Microfluidic chip and method of manufacturing the same

Abstract

The invention provides a method of fabricating a microfluidic chip, the method comprising forming one or more fluidic channels in a first substrate layer, providing a second substrate layer in contact with the first substrate layer, and bonding the first substrate layer and the second substrate layer together to form a wafer, and singulating the wafer to form the microfluidic chip, wherein singulating the wafer to form the microfluidic chip comprises irradiating the wafer with a laser, wherein the laser is focused inside the wafer to generate one or more laser-modified internal regions within the wafer, wherein the one or more laser-modified internal regions extend in a predetermined fracture plane that defines a desired arrangement of outlet surfaces of the microfluidic chip, and applying a mechanical stress to the wafer to cause the wafer to fracture along the predetermined fracture plane.

Description

Technical Field

[0001] This invention relates to microfluidic chips for aerosol systems (e.g., inhaler systems) and methods for manufacturing such microfluidic chips. In particular, this invention relates to improved methods for manufacturing microfluidic chips that can be used as micronozzles, and microfluidic chips produced by these methods. These methods offer high throughput and produce high-quality, high-performance microfluidic chips. Background Technology

[0002] Mechanical systems used to aerosolize fluids (typically liquids) are highly effective for delivering drug ingredients to the lungs, nose, eyes, skin, or mouth. The aerosols produced by such systems are typically monodisperse and more controllable than those produced by typical pump-type nebulizers. Therefore, targeted delivery with rapid absorption can be achieved while minimizing adverse effects such as uncontrolled droplet distribution at the start and end of droplet delivery.

[0003] For example, nebulizers and inhalers (such as soft fog inhalers) typically include microfluidic chips configured to transform liquids (i.e., liquid medications) into aerosols that can be inhaled by the user. These microfluidic chips include small nozzles (also called outlets) through which liquid is forced under high pressure to produce an aerosol. For example, the nozzles typically have a hydraulic diameter in the micrometer range—e.g., 1 to 200 micrometers (0.001 mm to 0.2 mm) or smaller. Such microfluidic chips are also often referred to as micronozzles or microstructured nozzles.

[0004] Microfluidic chips are typically fabricated by etching fluid channels onto the surface of a silicon layer. A glass layer is then bonded to the silicon wafer using anodic bonding, sealing the fluid channels between the two layers. The microfluidic chip is then diced from the assembled wafer using a grinding blade or disc. The blade and wafer are cooled by a flow of water or other liquid. The dicing creates a surface on the side of the chip, in which one or more nozzles from the fluid channels are positioned. During use, a jet of liquid, which can be used to generate an aerosol, is ejected from the nozzles.

[0005] This method of using mechanical cutting blades has various drawbacks. Notably, the process is messy because it involves material removal, generating a large amount of debris or slag. This waste can enter and clog the fluid channels within the microfluidic chip. Furthermore, the mechanical forces applied to the assembled wafer can cause the chip to shatter or break. Therefore, the yield—the percentage of microfluidic chips that function properly during use—is very low. Significant effort is required post-manufacturing to clean and test each microfluidic chip, and a large proportion of defective chips must be discarded.

[0006] In a further embodiment, the fluid channels within the chip can be filled with molten wax, which is then allowed to solidify prior to the dicing step. In these methods, debris and slag cannot enter the fluid channels during dicing due to the presence of wax in the channels. However, after dicing, the wax must be removed from the channels, and the microfluidic chip must be carefully cleaned. Furthermore, the wafer remains susceptible to breakage or fracture under the force of the dicing blade, and liquid is still required to cool the blade and wafer. Therefore, these manufacturing processes remain complex and costly to implement.

[0007] Therefore, it is desirable to provide a method for manufacturing microfluidic chips that is faster and has improved yield. This invention aims to solve at least some of the aforementioned problems. Summary of the Invention

[0008] This invention provides a method for manufacturing microfluidic chips that uses a laser to create an internal region of laser-modified material within a wafer. This internal region of laser-modified material forms a weak region within the wafer. Therefore, when the wafer is exposed to mechanical stress (e.g., tensile stress, bending stress, or shear stress), cracks tend to propagate from the laser-modified material, leading to wafer fracture. This method provides a clean and dry approach for manufacturing microfluidic chips.

[0009] Furthermore, the method described in this paper provides exceptionally clean, smooth, and accurate fracture. Therefore, microfluidic chips produced using the method described in this paper exhibit high yields and require minimal processing after separation from the rest of the wafer.

[0010] According to one aspect of the invention, a method for manufacturing a microfluidic chip for generating aerosols from a liquid is provided, wherein the method includes: forming one or more fluid channels in a surface of a first substrate layer; providing a second substrate layer in contact with a surface of the first substrate layer; and bonding the first and second substrate layers together to form a wafer, the wafer including one or more fluid channels extending therethrough; slicing the wafer to form a microfluidic chip, wherein the fluid channels in the microfluidic chip define at least one nozzle in an outlet surface of the microfluidic chip; and wherein slicing the wafer to form the microfluidic chip includes irradiating the wafer with a laser, wherein the laser is focused inside the wafer to generate one or more laser-modified material interior regions within the wafer, wherein the one or more laser-modified material interior regions extend in a predetermined fracture surface defining a desired arrangement of the outlet surface of the microfluidic chip; and applying mechanical stress to the wafer to cause the wafer to fracture along the predetermined fracture surface and form the outlet surface and nozzle of the microfluidic chip.

[0011] This method uses a laser to modify the material within a wafer to precisely control where the wafer will fracture under mechanical stress, such as tensile, bending, or shear stress. Near the high-energy laser focal point, a significant amount of energy from the laser is absorbed by the wafer material, melting, carbonizing, forming cracks, or otherwise modifying the material within the wafer at the focal point. Far from the focal point, the wafer material remains unchanged. Therefore, it can be understood that the laser-modified material region is the area where the material properties of the substrate forming the wafer are permanently altered. The laser-modified material region is integrally formed within or inside the wafer, rather than on the outer surface of the wafer.

[0012] By precisely controlling the location and manner of wafer breakage, the position of the exit surface of the microfluidic chip relative to its internal fluid channels can be precisely controlled. Therefore, one or more nozzles (i.e., the exits) formed in the exit surface are also precisely positioned. Furthermore, the nozzles have a consistent shape and are formed in a smooth surface. Thus, during use, the liquid jet guided from the nozzles is typically guided as intended, and the microfluidic chip can reliably form aerosols.

[0013] For example, a microfluidic chip can be configured such that two or more liquid jets from two or more respective nozzles are directed toward each other, causing them to collide and break the jets into aerosols. Similarly, a liquid jet from one nozzle can be directed to collide with a wall or feature to generate an aerosol. This method allows for the consistent fabrication of microfluidic chips such that liquid jets collide with each other and / or with walls in a desired manner.

[0014] In microfluidic chips, the efficiency of aerosolization depends (among other factors) on: how much overlap there is between the impacting jets, or, in the case of a single jet, the extent to which the jet hits the intended target; how far the collision occurs from the nozzle; and the jet velocity. Microfluidic chips fabricated using the methods discussed in this paper avoid errors or surface defects that could cause jets to only partially hit or miss their intended target, alter the collision or impact location, or affect jet velocity. Regarding the issue of jet velocity, it is understandable that if the wafer is incorrectly diced, the exit surface may be positioned further away from the inlet in the microfluidic chip than intended, meaning that the channels within the chip will be longer than expected, the pressure drop across them will be greater, and the liquid will be ejected at a lower velocity. Similarly, if the nozzle is relatively close to the inlet of the microfluidic chip, the channels will be shorter than expected, and the liquid in the jet may be ejected at a particularly high velocity.

[0015] "Splitting" should be understood as the wafer being cut, i.e., separated or split from other parts of the wafer. In a particularly preferred embodiment, the wafer can be cut to form multiple microfluidic chips. Such processes for manufacturing multiple microfluidic chips from the same wafer will be discussed further below.

[0016] In the microfluidic chip produced by this method, fluid channels can extend from one or more inlets in the microfluidic chip to nozzles. The fluid channels initially formed in the surface of the first substrate layer can be open channels, which are closed when a second substrate layer is placed on top. This is a convenient way to form internal channels extending through the wafer. The depth of the fluid channels can range from 1 micrometer to 50 micrometers, preferably from 1 micrometer to 25 micrometers, more preferably from 1 micrometer to 10 micrometers, and even more preferably from 2 micrometers to 8 micrometers. Thus, the fluid channels define themselves across an extended fluid channel plane. If the fluid channels have a consistent depth, the fluid channel plane will be parallel or substantially parallel to the surface of the first substrate layer on which the fluid channels are formed.

[0017] Microfluidic chips produced using this method can be configured to receive liquids with pressures in the range of 50 to 600 bar, or preferably 100 to 400 bar, more preferably 150 to 350 bar, and even more preferably 200 to 300 bar.

[0018] The predetermined fracture surface (and therefore the outlet surface of the microfluidic chip) is preferably orthogonal or substantially orthogonal to the fluid channel plane. For example, the predetermined fracture surface and outlet surface of the microfluidic chip can be arranged at an angle in the range of 80 to 100 degrees relative to the fluid channel plane.

[0019] The first and second substrate layers are preferably planar material blocks, with one dimension being relatively smaller than the other two. Fluid channels formed in the first substrate layer are preferably open grooves or trenches formed in the surface of the first substrate layer. These open grooves or trenches are closed by providing and bonding a covering second substrate layer.

[0020] Preferably, the distance between each nozzle and the corresponding nearest laser-modified material portion is at least 15 micrometers, more preferably at least 20 micrometers, more preferably at least 25 micrometers, and even more preferably at least 30 micrometers. Providing an appropriate spacing between the laser-modified material and the desired location of the nozzle within the predetermined fracture surface is crucial for ensuring high yield of microfluidic chips capable of reliably generating aerosols. If the laser heats the material too close to the fluid channel within the predetermined fracture surface of the wafer, the fluid channel may be damaged or deformed as the surrounding material is modified. Therefore, the nozzles formed in the microfluidic chip may fail to guide the liquid jet in its intended direction and / or at a sufficient flow rate.

[0021] For example, in a direction parallel to the fluid channel plane, the distance between each nozzle and the corresponding nearest laser-modified material portion may be at least 15 micrometers, preferably at least 20 micrometers, more preferably at least 25 micrometers, and even more preferably at least 30 micrometers, and / or in a direction perpendicular to the fluid channel plane, the distance between each nozzle and the corresponding nearest laser-modified material portion is at least 15 micrometers, preferably at least 20 micrometers, more preferably at least 25 micrometers, and even more preferably at least 30 micrometers.

[0022] Alternatively, the distance between each nozzle and the corresponding nearest laser-modified material portion is at most 250 micrometers, preferably at most 200 micrometers, more preferably at most 150 micrometers, even more preferably at most 125 micrometers, and even more preferably at most 100 micrometers. Sufficient proximity of the laser-modified material region to the desired location of the nozzle within the predetermined fracture surface is also important for ensuring high yields of microfluidic chips capable of reliably generating aerosols. If the laser-modified material is far from the nozzle, the wafer may not fracture smoothly through the fluid channel. Therefore, the nozzle position and orientation will be unreliable, and the liquid jet from the nozzle may not be oriented in the intended direction and / or may not provide sufficient flow rate.

[0023] For example, in the direction perpendicular to the fluid channel plane, the distance between each nozzle and the corresponding nearest laser-modified material portion can be up to 150 micrometers, preferably up to 100 micrometers, more preferably up to 75 micrometers, and even more preferably up to 50 micrometers; and / or in the direction parallel to the fluid channel plane, the distance between each nozzle of the microfluidic chip and the corresponding nearest laser-modified material portion is preferably up to 150 micrometers, preferably up to 100 micrometers, and even more preferably up to 75 micrometers.

[0024] Therefore, each of the at least one nozzle contained in the exit surface is preferably 15 to 250 micrometers away from the corresponding nearest portion of the laser-modified material, more preferably 20 to 150 micrometers, even more preferably 25 to 100 micrometers, and even more preferably 25 to 75 micrometers away.

[0025] Preferably, the maximum dimension of each nozzle in the plane of the outlet surface is 25 micrometers or less, more preferably 20 micrometers or less, and more preferably 15 micrometers or less. For example, the height and width dimensions of the nozzle in the outlet surface can each range from 1 to 25 micrometers, more preferably from 3 to 15 micrometers. In a preferred embodiment, the nozzle height is approximately 5 micrometers and the width is approximately 13 micrometers. For example, the nozzle can be designed to have a height of 5 micrometers and a width of 10 micrometers in the outlet plane. Such nozzles can be considered micro-nozzles with micrometer-level dimensions. Similarly, the channel forming the nozzle is a microfluidic channel, and the chip is a microfluidic chip. Likewise, the outlet channel forming the nozzle (which is arranged at an angle relative to the outlet plane) can have a depth of approximately 5 micrometers (e.g., 3 to 7 micrometers) and a width of approximately 7 micrometers (e.g., 5 to 10 micrometers).

[0026] Preferably, the fluid channel defines two nozzles in the outlet surface of the microfluidic chip, the two nozzles being configured to direct their respective liquid jets toward each other. This collision generates a fine aerosol of liquid particles with a uniform particle size. Preferably, the distance between the two nozzles is at least 20 micrometers. For example, the distance between the two nozzles is preferably in the range of 20 to 100 micrometers. More preferably, the distance between the two nozzles is in the range of 25 to 60 micrometers, and even more preferably in the range of 30 to 50 micrometers. However, other distances may also be suitable.

[0027] Alternatively, the microfluidic chip may include a single nozzle configured to direct a liquid jet toward a wall or feature of the system, away from the microfluidic chip. Aerosols containing liquid particles can be formed by such collisions.

[0028] Preferably, the first and second substrate layers are formed of silicon or glass. In a particularly preferred embodiment, the first and second substrate layers are formed of the same material. Preferably, each of the first and second substrate layers is formed of silicon. The advantage of using first and second substrate layers formed of the same material is that the same laser and / or laser setup can be applied across the entire predetermined fracture surface of the substrate. This simplifies the process of fabricating microfluidic chips. Otherwise, it might be necessary to change the laser and / or laser setup between different materials forming the wafer. It is particularly advantageous to use a single laser to form all laser-modified material regions (internal weak regions) on the predetermined fracture surface because it eliminates the need to align or register multiple lasers and the corresponding laser-modified material regions they collectively form. When laser-modified materials formed by different lasers are not aligned in the same plane, steps or discontinuities may occur when dicing the wafer to form the exit surface.

[0029] Preferably, one or more laser-modified material interior regions comprise a plurality of laser-modified material linear regions extending in a direction parallel to the fluid channel plane. A linear region should be understood as having an elongated shape within a predetermined fracture surface, with one dimension significantly longer than another. To form these linear regions, a laser focus can be linearly moved or lateralized within the wafer to create continuous embedded laser-modified material regions within the wafer. The laser focus can move continuously or intermittently on the predetermined fracture surface. Similarly, the laser can be applied continuously during movement or intermittently as its focus moves across the predetermined fracture surface. The laser-modified material does not necessarily have to be formed as a linear region. In alternative embodiments, the laser-modified material regions can be curved or formed as circular or square. Likewise, the laser-modified material regions do not need to be parallel to the fluid channel plane. Nevertheless, laser-modified material linear regions parallel to the fluid channel plane and / or parallel to the wafer surface are particularly easy to generate because the laser can be applied at a consistent depth within the wafer relative to the fluid channel and / or the wafer exterior.

[0030] In a preferred embodiment, one or more laser-modified material interior regions may include a plurality of linear laser-modified material regions extending in a direction parallel to the fluid channel plane (i.e., the plane extending from which the fluid channel is initially formed in the surface of the first substrate layer), wherein each linear region is provided at a different distance from the fluid channel plane in a direction perpendicular to the fluid channel plane. To achieve this, the laser may move or laterally across a predetermined fracture surface at a series of different depths relative to the wafer surface and / or the fluid channel plane.

[0031] Preferably, at least some of the laser-modified material linear regions extend across the entire width of the predetermined fracture surface in a direction parallel to the fluid channel plane. In some embodiments, each laser-modified material linear region extends across at least 75%, more preferably at least 80%, and even more preferably at least 90% of the width of the predetermined fracture surface.

[0032] Alternatively, at least some of the linear regions of the laser-modified material may be arranged into groups of collinear regions of the laser-modified material, wherein each group of collinear regions of the laser-modified material comprises at least two linear regions of the laser-modified material separated by unmodified material. To form such groups of laser-modified material regions, a laser may be applied to multiple individual portions of a straight line at a constant depth within a predetermined fracture surface.

[0033] In a particularly preferred embodiment, the wafer may be irradiated to form a first plurality of laser-modified material linear regions extending across the entire width of a predetermined fracture surface on one side of the fluid channel plane, and a second plurality of laser-modified material linear regions on the opposite side of the fluid channel plane, wherein the second plurality of laser-modified material linear regions are arranged into groups of laser-modified material collinear regions, wherein each group of laser-modified material collinear regions includes at least two laser-modified material linear regions separated by unmodified material.

[0034] In the embodiments described above that include groups of collinear regions of laser-modified materials, the corresponding unmodified material portions that separate the groups of collinear regions are preferably aligned in a direction parallel to the fluid channel plane, such that these groups of collinear regions define unmodified material regions extending between them. These unmodified material regions can extend through the height of the wafer in a direction perpendicular to the fluid channel plane.

[0035] Preferably, the distance between the laser-modified material regions in each group of collinear laser-modified material regions is in the range of 100 to 300 micrometers, more preferably 125 to 250 micrometers, and even more preferably in the range of 125 to 200 micrometers.

[0036] Preferably, the nozzle is positioned within an unmodified material region. More preferably, the unmodified material region extends from the nozzle to at least one edge of a predetermined fracture surface in a direction perpendicular to the fluid channel plane. Thus, the unmodified material region can extend to the upper or lower edge of the predetermined fracture surface and the final outlet surface. These arrangements provide particularly consistent nozzle positioning within the microfluidic chip, thus offering particularly high yields. Similarly, this method results in nozzles with consistent geometry and dimensions—i.e., nozzles with straight edges and regular shapes can be reliably produced.

[0037] In a preferred embodiment, the nozzle is positioned between two adjacent linear regions of the laser-modified material in a direction perpendicular to the fluid channel plane; or between two collinear regions of the laser-modified material in a direction parallel to the fluid channel plane.

[0038] Preferably, in a direction perpendicular to the fluid channel plane, the distance between the centerlines of adjacent linear regions of the laser-modified material or the distance between the centerlines of adjacent groups of collinear regions is in the range of 50 to 300 micrometers, more preferably 75 to 200 micrometers, and even more preferably 75 to 150 micrometers. This distance between adjacent linear regions or groups of collinear regions is commonly referred to as the stripe distance. The above data results in a smooth exit surface because cracks propagate in a predetermined fracture surface between adjacent linear regions.

[0039] Preferably, irradiating the wafer with a laser comprises irradiating the wafer from a single side with a laser. This provides an advantage over irradiating the wafer from both sides because it is difficult to align or register the laser-modified material regions formed by laser beams incident from different sides of the wafer. If the laser-modified material is not aligned in a single predetermined fracture surface, the wafer will not fracture in a smooth and consistent manner, and may result in microfluidic chips with notches or steps on their exit surfaces. If these notches or steps affect the position and orientation of the nozzles in the exit surface, they will affect the performance of the microfluidic chip. Furthermore, irradiating the wafer from a single side avoids the need to use multiple lasers positioned on different sides of the wafer, and / or avoids the need to flip or rotate the wafer relative to the laser source.

[0040] Preferably, one or more laser-modified material interior regions include linear laser-modified material regions extending in a direction parallel to the fluid channel plane, wherein at least one linear laser-modified material region is provided on each side of the fluid channel plane, and wherein irradiating the wafer with a laser includes irradiating the wafer from a single side of the wafer to form one or more nearest linear laser-modified material regions on each side of the fluid channel plane. Thus, two or more laser-modified material regions can be formed on each side of the fluid channel plane, wherein the regions are formed at different distances from the fluid channel plane. Furthermore, a single laser applied from a single side of the wafer can be used to form the laser-modified material region closest to the nozzle on either side of the fluid channel plane. For example, one, two, three, or more nearest linear regions or groups of collinear regions on either side of the fluid channel plane can be irradiated by a single laser on the same side of the wafer. This helps ensure that the laser-modified regions are all located in the same plane (predetermined fracture surface) and that when the wafer is diced, there are no breaks or ridges formed across the nozzle. The remaining laser-modified material regions can be formed by different lasers, and / or by using the same laser applied from opposite sides of the laser-modified material, but this is not necessary. In some cases, all laser-modified material regions are formed using the same laser on the same side of the material.

[0041] In practice, it may be efficient to use a single laser from one side of the wafer to form all the laser-modified material regions on the first side of the fluid channel plane, and to form one or more closest laser-modified material regions on the opposite second side of the fluid channel plane, and then use a laser from the opposite side of the wafer to form the remaining laser-modified material regions. Even if the laser-modified material formed from the opposite sides of the wafer cannot be aligned and ridges, notches, or other discontinuities are formed, these discontinuities will be located away from one or more nozzles and will not affect the performance of the microfluidic chip.

[0042] Preferably, the laser-modified material extends over at least 5%, more preferably at least 10%, more preferably at least 20%, and even more preferably at least 25% of the predetermined fracture surface by area; and / or the laser-modified material extends over at most 75%, preferably at most 60%, and more preferably at most 50% of the predetermined fracture surface by area. Providing sufficient laser-modified material within the wafer ensures that the wafer is diced as intended to produce a smooth and consistent exit surface. Conversely, applying excessive laser energy to the wafer to form a large amount of laser-modified material is inefficient and may damage or deform the fluid channels formed within the wafer.

[0043] The process described above, including all preferred and optional features, can also be used to form other surfaces of the wafer. For example, the wafer can be irradiated with a laser within a second predetermined fracture surface corresponding to a desired location on the entry surface of the microfluidic chip. The wafer can then be cleaved to form the entry surface by applying mechanical force.

[0044] The method described above can be used to produce a large number of microfluidic chips from a single wafer. The process of forming laser-modified material regions within the wafer and applying mechanical force can be used to dicing the wafer into monolithic pieces, dividing it into multiple independent chips. This provides an efficient way to produce large quantities of microfluidic chips.

[0045] For example, the method can be implemented such that forming one or more fluid channels in the surface of a first substrate layer includes forming an array of individual fluid channel units in the surface of the first substrate layer, wherein each individual fluid channel unit includes a fluid channel of a single microfluidic chip; and wherein the method includes dicing a wafer into a plurality of microfluidic chips, each microfluidic chip containing a fluid channel of a corresponding individual fluid channel unit.

[0046] According to another aspect of the invention, a microfluidic chip for generating aerosols from a liquid is provided, the microfluidic chip including one or more inlets for receiving the liquid, the inlets being formed in an inlet surface of the microfluidic chip; one or more nozzles configured to emit liquid jets, the nozzles being formed in an outlet surface of the microfluidic chip; and one or more fluid channels connecting the one or more inlets to the one or more nozzles, wherein the outlet surface of the microfluidic chip includes one or more laser-modified material regions.

[0047] Microfluidic chips can be manufactured using any of the methods discussed above (including any preferred or optional features). Microfluidic chips can provide any of the benefits and advantages discussed above. In particular, higher yields mean that, on average, producing microfluidic chips is more economical.

[0048] The microfluidic chip can be configured to receive liquids at one or more inlets with pressures in the range of 50 to 600 bar, preferably 100 to 400 bar, more preferably 150 to 350 bar, and even more preferably 200 to 300 bar. Alternatively, the microfluidic chip can be configured to dispense droplets with an average diameter in the range of 1 to 10 micrometers, preferably 2 to 6 micrometers, and more preferably 3 to 5 micrometers.

[0049] According to a further aspect of the invention, an inhaler system incorporating a microfluidic chip is provided, as discussed in conjunction with the foregoing aspects of the invention. These systems may include any preferred or optional features discussed above with reference to the foregoing aspects of the invention, and provide corresponding benefits.

[0050] The inhaler system can be configured to drive liquid through a microfluidic chip to generate an aerosol and deliver the aerosol to the user. The user can then inhale the aerosol.

[0051] Preferably, the inhaler system is a soft mist inhaler (SMI) system. A soft mist inhaler (SMI) is an inhaler that produces a relatively slowly diffusing aerosol (mist). The inhaler system can be configured to dispense the aerosol at a velocity of 2 m / s or less, preferably 1.6 m / s or less, more preferably less than 1 m / s, when measured at a distance of 10 cm from the mouthpiece or nozzle, and / or the dispensing or nebulization of one dose requires a time longer than 0.7 seconds, and preferably at least 1 second.

[0052] Preferably, the inhaler system is configured to dispense fluid in puffs ranging from 0.5 μL to 50 μL, more preferably from 0.5 μL to 30 μL, and even more preferably from 10 to 20 μL. The intended dose of drug from the inhaler may include a single puff or multiple puffs (e.g., two puffs). The inhaler system may be configured to deliver liquid to the inlet of the microfluidic chip at a pressure ranging from 50 to 600 bar, or preferably from 100 to 400 bar, more preferably from 150 to 350 bar, and even more preferably from 200 to 300 bar. This pressure produces high-quality microaerosols. Preferably, the inhaler system is configured to dispense droplets with an average diameter ranging from 1 to 10 micrometers, preferably from 2 to 6 micrometers, and even more preferably from 3 to 5 micrometers.

[0053] Preferably, the inhaler system is a multi-dose inhaler system, wherein the shrinkable pouch of the cartridge is configured to store multiple doses of liquid medication. Preferably, the capacity or internal volume of the shrinkable pouch is in the range of 0.5 to 10 ml, more preferably in the range of 1 to 5 ml.

[0054] Preferably, the cartridge and inhaler system discussed above contains a liquid drug stored therein. Attached Figure Description

[0055] The invention will now be discussed with reference to the following figures:

[0056] Figure 1 A microfluidic chip according to an embodiment of the present invention is shown schematically in a three-dimensional view;

[0057] Figures 2a to 2f A perspective view schematically illustrates an embodiment of the present invention. Figure 1 A series of steps in the manufacturing method of microfluidic chips;

[0058] Figure 3a The diagram shows a line pattern in which a laser can be applied to a predetermined fracture surface within a wafer during the fabrication of a microfluidic chip according to the present invention. Figure 3b and Figure 3c Showing the use Figure 3a Microscopic image of the outlet surface of a microfluidic chip according to an embodiment of the present invention, fabricated using a pattern of laser-modified material;

[0059] Figure 4a The diagram shows a line pattern in which a laser can be applied to a predetermined fracture surface within a wafer during the fabrication of a microfluidic chip according to the present invention. Figure 4b and Figure 4c Showing the use Figure 4a Microscopic image of the outlet surface of a microfluidic chip according to an embodiment of the present invention, fabricated using a pattern of laser-modified material;

[0060] Figure 5a The diagram shows a line pattern in which a laser can be applied to a predetermined fracture surface within a wafer during the fabrication of a microfluidic chip according to the present invention. Figure 5b and Figure 5c Showing the use Figure 5a Microscopic image of the outlet surface of a microfluidic chip according to an embodiment of the present invention, fabricated using a pattern of laser-modified material;

[0061] Figure 6a and Figure 6b Showing the use Figure 5a Microscopic image of the outlet surface of a further microfluidic chip according to an embodiment of the present invention, fabricated using a pattern of laser-modified material. Figure 5c Showing Figure 5b Nozzles of microfluidic chips;

[0062] Figure 7 The illustration schematically shows a series of steps in a microfluidic chip manufacturing method according to an embodiment of the present invention;

[0063] Figure 8a , 8bFigures 8c and 8c show microscope images of the outlet surface of a further microfluidic chip according to an embodiment of the present invention;

[0064] Figure 9a and Figure 9b Showing according to Figure 3a Microscopic image of a nozzle in the outlet face of a further microfluidic chip according to an embodiment of the present invention, showing a pattern of laser-modified material.

[0065] Figure 10 The diagram shows a line pattern in which a laser can be applied to a predetermined fracture surface within a wafer during the fabrication of a microfluidic chip according to the present invention.

[0066] Figures 11a to 11e The illustration schematically shows a series of steps in a method for manufacturing a plurality of microfluidic chips according to an embodiment of the present invention;

[0067] Figure 12 Etching patterns for individual fluid channel units are shown, which can be used to fabricate microfluidic chips according to embodiments of the present invention;

[0068] Figure 13 An inhaler system incorporating a microfluidic chip according to the present invention is shown. Detailed Implementation

[0069] This invention provides a reliable and clean method for manufacturing microfluidic chips. This method achieves a high yield for successfully manufacturing microfluidic chips. Microfluidic chips produced using this method are of high quality and consistently produce aerosols for use in inhalers.

[0070] Figure 1 A microfluidic chip 50 according to the present invention is shown. The microfluidic chip 50 is configured to generate an aerosol from a liquid (e.g., a drug or pharmaceutical agent). The microfluidic chip 50 is well-suited for use in an inhaler. The inhaler can push a liquid drug through the microfluidic chip 50 to form an aerosol, which can then be dispensed to the user so that the user can inhale the aerosol.

[0071] The microfluidic chip 50 is cubical in shape and has an inlet surface 52 and an outlet surface 54. The inlet surface 52 and the outlet surface 54 are arranged opposite to each other on opposite sides of the microfluidic chip. Figure 1 The image shows the outlet surface 54, while the inlet surface 52, as shown, is located at the rear of the microfluidic chip.

[0072] In use, the liquid travels along the x-axis from the inlet face 52 through the microfluidic chip 50 to the outlet face 54. The liquid can travel through the microfluidic chip 50 from one or more inlets (not shown) in the inlet face 52 to two nozzles 56 (often referred to as "outlets") on the outlet face 56 of the microfluidic chip 50. Each nozzle is configured to release a liquid jet. The arrangement of the nozzles causes the two liquid jets to be directed toward each other and collide. The collision of the two liquid jets aerosolizes the liquid.

[0073] Figures 2a to 2g The manufacturing process is shown schematically. Figure 1 The figures illustrate the sequential steps in the method for producing a microfluidic chip 50. For ease of understanding, these figures show the production of a single microfluidic chip 50 from a cubic wafer 30. However, in a preferred embodiment, a large number of microfluidic chips (e.g., more than 100 chips) can be produced from each wafer. The following description, in conjunction with Figure 11 and... Figure 12 These methods for forming multiple microfluidic chips from a single wafer are discussed.

[0074] Initially, providing such Figure 2a The first substrate layer 10 is shown. The first substrate layer 10 is preferably formed of silicon. However, other materials, such as glass, may also be used. The first substrate layer 10 is cubic and substantially planar, containing a depth dimension (parallel to the z-axis, as shown) smaller than its other dimensions (parallel to the x and y axes, as shown). The first substrate layer 10 may have a depth or thickness parallel to the z-axis in the range of 0.25 mm to 2 mm, preferably in the range of 0.5 mm to 1.5 mm. The first substrate layer 10 may have edges with lengths in the range of 1 mm to 4 mm, preferably in the range of 1.5 mm to 3 mm, along the x and y axes.

[0075] exist Figure 2b In this process, fluid channels 14 are formed in the upper surface 12 of the first substrate layer 10. At this stage, the fluid channels 14 are open channels extending into the upper surface 12. The fluid channels 14 extend across the upper surface 12. The fluid channels 14 include a relatively wide inlet channel 14a near the rear edge 10a of the first substrate layer 10, and two outlet channels 14b at opposite front edges 10b of the first substrate layer 10. The depth of the fluid channels 14 can be in the range of 1 micrometer to 50 micrometers, preferably 1 micrometer to 25 micrometers, more preferably 1 micrometer to 10 micrometers, and even more preferably 2 micrometers to 8 micrometers. This depth can be measured from the upper surface 12 of the first substrate layer 10 forming the fluid channels 14. The two outlet channels 14b are oriented at an angle to each other and converge at a triangular intersection. Therefore, liquid jets passing through these outlet channels 14b and ejected from nozzles formed by these channels 14b tend to collide.

[0076] As can be seen, the fluid channel 14 extends in a plane parallel or substantially parallel to the upper surface of the first substrate layer, as shown in the figure, and this plane is parallel to the xy plane. The fluid channel 14 defines a fluid channel plane, that is, the plane in which the fluid channel 14 extends. This fluid channel plane can be defined by a centerline of the depth of the fluid channel 14, and since the fluid channel 14 has a substantially constant depth, this plane is parallel to the upper surface 12 of the first substrate layer and is located at a certain distance below the upper surface 12 of the first substrate layer 10, a distance equal to half the depth of the fluid channel 14.

[0077] The fluid channel 14 is a groove or trench in the upper surface 12 of the first substrate layer. The fluid channel 14 is preferably etched into the upper surface 12 using deep reactive ion etching (also known as DRIE or D-RIE), during which the following alternation occurs: the upper surface of the first substrate layer is bombarded with plasma ions through an etching mask to remove a layer from the surface; subsequently, an inert passivation layer is deposited to protect the etched surface and sidewalls of the etched channel from further etching. However, in alternative embodiments, the fluid channel 14 can be etched or engraved using any other suitable method.

[0078] Figure 2b The fluid channel 14 shown is relatively simple. However, in a further embodiment, the fluid channel 14 may include structures or protrusions configured to regulate the flow of fluid through the microfluidic chip 50 and / or filter large particles in the liquid passing through it so that these particles do not clog the nozzles 56 of the microfluidic chip 50.

[0079] Subsequently, as Figure 2c As shown, the fluid channel 14 is covered by providing a second substrate layer 20 to the upper surface 12 of the first substrate layer 10. The second substrate layer 20 is bonded to the upper surface 12 of the first substrate layer 10 to permanently enclose the fluid channel 14 within the wafer 30 formed by the two substrate layers 10 and 20. Thus, the fluid channel 14 is enclosed within the wafer 30 and extends through the wafer 30.

[0080] The second substrate layer 20 is planar, with one dimension (depth) smaller than its other two dimensions. The second substrate layer 20 has dimensions similar to the first substrate layer 10, with its width and length equal to or substantially equal to the corresponding dimensions of the first substrate layer 10. Preferably, the second substrate layer 20 has a depth dimension similar to or equal to that of the first layer 10. Therefore, the second substrate layer 20 can have a depth or thickness parallel to the z-axis in the range of 0.25 mm to 2 mm, preferably in the range of 0.5 mm to 1.5 mm. The second substrate layer 20 can have edges with lengths in the range of 1 mm to 4 mm, preferably in the range of 1.5 mm to 3 mm, along the x and y axes. As shown, the side surfaces of the second substrate layer 20 are coplanar with the side surfaces of the first substrate layer 10. However, these features are not mandatory; in further embodiments, the second substrate layer may contain different dimensions and / or be offset relative to the first substrate layer.

[0081] The second substrate layer 20 is preferably formed of silicon. However, in alternative embodiments, other materials such as glass may also be used, as with the first substrate layer 10. Preferably, both substrate layers 10, 20 are formed of the same material to allow for fusion bonding and to enable the formation of laser-modified material regions within wafer 30 (discussed below) using a single laser with a consistent setup. When using different materials—for example, when the first substrate is silicon and the second substrate layer is glass—different setups or lasers may be required to form laser-modified material within each layer. Therefore, wafer 30 composed of substrate layers formed of a single material is simpler to process.

[0082] When both the first and second substrate layers 10 and 20 are formed of silicon, they are preferably bonded together by melt bonding. Melt bonding directly creates chemical bonds between atoms of the same material in both layers 10 and 20. Melt bonding may involve cleaning the surfaces of the first and second substrate layers 10 and 20 to be bonded, bringing the surfaces of the first and second substrate layers 10 and 20 into contact, and heating the first and second substrate layers 10 and 20 to anneal these layers and form a bond between them. However, in further embodiments, alternative bonding methods, such as anodic bonding, can be used. When the first and second substrate layers 10 and 20 are formed of different materials (e.g., the first substrate layer 10 is formed of silicon and the second substrate layer 20 is formed of glass), anodic bonding is a suitable method.

[0083] like Figure 2b and 2c As shown, the fluid channels 14 formed in the upper surface 12 of the first layer 10 do not extend to the front or rear edges 10a, 10b of the first substrate layer 10. Similarly, the fluid channels 14 do not extend to the front or rear of the wafer 30. Instead, in order to form from the fluid channels 14... Figure 1The visible nozzle 56 must penetrate the exit channel 14b formed within the wafer 30 to cleave (cut) the wafer 30.

[0084] To help understand this segmentation, Figure 2b and Figures 2c to 2e The predetermined fracture surfaces O and O′ extending through the first substrate layer 10 and wafer 30 are marked with dashed lines, respectively. The predetermined positions N and N′ of the nozzle 56 are also marked with dashed lines. Figure 2b and Figures 2c to 2e The figure is shown in dashed lines. A predetermined fracture surface O′ in the wafer defines a preferred location for the outlet surface 54 of the microfluidic chip 50, and thus defines a preferred plane along which the wafer 30 is cleaved to form the outlet surface 54. It can be seen that the predetermined fracture surface O′ and the final outlet surface 54 of the microfluidic chip 50 extend perpendicularly to the fluid channel plane (i.e., the plane in which the fluid channel 14 extends). Specifically, as shown, the outlet surface extends parallel to the yz plane, while the fluid channel 14 extends parallel to the xy plane. Figure 2b As can be seen most clearly, wafer 30 divided in this way will generate nozzles 56 from exit channels 14b facing each other. Therefore, the liquid flowing through exit channels 14b will be ejected from nozzles 56 as two jets, which can collide and form an aerosol.

[0085] In addition, Figures 2c to 2g In the diagram, the dashed line L indicates the location of the original interface between the first and second substrate layers 10 and 20 before they are bonded. This dashed line L is provided for ease of understanding only and may not be visible in practice, especially when the first and second substrate layers 10 and 20 are formed of the same material.

[0086] In order to cleave the wafer 30 along the predetermined fracture surface O′, the wafer 30 is irradiated with a laser to produce a weakened laser-modified material region 32 from which cracks can propagate and along which the wafer 30 will fracture when mechanical stress is applied.

[0087] like Figure 2dAs shown, wafer 30 is irradiated by a laser beam 42 from a laser source 40. The laser beam 42 is focused onto a focal point 44 located within a predetermined fracture surface O′ within wafer 30. At the focal point 44, the laser beam 42 has sufficient intensity to heat and modify the material of wafer 30, forming a laser-modified material region 32. In some embodiments, the material of wafer 30 locally at the focal point 44 may be melted or cracked. In other embodiments, the material of wafer 30 locally at the focal point is carbonized and weakened, resulting in reduced physical strength. Far from the focal point 44, the intensity of the laser energy is low enough that the material of wafer 30 is not modified by the laser beam 42. Therefore, the laser-modified material region within wafer 30 is relatively isolated and confined to the predetermined fracture surface O′ where the laser is applied. Under stress, cracks can propagate relatively easily from the laser-modified material region 32. The laser-modified material regions 32 are integrally located within wafer 30 and are regions where the material properties of the material forming wafer 30 are permanently modified by the energy applied by the laser beam 44.

[0088] It is understood that various laser sources 40 operating with different characteristics can be used to form laser-modified materials within the wafer 30. Preferably, the laser beam 44 melts or cracks the material within the wafer 30 at its focal point 44, but not elsewhere on the wafer 30. When the wafer 40 is formed of a semiconductor material such as silicon, the material within which the laser focal point is located can be irradiated, and the electric field strength at the light convergence point is at least 1 x 10⁻⁶. 8 W / cm 2 The pulse width is 1 microsecond or less. When wafer 40 is formed of glass, the material within it can be irradiated with a laser, and the electric field strength at the point of convergence is at least 1 x 10⁻⁶. 8 W / cm 2 Preferably at least 1x10 11 W / cm 2 The pulse width is 1 microsecond or less.

[0089] When the first and / or second substrates are formed of silicon, the laser source 40 can be a semiconductor laser-pumped ND:YAG laser. In a preferred embodiment, the laser source 40 can operate with a wavelength of 1064 nm and a laser spot cross-sectional area of ​​3.14 x 10⁻⁶ nm. -8 cm 2 In Q-switched pulse oscillation mode, the repetition frequency is 100 kHz; a pulse width of 30 ns is used; the output is 20 microjoules per pulse; it has linear polarization; and the laser beam profile is TEM. 00In this embodiment, the laser beam 42 is focused by an optically converging lens with the following parameters: magnification of 50x; numerical aperture of 0.55; and transmittance of at least 60% at the laser wavelength. The focal point 44 of the laser beam 42 also traverses the wafer 30 at a speed of 100 mm / s. This movement of the laser beam 42 relative to the wafer 30 can be achieved by moving the wafer 30 (e.g., mounting the wafer 30 on a movable mounting stage), adjusting the arrangement of lenses, mirrors, or other optical elements, or by moving the laser and lens together relative to the wafer 30. Under the above conditions, the depth of the formed laser-modified material region in the direction perpendicular to the fluid channel plane (i.e., the z-direction as shown in the figure) is approximately 100 micrometers.

[0090] When the first and / or second substrates are formed of glass (e.g., Pyrex (registered trademark (RTM))), the laser source 40 can be a semiconductor laser-pumped ND:YAG laser. In a preferred embodiment, the laser source 40 can operate with a wavelength of 1064 nm and a laser spot cross-sectional area of ​​3.14 x 10⁻⁶ nm. -8 cm 2 In Q-switched pulse oscillation mode, the repetition frequency is 100 kHz; a pulse width of 30 ns is used; the output is less than 1 millijoules per pulse; linear polarization is used; and the laser beam profile is TEM. 00 In this embodiment, the laser beam 42 is focused by an optically converging lens with the following parameters: magnification of 50x and numerical aperture of 0.55, or magnification of 100x and numerical aperture of 0.80; and a transmittance of at least 60% at the laser wavelength. The focal point 44 of the laser beam 42 also traverses the wafer 30 at a speed of 100 mm / s. This movement of the laser beam 42 relative to the wafer 30 can be achieved by moving the wafer 30 (e.g., mounting the wafer 30 on a movable mounting stage), adjusting the arrangement of lenses, mirrors, or other optical elements, or by moving the laser and lens together relative to the wafer 30. Under the above conditions, it has been found that the size of the laser-modified material region is approximately 100 micrometers deep in the direction perpendicular to the fluid channel plane (i.e., the z-direction as shown in the figure).

[0091] Suitable lasers include the DFL7340 and DFL7341 manufactured by DISCO (registered trademark). Alternative lasers may also be used as laser source 40, preferably Nd:YVO4 lasers, Nd:VLF lasers, Ti:sapphire lasers, Nd:YVO4 lasers, or Nd:YLF lasers.

[0092] The laser source 40 and / or laser beam 42 can be controlled to move the position of the focal point 44 of the laser beam 42. This causes the focal point 44 of the laser beam 42 to be transversely moved along a predetermined fracture surface O′ through the wafer 30, forming linear internal regions 32a, 32b, and 32c of the laser-modified material 32 along the predetermined fracture surface O′. For example, as due to... Figure 2d As indicated by arrow M, the laser source 40 can be moved relative to the wafer 30. Alternatively, the laser source 40 itself may be stationary, but may include an optical system configured to adjust the position and / or depth of the laser beam focus 44 relative to the laser source 40 and the wafer 30. The focus 44 of the laser beam 42 can move continuously or intermittently to form individual strips of the laser-modified material. Similarly, the laser beam 42 can operate continuously or intermittently while its focus 44 traverses across the wafer 30.

[0093] like Figure 2d and 2e As shown, preferably, the focal point 44 is transversely moved across the wafer 30 to form a series of linear regions 32a, 32b, 32c, 32d of the laser-modified material 32 at different depths within the wafer 30 (i.e., at different distances from the plane extending from the fluid channel 14). The linear regions 32a, 32b, 32c, 32d extend in a direction substantially parallel to the xy plane and the plane extending from the fluid channel 14. However, this is not mandatory; in further embodiments, the laser-modified material regions 32 can be formed in various patterns across a predetermined fracture surface O′. Figure 2d and 2e In the illustrated embodiment, the linear regions 32a, 32b, 32c, and 32d can also be referred to as strips of the laser-modified material 32. As shown, each linear region 32a, 32b, 32c, and 32d of the laser-modified material 32 extends across most of the width of the microfluidic wafer 30. However, this is not mandatory; in further embodiments, the laser-modified material regions may extend across the entire width or be arranged as a group of collinear laser-modified material regions (discussed below).

[0094] Figure 2d The diagram shows the arrangement of the wafer 30 and the laser beam source 40 halfway through the irradiation process. Two linear regions 32a and 32b of the laser-modified material 32 have been completed, and the focal point 44 of the laser beam 42 is being transversely shifted to form a third linear region 32c of the laser-modified material 32. After laser irradiation is complete, as shown... Figure 1 and 2e As shown in 2g, four linear regions 32a, 32b, 32c, and 32d of laser-modified material 32 are formed within the predetermined fracture surface O′, wherein two linear regions of laser-modified material 32 are present on each side of the fluid channel plane and on each side of the original interface L between the first substrate layer and the second substrate layers 10 and 20.

[0095] After creating the laser-modified material interior region 32 within the wafer 30, the wafer 30 can be segmented or fractured by applying mechanical stress across a predetermined fracture surface O′. In a preferred embodiment, as... Figure 2d As shown, tensile stress perpendicular to the predetermined fracture surface—that is, along the x-direction—can be applied, such as due to Figure 2e As indicated by arrow S in the diagram. Under this tensile stress, the crack can propagate or extend between the regions of the laser-modified material 32 within the predetermined fracture surface O′. The propagated crack forms a clean and reliable fracture along the predetermined fracture surface O′ in the wafer 30. In a further embodiment, alternative mechanical stresses—such as bending stress, where one side of the wafer 30 is subjected to tensile stress and the opposite side to compressive stress, or shear stress—can be applied to the wafer 30.

[0096] This fracture in wafer 30 forms the exit surface 54 and nozzle 56 of the final microfluidic chip—as Figure 2f As shown. The exit surface 54 formed by the controlled fracture process described above is generally smoother and cleaner than an equivalent surface formed by mechanical cutting techniques. Furthermore, the position of the exit surface 54 relative to the fluid channel 14 within the microfluidic chip 50 is highly consistent. Therefore, the relative arrangement of the nozzles 56 is also highly consistent. This combination of features helps ensure that the liquid jets ejected from the two nozzles 56 reliably collide with each other and uniformly form an aerosol.

[0097] Optionally, the wafer 30 can be further diced to form an inlet surface 52, in which one or more inlets (not shown) are formed, through which liquid can enter the fluid channel 14 within the microfluidic chip 50. A preferred location for this surface is... Figure 2g The inlet face 52 is indicated by a dashed line K. The wafer 30 can be diced to form the inlet face 52 using the same technique discussed above regarding the exit face 54. Alternatively, mechanical cutting or any other suitable method can be used. (Remove) Figure 2g The rear of wafer 30 shown can produce, for example, Figure 1 The microfluidic chip 50 shown.

[0098] like Figures 2a to 2g As shown, the inlet surface 52 of the microfluidic chip 50 can be formed after the outlet surface 54. However, this is not necessary; in further embodiments, the inlet surface 52 can be formed before or substantially simultaneously with the outlet surface 54.

[0099] It should be understood that the location, size, and orientation of one or more inlets are less important to aerosol generation than the location of nozzle 56. Therefore, a variety of methods can be used to form inlets for the microfluidic chip 50 through which liquid can enter the fluid channel 14. Inlets can be formed by the etching process discussed above, or by cutting them into the wafer 30 using a drill bit or other cutting tools.

[0100] Figure 1 The final visual appearance of the microfluidic chip 50 shown is particularly striking. The laser-modified material region 32 can be easily observed on the exit surface 54 of the microfluidic chip 50—for example, under a microscope. The laser-modified material region 32 appears as a darkened or blackened area of ​​material. The remaining unmodified material surrounding the laser-modified material region 32, forming the exit surface 54, appears particularly smooth because it is formed through a fracture process. Therefore, it is easy to distinguish the microfluidic chip 50 manufactured according to the above method from microfluidic chips manufactured using conventional methods involving mechanical cutting. Microfluidic chips produced using these cutting methods have an exit surface with a consistent appearance—that is, their material is similar in color and has a consistent texture and roughness to the rest of the material. The striking appearance of the microfluidic chip formed by the above method can be seen in… Figure 3b , 4b As seen in 5b and 6, this will be discussed further below.

[0101] Figure 1 The arrangement of the laser-modified material 32 shown in Figure 2 is a simplified schematic embodiment. The four laser-modified material regions 32 are formed as linear regions extending across most of the width of the microfluidic chip exit surface 54.

[0102] Figures 3 through 5 illustrate further embodiments of patterns of laser-modified materials that can be formed using a laser, and a series of images of microfluidic chips 60, 70, and 80 fabricated using these strip patterns, obtained by microscopy. In each case, the exit surface of the microfluidic chips 60, 70, and 80 has a greater number of laser-modified material regions.

[0103] In more detail, Figure 3a , 4a Figures 5a and 5a show schematic diagrams of three patterns in which lasers can be focused onto predetermined fracture surfaces O′ within the wafer to form internal regions 62, 72, and 82 of the laser-modified material.

[0104] After laser irradiation along these lines, the wafers can be diced using the internal regions 62, 72, and 82 of these laser-modified materials. Figure 3b , 4bFigures 5b and 5b respectively show microscopic images of the exit surfaces 64, 74, and 84 of microfluidic chips 60, 70, and 80 fabricated using their respective laser-modified material patterns 62, 72, and 82. Figure 3b , 4b The images of 5b were obtained using a Keyence (registered trademark) VHX-700 microscope at 100x magnification. Figure 3c , 4c Figures 5c show microscopic images of nozzles 66, 76, and 86 formed in their respective microfluidic chips 60, 70, and 80, obtained using a Tescan (registered trademark) VEGA3 SEM microscope at increased magnifications (3560x, 3380x, and 3470x, respectively).

[0105] Figure 3b and 3c The microfluidic chips 60, 70, and 80 shown in 4b and 4c, as well as 5b and 5c, each have a total thickness or depth of about 1.4 mm (e.g., from 1000 to 2000 micrometers) in the z direction and a width of about 2.5 mm (e.g., from 2000 to 3000 micrometers) in the y direction.

[0106] In more detail, Figure 3a The figure shows a line pattern 62' of laser-modified material formed across a predetermined fracture surface O′ across the wafer. The predetermined positions of a pair of nozzles N′ are marked with dashed lines, as well as the position of the initial interface L between the first and second substrate layers used to form the wafer and microfluidic chip before the first and second substrate layers are bonded together. The interface L between the first and second substrate layers, as well as the fluid channel plane (the plane extending from which the fluid channel extends), are parallel to the y-axis as shown.

[0107] Laser can follow Figure 3a The line pattern 62′ shown is focused to produce a corresponding linear region pattern 62 of the laser-modified material. Figure 3b The image shows the resulting microfluidic chip 60 and the linear region 62 of laser-modified material seen on the exit surface 64 of the chip 60, with the nozzle 66 within the exit surface 64... Figure 3c The details are shown in the image.

[0108] Figure 3a , 3b The laser-modified material pattern 62 shown in 3c is roughly similar to... Figure 1The embodiment shown in Figure 2. A plurality of laser-modified material linear regions 62 are formed in a predetermined fracture surface O′. These linear regions extend parallel or substantially parallel to the fluid channel plane (shown by the predetermined position of the nozzle N′) and parallel or substantially parallel to the original interface L between the first and second substrate layers forming the microfluidic chip 60 (i.e., parallel to the y-axis as shown). Each laser-modified material linear region 62 extends across the entire width of the predetermined fracture surface O′ and the microfluidic chip 70 in the y-direction (although this is not mandatory). The plurality of laser-modified material linear regions 62 can be grouped into a first plurality of linear regions 62a formed above the plane of the fluid channel extension (i.e., on the first side of the fluid channel plane), and a second plurality of linear regions 62b formed below the plane of the fluid channel extension (i.e., on the opposite second side of the fluid channel plane). The first plurality of linear regions 62a are formed by applying laser light along the first plurality of lines 62a′ in the predetermined fracture surface O′, while the second plurality of linear regions 62b are formed by applying laser light along the first plurality of lines 62b′ in the predetermined fracture surface O′.

[0109] In the direction perpendicular to the fluid channel plane, the gap between the nearest portions of adjacent linear regions 62 of the laser-modified material is typically in the range of 40 to 100 micrometers, and more preferably 50 to 90 micrometers. The distance between the centerlines of adjacent linear regions 62 of the laser-modified material is typically in the range of 50 to 150 micrometers, preferably in the range of 60 to 140 micrometers. Furthermore, the average thickness of the linear regions 62 of the laser-modified material is typically in the range of 10 to 75 micrometers, preferably in the range of 20 to 50 micrometers. The nozzle 66 has a height of approximately 5 micrometers perpendicular to the fluid channel plane (the plane on which the fluid channel extends), and a width of approximately 10 to 13 micrometers parallel to the plane on which the fluid channel extends (i.e., the dimension in the y-direction). These data are not mandatory; in further embodiments, the height and width of each nozzle 66 can range from 1 micrometer to 50 micrometers, preferably 3 to 25 micrometers. The distance between a pair of nozzles 66 is typically in the range of 30 to 75 micrometers, preferably in the range of 30 to 60 micrometers.

[0110] The nozzle 66 is preferably centered between two linear regions 62 of the laser-modified material in a direction perpendicular to the plane of the fluid channel. Therefore, the nozzle 66 can be positioned such that it is within 25% to 75% of the distance between the two closest linear regions 62 of the modified material above and below the nozzle 66.

[0111] Figure 4aThe figure shows a further line pattern 72' for forming the laser-modified material 72 across a predetermined fracture surface O' of the wafer. Similarly, the predetermined positions of a pair of nozzles N' and the initial interface L between the first and second substrate layers for forming the wafer are indicated by dashed lines. The nozzles N' also indicate the positions of fluid channel planes extending parallel to the y-axis through the wafer. A laser can be focused along the line pattern 72' in the figure to produce the corresponding laser-modified material region pattern 72. Figure 4b and 4c The microfluidic chip 70 manufactured using the laser-modified material pattern 72 is shown.

[0112] Figure 4a , 4b The laser-modified material pattern 72 shown in 4c includes a plurality of laser-modified material linear regions 72 formed in a predetermined fracture surface O′. These linear regions extend parallel or substantially parallel to a fluid channel plane defined by fluid channels extending through the microfluidic chip 70, and parallel or substantially parallel to the original interface L between the first and second substrate layers forming the microfluidic chip 70 (i.e., parallel to the y-axis as shown). The plurality of laser-modified material linear regions 72 can be further grouped into a first plurality of linear regions 72a located above the plane of the fluid channel extension (i.e., on the first side of the fluid channel plane), and a second plurality of linear regions 72b located below the plane of the fluid channel extension (i.e., on the opposite second side of the fluid channel plane). The first plurality of linear regions 72a are formed by applying laser light along the first plurality of lines 72a′ in the predetermined fracture surface O′, while the second plurality of linear regions 72b are formed by applying laser light along the first plurality of lines 72b′ in the predetermined fracture surface O′.

[0113] Unlike the embodiment shown in Figure 3, the lines 72a′, 72b′ to which the laser should be applied, and the linear region 78 of the laser-modified material, do not extend across the entire width of the microfluidic chip 70. Instead, Figure 4aThe lines 72' shown are separated by regions 78' where laser light should not be applied. Therefore, in the microfluidic chip 70 manufactured according to this pattern, each of the first and second plurality of linear regions 72a, 72b is arranged as pairs of collinear regions 72 of laser-modified material, such that the two collinear regions 72 in each pair are separated by unmodified material. The gaps between each pair of collinear regions 72 are aligned in the z-direction, perpendicular to the fluid channel plane. Therefore, unmodified material regions 78 are formed perpendicular to the plane forming the fluid channel across the outlet surface 74 of the microfluidic chip 70. Nozzles 76 are positioned within these unmodified material regions 78, positioned between the pairs of collinear regions 72 of laser-modified material in the y-direction. Preferably, a pair of nozzles 76 are centrally positioned within the unmodified material regions 78 (i.e., centrally positioned between the pairs of collinear regions 72 of laser-modified material in the y-direction). For example, the center of the pair of nozzles can be located in the range of 20% to 80% of the distance across the unmodified material region 78, more preferably in the range of 25% to 75% of the distance.

[0114] The unmodified material region 78 extends across the entire height of the microfluidic chip 70 (although this is not mandatory; in some cases, the unmodified material region may extend across at least 75% or at least 50% of the chip height). The unmodified material region 78 typically has a width in the range of 100 to 300 micrometers. The nozzle 76 is preferably centered in the z-direction perpendicular to the fluid channel plane between two pairs of adjacent laser-modified material linear regions 72. Thus, the nozzle 76 can be positioned such that it lies within 25% to 75% of the distance between the two closest pairs of collinear laser-modified material regions 72 above and below the nozzle 76 in the direction perpendicular to the fluid channel plane.

[0115] The gap between adjacent linear regions 72 of laser-modified material in the z-direction, the distance between the centerlines of adjacent linear regions 72 of laser-modified material in the z-direction, and the thickness of the linear regions 72 of laser-modified material are similar to the corresponding dimensions discussed above with reference to FIG3. The nozzle 76 has similar dimensions and spacing to those in the corresponding figures discussed above with reference to FIG3.

[0116] Figure 5a The figure shows a further line pattern 82' for forming the laser-modified material 82 across a predetermined fracture surface O' of the wafer. Similarly, the predetermined positions of a pair of nozzles N' and the initial interface L between the first and second substrate layers for forming the wafer are indicated by dashed lines. A laser can be focused along the line pattern 82' shown in this figure to produce the corresponding laser-modified material region pattern 82. Figure 5b and 5c The microfluidic chip 80 manufactured using the laser-modified material pattern 82 is shown.

[0117] Figure 5b The laser-modified material pattern 82 shown includes multiple laser-modified material linear regions 82 formed in a predetermined fracture surface O′. These linear regions extend parallel or substantially parallel to the plane (i.e., the fluid channel plane) through which the fluid channel extends through the microfluidic chip 80. These linear regions also extend parallel or substantially parallel to the original interface L between the first and second substrate layers forming the microfluidic chip 80 (i.e., parallel to the y-axis as shown).

[0118] The multiple laser-modified material linear regions 82 can be further grouped into a first plurality of linear regions 82a located above the plane extending from the fluid channel (i.e., on the first side of the fluid channel plane), and a second plurality of linear regions 82b located below the plane extending from the fluid channel (i.e., on the opposite second side of the fluid channel plane). The first plurality of linear regions 82a are formed by applying laser light along the first plurality of lines 82a' in a predetermined fracture surface O', while the second plurality of linear regions 82b are formed by applying laser light along the first plurality of lines 82b' in the predetermined fracture surface O'.

[0119] The linear regions 82a in the first plurality (i.e., the regions on one side of the fluid channel plane) extend across the entire width of the microfluidic chip 80. Conversely, the linear regions 82b in the second plurality are formed as a series of pairs of collinear regions 82 of laser-modified material. The two collinear regions 82 of laser-modified material in each pair are separated by unmodified material. Therefore, the unmodified material defines a gap between the two collinear regions 82 of laser-modified material in each pair within the second plurality of linear regions 82b. The gaps in each pair of collinear regions 82 of laser-modified material in the second plurality are aligned in the z-direction perpendicular to the fluid channel plane and define an unmodified material region 88. This unmodified material region 88 corresponds to... Figure 8a The gap in the line pattern shown is where no laser is applied to the predetermined fracture surface O′.

[0120] Nozzles 86 are positioned in the y-direction between pairs of collinear regions 82b of the laser-modified material. Therefore, the unmodified material region 88 extends from nozzles 86 across the outlet surface 84 of the microfluidic chip 80 to the bottom edge 84b of the microfluidic chip 80. Preferably, the pair of nozzles 86 are centrally positioned within the unmodified material region 88 (i.e., centrally positioned in the y-direction between the pairs of collinear laser-modified material regions 82). For example, the center of the pair of nozzles can be positioned within a range of 25% to 75% of the distance spanning the unmodified material region 88.

[0121] Furthermore, nozzle 86 is positioned between the closest linear regions among the first plurality of regions and the closest pair of collinear regions among the second plurality of regions. Preferably, in a direction perpendicular to the fluid channel plane, nozzle 86 is preferably centered between the two closest linear regions 82 of the laser-modified material above and below nozzle 86. Nozzle 66 may be positioned such that, in a direction perpendicular to the fluid channel plane, it is within 25% to 75% of the distance between the two closest linear regions 62 of the modified material above and below nozzle 66.

[0122] The unmodified material region 88, defined by the second plurality of linear regions, typically has a width ranging from 100 to 300 micrometers. The gap between adjacent laser-modified material linear regions 82 in the z-direction, the distance between the centerlines of adjacent laser-modified material linear regions 82 in the z-direction, and the thickness of the laser-modified material linear regions 82 are similar to the corresponding dimensions discussed above with reference to Figures 3 and 4. The nozzle 86 has similar dimensions and spacing to those in the corresponding figures discussed above with reference to Figures 3 and 4.

[0123] Figure 6a and 6b Further images are shown, obtained using a Keyence (registered trademark) VHX-700 microscope at magnifications of 400x and 1000x respectively, demonstrating the use of... Figure 5a The line pattern 82′ shown depicts the outlet surface of the microfluidic chip 80. It can be seen that laser-modified material regions 82 are formed across the outlet surface. These regions are linear and aligned parallel to the direction in which the fluid channel extends through the microfluidic chip 80, a direction observable from the position of the nozzle 86. The linear region 82a of the laser-modified material 82 above the nozzle 86 and above the fluid channel plane extends across the entire width of the outlet surface. The linear region 82b of the laser-modified material 82 below the nozzle 86 (i.e., on the opposite side of the plane forming the fluid channel) is discontinuous, formed by multiple collinear laser-modified material regions 82. The gaps between the collinear laser-modified material regions 82 form relatively smooth unmodified regions 88. The nozzle 86 is aligned and positioned within the unmodified region 88, as shown, which extends from the nozzle 86 to the bottom edge of the outlet surface.

[0124] Although Figure 1 Figure 6 illustrates a specific embodiment of the laser-modified material arrangement on the microfluidic chip and its outlet surface. However, it should be understood that various laser-modified material arrangements can be formed on the predetermined fracture surface O′ of the wafer. For example, in a further embodiment, the laser-modified material does not need to be formed as a linear region. Similarly, the laser-modified material region does not need to be arranged parallel to the fluid channel plane extending from the fluid channel.

[0125] Preferably, sufficient laser-modified material is provided on the predetermined fracture surface O′ to ensure that the crack propagates through the predetermined fracture surface O′ and the wafer is cleaved as intended under mechanical stress. The laser-modified material may be formed on at least 5%, preferably at least 10%, more preferably at least 15%, and even more preferably at least 20% of the area of ​​the predetermined fracture surface.

[0126] When the laser-modified material is provided as a linear region parallel to the plane of the fluid channel extending from the fluid channel, the laser is preferably applied in the form of strips across substantially the entire width of the predetermined fracture surface O′ to ensure that the wafer is smoothly cleaved across its entire width. These strips may be formed from a single linear region or a set of collinear regions. In each case, the laser-modified material region extends across at least 75%, more preferably at least 80%, and even more preferably at least 90% of the width of the microfluidic chip exit surface.

[0127] However, it is important to ensure that the laser beam's focus is not applied to the material in the predetermined fracture surface O′ too close to the intended location on the nozzle. If the laser is applied too close to the fluid channel, the heat from the laser may melt or crack the material in a localized area of ​​the nozzle, or affect the nozzle's shape. If nozzles are damaged in this way, they may fail to guide the liquid jet in the intended manner. Consequently, the liquid jet from the nozzle may not strike the target correctly and may not form an aerosol. For example, the jet may only partially strike or miss its intended target, or the jet velocity may be higher or lower than expected.

[0128] Figure 9a and 9b Examples of two pairs of nozzles 90, 95 that do not exhibit the expected rectangular shape are shown. Figure 9a The images were obtained using a Tescan (registered trademark) VEGA3 SEM microscope at a magnification of 3110x. Figure 9b The images were obtained using a Keyence VHX-700 microscope at 1000x magnification. In each case, the microfluidic chip was fabricated according to the laser-modified material pattern discussed above with reference to Figure 3. However, in each case, the distance between the nozzles 90, 95 and the nearest laser-modified material regions 91, 96 is very close. Therefore, as in Figure 3c , 4c As seen in the embodiment shown in 5c, the nozzle is not rectangular and uniform. Instead, in Figure 9a In the middle, a series of "tooth marks" or recesses 92 are formed in the opening leading to the nozzle 90. These recesses 92 can... Figure 9a Seen above nozzle 90. In contrast, Figure 9bThe nozzle 95 shown also exhibits these "tooth marks" or indentations 92, and a notch 97 is formed in the outlet surface below each nozzle 95. It contains... Figure 9a and 9b The microfluidic chip with the deformed nozzle shown cannot consistently generate impacting liquid jets or consistently produce aerosols. Therefore, the manufacturing yield of a functional microfluidic chip is reduced.

[0129] To avoid these problems and improve yield, preferably, the nozzle (and the predetermined position of the nozzle) is at least 15 micrometers away from the corresponding nearest laser-modified material region. More preferably, the distance between each nozzle and the corresponding nearest laser-modified material portion is at least 15 micrometers, 20 micrometers, 30 micrometers, or 35 micrometers. In a particularly preferred embodiment, the distance between each nozzle and the corresponding nearest laser-modified material portion in a direction parallel to the fluid channel plane is at least 15 micrometers, or more preferably 20 micrometers, 25 micrometers, or 30 micrometers, and / or the distance between each nozzle of the microfluidic chip and the corresponding nearest laser-modified material portion in a direction perpendicular to the fluid channel plane is at least 15 micrometers, or more preferably 20 micrometers, 25 micrometers, or 30 micrometers. Therefore, microfluidic chips manufactured using the laser patterns according to the embodiments shown in Figures 4, 5, and 6 tend to provide higher yields than the patterns in Figure 3 because the unmodified regions 78, 88 where the nozzles 76, 86 are located provide greater margin for material modification. Errors in laser focus positioning are unlikely to affect the performance of the microfluidic chip.

[0130] Conversely, if the laser-modified material is too far from the intended position of the nozzle, the wafer may not be able to fracture to leave a smooth surface on the nozzle. Due to the large gap between the laser-modified material area and the nozzle, ridges or discontinuities may form, affecting the relative positioning of the nozzle and the direction of the liquid jet ejection from the microfluidic chip. For example, in Figure 4b and 4cA ridge 79 extending between the two nozzles can be observed, resulting from a large area of ​​unmodified material 78 extending across the entire height of the microfluidic chip. While in this embodiment, the ridge 79 is small enough and sufficiently centered between the nozzles that it does not affect the performance of the microfluidic chip shown in FIG. 4, the margin of error for the nozzle 76 position is reduced. Therefore, microfluidic chips fabricated according to the patterns shown in FIG. 5 and 6 tend to offer improved yields compared to FIG. 4 (and FIG. 3 as described above). Thus, the distance between each nozzle of the microfluidic chip and the corresponding nearest laser-modified material portion is at most 250 micrometers, preferably at most 200 micrometers, more preferably at most 150 micrometers, even more preferably at most 125 micrometers, and even more preferably at most 100 micrometers. For example, the distance between each nozzle of the microfluidic chip and the corresponding nearest laser-modified material portion in a direction perpendicular to the fluid channel plane is preferably at most 100 micrometers, preferably at most 75 micrometers, and even more preferably at most 50 micrometers. Furthermore, the distance between each nozzle of the microfluidic chip and the corresponding nearest laser-modified material portion in a direction parallel to the fluid channel plane is preferably at most 150 micrometers, more preferably at most 100 micrometers, and even more preferably at most 75 micrometers.

[0131] It should be noted that, Figure 1 Each pair of nozzles shown in Figures 2 and 3 through 6 is located at the center of the outlet surface of the corresponding microfluidic chips 50, 60, 70, and 80. Therefore, each pair of nozzles is located approximately halfway down the depth of the microfluidic chip (perpendicular to the fluid channel plane extending from which the fluid channel extends and parallel to the z-axis as shown), which is typical when the substrate layers forming the wafer are of equal thickness. Furthermore, each pair of nozzles is located approximately halfway down the width of the outlet surface (parallel to the fluid channel plane and parallel to the y-axis as shown). However, this is not mandatory. For example, in some embodiments, the two substrate layers used to fabricate the microfluidic chip may have different depths, such that the nozzles of the microfluidic chip are located at different heights within the microfluidic chip. Additionally, the fluid channels formed within the microfluidic chip may include a layout that results in the nozzles not being located at the center of the outlet surface width.

[0132] In addition, although Figure 1In Figures 2 and each of Figures 3 through 6, microfluidic chips 50, 60, 70, and 80 include a pair of nozzles, but this is not mandatory. For example, alternative microfluidic chips may include a set of three or more nozzles configured to direct their respective liquid jets so that they collide with each other to form an aerosol. In a further embodiment, the microfluidic chip may include a single nozzle configured to direct a liquid jet into a wall or other permanent structure. When the liquid jet collides with the wall, the liquid may aerosolize. This wall or other permanent structure may be part of a device (e.g., an inhaler) in which the microfluidic chip is placed. Similarly, in a further embodiment, the microfluidic chip may include multiple pairs or sets of nozzles, wherein each pair or set is configured to cause its respective liquid jets to collide with each other.

[0133] Preferably, in the method discussed above, the laser beam is applied to the microfluidic chip from one side of the wafer—that is, one side of the fluid channel plane extending from the fluid channel. In practice, as... Figure 2d As shown, the laser source 40 located above the wafer 30 is used to irradiate the wafer and form regions 32 and 32b of laser-modified material 32 above the fluid channel plane extending the fluid channel, and regions 32c and 32d of laser-modified material below the fluid channel plane (and located above and below the initial position of the interface L between the first substrate layer and the second substrate layers 10 and 20).

[0134] Compared to the "double-sided" method, which applies a laser beam to the wafer from each side, the "single-sided" method is faster and more efficient. For example, it eliminates the need for a separate laser source on each side of the wafer. Similarly, it eliminates the need for methods that use a single laser source and involve additional steps—such as irradiating the first side of the wafer with a laser relative to the plane of the fluid channel, then rotating or flipping the wafer 180 degrees, and subsequently irradiating the second side of the wafer.

[0135] Figure 7 The steps in this bifacial method involving flipping wafer 100 to fabricate microfluidic chips are shown. (As...) Figure 7 As shown on the left, laser source 110 applies laser beam 111 to a first side 101 of wafer 100 to form a first plurality of laser-modified material regions (e.g., the first plurality of laser-modified material regions discussed above with reference to Figures 3 to 5) on the first side of the fluid channel plane. The wafer is then rotated or flipped 180 degrees. Subsequently, laser source 110 applies laser beam 111 to an opposite second side 102 of wafer 100 to form a second plurality of laser-modified material regions (e.g., the second plurality of laser-modified material regions discussed above with reference to Figures 3 to 5) on the second side of the fluid channel plane.

[0136] Compared to the double-sided method, the single-sided method can improve the yield of microfluidic chips with correctly formed aerosols. This is because it is difficult to align the laser-modified material regions formed by laser irradiation from different sides of the wafer relative to the fluid channel plane extending relative to the fluid channel, causing their positions to correspond to the predetermined fracture surface. Any misalignment between the laser-modified material regions can create steps or gaps in the exit surface of the microfluidic chip as cracks propagate along different paths within the wafer.

[0137] A comparison of microfluidic chips fabricated using single-sided and double-sided methods is shown. Figure 8a , 8b And in 8c. Figure 8a , 8b The images in 8c were obtained using a Keyence (registered trademark) VHX-700 microscope at magnifications of 100x, 100x, and 700x, respectively.

[0138] Figure 8a A portion of the outlet surface of a microfluidic chip 120 formed using a one-sided method is shown. The microfluidic chip 120 includes a substantially flat outlet surface without any notches or ridges. The edges 121 of the microfluidic chip 120 can be seen to be straight.

[0139] on the contrary, Figure 8b A microfluidic chip 130 formed using a double-sided method is shown. As shown, the edge 131 of the microfluidic chip 130 is not straight because the positioning of the laser-modified material formed by laser beams incident from different sides of the wafer was misaligned during manufacturing. Figure 8b The microfluidic chip 130 shown includes a prominent notch 132 on its outlet surface. This notch 132 allows for... Figure 8c At a higher magnification, Figure 8c The area of ​​the microfluidic chip 130 shown in the image is approximately composed of Figure 8b The dotted box above shows the notch 132. Although the notch 132 is most easily seen at the edge 131 of the microfluidic chip 130, it extends across the entire width of the outlet surface of the microfluidic chip 130.

[0140] Such as Figure 8b and 8c The notch in the illustrated embodiment affects the relative position of the nozzles within the outlet surface of the microfluidic chip, as well as the direction in which the liquid jet is guided from the microfluidic chip. Therefore, a one-sided approach to manufacturing microfluidic chips tends to provide improved yield because the liquid jet ejected from the chip is more likely to collide in the intended manner and form an effective aerosol.

[0141] Nevertheless, the double-sided method can still produce microfluidic chips with relatively high yields if the transition between laser-modified material regions formed from different sides of the wafer using a laser is not close to the nozzle or the predetermined position of the nozzle. For example, in a preferred embodiment, the method includes irradiating the wafer with a laser to form a plurality of laser-modified material linear regions, wherein the laser-modified material linear regions extend in a direction substantially parallel to the fluid channel plane extending from the fluid channel, and wherein two or more laser-modified material linear regions are provided at different distances from the fluid channel plane on either side, as shown in Figures 2, 3, 4, and 5, and wherein at least these laser-modified material linear regions closest to the fluid channel plane on each side of the fluid channel plane are formed using a laser beam from a laser source located on one side of the wafer relative to the fluid channel plane. Therefore, at least the laser-modified material linear regions (or the closest collinear region groups) on each side of the nozzle in a direction perpendicular to the fluid channel plane are irradiated from the same side of the wafer. In a further preferred embodiment, at least two, three, or four linear regions of laser-modified material closest to the fluid channel plane on each side are formed using a laser beam from a laser source on one side of the wafer.

[0142] For example, Figure 10 Showing Figure 3a The modified version of the line pattern shown is provided, wherein the different shaded lines of the line pattern correspond to areas of laser-modified material that should be formed using lasers from opposite sides of wafer 30. Figure 10 The line pattern 132' shown can be used to produce lines with similar characteristics. Figure 3b and 3c The microfluidic chip showing the outlet surface and nozzle.

[0143] and Figure 3a Same, Figure 10The diagram shows a linear array 132' corresponding to the path on which the laser focus should be applied in the predetermined fracture surface O', and the resulting location of a linear region of laser-modified material within the predetermined fracture surface O'. Line 132' extends parallel to the y-direction and parallel to the fluid channel plane extending from the fluid channel and the initial interface L between the first and second substrate layers. The predetermined location of the nozzle is defined by the location of the fluid channel and is indicated by the dashed line N'. The predetermined location of the nozzle N' also indicates the location of the fluid channel plane within the wafer. It can be seen that all lines 132a' above the fluid channel plane and the two closest lines 132b' below the fluid channel plane (as shown by the bold downward shading) will be irradiated using a laser beam emitted from a source located on the same side of the wafer. All the remaining lines 132c' extending away from the fluid channel plane (shown by the fine upward shading) will be irradiated using a laser source located on the opposite side of the wafer—for example, a second laser source located on the opposite side of the wafer or the same laser source relative to that laser source after wafer flipping.

[0144] The above reference Figures 1 to 10 The process described for wafer dicing can also be used in methods for forming multiple microfluidic chips from a single wafer. See below for reference. Figures 11a to 11e These processes are discussed. According to the method steps of these embodiments of the invention, multiple microfluidic chips are simultaneously formed from the same wafer.

[0145] Fluid channels for multiple microfluidic chips can be formed inside a large wafer, which is then diced using the laser irradiation process discussed above to form individual microfluidic chips. This monolithic process is particularly efficient. Furthermore, this process and the microfluidic chips offer the benefits corresponding to the embodiments discussed above.

[0146] Figure 11a The steps of providing a first substrate layer 210 and forming a fluid channel array 214 in the surface 211 of the substrate layer 210 are shown. The fluid channels 214 correspond to a plurality of microfluidic chips and include an array of repeating identical individual fluid channel units 215. Each individual fluid channel unit corresponds to a single microfluidic chip and contains fluid channels for said microfluidic chip. (Refer to the above text.) Figure 2b As discussed, the fluid channel 214 can be etched into the surface of the first substrate layer 210. Subsequently, a second substrate layer 220 is provided over the first substrate layer 210, and the first and second substrate layers 220, 210 are bonded together to form a structure as described above. Figure 11b The single wafer 230 is shown. This bonding step is equivalent to the one referenced above. Figure 2c The steps discussed enclose the fluid channel 214 within the wafer 230. The first and second substrate layers 210 and 220, as well as the wafer 230, are circular, although this is not mandatory.

[0147] Subsequently, as Figure 11c As shown, a laser beam 242 from a laser source 240 is used to irradiate a wafer 230. The laser beam 242 is focused within the wafer 230 to form an array of internal regions of a laser-modified material 232 within the wafer 230, the locations of which relate to an array of predetermined fracture surfaces that define the boundaries of multiple microfluidic chips formed using this process. The laser-modified material 232 is weaker than the surrounding material of the wafer 230, and cracks will propagate from the laser-modified material 232 under stress. The locations of the laser-modified material 232 formed within the wafer 230 correspond to the boundaries between repeating fluid channel units 215 within the wafer 230, such that dicing the wafer along the laser-modified material 232 will divide the wafer 230 into individual microfluidic chips. The process of forming the laser-modified material 232 corresponds to the methods discussed above, particularly regarding... Figure 2d The method involves laser-modified material 232 preferably arranged to cut through fluid channels to form nozzles and inlets in the corresponding inlet and outlet surfaces of the microfluidic chip.

[0148] As previously described, after the laser-modified material 232 is generated, mechanical stress is applied to the wafer 230 to cause cracks to propagate from the laser-modified material 232 through the wafer 230, thereby dicing or cutting the wafer 230 into individual microfluidic chips. This corresponds to the above reference. Figure 2e and 2f The process described.

[0149] exist Figure 11d and 11e The schematic cross-section shows a preferred process for applying mechanical stress and dividing wafer 230 in this manner. (e.g.) Figure 11d As shown, wafer 230 is first applied to expandable dicing tape 240, which is secured by clamps 250 along its edges. Subsequently, piston 260 rises from below the dicing tape 240, contacting the side of the dicing tape 240 opposite to the side on which wafer 230 was applied. The movement of the piston is controlled by… Figure 11e Arrow P indicates that piston 260 deflects the cutting tape 240 relative to clamp 250. This deflection of the cutting tape 240 causes it to expand in a plane parallel to the extension direction of wafer 230, thus applying tensile stress to wafer 230. The expansion of the cutting tape 240 is caused by… Figure 11e Arrow D is shown in the diagram. Although the expansion is... Figure 11eWhile displayed as a single dimension, in practice it preferably occurs in two dimensions, namely radially from the center of wafer 230, as jig 250 extends around the periphery of cutting tape 240. The tensile stress applied to wafer 230 causes cracks to propagate from laser-modified material 232, separating wafer 230 into individual microfluidic chips 270, each including a separate set of fluid channels, inlets, and nozzles, and configured to generate an aerosol from the liquid received at its inlet.

[0150] Figure 12 The image shows the etched pattern of an individual fluid channel unit 215 within a larger array of identical fluid channel units. Such etched patterns are well-suited for use in... Figures 11a to 11e The method shown uses a fluid channel unit 215 comprising a plurality of inlet channels 215a and two outlet channels 215b, which converge at an intersection in a triangular arrangement. An internal cavity 215c is provided between the inlet channels 215a and the outlet channels 215b. In a particularly preferred embodiment, the internal cavity 215c includes an array of protrusions that can filter liquid passing through the final microfluidic chip.

[0151] Figure 12 The dashed lines H and V separate fluid channel unit 215 from adjacent fluid channel units and form a predetermined fracture surface. The wafer with the fluid channel units formed can be irradiated with a laser along these lines to create laser-modified material regions within the wafer. These laser-modified material regions are weak points from which cracks can easily propagate when mechanical stress is applied to the wafer. Of particular note is... Figure 12 A horizontal dashed line H extends through the inlet channel 215a of the first fluid channel unit 215 and the outlet channel 216b of the adjacent second fluid channel unit 216. Dividing the wafer along this line simultaneously forms the inlet surface of the first microfluidic chip containing the fluid channel inlet, and the outlet surface of the second microfluidic chip containing the nozzle connected to the outlet channel. This minimizes the number of lines required to divide the wafer to obtain the microfluidic chip and increases the number of chips that can be accommodated on each wafer. Nevertheless, various arrangements of fluid channels on the wafer and methods of wafer dicing are possible.

[0152] The microfluidic chip described above can be used to generate aerosols within an inhaler system. In particular, this microfluidic chip is well-suited for use in soft mist inhaler systems, where it can receive liquid medications under pressure and convert them into inhalable aerosols.

[0153] Figure 13 An inhaler system 300 incorporating a microfluidic chip 400 according to any of the above embodiments is shown. The inhaler system 300 is configured to store liquid medication and dispense it as an aerosol.

[0154] The inhaler system 300 includes a body 310 into which a replaceable cartridge 320 can be inserted. The cartridge 320 includes an internal volume 321 in which liquid, such as a liquid medication, can be stored. The inhaler system 300 also includes a cartridge cap 330 configured to attach to the body 310 and surround and protect the cartridge 320 inserted into the body 310.

[0155] The inhaler system 300 also includes a hollow tube 340 through which the contents of the cartridge 320 are dispensed. Inserting the cartridge 320 into the inhaler system 300 involves pushing the proximal end 341 of the tube 340 into the cartridge 320. The cartridge 320 can be manually inserted into the inhaler system 300, but this is not mandatory.

[0156] A one-way valve 343 (sometimes also called a check valve) is provided at the distal end 342 of the tube 340 opposite its proximal end 341. As shown, the one-way valve 343 is located within the tube 340 and is configured to allow fluid to flow in the direction from the proximal end 341 to the distal end 342 of the tube 340, but prevent fluid from flowing in the opposite direction. In an alternative embodiment, the one-way valve 343 may be located at another location within the fluid path of the contents of the cartridge 310 out of the inhaler system 300.

[0157] The inhaler system 300 also includes a filter 350 configured to receive liquid that has passed through the tube 340. The filter 350 is configured to allow liquid to pass through but prevent solid particles within the liquid from passing through. The microfluidic chip 400 according to the invention is configured to receive the liquid that has passed through the filter 350 and convert the liquid passing through it into an aerosol. The aerosol can then be dispensed to a user through a mouthpiece 360, which the user can insert into their mouth. The mouthpiece 360 ​​is protected by a mouthpiece cap 361. The mouthpiece cap 361 is mounted on a hinge 362 and is rotatable about the hinge 362 between open and closed positions. Figure 5 shows the mouthpiece cap 361 in the closed position.

[0158] The inhaler system 300 also includes a tensioner body 370 configured to receive the cap of the cartridge 320 when it is inserted into the inhaler system 300. The tensioner body 370 is connected to the body 310 by a spring 380, which biases the tensioner body 370, the tube 340, and any cartridge 320 received in the inhaler system 300 toward the mouthpiece 360 ​​of the inhaler system 300.

[0159] When the inhaler system 300 is to be used, the tensioner body 370, tube 340, and cartridge 310 are moved away from the mouthpiece 360 ​​to precharge the system. This movement increases the size of the precharge volume 390 between the distal end 342 of the tube 340 and the filter 350. As this volume increases, its pressure decreases, drawing liquid from the cartridge 320 through the tube 340 and past the check valve 343. The inhaler system 300 is then triggered by releasing the tensioner body 370, tube 340, and cartridge 310. A spring 380 forces the tensioner body 370, tube 340, and cartridge 310 back toward the mouthpiece 360, thereby driving the liquid in the precharge volume 390 through the filter 350 and through the microfluidic chip 400 under high pressure, as the liquid cannot flow back through the one-way valve 343. Specifically, the inhaler system 300 provides the liquid microfluidic chip 400 with a pressure ranging from 50 to 600 bar, preferably 100 to 400 bar, more preferably 150 to 350 bar, and even more preferably 200 to 300 bar. The microfluidic chip 400 and its nozzle generate an aerosol mist from the liquid, which the user inhales through the mouthpiece 360. If multiple aerosol sprays are required to form an appropriate dose of medication, the pre-filling and triggering steps can be repeated. Inhalers and cartridges with alternative triggering mechanisms are also possible.

[0160] The inhaler system 300 is a soft mist inhaler system that produces a relatively slowly diffusing aerosol (mist). The inhaler system 300 can be configured to dispense the aerosol at a velocity of 2 m / s or less, preferably 1.6 m / s or less, more preferably less than 1 m / s, when measured at a distance of 10 cm from the mouthpiece or nozzle, and / or the dispensing or nebulization of one dose requires a time longer than 0.7 seconds, and preferably at least 1 second.

[0161] Preferably, the inhaler system is configured to dispense fluid in doses ranging from 0.5 μL to 50 μL, more preferably from 0.5 μL to 30 μL, and even more preferably from 10 to 20 μL. The intended dose of medication from the inhaler may include a single inhalation or multiple inhalations (e.g., two inhalations). Preferably, the inhaler system 300 and the microfluidic chip 400 are configured to dispense droplets with an average diameter ranging from 1 to 10 micrometers, preferably from 2 to 6 micrometers, and more preferably from 3 to 5 micrometers.

[0162] Preferably, the inhaler system 300 is a multi-dose inhaler system, wherein the cartridge 320 is configured to store multiple doses of liquid medication. Preferably, the capacity or internal volume of the cartridge 320 is in the range of 0.5 to 10 ml, more preferably in the range of 1 to 5 ml.

[0163] The methods, microfluidic chips, and inhaler systems discussed above have high manufacturing yields, are easy and clean to manufacture, and are economical to produce.

Claims

1. A method for manufacturing a microfluidic chip for generating aerosols from a liquid, wherein, The method includes: One or more fluid channels are formed in the surface of the first substrate layer, wherein the fluid channels extend in a fluid channel plane; A second substrate layer is provided in contact with the surface of the first substrate layer, and the first substrate layer and the second substrate layer are bonded together to form a wafer, the wafer including the one or more fluid channels extending therethrough; The wafer is diced to form the microfluidic chip; Wherein, the fluid channel in the microfluidic chip defines at least one nozzle in the outlet surface of the microfluidic chip; And wherein dicing the wafer to form the microfluidic chip includes: The wafer is irradiated with a laser, wherein the laser is focused inside the wafer to create one or more laser-modified material interior regions within the wafer; Wherein, the one or more laser-modified material interior regions extend within a predetermined fracture surface that defines the desired arrangement of the outlet surface of the microfluidic chip; and Mechanical stress is applied to the wafer to cause the wafer to fracture along the predetermined fracture surface and form the outlet surface and nozzle of the microfluidic chip.

2. The method according to claim 1, wherein the distance between each nozzle and the corresponding nearest laser-modified material portion is at least 15 micrometers, preferably at least 20 micrometers, more preferably at least 25 micrometers, and even more preferably at least 30 micrometers.

3. The method according to any one of the preceding claims, wherein: In a direction parallel to the plane of the fluid channel, the distance between each nozzle and the corresponding nearest laser-modified material portion is at least 15 micrometers, preferably at least 20 micrometers, more preferably at least 25 micrometers, and even more preferably at least 30 micrometers; and / or In a direction perpendicular to the plane of the fluid channel, the distance between each nozzle and the corresponding nearest laser-modified material portion is at least 15 micrometers, preferably at least 20 micrometers, more preferably at least 25 micrometers, and even more preferably at least 30 micrometers.

4. The method according to any one of the preceding claims, wherein the distance between each nozzle and the corresponding nearest laser-modified material portion is at most 250 micrometers, preferably at most 200 micrometers, more preferably at most 150 micrometers, even more preferably at most 125 micrometers, and even more preferably at most 100 micrometers.

5. The method according to any one of the preceding claims, wherein: Wherein, in a direction perpendicular to the plane of the fluid channel, the distance between each nozzle and the corresponding nearest laser-modified material portion is at most 150 micrometers, preferably at most 100 micrometers, more preferably at most 75 micrometers, and even more preferably at most 50 micrometers; and / or In a direction parallel to the plane of the fluid channel, the distance between each nozzle and the corresponding nearest laser-modified material portion is at most 150 micrometers, preferably at most 100 micrometers, and even more preferably at most 75 micrometers.

6. The method according to any one of the preceding claims, wherein, The maximum size of each nozzle in the plane of the outlet surface is 25 micrometers or less, preferably 15 micrometers or less, more preferably 10 micrometers or less, and even more preferably 5 micrometers or less; Preferably, the height and width of the nozzle on the outlet surface are each in the range of 1 to 25 micrometers, more preferably in the range of 3 to 15 micrometers.

7. The method according to any one of the preceding claims, wherein, The fluid channel defines at least two nozzles in the outlet surface of the microfluidic chip, the at least two nozzles being configured to direct their respective liquid jets toward each other.

8. The method according to claim 7, wherein, The distance between any two of the at least two nozzles is in the range of 20 to 100 micrometers, more preferably in the range of 25 to 60 micrometers, and even more preferably in the range of 30 to 50 micrometers.

9. The method according to any one of the preceding claims, wherein, The first substrate layer and the second substrate layer are formed of silicon or glass.

10. The method according to any one of the preceding claims, wherein, The first substrate and the second substrate are formed of the same material, wherein preferably, the first substrate and the second substrate are formed of silicon.

11. The method according to any one of the preceding claims, wherein, The one or more laser-modified material interior regions include multiple laser-modified material linear regions extending in a direction parallel to the fluid channel plane.

12. The method according to claim 11, wherein, At least one of the linear regions of the laser-modified material extends across the entire width of the predetermined fracture surface in a direction parallel to the plane of the fluid channel.

13. The method according to claim 11, wherein, The linear regions of the laser-modified material are arranged into a group of collinear regions of the laser-modified material; Each group of collinear regions of laser-modified materials includes at least two linear regions of laser-modified materials separated by unmodified materials.

14. The method according to claim 13, wherein, The corresponding unmodified material portions of the laser-modified materials separated in the collinear region group of the laser-modified materials are preferably aligned in a direction parallel to the plane of the fluid channel, such that the collinear region group of the laser-modified materials defines the unmodified material regions extending between them.

15. The method according to claim 13 or claim 14, wherein, The distance between the laser-modified material regions in each collinear region group of laser-modified materials is in the range of 100 to 300 micrometers, preferably 125 to 250 micrometers, and even more preferably 125 to 200 micrometers.

16. The method according to any one of claims 13 to 15, wherein, The nozzle is positioned within the unmodified material region, and preferably, the unmodified material region extends from the nozzle to at least one edge of the predetermined fracture surface in a direction perpendicular to the plane of the fluid channel.

17. The method according to any one of claims 11 to 16, wherein, The nozzle is positioned at: Between two adjacent linear regions of laser-modified material in a direction perpendicular to the plane of the fluid channel; or Between two collinear regions of laser-modified materials in a direction parallel to the plane of the fluid channel.

18. The method according to any one of claims 11 to 17, wherein, In a direction perpendicular to the plane of the fluid channel, the distance between the centerlines of adjacent linear regions of laser-modified material or the distance between the centerlines of adjacent collinear regions is in the range of 50 to 300 micrometers, more preferably 75 to 200 micrometers, and even more preferably 75 to 150 micrometers.

19. The method according to any one of the preceding claims, wherein, Irradiating the wafer with a laser includes irradiating the wafer with a laser from one side of the wafer.

20. The method according to any one of the preceding claims, wherein, The one or more laser-modified material internal regions include linear regions of laser-modified material extending in a direction parallel to the fluid channel plane. At least one linear region of the laser-modified material is provided on each side of the fluid channel plane; And the process of irradiating the wafer with a laser includes: The wafer is irradiated with a laser from one side to form one or more linear regions of the nearest laser-modified material on each side of the fluid channel plane.

21. The method according to any one of the preceding claims, wherein: The laser-modified material extends over at least 5%, preferably at least 10%, more preferably at least 20%, and even more preferably at least 25% of the predetermined fracture surface by area; and / or The laser-modified material extends over a maximum of 75%, preferably a maximum of 60%, and more preferably a maximum of 50% of the predetermined fracture surface by area.

22. The method according to any one of the preceding claims, wherein: Forming one or more fluid channels in the surface of the first substrate includes forming an array of individual fluid channel units in the surface of the first substrate, wherein each individual fluid channel unit includes a fluid channel for a single microfluidic chip; Furthermore, the method includes dividing the wafer into multiple microfluidic chips, each microfluidic chip containing the fluid channels of a corresponding individual fluid channel unit.

23. A microfluidic chip for generating aerosols from liquids, the microfluidic chip comprising: One or more inlets for receiving liquid, the inlets being formed in the inlet surface of the microfluidic chip; One or more nozzles configured to emit liquid jets are formed in the outlet surface of the microfluidic chip; One or more fluid channels connecting the one or more inlets to the one or more nozzles; The outlet surface of the microfluidic chip includes one or more laser-modified material regions.

24. The microfluidic chip according to claim 23, manufactured by the method according to any one of claims 1 to 22.

25. An inhaler system comprising a microfluidic chip according to claim 23 or claim 24.

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