The present invention generally relates to methods and apparatus for the parallel deposition, synthesis and screening of an array of diverse materials at known locations on a single substrate surface. More specifically, the invention is directed to potential masking systems and methods for applying a spatially varying potential across a substrate to deliver different materials to spatially addressable locations on the substrate.
The discovery of new materials with novel chemical and physical properties often leads to the development of new and useful technologies. Currently, there is a tremendous amount of activity in the discovery and optimization of materials, such as superconductors, zeolites, magnetic materials, phosphors, nonlinear optical materials, thermoelectric materials, high and low dielectric materials and the like. Unfortunately, even though the chemistry of extended solids has been extensively explored, few general principles have emerged that allow one to predict with certainty the composition, structure, and reaction pathways for the synthesis of such solid state compounds.
The preparation of new materials with novel chemical and physical properties is at best happenstance with our current level of understanding. Consequently, the discovery of new materials depends largely on the ability to synthesize and analyze new compounds. Given approximately 100 elements in the periodic table that can be used to make compositions consisting of three, four, five, six or more elements, an incredibly large number of possible new compounds remains largely unexplored. As such, there exists a need in the art for a more efficient, economical and systematic approach for the synthesis of novel materials and for the screening of such materials for useful properties.
One of the processes whereby nature produces molecules having novel functions involves the generation of large collections (libraries) of molecules and the systematic screening of those collections for molecules having a desired property. An example of such a process is the humoral immune system which in a matter of weeks sorts through some 1012 antibody molecules to find one which specifically binds a foreign pathogen (Nisonoff et al., The Antibody Molecule (Academic Press, New York, 1975)). This notion of generating and screening large libraries of molecules has recently been applied to the drug discovery process.
Using this logic, methods have been developed for the synthesis and screening of large libraries of up to 1014 molecules of peptides, oligonucleotides and other small molecules. Geysen et al., for example, have developed a method wherein peptide syntheses are carried out in parallel on several rods or pins (J. Immun. Meth. 102:259-274 (1987), incorporated herein by reference for all purposes). Generally, the Geysen et al. method involves functionalizing the termini of polymeric rods and sequentially immersing the termini in solutions of individual amino acids. In addition to the Geysen et al. method, techniques have recently been introduced for synthesizing large arrays of different peptides and other polymers on solid surfaces. Pirrung et al. have developed a technique for generating arrays of peptides and other molecules using, for example, light-directed, spatially-addressable synthesis techniques (U.S. Pat. No. 5,143,854 and PCT Publication No. WO 90/15070, incorporated herein by reference for all purposes). In addition, Fodor et al. have developed, among other things, a method of gathering fluorescence intensity data, various photosensitive protecting groups, masking techniques, and automated techniques for performing light-directed, spatially-addressable synthesis techniques (Fodor et al., PCT Publication No. WO 92/10092, the teachings of which are incorporated herein by reference for all purposes).
Using these various methods, arrays containing thousands or millions of different elements can be formed (U.S. patent application Ser. No. 08/805,727, filed Dec. 6, 1991, the complete disclosure of which is incorporated herein by reference for all purposes). As a result of their relationship to semiconductor fabrication techniques, these methods have come to be referred to as xe2x80x9cVery Large Scale Immobilized Polymer Synthesis,xe2x80x9d or xe2x80x9cVLSIPS(trademark)xe2x80x9d technology. Such techniques have met with substantial success in screening various ligands such as peptides and oligonucleotides to determine their relative binding affinity to a receptor such as an antibody.
The solid phase synthesis techniques currently being used to prepare such libraries involve the sequential coupling of building blocks to form the compounds of interest. For example, in the Pirrung et al. method polypeptide arrays are synthesized on a substrate by attaching photo-removable groups to the surface of the substrate, exposing selected regions of the substrate to light to activate those regions, attaching an amino acid monomer with a photo-removable group to the activated region, and repeating the steps of activation and attachment until polypeptides of the desired length and sequence are synthesized. These solid phase synthesis techniques cannot readily be used to prepare many inorganic and organic compounds.
In PCT WO 96/11878, the complete disclosure of which is incorporated herein by reference, methods and apparatus are disclosed for preparing a substrate with an array of diverse materials deposited in predefined regions. Some of the methods of deposition disclosed in PCT WO 96/11878 include sputtering, ablation, evaporation, and liquid dispensing systems. Using the disclosed methodology, many classes of materials can be generated combinatorially including inorganics, intermetallics, metal alloys, and ceramics.
In order to provide an efficient approach to synthesizing and screening new materials, a method of forming arrays of materials with varying chemical composition, concentration, stoichiometry and thickness at known locations on a substrate is desirable.
The present invention provides methods and apparatus for depositing various components onto a substrate to form an array of diverse materials, the materials being deposited in predefined regions. In particular, the present invention provides potential masking methods and systems which generate spatially varying electric, magnetic and/or chemical potentials across a substrate. These spatially varying potentials are used to deposit patterned combinatorial libraries in which the individual materials vary in chemical composition, concentration, stoichiometry, and/or thickness.
Once an array is prepared, a variety of characterization techniques may be used to rapidly screen and/or characterize the large number of materials contained on the array. A few of the material properties which may be easily investigated using this system include conductivity, super-conductivity, resistivity, thermal conductivity, anisotropy, hardness, crystallinity, optical transparency, magnetoresistance, permeability, frequency doubling, photoemission, coercivity, and dielectric strength. As a result of this rapid screening process, new compositions with new physical properties can be quickly identified. Once identified, a variety of well known methods can be used to prepare the materials on a larger scale.
Systems of the present invention comprise one or more source materials and a potential assembly for applying a spatially varying potential across a substrate, thus enabling components of the source materials to be deposited at spatially addressable locations on the substrate. The components may be deposited either in discrete arrays or in continuously varying patterns. Although the present invention potentially has the ability to create any number of different materials on a single array, typically an array will contain more than 9 different materials. Typically the array will contain at least 50 different materials, although for specific applications the array may contain more than 100 different materials, more than 103 different materials, more than 104 materials, more than 105 different materials, or more than 106 different materials.
In some embodiments of the invention, the system will comprise an array of discrete potential generating devices (e.g., electrodes, magnets) positioned adjacent to or embedded within the substrate. Each discrete potential generating device defines a library region or element on the substrate. By varying the potential at each device site, a slightly different component will be deposited onto the corresponding library region. In other embodiments of the invention, the spatially varying potential is created by a continuously varying potential element, such as a resistive electrode or a diffusive transport matrix. In these embodiments, the potential element will cause components of the source material(s) to deposit in a continuously varying pattern onto the substrate.
In one embodiment of the invention, the potential assembly applies a spatially varying electric potential across a substrate to selectively deposit components of the source material onto spatially addressable locations. In this embodiment, the substrate is brought into contact with an ionic solution or vapor stream and the voltage and/or current density is varied across the substrate to produce a spatially varying electric potential. The source material is introduced into the ionic solution or vapor stream such that components of the source material electrochemically deposits onto the substrate in accordance with the spatially varying potential. Generally, deposition and oxidation or reduction of the charged species from the ionic solution or vapor stream occurs onto those library elements with sufficient electrical potential to overcome the requisite oxidation or reduction potential.
The spatially varying electric potential may be applied to the substrate by an array of spatially addressable working electrodes coupled to or embedded within the substrate. Other methods of applying the spatially varying electric potential include a gradient-swept continuous electrode and/or an electrostatic micropattern. In one embodiment utilizing working electrodes, the array may also include one or more reference electrodes, the reference electrodes being suitably positioned to provide the requisite potentials at the library regions (galvanostatic). In a second embodiment, each working electrode has a reference electrode and a counter electrode (potentiostatic). In other embodiments, the composition of the ionic solution or vapor stream is varied while varying the relative voltages or currents applied to the individual library regions.
In another embodiment of the invention, the potential assembly applies a spatially varying magnetic potential across the substrate to selectively deposit components of the source material onto spatially addressable locations. In this embodiment magnetic field gradients can be produced by locating individually addressable electromagnets adjacent to the individual library regions. Alternatively, the potential assembly may comprise one or more magnetic films with domain maps created to produce pre-determined magnetic field gradients across the substrate. Source materials, such as dry powders, suspensions, or molecules, are delivered adjacent to the substrate and are attracted to the substrate in proportion to the spatially varying field strength and the magnetic moment of the individual components. The source materials in this embodiment may include any material with a sufficiently large magnetic moment (e.g., Fe, Co, Ni) or any material attached to such a magnetic carrier.
In yet another embodiment of the invention, the potential mask assembly applies a spatially varying chemical potential across the substrate to selectively deposit components of the source material onto spatially addressable locations on the substrate. In this embodiment, chemical potential gradients drive diffusion when the concentration of species varies in space. In a specific embodiment, the delivery system comprises an isotropic point molecular source positioned relative to the substrate such that the flux of molecules deposited on the substrate varies as the inverse square of the distance to the substrate. Thus, the spatial locations nearest the source receive the largest deposition rate and the spatial locations farthest away from the source receive the lowest deposition rate. Suitable techniques of generating a molecular source include laser deposition, electron beam evaporation, radiofrequency sputtering in a vacuum, aerosolized spray, evaporation in a fill gas, or a dispensed liquid point source. The transport matrix between the source and the substrate may comprise a vacuum space, liquid solvent, polyelectrolyte, neutral porous solid, or an intentionally heterogeneous material that creates a diffusion gradient. Finally, the electrochemical arrays of the present invention may also be used as a screening technique. In this embodiment the individual electrodes comprising the arrays can be used to make electrochemical measurements and/or magnetic measurements of the materials located at the predefined regions (e.g., cyclic photometry, over-potential measurement, open circuit potential measurements, as well as other electrochemical measurements well known in the field).