Methods for filing a sample array by droplet dragging

#The present invention pertains to methods for manufacturing and using apparatus for manipulating, transporting, and analyzing a large number of microscopic samples of a liquid or of materials including cells currently or formerly in liquid suspension.

#Chemistry on the micro-scale, involving the reaction and subsequent analysis of quantities of reagents or analytes of order microliters or smaller, is an increasingly important aspect of the development of new substances in the pharmaceutical and other industries. Such reaction and analysis may accommodate vast libraries containing as many as a million compounds to be reacted and analyzed under various conditions. Significant problems associated with current technologies as applied to chemical analysis of vast numbers (potentially on the order of hundreds of thousands or millions per day) of compounds include the problem of handling vast numbers of compounds and reactions in parallel.

#Existing technology relies on 96-, 384-, or 1536-well plates containing quantities between approximately 1 microliter and 1 milliliter of liquid compound per well, and, generally, involves chemical reactions and analysis in wells disposed with single openings on flat surfaces such as polystyrene. It is not practical to apply existing technology in the art to form million-well microtiter plates. There is a need, therefore, for new approaches that permit the analysis of a million samples in a laboratory format.

#The invention will be more readily understood by reference to the following description, taken with the accompanying drawings, in which:

#FIGS. 1a and 1b show a top and exploded cross-sectional views, respectively, of a high-density array of through-holes in accordance with one embodiment of the present invention;

#FIG. 1c shows a schematic side view of a continuous sheet array of through-holes in accordance with another embodiment of the present invention;

#In accordance with the present invention, methods are provided for producing different chemical reactions within an array of through-holes. The invention is advantageously employed, for example, in screening operations, where different reaction conditions are advantageously provided among the various through-holes of the array. As an example of the many modalities of use of the invention, different chemical species may be loaded into different through-holes of the array, and concentrations of the various species might also be differentiated among the various through-holes. The invention may thus provide a method for screening compound libraries, for example, to predict the ability of each compound to be absorbed by a patient.

#In accordance with preferred embodiments of the invention, a high-density array of through-holes is provided, as now discussed with reference to FIGS. 1a and 1b. FIG. 1a shows a top view of a platen 10, otherwise referred to herein as a “substrate,” “sample wafer,” or “through-hole plate.” Platen 10 is the carrier of a large number of through-holes 12 which traverse platen 10 from a top surface 14 to an opposing surface 16 of the platen, as shown in the cross-sectional side view of FIG. 1b. While the term “platen” may refer to a structure having substantially parallel plane surfaces and transverse dimensions substantially exceeding the thickness of the structure, alternative geometries are within the scope of the present invention, and use of the term “platen” is not restrictive. A prism-shaped geometry is described below, for example.

#Through-holes 12 constitute assay wells (or “microwells”) in accordance with an embodiment of the invention. Through-holes 12 may be shaped as circular right cylinders, or, alternatively, may have rectangular cross-sections. Otherwise-shaped through-holes are also within the scope of the present invention.