Sensor assembly and porous membrane sensor element

Abstract

To provide a porous membrane sensor element for detection of an analyte in a complex fluid sample.SOLUTION: A porous membrane sensor element 100 comprises: a porous membrane sensor housing 101 penetrated by a flow channel 102 defining an axial direction, the flow channel comprising a sample space 103; a porous membrane 110 with a front side defining a sensor surface for contacting the fluid sample, the sensor surface facing towards the sample space, the porous membrane comprising pores extending from respective openings at the sensor surface into the porous membrane, where the pores are configured with regard to the analyte for diffusive fluid communication with the sample space; and an optical subassembly comprising a light guide core 120, where the light guide core comprises an input branch 121, an output branch 122, and a coupling interface 123 arranged to contact a backside of the porous membrane opposite to the front side and facing away from the sample space.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to a porous membrane sensor element for detecting analytes in complex fluid samples. According to a further aspect, the present invention relates to a sensor assembly comprising a porous membrane sensor element integrated into a sample chamber of such a porous membrane sensor element. According to particular aspects, the present invention relates to a reusable porous membrane sensor element and a reusable sensor assembly comprising such a reusable porous membrane sensor element. According to a further aspect, the reusable porous membrane sensor element is adapted for use in a multi-parameter analytical instrument, such as an analytical instrument for analyzing multiple parameters in a body fluid sample. According to yet a further aspect, a reusable sensor assembly comprising such a reusable porous membrane sensor element is adapted for use in a multi-parameter analytical instrument, such as an analytical instrument for analyzing multiple parameters in a body fluid sample. [Background technology]

[0002] The detection of analytes in complex fluids containing continuous and discontinuous portions is a challenging yet frequently encountered measurement problem. Typically, the measurement involves sample preparation steps, including separation by, for example, filtration, precipitation, and / or centrifugation, followed by a detection measurement step using a chemical indicator reaction and / or physical interaction that is sensitive to the analyte in question. A difficult challenge in this context often lies in the preparation and presentation of an appropriate sample for detection without compromising the measurement, especially when the available sample volume is small and the analyzed fluid is highly complex. Moreover, in such situations, multiple parameters are frequently determined for the same sample, which imposes additional constraints on the integration of a given measurement for analyte detection with measurements of other parameters.

[0003] Therefore, there is a need for a highly sensitive, yet simple and rapid technique that allows for the selective detection of analytes in complex fluids that is further amenable to easy integration with other measurement techniques for determining multiple parameters of the same sample. Furthermore, the desired technique is needed to provide gentle separation, extraction, and / or isolation of analytes for detection measurements, i.e., without compromising the remainder of the fluid being analyzed.

[0004] Such detection techniques are relevant to a variety of industries ranging from the food industry to wastewater treatment to pharmaceutical applications and medical devices, where known techniques often require large sample volumes and time-consuming analytical procedures.

[0005] One example of the application of such measurement techniques relates to the detection of analytes in bodily fluids, such as a patient's blood sample. The analyte can be any laboratory test parameter for bodily fluid analysis that is detectable by light, e.g., spectrophotometry. As one source of interference in blood analysis, hemolysis can affect the measurement of several blood parameters, as determined in a blood parameter analyzer. Therefore, ignoring the level of free hemoglobin in a blood sample can mislead an unwitting individual, resulting in an incorrect diagnosis based on the affected blood parameter value. However, until now, reliably determining the level of free hemoglobin present in the plasma portion of a whole blood sample has involved a complex process requiring separation of the plasma portion from cellular components and subsequent analysis of the separated plasma portion. Such procedures are time-consuming and can be prohibitively expensive when only very small samples are available at a time, such as in neonatal care with continuous monitoring of blood parameters in infants. Another approach to measuring components present in the plasma portion of whole blood involves separating the plasma portion from cellular components by microfiltration techniques, e.g., in a microfluidic device, before analyzing the plasma portion in a dedicated measurement in the microfluidic device. For example, a recent scientific article by Archibong et al., published in Sensing and Bio-Sensing Research 3 (2015), pp. 1-6, describes a miniature measurement chamber for optically analyzing the plasma fraction separated from a whole blood sample. In this type of device, a miniature microfluidic chamber is attached to an optical fiber interface. The bottom of the microfluidic chamber consists of a porous membrane that allows fluids and chemical compounds to flow inside the device while simultaneously filtering out unwanted particles. The inside of the microfluidic chamber, which receives the filtrate, can be optically probed by a single optical fiber in a normal-incidence reflection geometry.However, due to clogging issues, the disclosed devices are best served as disposables rather than for continuous and repeated use, as complete washing off of the sample after measurement can be difficult, or at least very time-consuming, and unreliable, running the additional risk of cross-contamination between subsequent samples. Furthermore, in this particular type of device, pressure-induced deformation of the filtration membrane, which results in a change in the optical path to probe the filtrate, can pose an additional challenge to obtaining quantitative results from the optical probe.

[0006] As a further example, namely in applications in the food industry such as the dairy industry, most traditional methods of filtration and detection involve filters, strainers, etc. for visual inspection of residues, spectroscopic measurements, or bacterial counting, which have the above-mentioned drawbacks of requiring relatively large sample volumes and involving time-consuming measurement procedures that are harmful to the sample and incompatible with integrated multi-parameter measurements performed on the same sample. Similar challenges are also encountered in the field of environmental technology, such as wastewater analysis and treatment, where most traditional methods of filtration and detection involve filters, strainers, etc. for spectroscopic measurements of residues and bacterial counting.

[0007] Filtration-based techniques have several drawbacks when used to analyze, for example, whole blood samples. Filtration devices inherently rely on fluid flow of at least the filtrate from the sample feed through the filter pores to the filtrate analysis / measurement chamber. In a through-flow geometry, debris (here, red blood cells) gradually clogs the filtration pores. In a cross-flow geometry, debris is brought along the surface of the filtration membrane, which reduces, but does not eliminate, the clogging problem, especially when the system is intended for repeated use (more than 10-100 samples). The cross-flow geometry also creates friction and shear interactions between the debris and the surfaces of the filtration device.

[0008] Improved separation and measurement techniques that address these issues are disclosed by the applicant in co-pending international patent applications WO2017 / 085162A1, WO2017 / 085180A1, and WO2019 / 197308A1, which are incorporated herein by reference.

[0009] Again, a particularly challenging application area is the analysis of body fluids in a point-of-care configuration. Modern point-of-care analytical devices that analyze multiple parameters in body fluid samples, such as for the analysis of arterial or venous blood, are subject to strict requirements and constraints for patient safety, ease of use, short measurement times in the sub-minute range, reliability / reproducibility, accuracy of quantitative output, and compliance with quality control systems and safety directives for medical measurement devices, to name just a few. Accurate and compliant results must be obtained for very small volumes of sample fluid (typically less than 100 μl, or even less than 50 μl) consistent with the above-mentioned requirements and constraints. Therefore, most advanced point-of-care analytical systems are designed around automated fluid handling and measurement infrastructures with compact sensor assemblies at their core. Such sensor assemblies are intended for repeated use and typically have a sample space defined by sample chamber walls with a miniaturized, high-precision sensor directly integrated into at least one of the walls. An example of such a sensor assembly for body fluids is disclosed, for example, in European Patent Specification EP 2147307 B1. The sensor assembly of EP 2 147 307 B1 comprises electrochemical and optical sensor elements that are particularly suitable for simultaneously measuring a number of different parameters in a body fluid sample, such as blood parameters. It is therefore desirable that new measurement techniques that meet the above-mentioned need for highly sensitive, simple and selective detection of analytes in complex fluids should be suitable for integration with such sensor assemblies having sample channel widths in the millimeter range and sample channel heights in the sub-millimeter range.

[0010] A device for detecting an analyte in a fluid sample by means of an optical probe is described in the applicant's above-mentioned application WO 2019 / 197308 A1, in which a porous sensor element is arranged in a chamber wall of a sample chamber adapted to hold a fluid sample, the sensor surface having open pores facing towards the sample chamber so as to contact the fluid sample and adapted to receive within the pores the analyte from at least a continuous portion of the complex fluid sample by diffusion. Summary of the Invention [Problem to be solved by the invention]

[0011] However, there remains a need for improved apparatus and methods for detecting analytes in fluids with a fast and reliable response that can be implemented in a miniaturized manner. Additionally, there is a particular need to provide porous membrane sensor elements that are compatible with optical probes and that facilitate tight integration within sensor assemblies and devices for analyzing fluid samples, such as within automated point-of-care analyzer systems for body fluids. More generally, there remains a need for improved apparatus and methods for detecting substances in portions of complex fluids, such as whole blood samples, with a fast and reliable response that are adapted for miniaturization and integration in fluid analytical systems, particularly analytical systems for measuring multiple parameters on the same fluid sample.

[0012] Thus, according to one aspect, it is an object of the present invention to provide an improved detection device and / or method that overcomes at least some of the drawbacks of known devices, sensors, systems, and / or methods for specifically detecting an analyte in successive portions of a complex fluid, e.g., for detecting an analyte in the plasma portion of a whole blood sample. According to a further aspect, it is an object of the present invention to provide such a detection device that can be miniaturized for integration into a sensor assembly. [Means for solving the problem]

[0013] According to one aspect, the object is achieved by a porous membrane sensor element as set forth in claim 1 and advantageous embodiments as defined in the dependent claims referencing it and as further disclosed in the present application. According to a further aspect, the object is also achieved by a sensor assembly comprising such a porous membrane sensor element. In one or more aspects, the object is further achieved by a reusable porous membrane sensor element as disclosed herein, adapted for use in a multi-parameter analytical instrument, such as an analytical instrument for analyzing multiple parameters in a body fluid sample, and a reusable sensor assembly comprising such a reusable porous membrane sensor element. Also, each aspect should not necessarily be construed as an individual aspect, i.e., different aspects may be readily combinable.

[0014] In the context of point-of-care measurement systems (also referred to in the art as "bedsite" systems), and similarly in laboratory settings, blood gas analysis is often undertaken by users, such as nurses, who may not be users trained in the use of blood gas analyzers. In particular, the user's correct placement of a handheld blood sample container, such as a syringe or capillary tube, on the blood gas analyzer's inlet structure has proven to present a challenging situation in drawing a blood sample into the blood gas analyzer. Incorrect placement and alignment of the blood sample container with the inlet structure can not only result in annoying delays and / or frustration in the user's daily workflow, but can also result in loss of the blood sample or contamination of the blood gas analyzer or its surroundings.

[0015] According to a particular aspect of the present invention, it is provided to use a system / method according to any of the embodiments herein for point-of-care (POC) measurements of analyte parameters in body fluids, and in particular in whole blood samples.

[0016] POC measurements are also referred to in the art as "bed-site" measurements. In this context, the term "point-of-care measurement" should be understood to mean measurements performed in close proximity to the patient, i.e., not in a laboratory. Thus, according to this embodiment, a user of the blood gas analyzer measures a whole blood sample in a handheld blood sample container near the patient from whom the blood sample is drawn, for example, in the hospital room or ward housing the patient's bed, or in a nearby room in the same hospital department. In such use, the user's level of expertise often varies from novice to experienced, and the ability of the blood gas analyzer to automatically output instructions tailored to each individual user's skill based on sensor input is therefore particularly beneficial in such environments.

[0017] According to one aspect, the present invention relates to a porous membrane sensor element for detecting an analyte in a complex fluid sample, comprising: a porous membrane sensor housing penetrated by a flow channel defining an axial direction, the flow channel comprising a sample space; a porous membrane having a front surface defining a sensor surface in contact with the fluid sample, the sensor surface facing towards the sample space, the porous membrane comprising pores extending into the porous membrane from respective openings in the sensor surface, the pores being configured for diffusive fluid communication with the sample space for the analyte; and an optical subassembly comprising a light guide core having an input branch, an output branch, and a coupling interface arranged to contact a rear surface of the porous membrane opposite the front surface and facing away from the sample space, the input branch and the output branch being oriented towards the coupling interface, the input branch and the output branch being arranged in a common light guide plane arranged orthogonal to the sensor surface.

[0018] The porous membrane sensor element is useful for analyzing complex fluids containing continuous and discontinuous portions, and particularly for selectively detecting analytes in continuous portions of complex fluids. As described in more detail below, the porous membrane sensor element is particularly useful for miniaturization and / or integration in sensor assemblies, and particularly for use in fluid analyzer configurations that measure multiple analyte parameters, for example in modern hematology analyzers.

[0019] In some embodiments, a sample space is formed in the flow channel between the inlet and the outlet. Furthermore, a porous membrane is disposed on the wall of the sample space, with the pore openings on the sensor surface facing toward the sample space. Thus, the sample space can be arranged so that a fluid sample of the complex fluid introduced through the inlet is presented at the sensor surface of the porous membrane facing toward the sample space. As described in more detail below, at least a portion of the complex fluid is in diffusional communication with pores, such as dead-end pores, of the porous membrane, introducing a representative subsample into the pores. Then, as discussed elsewhere herein, an optical subassembly coupled to the rear surface of the porous membrane allows selective optical measurements to be performed on the subsamples in the pores from the rear surface of the porous membrane. After the measurements are performed, the fluid sample can be removed from the sample space to the outlet and rinsed with a rinse fluid. Rinsing the sample space also rinses the pores for analytes by diffusive transport using the rinse fluid in the sample space. The porous membrane sensor element can then be reused for new measurements on additional fluid samples different from the previous fluid sample.

[0020] In some embodiments, a porous membrane having dead-end pores is positioned in diffusion communication with a sample space formed in a flow channel extending from an inlet to an outlet, thereby providing a reusable device that allows measurements on multiple fluid samples during each measurement cycle. Typically, each measurement cycle includes presenting a fluid sample in the sample space, performing measurements on subsamples of the fluid sample that are in diffusion communication with the pores of the porous membrane, as further detailed elsewhere herein, removing the sample from the sample space, and rinsing the sample space with a rinse fluid. This configuration of a porous membrane in diffusion communication with a sample space formed in a flow channel thereby allows for the integration of optical measurements in a reusable sample assembly adapted for use in an analytical device that measures multiple parameters.

[0021] The analyte is extracted from the fluid sample into the porous membrane by diffusion. The analyte can then be detected by an optical probe using an optical subassembly. The term "detection," as used herein, is intended to include merely steady-state detection of the presence of a given analyte and / or a quantitative measurement, such as a measurement to determine the concentration of the analyte in a complex fluid sample. The pores of the porous membrane are in diffusive fluid communication with the sample chamber. The pores are configured for diffusive fluid communication between the fluid in the pores and the fluid sample in the sample space of the porous membrane sensor element with respect to the analyte. Thus, the pores are configured to exchange the analyte with the continuous portion of the complex fluid sample in the sample chamber through diffusive transport while preventing much larger particles of the discontinuous phase of the complex fluid sample from entering the pores.

[0022] The terms "optical" and "light," and related terms, generally refer to electromagnetic radiation within the visible, infrared, and ultraviolet spectral ranges; the term "visible" typically refers to electromagnetic radiation having wavelengths in the range of 400 nm to 700 nm; the term "infrared" broadly refers to electromagnetic radiation having wavelengths in the range of 700 nm to 1 mm, "near infrared" having typical subranges of about 700 nm to 3 μm, "mid infrared" having typical subranges of 3 μm to 50 μm, and "far infrared" having typical subranges of 50 μm to 1 mm; and the terms "ultraviolet" or "UV" broadly refer to electromagnetic radiation having wavelengths in the range of 10 nm to 400 nm, "near ultraviolet" having typical subranges of 300 nm to 400 nm, "mid ultraviolet" having typical subranges of 200 nm to 300 nm, and "far ultraviolet" having typical subranges of 122 nm to 200 nm. Those skilled in the art will understand that the usefulness of the spectral ranges described for a given sensor element, and in particular for a given semi-transparent film material, depends on the suitability of the spectral ranges and materials for propagating input and output light through those materials.

[0023] The porous membrane is a semi-transparent membrane. The term "semi-transparent" refers to the property of a material that allows light to pass through it. The term "transparent" refers to the property of a material that allows light to pass through it without being scattered. Therefore, the term "transparent" is considered a subset of the term "semi-transparent." Typically, the rear surface of the semi-transparent membrane is parallel to the front surface, and an additional transparent backing may be applied to the rear surface to provide mechanical support that reinforces / strengthens the semi-transparent membrane from the rear surface. The backing may be, or at least include, a transparent pad that fills the gap between the semi-transparent membrane and additional optical components of the sensor element, such as the input port and / or output port. Any gap between the rear surface of the semi-transparent membrane and any of the additional optical components may be completely filled with the transparent pad component.

[0024] The input branch forms an optical input port connected to a rear surface of the semi-transparent membrane, the rear surface facing away from the front surface. The optical input port is adapted to send probe light to a probe region of the semi-transparent membrane through a coupling interface at the rear surface. The output branch forms an optical output port connected to the rear surface of the semi-transparent membrane. The optical output port is adapted to collect an optical response from the semi-transparent membrane through a coupling interface at the rear surface. The optical input port is configured to send probe light into the semi-transparent membrane through the rear surface. The optical output port is configured to collect an optical response to the probe light from the semi-transparent membrane through the rear surface. Both injecting probe light and collecting an optical response from the rear surface of the semi-transparent membrane realizes a compact design that enables integration of the sensor element into a miniaturized sample assembly with a very small sample chamber designed for analyzing very small volumes of sample fluid.

[0025] The term "fluid" refers to liquids and / or gases, including complex fluids containing continuous and discontinuous phases, such as particulate phases. Examples of relevant fluids that may be analyzed using embodiments of the present invention include, but are not limited to, bodily fluids, particularly whole blood samples, the plasma portion of whole blood, spinal fluid, urine, pleural fluid, and peritoneal fluid. Further examples of relevant fluids include wastewater, fluids prepared for injection of any kind, fluids with components detectable by spectroscopy, or gases such as air, carbon dioxide-containing gases, and carbon monoxide-containing gases. The term "sample" refers to the portion of the fluid used or required for analysis using the porous membrane of the present invention.

[0026] The term "complex fluid," as used herein, refers to a fluid having continuous and discontinuous portions, such as a liquid portion and a particulate portion. Typically, the analyte is a component of the continuous portion of a complex fluid sample. Thus, the analyzed fluid includes at least a continuous portion containing the analyte. The analyzed fluid can further include discontinuous portions, i.e., particulate portions. The particulate portion can include, for example, solid particles, debris and other contaminants, biological cells (such as red blood cells) or microorganisms, liquid droplets, gas bubbles, and combinations thereof. The analyzed fluid can be a whole blood sample, the plasma portion of whole blood, spinal fluid, urine, pleura, peritoneal fluid, wastewater, any type of fluid prepared for infusion, a fluid having components detectable by optical probes such as spectroscopy, or a gas, such as air, a carbon dioxide-containing gas, or a carbon monoxide-containing gas.

[0027] The term "whole blood" refers to blood composed of blood plasma and cellular components. Plasma represents approximately 50% to 60% of the volume, and cellular components represent approximately 40% to 50% of the volume. The cellular components are erythrocytes (red blood cells), leukocytes (white blood cells), and thrombocytes (platelets). Preferably, the term "whole blood" refers to whole blood from a human subject, but it can also refer to whole blood from an animal. Erythrocytes comprise approximately 90% to 99% of the total number of whole blood cells. In their intact state, they are shaped as biconcave discs approximately 7 μm in diameter and 2 μm thick. Erythrocytes are highly flexible, which allows them to pass through very narrow capillaries, reducing their diameter to approximately 1.5 μm. One of the core components of red blood cells is hemoglobin, which binds oxygen for transport to tissues and then releases oxygen and binds carbon dioxide for delivery to the lungs as a waste product. Hemoglobin is responsible for the red color of red blood cells, and therefore blood as a whole. White blood cells comprise less than 1% of the total number of blood cells. They have a diameter of about 6 μm to about 20 μm. White blood cell particles are involved in the body's immune system, for example, against bacterial or viral invasion. Platelets are the smallest blood cells, measuring about 2 μm to about 4 μm in length and about 0.9 μm to about 1.3 μm in thickness. They are cell debris that contain enzymes and other substances important for clotting. In particular, they form temporary platelet clots that help seal blood vessel breaches.

[0028] The term "blood plasma" or "plasma" refers to the liquid portion of blood and lymph, which constitutes about half of the volume of blood (e.g., about 50%-60% by volume). Plasma is cell-free. It contains all clotting factors, especially fibrinogen, and contains about 90%-95% water by volume. Plasma components include electrolytes, lipid metabolites, markers for, e.g., infection or tumor, enzymes, substrates, proteins, and additional molecular components.

[0029] The term "wastewater" refers to water that has been used for washing, for sinking, or in a manufacturing process and therefore contains waste and / or particles and is therefore not suitable for preparing food or drink.

[0030] As further explained below, the analyte can be any substance detectable by an appropriate probe technique, such as an optical probe. For example, the analyte can be a subset of molecules that may be present in the continuous phase of the fluid being analyzed. For example, when analyzing a whole blood sample, the analyte can be a specific drug, and the measurement can be to determine the drug content in the plasma phase, for example, to determine drug intake and adjust drug dosing accordingly. In another example of analyzing a whole blood sample, the analyte can be hemoglobin to determine the degree of hemolysis. More generally, the porous membrane sensor element can be configured to detect high molecular weight analytes. In the context of this application, the term "high molecular weight" refers to a molecular weight of 1.66×10 -20 g (10,000 Da) or more, e.g., 4.98 × 10 -20 g (30,000 Da) or more, or e.g., 8.30 × 10 -20 An example of detecting high molecular weight analytes in successive portions of a complex fluid is detecting hemolysis in a whole blood sample.

[0031] As described above, the porous membrane sensor element has a sensor surface that contacts the fluid to be analyzed. The sensor surface is formed on the front surface of a semitransparent membrane, and a reflective layer is applied to the front surface. The semitransparent membrane contains small pores, preferably blind pores, that extend from the front surface through the reflective layer and into the semitransparent membrane. Each small pore has an opening through which it can communicate with the fluid space at the front surface of the semitransparent membrane. Thus, the pores allow fluid communication between the pore and the fluid space through the reflective layer. The pores extend from their respective openings at the front surface into the semitransparent membrane toward the rear surface. Preferably, the pores are "blind," meaning that the ends of the pores are within the semitransparent membrane. Blind pores do not continue all the way through the semitransparent membrane to the rear surface or to any common reservoir or receptacle within the membrane. The pores are only in fluid communication with the fluid space at the front surface of the semitransparent membrane. It should be noted that in some embodiments, the dead-end pores may extend both vertically and horizontally, and thus at least some of the pores may be connected to one another, forming an X-, Y-, V-, or similar interconnected shape. Such configurations are considered similar to dead-ends because the pores are filled only from the front, and no appreciable net mass transfer through the pores occurs under operation, even when the pores cross one another.

[0032] The semi-transparent membrane can be made from a transparent polymeric membrane, and pores are produced therein using so-called track etching techniques, for example as disclosed in co-pending International Patent Applications WO2017 / 085162A1 and WO2017 / 085180A1, which are incorporated herein by reference.

[0033] The pores form vials / cuvettes that selectively accept analytes from a first portion of the fluid, particularly by diffusion / diffusive transport, while effectively preventing particulate matter from entering the pores. These vials / cuvettes are positioned at least within the probe region for efficient interaction between the probe light and the analyte. The pore openings are dimensioned to maintain particulate matter from the fluid to be analyzed outside the pores while allowing analytes from further portions, e.g., successive portions, to enter the semi-transparent membrane through the pores, so that probe light injected from the input port can interact with the analytes and thus detect them with the optical probe. By appropriately dimensioning the pore openings at the front surface, for example, it is possible to prevent red blood cells of the whole blood sample at the sensor surface from entering the pores while allowing relevant components in the plasma portion of the whole blood sample to enter the pores. The relevant components are substances present in the plasma portion of the whole blood sample (or more generally in the relevant portion of the fluid sample) that will be measured / detected using the sensor.

[0034] This configuration allows a small but representative portion of the analyte to be gently extracted from the complex fluid and efficiently exposed to the probe light in the probe region with a high degree of overlap. This separation is achieved in a particularly simple and fast manner, as the probe region is located directly on the surface of the semi-transparent membrane with pores that penetrate directly into the membrane and with a relatively short distance from their respective openings in the sensor surface to the sensing location, thus facilitating particularly rapid diffusive exchange of the sample.

[0035] Typical cross-sectional dimensions of the pores are in the micron and submicron range, up to about 100 nm. Analyte transport into and out of the pores is achieved by diffusion. For efficient operation, the pores are filled with a priming fluid, which is preferably filled into the pores during a priming step, for example, before performing the first detection measurement. The priming fluid may not affect the analyzed fluid. Therefore, the priming fluid must be compatible with the analyzed fluid. Advantageously, the priming fluid may be a flushing fluid, such as an aqueous buffer solution, which may also be used to flush the sample chamber between filling, emptying, and refilling procedures to replace the sample of the analyzed fluid. The flushing fluid may also be a reference or calibration fluid.

[0036] Advantageously, according to some embodiments, the pore is filled with a liquid. Priming the pore with a known liquid allows sub-samples representing relevant components in the fluid to be analyzed to be extracted into the pore solely by diffusion. This allows for fast, efficient, and well-controlled exchange of analytes into and out of the optical probe region via the pore. Advantageously, according to some embodiments, the liquid is an aqueous solution. This is particularly useful for detecting water-soluble analytes. Alternatively, the pore could be filled with a non-aqueous liquid, which is particularly useful, for example, when the fluid to be analyzed is also a non-aqueous liquid.

[0037] In operation, the front surface of the semi-transparent membrane can be in contact with, for example, a whole blood sample or fluid. Small pores in the semi-transparent membrane communicate with the whole blood sample or fluid through openings in the front surface. The pore openings are sized to selectively extract a subsample of the plasma phase of a whole blood sample or a subsample of a fluid containing an analyte. Red blood cells cannot enter the pores through the openings on the front surface of the semi-transparent membrane. Nothing larger than the pore diameter can enter the pores, except for, for example, any debris contained in the fluid. As mentioned, the pores are preferably dead-ends that only communicate with the front surface of the semi-transparent membrane; i.e., a subsample is extracted for an optical probe inside the pore and, after measurement, is discharged again through the same opening in the front surface of the semi-transparent membrane. The subsample volume corresponds to the total internal volume of the pores. No filtrate filtration or net mass transfer occurs through the pore-containing layer, either into any common filtrate receiver or to any filtrate outlet. Optical detection is then performed only on the subsample contained within the pore. The reflective layer optically separates the optical probe region within the translucent membrane from the fluid space containing the whole blood sample or fluid. By optically separating the probe region from the fluid space, any contribution of intact red blood cells of the whole blood sample or debris in the fluid to the probed signal can be effectively suppressed. Therefore, the measurement is specific to the analyte content in the fluid.

[0038] A small sub-sample having a representative content of relevant components can be transferred to the pores by any suitable technique. The small, dead-end pores allow for very efficient and fast extraction of the sub-sample for the optical probe from the whole blood sample or fluid through the front opening by capillary forces and / or diffusion. In a typical mode of operation, the front surface of the semi-transparent membrane is contacted by a rinse fluid before the front surface is contacted with the whole blood sample or fluid to be analyzed. This allows the pores to be "primed" with a pre-fill of a liquid compatible with the whole blood sample or fluid, and in particular, a liquid compatible with the plasma phase, if the fluid is whole blood, such as aqueous solutions commonly used for rinsing, calibration, and / or quality control purposes in hematology analyzers. For example, a typical rinse fluid used for rinsing in whole blood analysis systems can be used as such a liquid. The rinse fluid has a K value of 0.01% at a concentration corresponding to human plasma. + , Na + , Cl - , Ca 2+ , O2, pH, CO2, and HCO 3- When a whole blood sample or fluid is then contacted with the plasma-compatible / fluid-compatible liquid-primed front surface, a representative subsample of the components in the plasma phase of the whole blood sample or fluid is extracted and transported into the pre-filled pores in a very efficient and gentle manner by diffusion of the relevant components. In particular, any concentration gradient of analyte content between the fluid in the pore and the reference liquid drives diffusional transport, thereby producing a subsample within the pore with an analyte concentration representative of the analyte concentration in the fluid.

[0039] The subsample volume corresponds to the total internal volume of the pores. No filtrate filtration or net mass transfer occurs through the pore-containing layer during measurement, either into any common filtrate receiver or to any filtrate outlet. Optical detection is then performed based solely on the subsample contained within the pores. Confinement of the input light in the semitransparent membrane optically separates the optical probe from the fluid space containing the whole blood sample or fluid. By optically separating the optical probe from the fluid space, the contribution of intact red blood cells in the whole blood sample or debris in the fluid to the detection signal can be effectively suppressed. Therefore, the measurement is specific to the analyte content in the fluid.

[0040] The following embodiments disclose advantageous rules and ranges for pore sizing, particularly for use in sensor elements in the context of optically probing body fluids. Furthermore, according to some embodiments of the sensor element, the cross-sectional dimension of the pore opening is about 1 μm or less, about 800 nm or less, preferably about 500 nm or less, or even about 400 nm or less. Depending on the application, the cross-sectional dimension of the pore opening is preferably made to balance size selectivity (smaller pore opening diameter) with rapid exchange of sub-samples / analytes (larger pore opening diameter). The given values ​​are useful, for example, for the analysis of body fluids such as whole blood, especially with analytes in the plasma fraction.

[0041] Furthermore, according to some embodiments of the sensor element, the cross-sectional dimension of the pore opening is at least 200 nm. The cross-sectional dimension of the pore opening is preferably adapted to balance size selectivity (smaller pore opening diameter) with rapid exchange of sub-samples / analytes (larger pore opening diameter), depending on the application. The recited range of values ​​is useful, for example, for the analysis of body fluids such as whole blood, especially with analytes in the plasma fraction.

[0042] Furthermore, according to some embodiments of the sensor element, the axial length of the pore along the pore is less than 100 μm, less than 50 μm, and preferably less than 30 μm. Preferably, the pore length is tuned to balance the desire for increased sample volume (longer pore length) to interact with the optical probe field in the probe region with rapid sample / analyte exchange (shorter pore length), depending on the application. The given value is particularly useful for analyzing bodily fluids such as whole blood with the analyte in the plasma portion of the whole blood sample.

[0043] Furthermore, according to some embodiments of the sensor element, the axial length of the pore along the pore is at least 1 μm, at least 2 μm, at least 5 μm, and preferably at least 10 μm. Preferably, the pore length is tuned to balance the desire for increased sample volume (longer pore length) to interact with the optical probe field in the probe region with rapid sample / analyte exchange (shorter pore length), depending on the application. The given value is particularly useful for analyzing bodily fluids such as whole blood, with the analyte in the plasma portion of the whole blood sample.

[0044] Furthermore, according to some embodiments of the sensor element, the pores are straight. Straight pores facilitate efficient transport through the length of the pore, thereby achieving fast sub-sample / analyte exchange.

[0045] Furthermore, according to some embodiments of the sensor element, the pores are track-etched pores formed by exposing the semi-transparent membrane to directional ion bombardment followed by chemical etching. Track etching is particularly well suited for forming linear, narrow, but deep pores, e.g., of the dimensions described above. The pores can be formed in a unidirectional arrangement resulting from, e.g., a single directional ion bombardment exposure. Alternatively, the pores can be formed in a multidirectional arrangement by applying multiple directional ion bombardment exposures from different directions. Thus, the pore arrangement can be generated / defined, e.g., by one or more directional ion bombardment exposures prior to performing the etching step.

[0046] Suitable translucent membranes can be produced, for example, from transparent polymer membranes with so-called track-etched pores, similar to those commercially available from the company IT4IP (IT4IP SA / Avenue Jean-Etienne Lenoir 1 / 1348 Louvain-la-Neuve / Belgium), with the modification that the pores are closed at one end. The through-holes in the membrane can be closed, for example, by laminating a backing sheet to the rear of the porous membrane or by decelerating the ions, so that the tracks of ion bombardment, and therefore the pores etched according to these tracks, end up forming dead-end pores in the transparent polymer membrane. Typically, the membrane is backed by a rigid transparent element to provide the translucent membrane with sufficient mechanical strength.

[0047] Preferably, the semi-transparent membrane should be made of a material that does not absorb light, and at the same time, it should be possible to create dead-end pores in the material, for example, by track etching the material. Suitable materials for this are, for example, polyethylene terephthalate (PET or PETE), or PET analogs (polyethylene terephthalate polyester (PETP or PET-P)), or polycarbonate (PC). The semi-transparent membrane can include a hydrophilic coating, for example, of polyethylene glycol (PEG), to increase diffusion into the pores. The hydrophilic coating can be selected to configure the sensor element for certain operating modes. In some operating modes, the sensor element never completely dries out once it is in use, and therefore only needs to be hydrophilic at start-up. For other operating modes of the sensor element, a coating is applied that permanently maintains hydrophilicity throughout the sensor element's lifetime. This enables an operating mode that allows the sensor element to completely dry out between subsequent uses while still maintaining rapid sub-sample extraction from a liquid sample presented to the sensor surface. Thus, even though the sensor element is allowed to dry out between uses, a fast measurement turnaround can be achieved from contacting the sensor surface with a liquid sample to obtaining an optical probe result.

[0048] Advantageously, according to some embodiments of the sensor element, the porosity of a given volume of semi-transparent membrane comprising pores at least in the probe region is between 50% and 5% by volume, between 30% and 10% by volume, or about 15% by volume. The porosity can be characterized by the volume of the voids created in the semi-transparent membrane by the pores, i.e., the pore volume, which refers to the volume of the semi-transparent membrane penetrated by the pores, where this volume is defined as the volume between the front area in which the pores are distributed and the same parallel area shifted into the semi-transparent membrane by the maximum penetration depth of the pores into the semi-transparent membrane, as viewed in a vertical direction perpendicular to the sensor surface.

[0049] Additionally, porosity can be further characterized by the integrated pore volume, which is equal to the sub-sample volume available to the optical probe. Conveniently, pore volume can be expressed as an equivalent pore volume depth DELTA, which is the pore volume referenced to the corresponding frontal area over which the pore openings are distributed. Thus, the porosity of a semi-transparent membrane can be converted to an equivalent pore volume depth DELTA as follows: Pores with openings within a given frontal area A have a total pore volume V. The equivalent pore volume depth is then calculated by dividing the total pore volume by the given frontal area: DELTA = V / A.

[0050] Advantageously, according to some embodiments, the equivalent pore volume depth DELTA is less than 20 μm, or less than 15 μm, or less than 10 μm, or in the range of 3 μm to 5 μm, and the equivalent pore volume depth DELTA is defined as the total pore volume V divided by the front surface area A over which the pore openings are distributed. This results in small subsamples with representative concentrations of relevant components. A small subsample volume is desirable to facilitate fast subsample exchange, thereby reducing the response time of the sensor element and the cycle time of measurements using the sensor element. A small subsample volume is further desirable to prevent the effects of boundary layer reduction of the plasma portion in the whole blood sample near the front surface of the semi-transparent membrane. Otherwise, such effects may occur in small, still-lasting samples; for example, if the equivalent pore volume depth exceeds a critical value, red blood cells may hinder efficient diffusion exchange of relevant components from the whole blood sample volume toward the boundary layer at the front surface of the semi-transparent membrane.

[0051] Preferably, the equivalent pore volume depth DELTA is at least 1 μm, alternatively at least 2 μm, or in the range of 3 μm to 5 μm, where the equivalent pore volume depth is defined as above. Larger sub-sample volumes are desirable to achieve better signal-to-noise levels, as larger sub-sample volumes contribute to optically probed information about relevant components in plasma.

[0052] Furthermore, according to some embodiments, a useful compromise between reducing response time, reducing cycle time, and / or preventing the effects of decay in small yet persistent whole blood samples or fluids on the one hand, and the required or desired signal-to-noise ratio on the other hand, is found for an equivalent pore volume depth DELTA in the range of 1 μm to 20 μm, preferably 2 μm to 10 μm, or in the range of about 4 μm to 5 μm.

[0053] Furthermore, according to some embodiments of the sensor element, the inner wall surfaces of the pores are hydrophilic, for example, coated with a hydrophilic coating, which allows for efficient capillary-driven filling of the dry pores with liquid. Furthermore, the hydrophilic coating prevents certain hydrophobic substances, such as hydrophobic dyes, hemoglobin, and other proteins, from accumulating inside the pores, which would otherwise gradually cause fouling on the sensor and make it difficult to wash them off with aqueous solutions.

[0054] The porous membrane sensor further comprises a reflective layer disposed on the front surface of the semitransparent membrane. The contents of the pores can be optically probed conveniently from the rear surface of the semitransparent membrane, or more commonly from the side of the reflective layer facing the semitransparent membrane, with the reflective layer on the front surface optically isolating the optical probe region comprising the pores from the fluid in contact with the front surface of the semitransparent membrane. The reflective layer is adapted to reflect light reaching the reflective layer from a direction from the rear surface of the semitransparent membrane, thereby preventing the probe light from reaching and interacting with the fluid at the front surface of the semitransparent membrane. Thus, optical probing is selectively performed only on the subsample inside the pores.

[0055] Advantageously, according to some embodiments, the reflective layer is made of metal, as such metal coatings can be applied in a well-controlled manner that is relatively economical yet has sufficient reflectivity.

[0056] Advantageously, according to some embodiments, the reflective layer is made of platinum, palladium, or an alloy containing platinum or palladium as the main component. These materials exhibit good reflectivity in the spectral range of the electromagnetic spectrum (deep violet to blue) relevant to the detection of certain substances, such as free hemoglobin, for example, by absorbance probes. Furthermore, these materials are biocompatible, for example, do not cause artificial hemolysis. Furthermore, these materials are generally chemically stable, especially in the chemical environment of biological fluids such as whole blood samples or any of the aforementioned bodily fluids.

[0057] Alternatively, according to some embodiments, the reflective layer can be made of silver or aluminum. Even more advantageously, according to some embodiments, the surface of the reflective layer facing the sample volume is covered by a further passivation layer, thereby enhancing the lifetime of the device, especially when silver or aluminum is used as the reflective layer material. Suitable passivation can be made, for example, of a thin layer of SiO , which preferably must be transparent and thin enough not to obstruct the opening of the pores. These materials can also provide good reflectivity in the relevant spectral range (red) and are biocompatible and chemically stable in the environment.

[0058] Advantageously, in some embodiments, the thickness of the reflective layer is between 10 nm and 100 nm, depending on the metal used. Such a layer thickness allows the reflective layer to be applied by vapor deposition techniques without clogging the pore openings in the sensor surface. At the same time, the layer thickness must be sufficient to provide sufficient attenuation of light propagating into the sample volume to ensure enhanced optical isolation between the probe region and the sample volume containing the fluid being analyzed, e.g., a whole blood sample. Preferably, the transmitted light is less than 5%, less than 1%, or even less than 0.1% of the spectral detection range, i.e., the spectral range in which the signal representing the relevant component appears. For example, to measure hemoglobin in the plasma portion of a whole blood sample, suitable spectral ranges are 380 nm to 700 nm, 380 nm to 450 nm, 400 nm to 430 nm, or approximately 416 nm.

[0059] Advantageously, the sensor surface is planar, thereby facilitating or at least improving the conditions for a reliable optical probe. Advantageously, according to some embodiments, the sample space of the porous membrane sensor element has a cylindrical shape defined by a top wall, a bottom wall opposite the top wall, and a peripheral wall connecting the top and bottom walls, with the feed holes being located at the upstream end of the sample space, i.e., as seen in the direction towards the inlet, and the discharge holes being located at the downstream end of the sample space, i.e., as seen in the direction towards the outlet. Preferably, the porous membrane sensor element is located in the top wall. According to some embodiments, the cylindrical shape can have a circular or elliptical cross section as seen in a cut plane parallel to the sensor surface. Furthermore, according to some embodiments, the cylindrical shape can have a polygonal cross section as seen in a cut plane parallel to the sensor surface.

[0060] Advantageously, the feed holes and the discharge holes are arranged on the peripheral wall. Preferably, the feed holes and the discharge holes are arranged opposite each other. This allows a simple flow pattern for the flow through the sample space of the porous membrane sensor element when performing a fluid processing operation. Therefore, a smoother and more efficient exchange of fluids contacting the sensor surface during the fluid processing operation is realized. Furthermore, this can reduce cross-contamination.

[0061] Advantageously, the height of the sample space of the porous membrane sensor element, as viewed in the direction from the top wall to the bottom wall, is less than half, or less than one-third, or less than one-fifth, or even less than one-tenth of the cross-sectional dimension of the sample space of the porous membrane sensor element. This allows smaller volumes of fluid sample to be required without compromising the quality of the measurements made in the porous membrane sensor element. This feature further benefits from the inventive finding that measurements of porous membrane sensor elements, especially for high molecular weight analytes, rely on diffusion exchange of analytes with a relatively thin border layer of a complex fluid sample that contacts the sensor surface.

[0062] Advantageously, the bottom wall is curved to reduce the distance of the bottom wall from the top wall in the center of the sample space of the porous membrane sensor element compared to its peripheral portion. Preferably, the porous membrane is arranged on the top wall. Preferably, in this embodiment, the porous membrane is planar. The bottom wall may be curved to bulge along the direction from the feed / discharge holes to the top wall, at least so that the bottom wall is closer to the top wall in the center than at the feed / discharge holes.

[0063] Further advantageous embodiments are set forth below, whereby similar and further advantages are realized as disclosed in the present application. Furthermore, according to some embodiments of the porous membrane sensor element, the input branch and the output branch enclose an acute angle at least at the coupling interface.

[0064] Furthermore, according to some embodiments of the porous membrane sensor element, the input branch and the output branch are straight. Furthermore, according to some embodiments of the porous membrane sensor element, the input branch and the output branch are arranged in a backscattering configuration.

[0065] Furthermore, according to some embodiments of the porous membrane sensor element, the sensor surfaces are arranged axially parallel. Furthermore, according to some embodiments of the sensor assembly, the sensor surface is arranged parallel to the flow direction from the inlet to the outlet for fluid processing in the sample space of the porous membrane sensor element, thereby realizing efficient contact of the sensor surface with the fluid sample. Furthermore, smooth and efficient exchange of fluids contacting the sensor surface during fluid processing operations is realized, thereby reducing cross-contamination.

[0066] Furthermore, according to some embodiments of the porous membrane sensor element, the common light guide planes are arranged orthogonally in the axial direction. Furthermore, according to some embodiments of the porous membrane sensor element, the input branch, the output branch, and the coupling interface are integrally formed in a single piece.

[0067] Furthermore, according to some embodiments of the porous membrane sensor element, the light guide core further comprises an inspection port directed toward the bonding interface. As described in more detail below, the inspection port is particularly useful, for example, during fabrication of the porous membrane sensor element for proper alignment of the bonding interface of the light guide core with the porous membrane, and / or for inspecting for bubble formation in a pad composition applied between the bonding interface and the porous membrane. The inspection port may further be configured as an optical dump to collect and extract excess input light that would otherwise reach the output branch and cause undesirable background noise. The signal-to-noise ratio for detecting signals from optical interactions with the subsample in the pore can be enhanced in this way.

[0068] Furthermore, according to some embodiments of the porous membrane sensor element, the test port is coplanar with the input and output branches. This allows the test port to be configured as a particularly efficient optical dump, collecting and extracting excess input light that would otherwise reach the output branch and cause undesirable background noise. The signal-to-noise ratio for detecting signals from optical interactions with the subsample in the pore can be enhanced in this way.

[0069] Furthermore, according to some embodiments of the porous membrane sensor element, the test port is arranged in a forward scattering configuration with respect to the input branch. In this embodiment, the test port is configured as a much more efficient optical dump that collects and extracts excess input light that would otherwise reach the output branch and cause undesirable background noise. In particular, specular reflection of the input light can be extracted thereby. Therefore, the signal-to-noise ratio for detecting signals from optical interactions with the subsample in the pore can be enhanced in this way.

[0070] Advantageously, according to some embodiments, the test port can be terminated with an absorbing element, such as a blackened end face, an absorbing surface treatment, or any equivalent optical termination, especially after assembly of the porous membrane sensor element. Excess input light can thereby be efficiently removed from the light guide core. Therefore, the signal-to-noise ratio for detection of the signal from the optical interaction with the sub-sample in the pore can be further enhanced in this way.

[0071] Furthermore, according to some embodiments of the porous membrane sensor element, the test port is integrally formed with the input branch, the output branch, and the coupling interface in a single piece. This embodiment allows for suppression of troublesome optical interference in the light guide core. The signal-to-noise ratio for the detection of signals from optical interactions with the sub-sample in the pore can thus be further enhanced.

[0072] Furthermore, according to some embodiments of the porous membrane sensor element, the single part further comprises a mechanical bridge, the mechanical bridge mechanically connecting the input branch and the output branch at a distal portion thereof, with proximal portions of the input branch and the output branch facing towards the coupling interface.

[0073] Furthermore, according to some embodiments of the porous film sensor element, the optical subassembly further comprises a light guide shell surrounding the light guide core. The light guide shell is adapted to provide mechanical support to the light guide, allowing for easy handling, alignment, and / or inspection of the light guide portion during production of the sensor element. This enhances the quality of the sensor element product. Preferably, the light guide shell is configured to optically sheathe the light guide core. This avoids crosstalk from the input branch being directly shunted to the output branch. Preferably, the guide shell is made of an opaque material to block any stray light that may emanate from the light guide. Thus, the light guide shell effectively suppresses crosstalk between the input and output branches that would otherwise shunt the desired signal resulting from the probe interaction in the porous film sensor. This can significantly enhance the signal-to-noise ratio.

[0074] Advantageously, according to some embodiments, the light guide shell is formed as two half shells with respective cavities for receiving the light guide core therein. Advantageously, the two half shells are shaped to completely enclose the light guide in a direction transverse to the direction of propagation of the guided light. Thus, providing the light guide shell with two half shells allows for protection of the light guide for easy handling, alignment, and / or inspection of the light guide portions during production of the sensor element. Furthermore, the complete encapsulation also provides protection against stray light, thereby improving the signal-to-noise ratio of the signal probing the porous membrane.

[0075] Advantageously, according to some embodiments, the light guide shell is formed as a single-piece shell open at the top, with the depth of the cavity dimensioned to completely accommodate the light guide therein. Stray or shunt light can thereby be blocked and / or trapped. Crosstalk from the input branch to the output branch is therefore suppressed. Advantageously, the light guide is embedded in the cavity in a pad material having an optical refractive index within the relevant wavelength range, thereby ensuring light guidance for the light traveling along the input and output branches. The pad material can be of any suitable composition, such as a transparent UV-curable composition. The relevant wavelength range is determined by the wavelength ranges for the input and output light, for which the sensor element is designed. Providing a single-piece shell as the light guide shell has the unexpected advantage that it allows for easy inspection of the quality of filling the void between the light guide and the light guide shell with pad material during and / or after the embedding step, making the production of sensor elements more precise and reliable. Surprisingly, good shunt light suppression is nevertheless achieved, particularly when the sensor element is integrated into a sensor assembly having an "open" top of the light guide shell of the sensor element abutting a cooperating wall of the sensor port and / or frame structure to which the porous membrane sensor element is mounted.

[0076] Furthermore, according to some embodiments of the porous membrane sensor element, the light-guide shell further comprises engagement means configured to engage with corresponding guiding means on the porous membrane sensor housing, the engagement means and cooperating guiding means being adapted to secure the light-guide core relative to the porous membrane sensor housing, thereby facilitating easy assembly of the sensor element and at the same time providing enhanced precision for alignment of the optical subassembly relative to the porous membrane and sample chamber in the porous membrane sensor housing.

[0077] Advantageously, according to some embodiments of the porous membrane sensor element, the light guide core has vertically protruding distance elements, such as one or more vertically protruding noses, thereby facilitating easy vertical alignment of the light guide core relative to the porous membrane, for example when mounted in abutment with cooperating surfaces of the sensor port and / or frame structure of the sensor assembly.

[0078] According to a further aspect, a sensor assembly for analyzing a complex fluid sample comprises a sample chamber extending from an inlet to an outlet, the inlet-to-outlet direction defining a flow direction for fluid processing in the sample chamber, the sensor assembly further comprising a porous membrane sensor element according to any of the embodiments disclosed herein, wherein the flow channel of the porous membrane sensor element is integrated into the sample chamber.

[0079] Operation of a sensor assembly typically involves filling the sample chamber with fluid by flowing a volume of fluid from an inlet through the sample chamber to an outlet, stopping the flow when filling is complete, and performing measurements on the fluid sample thus presented in the sample chamber. For example, the fluid processing step may include flushing, i.e., flowing a flushing fluid through the sample chamber in the direction of flow from the inlet to the outlet, to remove any previously presented fluid sample and any contaminants, e.g., resulting from the previously presented fluid sample, from the sample chamber. Furthermore, operation of a measurement device using a sensor assembly typically includes calibrating the device by measurements made on a calibration fluid present in the sample chamber. Thus, operation of a sample assembly involves frequent fluid processing operations, such as filling, draining, and refilling the sample chamber by flowing different fluids through the sample chamber in the direction of flow from the inlet to the outlet.

[0080] Advantageously, according to some embodiments, the first sample space is formed as a channel having a top wall, a bottom wall, and side walls connecting the top and bottom walls, thereby defining a substantially rectangular cross section as seen in a cut plane perpendicular to the main direction of the first sample space from inlet to outlet. Advantageously, the rectangular cross section of the first sample space has a width as seen in a transverse direction parallel to the top and bottom walls of a few millimeters, for example up to 10 mm, up to 5 mm, or up to 3 mm, and at least 1 mm, or at least 2 mm, for example, in the range of about 2.4 mm, and a height as seen in a direction perpendicular to the top and bottom walls of sub-millimeters, for example, less than 1 mm, less than 0.8 mm, less than 0.5 mm, and at least 0.1 mm, or at least 0.2 mm, or at least 0.3 mm, for example, in the range of about 0.4 mm.

[0081] Furthermore, according to some embodiments of the sensor assembly, the flow channel of the porous membrane sensor element is integrated into the sample chamber in a downstream portion of the sample chamber, between the first sample space and the outlet.

[0082] Furthermore, according to some embodiments of the sensor assembly, the first sample space comprises an additional sensor for detecting an additional analyte in the fluid sample. Furthermore, according to some embodiments of the sensor assembly, the first sample space comprises one or more additional sensor elements for detecting respective additional analytes, whereby the sensor assembly is adapted for simultaneous analysis of multiple analytes, including both analytes detectable by the porous membrane sensor element and additional analytes detectable by one or more additional sensor elements disposed in the first sample space.

[0083] Furthermore, according to some embodiments, the sensor assembly, or a measurement arrangement configured to receive the sensor assembly, further comprises a light source connected to the optical input port, the light source configured to emit probe radiation. Furthermore, according to some embodiments, the sensor assembly further comprises a detector connected to the optical output port, the detector configured to detect light emerging from the probe region in response to illumination of the probe region through the input port by the light source, the detector adapted to generate a signal representative of the detected light. For the system to function, the light source may be any light source that transmits light within the region where the analyte within the pore absorbs light or otherwise provides an optically stimulated response. Due to their characteristics with respect to size, weight, efficiency, etc., light-emitting diodes are preferred for embodiments intended for miniaturization and / or integration within the assembly. The detector may be any optical detection arrangement suitable for detecting an optical response received from the optical output port and analyzing the optical response to generate an output signal indicative of the analyte being detected. Advantageously, according to one embodiment, the detector may include a spectrophotometer, and the optical probe device is configured to spectrophotometrically analyze the light emerging from the probe region. This allows for the resolution of the spectroscopic signature of one or more relevant components of the light emerging from the sub-sample within the probe region. For purposes of miniaturization and compactness, for example in the context of a point-of-care configuration, the detector can comprise a photodiode or spectrometer capable of detecting absorption across the entire spectrum. Alternatively, an array or diodes can be used, with each diode emitting light at a different wavelength and the photodiode being used as the detector. The diodes can be multiplexed to emit light at different intervals. Absorption is then found by comparing the light emitted from the diode at a particular interval compared to the light detected by the photodiode.

[0084] According to yet a further aspect of the present invention, there is provided a method for optically detecting an analyte, such as hemoglobin, in a fluid, the method comprising the steps of providing a fluid sample in a sample chamber and optically probing said fluid sample for an analyte and optionally further analytes as discussed herein in this disclosure of porous membrane sensor elements and sensor assemblies, achieving at least the same advantages as discussed with respect to the respective embodiments.

[0085] According to some embodiments, a method for detecting an analyte sample in a complex fluid includes the steps of providing a sensor assembly as disclosed above, contacting the sensor surface of a porous membrane sensor element with a reference liquid so as to fill the pores with the reference liquid, contacting the sensor surface with a sample of the complex fluid to be analyzed, waiting a diffusion time to allow analytes in the complex fluid to diffuse into the pores for stabilization, injecting input light from the rear surface of the porous membrane into a probe region, collecting light emitted from the pores toward the rear surface of the porous membrane in response to the input light, thereby optically probing the fluid inside the pores, and establishing the analyte level of the complex fluid based on the results of the optical probe. Preferably, the reference liquid is an aqueous solution compatible with the fluid, and in particular with portions thereof that may enter the pores, such as liquids for rinsing, calibration, and / or quality control. Advantageously, the analyte is optically detected in the pore by a color change due to the presence of the analyte in an amount representative of that in the extracted subsample. Advantageously, according to some embodiments, the optical probe includes a step of performing a spectrophotometric analysis of the light emerging from the pore as an optical response to the probe input light. Advantageously, according to some embodiments, the optical probe measures absorbance, which has the advantage of a relatively simple yet effective configuration. In particular, the method includes a fluid treatment step for contacting the sensor surface of the porous membrane sensor element with the complex fluid sample to be analyzed. When performed using a sensor assembly including a porous membrane sensor element integrated into its downstream portion, these fluid treatment steps include flowing the complex fluid to be analyzed through the inlet of the sample chamber, through the first sample space, through a connecting feed channel connecting the first and second sample spaces, through the flow channel comprising the sample space of the porous membrane sensor element, and through the outlet until a predetermined criterion for determining that the sample chamber is full is met. The criterion can be determined, for example, by suitable fluid interface detectors located at the inlet and outlet of the sample chamber.

[0086] Although the present invention has been described herein primarily with reference to its use in the context of analyzing blood analyses, those skilled in the art will appreciate that the present invention may be used in an equivalent manner in other contexts without departing from the scope of the present invention.

[0087] For example, the sensor element may be used in a reader for a chromogenic / consumption assay. Such a device has the advantage that a separation step is not required to prepare plasma prior to the assay. For example, the following types of assays can be performed using a device including a sensor element according to embodiments of the present invention: A sandwich assay, in which a receptor ligand can bind to the inside of a membrane channel. An assay in which a portion is bound within a pore, such as the bromocresol green-albumin assay, uses bromocresol green (BCG), which specifically forms a colored complex with albumin. The color intensity measured at 620 nm is directly proportional to the albumin concentration in the fluid, and an enzyme activity assay, such as an aspartate aminotransferase (AST) activity assay kit, involves the transfer of an amino group from aspartate to α-ketoglutarate to generate glutamate, resulting in a colorimetric (450 nm) product proportional to the presence of AST enzyme activity.

[0088] The sensor element can also be used in non-medical applications such as beer brewing, wastewater analysis, food testing, and dye production monitoring operations. In beer brewing, accurate color is required. The sensor element can be used to determine whether beer has a desired color by measuring the liquid and comparing the reading to a liquid of the correct color. Wastewater can be analyzed for the presence or absence of ingredients. In food testing of liquids such as milk, juice, and other slurries, the sensor element can be used to analyze for the presence or absence of ingredients or analytes. The sensor element can further be useful in the production of certain chemical products, for example, in the dye industry, to obtain metrics during the production of a desired color, desired content, or other chemical property of the product.

[0089] Advantageously, according to some embodiments, a sensor element or a blood analysis system comprising such a sensor element further comprises a processor configured to compare the signal generated by the detector with predefined calibration standards to produce a quantitative measure of the analyte level in the fluid. Furthermore, advantageously, according to some embodiments, the calibration standards are obtained based on a dye-based calibration solution, such as an aqueous solution containing tartrazine dye. Preferably, the dye-based aqueous solution is prepared from a typical water wash solution to which a calibration dye, such as tartrazine, has been added. The above embodiment includes the following aspects. (Form 1) 1. A porous membrane sensor element for detecting an analyte in a complex fluid sample, comprising: a porous membrane sensor housing penetrated by a flow channel defining an axial direction, the flow channel comprising a sample space; a porous membrane having a front surface defining a sensor surface in contact with the fluid sample, the sensor surface facing the sample space, the porous membrane comprising pores extending into the porous membrane from respective openings in the sensor surface, the pores being configured for diffusive fluid communication with the sample space for the analyte; an optical subassembly comprising a light guide core, the light guide core comprising an input branch, an output branch, and a coupling interface arranged to contact a rear surface of the porous membrane opposite the front surface and facing away from the sample space, the input branch and the output branch being directed toward the coupling interface; Equipped with A porous membrane sensor element, wherein the input branch and the output branch are arranged in a common light guide plane that is orthogonal to the sensor surface. (Form 2) 2. The porous membrane sensor element of claim 1, wherein the input branch and the output branch enclose an acute angle at least at the coupling interface. (Form 3) 3. The porous membrane sensor element of aspect 1 or 2, wherein the input branch and the output branch are straight. (Form 4) 4. The porous membrane sensor element of any one of aspects 1 to 3, wherein the input branch and the output branch are arranged in a backscattering configuration. (Form 5) 5. The porous membrane sensor element according to any one of aspects 1 to 4, wherein the sensor surface is arranged parallel to the axial direction. (Form 6) 6. The porous membrane sensor element of any one of aspects 1 to 5, wherein the common light guide plane is arranged perpendicular to the axial direction. (Form 7) 7. The porous membrane sensor element of any one of aspects 1 to 6, wherein the input branch, the output branch, and the coupling interface are integrally formed in a single piece. (Form 8) 8. The porous membrane sensor element of any one of claims 1 to 7, wherein the light guide core further comprises an inspection port directed toward the coupling interface. (Form 9) 9. The porous membrane sensor element of claim 8, wherein the test port is coplanar with the input branch and the output branch. (Form 10) 10. The porous membrane sensor element of claim 8 or 9, wherein the test port is arranged in a forward scattering configuration relative to the input branch. (Form 11) 11. The porous membrane sensor element of any one of aspects 8 to 10, wherein the test port is integrally formed with the input branch, the output branch, and the coupling interface in a single piece. (Form 12) 12. The porous membrane sensor element of claim 7 or 11, wherein the single part further comprises a mechanical bridge. (Form 13) 13. The porous film sensor element of any one of claims 1 to 12, wherein the optical subassembly further comprises a light guide shell surrounding the light guide core. (Form 14) A porous membrane sensor element as described in claim 13, wherein the light guide shell further comprises an engagement means configured to engage with a corresponding guide means on the porous membrane sensor housing, and the engagement means and cooperating guide means are adapted to fix the light guide core relative to the porous membrane sensor housing. (Form 15) 1. A sensor assembly for analyzing a complex fluid sample, comprising: a sample chamber extending from an inlet to an outlet, the direction from the inlet to the outlet defining a flow direction for fluid processing in the sample chamber; 15. The sensor assembly further comprising a porous membrane sensor element according to any one of claims 1 to 14, wherein the flow channel of the porous membrane sensor element is integrated into the sample chamber. (Form 16) 16. The sensor assembly of claim 15, wherein the flow channel of the porous membrane sensor element is integrated into the sample chamber in a downstream portion of the sample chamber between the first sample space and the outlet. (Form 17) 17. The sensor assembly of claim 16, wherein the first sample space comprises a further sensor for detecting a further analyte in the fluid sample.

[0090] Preferred embodiments of the present invention will now be described in more detail with reference to the accompanying drawings. [Brief explanation of the drawings]

[0091] [Figure 1] FIG. 1 is an exploded view of a porous membrane sensor element for detecting an analyte in a fluid with an optical probe, according to one embodiment. [Figure 2] 2 is a cross-sectional view of the porous membrane sensor of FIG. 1 in an assembled state, as seen in a cut plane perpendicular to the axial direction S. FIG. [Figure 3] FIG. 2 is a diagram of the individual components of the porous membrane sensor element of FIG. 1. [Figure 4] FIG. 2 is a diagram of the individual components of the porous membrane sensor element of FIG. 1. [Figure 5] FIG. 2 is a diagram of the individual components of the porous membrane sensor element of FIG. 1. [Figure 6] FIG. 1 is a cross-sectional detail view of an inlet portion of a sensor assembly for detecting multiple analytes in a fluid sample, according to one embodiment. [Figure 7] FIG. 7 is a cross-sectional detail view of the outlet portion of the sensor assembly of FIG. 6, including the porous membrane sensor element. [Figure 8]FIG. 8 is a perspective view of the sensor assembly of FIGS. 6 and 7 showing the inlet and outlet portions of the sensor assembly of FIGS. 6 and 7, including the porous membrane sensor element. [Figure 9] 9 is a cross-sectional detailed view of a liquid sample analyzer having a sensor assembly as shown in FIG. 8, as seen in a cross section perpendicular to the axial direction S of the porous membrane sensor element. [Figure 10] 1 is a diagram of a liquid sample analyzer according to one embodiment. [Figure 11] FIG. 10 is an exploded view of a porous membrane sensor element for detecting an analyte in a fluid with an optical probe according to a further embodiment. [Figure 12] 12 is an exploded view of the porous membrane sensor element of FIG. 11 together with the cooperating frame structure of the sensor assembly showing its inlet and outlet portions. DETAILED DESCRIPTION OF THE INVENTION

[0092] 1-5, a porous membrane sensor element 100 according to one embodiment will be described. FIG. 1 shows an exploded view of the components of the porous membrane sensor element 100. The porous membrane sensor element 100 comprises a porous membrane sensor housing 101 penetrated by a flow channel 102 defining an axial direction S as indicated by the dashed line in FIG. 1. The flow channel 102 defines a sample space 103 having an opening adapted to receive a planar porous membrane 110 that seals the sample space 103. The porous membrane 110 is made of a translucent material and has a front surface defining a sensor surface facing into the sample space 103 that contacts the fluid sample to be analyzed. Pores are provided extending from the sensor surface into the translucent material as discussed elsewhere herein. Suitable porous membranes are described, for example, in applicant's international patent applications WO2017 / 085162A1, WO2017 / 085180A1, and WO2019 / 197308A1, which are incorporated herein by reference. The sensor surface further comprises a reflective layer, typically made of a metallic material, as also described in these references.

[0093] The porous film sensor element 100 further comprises an optical probe subassembly having a light guide core component 120. The light guide core component 120 has an input branch 121 and an output branch 122 arranged at an acute angle to each other in a common light guide plane, with both the input and output branches 121, 122 directed toward an optical coupling interface 123. The coupling interface portion 123 is for optically coupling the optical probe subassembly to the rear surface of the porous film. The light guide core 120 is held in a corresponding cavity within the light guide shells of the optical probe subassembly, seen herein as two cooperating half shells 130A, 130B. The light guide shells 130A / B are shaped and dimensioned to engage cooperating guide means on the porous film sensor housing 101, thereby facilitating easy assembly and subsequently mechanically supporting and securely fixing the light guide core 120 to the porous film sensor housing 101. In order to improve the accuracy of the alignment between the coupling interface 123 and the probe region of the porous membrane 110 during assembly of the porous membrane sensor element, and in particular with respect to the sample space 103, a test port 124 is provided that provides direct optical access for testing said alignment of the coupling interface 123. In a particularly advantageous embodiment, as shown herein, the test port 124 is arranged flush with the input and output branches and tilted forward. Thereby, the test port also accepts and extracts so-called shunt light, i.e., light that would otherwise reach the output branch 122. The test port 124 therefore also contributes to improving the optical signal-to-noise ratio, for example when configured as shown herein.

[0094] The light guide core component 120 may further comprise a bridge 125 that mechanically connects the distal ends of the input and output branches 121 and 122 to one another. This reduces the risk of damaging the fragile branches of the light core component, for example, when handling the components during assembly. More importantly, the mechanical bridge 125 also acts as a stiffening element, thereby reducing the sensitivity of the porous membrane sensor element to, for example, vibrations and / or other mechanical interferences under operation.

[0095] 2 shows a cross-sectional view of the assembled porous sensor element 100 as seen in a cut plane substantially perpendicular to the aforementioned axial direction S as defined by the flow channel 102 passing therethrough. In particular, FIG. 2 shows the placement of the coupling interface 123 relative to the porous membrane 110 and the sample space 103. The coupling interface 123 contacts the rear surface of the semitransparent porous membrane 110, allowing probe light injected from the input branch 121 to couple into the semitransparent porous membrane 110, where it can interact with analytes present in the pores. The coupling interface is further positioned to allow light emanating from the rear surface of the semitransparent porous membrane 110, in particular light scattered by the pores, to be collected by the output branch 122, thus conveying information about the fluid inside the optically probed pores as a signal. The optical subassembly formed by the light guide core 120 and the light guide shell 130 is mounted to the porous membrane sensor housing 101, with the sides and recesses 139 of the light guide shells 130A / B engaging cooperating guide means 106, 107, 109 on the porous membrane sensor housing 101. Such further details of the components of the porous membrane sensor element 100 are best seen in Figures 3-5, which show the light guide shell 130B, the light guide core 120, and the porous membrane sensor housing 101 (without the porous membrane 110), respectively. The light guide shell 130B has cavities 131, 132, 134, 135 that receive the input branch 121, output branch 122, test port 124, and mechanical bridge 125 of the light guide core 120, respectively, and are shaped to correspond to the input branch 121, output branch 122, test port 124, and mechanical bridge 125 of the light guide core 120. An opening 133 disposed within the recess 139 is for receiving the optical coupling interface 123 of the light guide core 120. Alignment features, such as teeth 136 protruding into the cavity, allow for maintaining a desired gap between the light guide core and the cavity wall. The gap can be maintained as an air gap. However, it is preferred that the gap be filled with a transparent padding material, which can act as a covering for the light guide core.Preferably, the light guide shell is made of an absorbing material to suppress optical crosstalk, shunting light from the input branch 121 to the output branch 122 without interacting with the pores of the porous membrane 110. The optical coupling interface may further comprise one or more steps 126, also referred to herein as a "grating." The one or more steps 126 provide an end face oriented substantially perpendicular to the direction of the input branch, thus leaving a wedge-shaped gap between the coupling interface 123 and the rear surface of the porous membrane 110, which is preferably filled with a transparent pad material. The stepped interfaces 123, 126 facilitate improved coupling of the input light into the porous membrane 110. As best seen in FIGS. 2 and 4, the particular embodiment shown herein has two steps 126 in the optical coupling interface 123.

[0096] When configured as a shunt light chimney, the input and output branches 121, 122, and, where applicable, the test port 124, are arranged in a common plane of the light guide core 120, which is disposed orthogonal to the sensor surface of the planar porous membrane 110. Thus, the plane of the light guide core includes a plane perpendicular to the sensor surface, as shown in FIG. 5 by the dashed line labeled "O." The input and output branches 121, 122 of the light guide core 120 are arranged in a backscattering configuration, i.e., they are provided in the same quadrant of the common plane of the light guide core on the same side of the perpendicular plane O of the porous membrane sensor surface. This effectively suppresses specular reflection artifacts of light originating from the input and reaching the output without interacting with the pores in the membrane.

[0097] 6-9, a sensor assembly 200 having a porous membrane sensor element 100 integrated into its outlet portion will now be described. Sensor assembly 200 is for use in a fluid sample analyzer device, such as liquid sample analyzer 1, which is further described below with reference to FIG. 10 . The sensor assembly has a body 201 and a sample chamber extending inside body 201 from an inlet 210 to an outlet 220. The sample chamber has a first sample space 202 extending from an upstream end in fluid communication with inlet 210 to a downstream end in fluid communication with outlet 220. The first sample space comprises at least one, and typically multiple, additional sensors adapted to detect respective analytes. Thus, sensor assembly 200 is adapted to analyze complex fluid samples for multiple analytes and is similar to or adapted to known sensor assemblies that detect multiple analytes in complex fluid samples, such as whole blood samples or other bodily fluids.

[0098] However, the sensor assembly 200 differs from known sensor assemblies of this type in that the sensor assembly 200 comprises a porous membrane sensor element 100 as disclosed herein. Preferably, as shown in Figures 6-8, the porous membrane sensor element 100 is integrated into the outlet portion of the sample chamber downstream of the first sample space 202, between the first sample chamber 202 and the outlet 220. Nevertheless, it is also conceivable to integrate a porous membrane sensor element 100 as disclosed herein in a similar manner into the inlet portion of the sample chamber upstream of the first sample space 202, between the inlet 210 and the first sample space 202.

[0099] The coplanar arrangement of the input and output branches 121, 122 in the backscattering configuration allows for a challenging low-profile integration for the porous sensor element 100, which can further work for optical probes with the input and output located on the same side. The flat profile, as best seen in FIG. 8 , also allows the porous membrane sensor element 100 to be integrated such that the sensor assembly 200 is molded in a manner compatible with existing sensor assemblies not equipped with a porous membrane sensor element. That is, for example, this lends to backward compatibility of the sensor assembly 200 with fluid analyzer devices that do not have the option of optically probing the porous membrane sensor.

[0100] FIG. 9 shows a cross-sectional detailed view of a liquid sample analyzer port 300 having a sensor assembly 200 as described above, as seen in a cut plane perpendicular to the axial direction S of the porous membrane sensor element 100. The liquid analyzer port 300 is configured to receive the sensor assembly 200 for performing fluid processing operations and optical probe measurements. The analyzer port 300 includes a light source 301 adapted to inject probe light into the input branch 121. The probe light reaches the coupling interface 123 and can interact with analytes in the pores of the porous membrane 110. Scattered light can be collected through the interface 123 by the output branch 122 and transmitted to the photodetector 302. The photodetector 302 can then generate a detector signal indicative of the analytes in the pores of the porous membrane 110 and, therefore, in the complex fluid sample in the sample space 103.

[0101] FIG. 10 schematically illustrates a liquid sample analyzer 1 having an analytical section with a signal processor 8, one or more analyte sensors 3(a-i), 4, a measurement chamber 2, and a fluid processing infrastructure 20. To perform a measurement, a user can provide a liquid sample to the input port 12a / b of the analyzer 1. The liquid sample is transferred through the inlet port 6 to a first sample space 2 of the sample chamber, which includes multiple analyte sensors 3, 4. The analyte sensors 3, 4 are arranged to perform substantially simultaneous measurements of analyte parameters in a complex liquid sample, such as a whole blood sample. Preferably, the sample volume required to obtain accurate and reliable data is as small as possible. Detailed examples of sensor assembly designs particularly suited for simultaneously measuring multiple different parameters in body fluids, particularly whole blood, and their use in hematology analyzers can be found, for example, in EP 2 147 307 B1. After preprogrammed instructions are loaded into the signal processor 8 and / or after user input, measurements are performed using the analyte sensors 3, 4. The analyte sensors 3, 4 generate signals representative of physical parameters for the respective analytes and provide these signals to an analytical signal processor 8. The signal processor 8 is adapted to receive and process the signals from the analyte sensors 3, 4 and present the processed signals as output to a user or for subsequent / further data analysis. After measurement, the liquid sample is drained and the sample chamber is ready for the next measurement.

[0102] The embodiment of the analyzer shown in FIG. 10 is particularly adapted for measuring blood parameters and further comprises an optional oxygenation measurement device 9 downstream of the sample assembly. Thus, typically, performing measurement, calibration, and quality control procedures involves loading, unloading, rinsing, cleaning, and reloading different liquids, which can be accomplished by a fluid processing infrastructure 20. Fluid processing can be controlled in an automated manner by the signal processor 8 according to preprogrammed instructions and / or user input. The fluid processing infrastructure 20 includes several reservoirs 21 pre-filled with processing liquids (RINSE / CAL1, CAL2, QC1, QC2, QC3) for rinsing / washing, calibration, and quality control operations. The processing liquids (RINSE / CAL1, CAL2, QC1, QC2, QC3) have known compositions. The exact composition of a given batch can be stored on a chip 25 that can be attached to a cassette containing the reservoirs 21 and can be read by the signal processor 8. The processing fluid (RINSE / CAL1, CAL2, QC1, QC2, QC3) for a given processing step can be selected by fluid selector valve 22 and delivered to the sample chamber through inlet port 6 via supply line 12c. Proper filling of the sample chamber can be monitored and verified by visual inspection or according to known procedures by observing the propagation of the liquid interface through the system, for example, by liquid sensors 10a, 10b, 10c located upstream and downstream of the sample chamber, at inlet 6 ("LS Int" 10a), outlet 7 ("LS BG" 10b), and immediately after the oxygenation measurement device 9 ("LS OXI" 10c), respectively. Fluid flow through the analyzer is driven by pump 23, here a peristaltic hose pump, located downstream of the sample chamber and oxygenation measurement device 9 and connected thereto via fluid line 13. Discharged fluid is ultimately transported to waste reservoir 24 via fluid line 14.

[0103] Upon startup, the analytical device 1 executes a self-control routine during run-time in an ongoing manner. If any abnormalities are detected, the analytical device 1 may indicate the deviation to the user and further indicate methods for overcoming the error condition. On the other hand, if the analytical device indicates normal operation, measurements may be performed immediately. Advantageously, according to some embodiments, the self-control routine may be performed during idle time, i.e., when the analytical device is idle and not being used to perform actual measurements on user samples. The self-control routine may include, for example, successive repeat measurements performed on a calibration-grade processing solution with a precisely known composition, such as stored on the chip 25. The signals obtained for each of the different analyte sensors 3, 4 relative to the well-known composition may then be used to continuously update the baseline for each analyte measurement.

[0104] A porous membrane sensor element 100 having a second sample space 102 is integrated into the downstream part of the sample chamber between the first sample space 2 and the outlet 7. The second sample space is connected to the first sample space through a short feed channel as described above with reference to Figure 7.

[0105] A porous membrane sensor element 100 according to a further embodiment will now be described with reference to Figures 11 and 12. Figure 11 shows an exploded view of the components of the porous membrane sensor element 100. Figure 12 shows an exploded view of the porous membrane sensor element of Figure 11 upside down, together with the cooperating frame structure of the sensor assembly 200 having inlet and outlet portions 210, 220. The porous membrane sensor element 100 comprises a porous membrane sensor housing 101 and a planar porous membrane 110, as already described above with reference to Figures 1 to 5.

[0106] The porous film sensor element 100 further comprises an optical probe subassembly having a light guide core component 120, also as described above with reference to FIGS. 1-5. The light guide core 120 is held within a corresponding cavity in a light guide shell 130 of the optical probe subassembly. However, instead of the two cooperating half shells 130A, 130B shown in the embodiment of FIGS. 1-5, the light guide shell 130 of the embodiment shown in FIGS. 11 and 12 is formed as a single-piece shell that is open at its upper side. The depth of the cavity in the light guide shell 130 of FIGS. 11-12 is dimensioned to fully receive the light guide core therein. Stray or shunt light can thereby be blocked and / or trapped. Crosstalk from the input branch to the output branch is therefore suppressed. The light guide shell 130 is again shaped and dimensioned to engage cooperating guide means on the porous membrane sensor housing 101, as described above with reference to Figures 1 to 5, thereby facilitating easy assembly and subsequently mechanically supporting and securely fixing the light guide core 120 to the porous membrane sensor housing 101.

[0107] Alignment features, such as teeth protruding into the cavity, allow a desired gap to be maintained between the light guide core and the cavity wall. The gap can be maintained as an air gap. However, the gap is preferably filled with a transparent pad material, which can act as a coating for the light guide core. Advantageously, the light guide core is completely embedded in the pad material. By way of example, the pad can be a UV-curable composition. Furthermore, advantageously, the light guide core 120 has a vertically protruding distance element, such as a vertically protruding nose 129, which facilitates easy vertical alignment of the light guide core relative to the porous membrane when mounted in abutment with a cooperating surface of the sensor port and / or frame structure of the sensor assembly 200, as shown in FIG. 12 . The light guide shell is preferably made of an absorbent material to suppress optical crosstalk, which shunts light from the input branch 121 to the output branch 122 without interacting with the pores of the porous membrane 110. Additionally, the light guide shell 130 may advantageously be provided with snap-fit ​​engagement means, such as snap-fit ​​fasteners 138, to facilitate precise, reliable, and easy attachment to a cooperating flange 238 on the frame structure of the sensor assembly 200, as best seen in FIG. 12.

Claims

1. 1. A porous membrane sensor element for detecting an analyte in a complex fluid sample, comprising: a porous membrane sensor housing penetrated by a flow channel defining an axial direction, the flow channel comprising a sample space; a porous membrane having a front surface defining a sensor surface in contact with the fluid sample, the sensor surface facing the sample space, the porous membrane comprising pores extending into the porous membrane from respective openings in the sensor surface, the pores being configured for diffusive fluid communication with the sample space for the analyte; an optical subassembly comprising a light guide core, the light guide core comprising an input branch, an output branch, and a coupling interface arranged to contact a rear surface of the porous membrane opposite the front surface and facing away from the sample space, the input branch and the output branch being directed toward the coupling interface; Equipped with the input branch and the output branch are arranged in a common light guide plane that is orthogonal to the sensor plane; The porous film sensor element, wherein the optical subassembly further comprises a light guide shell surrounding the light guide core, the light guide shell comprising an opaque material.

2. The porous membrane sensor element of claim 1 , wherein the input branch and the output branch enclose an acute angle at least at the coupling interface.

3. 3. The porous membrane sensor element according to claim 1, wherein the input branch and the output branch are straight.

4. The porous membrane sensor element of claim 1 , wherein the input branch and the output branch are arranged in a backscattering configuration.

5. The porous membrane sensor element according to claim 1 , wherein the sensor surface is arranged parallel to the axial direction.

6. 6. The porous membrane sensor element according to claim 1, wherein the common light guide plane is arranged perpendicular to the axial direction.

7. The porous membrane sensor element of claim 1 , wherein the light guide core further comprises an inspection port directed towards the coupling interface.

8. 8. The porous membrane sensor element of claim 7, wherein the test port is coplanar with the input branch and the output branch.

9. 9. The porous membrane sensor element of claim 7 or 8, wherein the test port is arranged in a forward scattering configuration relative to the input branch.

10. 10. The porous membrane sensor element of claim 7, wherein the test port is integrally formed in a single piece with the input branch, the output branch, and the coupling interface.

11. The porous membrane sensor element of claim 10, wherein the single part further comprises a mechanical bridge.

12. 12. The porous membrane sensor element of claim 1, wherein the light guide shell further comprises an engagement means configured to engage with a corresponding guide means on the porous membrane sensor housing, the engagement means and cooperating guide means being adapted to fix the light guide core relative to the porous membrane sensor housing.

13. 13. A porous membrane sensor element according to any one of claims 1 to 12, wherein the light guide shell comprises a single-piece shell, the depth of the cavity being dimensioned to fully receive the light guide therein.

14. 1. A sensor assembly for analyzing a complex fluid sample, comprising: a sample chamber extending from an inlet to an outlet, the direction from the inlet to the outlet defining a flow direction for fluid processing in the sample chamber; 14. The sensor assembly further comprising a porous membrane sensor element according to any one of claims 1 to 13, wherein the flow channel of the porous membrane sensor element is integrated into the sample chamber.

15. 15. The sensor assembly of claim 14, wherein the flow channel of the porous membrane sensor element is integrated into the sample chamber in a downstream portion of the sample chamber between a first sample space and the outlet.

16. 16. The sensor assembly of claim 15, wherein the first sample space comprises an additional sensor for detecting an additional analyte in the fluid sample.

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