MANUFACTURING PROCEDURE FOR LABORATORY INTEGRATED ON A CHIP

Abstract

Laboratory on chip and its layered manufacturing method, wherein the method includes: designing, by means of a computer program, a printed circuit (7), mixing and reaction cavities (3) of fluids, microchannels (2) and spaces (15) for the placement of electronic components to be found in each layer, mechanizing in one or more biocompatible substrates the different voids and passages that will make up the mixing and reaction cavities (3), microchannels (2), holes (8) that join the microchannels and spaces for the subsequent placement of electronic components (15), metallizing with a biocompatible conductive material those surfaces in which the printed circuit will be integrated (7) according to the design performed in the first step, generating the printed circuit (7) by photolithography and acid attack, bonding the electronic components in the corresponding spaces (15), joining all the layers that make up the final laboratory.

Claims

1-4. (canceled)

5. Method of layered manufacturing a lab-on-chip, comprising the following steps: designing, by means of a computer program, a printed circuit (7), mixing and reaction cavities (3) for fluids, microchannels (2) and spaces (15) for the placement of electronic components to be found in each layer; mechanizing in one or more biocompatible substrates the different voids and passages that will make up the mixing and reaction cavities (3), microchannels (2), holes (8) that join the microchannels and spaces for the subsequent placement of electronic components (15); metallizing with a biocompatible conductive material those surfaces in which the printed circuit (7) will be integrated according to the design made in the first step; generating the printed circuit (7) by photolithography and acid attack; bonding the electronic components in the corresponding spaces (15); wherein the electronic components are actuators (11) or sensors (10), joining all the layers that make up the final laboratory, wherein the metallization is carried out by the adhesion of a pre-elaborated biocompatible conductive material to the biocompatible substrate by means of a resin, wherein the biocompatible substrate/s comprise/s one or more of the following materials: polymethylmethacrylate (PMMA), polyethylene terephthalate (PET), polydimethylsiloxane (PDMS), poly 3,4-ethylenedioxythiophene (PEDOT), copolymer of cyclic olefin (COC), polycarbonate, or silicon.

6. Method according to claim 5, wherein the biocompatible conductive materials are one or more of the following: aluminum, silver, gold, platinum, titanium, ITO, graphene or nitinol.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0011] To complement the description that is being made and in order to help a better understanding of the features of the invention, a set of figures is included as an integral part of said description where, by way of illustration and not limitation, the following has been represented:

[0012] FIG. 1.—Plan view of a laboratory on chip according to the invention.

[0013] FIG. 2.—3D view of the laboratory according to the invention

[0014] FIG. 3.—Plan [A] and section [B] view of a laboratory on chip of the invention.

[0015] FIG. 4.—Sectional view of the manufacturing process of the upper layer of the microfluidic chip of FIG. 3.

[0016] FIG. 5.—Sectional view of the manufacturing process of the intermediate layer of the microfluidic chip of FIG. 3.

[0017] FIG. 6.—Sectional view of the manufacturing process of the lower layer of the microfluidic chip of FIG. 3.

[0018] FIG. 7.—Sectional view of the process for bonding the upper [A], intermediate [B] and lower [C] layers to give rise to the complete microfluidic chip [D]

DESCRIPTION OF THE INVENTION

[0019] The invention consists of a laboratory integrated on a chip and its manufacturing process. The laboratory has the following features:

[0020] a) One or several three-dimensional structures of biocompatible microchannels and susceptible to thermal processes limited by the melting temperature of the substrate material, which allow i) to perform on a simultaneous basis processes with different performance requirements on the same sample or different types of samples, ii) incorporate microfluidic processes that use physical effects that occur in three-dimensional structures such as decanting of particles in suspension in a fluid without incorporating filters or iii) physically section different areas of the chip to isolate them as required (chemical, thermal or optical insulation).

[0021] b) One or more biocompatible printed electronic circuits, which allow i) measuring and internally operating on microfluidic processes locally (only on one area of the chip), ii) heating only one area of the chip and making exact measurements on it without affecting the rest of the processes carried out therein, being able to transmit electrical signals in the desired areas of the chip, both to carry out electronic readings and to operate actuators (heaters, lights, sensors, etc.) integrated on the chip, iii) generating active structures such as heaters, electrodes or antennas using the electrical track design itself, iv) incorporating electronic components (sensors or actuators) connected to the electrical tracks within the chip itself, which are in contact with or very close to the fluids or areas that may require them, or v) ensuring complete electrical connectivity of the chip with any actuator, sensor or external controller.

[0022] With reference to FIG. 1, a laboratory on chip according to the invention is provided with multiple microchannels (2) in which measurement or reaction chambers (3) are located where analyzes are carried out. It also contains a printed electronic circuit (7) in which several thermal actuators have been defined in the form of heaters (12), several sensors in the form of electrodes (13) and electronic components (10) have been included. Fluidic processes such as mixing, filtering, decanting or heating of fluids will be carried out in the microchannels.

[0023] In FIG. 3, a drive layer can be seen, wherein a fluid (4) separated from an external drive system (not shown in the figures) is encapsulated by means of a piston (5); an intermediate layer wherein the measurement or reaction chamber is located (3); and a metallic lower layer with a printed electronic circuit (7) on which there are electronic components, sensors (10) and actuators (11) that carry out measurements and the control of processes of the measurement and reaction chamber (3). All the microchannels (2) of the different layers are connected to each other and to the outside of the chip through holes (8). The printed electronic circuit communicates with the outside through electronic contacts (6) defined for this purpose.

[0024] The manufacturing method of the invention comprises, in a first step, the design by means of methods implemented by a complete chip processor with all the channels, circuits and actuators that it will require for a specific analytic. This design is carried out on a computer, for example, with a suitable program, such as AutoCAD® and the like.

[0025] The manufacture of the upper layer as shown in FIG. 4, begins with the use of the base material (1) from which a reduced-size part is obtained that is subsequently machining, for which some of the usable processes are CNC machining, laser ablation and injection molding of thermoplastic parts or hot embossing. By means of said machining the through holes (8, FIGS. 4B, 4C) and the microchannels (2, FIG. 4D) joined by said holes are created.

[0026] In FIG. 5 the method of manufacturing the intermediate layer of the microfluidic chip of FIG. 3 can be seen. In the method the measurement chambers (3) and also the cavities (15) that house the electronic components inside once the layers are bonded, are manufactured.

[0027] In FIG. 6, the method of manufacturing the lower layer of the chip in FIG. 3 can be seen. Starting [A] with a biocompatible substrate (1), the metallization process [B] is carried out, from which the printed circuit will emerge (7). A photoresin (9) is deposited on the metal layer [C] to allow performing a developing process by photolithography [D] and acid attack [E] to manufacture the biocompatible printed electronic circuit. Once the exposed bonding resin (6) has been removed [F], the necessary microchannels and through holes (8) [G] are manufactured. In this case there are only through holes (8).

[0028] Finally, before bonding the layers that make up the microfluidic chip, the actuators (10) and sensors (11) or heaters are placed on the areas of the chip designed for them [H]. In other implementations, heaters or antennas can be added.

[0029] More particularly, the biocompatible metal layer can be deposited by methods such as electroplating, sputtering, or adhering metal foil to the substrate. A functionalization process is carried out on this metallic layer by means of photolithography, firstly depositing a layer of photosensitive resin (6) that will be selectively activated by exposing specific areas of the surface using photosensitive resin sensitizing agents (ultraviolet, visible or infrared light depending on the type of photosensitive resin). Once the resin is exposed, the resin will be developed and the metal deposited on the sensitized areas of said resin by an etching or chemical etching process will be removed, generating a specific metallization pattern as previously set forth. Metallization is performed with a conductive biocompatible material such as aluminum, gold, titanium, ITO or nitinol, from the polymeric substrate of, for example, PMMA.

[0030] To carry out the metallization of the surface, firstly, we proceed to the cleaning and removal of possible residues from the polymeric surface with the help of volatile solvents such as ethanol or acetone, which evaporate quickly without leaving residues on the surface, which is also sterilized. Once cleaned, an adhesive resin, for example epoxy, is deposited, generating a uniform layer with a thickness in the order of tens of microns. The metallic foil is deposited on this still fresh layer and uniform pressure is applied over the entire surface to ensure the continuity of the layer. For this, several methods are used: applying pressure through the use of hot roll laminators or inserting the part into an automated hot plate press. The process requires a temperature between 65° C. and 100° C. for the specific curing of the resin, as well as a pressure exerted of between 0.5 to 3 tons for about 5 to 15 minutes.

[0031] The acid attack can be carried out with different solutions such as, for example, 37% fuming hydrochloric acid and hydrogen peroxide of 110 volumes in equal parts. This solution is capable of attacking metal without damaging the polymeric substrate, thereby leaving an electronic circuit printed on a polymeric surface whose exposed parts still have a layer of the adhesive resin used for metallization. This resin together with the bonding resin of the metallic layer that is exposed after the process are eliminated through the use of organic solvents such as acetone, isopropanol or ethanol, which attack the resins without damaging the base polymeric substrate or the printed electronic circuit.

[0032] Thus, there remains a part on which a specific metallic design will be obtained that can serve as the basis for the integration of electronic elements within the device and the transmission of electrical signals bidirectionally with the attached electronics system.

[0033] The closing piston (5) separates the encapsulated fluid (4) in the lab-on-chip from an external impulse mechanics that operates it through a mobile piston that is connected to a hole in the piston (14). It is possible that the piston operates the fluid in both directions, producing its impulse or suction. The movement of the piston is controlled by an external electronic system that is automated by means of specific software for the specific type of analysis to be performed.

[0034] Joining of layers that make up the device (FIGS. 7A-7D) is made using organic solvents and the use of a combination of pressure and temperature, which may or may not be assisted by the additional use of adhesives. Through this manufacturing process the complete device with multiple layers is obtained as shown in FIG. 7D.

[0035] The final device can have several polymer layers, even of different thicknesses between 1 and 10 mm, with microchannels that are connected to each other by means of the chambers (3) designed for this purpose, and different printed electrical layers that may be connected by physically contacting each other on certain areas by overlapping layers or pathways.

[0036] By combining these structures, a series of functionalities can be performed that allow the study of certain parameters through the use of three widely used analytical techniques: the amplification and detection of genetic sequences by means of the polymerase chain reaction (or PCR), the detection and quantification of specific antibodies and antigens using the enzyme-linked absorption immunoassay technique (or ELISA) and the detection of biochemical parameters and ions through the use of electrodes or electrochemical detection. The data collected by the sensors will serve to monitor the progress of the fluids within the microchannels (2), and can be used to feed back the operation of the actuator and, therefore, perform precisely and safely controlled volume impulses or even vary the temperature of said liquid using Peltier cells, variable temperature resistances (NTCs) or thermal resistances. In addition, the communication of the data collected by these sensors, such as, for example, integrated thermal sensors (NTC) or optical actuators (LED) to an electronics attached to the actuator platform (not shown in the figures) will generate a closed circuit in which it can visualize, control and space-temporarily parameterize each of the actions of the mechanical system, as well as monitor the advance of fluids within the microchannels (2) in real time.

[0037] The laboratory is also provided with independent and active heating zones that can be heating tracks on the metallization layer (for those applications where the heating rate is not so high priority) or rapid heating cartridges.

[0038] In order to control those electronic components included in the laboratory and collect data from the laboratory's sensors, a series of contact electrodes have been configured that, through their connection to the central electronics, are capable of transmitting the information collected by sensors and measuring electrodes of the part comprising the microchannels and communicating them to the processor integrated in the analysis system.

[0039] By virtue of the use of inexpensive materials that are easy to manipulate or manufacture, such as PMMA, the metallization step by photolithography and the manufacture of the microchannels by laser engraving, micro-milling or hot embossing, it is possible to carry out the entire process on an industrial and serial basis.

[0040] By virtue of the creation of three-dimensional microfluidic lab-on-chip structures, being biocompatible and susceptible to thermal processes limited by the melting temperature of the substrate material (e.g. polymethylmethacrylate 105° or COC 160°) the following objectives are achieved:

[0041] a) To perform on a simultaneous basis different physical, chemical or biological processes with different performance requirements on the same sample or different types of samples.

[0042] b) To incorporate microfluidic processes that use physical effects that occur in three-dimensional structures such as decanting of particles in suspension in a fluid without incorporating filters.

[0043] c) To physically section different areas of the chip to isolate them as required (chemical, thermal or optical insulation).

[0044] By virtue of the fact that any area of the lab-on-chip can be converted into a biocompatible printed circuit, the following objectives are achieved:

[0045] a) To be able to measure and act internally on microfluidic processes locally (only on one area of the chip). To be able to heat only one area of the chip and make exact measurements on it without having to affect the rest of the processes carried out on it.

[0046] To be able to transmit electrical signals in the desired areas of the chip, both to carry out electronic readings and to operate actuators (heaters, lights, sensors, etc.) integrated on the chip.

[0047] b) To generate active structures such as heaters, electrodes or antennas using the design of the electrical track itself.

[0048] c) To be able to incorporate electronic components (sensors or actuators) connected to the electrical tracks inside the chip itself, which are in contact with or very close to the fluids or areas that may require them, eliminating all maximum possible interfering with the operation or measurement.

[0049] d) To ensure complete electrical connectivity of the chip with any external actuator, sensor or controller.