Abstract:
A liquid chromatography chip may include an analytical column. After an analyte has traveled through an analytical column defined by the chromatography chip, the analyte is routed, either directly or indirectly, to a port defined by the chromatogrpahy chip, instead of to a spray tip on-board the chromatography chip. The port may be in fluid communication with a tube or conduit that may, in turn, be coupled to another device. Such an arrangement provides for flexible interface of the chromatography chip to another device.

Description:
BACKGROUND 
     Liquid chromatography is a process by which a substance may be separated into its constituent ions or molecules. Typically, the substance is dissolved in a solvent and is driven through an analytical column by a pump. The analytical column is filled with a packing material known as a “stationary phase.” The various components of the solution pass through the stationary phase at different rates, due to their interaction with the stationary phase. 
     Liquid chromatography may be used as an initial phase prior to further analysis via a mass spectrometer. Per such an arrangement, a substance to be analyzed is first separated into its constituents by a liquid chromatograph. Thereafter, time-sequenced samples are delivered from the output of the liquid chromatograph to the input of the mass spectrometer, i.e., into the ion source of the mass spectrometer. 
     In instances in which the mass spectrometer utilizes electrospray ionization, it is known to embody the liquid chromatograph as a small polymeric chip. In other words, the analytical column exists as a channel (packed with a treated stationary phase material) extending through the body of the chip. The output of the packed channel is connected to a second channel that extends to distal region of the chip, which is fashioned as a spray tip. The spray tip portion of the chip is inserted into the ion source of the mass spectrometer. Thus, the substance to be analyzed is separated into its constituents by the packed column embodied on the chip, and is then delivered, via the spray tip, into the mass spectrometer for further analysis. 
     The above-described scheme exhibits certain characteristics. To properly interface the chromatography chip with the ion source of the mass spectrometer, the spray tip region of the chip must be precisely shaped to mate with the ion source. Additionally, the chip must be precisely oriented relative to the mass spectrometer. Thus, the chromatography chip must be designed in light of the specific mass spectrometer to which it is to be mated, meaning that it cannot effectively function as a stand-alone unit. 
     SUMMARY 
     In general terms, the present invention is directed to a chromatography chip that routes an analyte to a port defined by the chromatography chip, rather than to a spray tip on-board the chromatography chip. 
     According to one embodiment, a liquid chromatography device may include a chip having a body with a first surface and an oppositely disposed second surface. The body may define a first channel having an input end and an output end. Also, the first channel may contain a chemically treated material. The second surface of the chip body may define a first void that is in fluid communication with the input end of the first channel. The body may define a second channel in fluid communication with the output end of the first channel. The second channel may be in fluid communication with a second void defined by the second surface of the chip body. 
     According to another embodiment, a liquid chromatography system includes a chip having a body with a first surface and an oppositely disposed second surface. The body defines a first channel having an input end and an output end. The first channel contains a chemically treated material. The first channel is in fluid communication with a first void defined by the second surface of the chip body. The system also includes a stator coupled to the first surface of the chip. Additionally, the system includes a rotor having a chip-side surface coupled to the second surface of the chip. The chip-side surface of the rotor has a groove thereon. Still further the system may include an actuator coupled to the rotor and arranged to rotate the rotor so that, at some point in the rotation of the rotor, the groove on the rotor comes into fluid communication with the first void on the second surface of the chip. 
     According to yet another embodiment, a method of liquid chromatography includes pumping a mobile phase fluid carrying an analyte to one of a plurality of channels extending through a stator. The method also includes receiving the mobile phase fluid carrying the analyte in one of a plurality of channels defined by a chip. Still further, the method includes driving the mobile phase fluid through a path extending through at least one channel defined by the chip. The at least one channel contains a chemically treated material. Thus, an effluent is yielded from the at least one channel. The composition of the effluent varies with time. Finally, the effluent is delivered to a tube. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1A  depicts a stator-side view of one possible embodiment of a chromatography chip. 
         FIG. 1B  depicts a simplified side-view of the chromatography chip of  FIG. 1A . 
         FIG. 2A  depicts a side-view of one possible embodiment of a chromatography system. 
         FIG. 2B  depicts a rotor that, according to one possible embodiment, may be an element of the system depicted in  FIG. 2B . 
         FIG. 3  depicts a stator-side view of one possible embodiment of a chromatography chip. 
         FIG. 4  depicts a portion of a path through which a fluid runs during one possible embodiment of a desalting process. 
         FIG. 5  depicts another portion of a path through which a fluid runs during one possible embodiment of a desalting process. 
         FIG. 6  depicts yet another portion of a path through which a fluid runs during one possible embodiment of a desalting process. 
         FIG. 7  depicts a stator-side view of one possible embodiment of a chromatography chip. 
         FIG. 8  depicts a portion of a path through which a fluid runs during one possible embodiment of a chromatography process. 
         FIG. 9  depicts a portion of a path through which a fluid runs during one possible embodiment of a chromatography process. 
     
    
    
     DETAILED DESCRIPTION 
     Various embodiments of the present invention will be described in detail with reference to the drawings, wherein like reference numerals represent like parts and assemblies throughout the several views. Reference to various embodiments does not limit the scope of the invention, which is limited only by the scope of the claims attached hereto. Additionally, any examples set forth in this specification are not intended to be limiting and merely set forth some of the many possible embodiments for the claimed invention. 
       FIG. 1A  depicts an embodiment of a liquid chromatography device  100 . A simplified, partial side view of the liquid chromatography device, projected across line  102 , is presented in  FIG. 1B . For the sake of simplicity, only the channels extending between ports identified by reference numerals in  FIG. 1A  are depicted in  FIG. 1B . The chromatography device  100  is embodied as a thin wafer or chip, and is referred to herein as a “chromatography chip.” 
     In the exemplary embodiment, the chromatography chip  100  is polymeric, although it could be made from other materials. For example, the chromatography chip may be fabricated from polyimide, amongst other possibilities. The chromatography chip  100  has an upper surface  104 , which is shown in  FIG. 1A , and an opposed lower surface  106 , which is not visible in  FIG. 1A , but is depicted in  FIG. 1B . The upper and lower surfaces  104  and  106  are depicted as being rectangular. In principle, the shape of the upper and lower surfaces  104  and  106  is a matter of design choice, and may take on any form. 
     In the exemplary embodiment, the chromatography chip  100  is thin. For example, according to one embodiment, the chromatography chip  100  is about 30 mils thick (i.e., the upper and lower surfaces  104  and  106  are separated from one another by 30 mils), and may be embodied as multiple stacked chromatography chips. According to another embodiment, the chromatography chip is about one inch in width, and is about two to about six inches in length. The aforementioned dimensions of the chromatography chip are the subjects of design choice. Therefore, various embodiments of the chromatography chip may be wider and/or longer, depending whether a stacked embodiment is used, or whether the chip includes multiple sample processing channels, etc. 
     The figures presented herein, including  FIGS. 1A and 1B , are not drawn to scale. For the sake of illustration, certain features that would otherwise be quite small have been depicted as exaggeratedly large. For example, the thickness of the chromatography chip  100  has been exaggerated, in order to provide a better view of certain features of the chromatography chip  100 . The size of other features has also been distored, for similar reasons. 
     The upper surface  104  of the chromatography chip  100  defines a set of holes or ports, one of which is identified by reference numeral  108 . The lower surface  106  of the chip also defines a set of ports, two of which are identified by reference numerals  110  and  112 . In  FIG. 1A , ports that are defined by the upper surface  104  (e.g., port  108 ) are depicted with a solid line. On the other hand, ports that are defined by the lower surface  106  (e.g., ports  110  and  112 ) are depicted with a dashed line. 
     A port is a void defined by a surface  104  or  106  of the chromatography chip  100 . According to one embodiment, the ports are about two microns in diameter. Of course, the aforementioned diameter is a matter of design choice, and may therefore vary, as is understood in the art. Each port provides access to a channel. For example, in the case of port  108 , access is provided to channel  114 , which extends from the upper surface  104  to the lower surface  106 , terminating at port  116  defined in the lower surface  106  of the chip  100 . Therefore, a device, such as a tube or conduit, in fluid communication with port  108  is also in fluid communication with port  116  by virtue of the channel  114  that extends between them. Turning to another example, in the case of port  110 , access is provided to channel  118 , which runs along a tripartite path: (1) beginning at port  110  and extending towards the upper surface  104 ; (2) extending through the chip body  100 , in a partially width-wise and partially length-wise direction; and (3) extending again toward the lower surface, and terminating at port  112 . Thus, a device in fluid communication with port  110  is also in fluid communication with port  112  by virtue of the channel  118 . 
     Each channel may be terminated by two ports. A channel may be terminated by two ports defined by the same surface (i.e., both ports are on the lower surface  106 , or both ports are on the upper surface  104 ), in which case the channel extends length-wise and/or width-wise through the body of the chip before returning to the surface from which it originated. Alternatively, a channel may be terminated by ports on opposed surfaces. For example, such a channel may extend along the z-axis of the chip  100 , directly coupling the oppositely opposed ports, as shown by channel  114 . On the other hand, such a channel may extend length-wise and/or width-wise through the body of the chip before extending to a port on the opposite surface. In some exemplary embodiments of a chromatography chip, one or more channels may be linear. In other embodiments, one or more channels may be non-linear. 
     A chromatography chip, such as the one depicted in  FIGS. 1A and 1B  may be used in connection with a system, such as that depicted in  FIGS. 2A and 2B . The system includes a stator  200 , a chromatography chip  202 , and a rotor  204 . 
     In  FIG. 2A , the exemplary embodiment of the chromatography chip  202  is depicted from a side view, with its upper surface  206  abutting the stator  200 , and its lower surface  208  abutting the rotor  204 . Hence, the upper surface of the chromatography chip  202  may be referred to herein as the “stator-side surface,” and the lower surface  208  may be referred to herein as the “rotor-side surface.” 
     The chromatography chip depicted in  FIG. 2A  contains two ports  210  and  212  on the upper surface  206 , and two ports  214  and  216  on the lower surface  208 . A practical commercial embodiment of a chromatography chip may contain many more ports, as discussed below. The chromatography chip  202  presented in  FIG. 2A  is simplified for the sake illustrating the combined functionality of the stator  200 , chromatography chip  202 , and rotor  204 . 
     The stator  200  couples to the upper surface of the chip  206 , and functions as an input manifold. A fluid to be introduced into port  210  on the upper surface  206  of the chromatography chip  202  may be injected into port  218  of the stator  200 . The fluid then travels through a channel  220  extending length-wise through the stator  200 , and arrives at port  210 . Upon reaching port  210 , the fluid travels through channel  222 , and arrives at port  214  on the lower surface  208  of the chromatography chip  202 . 
     The rotor  204  serves the purpose of selectively providing fluid communication between ports on the lower surface  208  of the chromatography chip  202 . A view of the chip-side surface of the rotor  204  is presented in  FIG. 2B . As can be seen in  FIG. 2B , the rotor  204  includes a groove  224  etched into the surface of the chromatography chip. According to one embodiment, the groove  224  may be on the order of 0.001 inches deep. Although not depicted in  FIG. 2B , the rotor  204  may be rotated by an actuation device, such as a servomotor, for example. Rotation of the rotor  204  causes concomitant rotation of the groove  224 . By rotating the rotor  204  to a defined angle, the groove  224  may be oriented so that one extremity  226  of the groove  224  aligns with port  214 , and another extremity  228  aligns with port  216 . When thus positioned, the groove  224  provides fluid communication between the ports  214  and  216 . Rotation of the rotor  204  to another angle may cause port  214  to come into fluid communication with another port on the lower surface  208  of the chromatography chip  202 , or may cause port  214  to be terminated (i.e., not in fluid communication with any other port). 
     As depicted in  FIG. 2A , the groove  224  is oriented so that fluid communication is provided between ports  214  and  216 . Therefore, fluid reaching port  214  travels through the groove  224 , and is reintroduced into the chromatography chip at port  216 . Thereafter, the fluid travels through the channel  230 , and is communicated to channel  232 , which extends length-wise through the chromatography chip body  202 . Channel  232  may be packed with packing material, such as silica beads, for example, causing the channel  232  to function as an analytical column. Thus, fluid reaching channel  232  is separated into its constituent molecules, which are communicated via channel  234  to port  212  as a function of time. Thereafter, the column  232  effluent exits the system by way of stator channel  236 , reaching an output port  238  on the upper surface of the stator  200 . 
     A tube or conduit  240  may be connected to port  238 . According to one embodiment, the tube  240  may be fashioned as a fused silica conduit or other appropriate conduit, having an inner diameter on the order of approximately 2-1000 micrometers. The aforementioned diameter of the tubing  240  is a design choice governed by other factors and may therefore vary, as is understood in the art. The tube  240  may provide fluid communication to any desired device. For example, the tube  240  may provide fluid communication with a spray tip that is embedded in the ion source of a mass spectrometer, or to other devices, such as fraction collectors, matrix-assisted laser desorption (MALDI) plates, ultraviolet cells, etc. Accordingly, the chromatography chip depicted in  FIG. 2A  (an in the other figures herein) does not include a spray tip. Thus, the system shown in  FIG. 2A  functions as a stand-alone chromatography unit that may be coupled, via the tube  240  to any desired device. Such device may include, without limitation, a mass spectrometer, an ultraviolet cell, a fraction collector or a MALDI plate, etc. 
     Returning to  FIG. 1A , certain features of the chromatography chip  100  are of note, but not essential. As shown therein, the chromatography chip  100  includes a trapping column  120  and an analytical column  122 . As described below, the chromatography chip  100  may be mated with a rotor, so that an analyte carried by a fluid is trapped at the head of the trapping column, and is desalted. Thereafter, the rotor may be rotated, so as to cause the analyte to pass through the trapping column  120 , and enter the analytical column  122 , whereupon the analyte is separated into its constituents, which exit the analytical column  122  as a function of time. Thereafter, the column effluent is directed to a port in communication with the stator, whereupon it is directed via a tube to to a desired device, as described previously. 
     To permit the aforementioned operation to occur with simple rotation of a rotor, the ports on the lower surface  106  (i.e., rotor-side surface) of the chromatography chip  100  may be arranged along one or more concentric circular paths, as shown in  FIG. 1A . Thus, as shown in  FIG. 1A , the ports on the lower surface  106  of the chromatography chip  100  are arranged along two concentric circular paths. 
     Also of note in  FIG. 3 , is that the chromatography chip  300  possesses a plurality of ports that lead neither to a trapping column, nor to an analytical column. The provision of such ports permits the combination of the stator, rotor, and chromatography chip to cooperatively function as a switching device that directs fluid from one unit of equipment to another, for example. Alternatively, such ports may be used to provide a mechanism by which multiple pumps may coupled to the columns therein. 
       FIG. 3  depicts an exemplary chromatography chip  300  (view of top surface) arranged to initially desalt and then separate an analyte. The discussion related to  FIG. 3-9  is one example in which a stator, rotor, and chromatography chip cooperatively function so as to initially couple one pump to a given column, and to subsequently couple a different pump to that column. The depiction of  FIG. 3  includes three heavy dashed lines  302 ,  304 , and  306 . These heavy dashed lines represent fluid pathways (or grooves) provided by a rotor, which abuts the lower surface of the chromatography chip  306 , and is therefore not visible in  FIG. 3 . Given the orientation of the rotor in  FIG. 3 , an analyte delivered to the chip  300  undergoes a desalting process or washing, as described below. 
     Initially, a fluid carrying an analyte is propelled by force of a pump, such as a capillary pump, through an input port on a stator, which is in fluid communication with port  308  on the upper surface of the chromatography chip  300 . (For the sake of illustration, the fluid carrying the analyte is assumed to be water. Of course, other fluids may be used, as is understood by those of skill in the art.) A capillary pump is a variety of pump that exhibits a flow rate on the order of picoliters/min to microliters/min. The fluid flows through the port  308 , and traverses a channel  400  coupled thereto (see  FIG. 4 ), reaching a port  402  on the lower surface of the chromatography chip  300 . A groove  302  provides fluid communication between port  402  and port  310 , and therefore the fluid travels to port  310 . 
     Port  310  is in fluid communication with channel  312 , which is packed with a hydrophobic packing material or other material(s) required for the method used in the chemical process. Accordingly, the water passes through the column  312 , while the analyte remains at the head of the column. For this reason channel  312  is referred to as a “trapping column” (the analyte remains “trapped” at the head of the column). As the water passes through the column  312 , it carries away contaminant salts that may be commingled with the analyte, a process known as “desalting.” The water and salts dissolved therein constitute a waste fluid that is carried to port  314  on the lower surface of the chromatography chip  300 , leaving the adsorbed hydrophobic material on the trapping column. 
     Groove  304  provides fluid communication between port  314  and port  500  ( FIG. 5 ) on the lower surface of the chromatography chip  300 . Therefore, the waste fluid flows from port  314  to port  500 . A channel  600  ( FIG. 6 ) couples port  500  on the lower surface of the chip  300  to port  316  on the upper surface of the chromatography chip  300 , and the waste fluid therefore exits the chip  300  by way of port  316 , and enters a channel  602  that extends through the stator. A tube or conduit  604  is coupled to the stator at port  606 . Therefore, the waste fluid is removed from the stator via the tube  604 , and carried to a waste fluid receptacle (not depicted). 
     The previously described desalting process may continue for several minutes, until the analyte is determined to be sufficiently purified or deslated. Thereafter, the rotor may be rotated in the clockwise direction, causing the grooves to form the couplings depicted in  FIG. 7 . 
     As can be seen from  FIG. 7 , port  308  is no longer in fluid communication with port  310 . Instead, port  700  is in fluid communication with port  310 . As shown in  FIG. 8 , port  700  is in fluid communication with port  800  of the stator (via channel  802 ). A pump, such as a nanopump, may drive a hydrophilic fluid, such as acetonitrile, through the port  800 , and therefore through channel  802 , meaning that the hydrophilic fluid enters the chromatography chip  300  by way of port  700 . A nanopump is a variety of pump that exhibits a flow rate on the order of microliters to low nanoliters per minute. A channel  803  couples port  700  to port  804  on the lower surface of the chip. Accordingly, the hydrophilic fluid exits the chip  300  by way of port  804 . 
     Groove  302  provides fluid communication between port  804  and port  310 . Therefore, the hydrophilic fluid re-enters the chip at port  310 . Upon re-entry of the hydrophilic fluid, it passes through the head of the trapping column  312 , thereby dissolving the hydrophobic analyte and carrying it through the trapping column  312 , whereupon the column effluent exits the chromatography chip by way of port  314  at the lower surface of the chip  300 . 
     By virtue of the orientation of the rotor, groove  304  provides fluid communication with port  701 . Thus, the effluent re-enters the chip  300  by way of port  701 , and flows through channel  702 . Channel  702  is packed with a packing material such as silica treated beads, thereby separating the effluent-analyte solution into its consituent molecules, which exit the column  702  with a composition that is a function of time. 
     Alternately referring to  FIG. 9  and  FIG. 7 , upon exit from the analytical column  702 , the column effluent traverses channel  704 , and exits the chip  300  by way of port  706 . Groove  306  on the rotor provides fluid communication between port  706  and port  900  on the lower surface of the chromatography chip. Accordingly, the effluent re-enters the chromatography chip  300  at port  900 , and flows through channel  902 , exiting the chromatography chip at port  708  on the upper surface of the chromatography chip  300 . 
     Upon exiting the chromatography chip, the effluent travels to output port  906  on the stator, by way of channel  904 . Thereafter, the effluent is carried to by way of a tube or conduit to a device coupled thereto, such as a spray tip embedded in an ion source of a mass spectrometer or other anayltical devices, including MALDI plates, etc. 
     The various embodiments described above are provided by way of illustration only and should not be construed to limit the invention. Those skilled in the art will readily recognize various modifications and changes that may be made to the present invention without following the example embodiments and applications illustrated and described herein, and without departing from the true spirit and scope of the present invention, which is set forth in the following claims. 
     Furthermore, in the foregoing detailed description, various features are occasionally grouped together in a single embodiment for the purpose of streamlining the disclosure. This method of disclosure is not to be interpreted as reflecting an intention that the claimed embodiments of the subject matter require more features than are expressly recited in each claim. Rather, as the following claims reflect, inventive subject matter lies in less than all features of a single disclosed embodiment. Thus, the following claims are hereby incorporated into the detailed description, with each claim standing on its own as a separate preferred embodiment. 
     The Abstract is provided to comply with 37 C.F.R. Section 1.72(b) requiring an abstract that will allow the reader to ascertain the nature and gist of the technical disclosure. It is submitted with the understanding that it will not be used to limit or interpret the scope or meaning of the claims.