Concentration determination in conjuction with generation of treatment fluid for use in dialysis

Abstract

In a system, a mixing sub-system (10) is arranged to generate treatment fluid for use in dialysis, by mixing water and one or more concentrates. A pumping device (FP2) is configured to drive a first concentrate among the concentrate(s) along a concentrate flow path in the mixing sub-system. A restrictor (21) is arranged to define a confined passage in the concentrate flow path, and a sensor sub-system (22, 23) is configured to provide a first signal representative of a pressure difference between upstream and downstream ends of the restrictor as a function of time. A processing sub-system (30) performs a method of determining a concentration value of the first concentrate by obtaining the first signal while the pumping device is operated to drive the first concentrate through the restrictor, and determines the concentration value based on a waveform in the first signal.

Description

[0001] CONCENTRATION DETERMINATION IN CONJUCTION WITH GENERATION OF TREATMENT FLUID FOR USE IN DIALYSIS

[0002] Technical Field

[0003] The present disclosure relates generally to dialysis, and in particular to systems for generating treatment fluid for use in dialysis therapy.

[0004] Background Art

[0005] Dialysis therapy is a therapy that replaces the normal blood-filtering function of the kidneys. It is used when the kidneys are not working well, which is known as kidney failure and includes acute kidney injury (AKI) and chronic kidney disease (CKD). Dialysis therapy involves removal of water from the blood of the patient suffering from kidney failure, as well as exchange of solutes with the blood. One example of dialysis therapy is extracorporeal blood therapy, in which blood is circulated outside of the patient and interfaced with one or more treatment fluids. Modalities of extracorporeal blood therapy include hemodialysis (HD), hemofiltration (HF) and hemodiafiltration (HDF). Another example of dialysis therapy is peritoneal dialysis (PD), in which a treatment fluid is infused into the peritoneal cavity of the patient to interface with the blood of the patient through the peritoneal membrane.

[0006] Over time, dialysis therapy consumes large quantities of treatment fluid. In some modalities of dialysis therapy, pre-made (ready-made) treatment fluid is delivered in prefilled bags to the point of care. For example, conventional PD is performed by use of prefilled bags. AKI machines are configured to use prefilled bags of medical fluid, by staff installing a prefilled bag before treatment and replacing the prefilled bag as required. On the other hand, CKD machines have integrated capability to generate medical fluid on-demand by mixing one or more concentrate fluids with water, so- called on-line fluid generation. Recently, PD machines with integrated capability of online fluid generation have been proposed. The concentrate fluids are supplied in prefilled bags, which are significantly smaller than the prefilled bags of medical fluid.

[0007] Local production of medical fluid at the point of care is attractive since it reduces the cost and environmental impact of transporting large amounts of ready-made fluid and the burden of storing and handling the heavy bags of ready-made fluid.

[0008] The fluid in a prefilled bag for use in dialysis therapy has a nominal composition, which needs to be met within predefined tolerances. During storage of pre-filled bags, water may evaporate from the fluid inside the bags, through the wall material of the bag, causing the concentration of the fluid to increase over time. Concentrate fluids are more sensitive to evaporative water loss than ready-made fluids, because of their smaller water content. By the evaporative water loss, the concentrate fluid in the bag will become more concentrated, and thus increasingly deviate from its nominal composition, as water evaporates from the bag.

[0009] Evaporative water loss may be quantified by measuring the electrical conductivity of the respective concentrate fluid, and the dosing of the concentrate fluid may then be adjusted during generation of treatment fluid to account for the evaporative water loss. However, this approach presumes that the concentrate fluid at its nominal composition has a conductivity that allows the evaporative water loss to be quantified with reasonable accuracy. This is not the case for all types of concentrate fluids. Some concentrate fluids may consist of substances that do not dissociate into constituent ions and thus are poor conductors of electricity. One such substance is glucose, which is commonly used as an osmotic agent in treatment fluid for PD ("PD fluid"). Thus, it is difficult to verify the composition of a glucose concentrate based on electrical conductivity.

[0010] There is a need for an alternative technique of verifying and / or determining the concentration or composition of a concentrate fluid for use in generation of treatment fluid. The technique is not limited to concentrate fluids that have low conductivity, since there may be other reasons for not performing a conductivity measurement to verify the composition of a concentrate fluid.

[0011] Summary

[0012] It is an objective to at least partly overcome one or more limitations of the prior art.

[0013] One objective is to provide an alternative technique of verifying and / or determining the concentration or composition of a concentrate fluid for use in generation of treatment fluid.

[0014] Another objective is to provide such a technique that is simple to implement and perform.

[0015] A further objective is provide such a technique that can be performed for small amounts of concentrate fluid.

[0016] One or more of these objectives, as well as further objectives that may appear from the description below, are at least partly achieved by a system for generating treatment fluid for use in dialysis therapy, a computer-implemented method, and a computer-readable medium, embodiments thereof being defined by the dependent claims. Still other objectives, as well as aspects, embodiments, technical effects, features and advantages may appear from the following detailed description, from the attached claims as well as from the drawings.

[0017] Brief Description of the Drawings

[0018] FIG. 1 is a block diagram of an example system for generating treatment fluid.

[0019] FIGS 2A-2C are block diagrams of example restrictor arrangements in the system of FIG. 1

[0020] FIG. 3 are section views of an example fluid pump during a pumping cycle.

[0021] FIGS 4A-4B are plots of simulated pressure drop over a restrictor, and a corresponding derivative signal, during a pumping cycle, and FIGS 4C-4D are corresponding plots of measurement data.

[0022] FIGS 5-8 are flow charts of example methods performed in relation to a system for generating treatment fluid.

[0023] FIG. 9 is a block diagram of an example data processing system for use in the methods of FIGS 5-8.

[0024] FIGS 10A-10B are plots of simulated pressure drop over a restrictor for concentrate fluids at different glucose concentrations, for two different pumping speeds.

[0025] FIGS 11A-11C are plots of measured pressure drop over a restrictor for concentrate fluids at different glucose concentrations, for three different pumping speeds.

[0026] FIGS 12A-12C are plots of derivative signals for the data in FIGS 11A-11C.

[0027] FIGS 13A-13C are plots of derivative signals at three pumping speeds with the derivative signals being divided into signal segments.

[0028] FIG. 14 is a block diagram of an example machine that may implement the methods, procedures and functions described herein.

[0029] Detailed Description of Example Embodiments

[0030] Embodiments will now be described more fully hereinafter with reference to the accompanying drawings, in which some, but not all, embodiments are shown. Indeed, the subject of the present disclosure may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure may satisfy applicable legal requirements.

[0031] Also, it will be understood that, where possible, any of the advantages, features, functions, devices, and / or operational aspects of any of the embodiments described and / or contemplated herein may be included in any of the other embodiments described and / or contemplated herein, and / or vice versa. In addition, where possible, any terms expressed in the singular form herein are meant to also include the plural form and / or vice versa, unless explicitly stated otherwise. As used herein, "at least one" shall mean "one or more" and these phrases are intended to be interchangeable. Accordingly, the terms "a" and / or "an" shall mean "at least one" or "one or more", even though the phrase "one or more" or "at least one" is also used herein. As used herein, except where the context requires otherwise owing to express language or necessary implication, the word "comprise" or variations such as "comprises" or "comprising" is used in an inclusive sense, that is, to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments.

[0032] As used herein, the terms "multiple", "plural" and "plurality" are intended to imply provision of two or more elements. The term "and / or" includes any and all combinations of one or more of the associated listed elements.

[0033] It will furthermore be understood that although the terms first, second, etc. may be used herein to describe various elements, these elements should not be limited by these terms. These terms are only used to distinguish one element from another. For example, a first element could be termed a second element, and, similarly, a second element could be termed a first element, without departing the scope of the present disclosure.

[0034] Well-known functions or constructions may not be described in detail for brevity and / or clarity. Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0035] As used herein, "dialysis therapy" refers to any therapy that replaces or supplements the renal function of a patient by use of a treatment fluid. Dialysis therapy includes, without limitation, extracorporeal (EC) blood therapy and peritoneal dialysis (PD) therapy.

[0036] As used herein, "treatment fluid" refers to any fluid that is consumed as a result of dialysis therapy. Treatment fluid includes, without limitation, dialysis fluid for infusion into the peritoneal cavity during PD therapy, dialysis fluid for supply to a dialyzer during EC blood therapy, as well as replacement fluid and substitution fluid for infusion into blood during EC blood therapy.

[0037] As used herein, a "concentrate fluid" or "concentrate" is a water-containing liquid that contains one or more compounds ("solutes") at a concentration that is higher than at the final use of the liquid. Thus, a concentrate is produced to be diluted by a solvent, also denoted "base fluid" herein. For example, the base fluid may be water or another water-containing concentrate.

[0038] Like reference signs refer to like elements throughout. FIG. 1 is a block diagram of an example system for generating treatment fluid for use in dialysis therapy. In the illustrated example, the treatment fluid, TF, is generated by mixing product water, PW, with two concentrate fluids, CF1 and CF2, although any number of concentrate fluids may be used. The system may be seen to include a mixing sub- system 10 that is operable to perform this task. The product water may be purified water that meets requirements for use in dialysis therapy, for example "water for dialysis" or "water for injection". In FIG. 1, the mixing sub-system 10 includes a main flow line or path LI, which extends from an inlet Ila for product water to an outlet 1 lb for treatment fluid. The inlet I la and the outlet 1 lb may or may not be configured as ports or connectors. A first supply line L2 for the first concentrate CF1 is fluidly connected to the main line LI at a first juncture 12b, and a second supply line L3 for the second concentrate CF2 is fluidly connected to the main line LI at a second juncture 13b. The first supply line L2 extends to the juncture 12b from a port or connector 12a on a first container or bag 12 that holds CF1. A first supply pump FP2 is arranged in the supply line L2 to provide a flow of CF1 into the main line LI. The second supply line L3 extends to the juncture 13b from a port or connector 13a on a second container or bag 13 that holds CF2. A second supply pump FP3 is arranged in the supply line L3 to provide a flow of CF2 into the main line LI.

[0039] A mixing device 14 is arranged in the main line LI downstream of the junctures 12b, 13b and is configured to promote the mixing of CF1 and CF2 with PW. For example, the mixing device 14 may comprise a tank and / or an in-line mixer. A main fluid pump FP1 is arranged in the main line downstream of the mixing device 14. In the illustrated example, a conductivity sensor 15 and a temperature sensor 16 are arranged in the main line 1 downstream of the main pump FPL The sensors 15, 16 may or may not be combined into a unitary device. A bypass valve 17 is arranged in the main line LI, downstream of the sensors 15, 16 and in fluid communication with a drain line 18, which extends to a drain or a reservoir 30 for collecting discarded fluid. The bypass valve 17 is operable to selectively direct the fluid flow on the main line LI to the outlet 1 lb or into the drain line 18.

[0040] As will be described below, the system further comprises a restrictor arrangement 20, which is arranged in the first supply line L2. In the illustrated example, the restrictor arrangement 20 is placed between the container 12 and the pump FP2, but it may alternatively be placed between the pump FP2 and the juncture 12b. The restrictor arrangement 20 is configured to provide an output signal S4.

[0041] The operation of the mixing sub-system 10 is controlled by control signals C1-C4 that are generated by a control device (not shown). Control signals C1-C3 are provided to the pumps FP1-FP3 to set their pumping speeds, and control signal C4 is provided to the bypass valve 17 to either direct the fluid flow to the outlet (production state) or into the drain line 18 (discard state). In the illustrated example, the mixing sub-system 10 also provides output signals SI -S3. Output signals SI, S2 are representative of the conductivity and the temperature, respectively, of passing fluid. As shown, an output signal S3 may be provided to represent the current pumping speed of the pump FP2. The output signal S3 may, for example, be given by a conventional speed sensor, which may include a magnetic sensor, an optical sensor, a Hall effect sensor, an eddy-current tachometer, an inductive speed sensor, etc. At least some of the output signals S1-S3 may be used by the control device to operate the mixing sub-system 10.

[0042] In some embodiments, the containers 12, 13 are configured to be releasably connected to the supply lines L2, L3. Thereby, the respective container 12, 13 may be replaced whenever necessary, for example based on the amount of remaining concentrate in the container 12, 13.

[0043] The system is operable in a production phase, in which TF is generated and supplied via the outlet 10b. In the production phase, the speed of the main pump FP1 is set for the mixing sub-system 10 to provide TF at a desired flow rate. The speeds of the supply pumps FP2, FP3 are set to achieve a desired dilution of the respective concentrate CF1, CF2 by the product water PW. The speeds of the supply pumps FP2, FP3 may be set to result in nominal dilution ratios, which are predefined for a nominal composition of the respective concentrate CF1, CF2.

[0044] The composition of the concentrate in the container 12, 13 is likely to change over time from its production, as a result of water vapor escaping from the concentrate through the container material. During storage, water evaporation from a concentrate container may be mitigated by covering it by a protective material, known as an "overpouch". However, as the over-pouch is removed when the container is attached to the system 10, the evaporation rate will increase significantly. Since concentration containers are typically made of flexible material, in the form of flexible bags, the shape of the container may change as the concentrate is consumed. In use, the volume of the concentrate may therefore decrease faster than the surface area of the container material that is available for water diffusion out of the container. This would result in an increasing up-concentration rate of the concentrate in the container as the concentrate is consumed.

[0045] The Applicant has found that evaporation of water from the concentrate containers 12, 13 may cause the treatment fluid to be generated with an erroneous composition, unless proper counter-measures are taken. One such counter-measure would be to perform a measurement on the respective concentrate to detect if its composition deviates from the nominal composition. If so, the dilution ratio of the concentrate may be adjusted to compensate for the difference in composition.

[0046] One way of performing such a measurement is to pump the concentrate through a conductivity sensor and evaluate the measured conductivity in relation to a nominal conductivity. A deviation between measured conductivity and nominal conductivity is equal to a difference between the actual composition and the nominal composition, which is turn can be translated into a required change of the dilution ratio to achieve a target composition of the treatment fluid.

[0047] In the example of FIG. 1, the conductivity of the concentrate CF1 may be measured by jointly operating the pumps PF1, PF3 to pump CF1 through the conductivity sensor 15, while the bypass valve 17 is set to direct CF1 into the drain line 18. The measurement may be made for diluted or undiluted concentrate. In other words, the supply of PW may or may not be blocked during the measurement.

[0048] This measurement presumes that the concentrate CF1 is electrically conductive to such an extent that the effect of evaporation can be detected. This is not always the case. For example, when generating a PD fluid, one of the concentrates may be a glucose concentrate, which has a very low electrical conductivity. In the following, it is assumed that CF1 is a glucose concentrate, and that CF2 is an electrolyte concentrate, and TF is a PD fluid.

[0049] By insightful reasoning, the Applicant has realized that the evaporation will change (increase) the viscosity of the glucose concentrate, and that the change in viscosity will change (increase) the flow resistance for the glucose concentrate. By quantifying the flow resistance, it is possible to quantify the change in composition caused by the evaporation. This measurement principle is implemented through the provision of the restrictor arrangement 20 in FIG. 1 and a processing sub-system 30, denoted "evaluation device" in the following.

[0050] The evaluation device 30 is configured to calculate a concentration value CV for glucose in CF1 based on an output signal S4 from the restrictor arrangement 20. The output signal S4 is representative of a pressure drop within the restrictor arrangement 20, may be denoted "pressure drop signal", "pressure signal" or "first signal". As indicated by dashed arrows, the evaluation device 30 may optionally receive the signal S3 for determination of the current speed of the pump FP2. Alternatively or additionally, the device 30 may receive the control signal C2 to determine the current speed of FP2. Examples of the data processing by the device 30 are given below with reference to FIGS 5-8. In some embodiments, the device 30 may also control the operation of the mixing sub-system 10 and thus form a control device for the mixing sub- system. FIG. 2A shows an example of the restrictor arrangement 20 as installed in the supply line L2, between an upstream line segment L2a and a downstream line segment L2b. The restrictor arrangement 20 comprises a restrictor 21 that defines a confined passage, which is configured to locally increase the flow resistance for CF1 significantly. In the illustrated example, the restrictor 21 is disposed in a connecting line segment 24 that extends between the upstream and downstream line segments L2a, L2b. Pressure sensors 22, 23 are arranged to measure the fluid pressure upstream and downstream, respectively, of the restrictor 21 and provide a respective pressure signal S4a, S4b. The difference between the signals S4a, S4b represents the pressure drop over the restrictor 21. The pressure drop is thus a pressure difference between the upstream end (inlet) and the downstream end (outlet) of the restrictor 21. It is to be understood that the output signal S4 in FIG. 1 may be composed of both pressure signals S4a, S4b, or a difference signal obtained from the pressure sensors 22, 23. It is also conceivable that the restrictor arrangement 20 has a pressure sensor on only one side of the restrictor 21, if the fluid pressure on the other side of the restrictor 21 has a fixed and known value. For example, the system 10 may designed so that the fluid pressure upstream or downstream of the restrictor 20 is maintained at atmospheric pressure. In the example of FIG. 2A, if the container 12 (FIG. 1) is a flexible bag, the fluid pressure upstream of the restrictor 21 may be assumed to be atmospheric, optionally corrected for a pressure drop in the line segment L2a. In another example, not shown, the restrictor arrangement 20 is arranged in the supply line L2 downstream of the pump FP2 (cf. FIG. 1) and the mixing device 14 (FIG. 1) is maintained at a predefined pressure. Here, the fluid pressure downstream of the restrictor 21 may be assumed to correspond to this predefined pressure, optionally corrected for a pressure drop between the downstream end of the restrictor 21 and the mixing device 14.

[0051] The configuration in FIG. 2A has the potential drawback that CF1 is always pumped through the restrictor 21. This will increase the power consumption of the fluid pump FP2.

[0052] This problem is mitigated by the configuration in FIG. 2B, where the connecting line segment 24 includes a valve 25, and the restrictor 21 is disposed in a bypass line (first pathway) 24' that is fluidly connected to the connecting line segment (second pathway) 24 upstream and downstream of the valve 25. The valve 25 is switched between an open state and a closed state by a control signal C5. The restrictor arrangement 20 in FIG. 2B is thus operable to selectively direct CF1 on the bypass line 24' through the restrictor 21, when the pressure drop is to be measured, and otherwise direct CF1 along the connecting line segment 24, in which the flow resistance is much lower by the absence of a restrictor. Yet another configuration is shown in FIG. 2C. Here, the restrictor arrangement 20 includes two restrictors 21, 21' and a valve 25 that is operable, by the control signal C5, to selectively direct CF1 along a first bypass line (first pathway) 24' through the restrictor 21, along the connecting line segment (second pathway) 24, or alone a second bypass line (third pathway) 24" through the further restrictor 21'. The restrictors 21, 21' are configured to provide different flow resistance. By separately passing CF1 through restrictors with different flow resistance, a more accurate determination of the glucose concentration is enabled.

[0053] FIGS 2A-2C are only examples. The above-stated functionality of the respective configuration may be achieved in many different ways. For example, any number of pathways may be defined within the restrictor arrangement 20. Any type of valve subsystem may be used, including a single valve or plural valves in any suitable configuration. Further, the sensor sub-system for measuring the pressure drop over the respective restrictor may be configured differently. As noted, a single pressure sensor may be used. Alternatively, more than two pressure sensors may be used. Any type of pressure sensor may be used, for example operating by resistive, capacitive, inductive, magnetic or optical sensing, and using one or more diaphragms, bellows, Bourdon tubes, piezo-electrical components, semiconductor components, strain gauges, resonant wires, accelerometers, etc.

[0054] FIG. 3 are section views of an example positive displacement pump that may be installed as FP2 in the system 10 of FIG. 1. The pump in FIG. 3 is merely given as an example of a compact and robust fluid pump that may be operated to provide a consistent flow of CF1 through the supply line L2. Like any positive displacement pump, the pump FP2 performs a sequence of pumping cycles, where each pumping cycle PC comprises an intake phase and a discharge phase. In the intake phase, CF1 is drawn into the pump through an inlet port. In the discharge phase, CF1 is driven out of the pump through an outlet port. In FIG. 3, the pump FP3 is shown during the intake phase (left), at the transition from the intake phase to the discharge phase (middle), and during the discharge phase (right). The pump FP2 thereby performs, during each pumping cycle, a first phase of driving CF1 through the restrictor arrangement 20 and a second phase of blocking passage of CF1 through the pump FP2. The first phase corresponds to the discharge phase if the restrictor arrangement 20 is arranged downstream of FP2, and the intake phase if the restrictor arrangement 20 is arranged upstream of FP2.

[0055] In the specific example of FIG. 3, the pump FP2 comprises a housing 40 that defines a sequence of an inlet channel 41a, a pumping chamber 43 and an outlet channel 41b. The housing further defines a piston chamber 41, in which a piston 42 is arranged for combined reciprocation and rotation. A bottom end of the piston 42 has a recessed portion 42', which defines a rectangular tray. As the piston 41 reciprocates and rotates in the piston chamber 42, the rectangular tray acts as an integrated valve that selectively blocks the outlet channel 41b and opens the inlet channel 41a during the intake phase (left), and opens the outlet channel 41b and blocks the inlet channel 41a during the discharge phase (right).

[0056] FIGS 4A- 4B are graphs of simulated data for a restrictor during a pumping cycle performed by FP2. A simple simulation model has been used, which is based on conventional equations for head friction and friction factors. FIG. 4A shows the pressure drop over a restrictor as a function of time during a pumping cycle PC, and FIG. 4B shows the first-order derivative of the signal in FIG. 4A. The first cycle of driving CF1 through the restrictor results in a bell-shaped curve in FIG. 4A, and the second cycle of blocking passage through the pump (and the restrictor) results in a lack of pressure drop. It is also seen that temporal changes in pressure drop is emphasized in FIG. 4B.

[0057] FIGS 4C-4D are graphs of measured data that corresponds to the simulated data in FIGS 4A-4B. FIG. 4C shows the measured pressure drop as a function of time, and FIG. 4D shows the first-order derivative of the signal in FIG. 4C. There is a general correspondence between the measured and simulated data, although the signal changes are less distinct in the measured data. One reason for the differences is believed to be that the simulation model does not account for the inertia of the fluid.

[0058] The measurement technique presented herein is based on the insight that the waveform of the pressure drop over a restrictor during a pumping cycle varies in dependence of the viscosity of CF1, and thus in dependence of the glucose concentration. As used herein, "waveform" refers to signal values as a function of time during at least part of a pumping cycle. The waveform may correspond to a single pumping cycle, or a plurality of pumping cycles. FIG. 4C depicts a waveform of the pressure drop for a complete pumping cycle, and FIG. 4D depicts a waveform of the first order-derivative of the pressure drop for a complete pumping cycle. In the following, the waveform of the pressure drop is denoted PDW, and the first-order derivative of PDW is denoted DPDW. It is desirable for PDW and / or DPDW to be highly non-uniform. This is inherently achieved when the pump FP2 is a positivedisplacement pump. The restrictor is suitably designed to generate, in view of the flow generated by the pump FP2, a PDW that varies significantly with glucose concentration and has a magnitude that results in a sufficient accuracy of the estimated glucose concentration (CV). FIG. 5A is a flowchart of an example method 100 that may be performed by the evaluation device 30 in the system of FIG. 1. The method 100 may be performed during regular operation of the mixing sub-system 10, while the mixing sub-system 10 is operated to generate the treatment fluid. Herein, regular operation is also denoted "production phase". Alternatively or additionally, the method 100 may be performed during a dedicated measurement phase, in which the operation of the mixing sub-system 10 is actively changed for the purpose of determining the concentration value. One advantage of having a measurement phase is that speed of the pump FP2 may be set to any desirable value, for example a predefined speed that is known to result in accurate estimation of the glucose concentration. It is also possible to perform the measurement phase at more than one speed of the pump FP2 (cf. FIG. 5B). Further, the bypass valve 17 may be operated to divert flow in the main line LI into the drain line 18 during the measurement phase. Still further, the mixing sub-system 10 may be operated in the measurement phase to only pump CF1 through the supply line L2 and along the main line towards the outlet 1 lb. Thus, the pump FP3 and the inflow of PW may be stopped during the measurement phase. This allows the temperature sensor 16 to measure the temperature of CF1 (cf. sub-step 103c below). If the restrictor arrangement 20 defines plural pathways, as in FIGS 2B-2C, the restrictor arrangement 20 may be operated to open a non-restricted pathway (24 in FIGS 2B-2C) in the production phase, and to open a restricted pathway (24', 24" in FIGS 2B-2C) in the measurement phase. In other words, the one or more restrictors 21, 21' in the restrictor arrangement 20 is bypassed in the production phase.

[0059] Thus, the method 100 may or may not include a step 101 of actively controlling the mixing sub-system 10 for the purpose of determining the glucose concentration. Step 101 presumes that the evaluation device 30 is capable of controlling the mixing sub- system 10 or is communicatively coupled to a separate control device for operating the mixing sub-system 10. Step 101 would be excluded when the method 100 is performed during the production phase.

[0060] In step 102, the signal S4 is obtained to represent the measured pressure difference ("pressure drop") over the restrictor 21 as a function of time, while the pump FP2 is operated to drive CF1 through the restrictor 21.

[0061] In step 103, the glucose concentration of CF1 is determined based on a waveform ("first waveform") in the pressure signal from step 102. Step 103 may be performed in a variety of different ways. In some embodiments, the first waveform (PDW) and / or a second waveform ("derivative waveform", or DPDW) that corresponds to a first-order derivative of the first waveform is analyzed for determination of the glucose concentration. Step 103 may thus involve a sub-step 103a of generating DPDW as a first-order time derivative of PDW, for example by conventional differentiation. As noted, temporal changes may be enhanced in DPDW and thereby easier to detect. At the same time, the differentiation is likely to increase the impact of noise in DPDW compared to PDW. For this reason, it may be advantageous to perform a combined analysis of PDW and DPDW in step 103.

[0062] In some embodiments, step 103 involves a sub-step 103b of determining a measured set of values ("feature values") of one or more predefined signal features in PDW and / or DPDW, and use the measured set for determining the glucose concentration. After significant experimentation, the Applicant has identified signal features that are significantly influenced by the glucose concentration of CF1. The signal feature(s) of most relevance may differ depending on configuration and operation of the system. Examples are given below with reference to FIGS 10-13.

[0063] In some embodiments, at least one of the signal features is defined in relation to a pumping cycle of the pump FP2. This means that the signal feature is a recurring characteristic in the pressure signal (and its derivative), for each pumping cycle, at least for some operating conditions of the system. Given the repetitive nature of the pumping cycles, this makes it possible to determine a feature value by aggregation over plural pumping cycles. For example, the feature value may be determined by aggregating PDW or DPDW for a plurality of pumping cycles and by extracting the feature value from the aggregated PDW or DPDW. Alternatively, the feature value may be determined by aggregating values that are extracted from PDW or DPDW for a plurality of pumping cycles. The aggregation will increase the accuracy of the feature value and potentially increase the accuracy of the estimated glucose concentration. The recurrent or repeating nature of the signal feature may also facilitate its detection in PDW or DPDW.

[0064] When the signal features are defined in relation to a pumping cycle, the start and end of the respective pumping cycle will be determined in sub-step 103b. This determination is facilitated if the current speed of the pump FP2 is known. In some embodiments, the current speed is obtained from the speed signal S3 or the control signal C2 for FP2 (cf. FIG. 1). Alternatively, sub-step 103b may presume that the pump the pump FP2 is operated at a predefined speed. In a further alternative, the speed is estimated from PDW and / or DPDW.

[0065] In some embodiments, step 103 involves a sub-step 103c of adjusting PDW and / or DPDW, or the measured set of feature values obtained in sub-step 103b, as a function of the current temperature of CF1. Specifically, sub-step 103c may perform a conversion to a nominal temperature, by use of a predefined conversion function. In the example of FIG. 1, the current temperature may be given by signal S2 from the temperature sensor 16, for example when CF1 is pumped through the main line LI during the measurement phase. The temperature value given by signal S2 may optionally be compensated for temperature losses to derive an estimate of the temperature of CF1 at the restrictor arrangement 20. In an alternative embodiment, the temperature of CF1 is controlled to be stable during method 100, for example by use of a heater or a heat pump located upstream of the restrictor arrangement 20, for example in the supply line L2 or inside or in contact with the container 12. The heater may be of any type, for example a resistive heater. The heat pump may operate to transfer thermal energy using a refrigeration cycle. In a variant, the heat pump comprises a Peltier element.

[0066] The measured set from sub-step 103b, optionally adjusted by sub-step 103c, may be processed in different ways to derive the glucose concentration.

[0067] In some embodiments, represented by sub-steps 103dl-103d2, the glucose concentration is determined by use of a look-up table (LUT) that associates individual sets of tabulated values with a corresponding concentration value. Each of the tabulated values is given for a respective signal feature and thus corresponds to a feature value in the measured set. Thus, step 103 may involve a sub-step 103dl of retrieving the LUT from a memory (cf. 32 in FIG. 14), and a sub-step 103d2 of mapping the measured set to the LUT to find a sufficiently matching set of tabulated values, and determine the glucose concentration based on the concentration value associated with the matching set. It is also conceivable that the glucose concentration is determined by interpolation or extrapolation among concentration values in the LUT if there is more than one sufficiently matching set in the LUT.

[0068] In some embodiments, represented by sub-step 103e, the glucose concentration is determined by operating a predefined calculation function on the measured set of feature values. The calculation function may include any conventional regression algorithm, such as linear regression, support vector machine (SVM), Gaussian process regression (GPR), etc. In one embodiment, the calculation function is a neural network that has been trained to determine glucose concentration based on a set of feature values.

[0069] In some embodiments, as indicated for sub-step 103e, the calculation function may operate on PDW and / or DPDW, instead of or in addition to the measured set of feature values. Lor example, it is conceivable for a neural network to be trained to determine the glucose concentration based on PDW and / or DPDW.

[0070] The glucose concentration from step 103 may be used in different ways. In some embodiments, as indicated by step 104, the evaluation device 30 provides the glucose concentration for use by a separate control device (not shown) to control the mixing sub-system 10 to generate the treatment fluid. In some embodiments, as indicated by step 105, the evaluation device 30 is operable to provide control signals for causing the mixing sub-system 10 to generate the treatment fluid, where at least one of the control signals is set based on the glucose concentration. For example, the evaluation device 30 may selectively change the speed of the pump FP2 to account for a deviation between the glucose concentration from step 103 and the nominal glucose concentration of CF1. In some embodiments, as indicated by step 106, the evaluation device 30 is operable to validate CF1, by evaluating the deviation between the glucose concentration from step 103 and the nominal glucose concentration of CF1. If CF1 fails the validation, the evaluation device 30 may take dedicated action, for example output an alert signal for the operator of the system, or stop the mixing sub-system.

[0071] It may be beneficial to perform the determination of the glucose concentration in step 103 for more than one speed setting of the pump FP2, since PDW and DPDW are likely to change with the flow rate through the restrictor 21. Thus, by obtaining pressure drop data at plural speeds, the accuracy of the glucose concentration may be improved. FIG. 5B shows an example method 100 in which the evaluation device 30 obtains the pressure signal at a plurality of speeds of the pump FP2 and determines the glucose concentration based on PDW, given by the pressure signal, for each of the plurality of speeds. The method 100 in FIG. 5B includes a step 101, in which the mixing subsystem 10 is set in the measurement phase and the pump FP2 is operated at a first pumping speed. In step 102', the signal S4 is obtained and pressure drop data is extracted from S4. For example, the pressure drop data may include PDW and / or a set of values for one or more signal features in PDW. Step 102' may include sub-step 103a (FIG. 5A), and the pressure drop data may include DPDW and / or a set of values for one or more signal features in DPDW. By step 111, steps 101-103 are performed for at least two different speeds of the FP2. The speeds may be predefined. When step 110 determines that the measurement phase has been performed for a predefined number of speeds, step 103 is performed to determine the glucose concentration of CF1, for example in accordance with sub-steps 103dl, 103d2, or in accordance with sub-step 103e.

[0072] It may be desirable for at least one of the speeds to result in a laminar flow through the restrictor 21, and at least one of the speeds to result in a turbulent flow through the restrictor 21. This has been found to result in largely differing PDWs (and thus DPDWs), which may improve the accuracy of the glucose concentration determined by step 103. As used herein, a laminar flow has a Reynolds number (Re) of less than 2,000, and a turbulent flow has a Reynolds number above 4,000. An alternative to using plural pumping speeds is to change the temperature of CF1 while maintaining a fixed pumping speed. The temperature may be changed by the above-mentioned heater or heat pump upstream of the restrictor arrangement 20. The method in FIG. 5B may be used to represent this variant, where pressure drop data is obtained in step 102' as the mixing sub-system is operated with different temperatures of CF1, and step 103 is performed to determine the glucose concentration of CF1 based on the pressure drop data from step 102'.

[0073] The Applicant has found that the signal features with the strongest correlation with glucose concentration may differ depending on the speed of the pump FP2. Thus, in some embodiments, the one or more predefined signal features to be used in sub-step 103b are selected based on the related speed of the pump FP2. As noted above, the related speed may be given by the signal S3 or the control signal C2 (FIG. 1).

[0074] When the measured set of feature values from sub-step 103b is determined for different speeds, the look-up table (LUT) is defined to include data for the different speeds and will be queried in sub-step 103d2 in view of the speed associated with the respective measured set. Correspondingly, sub-step 103e may be performed in view of the speed(s) associated with the pressure drop data that is input to the calculation function.

[0075] FIGS 10-13 are included to show that PDW and DPDW change with glucose concentration of CF1 and speed of the pump FP2. FIGS 10A-10B are plots of simulated data, in which the pump FP2 is a piston pump with a stroke volume of 0.5 mL, the smallest diameter of the passage within the restrictor 21 is 0.5 mm, and the length of the restrictor is 10 mm. FIGS 11A-11C, 12A-12C and 13A-13C are plots of measured data for the same piston pump and a restrictor diameter of 0.4 mm.

[0076] FIG. 10A shows the simulated pressure drop during part of a pumping cycle as a function of time when the pump FP2 is operated to generate a flow rate of 100 mL / min through the restrictor, for five different glucose concentrations (40%, 45%, 50%, 55%, 60% by volume). It is realized that each of the curves in FIG. 10A may be a PDW. Clearly, PDW changes significantly with glucose concentration. PDWs for lower glucose concentrations (40%, 45%, 50%) exhibit step-changes, which correspond to transitions between laminar flow and turbulent flow during the pumping cycle. As seen, the timing of the transitions differ depending on glucose concentration.

[0077] FIG. 10B corresponds to FIG. 10A and is given for a flow rate of 140 mL / min through the restrictor. Like in FIG. 10A, PDW changes significantly with glucose concentration. By comparing FIG. 10A and FIG. 10B, it seen that PDW also changes with pumping speed. FIGS 11A-11C show measured PDWs during a pumping cycle for three glucose concentrations (40%, 50%, 59%), with FIGS 11A-11C being obtained for a flow rate of 25 mL / min, 75 mL / min, and 125 mL / min, respectively. While the step-changes caused by transitions between laminar and turbulent flows may not be readily apparent in the experimental data of FIGS 11A-11C, it is not unlikely that the transitions may be more pronounced for a restrictor of different dimensions.

[0078] FIGS 12A-12C show DPDWs corresponding to the PDWs in FIGS 11A-11C. As seen, changes in the respective PDW are emphasized by the differentiation, at the expense of a relative increase in signal noise.

[0079] Based on the simulated and measured data in FIGS 10-12, the Applicant has identified relevant features that may be detected and quantified in PDW and / or DPDW. The relevant features include, without limitation:

[0080] 1) A signal value at one or more selected locations in PDW or DPDW. In one example, the signal value in DPDW may be representative of the initial gradient in PDW. In this context, a "location" corresponds to a relative time point during the pumping cycle and may be given in any suitable unit such as a relative time, a sample number, etc.

[0081] 2) The location within the pumping cycle of a step-change that corresponds to a transition from laminar flow to turbulent flow, or vice versa.

[0082] 3) The magnitude of a step-change that corresponds to a transition from laminar flow to turbulent flow, or vice versa.

[0083] 4) Presence or absence of a step-change that corresponds to a transition from laminar flow to turbulent flow, or vice versa.

[0084] 5) The peak-to-peak value in PDW. The peak-to-peak value corresponds to the difference between the maximum and minimum signal values in PDW and is thus an amplitude of PDW. Stated differently, the peak-to-peak value is the pressure range of PDW.

[0085] 6) The maximum value in the PDW.

[0086] 7) The location within the pumping cycle of the maximum value in PDW.

[0087] 8) The maximum value in DPDW. This corresponds to the largest signal change (gradient) in PDW.

[0088] 9) The location within the pumping cycle of the maximum value in DPDW.

[0089] 10) The minimum value in DPDW. This corresponds to the smallest signal change (gradient) in PDW.

[0090] 11) The location within the pumping cycle of the minimum value in DPDW.

[0091] 12) An aggregation of signal values in PDW or DPDW, or part thereof. The aggregation may be made for consecutive signal values and may represent the area under PDW or DPDW, or part of PDW or DPDW. The area under PDW or DPDW may or may not be given in relation to a non-zero baseline.

[0092] In some embodiments, one or more signal segments are identified within PDW or DPDW by detection of one or more predefined signal characteristics, and at least one signal feature is defined to represent such a signal segment. The use of signal segments will be exemplified with reference to FIGS 13A-13C, which show DPDWs generated by differentiation of PDWs, which are obtained from the signal S4 while the pump FP2 is operated to pump CF1 with a glucose concentration of 50% through the restrictor 21 at a flow rate of 50 mL / min (FIG. 13A), 75 mL / min (FIG. 13B) and 125 mL / min (FIG. 13C). In FIGS 13A-13C, six signal segments or "zones" have been identified, designated Z1-Z6, based on one or more predefined characteristics for the respective zone. In the illustrated examples, a linear function F1-F6 has been fitted by linear regression to the signal values within the respective signal segment Z1-Z6. Any type of linear regression may be used, for example least-squares regression. The respective function is a linear function of time and is defined by an offset and a gain, where the offset is the intercept of the linear function, and the gain is the gradient or slope of the linear function. Each function may further be associated with a quality parameter that is indicative of the difference between the signal values in the signal segment and the linear function. For example, the quality parameter may represent a residual of the linear regression.

[0093] The identification of zones in the PDW and DPDW may be performed in different ways. In one example, an algorithm for identifying points of interest ("key points") is operated on the PDW or DPDW. The algorithm may be configured to identify or detect a predefined number of key points in an input signal. A key point may, for example, be a deflection point, a tipping point, a breakpoint, a local extreme, or a derivative (first- order, second-order, etc.). The zones Z1-Z6 in FIGS 13A-13C have been identified by use of an algorithm which is pre-configured to find five key points. Such an algorithm may be pre-configured to find any desired number of key points. The zones may alternatively or additionally be determined by use of an algorithm that is configured to identify a predefined number of regions of interest in the input signal. A region of interest may have a predefined characteristic, such as a shape, a derivative (first-order, second-order, etc.), a signal variability, etc.

[0094] In another example, a few predefined base features may be identified or detected in the input signal, and the zones may be defined in relation to these predefined base features. Examples of predefined base features include maximum signal level, minimum signal level, maximum derivative (first-order, second-order, etc.), derivative above a threshold value, etc.

[0095] Based on the measured data in FIGS 13A-13C, the Applicant has identified further relevant features that may be detected and quantified in DPDW. The further relevant features include, without limitation:

[0096] 13) The location and / or extent of a selected signal segment within the pumping cycle. The location of the selected segment may be given by its start location or end location. The extent of the selected segment is given by the time distance, for example in relation to a pumping cycle, between the start and end locations of the selected segment.

[0097] 14) The slope of the linear function fitted to the signal values in a selected signal segment.

[0098] 15) The offset of the linear function fitted to the signal values in a selected signal segment.

[0099] 16) The quality parameter for the linear function as fitted to the signal values in the selected signal segment.

[0100] FIG. 6 is a flow chart of an example method 200 that may be performed by the evaluation device 30 during a calibration phase. The purpose of the method 200 is to calibrate the signal values in the PDW. This is achieved by operating the mixing subsystem 10 to drive a reference fluid through the restrictor 21 and obtaining a reference waveform (RPDW) from the signal S4. The reference fluid may be any fluid that is available to the mixing sub-system 10, for example PW, CF2, or a mixture of PW and CF2. In the specific example of FIG. 1, the mixing sub-system 10 needs to be reconfigured to enable the calibration method 200. For example, during the calibration phase, the container 12 may be replaced for another container that holds the reference fluid. It is realized that in a commercial implementation, the mixing sub-system 10 may be automatically operable to direct PW, or any other reference fluid, through the restrictor 21 without requiring a preceding manual intervention by the operator. For example, the calibration phase may be performed in connection with regular priming of the mixing sub-system 10. The priming fluid used for priming may also be used as reference fluid for the calibration phase. For example, PW may be used as priming fluid. When the glucose concentration is determined by the method 100, step 103 is modified to account for the difference between PDW and RPDW. For example, the feature value determined by sub-step 103b may be given by the difference between a value determined in PDW for a signal feature and a value determined in RPDW for the same signal feature. Alternatively or additionally, some of the sub-steps of step 103 may be operated on a difference waveform given by the difference between PDW and RPDW.

[0101] The calibration method 200 comprises a step 201 of operating the mixing subsystem 10 in the calibration phase to drive a reference fluid through the restrictor 21, by the fluid pump FP2 or another fluid pump (not shown) in the mixing sub-system. The flow rate of the reference fluid through the restrictor 21 is suitably similar (or identical) to the flow rate of CF1 through the restrictor 21 in the measurement phase (method 100). In the calibration phase, the mixing sub-system 10 is operated to direct the reference fluid to the drain 30 (FIG. 1). The calibration phase may be performed in conjunction with a measurement phase or separate thereform. In step 202, the signal S4 is obtained from the restrictor arrangement 20, while the reference fluid is driven through the restrictor 21. In step 203, reference data representing RPDW is stored in memory. Depending on implementation, the reference data may include RPDW, an aggregated RPDW, a first-order derivative of RPDW or the aggregated RPDW, or a set of values for one or more predefined signal features in RPDW or the first-order derivative of RPDW, or any combination thereof. FIG. 6 also indicates that the method 100 includes a modified version of step 103, represented as step 103', in which the glucose concentration is determined based on PDW from step 102 and the reference data from step 203. If the measurement phase of the method 100 involves plural pumping speeds, the method 200 may be performed for flow rates that matches these pumping speeds.

[0102] FIG. 7 is a flow chart of an example method 300 that corresponds to the method 100 and may be performed when the restrictor arrangement 20 comprises more than one restrictor, for example two restrictors 21, 21' in different pathways 24', 24" as shown in FIG. 2C. In the method 300, a PDW is obtained for each of the restrictors 21, 21', and the glucose concentration is determined based on all of the thus-obtained PDWs. In step 301, the mixing sub-system 30 is set to operate in the measurement phase. In step 302, the mixing sub-system 30 is operated to drive CF1 through a first restrictor, for example restrictor 21. In the example of FIG. 2C, the valve sub-system 25 is set to block pathways 24, 24" and open pathway 24'. In step 303, a first instance of the first waveform (PDW1) is obtained from the pressure signal during step 302. In step 304, the system is operated to drive CF1 through a second restrictor, for example restrictor 21'. In the example of FIG. 2C, the valve sub-system 25 is set to block pathways 24, 24' and open pathway 24". In step 305, a second instance of the first waveform (PDW2) is obtained from the pressure signal during step 304. In step 306, the glucose concentration is determined based on PDW 1 and PDW2. Step 306 may be performed similarly to step 103 in the method 100 (FIG. 5A), but based on more input data to potentially increase the accuracy of the determined glucose concentration. In step 307, the mixing sub-system 10 is set to operate in the production phase, and the restrictor arrangement 20 is operated to bypass the first and second restrictors 21', 21". In the example of FIG. 2C, the valve sub-system 25 is set to open pathway 24 and block pathways 24', 24" in the production phase.

[0103] It is to be understood that the pumping speed of the pump FP2 may or may not be the same between step 302 and step 304. It is also conceivable that the pump FP2 is operated at plural pumping speeds in step 302 or step 304, and that step 303 / 305 may involve determining PDW1 / PDW2 at each of the plural pumping speeds.

[0104] FIG. 8 is a flow chart of an example validation procedure that may be part of step 103 in the method 100 (FIG. 5A). The purpose of the validation procedure is to validate the glucose concentration that is determined in step 103 and only output the glucose concentration if it passes the validation. The validation procedure thus serves to reduce the risk that an erroneous glucose concentration is provided and / or used by the evaluation device 30. In some embodiments, the validation procedure performs a joint determination of the glucose concentration and an estimated dimension of the restrictor based on PDW, and discards the concentration value if a difference between the estimated dimension and an actual dimension of the restrictor exceeds a threshold. The joint determination may involve an iterative calculation, for example by use of an optimizer, for example a non-linear solver. There are many conventional optimizers that may be used and / or adapted for use in the validation procedure, for example as included in ALGLIB, NLopt, SciPy, or IPOPT. An example of such an embodiment is shown in FIG. 8. In step 401, calculation input data for the optimizer is obtained. The calculation input data may include one or more dimensional values for the restrictor, for example length and / or internal diameter, as well as a start value for the glucose concentration. In step 402, the optimizer is operated on the calculation input data and pressure input data that represents the pressure signal (step 102). The pressure input data may include any of PDW, DPDW, a set of values for one or more signal features in PDW and / or DPDW. The optimizer thereby generates estimations of the dimensional value(s) and the glucose concentration, as well as pressure output data that corresponds to the pressure input data. In step 403, the difference between the pressure output data and the pressure input data is evaluated. If the difference exceeds one or more thresholds, step 404 is performed to update the calculation input data with the estimations from step 402, whereupon step 402 is repeated for the thus-updated calculation input data. If the difference is deemed acceptable in step 403, step 405 is performed to evaluate if the respective dimensional value of the restrictor, as estimated in the last iteration of step 402, is sufficiently close to actual dimension of the restrictor. Thus, step 405 presumes that the dimensions of the restrictor are known. If all dimensional values are acceptable, the glucose concentration estimated in the last iteration of step 402 is provided, for example for use by any one of steps 104-106. If significant deviation is found in step 405 between the dimensional value(s) and the actual dimension of the restrictor, step 407 is performed to discard the glucose concentration from step 402. Step 407 may involve causing the evaluation device 30 to take dedicated action, for example output an alert signal for the operator of the system, or stop the mixing sub-system.

[0105] FIG. 9 is a block diagram of an example evaluation device 30. In the illustrated example, the evaluation device 30 is arranged to receive the signal S4 from the restrictor arrangement 20. A first module 41 is configured to process the signal S4 for extraction of PDW. A second module 42 is configured to process PDW for generation of DPDW, for example in accordance with sub-step 103a (FIG. 5A). A third module 43 is configured to process PDW and / or DPDW for determination of a set of values of signal features in PDW and / or DPDW, for example in accordance with sub-step 103b (FIG. 5A). The resulting measured set of feature values is designated [SF] in FIG. 9. A fourth module 44 is configured to determine the glucose concentration CV based on [SF], for example in accordance with sub-steps 103dl-103d2 or sub-step 103e. A fifth module 45 is configured to validate CV based on PDW, for example in accordance with the procedure in FIG. 8, and selectively output CV.

[0106] FIG. 14 is a block diagram of an example evaluation device 30, which may be configured to perform any of the methods, procedures and functions described herein, or part thereof, by a combination of software and hardware circuitry, or exclusively by specific hardware circuitry. For example, the device 30 in FIG. 14 may implement the modules 41-45 in FIG. 9. In FIG. 14, the device 30 comprises processor circuitry 31, which may be or include a central processing unit (CPU), graphics processing unit (GPU), microcontroller, microprocessor, ASIC, FPGA, or any other specific or general processing device. The device 30 may execute instructions stored in a computer memory, such as memory 32, in order to control the operation of the device 30. The instructions when executed by the processor circuitry 31 may cause the device 30 to perform any of the methods described herein, or part thereof. The memory 32 may comprise one or more of a buffer, flash memory, hard drive, removable media, volatile memory, non-volatile memory, random access memory (RAM), or another suitable data storage device. Such a memory 32 is considered a non-transitory computer readable medium. The instructions may be supplied to the device 30 on a computer-readable medium, which may be a tangible (non-transitory) product (for example magnetic medium, optical disk, read-only memory, flash memory, etc.) or a propagating signal. The device 30 includes an I / O interface 33a, which may include any conventional communication interface for wired or wireless communication. As shown, the device 30 is arranged to receive one or more input signals Si (cf. S2, S3, S4 in FIG. 1). The device 30 may comprise a further interface 33b for connection to an interface device 34 for user interaction. The interface device 34 may include one or more of a display, a touch screen, a speaker, one or more signaling lamps, a keyboard / keypad, a microphone, a computer mouse, a projector, a camera, etc.

[0107] In the foregoing, it has been assumed that CF1 is a glucose concentrate. However, the disclosure is in no way limited to such a concentrate, nor to determination of glucose concentration. Glucose is an example of a monosaccharide, and the technique is equally applicable to other monosaccharides that may be included in a dialysis concentrate. Generally, any dialysis concentrate that has a viscosity that changes with the concentration of an included substance may be evaluated by the technique presented herein for determination of a concentration value of the substance.

[0108] The technique disclosed herein uses standard off-the-shelf components, such as restrictors and pressure sensors. It provides an alternative technique for identifying the glucose concentration. The cost and complexity for implementing the technique idea is low since most systems for generating treatment fluid will anyway include most of the components used by the technique, such as the fluid pump FP2, at least one of the pressure sensors 22, 23, the bypass valve 17, the drain line 18, etc. Possibly, only the restrictor 21 needs to be added to such a system, together with an appropriately configured evaluation device 30. The technique is also simple to perform and may even be executed during regular production of treatment fluid. Further, even if a measurement phase is implemented during which the concentrate sent to drain, the waste of concentrate is limited since the required amount of concentrate to be driven through the restrictor arrangement during the measurement phase is small.

[0109] If the pulsation in the signal S4 is too fast relative to the available sampling rate of signal values by the evaluation device, it is conceivable to increase the compliance of the supply line L2 upstream of the restrictor arrangement 20, for example using (more) flexible tubing for the supply line L2 or by adding a compliance chamber.

[0110] While the subject of the present disclosure has been described in connection with what is presently considered to be the most practical embodiments, it is to be understood that the subject of the present disclosure is not to be limited to the disclosed embodiments, but on the contrary, is intended to cover various modifications and equivalent arrangements included within the scope of the appended claims.

[0111] Further, while operations are depicted in the drawings in a particular order, this should not be understood as requiring that such operations be performed in the parti- cular order shown or in sequential order, or that all illustrated operations be performed, to achieve desirable results.

[0112] In the following, clauses are recited to summarize some aspects and embodiments as disclosed in the foregoing.

[0113] Cl. A system for generating a treatment fluid for use in dialysis, said system comprising: a mixing sub-system (10), which is arranged to receive water and one or more concentrates and operable to generate the treatment fluid by mixing the water and the one or more concentrates, wherein the mixing sub-system (10) comprises a pumping device (FP2), which is configured to drive a first concentrate among the one or more concentrates along a concentrate flow path in the mixing sub-system (10); said system further comprising: a restrictor (21) defining a confined passage in the concentrate flow path; a sensor sub-system (22, 23) configured to provide a first signal representative of a pressure difference between upstream and downstream ends of the restrictor (21) as a function of time; and a processing sub-system (30) configured to obtain the first signal from the sensor sub-system (22, 23) while the pumping device (FP2) is operated to drive the first concentrate through the restrictor (21), and determine a concentration value for a substance in the first concentrate based on a waveform in the first signal.

[0114] C2. The system of Cl, wherein the first concentrate has a viscosity that changes with the concentration value.

[0115] C3. The system of C2, wherein the viscosity increases with increasing concentration of the substance.

[0116] C4. The system of any preceding clause, wherein the substance is a monosaccharide, for example glucose.

[0117] C5. The system of any preceding clause, wherein the processing sub-system (30) is configured to determine the concentration value based on a speed value associated with the waveform, the speed value representing a pumping speed of the pumping device (FP2).

[0118] C6. The system of any preceding clause, wherein the processing sub-system (30) is configured to obtain the first signal at a plurality of different pumping speeds of the pumping device (FP2) and to determine the concentration value based on the waveform, given by the first signal, at each of the plurality of different pumping speeds.

[0119] C7. The system of any preceding clause, wherein the first signal represents the pressure difference as a function of time during a sequence of pumping cycles (PC) of the pumping device (FP2), wherein each of the pumping cycles (PC) comprises a first phase in which the pumping device (FP2) is operated to drive the first concentrate through the restrictor (21), and second phase in which the pumping device (FP2) is operated to prevent passage of the first concentrate through the pumping device (FP2), and wherein the waveform corresponds to the pressure difference as a function of time during at least part of a pumping cycle.

[0120] C8. The system of C7, wherein the pumping device (FP2) is a positive displacement pump.

[0121] C9. The system of C7 or C8, wherein the processing sub-system (30) is configured to determine a set of values of one or more predefined features in the waveform and / or in a derivative waveform that represents a first-order derivative of the waveform, and determine the concentration value based on the set of values.

[0122] CIO. The system of C9, wherein at least one predefined feature is defined in relation to a respective pumping cycle among the sequence of pumping cycles (PC) so that the at least one predefined signal feature is a recurring characteristic in the first signal.

[0123] Cl l. The system of CIO, wherein the processing sub-system (30) is configured to determine a value of the at least one predefined feature by aggregating the recurring characteristic for a plurality of pumping cycles.

[0124] C12. The system of any one of C9-C11, wherein the processing sub-system (30) is configured to obtain a signal indicative of a current pumping speed of the pumping device (FP2), and select the one or more predefined features based on the current pumping speed of the pumping device (FP2).

[0125] C13. The system of any one of C9-C12, wherein the one or more predefined features comprise at least one of: a pressure range of the waveform during a pumping cycle; a maximum value of the waveform during a pumping cycle; an aggregation of signal values in the waveform during a pumping cycle; a signal value of the waveform at a selected location within a pumping cycle; a maximum value of the derivative waveform during a pumping cycle; a minimum value of the derivative waveform during a pumping cycle; a signal value of the derivative waveform at a selected location within a pumping cycle; a slope of a linear time-dependent function (F1-F6) fitted to a signal segment (Z1-Z6) of the derivative waveform, the signal segment corresponding to a subset of a pumping cycle and being determined by detection of one or more predefined characteristics in the derivative waveform; an offset value for a linear time-depending function (F1-F6) fitted to a signal segment (Z1-Z6) of the derivative waveform, the signal segment (Z1-Z6) corresponding to a subset of a pumping cycle and being determined by detection of one or more predefined characteristics in the derivative waveform; a location and / or an extent of a signal segment (Z1-Z6) of the derivative waveform, the signal segment (Z1-Z6) corresponding to a subset of a pumping cycle and being determined by detection of one or more predefined characteristics in the derivative waveform; or a difference between a linear time-dependent function (F1-F6) and a signal segment in the derivative waveform, the linear time-depending function (F1-F6) being fitted to the signal segment (Z1-Z6), and the signal segment (Z1-Z6) being determined by detection of one or more predefined characteristics in the derivative waveform.

[0126] C14. The system of any one of C9-C13, wherein the processing sub-system (30) is further configured to: obtain a temperature signal representative of a current temperature of the first concentrate, and adjust the set of values based on the current temperature.

[0127] C15. The system of any one of C9-C14, wherein the processing sub-system (30) is configured to determine the concentration value by use of a look-up table that associates a respective set of tabulated values of the one or more predefined features with a corresponding concentration value.

[0128] C16. The system of any one of C1-C6, wherein the processing sub-system (30) is configured to determine the concentration value by use of a calculation function that is configured to operate on the waveform, on a derivative waveform that represents a first- order derivative of the waveform, or on a set of values of one or more predefined features in the waveform and / or the derivative waveform.

[0129] C17. The system of C16, wherein the calculation function is a trained neural network.

[0130] Cl 8. The system of any preceding clause, wherein the processing sub-system (30) is configured to jointly determine the concentration value and an estimated dimension of the restrictor (21) based on the waveform, wherein the processing sub-system (30) is configured to discard the concentration value if a difference between the estimated dimension and an actual dimension of the restrictor (21) exceeds a threshold.

[0131] C19. The system of any preceding clause, wherein the mixing sub-system (10) is operable in a calibration phase, in which a reference fluid is driven through the restrictor (21), wherein the processing sub-system (30) is configured to obtain a reference waveform in the first signal as provided by the sensor sub-system (22, 23) during the calibration phase, the reference waveform corresponding to the first signal, and wherein the processing sub-system (30) is configured to determine the concentration value based on the waveform and the reference waveform.

[0132] C20. The system of Cl 9, wherein the reference fluid is one of the water, a second concentrate among the one or more concentrates, or a mixture of the water and the second concentrate.

[0133] C21. The system of any preceding clause, wherein the processing sub-system (30) is further configured to provide control signals for operating the mixing sub-system (10) to generate the treatment fluid, and wherein the processing sub-system (30) is configured to set at least one of the control signals based on the concentration value.

[0134] C22. The system of any preceding clause, wherein the mixing sub-system (10) comprises a first fluid line (LI), which is arranged to receive the first concentrate from the concentrate flow path and direct the water and the first concentrate through a mixing device (14).

[0135] C23. The system of any preceding clause, wherein the processing sub-system (30) is configured to switch the mixing sub-system (10) between a production phase, in which the mixing sub-system (10) is configured to generate the treatment fluid by mixing the water and the one or more concentrates, and a measurement phase, in which the pumping device (FP2) is operated to drive the first concentrate through the restrictor (21).

[0136] C24. The system of C23, wherein the concentrate flow path comprises a first path segment (L2a) and a second path segment (L2b), which are fluidly connected by a plurality of pathways, and a valve sub-system (25) that is operable to individually open the pathways, wherein the restrictor (21) is arranged in a first pathway (24') among the plurality of pathways, and wherein the processing sub-system (30) is configured to operate the valve sub-system (25) to open the first pathway (24') during the measurement phase and to operate the valve sub-system (25) to open a second pathway (24) among the plurality of pathways during the production phase.

[0137] C25. The system of C24, wherein the plurality of pathways comprises a third pathway (24") with a further restrictor (2T), which defines a further confined passage and which differs from the restrictor (21) in the first pathway (24') by at least one dimension of the further confined passage, wherein the sensor sub-system (22, 23) is further configured to provide the first signal to represent the pressure difference between upstream and downstream ends of the further restrictor (21) as a function of time, and wherein the processing sub-system (30) is configured to operate the valve sub-system (25) to sequentially open the first and third pathways (24', 24") during the measurement phase, and to determine the concentration value based on the waveform in the first signal when the first pathway (24') is open, and an additional waveform in the first signal when the third pathway (24") is open.

[0138] C26. A computer-implemented method of data processing in relation to a system for generating a treatment fluid for use in dialysis, said system comprising a mixing sub- system, which is arranged to receive water and one or more concentrates and generate the treatment fluid by mixing the water and the one or more concentrates, wherein the one or more concentrates comprises a first concentrate, said method comprising: obtaining (102), while the mixing sub-system operates to drive the first concentrate along a concentrate flow path through a restrictor that defines a confined passage in the concentrate flow path, a first signal representative of a pressure difference between upstream and downstream ends of the restrictor as a function of time; determining (103) a concentration value for a substance in the first concentrate based on a waveform in the first signal; and providing (104-105) the concentration value for use in controlling the system.

[0139] C27. The method of C26, wherein the first concentrate is driven along the concentrate flow path through the restrictor by a pumping device, wherein said obtaining (102) the first signal comprises: obtaining the first signal at a plurality of different pumping speeds of the pumping device, wherein the concentration value is determined based on the waveform, given by the first signal, at each of the plurality of different pumping speeds.

[0140] C28. The method of C26 or C27, wherein the first signal represents the pressure difference as a function of time during a sequence of pumping cycles of the pumping device, wherein each of the pumping cycles comprises a first phase in which the pumping device is operated to drive the first concentrate through the restrictor, and second phase in which the pumping device is operated to prevent passage of the first concentrate through the pumping device, and wherein the waveform corresponds to the pressure difference as a function of time during at least part of a pumping cycle.

[0141] C29. The method of C28, wherein said determining (103) the concentration value comprises: determining (103a, 103b) a set of values of one or more predefined features in the waveform and / or in a derivative waveform that represents a first-order derivative of the waveform, wherein the concentration value is determined based on the set of values.

[0142] C30. The method of C29, wherein at least one predefined feature is defined in relation to a respective pumping cycle among the sequence of pumping cycles (PC) so that the at least one predefined signal feature is a recurring characteristic in the first signal.

[0143] C31. The method of C30, wherein a value of the at least one predefined feature is determined by aggregating the recurring characteristic for a plurality of pumping cycles.

[0144] C32. The method of any one of C29-C31, further comprising: obtaining a signal indicative of a current pumping speed of the pumping device (FP2), and selecting the one or more predefined features based on the current pumping speed of the pumping device (FP2).

[0145] C33. The method of any one of C29-C32, wherein said determining (103) the concentration value comprises: determining a current temperature of the first concentrate, and adjusting (103c) the set of values based on the current temperature. C34. The method of any one of C29-C33, wherein said determining (103) the concentration value comprises: retrieving (103dl) a look-up table that associates a respective set of tabulated values of the one or more predefined signal features with a corresponding concentration value, and mapping (103d2) the set of values to the lookup table.

[0146] C35. The method of any one of C26-C28, wherein said determining (103) the concentration value comprises: operating (103e) a predefined calculation function on the waveform, a derivative waveform that represents a first-order derivative of the waveform, or a set of values of one or more predefined features in the waveform and / or the derivative waveform.

[0147] C36. The method of C35, wherein said determining (103) the concentration value comprises: jointly determining (401-404) the concentration value and an estimated dimension of the restrictor based on the waveform, and discarding (407) the concentration value if a difference between the estimated dimension and an actual dimension of the restrictor exceeds a threshold.

[0148] C37. The method of any one of C26-C36, further comprising: obtaining (202) a reference waveform from the first signal while the mixing sub-system operates to drive a reference fluid along the concentrate flow path through the restrictor, wherein the concentration value is determined based on the waveform and the reference waveform.

[0149] C38. The method of any one of C26-C37, further comprising: providing (105) control signals for operating the mixing sub-system to generate the treatment fluid, wherein at least one of the control signals is based on the concentration value.

[0150] C39. The method of C38, further comprising: switching the mixing sub-system between a production phase (307), in which the mixing sub-system is operated to generate the treatment fluid by mixing the water and the one or more concentrates, and a measurement phase (301), in which the mixing sub-system is operated (302) to drive the first concentrate on the concentrate flow path through the restrictor.

[0151] C40. The method of C39, wherein the mixing sub-system, in the production phase (307), is operated to drive the first concentrate on the concentrate flow path while bypassing the restrictor.

[0152] C41. The method of C39 or C40, wherein the mixing sub-system, in the measurement phase (301), is further operated to separately drive (304) the first concentrate on the concentrate flow path through a further restrictor, which defines a further confined passage and which differs from the restrictor by at least one dimension of the further confined passage, said method further comprising: obtaining (305) a further instance of the first signal while the mixing sub-system operates to drive the first concentrate through the further restrictor, wherein the concentration value is determined based on the waveform in the first signal and an additional waveform in the further instance of the first signal.

[0153] C42. A computer-readable medium comprising computer instructions which, when executed by processor circuitry (31), causes the processor circuitry (31) to perform the method of any one of C26-C41.

Claims

CLAIMS1. A system for generating a treatment fluid for use in dialysis, said system comprising: a mixing sub-system (10), which is arranged to receive water and one or more concentrates and operable to generate the treatment fluid by mixing the water and the one or more concentrates, wherein the mixing sub-system (10) comprises a pumping device (FP2), which is configured to drive a first concentrate among the one or more concentrates along a concentrate flow path in the mixing sub-system (10), said system further comprising: a restrictor (21) defining a confined passage in the concentrate flow path, a sensor sub-system (22, 23) configured to provide a first signal representative of a pressure difference between upstream and downstream ends of the restrictor (21) as a function of time, and a processing sub-system (30) configured to obtain the first signal from the sensor sub-system (22, 23) while the pumping device (FP2) is operated to drive the first concentrate through the restrictor (21), and determine a concentration value for a substance in the first concentrate based on a waveform in the first signal.

2. The system of claim 1, wherein the first concentrate has a viscosity that changes with the concentration value.

3. The system of claim 2, wherein the viscosity increases with increasing concentration of the substance.

4. The system of any preceding claim, wherein the substance is a monosaccharide, for example glucose.

5. The system of any preceding claim, wherein the processing sub-system (30) is configured to determine the concentration value based on a speed value associated with the waveform, the speed value representing a pumping speed of the pumping device (FP2).

6. The system of any preceding claim, wherein the processing sub-system (30) is configured to obtain the first signal at a plurality of different pumping speeds of the pumping device (FP2) and to determine the concentration value based on the waveform, given by the first signal, at each of the plurality of different pumping speeds.

7. The system of any preceding claim, wherein the first signal represents the pressure difference as a function of time during a sequence of pumping cycles (PC) of the pumping device (FP2), wherein each of the pumping cycles (PC) comprises a first phase in which the pumping device (FP2) is operated to drive the first concentrate through the restrictor (21), and second phase in which the pumping device (FP2) is operated to prevent passage of the first concentrate through the pumping device (FP2), and wherein the waveform corresponds to the pressure difference as a function of time during at least part of a pumping cycle.

8. The system of claim 7, wherein the pumping device (FP2) is a positive displacement pump.

9. The system of claim 7 or 8, wherein the processing sub-system (30) is configured to determine a set of values of one or more predefined features in the waveform and / or in a derivative waveform that represents a first-order derivative of the waveform, and determine the concentration value based on the set of values.

10. The system of claim 9, wherein at least one predefined feature is defined in relation to a respective pumping cycle among the sequence of pumping cycles (PC) so that the at least one predefined signal feature is a recurring characteristic in the first signal.

11. The system of claim 10, wherein the processing sub-system (30) is configured to determine a value of the at least one predefined feature by aggregating the recurring characteristic for a plurality of pumping cycles.

12. The system of any one of claims 9-11, wherein the processing sub-system (30) is configured to obtain a signal indicative of a current pumping speed of the pumping device (FP2), and select the one or more predefined features based on the current pumping speed of the pumping device (FP2).

13. The system of any one of claims 9-12, wherein the one or more predefined features comprise at least one of: a pressure range of the waveform during a pumping cycle; a maximum value of the waveform during a pumping cycle; an aggregation of signal values in the waveform during a pumping cycle;a signal value of the waveform at a selected location within a pumping cycle; a maximum value of the derivative waveform during a pumping cycle; a minimum value of the derivative waveform during a pumping cycle; a signal value of the derivative waveform at a selected location within a pumping cycle; a slope of a linear time-dependent function (F1-F6) fitted to a signal segment (Zl- Z6) of the derivative waveform, the signal segment corresponding to a subset of a pumping cycle and being determined by detection of one or more predefined characteristics in the derivative waveform; an offset value for a linear time-depending function (F1-F6) fitted to a signal segment (Z1-Z6) of the derivative waveform, the signal segment (Z1-Z6) corresponding to a subset of a pumping cycle and being determined by detection of one or more predefined characteristics in the derivative waveform; a location and / or an extent of a signal segment (Z1-Z6) of the derivative waveform, the signal segment (Z1-Z6) corresponding to a subset of a pumping cycle and being determined by detection of one or more predefined characteristics in the derivative waveform; or a difference between a linear time-dependent function (F1-F6) and a signal segment in the derivative waveform, the linear time-depending function (F1-F6) being fitted to the signal segment (Z1-Z6), and the signal segment (Z1-Z6) being determined by detection of one or more predefined characteristics in the derivative waveform.

14. The system of any one of claims 9-13, wherein the processing sub-system (30) is further configured to: obtain a temperature signal representative of a current temperature of the first concentrate, and adjust the set of values based on the current temperature.

15. The system of any one of claims 9-14, wherein the processing sub-system (30) is configured to determine the concentration value by use of a look-up table that associates a respective set of tabulated values of the one or more predefined features with a corresponding concentration value.

16. The system of any one of claims 1-6, wherein the processing sub-system (30) is configured to determine the concentration value by use of a calculation function that is configured to operate on the waveform, on a derivative waveform that represents a first-order derivative of the waveform, or on a set of values of one or more predefined features in the waveform and / or the derivative waveform.

17. The system of claim 16, wherein the calculation function is a trained neural network.

18. The system of any preceding claim, wherein the processing sub-system (30) is configured to jointly determine the concentration value and an estimated dimension of the restrictor (21) based on the waveform, wherein the processing sub-system (30) is configured to discard the concentration value if a difference between the estimated dimension and an actual dimension of the restrictor (21) exceeds a threshold.

19. The system of any preceding claim, wherein the mixing sub-system (10) is operable in a calibration phase, in which a reference fluid is driven through the restrictor (21), wherein the processing sub-system (30) is configured to obtain a reference waveform in the first signal as provided by the sensor sub-system (22, 23) during the calibration phase, the reference waveform corresponding to the first signal, and wherein the processing sub-system (30) is configured to determine the concentration value based on the waveform and the reference waveform.

20. The system of claim 19, wherein the reference fluid is one of the water, a second concentrate among the one or more concentrates, or a mixture of the water and the second concentrate.

21. The system of any preceding claim, wherein the processing sub-system (30) is further configured to provide control signals for operating the mixing sub-system (10) to generate the treatment fluid, and wherein the processing sub-system (30) is configured to set at least one of the control signals based on the concentration value.

22. The system of any preceding claim, wherein the mixing sub-system (10) comprises a first fluid line (LI), which is arranged to receive the first concentrate from the concentrate flow path and direct the water and the first concentrate through a mixing device (14).

23. The system of any preceding claim, wherein the processing sub-system (30) is configured to switch the mixing sub-system (10) between a production phase, in which the mixing sub-system (10) is configured to generate the treatment fluid by mixing the water and the one or more concentrates, and a measurement phase, in which thepumping device (FP2) is operated to drive the first concentrate through the restrictor (21).

24. The system of claim 23, wherein the concentrate flow path comprises a first path segment (L2a) and a second path segment (L2b), which are fluidly connected by a plurality of pathways, and a valve sub-system (25) that is operable to individually open the pathways, wherein the restrictor (21) is arranged in a first pathway (24') among the plurality of pathways, and wherein the processing sub-system (30) is configured to operate the valve sub-system (25) to open the first pathway (24') during the measurement phase and to operate the valve sub-system (25) to open a second pathway (24) among the plurality of pathways during the production phase.

25. The system of claim 24, wherein the plurality of pathways comprises a third pathway (24") with a further restrictor (2T), which defines a further confined passage and which differs from the restrictor (21) in the first pathway (24') by at least one dimension of the further confined passage, wherein the sensor sub-system (22, 23) is further configured to provide the first signal to represent the pressure difference between upstream and downstream ends of the further restrictor (21) as a function of time, and wherein the processing sub-system (30) is configured to operate the valve sub-system (25) to sequentially open the first and third pathways (24', 24") during the measurement phase, and to determine the concentration value based on the waveform in the first signal when the first pathway (24') is open, and an additional waveform in the first signal when the third pathway (24") is open.

26. A computer-implemented method of data processing in relation to a system for generating a treatment fluid for use in dialysis, said system comprising a mixing sub- system, which is arranged to receive water and one or more concentrates and generate the treatment fluid by mixing the water and the one or more concentrates, wherein the one or more concentrates comprises a first concentrate, said method comprising: obtaining (102), while the mixing sub-system operates to drive the first concentrate along a concentrate flow path through a restrictor that defines a confined passage in the concentrate flow path, a first signal representative of a pressure difference between upstream and downstream ends of the restrictor as a function of time, determining (103) a concentration value for a substance in the first concentrate based on a waveform in the first signal, andproviding (104-105) the concentration value for use in controlling the system.

27. The method of claim 26, wherein the first concentrate is driven along the concentrate flow path through the restrictor by a pumping device, wherein said obtaining (102) the first signal comprises: obtaining the first signal at a plurality of different pumping speeds of the pumping device, wherein the concentration value is determined based on the waveform, given by the first signal, at each of the plurality of different pumping speeds.

28. The method of claim 26 or 27, wherein the first signal represents the pressure difference as a function of time during a sequence of pumping cycles of the pumping device, wherein each of the pumping cycles comprises a first phase in which the pumping device is operated to drive the first concentrate through the restrictor, and second phase in which the pumping device is operated to prevent passage of the first concentrate through the pumping device, and wherein the waveform corresponds to the pressure difference as a function of time during at least part of a pumping cycle.

29. The method of claim 28, wherein said determining (103) the concentration value comprises: determining (103a, 103b) a set of values of one or more predefined features in the waveform and / or in a derivative waveform that represents a first-order derivative of the waveform, wherein the concentration value is determined based on the set of values.

30. The method of claim 29, wherein at least one predefined feature is defined in relation to a respective pumping cycle among the sequence of pumping cycles (PC) so that the at least one predefined signal feature is a recurring characteristic in the first signal.

31. The method of claim 30, wherein a value of the at least one predefined feature is determined by aggregating the recurring characteristic for a plurality of pumping cycles.

32. The method of any one of claims 29-31, further comprising: obtaining a signal indicative of a current pumping speed of the pumping device (FP2), and selecting the one or more predefined features based on the current pumping speed of the pumping device (FP2).

33. The method of any one of claims 29-32, wherein said determining (103) the concentration value comprises: determining a current temperature of the first concentrate, and adjusting (103c) the set of values based on the current temperature.

34. The method of any one of claims 29-33, wherein said determining (103) the concentration value comprises: retrieving (103dl) a look-up table that associates a respective set of tabulated values of the one or more predefined signal features with a corresponding concentration value, and mapping (103d2) the set of values to the lookup table.

35. The method of any one of claims 26-28, wherein said determining (103) the concentration value comprises: operating (103e) a predefined calculation function on the waveform, a derivative waveform that represents a first-order derivative of the waveform, or a set of values of one or more predefined features in the waveform and / or the derivative waveform.

36. The method of claim 35, wherein said determining (103) the concentration value comprises: jointly determining (401-404) the concentration value and an estimated dimension of the restrictor based on the waveform, and discarding (407) the concentration value if a difference between the estimated dimension and an actual dimension of the restrictor exceeds a threshold.

37. The method of any one of claims 26-36, further comprising: obtaining (202) a reference waveform from the first signal while the mixing sub-system operates to drive a reference fluid along the concentrate flow path through the restrictor, wherein the concentration value is determined based on the waveform and the reference waveform.

38. The method of any one of claims 26-37, further comprising: providing (105) control signals for operating the mixing sub-system to generate the treatment fluid, wherein at least one of the control signals is based on the concentration value.

39. The method of claim 38, further comprising: switching the mixing sub-system between a production phase (307), in which the mixing sub-system is operated to generate the treatment fluid by mixing the water and the one or more concentrates, and a measurement phase (301), in which the mixing sub-system is operated (302) to drive the first concentrate on the concentrate flow path through the restrictor.

40. The method of claim 39, wherein the mixing sub-system, in the production phase (307), is operated to drive the first concentrate on the concentrate flow path while bypassing the restrictor.

41. The method of claim 39 or 40, wherein the mixing sub-system, in the measurement phase (301), is further operated to separately drive (304) the first concentrate on the concentrate flow path through a further restrictor, which defines a further confined passage and which differs from the restrictor by at least one dimension of the further confined passage, said method further comprising: obtaining (305) a further instance of the first signal while the mixing sub-system operates to drive the first concentrate through the further restrictor, wherein the concentration value is determined based on the waveform in the first signal and an additional waveform in the further instance of the first signal.

42. A computer-readable medium comprising computer instructions which, when executed by processor circuitry (31), causes the processor circuitry (31) to perform the method of any one of claims 26-41.

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