Multi-channel microfluidic system design with balanced fluid flow distribution

• US 6,637,463 B1
• Filed: 05/10/2002
• Issued: 10/28/2003
• Est. Priority Date: 10/13/1998
• Status: Expired due to Fees

• Current Assignee: Roche NimbleGen, Inc. (Roche Holding AG)
• Original Assignee: BioMicro Systems, Inc. (Danaher Corporation)
• Inventors: Lei, Ming, Adey, Nils B., McNeely, Michael R.
• Primary Examiner(s): CHAMBERS, A MICHAEL
• Application Number:
  US10/142,555
• Time in Patent Office: 536 Days
• Field of Search: 137/806, 137/833, 137/841, 204/451, 204/601
• US Class Current: 137/803
• CPC Class Codes: B01F 2101/23 Mixing of laboratory samples e.g. in preparation of analysing or testing properties of materials
• CPC Class Codes: B01F 25/31 in conduits or tubes through which the main component flows
• CPC Class Codes: B01F 25/432 with means for dividing the material flow into separate sub-flows and for repositioning and recombining these sub-flows; Cross-mixing, e.g. conducting the outer layer of the material nearer to the axis of the tube or vice-versa
• CPC Class Codes: B01F 25/43211 using a simple by-pass for separating and recombining the flow, e.g. by using branches of different length
• CPC Class Codes: B01F 33/30 Micromixers
• CPC Class Codes: B01F 35/715 Feeding the components in several steps, e.g. successive steps
• CPC Class Codes: B01F 35/7172 using capillary forces
• CPC Class Codes: B01J 19/0093 Microreactors, e.g. miniaturised or microfabricated reactors laboratory containers with capillary fluid transport in microfabricated channels or chambers B01L3/5027
• CPC Class Codes: B01J 2219/00837 comprising coatings other than catalytically active coatings
• CPC Class Codes: B01J 2219/00891 Feeding or evacuation
• CPC Class Codes: B01J 2219/00995 Mathematical modeling
• CPC Class Codes: B01L 13/02 for receptacle or instruments
• CPC Class Codes: B01L 2200/025 Align devices or objects to ensure defined positions relative to each other
• CPC Class Codes: B01L 2200/0621 Control of the sequence of chambers filled or emptied
• CPC Class Codes: B01L 2200/0684 Venting, avoiding backpressure, avoid gas bubbles
• CPC Class Codes: B01L 2200/10 Integrating sample preparation and analysis in single entity, e.g. lab-on-a-chip concept
• CPC Class Codes: B01L 2200/12 Specific details about manufacturing devices
• CPC Class Codes: B01L 2300/0864 comprising only one inlet and multiple receiving wells, e.g. for separation, splitting
• CPC Class Codes: B01L 2300/0867 Multiple inlets and one sample wells, e.g. mixing, dilution
• CPC Class Codes: B01L 2300/087 Multiple sequential chambers
• CPC Class Codes: B01L 2300/0874 : Three dimensional network
• CPC Class Codes: B01L 2300/0883 : Serpentine channels
• CPC Class Codes: B01L 2300/0887 : Laminated structure
• CPC Class Codes: B01L 2300/165 : Specific details about hydrophobic, oleophobic surfaces
• CPC Class Codes: B01L 2300/18 : Means for temperature control
• CPC Class Codes: B01L 2400/0406 : capillary forces
• CPC Class Codes: B01L 2400/0487 : fluid pressure, pneumatics
• CPC Class Codes: B01L 2400/0688 : surface tension valves, capillary stop, capillary break
• CPC Class Codes: B01L 2400/0694 : vents used to stop and induce flow, backpressure valves
• CPC Class Codes: B01L 2400/086 : using baffles or other fixed flow obstructions
• CPC Class Codes: B01L 3/502723 : characterised by venting arrangements
• CPC Class Codes: B01L 3/502738 : characterised by integrated valves microvalves F16K99/0001
• CPC Class Codes: B01L 3/502746 : characterised by the means for controlling flow resistance, e.g. flow controllers, baffles B01L3/502738 takes precedence
• CPC Class Codes: F15C 1/14 : Stream-interaction devices; Momentum-exchange devices, e.g. operating by exchange between two orthogonal fluid jets ; Proportional amplifiers
• CPC Class Codes: F15C 1/146 : multiple arrangements thereof, forming counting circuits, sliding registers, integration circuits or the like F15C1/12 take precedence
• CPC Class Codes: F28F 2210/02 : with particular branching, e.g. fractal conduit arrangements
• CPC Class Codes: F28F 2245/04 : hydrophobic
• CPC Class Codes: F28F 2260/02 : having microchannels
• CPC Class Codes: G01N 2035/00237 : Handling microquantities of analyte, e.g. microvalves, capillary networks
• CPC Class Codes: G01N 2035/00366 : Several different temperatures used
• CPC Class Codes: G01N 2035/00544 : using fluid flow
• CPC Class Codes: G01N 35/08 : using a stream of discrete samples flowing along a tube system, e.g. flow injection analysis
• CPC Class Codes: G01N 35/1004 : Cleaning sample transfer devices
• CPC Class Codes: Y10T 137/206 : Flow affected by fluid contact, energy field or coanda effect [e.g., pure fluid device or system]
• CPC Class Codes: Y10T 137/2076 : Utilizing diverse fluids
• CPC Class Codes: Y10T 137/2267 : Device including passages having V over gamma configuration

Abstract

Methods and apparatus are presented for controlling fluid flow through flow paths with pressure gradient fluid control. Passive fluid flow barriers may be used to act as valves, thereby allowing the flow of fluids through flow paths to be regulated so as to allow fluids to be introduced via a single channel and subsequently split into multiple channels. Flow through the flow paths can be regulated to allow a series of sister wells or chambers to all fill prior to the fluid flowing beyond any one of the sister wells or chambers. Each flow path may have multiple segments, at least one of which is designed to balance the pressure drops of the flow paths to provide uniform flow of fluids through the flow paths. The configurations of the wells may also be modified by adding vents or flow dividers to enhance fluid flushing and gas removal capability.

Claims

1. A method for moving a first fluid through a microfluidic circuit comprising an inlet, an outlet, a plurality of flow paths providing fluid communication between said inlet and said outlet, and a plurality of wells, wherein each flow path passes through and includes one said well, and wherein the resistances of the flow paths to fluid flow are selected to produce flow rates of fluid through the flow paths in substantially fixed ratios with respect to flow rates through other flow paths under wetted fluid circuit conditions, the method comprising:

pressurizing the first fluid to induce entry of the first fluid through said inlet, into the flow paths, and into said wells to fill said wells;

further pressurizing the first fluid to induce the first fluid to substantially simultaneously commence flowing out of said wells into downstream portions of said flow paths; and

continuing to pressurize the first fluid to urge the first fluid to flow through each of the flow paths to move said first fluid through downstream portions of said flow paths, wherein said first fluid flows through said flow paths at relative flow rates defined by the resistances of the flow paths.

2. The method according to claim 1, wherein urging the first fluid to flow through each of the flow paths comprises moving the first fluid through a substantially equal pressure drop in each flow path.

3. The method according to claim 1, wherein moving the first fluid through a substantially equal pressure drop in each flow path comprises moving the first fluid through a plurality of segments in each flow path, wherein corresponding segments of the flow paths are different in length, cross sectional area, or surface roughness.

4. The method according to claim 1, wherein pressurizing the first fluid to induce entry of the first fluid into each of the wells comprises pressurizing the first fluid within the inlet from which the flow paths branch.

5. The method according to claim 1, wherein further pressurizing the first fluid to induce the first fluid to substantially simultaneously commence flowing into downstream portions of the flow paths comprises increasing the fluid pressure to induce the first fluid to flow past a plurality of passive fluid flow barriers positioned within the flow paths.

6. The method according to claim 1, wherein the first fluid is pressurized by pressurizing a second fluid located upstream of and in communication with said first fluid in said microfluidic circuit to urge said first fluid through said microfluidic circuit downstream of said second fluid.

7. The method according to claim 6, wherein the first fluid and second fluid are two different liquids.

8. The method according to claim 6, wherein the first fluid is a liquid and the second fluid is a gas or gaseous mixture.

9. The method according to claim 6, wherein the first fluid and the second fluid are introduced to the inlet via separate ports or channels communicating with said inlet.

10. The method according to claim 6, wherein each flow path comprises an entrance channel leading to the inlet of the well, and wherein a quantity of-first fluid moving into the microfluidic circuit followed by the second fluid is just sufficient to fill the wells and entrance channels.

11. The method according to claim 1, wherein the flows through said plurality of flow paths are substantially equal.

12. A microfluidic fluid circuit comprising:

an inlet;

an outlet; and

a plurality of flow paths that branch from the inlet, each providing a fluid connection between the inlet and the outlet;

wherein at least a portion of each said flow path comprises a microchannel, and wherein each flow path is configured to produce a predetermined pressure drop for fluid flowing through the flow path at a predetermined flow rate, and wherein the resistance of each said flow path to fluid flow has been selected to produce flow rates of fluid through the flow paths in predetermined ratio with respect to other flow paths under wetted fluid circuit conditions.

13. The microfluidic fluid circuit according to claim 12, wherein at least two of the flow paths contain passive fluid flow barriers, whereby fluid is prevented from advancing past a passive fluid flow barrier under non-wetted fluid circuit conditions until the fluid at the passive fluid flow barrier reaches a threshold pressure, thereby providing controlled filling of a portion of the microfluidic circuit upstream of the passive fluid flow barrier.

14. The microfluidic fluid circuit according to claim 13, wherein each of the passive fluid flow barriers comprises a short microchannel narrowing.

15. The microfluidic fluid circuit according to claim 13, wherein the passive fluid flow barrier is produced by a region of the flow path differs from adjacent regions by having a different cross sectional area, contact angle of the material forming the flow, or surface tension of the flowing fluid.

16. The microfluidic fluid circuit according to claim 13, wherein the passive fluid flow barrier is located in a microchannel and is caused by a modified microchannel surface property, by an abrupt microchannel narrowing, or an abrupt microchannel widening.

17. The microfluidic fluid circuit according to claim 12, wherein the flow paths are configured such that the flow rate on a given flow path is determined with respect to other flow paths by a difference in the length of at least a portion of the flow path.

18. The microfluidic fluid circuit according to claim 12, wherein the flow paths are configured such that the flow rate on a given flow path is determined with respect to other flow paths by a difference in the cross sectional area of at least a portion of the flow path.

19. The microfluidic fluid circuit according to claim 12, wherein the flow paths are configured such that the flow rate on a given flow path is determined with respect to other flow paths by a difference in the surface roughness of at least a portion of the flow path.

20. The microfluidic circuit according to claim 12, wherein the plurality of flow paths comprises at least four flow paths.

21. The microfluidic circuit according to claim 12, wherein each flow path comprises a filling portion and a draining portion, the microfluidic circuit further comprising a plurality of wells, each of which communicates with a flow path to receive fluid from the associated filling portion and to expel fluid to the associated draining portion.

22. The microfluidic circuit according to claim 21, wherein each of the draining portions comprises at least a first exit channel that intersects the associated well via a first juncture to receive fluid from the well, wherein the first exit channel forms a narrowing with respect to the well to provide the passive fluid flow barrier.

23. The microfluidic circuit according to claim 22, wherein the first juncture is either formed of or coated with a hydrophobic material.

24. The microfluidic circuit according to claim 21, further comprising:

a main distribution channel from which entrance channels branch to each of the wells;

a plurality of exit channels;

a plurality of extension channels; and

at least one waste collection channel;

wherein at least one exit channel conveys fluid from each well to an extension channel;

each extension channel conveys fluid to the waste collection channel;

the filling portion of each flow path comprises an entrance channel and a portion of said main distribution channel between said inlet and said entrance channels; and

the draining portion of each flow path comprises at least one exit channel, an extension channel, and at least a portion of said waste collection channel.

25. The microfluidic circuit of claim 24, wherein at least two of the extension channels comprise different length, cross sectional area, shape, or surface roughness characteristics.

26. The microfluidic circuit according to claim 21, further comprising:

a main distribution channel from which entrance channels branch to each of the wells;

a plurality of exit channels; and

at least one waste collection channel;

wherein at least one exit channel conveys fluid from each well to the waste collection channel;

the filling portion of each flow path comprises an entrance channel and a portion of said main distribution channel between said inlet and said entrance channels; and

the draining portion of each flow path comprises at least one exit channel, an extension channel, and at least a portion of said waste collection channel.

27. The microfluidic circuit of claim 26, wherein at least two of the exit channels comprise different length, cross sectional area, shape, or surface roughness characteristics.

28. The microfluidic circuit according to claim 12, wherein the configurations of the flow paths are designed to produce flow rates that are substantially equal under wetted fluid circuit conditions.

29. The microfluidic circuit according to claim 12, further comprising an outlet into which the flow paths converge.

30. The microfluidic circuit according to claim 12, wherein at least two of the flow paths contain valves to provide controlled filling of a portion of the microfluidic circuit upstream of the valves, said valves selected from the group consisting of mechanically activated valves, thermally activated valves, electrically activated valves, pneumatically activated valves, and hydraulically activated valves.

31. A microfluidic circuit comprising:

an inlet;

an outlet; and

a flow path between said inlet and said outlet, said flow path comprising a well structure in fluid communication between said inlet and said outlet, said well structure comprising;

a well defined by a wall;

a first exit channel that intersects the well via a first juncture with the wall; and

a second exit channel that intersects the well via a second juncture with the wall;

wherein the first and second junctures are displaced from each other along the wall to receive fluid from different portions of the well, each of the first and second junctures comprising an abrupt narrowing that forms a passive fluid flow barrier tending to restrict advancement of fluid from the well into the exit channel.

32. The microfluidic circuit according to claim 31, wherein said well structure further comprises a third exit channel that intersects the well via a third juncture with the wall, wherein the third juncture is displaced from the first and second junctures along the wall, wherein the third juncture comprises an abrupt narrowing that forms a passive fluid flow barrier.

33. The microfluidic circuit according to claim 32, wherein said well structure further comprises an entrance channel that conveys fluid into the well, wherein the entrance channel is disposed directly opposite the second juncture.

34. The microfluidic circuit according to claim 33, wherein the first and third junctures are symmetrically disposed on either side of the second juncture so that fluid proximate the wall between the first juncture and the entrance channel is generally directed into the first juncture, and fluid proximate the wall between the third juncture and the entrance channel is generally directed into the third juncture.

35. The microfluidic circuit according to claim 31, wherein the first and second exit channels join each other downstream from the well.

36. The microfluidic circuit according to claim 31, wherein the first and second junctures are positioned to receive gas bubbles from the well to facilitate removal of gas from the well.

37. A microfluidic circuit comprising:

an inlet;

an outlet; and

a flow path between said inlet and said outlet, said flow path comprising a well structure in fluid communication between said inlet and said outlet, said well structure comprising;

a well defined by a wall;

a first exit channel that intersects the well via a first juncture with the wall; and

a first flow divider positioned within the well to separate fluid entering the well into first and second streams, at least one of which is oriented to direct fluid proximate the wall toward the first juncture.

38. The microfluidic circuit according to claim 37, wherein said well structure further comprises a-second exit channel that intersects the well via a second juncture with the wall, wherein the first flow divider is positioned to direct the first flow into the first exit channel and the second flow into the second exit channel.

39. The microfluidic circuit according to claim 38, wherein said well structure further comprises a second flow divider positioned alongside the first flow divider so that fluid entering the well is further separated to form a third flow.

40. The microfluidic circuit according to claim 39, wherein said well structure further comprises a third exit channel that intersects the well via a third juncture with the wall, wherein the third exit channel is positioned to receive the third flow.

41. A microfluidic circuit comprising:

an inlet;

an outlet; and

a flow path between said inlet and said outlet, said flow path comprising a well structure in fluid communication between said inlet and said outlet, said well structure comprising;

a well defined by a wall and having an inlet end and an outlet end; and

a first exit channel that intersects the well via a first juncture with the wall at said outlet end;

wherein the cross sectional area of said well increases gradually from said inlet end to the central region of said well, and decreases abruptly from the central region of said well to said outlet end, to give said well a generally pear-shaped configuration.

42. A microfluidic circuit comprising:

an inlet; and

at least two flow paths that branch from the inlet, each flow path comprising;

a fluid handling structure;

a filling portion adapted to receive fluid from the inlet and deliver fluid to the fluid handling structure; and

a draining portion adapted to receive fluid from the fluid handling structure;

wherein each flow path has a resistance to fluid flow that has been selected to produce flow rates of fluid through the flow paths in predetermined ratio with respect to other flow paths under wetted fluid circuit conditions.

43. The microfluidic circuit according to claim 42, wherein the fluid handling structure comprises a well.

44. The microfluidic circuit according to claim 42, wherein the fluid handling structure comprises a channel.

45. The microfluidic circuit according to claim 42, wherein the fluid handling structure comprises a chamber containing a matrix material.

46. The microfluidic circuit according to claim 42, wherein the resistances of the flow paths are in a predetermined ratio to give flows in a predetermined ratio when the pressure drops over the flow paths are equal.

47. The microfluidic circuit according to claim 42, wherein the resistances of the, flow paths to fluid flow are in fixed proportion with respect to each other to give uniform flow through the flow paths when the pressure drops over the flow paths are in the same said fixed proportion with respect to each other.

48. The microfluidic circuit according to claim 42, wherein each flow path further comprises a passive fluid flow barrier downstream of said fluid handing structure, wherein said passive fluid flow barriers on said flow paths cause fluid entering said fluid circuit under non-wetted conditions to fill all fluid handling structures before moving into portions of said microfluidic circuit downstream of said passive fluid flow barrier.

49. The microfluidic circuit according to claim 42, wherein the draining portions of said flow paths are unequal to each other in length.

50. The microfluidic circuit according to claim 42, wherein each flow path comprises a passive fluid flow barrier that causes fluid advancing through the microfluidic circuit preferably to flow in an adjoining flow path connected upstream of said passive fluid flow barrier rather than to flow past said passive fluid flow barrier to provide controlled filling of a portion of the microfluidic circuit.

51. A microfluidic circuit comprising:

an inlet,

a main distribution channel adapted to receive fluid from said inlet; and

a plurality of entrance channels branching off said main distribution channel at multiple locations to deliver fluid to a plurality of flow paths, said entrance channels having cross-sectional areas or shapes selected in relation to the cross-sectional area of said main distribution channel such that when said microfluidic circuit is nonwetted fluid flows preferentially into and fills said main distribution channel before flowing into said entrance channels, and wherein the resistance of each said flow path to fluid flow has been selected to produce flow rates of fluid through the flow paths in predetermined ratio with respect to other flow paths under wetted fluid circuit conditions.

52. The microfluidic circuit of claim 51, further comprising

a plurality of wells, each adapted to receive fluid from said main distribution channel via one said entrance channel and sized to permit a desired fluid handling step to be performed within said well;

a plurality of extension channels, each having at least one microscale dimension and adapted to receive fluid from one said well; and

at least one outlet feature adapted to receive fluid from said plurality of extension channels;

wherein said plurality of flow paths lead from said inlet to said outlet feature and are defined by said fluid circuit, each flow path comprising at least one said entrance channel, one said well, and one said extension channel, and at least a portion of at least one of said main distribution channel and said outlet feature;

wherein said microfluidic circuit is configured to provide fluid flows in predetermined ratio to each other on said flow paths by providing predetermined resistances to fluid flow on all flow paths.

53. The microfluidic circuit of claim 51 wherein the resistances of said extension channels to fluid flow are designed to differ from the extension channels on other flow paths to compensate for differences in resistance to fluid flow in other portions of the flow paths.

54. The microfluidic circuit of claim 51, wherein the resistances of said extension channels vary due to differences with respect to other extension channels in at least one of the extension channel length, depth, width, diameter, or surface roughness.

55. The microfluidic circuit of claim 51, wherein said at least one outlet feature comprises an outlet channel.

56. The microfluidic circuit of claim 51, wherein said at least one outlet feature comprises a waste reservoir.

57. The microfluidic circuit of claim 51, wherein said at least one outlet feature comprises a waste collection channel leading to an outlet channel.

58. The microfluidic circuit of claim 51, further comprising a plurality of exit channel arrays, each exit channel array in fluid communication between one said well and one said extension channel.

59. The microfluidic circuit of claim 51, further comprising a passive fluid flow barrier between said well and said extension channel, said passive fluid flow barrier temporarily stopping the flow of fluid entering said microfluidic circuit, fluid flow being stopped after said well has been filled and resuming after fluid entering said microfluidic circuit has attained a predefined pressure level.