Systems and methods of blood-based therapies having a microfluidic membraneless exchange device

• US 7,588,550 B2
• Filed: 07/11/2007
• Issued: 09/15/2009
• Est. Priority Date: 03/14/2003
• Status: Expired due to Fees

• Current Assignee: Columbia University
• Original Assignee: Trustees Of Columbia University In The City Of New York (Columbia University)
• Inventors: Shaplely, Nina C., West, Alan C., Leonard, Edward F., Tang, Zhongliang
• Primary Examiner(s): Deak; Leslie
• Assistant Examiner(s): MARCETICH, ADAM M
• Application Number:
  US11/776,360
• Publication Number:
  US 20080009780A1
• Time in Patent Office: 797 Days
• Field of Search: 210/97, 210/137, 210/200, 210/203, 210/209, 210/511, 210/634, 210/645, 210/646, 210/647, 210/767, 210/806, 604/5.01, 604/5.04, 604/6.01, 604/6.02, 604/6.09, 604/6.11, 422/81, 422/82, 422/99, 422/101, 209/155, 209/156
• US Class Current: 604/5.04
• CPC Class Codes: A61M 1/14 Dialysis systems; Artificial kidneys; Blood oxygenators semi-permeable membranes characterised by the material, manufacturing processes therefor B01D71/00; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
• CPC Class Codes: A61M 2206/11 Laminar flow
• CPC Class Codes: B01D 11/0288 Applications, solvents
• CPC Class Codes: B01D 11/0492 Applications, solvents used
• CPC Class Codes: B01D 11/0496 by extraction in microfluidic devices
• CPC Class Codes: B01L 3/5027 by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip B01L3/5023 takes precedence; micromixers B01F33/30; microreactors for synthesis B01J19/0093; microcapillary devices in general B81B1/00

Abstract

The present invention is directed to devices, systems and methods for removing undesirable materials from a sample fluid by contact with a second fluid. The sample fluid flows as a thin layer adjacent to, or between, concurrently flowing layers of the second fluid, without an intervening membrane. In various embodiments, a secondary separator is used to restrict the removal of desirable substances and effect the removal of undesirable substances from blood. The invention is useful in a variety of situations where a sample fluid is to be purified via a diffusion mechanism against an extractor fluid. Moreover, the invention may be used for the removal of components from a sample fluid that vary in size. When blood is the sample fluid, for example, this may include the removal of ‘small’ molecules, ‘middle’ molecules, macromolecules, macromolecular aggregates, and cells, from the blood sample to the extractor fluid.

Claims

1. A method of performing a blood treatment, comprising:

along a microfluidic channel, placing blood from a patient in direct contact with an extraction fluid, without mixing, such that blood proteins and uremic toxins move from the blood into the extraction fluid;

moving the extraction fluid out of contact with the blood at an end of the channel and into contact with a membrane at a pressure, and thereby passing water and uremic toxins in the extraction fluid through the membrane at a pressure sufficient to concentrate the blood proteins in a fraction of the extraction fluid and placing the resulting fraction in direct contact with the blood at a beginning of the channel, a recirculation of extraction fluid resulting in a concentration of blood proteins such that blood proteins are returned to the blood in the channel by diffusion.

2. The method of claim 1, wherein the placing includes preventing cells from moving from the blood into the extraction fluid.

3. The method of claim 1, wherein the placing includes flowing the blood and extraction fluid through the microfluidic channel, the channel having a ratio of width (the dimension perpendicular to flow direction and parallel to the interface between the blood and extraction fluid) and height (the direction normal to the interface between the blood and extraction fluid) that is more than 10.

4. The method of claim 3, wherein the placing includes flowing the blood and extraction fluid through the microfluidic channel, which has a ratio of width to height that is more than 50.

5. The method of claim 3, wherein the channel height is less than 100 microns.

6. The method of claim 1, wherein the extraction fluid includes dialysate.

7. The method of claim 6, wherein the placing includes creating a laminar flow of the blood and extraction fluids including two layers of extraction fluid with a blood layer sandwiched between them.

8. The method of claim 1, wherein the placing includes creating a laminar flow of the blood and extraction fluids.

9. The method of claim 1, wherein the placing includes creating a laminar flow of the blood and extraction fluids including two layers of extraction fluid with a blood layer sandwiched between them;

the flow being created in the microfluidic channel, which has a ratio of width (the dimension perpendicular to flow direction and parallel to the interface between the blood and extraction fluid) to height (the direction normal to the interface between the blood and extraction fluid) of more than 10 and has a height of less than 100 microns.

10. The method of claim 1, wherein the placing includes creating a laminar parallel flow of the blood and extraction fluids including two layers of extraction fluid with a blood layer sandwiched between them, the total volume flow rate of blood and the total volume flow rate of extraction fluid being approximately the same.

11. The method of claim 1, wherein the placing includes creating a laminar flow of the blood and extraction fluids including two layers of extraction fluid and a blood layer sandwiched between them, the total volume flow rate of blood in the blood layer and the total volume flow rate of extraction fluid in the two extraction fluid layers being approximately the same.

12. The method of claim 1, wherein the passing includes circulating the extraction fluid across a single side of the membrane without passing it through the membrane such that the resulting fraction is depleted of water and uremic toxins.

13. The method of claim 1, wherein the placing includes pumping the extraction fluid using a first pump and pumping the blood using a second pump.

14. The method of claim 1, wherein the placing includes flowing the blood and extraction fluid to form a flat blood layer such that blood cells tend to drift toward a center of the blood layer.

15. The method of claim 1, wherein the placing includes flowing the blood and extraction fluid to form a flat blood layer and at least one extraction fluid layer, the combined blood layer and at least one extraction fluid layer defining a velocity profile in which the blood layer coincides with a region of minimum shear rate such that cells tend to remain in the blood layer as a result of a tendency of cells to migrate away from high shear rate regions of a flow.

16. The method of claim 1, wherein the placing includes creating a laminar parallel flow between walls of the microfluidic channel that includes two layers of extraction fluid with a blood layer sandwiched between them, the flow being such that the cells within the blood layer do not contact the walls.

17. A method of performing a blood treatment, comprising:

establishing a flow of blood and extraction fluid in a channel such that the blood and extraction fluid are in direct contact and such that entering and exiting flows of each of the blood and extraction fluid into and from the channel are established, respectively, at opposing ends of the channel, the exiting flow of extraction fluid containing blood proteins diffused there into;

conveying a portion of the extraction fluid in the extraction fluid exiting flow to the extraction fluid entering flow and further passing the extraction fluid portion across a membrane at a pressure such as to expel water and uremic toxins therethrough; and

permitting proteins to concentrate in the extraction fluid such that a quantity of the blood proteins leaving the channel in the extraction fluid exiting flow is substantially equal to the quantity of the blood proteins returned to the channel entering flow.

18. The method of claim 17, wherein the establishing includes retaining blood cells in the blood exiting flow and preventing them from leaving in the extraction fluid exiting flow by maintaining a lower shear rate at a location of the channel coinciding with the blood exiting flow than a shear rate at one or more locations of the channel coinciding with the extraction fluid exiting flow.

19. A method of performing a blood treatment, comprising:

flowing blood and dialysate into a microfluidic channel such that the blood and dialysate are in direct contact but remain in separate layers in the channel;

the flowing being such that a lower shear rate is maintained in the blood layer than a shear rate maintained in one or more dialysate layers, the difference in shear rate being sufficient to cause blood cells to be retained in the blood layer while permitting blood proteins and uremic toxins to diffuse into the one or more dialysate layers;

passing dialysate exiting the channel across one side of a membrane at a pressure such that water and uremic toxins flow through the membrane and out of the dialysate while preventing blood proteins from passing through the membrane thereby retaining the blood proteins in the dialysate such that the blood proteins concentrate in the dialysate and thereafter returning the dialysate and blood proteins back to the channel such that blood proteins are returned to the blood in the channel.

20. A method of performing a blood treatment, comprising:

passing, through a channel, blood from a patient and an extraction fluid, such that the blood and extraction fluid are in direct contact without mixing, the channel being configured such that substantial quantities of albumin and uremic toxins move from the blood into the extraction fluid;

placing the extraction fluid in contact with a membrane under pressure and, as a result, passing water and uremic toxins in the extraction fluid through the membrane;

placing processed extraction fluid in direct contact with blood; and

permitting the albumin to concentrate in the extraction fluid such that the substantial quantities of albumin are returned to the blood in the placing, wherein the flow of blood and extraction fluid in the channel during the passing, and the configuration of the channel, are such that blood is isolated from the channel walls by the extraction fluid and such that upon exiting the channel, a quantity of urea in the blood is substantially the same as a quantity of urea in the extraction fluid.

21. The method of claim 20, wherein the placing processed extraction fluid in direct contact with blood includes passing the processed extraction fluid through the channel.

22. The method of claim 20, wherein the placing processed extraction fluid in direct contact with blood includes passing the processed extraction fluid through the channel and the secondary treatment device is a membrane and the passing therethrough is effective to concentrate the albumin in a fraction of the extraction fluid.

23. A method of performing a blood treatment, comprising:

passing, through a channel, blood from a patient and an extraction fluid such that the blood and extraction fluid are in direct contact, the channel being configured such that substantial quantities of albumin and uremic toxins move from the blood into the extraction fluid;

removing the extraction fluid from the channel and flowing the extraction fluid on a side of a membrane, while providing a transmembrane pressure, and thereby passing water and uremic toxins in the extraction fluid through the membrane to concentrate the albumin in a fraction of the extraction fluid and returning at least a portion of the fraction back to the channel to be passed again therethrough in direct contact with blood, such that albumin is concentrated in the blood and thereby returned to the blood, wherein the flow of blood and extraction fluid in the channel during the passing and the configuration of the channel are such that blood is isolated from the channel walls by the extraction fluid and such that, upon exiting the channel, a quantity of urea in the blood is substantially the same as a quantity of urea in the extraction fluid.

24. A method of performing a blood treatment, comprising:

placing blood and an extraction fluid in non-mixing direct contact to produce a resulting extraction fluid containing non-cellular components, including albumin, transferred from the blood into the second extraction fluid;

removing the resulting extraction fluid from contact with the blood;

subjecting the resulting extraction fluid to a medical process including flowing the resulting extraction fluid alone a membrane with a transmembrane pressure sufficient to ultrafilter the resulting extraction fluid such that albumin is concentrated therein; and

placing the ultrafiltered extraction fluid back in direct contact with the blood such that at least the albumin is returned to the blood by diffusion resulting from the concentration of the at least the albumin in the ultrafiltered extraction fluid.

25. The method of claim 24, wherein the concentration of albumin in the extraction fluid is permitted to increase to the point where it is approximately the same as a concentration of albumin in the blood.

26. The method of claim 24, wherein the placing the blood and an extraction fluid includes flowing the blood and the extraction fluid in a microfluidic channel.