Tip design and random access array for microfluidic transfer

Details Tip design and random access array for microfluidic transfer Tip design and random access array for microfluidic transfer

1999-12-10

2003-04-22

Warden, Jill (Department: 1743)

Chemical apparatus and process disinfecting, deodorizing, preser

Control element responsive to a sensed operating condition

C436S180000, C073S863320, C073S863310, C073S863540, C073S864000, C073S864010, C073S864110, C073S864240, C073S864250, C073S864310, C073S864350

Reexamination Certificate

active

06551557

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the transfer of microfluidic quantities of fluids and, in particular, to a tip design and random access tip array for genomic applications and high throughput screening.
2. Background of the Related Art
There is an ongoing effort, both public and private, to spell out the entire human genetic code by determining the structure of all 100,000 or so human genes. Also, simultaneously, there is a venture to use this genetic information for a wide variety of genomic applications. These include, for example, the creation of microarrays of DNA material on targets or substrates to create an array of spots on microscope slides or biochip devices. These arrays can be used to read a particular human's genetic blueprint. The arrays decode the genetic differences that make one person chubbier, happier or more likely to get heart disease than another. Such arrays could detect mutations, or changes in an individual's chemical or genetic make-up, that might reveal something about a disease or a treatment strategy.
It can be a difficult task to efficiently and accurately create DNA microarrays. The desired density of the microarrays can be as high as several thousand dots/cm
2
. Moreover, the desired volume transfer can be low enough to be in the picoliter range.
One typical way of forming DNA microarrays utilizes pins that can be dipped into solutions of the sample fluid(s) and then touched to a surface to create a small spot or dot. The pins are typically thin rods of stainless steel which have a sharpened fine point to provide a small spot size. Undesirably, the sharp point makes the pins fragile and repeated contact with the surface can lead to damaged pins. This can affect the accuracy of the volume transferred, and hence result in unrepeatable and inconsistent performance. Also, these pins generally allow only a single spot to be formed from a single dip.
More recently, pins have been made with a small slot to permit multiple spotting from a single dip of the sample fluid. Undesirably, the slot can render the pins even more fragile. Another disadvantage of the slotted pin technology is that there is a large variation in the spot size and volume transfer between the first transfer and subsequent transfers—this variation can be as much as 50%. Also, the fluid sample in the slot is undesirably exposed to the atmosphere during the transfer step. This can lead to contamination and evaporation of valuable fluid. Moreover, the pins can have limited reproducibility due to surface tension changes within the slot as solution is dispensed and as solution evaporates from the exposed pin. Additionally, thorough cleaning of the slotted pins can be difficult and time-consuming.
In many cases, the spotting pins are held in a pin holder which allows multiple pins to be dipped into the sample solution and spotted onto the target, typically a glass slide. The spacing between the pins typically corresponds to the spacing between the wells of the source plate. To create high density microarrays, the pins are simultaneously dipped and then spotted. Subsequent spotting is accomplished by offsetting the spotting position by a small distance. One of the disadvantages of this spotting technique is that the location of the samples (spots) on the slide does not correspond to the location of the samples (wells) in the source plate. Another disadvantage is that samples cannot be randomly accessed from the source plate and randomly printed on the slide. These disadvantages diminish the versatility and utility of such conventional microarraying technology.
Conventional pin transfer technology is also used in other applications such as high throughput screening (HTS). High throughput screening involves compound or reagent reformatting from a source plate to an assay plate. For example, test compounds, dissolved in DMSO are transferred from a 96 well plate to a 96, 384 or 1536 well microtiter plate. Typically, the desired transfer volume is higher than that for genomic arraying and is in the range from about 1 to 200 nanoliters (nL) or more. Undesirably, conventional pin transfer technology when utilized for compound reformatting can also suffer from some or all of the above disadvantages.
Microfluidic transfer of liquids can also be performed using an aspirate-dispense methodology. State-of-the-art aspirate-dispense methods and technologies are well documented in the art, for example, as disclosed in U.S. Pat. No. 5,741,554, incorporated herein by reference. These typically use pick-and-place (“suck-and-spit”) fluid handling systems, whereby a quantity of fluid is aspirated from a source and dispensed onto a target for testing or further processing. But to efficiently and accurately perform aspirate and dispense operations when dealing with microfluidic quantities, less than 1 microliter (&mgr;L), of fluid can be a very difficult task. The complexity of this task is further exacerbated when frequent transitions between aspirate and dispense functions are required. Many applications, such as DNA microarraying and HTS, can involve a large number of such transitions. In these and other applications it is desirable, and sometimes crucial, that the aspirate-dispense system operate efficiently, accurately and with minimal wastage of valuable reagents.
Therefore, there is a need for an improved technology and methodology that provides efficient, repeatable and accurate transfer of microfluidic quantities of fluid while reducing wastage of such fluids.
SUMMARY OF THE INVENTION
The present invention overcomes some or all of the above disadvantages by providing a ceramic tip and a random access print head for the transfer of microfluidic quantities of fluid. Advantageously, the print head can randomly collect and deposit fluid samples to transfer the samples from a source plate to a target. The print head can also be programmed to create a direct map of the fluid samples from the source plate on the target or to create any desired pattern or print on the target. The tip and print head can be used for a wide variety of applications such as DNA microarraying and compound reformatting. In one preferred embodiment, the tip is used as a capillary or “gravity” pin to draw or collect source fluid and “spot,” deposit or contact dispense the fluid onto the target via physical contact (touch-off). In another preferred embodiment, the tip is used in conjunction with an aspirate-dispense system to actively aspirate source fluid and deposit the fluid via a contact or non-contact approach. Advantageously, the tip provides improved, accurate and repeatable microfluidic transfer.
In accordance with one preferred embodiment the present invention provides a contact transfer tip for micro-fluidic dispensing of fluid from a fluid source onto a desired target substrate. The contact transfer tip generally comprises a substantially cylindrical upper body portion, a substantially tapered lower body portion and a lumen cavity. The substantially cylindrical upper body portion has a first outside diameter. The substantially tapered lower body portion has a second outside diameter at a transition portion thereof which is substantially equal to the first outside diameter of the upper portion. The substantially tapered lower body portion further has a third diameter at a lower-most end thereof which is smaller than the first or second diameters and which approximately equals the diameter of a spot or dot of fluid desired to be deposited onto the target substrate. The upper and lower body portions are coaxially aligned relative to one another about a central axis. The lower-most end of the lower body portion is substantially flat and lies in a plane substantially normal to the central axis. The lumen cavity is formed so that it extends substantially completely through the upper and lower body portions and forms an orifice or opening at the lower-most end of the lower body portion. The orifice is adapted to admit a quantity of the fluid into the lumen cavi

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