Patent Application
20050077657
The field of the invention is that of simultaneously testing many compounds for biological/chemical interactions. In particular, the current invention is a device/structure and a method to test drug interactions.
In the pharmaceutical industry, it is necessary to test the reaction (including biological activity) of chemical A to chemicals B1-Bn where n can be a large number, on the order of millions.
A popular method is that of providing an array of substances B1-Bn on a plastic card and placing substance A in contact with each of the Bn. Commercially available plastic card arrays include 96 and 384 wells. The well diameters are of the order of few millimeters. The method of chemical placement or dispensing usually is by micro pipettes. There are computer assisted scanners used to type the chemical interactions.
Since there are millions of combinations of chemicals to test to exhaust the possibilities, it takes years for companies that are involved in drug discovery, to bring a successful drug to the market. With the current speed of computer assisted scanning devices, it is possible to reduce the drug discovery time, for example, by increasing the number of samples scanned at a time. This is possible if we can pack more number of wells, for example, in a given volume. A larger number of wells in a given volume also reduces the amount of costly chemicals to be used in a given well.
The plastic cards are usually formed by extrusion and the precision of the hole diameter and location within the array is not adequate enough to fabricate micro holes and channels. This essentially limits the extendability of plastic in this field.
The pharmaceutical industry is searching energetically for micro devices, with multiple thousands of wells with diameters of the order of 100 microns and channels connecting the selective wells at different levels within the array.
The invention relates to a ceramic device with micro wells and micro channels and a method for formation thereof.
A feature of the invention is the fabrication of an array of micro wells and micro channels in a ceramic structure by laminating multiple personalized green sheets.
In an aspect of the invention, a multi-layer array of wells and channel structure contains a set of structures filled with a material that can be removed after sintering to form channels.
Another feature of the invention is the use of a sacrificial material that leaves a residue of a porous structure whose pores are connected after sintering.
Another feature of the invention is the use of a sacrificial material that remains in the ceramic structure during the sintering process to preserve a porous structure and that is removed after the sintering process.
Another aspect of the invention is the control of the channel volume during sintering process.
The lamination process involves heat, pressure and time. The preferred lamination pressure is under 800 psi, the temperature is under 90 deg C. and for a time of less than 5 minutes. The sintering process involves the material of choice and the binder system used to form the greensheets.
According to the invention, the greensheets are formed from a substance such as alumina, glass, ceramic and glass and ceramic. The technique for forming vertical apertures and horizontal channels is material removal by techniques such as punching the material out including nibbling, laser drilling, e-beam drilling, sandblasting and high pressure liquid jets. A single sheet may have up to several thousands holes and channels per square inch.
Micromolding by pressing the material to the side and distorting the greensheet is not included in the preferred embodiments and will be referred to generally as a material displacement technique. Such techniques are undesirable, since the desired well and channel position accuracy with respect to each other is very small, e.g. a few microns, and the distortions introduced by material displacement techniques are a significant obstacle to providing the desired accuracy.
According to a design choice, the vertical holes in the greensheet may be filled with a fugitive material that escapes during the sintering step or they may be filled with a material that remains during sintering and is removed afterward. Alternately, a fugitive material that is removed during sintering as well as a temporary material that is removed post sintering can be used.
The fugitive materials for a first embodiment may be any compatible organic material such as terepthalic acid, carbon, or other organic materials. In a second embodiment, the material filling passageways may be a mixture of particles with pores in between and a temporary material filling the pores. The particles are durable and remain in the final product. The temporary material is removed after sintering to open up the pores.
The materials to form the porous structures in the second embodiment may be ceramics such as alumina, glass ceramic, aluminum nitride and borosilicate glass, illustratively in a particle size of less than 40 microns. The ratio of materials is chosen such that there is a matrix of durable material interspersed with the temporary material that extends continuously through the matrix so that, when the temporary material is removed, there remains a set of passages that permit the reagent to flow.
In a first embodiment of the invention, some of the greensheets contain the fugitive material in the passages that will become vertical channels after the fugitive material escapes during sintering. The process of removing the fugitive material may involve heating it past the boiling or subliming temperature, so that the material goes off in vapor form into the ambient; or the technique may involve burning or other chemical reaction that combines the molecules of the fugitive material with the molecules of a reactant gas to from a substance that is a gas and goes into the ambient. The form of the fugitive material is preferably one that is easy to apply into the apertures in the greensheet, e.g. in the form of a paste.
In the second embodiment, a first material that will remain in the final product is combined with a second material that will form a porous structure on being sintered; e.g. a mixture of fugitive material in particle form, the particle size being sufficiently large that the particles touch in the unfired state. Therefore, a continuous open structure will remain in an open-pore matrix after sintering to permit the passage of a test material through the pores from one side of the plate 10 to the other. The unsintered porous body in the channel forms controlled open volume and channel dimensions that have a specified fraction of open space after firing.
An example of filler material may be alumina or zirconia, and/or metals such as molybdenum, copper, silver or nickel. Materials that may be removed by subliming include molybdenum, copper and nickel. Materials that may be removed by heating above the melting point include copper, silver and nickel.
Referring to
As shown in
Next, as shown in
In the bottom row, two greensheets 130 and 140 are aligned before the laminating step of
Alternative forms of the invention include using a densifiable material for the greensheets and filling the openings with a non-densifiable material in order to preserve the dimensions of the passages. For example, the matrix material may be an inorganic phase like alumina mixed with glass frit for densification, whereas the non-densifiable phase in the channel (and or holes) could be just larger ceramic particles like alumina.
Additionally, the material in the passages may be one that forms a non-porous sheath on being sintered, so that the passages receive a liner, such as that the sheath has alternate surface energy/activity than the matrix material/the body of the plate 10. The material for the sheath can be inorganic, metal or composite. The sheath formation may be due to chemical decomposition between a first material in the laminate and a second material in the filler or in the ambient gas and/or the sheath formation may be due to vapor phase deposition. As another option, the liner could be produced by a vapor emitted by the filler material that deposits on the walls or reacts with a material contained in the laminate.
While the invention has been described in terms of a several preferred embodiments, those skilled in the art will recognize that the invention can be practiced in various versions within the spirit and scope of the following claims.
