Patent Publication Number: US-11638918-B2

Title: Blood plasma separation device

Description:
RELATED APPLICATION 
     The current application claims priority to U.S. Patent Application No. 62/722,050 filed on Aug. 23, 2018, the contents of which are hereby fully incorporated by reference. 
    
    
     FIELD 
     This application relates to separating blood plasma from whole blood. 
     BACKGROUND 
     It can be useful to separate blood plasma from whole blood, for example to facilitate analysis of one or more components of the blood plasma. 
     SUMMARY 
     Blood plasma separation devices, and methods of making and using the same, are provided herein. 
     A device for separating blood plasma from whole blood includes a first reservoir and a second reservoir. The first reservoir is configured to receive a sample of whole blood including red blood cells. The first reservoir includes a collection region and a constricted region. The second reservoir is fluidically connected to the constricted region of the first reservoir, such that, responsive to centrifugal force applied to the device, the sample of whole blood disposed within the first reservoir separates into a first fraction and a second fraction. The first fraction is located in the collection region and includes blood plasma from which substantially all red blood cells have been removed. The second fraction is located in the second reservoir and includes blood plasma and red blood cells that have been removed from the first fraction by the centrifugal force. The constricted region inhibits the second fraction from entering the collection region. 
     An outlet can be provided that is fluidically connected to the collection region. In addition, a channel can fluidically connect the outlet to the collection region. Such angle can be disposed at an acute angle relative to the collection region. The channel can be configured to substantially fill with the first fraction via capillary action responsive to termination of the centrifugal force. 
     The first reservoir can include a sample reservoir and a plasma reservoir fluidically connected to one another. With such arrangements, the sample reservoir can include an inlet configured to receive the sample of whole blood and the plasma reservoir can include the collection region and the constricted region. The sample reservoir, plasma reservoir, and second reservoir can each include one or more respective sidewalls and a respective lower surface. A cover (or other housing element) can be disposed over the sample reservoir, plasma reservoir, and second reservoir. The respective lower surface of the plasma reservoir can be closer to the cover than are the respective lower surfaces of the sample reservoir and the second reservoir. An upper surface of the sample of whole blood disposed within the sample reservoir can be further from the cover than is the lower surface of the plasma reservoir. The sample of whole blood disposed within the sample reservoir can flow upward toward the cover to contact the lower surface of the plasma reservoir responsive to the centrifugal force applied to the device. 
     In some variations, a first one of the sidewalls of the sample reservoir can be disposed at an angle (e.g., obtuse angle, etc.) angle relative to the lower surface of the sample reservoir. With such an arrangement, substantially all of the sample of whole blood disposed within the sample reservoir can flow upward along the first one of the sidewalls of the sample reservoir responsive to the centrifugal force applied to the device. 
     A portion of the sample of whole blood contacting the lower surface of the plasma reservoir can flow downward away from the cover to contact the lower surface of the second reservoir responsive to the centrifugal force applied to the device. The portion of the sample of whole blood contacting the lower surface of the plasma reservoir can flow downward along a first one of the sidewalls of the second reservoir responsive to the centrifugal force applied to the device. 
     The first and second fractions can each contact the cover after termination of the centrifugal force. The cover can be at least partially optically transparent. The cover can include a first aperture via which the sample reservoir receives the sample of whole blood and a second aperture via which the first fraction is withdrawn. The first aperture can be disposed over the sample reservoir. The second aperture can be disposed over the plasma reservoir. A channel can be provided that fluidically connects the outlet to the collection region, wherein the second aperture is located over the channel. The first and second apertures can each be configured to receive a pipette tip. 
     The cover can include a vent disposed over the sample reservoir. 
     The first fraction can substantially fill the plasma reservoir responsive to the centrifugal force. 
     The second fraction can substantially fill the second reservoir responsive to the centrifugal force. 
     The sample reservoir, the plasma reservoir, and the second reservoir can be arranged linearly with one another. 
     A meniscus of the first fraction can be disposed within the collection region. 
     In some variations, at least 75% of the red blood cells in the sample of whole blood are removed from the first fraction. In other variations, at least 99% of the red blood cells in the sample of whole blood are removed from the first fraction. In still other variations, 100% of the red blood cells in the sample of whole blood are removed from the first fraction. 
     The first reservoir can have varying volumes. For example, the first reservoir can have a volume about 25 μL to about 1 mL, or about 50-500 μL, or about 100-250 μL. 
     The second reservoir can have varying volumes. For example, the second reservoir can have a volume of about 20-80% of a volume of the first reservoir, or a volume of about 40-60% of a volume of the first reservoir. 
     A rotatable disc can be provided in which the first and second reservoirs are disposed. 
     In an interrelated aspect, blood plasma is separated from whole blood by receiving, by a first reservoir of a device, a sample of whole blood comprising red blood cells. The first reservoir includes a collection region and a constricted region. A centrifugal force is applied to the device to separate the sample of whole blood into a first fraction and a second fraction. The first fraction is located in the collection region and includes blood plasma from which substantially all red blood cells have been removed. The second fraction is located in a second reservoir of the device and includes blood plasma and red blood cells that have been removed from the first fraction by the centrifugal force. The constricted region inhibits the second fraction from entering the collection region. 
    
    
     
       BRIEF DESCRIPTION OF DRAWINGS 
         FIGS.  1 A- 1 B  respectively schematically illustrate plan and cross-sectional views of an exemplary blood plasma separation device, according to various configurations provided herein. 
         FIGS.  1 C- 1 D  schematically illustrates cross-sectional views of the exemplary blood plasma separation device of  FIGS.  1 A- 1 B  during use, according to various configurations provided herein. 
         FIGS.  2 A- 2 D  schematically illustrate cross-sectional views of alternative blood plasma separation devices, according to various configurations provided herein. 
         FIG.  3    schematically illustrates a plan view of another alternative blood plasma separation device, according to various configurations provided herein. 
         FIGS.  4 A- 4 B  schematically illustrate plan and cross-sectional perspective views of components of another alternative blood plasma separation device, according to various configurations provided herein. 
         FIG.  5    schematically illustrates a plan view of a disc including the device of  FIGS.  4 A- 4 B , according to various configurations provided herein. 
         FIG.  6    illustrates an exemplary flow of operations in a method of using the devices of  FIGS.  1 A- 5   , according to various configurations provided herein. 
         FIGS.  7 A- 7 D  schematically illustrate plan views of components of a blood plasma separation device during operations of the method of  FIG.  6   , according to various configurations provided herein. 
     
    
    
     DETAILED DESCRIPTION 
     Blood plasma separation devices, and methods of making and using the same, are provided herein. The present blood plasma separation devices and methods suitably can be used to separate blood plasma from one or more other components of a sample of whole blood based on centrifugal forces. For example, the present blood plasma separation devices and methods can be used to separate blood plasma from blood cells within the sample of whole blood, so as to generate a fraction from which substantially all blood cells have been removed. Such fraction, which can primarily contain plasma, can collect within a first reservoir, and a fraction containing blood cells that have been removed can collect within a second reservoir. In some configurations provided herein, a constriction within the device inhibits blood cells from reentering the fraction that primarily contains plasma. 
       FIGS.  1 A- 1 B  respectively schematically illustrate plan and cross-sectional views of an exemplary blood plasma separation device, according to various configurations provided herein. Device  100  illustrated in  FIGS.  1 A- 1 B  can include first reservoir  110  configured to receive a sample of whole blood comprising red blood cells. First reservoir  110  optionally can include collection region  111  and constricted region  112 . Device  100  further can include second reservoir  120  that is fluidically connected to constricted region  112  of first reservoir  110 . Optionally, first reservoir  110  and second reservoir  120  are arranged linearly with one another, and as a further option collection region  111 , constricted region  112 , and second reservoir  120  are arranged linearly with one another. 
     Optionally, device  100  includes inlet  113  via which first reservoir  110  can receive a sample of whole blood. Additionally, or alternatively, device  100  optionally includes outlet  114  via which a fraction primarily containing plasma can be withdrawn following centrifugation in a manner such as described herein with reference to  FIGS.  1 C- 1 D,  6 , and  7 A- 7 D . Additionally, or alternatively, device  100  optionally includes vent  115  via which air can escape from first reservoir  110  when a sample of whole blood is received within that reservoir, e.g., via optional inlet  113 . Optionally, inlet  113 , outlet  114 , and/or vent  115  can be defined within cover  116 , e.g., as optional first, second, and/or third apertures defined through cover  116 , one or more of which apertures can be configured to receive a pipette tip. 
     First reservoir  110  and second reservoir  120  can have any suitable configuration and include any suitable number of upper surfaces (covers), lower surfaces (covers), and/or sidewalls which respectively can be discrete elements or can be integrally formed with one another, for example as described in greater detail herein with reference to  FIGS.  2 A- 2 D . In the nonlimiting configuration illustrated in  FIG.  1 B , first reservoir  110  includes upper surface (first cover)  116 , sidewall(s)  117 , and lower surface (second cover)  118  together providing an open area  119 , and second reservoir  120  includes upper surface (third cover)  123 , sidewall(s)  121 ,  122 , and lower surface (fourth cover)  124  together providing an open area  125 . It should be appreciated that terms such as “upper,” “lower,” “sidewall,” and “cover” are not intended to be limiting of any particular orientation of the devices and methods provided herein, but instead to provide helpful terms by which various components optionally can be referred for the illustrated orientation and configuration. In the configuration illustrated in  FIG.  1 B , the lower surface  118  and cover  116  of first reservoir  110  are closer to one another than the lower surface  124  and cover  123  of second reservoir  120 . One or more covers of device  100 , e.g., one or more of upper surface  116 , upper surface  123 , lower surface  118 , and/or lower surface  124  independently can be at least partially optically transparent. 
     Optional inlet port (first aperture)  113  can be disposed over a first region of open area  119 , which is configured to receive a sample of whole blood and optionally can be considered to be a sample reservoir. Optional outlet port (second aperture  114 ) can be disposed over a second region of open area  119 , which can be considered to be a plasma reservoir and is configured to collect a primarily plasma fraction which is generated responsive to centrifugal force in the direction indicated by the large arrow. It should be appreciated that a sample of whole blood can be introduced into open area  119  of collection region  111  via any suitable inlet, and is not limited to an aperture through a cover disposed over open area  119 . For example, the sample of whole blood can be introduced into collection region  111  via a channel configured similarly to channel  330  described with reference to  FIG.  3   . It should also be appreciated that a fraction primarily containing blood plasma can be removed from open area  119  of collection region  111  via any suitable outlet, and is not limited to an aperture through a cover disposed over open area  119 . For example, the fraction can be removed from collection region  111  via a channel configured similarly to channel  330  described with reference to  FIG.  3   . Such channel optionally can include an outlet configured similarly to outlet  314  described with reference to  FIG.  3   , or optionally can be connected to another device, for example configured to perform further processing of the fraction. 
     Responsive to centrifugal force applied to device  100 , the sample of whole blood disposed within first reservoir  110  separates into a first fraction and a second fraction. For example,  FIGS.  1 C- 1 D  schematically illustrate a cross-sectional view of the exemplary blood plasma separation device of  FIGS.  1 A- 1 B  during use, e.g., during operations of the method of  FIG.  6    and similarly as illustrated in  FIGS.  7 A- 7 B , according to various configurations provided herein. As illustrated in  FIG.  1 C , first reservoir  110  can receive a sample  130  of whole blood via optional inlet port (aperture)  113 . Responsive to centrifugal force in the direction indicated by the large arrow, for example by spinning a disc that includes device  100  in a manner similar to that illustrated in  FIG.  5   , the sample of whole blood separates into a first fraction  131  and a second fraction  132  in a manner such as schematically illustrated in  FIG.  1 D . First fraction  131  can be located at least in collection region  111  and can include blood plasma from which substantially all red blood cells have been removed, for example in a manner similar to that described herein with reference to  FIG.  7 C . Second fraction  132  can be located in second reservoir  120  and can include blood plasma and red blood cells that have been removed from the first fraction by the centrifugal force. As used herein, removal of “substantially all” red blood cells is intended to mean that at least 75% of the red blood cells in the sample of whole blood are removed from the first fraction, or at least 99% of the red blood cells in the sample of whole blood are removed from the first fraction, or 100% of the red blood cells in the sample of whole blood are removed from the first fraction. Such separation of red blood cells (and optionally other types of blood cells) from the blood plasma can be achieved, for example, by applying sufficient centrifugal force to device  100  for a sufficient amount of time. For example, a disc in which device  100  is included can be spun at a rate of 1000 or more revolutions per minute (RPM), a rate of 2000 RPM or more, a rate of 3000 RPM or more, or a rate of 4000 RPM or more, for a sufficient amount of time to remove substantially all red blood cells from the sample of whole blood so as to generate first fraction  131 . 
     In some configurations, responsive to the centrifugal force applied to the device (e.g., via such spinning), optionally a portion of the sample of whole blood  113  contacting the lower surface  118  of collection region  111  flows downward away from cover  116  to contact the lower surface  124  of the second reservoir  120 . Optionally, first fraction  131  substantially fills a portion of the first reservoir  110  responsive to the centrifugal force, e.g., substantially fills constricted region  112  and a portion of collection region  111 . Additionally, or alternatively, optionally second fraction  132  substantially fills second reservoir  120  responsive to the centrifugal force. As a further or alternative option, first fraction  131  contacts cover  116 , and second fraction contacts cover  123 , after termination of the centrifugal force. Optionally, first fraction  131  suitably can be removed from first reservoir  110  via any suitable outlet fluidically connected to collection region  111 . For example, first fraction  131  can be removed via optional outlet port  114 , or via a channel configured similarly to channel  330  described with reference to  FIG.  3    which optionally can include an outlet port or can be connected to another device. As yet another option, first fraction  131  can remain within first reservoir  110 , e.g., can be optionally analyzed, for example via optical analysis through upper surface  116  and/or lower surface  118  each of which optionally can be at least partially optically transparent. 
     In various configurations provided herein, constricted region  112  optionally inhibits second fraction  132  from entering collection region  111 , e.g., after the centrifugal force is removed. As such, constricted region  112  optionally can inhibit red blood cells (and optionally other types of blood cells) within second fraction from reentering the plasma within first fraction  131 , such that substantially all red blood cells continue to be excluded from first fraction  131  even after the centrifugal force is removed. 
     The constricted region  112  can for venting of air as well as constrict fluid flow to prevent movement of cells after separation. The constricted region  112  can, in some variations, have a cross section with at least one of the dimensions less than 1 mm. The constricted region  112  can have a cross-section that is square, rectangular, and/or circular/semi-circular or any other shape. It is currently 1 mm×0.5 mm but could be other dimensions that similarly constrain flow. 
     Additionally, or alternatively, in the exemplary configuration illustrated in  FIGS.  1 A- 1 D , open area  119  optionally is shallower than, and positioned higher than, open area  125 , and as a result blood cells that are forced into second reservoir  120  by centrifugal forces can be inhibited from reentering the plasma of first fraction  131 . Optionally, meniscus  133  of first fraction  131  is disposed within collection region  111 , e.g., such as illustrated in  FIG.  1 D . For example, meniscus  133  can extend between the upper and lower surfaces  116 ,  118  of collection region  111 . 
     Note that first reservoir  110  (and components thereof) and second reservoir  120  (and components thereof) can have any suitable volume, configuration, and dimensions. As one nonlimiting example, first reservoir  110  optionally can have a volume about 25 μL to about 1 mL, or about 50-500 μL, or about 100-250 μL. Additionally, or alternatively, second reservoir  120  optionally can have a volume of about 20-80% of a volume of first reservoir  110 , or a volume of about 40-60% of a volume of first reservoir  110 . For example, second reservoir  120  optionally can be sized so as to accommodate substantially all of the red blood cells within whole blood sample  130 , e.g., following separation of that sample into first and second fractions. 
     As noted elsewhere herein, first reservoir  110  and second reservoir  120  can have any suitable configuration and include any suitable number of upper surfaces (covers), lower surfaces (covers), and/or sidewalls which respectively can be discrete elements or can be integrally formed with one another. For example, in the nonlimiting example illustrated in  FIGS.  1 A- 1 D , optionally the upper surfaces, lower surfaces, and sidewalls can be provided as discrete elements which are suitably coupled to one another.  FIGS.  2 A- 2 D  schematically illustrate cross-sectional views of alternative blood plasma separation devices, according to various configurations provided herein. Alternative device  200  illustrated in  FIG.  2 A  can include upper surfaces, lower surfaces, and sidewalls which are configured similarly as device  100  described with reference to  FIGS.  1 A- 1 D , but in which some of such elements are integrally formed with one another. For example, device  200  can include sidewall element  230  within which respective sidewalls of collection region  211 , constricted region  212 , and second reservoir  220  can be integrally disposed. Device  200  also can include first cover element  240  within which respective upper surfaces of collection region  211 , constricted region  212 , and second reservoir  220  can be integrally disposed. Device  200  also can include second cover element  250  within which respective lower surfaces of collection region  211 , constricted region  212 , and second reservoir  220  can be integrally disposed. Sidewall element  230 , first cover element  240 , and second cover element  250  can be discrete from one another and suitably coupled to one another. 
     Alternative device  200 ′ illustrated in  FIG.  2 B  can include upper surfaces, lower surfaces, and sidewalls which are configured similarly as device  100  described with reference to  FIGS.  1 A- 1 D , but in which some of such elements are integrally formed with one another. For example, device  200 ′ can include combined sidewall/cover element  250  within which respective sidewalls and lower surfaces of collection region  211 , constricted region  212 , and second reservoir  220  can be integrally disposed. Device  200  also can include cover element  240  within which respective upper surfaces of collection region  211 , constricted region  212 , and second reservoir  220  can be integrally disposed. Combined sidewall/cover element  250  and cover element  240  can be discrete from one another and suitably coupled to one another. 
     Alternative device  200 ″ illustrated in  FIG.  2 C  can include upper surfaces, lower surfaces, and sidewalls which are configured similarly as device  100  described with reference to  FIGS.  1 A- 1 D , but in which some of such elements are integrally formed with one another. For example, device  200 ″ can include combined sidewall/cover element  270  within which respective sidewalls and upper surfaces of collection region  211 , constricted region  212 , and second reservoir  220  can be integrally disposed. Device  200  also can include cover element  250  within which respective lower surfaces of collection region  211 , constricted region  212 , and second reservoir  220  can be integrally disposed. Combined sidewall/cover element  270  and cover element  250  can be discrete from one another and suitably coupled to one another. 
     Alternative device  200 ′″ illustrated in  FIG.  2 D  can include upper surfaces, lower surfaces, and sidewalls which are configured similarly as device  100  described with reference to  FIGS.  1 A- 1 D , but in which all of such elements are integrally formed with one another. For example, device  200 ′ can include combined sidewall/cover element  280  within which respective sidewalls, upper surfaces, and lower surfaces of collection region  211 , constricted region  212 , and second reservoir  220  can be integrally disposed. 
     As noted elsewhere herein, the first fraction can be removed from the collection region of the first reservoir using any suitable outlet fluidically connected to the collection region, or optionally can be left in place. Optional outlet port  114  illustrated in  FIGS.  1 A- 1 D  provides one example of such an outlet. Another example is illustrated in  FIG.  3   , which schematically illustrates a plan view of another alternative blood plasma separation device, according to various configurations provided herein. Device  300  illustrated in  FIG.  3    includes first reservoir  310  which can be configured to receive a sample of whole blood comprising red blood cells, and can be configured similarly to first reservoir  110  described with reference to  FIGS.  1 A- 1 D . For example, first reservoir  310  optionally can include collection region  311  and constricted region  312 . Device  300  further can include second reservoir  320  that is fluidically connected to constricted region  312  of first reservoir  310  and can be configured similarly to second reservoir  120  described with reference to  FIGS.  1 A- 1 D . Optionally, device  300  includes inlet  313  via which first reservoir  310  can receive a sample of whole blood in a manner similarly as inlet  113  described with reference to  FIGS.  1 A- 1 D , or other suitable structure for introducing a sample of whole blood to first reservoir  310 . Additionally, or alternatively, device  300  optionally includes vent  315  via which air can escape from first reservoir  310  when a sample of whole blood is received within that reservoir, e.g., via optional inlet  313 . 
     Device  300  illustrated in  FIG.  3    optionally further includes channel  330  which is fluidically connected to the collection region  311 . Channel  330  optionally is configured to substantially fill with the first fraction via capillary action responsive to termination of the centrifugal force. In some configurations, optional channel  330  is configured to fluidically connect an outlet  314  to the collection region  311 , and the first fraction can be withdrawn from collection region  311  via channel  330  and outlet  314 . In other configurations, optional channel  330  is coupled to another device (not specifically illustrated) which can receive the first fraction via the channel. Additionally, or alternatively, channel  330  optionally is disposed at an acute angle relative to the collection region  311 , which can inhibit red blood cells from entering the first fraction within the channel. 
     Still other configurations can be envisioned. For example,  FIGS.  4 A- 4 B  schematically illustrate plan and cross-sectional perspective views of components of another alternative blood plasma separation device, according to various configurations provided herein. In the exemplary configuration illustrated in  FIGS.  4 A- 4 B , device  400  includes first reservoir  410 , second reservoir  420 , and channel  430 . First reservoir  410  includes sample reservoir  416  and plasma reservoir  417  which are fluidically connected to one another. Plasma reservoir  417  optionally can include collection region  411  and constricted region  412  which respectively can be configured similarly as collection region  111  and constricted region  112  described with reference to  FIGS.  1 A- 1 D . The sample reservoir  416 , plasma reservoir  417 , and second reservoir  420  each can include one or more respective sidewalls and a respective lower surface, as well as a respective upper surface (omitted in  FIG.  4 B  for clarity), e.g., a cover disposed over the sample reservoir, plasma reservoir, and second reservoir. Any suitable ones of the upper surfaces, lower surfaces, and sidewalls can be discrete from one another or integrally formed with one another, e.g., in a manner similar to that described with reference to  FIGS.  2 A- 2 D . For example, in the nonlimiting example shown in  FIGS.  4 A- 4 B , the sidewalls and lower surfaces of sample reservoir  416 , plasma reservoir  417 , and second reservoir  420  can be integrally formed with one another as a single element, and an integrally formed cover suitably can be attached to such element so as to provide upper surfaces of sample reservoir  416 , plasma reservoir  417 , and second reservoir  420 , e.g., in a manner similar to that described with reference to  FIG.  2 B . Optionally, sample reservoir  416 , plasma reservoir  417 , and second reservoir  420  are arranged linearly with one another, e.g., such as illustrated in  FIGS.  4 A- 4 B . 
     The cover of device  400 , which can form the upper surfaces of the first and second reservoirs  410 ,  420 , optionally can include first aperture (inlet port)  413  via which sample reservoir  416  can receive the sample of whole blood, and/or second aperture  414  (outlet port) via which the first fraction can be withdrawn. First aperture  413  optionally can be disposed over sample reservoir  416  and configured similarly as first aperture (inlet port)  113  described with reference to  FIGS.  1 A- 1 D . Optionally, second aperture  414  can be disposed over the plasma reservoir  417  and configured similarly as second aperture  413  described with reference to  FIGS.  1 A- 1 D . Alternatively, in the exemplary configuration illustrated in  FIG.  4 A , device  400  optionally includes channel  430  which is fluidically connected to the collection region  411 , for example to plasma reservoir  417 . Channel  430  optionally is configured to substantially fill with the first fraction via capillary action responsive to termination of the centrifugal force. In some configurations, optional channel  430  is configured to fluidically connect outlet  414  to the collection region  411 , and the first fraction can be withdrawn from collection region  411  via channel  430  and outlet  414 . In other configurations, optional channel  430  is coupled to another device (not specifically illustrated) which can receive the first fraction via the channel. Additionally, or alternatively, channel  430  optionally is disposed at an acute angle relative to the collection region  411 , which can inhibit red blood cells from entering the first fraction within the channel. If present, each of first aperture  413  and second aperture  414  independently optionally can be configured to receive a pipette tip. Additionally, or alternatively, the cover of device  400  optionally includes vent  415  disposed over sample reservoir  416  so as to provide an outlet for air that is displaced when depositing a sample of whole blood into sample reservoir  416 . Additionally, or alternatively, the cover of device  400  optionally can be at least partially optically transparent, for example to facilitate visual or optical analysis of the blood sample or fractions within the device. 
     In the exemplary configuration illustrated in  FIGS.  4 A- 4 B , the respective lower surface  418  of the plasma reservoir  417  optionally is closer to the cover (not shown in  FIG.  4 B , but generally extending in a plane immediately above first and second reservoirs  410 ,  420 ) than are the respective lower surfaces  441 ,  421  of the sample reservoir  416  and second reservoir  420 . Optionally, an upper surface (exemplary level indicated with dotted lines in  FIG.  4 B ) of the sample of whole blood disposed within the sample reservoir  420  is further from the cover than is the lower surface  418  of plasma reservoir  417 . As such, when the sample of whole blood initially is deposited within sample chamber  416 , the sample remains within that chamber under the force of gravity until centrifugal force is applied. Then, responsive to the centrifugal force applied to device  400 , the sample of whole blood disposed within sample reservoir  416  flows upward toward the cover to contact lower surface  418  of plasma reservoir  417 . For example, optionally a first one of the sidewalls  419  of sample reservoir  416  can be disposed at an obtuse angle relative to lower surface  441  of the sample reservoir. Responsive to the centrifugal force applied to device  400 , substantially all of the sample of whole blood disposed within sample reservoir  416  flows upward along sidewall  419  of the sample reservoir, e.g., to contact lower surface  418  of plasma reservoir  417 . As a further option, responsive to the centrifugal force applied to device  400 , a portion of the sample of whole blood contacting the lower surface  418  of plasma reservoir  417  flows downward away from the cover to contact lower surface  421  of second reservoir  420 . For example, responsive to the centrifugal force applied to device  400 , the portion of the sample of whole blood contacting lower surface  418  of plasma reservoir  417  flows downward along a first one of the sidewalls  422  of second reservoir  420 . 
     In a manner similar to that described with reference to  FIGS.  1 A- 1 D , in some configurations the first and second fractions each contact the cover of device  400  after termination of the centrifugal force. Additionally, or alternatively, optionally the first fraction can substantially fill plasma reservoir  417  responsive to the centrifugal force, e.g., in a manner similar to that described with reference to  FIGS.  1 A- 1 D . Additionally, or alternatively, optionally the second fraction substantially fills second reservoir  420  responsive to the centrifugal force, e.g., in a manner similar to that described with reference to  FIGS.  1 A- 1 D . Additionally, or alternatively, optionally a meniscus of the first fraction is disposed within the collection region, e.g., in a manner similar to that described with reference to  FIGS.  1 A- 1 D . For example, meniscus  133  can extend between the upper and lower surfaces of collection region  411 , e.g., within plasma reservoir  417  in a manner similar to that described with reference to  FIG.  1 D . 
     As noted elsewhere herein, centrifugal force can be applied to the present devices so as to separate a sample of whole blood into the first and second fractions. For example,  FIG.  5    schematically illustrates a plan view of a disc including the device  400  of  FIGS.  4 A- 4 B , according to various configurations provided herein. The rotatable disc in which first and second reservoirs are disposed, can be spun at any suitable rate, and for any suitable amount of time, so as to generate the first and second fractions in a manner such as exemplified herein. Note that although disc  500  specifically illustrated in  FIG.  5    includes the device  400  of  FIGS.  4 A- 4 B , disc  500  instead can include any other device provided herein, such as any of devices  100 ,  200 ,  200 ′,  200 ″,  200 ′″,  300 , or  400 . 
       FIG.  6    illustrates an exemplary flow of operations in a method of using the devices of  FIGS.  1 A- 5   , and  FIGS.  7 A- 7 D  schematically illustrate plan views of components of a blood plasma separation device during operations of the method of  FIG.  6   , according to various configurations provided herein. Method  600  illustrated in  FIG.  6    can include receiving, by a first reservoir of a device, a sample of whole blood comprising red blood cells ( 610 ). The first reservoir can include a collection region and a constricted region, e.g., in a manner such as described with reference to the first reservoirs of any of devices  100 ,  200 ,  200 ′,  200 ″,  200 ′″,  300 , or  400 . For example, in the nonlimiting example illustrated in  FIG.  7 A , the first reservoir can include sample reservoir  416  and plasma reservoir  417  fluidically connected to one another, wherein sample reservoir  416  includes inlet  413  configured to receive the sample of whole blood and plasma reservoir  417  includes the collection region and the constricted region. Sample chamber  416  can be filled with a sample of whole blood through optional inlet port  413  or other suitable structure. 
     Method  600  illustrated in  FIG.  6    can include applying a centrifugal force to the device to separate the sample of whole blood into a first fraction and a second fraction ( 620 ). The first fraction can be located in the collection region and including blood plasma from which substantially all red blood cells have been removed. The second fraction can be located in a second reservoir of the device and comprising blood plasma and red blood cells that have been removed from the first fraction by the centrifugal force. The constricted region can inhibit the second fraction from entering the collection region. For example, in the nonlimiting example illustrated in  FIG.  7 B , as a disc or other structure including the device (e.g., disc  500 ) begins to spin to generate centrifugal force, the sample of whole blood migrates to substantially fill second reservoir  420  and plasma reservoir  417 . For example, responsive to the centrifugal force, the sample of whole blood disposed within sample reservoir  416  flows upward toward the cover to contact lower surface  418  of plasma reservoir  417 . Illustratively, in a manner such as described with reference to  FIGS.  4 A- 4 B , a first one of the sidewalls  419  of sample reservoir  416  can be disposed at an obtuse angle relative to the lower surface of the sample reservoir, and responsive to the centrifugal force applied to the device, substantially all of the sample of whole blood disposed within sample reservoir  416  flows upward along the first one of the sidewalls  419  of sample reservoir  416 . Further, in a manner such as described with reference to  FIGS.  4 A- 4 B , optionally responsive to the centrifugal force applied to the device, a portion of the sample of whole blood contacting lower surface  418  of plasma reservoir  417  flows downward away from the cover to contact lower surface  421  of second reservoir  420 , e.g., downward along a first one of the sidewalls  422  of the second reservoir. 
     After continuing to spin the disc or other structure including the device at a suitable rate and for a suitable amount of time, substantially all red blood cells within the sample of whole blood form a pellet in second reservoir  420  to form a second fraction, and blood plasma from which substantially all red blood cells have been removed forms a first fraction that substantially fills plasma reservoir  417 , such as illustrated in  FIG.  7 C . For example, the first fraction optionally substantially fills plasma reservoir  417  responsive to the centrifugal force, and/or the second fraction substantially fills second reservoir  420  responsive to the centrifugal force. At least 75%, at least 99%, or even 100% of the red blood cells in the sample of whole blood optionally can be removed from the first fraction. 
     Method  600  illustrated in  FIG.  6    optionally includes removing the first fraction from the collection region. For example, optionally an outlet fluidically connects to the collection region (e.g., to plasma reservoir  417 ), such as outlet port (aperture)  414  illustrated in  FIGS.  4 A- 4 B and  7 D , or outlet port  114  illustrated in  FIGS.  1 A- 1 D , or outlet port  314  illustrated in  FIG.  3   . As a further option, a channel fluidically connects the outlet to the collection region, such as channel  330  illustrated in  FIG.  3    or channel  414  illustrated in  FIGS.  4 A- 4 B and  7 D . In a manner such as described elsewhere herein, the channel optionally can be disposed at an acute angle relative to the collection region. As illustrated in  FIG.  7 D , the channel optionally substantially fills with the first fraction via capillary action responsive to termination of the centrifugal force. Additionally, or alternatively, the first and second fractions each optionally can contact the cover of the device after termination of the centrifugal force. 
     In some configurations, the present devices and methods are based on centrifugal separation of whole blood into red blood cell and plasma components, which respectively can be referred to herein as second and first fractions. The present devices optionally can sit radially on a disc, e.g., such as illustrated in  FIG.  5   , in which whole blood can be loaded through an inlet port (fill hole) into a first reservoir, such as a sample reservoir (fill chamber) which can be closer to the center of the disc than are other components of the present devices. In one nonlimiting example, the sample reservoir includes a 5 mm deep area designed to hold sufficient volume based on a 110 μL sample size, for example to inhibit or prevent spillage of the blood either into the optional outlet channel during fill, or into the fill and outlet holds during spin start. As the disc is accelerated, blood transfers towards the outside (circumference) of the disc, filling the second reservoir which in one nonlimiting example includes a 5 mm deep chamber at the bottom of the design, as well as the plasma reservoir/collection region which in one nonlimiting example is in the middle of the design. The relatively low depth (shallowness) of the plasma reservoir can inhibit or prevent collapse of the plasma-air interface after spinning has stopped, such that a meniscus of the plasma can remain within the plasma reservoir in a manner similar to that illustrated in  FIG.  1 D . As spinning continues, plasma and red blood cells separate based on centrifugal forces. Optionally, the second reservoir can be designed such that it can contain more than about 60.9% volume of a 110 μL loaded blood. The 60.9% hematocrit level (“worst case hematocrit”) represents average hematocrit plus 3 standard deviations, which should account for 99.7% of the population. Therefore, in some configurations substantially all of the red blood cells become disposed in the second reservoir as a result of the centrifugal forces, and blood plasma from which substantially all of the red blood cells have been removed becomes disposed in the collection region of the first reservoir (plasma reservoir). As the disc stops spinning, plasma gets drawn into an outlet channel (which can have an exemplary cross-sectional area of about 0.5 mm by 0.5 mm) via capillary force, thus allowing for an air-free aspiration of plasma from an outlet port coupled to, e.g., positioned above, the outlet channel. In some configurations, the only vent during aspiration of the plasma is the inlet port, allowing fluid to be collected until air connects the inlet and outlet ports to one another within the device (referred to as airknifing). Such airknifing together with the constriction region can stabilize the red blood cells within the second reservoir and allow retrieval of substantially only the first fraction without reintroduction of red blood cells from the second fraction. 
     The present devices can be constructed using any suitable materials or combination of materials, such as any suitable combination of polymer, glass, metal, and semiconductor. Additionally, the present devices can be constructed using any suitable fabrication technique(s), such as molding, 3D printing, machining, using laminate assemblies, thermoforming, chemical or laser etching, casting, and/or hot embossing. 
     In the descriptions above and in the claims, phrases such as “at least one of” or “one or more of” may occur followed by a conjunctive list of elements or features. The term “and/or” may also occur in a list of two or more elements or features. Unless otherwise implicitly or explicitly contradicted by the context in which it is used, such a phrase is intended to mean any of the listed elements or features individually or any of the recited elements or features in combination with any of the other recited elements or features. For example, the phrases “at least one of A and B;” “one or more of A and B;” and “A and/or B” are each intended to mean “A alone, B alone, or A and B together.” A similar interpretation is also intended for lists including three or more items. For example, the phrases “at least one of A, B, and C;” “one or more of A, B, and C;” and “A, B, and/or C” are each intended to mean “A alone, B alone, C alone, A and B together, A and C together, B and C together, or A and B and C together.” In addition, use of the term “based on,” above and in the claims is intended to mean, “based at least in part on,” such that an unrecited feature or element is also permissible. 
     The subject matter described herein can be embodied in systems, apparatus, methods, and/or articles depending on the desired configuration. The implementations set forth in the foregoing description do not represent all implementations consistent with the subject matter described herein. Instead, they are merely some examples consistent with aspects related to the described subject matter. Although a few variations have been described in detail above, other modifications or additions are possible. In particular, further features and/or variations can be provided in addition to those set forth herein. For example, the implementations described above can be directed to various combinations and subcombinations of the disclosed features and/or combinations and subcombinations of several further features disclosed above. In addition, the logic flows depicted in the accompanying figures and/or described herein do not necessarily require the particular order shown, or sequential order, to achieve desirable results. Other implementations may be within the scope of the following claims.