Microarray fabrication techniques and apparatus

Abstract

Disclosed is a microarray printing system and methods of printing probe microarrays. The system has a print head formed of one or more bundles of individual capillaries, such as light-guiding capillaries. The bundles may especially be random bundles of capillaries that provide a large number of probes on the surface of a substrate. Methods of registering or correlating the distal and proximal ends of the capillaries are also provided. Further, the invention provides methods and equipment for identifying defective microarrays that are missing one or more probes from the surface of the microarray.

What is claimed is:  
     
         1 . A capillary bundle comprising a plurality of individual capillaries having proximal and distal ends, each of said capillaries having a channel extending from the proximal end to the distal end of the capillary and having a channel-facing wall, wherein said proximal ends of the individual capillaries are secured to one another in a solid mass such that the proximal ends of said capillaries are substantially coplanar in a static array in a facet of the solid mass.  
     
     
         2 . A capillary bundle according to  claim 1 , wherein each proximal end of said plurality of capillaries has a vertical height above a reference plane and at least one of said capillaries has a minimum vertical height and at least one of said capillaries has a maximum vertical height, and the difference between the minimum vertical height and the maximum vertical height is no more than about 100 micron.  
     
     
         3 . A capillary bundle according to  claim 1  or  2 , wherein said plurality of capillaries comprises light-conducting capillaries.  
     
     
         4 . A capillary bundle comprising a plurality of capillaries having proximal and distal ends, each of said capillaries having a channel extending from the proximal end to the distal end of the capillary and having a channel-facing wall, wherein said proximal ends of the individual capillaries are secured to one another such that the proximal ends of said capillaries are substantially coplanar in a static array in a facet and wherein said plurality of capillaries are secured to one another to form a random bundle so that the distal ends of the capillaries are grouped in a first arrangement, the proximal ends are grouped in a second arrangement, and the first arrangement is not identical to the second arrangement, and wherein the bundle has a print density of at least about 500 probes per cm 2 .  
     
     
         5 . A capillary bundle according to  claim 4 , wherein said plurality of capillaries comprises light-conducting capillaries.  
     
     
         6 . A method of printing a microarray comprising providing a capillary bundle comprising a plurality of individual capillaries having proximal and distal ends, each of said capillaries having a channel extending from the proximal end to the distal end of the capillary and having a channel-facing wall, wherein said proximal ends of the individual capillaries are secured to one another in a solid mass such that the proximal ends of said capillaries are substantially coplanar in a static array in a facet of the solid mass, passing a probe-containing fluid through a capillary of said capillary bundle, and printing said microarray on a substrate.  
     
     
         7 . A method of printing according to  claim 6 , wherein said plurality of capillaries comprises light-conducting capillaries.  
     
     
         8 . A method according to  claim 6 , wherein said plurality of capillaries are secured to one another to form a random bundle so that the distal ends of the capillaries are grouped in a first arrangement, the proximal ends are grouped in a second arrangement, and the first arrangement is not identical to the second arrangement.  
     
     
         9 . A method of making a capillary bundle suitable for printing a probe microarray on a substrate, said method comprising 
 a) forming a random bundle of a plurality of capillaries having distal and proximal ends; and    b) securing the proximal ends of the capillaries to form a solid mass containing the proximal ends of said capillaries, said solid mass having a facet and said proximal ends being substantially coplanar at said facet.    
     
     
         10 . A method according to  claim 9  wherein said capillaries are light-conducting capillaries.  
     
     
         11 . A method according to claims  10  wherein said method further comprises registering the proximal ends of the capillaries to the distal ends of the capillaries.  
     
     
         12 . A method according to  claim 11 , wherein the act of registering the proximal ends to the distal ends comprises launching light into a distal end of a first capillary, observing the light exiting a proximal end of the first capillary, and recording information that correlates the distal end of the first capillary to the proximal end of the first capillary.  
     
     
         13 . A probe microarray comprising no less than 500 non-identical probes in a honeycomb pattern in an area of no more than 1 cm 2  on a substrate.  
     
     
         14 . A probe microarray comprising a random arrangement of no less than 500 non-identical probes in an area of no more than 1 cm 2  on a substrate.  
     
     
         15 . A probe microarray according to  claim 13  or  14 , wherein said probes are selected from the group consisting of oligonucleotides, polypeptides, cells, and compounds.  
     
     
         16 . A probe microarray according to  claim 13  or  14 , where said microarray comprises at least about 10,000 probes.  
     
     
         17 . A light-conducting capillary that transports both light and a fluid from a distal end to a proximal end of said capillary, wherein said light-conducting capillary is formed of a material that has a refractive index selected so that said capillary transports said light.  
     
     
         18 . A light-conducting capillary according to  claim 17 , wherein said capillary is configured to transport both said light and said fluid simultaneously, and wherein the refractive index is selected so that the light transmits from the distal end to the proximal end of the capillary as said fluid travels through said capillary.  
     
     
         19 . A light-conducting capillary, said capillary having a first portion having a first refractive index and a second portion having a second refractive index, said second refractive index being greater than said first refractive index, said capillary further having a proximal end, a distal end, an axis, an inner wall defining a channel through the capillary, and an outer wall, said inner wall extending coaxially with the axis of the capillary, said outer wall extending coaxially with the axis of the capillary; wherein the first portion and the second portion are configured such that a light beam launched into the proximal end is transmitted along the capillary and exits the capillary at the distal end; said channel having a cross-sectional area, and wherein the cross-sectional area of the channel is sufficiently large that a fluid entering the channel at the proximal end of the capillary discharges at the distal end of the capillary.  
     
     
         20 . A capillary according to  claim 19 , wherein the second portion comprises silica doped with an impurity that increases the refractive index of silica, and wherein the first portion comprises silica having a lower refractive index than said second portion.  
     
     
         21 . A capillary according to  claim 17  or  19 , wherein the outer diameter of said capillary is less than about 300 micron.  
     
     
         22 . A capillary according to  claim 17  or  19 , wherein the outer diameter is less than about 100 micron.