Methods and systems for monitoring and controlling fluid flow rates in microfluidic systems

• US 6,001,231 A
• Filed: 07/15/1997
• Issued: 12/14/1999
• Est. Priority Date: 07/15/1997
• Status: Expired due to Term

• Current Assignee: Caliper Holdings Incorporated
• Original Assignee: Caliper Holdings Incorporated
• Inventors: Kopf-Sill, Anne R.
• Primary Examiner(s): Le, Long V.
• Assistant Examiner(s): NOGUEROLA, ALEXANDER STEPHAN
• Application Number:
  US08/895,058
• Time in Patent Office: 882 Days
• Field of Search: 204/450, 204/451, 204/452, 204/454, 204/600, 204/601, 204/603, 204/456, 204/461, 204/606, 204/612
• US Class Current: 204/454
• CPC Class Codes: B01L 2200/143 Quality control, feedback systems
• CPC Class Codes: B01L 2300/0816 Cards, e.g. flat sample carriers usually with flow in two horizontal directions
• CPC Class Codes: B01L 2300/0867 Multiple inlets and one sample wells, e.g. mixing, dilution
• CPC Class Codes: B01L 2400/0418 electro-osmotic flow [EOF]
• CPC Class Codes: B01L 2400/0487 fluid pressure, pneumatics
• CPC Class Codes: B01L 2400/082 Active control of flow resistance, e.g. flow controllers
• 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: G01N 27/44752 Controlling the zeta potential, e.g. by wall coatings

Abstract

The present invention generally provides methods and systems for monitoring and controlling electroosmotic flow rates in microfluidic systems. Generally, such methods and systems monitor flow rates in electroosmotically driven microfluidic systems by flowing signaling elements within these channels and measuring the flow rate of these signals. The methods of monitoring flow rates are also applied to methods and systems for continuously monitoring and controlling these flow rates in electroosmotically driven microfluidic systems.

Claims

1. A method of monitoring an electroosmotic flow rate of fluid in a microfluidic device having at least first and second intersecting microscale channels disposed therein, the method comprising:

flowing a first fluid along the first channel by applying a voltage gradient across a length of the first channel;

injecting a detectable amount of a signaling compound into the first channel;

determining the flow rate of the first fluid in the first channel from the rate at which the signaling compound flows from a first point in the first channel to a second point in the first channel;

while the first fluid is disposed in the first channel, flowing a second fluid different from the first fluid along the second channel by applying a voltage gradient across a length of the second channel;

injecting a detectable amount of a signaling compound into the second channel; and

determining the flow rate of the second fluid in the second channel from the rate at which the signaling compound flows from a first point in the second channel to a second point in the second channel.

2. The method of claim 1, wherein the signaling compound produces an optically detectable signal.

3. The method of claim 2, wherein the signaling compound is chemiluminescent.

4. The method of claim 2, wherein the signaling compound is fluorescent.

5. The method of claim 2, wherein the signaling compound is chromophoric.

6. The method of claim 2, wherein the signaling compound is colloidal.

7. The method of claim 1, wherein:

the step of injecting a detectable amount of a signaling compound into the first channel comprises periodically injecting a detectable amount of a signaling compound into the first channel at a first point; and

the step of determining the flow rate comprises;

detecting a periodic signal from the signaling compound at a second point in the first channel, the second point being removed from the first point; and

identifying a variation in flow rate from a variation in the periodic signal detected in the detecting step.

8. The method of claim 7, wherein the microfluidic device is employed in the performance of a chemical reaction which results in the production of a first detectable signal, and wherein the detectable signaling compound produces a second detectable signal that is distinguishable from the first detectable signal, and the detecting step comprises detecting the second detectable signal and distinguishing the second detectable signal from the first detectable signal.

9. The method of claim 7, wherein the steps of periodically injecting and detecting are carried out substantially concurrently with the performance of the chemical reaction which results in the production of the first detectable signal.

10. In a microfluidic system employing at least first and second intersecting microscale channels disposed in a body structure, which system is used for analyzing a result of a chemical reaction which result produces a first detectable signal, a method of monitoring a flow rate of a fluid in the first channel, comprising:

flowing a first fluid in the first channel;

injecting into the first channel, a detectable amount of a signaling compound, which signaling compound produces a second detectable signal that is capable of being distinguished from the first detectable signal;

detecting the second detectable signal and distinguishing the second detectable signal from the first detectable signal;

while the first fluid is disposed in the first channel, flowing a second fluid different from the first fluid in the second channel;

injecting into the second channel, a detectable amount of a signaling compound, which signaling compound produces a third detectable signal that is capable of being distinguished from the first detectable signal;

detecting the third detectable signal and distinguishing the third detectable signal from the first detectable signal; and

,

calculating the flow rate of fluid within the first and second channels from the amount of time between the injecting step and the detecting step in each respective channel.

11. The method of claim 10, wherein the first detectable signal comprises a light emission having a first wavelength, and the second detectable signal comprises a light emission having a second wavelength distinct from the first wavelength.

12. The method of claim 11, wherein the first detectable signal is produced by a first of a fluorescein containing compound and a rhodamine containing compound, and the second detectable signal is produced by a second of a fluorescein containing compound and a rhodamine containing compound.

13. A method of controlling an electroosmotic flow rate of a fluid in a microfluidic device having at least first and second intersecting microscale channels disposed therein, comprising:

electroosmotically flowing a first fluid in the first microscale channel by applying a voltage gradient across a length of the first channel;

determining an actual flow rate of the fluid in the first channel;

comparing the actual flow rate with a desired flow rate;

increasing or decreasing the voltage gradient based upon the comparison of the actual flow rate in the first channel to the desired flow rate in the first channel, until the actual flow rate in the first channel is equal to the desired flow rate in the first channel;

while the first fluid is disposed in the first channel, electroosmotically flowing a second fluid different from the first fluid along the second channel by applying a voltage gradient across a length of the second channel;

determining an actual flow rate in the second channel;

comparing the actual flow rate in the second channel to a desired flow rate in the second channel; and

,

increasing or decreasing the voltage gradient applied across the length of the second channel until the actual flow rate in the second channel is approximately equal to the desired flow rate in the second channel.

14. The method of claim 13, wherein the step of determining the actual flow rate in the first channel comprises injecting a detectable amount of a signaling compound into the first channel at a first point in the first channel, and determining the actual flow rate of fluid in the first channel from the rate at which the signaling compound flows along the first channel.

15. Thc method of claim 13 wherein the step of determining the actual flow rate in the second channel comprises injecting a detectable amount of a signaling compound into the second channel at a first point in the second channel;

and determining the actual flow rate of fluid in the second channel from the rate at which the signaling compound flows along the second channel.

16. The method of claim 13 wherein the microfluidic device further comprises at least a third microscale channel disposed therein, and further comprising the steps of:

flowing the fluid along the third channel by applying a voltage gradient across a length of the third channel;

determining an actual flow rate in the third channel;

comparing the actual flow rate in the third channel to a desired flow rate in the third channel; and

increasing or decreasing the voltage gradient applied across the length of the third channel until the actual flow rate in the third channel is approximately equal to the desired flow rate in the third channel.

17. The method of claim 16, wherein the step of determining the actual flow rate in the third channel comprises injecting a detectable amount of a signaling compound into the third channel at a first point in the third channel;

and determining the actual flow rate of fluid in the third channel from the rate at which the signaling compound flows along the third channel.

18. The method of claim 16, wherein the third channel intersects and is in fluid communication with at least one of the first channel and the second channel.

19. The method of claim 13, wherein the step of determining the actual flow rate of the fluid in the first channel comprises:

detecting the detectable amount of signaling compound at a second point in the first channel;

calculating the flow rate of fluid in the first channel from the distance between the first point in the first channel and the second point in the first channel, and the time required for the signaling to flow from the first point in the first channel to the second point in the first channel.