Abstract:
A method for fabrication of a lab-on-a-chip system makes use of first and second mold parts, which are adapted to join each other to form a cavity to accommodate a positioning means and a support structure. The method includes receiving the chip in the positioning means, forming the cavity by joining the first and second mold parts, securing the chip with a fluid port of the chip to rest on the support structure for the support structure to mask the fluid port, introducing a molding material into the cavity to over-mold at least part of the chip and a volume extending away from the chip, separating the first and second mold parts, and extracting the chip from the mold. A fluid channel is formed by the support structure.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is the U.S. National Phase under 35. U.S.C. §371 of International Application PCT/NO2014/050069, filed Apr. 30, 2014, which claims priority to Norwegian Patent Application No. 20130600, filed Apr. 30, 2013. The disclosures of the above-described applications are hereby incorporated by reference in their entirety. 
     INTRODUCTION 
     This invention relates to a heterogeneous chip system comprising a prefabricated first chip integrated into a moulded part, typically realized in a material that is different from the material of the first chip, the chip system having fluid channels or fluid conduits, and where the channels or conduits of the first chip and the moulded part are in fluidic communication with each other. A method is described for fabricating a heterogeneous chip system in a single operation. 
     The first chip in this invention can be made of a variety of materials. It can be a single- or a multilayer silicon chip, bonded silicon-silicon chip, silicon-glass chip, glass-glass chip, metal chip, polymer chip, etc. It can be active or passive, and it contains fluid channels. The moulded part in this invention is typically moulded in a polymer material. It can be active or passive, and it contains fluid channels. 
     The chip system in this invention relates to the combined system of a moulded part and one or more chips, with the chip (or chips) being embedded in the moulded part. The chip system can, in a specific embodiment, be a Lab-on-a-Chip system. 
     Lab-on-a-Chip systems can be realized in a variety of materials, such as polymers (hard or soft polymers, thermoplastic or thermoset polymers), paper, glass, and silicon-based materials. The material of choice depends on the application requirements; functionality, price, disposability, biocompatibility, physical properties, etc., and is often a trade-off between the advantages and disadvantages of a given material. Thermoplastic polymers are well suited for fabrication of low-cost Lab-on-a-Chip systems in large series by injection moulding, but the geometrical structure definition (e.g. aspect ratio) and the functionalities may be limited compared to, e.g., silicon-based micromachining technology. Functionalities that cannot suitably be implemented with polymers, or better implemented with other materials, include, e.g., special optical properties (silicon nitride waveguides, gold for surface plasmon resonance, glass for high optical quality), special biofunctionalities (non-specific adsorption, wettability, surface chemistry for functionalization), actuation functions (pneumatic PDMS valves, silicon micropumps, capillary pumps and valves), sensing functions (photonic biosensors, fluorescence-based assays, cantilever sensors, electrochemical sensors, nanorods and nanoparticle (magnetic and non-magnetic) based arrays, biochemical assays) and thermal control. 
     To create highly functional low-cost Lab-on-a-Chip systems, different materials and different manufacturing technologies should be combined. 
     The integration of various components in a single Lab-on-a-Chip system is presently either avoided, or implemented by connecting various microfluidic components to form a system consisting of simpler subcomponents by various assembly methods, such as adhesive bonding, welding, mechanical assembly (pressure and gasket), click-in systems, as well as various so-called plug-and-play platforms providing standardised means to assemble multicomponent systems, at the cost of increased dead-volume due to the interconnects. In addition to these interconnect technologies aimed at joining several components together in a system set-up, a variety of methods and systems for packaging and chip-to-world interfacing of microfluidic and Lab-on-a-Chip components have been developed. These typically require manual assembly, and often involve either packaging of the chip inside some carrier substrate or chip frame containing gaskets and external fluidic connectors, or clamping or adhesive bonding of fluidic connectors directly to the chip. 
     The object of the present invention is to provide a method for direct integration of various components/chips into a heterogeneous Lab-on-a-Chip system in a single manufacturing step while providing fluid connections between the components. 
     SUMMARY OF THE INVENTION 
     The invention provides a method for fabrication of a Lab-on-a-Chip system, the features of which method are recited in the accompanying patent claim  1 . 
     Features of embodiments of the method of the invention are recited in the accompanying patent claims  2 - 4 . 
     The invention provides a Lab-on-a-Chip system, the features of which system are recited in the accompanying patent claim  5 . 
     Features of embodiments of the system of the invention are recited in the accompanying patent claims  6 - 9 . 
    
    
     
       DESCRIPTION OF THE INVENTION 
       In the following, the invention will be described by way of example and with reference to the accompanying drawings, in which: 
         FIG. 1  is a detail perspective view drawing illustrating the first mould half  100  with structures for positioning and supporting the first chip and holding it in place, and structures for making channels in the moulded part; 
         FIG. 2  is a detail perspective view drawing illustrating the first mould half  100  with an inserted first chip  300 ; 
         FIG. 3  is a cross section drawing of a cross section made in plane AA′ of  FIG. 2 , of the first mould half  100  and the second mould half  200 , illustrating the first chip  300  held in place by the structures in the first mould half and by the clamping force of the second mould half. In this figure the mould is closed, forming a cavity to be filled by the polymer material; 
         FIG. 4  is a cross section drawing of a cross section made in plane AA′ of  FIG. 2 , of a heterogeneous chip system according to the present invention, i.e. a first chip  300  integrated in a moulded part  400 , resulting from the insert moulding process with the first chip as the insert, having channels  420  formed therein by the structures  120 . The chip system is laminated with a foil or plate  500 , typically in a secondary process, closing the channels  420  in the chip system to form conduits, except for some fluidic ports  410  for connecting the fluid conduits in the chip system to an external device. Some other areas may also not be laminated, e.g., areas for electrical connections to the first chip, such as, e.g., a central area that has not been overmolded due to masking provided by a central support structure  130  in  FIG. 1 ; 
         FIG. 5 a    is a cross section drawing of a chip system according to the present invention, similar to the cross section drawing of  FIG. 4 , but in this illustration the first chip has a ledge  330  with moulded material extending into and filling the ledge;  FIG. 5 b    is a perspective view drawing of the first chip with a ledge  330  as shown in the illustration of  FIG. 5   a;    
         FIG. 6 a    is a cross section drawing of a chip system according to the present invention, similar to the cross section drawings of  FIGS. 4 and 5   a , corresponding to plane AA′ indicated in  FIG. 2 , but the first chip has trenches,  340 , around its fluidic ports and moulded material extending into and filling the trenches; and 
         FIG. 6 b    is a perspective view drawing of the first chip with a ledge and with trenches  340  around the fluidic ports, as illustrated in  FIG. 6   a.    
     
    
    
     According to the invention, a pre-fabricated first chip is integrated into a moulded part in an insert moulding process. The mould is constructed so that fluidic connections are established between the first chip and the moulded part. The first chip has special design features ensuring a robust integration and leakage-free fluidic connections. 
     The first chip (which can be made of a variety of materials such as e.g. a single or multilayer silicon chip, bonded silicon-silicon chip, silicon-glass chip, glass-glass chip, metal chip, polymer chip) is positioned and fixed in the mould, which can be done manually, such as for small scale or prototype production, or by means of a robot or other form of feeding system. After positioning and fixing the first chip in the mould, the mould is closed, forming a cavity around the first chip, and the cavity is filled with the moulding material, e.g., a polymer melt injected in an automated injection moulding process. The first chip is partly overmoulded by the flowing moulding material, to obtain the final product of a chip system comprising a moulded part with the first chip integrated therein. 
     The Mould 
     The mould of the invention has structures and features for positioning and holding the chip in place during moulding, and structures for making the fluidic connections between the first chip and the moulded part. The mould typically has at least two parts, as shown in  FIG. 3  by the two mould halves,  100  and  200 , and it is typically machined in steel or other suitable metallic material, or other temperature resistant material. 
     The first chip can be held in place by a combination of frame structures  110  in the first mould half  100  and a clamping force provided by a clamping element of the second mould half  200  and introduced by the closing of the two mould halves, as seen in  FIGS. 1-3 . 
     Inserting the first chip may cause wear of the contacting mould surfaces of the frame structures  110 . Hence, it may be necessary to coat the contacting surfaces of such frame structures with a wear resistant coating, such as, e.g., a coating of TiN. Furthermore, the outer corners of the frame structures should have a sufficiently large radius in order not to cause crack formation in the moulded part. 
     In addition to such frame structures for holding the first chip in the mould, vacuum could be used to hold the first chip in place prior to mould closing, e.g., via vacuum ports  140  in the frame structure  110  surface contacting the inserted chip. With a vacuum solution, the frame structures need not be very high, thus making it easier to insert the chip, and reducing the possible wear issue. 
     In most moulding processes/machines, the opening and closing movement of the mould is horizontal. For insert moulding, vertical moulding machines are sometimes used. A vertical machine with the first chip inserted in the bottom mould half, i.e., with the orientation as in  FIG. 3 , would ease the process of inserting the first chip and holding it in place in the mould (prior to mould closing). 
     In order to ensure a gentle, but sufficient, clamping force on the first chip during moulding, i.e., a vertical force in  FIG. 3 , the second mould half  200  may have an element  210  compensating for variations in the thickness of the inserted first chip  300 , thereby limiting the maximum clamping-induced mechanical stress and possible damage of the first chip. The position of this compensating element  210  relative to the second mould half surface  220  could also be adjustable. The size and position of the compensating element  210  is adapted so that it presses against the first chip  300 , perpendicular to its plane, with enough force to avoid moulding material flowing into the areas of the first chip that need to be exposed on the final moulded part, and avoid flow-induced movement or deformation of the first chip, while not damaging or breaking the first chip. 
     A simple embodiment of a compensating element  210  could be a steel mould insert coated with a polymer or rubber, e.g. Teflon or a fluorinated rubber with high temperature resistance, and good release from the moulded part during demoulding. Another embodiment of a compensating element  210  could control the clamping force on the first chip  300 , and keep the clamping force constant (in all mould cycles) by adjusting the position of the compensating element along the clamping axis in each moulding cycle. The position adjustment could be implemented with a spring action or by an actuation device (electric, pneumatic, hydraulic) in combination with a force measurement. 
     The first mould half  100  has structures  120  which cover and protect the fluidic ports  310  on the first chip during the moulding process. Hence, these structures  120  form the fluidic interface between the first chip and the moulded part, of the chip system, and they also form channels  420  in the moulded part  400 . 
     The first mould half  100  can have structures  130 ,  110  which cover and protect electrical interconnects or pads on the first chip  300 . 
     So, to summarize, with appropriate structures  120  in the first mould half, fluidic connections between the first chip  300  and the moulded part  400  of the system are realized directly in the moulding process. Additionally, electrical connection points or other connection points on the first chip can be kept clear of moulding material during moulding by appropriately designed mould structures  110 ,  130 . 
     Processes and Materials 
     Lab-on-a-Chip systems aimed at commercial use have typically been developed for the point-of-care market, which implies disposable, low-cost devices. The prevailing technology for fabrication of such systems is, at present, injection moulding, using thermoplastic polymer materials, typically transparent amorphous polymer such as PMMA, COC, COP, PC or PS. Injection moulding of thermoplastic materials offers low cost per unit. 
     The present invention for fabricating heterogeneous lab-on-a-chip systems is well suited for injection moulding with thermoplastic polymer materials. 
     However, the invention is not restricted to injection moulding of thermoplastic materials, including special injection moulding process such as injection-compression moulding. The invention is also suitable for moulding of other materials, such as thermoset polymers (e.g. silicone rubber or polyurethane), metal powders, and ceramic powders. Furthermore, the invention is also suitable for other fabrication processes (with various materials) involving flowing materials, such as compression moulding, transfer moulding, vacuum casting, hot embossing, thermoforming, micro/nano imprinting, various processes involving UV curing, as well as extrusion processes and coating. 
     The invention is basically independent of the choice of moulding material, and the moulding material is primarily selected based on the specifications of the given Lab-on-a-Chip system. However, secondarily, for a given first chip (material and geometry), some moulding materials (type and grade) may have certain advantages in terms of obtaining reliable and leakage-free fluidic connections between first chip and moulded part. 
     In terms of achieving good adhesion between chip and moulded part, the moulding material could be selected among available materials with proven adhesion performance for the given chip material. This could, e.g., be a polymer moulding material forming hydrogen bonds, or even covalent chemical bonds, with the surface of the chip. 
     In order to reduce thermal and flow-induced stresses in the moulded part  400 , optimization of the moulding conditions may be required. Pre-heating of the inserted first chip  300  may be beneficial. Active or passive local heating of the mould wall in the area of the rather thin section to be filled under the inserted first chip  300  may ease the filling of this section, reduce the severity of weld lines, and reduce stresses in the moulded part. A simple implementation of this could be passive local heating by using a temperature resistant polymer material in the mould wall, thereby locally reducing the solidification rate of flowing moulding material. 
     When considering injection moulding of amorphous transparent thermoplastic polymer materials, the performance of the Lab-on-a-Chip system of this invention may be optimized by selecting a material with the most suitable viscosity (molecular weight distribution). Typically three materials in the same polymer family, but with different viscosities, could be used in optimization moulding trials. A material with low viscosity is advantageous in terms of filling the typically thin sections between the inserted chip and the mould wall. On the other hand, the viscosity (and, hence, the molecular weight) should be above a certain level for the material to have sufficient resistance to crack formation (crack formation due to geometry/notch effects and due to process-induced residual stresses). It is also known that some of the amorphous transparent polymer materials, such as polycarbonate, are more resistant to crack formation than others. Finally, amorphous polymers have relatively small shrinkage upon solidification, which is an advantage for this insert moulding process. 
     Features of the First (Inserted) Chip 
     In order to provide leakage-free fluidic connections between the first chip  300  and the moulded part  400 , and avoid long-term failures (e.g. delamination between the first chip and the moulded part), there must be adequate adhesion between the first chip and the moulded part. This can be ensured by chemical means and/or by mechanical means. 
     If the first chip is made of silicon, vacuum dehydration of the silicon chip may be sufficient to provide adequate adhesion. In other cases the first chip may need surface treatment prior to moulding, or coupling agents can be added to the polymer. (Note that many polymers for injection moulding have additives for easy release from moulds. This may impede the adhesion between the polymer and first chip.) A common way to improve the adhesion between an inorganic material (the typical material in the first chip) and an organic polymer is to perform a silane surface treatment of the inorganic surface, with a silane molecule that gives a good bond (not necessarily covalent bonds) to the chosen polymer or class of polymers. The silane treatment can be performed by wet chemistry or, more cost-effective, in a plasma-induced process. In-mould plasma treatment (also roughening the surface) or just plasma cleaning are also alternatives. 
     However, chemical surface treatments add complexity and cost to the process. There are other ways to avoid leakage in the interface between the first chip and the moulded part. 
     Trenches/grooves  340  can be machined around the fluidic ports  310  on the first chip  300 , as illustrated in  FIGS. 6 a  and 6 b   . These trenches/grooves can function as mechanical gaskets; the moulding material is forced into the trenches during moulding, creating a liquid-proof seal around the fluidic ports  310 . There can be one or several trenches around a port. If the first chip is made of silicon, trenches with a negative draft angle can be made, with appropriate silicon micromachining processes, thereby making a strong mechanical anchoring of the polymer onto the silicon chip (trenches). Even simpler, introduction of roughness or random geometrical structures on the surface area fluidic inlets of the first chip may also facilitate leakage-free connections. 
     Trenches and other geometrical structures can be implemented as an integrated part of the first chip manufacturing process, or as a final step of the first chip manufacturing process. The structures can be realized by a variety of micromachining methods such as wet or dry etching, dicing, laser ablation, etc. 
     In order to ensure a robust mechanical integration, and to prevent the inserted first chip  300  to be pushed from the support  110 ,  120 ,  130  due to the shrinkage of the moulding material upon solidification, additional holding structures can be introduced for the first chip. These structures can be realized as grooves into the first chip, or as ledges  330  around the top surface of the first chip, as illustrated in  FIGS. 5 a , 5 b , 6 a  and 6 b   . If the first chip is a silicon chip or a silicon-glass chip, such a ledge can be realized by a two-step wafer dicing process. 
     When the moulding process is finalized, the first chip is integrated in the moulded part. In the realization shown in  FIGS. 3-5 , the first chip  300  can have channels micromachined in silicon, and a transparent glass lid towards the compensating element  210  in the second mould half  200 . Hence the glass lid will be flush with the surface of the moulded part  400  after moulding. In this way, excellent optical access to the channels inside the first chip is ensured. Such access is important in applications where imaging or optical readout of the chip functions are necessary. In cases where optical access is not essential, the top surface of the first chip  300  can be immersed in the bulk of the moulded part  400 . 
     The first chip  300  can contain a variety of passive structures or active structures or a combination of both. Specifically it can contain channels, chambers, filters, metering structures, mixing structures, particle traps, arrays of rods, three-dimensional structures. The first chip can have active elements, such as a pump, a valve, a heating element, a pressure sensor, a temperature sensor, an accelerometer, a mass flow meter, or any type of micro-electro-mechanical, micro-opto-electro-mechanical, bio-micro-electro-mechanical, or other type of sensor or actuator. It can be a chemical sensor, a biosensor, in particular an optical, mechanical, electrochemical, acoustic, or photonic biosensor, and energy harvesting device, or a bioreactor or chemical reactor. The first chip can contain nanostructures and nanoparticles, as well as pre-stored chemicals. The first chip can also contain biofunctionalized and bioactive areas, and chemically modified areas, such as anchor points for subsequent biofunctionalization. 
     Secondary Processes 
     Secondary processing steps that are established for moulded Lab-on-a-Chip systems, such as chemical surface treatment of the moulded channels, can also be implemented for the moulded parts made with this invention. 
     The final fabrication step is typically to seal off the (open) moulded channels  420 . The conventional way to do this is to apply a foil or plate  500  by, e.g., adhesive bonding or welding. 
     DESCRIPTION OF REFERENCE NUMERALS 
     
         
           100 : First mould half 
           110 : Frame structures for holding the inserted first chip in place 
           120 : Structures forming channels in the moulded part and fluidic connections between the chip and the moulded part 
           130 : Structure which forms an exposed area to the first chip, e.g., for electrical connections to the first chip, and also supports the first chip mechanically in the process 
           140 : Possible positions for vacuum ports 
           200 : Second mould half 
           210 : Compensating element 
           220 : Mould surface of the second mould half 
           300 : The prefabricated inserted first chip 
           310 : Fluidic ports on the first chip 
           320 : Channel through the first chip 
           330 : Ledge on the first chip 
           340 : Trenches around the fluidic ports  310  on the first chip  300   
           400 : Moulded part 
           410 : Fluidic ports in the moulded part 
           420 : Channels in the moulded part 
           500 : Lamination foil or plate