The invention relates to an apparatus for preparing a diluted sample fluid, for instance for analysation purposes, comprising: a sample supply means arranged to supply a sample fluid; a diluent supply means arranged to supply a diluent fluid; a mixing container arranged to mix the sample fluid and the diluent supplied by said supply means so as to form a diluted sample fluid, said mixing container comprising at least one fluid supply opening connected to said sample supply means and said diluent supply means, and a fluid discharge opening for discharging diluted sample fluid; and a heat exchanging means arranged to control the temperature of the diluted sample fluid by selective cooling and/or heating. Such an apparatus is described in patent application publication US 2002/0154567 Al.

The apparatus of the current invention is in particular suited as a reagent production unit for automated and systematic haematology analyses. For such application blood sample fluid is diluted and mixed with purified water as diluent to a mixture with a predetermined concentration and temperature. The accuracy of the sample dilution concentration, homogeneity and temperature is very important, as is the reagent production cycle time.

The invention aims at a more accurate, efficient, energy saving, space saving, cost saving, robust and/or maintenance free solution for preparing a diluted sample fluid for analysation purposes. In particular the invention aims to increase the efficiency, productivity and quality of the sample analysing process.

According to one aspect of the invention said heat exchanging means comprises a plurality of heat exchanging elements in the inner volume of said mixing container extending in the fluid flow path between the at least one fluid supply opening and the fluid discharge opening, said plurality of heat exchanging elements causing said sample fluid and said diluent to mix while heat is being exchanged between said elements and said mixing sample fluid and diluent when flowing from said fluid supply opening to said fluid discharge opening.

In accordance with the invention, the inner volume of the mixing container is preferably as small as possible, preferably the inner volume is just large enough to be able to achieve the required temperatures and homogeneity of the diluted sample fluid during one passage of the fluid in most cases. Preferably said heat exchanging elements extend such that they subsequently separate and join the fluid flow path in said mixing container multiple times, said multiple separating and joining sequence causing said sample fluid and said diluent to mix while heat is being exchanged between said elements and said mixing sample fluid and diluent when flowing from said fluid supply opening to said fluid discharge opening.

Said heat exchanging elements are preferably in heat conducting communication with the inner surface area of the wall of said mixing container and wherein said temperature control means further comprises at least one heat exchanging plate which is attached to and in heat-conducting contact with the larger part of the outer surface area of the wall of said mixing container, such that heat can be exchanged between said heat exchanging plate and said heat exchanging elements in the inner volume of the mixing container. One additional advantage of the possibility to heat the surface of the walls of the mixing container is that thereby undesirable micro-bubbles in the fluid can be removed. The inner surface of the mixing container is preferably treated or coated with a substance, such as heparin, to avoid blood clotting activation.

In the preferred embodiment said heat exchanging plate comprises a thermoelectric Peltier element. In a further preferred embodiment an outer wall of said Peltier element is integral with and forms a substantially flat walls of said mixing container. Said temperature control means preferably comprises two of said heat exchanging plates, each one of said plates being attached to and in heat-conducting contact with the larger part of the outer surface area of at least one flat wall of said mixing container. Said mixing container preferably comprises two substantially flat walls extending parallel to each other at a short distance from each other compared to the circumferential dimensions of said walls, wherein said heat exchanging elements extend perpendicular to and between said two walls.

Preferably said fluid supply opening and said fluid discharge opening extend near opposite outer ends of said flat walls. Preferably said flat walls are substantially rectangular and said fluid supply opening and said fluid discharge opening extend near diagonally opposite outer ends of said flat walls. Preferably said mixing container with said fluid supply opening, said fluid discharge opening and said heat exchanging elements in the inner volume of said mixing container are made of one piece of material. Said mixing container is preferably made of a ceramic material, such as A1 ₂ 0 ₃ . An advantage of such a monolithic mixing container is that no undesired cavities are present where fluid would remain behind. The outer surface of said heat exchanging plate(s) opposite the wall(s) of said mixing container is/are preferably in contact with a heat exchanging fluid of a heat exchanging device. Said heat exchanging device preferably comprises a fluid circuit and a pump for pumping a fluid to and from the outer surface of said heat exchanging plate(s). The outer surface of said heat exchanging plate(s) opposite the wall(s) of said mixing container is/are preferably provided with heat conducting cooling fins.

Said heat exchanging elements preferably have a circular cross section, seen in a cross section parallel to said two flat walls of said mixing container. Preferably said heat exchanging elements are arranged in a two dimensional matrix, seen in a cross section parallel to said two flat walls of said mixing container, wherein said matrix comprises a multitude of elements in each of said two dimensions. More preferably said heat exchanging elements are arranged in a hexagonal packed configuration, seen in a cross section parallel to said two flat walls of said mixing container. Said fluid discharge opening and said fluid supply opening of said mixing container are preferably mutually connected by means of a fluid recycling bypass, and said apparatus is provided with temperature control means arranged to measure the temperature of said diluted sample fluid discharged from said fluid discharge opening and to cause said diluted sample fluid to recycle through said fluid recycling bypass and said mixing container until a predetermined temperature of the diluted sample fluid has been reached. This configuration can also be used to initially mix the fluid at a higher temperature than the desired final temperature of the diluted sample fluid, and then cool the fluid down to the desired final temperature by recycling it through the mixing chamber, which can be more efficient for certain sample fluids. A further advantage thereof is that the boundary layer, i.e. the fluid layer near the walls of the container which is not moving, which impedes mixing, is smaller at higher temperatures. Said apparatus is furthermore preferably provided with temperature control means arranged to measure the temperature of said diluted sample fluid and to adapt the fluid flow rate of said diluted sample fluid through said mixing container in dependence of the measured temperature, in order to regulate the temperature of the fluid at the discharge opening. Preferably said apparatus is provided with thermostatic temperature control means arranged to measure the temperature of said diluted sample fluid and to selectively cause the heat exchange means to heat or cool the diluted sample fluid flowing through said mixing container.

Preferably said apparatus comprises an intermediate diluted sample fluid container in said fluid recycling bypass arranged to collect sample fluid from said sample supply means, diluent fluid from said diluent supply means and mixed diluted sample fluid from said discharge opening of said mixing container, and arranged to supply fluid from said intermediate diluted sample fluid container to said mixing container. Said intermediate diluted sample fluid container is preferably connected to a mixed diluted sample fluid storage container, and said apparatus is provided with mixed diluted sample fluid discharge control means arranged to cause mixed diluted sample fluid to flow from said intermediate diluted sample fluid container to said mixed diluted sample fluid storage container if the temperature of said mixed diluted sample fluid has a predetermined required value.

Said apparatus is furthermore preferably provided with means arranged to measure a dilution value of the mixed diluted sample fluid and to selectively allow and stop sample fluid and/or diluent fluid to flow to said intermediate diluted sample fluid container in dependency of said

measurement, and said mixed diluted sample fluid discharge control means are furthermore arranged to cause mixed diluted sample fluid to flow from said intermediate diluted sample fluid container to said mixed diluted sample fluid storage container only if the dilution value of said mixed diluted sample fluid has a predetermined required value.

In another embodiment the apparatus comprises several mixing containers in series, each with their own heat exchanging means and temperature, dilution concentration and/or homogeneity control means, with the options to dilute the diluted sample fluid in stages and/or to add further sample fluids to the diluted sample fluid at different stages.

Apart from sample analysis, the apparatus of the invention can for instance also be used in heart surgery, to cool and/or heat blood (as "diluent fluid") to a temperature where it more easily releases C0 ₂ and absorbs 0 ₂ (possibly at two different temperatures) and to readjust the temperature before it reenters the body. At the same time saline or concentrated blood products can be added (as "sample fluids"). The current description as well as the attached claims are to be interpreted in a manner so as to include such applications.

The invention will now be illustrated by means of a preferred embodiment, with reference to the drawings, wherein:

Figure 1 is a perspective view of a fluid mixing and temperature control device used in an apparatus in accordance with the invention; Figure 2 is a cross section of a perspective view of the device of figure 1 ; Figure 3 is a partially open perspective view of a mixing container used in the device of figure 1 ;

Figure 4 is a cross section of a perspective view of the mixing container of figure 3; and Figure 5 is a schematic view of an apparatus in accordance with the invention.

According to figures 1 and 2 a fluid mixing and temperature control device is shown which is used in an apparatus for preparing a diluted sample fluid for analysation purposes in accordance with the invention. The apparatus will be described hereinafter with reference to figure 5.

The device as shown in figures 1 and 2 comprises a mixing container 1 , as shown in more detail in figures 3 and 4. The mixing container 1 is made from sintered ceramic powder material, and comprises two parallel rectangular flat walls 2, 3 at a relatively short distance from each other, which walls are interconnected by a multitude of heat exchanging and flow separation elements 4 and a circumferential wall 5. A fluid supply opening and connector 6 is present in the wall 2 near one corner thereof, and a fluid discharge opening and connector 7 is present in the wall 2 near the diagonally opposite corner thereof.

The elements 4 are generally pillar shaped, having a circular cross section, and having cross sectional diameters which are smaller in the part between the walls 2, 3 than in the parts directly adjacent the walls 2, 3. The elements 4 are arranged in a hexagonal packed configuration, i.e. except near the edges of the device each element 4 is surrounded by six other elements 4, wherein the mutual distances between the elements 4 define flow paths for the fluid. Along an edge on one side adjacent the fluid supply opening 6 a fluid supply channel 8 is present in the container 1, and along the opposite edge adjacent the discharge opening 7 a fluid discharge channel 9 is present in the container 1. The elements 4' directly adjacent the channels 8, 9 and the elements 4 have an elongated cross section, so as to act as flow distribution elements. As the mixing container 1 is entirely symmetrical, it can be used both ways, i.e. the supply side can also act as discharge side and vice versa. When fluid flows from supply opening 6 to the discharge opening 7, the elements 4 will force the fluid flow to divide in several sub-flows and join the sub-flows together after each element 4, and cause the fluid to flow following a more or less random path, thereby causing the fluid to mix thoroughly.

The elements 4 also act as heat exchanging elements, as they are made from heat conducting material and connected to the heat conducting walls 2, 3. As shown in figure 2, on almost the entire outer surface of the outer side of the walls 2, 3 two plate shaped thermoelectric Peltier elements 11 , 12 are mounted, which are capable of cooling or heating the walls 2, 3, and thereby the elements 4 and the fluid flowing through the mixing container 1. Alternatively the Peltier elements 11, 12 form the walls 2, 3 of the mixing container 1. A heat conducting frame 13a, 13b, 13c, 13d encloses the sandwich construction formed by the container 1 and the elements 11, 12. On the outside of the frame adjacent the Peltier elements heat exchanging devices 14, 15 are mounted, which heat exchanging devices are commonly known liquid cooling devices as used to cool for instance computer CPUs. As shown in Figure 1, these heat exchanging devices each use a fan 16 to cool or heat a liquid flow through a chamber 17 formed adjacent the Peltier elements 11, 12. These heat exchanging devices 14, 15 are used to cool or heat the outer side of the Peltier elements, where necessary, using ambient air. In order to further promote cooling or heating of the Peltier elements 11, 12 heat conducting fins 18 are present inside the chamber 17 adjacent the Peltier elements 11, 12.

With reference to figure 5, the apparatus for preparing a diluted sample fluid for analysation purposes comprises the mixing chamber 1 with amongst others supply opening 6 and discharge opening 7, Peltier elements 11, 12, and cooling devices 14, 15 with fans 16 as described before. The apparatus is connected to a computer network 100 such that users can easily control the apparatus, an operating computer 101 and interface 102 which is programmed to control the apparatus. The apparatus comprises a diluent inlet device 103 and a diluent buffer 104, and two sample fluid containers 105a, 105b. Two sample fluid containers 105a, 105b are used if for instance two samples are to be mixed which cannot be mixed in concentrated form, but which can be mixed in diluted form. In such a case the first sample is diluted and thereafter the second sample is added to the mix. The diluent buffer 104 and the sample fluid containers are connected to an intermediate diluted sample fluid container 106. The operating computer 101 controls the flow of both the diluent and sample fluid to said container 106 in order to obtain roughly a required dilution concentration.

The diluted sample fluid is then pumped via fluid supply opening 6 to the mixing container 1 , where it is mixed and heated or cooled to a required temperature by the Peltier elements as described before. The heating and cooling power of the Peltier elements are controlled by a temperature sensor 107 near the discharge opening, Clickson thermostats 108 and a TEC controller 109. From the discharge opening 7 the diluted sample fluid is pumped to the container 106. Means 107for measuring the temperature, dilution concentration and homogeneity of the fluid are present near the discharge opening 7. The dilution value can for instance be determined by measuring the electrical conductivity, the viscosity, the 02 concentration and/or the pH of the fluid. As long as not all of these values are at the required level, a pump 111 will pump the fluid from the container 106 through a fluid recycle bypass 112 back to the mixing container 1, while at the same time either or both extra diluent is added to the container 106 and/or the Peltier elements 11, 12 are activated in order to achieve exactly the required temperature, dilution concentration and/or homogeneity values.

Once the measuring means 110 measure the correct values, the diluted sample fluid is pumped form the container 106 to an extraction container 113 and from there either directly to an analyser apparatus 114 or to a storage container 115. A further pump 116 can then pump the diluted sample fluid from the storage container to the extraction container 113 when it is needed in the analyser apparatus 114. It should be noted that storage of the diluted fluid in the intermediate fluid container 106 is optional, as the apparatus can also operate in a continuous flow mode, wherein the diluted sample fluid flows directly from the discharge opening 7 of the mixing container 1 to the analyser apparatus 114. The invention has thus been described by means of a preferred embodiment. It is to be understood, however, that this disclosure is merely illustrative. Various details of the structure and function were presented, but changes made therein, to the full extent extended by the general meaning of the terms in which the appended claims are expressed, are understood to be within the principle of the present invention. The description and drawings shall be used to interpret the claims. The claims should not be interpreted as meaning that the extent of the protection sought is to be understood as that defined by the strict, literal meaning of the wording used in the claims, the description and drawings being employed only for the purpose of resolving an ambiguity found in the claims. For the purpose of determining the extent of protection sought by the claims, due account shall be taken of any element which is equivalent to an element specified therein.