Modular diagnostic information acquiring device

Abstract

Disclosed is a modular diagnostic information acquiring device with a base device (1), a microfluidic chip (2), and an optical measurement device. The base device (1) includes a patient body attachment interface, a microfluidic chip receptacle for removably accommodating the microfluidic chip (2) and a pneumatic control device. The microfluidic chip includes a pneumatic microfluidic chip compartment (23), wherein the pneumatic microfluidic chip compartment (is pneumatically coupled with the pneumatic control device and an optical measurement compartment. The optical measurement compartment inlet is fluidically coupled with the pneumatic microfluidic chip compartment. The optical measurement compartment and the optical measurement device are optically coupled, thereby allowing optical measurements inside the optical measurement compartment. The modular diagnostic information acquiring device is configured to autonomously execute a measurement protocol. The measurement protocol including repeatedly executing a measurement cycle. Each measurement cycle includes a respective sampling phase and a subsequent respective measuring phase. In the sampling phase, a whole blood sample is aspirated into the pneumatic microfluidic chip compartment. In the measuring phase, the whole blood sample is forced out of the pneumatic microfluidic chip compartment and an assay, the assay including either the whole blood sample or a component of the whole blood sample, is forced through the optical measurement compartment. A series of optical measurement data is acquired from the assay while passing the optical measurement compartment.

Description

[0001] MODULAR DIAGNOSTIC INFORMATION ACQUIRING DEVICE

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to modular diagnostic information acquiring devices as well as components thereof, in particular microfluidic chips and base devices. The modular diagnostic information acquiring device is in particular useful for detecting and / or quantifying a variety of biomarkers in blood samples of a patient over an extended time period.

[0004] BACKGROUND OF THE INVENTION

[0005] The detection and in many cases quantification respectively concentration determination of biomarkers in blood samples (referred to as diagnostic information acquiring) is of great importance in a variety of medical and clinical as well as pharmaceutical and general research applications. In many cases, it is required or at least highly desirable to monitor the presence and / or concentration of one or more biomarkers over an extended time period in a repeated or quasi-continuous manner, such as, e.g., every 30 minutes. Further, it is often desirable or even crucial to do the diagnostic information acquiring as well as the evaluation of the acquired data and their presentation, e.g. in the form of graphs respectively diagrams and / or tables, in a point-of care context and substantially in real time. Further, it is often desirable to further evaluate such data and / or store them over an extended period of time, e.g., in the context of pharmaceutical or nutrition research.

[0006] No satisfying solution is available for this task according to the state of the art, since the required equipment is expensive, generally bulky and requires particularly trained personnel.

[0007] It is an overall objective of the present disclosure to provide devices that can be used for diagnostic information acquisition and favorably data evaluation as well as result presentation over an extended time period and favorably in real time. Favorably, the device is simple and substantially fail-safe and can accordingly be used and operated by persons with limited training. Favorably, problems of prior art devices are overcome fully or at least in part.

[0008] SUMMARY OF THE INVENTION

[0009] In an aspect, the overall objective is achieved by a modular diagnostic information acquiring device. The modular diagnostic information acquiring device generally includes a base device, a microfluidic chip, an optical measurement device, and a data processing device. The microfluidic chip is generally a disposable device and used for an application time in a range of, e.g. one day, while the other components are durable respectively reusable which may and typically are used repeatedly and may also be used for more than one patient.

[0010] The base device includes a patient body attachment interface that is configured for removably attaching the base device to a patient's body directly and / or via an attachment interface device for an application time. As discussed further below in more detail, attaching the base device may in particular be done via a harness device as attachment interface device.

[0011] Alternatively, however, the base device may be directly attached to a patient's body adhesively, e.g. via an adhesive layer at a surface of the base device facing the patient's body respectively skin. In a further design, the base device may be attached to the patient's body via a cradle device as attachment interface device. Such cradle device may be configured for adhesively attachment to the patient's skin and may be configured for releasably coupling, e.g. via a snap-fit connection or a base device receptacle, to the base device. Such cradle device is generally a single-use device and may be part of a modular diagnostic information acquiring device in accordance with the present disclosure.

[0012] The base device further includes a microfluidic chip receptacle for removably accommodating the microfluidic chip in an operational configuration. The microfluidic chip and the microfluidic chip receptacle may be configured for maintaining the microfluidic chip in a well-defined and fixed manner, for example by elastic or non-elastic clamping and / or interlocking. In an operational configuration, all fluidic connections of the microfluidic chip, including pneumatic connections, as discussed further below, are fluidically tight. In an embodiment, the microfluidic chip receptacle includes a slider into which the microfluidic chip can be inserted outside of a housing of the base device.

[0013] The base device further includes a pneumatic control device. The pneumatic control device is configured to provide alternatively a pneumatic pushing pressure and a pneumatic suction pressure at a pneumatic microfluidic chip interface.

[0014] The base device further includes an optical probe. The optical probe is configured for optically coupling to the optical measurement device.

[0015] Typically, the base device further includes a generally closed base device housing in which the other components of the base device are arranged.

[0016] The microfluidic chip includes a sample inlet, the sample inlet being configured for fluidically coupling to a sampling blood vessel of a patient as discussed further below in more detail.

[0017] The microfluidic chip further includes an assay disposal outlet.

[0018] The microfluidic chip further includes a pneumatic microfluidic chip compartment. The pneumatic microfluidic chip compartment is pneumatically coupled with the pneumatic control device via the pneumatic microfluidic chip interface. In typical designs, the volume of the pneumatic microfluidic chip compartment is in a arrange of 0.1ml to 0.5ml, for example 0.2 ml, in a range of 0.1ml to 0.2ml or a range of 0.2ml to 0.5ml. Generally, the volume of the pneumatic microfluidic chip compartment corresponds to or is somewhat larger than the volume of the whole blood sample that is aspired in each measurement cycle as discussed further below.

[0019] The pneumatic microfluidic chip compartment generally has further a pneumatic microfluidic chip compartment inlet and a pneumatic microfluidic chip compartment outlet. Via the pneumatic microfluidic chip compartment inlet, whole blood samples enter the pneumatic microfluidic chip compartment in a sampling phase and subsequently and subsequently exit the pneumatic microfluidic chip compartment via pneumatic microfluidic chip compartment outlet in a measuring phase as discussed further below in more detail.

[0020] Regarding the fluidic setup, the pneumatic microfluidic chip compartment provides the interface of a pneumatic system and a liquid-filled system of the modular diagnostic information acquiring device, wherein the liquid is in particular full blood respectively its components. At the pneumatic microfluidic chip compartment, gas, in particular air, comes into contact with blood.

[0021] For coupling the microfluidic chip, in particular the pneumatic microfluidic chip compartment, with the pneumatic control device, the microfluidic chip may comprise a pneumatic control device interface, e.g. in form of an orifice. The pneumatic control device may be coupled with the pneumatic microfluidic chip compartment via a pneumatic coupling channel of the microfluidic chip. In an operational configuration, a fluidic, in particular pneumatic, and gastight coupling is present between the pneumatic microfluidic chip interface of the pneumatic control device and the pneumatic control device interface of the microfluidic chip. In this way, gas, in particular air, can be withdrawn from the pneumatic microfluidic chip compartment or be forced into the pneumatic microfluidic chip compartment by the pneumatic control device as discussed further below in more detail. The microfluidic chip may include a liquid retaining device. Such liquid retaining device may be fluidically arranged between the pneumatic control device interface and the pneumatic microfluidic chip compartment. In particular, the liquid retaining device may be arranged at the opening of the pneumatic coupling channel into the pneumatic microfluidic chip compartment respectively in the pneumatic microfluidic chip compartment in vicinity to the pneumatic microfluidic chip compartment. The liquid retaining device is configured to allow the passage of gas in a bidirectional manner but to prevent or substantially prevent the passage of liquid, in particular blood, in particular in a direction out of the pneumatic microfluidic chip compartment respectively towards the pneumatic control device. The liquid retaining device may, e.g. be designed as a static valve or nozzle, respectively. The expression "coupled" is, in particular in a pneumatic or generally fluidic context, to be understood as a connection respectively coupling that allows the transfer of gas respectively fluid between the mentioned components, structures or devices. It does, however, not necessarily imply that the coupling is direct. Further intermediate components, structures or devices may accordingly be arranged in between. Unless stated otherwise, the coupling is in any case a well-defined coupling via corresponding structures, and not a coupling via the environment.

[0022] The microfluidic chip further includes a check valve. The sample inlet is fluidically coupled with the pneumatic microfluidic chip compartment, specifically the pneumatic microfluidic chip compartment inlet, via the check valve. Between the sample inlet and a check valve inlet as well as between a check valve outlet and pneumatic microfluidic chip compartment inlet corresponding connection channels may be foreseen in the microfluidic chip. Generally, such connection channels are unbranched.

[0023] For the check valve, a variety of designs is known in the art that may be used. Bay way of example, the check valve may include a movable and biased, in particular elastically biased, flap member. Preferably, the check valve does not include moving parts, but is a passive respective static check valve. In a particular embodiment, the check valve is designed as Tesla valve or a variant thereof. The check valve ensures that no back-flow of liquid, in particular blood, out of the sample inlet may occur.

[0024] The microfluidic chip further includes an optical measurement compartment. The optical measurement compartment has an optical measurement compartment inlet and an optical measurement compartment outlet, wherein the optical measurement compartment inlet is fluidically coupled with the pneumatic microfluidic chip compartment and the optical measurement compartment outlet is fluidically coupled with the assay disposal outlet. The optical measurement compartment and the optical measurement device are optically coupled via the optical probe thereby allowing optical measurements inside the optical measurement compartment. For the optical coupling, the optical beams between the optical probe and the inner volume of the optical measurement compartment pass through the material of the microfluidic chips which delimits the optical measurement compartment towards the optical probe, respectively the optical coupling is via the material of the microfluidic chip respectively a layer material layer thereof.

[0025] In an embodiment, the pneumatic microfluidic chip compartment outlet is directly fluidi- cally coupled with the optical measurement compartment inlet by a corresponding connection channel. In other embodiments, one or more further microfluidic structures respectively microfluidic devices as discussed further below, such as a separation device and a paramagnetic particle retaining device, are fluidical ly arranged between the pneumatic microfluidic chip compartment outlet and the optical measurement compartment inlet, respectively the pneumatic microfluidic chip compartment and the optical measurement compartment are fluidically coupled via such one or more devices in typically serial fluidic arrangement.

[0026] The microfluidic chip is generally a lab-on-a-chip device and typically realized with technologies as generally known in the art. In a particular embodiment, the microfluidic chip is realized as a sandwich of two, three or more generally co-planar layers, with microfluidic structures in one or more layers that are connected by way of bonding, thereby forming a stack of layers. The required microfluidic structures may be realized in one, two or more layers. Further, some or all microfluidic structures may be divided into two or more of the layers, in particular adjacent layers. The microfluidic chip respectively its layers or is favourable made from a biocompatible and substantially inert substrate material, such as fused silica (SiO2) and / or borosilicate glass. For exemplary purposes, an outermost layer that faces the optical probe and through which the optical beams pass is referred to as top layer. An opposed outermost layer is referred to as bottom layer. The outer surface of the top layer is referred to as top surface and the outer surface of the bottom layer is referred to as bottom surface of the microfluidic chip. Typically, all layers are parallel respectively have a generally constant thickness. In particular, the top surface and the bottom surface of the microfluidic chip are generally parallel to each other. It is noted that the expressions "top" and "bottom" only serve exploratory and illustrative purposes. Operation of the modular diagnostic information acquiring device is generally orientation-independent. The modular diagnostic information acquiring device is configured to autonomously execute a measurement protocol. The measurement protocol includes repeatedly executing a measurement cycle. Each measurement cycle generally includes a respective sampling phase and a subsequent respective measuring phase.

[0027] In each sampling phase, a whole blood sample is aspirated through the sample inlet via the check valve into the pneumatic microfluidic chip compartment by creating a pneumatic suction pressure (respectively under-pressure) inside the pneumatic microfluidic chip compartment via the pneumatic control device. The volume of the whole blood samples is in a typical embodiment 0.5ml or less. The total blood volume that is drawn from the patient body during a plurality of measurement cycles respectively in the execution of a complete measurement protocol is favorably limited to 5ml to 10ml for a whole day.

[0028] In each measuring phase, the previously aspirated whole blood sample is forced out of the pneumatic microfluidic chip compartment by creating a pneumatic pushing pressure (respectively over-pressure) inside the pneumatic microfluidic chip compartment via the pneumatic control device. When the whole blood sample is forced out of the pneumatic microfluidic chip compartment, an assay, the assay including the whole blood sample or a component of the whole blood sample, is forced by the pneumatic pushing pressure through the optical measurement compartment and is expelled from the microfluidic chip via the assay disposal outlet. Further, in each measuring phase, a series of optical measurement data is acquired from the assay while passing the optical measurement compartment. When forcing the whole blood sample out of the pneumatic microfluidic chip compartment and through the further fluidic volume of the microfluidic chip, liquid, in particular blood, is successively replaced by gas, in particular air. Following the measuring phase, the fluidic volume of the microfluidic chip downstream of the pneumatic microfluidic chip compartment, is generally filled with gas, in particular air. During the measuring phase, both liquid and gas are accordingly present, with the gas, in particular air, pushing the liquid in front of it.

[0029] It is noted that throughout the document the expression "includes" and "including" are to be understood as encompassing the case of "consists of" and "consisting of", respec- tively "is". For example, the assay may accordingly be the whole blood sample, a component of the whole blood sample, or the whole blood sample respectively a component thereof plus additional further components as discussed below.

[0030] Typically, the duration of the sampling phase, is e.g., one minute or less. The measuring phase is generally longer than the sampling phase and may have, e.g., a duration in a range of, e.g., two minutes. During the measuring phase, the first sample is forced in a continuous manner out of the pneumatic microfluidic chip compartment and optical measurement data are continuously respectively quasi-continuously acquired as the assay passes the optical measurement compartment. In a typical measurement protocol, the series of optical measurement data includes, e.g., 100 to 1000 sequentially acquired sets of optical measurement data.

[0031] The repetition time for consecutive executions of the of the measurement cycle may typically be in a range of 5min to 1 h, such as 30min, in dependence of the specific clinical respectively diagnostic needs.

[0032] Each set of optical measurement data may be or include an intensity spectrum, such as a Raman spectrum.

[0033] The series of optical measurement data acquired in each measuring phase are generally integrated in the interest of signal quality respectively to increase the signal-to-noise ratio (SNR), as generally known in the art. Such integration is typically carried out by the optical measurement device, e.g. Raman spectrometer, but may also be done by the data processing device.

[0034] The data processing device is generally configured, for each measurement cycle, to evaluate the respective series of optical measurement data, thereby generating respective measurement result data, and to store the respective measurement result data and / or communicate the measurement result data to a remote device, in each case along with a respective measurement cycle time stamp. The measurement cycle time stamp is unique for each measurement cycle. Alternatively or favorably additionally to the measurement cycle time stamp, a measurement cycle counter that is incremented for each new measurement cycle may be stored.

[0035] A remote device may be used, e.g. for long-term data storage respectively archiving, as well as further data evaluation purposes. Such remote device may, e.g., be a server or data center at a doctor, hospital, or research institute, or otherwise. It is noted that the remote device can be, but is not necessarily a single physical device and is not necessarily at a particular well-defined location, but may also be realized in a cloud. In an embodiment, the remote device is part of the modular diagnostic information acquiring device.

[0036] Biomarkers that may be detected and optionally quantified by way of the optical measurements include, e.g., blood Glucose, serum lactate, plasma lactate, serum creatinine, blood haemoglobin concentration, in particular oxygenated and and / or dyoxigenated haemoglobin. Since these biomarkers refer in each case to particular molecules, they are referred to as molecular biomarkers. Further biomarkers that may in an embodiment be measured respectively recorded by way of additional sensors are physical and / or chemical characteristics of the whole blood sample and / or the assay, e.g. the blood sample temperature and / or the blood sample pH value of the whole blood sample as discussed further below.

[0037] The modular diagnostic information acquiring device typically includes or is configured for operational coupling to a control unit. The control unit is configured for controlling the overall operation of the modular diagnostic information acquiring device and its components, in particular the execution of the measurement protocol as discussed above and further below. The control unit is generally an electronics unit and may comprise or more microcontrollers or microcomputers with corresponding firmware, ASICS and further circuitry as generally known in the art. In a typical design, the control unit is an integral part of the base device, which, however is not essential. Further, the modular diagnostic information acquiring device typically includes a generally electrical power supply, such as a rechargeable or non-rechargeable battery. The modular diagnostic information acquiring device may include or be configured for operational coupling to a user interface. The user interface may be used for controlling operation of the modular diagnostic information acquiring device, but also for user interaction in the context of, e.g., storing presenting and / or transmitting measurement result data. In an embodiment, the user interface, e.g. a graphical user interface (GUI), is fully or partly integrated in the control unit and / or the data processing device. In an embodiment, a generally commercial computing device, such as a laptop computer or tablet computer with corresponding software may serve as data processing device and also provide the user interface.

[0038] Favorably, the modular diagnostic information acquiring device is configured for displaying measurement result data and / or data respectively information derived therefrom, such as the presence and / or concentration of one or more biomarkers, substantially in real time, e.g. via tables, diagrams and / or graphs on the user interface.

[0039] Typically, the base device further includes an assay disposal receptacle that is configured to accommodate a assay disposal. In an operational configuration, the assay disposal is fluidically coupled with the assay disposal outlet of the microfluidic chip in a fluidically tight manner. Further, the base device may in an embodiment include an auxiliary disposal receptacle that is configured to accommodate an auxiliary disposal. Such auxiliary disposal is in an operational configuration fluidically coupled with an auxiliary disposal outlet of the microfluidic chip as discussed further below in a fluidically tight manner. A first and auxiliary disposal may be separate or may be a shared disposal. The disposal respectively disposals may have in each case in an integrated check valve respectively non-return valve that prevents any backflow from the disposal, in particular during handling by a user.

[0040] The measurement protocol typically defines one or more of data such as the time interval for starting consecutive measurement cycles respectively the frequency of the measurement cycle, the duration of the sampling phase and / or the measuring phase, settings respectively parameters of the optical measurement device, such as the required power of the light source, and the number of sets of optical measurement data. Further, the measurement protocol may include parameters of the data evaluation, in particular one or more biomarkers that shall be identified and / or quantified (referred to as biomarkers of interest in the following). Further aspects of the measurement protocol are discussed further below. In a nutshell, the measurement protocol is determined by and linked to the specific clinical respectively diagnostic application.

[0041] While the base device is generally universal and generally independent from the measurement protocol, the measurement protocol is generally linked to the design of the microfluidic chip. Specifically, different measurement protocols typically require differently designed microfluidic chips as discussed further below in more detail.

[0042] A modular diagnostic information acquiring device in accordance with the present disclosure may be used in a variety of ways and applications scenarios, some of which are briefly outlined in the following for illustrative and exemplary purposes.

[0043] In an Intensive Care Unit (ICU) application, the modular diagnostic information acquiring device may, e.g., be used to monitor blood oxygen saturation in real time. Blood oxygen saturation is an important measure of respiratory function, particularly providing dynamic information regarding changes of hemoglobin (Hb) that is bound with oxygen in the blood. Further, the metabolism of a patient may be monitored by detecting and favourable quantifying in real-time plasma lactate or serum lactate, thereby allowing an early detection of hyperlactatemia. This application may, e.g. be used for patients with shock or other severe hypoxic conditions, where early intervention is critical. Further, the serum creatinine level may be monitored in real time. In particular, relative concentration changes in the serum creatinine can for ICU patients serve as a measure of the renal function. Elevated levels of serum creatinine could indicate kidney dysfunction as serum creatinine is a waste product that is filtered out of the blood by the Kidneys.

[0044] In ambulance or Accident and Emergency (A&E) applications, a modular diagnostic information acquiring device in accordance with the present disclosure can be used for the real-time monitoring and supervision of vital parameters and conditions, in particular during intravenous infusions. In particular, in A&E applications, it may be required to place a peripherally inserted central catheter (PICC) as discussed further below for the fluidic access respectively drawing the blood samples. In the A&E context, the modular diagnostic information acquiring device may in particular be used in case of patients needing a comparatively extended transport time to reach a hospital, and nutrition and / or drugs are intravenously administered during the transport. The same may hold true even without extended transport time in particularly critical cases.

[0045] By way of example, a modular diagnostic information acquiring device in accordance with the present disclosure may be used in the context of a cardiovascular illness to monitor one or more of C-reactive protein (CRP), lactate and glucose as Biomarkers of interest. Via CRP, vascular inflammation can be detected respectively monitored. Tissue oxygenation may be monitored via lactate and metabolic irregularities via glucose. For instance, elevated lactate can signal compromised oxygen delivery, which is crucial for heart failure patients. For a sepsis and / or infection illness, biomarkers of interest may be CRP, lactate, and / or pH value. By way of an elevated CRP level, systemic inflammation may be detected. Lactate and pH values shed light on tissue perfusion and metabolic acidosis as vital metrics in septic shock scenarios.

[0046] Further, the modular diagnostic information acquiring device may be used in pharmaceutical and general clinical research to investigate the impact of pharmaceuticals respectively drugs and / or particular types of foodstuff on various biomarkers. Similarly, it may be used in the diagnosis of diseases that affect the occurrence and / or concentration of various biomarkers, as well as for determining appropriate medication to obtain a desired therapeutic effect, as reflected by one or more biomarkers.

[0047] In all such exemplary applications as mentioned, the suitability for point-of-care application is of particular relevance. In the context of life science laboratories, the modular diagnostic information acquiring device may further be used for quality control (QC) purposes. Here, the base device may in some applications not be attached to the body of a patient but the samples may be drawn from a blood sample tube.

[0048] Overall, the design and characteristics of a modular diagnostic information acquiring device in accordance with the present disclosure is suited for diagnostic information acquisition and evaluation in a point of care context. Further, the number of disposables is limited and such disposables can be manufactured at large scale and at comparatively low costs. In particular a sampling cannula and the microfluidic chip are disposables, while the other and in particular the technically complex and costly components, such as the base device and the optical measurement device as well as the data processing device are permanent respectively reusable.

[0049] In an embodiment, the sampling cannula, together with corresponding tubing, and the microfluidic chip may, optionally together with the assay disposal and an optional auxiliary disposal, be provided as a disposable kit, separate from the base device. Such disposable kit may also include a priming chip as discussed further below.

[0050] In an embodiment, the microfluidic chip includes a separation device. The separation device is configured to separate fluid including whole blood that enters the separation device at a separation device inlet into a first fluid component at a first separation device outlet and a second fluid component at a second separation device outlet. Generally, the first fluid component includes either plasma or serum. Favorably, if the first fluid component includes plasma, it includes all or substantially all blood plasma of the whole blood sample, respectively the second fluid component includes no or substantially no blood plasma. Similarly, if the first fluid component includes serum, it favorably includes all or substantially all serum of the whole blood sample, respectively the second fluid component includes no or substantially no serum. That is, the first fluid component may be or include all respectively substantially all plasma, or all or substantially all serum. The blood component that is to be analyzed is referred to as blood component of interest.

[0051] As discussed further below in more detail, the separation into the first fluid component and the second fluid component is generally done by way of magnetic forces acting on the fluid in the separation device.

[0052] The separation device inlet is fluidically coupled the pneumatic microfluidic chip compartment and the first separation device outlet is fluidically coupled with the optical measurement compartment inlet. The optical measurement compartment accordingly is fluid- ically coupled with the pneumatic microfluidic chip compartment via the separation device. The assay that enters the optical measurement compartment accordingly is or includes the fluid of the first fluid component.

[0053] The microfluidic chip of such embodiment may further include an auxiliary disposal outlet and the second separation device outlet may be fluidically coupled, in particular directly fluidically coupled, with the auxiliary disposal outlet. The second fluid component is the remaining portion of the fluid that is not the first fluid component.

[0054] A separation device is generally present if the liquid that shall be analyzed is not whole blood, but only either plasma or serum. The question of whether plasma or serum shall be analyzed depends on the biomarkers of interest since such biomarkers may be present substantially only or in significantly different concentration in plasma and serum, respectively. In some cases, however, whole blood may be used for the analysis. In such cases, a separation device and further related devices as discussed further below may not be present.

[0055] It is noted that the whole blood sample that enters the separation device may also include intentionally added particles and components as discussed further below. Such further particles or components may generally form a uniform mixture with the whole blood as such, but may also particularly bind to a blood component.

[0056] In particular in an embodiment with a separation device, the microfluidic chip may include a mixing device. The mixing device may in particular be a static mixing device. The mixing device is generally fluidically arranged upstream of the separation device, respectively between the pneumatic microfluidic chip compartment and the separation device. The mixing ensures a substantially uniform mixture of the whole blood sample with other substances such as anticoagulant-coated paramagnetic particles or coagulant-coated paramagnetic particles as discussed below. For the microfluidic structure of the mixing device, a number of designs is known in the art. In a particular embodiment, the mixing device is a reversed Tesla valve or a variant thereof. In further embodiments, the mixing device is a dynamic mixing device with one or more moving, e.g. rotating mixing members that may be driven, e.g., by a rotating electromagnetic field. In a particular embodiment with a separation device, the separation device may include a separation channel and the modular diagnostic information acquiring device further includes a separation magnet arrangement. Fluid is in the separation channel accordingly exposed to a magnetic field generated by the separation magnet arrangement.

[0057] The separation magnet arrangement may in an embodiment include a plurality of magnet elements that are arranged one after the other along the separation channel. In a particular embodiment, the separation magnet arrangement is realized as Halbach array with a plurality of magnets that are arranged one after the other along an axis, parallel to a longitudinal axis of the separation channel, with the direction of magnetization being rotated by 90 degrees around the longitudinal axis between in each case adjacent respectively consecutive magnets.

[0058] In an embodiment, the separation magnet arrangement, e.g. Halbach array, is part of the base device. It may, e.g. be integrated into a platform or fixture for the microfluidic chip, such as a pneumatic control device body as discussed further below, or a mounting platform for the microfluidic chip. The separation magnet arrangement is generally arranged in direct vicinity respectively contact to the microfluidic chip and aligned with the separation channel in order to ensure good magnetic coupling. In an alternative design, the separation magnet arrangement may be directly integrated into the microfluidic chip.

[0059] Magnetic or paramagnetic particles in the separation channel will, together with thereto adhering substances, aggregate along the separation channel at the side adjacent to the magnet elements, but not at the opposite side. The cross sectional area of the separation channel is accordingly substantially divided into a first cross sectional channel area where the magnetic or paramagnetic particles and thereto adherent substances respectively component(s) will aggregate and flow along the length of separation channel, and an adjacent second cross sectional channel area where non-magnetic substances respectively component(s) of the whole blood sample will flow along the length of the separation channel. The separation between the first cross sectional channel area and the second cross sectional channel area is generally transverse to the longitudinal extension direction of the separation channel. While other designs may be used as well, the separation channel may be straight over a major part of its length, or may be meander-shaped in the interest of a compact layout.

[0060] In a particular embodiment, the microfluidic chip is configured for adding paramagnetic particles, in particular superparamagnetic iron oxide nanoparticles (SPIONs), to the whole blood sample upstream of the separation device. The fluid entering the separation device will accordingly include the paramagnetic particles.

[0061] In a particular embodiment, the paramagnetic particles are anticoagulant-coated. The anticoagulant may, e.g. be heparin. The paramagnetic particles may optionally additionally be coated with PEG. In the separation device, the SPIONs will be attracted by the magnet elements, pulling the plasma along with them in the first cross sectional channel area, while further components of the whole blood sample, in particular blood cells and platelets, accumulate in the second cross sectional channel area. In such arrangement, the first fluid component and accordingly the assay includes the plasma, and the further blood components form the second fluid component that exits the separation channel at the auxiliary disposal outlet and is directly disposed of.

[0062] In another embodiment, the paramagnetic particles, in particular SPIONs, are coagulant- coated. The coagulant, may. e.g. be thrombin or calcium chloride. This type of embodiment may be used if the first blood component of interest that shall be analyzed is the serum and the assay accordingly includes the serum. Within the separation device, a clotting process is initiated due to the coagulant, thereby forming a clot. The clot includes the blood components apart from the serum, in particular blood cells, platelets, and clotting factors, thereby separating the serum as blood component of interest. The serum forms he first fluid component respectively blood component of interest and exits the separation device together with the SPIONs at the first separation device outlet, while the clot respectively the further components as mentioned exit the separation device at the second separation device outlet and are discarded. A typical application example where the blood component of interest is the serum is for patients having a history of kidney disease or particular kidney risk factors. Here measurement of the serum creatinine concentration aids in early detection and monitoring of kidney disease. The patient care is particularly enhanced due to the accuracy, rapidity, and minimal blood sample requirements of a modular diagnostic information acquiring device in accordance with the present disclosure.

[0063] In a particular embodiment, the microfluidic chip includes a paramagnetic particle reservoir. The paramagnetic particle reservoir is fluidically arranged upstream of the separation device. The paramagnetic particle reservoir stores paramagnetic particles in solid form. Upon the whole blood sample passing through the paramagnetic particles reservoir, paramagnetic particles are loosened and carried along with the whole blood sample. The paramagnetic particles may be deposited at one or more inner surface of the pneumatic microfluidic chip compartment, for example as paramagnetic particle coating, film, or layer. The paramagnetic particles may be coated as mentioned before.

[0064] The paramagnetic particle reservoir may be the pneumatic microfluidic chip compartment, i.e. the paramagnetic particles may be deposited inside the pneumatic microfluidic chip compartment. In another design, a dedicated separate paramagnetic particle reservoir is foreseen and is fluidically arranged between the pneumatic microfluidic chip compartment outlet and the separation device inlet. In a further variant, a fluidic channel respectively conduit downstream of the pneumatic microfluidic chip compartment serves as paramagnetic particle reservoir. In a further variant, paramagnetic particles are provided in a paramagnetic particle reservoir, e.g. paramagnetic particle cartridge or paramagnetic particle pouch, separate from the microfluidic chip. For such design, the microfluidic chip may have a paramagnetic particle inlet that is fluidically arranged between the pneumatic microfluidic chip compartment outlet and the separation device inlet.

[0065] In a variant, the paramagnetic particles, in particular SPIONs are as such not coated. In such embodiment, the microfluidic chip includes an anticoagulant or a coagulant reservoir, which stores a coagulant agent or anticoagulant agent in solid form. Adding anticoagulant, e.g. Heparin, is especially favourable if the blood component of interest is plasma and the assay accordingly includes plasma, or if whole blood is to be analyzed. The anticoagulant prevents clogging in such cases. For adding anticoagulant, generally the same approaches may be used as discussed above. Further, anticoagulant may be provided in a separate reservoir, such as a cartridge or pouch. A dedicated anticoagulant respectively coagulant reservoir may be foreseen, or the anticoagulant respectively coagulant may be deposited in a fluidic cannel or conduit or within the pneumatic microfluidic chip compartment which in this case also serves as anticoagulant storage compartment respectively coagulant storage compartment. Further, an anticoagulant reservoir or coagulant reservoir may be provided separate from the microfluidic chip, as discussed before for a separate paramagnetic particle reservoir. The anticoagulant or coagulant may be added to the whole blood sample upstream or downstream of the paramagnetic particles.

[0066] In a particular embodiment, the modular diagnostic information acquiring device includes a paramagnetic particle retaining device. The paramagnetic particle retaining device is configured for retaining paramagnetic particles comprised in the assay upstream of the optical measurement compartment. The paramagnetic particle retaining device may in particular include a retaining channel in which the paramagnetic particles are retained and accumulated by way of magnetic attraction when being passed by the assay. Via the paramagnetic particle retaining device, the paramagnetic particles are accordingly prevented from passing the optical measurement compartment, where they might interfere with the optical measurement.

[0067] For magnetically attracting the paramagnetic particles, a retaining magnet arrangement may be provided as part of the base or may in another variant also be part of the microfluidic chip, similar to the separation magnet arrangement.

[0068] The retaining magnet arrangement includes at least one retaining magnet and may in a variant be designed in principle similar to the separation magnet arrangement as discussed above e.g. as Halbach array. Like the separation device arrangement, the retaining device arrangement may be part of the base and arranged as discussed above, but may in another variant also be part of the microfluidic chip. In an embodiment, with a paramagnetic particle retaining device, the microfluidic chip includes a paramagnetic particle accumulation room. The paramagnetic particle accumulation room is a fluidic room upstream of the optical measurement compartment in which the paramagnetic particles are accumulated and accordingly retained by way of the magnetic forces exerted by the retaining magnet arrangement. The paramagnetic particle accumulation room may in particular be a flow channel or conduit respectively a portion thereof that is fluidically arranged between the first separation device outlet and the optical measurement compartment inlet. In an embodiment, the paramagnetic particle accumulation room includes immobilized ferromagnetic particles, such as iron microparticles. The ferromagnetic particles amplify and concentrate the magnetic field of the separation magnet arrangement.

[0069] In an embodiment, the microfluidic chip embodiment, the microfluidic chip is configured for adding anticoagulant to the whole blood sample. Apart from anticoagulant-coated paramagnetic particles as discussed before, adding anticoagulant to the whole blood sample may be added to prevent clogging if the assay incudes the whole blood. For adding anticoagulant, generally the same approaches may be used as discussed above. A dedicated anticoagulant reservoir may be foreseen, or the anticoagulant may be deposited in a fluidic cannel or conduit or within the pneumatic microfluidic chip compartment which in this case also serves as anticoagulant storage compartment. Further, anticoagulant may be provided in a separate reservoir, such as a cartridge or pouch.

[0070] In an embodiment, the optical measurement device includes a Raman spectrometer and the optical probe includes a Raman probe. The optical measurement data include for such design in each case a respective Raman spectrum. In further embodiment, the optical measurement device may additionally or alternatively to a Raman spectrometer include another type of spectrometer, in particular a fluorescence spectrometer. While the present disclosure is mainly focused on Raman spectrometers and Raman spectroscopy, it is noted that the same basic principles as well as design options may be equally applied to other types of spectrometers and generally optical measurement devices as applicable. It is noted that a typically present light source, in particular laser light source, is considered as an integral part of the optical measurement device, for example spectrometer, without being separately mentioned. In a particular embodiment with a Raman spectrometer, the modular diagnostic information acquiring device is configured for acquiring Raman spectra using at least two of Spontaneous Raman Spectroscopy, Surface-Enhanced Raman Spectroscopy (SERS), and Confocal Raman Spectroscopy. In dependence of the biomarker or biomarkers that shall be identified and / or quantified, one or more types of Raman spectra may be acquired. Regarding the Raman spectrometer as such, no difference is generally present for Spontaneous Raman Spectroscopy and SERS. For Confocal Raman Spectroscopy, in contrast, a confocal pinhole is generally present in the optical path of the incident light beam as provided by the light source. For this purpose, the optical measurement device respectively Raman spectrometer or the optical probe respective Raman probe may include a pinhole aperture that is selectively movable into or out of the optical path by way of an e.g. motorized actuator. Movement of the pinhole aperture to be in or out of the optical path is favorably automatically controlled as defined by the measurement protocol.

[0071] In an embodiment, the microfluidic chip includes a measurement protocol data storage device. The measurement protocol data storage device stores measurement protocol data indicative of a desired measurement protocol. The base device may include a measurement protocol data reading device. The measurement protocol data reading device is configured to read the measurement protocol data from the measurement protocol data storage device. The modular diagnostic information acquiring device of such embodiment is configured to execute the desired measurement protocol.

[0072] Generally, the measurement protocol includes variable parameters as mentioned above that may be set in dependence of the application, such as the required power of the light source and filter settings as well as data related to the design and characteristics of the microfluidic chip, e.g., whether the microfluidic chip is designed for the analysis of blood plasma, serum or whole blood. In an embodiment, the measurement protocol includes the complete data, such as parameters, that uniquely define a particular diagnostic application. By using a specific type of microfluidic chip, all relevant data and parameters are accordingly defined in accordance with the clinical application and the modular diagnostic information acquiring device is automatically configured in accordance with such application, without requiring manual configuration and / or settings. It is noted however, that the hardware layout, specifically the fluidic layout, may be identical for different clinical applications respectively different measurement protocols. In such case, the only difference between the respective microfluidic chips may be in the stored measurement protocol data.

[0073] In an embodiment, the measurement protocol data directly are or include technical information such as the type or types of Raman spectroscopy as mentioned before, power settings, filter settings, the number of measurement cycles, the repetition period of measurement cycles, the duration of the sampling and / or the measuring phase in each measurement cycle, and the like. In other embodiments, however, the stored measurement protocol data is an e.g. numeric identifier that is associated with a particular measurement protocol, while the underlying technical information for each measurement protocol is stored separately, e.g. by the modular diagnostic information acquiring device, for example in form of a table in the base device, for example in the control unit, or is retrieved from a remote database that may be stored by a server, in the cloud or the like. Retrieving some or all measurement protocol data from a remote database has the advantage that the manufacturer may continuously optimize, update or generally modify the measurement protocols as appropriate as well add additional protocols. Optionally, measurement protocols may be provided by further generally trusted and verified providers.

[0074] It is noted that different measurement protocols may require differently designed microfluidic chips. However, typically different measurement protocols, e.g. for the detec- tion / quantification of different biomarkers, may also be executed using the same type of microfluidic chip, respectively a microfluidic chip may be designed for executing a number of different measurement protocols. Here, the measurement protocol data may optionally include data for each of the measurement protocols and a user-selection of measurement protocol to be used may be made, e.g. via a user-interface.

[0075] For the measurement protocol data storage device and the measurement protocol data reading device, a variety of technologies as known in the art may be used. In an embodiment, the measurement protocol data storage device includes a bar code device and the measurement protocol data reading device includes a barcode reader. In another embodiment, the measurement protocol data storage device is am RFID chip and the measurement protocol data reading device is an RF reader. In a further embodiment, the measurement protocol data storage device is an electrically connectable semiconductor storage device, such as a ROM (Read Only Memory) device, and the measurement protocol data reading device is a corresponding electronic reading device. Independent form the technology used, the measurement protocol data are generally factory- stored by the supplier and can favorably not be subsequently altered or modified. The measurement protocol data storage device is accordingly favorably a read-only device.

[0076] In an embodiment, the optical measurement compartment includes a number of optical measurement compartment sections. The optical measurement compartment sections may be fluidically arranged in series and / or in parallel. The optical measurement compartment sections are in each case optically coupleable with the optical probe. The optical measurement compartment sections form, in combination, the optical measurement compartment and may be connected via interconnecting fluidic channels or merge directly into another.

[0077] Foreseeing more than one optical measurement compartment section is favourable if different types of optical measurements, for example different types of Raman spectroscopy as mentioned, shall be performed. Generally, there is at least one optical measurement compartment section present for and associated with each type of optical measurement. Regarding the fluidic layout, a serial fluidic arrangement is generally favourable in particular for complexity reasons. However, a parallel arrangement may be used in dependence of the application, e.g. to avoid cross-interference and contamination if particles or reagents are be present in one or more optical measurement compartments.

[0078] In an embodiment, the optical measurement compartment respectively one, more or all optical measurement compartment sections may generally be passive fluidic rooms that are passed through by the assay that shall be analyzed. In further embodiments, however, reagents that react with the assay and / or optically interact with the assay may be present in the optical measurement compartment respectively one or more measurement room compartments. In an embodiment with a number of optical measurement compartment sections, at last one optical measurement compartment section is a SERS measurement room compartment. Each SERS measurement room compartment includes a reservoir of metallic particles, in particular noble metal particles, such as gold particles. The metallic particles may in particular form a particle layer or particle coating on an inner surface of the respective SERS measurement room compartment. The particles are generally immobilized and not carried away with the fluid. As generally known in the field of Raman spectroscopy, SERS can significantly enhance the sensitivity respectively the Limit of Detection (LoD).

[0079] In an embodiment, the microfluidic chip includes a calibration device. The calibration device includes at least one calibration material. Each calibration material has pre-known characteristics regarding at least one type of optical measurement. The calibration material or calibration materials form an internal calibration standard that is freshly provided as integral part of each new microfluidic chip. The calibration device is configured such that optical measurement data can be acquired from each calibration material with the optical measurement in the same way as from the assay. In embodiments where more than one type of optical measurement is used, e.g. more than one type of Raman spectroscopy as mentioned, different calibration materials may optionally be foreseen for different types of optical measurement.

[0080] Calibration is in particular favourable for adjusting parameters, in particular the focus, after insertion of a microfluidic chip and prior to the actual start of the application respectively the filling with liquid and / or the starting the execution of the measurement protocol. Due to manufacturing and positioning tolerances, the focal plane for which the optical measurement device needs to be adjusted is generally not strictly constant but may vary. By way of calibration, such tolerances can be compensated for. The modular diagnostic information acquiring device is favorably configured to automatically respectively autonomously execute a calibration routine. The calibration routine may include varying the focus of the optical measurement device until an optimal measurement is achieved for the calibration material or calibration materials. For an optimal measurement, the measurement data, in particular an acquired spectrum, e.g. Raman spectrum, has a maximum signal of the acquired spectrum, e.g. Raman spectrum, in accordance with the calibration material, and / or minimum noise and generally distortions. In addition or alternatively to the focus, further settings such as power of the illumination light source and / or signal processing parameters may be adjusted respectively tuned as appropriate.

[0081] While a single calibration material is generally sufficient, a number of more than one calibration material may be foreseen and result in a combined calibration spectrum with components corresponding to the different calibration materials. Further, the calibration device may have separate sections for each calibration material.

[0082] The calibration material or calibration materials may be arranged in form of a layer or coating. Favorably, the calibration material or calibration materials is / are in any case arranged in a thin well, defined-plane to allow good focusing.

[0083] The calibration device may include a calibration device compartment having a calibration device compartment inlet and a calibration device compartment outlet being arranged fluidically in series with the optical measurement compartment. The calibration material or calibration materials may be arranged in the calibration device compartment. In use, the calibration device compartment is accordingly filled with respectively flown through by the liquid of the assay.

[0084] In principle, it is also possible to provide a calibration device that is not flown through by liquid. In any case, the calibration device must be as close to the optical measurement compartment and aligned with the optical measurement compartment to ensure that a focal plane that is determined via the calibration device holds true for the optical measurement compartment.

[0085] Setting the respectively adjusting the focus in a calibration routine as discussed before may favorably be done in a preparatory step where the microfluidic chip is accommodated in the microfluidic chip receptacle, but before the first measurement cycle where the microfluidic chip respectively its fluidic system is filled for the first time. In an embodiment, the modular diagnostic information acquiring device may be configured to repeatedly execute a calibration checking routine while executing the measurement protocol, for the example after before, each, second or each fifth measurement cycle. The calibration checking routine is favorably executed after completing a measuring phase and before the next following sampling phase, or between the sampling phase and the measuring phase. In these situations, the fluidic system respectively the fluidic volume downstream of the pneumatic microfluidic chip compartment and in particular a calibration compartment is empty or substantially empty.

[0086] In a calibration checking routine as mentioned it may be checked whether the focus setting is correct and / or whether the measured optical characteristics, for example Raman spectrum, of the at least one calibration material is as expected. In this way, any undesired changes or drifts that may occur while executing the measurement protocol can be detected. In an embodiment, the calibration checking routine is or includes a calibration adjustment routine, wherein one or more parameters, in particular the focus setting as discussed above, is adjusted as needed in the calibration adjustment routine.

[0087] In an embodiment, data concerning the calibration routine as well as subsequent calibration checking and / or calibration adjustment routines, such as "passed" respectively "failed" information and or / data concerning adjustments that are made is stored along with or as part of the measurement result data, favorably together with the corresponding time stamp.

[0088] A suited calibration material, may e.g., be Polyethlene glycol (PEG), silicon, polystyrene or Polytetrafluoroethylene (Teflon).

[0089] In an embodiment, an optical measurement compartment height, transverse to a flow direction, is non-constant. The flow direction is the flow direction of the fluid through the optical measurement compartment, respectively the flow direction of the assay. In an embodiment, the optical measurement compartment height is stepped.

[0090] A non-constant optical measurement compartment height results in a corresponding difference in the material amount of the assay, in particular plasma or serum, that is used for the optical measurement. Spontaneous Raman Spectroscopy and SERS. The optical measurement compartment height may in particular be different for different optical measurement compartment sections as discussed above. Generally, the volume that that is considered for the measurement is favorably large in particular for spontaneous Raman spectroscopy in the interest of a good signal-to-noise ratio. This calls for a comparatively large measurement compartment height. For the very sensitive SERS, in contrast, a small volume and accordingly a small height of the optical measurement room is favourable. The same applies for calibration.

[0091] The height of the optical measurement room compartment and generally of each room or fluidic channel of the microfluidic chip is to be understood as dimension in direction transverse to the top surface and the bottom surface of the microfluidic chip. A dimension transverse to the height and transverse to the flow direction is referred to as width.

[0092] In an embodiment, the base device includes a beam directing device. The beam directing device is generally optically arranged between the optical probe and optical measurement compartment. The beam directing device is configured to vary an optical coupling position for coupling the optical measurement compartment with the optical measurement device via the optical probe, and / or to vary an optical focusing.

[0093] The beam directing device is generally configured for optical beam deflection and may in particular include one or more beam deflecting devices, in particular mirrors and / or prismatic elements. In a typical embodiment, a single beam deflecting device is foreseen. In an embodiment, the microfluidic chip is accommodated in the microfluidic chip receptacle such that the top surface of the microfluidic chip is tangential respectively parallel with the optical axis of the optical probe. In such arrangement, the beam directing device may be configured for an optical beam deflection by 90 degrees, resulting in the optical beam passing through a delimiting wall of the optical measurement compartment as discussed in an orthogonal manner.

[0094] For varying the optical coupling position, the beam directing device respectively a beam deflecting device thereof is movable relative to the microfluidic chip together with the optical probe. The beam deflecting device may in particular be displaceable parallel to the top surface of the microfluidic chip. By varying the optical coupling position, the optical coupling may in particular be altered or switched between different measurement room compartments, and / or a calibration device as discussed above.

[0095] In an embodiment, the beam deflecting device is movable along a single linear axis, thereby a allowing a variation of the optical coupling position along such axis. This design is suited if different measurement room compartments as well as a calibration device are arranged linearly one after the other. In alternative embodiments, where measurement room compartments respectively the calibration device are distributed two-dimension- ally, the beam directing device may be configured for two-dimensional variation of the optical coupling position, e.g., by the beam deflecting device being displaceable in two mutually orthogonal directions. For moving the beam deflecting device, a beam directing drive may be foreseen and coupled with the beam deflecting device. The beam directing drive may include one or more actuators, such as motors or piezo actuators under control of the control unit. In an embodiment, the beam directing drive includes a translation stage with one or more mutually orthogonal movement axes.

[0096] It is noted that when adjusting respectively varying the optical coupling position as described before, the focusing is not changed since the optical probe and the beam deflecting device general move together. For adjusting the focusing, the beam directing device is configured for moving the beam deflecting device and the optical probe relative to each other along an axis of the optical probe, in particular by moving the beam deflecting device, while maintaining the position of the optical probe.

[0097] In an embodiment, the optical measurement device is structurally separate from the base device, wherein the optical measurement device and the base device are fiber-optically coupled or configured for fiber optic coupling. A releasable optical connector or releasable optical connectors may be foreseen at the side of the optical measurement device and / or the base device. Providing the optically measurement device structurally separate from the base device may in particular be foreseen for practical reasons in the interest of a compact base device. It is noted that the base device generally needs to be placed at a particular position of the body due to the required fluidic coupling, while there is more flexibility for carrying the optical measurement device. In dependence of the overall design and the grade of integration and miniaturization, however, the optical measurement device may also be integrated into the base device respectively form a common compact unit with the base device.

[0098] In an embodiment, the pneumatic control device includes a pump, a pump bypass channel in parallel fluidic arrangement with the pump, and a pneumatic buffer compartment. The pump and the pump bypass channel are fluidically arranged between the pneumatic microfluidic chip compartment and the pneumatic buffer compartment. The pump is configured to generate in operation a pumping pressure difference with a pressure at the pneumatic microfluidic chip interface being lower than a pressure at the pneumatic buffer compartment. Via the pump, a relative overpressure can accordingly be generated and maintained in the pneumatic buffer compartment as compared to the pneumatic microfluidic chip compartment. Operation of the pneumatic control device as discussed in the following is generally controlled by the control unit. A filter device may be foreseen in order to prevent contamination, in particular in an arrangement in vicinity of respectively close to the pump and / or as an integral part of the pump, as generally known in the art. The pump is a gas pump.

[0099] In operation of the modular diagnostic information acquiring device in combination with a port device as discussed further below, operation of the pneumatic control device for each measurement cycle may be as follows:

[0100] (i) The pump is operated with the sampling cannula tip being positioned in the air respectively outside of the port chamber of a port device, not in fluidic coupling with the sampling blood vessel, corresponding to the retracted sampling cannula position. Gas respectively air is accordingly aspired via the sampling cannula and forced via the microfluidic chip respectively the pneumatic microfluidic chip compartment into the pneumatic buffer compartment. The pressure inside the pneumatic pressure compartment is accordingly increased. (ii) While further operating the pump, the sampling cannula is moved such that the sampling cannula tip is placed inside the generally blood-filled port chamber of the port device corresponding to the advanced sampling cannula configuration.

[0101] (iii) The pumping power of the pump is increased. Thereby, fluid, in particular whole blood, is drawn into the sampling cannula and into the microfluidic chip device, in particular into the pneumatic microfluidic chip compartment, corresponding to the sampling phase.

[0102] (iv) The sampling cannula is moved from the advanced sampling cannula configuration into the retracted sampling cannula configuration.

[0103] (v) The pumping power of the pump is reduced or operation of the pump is stopped. Thereby, gas is forced out of the pneumatic buffer compartment via the pump bypass channel into the pneumatic microfluidic chip compartment, thereby displacing the while blood sample from the pneumatic microfluidic chip compartment, corresponding to the measuring phase.

[0104] As long as an overpressure is present in the pneumatic buffer compartment, the flow through the pump and the flow through the pump bypass channel are generally opposite to each other. The pump generates a gas flow from the pneumatic microfluidic chip compartment towards the pneumatic buffer compartment. The overpressure in the pneumatic buffer compartment, however, causes a flow in the opposite direction through the pump bypass channel towards the pneumatic microfluidic chip compartment. As long as an overpressure is present in the pneumatic microfluidic chip compartment, the effective flow can be regulated via the pumping power. If the pump is operated with a volume flow through the pump that is larger than the volume flow through the pump bypass channel, the effective volume flow is from the pneumatic microfluidic chip compartment into the pneumatic buffer compartment, while there is some smaller flow in the opposite direction via the pump bypass channel. This is generally the mode of operation in the sampling phase. As the pump is adjusted to reduce the gas flow through the pump, the effective flow from the pneumatic microfluidic chip compartment into the pneumatic buffer compartment will be reduced. At some equilibrium, the flow from the pneumatic microfluidic chip compartment into the pneumatic buffer compartment corresponds to the flow from the pneumatic buffer compartment via the pump bypass channel into the pneumatic microfluidic chip compartment, resulting in the pressures of the pneumatic microfluidic chip compartment and the pneumatic buffer compartment being stationary respectively constant. Further reduction of the pump flow beyond the equilibrium causes the flow from the pneumatic buffer compartment into the pneumatic microfluidic chip compartment via the pump bypass channel to prevail over the flow from the pneumatic microfluidic chip compartment into the pneumatic buffer compartment via the pump. This is generally the mode of operation in the measuring phase. By controlling the operation of the pump, the gas flow can accordingly be adjusted as needed. It is noted that the direction of flow through the pump is not reversed for the measuring phase as compared to the sampling phase, i.e. the pumping direction is not reversed.

[0105] The pump is typically designed to generate a pressure difference in a range of 0 to 200mbar. In operation, a suction pressure in a range of, e.g. -10 to -150 mbar can favorably be created in a subcutaneously implanted port device as discussed further below. In an embodiment, the pump is a miniaturized gas pump that may, e.g., be realized as disk pump. Other types of pumps, however, also be used. The maximum over pressure (as compared to atmospheric pressure) in the pneumatic buffer compartment may, e.g. be 400 mbar. The pneumatic buffer compartment has in a typical embodiment a volume of, e.g. 5ml. In any case, the volume of the pneumatic buffer compartment and over pressure that is generated by the pump inside the pneumatic buffer compartment are dimensioned such that a whole blood sample can be forced out of the pneumatic microfluidic chip compartment in the measuring phase.

[0106] The pump bypass channel may, e.g., have a fluidic resistance of 20kLohm pursuant to http: / / 67.199.46.28 / engineering / gases / calculate-flow-resistance-gases.cfm for the other main data of the pneumatic control device being as given above. In operation of the pump as discussed above, the pump bypass channel generally is associated with a flow opposite to the direction of the pressure difference created by the pumping pressure and accordingly provides a feedback mechanism. This feedback mechanism ensures stable pressure levels within the fluidic system, enabling fluid to be dispensed without excess pressure build-up, which could otherwise hinder the operation. In an embodiment, the pneumatic control device further includes a pressure sensor that is favorably arranged at the interface of pump and the pneumatic buffer compartment respectively measures the pressure in a conduit that connects the pneumatic buffer compartment and the pump or inside the pneumatic buffer compartment. The pressure sensor provides sensor feedback for controlling operation of the pump. The signal provided by the pressure sensor is generally evaluated by the control unit. The pressure sensor may, e.g., be a piezoresistive silicon absolute pressure sensor.

[0107] In an embodiment, the pneumatic control device further includes a venting valve and a venting port that provides a fluidic coupling to the environment. The venting valve is generally a switching valve and controlled by the control unit. It may, e.g. be a miniaturized solenoid valve or a piezo valve. The venting valve is fluidically arranged between the pneumatic buffer compartment and the venting port. In a closed state of the venting valve, the pneumatic system of the pneumatic control device and the microfluidic chip is isolated from the environment. By opening the venting valve, the over pressure in the pneumatic system, in particular the pneumatic control device, is relieved to ambient pressure. During each measurement cycle, specifically the sampling phase and the subsequent measuring phase, the venting valve is closed. Between the measurement cycles, respectively before and / or after each measurement cycle, the venting valve is opened for pressure equalization.

[0108] In an embodiment, modular diagnostic information acquiring device, in particular the base device, includes a liquid detector, in particular a blood detector. The liquid detector may be configured to detect if liquid, in particular blood, is drawn from the pneumatic microfluidic chip compartment into the pneumatic coupling channel, respectively towards the pneumatic microfluidic chip interface of the pneumatic control device. This may be the case if the pumping power is too high. The pumping power may be reduced in this case. The liquid detector may in particular include an optical sensor, for example a time- of-flight (ToF) or an intensity sensor and provides a measurement signal in dependence of the medium (i.e. gas, in particular air, or liquid, in particular blood) at a measurement position. The measurement position may be in the pneumatic coupling channel at or close to the opening into the pneumatic microfluidic chip compartment. The pneumatic control device is generally non-disposable but is an integral part of the base device. It may include a pneumatic control device body that can be realized, e.g., from structured plastic material and include a pneumatic manifold with the required channels respectively conduits as mentioned above and further below and may optionally include the pump bypass channel. The pneumatic control device body may include fluidic respectively pneumatic devices and interfaces as needed, e.g. the pneumatic microfluidic chip interface, the pump, the pneumatic buffer compartment, the pressure sensor, the venting valve and optionally further connection. Such interfaces are in each case designed for a tight fluidic coupling. Further, the pneumatic control device body may include feedthrough channels that are configured to receive conduits for coupling to a sampling cannula as discussed above and / or the first and optionally auxiliary disposal. In any case, the non-disposable pneumatic control device body favorably never directly contacts liquids such as whole blood or its components, reagents, or the like.

[0109] For establishing tight fluid couplings, a respective deformable, e.g. ring-shaped or cupshaped, sealing member may be foreseen for each fluidic interface, respectively liquid and pneumatic interface, at the pneumatic control device body at the interface to the generally rigid microfluidic chip. When establishing the connection with the microfluidic chip, some under-pressure respectively section results from the deformation of the deformable sealing members, thereby ensuring a tight coupling.

[0110] As mentioned before, the pneumatic control device body may include further elements and devices that are not directly functionally linked to the pneumatics, such as a separation magnet arrangement, e.g. Halbach array, and retaining magnet arrangement. Further sensors such as a liquid sensor as mentioned before may be integrated into the pneumatic control device body.

[0111] In particular, for the pneumatic microfluidic chip interface, a tight releasable coupling is generally required. In an embodiment, the pneumatic control device body may serve as microfluidic chip receptacle or part of the microfluidic chip receptacle.

[0112] In a particular design, the pneumatic control device body has a generally planar microfluidic chip interface surface that is contacts in an operational configuration the bottom surface of the microfluidic chip in a flat respectively planar manner and carry the fluidic interfaces. The pneumatic microfluidic chip interface may be or include an aperture in the microfluidic chip interface surface.

[0113] In an embodiment, a microfluidic chip pressing device is foreseen which presses, in an operational configuration, the microfluidic chip against the microfluidic chip interface surface of the pneumatic control device body in an elastic respectively biased manner. The microfluidic chip pressing device may contact the top surface of the microfluidic chip in a flat respectively planar manner, or may include a number of, e.g., sphere-shaped pressing protrusions that establish in each case a contact, in particular a point contact, with the top surface of the microfluidic chip. For this purpose, e.g. the microfluidic chip pressing plate or the pressing protrusions as mentioned may be spring-biased. The microfluidic chip may at the microfluidic chip top surface have corresponding recesses, e.g. depressions that receive in each case a pressing protrusion. Thereby, correct positioning of the microfluidic chip relative to the pneumatic control device body is at the same time achieved. Alternatively, other kinds of positioning devices, such as abutments may be provided for ensuring correct positioning of the microfluidic chip.

[0114] In an embodiment, all fluidic interfaces of the microfluidic chip are arranged on the same side, in particular at the bottom surface, while the optical connection is via the opposite top surface as discussed before.

[0115] In an embodiment, the modular diagnostic information acquiring device further includes one or more additional blood sample characteristic measuring devices for detecting and or quantifying biomarkers in form of chemical or physical characteristics of the whole blood sample, such as blood sample temperature and / or blood sample pH value. The modular diagnostic information acquiring device may accordingly include a blood sample temperature measurement sample and / or a blood sample pH value sensor. Such devices may in particular be configured for measurement upstream of the pneumatic microfluidic chip compartment.

[0116] In an embodiment, one or more blood sample characteristic measuring devices are partly integrated into the base device and partly into the microfluidic chip as disposable. A blood sample pH value sensor may include a pH sensitive dye that is arranged in the microfluidic chip, in particular upstream of the pneumatic microfluidic chip compartment. The pH sensitive dye optically couples with an optical pH value measurement module of the base device. The optical pH measurement device may illuminate the pH sensitive dye e.g. using an LED and measure the typically fluorescence light that is emitted back form the dye.

[0117] A blood sample temperature sensor may, for example, include an infrared temperature measurement module that is configured for optically coupling with the whole blood sample directly. In another embodiment, a blood sample temperature sensor may include a temperature sensitive dye that is arranged in the microfluidic chip as discussed above for a pH sensitive dye and produces temperature-dependent fluorescence, and a corresponding optical temperature measurement module for illumination and measuring the light that is emitted back form the dye. The optical temperature measurement module may be part of the base device.

[0118] The control device may be configured for evaluating the sensor signal or signals provided by the one or more blood sample characteristic measurement devices. Favorably, such blood sample characteristic measurements, are executed in each measurement cycle and the corresponding measurement data, e.g. blood sample temperature and / or blood sample pH value, form part of the measurement result data and are associated with a respective measurement cycle time stamp corresponding to the respective measurement cycle. Such blood sample characteristics may supplement the other measurement result data and provides additional diagnostic information.

[0119] In an embodiment, the base device includes a sampling cannula actuator. The sampling cannula actuator is configured for repeatedly moving a sampling cannula in fluidic coupling with the sample inlet of the microfluidic chip between a projecting sampling cannula configuration and a retracted sampling cannula configuration. The sampling cannula projects out of the base device beyond the patient body attachment interface in the projecting sampling cannula configuration and does not project out of the base device in the retracted sampling cannula configuration. In such embodiment, the modular diagnostic information acquiring device, in particular a control unit thereof, is configured to control the sampling cannula actuator such that the sampling cannula is in the projecting sampling cannula configuration in each case for the sampling phase and is in the retracted sampling cannula configuration in each case for the measuring phase.

[0120] The sampling cannula actuator may, for example, include a solenoid actuator or a piezoelectric actuator or another type of miniaturized actuator such as a DC motor or brushless DC motor. In order to compensate for the relative displacement between the sampling cannula and the microfluidic chip when moving the sampling cannula between the retracted and the projecting sampling cannula position, a displacement compensation device may be provided. Such displacement compensation device may, e.g., be formed by a length of flexible tubing or a telescopic tubing arrangement. The displacement length may typically be in a range from 5mm to 15mm.

[0121] In an embodiment, the modular diagnostic information acquiring device further includes a harness device. The harness device may in particular be an arm harness or a chest harness. The harness device and the base device are generally configured for releasable mutual coupling, in particular by way ay of magnetic coupling and / or mechanical latching.

[0122] Such harness device is generally known in the art and may be a textile device that is carried by the patiently directly on the skin and provides an interface for attaching a device, for example the base device of a modular diagnostic information acquiring device in accordance with the present disclosure to the body for a limited time period and in a removable manner. The harness device is in particular suited for attaching the base device in a position that is determined by an implanted port device and allows the sampling cannula to penetrate the skin and a port membrane of an implanted port device in a secure and reliable manner. For the magnetic coupling, either of the base device and the harness device may include a magnetic device which may include one or more permanent magnets, and the other of the base device and the harness device may include a corresponding ferromagnetic device as counterpart. Alternatively, each of the base device and the harness device may include a corresponding magnetic device, with the magnetic devices being configured for mutual attraction. For releasable mechanical latching, corresponding latching structures may be foreseen at the base device and the harness device. The latching structures may further be foreseen to provide an acoustic feedback signal, such as a "click" sound, upon engagement.

[0123] The harness device generally has a sampling cannula aperture in form of a through-hole for the sampling cannula to extend therethrough.

[0124] In an embodiment, the base device includes a position sensing device. The position sensing device is configured to detect if the base device assumes a target application position with respect to a target body location. The target body location may in particular be defined by a subcutaneously implanted port device.

[0125] In a typical application scenario as generally assumed in this document, the modular diagnostic information acquiring device is used in combination with an implanted port device as generally known in the art. Such port devices have a port body which defines a port chamber that is at a skin-facing side covered and closed by a pierceable port membrane. The port device further includes a catheter that fluidically couples the port chamber in an implanted state with a sampling position within the body from where the whole blood samples are drawn.

[0126] The port device may, for example be configured to access a sampling position in the Superior Vena Cava (SVC). Alternatively to an implantation of the port device in the chest region and attaching the base device via a chest harness, the port device may be a Peripherally Inserted Central Catheter (PICC) device where the port chamber with the pierceable port membrane may be implanted on the arm. In such configuration, an arm harness may be used for attaching the base device.

[0127] Prior to executing the measurement protocol, the port device needs to be primed by filling its fluidic volume, specifically of the catheter and the port chamber, with patient's blood. At the time of implantation, the fluidic volume is generally filled with saline solution. For the priming, the saline solution, followed by some blood, may be drawn, generally in the same way as whole blood samples are aspirated in each sampling phase as discussed before. For such preparatory step, a dedicated priming chip, distinct from the microfluidic chip and a corresponding priming disposal may be provided. Such priming chip may be also have pneumatic interface to the pneumatic control device. The modular diagnostic information acquiring device may be configured, prior to executing the measurement protocol, to execute a priming routine with the priming chip being present rather than the microfluidic chip. The priming routine may include moving the sampling cannula into the projecting sampling cannula position, controlling the pneumatic control device to aspire a liquid volume which is fed via the priming chip into the priming disposable, and moving the sampling cannula back into the retracted sampling cannula position. Subsequently, the priming chip is removed and replaced with the microfluidic chip. It is noted that, if dimensioned accordingly, either the assay disposal or auxiliary disposal as discussed before, may also serve as priming disposal.

[0128] In a further variant, a syringe as generally used in the art is used for the priming, prior to attaching the modular diagnostic information acquiring device.

[0129] It is noted that the fluidic volume of the port device is typically in a range of 1ml to 4ml and accordingly larger than the volume of the whole blood sample in each measurement cycle. The blood characteristics of the patient's blood in the sampling blood vessel are accordingly determined by the modular diagnostic information acquiring device with some time delay as determined by the volumes of the whole blood sample, the fluidic volume of the port device, and the cycle time. Such time delay, however, is constant and can accordingly be taken into account in the data evaluation.

[0130] The area of the pierceable port membrane that is available for piercing with the sampling cannula is in any case rather limited and has a typical size, of, e.g., 10 - 15mm in diameter. A position sensing device is therefore helpful for correct positioning. The target body location and accordingly the corresponding target application position are determined by the implantation position of the port body.

[0131] In an embodiment, the position sensing device is or includes one or more distance sensors, such as ultrasonic or optical time-of-flight (ToF) sensors. The positioning of the port device, in particular the port body under the skin generally results in a bulge being formed in this region. Consequently, the distance to a generally flat surface of the base device that faces the skin will be smaller in the region of and close to the port body as compared to a laterally more remote region. The signal provided by the distance sensing device may be evaluated by the control unit, respectively the control unit is configured to evaluate the signal provided by the position sensing device and determine if the base device has assumed the target application position. Favorably, subsequent steps such as moving the sampling cannula into the projecting sampling cannula configuration as explained above and generally executing the measurement protocol is possible only in the correct target application position. Optionally, the control unit is further configured to evaluate the signal provided by the position sensing device continuously or repeatedly, in particular regularly, during execution of the measurement protocol and provide an alarm indication if the position of the base device does not correspond to the target application position.

[0132] In an embodiment, the position sensing device is deactivatable, thereby allowing an operation of the modular diagnostic information acquiring device without the position sensing device indicating a correct target application position. This may be useful, e.g. if the modular diagnostic information acquiring device is used for QC purposes in a laboratory as mentioned before. Information on whether or not the position sensing device shall be activated may optionally be included in the measurement protocol data.

[0133] In a further aspect, the overall objective is achieved by a base device for use in a modular diagnostic information acquiring device. Typically but not necessarily, the modular diagnostic information acquiring device is a modular diagnostic information acquiring device according to any embodiment as discussed above and / or further below. The base device may include a patient body attachment interface. The patient body attachment interface is configured for removably attaching the base device to a patient's body directly and / or via an attachment interface device for an application time. The base device may further include a microfluidic chip receptacle. The base device may further include a pneumatic control device, the pneumatic control device is configured to provide alternatively a pneumatic pushing pressure and a pneumatic suction pressure at a pneumatic microfluidic chip interface. The base device may further include the optical probe. In an embodiment of a base device, the base device includes a control unit. The control unit is configured to control operation of the modular diagnostic information acquiring device to execute a measurement protocol, the measurement protocol including repeatedly executing a measurement cycle.

[0134] In a further aspect, the overall objective is achieved by a microfluidic chip for use in a modular diagnostic information acquiring device. Typically, but not necessarily, the modular diagnostic information acquiring device is a modular diagnostic information acquiring device according to any embodiment as discussed above and / or further below. The microfluidic chip may include a sample inlet, the sample inlet being configured for fluidically coupling to a sampling blood vessel, e.g. the Superior Vena Cava, of a patient. The microfluidic chip may further include an assay disposal outlet. The microfluidic chip may further include a pneumatic microfluidic chip compartment, wherein the pneumatic microfluidic chip compartment is configured for pneumatically coupling with a pneumatic control device, in particular via a pneumatic microfluidic chip interface of the pneumatic control device and a pneumatic control device interface of the microfluidic chip. The microfluidic chip may include a check valve, wherein the sample inlet is fluidically coupled with the pneumatic microfluidic chip compartment via the check valve. The microfluidic chip may further include an optical measurement compartment. The optical measurement compartment has an optical measurement compartment inlet and an optical measurement compartment outlet. The optical measurement compartment inlet is fluidically coupled with the pneumatic microfluidic chip compartment and the optical measurement compartment outlet is fluidically coupled with the assay disposal outlet. The optical measurement compartment is configured for optical coupling with an optical measurement device, in particular via an optical probe, thereby allowing optical measurements inside the optical measurement compartment.

[0135] It is to be understood that both the foregoing general description and the following detailed description present embodiments, and are intended to provide an overview or framework for understanding the nature and character of the disclosure. The accompanying drawings are included to provide a further understanding, and are incorporated into and constitute a part of this specification. The drawings illustrate various embodiments, and together with the description serve to explain the principles and operation of the concepts disclosed.

[0136] BRIEF DESCRIPTION OF THE DRAWINGS

[0137] The herein described invention will be more fully understood from the detailed description given herein below and the accompanying drawings which should not be considered limiting to the invention described in the appended claims. The drawings show:

[0138] Fig. 1 an embodiment of a modular diagnostic information acquiring device in accord in a schematic view;

[0139] Fig. 2 aspects of the fluidic / pneumatic architecture of an embodiment of a modular diagnostic information acquiring device in a schematic view;

[0140] Fig. 3 further aspects of the fluidic / pneumatic architecture of an embodiment of a modular diagnostic information acquiring device in a schematic view;

[0141] Fig. 4 a microfluidic chip and its optical coupling to a Raman spectrometer;

[0142] Fig. 5 the fluidic layout of an exemplary microfluidic chip in a schematic top view;

[0143] Fig. 6 an exemplary arrangement of a microfluidic chip together with a pneumatic control device body and a microfluidic chip pressing device in a schematic side view;

[0144] Fig. 7 the arrangement of a Halbach array;

[0145] Fig. 8 the control architecture of a modular diagnostic information acquiring device in a schematic view. DESCRIPTION OF THE EMBODIMENTS

[0146] Reference will now be made in detail to certain embodiments, examples of which are illustrated in the accompanying drawings, in which some, but not all features are shown. Indeed, embodiments disclosed herein may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein, rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. Whenever possible, like reference numbers will be used to refer to like components or parts.

[0147] Figure 1 shows an embodiment of a modular diagnostic information acquiring device in a schematic functional view. The modular diagnostic information acquiring device includes a base device 1 , a microfluidic chip 2, a Raman spectrometer 3 as optical measurement device, and a data processing device 5.

[0148] In the shown setup, the Raman spectrometer 3 and the base device 1 are structurally separate and are coupled via a fiber optical cable 3' that is favorably releasable at the side of the base device 1 and / or the Raman spectrometer 3.

[0149] The base device and the Raman spectrometer 3 are operationally coupled with the data processing device 5 via corresponding wired or wireless communication links (indicated by dashed arrows), such as a Universal Serial Bus (USB) connection, Bluetooth, WLAN, or the like. The data processing device 5 may in the shown design be realized, e.g., by a tablet computer and may include user interface 51. In dependence of the overall setup and system architecture, a direct communication link between the base device 1 and the Raman spectrometer 3 may be foreseen. Optionally, the data processing device 5 may be operationally coupled with a remote device 6 as mentioned in the general description and may communicate therewith, e.g., using an internet-based protocol.

[0150] The Raman spectrometer 3 includes, in addition to the spectrometer as such, the required light source, in particular laser light source for excitation as well as typically some data processing, e.g. for the purposes of filtering, noise reduction, general artefact reduction and the like. Generally, data corresponding to the acquired Raman spectra are transmitted to the data processing device 5. The assignment and distribution of functionality, however, may be chosen as appropriate.

[0151] In an operational configuration, a sampling cannula 4 is foreseen. In a projecting sampling cannula configuration (shown with solid lines), the sampling cannula 4 projects out of the base device 1 respectively beyond a bottom surface of a housing of the base device 1. In this configuration, fluidic coupling with a sampling blood vessel of a patient, in particular via an implanted port device, is possible. In an alternative retracted sampling cannula configuration (shown with dashed lines), the sampling cannula 4 does not project out of the base device respectively is retracted into the base device in the depicted embodiment. The movement is indicated by an arrow parallel to the sampling cannula 4. For the movement, a sampling cannula actuator (not separately shown in Figure 1) can be foreseen as part of the base device. 1.

[0152] Further, the base device 1 includes a patient body attachment interface 19 that is configured for releasable coupling with a harness device 9, e.g. a chest harness or arm harness in particular by way of magnetic coupling and / or mechanical latching as discussed above.

[0153] Figure 1 further depicts exemplarily three microfluidic chips 2, with the number being merely exemplary. Different microfluidic chips may have identical designs and be used for the same measurement protocol. Further, they may have an in principle identical or substantially identical design, but differ regarding the measurement protocol. Also, different microfluidic chips may be differently designed for the execution of different measurement protocols. The design differences may refer to the fluidic layout and dimensioning, but also to auxiliary substances or particles, such as SPIONs and their use, as explained above in the general description. By way of example, a microfluidic chip 2 may be designed for the analysis of plasma as blood component of interest, another microfluidic chip 2 may be designed for the analysis of serum as blood component of interest, and a third microfluidic chip 2 may be designed for the analysis of whole blood.

[0154] Data indicative of the measurement protocol for each microfluidic chip 2 are in the depicted embodiment stored on a bar code 21 as exemplary measurement protocol data storage device. For operation, anyone of the microfluidic chip 2 may inserted into base device 1 by accommodating it in the microfluidic chip receptacle 11. A barcode reader 12 as exemplary measurement protocol data reading device reads the barcode and the modular diagnostic information acquiring device is controlled accordingly. It is noted that the barcode 21 or generally the measurement protocol data storage device may also store additional information such as a lot number or serial number of the microfluidic chip 2.

[0155] Figure 2 schematically depicts the fluidic architecture of an embodiment of a modular diagnostic information acquiring device in accordance with the present disclosure along with further elements in an operational configuration, with fluidic connections being shown as dotted lines. In a practical design, such fluidic connections may be realized by conduits respectively fluidic channels. It is noted that a dedicated gas respectively air connection is generally referred to as pneumatic connection, but also forms a fluidic connection a general sense.

[0156] The modular diagnostic information acquiring device cooperates with a subcutaneously implanted port device 7. The port device 7 which is as such known in the art is implanted with a catheter 71 being inserted into a sampling blood vessel of the patient, exemplary the Superior Vena Cava 99, with an upstream end 711 being placed inside the vessel. The opposite downstream end 712 the catheter 71 opens into the port chamber 72 of the port device 7. The port chamber 72 is generally delimited by port body 73. At the side directed towards the skin 98, however, it is closed by a pierceable port membrane 74, thereby enabling transcutaneous fluidic access via the sampling cannula 4.

[0157] For drawing a whole blood sample, the disposable sampling cannula 4 pierces the skin 98 and the pierceable port membrane 74, such that the sampling cannula tip 41 at the upstream end of the sampling cannula 4 is placed inside the port chamber 72, as depicted. This is the configuration in the sampling phase. For the subsequent measuring phase, the sampling cannula 4 is retracted as mentioned before.

[0158] The downstream end 42 (opposed end to the sampling cannula tip 41) of the sampling cannula 4 is fluidically coupled with the inlet side of a check valve 22 of the microfluidic chip 2. Optionally, a further safety check valve (not depicted in Figure 2, see Figure 3) may be arranged upstream of the check valve 22 and outside of the microfluidic chip 2 for safety and redundancy purposes. An outlet side of the check valve 22 is fluidically coupled with the pneumatic microfluidic chip compartment 23. In a particular design, the check valve 22 is a Tesla valve, but may also be another type of check valve as appropriate. The check valve 22 is arranged such that a liquid flow from the sampling cannula 4 into the pneumatic microfluidic chip compartment 23 is enabled but a liquid flow, in particular blood flow, in the reverse direction is prevented.

[0159] The pneumatic microfluidic chip compartment 23 is further pneumatically coupled to the pneumatic control device 13 which is part of the base device 1 and discussed further below in more detail. Via the pneumatic control device 13 and the pneumatic coupling, a pneumatic pushing pressure respectively over pressure or alternatively a pneumatic suction pressure respective under pressure can be generated inside the pneumatic microfluidic chip compartment 23.

[0160] By generating a pneumatic section pressure inside the pneumatic microfluidic chip compartment 23, a whole blood sample can be aspired respectively drawn from the port chamber 72 via the sampling cannula 4 and the check valve 22.

[0161] A liquid detector 14' is in the depicted embodiment foreseen in the base device 1 to detect any potential blood flow from the pneumatic microfluidic chip compartment 23 towards the pneumatic control device 13 as discussed above in the general description and further below.

[0162] In the depicted embodiment, an additional blood characteristics measuring device is foreseen as part of the base device 1. This blood characteristics measurement device includes an optical blood characteristics measurement module 14, which may, e.g., be an optical pH value measurement module and / or an optical temperature measurement module. The optical measurement module is arranged for optically coupling with a corresponding temperature sensitive respectively pH-sensitive dye (not separately referenced) upstream of the check valve 22 and the pneumatic microfluidic chip compartment 23 as discussed in the general description above. In the depicted embodiment, the microfluidic chip 2 further includes a paramagnetic particle reservoir 29 that comprises paramagnetic particles, in particular SPIONs. If the blood component of interest respectively the assay to be analyzed is plasma, the paramagnetic particles are generally anticoagulant-coated. If the blood component of interest respectively the assay to be analyzed is serum, the paramagnetic particles are generally coagulant coated.

[0163] It is noted that the paramagnetic particle reservoir is shown as dedicated component that is passed by the whole blood sample. Alternatively, it may be integral respectively formed by a coupling channel or the pneumatic microfluidic chip compartment 23.

[0164] The generally coated paramagnetic particles may be provided in the form of a layer, coating or a film on one or more liquid-contacting respectively inner surfaces of the microfluidic chip 2. When passed by liquid, in particular whole blood in the measuring phase, it is enriched with paramagnetic particles that are accordingly added to the whole blood.

[0165] As appropriate in dependence of the corresponding measurement protocol, one or more additional substance reservoirs may be foreseen for adding further reagents respectively auxiliary substances in the same manner. Further, paramagnetic particles and / or other auxiliary substances may be provided in separate reservoirs as mentioned in the general description above.

[0166] Downstream of the pneumatic microfluidic chip compartment 23, a mixing device 24 is first arranged. An inlet side of the mixing device is fluidically coupled, in particular directly fluidically coupled, with the pneumatic microfluidic chip compartment 23. The mixing device 24 serves the purpose of mixing the whole blood sample with the auxiliary substance or substances as mentioned before. The mixing device 24 may, e.g., be realized by a reversed Tesla valve or another static mixing device as known in the art.

[0167] Downstream of the mixing device 24, a separation device 25 is arranged. An inlet side of the separation device 24 respectively a separation device inlet 25a is fluidically cou- pled, in particular directly fluidically coupled, with a mixing device outlet side. The separation device 25 includes a separation channel and a separation magnet arrangement 25' in form of a Halbach array which is in this design part of the base device 1 is arranged in magnetic coupling with the mixing channel as discussed above in the general description. Alternatively, the separation magnet arrangement 25' may be part of the microfluidic chip 2.

[0168] In the separation device 25, entering fluid, in particular the whole blood sample, generally in mixture with added auxiliary substances respectively particles as mentioned before, is separated into a first fluid component and a second fluid component. Either of the first fluid component is or includes the plasma and the other of the first fluid component and the second fluid component is or includes the serum. The first fluid component includes the blood component of interest and generally forms the assay. The first fluid component leaves the separation device separation device 25 at a first separation device outlet 25b. The second fluid component leaves the separation device 25 at a second separation device outlet 25c that is fluidically coupled to an auxiliary disposal 8'. The second fluid component is accordingly directly discarded.

[0169] The first blood component leaves the separation device 25 at a first separation device outlet and passes a paramagnetic particle retaining device 26 in form of a retaining channel the paramagnetic particles are magnetically attracted and retained via a retaining magnet arrangement 26' that may be designed similar to the separation magnet arrangement respectively Halbach array 25. At the outlet side of the paramagnetic particle retaining device 26, the assay is present in its final form. Downstream of the paramagnetic particle retaining device 26, a calibration device 27 and an optical measurement compartment 28 with two optical measurement compartment sections 28a, 28b are fluidically arranged in series and flown through by the assay. In a calibration device compartment (not separately referenced) of the calibration device 27, calibration material (not separately shown) such as PEG and / or other materials as mentioned before is present. The calibration material is generally immobilized and is not carried on with the assay. An inlet side of the first respectively most upstream optical measurement compartment section, in the shown embodiment optical measurement compartment section 28a, forms the optical measurement compartment inlet 281 and an outlet side of the last respectively most downstream optical measurement compartment section, in the shown embodiment optical measurement compartment section 28b, forms the optical measurement compartment outlet 282.

[0170] The optical measurement compartment section 28a is SERS measurement room compartment with a reservoir of noble metallic particles (not separately shown) that interact with the first blood sample respectively its components, in particular biomarkers. The noble metallic particles in the SERS measurement room comportment 28a are immobilized. The other optical measurement compartment section 28b is a plain compartment that is used for Spontaneous Raman Spectroscopy and / or Confocal Raman Spectroscopy. Each of the calibration device 27 and the optical measurement compartment sections 28a, 28a can optically couple to the Raman spectrometer 3 as discussed above and further below.

[0171] Downstream of the optical measurement compartment 28 respectively the optical measurement compartment section 28b, an assay disposal 8 is arranged to which the assay is discarded after exiting the microfluidic chip 2 at a assay disposal outlet.

[0172] Figure 3 further illustrates the fluidic / pneumatic architecture of a modular diagnostic information acquiring device in accordance with the present disclosure and in particular the design of the pneumatic control device 13.

[0173] The downstream end 42 of sampling cannula 4 is fluidically coupled to the sample inlet 2a of microfluidic chip 2 via a spring-loaded safety check valve 4a. The sample inlet 2a is fluidically coupled, in particular directly fluidically coupled, to the inlet side of check valve 22 (see also Figure 2). It is noted that the safety check valve 4a and the check valve 22 are fluidically arranged in series. The assay disposal outlet 2b of the microfluidic chip 2 is fluidically connected to the assay disposal 8 and the auxiliary disposal outlet 2c of the microfluidic chip 2 is fluidically connected to the auxiliary disposal 8' (see also Figure 2).

[0174] The pneumatic control device 13 which is part of the base device 1 includes the pump 131 which may in particular be a miniaturized disk pump, and the pump bypass channel 132 in parallel fluidic arrangement. At one side, the pump 131 and the pump bypass channel 132 are fluidically connected to the microfluidic chip 2 at a gas-tight pneumatic microfluidic chip interface 13a. The pneumatic microfluidic chip interface 13a is fluidically coupled in particularly directly fluidically coupled, with the pneumatic microfluidic chip compartment 23 (see Figure 2) via a corresponding channel of the microfluidic chip 2.

[0175] The other side of the pump 131 and the pump bypass channel 132 is fluidically coupled to pneumatic buffer compartment 133. The direction of the air respectively gas flow through the pump 131 and the pump bypass channel 132 is indicated by corresponding arrows. The gas flow that is generated by the pump 131 is directed out of the pneumatic microfluidic chip compartment 23 and into the pneumatic buffer compartment 133, while the flow through the pump bypass channel is opposed. As discussed above in the general description, the pump rate of the pump 131 is variable. If the flow through the pump

[0176] 131 prevails over the flow through the pump bypass channel 132, air respectively gas is suck out of the fluidic system of the microfluidic chip 2, in particular the pneumatic microfluidic chip compartment 23. If the flow through the pump bypass channel prevails

[0177] 132 over the flow through the pump 131 , air respectively gas is forced form the pneumatic buffer compartment 133 into the fluidic system of the microfluidic chip 2, in particular into the pneumatic microfluidic chip compartment 23.

[0178] A pressure sensor 135 is arranged at the interface of the pneumatic buffer compartment

[0179] 133 with the pump 131 and the pump bypass channel 132. The Pressure sensor 135 measures the inner pressure of the pneumatic buffer compartment 133. By way of feedback provided by the pressure sensor 135, the pump 131 is controlled for the sampling phase respectively the measuring phase.

[0180] Further, a venting valve 134 in form of a switching valve is provided for venting the pneumatic buffer compartment 133 to the environment between consecutive measurement cycles.

[0181] Figure 4 further illustrates an exemplary microfluidic chip 2 of an embodiment of a modular diagnostic information acquiring device in accordance with the present disclosure and its optical coupling to the Raman spectrometer 3 in a schematic view; In the depicted embodiment, the microfluidic chip 2 is designed as a sandwich of two bonded layers, namely a top layer 2' and a bottom layer 2". All pneumatic / fluidic interfaces, namely the sample inlet 2a, as well as the disposal outlets 2b, 2c, and the pneumatic control device interface 2d for coupling to the pneumatic microfluidic chip interface 13a (all not shown in Figure 4, see Figure 3) may be arranged in the bottom layer 2".

[0182] In the depicted embodiment, a Raman probe 15 as optical probe of the base device 1 is coupled with the Raman probe 3 via fiber optical cable 3'. It is noted that in a practical design, the fiber optical cable 3' generally includes separate fiber optical strands for the illumination by a light source, in particular laser light source, of the Raman spectrometer 3 and for the received light that is analyzed by the Raman Spectrometer 3. As schematically shown, the Raman spectrometer 3 includes in addition to the generally present components as known in the art a pinhole diaphragm 31 that is movable into the optical illumination path for confocal Raman spectroscopy.

[0183] The optical axes of the illumination and the received light of the Raman probe 15 coincide in a common optical axis oa as indicated. The optical axis oa is generally parallel to the top surface of the microfluidic chip 2, in particular to the top surface of the microfluidic chip 2. In the shown design, the base device 1 includes a beam directing device 16 with a mirror 161 as beam deflecting device. The mirror is coupled to and movable via translational stage 162 under control of the control unit of the modular diagnostic information acquiring device. The mirror 161 is arranged in an angle of 45 degrees to the optical axis oa as defined by the Raman probe 15, thereby deflecting optical beams by 90 degrees. The corresponding deflected optical axis oa' is accordingly transverse to the top surface of the microfluidic chip respectively its top layer 2'. By translating the mirror 161 as indicated by the corresponding arrow, the position where the deflected optical axis respectively the light beams hit the top surface of the microfluidic chip 2 and accordingly the optical coupling position can be varied for measurement in either of the optical measurement compartment sections 28a, 28b or the calibration device 27 respectively its calibration device compartment. In designs where the calibration device 27 and the optical measurement compartment sections 28a, 28b are fluidically arranged in series one after the other, linear displacement of the mirror 161 along a single axis respectively with a single degree of freedom is generally sufficient for optically coupling to each of them in other designs, however, the translational stage 162 may allow movement if the mirror 162 along more than one axis, in particular along two mutually orthogonal axes parallel to the microfluidic chip 2 respectively its top surface.

[0184] Figure 5 schematically shows an embodiment of a microfluidic chip 2 and specifically its fluidic layout in a schematic top view. In many aspects, the microfluidic chip 2 corresponds to the embodiment as depicted in Figure 2. Therefore, the following description is focused on particular aspects. The pneumatic control device interface 2d (that fluidically respectively pneumatically couples with the microfluidic chip device interface 13a of the pneumatic control device 13 as discussed above) is fluidically coupled to the pneumatic microfluidic chip compartment 23 via pneumatic coupling channel 23a. The pneumatic coupling channel 23a may include a liquid retaining device (not separately shown) at the opening into the pneumatic microfluidic chip compartment 23, as explained above in the general description.

[0185] In the design depicted in Figure 5, the paramagnetic particle reservoir 29 is further integral with the pneumatic microfluidic chip compartment 23. The paramagnetic particles, in particular SPIONs, are deposited inside the pneumatic microfluidic chip compartment 23.

[0186] Regarding the optical measurement compartment 28a and the calibration device 27, the calibration device 27 is in this design fluidically arranged between an optical measurement room compartment section 28b that is configured for spontaneous Raman spectroscopy, and the SERS measurement room compartment section 28a. The optical measurement room compartment section 28b may part of a general fluidic channel of comparatively large cross sectional area and in particular height as discussed above. The SERS measurement room compartment 28a and the fluidic chamber of the calibration device 27 may be realized as chambers of e.g. circular top view and have in particular a small height, e.g. in a range of 20 nanometer to 500 nanometer.

[0187] Together with the microfluidic chip 2, the separation magnet arrangement 25' is shown. The separation magnet arrangement 25', realized as Halbach array, is arranged laterally in vicinity and parallel to the in this design straight separation channel of the separation device 25.

[0188] Figure 6 schematically depicts an exemplary arrangement of a microfluidic chip 2 in relation to the pneumatic control device body 136 of a pneumatic control device 13 as discussed above and a microfluidic chip pressing device 137. The microfluidic chip 2 is arranged in a micro fluidic chip receptacle (not referenced) between the pneumatic control device body 136 and micro fluidic chip pressing device 137. As the microfluidic chip pressing device 137 is arranged between the microfluidic chip 2 and the Raman probe 15 with the beam directing device 16 (see Figure 4), it is favorably frame-shaped to only cover an edge area of the microfluidic chip 2, thereby allowing optical coupling of the Raman probe 15 via the beam directing device with the optical measurement compartment 28. The microfluidic chip pressing device 137 includes spring loaded pressing protrusion 138 that force the microfluidic chip 2 against the pneumatic control device body 136 respectively its top surface. The top surface of the microfluidic chip 2 may have corresponding recesses respectively depressions (not referenced).

[0189] As also visible in Figure 6, the separation magnet arrangement 25' is arranged in the pneumatic control device body 136. A corresponding arrangement may be used for the retaining magnet arrangement 26' (not shown in Figure 6). Figure 7 schematically shows the arrangement of a Halbach array as separation magnet arrangement 25'.

[0190] Figure 8 schematically shows major aspects of the control structure of an exemplary embodiment of a modular diagnostic information acquiring device in accordance with the present disclosure in a functional view. Reference is in this regard additionally made in particular to Figure 1 . Major directions of the signal respectively information flow are indicated by dashed arrows. It is noted, however, that signal respectively information flow in the opposite directions may be possible as well, e.g. for feedback purposes.

[0191] The generally computerized control unit 17 is an integral part of the base device 1 and serves as central control, coordination as well as supervision instance of the modular diagnostic information acquiring device and its diverse operations and procedures as discussed. Regarding the pneumatic control device 13, the unit 17 controls operation of the pump 131 based on feedback provided by pressure sensor 135. Further, the control unit 17 controls operation of the venting valve 134.

[0192] Regarding the setting of the sampling cannula 4, the control unit 17 controls the sampling cannula actuator 18 for movement of the sampling cannula 4 as discussed above in the context of Figure 1 . The control unit 17 further evaluates the signal provided the position sensing device 191 and enables a movement of the sampling cannula 4 from the retracted sampling cannula position into the projecting sampling cannula position only if the base device 1 is correctly positioned with respect to an implanted port device as discussed above.

[0193] In each measuring phase as well as for calibration, the control unit 17 controls the translational stage 162 for varying the optical coupling position as discussed above.

[0194] Further, the control unit 17 evaluates the measurement protocol data as read by the bar code reader 12 from the bar code 21 on the microfluidic chip 2 and controls operation in accordance with the respective measurement protocol.

[0195] Generally, the Raman spectrometer 3 favorably communicates the data of the acquired Raman spectra via a corresponding communication interface directly to the data processing device 5 where they are further processed, stored and displayed on the user interface 51 and optionally transmitted to the remote device 6. A direct communication between the control unit 17 and the Raman spectrometer 3 is in the sown arrangement used for general control purposes, e.g. for the triggering the acquisition of the single Raman spectra, and for moving the pinhole diaphragm 31.

[0196] As noted before, the base device 1 and in particular the control unit 17 does typically not include an own user interface but is operated and controlled by a user via the user interface 51 of the data processing device 5, e.g. a tablet computer. Some user interface of e.g. limited capability may, however, be optionally present at the base device 1. REFERENCE SIGNS

[0197] 1 base device

[0198] 11 microfluidic chip receptacle

[0199] 12 barcode reader (measurement protocol data storage device)

[0200] 13 pneumatic control device

[0201] 13a pneumatic microfluidic chip interface

[0202] 131 pump

[0203] 132 pump bypass channel

[0204] 133 pneumatic buffer compartment

[0205] 134 venting valve

[0206] 135 pressure sensor

[0207] 136 pneumatic control device body

[0208] 137 microfluidic chip pressing device

[0209] 138 pressing protrusion

[0210] 14 optical blood characteristics measurement module

[0211] 14' liquid detector

[0212] 15 Raman probe (optical probe)

[0213] 16 beam directing device

[0214] 161 mirror (beam deflecting device)

[0215] 162 translational stage

[0216] 17 control unit

[0217] 18 sampling cannula actuator

[0218] 19 patient body attachment interface

[0219] 191 position sensing device

[0220] 2 microfluidic chip

[0221] 2' top layer of microfluidic chip

[0222] 2" bottom layer of microfluidic chip

[0223] 2a sample inlet

[0224] 2b assay disposal outlet

[0225] 2c auxiliary disposal outlet

[0226] 2d pneumatic control device interface

[0227] 21 bar code (measurement protocol data storage device)

[0228] 22 check valve 23 pneumatic microfluidic chip compartment

[0229] 23a pneumatic coupling channel

[0230] 24 mixing device

[0231] 25 separation device

[0232] 25a separation device inlet

[0233] 25b first separation device outlet

[0234] 25c second separation device outlet

[0235] 25' separation magnetic arrangement

[0236] 26 paramagnetic particle retaining device

[0237] 26' retaining magnet arrangement

[0238] 27 calibration device

[0239] 28 optical measurement compartment

[0240] 28a SERS measurement room compartment (optical measurement compartment section)

[0241] 28b optical measurement compartment section

[0242] 281 optical measurement room compartment inlet

[0243] 282 optical measurement compartment outlet

[0244] 29 paramagnetic particle reservoir

[0245] 3 Raman spectrometer (optical measurement device)

[0246] 31 pinhole diaphragm

[0247] 3' fiber optical cable

[0248] 4 sampling cannula

[0249] 41 sampling cannula tip (upstream end of sampling cannula)

[0250] 42 downstream end of sampling cannula

[0251] 4a safety check valve

[0252] 5 data processing device

[0253] 51 user interface

[0254] 6 remote device

[0255] 7 port device

[0256] 71 catheter

[0257] 711 upstream end of catheter

[0258] 712 downstream end of catheter

[0259] 72 port chamber

[0260] 73 port body 74 pierceable port membrane

[0261] 8 assay disposal

[0262] 8' auxiliary disposal

[0263] 9 harness device 98 skin

[0264] 99 Superior Vena Cava (sampling blood vessel) oa optical axis oa' deflected optical axis

Claims

CLAIMS1 . Modular diagnostic information acquiring device, including a base device (1), a microfluidic chip (2), an optical measurement device, and a data processing device (5), wherein the microfluidic chip (2) can be removably accommodated by the base device (1), the base device (1) including: a patient body attachment interface (19), the patient body attachment interface (19) being configured for removably attaching the base device (1) to a patient's body directly and / or via an attachment interface device for an application time, a microfluidic chip receptacle (11) for removably accommodating the microfluidic chip (2) in an operational configuration, a pneumatic control device (13), the pneumatic control device (13) being configured to provide alternatively a pneumatic pushing pressure and a pneumatic suction pressure at a pneumatic microfluidic chip interface (13a), an optical probe, the optical probe being configured for optically coupling to the optical measurement device, the microfluidic chip (2) including: a sample inlet (2a), the sample inlet (2a) being configured for fluidically coupling to a sampling blood vessel of a patient, an assay disposal outlet (2b), a pneumatic microfluidic chip compartment (23), wherein the pneumatic microfluidic chip compartment (23) is pneumatically coupled with the pneumatic control device (13) via the pneumatic microfluidic chip interface (13a), a check valve (22), wherein the sample inlet (2a) is fluidically coupled with the pneumatic microfluidic chip compartment (23) via the check valve (22), an optical measurement compartment (28), the optical measurement compartment (28) having an optical measurement compartment inlet (281) and an optical measurement compartment outlet (282), wherein the optical measurement compartment inlet (281) is fluidically coupled with the pneumatic microfluidic chip compartment (23) and the optical measurement compartment outlet (282) is fluidically coupled with the assay disposal outlet (2b),wherein the optical measurement compartment (28) and the optical measurement device are optically coupled via the optical probe, thereby allowing optical measurements inside the optical measurement compartment (28), wherein the modular diagnostic information acquiring device is configured to autonomously execute a measurement protocol, the measurement protocol including repeatedly executing a measurement cycle, each measurement cycle including a respective sampling phase and a subsequent respective measuring phase, wherein, in the sampling phase, a whole blood sample is aspirated through the sample inlet (2a) via the check valve (22) into the pneumatic microfluidic chip compartment (23) by creating the pneumatic suction pressure inside the pneumatic microfluidic chip compartment via the pneumatic control device (13), wherein, in the measuring phase,- the whole blood sample is forced out of the pneumatic microfluidic chip compartment (23) by creating a pneumatic pushing pressure, an assay, the assay including either the whole blood sample or a component of the whole blood sample, is forced by the pneumatic pushing pressure through the optical measurement compartment (28) and is expelled from the microfluidic chip (2) via the assay disposal outlet (2b), a series of optical measurement data is acquired from the assay while passing the optical measurement compartment (28), wherein the data processing device (5) is configured, for each measurement cycle, to evaluate the respective series of optical measurement data, thereby generating respective measurement result data, and to store the respective measurement result data and / or communicate the measurement result data to a remote device (6), in each case along with a respective measurement cycle time stamp, the measurement cycle time stamp being unique for each measurement cycle.

2. Modular diagnostic information acquiring device according to claim 1 , wherein the microfluidic chip (2) includes a separation device (25), the separation device (25) being configured to separate fluid including whole blood that enters the separation device (25) at a separation device inlet (25a) into a first fluid component at a firstseparation device outlet (25b) and a second fluid component at a second separation device outlet (25c), wherein the first fluid component includes either plasma or serum, wherein the separation device inlet (25a) is fluidically coupled with the pneumatic microfluidic chip compartment (23) and the first separation device outlet (25b) is fluidically coupled with the optical measurement compartment inlet (281), wherein the microfluidic chip (2) further includes an auxiliary disposal outlet (2c) and the second separation device outlet (25c) is fluidically coupled with the auxiliary disposal outlet (2c).

3. Modular diagnostic information acquiring device according to claim 2, wherein the microfluidic chip (2) includes a mixing device (24), the mixing device (24) being in particular a static mixing device (24), the mixing device (24) being fluidically arranged upstream of the separation device (25).

4. Modular diagnostic information acquiring device according to anyone of claims 2 or 3, wherein the separation device (25) includes a separation channel and the modular diagnostic information acquiring device further includes a separation magnet arrangement (25'), such that fluid is in the separation channel exposed to a magnetic field generated by the separation magnet arrangement (25').

5. Modular diagnostic information acquiring device according to anyone of claims 2 to 4, wherein the microfluidic chip (2) is configured for adding paramagnetic particles, in particular superparamagnetic iron oxide nanoparticles (SPIONs) to the whole blood sample upstream of the separation device (25).

6. Modular diagnostic information acquiring device according to claim 5, wherein the paramagnetic particles are anticoagulant-coated.

7. Modular diagnostic information acquiring device according to claim 5, wherein the paramagnetic particles are coagulant-coated.

8. Modular diagnostic information acquiring device according to anyone of claim 5 or claim 6, wherein the microfluidic chip (2) includes a paramagnetic particle reservoir (29), the paramagnetic particle reservoir (29) being arranged fluidically upstream of the separation device (25), the paramagnetic particle reservoir (29) storing paramagnetic particles in solid form, such that paramagnetic particles are loosened and carried along with the whole blood sample upon passing through the paramagnetic particle reservoir (29).

9. Modular diagnostic information acquiring device according to anyone of claims 5 to 8, wherein modular diagnostic information acquiring device includes a paramagnetic particle retaining device (26), the paramagnetic particle retaining device (26) being configured for retaining paramagnetic particles comprised in the assay upstream of the optical measurement compartment (28), wherein the paramagnetic particle retaining device in particular includes a retaining magnet arrangement (26').

10. Modular diagnostic information acquiring device according to anyone of the preceding claims, wherein the optical measurement device includes a Raman spectrometer (3) and the optical probe includes a Raman probe (15), wherein the optical measurement data include in each case a respective Raman spectrum.1 1 . Modular diagnostic information acquiring device according to claim 10, wherein the modular diagnostic information acquiring device is configured for acquiring Raman spectra using at least two of Spontaneous Raman Spectroscopy, Surface-Enhanced Raman Spectroscopy (SERS), and Confocal Raman Spectroscopy.

12. Modular diagnostic information acquiring device according to any one of the preceding claims, wherein the microfluidic chip (2) includes a measurement protocol data storage device (21), the measurement protocol data storage device (21) storing measurement protocol data indicative of a desired measurement protocol, wherein the base device (1) includes a measurement protocol data reading device (12), the measurement protocol data reading device (12) being configured to readthe measurement protocol data from the measurement protocol data storage device (21).

13. Modular diagnostic information acquiring device according to anyone of the preceding claims, wherein the optical measurement compartment (28) includes a number of optical measurement compartment sections (28a, 28b), the optical measurement compartment sections (28, 28b) being fluidically arranged in series and / or in parallel.

14. Modular diagnostic information acquiring device according to anyone of the preceding claims, wherein at last one optical measurement compartment section is a SERS measurement room compartment (28a), wherein each SERS measurement room compartment (28a) includes a reservoir of metallic particles, in particular noble metal particles, the metallic particles forming in particular a particle layer or particle coating on an inner surface of the respective SERS measurement room compartment (28a).

15. Modular diagnostic information acquiring device according to anyone of the preceding claims, wherein the microfluidic chip (2) includes a calibration device (27), wherein the calibration device includes at least one calibration material, wherein each calibration material as pre-known optical characteristics.

16. Modular diagnostic information acquiring device according to anyone of the preceding claims, wherein an optical measurement compartment height, transverse to a flow direction, is non-constant.

17. Modular diagnostic information acquiring device according to anyone of the preceding claims, wherein the base device (1) includes a beam directing device (16), wherein the beam directing device (16) is optically arranged between the optical probe and the optical measurement compartment (28), the beam directing device (16) being configured to vary an optical coupling position for coupling the optical measurement compartment (28) with the optical measurement device via the optical probe and / or to vary an optical focusing.

18. Modular diagnostic information acquiring device according to anyone of the preceding claims, wherein the optical measurement device is structurally separate from the base device (1), wherein the optical measurement device and the base device (1) are fiber-optically coupled or configured for fiber optic coupling.

19. Modular diagnostic information acquiring device according to anyone of the preceding claims, wherein the pneumatic control device (13) includes a pump (131), a pump bypass channel (132) in parallel fluidic arrangement with the pump (131), and a pneumatic buffer compartment (133), wherein the pump (131) and the pump bypass channel (132) are fluidically arranged between the pneumatic microfluidic chip compartment (23) and the pneumatic buffer compartment (133), wherein the pump is configured to generate a pumping pressure difference with a pressure a pneumatic microfluidic chip interface (13a) being lower than a pressure at the pneumatic buffer compartment (133).

20. Modular diagnostic information acquiring device according to anyone of the preceding claims, wherein the base device (1) includes a sampling cannula actuator (18), wherein the sampling cannula actuator (18) is configured for repeatedly moving a sampling cannula (4) in fluidic coupling with the sample inlet (2a) between a projecting sampling cannula configuration and a retracted sampling cannula configuration such that the sampling cannula (4) projects out of the base device (1) beyond the patient body attachment interface (19) in the projecting sampling cannula configuration and does not project out of the base device (1) in the retracted sampling cannula configuration, wherein the modular diagnostic information acquiring device is configured to control the sampling cannula actuator (18) such that the sampling cannula (4) is in the projecting sampling cannula configuration in each case for the sampling phase and is in the retracted sampling cannula configuration in each case for the measuring phase.

21. Modular diagnostic information acquiring device according to anyone of the preceding claims, the modular diagnostic information acquiring device further including a harness device (9), the harness device being in particular an arm harness ora chest harness, the harness device (9) and the base device (1) being configured for releasable mutual coupling, in particular by way of magnetic coupling and / or mechanical latching.

22. Modular diagnostic information acquiring device according to anyone of the preceding claims, wherein the base device (1) includes a position sensing device (191), the position sensing device (191) being configured to detect if the base device (1) assumes a target application position with respect to a target body location, the target body location being in particular defined by a subcutaneously implanted port device (7).

23. Base device (1) for use in a modular diagnostic information acquiring device, in particular a modular diagnostic information acquiring device according to anyone of claims 1 to 22, the base device including: a patient body attachment interface (19), the patient body attachment interface (19) being configured for removably attaching the base device (1) to a patient's body directly and / or via an attachment interface device for an application time, a microfluidic chip receptacle (11), an optical probe, the optical probe being configured for optically coupling to the optical measurement device, a pneumatic control device (13), the pneumatic control device (13) being configured to provide alternatively a pneumatic pushing pressure and a pneumatic suction pressure at a pneumatic microfluidic chip interface (13a).

24. Base device (1) according to claim 23, the base device (1) including a control unit (17), the control unit (17) being configured to control operation of the modular diagnostic information acquiring device to execute a measurement protocol, the measurement protocol including repeatedly executing a measurement cycle.

25. Microfluidic chip (2) for use in a modular diagnostic information acquiring device, in particular a modular diagnostic information acquiring device according to anyone of claims 1 to 22, the microfluidic chip (2) including:a sample inlet (2a), the sample inlet (2a) being configured for fluidically coupling to a sampling blood vessel of a patient, an assay disposal outlet (2b), a pneumatic microfluidic chip compartment (23), the pneumatic microfluidic chip compartment (23) being configured for pneumatically coupling with a pneumatic control device (13), a check valve (22), wherein the sample inlet (2a) is fluidically coupled with the pneumatic microfluidic chip compartment (23) via the check valve (22), an optical measurement compartment (28), the optical measurement compart- ment (28) having an optical measurement compartment inlet and an optical measurement compartment outlet, wherein the optical measurement compartment inlet is fluidically coupled with the pneumatic microfluidic chip compartment (23) and the optical measurement compartment outlet is fluidically coupled with the assay disposal outlet (2b), wherein the optical measurement compartment (28) is configured for optically coupling with an optical measurement device, thereby allowing optical measurements inside the optical measurement compartment (28).

Images