Patent Publication Number: US-7223949-B2

Title: Analysis apparatus having improved temperature control unit

Description:
FIELD OF THE INVENTION 
   The present invention is generally directed to substance analysis apparatus. More particularly, the present invention is directed to a chemical/biological analysis apparatus having an improved temperature control unit for controlling the temperature of a substance passing through a microfluidic channel, such as a capillary column. 
   BACKGROUND OF THE INVENTION 
   Accurate and reproducible temperature control is required for a large number of applications in biological and chemical analysis. Such temperature control may require either a stable constant temperature over a definite time period or a temperature that varies in a predetermined manner during the overall analytical process. In general, techniques for molecular separation often benefit from temperature control. Biochemical and biophysical reactions occurring in connection with cellular assays and assays for blood chemistry and immunology also frequently involve steps that require controlled temperature. 
   Capillary electrophoresis is recognized as a powerful technique that can separate molecules based on size and/or charge and is one analysis technique that increasingly requires such accurate and reproducible temperature control. For example, certain applications for molecular separation by capillary electrophoresis depend on maintaining constant temperature over a predetermined length of the capillary. Such applications include DNA sequencing and constant denaturant capillary electrophoresis. Other applications rely on increasing or decreasing the temperature over a predetermined length of the capillary in accordance with a predefined temperature profile (i.e. temperature gradient capillary electrophoresis and cycling temperature capillary electrophoresis). 
   Recent work in the area of capillary electrophoresis has given rise to a method for periodically varying the temperature of an air oven to conduct mutation analysis in a modified DNA sequencer. However, such processes are often difficult to control in a conventional air oven. By using the air oven to control the temperature of a substance passing through a capillary column, the periodicity and amplitude of the temperature cycles are highly dependent on the overall volume of the oven chamber and the typically large combined heat capacity of everything in it. Rapid and accurate temperature control is virtually impossible to achieve. Relatively complex electromechanical configurations are also required to achieve even a minimal degree of temperature control. 
   In U.S. patent application Ser. No. 09/979,622, filed on Mar. 7, 2000, Foret et al. describe an apparatus that may be used to control the temperature of a substance passing through a capillary column. As shown in FIG. 2 of that application, the apparatus includes a heater body that is constructed as a cylindrical volume of thermally conductive material. The heater body is completely surrounded by an electrically powered heating element that, in turn, is completely surrounded by a cylinder constructed from a thermally insulating material. The thermally conductive material has a hole drilled through its length. A stainless steel tube is inserted through this hole and is permanently embedded within the thermally conductive material using thermal epoxy. The capillary, carrying a gel matrix through which the sample is to travel, is passed through this stainless steel tube. A plurality of these structures are combined to form a capillary array. Each individual capillary column of the capillary array is thermally insulated from every other individual capillary column. 
   A stated application of the Foret et. al. apparatus is constant denaturant capillary electrophoresis (CDCE). However, the present inventors have recognized several disadvantages inherent in the design of this apparatus that can make it unsuitable for CDCE applications (as well as other temperature dependent analytical processes) on a large commercial scale. For example, it is difficult to efficiently and economically incorporate the apparatus into existing analyzer designs. Generally speaking, the apparatus can also be difficult to manufacture and use due to its complex design. In addition, the temperature of the apparatus is difficult to accurately reset to an initial target temperature. Further, the overall concentric construction of the apparatus is designed to maintain long-term temperature stability at the expense of speed in achieving a target temperature. This may make the apparatus difficult to use in processes requiring a rapidly varying temperature profile. 
   SUMMARY OF THE INVENTION 
   An apparatus for use in controlling the temperature of one or more substances passing through one or more microfluidics channels in an analysis device is set forth. The apparatus comprises a heating unit having first and second surfaces. The first surface of the heating unit is constructed so that it is at least partially exposed for cooling of the heating unit. The apparatus also comprises a thermally conductive medium that is disposed proximate the second surface of the heating unit. The one or more microfluidics channels are disposed in the thermally conductive medium. In one embodiment, the one or more microfluidics channels are in the form of a plurality of capillary columns, such as those used in instruments for capillary electrophoresis. Each capillary columns is substantially surrounded by the material forming the thermally conductive medium. In another embodiment, the thermally conductive medium, along with the corresponding plurality of capillary columns, can be easily disengaged from the heating unit in a non-destructive manner thereby allowing the heating unit to be reused. 

   
     BRIEF DESCRIPTION OF THE DRAWINGS 
       FIG. 1  is a schematic diagram of one embodiment of a capillary electrophoresis system that may use an improved temperature control unit. 
       FIG. 2  is a cross-sectional view of one embodiment of a temperature control unit suitable for use in the capillary electrophoresis system shown in  FIG. 1 . 
       FIG. 3  is a cross-sectional view of a second embodiment of a temperature control unit suitable for use in the capillary electrophoresis system shown in  FIG. 1 . 
       FIG. 4  is a cross-sectional view of a third embodiment of a temperature control unit suitable for use in the capillary electrophoresis system shown in  FIG. 1 . 
       FIG. 5  is a cross-sectional view of a fourth embodiment of a temperature control unit suitable for use in the capillary electrophoresis system shown in  FIG. 1 . 
       FIG. 6  is a cross-sectional view of a fifth embodiment of a temperature control unit suitable for use in the capillary electrophoresis system shown in  FIG. 1 . 
       FIG. 7  is a cross-sectional view of a sixth embodiment of a temperature control unit suitable for use in the capillary electrophoresis system shown in  FIG. 1 . 
       FIGS. 8A through 8C  illustrate an embodiment of a temperature control unit similar to the one shown in  FIG. 2  as it may be adapted into an overall capillary insertion unit for use in a corresponding analysis apparatus. 
       FIGS. 9A and 9B  illustrate a further embodiment of a temperature control unit in which the thermally conductive medium portion and the heating unit portion of the temperature control unit are manufactured as completely separate and separable units. 
       FIGS. 10A through 10D  show a still further embodiment of a temperature control unit that is particularly suitable for widespread economical commercial use. 
       FIG. 11  is a graph of temperature versus time for one embodiment of a temperature control unit as it is operated at a constant target temperature. 
       FIG. 12  is a graph of temperature versus time for the embodiment of temperature control unit tested in  FIG. 8  as it is operated with a varying temperature profile. 
   

   DESCRIPTION OF ONE OR MORE PREFERRED EMBODIMENTS OF THE INVENTION 
   The apparatus of the present invention can be adapted for use in a wide range of biological and chemical analysis instruments that require static and/or varying temperature control of a substance passing through a microfluidic flow channel, such as a capillary column. For example, the apparatus can be adapted for use in instruments employed in flow cytometry, liquid chromatography, gas chromatography, capillary electrophoresis, etc. For purposes of the following discussion, various embodiments of the apparatus will be described in the context of a capillary electrophoresis system suitable for constant and/or varying temperature processes. 
     FIG. 1  illustrates one embodiment of a capillary electrophoresis system, shown generally at  10 . As shown, the electrophoresis system  10  includes a sample introduction unit  15  that provides one or more substances that are to be analyzed. The samples are provided to the input of a first electrode unit  20 . The first electrode unit  20  typically includes an electrode disposed in a buffer solution. The buffer solution serves as a solvent for the one or more substances that are to be analyzed. 
   The one or more substances that are to be analyzed are driven from the first electrode unit  20  to a second electrode unit  30  under the influence of an electric field generated between the corresponding anode and cathode. To this end, the electrode of the first electrode unit  20  is connected to a first terminal of power supply  25  and may serve as either the anode or cathode depending on the analyte. A second electrode is disposed in a buffer solution in the second electrode unit  30  and is connected to a second terminal of the power supply  25 . The second electrode may serve as the other of the anode or cathode depending on the particular analyte involved in the capillary electrophoresis process. 
   The buffer solution containing the substance(s) for analysis proceeds from the first electrode unit  20  and flows toward the second electrode unit  30  through a plurality of capillary columns  35 . Samples can be introduced into the capillary columns  35  using established hydrodynamic or electrokinetic injection methods. Each capillary column  35  of the capillary array may have either the same or different instructions. For example, the capillaries may comprise a fused silica interior that is surrounded by a polyimide coating. Other capillary constructions may include a porous gel through which the samples must travel. 
   Capillary columns  35  pass through a temperature control unit  40 . Temperature control unit  40 , as will be discussed in further detail below, is adapted to quickly drive the temperature of the capillary columns  35  to a given target temperature. The target temperature may be held constant over the duration of the capillary electrophoresis process or may be quickly varied during the process in accordance with a predetermined temperature profile. 
   Temperature control unit  40  cooperates with a thermal controller  45  to execute the predetermined temperature profile. To this end, temperature control unit  40  includes one or more temperature sensors that are disposed to monitor the temperature at selected portions of the temperature control unit  40 . Thermal controller  45  is responsive to the signals provided by the one or more temperature sensors and adjusts, for example, the power provided to the heating unit of the temperature control unit  40  accordingly. Thermal controller  45  may be microprocessor based and may execute the predetermined temperature profile in response to user input parameters. The input parameters may be communicated to the thermal controller  45  through a general process controller  50  that, in turn, receives temperature processing parameters or the like from an operator at a corresponding human interface device  55 . Human interface device  55  may take on various forms including, but not limited to, a keyboard, a touchscreen monitor, etc. 
   Alternatively, an existing capillary electrophoresis instrument may be retrofit with a stand-alone temperature control retrofit package including a temperature control unit  40  and thermal controller  45  having its own, independent human interface device. In such instances, the temperature control unit  40  and thermal controller  45  are constructed to operate beyond the direct control of the existing portions of the instrument. Further, although the embodiment of  FIG. 1  includes only a single temperature control unit, it will be recognized that a plurality of such control units may be disposed in parallel with or in series with one another, depending on processing requirements. 
   Notwithstanding the data entry method, the thermal controller  45  ultimately receives temperature parameters and drives the temperature control unit  40  in accordance with a predetermined temperature profile based on those parameters. The predetermined temperature profile may be static or dynamic. In the case of a dynamic profile, for example, thermal controller  45  may generate a waveform comprised of discrete target values in response to a cycle period and temperature amplitude range input by the human operator. These target values, in turn, may be used to control the operation of a typical PID controller to drive the state of the temperature control unit  40  to the desired temperature values over time. 
   The samples exiting temperature control unit  40  through capillary columns  35  are provided to the input of a detection chamber  60 . Within detection chamber  60  there are one or more sensors that are disposed to detect one or more parameters of the sample as it passes therethrough. Such parameters include, for example, electromagnetic absorbance, fluorescence, mass spectrometry, amperometry, conductivity, etc. The operation of the sensors may be controlled by an analysis unit  65 . Analysis unit  65  is further programmed to receive the data from the sensors within detection chamber  60  and provide it to the general process controller  50  for printing or other display in an intelligent format susceptible of direct or indirect interpretation by a user. 
   Samples passing through capillary columns  35  exit detection chamber  60  and ultimately flow into the second electrode unit  30 . Samples arriving at the second electrode unit  30  may be discarded or provided to the input of yet another analysis unit of the same or different type. 
     FIG. 2  illustrates one embodiment of a temperature control unit  40  suitable for use in the capillary electrophoresis system  10  shown in  FIG. 1 . In this embodiment, the temperature control unit  40  is generally comprised of a heating unit  70  and a thermally conductive medium  75  in which an array of capillary columns  35  are disposed. Heating unit  70  may be generally planar in shape and have a first side  80  that is at least partially exposed to facilitate cooling of the heating unit. Cooling at first side  80  may be facilitated in accordance with any one of a variety of different methods. For example, first side  80  may merely be exposed to ambient environment conditions. Alternatively, a flow of cooling gas or liquid may be driven into contact with the first side  80 , as generally shown by arrow  97 . Still further, a cooling unit, such as a Peltier cooler, may be disposed proximate first side  80  to cool heating unit  70  in response to electrical signals and/or power received from thermal controller  45 . 
   Heating unit  70  may consist of a single heating element  90  or, as shown in  FIG. 2 , may be formed as a multilayer composite. Heating element  90 , for example, may be in the form of a thermofoil heater, such as one available from Minco™. In the illustrated multilayer composite, heating unit  70  is comprised of heating element  90  and an intermediate conductive or convective layer  95  that is disposed between heating element  90  and thermally conductive medium  75 . Layer  95  may be comprised of a thermally conductive gas, liquid or solid. In the illustrated embodiment, layer  95  is comprised of a thin metal plate of, for example, aluminum or copper. 
   Thermally conductive medium  75  is disposed proximate a second side  85  of the heating unit  70  in such manner as to allow effective thermal energy transfer therebetween. In turn, thermally conductive medium  75  is used to transfer thermal energy to and from the capillary columns  35  of the capillary array. In order to maximize this thermal energy transfer, it is desirable to maximize the surface contact between the exterior walls of the capillary columns  35  and medium  75 . To this end, thermally conductive medium  75  is preferably formed from a material that may be molded to conform to the shape of the capillary columns  35 . This may be achieved in a variety of different manners. For example, the moldable material used to form medium  75  may be comprised of a pair of thermally conductive sheets  100  and  105  that are adapted to closely fit capillary columns  35  therein when the sheets  100  and  105  are brought together in the illustrated manner. Preferably, the material used to form the sheets is sufficiently deformable so as to substantially engage and substantially surround the capillary columns  35  when the sheets are pressed together. Various conductive rubber materials, such as silicone, can be used to form a medium  75  having such characteristics. Sheets  100  and  105  may alternatively include pre-manufactured slots  110  into which the capillary columns  35  are placed. The capillary columns  35  are secured within the pre-manufactured slots  110 , for example, with a thermal paste whereby a thermally conductive material completely surrounds each column. 
   Although  FIG. 2  shows thermally conductive medium  75  formed as two distinct sheets, medium  75  may likewise be formed from a single sheet of material. For example, thermally conductive medium  75  may be formed by directly pouring or painting a thin layer of thermally conductive silicone rubber material in its semi-liquid form onto surface  85  and around the capillary columns  35  of capillary array, setting capillary columns  35  therein and letting the material mold or cure itself into a thin, solid rubber sheet. 
   Preferably, a high thermal conductivity silicone gel is used to form the thermally conductive medium  75 . The objective is to ensure efficient heat transfer to and from the heating unit  70  and medium  75  to ultimately control the temperature of the substances passing through the corresponding capillary columns  35 . Thermal conductivities equal to or greater than 0.5 W/(m.k) are desirable, with thermal conductivity values greater than 1.00 W/(m.k) being preferable. Heat-dissipating silicone gels having thermal conductivities as high as 1.26 W/(m.k) are available from Asahi Rubber. 
   Thermally conductive medium  75  preferably has a thickness between 0.05 mm to 5 mm. In most instances, enclosing the capillary columns  35  between two 1 mm thick sheets of silicone gel is sufficient. Thinner silicone gel sheets (i.e., 0.3 mm thick sheets) are also commercially available and may be employed in the temperature control unit  40 . 
     FIG. 2  also illustrates exemplary placement of one or more temperature sensors  115  in the temperature control unit  40 . For example, a first one of the temperature sensors  115  may be disposed at the first side  80  of heating unit  70  proximate heating element  90  while a second one of the temperature sensors  115  may be disposed at the second side  85  proximate thermally conductive medium  75 . Signals provided by one or both of the temperature sensors  115  are received at thermal controller  45  and used to monitor the temperature at the selected portions of the temperature control unit  40  so that thermal controller  45  can properly drive temperature control unit  40  in accordance with the predetermined temperature profile. 
     FIG. 3  illustrates an alternative embodiment of temperature control unit  40 . In this embodiment, heating unit  70  extends beyond the perimeter of the thermally conductive medium  75  so that the exposed cooling surface  80   a  and second surface  85  are disposed at the same side of the heating unit  70  and are generally coplanar with one another. One or more further temperature sensors  120  may be disposed in the extended region proximate the exposed cooling surface  80   a . Surface  80   b , which is disposed opposite surface  85 , may be partially or fully insulated or, as illustrated, exposed to increase the area available for cooling of the heating unit  70 . Any of the cooling techniques noted above may be applied to surface  80   a  and/or surface  80   b.    
     FIG. 4  illustrates a still further embodiment of the temperature control unit  40 . This embodiment is somewhat similar to the embodiment shown in  FIG. 3 . However, only the heating element  90  extends beyond the perimeter of the thermally conductive layer  75 . 
     FIGS. 5 and 6  illustrate embodiments of the temperature control unit  40  in which an insulating layer  125  is disposed over at least a portion of the surface of the thermally conductive medium  75 . In the embodiment of  FIG. 5 , the insulating layer  125  is disposed directly over only that portion of the surface of the thermally conductive medium  75  which is coextensive with the array of capillary columns  35 . In contrast to the direct contact between the thermally conductive medium  75  and the insulating layer  25  shown in  FIG. 5 , the embodiment of  FIG. 6  includes a thermal insulating layer  125  that is disposed over an additional intermediate conductive layer  130 . Intermediate conductive layer  130  is at least coextensive with the array of capillary columns  35 . In each embodiment, a further temperature sensor  135  is provided to measure the temperature at the interiorly disposed surface of the insulating layer  125 . Embodiments of the temperature control unit  40  employing the illustrated thermal insulating layer  125  are particularly useful in analytical processes requiring strict temperature stability and gradual cooling ramps. 
     FIG. 7  illustrates an embodiment of the temperature control unit  40  that is particularly useful in analytical processes requiring high cooling rates in the processing temperature profile. In this embodiment, a heat dissipation unit  140  is disposed proximate the thermally conductive medium  75 . The heat dissipation unit  140  may be an active device, such as a Peltier cooler, or a passive layer, such as a metal layer. As shown, the heat dissipation unit  140  may be disposed directly on the outer surface  85  of medium  75  to dissipate heat as needed. Preferably, thermal controller  45  is used to control the operation of heat dissipation unit  140  in response to the predetermined temperature profile required for the analytical process in those instances in which the heat dissipation unit  140  is an active device. Although the heat dissipation unit  140  shown in  FIG. 7  is coextensive with the entire outer surface  85  of medium  75 , only a portion of the outer surface may be so contacted. To further enhance the heat dissipation abilities of the unit  140 , it may be provided with a plurality of fin-shaped heat sinks  145 . 
   In each of the foregoing embodiments, the thermally conductive medium  75  and the heating unit  70  may be constructed so that the thermally conductive medium  75 , along with the corresponding capillary array, can be secured with and separated from heating unit  70  in a non-destructive manner. Releasable securement of these elements can be achieved using one or more of a variety of securement techniques. For example, a thermally conductive adhesive may be applied at the interface between heating unit  70  and thermally conductive medium  75 . Alternatively, non-destructive, releasable securement may be achieved using an intermediate thermally conductive layer having an adhesive on both sides thereof. In either instance, the adhesive may be in the form of a separately applied layer or may be in the form of a tacky surface inherently produced by the material used as the thermally conductive layer (i.e., the inherent tackiness of a silicone gel layer). Still further, standard mechanical fasteners (i.e., screws, clamps, tape, etc.) may be used to secure the heating unit  70  and thermally conductive medium  75  together. 
   When the temperature control unit  40  is manufactured so that the thermally conductive medium  75  is readily separated from the heating unit  70  without damage to the heating unit  70 , the thermally conductive medium  75  including the corresponding capillary column array may constitute a disposable element of the overall unit  40 . As such, the thermally conductive medium  75  and the spent capillary columns  35  may be readily removed from the heating unit  70  and replaced with a new thermally conductive medium  75  having new capillary columns  35  when necessary. This capability makes the use of the temperature control unit  40  highly economical in instances in which the effective life of the capillary columns  35  is shorter than the effective life of the elements comprising the heating unit  70 . 
     FIGS. 8A through 8C  illustrate an embodiment of the temperature control unit similar to the one shown in  FIG. 2  as it may be adapted into an overall capillary insertion unit  150  for use in a corresponding analysis apparatus.  FIG. 8A  is a top partial cross-sectional view of the insertion unit  150  while  FIGS. 8B and 8C  are bottom and top plan views thereof. As shown in each view, a plurality of capillary columns  35  extended from each end  155  and  160  of temperature control unit  40 . The capillary columns  35  extending from end  155  are attached to an inlet unit  165  that is adapted to receive the sample from the corresponding analysis apparatus. Similarly, the plurality of capillary columns  35  extending from end  160  proceed to engage an outlet unit  170  that is adapted for connection to a subsequent section of the corresponding analysis apparatus, such as the detection chamber portion thereof. As shown in  FIG. 8C , an additional metal plate  175  is disposed over at least a portion of the exterior surface of conductive rubber sheet  110  and the entire temperature control unit is held together with, for example, strips of thermal tape  180 . An exemplary capillary holder for use in the capillary insertion unit  150  is shown in U.S. Pat. No. 5,900,132, issued on May 4, 1999 to Keenan et al., entitled “Capillary Holder”. 
   Capillary insertion unit  150  may be provided as a single assembly to an end-user of the analysis apparatus thereby greatly simplifying the installation process. Although a specific construction for the temperature control unit  40  a shown in connection with the insertion unit  150 , it will be recognized that any of the embodiments discussed herein may be provided in the form of unit  150 . 
     FIGS. 9A and 9B  illustrate a further embodiment of a temperature control unit  30  that is particularly suitable for widespread and economical commercial use. In this embodiment, the thermally conductive medium  75  portion and the heating unit  70  portion of the temperature control unit  30  are manufactured as completely separate and separable units. Heating unit  70  is comprised of three adjacent layers. First, a heating element  90  is disposed as the lower layer of the overall unit and has a lower surface that is at least partially exposed for cooling. An intermediate thermally conductive layer  95 , preferably formed from a metal, is disposed over a first side of the heating element  90 . Finally, a thin layer of conductive rubber  185  is disposed over the intermediate thermally conductive layer  95  and forms the uppermost layer of the heating unit  75 . 
   The thermally conductive medium  75  of this embodiment is likewise comprised of three layers. More particularly, thermally conductive medium  75  includes a lower thermally conductive layer  190  and an upper thermally conductive layer  195  that sandwich an intermediate thermally conductive rubber layer  200  therebetween. Preferably, layers  190  and  195  are formed from thermally conductive metal plates. The plurality of capillary columns  35  are substantially surrounded by the material forming conductive rubber layer  200  to thereby maximize thermal energy transfer between the capillary columns and the surrounding medium. Conductive rubber layer  200  may be constructed in one of the manners described above. 
   In commercial use, thermally conductive medium  75  and heating unit  70  may be provided as separate commercial units. Heating unit  70  may thus be reused with multiple thermally conductive mediums  75 .  FIG. 9B  shows the heating unit  70  and the thermally conductive medium  75  assembled with one another for operation in a corresponding analysis device. Unit  70  and medium  75  are held together by one or more fasteners, clamps and/or latches  205  so that the upper surface of conductive rubber layer  185  is placed in secure thermal contact with the bottom surface of metal layer  190 . 
     FIGS. 10A through 10D  show a still further embodiment of a temperature control unit  40  that is particularly suitable for widespread economical commercial use. In accordance with this embodiment, first and second portions  210  and  215  of the temperature control unit  40  are connected by a hinge, shown generally at  220 . The first and second portions  210  and  215  can be rotated with respect to one another between an open position, shown in  FIG. 10B , and a closed position shown in  FIG. 10C . 
   The basic components of the temperature control unit  40  while in the open position are illustrated in  FIG. 10A . As shown, the first portion  210  of the temperature control unit  40  includes a plate  225  that, for example, is comprised of metal or another highly thermally conductive and rigid material. The second portion  215  of the temperature control unit  40  is comprised of a solid-state heating element  90  having a first side that is at least partially covered by a plate  230 . 
   In the closed position of  FIG. 10C , the array of capillary columns  35  are surrounded by a thermally conductive rubber material. The thermally conductive rubber material can be applied in any one of the manners described above.  FIG. 10B  shows the thermally conductive rubber material applied as two separate sheets  100  and  105 . Sheet  100  is disposed to cover at least a portion of the interior surface of the upper portion  210  of the temperature control unit  40  while sheet  105  is disposed to cover at least a portion of the interior surface of the lower portion  215 . The array of capillary columns  35  are arranged in the desired manner on the surface of sheet  105  before the upper and lower portions  210  and  215  are moved about hinge  220  to the closed position of  FIG. 10C  where the upper and lower portions are secured with one another by, for example, one or more fasteners, clamps or latches  205 . Preferably, the surfaces of sheets  100  and  105  deform under the pressure provided by fastener  205  so that the thermally conductive rubber material substantially surrounds the exterior surface of the capillary columns  35  and thereby maximizes thermal energy transfer between the rubber material and the capillary columns. 
   Alignment of the capillary columns  35  on the surface of sheet  105  can be difficult, particularly where a large number of capillary columns are used in the analysis process.  FIG. 10D  is a top plan view of an arrangement of components that may be used to assist in this alignment process. In accordance with this arrangement, the capillary columns  35  are aligned with one another in one or more capillary guides. The illustrated embodiment employs both a capillary inlet guide  235  and a capillary outlet guide  240 . 
   Capillary guides  235  and  240  may be constructed in a variety of manners. In one of its simplest forms, each guide  235  and  240  may be constructed as a block of material having a plurality of channels disposed therein corresponding to the desired alignment for the capillary columns. In such instances, the end-user may be charged with the responsibility for placing the capillary columns  35  in the respective channels. Alternatively, capillary guides  235  and  240  may be provided with the corresponding capillary columns  35  fixed therein as a single commercial unit. The end-user need only open the temperature control unit  40  in the manner shown in  FIG. 10B , align the capillary guides  235  and  240  on each side of the temperature control unit  40 , and close the temperature control unit  40  to the condition shown in  FIG. 10C . 
   While the heating rate of the temperature control unit  40  is dependent on the material and mass of the intermediate conductive layer  95  and the power of the heating element  90 , its cooling rate will generally depend on the overall area of the surfaces of the temperature control unit  40  that are exposed to the surrounding medium and the temperature difference between those surfaces and the environment immediately surrounding it. Generally stated, the cooling rate is dependent on the ratio of the thermal mass of the temperature control unit  70  to the total area of the temperature control unit that is exposed to the ambient environment and/or cooling unit. Lower ratios make the temperature control unit  40  highly suitable for use in processes requiring rapid temperature changes over time. In contrast, higher ratios make the temperature control unit  40  more suitable for use in processes requiring the temperature to remain highly stable. The chosen ratio may be tailored to meet the demands of a wide range of temperature controlled processes. 
     FIG. 11  is a graph of temperature versus time of a temperature control unit  40  constructed in accordance with the specific embodiment shown in  FIG. 8  and operated at a constant target temperature of 50° C. The heating unit  70  was designed to have a thermal mass to open surface area ratio of approximately 3.14 grams/square inch. As shown in  FIG. 11 , the temperature control unit  40  successfully maintained the temperature at 50° C. +/− 0.03° C., a degree of precision making the temperature control unit  40  highly suitable for analytical processes requiring strict temperature stability. 
     FIG. 12  is a graph of temperature versus time for the same temperature control unit  40  as it was operated to cycle the temperature over time. In the illustrated process, the temperature was varied between 49.5° C. and 50.5° C. (an amplitude of 1° C.) with a cycle period of 25 seconds. Again, the temperature control unit  40  accurately tracked the target temperatures and provided the desired oscillatory temperature waveform making this same temperature control unit  40  highly suitable for analytical processes requiring a temperature profile that varies quickly over time. Heating rates as high as approximately 0.125° C./second and cooling rates as high as approximately 0.06° C./sec (in an ambient environment at room temperature) have been observed in connection with this embodiment. As shown in  FIG. 12 , these rates are consistent with the 8 seconds it took to raise the temperature by 1 degree C. and approximately 17 sec to lower the temperature by 1 degree C., giving a total cycle period of 25 sec. It will be recognized, however, that the temperature control unit can be designed to accommodate different heating and cooling rates as required by the specific analytical process. 
   Numerous modifications may be made to the foregoing apparatus without departing from the basic teachings thereof. As noted above, the apparatus may be used in connection with a variety of different chemical and/or biological analytical instruments. Therefore, although the present invention has been described in substantial detail with reference to one or more specific embodiments, those of skill in the art will recognize that changes may be made thereto without departing from the scope and spirit of the invention as set forth in the appended claims.