Patent Application
20240351023
The present invention relates to modular, multi-layer microfluidic cartridges. More specifically, the present invention relates to modular, multi-layer microfluidic cartridges comprising integrated alignment features, and to methods for the assembly thereof. The cartridges may be used in medical diagnostics for evaluating a bodily fluid sample, including, for example, for evaluating coagulation in a blood sample. The devices and methods described herein can be used for various other applications as well.
Modular medical diagnostic cartridges often comprise a core element containing one or more molded fluidic flow paths and one or more cover layers, wherein the one or more cover layers is attached to the core element to fully enclose the flow path(s) and form one or more channels. In such cartridges, alignment between and among the one or more layers and the core element may be achieved with conventional manufacturing techniques. However, as channel size decreases and complexity increases—for example, where channels must overlap and/or align with particular features integrated into the cartridge (e.g., electronic sensors)—accurate alignment of layers to the core element becomes increasingly critical.
The challenges to manufacturing and assembling modular, multi-layer microfluidic cartridges do not necessarily exist for other multi-layer precision devices, such as, for example, electronic circuit boards (such as printed circuit boards). Printed circuit boards (PCBs) often comprise layers, each layer having a defined functionality, that are bound together in a multi-layer “book” by adhesives that are applied to the layers and that cover the entire surface between the layers.
Traditionally, in order for sheets (or layers) of materials to be adhered together, the sheets often are aligned by providing two orthogonal reference edges against which orthogonal straight sides of the sheets to be adhered are placed. The adhesive is often a sheet-type that is not tacky and that slides freely across a surface if kept cold. When held at a compound angle and vibrated, the sheets align to form a “book” ready to be bound. Pressure and heat can then be applied to cause the adhesive to flow and adhere surfaces together. However, for very thin sheets that are also flexible, and where the adhesive is tacky, a different method is needed because, if the sheet is at all non-flat and has any raised regions, a raised region can touch and prematurely adhere, thereby causing a wrinkle; in a microfluidic cartridge, such a wrinkle could produce a fluid short circuit between the adhered sheets and/or result in misalignment of features.
Once the multi-layer “book” is assembled and cured, connections are made between the sheets to create the overall functionality of the device. These connections between sheets are made by drilling vias that are then plated through without worry of leaving a through hole.
Alignment between components, including sheets of materials, is discussed by way of reference in Slocum, A. “Kinematic couplings: A review of design principles and applications”, Int. J. of Machine Tools and Manufacture (2009), doi: 10.1016/j.ijmachtools.2009.10.006, including references cited therein.
The manufacture and assembly of modular, multi-layer cartridges for use in precision diagnostics cannot rely on such legacy processes. For example, there is a concern of adhesive flowing into the fluid passages (e.g., channels). In addition, connection holes between the layers cannot readily be drilled as a post-layering process.
There therefore exists a need in the art for microfluidic cartridges that are suitable for use in, e.g., precision diagnostics, and for techniques for assembling such cartridges. In particular, there is a need for multi-layer microfluidic cartridges wherein the cartridge's layers are precisely and accurately aligned. The present invention addresses such needs.
The devices and methods described herein provide alignment features for modular, multi-layer microfluidic cartridges as well as methods related to the assembly of such cartridges.
Embodiments of the present invention provide a multi-layer cartridge comprising a base structure and one or more layers; the first of the one or more layers is bonded or adhered to the base structure and each subsequent layer is bonded or adhered to the previous layer, wherein the base structure and each of the one or more layers has alignment features comprising three slots that are oriented to allow for alignment between and among the base structure and the one or more layers. In particular, the three slots on the base structure and the three slots on each of the one or more layers have the same size, location, and angular orientation, such that the base structure's slots can accurately align with the slots of the one or more layers (e.g., in the X, Y planes, and with respect to rotation about a normal to the surface) to ensure that each of the one or more layers is adhered in a precise planar fashion and further to provide exact kinematic constraint. An assembly fixture may comprise pins (e.g., three round pins) whose locations align with the locations of the alignment features on the base structure and on each of the one or more layers (e.g., with the centroids of the three slots on the base structure and with the centroids of the three slots on each of the one or more layers), such that the assembly fixture can locate and hold flat each of the one or more layers with respect to the assembly fixture and its pins, and such that the assembly fixture's pins may then engage (couple) with the slots in the base structure to allow each of the one or more layers to be accurately brought into planar contact with the portion of the assembly containing the base structure. For the base structure and each of the one or more layers, the three slots engage with three round pins on the assembly fixture, such that the three slots' centers are located on a virtual triangle where the angle bisectors of the triangle's included angles meet at a point that is in the region of greatest alignment accuracy desired between the layered elements, and the slots' centers are located on the triangle vertices and their longitudinal axes are aligned with the corresponding angle bisectors at the triangle's vertices (see
In various embodiments, the assembly process described herein may be repeated to adhere or bond multiple layers to the portion of the cartridge assembly containing the base structure. In some of these embodiments, there also may be multiple alignment features to permit alignment of multiple layers around different points on or within the same cartridge.
The present invention relates to these and other important aspects, as described herein.
The features and advantages of the present invention may be more readily understood by those of ordinary skill in the art upon reading the following detailed description. It is to be appreciated that certain features of the invention that are described above and below in the context of separate embodiments may also be combined to form a single embodiment. Conversely, various features of the invention that are described in the context of a single embodiment for reasons of brevity may also be combined so as to form sub-combinations thereof. In addition, the drawings and specific embodiments of the invention described herein are illustrated by way of example, it being expressly understood that the description and drawings are only for the purpose of illustration and that the specific embodiments are not intended to define the limits of the present invention.
As shown in
The cartridge assembly 60 may comprise an array of components. In some embodiments, as shown in the embodiment in
In certain embodiments, a first pressure sensitive adhesive (PSA) layer 606, a second PSA layer 607, and a circuit board 800 are each kinematically aligned to the cartridge body 600 and adhered or bonded (e.g., with adhesive, laser or ultrasonically welded, heat sealed, etc.) to at least one of the other component layers (see, for example,
The cartridge body 600 can be made by precision injection molding of medical grade plastic for microfluidics (e.g., polycarbonate plastic). In some embodiments, particularly where very fine features are desired, the cartridge body may be injection molded using a Liquid Crystal Polymer known for its ability to form very fine features. Some of the smallest features that can be made by injection molding are on the order of about 40 micrometers wide, with a tolerance of plus or minus about 5 micrometers. The depth, for example, on a 40-micrometer wide channel is typically on the order of about 10 to about 20 micrometers. As the width increases to about 100 micrometers or more, features may become easier to manufacture and the cost of molds thus may be reduced. For molded features on the order of about 200 micrometers in size, tolerances may be on the order of about 5 percent. Vias (openings in elements that create vertical channels and allow for the transfer of fluid along the Z-axis of the cartridge system) are typically made using drop pins in the injection mold; because of these openings, seal layers may be required (in an illustrative embodiment, e.g., 604 may be bonded to seal the backside of 600, and circuit board layer 800 may be used to seal the cartridge on its frontside). Current manufacturing techniques allow for approximately 0.5 mm diameter drop pins with about a 3 degree taper.
Layers of PSA 606 and 607 (which may be in the form of a film) can be added to the cartridge to create fluid connections and additional vias and flow features (e.g., reservoirs for fluid logic). Layers of PSA can be mass produced by commercial laser cutting or by stamping (e.g., die cutting). Small production runs also can be achieved with off-the-shelf laser cutters, depending on the desired resolution. For example, a 40 W CO2 laser engraver (e.g., the OMTech laser K40 model) may have a resolution of about 1500 DPI, which translates to a minimum feature size of about 16.9 μm. Some units (e.g., the OMTech 50 W upgraded unit) are available at about 4500 DPI, which translates to a pitch of about 5.6 μm. Depending on the pattern and volume desired for the features, the PSA material may be die cut into a PSA layer having the desired geometry.
Each PSA layer may have an adhesive on its surface. In some embodiments, the adhesive may be exposed by peeling off a cover sheet, such as, for example, 3M 1513 double-sided adhesive tape. There are significant challenges in ensuring that thin adhesive layers (e.g., adhesive films) are placed with both precision and accuracy. For example, PSA layers typically are thin and compliant and thus easily deformed. Further, if the alignment of a PSA layer is off, features (e.g., vias) may not align. One advantage of using a PSA layer, which itself may have one or more integrated adhesive layers that may be made of particular chemical compositions, is that, depending on the adhesive, adhesion of the PSA layer to other cartridge elements may be achieved with little or no heat, making it less likely that the PSA layer will sag and/or flow into the microfluidic channels. In some embodiments, for example where test reagents are pre-deposited within the microfluidic channels (e.g., in chambers of the channels) to be sealed with a PSA layer, using a PSA layer with an adhesive that does not require high heat may ensure that reagents, such as proteins, do not denature (e.g., as a result of applying higher temperatures).
The PCB layer 800 can be rigid or flexible, or may itself comprise layers with one or more of such layers being flexible and other layer(s) being rigid. In an exemplary embodiment, a flexible PCB made of Kapton® is attached to (e.g., adhered to, laser welded to, etc.) a rigidized layer (such as a rigid PCB). Additionally, PCB layer 800 may comprise at least one set of contact pads 800a (see
In various embodiments, it may be desirable to maintain the fluid inside the fluidic testing region at a specific temperature. Thus, in certain embodiments the PCB layer 800 may comprise heating or other temperature-control elements (e.g., within the layers of the electronics) that are able to achieve and maintain a particular temperature or temperature range, such as, e.g., temperatures as low as about 20° C., and/or temperatures as high as about 45° C. For example, for a cartridge used to evaluate coagulation in a sample, the temperature can be about 37° C. Single or multiple temperature sensors and/or controller circuits can be included in the PCB layer 800, to monitor temperature and achieve and/or maintain a desirable temperature over all of the fluidic regions or over particular fluidic regions (such as those regions where reactions occur and/or measurements are taken). Temperature measurements also may be used by a testing unit for a specific feedback temperature control system.
In addition, in certain aspects, as the temperature increases above approximately 65° C., and with minimal structural support, it may become likely for one or more PSA layers to delaminate. Thus, it may be desirable to adjust to and/or maintain a particular temperature operational range (e.g., a temperature that does not exceed 65° C.), by any one or any combination of techniques and/or materials (such as those described above). In addition, techniques may be employed, and certain materials may be used, that help protect against delamination of the PSA (e.g., a PSA layer with particular adhesive properties may be used) or that eliminate this concern (e.g., laser welding or ultrasonic welding may be used in place of PSA, etc.).
In various embodiments, non-fluid flow regions of a cartridge may not all be filled (e.g., with plastic), particularly if the cartridge comprises one or more precise molded parts that have many microfluidic channels comprising well regions; otherwise, the cartridge can suffer from hot spots that may warp and/or may result in a loss of desired accuracy. Such is the case for annular region 605a, which in some embodiments must be left hollow. In such embodiments, however, the PSA layers 606 and 607 may depress into region 605a, and fluid pressure in the vias connecting the layers, and/or fluid pressure over the hollow annular region 605a, may cause one or more of the layers to separate, even though they had been adhered or bonded together. Support ring 605 thus may be inserted into the annular region to act as a back-up structure. In another embodiment, radial spokes in the base structure creating the hollow annular region can be included, such that the spokes are located underneath the PSA layers and in between where the radial microfluidic structures are located. In still other embodiments, support may be provided to the hollow annular region by filling the region with additional material through an overmold process, which may allow for a flat surface finish to be achieved.
In some embodiments, the cartridge comprises one or more waste bins. In certain embodiments, the waste bins are fixed-volume waste bins. For example, in some embodiments, the volume of waste bins, such as 90, may be larger than the volume of fluid introduced into the cartridge, thereby constituting a closed system in which no fluid exits the cartridge. Having such a closed system may be particularly desirable, for instance, for use with potentially contagious samples and/or harmful agents. In such embodiments, pressure in the waste bins may rise in proportion to the ratio of the fluid volume that is introduced to the volume of the waste bins. Additionally, as fluid is introduced, pressure may rise, placing increasing demand on, for example, the actuator (e.g., to drive the fluid) and the bond or adhesion strength needed between layers (e.g., to keep the fluid contained within desired channels).
In additional embodiments of the present invention, the waste bins may dynamically vary in size and may thus receive waste at a constant pressure. For example, a cylindrical volume 81w (not shown) may be located on the side of the cartridge 60 opposite from the input cylinder 81, making the cartridge appear symmetric externally. In certain such embodiments, a cylinder 81w may be sealed with an outwardly movable piston plug, thereby providing a dynamic waste volume receptacle. For example, the piston can be actuated near the open end of the cylinder, as waste enters the cylinder and fills the cylinder's volume, at which point the piston plug is pushed by a moving rod. In addition, the waste cylinder's piston can be located near the inner end, such that, as the input volume's piston moves into its cylinder, the waste volume's piston moves out towards its open end. In another embodiment, the waste volume is a bellows that expands to receive the waste volume.
When the cartridge (e.g., cartridge assembly 60) is inserted into a machine to actuate the cartridge and gather data on the fluid to be evaluated in the cartridge, it is critical to accurately align the cartridge to the machine. The anterior end of the cartridge assembly 60 thus may have a kinematic (exact constraint) region consisting of a V-shaped region 600a and a flat region 600b, which make 3-point contact with reference geometry, for example, to two dowel pins 301a and 301b that would be located in an instrument designed to receive the cartridge, as shown in
With respect to assembly of multi-layer microfluidic cartridges as described herein, alignment slots and pins are used to achieve accurate and precise alignment between the layers. In certain embodiments, the layers may have microfluidic features on the order of about 0.2 mm, and thus alignment between the layers (e.g., between the base structure and the next additional layer, and between each subsequent layer) should be sufficiently accurate to allow the cartridge to function as intended (e.g., alignment between the layers may need to be accurate to within about 40 microns). Such accurate alignment cannot be easily achieved by conventional edge contact alignment to an assembly fixture because of inadequate edge accuracy and because of inadequate accuracy of the positions of internal features with respect to an edge. For example, the outside edges on a molded part are far from internal precision features and are often thicker than the internal precision features, resulting in shrinkage-induced dimensional error. In addition, conventional alignment techniques that use pins in holes or pins in a hole and slot often over constrain or under constrain parts, resulting in assembly quality problems. In contrast, as described herein, slots are used as kinematic coupling points.
As described in embodiments herein, an exact constraint method is used to ensure accurate and precise alignment between the layers (e.g., the base structure, the PSA layers, the PCB layer, etc.). The method involves three kinematic alignment slots, such that the relative position of the kinematic alignment slots with respect to small microfluidic features is in exact precision alignment. Only the clearance space around a pin that fits in a slot could cause misalignment error, and because the slots' width can be made with great precision, and pins further may be ground with great precision, precise alignment between layers can be achieved to a level on the order of five to ten microns.
Three pins engaging with three slots (e.g., pins 961d in slots 600z) can thus uniquely define the position of a layer whose slots are engaged with the pins, even if the pins' centers themselves are not accurately aligned with the slot's centroids. In some embodiments, the pins are located on the cartridge's base structure; in other embodiments, the pins emanate from an assembly fixture.
For example, in some embodiments, the pins emanate from an assembly fixture such that the pins' centers are located at the ideal centers (centroids) of the slots in the layers; however, even if the location of the pins' centers are off by as much as about 0.5 mm within the slots, each layer's slots will find a unique location for the layer on the pins. And while each layer's slots are precisely located with respect to the layer's microfluidic features, having one or more layers stacked on one or more layers with the pins passing through each layer's slots will still ensure that the layers (and the layers' features) are precisely and accurately aligned with respect to each other. Using three slots and alignment pins as described herein, many layers may be stacked with great location precision and accuracy between and among the layers. Precision of placement is limited only by the precision of the molding process for the slots. Precise stacking of the layers is important for precise alignment of the layers' features, and can also be important to ensuring sufficient bonding or adhesion of the layers to each other.
In exemplary embodiments, the layers that are stacked on the cartridge body 600 are aligned using three slots 600a, 600b, and 600c arranged in a triangle shape, as shown in
This method of assembly may take various forms. For example, as shown in
In some embodiments, the next layer element to be adhered to or bonded with the layer held on the assembly fixture 961e is placed on a similar fixture (not shown, but referred to herein as fixture 961r) surface, which also may comprise a porous material that allows the layer to be held in place by a vacuum once it has been placed over the pins. The surface of such vacuum fixture 961r may comprise three slots with retractable guide pins, with the slots and the pins being located on the surface so as to match the location of the three slots on the layer. Once the layer is placed on the vacuum fixture surface and its position secured via the retractable pins, the vacuum may be turned on to hold the layer in place and the pins may then be retracted. The fixture 961r is then brought onto fixture 961e, where the pins in 961e engage the slots in the layer (and fixture 961r) to align the assembly fixture (and the layer(s) it holds) to the layer on fixture 961r. Fixture 961r then moves downward until the layers are within about 0.5 mm of contact, and the vacuum that holds the layer to 961r is turned to pressure to blow the 961r-held layer onto the layer on the assembly fixture 961e. Continued downward motion of 961r then creates bonding pressure between the two layers by compressing the compliant layer 961c.
Alternatively, in some embodiments, fixture 961e may function as a master vacuum chuck with three alignment pins having tapered ends whose length protruding from the chuck 961e is less than about half the depth of the kinematic alignment slots in the cartridge body 600. A second vacuum chuck 961e′ (not shown) also has three pins whose length protruding from the chuck 961e′ is less than about half the depth of the kinematic alignment slots in the cartridge body 600. The cartridge body 600 is then placed onto the chuck 961e′ and held by vacuum. A layer to be adhered or bonded to cartridge body 600 is placed on master chuck 961e. For example, a PSA layer (e.g., PSA layer 606) is placed on the chuck 961e, with the alignment slots of the PSA layer engaging the alignment pins on the chuck, and the vacuum is turned on to hold the PSA layer flat. If the adhesive on the PSA layer is covered, then such cover on the adhesive is removed. The chuck 961e′ (which holds cartridge body 600) is compliantly held, such as with a Remote Center Compliance (RCP) device often used in robotic assembly systems, and brought down onto the master chuck 961e such that the three tapered-end pins in chuck 961e engage the three slots in the cartridge body 600, and where any misalignment between the chucks due to robot inaccuracy will be accommodated by the RCP unit being displaced by the master chuck 961e pins engaging the cartridge body's slots. Once initial engagement is made, the vacuum of chuck 961e′ can be reversed to blow, and the cartridge body 600 will fall precisely onto the PSA layer held by the master chuck 961e. The robot arm removes chuck 961e′ and applies pressure with a compliant flat surface to adhere the cartridge body to the PSA layer. This assembly is then transferred back to the chuck 961e′ and a new layer is placed onto master chuck 961e and the process can be repeated.
In the above assembly modes, the backing plate 604, which may be relatively thick (e.g., about 1 mm), can be placed (e.g., manually, robotically, etc.) in an acceptable position on cartridge body 600. If desired, the backing plate 604 can also have slots and the assembly fixture 961e may be used to align and bond 600 and 604.
In some embodiments, the cartridge body 600 with its backing plate in place can float like an air hockey puck on a porous chuck 961e″ (not shown, and which may apply air pressure or vacuum). In such embodiments of the assembly process, PSA layer 606 is placed with its slots sliding over the pins of a master assembly fixture (e.g., 961e); such pins may be tapered. In embodiments where such master assembly fixture comprises a vacuum, the vacuum is turned on and any cover on layer 606's adhesive is removed. Further, the baseplate (which is the cartridge body 600 with its backing plate 604) with its slots is placed on chuck 961e″ (which may employ a vacuum) so it is free to float within a region that has radial clearance that is less than half the width of the cartridge body's alignment slots. No pins are needed in chuck 961e″. Soft radial springs, such as foam, also may be used to nominally locate the cartridge baseplate. Chuck 961e″ is parallel to assembly fixture 961e (which in this embodiment is a vacuum chuck controllably connected to air pressure or vacuum) held on a vertical motion slide or an assembly robot with layer 606 now facing downward. As 961e is lowered, the pins on 961e, which may have tapered ends, engage the cartridge body 600's slots, and since the baseplate is nominally located by the radial constraints, it will readily move to position with the pins on 961e piercing the cartridge body's slots. Motion continues downward until the PSA layer 606 contacts the front face 600f of the cartridge body 600, and continued force creates pressure so the PSA layer adheres to the cartridge body. The vacuum turns to pressure and the assembly fixture 961e is raised, leaving the PSA layer 606 adhered to face 600f of the cartridge body. The process may be repeated to add additional layers.
For example, PSA layer 607 similarly may be placed on fixture 961e and vacuumed down. Any adhesive layer cover sheet is removed, and the process above is repeated, wherein, now, layer 607 is adhered to layer 606. Finally, the PCB layer 800 is placed onto 961e and a vacuum is turned on to hold it. Any adhesive cover on the second side of 607 is removed and, again, since the assembly 604, 600, 606, and 607 is floating on the air-bearing chuck, when the PCB layer held to the assembly fixture 961e is lowered down, the assembly fixture 961e's pins will engage the slots in the cartridge body with its bonded or adhered layers, whose slots by the above process are all precisely aligned without resistance due to the air bearing float feature. Continued downward motion then pushes the PCB layer 800 precisely against the adhesive on layer 607, and resulting pressure adheres the PCB layer to the assembly. In certain embodiments, this process may thus complete a cartridge; in other embodiments, the assembly process may be repeated to bond or adhere additional layers to the assembly.
In general, parallelism between the chuck surfaces should be greater than about 0.1 mm and thus, use of a simple arbor press is not preferred in assembly. The vertical motion is best achieved with a precision press that uses rolling element linear guide bearings to keep the platens parallel with a closed structural loop, such that, when force is applied, there is no angular bending motion of the press's frame to cause uneven pressure. Alternatively, if a robotic system is used where alignment cannot be guaranteed to this level, a RCP device can be used to allow for angular float between the chucks.
It will be appreciated that the methods and systems described above are set forth by way of example, and that the examples do not limit the scope of the invention. In addition, the order or presentation of method steps in the description above is not intended to require this order of performing the recited steps, unless a particular order is expressly required or is otherwise clear from the context. Thus, while this invention has been particularly shown and described with references to certain embodiments thereof, it will be understood in light of the present disclosure by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention, for example as encompassed by the appended claims.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2022/039842 | 8/9/2022 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63232448 | Aug 2021 | US |
