RELATED APPLICATIONS

This application claims priority to U.S. provisional patent application Ser.

Nos. 61/287,949, filed December 18, 2009; 61/288,024, filed December 18, 2009; and 61/288,044, filed December 18, 2009, the entire disclosures of which are incorporated herein by this reference.

BACKGROUND OF THE INVENTION

In nano-scale liquid chromatography, it is generally desirable to achieve a low rate of elution of analytes. Although normal- scale High Performance Liquid

Chromatography (HPLC) is performed with mobile phase flow rates of about 0.1 to 5.0 mL/min and micro-scale HPLC is performed with mobile phase flow rates of about 1 to 100 μί/ηιίη, nano-scale HPLC requires mobile phase flow rates approximately in the 50-1000 nL/min range. Generally, pumps used in nano-scale chromatography require sensitive and accurate flow rate information for control and monitoring purposes.

Fluid flow rates can be determined by measuring the thermal energy in the fluid.

Existing thermal flow sensors capable of monitoring flows in approximately the nL/min ranges have various disadvantages. One class of thermal flow sensors tightly wrap a fine coil of resistance wire around the tube to measure temperature. This design can be difficult to manufacture because the fine coil must be precisely placed along the tube and consistently make contact with the tube. In addition, due to its large thermal mass, a lengthy coil and therefore a bulky coil is required to overcome its slow response to flow rate changes.

Another class of thermal sensors bonds an extremely small micro-fabricated device that contains two temperature sensors and heating element on one chip to a tube. Although the microfabricated flow sensor is sensitive and has a fast time response, it is costly to manufacture in small quantities using a microfabrication process.

Accordingly, there is a need for new devices for new flow sensing devices.

SUMMARY OF THE INVENTION

One aspect of the invention provides a flow sensing apparatus for sensing fluid flow. The flow sensing apparatus includes: a fluid channel that allows a fluid to flow in a first direction; a first infrared sensor arranged at a first position along the fluid channel such that it senses a temperature of the fluid; a second infrared sensor arranged at a second position along the fluid channel and separated from the first sensor by a predetermined distance along the fluid channel; and a heating element arranged between the first and second infrared sensors. The heating element is equally spaced from the first and second infrared sensors.

This aspect of the invention can have a variety of embodiments. The heating element can be supplied with a constant-power power supply. The flow sensing apparatus can include a controller that controls the power supplied to the heating element such that the temperature of the heating element is substantially constant.

The first and second infrared sensors can include pyrometer type sensors. The first and second infrared sensors can include thermopile type sensors. The first and second infrared sensors can be discrete thermopile elements in an array of the thermopile type sensors.

The flow sensing apparatus can include a controller that controls the power supplied to the heating element such that the heating element is maintained at a substantially constant temperature. The controller can be coupled to at least one of the thermopile elements to sense the temperature of the heating element.

In one embodiment, the flow sensing apparatus for sensing fluid flow is in or forms part of a nano-scale high-performance liquid chromatography apparatus

Another aspect of the invention provides a method of sensing a flow rate of a fluid. The method includes the steps of: injecting thermal energy at a fixed location along a fluid channel to raise the temperature of a fluid inside the fluid channel; sensing at a first location along the fluid channel a first thermal energy emission; and sensing at a second location adjacent to the first location along the fluid channel a second thermal energy emission. The first and second locations are approximately equally distant from the fixed location.

This aspect of the invention can have a variety of embodiments. The flow sensing method can include detecting a difference between the thermal energy emissions sensed at the first and second locations such that the difference correlates to a predetermined flow rate of the fluid inside the fluid channel. The flow sensing method can include a step of controlling the thermal energy injected at the fixed location along the fluid channel such that the fluid inside the fluid channel at the fixed location is approximately held at a constant temperature. The step of controlling the thermal energy injected into the fluid channel can cause a sensed flow rate to linearly correlate with actual flow for a predetermined range of flow rates.

In one embodiment, the fluid channel is in or forms part of a flow sensing apparatus for sensing fluid flow, e.g., such as the flow sensing apparatus described herein. In another embodiment, the flow sensing apparatus for sensing fluid flow is in or forms part of

a nano-scale high-performance liquid chromatography apparatus.

Another aspect of the invention provides a kit including a flow sensing apparatus for sensing fluid flow and instructions for installation and/or use. The flow sensing apparatus includes: a fluid channel that allows a fluid to flow in a first direction; a first infrared sensor arranged at a first position along the fluid channel such that it senses a temperature of the fluid; a second infrared sensor arranged at a second position along the fluid channel and separated from the first sensor by a predetermined distance along the fluid channel; and a heating element arranged between the first and second infrared sensors, the heating element being equally spaced from the first and second infrared sensors. In one embodiment, the instructions for installation comprise instructions for intalling the flow sensing apparatus in a nano-scale high-performance liquid

chromatography apparatus

Another aspect of the invention provides a High Performance Liquid

Chromatography (HPLC) device including a flow sensing apparatus for sensing fluid flow in a nano-scale high-performance liquid chromatography apparatus. The flow sensing apparatus includes: a fluid channel that allows a fluid to flow in a first direction; a first infrared sensor arranged at a first position along the fluid channel such that it senses a temperature of the fluid; a second infrared sensor arranged at a second position along the fluid channel and separated from the first sensor by a predetermined distance along the fluid channel; and a heating element arranged between the first and second infrared sensors, the heating element being equally spaced from the first and second infrared sensors.

BRIEF DESCRIPTION OF THE DRAWINGS

For a fuller understanding of the nature and desired objects of the present invention, reference is made to the following detailed description taken in conjunction with the accompanying drawing figures wherein like reference characters denote corresponding parts throughout the several views and wherein:

FIG. 1 is a conceptual view of thermal flow sensing measurements;

FIG. 2 is a schematic view of a thermal flow sensing apparatus;

FIG. 3 is a schematic view of a thermal flow sensing apparatus including at least two non-contact infrared sensors according to a one embodiment of the invention;

FIG. 4 is a plot of flow rate measurements against actual flow rates using the thermal flow sensing apparatus of FIG. 3;

FIG. 5 is a plot of flow rate sensitivity measurements for one one embodiment of the invention; and

FIG. 6 is a plot of flow rate measurement linearity in relation to actual flow rates.

DETAILED DESCRIPTION OF THE INVENTION

Infrared sensors have been used for non-contact temperature measurement in various applications and they can be adapted to thermal flow sensing in a nano-flow HPLC application.

FIG. 2 schematically depicts a thermal flow sensing apparatus. As shown in FIG. 2, a first temperature sensor 21 and a second temperature sensor 22 are disposed along a fluid channel 20, for example, a capillary tube or a micro-fluidic channel. The direction of fluid flow is denoted by an arrow 25, where the fluid generally flows from left to right in a downstream direction in FIG. 2. A heating element 23 powered by a heating power source 24 is disposed at a fixed location along the fluid channel and in between the first and second temperature sensors 21 and 22. As the heating element 23 introduces thermal energy into a fluid filled fluid channel 20, temperatures along the fluid channel may be measured by positioning the first and second temperature sensors 21 and 22 along the fluid channel.

FIG. 1 depicts fluid temperature measurements along a fluid filled fluid channel 20 as thermal energy is introduced at a fixed location along the fluid channel 20. When thermal energy is introduced into a liquid filled fluid channel at location P0 along the channel, the thermal energy will disperse along the channel in both the upstream and downstream directions due to thermal conduction and diffusion. In FIG. 1, the vertical axis denotes measured temperature and the horizontal axis denotes distance along the fluid channel 20. A temperature profile curve Ca will develop when a discrete section of the fluid in the fluid channel is continuously heated by the heating element 23 while the fluid is resting or under a so-called zero-flow condition. The shape of this temperature profile depends on the amount of heat added to the fluid and the upstream and downstream temperatures of the liquid. Assuming identical upstream and downstream fluid temperatures and a zero-flow condition, liquid temperatures Tl and T2 measured at the first and second sensors 21 and 22 that are placed at equal distances upstream and downstream from P0, denoted by PI and P2, will be equal as thermal conduction and diffusion will be approximately equal.

If liquid in the fluid channel is permitted to flow, the fluid temperatures at the first and second locations PI and P2 will depend upon the flow rate of liquid and the resulting heat convection. Curve Cb of FIG. 1 depicts a temperature profile as liquid begin to flow past P0, or the heated zone. Note that although Ca is substantially symmetrical about P0, Cb is not symmetrical about P0. This is due to an asymmetric convection of the heated fluid that occurs in the direction of the fluid flow. Therefore, under flowing conditions, fluid temperatures T3 and T4 measured at PI and P2, respectively, will be different from Tl and T2. A difference of T3 and T4, denoted by ΔΤ, may be calculated and correlated to the actual flow rate of the fluid that flowed inside the fluid channel 20.

To perform the above-mentioned temperature measurements, a number of sensing methods and apparatuses may be used. Generally, two temperature sensors are disposed along a fluid channel at equal distances upstream and downstream from the heating element. For example, FIG. 2 depicts the first temperature sensor 21 and second temperature sensor 22 disposed along the fluid channel 20 such that the distance from the heating element 23 to the temperature sensor 21 in an upstream direction and the distance from the heating element 23 to the temperature sensor 22 in a downstream direction are approximately equal.

Temperature measurements made at the first and second sensors 21 and 22 can be sampled, subtracted and electronically amplified by using an amplifier element 26 to provide a signal with noise minimized by a high degree of common-mode noise rejection. This allows detection and discrimination of extremely small upstream and downstream temperature differences. Temperature measurement can be made at inflection points along the temperature profile by changing the placement of the first and second temperature sensors 21 and 22 and/or by changing the amount of thermal energy added to the liquid by the heating element 23. For example, as shown in FIG. 1, PI and P2 were chosen to be the inflection points of the temperature profile Ca. Measurement at the inflection points can minimize the amount of time required to detect a difference between measured temperatures Tl and T3 or the difference between the temperatures T2 and T4 and thus maximize the upstream/downstream ΔΤ response of the amplifier element 26 to flow rate change.

Infrared sensors typically function based on the principle that the intensity of infrared emission of a black body can be correlated to its temperature. Generally, sensitive infrared sensors are available in two different types: pyrometers and thermopiles.

Pyrometers are typically used in motion sensing applications where changes in infrared radiation over short time periods are sensed. Pyrometers develop a surface charge on an inner element that quickly dissipates, and as a result, do not give a DC output. A DC output can be obtained by chopping the infrared signal incident on the detector and phase-locking the output with the chopping frequency.

A thermopile infrared sensor typically includes a small silicon chip around which many thermocouples are bonded to its perimeter and connected in series. By connecting the thermocouples in series, an amplification of the thermocouple signal can be achieved. Typically, up to about 30-50 thermocouples are bonded to the silicon chip, thereby achieving sensitivities of -30 V/W. In addition, the silicon chip can be coated with an infrared absorbing film to enhance its thermal response to infrared radiation.

For use in thermal flow sensing, according to the subject invention, two infrared sensors can be positioned close to a fluid channel in which fluid is flowing, the infrared sensors respectively being positioned upstream and downstream of a heating element. Both pyrometers and thermopiles are available as two-element sensors. Preferably the two sensors or sensing elements are aligned with the fluid channel and heating element. The output of each sensing element is fed into an amplifier such that only the difference between the temperatures measured by the sensing elements is amplified. This amplified signal is fed into an A/D converter for data collection and signal processing.

A thermal flow sensing apparatus and a method of sensing flow rates in nano- scale HPLC are provided according to the subject invention. The flow sensing apparatus preferably senses a temperature change along a capillary tube or a flow channel, and includes at least a heating element preferably disposed at a fixed location along the flow channel, a first temperature sensor disposed upstream from the heating element, and a second temperature sensor disposed downstream from the heating element, where the first and second temperature sensors preferably are non-contact temperature sensors. Furthermore, the first and second temperature sensors preferably are pyrometer type sensors or thermopile type sensors.

The heating element may be supplied with a constant-power power source or fitted with a constant-temperature controller that senses the output temperature of the heating element and controls the power input of the heating element to achieve a substantially constant temperature output.

FIG. 3 depicts a sensing arrangement through a capillary tube 301 suitable for nano-scale liquid chromatography in which a liquid flows through the capillary tube 301 generally in a direction denoted by the arrow 302. A heating element 303 can be disposed on a top portion of the capillary tube 301, or alternatively, the heating element can be disposed at another location such as a bottom portion of the capillary tube. A dual-element infrared sensor 304 preferably is disposed near a bottom portion of the capillary tube 301 such that a first temperature sensing region 305 is approximately centered at a first distance along the capillary tube 301 and upstream from the heating element 303, and a second temperature region 306 is approximately centered at a second distance along the capillary tube 301 and downstream from the heating element 304, where the first and second distances are substantially equal. Alternatively, it is possible for the respective distances between the first and second temperature regions and the heating element to be different, or for the dual-element infrared sensor to be replaced by two separate sensors. As described herein, the terms "sensor" and "sensing element" are used interchangeably, and refer to sensing arrangements that may include multiple separate elements as part of a single sensor, or alternatively, separate individual sensors capable of being used together.

The dual-element infrared sensor 304 preferably includes two thermopile infrared sensors. Negative nodes of the infrared sensors can be coupled to a common ground element 307, and positive nodes of the infrared sensor can be coupled to an amplifier 308, which amplifies the difference between the voltages at the positive nodes of the infrared sensors. The output of the amplifier 308 preferably is coupled to an analog-to-digital conversion unit of a microcontroller 309 for data collection and signal processing. According to at least one embodiment of the subject invention, the heating element 303 is preferably supplied with a constant power source and the dual-element infrared sensor 304 is preferably of the thermopile type.

FIG. 4 depicts measured flow rates plotted against actual flow rates under various constant power conditions supplied to a heating element applied to two different types of fluid channels. For each curve, a constant power was supplied to the heating element. For example, curve C8 depicts flow rates measured with a thermal sensing apparatus supplied by a 57.6mW constant power supply disposed about a stainless steel capillary tube, which is commonly used inside nano-scale HPLC apparatus. The flow rates measured with the thermal sensing apparatus are plotted against actual flow rates.

Curves C8 and C6 are relatively linear compared to curves CI -5 and C7 against the actual flow rate. Regardless of whether the measured flow rates are linear in relations to the actual flow rate, a number of well-known calibration methods may be used to map the measured flow rates to actual flow rates. For example, a look-up table or a linearization technique may be used to map individual measured flow rates to actual flow rates.

FIG. 5 depicts the sensitivity of measured flow rates (left vertical axis) plotted against voltage supplied to the heating element (horizontal axis) and the output temperature of the heating element (right vertical axis) plotted against the same horizontal axis. A higher value in the left vertical axis represents a higher output voltage in milli- volts by the infrared sensing element per given flow rate in micro-liter per minute.

According to at least one embodiment of the subject invention, the heating element 303 is preferably supplied with a power source and a closed-loop proportional- integral-derivative, or PID controller, which provides a constant-temperature heating element. FIG. 6 depicts the effect of using a PID controller to hold the temperature output of the heating element at a constant temperature. The curves C1-C4 depict measured flow rates in relations to actual flow rates. Curves CI and C2 depict flow rates measured on a 30 gauge stainless steel tube and C3 and C4 depict flow rates measured on a 50um fused silica tube. The PID controller extends the substantially linear portion of the measured flow rates. This allows a higher sensitivity of flow rate change at higher flow rates. According to another embodiment of the invention, a thermopile sensing element of a plurality of thermocouples may be disposed across the fluid channel from the heating element. At least one thermocouple of the plurality of thermocouples of thermopile may be used as the sensing element for the constant-temperature controller.

EQUIVALENTS

The functions of several elements may, in alternative embodiments, be carried out by fewer elements, or a single element. Similarly, in some embodiments, any functional element may perform fewer, or different, operations than those described with respect to the illustrated embodiment. Also, functional elements (e.g. , modules, computers, and the like) shown as distinct for purposes of illustration may be

incorporated within other functional elements, separated in different hardware or distributed in a particular implementation.

Although certain embodiments according to the invention have been described, the invention is not limited to just the described embodiments. Various changes and/or modifications can be made to any of the described embodiments without departing from the spirit or scope of the invention. Also, various combinations of elements, steps, features, and/or aspects of the described embodiments are possible and contemplated even if such combinations are not expressly identified herein.

INCORPORATION BY REFERENCE

The entire contents of all patents, published patent applications, and other references cited herein are hereby expressly incorporated herein in their entireties by reference.