable mould which serves as a substrate for deposition and by depositing one or more metallic materials by electroformation or an equivalent procedure in such a way that the deposited metal forms a shell (5, 7) by removing the mould from inside the shell by dissolving or smelting, and by connecting the shell at the spot of the valves to a refrigerator (25) and a heater (18). The deposition is carried out so that there is a higher thermal conductivity at the spot of the valves (10) than in the adjacent shell areas.

Description: Method for producing a he table and refrigerable element for a system handling small quantities of liquid, and an element manufactured by the method The present invention relates to a method for producing a heatable and refrigerable element f.or a system handling small quantities of liquid, said element being provided with flow channels and at least one liquid space communica- ting with said channels, and said element being functionally connected at a number of locations to a refrigerator and a heater. FI patent publication 57850 proposes a procedure and an apparatus for handling small quantities of liquid, whereby the liquid is manipulated within a system consisting of spaces or chambers for holding or processing the liquid and channels interconnecting them, each of said channels being provided with at least one valve which is shut by refrigeration. Each valve is connected to a continuously operated refrigerator and provided with a separate electric heating element, so that when the heating element is active it keeps the temperature of the valve above the congealing point of the liquid in question, thus keeping the valve open, and when inactive, it lets the liquid in the valve be frozen, thereby shutting the valve. Thus, the manipula¬ tion of the liquid in the system, based on moving the liquid from one space to another by virtue of pressure differences, is achieved by electrically controlling the heating elements of the valves. The apparatus presented in this publication is designed for use mainly as an automatic analyzer, in which the manipulation of the liquid is exclusively based on the pressure differences between the spaces and on elect¬ ronic control of the heating elements, using no movable mechanical parts. According to FI patent publication 57850, the refrigerable valves are formed by placing two blocks of material against each other in such manner " that a valve is formed between the opposite surfaces. One of these blocks contains the flow channels leading to the valves, while the other block, connected to the refrigerator, is provided with heating elements placed in the region of the valve (s) and used for opening and closing the valves. To regulate the heating and cooling of the valves, the valve areas are provided with heat insulation, and valves placed side by side are isolated from each other by freezing a liquid in the gaps between the surfaces of the valve body pieces. FI patent publication 70331 proposes an improved solution based on the aforementioned principle of forming a valve. The main feature of this solution is that the valves are formed by providing cut-outs on the surface of at least one of the oppositely placed blocks, and that the opposite surfaces of these blocks are coated with a thin layer of a chemically inert material which acts as a covering of the heating elements and heat insulation. In this solution, the valves can also be provided with inert stopping elements placed in said cut-outs to allow instantaneous shut-off of the liquid flow into the valve. According to the publica¬ tion, this inert material consists in the first place of a fluoropolymer, such as teflon, although precious metals are mentioned as a possible alternative. In practical ap¬ plications of the principle, a fluoropolymer has been used. It has been found that the solution proposed in the afore¬ mentioned FI patent publication 70331 has the disadvantage that in the course of time water penetrates through the thin polymer layer, resulting in the formation of ice under the layer in the areas subject to refrigeration. In practi¬ cal use, as the valve is alternately heated and refrige¬ rated, the melting and re-freezing of this external layer of ice increases the thermal load, resulting in a slower and less accurate operation of the valve. A similar effect also results from the fact that ice conducts heat consi¬ derably better than the polymer constituting the valve surface. Consequently, when the valve is being shut, the process of settlement of the boundary layer of the ice blockage is slow. Furthermore, the valve construction proposed by said FI patent publication 70331 has other drawbacks not associated with the material used as coating of the bodies between which the valves are formed. One of these drawbacks is the bulky construction, involving a large thermal mass and a low heating and refrigerating efficiency. Another disadvan¬ tage is found in the geometry of the valves and flow chan¬ nels, which is due to the fact that the bodies limiting the valves are manufactured by casting into moulds, in which technique the casting has to be subsequently removed from the mould. As a result, the valves and channels show sharp angles and corners which, due to capillary forces, retain some liquid, which constitutes an impediment to the cleaning and fast drying of the channels. This may result in dosage errors and contamination of the liquid. The object of the present invention is to create a new technique for producing elements containing flow channels and one or more spaces or chambers for a liquid whereby the aforementioned drawbacks associated with the previously known techniques are eliminated. The method of the invention is characterized in that the element is produced by use of removable mould serving as a substrate for deposition, by depositing one or more metallic materials in such a way that deposited metal forms the shell of the element, by removing the mould, and by connecting the shell at said locations to a refrigerator and a heater the production being carried out so that the thermal conductivity of the structure as obtained at the locations where the shell of the element has been connected to a refrigerator and a heater substantially exceeds the thermal conductivity of the shell areas adjacent to said locations. By applying the method of the invention, a metallic element with a very small thermal mass and a watertight shell is produced. These features allow an accurate and fast regula¬ tion of temperature. The definition stating that the thermal conductivity of the structure including the element and the connecting bridges to the heating and/or refrigerating means at the locations of the connections, substantially exceeds the thermal conductivity of the shell areas adjacent to said locations means in practice that the heat flux caused by a temperature difference through the locations referred to is preferably at least five times as high as the heat flux through the adjacent areas, and, depending on the case, may even be tenfold or higher. This is to say that a steep temperature gradient is formed between the locations which are connected to a refrigerator and a heater and the adjacent shell areas. An essential advantage of the solution of the invention is that the mould used in forming the element can easily be shaped in accordance with the desired shapes of the flow channels and liquid spaces. Thus, undesirable sharp angles and corners can be avoided, and, after deposition of the metal and removal of the mould, the result is an element whose flow channels can be flushed and dried quickly with a blast of air to ensure that no dosage errors will occur. As taught by the present invention, refrigerable valves can be formed in the element by making the flow channel sufficiently narrow at least in one dimension at the rele¬ vant location and coupling this location to a heater and a refrigerator. In addition to or instead of this, the element can be provided with liquid spaces connected either directly or indirectly to a heater and a refrigerator to allow fast and accurate regulation of the temperature of the liquid in the spaces. In liquid analyzing equipment such spaces are used for mixing and incubation purposes. An example of the possibilities of application of the solution of the invention is DNA processing in gene technology as proposed by US patent publication 4 683 202, involving the incuba- tion of a liquid sample in fast-changing temperatures to achieve certain reactions. According to this publication, the samples are processed inside a massive metal block in which the changes of temperature are much too slow in view of reliable completion of the reactions. This disadvantage can be avoided by using an element manufactured as provided by the present invention. Moreover,, the invention allows the automatization of the liquid handling processes, thus avoiding the contamination problems associated with manual procedures. The deposition of metal may be carried out by way of electroformation in which the mould is arranged to serve as a cathode in a solution containing metallic ions. A layer of metal is deposited on the mould, and when required this layer may serve as a substrate for deposition of a further layer of the same or a different metal. Alternative deposition techniques that may be used in the process of the invention include autocatalytic chemical reduction in which a metallic mould is submerged in a solu¬ tion containing a compound of the metal to be deposited, e.g. a salt of said metal, and a reducing agent. The reacti¬ on, which may require heating of the solution, will cause deposition of a layer of reduced metal onto the mould, another technique which may be used is chemical vapor reduc¬ tion which is rather similar but uses primarily organometal- lic compounds which are reducer in gas phase and deposited an a mould. A further alternative for carrying out the deposition is sputtering in which a piece of metallic material and a metallic mould are placed in a vacuum chamber and a voltage of the magnitude of a thousand or more volts is connected between said piece and the mould. The voltage will ionize the metal and draw it onto the mould so that a layer is formed. The specific advantage of this method is that it may be used for deposition of any metal or alloy that might be required. „ A still further alternative method for the deposition is evaporation of metallic material in a chamber in which the mould has been placed. The metal will deposite onto all available surfaces in the chamber including that of the mould. In ion plating evaporation is combined with above- mentioned sputtering, by which means a particularly fast deposition process is achieved. In the method of the invention, the shell of the element can be produced in two phases by first depositing a first metal layer over the whole surface of the mould and then another layer on the first layer on the specific locations to be connected to the heating and refrigerating means. After the first deposition phase, the areas outside those locations can be covered with a protective coating, e.g. lacquer, to prevent the deposition of metal on these areas during the next phase. For the successive deposition phases, it is preferable to select two metals differing in respect of thermal conducti¬ vity. In the first phase, a layer of the metal with the lower thermal conductivity value is deposited. This metal may be e.g. nickel or an alloy containing nickel, such as kobaltous nickel having a cobalt content of a few percent, or a non-crystalline alloy consisting of nickel, cobalt and manganese, which alloy has a low thermal conductivity in comparison to other metals and is therefore especially suited for the purposes of the invention. However, there are other metals, e.g. pure cobalt, iron, chrome and the precious metals, that can be used in the first deposition phase. In the second phase, a metal with a better thermal conductivity is used. Of these, pure copper is the prefera- ble choice, although e.g. silver may also be used. The thickness of the layer of metal, e.g. a nickel alloy, deposited in the first phase is preferably in the range 10-100 μm, while the layer of metal, preferably copper, deposited in the second phase is 10-500 μm thick. To achieve the desired difference in thermal conductivity or heat flux, the metal layer deposited in the second phase must generally be thicker than the layer deposited in the first phase. This is necessary especially when the same metal is used in both phases of deposition. In that case the result is an essentially homogenous element whose performance depends solely on the differences in the thickness of the shell at different locations. As the shell of the element is produced in two phases it is possible to use in both phases the same deposition tech¬ nique, e.g. electroformation. However, it is as well possi¬ ble to use different techniques in the different phases, e.g. electroformation for the deposition of the first metal layer and sputtering for the deposition of the second layer. With regard to the different techniques referred to in the foregoing the only limitation is that evaporation is not suitable for the second phase as it is not possible to restrict deposition of metal to the specific unprotected locations only, in all other techniques including ion pla¬ ting, the protective coating works by preventing deposition on the coated areas. To enable the mould to be removed from inside the deposited layer of metal, the mould can be made of a dissoluble mate¬ rial, such as aluminium. Aluminium is suitable for all the different deposition techniques which have been described. In this case the solvent used of removing the mould may be e.g. a strong and hot solution of lye. The mould will dis¬ solve more readily if it is partly or wholly tubular so that the dissolvent can be passed through it. Alternatively, the mould may be made of a material whose melting point is low enough to allow the mould to be removed from inside the metal shell by smelting. Such materials include certain metal alloys, e.g. alloys of tin, bismuth and lead, which have a melting point in the range of 69- 200°C, as well as wax and plastic. Moulds made of the JLatter materials, however, have to be metal plated before they can serve as substrates for the deposition of the metal layers (except for deposition by evaporation) . In some cases it may even be possible to use a mould com¬ posed of several parts which can be pulled out separately from inside the metal shell after the deposition phases and used again. The difference between this technique and the conventional metal mould process is the fact that the mould is made of separable parts, enabling it to be removed. For the connection of the shell of the element at the desi¬ red location to a refrigerator, the method of the invention uses a bar-shaped or a plate-like bridge made of a material having a good thermal conductivity, e.g. copper. An essen¬ tial consideration is that the bridge should have a small mass, so that it is capable of sufficiently fast operation. The heating of the shell can be implemented by providing the bridge connecting the refrigerator to the shell with a suitably insulated electric heating resistor. As soon as power is switched on, the heating effect of the resistor effectively eliminates the cooling effect of the refrigera¬ tor. In a preferable construction the bridge may consist e.g. of two layers of copper with an insulating layer of plastic between them, the resistor wire being contained within the plastic layer. Alternatively, the shell of the element may be heated by irradiation. It is possible to use electrically controlled radiation sources transmitting e.g. laser beams, mounted at suitable locations outside the shell. The bridge connecting the shell of the element to the refri- gerator can be attached to the shell by electrolytically depositing a layer of easily melting material, such as indium, onto the shell and then smelting this layer so that the material will merge the end of the bridge with the shell. To smelt this material, an oven may be used, but alternatively it is possible to make use of the electric resistor incorporated in the bridge by connecting it to a supply of electricity and letting the current flow until the heat thus generated causes the material to melt. While melting, the material, at first spread as an even layer, recedes towards the line of contact between the bridge end and the shell, forming a collar swell which, when solidi¬ fying, effectively integrates the bridge with the shell. To enable the processes inside the element to be monitored, it is possible, using the same technique as in the case of the bridges connecting the refrigerator to the shell, to attach temperature sensors having a low specific temperature onto the shell of the element as needed. These sensors can be merged with the shell by means of indium or a similar, easily melting material deposited on the shell, preferably simultaneously with the merging of said bridges. The tempe¬ rature sensors can continuously supply control information on the movements of the liquid in the system, on changes of temperature of the liquid or gas as well as the freezing and thawing of the liquid in the valves belonging to the system. As stated before, an element manufactured by the method of the invention can be so designed that it has one or more heatable and refrigerable regions where the flow channel is at least in one dimension narrow enough to allow these regions to act as valves that can block the channel by freezing. These may be so-called high-power valves which are able to block the passage of a liquid flowing through the valve, or they may be normal valves which are so dimen¬ sioned that their refrigerating capacity is sufficient to freeze stationary liquid inside the valve. Especially the high-power valves are best produced by using a bar-shaped mould which has a form corresponding to that of the flow channel to be formed and is flattened in such manner that, after deposition of the metal layers and removal of the mould, the result is a metal element in which, in the region where the mould was flattened, the channel inside it is a narrow slot constituting a valve. The direction in which the bar-shaped mould is flattened and the corresponding narrow passage are preferably at an angle of about 20-60° relative to the longitudinal direction of the mould and the flow channel formed by it. Such an oblique slot, which may additionally have a tapering form towards its outflow end, is most advantageous with regard to dynamic stopping of the liquid flow through the valve. The present invention also relates to an element manufactu¬ red by the method described above and designed for use in a system manipulating small quantities of liquid, comprising flow channels and at least one liquid space communicating with them, said element being functionally connected at a number of locations to a refrigerator and a heater. The element of the invention is characterized in that it com¬ prises a set of flow channels and one or more liquid spaces enclosed by an integral metal shell having essentially tubular sections, said shell being connected at a number of locations to a refrigerator and a heater, and that said locations together with the connections to a refrigerator and a heater are made up so that the thermal conductivity of the structure at these locations substantially exceeds the thermal conductivity of the adjacent shell areas. In its simplest form an element according to the invention may comprise just one liquid space of chamber and two or more flow channels connected to said space, each channel being provided with at least one valve formed by a location in the channel connected to a refrigerator and a heater. The valves thus enable an amount of liquid to be passed to the liquid space and closed therein by freezing the valves. However, to facilitate construction of larger liquid hand¬ ling systems one element preferably contains larger amounts of liquid spaces and/or flow channels and valves, depending on the needs of the system in question. The element of the invention may comprise one or more valves of the high-power type mentioned above that are capable of dynamically stopping the liquid flow, and, in addition to or instead of the high-power valves, one or more normal valves, also mentioned above, which can statically freeze the liquid present in the valve, and in addition to or instead of the valves one or more spaces or chambers in which the liquid is not congealed but which is still connec¬ ted to a refrigerator and provided with at least one heater so as to enable the temperature of the liquid in the space to be regulated. In an analyzer handling small quantities of liquid, such a space can serve as a mixing or incubation chamber, where fast and accurate variation of the temperatu¬ re of the liquid is required. As an element made in accordance with the present invention has been tested. No leakage of water vapor through deposited metallic flow channels has been observed as an irregular or lengthening response time. The thermal leakage through the valves in resting state is surprisingly in the order of 1/10 W in this metallic structure, when it is one or more Watts in the polymer structure described in the FI patent 70331. The typical opening and closing times of valves are tens to hundreds of milliseconds, in valves based on said pre¬ vious patent typically seconds. The apparent closing time for high-power valves as calculated from volume error made in stopping flow divided by flow rate typically gives 1/10 000s, with is more than ten times faster than with said previous patent and more than 100 times faster than a conventional solenoid valve, (if they could sense the incoming liquid) . The improvement in quantitative performan¬ ce of manipulating small liquid volumes is exemplified e.g. in dispensing 0.0625 ml liquid where the standard deviation of reproducebility was measured as 0.00001 ml, tens of times improvement over the said previous patent or over present conventional dispensing performance. In another test for an automatic dispensing of real small blood serum samples of 0.00022 ml the standard deviation was 0.0000007 ml inclu¬ ding all other variations from a photometric measurement, a volume too small for the said previous patent. A further benefit is the detection of an exact closing or opening time of each valve by detection the aborption or release of heat of fusion in each valve. Surprisingly, when an amount of 0.00002 ml of water based liquid freezes, that is the inside volume of a valve in the described system, the rate of cooling is so high, that the valve conduit cools below -20°C, then upon sudden closing in less than 0.02 seconds its temperature jumps more than 5-10 degrees, which is each time clearly detected with said thermal sensing element. Opening, absorbing the heat of fusion, is likewise easily detected thermally in each valve. An independent confirmation of valve opening and closing or liquid entering or leaving a channel or a space, can be obtained by applying and measuring responses to pressure di ferentials and loo- king for steady or changing pressure. This conveniently takes place as an additional benefit while moving liquids with pressure differentials. As to the preferred embodiments of the element of the inven- tion, reference is made to the above description of the method of the invention and to the claims to follow. In the following, the invention is described by the aid of examples with reference to the drawings attached, wherein: Fig. 1 presents a partial view of a mould used in the for¬ ming of a heatable and refrigerable element as provided by the invention. Fig. 2 represents the first phase of the electroforming of the shell of the element, during which a layer of metal is galvanically deposited on a mould. Fig. 2 a represents the first phase in an alternative pro¬ cess for forming the shell of the element, in which a layer of metal is deposited on a mould by sputtering in a vacuum chamber. Fig. 3 represents the removal of the mould by dissolution from inside the shell thus obtained, consisting of one layer of metal. Fig. 4 represents the metal shell thus obtained, certain parts of which are provided with a protective coating. Fig. 5 represents the second phase of the electroforming of the shell in which a second layer of metal is galvanically deposited on the unprotected areas of the shell. Fig. 6 shows a partial top view of a mould which has been flattened so as to produce a so-called high-power valve in the element to be formed. Fig. 7 represents the region of a valve after deposition of the first layer of the shell and removal of the mould. Fig. 8 shows a section VI11-VI11 through the valve in Fig. 7. Fig. 9 represents a part of a finished element constructed as provided by the invention, in which the valves are coup¬ led to a refrigerator by electrically heatable bridges. Fig. 10 shows a section through an element in which a tempe¬ rature sensor and an electrically heatable bridge leading to a refrigerator have been merged on the shell in the region of a valve. Fig. 11 shows a similar section through another element constructed as provided by the invention. Figure 1 shows part of a fairly soft, easily deformable mould 1, made of aluminium. The mould has been flattened at two locations 2 in order to produce high-power valves in the element to be formed. These flattened portions are also represented by Fig. 6, which will be described in greater detail later on. Between the flattened parts 2 a space for a liquid is formed by means of the mould 1, which has three bar-shaped branches 3 between the flattened regions to form flow channels communicating with the liquid space in the element. The mould is entirely of a tubular construction, so that it can be later removed from inside the element by passing a flow of a dissolvent through the ducts 4 inside the mould. In the first deposition phase illustrated by Fig. 2 the mould 1 serves as a cathode in a sulphamate solution from which a layer of cobaltous nickel is deposited on the mould, the resulting layer having a thickness of 10-100 μm, prefer¬ ably 30 μm, and a cobalt content a few per cent. This metal layer is identified by reference number 5 in Fig. 2. Upon completion of the deposition, the mould 1 is removed by supplying a hot, strong solution of NaOh into the ducts 4 inside it. The solution dissolves the aluminium mould but has no effect on the cobaltous nickel layer deposited on it. The result is a metal shell 5 of cobaltous nickel as shown in Fig. 3, the inside of which already has a shape corresponding to that of a finished element. As a preliminary measure before the second deposition phase, certain parts of the outer surface of the cobaltous nickel shell 5 thus obtained is covered with a protective coat 6 of e.g. lacquer as shown in Fig. 4. The shell 5 is then immersed as shown if Fig. 5 as a cathode in a solution of copper sulphate containing sulphuric acid. A copper layer 7 is now deposited only on those areas of the shell which are not covered with lacquer 6. The thickness of the copper layer may vary in the range 10-500 μm. As copper and cobal¬ tous nickel differ in respect of thermal conductivity, the areas of the shell provided with a copper layer 7 have a thermal conductivity about ten times as high as that of the areas consisting of cobaltous nickel only even when the two layers deposited are or equal thickness. The result of the second deposition phase is an element 12 consisting of a liquid space 8, valves 9 at either end of the space and three flow channels 11 communicating with the liquid space and provided with valves 10. The element is ready for connection to a refrigerator and heaters as explained below in connection with Fig. 9. If desired, the protective lac¬ quer 6 can be removed from the surface of the element, though this is not necessary. The above description in connection with figures 2-5 refers to production of the element by electroformation. Alternati¬ vely the production may utilize non-electrolytic deposition techniques in which the metal is reduced chemically, cata¬ lysed by the metal (or alloy) itself. According to the invention an element can be made autocatalytically from nickel and phosphor by depositing on aluminum mandrels nickel from NiSO * or from NiCla using NaH 2 P0 2 as reducing agent at the temperature of 90-92°C, whereby the amount of phosphor incorporated in the deposited nickel is controlled by adjusting the pH. The incorporated phosphor very benefi- cially reduces the thermal conductivity of deposit for the first deposition phase. An autocatalytically reduced layer of copper can be made similarly by using CuSC and formalde¬ hyde at the temperature of about +40°C. The deposition of metal layers according to the autocataly- tic chemical reduction techniques may be carried out gene¬ rally as described in the above with reference to figures 2-5, including removal of the mould and the protective coating preceding the second deposition phase. The essential difference is that no electric current is needed for accom¬ plishing the deposition of the metals. Figure 2 a shows an alternative technique in which a layer of metal 5 is deposited onto a metallic mould 1, which n may be of aluminium, by sputtering. In partial vacuum of ionized argon gas in a gas discharge chamber a there is connected a voltage of one thousand to few thousand volts DC or ra- diofrequency to a piece of the metal B to be deposited by sputtering, which is made cathode and the mould 1 is made anode. Although sputter deposition is considerably slower than previously explained deposition methods in liquid media, it has the great advantage of being able to deposit any metal or alloys a specific application requires. A high vacuum is the environment for evaporation deposition of metals which is not very suitable due to too high tempe¬ rature for moulds used in the present invention but its combination with sputtering results a deposition process known as ion plating which takes place in a suitable tempe¬ rature and can have even higher speeds than in liquid depo¬ sition processes. The form of the valves 9 at the ends of the liquid space 8 is illustrated by figures 7 and 8. From Fig. 6, represen¬ ting the region of the mould 1 where a valve 9 is formed, it can be seen that the bar-shaped mould has been flattened in a direction which is at an angle of about 45° to the longitudinal direction of the mould. The flattened portion of the mould is identified by reference number 13 in the figure. From Figs. 7 and 8 it can be seen that the cobaltous nickel shell 5 obtained after removal of the mould has a narrow slot 14, likewise at an angle of about 45° to the longitudinal direction of the flow channel 11 inside the shell, in the region of the flattened part of the mould. As shown, the slot or choke 14 tapers towards one end 15 in the direction of the liquid flow in the channel 11. The slot 14 may have a width in the range of approx. 200-30 μm at the inflow end 16 and approx. 30-2 μm at the outflow end 15. Such a design of the choke 14 ensures that the flow of liquid arriving into the valve consisting of the choke 14, which is connected to a refrigerator as explained below, will not flow straight through the slot 14 at its wider influx end 16 but, by virtue of capillary forces, will instead flow along the slot towards its narrower efflux end 15, so that the delay involved is sufficient to allow the liquid in the choke 14 to be frozen so as to close the valve. Fig. 9 represents an element 12 produced as illustrated by Figs. 1-5. The regions of the valves 9,10 are connected to a refrigerator by means of plate-like bridges 17, which are provided with electrical resistors 18 in such manner that the bridges also act as heaters. In the embodiment shown in the figure, the bridges 17 are pointed tongues of a single plate-like body 19, the tongue tips, which are suitably bent if necessary, being attached to the copper layers covering the regions of the valves 9,10. The bridges 17 are preferably composed of a double copper film, the resistor wires 18 being contained within a layer of plastic 21 (cf. Figs. 10 and 11) between the copper films 20. Fig. 10 illustrates the way in which the end of the bridge 17 is attached to the copper layer 7 on the shell of the element 12. A thin layer 22 of indium is deposited onto the copper layer 7 and then smelted so that it binds the bridge 17 and the copper layer 7 together. The joint is secured by a drop-like formation 23 of indium gathered by the agency of capillary forces around the tip of the bridge 17 during the smelting. As shown in Fig. 10, a temperature sensor 24 is connected to the copper layer 7 on the side of the valve 10 opposite to the bridge 17. The sensor 24 consists of a thermoelement, the ends of whose leads are merged with the copper 7 in the same manner as the tip of the bridge 17. The thermoele- ment 24 makes it possible to monitor the operational state of the valve and the changes of state of the liquid in it. Fig. 11 largely corresponds to Fig. 10 except that it shows an entire bridge 17 connected to a continuous-action refri¬ gerator 25. In addition, in the element shown in this figure the copper layer 7 surrounding the large liquid space 8, which may serve e.g. as a dosage space in an analyzer, is connected via a copper bridge 26 to the copper layer 7 surrounding the flow channel 11 leading to the space, said bridge 26 serving to maintain an equal temperature in these parts of the element. The figure shows an ice blockage 27 closing the valve 10 in the channel 11. It should be noted that the valve 10 shown in Figs. 10 and 11 is a so-called normal valve, in which stationary liquid is congealed by the action of the refrigerator 25 via the bridge 27 when the heating resistor is inactive. However, in the case of the high-power valves 9 represented by Figs. 7 and 8, which are capable of dynamically stopping the liquid flow, the copper layer 7 surrounding the valve is connected in the same way via a heatable bridge 17 to a refrigerator 25. Depending on the use for which the element is designed, it may be necessary to use a chemically inert precious metal to form the internal surfaces of the flow channels 11 and possible liquid spaces 8 of the element. In this case the manufacturing process described above can be modified e.g. by first depositing a nickel layer of a few μ onto the mould 1 and then a layer of a precious metal, e.g. gold, of about equal thickness onto the nickel layer. Next, a metal shell layer 5, e.g. of cobaltous nickel as explained above, is deposited on the precious metal in the manner illustrated by Fig. 2. The subsequent removal of the mould 1 can be effected using a strong solution of hydrochloric acid, which dissolves both the aluminium mould and the first nickel layer deposited on it, so that the layer of precious metal will constitute the internal surface of the element. After this, the manufacturing process is continued in the manner described above. The proposed element 12 is designed for use as a component in a system which manipulates or processes small quantities of liquid, especially in ah automatic analyzer operated under electronic control. Thus the element, suitably connec¬ ted to other elements manufactured in essentially the same way, may constitute part of a large assembly of equipment. However, even a simple element consisting of a liquid space communicating with a few flow channels provided with valves may suffice as an instrument for carrying out certain opera¬ tions with small quantities of liquid. It is obvious to a person skilled in the art that different embodiments of the invention are not restricted to the examples described above, but that they may instead be varied within the scope of the following claims. For instan¬ ce, in an element constructed as illustrated by Fig. 11, the liquid space 8 could be directly connected to a refrige¬ rator 25 by means of the same kind of bridge 17 provided with a heating resistor 18 as is used for connecting the valve 10. In this case the temperature in the space could be regulated so as to allow the space to serve as an incuba- tion chamber, and the end of the bridge 17 could be attached to the copper layer 7 surrounding the liquid space 8 with the aid of indium as explained in connection with Fig. 10. It is also possible to replace the thermoelement serving as a temperature sensor with some other type of sensor, e.g. a thermistor, having a sufficiently low thermal capaci¬ ty. Further, the heating resistor 18 incorporated in the bridge 17 can be made of a suitable material, such as nic¬ kel, that enables the resistor to act as a temperature sensor.

Claims: Claims 1. Method for producing a heatable and refrigerable ele¬ ment (12) for a system manipulating small amounts of liquid, said element being provided with flow channels (11) and at least one liquid space (8) communicating with said channels, and said element being functionally connected at a number of locations (9, 10) to a refrigerator (25) and a heater (18), characterized in that the element (12) is produced by use of a removable mould (1) serving as a substrate for deposition, by depositing one or more metallic materials in such a way that deposited metal forms the shell (5, 7) of the element, by removing the mould, and by connecting the shell at said locations (9, 10) to a refrigerator (25) and a heater (18), production being carried out so that the thermal conductivity of the structure as obtained at the locations where the shell of the element has been con¬ nected to a refrigerator and a heater substantially exceeds the thermal conductivity of the shell areas adjacent to said locations. 2. Method according to claim 1, characterized in that the element is produced by use of electroformation. 3. Method according to claim 1, characterized in that the element is produced by use of autocatalytic chemical reduction, in which at last one metallic material is reduced and deposited from a liquid phase. 4. Method according to claim 1, characterized in that the element is produced by use of chemical vapor deposition, in which at least one metallic material is reduced and deposited from a gaseous phase. 5. Method according to claim 1, characterized in that the element is produced by use of sputtering, in which metallic material is ionized in a vacuum chamber and drawn onto a mould by means of electric voltage. 6. Method according to claim 1, characterized in that the method utilizes evaporation techniques, in which metal¬ lic material is evaporated in a chamber and allowed to deposite on a mould placed in said chamber. 7. Method according to claim 1, characterized in that the shell (5,7) of the element is formed in two phases by first depositing a first layer of metal over the whole surface of the mould (1) and then a second metal layer on said first layer only on the locations to be connected to a heater (18) and a refrigerator (25). 8. Method according to claim 7, characterized in that after the first deposition phase the areas outside the heatable and refrigerable locations (9, 10) are covered with a protective coating (6), e.g. lacquer, to prevent the deposition of metal on these areas during the next phase. 9. Method according to claim 7 or 8, characterized in that a substantially thicker layer of metal is deposited in the second phase than in the first phase. 10. Method according to any one of the claims 7-9, charac- terized in that the metal deposited in the first phase, e.g. nickel, has a lower thermal conductivity than the metal deposited in the second phase, e.g. copper. 11. Method according to any one of the claims 7-10, charac- terized in that the mould (1) is removed after the first deposition phase. 12. Method according to any one of the preceding claims, characterized in that it uses a dissoluble mould (1), at least partially tubular in construction, which is removed by passing a flow of dissolvent through it. 13. Method according to any one of the preceding claims, characterized in that the " mould (1) is made of aluminium and that the dissolvent used for removing it is a solution of lye. 14. Method according to any one of the preceding claims, characterized in that the shell (5, 7) of the element (12) is connected to a refrigerator by a bar-shaped or a plate¬ like bridge (17) made of a material, such as copper, that has a high thermal conductivity. 15. Method according to claim 14, characterized in that the bridge (17) is provided with an insulated electric resistor (18) in such manner that the bridge also acts as a heater. 16. Method according to claim 14 or 15, characterized in that the bridge (17) is attached to the element by deposi¬ ting a suitable amount of an easily melting material (22), e.g. indium, on the shell (7) of the element and then smel- ting it so that the material (22, 23) merges the end of the bridge together with the shell. 17. Method according to any one of the preceding claims, characterized in that the element (12) is provided with a heatable and refrigerable region (9) which, at least in one dimension, is sufficiently narrow to allow it to act as a valve that block the flow channel (11) by freezing the liquid in it. 18. Method according to claim 17, characterized in that the valve (9) is produced by flattening a bar-shaped mould (1) in such manner that, after deposition of the metal layers and removal of the mould, the result is a narrow slot (14) in the flow channel inside the metal shell (5) in the region where the mould was flattened. 19. Method according to claim 14, characterized in that the bar-shaped mould (1) is flattened in a direction which is at an angle of approx. 20-60° relative to the longitu¬ dinal direction of the mould. 20. Element (12) manufactured by the method of one of the above claims, designed for use in a system manipulating small quantities of liquid, comprising flow channels (11) and at least one liquid space (8) communicating with them, said element being functionally connected at a number of locations (9, 10) to a refrigerator (25) and a heater (18) characterized in that the element (12) comprises a set of flow channels and one or more liquid spaces enclosed by an integral metal shell (5, 7) having essentially tubular sections, said shell being connected at a number of loca¬ tions (9, 10) to a refrigerator (25) and a heater (18), and that said locations together with the connections to a refrigerator and a heater are made up so that the thermal conductivity of the structure at these locations substan¬ tially exceeds the thermal conductivity of the adjacent shell areas. 21. Element according to claim 20, characterized in that the thickness of the shell (5, 7) at the locations (9, 10) where the shell is connected to a refrigerator (25) and a heater (18) substantially exceeds the thickness of the shell in the areas adjacent to said locations. 22. Element according to claim 20 or 21, characterized in that the element (12) comprises a thin, solid metal shell (5) extending over the whole area of the element, and, at the locations (9, 10) connected to a refrigerator (25) and a heater (18), another shell layer (7) made of a different metal having a higher thermal conductivity. 23. Element according to claim 22, characterized in that said solid metal shell (5) is made of nickel or a nickel alloy, and that said second shell layer (7) at the heatable and refrigerable locations (9, 10) is made of copper. 24. Element according to any one of the claims 20-23, , characterized in that the shell (7) of the element (12) is connected to a refrigerator (25) by means of a bar-shaped or a plate-like bridge (17) made of a material, e.g. copper, that has a high thermal conductivity. 25. Element according to claim 24,. characterized in that the bridge (17) is provided with an insulated electric resistor (18) in such manner that the bridge also acts as as a heater. 26. Element according to claim 24 or 25, characterized in that the bridge (17) is attached to the shell (7) of the element by merging with an easily melting material, e.g. indium (22, 23). 27. Element according to any one of the claims 20-26, characterized in that the heatable and refrigerable region (9) of the element (12) is, at least in one dimension, sufficiently narrow to allow it to act as a valve that blocks the flow channel (11) by freezing the liquid in it. 28. Element according to claim 27, characterized in that the valve (9) consists of a slot in the flow channel (11), said slot being oriented at an angle of approx. 20-60° relative to the longitudinal direction of the channel. 29. Element according to claim 27 or 28, characterized in that the valve (9, 10) is provided with a temperature sensor (24) enabling the operation of the valve to be monitored. 30. Element according to any one of the claims 20-29, characterized in that the element (12) comprises at least one mixing or incubation space (8) which is connected to a refrigerator and provided with at least one heater (18) to allow regulation of the temperature of the liquid in the space.

Inventors: KAARTINEN NIILO, KAARTINEN, NIILO
Applicants: KAARTINEN NIILO, KAARTINEN, NIILO
Application year: 1990
Main classification: G01N35
IPC codes: B01L3, C23C14, C23C16, C25D1, F17D1, G01N1, G01N35, G05D7