method for moistening a membrane in a membrane separator

专利摘要:
MEMBRANE SEPARATION DEVICES, SYSTEMS AND METHODS THAT EMPLOYE THE SAME AND DATA MANAGEMENT SYSTEMS AND METHODS. The present invention relates to a membrane separation device that is disclosed together with systems and methods that employ the device in blood processing procedures. In one embodiment, a rotating membrane separator is provided in which at least two zones or regions are created in the gap between the membrane and the shell so that the mixing of the fluid between the two regions is inhibited by a radial rib associated with the membrane that decreases the gap between the membrane and the shell to define two regions of fluid, the crest isolates the fluid in the two regions to minimize mixing between the two. Automated systems and methods are revealed to separate a unit of whole blood previously collected into components such as concentrated red cells and plasma to collect red cells and plasma directly from a donor in a single step and for washing cells. Data management systems and methods and pre-activation methods are also revealed.
公开号:BR112013022568B1
申请号:R112013022568-8
申请日:2012-03-09
公开日:2021-01-12
发明作者:Benjamin E. Kusters；Christopher J. Wegener；Kyungyoon Min
申请人:Fenwal, Inc.；
IPC主号:

专利说明:

[0001] [0001] The present application relates, in part, to separation devices of the type employing surfaces of relative rotation, at least one of which carries a membrane to filter a component of the fluid that passes between the surfaces; fluid flow circuits and systems that incorporate such a separator; and the use of such systems to separate biological cells such as red cells, plasma or white cells from whole blood, a storage medium, a suspension medium, a supernatant or the like. FUNDAMENTALS
[0002] [0002] Traditional blood collection continues to depend heavily on manual collection of whole blood from healthy donors through blood collection campaigns, donor visits to blood banks or hospitals and the like. In common manual collection, whole blood is collected simply by its flow, under the force of pregnancy and venous pressure, from the donor vein in a collection container. The amount of whole blood drawn is usually a "unit" which is about 450 ml.
[0003] [0003] More specifically, such collection typically employs a pre-assembled arrangement of tubing and containers or bags that include a flexible plastic primary container or bag to receive a donor whole blood unit and one or more "satellite" containers or bags . Blood is collected first in the primary container which also contains an anticoagulant (usually containing sodium citrate, phosphate and dextrose, often referred to as CPD). A preservative (often called an "additive solution" or AS and which normally contains a saline, adenine and glucose medium, which is referred to as SAG) can be included as part of a larger array of bags and tubes that are used in the processing after blood is collected.
[0004] [0004] After collecting a whole blood unit, it is common practice in the blood bank to transport the whole blood unit through connected tubing and containers to a blood component processing laboratory referred to as a "support laboratory" for additional processing. Additional processing commonly involves manually loading the primary container and associated tubing and satellite containers in a centrifuge to separate whole blood into components such as concentrated red cells and platelet-rich or platelet-poor plasma. These components are then manually expressed from the primary container into other pre-connected satellite containers and can be centrifuged again to separate the platelets from the plasma. Subsequently, blood components can be leukoreduced by filtration for further processing or storage. In short, this process is time consuming, laborious and subject to possible human error.
[0005] [0005] Another routine task performed by blood banks and transfusion centers is "cell washing." This can be done to remove and / or replace the liquid medium (or a part of it) in which the cells are suspended, to further concentrate or concentrate cells in a liquid medium and / or to purify a cell suspension by removing material unwanted cell phone or other material.
[0006] [0006] Previous cell washing systems typically involved centrifuging a cell suspension, decanting the supernatant, resuspending concentrated cells in new media, and possible repeating these steps until the cells in the suspension are supplied in a suitably high concentration or otherwise desirable. Centrifugal separators used in the processing of blood and blood components have typically been used in such cell washing methods.
[0007] [0007] These processes are also very time consuming, requiring repeated manual manipulation of blood or blood components and assembly or disassembly of various fluid processing devices. This, of course, increases not only the costs, but also the potential for human error or mistakes. Consequently, even with decades of advances in blood separation devices and processes, there is still a desire for better and / or more effective separation devices, systems and methods applicable to basic blood collection and processing modalities.
[0008] [0008] Although many of the previous blood separation procedures and devices have employed the principles of centrifugal separation, there is another class of devices based on the use of a membrane, which has been used for plasmapheresis, that is, separation of plasma from blood total. More specifically, this type of device employs surfaces of relative rotation, at least one of which carries a porous membrane. Typically, the device employs an external stationary housing and an internal rotating rotor covered by a porous membrane.
[0009] [0009] A well-known plasmapheresis device is the Autopheresis-C® separator sold by Fenwal, Inc. of Lake Zurich, Illinois. A detailed description of a rotating membrane separator can be found in U.S. Patent No. 5,194,145 to Schoendorfer, which is incorporated by reference into this document. This patent describes a spreader covered by a membrane that has an interior collection system arranged inside a stationary enclosure. The blood is fed in an annular space or between the spreader and the wrapper. The blood moves along the longitudinal axis of the envelope towards an outlet region with the plasma passing through the membrane and outside the envelope in a collection bag. The remaining blood components, primarily red blood cells, platelets and white cells, move to the exit region between the spreader and the sheath and are then normally returned to the donor.
[0010] [00010] The rotating membrane separators have been found to provide excellent plasma filtration rates due primarily to the unique flow patterns ("Taylor vortices") induced in the gap between the rotating membrane and the housing. Taylor's vortexes help to prevent blood cells from depositing in and encrusting or binding the membrane.
[0011] [00011] Although rotating membrane separators have been used extensively for the collection of plasma, they have not normally been used for the collection of other blood components, specifically red blood cells. Rotating membrane separators have also not been commonly used for cell washing. An example of a rotating membrane separator used in washing cells such as red blood cells is described in US Patent 5,053,121 which is also fully incorporated by reference. However, the system described therein uses two separate spreaders associated in series or in parallel to wash a patient's "bleed" blood. Other descriptions of the use of rotating membrane separators for the separation of blood or blood components can also be found in U.S. Patents 5,376,263; 4,776,964; 4,753,729; 5,135,667 and 4,755,300.
[0012] [00012] The claimed material disclosed in this document provides additional advantages in membrane separators, potential cost savings and several other advances and advantages over previous manual blood collection and processing. SUMMARY OF THE REVELATION
[0013] [00013] This subject has numerous aspects that can be used in various combinations and the disclosure of one or more specific modalities is for the purpose of disclosure and description and not limitation. This summary highlights only some of the aspects of this claimed matter and additional aspects are revealed in the drawings and in the more detailed description that follows.
[0014] [00014] According to one aspect of the disclosure, a method for pre-activating a membrane separator is provided. The membrane separator comprises a housing with a top and a bottom, with at least one adjacent door, each at the top and bottom of the housing, with the membrane arranged inside the housing so as to rotate around an axis generally oriented vertically . The method for pre-activation includes introducing a pre-activation fluid through the port adjacent to the bottom of the housing and then flowing the additional pre-activation fluid through the port adjacent to the bottom of the housing so that a fluid-air fluid interface pre-activation is formed that advances upward through the housing to displace air within the housing and to expel air through the door adjacent to the top of the housing, while simultaneously moistening the membrane. The additional pre-activation fluid continues to flow through the port adjacent to the bottom of the housing until the pre-activation fluid-air interface has advanced vertically across the entire membrane. The pre-activation fluid can comprise either a low-viscosity non-biological fluid or whole blood.
[0015] [00015] According to another aspect of the disclosure, a fluid processing circuit is provided that comprises a separator that includes surfaces of relative rotation within a housing in which at least one of the surfaces carries a porous membrane and the surfaces are separated for define a span that generally extends axially between the two. The housing includes at least one fluid inlet and at least one fluid outlet that communicates directly or indirectly with the span, with the outlet being located in a lower region of the housing and the inlet being located in a region of the housing axially spaced above the exit. The housing preferably has an upper end and a lower end in an operating position with the inlet near the upper end and the outlet near the lower end. The processing circuit further comprises a source of pre-activation fluid and a conduit that connects the source of pre-activation fluid to at least one outlet of the housing.
[0016] [00016] Additionally, the processing circuit may preferably comprise a rotor disposed within the housing with the outer surfaces of the rotor being spaced from an interior surface of the housing to define an annular gap between them. The membrane separator and housing are preferably relatively rotatable with each other around a generally vertical axis and the at least one outlet communicates directly with the gap between the membrane and the housing. The fluid inlet preferably communicates with the gap to deliver a fluid containing blood or blood components in the gap and at least one of the outer surface and the inner surface that carries a porous membrane with the fluid outlet that communicates directly with the span or with one side of the membrane facing the opposite side of the span or both. BRIEF DESCRIPTION OF THE DRAWINGS
[0017] [00017] These and other resources of the present claimed matter are described in the following detailed description and shown in the attached figures, of which:
[0018] [00018] Fig. 1 is a perspective view of a rotating membrane separator, in partial cross-section and with portions removed to show details.
[0019] [00019] Fig. 2 is a longitudinal cross-sectional view of the rotating membrane separator of Fig. 1.
[0020] [00020] Fig. 3 is a contour plot of the exit hematocrit and exit wall shear stress as a function of the relative filter length and spreader radius based on a theoretical design model.
[0021] [00021] Fig. 4 is a contour plot of the output hematocrit and the concentration of hemoglobin in the output plasma as a function of the relative filter length and spreader radius based on a theoretical design model for which the velocity tangential of the membrane is constant.
[0022] [00022] Fig. 5 is a contour plot of the output hematocrit and Taylor Number as a function of the relative filter length and spreader radius based on a theoretical design model.
[0023] [00023] Fig. 6 is a three-dimensional plot of the hemoglobin concentration in plasma as a function of the relative filtration length and spreader radius based on a theoretical design model.
[0024] [00024] Fig. 7 is a perspective view of a rotating membrane device or separator according to the present application.
[0025] [00025] Fig. 8 is a schematic cross-sectional view of a rotating membrane separator according to the present application in which the spreader includes a ridge which extends radially to define separate fluid regions.
[0026] [00026] Fig. 9 is a schematic view of an automated whole blood separation system for pre-collected whole blood processing that includes a disposable fluid flow circuit module and a durable controller or control module with the fluid flow circuit mounted on it.
[0027] [00027] Fig. 10 is a flow diagram showing a fluid flow modality through a fluid flow circuit as described in this document for processing a whole blood unit in a concentrated red cell product and a product of plasma.
[0028] [00028] Fig. 11 is similar to Fig. 9, but with a somewhat more detailed view of the components of a fluid flow circuit or disposable module and a durable controller module.
[0029] [00029] Fig. 12 is a schematic view of an alternative embodiment of the system according to the present disclosure in which the system is used for the separation of whole blood collected previously.
[0030] [00030] Fig. 12A is a schematic view of an additional alternative modality similar to Fig. 12.
[0031] [00031] Fig. 13 is a perspective view of a two pump blood separation system as shown in Figures 9, 11, 12 and 12A.
[0032] [00032] Fig. 14 is a schematic view of an additional alternative similar to Fig. 12, except for incorporating three pumps, which illustrates the system in the pre-activation phase.
[0033] [00033] Fig. 15 is a schematic view of the system of Fig. 14 illustrating the system in the separation phase.
[0034] [00034] Fig. 15A is a schematic view of an additional alternative three pump system similar to that in Figures 14 and 15.
[0035] [00035] Fig. 16 is a schematic view of an automated whole blood collection system according to the present disclosure that shows the system configuration for automated office collection and processing of a donor's whole blood in pre- activation.
[0036] [00036] Fig. 17 is a schematic view of the system in Fig. 16 showing the system configuration for collecting and separating whole blood in red blood cells and plasma.
[0037] [00037] Fig. 18 is a schematic view of the system in Fig. 16 showing the configuration of the system to rinse the system with anticoagulant after the end of the donor blood collection.
[0038] [00038] Fig. 19 is a schematic view of the system in Fig. 16 showing the system configuration at the end of the blood collection procedure.
[0039] [00039] Fig. 20 is a schematic view of the system of Fig. 16 showing the configuration of the system in the optional arrangement for filtering the red blood cells collected by a leukocyte filter.
[0040] [00040] Fig. 21 is a schematic view of an alternative embodiment of an automated whole blood collection system to that of Figures 16 to 20 in which the single-use disposable fluid circuit component comprises an integrated leukoreduction filter as part of the extraction line of the donor access device.
[0041] [00041] Fig. 22 is a schematic view of an alternative single-use disposable fluid circuit of Fig. 21 in which the leukoreduction filter is positioned on the extraction line downstream of the entry point where the anticoagulant is introduced. in whole blood.
[0042] [00042] Fig. 23 shows a disposable set useful in washing cells according to the method disclosed in this document.
[0043] [00043] Fig. 24 shows another embodiment of a disposable set useful in washing cells according to an alternative method disclosed in this document.
[0044] [00044] Fig. 25 shows an embodiment of the control panel of a device useful in washing cells according to the method disclosed in this document.
[0045] [00045] Figures 26 to 28 are flowcharts of the steps of the cell washing methods disclosed in this document.
[0046] [00046] Fig. 29 is a flow chart that illustrates a method of data management according to the present disclosure.
[0047] [00047] Fig. 30 is a schematic drawing of a data management system according to the present disclosure in combination with a collection container and a processing kit.
[0048] [00048] Fig. 31 is a flowchart that illustrates the various steps that comprise a method for data management in accordance with the present disclosure. DETAILED DESCRIPTION
[0049] [00049] A more detailed description of the rotary membrane separator according to the present disclosure and its use in various automated systems is presented below. It should be understood that the description below of specific devices and methods is intended to be exemplary and not exhaustive of all possible variations or applications. Thus, the scope of the disclosure is not intended to be limiting and should be understood as covering variations or modalities that may occur to people skilled in the art.
[0050] [00050] Turning to Figures 1 and 2, a rotating membrane or fractionation blood separation system, generally designated as 10, is shown. Such a system 10 is normally used to extract plasma from whole blood obtained from an individual human donor. To facilitate understanding, only the plasma separation device and the associated guidance unit are shown, although it should be understood that such a separator forms part of a disposable system that includes collection bags, bags of assets like saline or ACD, bags of return, piping, etc. and that there are also systems for instrumentation and control associated with the operation of the device.
[0051] [00051] System 10 includes a generally cylindrical housing 12 mounted concentrically around a central longitudinal axis. An inner member 14 is mounted concentric with the central axis. The housing and the inner member are relatively rotatable. In the preferred embodiment, as shown, the housing is stationary and the inner member is a rotating spreader that is rotatable concentrically within the cylindrical housing 12. The boundaries of the blood flow path are generally defined by the gap 16 between the inner surface of the housing 12 and the outer surface of the rotary spreader 14. The spacing between the housing and the spreader is sometimes referred to as shear gap. A common shear span can be approximately 0.067 to 0.127 cm (0.025 to 0.050 inch) and can be of a uniform dimension along the axis, for example, where the axis of the spreader and the housing is coincident. The shear gap can also vary circumferentially, for example, where the axis of the housing and spreader is deflected.
[0052] [00052] The shear span can also vary along the axial direction, for example, preferably an incremental span width in the flow direction to limit hemolysis. Such span width can be in the range of about 0.06 to 0.19 cm (0.025 to about 0.075 inch). For example, the geometrical axes of the housing and the rotor can be coincident and the diameter of the rotor decreases in the axial direction (flow direction) while the diameter of the interior surface of the housing remains constant or the diameter of the housing increases while the diameter of the rotor remains constant or both surfaces vary in diameter. For example, the span width can be about 0.088 cm (0.035 inch) upstream or at the entrance end of the span and about 0.15 cm (0.059 inch) at the downstream or terminal end of the span. The span width could be varied by varying the outer diameter of the rotor and / or the inner diameter of the surface of the opposite housing. The span width could change linearly or staggered or in any other way as desired. In any event, the span width dimension is preferably selected so that at the desired relative rotation speed, the Taylor-Couette flow, like the Taylor vortexes, is created in the span and hemolysis is limited.
[0053] [00053] Whole blood is fed from an inlet conduit 20 through an inlet orifice 22 that directs blood in the blood flow inlet region in a path tangential to the circumference around the upper end of spreader 14. At the lower end of the cylindrical housing 12, the inner housing wall includes an outlet hole 34.
[0054] [00054] The cylindrical housing 12 is completed by an upper end cap 40 which has an end boss 42, the walls of which are not magnetic and a lower end housing 44 which ends in a concentric plasma outlet hole 46 with the central axis.
[0055] [00055] The spreader 14 is pivotally mounted between the upper end cover 40 and the lower end housing 44. The spreader 14 comprises a shaped central mandrel or rotor 50, the outer surface of which is being shaped to define a series of separate circumferential grooves or ribs 52 that are separated by annular streaks 54. The surface channels defined by circumferential grooves 52 are interconnected by longitudinal grooves 56. At each end of mandrel 50, these grooves 56 are in communication with a central orifice 58 .
[0056] [00056] In the illustrated embodiment, the surface of the rotating spreader 14 is at least partially and is preferably substantially or entirely covered by a cylindrical porous membrane 62. The membrane 62 normally has a nominal pore size of 0.6 microns, but other sizes of pore can be used alternatively. The membranes useful in the washing methods described in this document can be membranes of fibrous mesh, fused membranes, membranes notched with tracks or other types of membranes which will be known to those skilled in the art. For example, in one embodiment, the membrane may have a polyester mesh (substrate) with nylon particles solidified in it, thus creating a tortuous path through which only components of certain dimensions can pass. In another embodiment, a membrane can be made of a thin (approximately 15 microns thick) blade, for example, polycarbonate. In this modality, the pores (holes) may be larger than those described above. For example, pores can be approximately 3 to 5 microns. The pores can be sized to allow small formed components (eg, platelets, microparticles, etc.) to pass while the desired cells (eg, white blood cells) are collected.
[0057] [00057] The rotating spreader is mounted on the upper end cap to rotate around a pin 64 which is suitable by pressing on the end cap 40 on one side and resting within a cylindrical support surface 65 on a final cylinder 66 which forms part of the rotary spreader 14. The internal spreader or external housing can be rotated by any suitable rotating guidance device or system. As shown, the final cylinder 66 is partly covered by a ring 68 of magnetic material used in the indirect orientation of the spreader 14. An activation motor 70 external to the housing 12 is coupled to rotate an annular magnetic guidance member 72 that includes at least one pair of inner permanent magnets 74. As the ring guide member 72 is rotated, a magnetic attraction between the ring 68 inside the housing 12 and the magnets 74 outside the housing locks the spreader 14 to the outer orientation, which causes the spreader 14 rotate.
[0058] [00058] At the lower end of the rotary spreader 14, the central outlet hole 58 communicates with a central hole 76 in an end support 78 that is concentric with the central axis. An end support seat is defined by an internal shoulder 80 which forms a lower edge of a central opening 82. The central opening 82 communicates with the plasma outlet hole 46. If the surface facing the interior of the housing is covered entirely or partially through a membrane, a fluid collection or collector can be provided below the membrane to collect plasma and direct it through a housing outlet (not shown). I. Membrane separator design
[0059] [00059] To maintain an aspect of the application, a rotating membrane separator is provided that provides improved plasma flow rates with a low acceptable level of hemolysis in the retained blood. Several factors are known to affect the filtration flow rate through rotating membrane separators that include the speed of rotation, the size of the gap between the rotating membrane and the casing, the effective area of the membrane, the concentration of red blood cells ( or hematocrit) and blood viscosity. Previous practices in the design of rotating membrane devices have been largely empirical aided to some extent by vague phenomenological descriptions of the effects of the various design parameters on performance and hemolysis. This proved to be ineffective in terms of development time and technical resources spent.
[0060] [00060] In contrast, the parameters of the rotating membrane separator of the present application were determined based on quantitative differential models that take into account the speed of local plasma across the membrane and the concentration of local hemoglobin. These differential models were integrated across the length of the device to provide a total plasma flow rate and plasma hemoglobin concentration at the device's outlet.
[0061] [00061] The method included the operational inputs based on the existing Plasmacell-C separator geometry and operating conditions including donor hematocrit, inlet blood flow rate, rotation speed and effective membrane area. The geometrical entries of the rotor radius, the width of the annular span and the length over which the integration is performed were also factored. See Table 1 below. To obtain predicted values for hypothetical separators, the motor radius and filter length were varied from about 1.0 to about 2.0 times the current Plasmacell-C values in 0.05 increments, providing a grid of 21x21 project space for each output variable of interest. For all devices, the housing taper and the exit gap were kept constant and the entry gap and rotation speed were varied accordingly. Models were also developed that related blood viscosity and density to hematocrit, temperature and anticoagulant concentration.
[0062] [00062] In an implantation of the method, the outputs of plasma flow rate and hemoglobin concentration were obtained for various values of the motor radius, the rotation speed and the integration length. The results of the models are shown in the overlapping contour plot of the output hematocrit and output wall shear stress (Fig. 3), the output hematocrit and the hemoglobin concentration in the output plasma (Fig. 4) and the hematocrit output and Taylor number (Fig. 5), all as a function of the relative filter length and spreader radius. As used herein, the "filtration length" is understood to be the axial length of the mandrel or central rotor 50 from the beginning to the end of the grooves or ribs 52. It generally represents the length of the membrane available for filtration. The "spreader radius" or "spreader diameter" is understood to be the radius or diameter of the rotor with the membrane attached. Fig. 6 shows the hemoglobin results in plasma as a function of the filter length and spreader radius in a three-dimensional plot showing the increase in hemoglobin with larger devices. These results were then evaluated to provide the best balance of high plasma flow rate with acceptably low levels of hemolysis.
[0063] [00063] The models indicated that the effective area of the membrane has the strongest positive influence on performance. Additionally, although the increase in the membrane area by increasing the diameter of the rotor impacts more positively on flow rates than the increase in the membrane area by increasing the length of the rotor, it also increases the potential for hemolysis due to the increased speed of the membrane and, thus, the increase in shear forces in the span.
[0064] [00064] Consequently, the models predict lengths and diameters for the rotor that would result in increased membrane areas whose use would also have acceptably low levels of hemolysis. The prototypical separators (based on the results of the models) were made and tested to validate the results predicted by the models. Table 2 below compares a current Plasmacell-C plasmapheresis device with two potential alternatives based on the models.
[0065] [00065] With reference to Table 2 and Fig. 7, a rotary membrane separator 10 includes a rotary spreader 14 which has a spreader diameter D, a filter length FL and an overall length LOA. In a common plasmapheresis device such as the Plasmacell-C separator, the rotor has a D diameter of approximately 2.8 cm (1.1 "), an FL filter length of approximately 7.62 cm (3") and a length of overall LOA of approximately 12.7 cm (5.0 ").
[0066] [00066] According to the present application, it has been found that the diameter of the membrane can be increased by up to about 2.0 times the diameter of the membrane found in a common plasmapheresis device while the length can be increased up to about 2 , 5 times the length of the rotating membrane in a common plasmapheresis device. An increase in the rotor size within these perimeters increases the area of the filtration membrane enough to provide a high plasma flow rate while providing an acceptably low level of hemolysis. In a specific example, a rotating membrane separator according to the present application can advantageously have a diameter of 4.19 cm (1.65 "), an FL filter length of 14.02 cm (5.52") and an overall LOA length of 19.5 cm (7.7 ").
[0067] [00067] Prototypical rotating membrane separators were tested with human and bovine blood to validate the results predicted by the models. Blood flow rates of 100 ml / min were obtained with spreader speeds ranging from 1,000 to 3,500 rpm. Output hematocrit levels of 80% and higher were obtained before high levels of membrane encrustation were experienced. The collection times for 880 ml of plasma were in the range of approximately 18 to 20 minutes.
[0068] [00068] As noted above, the residence time of the red blood cells in the shear gap has a direct relationship to the amount of hemolysis. In rotating membrane separation devices, there are flow regions along the axial length of the rotor where fluid flows are relatively inert, resulting in hemolysis deposits. To the extent that the red blood cells in the region of high hemolysis intermix with the flow in the region of low hemolysis, the quality of the collected red blood cells is impaired.
[0069] [00069] Consequently, to keep up with another aspect of the order, a method is provided to create separate fluid flow regions in the span of a rotating membrane separator without the use of seals. The separate flow regions reduce or minimize the influence of fluid mixing between the two flow regions. The separate flow regions are obtained by having a protruding rib or crest in the gap to reduce or minimize the gap between the spreader and the outer cylinder. Preferably, the ridge or rib is provided on the surface of the rotor in addition to where the rotating membrane is attached to it.
[0070] [00070] The ridge is preferably located in order to define the boundary of the high perfusion flow region. The radial size of the ridge is inversely proportional to the degree of mixing allowed between the two regions defined by it with a larger radial dimension for the ridge that allows less mixing. The axial dimension or length of the ridge is also inversely proportional to the degree of mixing allowed with a larger axial dimension allowing less mixing. The axial dimension of the ridge is preferably at least one span size to minimize the formation of adjacent Taylor vortices that cause undesired mixing.
[0071] [00071] With reference to Fig. 8, a schematic cross-sectional representation of a rotating diaphragm separation device 10 is shown. The device comprises a clamped outer cylinder 12 and a rotating inner cylinder 14 that has a filter member loaded in it. According to the present application, the inner cylinder is provided with a radial crest 90. This crest serves to divide the gap 16 between the spreader and the external housing in two regions of fluid. A first fluid region 92 has a non-sprayed inert flow region, usually over the portion of the spreader that extends beyond the filter membrane. A second fluid region 94 that normally comes into contact with the filter membrane has a highly sprayed flow region.
[0072] [00072] Because the first fluid region 92 is not sprayed, the blood residing in it is exposed to increased shear stresses for longer periods of time than the blood in the second fluid region 94. Thus, the blood in the first region fluid 92 can often become hemolyzed and has high concentrations of free hemoglobin (Hb). Crest 90 inhibits fluid flow between the two fluid regions, thereby minimizing the extent of mixing of blood contaminated with Hb in the first region 92 with the low Hb sage in the second region 94.
[0073] [00073] Although the ridge 90 is shown to be integrated with the rotor, it can also be formed inside the outer cylinder to obtain the same effect. As noted above, the axial dimension of the ridge must be at least one span size. A common rotating membrane separation device for performing plasmapheresis usually has a gap between the spreader and the containment wall between 0.058 cm (0.023 ") to 0.0673 cm (0.0265") and a ridge according to the present order it could have an axial dimension within the same general range. However, larger axial dimensions for the ridge will result in reduced mixing and, in one example, a rotor that has a radially extending ridge with an axial dimension of 0.234 cm (0.092 ") has been found to be effective. II. Systems and Methods for Processing Whole Blood Previously Collected
[0074] [00074] A rotating membrane separation device as described above can be advantageously used in various blood processing systems and methods for which prior art devices are generally not suitable, particularly systems and processes for obtaining red blood cells. In one type of system and method, the spreader can be used for processing the "support laboratory" of whole blood previously collected as shown in Figures 9 to 15A.
[0075] [00075] Turning now to Fig. 9, a disposable fluid flow circuit or module A and a durable reusable controller or module B configured to cooperate with and control flow through fluid circuit A are illustrated schematically. The disposable fluid circuit A as illustrated in Fig. 9 includes several components interconnected by flexible plastic tubing that defines flow paths between the components. The circuit is preferably fully pre-assembled and pre-sterilized with the possible exception of the whole blood container unit and the cell preservative container. More specifically, the disposable circuit illustrated in Fig. 9 includes a whole blood container 101, a cell preservation solution container 102, a blood component separator 108, a plasma collection container 112, a blood reduction filter. optional leukocyte 113 and a red cell collection container 115. Although not shown in Fig. 9, the reusable module B can have hangers with associated scales to support any or all of the containers 101, 102, 112 and 115. In several of the other modalities discussed in this document, such hangers / scales may not be illustrated, but are understood to be part of the systems described.
[0076] [00076] The whole blood collection container 101 can be any suitable container, but it is usually a pouch or flexible plastic bag in which approximately 450 ml of whole blood has been collected previously. Container 101 can be part of a separate system during collection and then joined to the rest of fluid circuit A or currently part of circuit A at the time of collection. At the time of collection, according to the standard procedure, whole blood is mixed with an anticoagulant located in the primary container to prevent premature clotting. Accordingly, "whole blood" as used herein includes blood mixed with anticoagulants.
[0077] [00077] Flexible plastic tubing 105 is attached to the whole blood collection vessel, such as by a sterile connection device or other suitable attachment mechanism and defines a whole blood fluid flow path between the whole blood vessel 101 and a junction with the cell preservative solution tubing 103 extending from the cell preservation solution container 102 to the flow path junction. The flow path junction between the whole blood flow path and the entire preservative flow path is located on an inlet clamp 116. From the junction, the flow path extends through tubing 107 to an inlet port in the 108 tab.
[0078] [00078] As shown in Fig. 9 of this description, the separator housing has an outlet that communicates with the gap between the housing and the rotor and with concentrated red cell flow path tubing 110 to extract concentrated red cells from the gap separator. In addition, the housing includes a rotor outlet that communicates with the membrane side facing out of the gap (e.g., the interior of the rotor) and communicates with the plasma flow path tubing 111.
[0079] [00079] To reduce the number of leukocytes that may be present in the red cells, the disposable fluid flow circuit A optionally includes a leukocyte reduction filter 113 which can be of any well known construction suitable for removing concentrated red cell leukocytes without causing unnecessary red cell hemolysis or reducing the number of red cells in the collected product. The concentrated red cell flow from the leukocyte reduction filter 113 through a continuation 114 of the concentrated red cell flow path in the storage vessel 15 which can be of any suitable plastic material compatible with red cell storage.
[0080] [00080] The durable or reusable controller module B, as shown in schematic Fig. 9, preferably includes a hematocrit sensor 104 to detect hematocrit and whole blood flowing from the whole blood container 101. The hematocrit detector can be any suitable design or construction, but preferably as described in US Patent 6,419,822 which is incorporated by reference herein.
[0081] [00081] The durable reusable controller or control module B also includes an inlet clamp 116 that can be operated to control fluid from the whole blood container 101 or cell preservative container 102 or, optionally, simultaneously and proportionally from both containers 101 and 102. To control the flow of blood in the separator, the reusable module includes an inlet pump 106 which can also be of any suitable construction and can be, for example, a peristaltic pump that operates by progressive compression or tightening of the tubing 107 that forms the inlet flow path in the separator, a flexible diaphragm pump or other suitable pump. A pressure sensor 117 communicates with the inlet flow path between the pump 106 and the separator 108 to determine the inlet pumping pressure. The sensor can send to the control system to provide an alarm function in the event of an overpressure condition or an underpressure condition or both.
[0082] [00082] To control the flow rate of concentrated red cells of the separator 108, the reusable module also includes an outlet pump 109 which is associated with the outflow path 110 and works in a similar way to that described in relation to the inlet pump 106. It can also be of any suitable construction such as a peristaltic pump, a flexible diaphragm pumping structure or any other suitable one. The plasma flow path 111 leaving the separator is preferably not controlled by a pump and the volumetric flow rate through the plasma flow path tubing is the difference between the pump inlet volumetric flow rate 106 and the flow rate. volumetric flow of pump output 109. The reusable module B may, however, also include a clamp 118 for controlling the flow of plasma through the plasma flow path tubing 111.
[0083] [00083] Disposable module A may also include a plasma collection container 112 in fluid communication with the plasma flow path to receive plasma separated by separator 108. Due to the plasma passing through a porous membrane in separator 108, the plasma which is collected in container 112 is largely cell-free plasma and may be suitable for administration to patients, freezing for storage or subsequent processing.
[0084] [00084] Fig. 10 shows in general the fluid flow path (s) through the system illustrated in Fig. 9. Specifically, it shows the whole blood flow from the single whole blood container unit 101 through the whole blood hematocrit detector 104 to a junction in the flow path located on binary clamp 116. The cell preservation solution, like a red cell preservation solution, flows from the red cell container 102 also into the junction at binary clamp 116. Depending on the processing stage, the binary clamp allows the flow of whole blood or cellular preservative downstream into the rest of the system. Optionally, clamp 116 can be a proportional clamp to allow a proportional flow of selected whole blood and red cell preservative simultaneously.
[0085] [00085] From binary clamp 116, whole blood or cell preservative fluid flows through the inlet pump 106 and into the separation device 108. As explained previously, the separation device employs a relative rotating housing and rotor, at least one of which carries a membrane through which the plasma is allowed to pass. In one embodiment, the membrane is loaded onto the rotor surface and the plasma passes through the membrane and through an internal passage maze inside the rotor that eventually leaves for the plasma collection vessel 112. When the membrane is mounted on the rotor, the device is commonly referred to as a rotating membrane separator as shown in Fig. 10. However, it must be recognized that the membrane could potentially be mounted on the inside surface of the housing facing the gap between the surface inside the housing wall and the outer surface of the membrane or a membrane can be loaded both on the outer surface of the rotor and on the inner surface of the housing so that the plasma flows through the membranes simultaneously, thereby potentially increasing the separation speed or performance of the separator 108. A from separator 108, the flow of red cells concentrated through the housing outlet that communicates with the gap between rotor and housing and the red cell flow path 110 and the outlet pump 109 which controls the volumetric flow rate of the concentrated red cells.
[0086] [00086] Although the hematocrit of concentrated red cells removed from separator 108 may vary, it is anticipated that the hematocrit of concentrated red cells will be approximately 80 to 85%. Outlet pump 109 pumps the concentrated red cells into the red cell collection vessel 115 and, optionally, through a leukocyte reduction filter located in the red cell flow path between pump 109 and collection vessel 115. A The force of the pump that pushes concentrated red cells through the leukocyte reduction filter helps to keep processing time within a reasonable range compared, for example, to the time it would need for gravity flow of concentrated red cells through a filter. leukocyte reduction in a manual configuration.
[0087] [00087] The plasma separated by the separator 108, as shown in Fig. 10, flows from the separator device, for example, from an outlet that communicates with a maze of passages inside the rotor through a single control clamp 118 and to the plasma collection vessel 112. As previously noted, due to the plasma passing through the membrane, it is largely cell-free and suitable for subsequent administration to patients, freezing and / or for processing as by fractionation to obtain plasma components for use in other therapeutic products. The system may also include a filter, such as a leukocyte reduction filter in the plasma flow line 111, if desired.
[0088] [00088] Fig. 11 illustrates a version of a potential system that employs both a disposable fluid circuit module A and a durable or reusable controller module B. Although shown assembled, fluid circuit module A and durable module B have separate and independent utility and can be used with other systems as well. As can be seen in Fig. 11, disposable module A is mounted conveniently facing the reusable module B which has associated hangers or supports, some of which can be associated with scales to support the various containers of the disposable system. The disposable module is, as previously indicated, preferably pre-assembled and pre-sterilized. The cell preservative solution container can be pre-attached as part of the disposable system or can be added later, such as by a sterile connection device or other suitable attachment. The whole blood container containing the whole blood unit previously collected can also be pre-attached to the pre-assembled fluid circuit or attached via a sterile connection device or other suitable attachment mechanism.
[0089] [00089] The face of the reusable module B includes, in this embodiment, a separate solution clamp 116a for controlling a flow of cell preservation solution from the solution container 102 which is locked from an elevated solution support post. The whole blood vessel 101 is locked on a scale. The balance can be of a conventional construction and can provide a weight measurement signal that can be used by the module B control system to detect the amount of whole blood remaining in the container and / or the amount of whole blood that has been processed through the system. The disposable system includes a red cell flow path 105 that extends from the whole blood container through the hematocrit detector 104 and a separate whole blood clamp 116b to control a flow of whole blood from the container into the system. The flow path of the cell preservative solution 103 and the whole blood flow path 105 combine at a junction, such as a v or y site, upstream of the inlet pump 106. The combined flow path extends across the inlet pump and for an inlet on the separator device 108. As shown in Fig. 11, the reusable module B includes an orientation unit, such as a magnetic orientation unit to cause rotation of the rotor inside the separator housing without requiring that guiding members or components physically extend through the accommodation. In this arrangement, the rotor includes a magnetically coupled guidance element that is rotated by the magnetic guidance unit associated with the reusable module. Such a system is more fully described in U.S. Patent 5,194,145 to Schoendrofer incorporated by reference herein.
[0090] [00090] The concentrated red cell outlet from separator 108 is attached to the red cell flow path 110 that extends through outlet pump 109 and to an entry in the optional leukocyte reduction filter 113. The filter medium located between the Inlet and outlet of the leukocyte reduction filter substantially removes leukocytes from red cells. From the filter outlet, the red cell flow path tubing 114 carries the red cells in the red cell collection vessel 115.
[0091] [00091] Plasma is conducted from the plasma outlet of the separator by a plasma flow control clamp 118 and into the plasma collection vessel 112. In a similar manner to the whole blood vessel, the concentrated red cell vessel 115 and the plasma container 112 are suspended on scales that can be in electronic communication with the control system of the durable or reusable module B to provide information related to the amount of concentrated red cells and / or plasma collected from whole blood or the collection rate .
[0092] [00092] Although this system has been illustrated with certain components and basic features as described above, this description is not intended to prevent the addition of other components such as sensors, pumps, filters or the like as they may be desired. For example, it may optionally be desired to filter plasma before it enters the plasma collection vessel or to omit a leukoreduction filter for red cells. Although the plasma removed from separator 108 is largely cell free, there may be an additional desire to filter the plasma for reasons of administration or subsequent processing. This description is not intended to prevent the possible addition of additional components or the elimination of one or more of the components described above.
[0093] [00093] Turning now to the processing of whole blood in the illustrated system, the separation process begins by pre-activating the system. "Pre-activation" refers to the method by which the filter membrane is prepared (ie, moistened) before use. Wetting with a fluid helps to displace air present in the membrane matrix before the pressure-induced fluid flow through the membrane. Typically, a low-viscosity non-biological fluid as a cell preservation solution (red cell solution as an Adsol solution) is used for moistening to allow for more effective displacement into the air. During pre-activation, a fluid is removed from the cell preservation solution bag 102 by the inlet pump 106 to the solution line 103, the whole blood line 105, the inlet line 107 and the rotating membrane device 108 completely filled with the solution. To ensure proper pre-activation, the inlet pump 106 can move both clockwise and counterclockwise during pre-activation. The purpose of solution pre-activation is to prevent an air-blood interface from forming by creating a solution-blood interface and to moisten the membrane within the separation device. Each of these is a measure taken to reduce hemolysis of red blood cells.
[0094] [00094] After the system is successfully pre-activated, the cell solution flow path 103 will be closed by the input clamp 116. The illustrated input clamp is a binary clamp that can close or the solution flow path from preservation of cell 103 or the whole blood flow path 107. The whole blood will then be pumped through the whole blood flow path 105 and the inlet path 107 through the inlet pump 106 in separator 108. The rates of flow of the inlet pump 106 can vary from about 10 ml / min to 150 ml / min depending on the desired product results for a specific procedure. As the whole blood leaves the whole blood container 101, it will pass through the whole blood hematocrit detector 104 which will generate an estimation of the whole blood hematocrit by IR LED reflectance measurements. The details of the hematocrit detector are explained in US Patent 6,419,822 (Title: Systems and methods for sensing red blood cell hematocrit) incorporated by reference. The whole blood hematocrit value is required for an initial control algorithm for the illustrated system, but may not be essential in other systems.
[0095] [00095] After whole blood has filled separator 108, the system will begin to draw plasma from the separator that separates whole blood entering the rotating membrane device in a red cell concentrate and virtually cell free plasma. Red blood cells packed with approximately 80 to 85% hematocrit will be pumped out of separator 108 by the red cell flow path 110 and to the red blood cell leucofilter 113 by the outgoing pump 109. The outgoing pump forces the blood cells red cells packed by the red blood cell leucofilter 113 and the red cell concentrate exiting the red blood cell leucofilter 13 by the red blood cell line 114 and the red blood cell product bag 115 will be successfully emptied of white blood cells and also emptied of platelets. It is also possible to complete an automated separation of whole blood without the use of a red blood cell leucofilter 113. In this case, the red blood cell leucofilter 114 would be removed from the system and the red blood cell product 115 would not be emptied of blood cells. white or platelets.
[0096] [00096] Throughout the procedure, the plasma will flow through the plasma flow path 111 to the plasma pocket 112 at a flow rate equal to the difference between the inlet pump flow rate 106 and the pump flow rate. output 109 as is currently done in other rotating diaphragm separation applications such as that applied by the Autopheresis-C® instrument sold by Fenwal, Inc .. The diaphragm pressure generated by the deviation in flow rates is monitored by the 117 pressure sensor. pressure measurements are used to control the plasma flow rate by using the algorithm described in US Patent Application Serial No. 13 / 095,633 filed April 27, 2011 (Title: SYSTEMS AND METHODS OF CONTROLLING FOULING DURING A FILTRATION PROCEDURE ) incorporated by reference in this document.
[0097] [00097] The system in Figures 9 to 11 will continue to separate packaged red blood cells and plasma until the whole blood bag 101 is empty as detected by the air passing through the whole blood hematocrit detector 104. At this point, the blood line whole blood 105 will be closed and the cell preservative solution line will be opened by the inlet clamp 116 to start rinsing or flushing the solution. During the rinsing of the solution, the preservative solution will be removed from the solution bag 102 and pumped into the separator 108 by the inlet pump 106. The plasma flow path 111 is closed by the plasma clamp 118 during the solution rinse. The solution rinse is used to discharge any remaining blood in the system to the red blood cell product container 115. Rinsing the solution will also increase the volume of the red blood cell product container 115 to the desired level for proper storage of red blood cells. After rinsing the solution, the separation of the whole blood unit is complete.
[0098] [00098] Turning to Fig. 12, an additional alternative two pump system is shown. This modality differs from that of Fig. 9 primarily in that fluid from the blood cell preservative solution is added after the red blood cells have been separated from the whole blood. More particularly, a container / pouch 101 containing whole blood previously collected (preferably already combined with an anticoagulant) is connected to the disposable system A via a segment of tubing 107 leading to blood separator 108. Pump 106 cooperates with tubing 107 to pump whole blood into the separator 108. Container 102 containing the preservative additive solution of red blood cells is connected to the collection container 115 for the separated red blood cells via tubing 114, whereby the separated red blood cells also are directed to vessel 115 through leukocyte filter 114.
[0099] [00099] The sterile connection of containers 101, 102 to the disposable system can be obtained in numerous different ways. Container 102 for the additive solution can be supplied as part of disposable system A and can be joined with the remainder of the disposable (after sterilization by, for example, processing with E-beam or gamma) during final packaging after the remainder of the disposable has been sterilized (by, for example, wet heat processing). Alternatively, container 102 can be formed integrated with the remainder of the disposable. In an additional alternative, both the container 102 and the whole blood container 101 can be separated from the rest of the disposable and connected at the time of use, for example, through sterile spigot connections 170, shown schematically in Fig. 10. Such spigot connections preferably include a 0.2 micron filter to maintain sterility.
[0100] [000100] In another aspect of this embodiment, the tubing 103 that connects the additive solution container 102 to the leukocyte filter 62 can also be cooperatively engaged by pump 109. Specifically, pump 109 can be a double head pump that flows both at additive solution as well as the red blood cells leaving the separator 108 to control the flow rate of each one based on the inside diameter of the tubes 103 and 110.
[0101] [000101] The modality of Figure 12 also uses an additional pressure sensor 117b to monitor the return pressure of the leukocyte filter 113. If the return pressure becomes excessive, as in the case of occlusion of the filter, the sensor will act to control the flow rate in a way that ensures that the disposable does not burst due to excess pressure. III. Membrane pre-activation
[0102] [000102] To keep up with another aspect of the development, a method for pre-activating a membrane filter is provided whereby the maximum amount of the surface area of the filter membrane is more likely to moisten, thereby maximizing the area of the membrane. membrane available for filtration / separation. Specifically, when the rotating membrane filter system is pre-activated as described above, with the rotating membrane oriented so that the axis of rotation is substantially vertical, the humidification solution enters the inlet port at the top of the rotary separator and the gravity pulls the fluid towards the outlet at the bottom of the separator. Under such circumstances, the surface tension of the pre-activation fluid will form an air-fluid interface that can move irregularly across the membrane surface, which creates disturbances. The result is that certain areas of the filter membrane may not be humidified during pre-activation, thereby increasing the potential for air to become trapped in the membrane matrix. The area of the non-humidified membrane then becomes unavailable for separation, which significantly affects the membrane separation efficiency until sufficient pressure is generated to displace the air.
[0103] [000103] Consequently, a method for pre-activating a membrane separator is provided that more uniformly humidifies the membrane surface by providing a more uniform air-fluid interface during pre-activation. For this purpose, the pre-activation fluid is introduced into the separator so that it works against the force of gravity as the fluid-air interface advances in an upward direction across the membrane surface. This helps to ensure a more uniform humidification of the membrane since the air displaced during pre-activation is able to move in a single direction without being trapped as the air-fluid interface advances through the membrane.
[0104] [000104] Thus, according to this alternative method for pre-activation, the pre-activation fluid is introduced into the separator through a door at the bottom of the separator. The pre-activation solution advances upwards in the separator housing against the force of gravity to humidify the membrane surface with air being expelled from the separator through a door at the top of the separator. Although this "bottom to top" pre-activation is described in the context of a rotating membrane separator, it is also applicable to any type of membrane separator that requires pre-activation fluid before use.
[0105] [000105] With reference to Figures 9 and 12, the separator 108 is oriented vertically so that the membrane separator and housing are relatively rotatable with each other around a generally vertical axis with the port to receive whole blood at the top of the separator and the ports through which separate RBCs and plasma exit at the bottom of the separator. Thus, according to a way to carry out this alternative pre-activation method and with reference to Figures 1 and 2, the pre-activation solution can be introduced through one of the outlet orifice 34 or the outlet orifice of plasma 46 from the rotating membrane separator 10 although air is expelled through the inlet port 22. According to another way to perform this alternative pre-activation method, the separator 10 can be inverted or face up for pre-activation of so that outlet orifice 34 and plasma outlet orifice 46 are at the top of separator 10 and inlet 22 is at the bottom of separator 10. The pre-activation solution can then be introduced through inlet 22 with the fluid-air interface of fluid advancing upward and air being expelled through either or both of the outlet orifices 34 and the plasma outlet orifice 46. After pre-activation, separator 10 can be returned to its original orientation with the orif inlet port 22 at the top and outlet port 34 and plasma outlet port 46 at the bottom.
[0106] [000106] An additional alternative in which the "bottom to top" pre-activation of blood separator 108 described above can be used is shown in Fig. 12A. In contrast to Fig. 12, entry line 107 for whole blood connects to the bottom port of separator 108 (to which exit line 110 had been attached in the mode of Fig. 12) while exit line 110 is connected to the port at the top of the separator 108 (to which the inlet line 107 had been attached in the mode of Fig. 12). To pre-activate the system in Fig. 12A, clamp 116B is opened and pump 106 is activated to flow whole blood (preferably with added anticoagulant) through the inlet line 107 so that it enters separator 108 through the door at the bottom end of the accommodation. As whole blood fills the separator housing, air is expelled through the top port to remove substantially all of the air from the device and the filter membrane is humidified.
[0107] [000107] After pre-activation is complete, the system continues to operate as shown in Fig. 12A to separate whole blood in plasma received in vessel 112 and red blood cells received in vessel 115. At the end of the separation procedure, separator can be rinsed with an additive solution from container 102.
[0108] [000108] Turning to Figures 14 and 15, an additional alternative blood separation system according to the present disclosure is shown. The system in Figures 14 and 15 is similar to that in Figures 9, 11 and 12 except that the durable module B includes a third pump 119 to selectively flow additive solution to any of the separators 108 during the pre-activation phase (as shown in Fig . 14) or to the red blood cells separated during the separation phase (as shown in Fig. 15). The system in Figures 14 and 15 also includes an additional clamp 120 to selectively allow or prevent a flow of fluid (separate red blood cells and additive solution) through the leucofilter 113 and into the red blood cell container 115. Before pre-activation, the clamp 20 may briefly remain open and pump 109 can pump residual air from container 115 and filter 113, which minimizes the amount of air remaining in container 115 at the end of the procedure. Similar to Fig. 12A, the system in Figures 14 and 15 employs bottom-to-top pre-activation of separator 108, except for the use of the additive solution for the pre-activation fluid instead of whole blood. During pre-activation of the system, as shown in Fig. 14, air from the disposable system A is pushed into the whole blood container 101.
[0109] [000109] During the separation phase, the system is operated as shown in Fig. 15. Upon completion of the separation phase, the additive solution is pumped into separator 108 (as shown in the pre-activation phase illustrated in Fig. 14 ) to rinse the separator.
[0110] [000110] Turning to Fig. 15A, an additional alternative system is shown. The system in Fig. 15A is similar to that in Figures 14 and 15 in that the reusable component B comprises three pumps 106, 109 and 119. However, the system in Fig. 15A is similar to that in Fig. 12A in which the inlet line 107 for whole blood is connected to the port at the bottom of the separator 108, while the outlet line for the separated red blood cells is connected to the port at the top of the separator. Thus, in the system in Fig. 15A, whole blood is used to pre-activate the system similar to the system in Fig. 12A. IV. Data Management Systems and Methods
[0111] [000111] The system described in this document can also incorporate data management solutions. Scales and the addition of label printing devices to the system could allow users to obtain product weight labels directly from the separation system at the end of the procedure. This eliminates manual weighing and data recording used in current processing methods. Module B can include a suitable user interface such as a touch screen, alphanumeric keypad or keyboard, as well as a scanner, to allow users to enter information such as the user donor identification number, blood bank identification, blood fluid circuit kit, batch numbers, etc., which could also improve the efficiency of data management in blood production centers.
[0112] [000112] More specifically and in accordance with another aspect of the present disclosure, a method is provided to automate the transfer of data associated with the whole blood collection vessel, as well as other information pertinent to the processing circuit used for subsequent blood separation total and the final storage container or containers for such separate blood component or components. This method is illustrated schematically in the flow chart of Fig. 29 where a source container is provided (step 122) that normally contains a unit of whole blood collected previously, although the source container may contain a previously processed blood product. The source container usually has data associated with it that relates to donor identification and collection time, place, etc., such data being preferably in a machine-readable format such as a barcode or an RFID tag. This data is then retrieved and transferred (step 124) and then associated with the processing circuit and final storage containers (step 126).
[0113] [000113] Turning to Fig. 30, a possible system for using a data management system according to the present disclosure is shown. A blood collection container 128 and a separate processing circuit 130 that has three final storage containers 132, 134 and 136 are provided. During the collection of whole blood, donor identification information is encoded and associated with the recipient for the collected whole blood. This can be done by manually placing a barcode label for the donor id on the container label, container pin or tubing. It can also be done by using an RFID writer at the collection point that transfers the donor ID from a collection scale or handheld device to an RFID tag attached to the collection container. The use of RFID allows a greater amount of information to be managed that includes data such as type of container-type, expiration date, collection time, collection volume, nurse identification, collection site and the like.
[0114] [000114] Automated data transfer between collection container 128 and processing kit 130 / storage containers 132, 134, 136 can occur in the context of the sterile connection of collection container 128 to processing kit 130. For example, an electromechanical system that obtains the sterile connection from the whole blood collection container to the processing kit can be used. Such a system is revealed in the Provisional Patent Applications of Serial No. US 61 / 578,690 and 61 / 585,467 filed on December 21, 2011 and January 11, 2012, respectively, which are incorporated by reference in this document. The sterile connection device can be self-sufficient, as shown in the provisional orders referenced above or integrated with the reusable module B described above. Alternatively, the data management system can simply be associated with the reusable module B without a sterile connection device associated with it. In any event, the sterile connection device or reusable module includes a programmable controller configured to automatically perform or prompt the user to perform the various steps of the data management method as described in greater detail below.
[0115] [000115] The data management system 138 incorporates a processing unit, a screen 140 to provide information to the user (such as requests and confirmations), a touchpad 142 that allows the user to enter information and a scanner / reader 144 to retrieve and transfer information between the collection container 128 and the processing kit 130. System 138 also provides the printing of barcode labels or data transfer to one or more RFID tags associated with the processing kit. Turning now to Fig. 31, a flow chart that generally illustrates the data management method is shown. The method includes loading the collection bag and the processing kit into the reusable module and / or sterile connection device (step 140). The data associated with the processing kit and the data associated with the collection container are retrieved (steps 142 and 144). As can be appreciated, the order in which these steps are performed is not critical. As noted above, this data can take the form of a bar code, an RFID tag or otherwise, the processing kit and its associated collection containers have the relevant data from the collection container associated with them. This can either take the form of printing barcode labels or writing data on an RFID tag (steps 146 and 148). The collection container and the processing kit are preferably connected in a sterile connection procedure (step 150), such as a connection that occurs in a moment during the performance sequence of the steps described above.
[0116] [000116] The blood in the collection container is then processed (step 152). The processing kit / storage container information is then retrieved and verified against the collection container data (steps 154 and 156). After such a check, the storage containers can be disconnected from the collection container (step 158).
[0117] [000117] The system of the present disclosure assists the user in carrying out the steps described above in which it provides requests and confirmations for the various steps. For example, if the identification information is in the form of a barcode, the system prompts the user to scan the barcode for the processing kit ID and the donor ID of the collection container. The system will then print replicated barcode labels on a printer that is either integrated into or attached to the system with the type and quantity of the labels being determined by the type of processing kit loaded. The system then prompts the user to apply the barcode labels to the final storage containers. After the system processes blood into components, the system prompts the user to scan the barcode IDs of the final component container so that the system can verify that the barcode information is correct before detaching the collection container storage containers and processing kit.
[0118] [000118] If the identifying information is associated with an RFID tag, the system automatically scans the RFID tag in the collection container and then automatically reads the information in the RFID included in the processing kit. The system then automatically replicates the collection container information to the RFID tag or tags associated with the processing kit storage containers. After the system processes the blood in the components according to the type of processing kit detected by the instrument, the system will read the RFID tag on the final component containers to allow verification of the identification information before detaching the blood storage containers of the processing kit and collection container.
[0119] [000119] It is contemplated that the system can employ both barcode and RFID as redundancy systems and include some or all of the steps described above, as applicable. Although the barcode scanner / RFID reader is described as being associated with the reusable module B, it can be a dedicated station physically separated from the processing machine itself, although connected by the data management software.
[0120] [000120] Although this method of data management has been described in connection with the collection of whole blood in a separate container from the processing kit and storage containers, it can also be used in connection with a system or kit in which the collection container is integrated into the processing kit and storage containers. In addition, the method can be used in connection with the processing of whole blood drawn directly from a donor as described below with donor identification data being provided by the donor and not by a collection vessel or in a cell washing procedure with the identification data being associated with the source container. V. Systems and Methods for Processing Whole Blood from a Donor
[0121] [000121] According to another aspect of the present disclosure, the rotating membrane separator described above can advantageously be used in a single step or "in-office" collection and separation of whole blood into blood components. As described below, an automated whole blood collection system is provided that separates whole blood into a single unit of red blood cells and plasma simultaneously with the collection of whole blood from a donor. The system is intended to be a one-step collection system, without reinfusion into the blood component donor. The system preferably comprises a disposable fluid flow circuit and a durable reusable controller that interfaces with the circuit and controls fluid flow at least. The flow circuit is preferably a single use pre-sterilized disposable fluid flow circuit that preferably comprises red blood cell and plasma collection containers, additive anticoagulant and red cell solution, a separator and a fistula to supply a passage for the donor's whole blood in the fluid circuit. The durable controller preferably comprises a microprocessor-controlled electromechanical device with valve, pumping and detection mechanisms configured to control the flow through the circuit, as well as security systems and alarm functions, suitable for a whole blood collection procedure.
[0122] [000122] The method of blood collection using the system comprises performing a vein puncture on a donor and extracting the donor's whole blood in the disposable circuit where it is handled by the instrument and the components of the fluid circuit to result in whole blood being separated into the desired red blood cell and plasma components. The donor remains connected to the system throughout the procedure and all fluids remain in the fluid path of the single use kit until the procedure is complete. As a "one-step" system, whole blood preferably passes through the flow circuit only once and no blood component returns to the donor.
[0123] [000123] The red blood cells that result from the collection do not necessarily need to be processed by leukoreduction. However, leukoreduction by filtration can be achieved with a leukoreduction filter preferably integrated into the single-use circuit or by using a separate processing circuit that is sterilized connected to the red blood cell collection vessel.
[0124] [000124] The instrument preferably includes an operator interface to enter information and / or display information such as a touch screen, alphanumeric keyboard, mouse, keyboard, etc. A message display allows the operator to control the procedure, gather information about its status and resolve any error conditions as they arise.
[0125] [000125] Turning to the drawings, Figures 16 to 19 show a schematic representation of an automated whole blood collection system, generally designated as 210 according to the present disclosure, at different stages or stages of operation. The system preferably includes a reusable hardware component 212 that preferably comprises pumps, clamps and pressure sensors to control fluid flow and a pre-assembled, sterile, single use disposable fluid circuit component 214 that can be mountable on the component hardware and includes several containers / bags, a donor or fistula access device and a blood separation chamber, all interconnected by a sterile fluid path, such as flexible plastic tubing. The containers / bags are normally retractable and made of a suitable plastic material as is known in the art. The material of the containers may differ depending on use and may include plasticizer-free materials such as DEHP-free polymers, particularly, but not exclusively, for the storage of red cells.
[0126] [000126] More specifically, the illustrated fluid circuit component or module 214 comprises a donor access device 216 that includes a first length of tubing 218 as the extraction line through which whole blood is drawn from a donor and introduced into the donor. fluid circuit 214. The donor access device 216 preferably comprises a needle and, in particular, a small gauge needle (gauge 18 to 21) for greater donor comfort with a needle guard if desired to prevent undue puncture of the needle. Tubing 218 communicates with a blood separation device generally referred to as 220 and, as described above, introduces whole blood into the separator.
[0127] [000127] A second length of tubing 222 provides fluid communication between the separator 220 and a first container / bag 224 for receiving the separated concentrated red blood cells, while a third length of tubing 226 provides fluid communication between the separator 220 and a second container / bag 228 for receiving plasma.
[0128] [000128] Fluid circuit 214 also comprises a source of anticoagulant (e.g., CPD) that is contained in a third container 230 that communicates with the first length of tubing 218 through a fourth length of tubing 232 that is joined to tubing 218 by, for example, a Y-connector. Fluid circuit 214 can also include a source of preservative solution for the red blood cells that must be delivered to container / bag 224. The preservative solution can be contained in a separate bag that is in communication with container 224. Alternatively, container 224 can be filled with an amount of preservative solution suitable for the amount of red blood cells to be received in it during the collection procedure.
[0129] [000129] Fluid circuit 214 also includes an integrated sampling system 234 for aseptic collection of blood samples before and during the donation process. The sampling system 234 comprises a bag that communicates with the first tubing length 218 of the donor access device through a fifth tubing length 236 upstream of the connection between tubing 218 and tubing 232, through which the anticoagulant is introduced. Piping 236 preferably communicates with piping 218 through a Y connector or similar device.
[0130] [000130] The durable hardware component 212 preferably comprises a first pump 238 that cooperates with tubing 218 to pump whole blood to the separation device 220 and a second pump 240 that cooperates with tubing 222 to transport substantially concentrated red blood cells from the separation chamber 220 for the first collection container 224. Pumps 238, 240 are preferably peristaltic or roller pumps that include a rotor with one or more rollers to compress the tubing to force the fluid to move through it, although other suitable pump designs, such as flexible diaphragm pumps, can also be used. The hardware component also preferably includes a third pump 242 that cooperates with tubing 232 to transport anticoagulant to the extraction line tubing 218 through which whole blood is transported to separator 220. Third pump 242 provides flow measurement anticoagulant and also facilitates pre-activation and rinsing of the system, as described below. However, the third pump 242 is optional and the anticoagulant can be measured for the whole blood collection line 218 by gravity flow with tubing 232 being sized to provide an adequate flow rate for the duration of the collection procedure.
[0131] [000131] Hardware component 212 also preferably comprises clamps 244, 246, 248 and 250 to occlude and selectively open tubing segments 218, 232, 222 and 226, respectively. The term "clamps" is used widely in this document and includes any mechanism that cooperates with the flow paths, for example, pipe segments, of the fluid circuit to selectively allow or prevent fluid flow through it. Hardware component 212 preferably also comprises pressure sensors 252, 254 in the extraction line tubing 218 near or adjacent to the needle (pressure sensor 252) and near or adjacent to the inlet to separator 220 (pressure sensor 254) to monitor the inlet pressure, such as to detect a collapse of the vein. A scale (not shown) is also preferably provided for at least the first container 224 to provide feedback on the volume of collected red blood cells.
[0132] [000132] To keep up with another aspect of the development, the reusable hardware component preferably comprises a programmable controller 256 to activate the pumps and clamps and monitor the pressure sensors and scales so that the whole blood collection procedure can be automated substantially. The 256 controller comprises a programmable microprocessor and preferably includes an operator interface, such as a touch screen and message display to allow the operator to enter and view data and control the procedure, gather information about the status of the procedure and troubleshoot any "error" conditions that may arise.
[0133] [000133] To perform an automated collection and separation procedure with the automated blood collection system 210 revealed so far, the disposable fluid circuit 214 is loaded in the operating position on the reusable hardware component 212 as shown in Fig. 16 of the attached drawings. In the phase or stage shown in Fig. 16, the system is pre-activated with a fluid to substantially remove air and humidify the filter membrane. In the primary stage, the first clamp 244 is closed in order to prevent fluid communication between the donor access device 216 and the blood separation chamber 220 and the anticoagulant is pumped through pumps 240 and 242 through tubing 218 through the separator 212 and piping 222 to pre-activate the system. The puncture of the vein is then performed in the donor with the needle of the donor access device to admit the whole blood in the tubing 218. At this point, the whole blood can be sampled through the sampling bag 234.
[0134] [000134] Turning to Fig. 17, after pre-activation, the first clamp 244 is opened to flow whole blood through tubing 218 to blood separator 220 through pump 238 to begin the collection / separation phase of the collection procedure. The anticoagulant continues to be measured in the tubing segment of the extraction line 218 by the tubing segment 232 via the third pump 242. The red blood cells exit the separator 220 through tubing 222. The fourth clamp 250 is opened to allow the plasma leaves separator 220 and travels through tube 226 to the second collection container 228. The first pump 238 shows the flow of whole blood to separator 220 with the inlet pressure being monitored by sensor 254 while red blood cells they are pumped from the separation chamber 220 by the second pump 240. The flow differential between the first pump 238 and the second pump 240 forces the separated plasma out of the separator 220 into the second collection vessel 228.
[0135] [000135] Referring to Fig. 18, when the volume of red blood cells in the first collection container 224 reaches a predetermined volume (as measured by the weight of the first collection container 224 as detected by the scale), the scale will supply the controller 256 a signal that asks the controller to finish the collection procedure by closing the first clamp 244, thereby occluding the extraction line 218. The donor access device 216 can be removed from the donor at that time. If the system is to be rinsed, the fourth clamp 250 is closed to occlude flow line 226 to the second collection vessel 228 for the plasma. The first pump 238 is deactivated while the third pump 242 continues to deliver anticoagulant to the separator 220 with the anticoagulant being exhausted to the first collection container 224 through the pipe segment 222.
[0136] [000136] Turning to Fig. 19, at the conclusion of the rinse cycle, the second clamp 246 and the third clamp 248 are closed and the second pump 240 and the third pump 242 are deactivated.
[0137] [000137] At this point, the first collection container 224 containing substantially concentrated red blood cells can be separated from the disposable fluid circuit 214 for storage or to facilitate leukofiltration. This can be done simply by suspending the collection container 224 and allowing gravity filtering of red blood cells through a leukoreduction filter in a final storage container. However, according to another aspect of the disclosure and as shown in Fig. 20, a third collection container 258 can be provided that is in fluid communication with the second collection container 224 through a pipe segment 260 with the pipe segment. tubing 260 being in fluid communication with the tubing segment 222 through a Y connector located on a tubing segment 222 between the outlet of the separator 220 and the second pump 240. The third clip 248 can then be opened to allow the flow of concentrated red blood cells out of collection vessel 224 with second pump 240 activated and pumping in the reverse direction to force the flow of concentrated red blood cells through the leukocyte reduction filter 262 and into collection vessel 258. pressure generated by pump 240 promotes the filtering process significantly compared to red cell leukofiltration fed by gravity.
[0138] [000138] As an additional alternative, leukoreduction can be performed in relation to whole blood during the extraction phase of the operation. Turning to Figures 21 and 22, the extraction line tubing 218 can include a leukocyte reduction filter 264 that is in line with tubing 218. Filter 264 is located upstream of the first pump 238 so that the The pump will exert sufficient extraction force on the blood to extract it through the filter 264 during collection. The leucofilter 264 can be located in the pipe segment 218 or upstream from where the anticoagulant is introduced into the system (as shown in Fig. 21) or downstream from where the anticoagulant is introduced into the extraction line 218 (as shown in Fig. 22). The downstream placement of the anticoagulant junction allows the use of the anticoagulant to discharge any remaining whole blood from the filter 264 after the donor extraction has ended. In addition, the placement of a leukoreduction filter in the extraction line tubing 218 eliminates the need for a separate downstream leukoreduction filtering step, thereby further simplifying the blood collection process.
[0139] [000139] The automated one-step whole blood collection system and the method described in this document are expected to improve the efficiency of the blood collection center and decrease operating costs by achieving separation of whole blood into cell components red blood and plasma without the need for subsequent manual operations. Additionally, the use of smaller caliber needles in the donor access device used with the system should improve donor comfort while the use of an extraction pump allows the system to obtain donation times similar to the collection of common whole blood. Additionally, by having whole blood collection controlled by a microprocessor, greater opportunities for data management are provided that are not normally found in current manual whole blood collection methods that include the use of integrated barcode readers and / or RFID technology as described above.
[0140] [000140] According to another aspect of the disclosure, methods, systems and devices useful in washing biological cells, such as blood cells or other blood or biological components, are described below. SAW. Cell Washing Systems and Methods
[0141] [000141] Biological cell washing can serve several purposes. For example, cell washing can be used to replace the liquid medium in which biological cells are suspended. In this case, a second liquid medium is added to replace and / or dilute the original liquid medium. Portions of the original liquid medium and the replacement liquid medium are separated from the cells. The additional replacement liquid medium can be added until the concentration of the original liquid medium is below a certain percentage. After that, the cells can be suspended, for example, in the replacement medium.
[0142] [000142] Cell washing can also be used to concentrate or additionally concentrate cells in a liquid medium. The cells suspended in a liquid medium are washed in such a way that a portion of the liquid medium is separated and removed from the cells.
[0143] [000143] Furthermore, cell washing can be used to remove unwanted particulates, such as crude particulates or unwanted cell material from a cell suspension of a particular size, or "purify" a desired cell suspension or other liquid.
[0144] [000144] The method, systems and apparatus described below can be used to wash cells for any of the reasons described above. More particularly, but without limitation, the methods, systems and apparatus described below can be used to wash blood cells such as red blood cells or white blood cells (leukocytes) or platelets.
[0145] [000145] In a particular embodiment, a suspension that includes white blood cells in a liquid culture medium can be washed to replace the liquid culture medium with another medium such as saline, before use or further processing. The cell suspension that includes white blood cells in a liquid culture medium is delivered and introduced into a separator, such as a rotating membrane separator. The rotating membrane separator has a membrane filter with a pore size smaller than white blood cells. In one embodiment, a liquid washing medium that includes the replacement liquid medium, such as saline, is also added to the separator to dilute the liquid culture medium. The separator is operated in such a way that liquids pass through the pores of the membrane and are extracted as waste. In this embodiment, as the liquid is extracted, the washing medium is added in such a way that the resulting cell suspension includes white blood cells suspended in the replacement liquid medium (for example, saline).
[0146] [000146] In another embodiment, the cell suspension can be concentrated (by removing supernatant) and the concentrated cell suspension collected in a container of the processing set. The replacement fluid can be introduced into the separator, combined with the cells concentrated in the container and the cells then resuspended with the replacement fluid. If necessary, resuspended cells / replacement fluid can be introduced into the separator to further concentrate the cells, remove supernatant and resuspend the concentrated cells with additional replacement fluid. This cycle can be repeated as needed.
[0147] [000147] Similar processes can be used to wash red blood cells suspended in a liquid storage medium. The cell suspension that includes red blood cells suspended in a liquid storage medium can be washed to replace the liquid storage medium with another medium, such as saline, before use or further processing. The cell suspension is delivered and introduced into a separator, such as a rotating membrane separator. The rotating membrane separator has a membrane filter with a pore size smaller than that of red blood cells. In one embodiment, a washing medium, i.e., liquid replacement medium such as saline, can also be added to the separator to dilute the liquid storage medium. The separator is operated in such a way that the liquid passes through the pores of the membrane and is extracted as waste. As the liquid is extracted, the washing medium is added in such a way that the resulting cell suspension includes red blood cells suspended in the replacement liquid medium (i.e., saline). Washing and / or replacement fluid can also be a storage medium that includes nutrients and other components that allow long-term storage of cells. Alternatively, in another embodiment, the red blood cells can first be concentrated and removed into a container as described in general above. The replacement fluid can then be combined with the red blood cells in the container. The replacement fluid can be introduced directly into the container or introduced into and through the separator and then into the container.
[0148] [000148] The systems, methods and apparatus for washing cells described in this document use a disposable set that includes a separator, such as a rotating membrane separator. The disposable set with the rotating diaphragm separator is mounted on the hardware component of the system, that is, a separation device. The separation device includes clamps, pumps, motors, air detection sensors, pressure transducer sensors, Hb detectors, scales and a control / microprocessor logic included in a microprocessor. The control / microprocessor logic receives input data and signals from the operator and / or the various sensors and controls the operation of the clamps, pumps and motors.
[0149] [000149] The cell suspension to be washed, that is, cells suspended in a medium, can be supplied in a sterile disposable source container that is sterilized connected to the disposable set. A washing medium, such as saline or other suitable liquid, is also sterilized or pre-attached to the disposable set. The control logic of the device operates the clamps and pumps to circulate the cell suspension through the tubing of the disposable assembly to the separator (rotating membrane). The separation device, through its control system, also directs the washing solution through the tubing of the disposable set to the rotating membrane separator. The cell suspension and washing solution can be mixed within the rotating membrane separator, can be mixed before entering the rotating membrane separator, or can be combined in a container after the cell suspension has been concentrated. Within the rotating membrane separator, the suspension medium is separated from the cells suspended therein. The suspension medium and the remaining washing medium (if the suspension medium and the washing medium were combined) exit through a waste port while the cells pass through a separate outlet port.
[0150] [000150] If additional washing and dilution are necessary, the washed cells can be recirculated by the separator with an additional volume of the washing solution. In one embodiment, the cells that are to be "washed" can be transferred to one or more containers in process as will be described below. The device control logic operates clamps and pumps to circulate the cell suspension of the in-process vessel through the tubing to an inlet of the rotary membrane separator or to an inlet of a second rotary membrane separator. The additional washing medium is added and the process is repeated until an acceptable amount or concentration of the cells is obtained. The final cell suspension containing the cells is preferably collected in a final product container.
[0151] [000151] According to the present disclosure, Figures 23 to 25 show exemplary systems useful in washing biological cells such as, but not limited to, red blood cells and white blood cells. As noted above, the specific modalities disclosed are intended to be exemplary and not limiting. Thus, in one embodiment, the system described in this document includes a disposable set 300 (Figures 23 or 24) and hardware component or device 400 (Fig. 25). It will be appreciated that the disposable processing assemblies 300 shown in Figures 23 and 24 are, in many respects, identical and common numerical references are used in both Figures 23 and 24 to identify identical or similar elements of the disposable processing assemblies. To the extent that disposable processing sets differ in structure or use, such differences are discussed below. The disposable set 300 is mounted on device 400 (Fig. 25) which is described in more detail below.
[0152] [000152] As shown in Figures 23-24, the separator 301 is integrated into the exemplary disposable set 300. Additionally, as will be described in more detail below, the disposable set 300 includes piping, Y connectors, bag (s) in process, sample bag (s), final product bag (s), waste bag (s) and sterile filter (s).
[0153] [000153] The cell suspension to be washed is normally supplied in a source container 302 shown in Figures 23 and 24 as disconnected from the disposable assembly. As noted above, the source container 302 can be attached (sterilized) at the time of use. The source container 302 has one or more receiving ports 303, 305, one of which can be adapted to receive a spike-type connector 304 (Fig. 23) from the disposable assembly 300. More particularly, the source container 302 is connected to the assembly disposable 300 through the spike-type connector 304 which is connectable to access port 303. Most preferably, however, the source containers (and the fluid in them) can be free from a spike-type connector (as shown in Fig. 24) and access in a sterile manner by using sterile anchoring devices such as BioWelder available from Sartorius AG or SCD MB Tubing Welder available from Terumo Medical Corporation. A second access port 305 can also be provided to extract fluid from the source pouch 302.
[0154] [000154] As further shown in Figures 23 to 24, a pipe segment 306 can optionally include a sampling subunit in a branch connector 308. A branch of branch connector 308 can include a flow path 310 that is carried to the bag or site of samples 312. A bag or sample site 312 allows the collection of a sample of the fluid from the incoming source. The flow to the bag or sample site 312 is normally controlled by a clamp 314. The other branch of the branch connector 308 is connected to the pipe 316. The pipe 316 is connected to additionally go from a branch connector downstream 318. The branch connector 318 communicates with a pipe 316 and a pipe 320 that provides a fluid flow path from the in-process bag 322 described in greater detail below. Piping segment 324 extends from one of the ports of a branch connector 318 and is joined to an additional port of the downstream branch connector 326. A separate flow path defined by pipeline 328 is also connected to a port of the branch connector 326. The tubing 328 may include a sterile in-line barrier filter 330 to filter out any particulate matter from a fluid before it enters the flow path leading to the second branch connector 326 and finally to the separator 301.
[0155] [000155] According to the system disclosed in this document, a washing solution can be attached (or pre-attached) to the set 300. As shown in Figures 23 and 24, piping 332 (defines a flow path) preferably includes a 334 type spike connector at the end of it. The spike type 334 connector is provided to establish flow communication with a flushing fluid container, such as a disposable bag containing saline or other solution (not shown). The washing medium or fluid flows from the washing fluid source through the second spike-type connector 334, through the pipe segment 332, where it is filtered through the sterile barrier filter 330 described above and then passes through the pipe 328 to the inlet. branched connector 326 described above.
[0156] [000156] The pipe segment 336 defines a flow path connected at one end to a branch connector port 326 and to an inlet port of the separator 301. Preferably, according to the present disclosure, the separator 301 is a rotating membrane of the type described above.
[0157] [000157] As shown in Figures 23, 24 and 25, the rotary membrane separator 301 has at least two exit ports. The outlet 646 of the separator 301 receives the washing residue (that is, the diluted suspension medium) and is connected to the pipe 338 which defines a flow path for a waste product container 340. The waste product container includes a additional connection port 341 for sampling or extracting residues from inside the product container.
[0158] [000158] The separator 301 preferably includes a second outlet 648 that is connected to the pipe segment 342. The other end of the pipe segment 342 is connected to the branch connector 344 which branches into and defines a flow path for one or more containers in process 322 and a flow path for an end product container 350. The end product container 350 can also include a sample bag 352 (see Fig. 23) and an access port or luer type connector 354. The bag sample 352 shown with a pre-attached tube holder 352 in Fig. 23 allows sample collection of the final product. The flow control for the sample bag 352 is preferably controlled by a clamp 356. The flow path through the access port 354 is controlled by the clamp 358.
[0159] [000159] Turning now to the washing method by using the kit 300 of Figures 23 and 24, the disposable set 300 is mounted first on the panel 401 of the separation device (ie hardware) 400 shown in Fig. 25 Device 400 includes peristaltic pumps, clamps and sensors that control the flow through the disposable assembly. More specifically, the control of pumps, clamps and the like is provided by a software-oriented microprocessor / controller of device 400. Piping segments 362, 366 and 368 (shown in Fig. 23) are selectively matched with 402 peristaltic pumps, 404 or 406 (shown in Fig. 25). (Waste line pump segment 368 can be relocated to separator outlet line 342 if desired). Once the disposable set 300 is mounted on the control panel 401 of the device 400, the cell suspension in the product pouch 302 is attached, as previously described, by the spike type connector 304 or by the sterile connection. A washing medium supplied in a container (not shown) is similarly attached. According to the operation of the device 400, the clamp 360 is opened and allows the cell suspension to flow from the product container 302.
[0160] [000160] The flow of the cell suspension is advanced by the action of the peristaltic pump through the pipe 324 designated by the pump segment 362 and in the rotating membrane separator 301. Similarly, the washing medium is advanced by the action of the peristaltic pumps along the length piping 328 designated by pump segment 366 with valves 362 and 364 in an open position. The washing medium flows through the tubing 332, through the sterile barrier filter 330, through the 328 tubing, through the Y connector 326 and into the rotating membrane separator 301. The washing medium and the cell suspension can be introduced sequentially into the membrane separator rotary 301, which allows mixing of the suspension and the washing solution to take place inside the separator chamber (gap) 301 or in a process container 322 as described below. Alternatively, the washing medium and the cell suspension can be combined prior to introduction into the separator 301 (for example) in the second branched connector 326.
[0161] [000161] In yet a further alternative, the cell suspension can first be introduced from the source container 302 into the separator 301, as described in general above. The cell suspension is concentrated within the separator 301, which allows the supernatant to pass through the membrane, through the outlet port 382, to the waste product container 340. The concentrated cells exit the separator 301 through the port 384 and are directed to the in-process container 322.
[0162] [000162] Once the separation of the concentrated cells from the supernatant from the cell suspension ends, the replacement fluid is introduced from a replacement fluid container (not shown) into separator 301 (to discharge any residual cells) and is similarly, directed through port 384 to the process vessel 322. The concentrated cells are resuspended in the replacement fluid within the process vessel 322 as shown in Fig. 23. If additional washing is desired or necessary, the system can be pre- similarly programmed or controlled to (re) introduce the resuspended cells / replacement fluid into separator 301 where the separation of concentrated cells from the supernatant is repeated. The final cell product is collected in the final product container 350, where it can be resuspended with the additional replacement fluid.
[0163] [000163] Regardless of the sequence of introduction of the cell suspension / washing solution or the disposable set used, the rotating action of the device causes the cells to separate from the rest of the fluid in which they were suspended and / or the solution washing. Preferably, the supernatant and the washing solution pass through the membrane while the desired cells are concentrated within the separator chamber. The waste resulting from the separation, which includes the washing medium and the supernatant medium, without port 382 and flows through the pipe 338 to the waste product container 340. The flow of waste is controlled by the peristaltic pump through a portion tubing 338 designated by pump segment 368 for waste product bag 340.
[0164] [000164] As described above, the separate and concentrated cell suspension exits the second outlet 384 of the rotary membrane separator 301. If no further washing is required, the control system closes clamp 370 and opens clamp 372. Closing the clip 370 prevents the washed cell suspension from flowing through tubing 346 and directs it through tubing 348 to the final product bag 350. The final product container 350 has an inlet to receive the washed and separated cell suspension. The final product container 354 is connected to a weight sensor 374. The separation device measures the weight 374 of the container to determine if the volume of cells collected in the final product container 350 is in the acceptable range and, therefore, if the washing cycle is complete.
[0165] [000165] If additional washing of the separate cell suspension is desired or necessary, the control system of the separation device closes clamp 372 and clamp 376 and opens clamp 370. Closing clamp 372 prevents cell suspension from flow through tubing 348 and direct it through tubing 346 to process bag 322. Process bag 322 has an inlet to receive the separate cell suspension. Process bag 322 is connected to a 378 weight sensor. The separation device control system determines the weight as detected by the weight sensor to determine whether enough of the separate cell suspension is present in process bag 322 to conduct another wash cycle. If it is determined that sufficient suspension is present and additional washing is desired, the control system of the separator device opens clamp 376 to open and direct the separate and diluted cell suspension through the outlet of the process bag 322, through tubing 320, on the branch connector 318 and by an air detector sensor 380. The air detector sensor 380 detects air in the cell suspension that passes through the pipe 324. The control and operation device measures the readings of the air detector sensor 380 and determines the processes additional steps to be taken.
[0166] [000166] The separate cell suspension that includes cells suspended in the diluted suspension medium is then passed through the washing process again, as described above. The washing process can be repeated as many times as desired and preferably until the separate and diluted cell suspension has an acceptable remaining concentration of the suspension medium. The final separated and diluted cell suspension is collected in the final product bag 350.
[0167] [000167] Alternatively, instead of repeatedly processing the fluid through a single in-process container, a "batch type" processing procedure can be followed by the use of two or more 322 process containers (in combination with the product container final 350).
[0168] [000168] The disposable processing assembly 300 of Fig. 24 is well suited, in particular, for such "batch type" processing. According to a cell washing procedure using the disposable assembly 300 of Fig. 24, the cells initially separated from the original suspension medium are removed from separator 301 and introduced into one of the process containers 322a. The replacement fluid is introduced into vessel 322a and the cells are resuspended. The resuspended cells in container 322a can then be introduced into separator 301 where they are separated from the supernatant. The concentrated cells exit via exit 648 in separator 301 and are introduced into a (second) fresh process vessel 322b. Additional replacement fluid can be introduced into process container 322b and the process repeated, if necessary, with an additional (third) fresh process container (not shown). The final cell product is then collected in the final product container 350 as described above.
[0169] [000169] According to the cell wash method "batch type" method described above, tubing segments 370a, 370b, 320a and 320b can be associated with clamps (not shown) to control flow to and from multiple process containers 322a and 322b. Thus, for example, a clamp on line 370a would be opened while a clamp on line 370b would be closed so that cells exiting separator 301 are directed to a (first) in-process container 322a.
[0170] [000170] For further washing, the cells resuspended in the fresh replacement fluid of the vessel 322a are introduced into the separator 301 where the cells are separated from the supernatant as previously described. The control system of device 400 closes the clamp (not shown in Fig. 24) on tubing segment 370a and opens the clamp (not shown in Fig. 24) on tubing segment 370b to allow cells to flow into the (second) container in fresh process 322b. After the final wash, the clips (not shown) in segments 370a, 370b, etc. they are closed and the clip 372 (as shown, for example, in Fig. 23) is opened to allow the collection of the final product in container 350.
[0171] [000171] Fig. 24 shows the front panel 401 of the separation device 400; that is, the hardware that includes peristaltic pumps 402, 404 and 406. As described above, pump segments 362, 364 and 368 of the disposable set are selectively associated with peristaltic pumps 402, 404, and 406. Peristaltic pumps articulate with the fluid assembly of Fig. 23 in pump segments 362, 364 and 368 and advances the cell suspension within the disposable assembly as will be understood by those skilled in the art. Control and operating device 400 also includes clamps 410, 412, 414. Clamps 410, 412, 414 and 416 are used to control the flow of the cell suspension through different segments of the disposable assembly as described above.
[0172] [000172] Device 400 also includes several sensors to measure various conditions. The sensor output is used by device 400 to operate the wash cycle. One or more pressure transducer sensors 426 can be provided on device 400 and can be associated with disposable assembly 300 at certain points to monitor pressure during a procedure. The pressure transducer 426 can be integrated with an in-line pressure monitoring site (in, for example, pipe segment 336) to monitor the pressure inside the separator 301. The air detector sensor 438 can also be associated with the disposable assembly 300 as needed. The 438 air detector is optional and can be provided to detect the location of the fluid / fluid-air interfaces.
[0173] [000173] Device 400 includes scales 440, 442, 444 and 446 from which the final bag, bag in process, cell suspension bag and any additional bag, respectively, can depend and be measured. The weights of the bags are monitored by the weight sensors and recorded during a washing procedure. From the measurements of the weight sensors, the device determines whether each bag is empty, partially full or full and controls the components of the control and operating device 200, such as peristaltic pumps and clamps 410, 412, 414, 416, 418 , 420, 422 and 424.
[0174] [000174] Device 400 includes at least one guiding unit or "spreader" 448 that indirectly directs the rotating membrane separator 301. The spreader 448 can consist of an activation motor connected and operated by the coupled device 400 to turn a magnetic ring-oriented member that includes at least one pair of permanent magnets. As the annular guiding member is rotated, the magnetic attraction between corresponding magnets within the rotating membrane separator housing causes the spreader inside the rotating membrane separator housing to rotate.
[0175] [000175] Figures 26 to 28 diagram the cell washing method as revealed in this document. The steps described below are performed by the device-oriented microprocessing unit 400 with certain steps performed by the operator as noted. Turning first to Fig. 26, the device is turned on in step 500. The device conducts checks for self-calibration 502 which include checking the peristaltic pumps, clamps and sensors. The device 400 then prompts the user to enter selected procedure parameters (step 504) such as the washing procedure to be performed, the amount of cell suspension to be washed, the number of washes that must occur, etc. The operator can then select and enter the procedure parameters for the washing procedure (step 506).
[0176] [000176] The device (by the controller) confirms the entry of parameter 506 and then requests the operator to load (step 510) the disposable set. The operator then loads the disposable assembly (step 512) onto the device panel 400. After installing the disposable assembly, the device confirms the installation as shown in (step 514).
[0177] [000177] After the disposable set is assembled, the device automatically checks to determine if the disposable set is installed properly (step 516). After the device determines that the disposable assembly is properly installed, the controller prompts the operator to connect the cell suspension and the washing medium (step 518). The operator then connects the washing medium (such as, but not limited to, saline) (step 520) to the disposable assembly via a spike connector as previously described. The operator then connects the cell suspension within a product bag (step 522) to the disposable assembly via a spike connector.
[0178] [000178] As shown in Fig. 27, after the cell suspension and the washing medium are connected to the disposable set, the operator confirms that the solutions are connected (step 524). The device asks the operator to take a sample of the cell suspension (step 526). The operator or device then opens the sample bag clamp 528 to introduce fluid into the sample bag (step 546). Once the sample bag is filled, it is then sealed and removed (542) from the disposable set. The operator confirms (step 544) that a sample has been taken. After removing the sample bag, the disposable set is pre-activated (step 546) for the washing process.
[0179] [000179] The separator device controller then starts the washing process. The cell suspension to be washed is transferred from its container (for example, 302 of Fig. 23) by the disposable set to the rotating membrane separator 301. Similarly, the washing medium is transferred from its source, by the set disposable for rotary membrane separator 301. In a preferred embodiment, cells from the original cell suspension are concentrated and / or collected or in a process bag (for further processing) or collected in a final product bag that is subsequently removed disposable set. If (additional) washing or dilution of the cell suspension is necessary, the cell suspension in the in-process bag can be washed (a second time) with the same or different washing medium or a different one following the process outlined above. Before the completion of each wash cycle, the volume or weight of the cell suspension is measured and recorded (step 550). When the concentration of the cells in the washing medium reaches an acceptable level, the final product bag is filled.
[0180] [000180] As shown in Fig. 28, once the desired volume of the final product is collected, the control and operation device requests the operator to sample and seal the final product bag (step 552). A sample bag is attached to the final product bag. The operator then seals and removes the washed cell suspension in the final product bag from the disposable assembly (step 552). The final product bag is then shaken (step 556). The operator opens the sample bag by removing a clamp (step 558). The sample bag is allowed to be filled (step 560). Once the sample bag is filled, the clamp is closed and the sample bag is sealed and removed (step 562). The operator then seals the disposable assembly lines (step 564) and confirms that the product bag has been sealed and removed, a sample bag has been filled and removed and that the disposable assembly lines have been sealed (step 566). The control and operating device then prompts the operator to remove the disposable set as shown in step 568. The operator then removes and discards the disposable set as shown in step 570.
[0181] [000181] In this way, a revolving membrane separator and improved methods and systems for using such a revolving membrane are revealed. The description provided above is for illustrative purposes only and is not intended to limit the scope of the disclosure to any specific method, system, apparatus or device described in this document.

权利要求:
Claims (4)
[0001]
Method for moistening a membrane (62) in a rotating membrane separator (10) in which the separator (10) comprises a housing (12) with a top and bottom, with at least one door (22, 34) adjacent to each one between the top and bottom of the housing (12) and with the membrane (62) supported therein, the membrane (62) having a surface through which separation occurs being oriented in a substantially vertical manner, with a gap (16) being defined between the housing (12) and the membrane (62), the method characterized by: introduce a pre-activation solution through the door (34) at the bottom of the housing (12) to the gap (16); flow additional pre-activation solution through the door (34) at the bottom of the housing (12) into the gap (16) so that a pre-activation solution-air interface is formed in the gap (16) between the housing ( 12) and the vertically oriented surface of the membrane (62) so that the interface advances upwards through the housing (12) and vertically along the membrane surface so that only the pressure at which the pre-activation solution in the gap (16) is subjected either to gravity to moisten the membrane (62) and to simultaneously move air within the housing (12) and expel air through the door (22) at the top of the housing (12); and continue to flow additional pre-activation solution through the port (34) at the bottom of the housing (12) into the gap (16) until the pre-activation fluid-air interface has advanced vertically across the entire membrane surface ( 62).
[0002]
Method according to claim 1, characterized by the fact that the membrane (62) is configured to rotate around an axis generally oriented vertically.
[0003]
Method according to claim 1 or 2, characterized by the fact that the pre-activation solution comprises a non-biological low viscosity fluid.
[0004]
Method according to claim 1 or 2, characterized by the fact that the pre-activation solution comprises whole blood.

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法律状态:
2018-04-03| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2019-07-16| B06T| Formal requirements before examination [chapter 6.20 patent gazette]|

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2020-07-07| B06A| Notification to applicant to reply to the report for non-patentability or inadequacy of the application [chapter 6.1 patent gazette]|

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2020-11-10| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-01-12| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 09/03/2012, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US201161451903P| true| 2011-03-11|2011-03-11|

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US61/451,903|2011-03-11|

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US201161537856P| true| 2011-09-22|2011-09-22|

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US61/537,856|2011-09-22|

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US201161538558P| true| 2011-09-23|2011-09-23|

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US61/538,558|2011-09-23|

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US201161550516P| true| 2011-10-24|2011-10-24|

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US61/550,516|2011-10-24|

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PCT/US2012/028550|WO2012125480A1|2011-03-11|2012-03-09|Membrane separation devices, systems and methods employing same, and data management systems and methods|

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