Patent Publication Number: US-2021161448-A1

Title: Biological fluid separation device

Description:
CROSS-REFERENCE TO RELATED APPLICATION 
     The present application claims priority to U.S. Provisional Application Ser. No. 62/681,894, entitled “Biological Fluid Separation Device”, filed Jun. 7, 2019, the entire disclosure of which is hereby incorporated by reference in its entirety. 
    
    
     BACKGROUND OF THE INVENTION 
     1. Field of the Disclosure 
     The present disclosure relates generally to devices adapted for use with biological fluids. More particularly, the present disclosure relates to devices adapted for separating components of biological fluids. 
     2. Description of the Related Art 
     Blood sampling is a common health care procedure involving the withdrawal of at least a drop of blood from a patient. Blood samples are commonly taken from hospitalized, homecare, and emergency room patients either by finger stick, heel stick, or venipuncture. Blood samples may also be taken from patients by venous or arterial lines. Once collected, blood samples may be analyzed to obtain medically useful information including chemical composition, hematology, or coagulation, for example. 
     Blood tests determine the physiological and biochemical states of the patient, such as disease, mineral content, drug effectiveness, and organ function. Blood tests may be performed in a clinical laboratory or at the point-of-care near the patient. One example of point-of-care blood testing is the routine testing of a patient&#39;s blood glucose levels which involves the extraction of blood via a finger stick and the mechanical collection of blood into a diagnostic cartridge. Thereafter, the diagnostic cartridge analyzes the blood sample and provides the clinician a reading of the patient&#39;s blood glucose level. Other devices are available which analyze blood gas electrolyte levels, lithium levels, and ionized calcium levels. Some other point-of-care devices identify markers for acute coronary syndrome (ACS) and deep vein thrombosis/pulmonary embolism (DVT/PE). 
     Blood samples contain a whole blood or cellular portion and a plasma portion. Plasma separation from whole blood has been traditionally achieved by centrifugation which typically takes 15 to 20 minutes and involves heavy labor or complex work flow. Recently there are other technologies that have been used or tried to separate plasma such as sedimentation, fibrous or non-fibrous membrane filtration, lateral flow separation, microfluidics cross flow filtration and other microfluidics hydrodynamic separation techniques. However many of those technologies have various challenges arranging from poor plasma purity, analyte bias or requiring specific coating to prevent analyte bias, high hemolysis, requiring dilution, long separation time, and/or difficult to recover the plasma. For example, most membrane based separation technologies suffer from an analyte bias problem, and often require specific coating treatments for the target analytes. Additionally, conventional separation technologies that occur while the device is directly connected to a patient thru a needle cause patient discomfort. 
     SUMMARY OF THE INVENTION 
     The present disclosure provides a blood separation device that decouples and separates the blood collection process from the plasma separation process. The blood separation device includes a sample collection module, an activation module, and a separation module. Because the plasma separation happens after the blood separation device is disconnected from a patient, the device performance is no longer affected by patient blood pressure and needle gauge, and patient discomfort is greatly reduced. 
     The present disclosure provides a blood separation device and a separation process that is fully compatible with a venous blood collection workflow without the need of centrifugation and power. Advantageously, the blood separation device of the present disclosure allows for the immediate separation of plasma during clinical blood draws and the ability for collection of the separated plasma sample in a self-contained plasma container for downstream diagnostics. 
     Furthermore, the blood separation device of the present disclosure provides for a separation device that only needs a short on-patient collection time that is no different than a conventional blood collection device using vacuum tubes, such as a BD Vacutainer® blood collection tube commercially available from Becton, Dickinson and Company, and corresponding venous access sets. Additionally, since the plasma separation happens after the device is disconnected from the patient, the device performance is no longer affected by patient blood pressure and needle gauge, and patient discomfort is greatly reduced. 
     Because the blood separation device of the present disclosure decouples and separates the blood collection process from the plasma separation process, the volume of the plasma generated is no longer limited by the allowable blood collection time on-patient. This enables the potential use of the blood separation device of the present disclosure for other high volume plasma applications beyond point of care. 
     Furthermore, another benefit of decoupling the separation from the collection process is that the separation time, plasma quality, and yield is no longer affected by the needle gauge and patient blood pressure. If the separation happens while a device is directly connected to a patient thru a needle, lower needle gauge and higher patient blood pressure reduce the separation time, yield and increases the hemolysis, whereas higher needle gauge and lower patient blood pressure increases the separation time, yield and decreases the hemolysis. By isolating the plasma separation process from the blood collection workflow using a blood separation device of the present disclosure, the blood collection sets and patient blood pressure will only affect the blood collection time while not varying the separation time, yield and hemolysis level. 
     In accordance with an embodiment of the present invention, a blood separation device adapted to receive a blood sample having a first phase and a second phase includes a sample collection module having a housing defining a collection chamber; an activation module connected to the sample collection module, the activation module having a first seal and a second seal for sealing the housing, the first seal transitionable from a closed position in which the collection chamber has a first pressure to an open position, by actuation of a portion of the activation module, in which the collection chamber is in fluid communication with a second pressure greater than the first pressure; and a separation module in fluid communication with the collection chamber of the sample collection module, the separation module defining a first chamber having a first volume and a second chamber having a second volume and including a separation member disposed between the first chamber and the second chamber, wherein the first volume and the second volume are different. 
     In one configuration, the activation module includes a switch, wherein actuation of the switch transitions the first seal to the open position. In another configuration, the switch comprises a push button defining a vent hole therethrough and a piercing portion, wherein actuation of the switch moves the piercing portion to break the first seal thereby transitioning the first seal to the open position. In yet another configuration, with the first seal in the open position, the collection chamber of the sample collection module is in fluid communication with the second pressure via the vent hole of the switch. In one configuration, the second seal comprises a cap having a pierceable self-sealing stopper within a portion of the cap. In another configuration, the blood separation device is connectable to a blood collection device via the cap. In yet another configuration, the activation module defines an inlet channel, and wherein with the blood collection device connected to the blood separation device via the cap, the collection chamber receives the blood sample via the inlet channel. In one configuration, the collection chamber includes an inlet end and an exit end and defines a plurality of sequential flow direction alternating collection channels. In another configuration, the collection chamber includes an inlet end and an exit end and defines a first collection channel extending from the inlet end to the exit end, a second collection channel in communication with a portion of the first collection channel and extending from the exit end to the inlet end, and a third collection channel in communication with a portion of the second collection channel and extending from the inlet end to the exit end. In yet another configuration, the inlet end of the collection channels is in fluid communication with the inlet channel of the activation module. In one configuration, the blood sample travels through the first collection channel in a first direction, the blood sample travels through the second collection channel in a second direction opposite the first direction, and the blood sample travels through the third collection channel in a third direction opposite the second direction. In another configuration, the first collection channel is spaced from the second collection channel which is spaced from the third collection channel. In yet another configuration, the first chamber includes a first chamber inlet and a first chamber outlet, and the second chamber includes a second chamber outlet. In one configuration, the first chamber inlet is in fluid communication with the exit end of the collection channels. In another configuration, with the first seal in the open position, a first pressure difference between the second pressure defined by atmospheric pressure and the first pressure defined within the collection chamber draws the blood sample into the first chamber. In yet another configuration, with the first seal in the open position, the first volume and the second volume being different provides a second pressure difference between the first chamber and the second chamber to drive the second phase of the blood sample through the separation member into the second chamber. In one configuration, the separation member traps the first phase in the first chamber and allows the second phase to pass through the separation member into the second chamber. In another configuration, the blood separation device includes a second phase collection container in communication with the second chamber outlet, wherein the second phase collection container receives the second phase. In yet another configuration, the blood separation device includes a blood sample discard chamber in communication with the first chamber outlet, wherein the blood sample discard chamber receives the first phase. In one configuration, the separation member comprises a track-etched membrane. In another configuration, with the blood collection device connected to the blood separation device via the cap, the collection chamber receives the blood sample via the inlet channel. In yet another configuration, with the blood collection device disconnected from the blood separation device, and wherein upon actuation of the switch to transition the first seal to the open position, the first pressure difference between the second pressure defined by atmospheric pressure and the first pressure defined within the collection chamber draws the blood sample into the first chamber. In one configuration, with the first seal in the open position, the first volume and the second volume being different provides the second pressure difference between the first chamber and the second chamber to drive the second phase of the blood sample through the separation member into the second chamber. In another configuration, with the second phase contained within the second phase collection container, the second phase collection container is removable from the blood separation device. In yet another configuration, the first phase is a cellular portion and the second phase is a plasma portion. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The above-mentioned and other features and advantages of this disclosure, and the manner of attaining them, will become more apparent and the disclosure itself will be better understood by reference to the following descriptions of embodiments of the disclosure taken in conjunction with the accompanying drawings, wherein: 
         FIG. 1  is a perspective view of a blood separation device in accordance with an embodiment of the present invention. 
         FIG. 2  is an exploded, perspective view of a blood separation device in accordance with an embodiment of the present invention. 
         FIG. 3  is a perspective view of a first step of using a system of the present disclosure in accordance with an embodiment of the present invention. 
         FIG. 4  is a perspective view of a second step of using a system of the present disclosure in accordance with an embodiment of the present invention. 
         FIG. 5  is a perspective view of a third step of using a system of the present disclosure illustrating the device of the present disclosure separates plasma independent of the device orientation in accordance with an embodiment of the present invention. 
         FIG. 6  is a perspective view of a fourth step of using a system of the present disclosure in accordance with an embodiment of the present invention. 
         FIG. 7A  is a perspective view of an activation module of a blood separation device in a closed position in accordance with an embodiment of the present invention. 
         FIG. 7B  is a cross-sectional view of the activation module of  FIG. 7A  in accordance with an embodiment of the present invention. 
         FIG. 8A  is a perspective view of an activation module of a blood separation device in an open position in accordance with an embodiment of the present invention. 
         FIG. 8B  is a cross-sectional view of the activation module of  FIG. 8A  in accordance with an embodiment of the present invention. 
         FIG. 9  is a perspective view of a collection chamber of a blood separation device in accordance with an embodiment of the present invention. 
         FIG. 10  is a perspective view of a collection chamber of a blood separation device in accordance with another embodiment of the present invention. 
         FIG. 11  is a perspective view of a blood separation device in accordance with an embodiment of the present invention. 
         FIG. 12  is a perspective view of a portion of a separation module of a blood separation device in accordance with an embodiment of the present invention. 
         FIG. 13  is a perspective view of a blood separation device in accordance with an embodiment of the present invention. 
     
    
    
     Corresponding reference characters indicate corresponding parts throughout the several views. The exemplifications set out herein illustrate exemplary embodiments of the disclosure, and such exemplifications are not to be construed as limiting the scope of the disclosure in any manner. 
     DETAILED DESCRIPTION 
     The following description is provided to enable those skilled in the art to make and use the described embodiments contemplated for carrying out the invention. Various modifications, equivalents, variations, and alternatives, however, will remain readily apparent to those skilled in the art. Any and all such modifications, variations, equivalents, and alternatives are intended to fall within the spirit and scope of the present invention. 
     For purposes of the description hereinafter, the terms “upper”, “lower”, “right”, “left”, “vertical”, “horizontal”, “top”, “bottom”, “lateral”, “longitudinal”, and derivatives thereof shall relate to the invention as it is oriented in the drawing figures. However, it is to be understood that the invention may assume alternative variations and step sequences, except where expressly specified to the contrary. It is also to be understood that the specific devices and processes illustrated in the attached drawings, and described in the following specification, are simply exemplary embodiments of the invention. Hence, specific dimensions and other physical characteristics related to the embodiments disclosed herein are not to be considered as limiting. 
       FIGS. 1 and 2  illustrate an exemplary embodiment of a blood separation device of the present disclosure. Referring to  FIGS. 1 and 2 , a blood separation device  10  of the present disclosure is adapted to receive a biological fluid, such as a blood sample  12  ( FIGS. 3-6 ) having a first phase  14  and a second phase  16 . The first phase  14  of the blood sample  12  is a cellular portion and the second phase  16  of the blood sample  12  is a plasma portion. 
     A blood separation device  10  of the present disclosure decouples and separates the blood collection process from the plasma separation process. Because the plasma separation happens after the blood separation device  10  is disconnected from a patient, the device performance is no longer affected by patient blood pressure and needle gauge, and patient discomfort is greatly reduced. 
     Because the blood separation device  10  of the present disclosure decouples and separates the blood collection process from the plasma separation process, the volume of the plasma generated is no longer limited by the allowable blood collection time on-patient. This enables the potential use of the blood separation device  10  of the present disclosure for other high volume plasma applications beyond point of care. 
     The present disclosure provides a blood separation device  10  and a separation process that is fully compatible with a venous blood collection workflow without the need of centrifugation and power. Advantageously, the blood separation device  10  of the present disclosure allows for the immediate separation of plasma during clinical blood draws, with the device  10  off-patient, and the ability for collection of the separated plasma  16  sample in a self-contained plasma container, e.g., a second phase or plasma collection container  80 , for downstream diagnostics. 
     Furthermore, the blood separation device  10  of the present disclosure provides for a separation device that only needs a short on-patient collection time that is no different than a conventional blood collection device using vacuum tubes, such as a BD Vacutainer® blood collection tube commercially available from Becton, Dickinson and Company, and corresponding venous access sets. Additionally, since the plasma separation happens after the device  10  is disconnected from the patient, the device performance is no longer affected by patient blood pressure and needle gauge, and patient discomfort is greatly reduced. 
     Furthermore, another benefit of decoupling the plasma separation process from the collection process is that the separation time, plasma quality, and yield is no longer affected by the needle gauge and patient blood pressure. If the plasma separation process occurs while a device is directly connected to a patient thru a needle, lower needle gauge and higher patient blood pressure reduce the separation time, yield and increases the hemolysis, whereas higher needle gauge and lower patient blood pressure increases the separation time, yield and decreases the hemolysis. By isolating the plasma separation process from the blood collection process using a blood separation device  10  of the present disclosure, the blood collection sets and patient blood pressure will only affect the blood collection time while not varying the separation time, yield and hemolysis level. 
     Referring to  FIGS. 1-13 , in an exemplary embodiment, a blood separation device  10  generally includes a sample collection module  20 , an activation module  22 , and a separation module  24 . In one embodiment, after collecting a blood sample  12 , the blood separation device  10  is able to separate a second phase  16  of the blood sample  12  from a first phase  14  of the blood sample  12  as described in more detail below. Advantageously, the blood separation device  10  decouples and separates the blood collection process from the plasma separation process. In one embodiment, after plasma separation, a portion that is removable, e.g., a second phase collection container  80 , from the blood separation device  10  is able to transfer the second phase  16  of the blood sample  12  to a point-of-care testing device. 
     Referring to  FIGS. 1-6 and 9-11 , in an exemplary embodiment, the sample collection module  20  includes a housing  30  defining a collection chamber  32 . In one embodiment, the collection chamber  32  includes an inlet end or inlet  34  and an exit end or exit  36  and defines a plurality of sequential flow direction alternating collection channels  38 . 
     The collection chamber  32  utilizes multiple interconnected parallel channels  38  to maximize collection and storage space within the constrained diameter of a blood collection set and also to ensure that the capillary force dominates over gravity during filling. A blood sample  12  fills the interconnected channels  38  of the sample collection module  20  in a back-and-forth motion as shown in  FIGS. 9-11 . 
     For example, referring to  FIG. 9 , in a first exemplary embodiment, the collection chamber  32  of the sample collection module  20  defines a first collection channel  40  extending from the inlet end  34  to the exit end  36 , a second collection channel  42  in communication with a portion of the first collection channel  40  and extending from the exit end  36  to the inlet end  34 , and a third collection channel  44  in communication with a portion of the second collection channel  42  and extending from the inlet end  34  to the exit end  36 . Referring to  FIG. 9 , the first collection channel  40  is spaced from the second collection channel  42  which is spaced from the third collection channel  44 . 
     In this manner, referring to the arrow in  FIG. 9  indicating a flow path  100  of the blood sample  12  through the channels  38  of the collection chamber  32 , a blood sample  12  collected into the collection chamber  32  travels through the first collection channel  40  in a first direction, the blood sample  12  travels through the second collection channel  42  in a second direction opposite the first direction, and the blood sample  12  travels through the third collection channel  44  in a third direction opposite the second direction. Referring to  FIG. 9 , the collection chamber  32  utilizes multiple interconnected parallel channels  38  to maximize collection and storage space within the constrained diameter of a blood collection set and also to ensure that the capillary force dominates over gravity during filling. 
     In one embodiment, the entrance into the collection chamber  32  is the inlet  34  of the first collection channel  40  and the exit out of the collection chamber  32  is the exit  36  of the third collection channel  44 . The inlet  34  of the first collection channel  40  is in fluid communication with an inlet channel  66  ( FIGS. 7B and 8B ) of the activation module  22 , as described in more detail below. 
     Referring to  FIG. 10 , in a second exemplary embodiment, the collection chamber  32  of the sample collection module  20  defines a first collection channel  40  extending from the inlet end  34  to the exit end  36 , a second collection channel  42  in communication with a portion of the first collection channel  40  and extending from the exit end  36  to the inlet end  34 , a third collection channel  44  in communication with a portion of the second collection channel  42  and extending from the inlet end  34  to the exit end  36 , a fourth collection channel  46  in communication with a portion of the third collection channel  44  and extending from the exit end  36  to the inlet end  34 , and a fifth collection channel  48  in communication with a portion of the fourth collection channel  46  and extending from the inlet end  34  to the exit end  36 . Referring to  FIG. 10 , the first collection channel  40  is spaced from the second collection channel  42  which is spaced from the third collection channel  44  which is spaced from the fourth collection channel  46  which is spaced from the fifth collection channel  48 . 
     In this manner, a blood sample  12  collected into the collection chamber  32  travels through the first collection channel  40  in a first direction, the blood sample  12  travels through the second collection channel  42  in a second direction opposite the first direction, the blood sample  12  travels through the third collection channel  44  in a third direction opposite the second direction, the blood sample  12  travels through the fourth collection channel  46  in a fourth direction opposite the third direction, and the blood sample  12  travels through the fifth collection channel  48  in a fifth direction opposite the fourth direction. Referring to  FIG. 10 , the collection chamber  32  utilizes multiple interconnected parallel channels  38  to maximize collection and storage space within the constrained diameter of a blood collection set and also to ensure that the capillary force dominates over gravity during filling. 
     In one embodiment, the entrance into the collection chamber  32  is the inlet  34  of the first collection channel  40  and the exit out of the collection chamber  32  is the exit  36  of the fifth collection channel  48 . The inlet  34  of the first collection channel  40  is in fluid communication with an inlet channel  66  ( FIGS. 7B and 8B ) of the activation module  22 , as described in more detail below. 
     In other exemplary embodiments, the collection chamber  32  of the sample collection module  20  may define any odd number of channels  38  based on a specific volume requirement. Importantly, the collection chamber  32  of the sample collection module  20  utilizes multiple interconnected parallel channels  38  to maximize collection and storage space within the constrained diameter of a blood collection set and also to ensure that the capillary force dominates over gravity during filling. A blood sample  12  fills the interconnected channels  38  of the sample collection module  20  in a back-and-forth motion as described above. 
     In one exemplary embodiment, the plurality of sequential flow direction alternating collection channels  38  are configured in a parallel configuration as shown in  FIGS. 9 and 10 . In other exemplary embodiments, the collection channels  38  are configured in a spiral or meandering channel configuration or in other configurations that maximize collection and storage space within the constrained diameter of a blood collection set and also to ensure that the capillary force dominates over gravity during filling. 
     In an exemplary embodiment, the collection chamber  32  is designed to ensure that the blood  12  fills the channels  38  of the collection chamber  32  continuously without trapping air bubbles regardless of device orientation and blood flow rate. This is accomplished by controlling the diameter of the channels  38  for desired applications. For example, in an exemplary embodiment, to prevent the blood stream from breaking up and trapping air bubbles, the diameter of the channels  38  needs to simultaneously meet two requirements. First, the static pressure difference at the flow front at any orientation needs to be smaller than the Laplace pressure so that the meniscus will hold its shape. Second, the selected diameter needs to make sure that the inertia force is smaller than the surface tension at the highest flow rate. 
     Referring to  FIGS. 1, 2, and 7A-8B , in an exemplary embodiment, the activation module  22  is connected or connectable to the sample collection module  20  and includes a housing  49 , a first seal  50 , and a second seal  52  for sealing the blood separation device  10 , e.g., the housing  30  of the sample collection module  20 , the housing  49  of the activation module  22 , and a housing  68  of the separation module  24 . In this manner, the seals  50 ,  52  of the activation module  22  control the pressure within the blood separation device  10  as described in more detail below. The first seal  50  is transitionable from a closed position ( FIGS. 7A and 7B ) in which the collection chamber  32  has a first pressure P 1  ( FIG. 13 ) to an open position ( FIGS. 8A and 8B ), by actuation of a portion of the activation module  22 , in which the collection chamber  32  is in fluid communication with a second pressure P 2  ( FIG. 13 ) greater than the first pressure P 1 . 
     In an exemplary embodiment, referring to  FIGS. 7A-8B , the activation module  22  includes a switch  54 . In such an embodiment, actuation of the switch  54  transitions the first seal  50  from the closed position ( FIGS. 7A and 7B ) to the open position ( FIGS. 8A and 8B ). Referring to  FIGS. 7A-8B , the switch  54  comprises a push button  56  defining a vent hole  58  therethrough and a piercing portion  60 . In this manner, actuation of the switch, e.g., depressing or pushing the push button  56  into the position shown in  FIGS. 8A and 8B , moves the piercing portion  60  to break the first seal  50  thereby transitioning the first seal  50  to the open position. 
     With the first seal  50  in the open position, the collection chamber  32  of the sample collection module  20  is in fluid communication with a second pressure P 2  via the vent hole  58  of the switch  54 . The vent hole  58  provides a venting mechanism for the blood separation device  10 . For example, in one embodiment, the piercing portion  60  breaks the first seal  50 , e.g., an aluminum foil seal, to create a vent to power the plasma separation process. 
     The second pressure P 2  defined by atmospheric pressure is greater than the first pressure P 1  defined within the blood separation device  10 , e.g., the collection chamber  32  of the sample collection module  20 . In this manner, the pressure difference between the second pressure P 2  defined by atmosphere pressure and the residual vacuum in the blood separation device  10 , i.e., the first pressure P 1  defined within the blood separation device  10 , continuously drive the plasma separation process as described in more detail below. Advantageously, using the activation module  22  of the present disclosure, a user can precisely control when the plasma separation process begins. 
     In an exemplary embodiment, referring to  FIGS. 7A-8B , the second seal  52  of the activation module  22  includes a cap  62  having a pierceable self-sealing stopper  64  within a portion of the cap  62 . The cap  62  provides a mechanism for allowing the blood separation device  10  to be connectable to a blood collection device  200  ( FIG. 3 ) as described in more detail below. 
     In one exemplary embodiment, the cap  62  of the present disclosure may be formed substantially similar to a closure described in U.S. Provisional Application 62/666,765, filed May 4, 2018, entitled “Closure for a Biological Fluid Collection Device”, the entire disclosure of which is hereby expressly incorporated herein by reference. 
     Referring to  FIGS. 7A-8B , in one embodiment, the activation module  22  defines an inlet channel  66 . Referring to  FIG. 3 , with a blood collection device  200  connected to the blood separation device  10  via the cap  62 , the collection chamber  32  of the sample collection module  20  receives a blood sample  12  via the inlet channel  66 . A blood sample  12  flows from the inlet channel  66  of the activation module  22  to the plurality of channels  38  of the collection chamber  32  via the inlet  34 . 
     Referring to  FIGS. 1-6 and 11-13 , in an exemplary embodiment, the separation module  24  is in fluid communication with the collection chamber  32  of the sample collection module  20  and includes a housing  68  and defines a first chamber  70  having a first volume V 1  ( FIG. 13 ) and a second chamber  72  having a second volume V 2  ( FIG. 13 ) and including a separation member  74  disposed between the first chamber  70  and the second chamber  72 . The first volume V 1  of the first chamber  70  and the second volume V 2  of the second chamber  72  are different to create a second pressure difference between the first chamber  70  and the second chamber  72  to drive the second phase  16  of a blood sample  12  through the separation member  74  into the second chamber  72  as described in more detail below. In one embodiment, a portion of the separation module  24  forms a microfluidic chip. 
     Referring to  FIGS. 11 and 12 , in an exemplary embodiment, the separation member  74  traps the first phase  14  in the first chamber  70  and allows the second phase  16  to pass through the separation member  74  into the second chamber  72 . In one embodiment, the separation member  74  comprises a track-etched membrane. In certain configurations, the membrane may be less than 100 microns in thickness, such as from 5 to 25 microns in thickness. The membrane may have submicron pores or holes, such as from 0.2 to 0.8 microns in diameter. This dimensionality allows for continuous filtering of a plasma portion of a blood sample flowing parallel to the membrane surface, which prevents clogging of the membrane pores or holes. In other embodiments, the separation member  74  may comprise any filter, and/or any other separation device, that is able to trap the first phase  14  in the first chamber  70  and allow the second phase  16  to pass through the separation member  74  into the second chamber  72 . 
     Referring to  FIGS. 11 and 12 , the first chamber  70  includes a first chamber inlet  75  and a first chamber outlet  76 , and the second chamber  72  includes a second chamber outlet  78 . The first chamber inlet  75  is in fluid communication with the exit  36  of the collection channels  38 . In this manner, upon actuation of a portion of the activation module  22 , a blood sample  12  can flow from the collection chamber  32  of the sample collection module  20  to the first chamber  70  of the separation module  24  for plasma separation. 
     Referring to  FIGS. 1-6, 11, and 13 , the separation module  24  of the blood separation device  10  includes a second phase collection container  80  that is in communication with the second chamber outlet  78 . The second phase collection container  80  receives the second phase  16  of the blood sample  12 . The second phase collection container  80  is able to collect and store the separated second phase  16 . Advantageously, referring to  FIG. 6 , with the second phase  16  contained within the second phase collection container  80 , the second phase collection container  80  is removable from the blood separation device  10 . In this manner, the second phase  16  of a blood sample  12  can be collected or stored in a secondary second phase container, e.g., a second phase collection container  80 , for further diagnostic tests. For example, after separation, with the second phase collection container  80  removed from the blood separation device  10 , the second phase collection container  80  is able to transfer the second phase  16  of the blood sample  12  to a point-of-care testing device or other testing device. In an exemplary embodiment, the second phase collection container  80  includes structure allowing the second phase collection container  80  to dispense a portion of the plasma  16 , when desired. In one embodiment, the second phase collection container  80  is sealed via a cap or septum  81  to protectively seal the plasma portion  16  within the second phase collection container  80 . 
     Referring to  FIG. 11 , in an exemplary embodiment, a portion of the second chamber  72  of the separation module  24  is in fluid communication with an interior of the second phase collection container  80  to allow the plasma portion  16  to flow through the separation member  74  and the second chamber  72  into the interior of the second phase collection container  80  for collection. 
     Referring to  FIGS. 11-13 , the separation module  24  of the blood separation device  10  also includes a blood sample discard chamber  82  that is in communication with the first chamber outlet  76 . The blood sample discard chamber  82  receives the remaining first phase  14  of the blood sample  12  after a blood sample  12  flows over the separation member  74  in the first chamber  70 . In this manner, the remaining first phase  14  of the blood sample  12  can be collected and stored in the blood sample discard chamber  82 . Also, the blood sample discard chamber  82  ensures that the remaining first phase  14  of the blood sample  12  can be safely stored when the rest of the blood separation device  10  is discarded after use. 
     Referring to  FIGS. 3-6 , use of a blood separation device  10  of the present disclosure will now be described. 
     Referring to  FIG. 3 , a first step of using a blood separation device  10  of the present disclosure involves collecting a blood sample  12  from a patient, e.g., the blood collection process. For example, first, a given volume of a blood sample  12  from a patient is pulled into the collection chamber  32  of the blood separation device  10  under a vacuum force, immediately following the connection of the blood separation device  10  to a blood collection device  200 , such as a tube holder  202 . In one embodiment, such a connection consists of a non-patient needle (not shown) of the tube holder  202  piercing the stopper  64  of the cap ( FIG. 7B ). The opposite end of a line  204  of the tube holder  202  consists of a patient needle of a venous access set in communication with a patient. 
     Referring to  FIG. 3 , with the tube holder  202  of the blood collection device  200  connected to the blood separation device  10  via the cap  62  ( FIG. 7B ), the collection chamber  32  of the sample collection module  20  receives the blood sample  12  via the inlet channel  66  ( FIG. 7B ) of the activation module  22 . The blood separation device  10  of the present disclosure collects and stores a fixed amount of the patient&#39;s blood. In one exemplary embodiment, a blood separation device  10  of the present disclosure collects and stores 3 mL of a patient&#39;s blood in less than 30 seconds. 
     The blood sample  12  flows through the inlet channel  66  of the activation module  22  to the collection chamber  32  of the sample collection module  20 . Advantageously, during blood collection, the plurality of sequential flow direction alternating collection channels  38  of the collection chamber  32  maximize collection and storage space within the constrained diameter of a blood collection set and also to ensure that the capillary force dominates over gravity during filling. 
     A user can select one of the ways, sources, or methods that the blood separation device  10  is able to receive a blood sample  12 . For example, referring to  FIG. 3 , the blood separation device  10  of the present disclosure is able to receive a blood sample  12  from a conventional blood collection device  200 . For example, the blood collection device  200  may include a tube holder  202  and corresponding venous access set, such as a BD Vacutainer® blood collection tube commercially available from Becton, Dickinson and Company. In other alternative embodiments, blood is collected in a conventional blood collection tube or any other intermediate blood sample container. The blood sample container is then connected to the off-patient separation device to generate plasma. 
     Once a desired amount of a blood sample  12  is collected into the collection chamber  32  and the blood collection process is complete, the blood separation device  10  is disconnected from the blood collection device  200 . In this manner, a blood separation device  10  of the present disclosure decouples and separates the blood collection process from the plasma separation process. Because the plasma separation happens after the blood separation device  10  is disconnected from the patient, the device performance is no longer affected by patient blood pressure and needle gauge, and patient discomfort is greatly reduced. 
     Upon disconnection of the blood separation device  10  of the present disclosure from the blood collection device  200  and the patient, the collected blood remains stationary in the channels  38  until the plasma separation is activated. The blood separation device  10  accomplishes this by utilizing the second seal  52 , e.g., the stopper  64  of the cap  62 . The stopper  64  of the cap  62  ensures that the second seal  52  is properly resealed after a needle of the blood collection device  200  is retracted out from the stopper  64  so that there is no pressure difference between the front and back end of the stored blood within the blood separation device  10 . 
     Referring to  FIG. 4 , after the blood separation device  10  is disconnected from the blood collection device  200 , the plasma separation process can be started. Advantageously, the blood separation device  10  of the present disclosure does not require being connected to a patient to perform plasma separation. The plasma separation process is completely controllable and can be started at a convenient and desired time. 
     Referring to  FIG. 4 , the plasma separation process is started with the blood separation device  10  off-patient by simply actuating the switch  54  ( FIGS. 8A and 8B ), e.g., pushing the push button  56 , on the blood separation device  10 . Actuation of the switch  54  allows the blood separation device  10  to automatically generate plasma  16  from the blood sample  12  stored within the blood separation device  10 . 
     Actuation of the switch  54  transitions the first seal  50  to the open position ( FIG. 8B ), in which the collection chamber  32  is in fluid communication with a second pressure P 2  defined by atmospheric pressure that is greater than the first pressure P 1  defined within the collection chamber  32 . In this manner, the first pressure difference, e.g., the difference in pressure between the second pressure P 2  defined by atmospheric pressure and the first pressure P defined within the collection chamber  32 , draws the blood sample  12  into the first chamber  70  of the separation module  24 . In other words, the first pressure difference between the atmosphere pressure and the residual vacuum in the blood separation device  10  continuously drives the plasma separation within the blood separation device  10 . In an exemplary embodiment, the separation module  24  allows for continuous plasma separation as a blood sample  12  flows through the first chamber  70  and over the separation member  74  by utilizing a cross-flow filtration flow pattern in a microfluidic chip, e.g., the separation module  24  as shown in  FIG. 12 . In one configuration, the pressure in the collection chamber  32  is limited by the maximum allowable pressure difference across the membrane such that the end point pressure within the collection chamber  32  after blood collection and before filtration should be smaller than 5.5 psi. 
     Advantageously, the activation module  22  starts the plasma separation process after blood collection and with the blood separation device  10  disconnected from a blood collection device  200  and a patient. To start the plasma separation process after blood collection, it is essential to re-establish a pressure gradient on the stored blood within the collection chamber  32 . This is accomplished via the activation module  22  controlling the pressures within the blood separation device  10 . Before activation, the first seal  50  and the second seal  52  of the activation module  22  seal the housing  30  of the blood separation device  10  and with the first seal  50  in the closed position ( FIG. 7B ), the activation module  22  seals the collection chamber  32  at a first pressure P. After activation of the activation module  22 , the first seal  50  is transitioned to the open position ( FIG. 8B ), in which the collection chamber  32  is in fluid communication with a second pressure P 2  defined by atmospheric pressure that is greater than the first pressure P 1  defined within the collection chamber  32 . 
     Importantly, a second pressure difference is used within the blood separation device  10  to drive the plasma  16  to pass through the separation member  74  into the second chamber  72  and be collected within the second phase collection container  80 . With the first seal  50  in the open position ( FIG. 8B ), the first volume V 1  of the first chamber  70  of the separation module  24  and the second volume V 2  of the second chamber  72  of the separation module  24  being different provides the second pressure difference between the first chamber  70  and the second chamber  72  to drive the second phase  16  of the blood sample  12  through the separation member  74  into the second chamber  72  and to be collected within the second phase collection container  80 . In other words, the second pressure difference across the blood flow in the first chamber  70  and the plasma flow path in the second chamber  72  and their dynamic profiles during the separation provides a power source that further drives the plasma separation process. In an exemplary embodiment, controlling the second pressure difference across the blood flow in the first chamber  70  and the plasma flow path in the second chamber  72  and their dynamic profiles for a given plasma separation chip, e.g., separation module  24 , is achieved via setting the appropriate initial vacuum level and balancing the volume ratio of the blood sample discard chamber  82  and the second phase collection container  80 . In an exemplary embodiment, a volume of the blood sample discard chamber  82  is designed to ensure that the volume is big enough to have sufficient residual vacuum in the end to drive the blood flow without clogging the separation member  74 . In an exemplary embodiment, the volume also needs to be small enough so that at the end of the separation, the pressure in the blood sample discard chamber  82  is higher than a pressure in the second phase collection container  80  to keep the separation member  74  from collapsing. In one configuration, the volume of the blood sample discard chamber  82  is at least twice as large as the volume of the collection chamber  32 , and smaller than the volume of the second phase collection container  80  multiplied by the factor (1−yield)/yield. The pressure difference across the membrane may need to be smaller than 5.5 psi at all times during filtration. 
     Utilizing the first pressure difference and the second pressure difference within the blood separation device  10  forces the blood  12  to flow through the first chamber  70  and over the separation member  74 . As the blood  12  flows thru the separation module  24 , plasma  16  is continuously separated from the first phase  14  of the blood sample  12 . 
     During plasma separation, the separation member  74  allows the second phase or plasma  16  to pass through the separation member  74  into the second chamber  72  which can be collected or stored in a secondary plasma container, e.g., a second phase collection container  80 , for further diagnostic tests. Referring to  FIG. 11 , the arrow comprising a broken line indicates the second phase flow path  104  that the plasma  16  takes after passing through the separation member  74 . In one embodiment, after plasma separation, with the second phase or plasma  16  contained within the second phase collection container  80 , the second phase collection container  80  is removable from the blood separation device  10 . The second phase collection container  80  can then be used to transfer the plasma portion  16  to a point-of-care testing device or other diagnostic testing system. 
     During plasma separation, the separation member  74  traps the first phase  14  of the blood sample  12  within the first chamber  70 , e.g., the first phase  14  of the blood sample  12  is not allowed to pass through the separation member  74  into the second chamber  72 . Referring to  FIG. 11 , the arrow comprising a straight line indicates the flow path  102  that the blood sample  12  takes through the collection chamber  32  and the flow path  102  that the first phase  14  of the blood sample  12  takes after passing over the separation member  74  and to the blood sample discard chamber  82 . Referring to  FIGS. 11 and 12 , the first phase  14  of the blood sample  12  flows into the first chamber  70  through the first chamber inlet  75  and over the separation member  74  surface, and then exits the first chamber  70  via the first chamber outlet  76  into the blood sample discard chamber  82 . 
     In one exemplary embodiment, a blood separation device  10  of the present disclosure is able to generate 350 to 600 uL of plasma  16  from the stored 3 mL of blood in less than 7 minutes. 
     Referring to  FIG. 5 , the blood separation device  10  of the present disclosure allows for plasma separation to occur independent of an orientation of the blood separation device  10 . In other words, the blood separation device  10  separates plasma regardless of whether the blood separation device  10  is in an upright orientation, e.g., the blood separation device  10  is contained in a tube rack, or if the blood separation device  10  is lying in a flat orientation on a table or tray. 
     Referring to  FIG. 6 , with the second phase or plasma  16  contained within the second phase collection container  80 , the second phase collection container  80  is removable from the blood separation device  10 . The second phase collection container  80  can then be used to transfer the plasma portion  16  to a point-of-care testing device or other diagnostic testing system. In one embodiment, the second phase collection container  80  is removably connectable to the blood separation device  10  via a luer lock septum seal. 
     In other words, after plasma separation is completed, the plasma  16  within the second phase collection container  80  is removed from the blood separation device  10  for use in clinical tests. The rest of the blood separation device  10  can then be discarded. 
     As described herein, the present disclosure provides a blood separation device that decouples and separates the blood collection process from the plasma separation process. The blood separation device includes a sample collection module, an activation module, and a separation module. Because the plasma separation happens after the blood separation device is disconnected from the patient, the device performance is no longer affected by patient blood pressure and needle gauge, and patient discomfort is greatly reduced. 
     While this disclosure has been described as having exemplary designs, the present disclosure can be further modified within the spirit and scope of this disclosure. This application is therefore intended to cover any variations, uses, or adaptations of the disclosure using its general principles. Further, this application is intended to cover such departures from the present disclosure as come within known or customary practice in the art to which this disclosure pertains and which fall within the limits of the appended claims.