Blood separation and concentration system

• US 20030233064A1
• Filed: 04/23/2003
• Published: 12/18/2003
• Est. Priority Date: 04/24/2002
• Status: Active Grant

• Current Assignee: Biomet Manufacturing, LLC (Zimmer Biomet Holdings, Inc.)
• Original Assignee: Interpore Orthopaedics Inc. (Zimmer Biomet Holdings, Inc.)
• Inventors: Hood, Andrew G., Mathur, Surinder, Ponticiello, Michael, Arm, Douglas M.
• Granted Patent: US 7,806,845 B2
• Time in Patent Office: Days
• US Class Current: 604/4.01
• CPC Class Codes: A61M 1/34 Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
• CPC Class Codes: A61M 1/3403 Regulation parameters
• CPC Class Codes: A61M 1/36 Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
• CPC Class Codes: A61M 1/3603 in the same direction
• CPC Class Codes: A61M 1/3693 using separation based on different densities of components, e.g. centrifuging
• CPC Class Codes: A61M 1/3696 with means for adding or withdrawing liquid substances during the centrifugation, e.g. continuous centrifugation
• CPC Class Codes: A61M 1/38 Removing constituents from donor blood and storing or returning remainder to body , e.g. for transfusion
• CPC Class Codes: A61M 2205/50 with microprocessors or computers
• CPC Class Codes: B01D 19/0068 General arrangements, e.g. flowsheets B01D19/0063 takes precedence
• CPC Class Codes: B01D 21/262 by using a centrifuge
• CPC Class Codes: B01D 2221/10 Separation devices for use in medical, pharmaceutical or laboratory applications, e.g. separating amalgam from dental treatment residues apparatus for dental treatment A61C17/065
• CPC Class Codes: B01D 2311/04 Specific process operations in the feed stream; Feed pretreatment
• CPC Class Codes: B01D 2311/2619 UV-irradiation
• CPC Class Codes: B01D 2311/2676 Centrifugal separation
• CPC Class Codes: B01D 61/145 Ultrafiltration
• CPC Class Codes: B01D 61/16 Feed pretreatment
• CPC Class Codes: B01D 61/18 Apparatus therefor
• CPC Class Codes: B01D 61/22 Controlling or regulating
• CPC Class Codes: B04B 13/00 Control arrangements specially designed for centrifuges; Programme control of centrifuges control arrangements for feed, charge, or discharge B04B11/00
• CPC Class Codes: B04B 5/0442 with means for adding or withdrawing liquid substances during the centrifugation, e.g. continuous centrifugation
• CPC Class Codes: Y10T 29/49826 : Assembling or joining

Abstract

This invention provides an apparatus and methods to consistently separate and concentrate selected blood components. The system includes, e.g., a computerized fluid handling system to transfer blood components between a centrifugal blood separation disc, containers and a concentrator.

Claims

1. A disposable set comprising a separation disc, a concentrator and a second conduit, wherein the second conduit provides a fluid connection between the separation disc and the concentrator.

2. The disposable set of claim 1, further comprising a first conduit and one or more cassettes, which cassettes comprise the first conduit and/or the second conduit, which cassettes guidedly mount to system components, thereby providing operative mounting of the disposable set to the system components.

3. The disposable set of claim 2, wherein the system components comprise one or more valves, one or more detectors, and/or one or more pumps.

4. The disposable set of claim 2, wherein the disposable set is manufactured from plastic.

5. The disposable set of claim 2, wherein the disposable set is sterilized by gamma radiation.

6. The disposable set of claim 6, further comprising a sealed container which encloses the disposable set.

7. An apparatus to produce concentrated blood components, which apparatus comprises:

a) a separation disc which receives blood through a first conduit, which separation disc rotates to generate centripetal force, thereby separating the blood into two or more blood components according to density;

b) a control system operably connected to a first pump operably coupled to the first conduit, wherein the control system controls transfer of blood and/or blood components to the separation disc by controlling the pump; and

,

c) a concentrator which receives one or more of the blood components from the separation disc through a second conduit, which concentrator comprises at least one ultrafiltration membrane, which membrane comprises a retentate side and a permeate side wherein, during operation of the apparatus, the blood components being contacted to the retentate side of the membrane with a pressure gradient, thereby forcing one or more low molecular weight molecules through the membrane to a permeate side of the membrane and concentrating blood components.

8. The apparatus of claim 7, wherein the low molecular weight molecules comprise water.

9. The apparatus of claim 7, wherein the separation disc receives blood from a first container through the first conduit, which first container comprises from 100 ml to 500 ml of blood, which blood is processed by the apparatus automatically.

10. The apparatus of claim 7, wherein the separation disc is rotatably mounted to a centrifuge chamber.

11. The apparatus of claim 10, wherein the separation disc, the centrifuge chamber, the concentrator, and the control system are housed within a bench top housing.

12. The apparatus of claim 10, wherein the centrifuge chamber is vibration isolated.

13. The apparatus of claim 10, wherein the centrifuge chamber comprises an iris door.

14. The apparatus of claim 11, wherein the iris door is configured to center the separation disc, to comprise a port orienting keyway, to provide a mounting position for an RBC interface detector and/or to provide a force to maintain sealing pressure on a rotary seal.

15. The apparatus of claim 10, wherein an RBC interface detector is mounted to the centrifuge chamber in operative orientation to detect one or more RBC interfaces at one or more levels of the separation disc, which RBC interface detector is operably connected to the control system.

16. The apparatus of claim 15, wherein:

the control system is operably connected to a junction valve;

wherein the junction valve is operably coupled to the second conduit, whereby the separated components are alternately directed from the second conduit to a plasma container; and

,

the control system directs transfer of a low density component from the separation disc into the plasma container until the RBC interface is detected.

17. The apparatus of claim 7, wherein the control system is operably connected to a motor, which motor drives the rotation of the separation disc.

18. The apparatus of claim 17, wherein the control system directs the rotation of the separation disc to produce a force of about 2000×

g.

19. The apparatus of claim 7, wherein the control system optionally pauses separation or concentrations processes to allow sampling of blood components before completion of processing.

20. The apparatus of claim 15, wherein:

the control system is operably connected to a motor, which motor drives the rotation of the separation disc;

the control system is operably connected to a valve;

wherein the valve is operably coupled to the second conduit to control transfer of separated components in the second conduit; and

,

the control system directs opening of the valve and the rotation of the separation disc to produce a force of between about 500×

g and about 1000×

g after detection of the RBC interface.

21. The apparatus of claim 20, wherein the RBC interface detector is mounted on the apparatus to detect the RBC interface at a predetermined level, whereby separated components with desired composition are transferred in the second conduit.

22. The apparatus of claim 7, wherein the first conduit and the second conduit comprise peristaltic tubing.

23. The apparatus of claim 7, wherein the first conduit, the separation disc, the second conduit and/or the concentrator are disposable.

24. The apparatus of claim 7, wherein the first conduit, the separation disc, the second conduit and/or the concentrator are components of a disposable kit.

25. The apparatus of claim 24, wherein the apparatus has a top side, which disposable kit components are loaded into the top side of the apparatus.

26. The apparatus of claim 7, wherein the first conduit, the separation disc, the second conduit and/or the concentrator are sterilized with gamma radiation.

27. The apparatus of claim 7, wherein the separation disc comprises a rotary seal, which seal comprises a rubber seal spring press-fitted into a graphite seal.

28. The apparatus of claim 7, wherein the separation disc comprises a bowl, which bowl has an aspect ratio of 1 to 5 or less.

29. The apparatus of claim 7, wherein the separation disc comprises welded ribs.

30. The apparatus of claim 7, wherein the separation disc comprises radial channels.

31. The apparatus of claim 7, wherein the separation disc comprises an inlet port and an outlet port, which ports are oriented in the same direction.

32. The apparatus of claim 31, wherein the separation disc comprises a keyway which controls the direction of the inlet port and outlet port.

33. The apparatus of claim 7, wherein the first pump comprises a turn counter operably connected to the control system, which control system thereby monitors one or more transfer volumes.

34. The apparatus of claim 7, wherein an air detector is operably coupled to the first conduit, which air detector is operably connected to the control system.

35. The apparatus of claim 34, wherein the control system terminates operation of the first pump when the air is detected in the first conduit.

36. The apparatus of claim 35, wherein the first pump comprises a turn counter operably connected to the control system, which control system thereby determines a blood volume (V_b) transferred to the separation disc when the air is detected.

37. The apparatus of claim 7, wherein:

an air detector is operably coupled to the first conduit, which air detector is operably connected to the control system;

the first pump comprises a turn counter operably connected to the control system, whereby the control system determines a blood volume transferred (V_b) to the separation disc when the air is detected; and

,

the control system compares an expected blood volume (V_eb) entered by an operator to the blood volume (V_b) transferred, which computer directs one or more error notices to the operator if the blood volume (V_b) transferred is not within about 30% of the expected blood volume (V_eb).

38. The apparatus of claim 37, wherein the control system calculates an expected separated component volume (V_sce), which calculation comprises multiplying a separation factor by the lesser of the blood volume (V_b) or expected blood volume (V_eb).

39. The apparatus of claim 38, wherein the separation factor is set by operator input of a value ranging from about 0.25 to about 0.4.

40. The apparatus of claim 38, wherein the control system terminates operation of the first pump when a volume of the separated components (V_sc) equals the expected separated component volume (V_esc).

41. The apparatus of claim 40, wherein the control system directs termination of concentration when the volume of concentrated separated components (V_csc) equals the volume of the separated components (V_sc) multiplied by a concentration factor.

42. The apparatus of claim 38, wherein the concentration factor is set by operator input of a value ranging from about 0.2 to about 0.4.

43. The apparatus of claim 7, wherein the permeate side of the membrane drains into a filtrate container, which filtrate container comprises optical array volume detection, which optical array is operably connected to the control system, thereby transmitting the volume of filtrate (V_f) in the filtrate container.

44. The apparatus of claim 7, wherein a RBC detector is operably coupled to the second conduit, which RBC detector is operably connected to the control system.

45. The apparatus of claim 44, wherein the control system terminates operation of the first pump on the first conduit when RBCs are detected at the RBC detector.

46. The apparatus of claim 7, wherein the control system optionally pauses separation or concentrations processes to allow sampling of blood components before completion of processing.

47. The apparatus of claim 45, wherein:

the control system is operably connected to a junction valve, which junction valve is operably coupled to the first conduit, on actuation of which junction valve transfer of blood components from the separation disc is directed to a RBC holding container; and

,

the control system directs actuation of the junction valve and directs reverse flow of the first pump after the termination of operation, whereby a residual blood component is transferred from the separation disc to the RBC holding container.

48. The apparatus of claim 47, wherein one or more of the separated components is transferred to the RBC holding container, thereby reconstituting the residual blood component from the separation disc with separated components, which separated components were not received by the concentrator.

49. The apparatus of claim 48, wherein the reconstituted components are suitable for infusion into a patient.

50. The apparatus of claim 48, wherein the apparatus is configured to reprocess the reconstituted components.

51. The apparatus of claim 7, wherein the pressure gradient applied across the membranes comprises a vacuum pump in fluid communication with the permeate side of the membranes.

52. The apparatus of claim 7, wherein the ultrafiltration membrane has a molecular weight cut-off of from about 2 kDa to about 150 kDa.

53. The apparatus of claim 7, wherein the concentrator comprises a tangential flow filter.

54. The apparatus of claim 53, wherein the concentrator comprises a hollow fiber filter.

55. The apparatus of claim 7, wherein the second conduit is in fluid connection with a second container, and which second conduit is operably coupled to a second pump.

56. The apparatus of claim 55, further comprising a recirculating loop, which loop comprises the second conduit, the second container, the second pump and the concentrator, wherein the separated components are recirculated under control of the second pump.

57. The apparatus of claim 55, wherein the control system is operably connected to the second pump, whereby the control system controls transfer of separated components in the recirculating loop.

58. The apparatus of claim 7, wherein the one or more separated components comprise plasma, buffy coat, or RBCs.

59. The concentrated blood components of claim 7.

60. The concentrated blood components of claim 59, wherein the concentrated blood components comprise one or more growth factors present at a level 2-fold or more over peripheral blood levels.

61. The concentrated blood components of claim 60, wherein the growth factors are selected from the list consisting of EGF, IGF, PDGF, TGF, VEGF and FGF.

62. The concentrated blood components of claim 60, wherein the growth factor is EGF at a concentration of more than 100 pg per ml.

63. The concentrated blood components of claim 60, wherein the growth factor is FGF at a concentration of more than 150 pg per ml.

64. The concentrated blood components of claim 60, wherein the growth factor is VEGF at a concentration of more than 800 pg per ml.

65. The concentrated blood components of claim 60, wherein the growth factor is PDGF at a concentration of more than 30 ng per ml.

66. The concentrated blood components of claim 60, wherein the growth factor is TGF at a concentration of more than 200 ng per ml.

83. A method of producing concentrated blood components, the method comprising processing blood with the apparatus of claim 7.

67. A method for producing concentrated blood components, the method comprising:

a) detecting one or more RBC interfaces at one or more levels of a separation disc, which RBC interface levels are predetermined to provide a desired composition of one or more separated components;

b) collecting the separated components from an outlet port proximate to a rotational axis of the separation disc until RBCs are detected in the collection stream;

c) transferring the separated components through a conduit to a concentrator; and

,

d) concentrating the separated components, which concentration comprises ultrafiltration;

thereby producing concentrated blood components.

68. The method of claim 67, further comprising collecting a platelet poor blood plasma from the outlet port before the RBC interface is detected.

69. The method of claim 68, wherein thrombin is produced from prothrombin present in the platelet poor blood plasma.

70. The concentrated blood components produced by the method of claim 67.

71. The method of claim 67, further comprising isolating one or more growth factors, one or more compliment cascade proteins, or one or more coagulation factors from the concentrated blood components.

72. The method of claim 67, further comprising contacting the concentrated blood components with thrombin to prepare a fibrin gel, a wound sealant or a bone graft substitute.

73. The method of claim 67, wherein collecting the separated components comprises repeating cycles of collecting not more than about 10% of a separation disc volume and pausing collection for a time period.

74. The method of claim 67, further comprising optionally pausing separation or concentration processes and sampling of blood components before completion of processing.

75. The method of claim 67, further comprising loading blood or blood components into the rotating separation disc.

76. The method of claim 75, further comprising determining a total blood volume (V_b) loaded onto the separation disc, monitoring a separated component volume (V_sc), calculating an expected separated component volume (V_sce), and ending collection of separated components when the separated component volume (V_sc) equals the expected separated component volume (V_sce).

77. The method of claim 76, further comprising calculating the expected separated component volume (V_sce) as the total blood volume (V_b) multiplied by a separation factor.

78. The method of claim 67, further comprising determining a separated component volume (V_sc), calculating an expected concentrated component volume (V_cce), monitoring a concentrated component volume (V_cc), and ending concentration of separated components when the concentrated component volume (V_cc) equals the expected concentrated component volume (V_cce).

79. The method of claim 78, further comprising calculating the expected concentrated component volume (V_cce) as the separated component volume (V_sc) multiplied by a concentration factor.

80. The method of claim 78, wherein the concentrated component volume (V_cc) is calculated as the separated component volume (V_sc) minus a concentrator filtrate volume (V_f).

81. The method of claim 67, wherein detecting in a), collecting in b), transferring in c) and concentrating in d) are performed by a single bench top instrument.

82. The method of claim 67, further comprising monitoring detection in a), directing collection in b), directing transfer in c) and/or directing concentration in d) with a control system.

84. A method of manufacturing a disposable set, the method comprising:

fabricating a separation disc coupled through a conduit to a concentrator.

85. The method of claim 84, further comprising fabricating one or more cassettes configured to guidedly mount the disposable set to an apparatus.

86. The method of claim 85, further comprising loading the disposable set into the apparatus.

87. An apparatus to prepare concentrated blood components comprising:

a) a container comprising blood, which blood comprises blood components, which blood components comprise one or more high density components, one or more intermediate density components, and/or one or more low density components, which blood components further comprise low molecular weigh molecules and high molecular weight molecules;

b) a separation disc comprising a first port in fluid communication with the container through a first conduit, the separation disc comprising a second port proximate to a separation disc axis of rotation, which separation disc is rotatably mounted to the apparatus;

c) a pump operably coupled to the first conduit;

d) a concentrator in fluid communication with the second port of the separation disc through a second conduit, which concentrator comprises one or more ultrafiltration membranes, which membranes comprise retentate sides and permeate sides;

e) a valve operably coupled to the second conduit, which valve thereby controls transfer of blood components through the second conduit;

e) a control system operably connected to the valve, and which control system is operably connected to the pump, whereby the control system controls transfer of the blood between the container, the separation disc, and the concentrator; and

,

g) a detector operably connected to the control system and mounted on the apparatus in operative orientation to the separation disc, thereby detecting a fill level in the separation disc;

whereby,

the control system directs transfer of blood from the container to the separation disc;

which separation disc rotates, thereby creating a centripetal force;

which centripetal force separates blood components in order of density, thereby accumulating one or more high density components at a periphery of the separation disc and accumulating low density components and/or intermediate density components at the separation disc second port;

which high density component accumulates to a level detected by the detector;

which detector transmits a signal to the control system;

which control system directs the valve to open allowing low density components and/or intermediate density components to flow from the separation disc outlet port into the concentrator and onto the retentate sides of the membranes;

which membranes allow the low molecular weight molecules to pass from the retentate sides to the permeate sides, thereby concentrating the low density components and/or intermediate density components;

thereby preparing concentrated blood components.