System for automated biological sample processing

Abstract

The invention relates to a system and method for processing a biological sample, in particular of a human lipoaspirate In particular, the invention relates to optimizing the emulsification of the biological sample in an automated and controlled manner. Accordingly, a system (10) for processing a biological sample (24) is suggested, comprising a disposable fluidic system (100), comprising a first syringe (14) for receiving a biological sample (24), a second syringe (15), and two ports (28) being fluidically connected to each other, wherein each port (28) is configured to be fluidically connected with a respective one of the syringes (14, 15), an actuator (12), configured to displace a plunger (22) of a respective syringe (14, 15), and a control unit (32), configured to output a control signal to the actuator (12) to initiate at least one emulsifying cycle by conveying fluid comprised in one of the syringes (14, 15) to the other syringe (14, 15) via the fluidic connection based on the displacement of the respective plunger (22).

Description

[0001] System for automated biological sample processing

[0002] Technical field

[0003] The invention relates to a system and method for processing a biological sample, in particular of a lipoaspirate. In particular, the invention relates to optimizing the emulsification of the biological sample in an automated and controlled manner.

[0004] Technological Background

[0005] Patients suffering from a variety of diseases may benefit from the selective administration of autologous tissue and / or cell material. Such grafting approaches typically require that tissue and / or cells are removed from a patient. They may e.g. be re-administrated to the patient after appropriate processing. For example, a lipoaspirate may be removed from a patient during surgery, e.g. liposuction, and may be processed for isolation of target cells and / or enrichment of cells of the tissue sample and / or processing in order to remove unwanted components. The processed sample may thereafter be injected into the patient for therapeutic purposes. In particular, removed and processed adipose tissue may e.g. selectively be administered into one or more joints of the patients. Such an approach has been shown to be promising for the treatment of arthritis. Other applications refer e.g. to the field of plastic and aesthetic surgery.

[0006] To process the removed sample, the sample may be transferred to a device, such as a container, tube, or other receptacle. In case of a lipoaspirate, the processing of the removed biological sample and hence the preparation of graft material may e.g. involve additional enzymes (e.g. collagenase for therapeutic purposes) and / or the addition of other ingredients (e.g. platelet rich plasma or hyaluronic acid). The lipoaspirate or the modified lipoaspirate will typically be further processed by using e.g. a buffer solution for rinsing and washing. That step allows to discharge waste material. Upon termination of the processing, the processed sample, e.g. adipose tissue may be used for re-application to the same patient or another patient, i.e. as autologous or allogenous therapeutic material. In order to facilitate an efficient processing of the sample, disintegration of the sample is often required, e.g. to avoid clumps and to ensure efficient processing and enrichment of the desired cells or cell types. Such disintegration and / or enrichment may typically be enabled by means of a mechanical processor, such as a vortexer or a stirrer. It may also involve the use of a centrifuge. However, such mechanical devices, in particular centrifuges, are not necessarily available in a medical or laboratory setting, due to their size, weight, and their purchase costs. In addition, the use of centrifuges may even be detrimental to the cells of the sample, potentially resulting in cell or tissue damage.

[0007] It is also noted that implementation of a step of centrifugation requires the provision of a suitable sample container. Any such disposable containing contaminated biological material increases the complexity of the logistics and waste disposal process. It also requires manual handling and transfer of the removed biological sample to a suitable centrifuge vessel or container. Accordingly, any such manual handling steps may adversely affect the reproducibility of the sample processing.

[0008] From US 9 073 021 B2 a device and method for preparing an emulsion drug is known, wherein an emulsification is performed until a predefined upper threshold or an increase in the actuation force is detected.

[0009] US 2020 / 206703 A1 discloses a fluid mixing device and method enabling an inversion of a direction of displacement to facilitate emulsification.

[0010] WO 2024 / 003329 A1 discloses the use of mobile securing members between elongated containers to define predefined restraining surfaces.

[0011] Summary of the invention

[0012] Starting from the known prior art it is hence an object of the present invention to provide an improved processing mode for a biological sample, in particular by establishing cost-efficient preparation process in an automated and reproducible manner.

[0013] The above object is solved by means of a system for processing a biological sample, in particular a human tissue sample, characterized by the features of claim 1 . Further preferred embodiments are presented by the dependent claims, the description and the Figures.

[0014] Accordingly, in one aspect, a system for processing a biological sample is disclosed, comprising a disposable fluidic system, comprising a first syringe for receiving a biological sample, a second syringe, and two ports being fluidically connected to each other. Each port is configured to be fluidically connected with a respective one of the syringes. The system further comprises an actuator configured to displace a plunger of a respective syringe and a control unit. The control unit is configured to output a control signal to the actuator to initiate at least one emulsifying cycle by conveying fluid comprised in one of the syringes to the other syringe via the fluidic connection by means of displacement of the respective plunger.

[0015] By means of the actuator and the control unit, the fluid, i.e., the sample or a portion thereof and any optional solutions comprised in the syringe(s), may be injected from one syringe into the other syringe. The inventors found that efficient means are thereby established to emulsify or disintegrate of the sample. Accordingly, by applying the pressure to the fluid portion and by conducting a flow via the fluidic connection, clumps may gradually or instantly disintegrate, such that the cells of the sample may be dispersed as monocellular or oligocellular particles.

[0016] The controlled preparation or processing of the biological sample by means of the actuation of the respective plunger based on the control signal furthermore enables preparation or processing of the biological sample in an automated and reproducible manner. The need for manual handling and processing is hence significantly reduced. The inventive approach thus allows to only couple the disposable fluidic system to the actuator. The processing is hence simplified while effective emulsification may be enabled in a time-efficient manner. Moreover, centrifugation steps may be effectively and largely avoided, rendering the system both cost efficient and compatible with a larger number of medical and laboratory settings.

[0017] The fluidic coupling of two syringes allows, prior to the processing, to exclude any step of transferring the sample, e.g. the lipoaspirate sample, after its removal from the patient. By using syringes, standard disposables may be applied without the need for intricate disposable manufacturing. The implementation of a fluidic system furthermore enables the control and actuation of the system to e.g. be integrated and encased within a housing of a medical device. They may be separated from the fluidic components that are formed as disposables. In particular, the fluidic system may be formed as a pre-mounted single-use disposable, such that the risk of inadvertent contamination may be significantly reduced and sterile conditions may readily be established.

[0018] Depending on its envisaged use the pre-processed sample, e.g. an emulsified lipoaspirate, potentially containing an enriched fraction of cells of a desired cell type, such as stem cells, may be retrieved from the system for subsequent therapeutic application to the patient or for further and final processing.

[0019] While one of the syringes may initially accommodate the biological sample, the other syringe may be at least partially filled with a solution, e.g. a buffer or saline. Alternatively, both syringes may be filled with a respective portion of the sample and / or both syringes may be filled with a respective solution. The actual mode may depend on the envisaged use and / or processing of the sample. For example, a solution may be pre-filled in at least one of the syringes to ensure that a predefined volume of the sample with the solution is provided. Thereby, e.g. the (initial) displacement of the plunger and / or the mixing or pre-processing of the sample may be facilitated.

[0020] Preferably, the control unit is configured to output a control signal for two or more emulsifying cycles. The control signal is adapted to convey the total fluid volume or a predefined portion of the fluid volume present in one of the syringes to the other syringe for each emulsifying cycle.

[0021] For example, the sample may be fully conveyed and transferred from the first syringe to the second syringe during the first emulsifying cycle. It may then be fully conveyed from the second syringe to the first syringe during the second emulsifying cycle. Alternatively, the predefined portion of the total volume to be conveyed may e.g. be successively increased, e.g. by each or every second cycle. A smaller initial portion of the total fluid volume to be conveyed may be advantageous. In particular, mixing of a gradually increasing volume of the sample with buffer or any other solution present in the second syringe may be envisaged. Preferably, a plurality of emulsifying cycles, e.g. more than 5 or more than 10 cycles, may be performed.

[0022] In order to further control the conveying or transfer of the sample from one syringe to the other and vice versa and to specifically control the emulsifying process, the actuator preferably comprises a force sensor for detecting a force being exerted on the respective plunger and being communicatively coupled with the control unit. The control signal may preferably be adapted to displace the respective plunger for a given emulsifying cycle with a predefined force. The control unit may preferably be configured to adjust the control signal based on a comparison of the predefined force and an actual force measurement.

[0023] By applying a predefined force to the respective plunger, the pressure within the syringe and exerted onto the sample may be controlled. For the provision of a predefined force, the control unit may be preferably configured to (continuously) adjust the control signal based on the detected force exerted on the respective plunger. For example, the predefined force may be adjusted to the type and / or use of the biological sample to be processed, A larger cell and / or tissue density may e.g. require a higher force, while sensitive cells may e.g. be exposed to a lower force and a more gentle mode of mixing. The force applied to the plunger may hence fall within a pressure range considered as acceptable for the respective application within the syringe. The upper limit may optionally be dependent on the nature of the sample, cell-type, and / or syringe type being used. Accordingly, by applying the predefined force, turbulences and / or vortices may ensure appropriate conditions for an individual sample to undergo the target emulsification level.

[0024] The control unit may also be configured to output the control signal for a predefined number of emulsifying cycles. The predefined number of emulsifying cycles may e.g. ensure that a required emulsification level of the sample may be achieved, preferably even independently of the nature of the sample. The application of a predefined number of emulsifying cycles may be advantageously combined with the application of a predefined force. Alternatively, the predefined number of emulsifying cycles may be ensured independently of the force being applied to the plunger, e.g. to establish a simplified configuration.

[0025] As an alternative to foreseeing a predefined force, the actuator may also comprise a force sensor for detecting a force being exerted on the respective plunger and being communicatively coupled with the control unit. The control signal may be configured to compare an actual force measurement for a respective emulsifying cycle with a predefined lower force threshold and to output the control signal until said predefined lower force threshold is reached or exceeded for a respective emulsifying cycle.

[0026] By pushing the biological sample from the initial to the second syringe the biological sample, e.g. a lipoaspirate, is allowed to get emulsified. Accordingly, the viscosity of the sample may decrease, in particular upon applying multiple emulsifying cycles. The actual force may be compared with the predefined lower force threshold. In particular by maintaining a continuous displacement rate of the plunger, the comparison may hence indicate whether a corresponding target viscosity of the biological sample has been reached. In other words, if the viscosity of the biological sample gradually decreases, the force, which is required for the conveying the sample and for corresponding displacement of the plunger, is reduced. Thereby, it may be determined whether a target viscosity of the biological sample is achieved, once said lower force threshold is reached or exceeded. Thereby, the present invention enables emulsification of a sample, in particular a tissue sample. The viscosity of the sample may be reduced in the course of the emulsification step. In contrast to prior art methods which envisage increasing the viscosity upon emulsification, the present invention hence enables that a lower force threshold forms a measure for achieving a corresponding reduction of the viscosity towards a (lower) target viscosity.

[0027] The predefined predefined lower force threshold may hence preferably correspond to a predefined target viscosity being lower than a viscosity of the sample prior to or during the initiating emulsifying cycle. The emulsified sample preferably contains cells.

[0028] Preferably, a respective emulsifying cycle is terminated, even though the detected force may (temporarily) be below the lower force threshold. Thereby, temporary fluctuations potentially resulting in a premature interruption of the processing of the sample do not interfere with the quality of the process. At the same time, it is ensured that the biological sample is fully contained within a respective syringe after termination of the emulsifying cycle, which facilitates the collection and / or further processing of the emulsified sample. The control unit may accordingly output a control signal to the actuator to interrupt a subsequent emulsifying cycle.

[0029] By means of the implementation of a force sensor, a closed loop control for the processing of the sample or emulsification process can be implemented, which is either force or pressure driven. It may be realized by applying a particular force to the respective plunger, or by the respective plunger being actuated until a predefined lower force threshold is reached. In either case, the detected force may be used as a feedback signal to continue and / or to adjust the application of the force on the respective plunger. Thereby, efficient emulsification is ensured without disregarding the tolerance limits for the particular biological sample to be processed.

[0030] Preferably, the fluidic system comprises a tube fluidically connecting the ports. Preferably, it further comprises at least a first reservoir being fluidically connected to said tube and arranged downstream of the ports. By means of the tube, sensor measurements may be facilitated and / or may be performed in a standardized manner. Furthermore, the tube enables that further fluidic connections to the ports including the first reservoir may be facilitated. Furthermore, the fluidic system may comprise a first valve at the tube being configured and arranged to selectively block fluid communication between the ports. It may be arranged to enable fluid communication from one port to the downstream first reservoir in the blocked state. In addition, the fluidic system may comprise a second valve arranged upstream of the first reservoir and arranged to selectively block fluid communication between the ports and the first reservoir.

[0031] The tube may be formed of a U-shape, thereby connecting the first and the second syringe. The U-shape of the tube may allow for a parallel arrangement of the syringes (side-by-side arrangement). Alternatively, the tube may be formed as a straight component, e.g. of cylindrical shape, thereby allowing for an arrangement of the syringes face-to face (a serial arrangement). The side-by-side arrangement of the syringes may allow for more compact overall design of the inventive device.

[0032] By means of the preferred valve arrangement, the conveying of the fluid or portion of the biological sample may be provided in a selective manner. The fluid is either conveyed from one of the ports, which is coupled to the syringe comprising the emulsified sample, to the downstream reservoir, e.g. for collection or further processing of the emulsified sample. Alternatively, the fluid is only conveyed between the ports, i.e. between the syringes, upon actuation of the actuator and displacement of the respective plunger.

[0033] The valves, which may be formed as respective pinch valves, may be actuated by the control unit. Thereby, the valves may selectively adopt a closed state and an open state. The flow of the fluid is thus selectively restricted. In order to facilitate the conveying of the fluid to the downstream reservoir, a tube or tube system may be connected to the tube that fluidically connects the syringe ports, e.g. via one or more fluidic connectors or by a corresponding configuration of the respective valve. Preferably, the disposable fluidic system hence comprises one or more fluidic lines for a selective transfer of the fluid or a portion of the biological sample. The first reservoir may comprise a filter with a predefined filter pore size being arranged to filter the emulsified sample from the upstream port to the first reservoir. The filter size may e.g. correspond to a predefined mesh or pore size, which e.g. retains undesired larger particles or cells from passing through the filter. Thereby, the size and / or amount of any residual bubbles in the sample may be reduced. The filter hence enables an initial sorting or enrichment of the type(s) of target cell(s) being present in the filtrate to be subsequently used for therapeutic purposes. The filter pore size may hence be adapted to the nature of the biological sample that has been removed from the patient and the type of cells or components to be collected for subsequent transplantation. In case of an emulsified lipoaspirate, the characteristics of the filter(s) may be particularly adapted to the isolation of the stromal vascular fraction (SVF).

[0034] The first reservoir may preferably be in fluid communication with an upstream pump-driven solution reservoir. The control unit may be configured to actuate the pump to convey a portion of the solution to the emulsified sample received by the first reservoir. Accordingly, once the emulsified sample has been conveyed to the downstream first reservoir, a solution may be forwarded to the first reservoir, e.g. a buffer or rinsing solution, such as saline. That step may establish e.g. an emulsified lipoaspirate that may be rinsed in a first filter stage, thereby facilitating further transfer or conveying of the filtrate. By the same token, that step may facilitate the retrieval of the portion of (target) cells to be isolated from the sample. Furthermore, provision of a solution may ensure that a predefined volume of the sample mixture may be obtained, which may be advantageous e.g. for further processing.

[0035] The provision of the solution may be preferably enabled by an integrated pump, in particular a peristaltic pump. Said pump may hence be actuated by the communicatively coupled control unit. The second valve may preferably be closed upon actuation of the pump, thereby avoiding any potential retrograde backflow. The solution may hence be conveyed to the downstream first reservoir so as to provide a fraction of desired properties. The filtrate downstream of the filter of the first reservoir may be either used as such for therapeutic purposes or may undergo further processing steps.

[0036] The fluidic system preferably comprises at least one further downstream reservoir with a respective filter having a predefined filter pore size, which is typically smaller than the filter pore size of the preferred optional upstream filter. The system allows to subject the portion of the emulsified sample from the upstream first reservoir to said further reservoir to a further filtration step. Typically, the filter pore size of each successive reservoir comprises an ever reduced filter pore size. In other words, one or more reservoirs may be arranged in series, i.e. establishing a sequential fluid transfer, wherein the filter pore size decreases from the upstream reservoir to the downstream reservoir. Thereby, larger cells and particles including debris may be retained at one or more upstream filters, whereas downstream filters may e.g. enable a fine tuning of the conditions for isolation of the desired target cells or cell types according to their cell size. By means of introduction of the pump-driven solution and the one or more filters a washing and enrichment of the sample is hence enabled, which is supported by the by the preceding emulsification step. Depending on the number of downstream reservoirs and corresponding filters, more than one, e.g. 2 to 10 or 2 to 5 filtering process steps may be carried out with increasing filter density, e.g. mesh density. The ultimate or downstream-most filter may either retain the target cells as filtered solid (by selecting the filter pore size to be smaller than the size of the target cells) or may allow the target cells to pass through the filter by selecting the filter pore size to be larger than the size of the target cells.

[0037] Preferably, the downstream-most filter comprises a filter size of between 1 pm and 12 pm or of between 8 pm and 10 pm. Such a filter pore size has been found to be particularly advantageous, whenever the sample is a lipoaspirate. The target cell fraction may thus e.g. be the cells of the stroma vascular fraction (SVF), which typically have a size more than 10 pm. The filter pore size or mesh size may accordingly be chosen such that the target or desired cells to be isolated do not pass the filter, while smaller cells pass the filter and are disposed together with filtrate. In this regard, the filter pore size may also be chosen so as to isolate cells falling within a narrow size range while allowing undesired smaller cells to effectively pass the filter. In case of a lipoaspirate, erythrocytes or other components of the blood system may thus pass the ultimate filter and be collected as a filtrate for disposal. Accordingly, the filter pore size of the downstream-most filter may preferably be smaller than 10 pm.

[0038] To facilitate retrieval of the processed sample from the system, the fluidic system may preferably comprise a collector port downstream of the downstream-most reservoir. The collector port may typically be fluidical ly coupled to a collector reservoir or a processing module. In order to obtain or harvest the emulsified and cell-enriched sample, a port may hence be fluidically coupled to the downstream-most reservoir. Thereby, the portion of the sample comprised in said reservoir upstream of its filter may be directly collected. In this regard, a waste line or discharge line may be fluidically coupled to the downstream-most reservoir at a downstream end portion of the corresponding filter. As a result, undesired cells may be effectively removed from the system.

[0039] By the same token, the downstream-most reservoir may be fluidically connected to a processing module, which may be preferably integrated in the system, e.g. within a housing of a medical device. Thereby, the processed sample may be further processed without requiring any intermediate manual steps. The risk of potential contaminations or a potential volume loss of the retrieved portion of the sample is thus mitigated. To ensure that the sample is appropriately transferred, one or more valves may be present, which may be actuated by the control unit. According to a further aspect, a method for processing a biological sample is disclosed, comprising the steps of: providing a first syringe and a second syringe fluidical ly coupled to the first syringe; and providing a biological sample in one of the syringes; and initiating at least one emulsifying cycle by displacing a plunger of a respective syringe so as to convey fluid comprised in one of the syringes to the other syringe, wherein the displacement of a plunger of the respective syringe is performed by an actuator controlled by a control unit.

[0040] Rather than by manual emulsification of the sample, the processing is hence performed in an automated manner, as described above in view of the various features of the system according to the invention. In this regard, the features and advantages presented with respect to the system also apply to the method and vice versa, such that the advantages and potential embodiments may be, at least in part, not be presented again to avoid redundancy.

[0041] The displacement of the plunger may be performed by using a predefined force or one or more further emulsification cycles may be performed until a predefined lower force threshold is reached. The predefined lower force threshold preferably corresponds to a reduced (target) viscosity of the sample, in particular compared with a viscosity of the sample at the start of the initial emulsification cycle. As described above, feedback of a force sensor, e.g. a load cell, may be applied in order to enable a closed loop control. Thereby, e.g. a turbulence within the sample may be advantageously controlled or the emulsification may be continued until a desired viscosity level is observed. The detected force may hence be used as a feedback control signal to continue and / or to adjust the application of the force on the respective plunger so as to ensure efficient emulsification that is within tolerance limits for the particular sample.

[0042] The sample is preferably a tissue sample, in particular a semi-solid or gel-like tissue sample. In particular, the sample comprises cells. More preferably, the sample may comprise or consist of a lipoaspirate.

[0043] The emulsified sample may be conveyed from one of the syringes to a downstream first reservoir by using the actuator, wherein the emulsified sample is passed through a filter of the first reservoir. Furthermore, the control unit may actuate a pump of a solution reservoir upstream of the first reservoir to convey a portion of the solution to the emulsified sample received by the first reservoir. By arranging the filter at the first reservoir, undesired larger particles or cells may be prevented from passing through the filter. The size and / or amount of any residual bubbles in the sample may be reduced. The filter hence enables an initial sorting or concentration of the type(s) of cell(s) being present in the filtrate to be subsequently used. Once the emulsified sample has been conveyed to the downstream first reservoir, a solution may be introduced into the first reservoir, e.g. a buffer or rinsing solution, such as saline. Thereby, an initial rinsing or washing of the emulsified sample may be carried out. That step may facilitate further transfer or conveying of the filtrate and / or may facilitate the retrieval of the portion of (target) cells from the biological sample.

[0044] Preferably, the portion of the emulsified sample received by the first reservoir is conveyed to at least one further downstream reservoir preferably equipped with a respective filter having a predefined (smaller) filter pore size so as to separate (undesired) particles from the portion of the emulsified sample transferred from the upstream reservoir to the downstream reservoir. Typically, the cascade of filter of a successive reservoir are characterized by ever reduced filter pore sizes. As described above, a filter cascade may hence be foreseen, wherein the largest cells or larger debris are filtered at the upstream filter(s) and the smaller cells including the desired fraction of the sample are retained at the downstream filter. The final residual filtrate (containing no cells or undesired cells of smaller size, e.g. red blood cells, may be conveyed e.g. to a waste reservoir or a discharge line.

[0045] The downstream-most filter may preferably comprise a filter size of between 1 pm and 12 pm or of between 8 pm and 10 pm. Such filter size has been found to be particularly advantageous, whenever the sample is a lipoaspirate and e.g. cells of the stroma vascular fraction (SVF), which typically have a size more than 10 pm, are to be isolated. The filter pore size or mesh size may accordingly be chosen such that the target or desired cells to be retrieved do not pass the (ultimate) filter of the filter cascade. In this regard, the filter pore size may also be chosen so as to obtain cells with a narrow size range while effectively passing undesired cells, such as erythrocytes or other components of the blood system when processing a lipoaspirate. Accordingly, the filter pore size of the downstream-most filter is preferably smaller than 10 pm for such applications.

[0046] Accordingly, the biological sample, in particular a tissue or a human tissue sample, may preferably comprise or essentially consist of a lipoaspirate. For example, the biological sample or tissue sample may be a human lipoaspirate, hence forming a semi-solid and / or at least partially colloidal sample comprising a variety of cells, e.g. adipocytes and / or adipose derived stem cells (ADSC). Such stem cells may be the target cells to be isolated by the subsequent processing steps. In particular, the target cells to be obtained from the sample are found in a stromal vascular fraction (SVF). The lipoaspirate may have been removed during surgery of a patient, e.g. by liposuction, and may be re-administered as autologous cell transplantation to the patient after processing or preparation of the biological sample for therapeutic purposes, such as regeneration of tissue in the joint of a patient.

[0047] Brief description of the drawings

[0048] The present disclosure will be more readily appreciated by reference to the following detailed description when being considered in connection with the accompanying drawings in which:

[0049] Figure 1 shows a schematic depiction of a system according to the invention; and

[0050] Figure 2 shows a schematic depiction of components of a system according to the invention in a preferred embodiment.

[0051] Detailed description of preferred embodiments

[0052] In the following, the invention will be explained in more detail with reference to the accompanying figures. In the Figures, like elements are denoted by identical reference numerals and redundant description thereof is avoided.

[0053] In Figure 1 a schematic depiction of a system 10 is shown, which may be used for processing of a biological sample comprising e.g. tissue or cells, in particular for a lipoaspirate comprising adipose tissue. The system 10 comprises an actuator in the form of a pump 12, which may be mechanically coupled with a first syringe 14 and a second syringe 15 in an alternating manner, so as to convey a portion of the total fluid volume between the syringes 14, 15. In order to enable such a transfer of the fluid, the pump 12 comprises a pump actuator 16 and a piston head 18. The piston head may be driven in a longitudinal direction based on a corresponding actuation of the pump actuator 16. The piston head 18 may e.g. be mounted on a spindle in such a way that a rotation caused by the pump actuator 16 results only in a longitudinal displacement 34 of the piston head 18, as indicated by the double arrowheads. The piston head 18 may hence be configured for bi-directional longitudinal displacement, e.g. in a vertical up-down direction.

[0054] At the lower end portion of the piston head 18, i.e. the portion being arranged at a side facing away from the pump actuator 16, a force sensor 20 is foreseen, which may be formed as a load cell. The force sensor 20 is adapted to engage an outer end surface of a plunger 22 of a respective syringe 1 , 15 so as to enable a biasing of the fluid contained therein. In the present exemplary embodiment, the force sensor 20 contacts an end surface of a plunger 22 of the respective syringe 14, 15. Upon longitudinal displacement 34 of the piston head 18 towards the plunger 22, the plunger 22 is displaced. Thereby, a portion of the total volume of a sample 24 comprised within the syringe is conveyed from the syringe 14 to the other syringe 15. A fluidic connection between the syringes 1 , 15 is provided by means of a respective port 28 for connecting an outlet of the respective syringe 14, 15 at opposing end portions of a tube 30. The conveying of the sample 24 is hence enabled by the longitudinal displacement 34 of the plunger 22 and the corresponding movement of an upstream stop 26 of the syringe 14, 15.

[0055] The longitudinal displacement 34 of the piston head 18 is controlled by a control unit 32, which is communicatively coupled with the pump actuator 16 and the force sensor 20, as indicated by the dashed lines. The control unit 32 may e.g. elicit an initial actuation signal to the pump actuator 16 to initiate the dispensing for the syringe 14, as indicated in Figure 1. Upon longitudinal displacement 34 of the piston head 18, the control unit 32 receives force measurement signals from the force sensor 20 or, alternatively, via the pump actuator 16. The detected force may e.g. be compared with a predefined lower force threshold.

[0056] The control unit 32 outputs a control signal to the pump actuator 16 to control the longitudinal displacement 34 and the conveying of the portion of the total volume of sample 24, thereby establishing an emulsifying cycle of the sample 24. As described above, emulsification of the sample 24 may imply a viscosity decrease of the sample 24. Thus, the force required to displace the plunger 22 and the adjacent sample 24 may be reduced.

[0057] The control unit 32 may determine that a lower force threshold has not yet been reached; the sample 24 has thus not yet attained the target lower viscosity level. Such information may trigger a further emulsifying cycle by outputting a control signal to the pump actuator 16. The control signal may comprise a lateral position adjustment signal. Thereby, lateral displacement 38 may be instructed to the pump actuator 16. As a result thereof, the piston head 18 or the pump 12 as a whole may be brought into alignment with the plunger 22 of the other syringe 15, as indicated with the double arrowhead.

[0058] To facilitate lateral displacement 38, the system 10 comprises a drive 36, which may be formed as a linear gantry. Upon receiving the lateral position adjustment signal, the piston head 18 is retracted to its original position. Correspondingly, the pump 12 is moved to a predefined lateral position comprising the second syringe 15. A further emulsifying cycle may be initiated. Once the predefined lower threshold is reached or exceeded, the control unit 32 may stop the initiation of a further emulsifying cycle. E.g. a control signal may be forwarded to other components of the fluidic system, as shown in the exemplary embodiment depicted in Figure 2.

[0059] In Figure 2, optional components of the system 10 are shown. Essentially, all of the components may be advantageously provided as a disposable 100 or single-use item. They may be delivered in a pre-mounted state to facilitate installment. According to an exemplary embodiment, the tube 30 fluidical ly connecting the syringes 14, 15 is also fl ui dical ly coupled to a first reservoir 42. Said fluidic coupling is enabled by a further tube downstream of the connecting tube 30 and by valves 40. Valves 40 are arranged such that the conveying of the fluid or portion of the sample 24 may be established in a selective manner. The fluid is either conveyed from one of the ports 28, which is coupled to the syringe 14, 15 comprising the emulsified sample 24, to the downstream first reservoir 42, e.g. for collection or further processing of the emulsified sample 24. Alternatively, fluid is only conveyed between the ports 28, i.e. between the syringes 14, 15, upon actuation of the pump actuator 16 and displacement of the respective plunger 22.

[0060] The valves 40 may be formed as respective pinch valves and may be actuated by the control unit 32, not shown in Figure 2. Thereby, the valves 40 may selectively adopt a closed state and an open state. The first reservoir 42 comprises a filter having a predefined filter size or mesh size. Accordingly, the conveying of the sample 24 to the first reservoir 42 results in the collection of a filtrate. Undesired cells or components of the samples may be retained upstream of the filter. Thereby, an initial enrichment of the sample 24 may be envisaged or ensured.

[0061] Furthermore, the first reservoir 42 is fluidically coupled to a solution reservoir 50 at an upstream end. A volume of the solution may be transferred to the first reservoir 42 by using a pump, which is exemplarily depicted as a peristaltic pump 52. The peristaltic pump 52 may preferably not be configured as part of the overall disposable 100. Rather, it may be provided on the control side of the system 10 and be fluidically separated to avoid potential contamination. Alternatively, a different type of pump may be implemented in the system 10. In this regard, a corresponding disposable pump head may be integrated in the disposable fluidic system 100.

[0062] The solution may be introduced into the first reservoir 42, which may be formed e.g. as a container having an inlet and an outlet. A rinsing of the sample 24 may be performed, e.g. by using a buffer solution. The sample 24 has already been processed by the preceding emulsification. Still, the addition of the solution to the sample 24 in the first reservoir may further support the cells comprised in the sample 24 and being smaller than the predefined filter size to pass through the filter.

[0063] In the present example, the system 10 furthermore comprises a series of downstream reservoirs forming a filter cascade for the filtrate exiting the first reservoir 42. Accordingly, the filtrate may flow to a second reservoir 44, third reservoir 46, and fourth reservoir 48, wherein the respective filters successively exhibit an increased filter density, i.e. a reduced filter pore size. Larger cells may be retained in upstream reservoirs, while smaller cells may be transferred to downstream reservoirs in a gradual manner.

[0064] In order to facilitate the collection of the target cells, e.g. of a stromal vascular fraction, the fourth reservoir 48 comprises a filter size for collecting these target cells. They do not pass through the pores of that filter. The filter pore size may, however, be chosen such that smaller cells, e.g. (particular) blood cells, may be removed from the system 10, thereby decreasing that cell fraction while enabling enrichment of the target cells. In this regard, the filter pore size may be chosen, such that, for example, the first reservoir 42 may have a filter size of about 100 pm (+ / - 10), the second reservoir 44 may have a filter size of about 50 pm (+ / - 10), the third reservoir 46 may have a filter size of about 20 pm (+ / - 5), and the fourth reservoir 48 may have a filter size of about 10 pm (+ / - 2). More generally, the filter pore size may decrease along the chain of the reservoirs, e.g. by a factor of between 0.3 and 0.8 from one reservoir to the next.

[0065] At the downstream end of the disposable 100, a collection syringe 52 is fluidically coupled to the fourth reservoir 48 so as to collect the enriched target cells. Alternatively, the collected target cells may also be forwarded to a further processing module via a downstream fluidic connection 56, e.g. for further purification and / or processing of the sample 24. Downstream of the fourth reservoir 48 a waste reservoir or discharge line (not shown) may also be foreseen to collect the filtrate from the fourth reservoir 48. Thereby, the amount of solution provided to the sequential reservoirs 42-48 or corresponding filter cascade may be varied depending on nature and the characteristics of the sample to be processed.

[0066] It will be obvious for a person skilled in the art that these embodiments and items only depict examples of a plurality of possibilities. Hence, the embodiments shown here should not be understood to form a limitation of these features and configurations. Any possible combination and configuration of the described features can be chosen according to the scope of the invention.

[0067] List of reference numerals

[0068] 10 System

[0069] 12 Pump or actuator

[0070] 14 First syringe

[0071] 15 Second syringe

[0072] 16 Pump actuator

[0073] 18 Piston head

[0074] 20 Force sensor

[0075] 22 Plunger

[0076] 24 Sample

[0077] 26 Stop

[0078] 28 Port

[0079] 30 Tube

[0080] 32 Control unit

[0081] 34 Longitudinal displacement

[0082] 36 Drive

[0083] 38 Lateral displacement

[0084] 40 Valve

[0085] 42 First reservoir

[0086] 44 Second reservoir

[0087] 46 Third reservoir

[0088] 48 Fourth reservoir

[0089] 50 Solution reservoir

[0090] 52 Peristaltic pump

[0091] 54 Collection syringe

[0092] 56 Fluidic connection

[0093] 100 Disposable fluidic system

Claims

Claims1 . A system (10) for processing a biological sample (24), comprising a disposable fluidic system (100), comprising a first syringe (14) for receiving a biological sample (24), a second syringe (15), and two ports (28) being fluidically connected to each other, wherein each port (28) is configured to be fluidically connected with a respective one of the syringes (14, 15), an actuator (12), configured to displace a plunger (22) of a respective syringe (14, 15), and a control unit (32), configured to output a control signal to the actuator (12) to initiate at least one emulsifying cycle by conveying fluid comprised in one of the syringes (14, 15) to the other syringe (14, 15) via the fluidic connection based on the displacement of the respective plunger (22).

2. The system (10) according to claim 1 , wherein the control unit (32) is configured to output a control signal for two or more emulsifying cycles, wherein the control signal is adapted to convey the entire fluid or a predefined portion of the fluid present in a respective syringe (14, 15) to the respective other syringe (1 , 15) for each emulsifying cycle.

3. The system (10) according to claim 1 or 2, wherein the actuator (12) comprises a force sensor (20) for detecting a force being exerted on the respective plunger (22) and being communicatively coupled with the control unit (32), wherein the control signal is adapted to displace the respective plunger (22) for a respective emulsifying cycle with a predefined force and wherein the control unit (32) is configured to adjust the control signal based on a comparison of the predefined force with an actual force measurement.

4. The system (10) according to any of the preceding claims, wherein the control unit (32) is configured to output the control signal for a predefined number of emulsifying cycles.

5. The system (10) according to claim 1 or 2, wherein the actuator (12) comprises a force sensor (20) for detecting a force being exerted on the respective plunger (22) and being communicatively coupled with the control unit (32), wherein the control signal is configured to compare an actual force measurement for a respective emulsifying cycle with a predefined lower force threshold and to output the control signal until said predefined lower force threshold is achieved or exceeded for a respective emulsifying cycle.

6. The system (10) according to claim 5, wherein the predefined lower force threshold corresponds to a predefined target viscosity being lower than a viscosity of the sample prior to or during the initiating emulsifying cycle.

7. The system (10) according to any of the preceding claims, wherein the fluidic system (100) comprises a tube (30) fluidically connecting the ports (28) and further comprises at least a first reservoir (42) being fluidically connected to said tube (30) and arranged downstream of the ports (28).

8. The system (10) according to claim 7, wherein the fluidic system (100) further comprises a first valve (40) at the tube (30) being configured and arranged to selectively block fluid communication between the ports (28) and being arranged to enable fluid communication from one port (28) to the downstream first reservoir (42) in the blocked state.

9. The system (10) according to claim 7 or 8, wherein the fluidic system (100) further comprises a second valve (40) arranged upstream of the first reservoir (42) and arranged to selectively block fluid communication between the ports (28) and the first reservoir (42).

10. The system according to claim 7, wherein the fluidic system (100) comprises a tube (30) fluidically connecting the ports (28) and further comprises at least a first reservoir (42) being fluidically connected to said tube (30) and arranged downstream of the ports (28), wherein the fluidic system (100) further comprises a first valve (40) at the tube (30) being configured and arranged to selectively block fluid communication between the ports (28) and being arranged to enable fluid communication from one port (28) to the downstream first reservoir (42) in the blocked state, and wherein the fluidic system (100) further comprises a second valve (40) arranged upstream of the first reservoir (42) and arranged to selectively block fluid communication between the ports (28) and the first reservoir (42).1 1 . The system (10) according to any of claims 7 to 10, wherein the first reservoir (42) comprises a filter with a predefined filter size being arranged to filter the emulsified sample (24) from the upstream port (28) to the first reservoir (42).

12. The system (10) according to any of claims 7 to 11 , wherein the first reservoir (42) is in fluid communication with an upstream pump-driven solution reservoir (50), wherein the control unit (32) is configured to actuate the pump (52) to convey a portion of the solution to the emulsified sample (24) received by the first reservoir (42).

13. The system (10) according to claim 12, wherein the fluidic system (100) comprises at least one further downstream reservoir (44, 46, 48) with a respective filter having a predefined filter size and being arranged to filter the portion of the emulsified sample (24) from the upstream first reservoir (42) to said further reservoir (44, 46, 48), wherein each filter of a successive reservoir (44, 46, 48) comprises a reduced filter size.

14. The system (10) according to any of claims 11 to 13, wherein the downstream-most filter comprises a filter size between 1 pm and 12 pm or between 8 pm and 10 pm.

15. The system (10) according to any of claims 7 to 14, wherein the fluidic system (100) comprises a collector port downstream of the downstream-most reservoir, the collector port being fluidically coupled to a collector reservoir or a processing module.

16. A method for processing a biological sample, comprising the steps of: providing a first syringe and a second syringe fluidically coupled to the first syringe; and providing a biological sample in one of the syringes; and initiating at least one emulsifying cycle by displacing a plunger of a respective syringe so as to convey fluid comprised in one of the syringes to the other syringe, wherein the displacement of a plunger of the respective syringe is performed by an actuator controlled by a control unit.

17. The method according to claim 16, wherein the displacement of the plunger is performed using a predefined force or wherein one or more further emulsification cycles are performed until a predefined lower force threshold is achieved.

18. The method according to claim 16 or 17, wherein the predefined lower force threshold corresponds to a reduced viscosity of the sample.

19. The method according to any of claims 16 to 18, wherein the sample is a tissue sample.

20. The method according to claim 19, wherein the tissue sample is a semi-solid or gel-like tissue sample.

21. The method according to any of claims 16 to 20, wherein the sample comprises or consists of a lipoaspirate.

22. The method according to claim any of claims 16 to 21 , wherein the emulsified sample is conveyed from one of the syringes to a downstream first reservoir using the actuator, wherein the emulsified sample is preferably passed through a filter of the first reservoir.

23. The method according to claim 22, wherein the control unit actuates a pump of a solution reservoir upstream of the first reservoir to convey a portion of the solution to the emulsified sample received by the first reservoir.

24. The method according to claim 23, wherein the portion of the emulsified sample received by the first reservoir is conveyed to at least one further downstream reservoir with a respective filter having a predefined filter size so as to filter the portion of the emulsified sample from an upstream reservoir to the downstream reservoir, wherein each filter of a successive reservoir comprises a reduced filter size.

25. The method according to any of claims 22 to 24, wherein the downstream-most filter comprises a filter size between 1 pm and 12 pm or between 8 pm and 10 pm.

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