WO2010043966A2

WO2010043966A2 - Devices and methods for production of high-precision, multi-component devices

Info

Publication number: WO2010043966A2
Application number: PCT/IB2009/007305
Authority: WO
Inventors: Piero Zucchelli; Gian-Luca Lettieri; Martin O'keane; Giorgio Horak
Original assignee: Spinx, Inc.
Priority date: 2008-10-15
Filing date: 2009-10-15
Publication date: 2010-04-22
Also published as: WO2010043966A3; EP2346778A2

Abstract

The novel use of isostatic pressing or high energy rate forming in the production of high precision, multi-component devices for a variety of applications including, but not limited to, the domains of microfluidics, microtechnology, medical devices, biotechnology, life sciences and engineering. The high precision of said devices is not necessarily related to the dimensional accuracy of the device itself, although this could be a feature, but rather to the precision of the alignment of the sub-components with respect to each other in the final device. This production process has numerous advantages, including low recurring manufacturing costs, high throughput, large production capacity, homogeneous product quality and ease of process control.

Description

DEVICES AND METHODS FOR PRODUCTION OF HIGH PRECISION, MULTI-COMPONENT DEVICES

RELATED APPLICATIONS This application claims priority to US Provisional Application No. 61/105,573, filed on October 15, 2008, the contents of which are incorporated in their entirety by reference.

BACKGROUND OF THE INVENTION

A variety of microfluidic platforms exist commercially today, with each system typically utilizing some form of miniature consumable chip containing one or more micro- structured area intended for chemical, biological, or biochemical processes or reactions. A common challenge faced in the design and manufacture of such microfluidic devices is proper isolation and sealing of discrete elements of the microstructure, so that fluids or gases contained therein do not escape from the microfluidic device, nor undesirably contaminate nearby microfluidic structures nor diffuse into surrounding materials intended for containment and/or sealing purposes.

Microfluidic devices allow fluidic operations to be performed in small volumes, in order to achieve advantages in various activities spanning from life sciences to engineering applications. Microfluidic devices, with very few exceptions, consist of chips, also called substrates, which host microstructures inside in which fluids can be confined. In fact, it is well known within the art that small volumes of liquids in air or similar gaseous environments have a tendency to evaporate according to their liquid properties and environmental conditions. Likewise small volumes of gases would irrevocably mix with the surrounding atmosphere. It is evident that the advantages of smaller volumes are reflected in smaller amounts of fluids required to perform a given functionality which, for example, could be either achieving a chemical reaction or identifying molecules contained in the fluid or determining if a given chemical reaction had taken place. Assuming that this functionality can be achieved with a smaller amount of sample, new possibilities are opened both in terms of economical benefits (e.g. cost) and utility per unit volume of sample in circumstances where the amount of samples available is limited. In the latter case, there are important examples in life sciences such as tests on primary samples (e.g. cells, fluids or tissues directly coming from the patient).

Another advantage of microfluidic devices is the possibility to subdivide a given sample into a large number of smaller sub-samples, and therefore perform a plurality of tests in parallel using a constant or smaller amount of sample. This capability, also called hardware multiplexing of a test, is particularly valuable in some sectors where multiple hypotheses have to be probed and takes advantage of the fact that, with small, dense microstructures a compact fluid distribution scheme can be achieved on the same chip without the need of performing complex and error prone external fluidic operations. Unfortunately, the manufacture of microfluidic devices from a prospective of quality in a cost effective manner is difficult to achieve on a commercial scale.

The conceptual hypothesis that a large number of microstructures can be embedded into a small surface or volume of a chip and still be fluidically discrete (i.e.. the fluids cannot move unpredictably from one microstructure to the other) is clearly an important requirement for a large number of microfluidic technologies. This is necessary in order to reproduce the results independently of the surrounding conditions and to achieve the same functionality of macroscopic counterparts, where simple physical laws unquestionably prevent fluids in one container (beaker, vial, microplate, bottle, drum or similar) moving to another: diffusion distance, gravity, surface tension, viscosity, septa. However, manufacturing microstructures economically that maintain the integrity of these fluidically discrete structures is challenging and unmet by prior approaches.

SUMMARY OF THE INVENTION

Isostatic pressing is a technology that is used in a variety of industries. It is used in the production of work pieces as diverse as turbine blades to joint replacement prostheses. Isostatic pressing can be done with one of two media, with either gases or liquids to exert constant pressure on work pieces within a pressure vessel. The process is generally subdivided into Hot Isostatic Pressing ("HIP"), Warm Isostatic Pressing or Cold Isostatic Pressing ("CIP") depending on the temperature within the pressure vessel.

According to the disclosure the application of HIP or warm isostatic pressing or CIP or High Energy Rate Forming (HERF) to the production of high precision multi-component devices is disclosed. It is contemplated within the scope of the disclosure that isostatic pressing techniques can be carried out using liquids, gases or mixtures thereof. The isostatic pressing techniques carried out using liquids according to the disclosure can be either wet bag or dry bag in nature; in the former case the work piece comes into contact with the pressurizing medium, while in the latter case it does not. Moreover, the isostatic pressing technique could be carried with the pressurizing medium at a constant temperature or, by the use of external temperature control, according to pre-defined temperature cycles with the work pieces being heated and cooled during the course of the assembly process.

The multi-component devices produced in the assembly process according to the disclosure are microfluidic devices, biological substrates, chemical substrates, microtitre plates, cuvettes, or receptacles used in in-vitro diagnostic applications, receptacles used in bio-defense products, receptacles used for human vaccines and medication, receptacles used in veterinary medicine or even optically readable data storage media.

The manufacturing method according to the disclosure is equally applicable, for example, to the low cost manufacturing of compact disks, DVDs, Multi-layers DVD, Blue- ray and/or HD-DVD and similar devices. These devices are typically built by assembling different layers, where the digital information is often sandwiched between polymer substrates. The assembly process requires a large capacity manufacturing facility with high costs. Possible solutions, for example based on PSA adhesives or UV hardening glue or photoresists or glue, could be replaced by an isostatic process, possibly combined with UV activation and other chemical or physical means. The advantage of processing multiple devices in batch is obvious in terms of process time and cost.

The assembly process according to the disclosure in one illustrative embodiment consists of the following multiple operations: joining of two components; actual bonding by the application of heat and pressure, and embossing or engraving or substrate modifications capable of altering the form and the shape of one or multiple components of the device. The assembly process, therefore, could substitute other technologies like hot embossing or injection molding (component modifications) or be used for packaging and assembly operations and thereby replace industrial presses or lamination devices or vacuum packaging systems.

The multi-component devices produced according to methods of the disclosure are made of or contain materials or components such as but not limited to organic polymers, inorganic polymers, metals, ceramics, glass, quartz, composites, superconductors, printed circuit boards (typically copper conductive tracks on and through polymeric insulating layers laminated with epoxy), optical fibers, conductors designed to carry electricity and / or electrical signals.

According to the disclosure the production process leading to the fully assembled multi-component device is carried out in multiple steps or in a single step. The process assembles one or more device simultaneously. Delicate areas or features on the work pieces can be partially or completely shielded from the forces acting on the work piece, or are left completely exposed to said forces.

In one illustrative embodiment the components used in the final product are held accurately in position prior to final assembly by isostatic or HERF means by vacuum sealed plastic elements or by adhesives or by mechanical clips or by mechanical mating features in the work pieces to be assembled (e.g. tapered pin in tapered hole) or mechanical jigs or meshes or racks external to the work pieces to be assembled or thermal bonding or ultrasonic welding or laser welding or electron beam welding or brazing or shape memory alloy components activated by resistance heating or shape memory alloy components activated by heat.

According to the disclosure the packaging of the multi-component device inside the isostatic press or HERF apparatus has therefore multiple functional aspects: alignment of the assembly structure, transfer of heat and pressure selectively modulated to the device, and optionally also to record and measure temperature and pressure for quality control, traceability and reproducibility purposes. In one illustrative example, temperature and pressure recorders are embedded in every package or in a plurality of packages, including devices (for example, Pacoprobe films by Pacothane Technologies) capable of measuring the distribution of pressure (or temperature). In a further illustrative embodiment the same package could also be kept as final device wrapping for purposes of storage and/or distribution of the devices.

The device(s) completed by the assembly process according to the disclosure may be complete and ready for use as a stand alone product. Likewise, this packaging or assembly process could be a feeder step prior to subsequent operations in the overall production flow. Conversely, the assembled device produced by the assembly process could be later interfaced with or connected to other measurement or analysis systems, for example by electrical connections, optical fibers or the like.

It is an object of the disclosure that read out or analysis of the assembled device could be done by non-contact optical detection methods. It is a further object of the disclosure that the pressurizing medium may come directly into contact with the components making up the final assembly. In another illustrative embodiment, contact is excluded by the use of protective elements and/or packaging.

In yet a further object of the invention, when using composite materials, one or more elements of the matrix may be bonded by the use of the assembly process. For example, only polymeric matrix bonds to the mating component, carbon fibers embedded in the matrix are unaffected.

In another aspect of the disclosure the assembly process may be used to physically compress and increase the density of the final product.

In yet a further object of the disclosure the heating and cooling of the pressurizing medium may be used to heat treat the assembled device. For instance, common heat treatments of metals such as annealing, hardening, tempering or quenching may be carried out in this fashion. In one illustrative embodiment, an isostatic press renders the need for an industrial oven with accurate temperature control obsolete.

In another object of the disclosure the process parameters are chosen such that small and / or fragile features are not susceptible to damage by the assembly process. In another embodiment, such small and / or fragile features are equipped with protective covers designed to provide strain relief during the assembly process. It is contemplated within the scope of the disclosure that the strain relief could be constructed in such a way that no pressure acts on said features during the assembly process, or that only a portion of the force acting on unprotected areas acts on said features.

It is a further object of the disclosure that the vacuum sealed protective packaging can simultaneously shield the work pieces from the pressurizing medium and ensure pre- alignment of the components is maintained. One skilled in the art will understand that the protective packaging only prevents contract between work pieces and pressurizing medium, with the maintenance of component pre-alignment done by other means.

Another object of the disclosure is that pre-alignment retention can be achieved by bonding the components with adhesives, either conventional or pressure sensitive in nature. In yet a further object of the disclosure pre-alignment retention can be achieved with the help of mechanical fixtures or jigs into which the components are laid in the correct order. The jigs or mechanical fixtures could be made of rigid materials with appropriate openings allowing penetration of the pressurizing medium during the assembly process. In another embodiment, the jigs or mechanical fixtures are designed to transmit the pressure from the medium to the work pieces by during the assembly process.

In another aspect of the disclosure pre-alignment retention can by achieved with the help of common mechanical positioning features integrated into the components to be bonded such as a pin(s) in slot(s), or a tapered pin(s) in tapered hole(s). A further object of the disclosure is that pre-alignment can be achieved by pre- bonding the components by conventional thermal means (under suitable time, temperature and pressure conditions) prior to the final assembly process. The joins could be an unbroken closed path or at discrete points or lines or arc segments or curves or splines or a combination thereof.

In yet a further object of the disclosure pre-alignment retention can be achieved by the use of fasteners or clips or frames made from shape memory alloys. These parts are activated and induced to take up a suitable clamping form either by direct heating or resistance heating by electrical means. The activation can be provoked by the heating action of the pressurizing medium itself.

In another aspect of the disclosure pre-alignment retention can be achieved by ultrasonic welding of components prior to the assembly process. Typically, this would require small, spiked so-called "energy directors" being integrated into components to be assembled. Another object of the disclosure is that pre-alignment retention can be achieved by laser or electron beam welding of components together prior to final assembly.

In a further object of the disclosure re-alignment retention can be achieved by using magnets to hold pre-aligned "sandwiches" of components to be bonded in place.

In yet another object of the disclosure mechanical pre-alignment support(s) or plate(s) or plate(s) with negative recess(es) corresponding to part(s) to be assembled can be constructed in such a way as to provide a stable, inflexible base keeping the components to be assembled flat and / or orthogonal to each other during the assembly process. The mechanical support may or may not play a role in pre-alignment retention.

Another object of the disclosure is that mechanical parts like grids, meshes, nail- containing frames or specific geometries could be part of the package or of the device in order to be able to transfer the pressure from the fluid to the device but preserving, at the same time, specific geometrical features like planarity or shape, in order to avoid deformation of the device under the application of isostatic pressure. These mechanical parts could be either inside the package, for example as a metallic plate providing the planarity of the device, or outside the liquid-protecting package - allowing the liquid to flow in between the frame and the package and therefore fully applying the isostatic pressure on the device surface with exception of the contact points between the mechanical part and the package.

A further object of the disclosure is that mechanical pre-alignment support(s) or plate(s) or plate(s) with negative recess(es) corresponding to part(s) may become bonded to the work pieces during the assembly process, and have to be removed by post-processing. The release of said support(s) may be done by conventional machining (e.g. milling) or non- contact means, such as laser cutting. In yet another object of the disclosure is that when using isostatic methods, the work pieces can be subjected to pre-defined temperature cycling before, during or after the application of the isostatic pressure. The use of a fluid with a high heat capacity as pressurizing medium would make the system insensitive to instantaneous changes in environmental temperature, as the effect on the overall temperature of said medium would be insignificant. Similarly, the use of gases with relatively low heat capacities could be beneficial. The quick exchange of gases within the pressure vessel could rapidly heat or cool the work pieces. Additionally, rapid exhaust of gas from the pressure vessel, or the injection or extraction of heated of cooled gases could be used to rapidly change the pressure and temperature within the chamber. Thus, the compressible nature of gases could be exploited to achieve complex manufacturing cycles involving temperature, pressure and time.

Another object of the disclosure is that when using isostatic methods or high energy rate forming methods, the work pieces could be pre-heated to a given temperature before being introduced into the pressure vessel.

A further object of the disclosure is that the temperature distribution inside an isostatic liquid could be improved by means of active liquid circulation, achieved either by external pumps and piping, or by liquid circulation induced by moving elements inside the cavity - actuated from the inside or the outside of the vessel.

There are numerous advantages to the use of such a packaging process according to the disclosure for the production of high precision, multi-component devices for microfluidic, micro-technology, biomedical, biotechnology, life sciences and engineering applications.

Advantageously, once the investment in capital equipment has been made, the recurring manufacturing costs are relatively low. The methods and devices used to fix the pre-alignment of the components are, when chosen judiciously, a fraction of the manufacturing cost of the components being assembled. A further advantage of the method according to the disclosure is when compared to conventional assembly methods, the cycle time is much shorter and overall capacity of the process is much greater. Additionally, multiple devices can be assembled simultaneously, with the maximum number of parts that can be processed at once typically only limited by the size of the pressure vessel and the dimensions of the given work pieces plus any pre- alignment aids employed. When assembling large numbers of high precision, high value devices, the existence of a true mass production method according to the disclosure allows potential new markets previously inaccessible due to elevated piece part prices. An additional feature of the method according to the disclosure is the use of an alignment aid which concurrently protects the work pieces from the surrounding environment and the pressurizing medium will considerably simplify the production process. Time consuming and rate limiting measures needed to keep the work pieces clean and uncontaminated in an open process (e.g. lamination) are potentially avoided. Advantageously, expensive capital equipment such as assembly stations equipped with laminar flow, operator protective clothing, post assembly inspection, post assembly washing and / or de-contamination, and even clean rooms may no longer be required within a production process. At the same time, the protective pre-alignment conserving packaging means that damage arising from human and/or automatic handling are eliminated in all but the most extreme cases.

A further advantage of the method according to the disclosure is that isostatic and high energy rate forming methods eliminate the need for balancing or equalization or tuning steps prior to final assembly. The alignment of the static and moving halves of a single axis press used for component assembly in prior art method have to be adjusted and carefully inspected at regular intervals otherwise high scrap rates are likely. Using the aforementioned forming methods according to the disclosure, uniform pressure distribution is achieved by the process itself.

Another advantage of the method according to the disclosure is that the process controls needed to ensure a homogenous final assembly step are well known and commercially available. Taking isostatic pressing as an example, the control systems required to monitor temperature and pressure of the isostatic medium are usually already integrated into the press, and are based on established technologies that work extremely robustly.

A further advantage of the method according to the disclosure is that isostatic pressing and high energy rate forming methods lend themselves to automation, and given suitable risk management/health and safety precautions-could be set up to run overnight, thereby achieving further capacity increases with respect to conventional methods.

Another advantage of the method according to the disclosure is that the assembled components produced by these production techniques will be regular in nature and will show little or no effects of frictional effects or strain at the interfaces between sub-components. These benefits are due to the isostatic nature of the pressure application. The logical consequence is that, provided the alignment retention method(s) and/or device(s) and assembly process parameters are correctly chosen for a given final part, the production yield will be very high.

A further advantage of the method according to the disclosure is that the isostatic application of relatively large forces onto multiple components could be used to equalize irregularities and in homogeneities exhibited by the sub-components prior to final assembly. Another advantage of the method according to the disclosure is that pressure vessels can be constructed in all manner of size and shapes, and the pressurizing fluid commonly used (e.g. liquids and/or gases) can be obtained in large quantities, there is little limitation on the size of components which can be processed in this way. When working with smaller parts, using a larger pressure vessel would be a straightforward means of achieving an even greater throughput per cycle.

A further advantage of the method according to the disclosure is that the deployment of this process could also be used to limit the amount of consumable packaging needed during the production cycle. For example, protective packaging used to pre-align constituent components could also be used as the final packaging as seen by the customer. That is, after assembly by isostatic pressing or high energy rate forming the parts could be shipped to the end user. If needed, appropriate drying operations after wet bag processing could be inserted at a moderate cost.

BRIEF DESCRIPTION OF THE DRAWINGS Advantages of the present invention will become apparent to those skilled in the art upon reading and understanding the following detailed description with reference to the accompanying figures.

FIG. 1 is a drawing of a microfluidic device that can be manufactured by the method of the present disclosure; FIG. 2. depicts plastic components isostatically pressed at about 100 bar and about 40 bar with the intensity of the gray scale indicating the magnitude of pressure exerted on the component; and

FIG. 3 depicts the bonding of a thin plastic film onto the substrate of a microfluidic device containing microfluidic structures using the method according to the disclosure.

DETAILED DESCRIPTION OF THE INVENTION

Detailed embodiments of the present disclosure are disclosed herein, however, it is to be understood that the disclosed embodiments are merely exemplary of the disclosure, which may be embodied in various forms. Therefore, specific functional details disclosed herein are not to be interpreted as limiting, but merely as a basis for the claims and as a representative basis for teaching one skilled in the art to variously employ the present disclosure in virtually any appropriately detailed embodiment. Isostatic pressing is a technology that is used in a variety of industries. It is used in the production of work pieces as diverse as turbine blades to joint replacement prostheses. Isostatic pressing can be done with one of two media, with either gases or liquids to exert constant pressure on work pieces within a pressure vessel. The process is generally subdivided into Hot Isostatic Pressing ("HIP"), Warm Isostatic Pressing or Cold Isostatic Pressing ("CIP") depending on the temperature within the pressure vessel.

The HIP or WIP process is a compressive forming process in which a high pressure fluid of several hundreds to several thousands kgf/cm2 is applied under high temperature condition. These processes are distinguished by high working pressure and the capability of isostatic compression as compared with other processes, for producing sinters of high density from hardly workable powdery material or for solid phase diffusion bonding. Although it is possible to generate a temperature over 2,000 ⁰C (in the case of the HIP process, which employs a high pressure gas as a pressure medium), the WIP process, which uses a heat resistant oil, has an upper temperature limit at about 300 ⁰C. However, in the case of high density sintering or solid phase diffusion bonding of powder material, both of these processes need a pre-treatment for covering the entire work surface with a material that is capable of forming a hermetic seal.

Cold isostatic pressing (CIP) or isotropic pressing is where the whole surface of a molded article is pressurized uniformly in a pressure medium. Water is generally used as the pressure medium. High Energy Rate Forming, also known as HERF or explosive forming can be utilized to form a wide variety of metals. The process derives its name from the fact that the energy liberated due to the detonation of an explosive is used to form the desired configuration. The charge used is very small, but is capable of exerting tremendous forces on the work piece. In HERF chemical energy from the explosives is used to generate shock waves through a fluid (often liquid and sometimes water), which are directed to deform the work piece at very high velocities. HERF exerts even force over the entire surface of the work piece and can produce components, large in size, with a great deal of detail to very fine tolerances. As shown in Fig. 1 a design detail of a microfluidic device is depicted. The microfluidic device is shown in greater detail in Application WO07057788A2 entitled: "Dosimeter for Programmable Microscale Manipulation of Fluids"), the contents of which are incorporated in their entirety by reference. In this embodiment, the microstructure present is in the form of chambers and capillaries, and the fluids are moved or confined by a physical structure composed of a sandwich of two substrates and a film. A film or material layer separates the microstructures under normal conditions, and the fluidic connections desired can be achieved by perforating the film by means of localized external electromagnetic radiation.

The microfluidic device shown in Fig. 1 highlights the difficulty of the manufacturing process of microfluidic devices. In particular, the manufacturing of these devices is very difficult to carve channels and fluidic passages into the bulk material making up the substrate of a chip. In prior art methods, these microfluidic structures are typically embossed onto one or a plurality of its external surfaces, and the remaining open side of the microstructure is closed by means of a structure, hereafter referred to as a "cover", tightly sealed to the surface of the substrate. The cover could either be a bulk material substrate, with structures, microstructures, unstructured, or simply a film with sufficient fluidic isolation properties. The process of joining separate cover(s) and substrate(s) into a monolithic assembly will be referred to as "bonding" or "packaging process" or "assembly process". A challenging aspect of the packaging process is to guarantee an intact and durable fluidic seal over distances that are typically of the same order of magnitude as those of the microstructures, and in particular to avoid the occurrence of undesired fluidic connections (hereafter also referred to as "leaks", or "cross contamination").

Given that microfluidic chips are designed in such a way to facilitate the movement of fluids in microstructures, for example using capillaries with cross sections of few to tens of microns, it is evident that the smallest defects in the packaging process, resulting in gaps or un-bonded areas of just a few microns, will lead to undesired fluidic leaks with resulting sample losses or cross-contamination. It is understood by those skilled in the art that this requirement is amplified in microfluidic chips with respect to conventional fluidic devices, where various sealing techniques, for example vulcanization, rubber bands (o-rings), blown containers, polyethylene chambers and other solutions have proven to be effective, not to mention the fact that criticality of a volume is normally inversely proportionally to the volume of the initial sample with the consequence that the smallest leak in a microfluidic device has negative consequences that would probably pass unobserved in a macroscopic system.

According to one aspect of the disclosure, the packaging process by means of a manufacturing process is conceived to obtain very uniform and high quality packaging of the chips, in particular addressing the need of achieving locally, in regions of microscopic surface area, an effective bonding of the substrate cover.

In general terms, the use of isostatic pressing or high energy rate forming in the production of high precision, multi-component devices for microfluidic, micro-technology, biomedical, biotechnology, life sciences and engineering applications requires the following steps: pre-alignment of the components to be assembled; alignment frozen by a method or device that will withstand the isostatic pressing or high energy rate forming step; and final assembly by isostatic pressing or high energy rate forming, achieved by means of simultaneous application of heat and pressure. In some cases, additional chemical and / or surface treatment(s) could complement the process.

According to a further aspect of the disclosure the assembly of the microfluidic device by isostatic pressing, the following steps are used: pre-alignment of three plastic components consisting of two substrates and one, optionally pre-cut, thin plastic film; alignment of the components is aided by mechanical alignment features (pins and slots) in the substrates to aid said pre-alignment; and the resulting pre-aligned "sandwich" is to have the final packaging or assembly step done by warm isostatic pressing. In these terms, a self-aligning designed is considered equivalent to a pre-aligned assembly. Placement of a pre-aligned "sandwich" described above into thermoplastic packaging bags facilitates the production process according to the disclosure. It is contemplated within the scope of the disclosure that these bags could consist of commercially available solutions or custom designed jigs which are preferentially designed to prevent the liquid to coming in contact with the device. Evacuation of part of the air from the plastic bag containing the "sandwich", followed by heat sealing of the bag to fix the relative position of the pre-aligned parts. Final assembly in one illustrative embodiment was by warm isostatic pressing using a liquid at about 100 C as the pressurizing medium at about 100 bar and a cycle time of about 3 minutes. The process can be conveniently implemented in order to process multiple parts simultaneously.

It is contemplated within the scope of the disclosure that different embodiments of the disclosure, which can be implemented in various configurations and variants, for example, without pre-alignment requirements, without the necessity of bags, and without the necessity of solutions to keep the components precisely in place, or for a different pressure and temperature cycle. For example, the isostatic fluid could be chosen among the classes of gases and liquids. Examples of gases utilized within the inventive process include but are not limited to inert gases like Argon or Xenon, or Nitrogen or compressed air or any mixture of inert gases and other suitable gases.

According to the disclosure liquids utilized within the inventive process are water, glycol, oils, solvents, alcohols, hydrocarbons, or any mixture therefore. In some manufacturing embodiments, fluids with suitable properties, like low flammability, low toxicity, boiling point above the operating temperature, should be used for convenient operations.

Recommended process parameters for the assembly of plastic components by warm isostatic pressing using liquid as pressurizing medium are shown in Table 1 below, it is contemplated within the scope of the disclosure that different materials and devices could imply conditions outside those indicated: Table 1

Parameter Symbol Unit Min. Recommended Max.

Isostatic pressure P bar 1 10 300

Pressurizing medium (water) temperatutre T C 20 100 300

Pressing time t minutes 0.1 3 300

Number of parts processed n - 1 50 -

In a further illustrative embodiment additional elements can be integrated into the assembly package ("sandwich"), and not necessarily part of the assembly which is going to be produced.

As an example, rigid or flexible masks, or a combination of both, can be used to process parts that require suitable distribution of pressure because of their structures or shapes. For purposes of this disclosure a mask is a particular object, of planar or of three- dimensional shape, which is assembled together with the assembly package but ultimately doesn't take part to the final device, with the purpose of constituting a mechanical reference and/or modify the pressure or temperature conditions during the isostatic process. The principle of the Isostatic press guarantees identical pressure over the surface, however, the presence of device parts and/or structures with different mechanical resistance to pressure could result in local collapse of the parts to be assembled, and/or deformation of their shape, making the uniform pressure an undesirable feature. A perfectly rigid mask, because of its structure, will not allow local collapse since any change of the shape of the part will imply a local reduction of the pressure being applied. In case of deformable parts, the rigid mask will also act as a reference plane, giving to the parts the same planarity and surface finish characteristic of the mask. According to the disclosure, a rigid mask could also act as a general alignment frame, by positioning the parts of the assembly through pins, holes, mechanical connectors, holders boundaries or a combination of these and similar elements.

The use of the rigid mask therefore permits a selective distribution of the isostatic pressure on the components of the fluidic device. The rigid masks can be, for example, metallic structures. It is contemplated within the scope of the disclosure that other materials such as polymers, natural rubbers, ceramics, glass or mixtures thereof can be used too.

The advantages introduced by flexible masks consist in partially maintaining the isostatic pressure over a surface, which remains constant only if the pressure is averaged over a characteristics distance which is determined by the flexibility of the mask. Essentially, flexible masks allow maintaining an homogeneous pressure if the pressure is measured over a typical surface area, but allow having local differences if the pressure is measured over a smaller surface areas. This behaviour allows avoiding, for example, the collapse or damage of small structures. However, it is contemplated within the scope of the disclosure that, besides its main purpose, flexible masks enable a more efficient air evacuation during vacuum sealing of the assembly package. This effect is probably indirectly induced by the local inhomogeneity of pressure that can be achieved by the application of flexible masks.

The material used for flexible masks can range to metals or metallic but also to polymers, including also foam materials and composite structures. For these reasons, the choice of the flexible mask properties is critical for the optimization of the process, and can be achieved by modulating the thickness, the material, the shape, and the number of masks used for a particular purpose. EXAMPLES

Example I

Work was done exploring the suitability of warm isostatic pressing for the production of microfluidic devices, the findings are presented below. The homogeneity of the pressure exerted on the work pieces was demonstrated experimentally. The following image shows the pressure distribution on plastic components using liquid at about 100 C as the pressurizing medium during warm isostatic pressing. The isostatic pressures used were about 100 bar (left hand sample) and about 40 bar (right hand sample) respectively. The measurement was taken using apparatus loaded with pressure sensitive material (PacoProbe, Pacothane Technologies) whose color changes from white to red on the application of pressure, with the intensity of the color proportional to the pressure exerted. For purposes of this application the intensity of the pressure exerted is shown in gray scale wherein the shading change from white to black is achieved on the application of pressure, within the darkness of color proportional to the pressure exerted. As shown in Fig. 2, plastic components isostatically pressed at about 100 bar 201 and about 40 bar 203, with the intensity of the gray scale indicating the magnitude of pressure exerted on the component

Example II In a further experiment, warm isostatic pressing was successfully used to bond a thin film of cover material, in this case a plastic film, onto a plastic substrate containing intricate microfluidic structures. Close examination of the sample as depicted in Fig. 3 showed the bonding on the small surface areas between the microfluidic channels to have been successfully achieved. Delaminated areas were entirely missing from the sample. One experiment demonstrated the suitability of this method according to the disclosure for achieving homogeneous bonding of plastic microfluidic devices, with a durable and homogenous seal created over the microfluidic microstructures. It demonstrated the utility of isostatic pressing or high energy rate forming for the production of high-precision multi-component assemblies. In this disclosure, we present an application of the two aforementioned techniques to the production of high precision, multi-component devices for a variety of applications including, but not limited to, the domains of microfluidics, micro technology, medical devices, biotechnology, life sciences and engineering. The high precision of said devices is not per se related to the accuracy of the outer macroscopic geometry of the device, although this could be retained as a feature, but rather to the precision of the alignment of the subcomponents with respect to each other in the final assembly. There are numerous advantages arising from the method according to the disclosure including but not limited to high production capacity, short cycle time, homogenous product quality and low recurring manufacturing costs.

Although the process and the recommended parameters described herein is not the only general arrangement which would accomplish the goals of economical production costs, high throughput and high yield, one skilled in the art will understand that numerous permissible deviations are possible and are outlined below. For the sake of brevity, the term "assembly process" will be used to describe the final assembly of a multi-component device either by isostatic pressing or high energy rate forming.

Although the pressure, temperature and time recommendations within the illustrative embodiments herein relate to the assembly of thermoplastic components. It will be understood by one skilled in the art that when assembling materials with substantially different physical or biological or chemical properties (e.g. metals or ceramics) these parameters must be re-defined, and the new values may very well be out with the ranges mentioned earlier.

Although the assembly process can be used to assemble three or more sub- components into a bonded product that can essentially be considered monolithic, one skilled in the art will understand that the assembly process can proceed sequentially with the various constituent components being assembled in multiple discrete steps. Likewise the sequential assembly could be done with or without removing and reloading the parts from the pressure vessel. In the former case, parts could be added for the next bonding step, before reloading the pressure vessel. In the latter case, alternative bonding parameters could be applied to bond parts that remained discrete after previous bonding step(s).

Although in one illustrative embodiment, the assembly process takes place with the work pieces pre-heated to the same temperature as the pressurizing medium. One skilled in the art will understand that the work pieces and pressurizing medium are at the room temperature when the first come into contact and the energy is applied to heat both simultaneously.

Although in one illustrative embodiment an assembly process using fluid(s) as the pressurizing medium is disclosed, one skilled in the art will understand that lubricants may or may not be added to the pressurizing medium. Likewise one skilled in the art that gases, solids, liquids and mixtures thereof may be utilized as a pressurizing medium.

Although in one illustrative embodiment the component parts to be packaged by the assembly process can be manually or automatically loaded, either directly after an upstream forming operation, one skilled in the art will understand that other operations can be accomplished in between (e.g. cleaning or drying or measurement steps). Likewise, one skilled in the art will understand that component parts to be packaged by the assembly process can be inserted into the pressure vessel from a magazine of prepared, un-bonded parts made ready for final packaging. The invention according to the disclosure may be embodied in other forms without departing from the spirit or essential characteristics thereof. The embodiments disclosed in this application are to be considered in all respects as illustrative and not limiting. The scope of the invention is indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

What is claimed is:

1. A method of producing microfluidic devices comprising: aligning at least two components for assembly; fixing the alignment of said pre-aligned components to withstand high pressure; and assembling said multi-component devices by integrating said fixed pre-aligned components with a bonding treatment.

2. The method of claim 1, wherein said bonding treatment is isostatic pressing.

3. The method of claim 2, wherein said isostatic pressing is selected from the group consisting of hot isostatic pressing, warm isostatic pressing, and cold isostatic pressing.

4. The method of claim 2, wherein said isostatic pressing is performed with gases or liquids.

5. The method of claim 1, wherein said bonding treatment is high energy rate forming.

6. The method of claim 4, wherein said isostatic pressing is performed with a mixture of gas and liquid.

7. The method of claim 1, wherein said components are made of materials selected from the group consisting of polymers, metals, ceramics, glass, mineral, composites, and mixtures thereof.

8. The method of claim 1, wherein said pre-aligning is mediated by adhesives.

9. The method of claim 1, wherein said pre-aligning is mediated by mechanical components.

10. The method of claim 1, wherein said alignment is fixed by fasteners.

11. The method of claim 1 , wherein said alignment is fixed by vacuum packaging.

12. The method of claim 1, wherein said alignment is fixed by welding.

13. The method of claim 12, wherein said welding is selected from the group consisting of ultrasonic, laser, and electron beam.

14. The method of claim 1, wherein said alignment is fixed by a pre-bonding treatment.

15. The method of claim 14, wherein said pre-bonding treatment is selected from the group consisting of thermal, chemical, and mechanical.

16. A method of fixing the alignment of multiple components of a device during assembly, comprising: aligning at least two components for assembly; placing said pre-aligned components in a thermoplastic packaging bag; evacuating the air from said packaging bag; and heat-sealing said packaging bag to fix the position of said pre-aligned components.

17. A method of producing a high precision, multi-component, microfluidic device, comprising: aligning at least two components, wherein said components include at least one polymer substrate embossed with fluidic passages on at least one surface, at least one polymer cover configured to overlay said embossed polymer substrate, and optionally at least one thin film configured to separate two or more of said polymer substrates and said polymer covers; fixing the alignment of said components by vacuum packaging in a thermoplastic packaging bag; placing said vacuum packaged components in an isostatic press; and assembling said microfluidic device by integrating said aligned components by isostatic pressing under liquid with elevated temperature and increased pressure.

18. A method of producing a microfluidic device comprising: aligning at least two device components with at least one mask in an assembly; inserting at least one assembly in a thermoplastic bag; placing said bag in an isostatic press; and assembling said microfluidic device by isostatic pressing under liquid with elevated temperature and increased pressure.

19. The method of producing a microfluidic device as set forth in claim 18 wherein, said mask is flexible.

20. The method of producing a microfluidic device as set forth in claim 18 wherein said mask is rigid and provides reference positions or alignment means.