Blister and blister opening system with an actuating pusher

Abstract

The invention relates to a blister opening system comprising a blister body (1) arranged on a support surface (1'''), a header (2) with a propelling surface (2'), said header (2) being movable relative to the blister body (1) and transmitting a pushing force to the blister body (1) via the propelling surface (2') in a pushing direction (3), and a fluid outlet channel (4) fluidly connected to the blister body (1). The system is characterized in that the propelling surface (2') is arranged in a relative position between the header (2) and the blister body (1) such that the pushing direction (3) and the support surface (1''') form a relative angle (5) substantially different from 90°. The pushing force of the propelling surface (2') against the blister body (1) forms a gas-filled volume (1'') on the opposite side of the blister body (1) to the fluid outlet channel (4).

Description

Technical Field

[0001] The present invention belongs to the technical field of microfluidics. More specifically, the present invention relates to a blister opening system comprising an actuating pusher and a blister, which is used to store a fluid reagent and release the fluid reagent into a microfluidic circuit. The blister opening system is advantageously configured to avoid the injection of air bubbles into the microfluidic circuit when releasing the reagent.

Background Art

[0002] Most known reagent storage blisters used in microfluidic applications exhibit a dome-shaped body. To open these blisters and release their reagent, a cylindrical pusher is vertically placed on top of the blister and operated to exert a pressing force on the blister surface. Thereby, the volume of the blister is effectively reduced and the reagent is caused to flow out into the microfluidic circuit. As an example of these blisters and pushers, U.S. Patent No. 9,610,579 (B2) discloses some embodiments of a microfluidic blister comprising a deformable reservoir operated by a cylindrical pusher with a dome-shaped header configured to have an impelling surface. An example of the type of header is shown in FIG. 1 of the present application.

[0003] However, these known dome-shaped headers tend to inject a large amount of air bubbles when used to release the contents of the blister. This is mainly due to the fact that air is always enclosed in a part of the internal volume of the blister. As the pusher gradually deforms the top surface of the dome, this air moves downward and towards the edge of the blister. As a solution to avoid the inflow of air bubbles into the microfluidic circuit, ribs surrounding the top surface of the dome-shaped blister ensure its controlled folding, which aims to enclose air in the structure thereby defined. However, if the deformation is too large, this structure also collapses, resulting in an undesirable injection of air into the microfluidic circuit.

[0004] Alternative examples of other prior arts are advantageously configured to avoid air injection while at the same time not compromising the functionality of the blister (with respect to storage volume, the ability to achieve a leak-proof seal for the reagent to flow in a specific direction, etc.). As an example, U.S. Patent No. 8,083,716 (B2) discloses a plunger head in a fluid reservoir that is shaped to limit the presence of air bubbles in the fluid medium released from the reservoir. For this purpose, the plunger head has a shape with a concave region, thereby forming an air bubble trap region. However, these pushers have the problem that some of the formed air bubbles may still leak from the trap and flow into the microfluidic circuit.

[0005] Other alternatives for discharging air bubbles in a microfluidic system include the use of permeable membranes (see, for example, U.S. Patent No. 9,962,698 (B2) and Liu et al., "A membrane based, high-efficiency, microfluidic debubbler", Lab on a Crip, 11(9), 1688 - 1693 (2011)). These pushers also exhibit the drawback of injecting a small amount of air bubbles into the microfluidic circuit when the blister releases the liquid reagent. They are also more complex than other alternatives and are not suitable for mass production. SUMMARY OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION

[0006] The present invention proposes a solution to the above technical problems by a blister opening system with a novel pusher and blister design that avoids air injection without requiring a venting membrane or other equivalent means. MEANS FOR SOLVING THE PROBLEMS

[0007] A first object of the present invention relates to a blister opening system comprising the following. A blister body disposed on a support surface. The blister body is crushable by a pressing force and is configured to store a liquid volume. A header having a propulsion surface. The header is movable relative to the blister body, and is configured to transmit a pressing force to the blister body via the propulsion surface in a pressing direction by the relative movement. A fluid outlet channel fluidly connected to the blister body and configured such that when a pressing force is exerted on the blister body by the header, the liquid volume can flow from the blister body toward the fluid outlet channel.

[0008] An advantageous aspect of the present invention is that the propulsion surface of the header is configured as follows, at least at the relative position between the header and the blister body. The pressing direction and the support surface form a relative angle substantially different from 90°. The pressing force of the propulsion surface against the blister body forms a gas-enclosed volume in the blister body, and the gas-enclosed volume is disposed substantially on the opposite side of the blister body with respect to the fluid outlet channel.

[0009] In a preferred embodiment of the present invention, the propulsion surface of the header is configured to press the blister body and discharge at least 80% of the liquid volume stored in the blister body through the fluid outlet channel.

[0010] In a preferred embodiment of the present invention, the propulsion surface of the header is substantially inclined with respect to the support surface at the complementary angle of the relative angle defined by the pressing direction and the support surface.

[0011] In an alternative embodiment of the present invention, the propulsion surface of the header is substantially parallel to the support surface. More preferably, in those embodiments, the blister body includes a blister surface configured to contact the propulsion surface, and the blister contact surface is substantially inclined with respect to the support surface at the complementary angle of the relative angle defined by the pressing direction and the support surface.

[0012] In a further preferred embodiment of the present invention, the header of the blister opening system comprises a plunger or pusher actuated by actuating means.

[0013] In a further preferred embodiment of the present invention, the header comprises a notch, protrusion or recess arranged adjacent to the fluid outlet channel, thereby providing means for minimizing backflow. More preferably, the propulsion surface of the header comprises one or more recesses and / or depressions.

[0014] In a further preferred embodiment of the present invention, the propulsion surface of the header is flat. In such an embodiment, the blister body is preferably arranged on a support surface, said support surface defining an angle substantially different from 0° with respect to the propulsion surface of the header. Said angle, which is the complementary angle of the relative angle defined by the pressing direction and the support surface, provides means for advantageously defining the gas-filled volume.

[0015] In a preferred embodiment of the present invention, a part of the header (e.g., a notch) is configured to be switchable between at least two positions, in the first position the propulsion surface closes the fluid outlet channel, and in the second position the propulsion surface opens the outlet channel, thereby selectively adjusting the amount (volume) of liquid discharged into the microfluidic circuit through said channel.

[0016] In a more preferred embodiment of the present invention, the blister opening system further comprises a holder configured to have a cavity (blister pedestal) for arranging the blister body and actuating means comprising: A mechanical device comprising a piston connected to a spiral cam with a through hole. The hole of the spiral cam is intersected by said rotating camshaft. A stepper motor that actuates the camshaft to cause rotation of the camshaft, thereby causing displacement of the piston. In this way, the piston transmits a pressing force to the header according to the direction, angle, and speed of rotation of the camshaft.

[0017] In a more preferred embodiment of the present invention, the blister opening system is in the following cases, namely, when the piston reaches a predetermined maximum movement amount or a predetermined position, or when the header contacts the blister body further comprises a switch configured to stop the rotation of the camshaft in one of them.

[0018] In a more preferred embodiment of the present invention, the holder of the blister opening system further comprises a blister measurement device fluidly connected to the fluid outlet channel, and the blister measurement device is configured to measure the amount (volume amount) of liquid and gas discharged through the fluid outlet channel.

[0019] Within the scope of the present invention, the expression "substantially different from 0°" is understood as at least 10°. In addition, the expressions "substantially equal to 0°" or "substantially parallel" are understood as less than 5°. Further, the expression "substantially different from 90°" is understood as a deviation of at least ±10° with respect to 90°.

[0020] Finally, the expression "pressing direction" is defined as the direction perpendicular to the plane defined by the header and the blister body when the header exerts a pressing force on the blister body.

Brief Description of the Drawings

[0021]

Figure 1

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Figure 9

Explanation of Reference Numerals

[0022] To provide a better understanding of the technical features of the present invention, FIGS. 1 to 9 referred to herein are provided with a series of reference numerals shown here as being of an exemplary and non-limiting nature. 1 Blister body 1’ Liquid volume 1’’ Gas enclosed volume 1’’’ Support surface 2 Header (e.g., plunger or pusher) 2’ Propelling surface of the header 2’’ Notch 3 Pressing direction 4 Fluid outlet channel 5 Angle between the propulsion surface and the blister surface (second angle) 6 Surface of the blister body 7 Actuating means 7’ Piston 7’’ Spiral cam 7’’’ Camshaft 8 Holder 9 Blister measuring device 9’ Cavity of the blister measuring device 9’’ Channel of the blister measuring device 9’’’ Blister pedestal

Best Mode for Carrying Out the Invention

[0023] As described above in the previous section, the present invention relates to a blister opening system for discharging the contents of a blister body (1) into a microfluidic circuit without injecting air bubbles. The blister opening system comprises the following. A blister body (1) that is crushable by a pressing force and is configured to store a liquid volume (1’), typically containing one or more reagents. A header (2) having a propulsion surface (2’) configured to transmit a pressing force to the blister body (1). By moving relative to the blister body (1), this header (2) can transmit a pressing force to the blister body (1) through the propulsion surface (2’) in the pressing direction (3). The pressing direction (3) is perpendicular to the plane defined by the header (2) and the blister body (1) when the header (2) exerts a pressing force on the blister body (1). The fluid outlet channel (4) that is fluidly connected to the blister body (1) such that when a pressing force is exerted on the blister body (1), the liquid volume (1’) can be discharged from the blister body (1) towards the fluid outlet channel (4).

[0024] Advantageously in the present invention, the pressing direction (3) and the support surface (1''') form a relative angle (5) that is substantially different from 90°. This relative angle (5) is defined by the pressing direction (3) and the support surface (1'''). In addition, the pressing force of the propulsion surface (2') on the blister body (1) forms a gas-encapsulated volume (1'') in the blister body (1). The gas-encapsulated volume (1'') is arranged substantially opposite the blister body (1) with respect to the fluid outlet channel (4).

[0025] The intention of this blister opening system is to maximize the volume of liquid that can be discharged from the storage blister body (1) into the microfluidic circuit without injecting air bubbles into the microfluidic circuit.

[0026] Figures 2(a) to 2(c) show a pusher according to a preferred embodiment of the present invention, designated as pusher P02, arranged on the support surface (1'''). The support surface (1''') is not necessarily flat. In Figure 2 in more detail, a top view (Figure 2(a)), a front view (Figure 2(b)) and a side view (Figure 2(c)) of the pusher are respectively shown. Preferably in the present invention, the propulsion surface (2') of the header (2) is inclined at a constant angle α with respect to the support surface (1'''). The angle α is the complementary angle of the relative angle (5) defined by the pressing direction (3) and the support surface (1'''). As further explained in Figure 3, by optimizing the relative angle (5) value, the header (2) can minimize the release of air bubbles. In this embodiment, the header (2) is provided with a notch (2'').

[0027] The operating mechanism of the pusher P02 for operating the blister body (1) according to a preferred embodiment of the present invention is shown in FIGS. 3(a) to 3(d) in sequence. In the present embodiment, the propulsion surface (2') of the header (2) defines an angle α with respect to the support surface (1'''), whereby, as the header (2) crushes or contacts the surface (6) of the blister body (1), the liquid contained in the blister body (1) can be discharged into the microfluidic circuit through the fluid outlet channel (4). FIG. 3(a) corresponds to an initial case where the header (2) is approaching the blister body (1). FIGS. 3(b) to 3(c) show that when the propulsion surface (2') of the header (2) contacts the surface (6) of the blister body, the air volume in the blister body (1) is moved away from the fluid outlet channel (4), thereby avoiding the injection of air bubbles into the fluid outlet channel (4). As shown in FIG. 3(d), when the header (2) contacts the bottom of the blister body (1) in the fluid outlet channel, the discharge of the maximum liquid volume amount (1') occurs. In the present embodiment, the header (2) has a maximum height (H) on the side that closes the fluid outlet channel (4), while the height (h) in the opposite direction is smaller. At this point (see FIG. 3(d)), the air bubbles are blocked inside the blister body (1) in the gas-encapsulated volume (1'), and as a result, the movement of air bubbles through the fluid outlet channel (4) does not occur.

[0028] In the preferred embodiment of the present invention shown in FIGS. 2 to 3, the relative angle (5) is realized by configuring the header (2) to have a propulsion surface (2') inclined with respect to the support surface (1'''). Alternatively, it is also possible to design an inclined blister surface (6) while the propulsion surface (2') of the header (2) is flat (parallel to the support surface (1''')). Therefore, due to the existence of an angle that is substantially different from 0° defined between the pressing direction (3) and the support surface (1'''), that is, between the propulsion surface (2') of the header (2) and the main surface of the blister body (1) (either the support surface (1''') or the inclined blister surface (6)), the gas-encapsulated volume (1') in the blister body (1) is realized.

[0029] A further embodiment of the header (2) according to the present invention is shown in FIG. 4, where the pusher of P02 is compared with alternative pusher shapes designated as P03, P04, P05. As an example, the pusher P03 presents a flat propulsion surface (2'), in which case the blister surface (6) is inclined with respect to the header (2).

[0030] To verify the advantages of the present invention, a comparison was made between the various pusher shapes (P02 - P05) shown in FIGS. 2 - 4 and the shape (designated as P01) of FIG. 1. For this purpose, the maximum volume of liquid discharged through the fluid outlet channel (4) before the air bubbles are injected was measured. For each pusher shape, the volume of air was also measured. The smaller the volume of air, the better the performance of the pusher. In this test, by using the operating means (7), the mechanical device shown in FIG. 5 was applied to the operation of the blister. The operating means (7) preferably comprises the following. A mechanical device comprising a piston (7') and a perforated spiral cam (7'') connected to a rotating camshaft (7'''). The spiral cam (7'') has through holes, and the holes are intersected by the rotating camshaft (7'''). A stepper motor that actuates the camshaft (7''') to cause rotation of the camshaft (7'''), thereby causing displacement of the piston (7'). The piston (7') transmits a pressing force to the header (2) according to the direction, angle, and speed of rotation of the camshaft (7'''). The camshaft (7''') rotates at an angle corresponding to a specific number of steps given by the motor. The desired rotation speed and rotation direction of the camshaft (7''') can be set by the motor controller. When the camshaft (7''') rotates, the spiral cam (7'') arranged on its axis also rotates. Thereby, the piston (7') moves downward in a controlled manner towards the blister body (1). Preferably, when the piston (7') reaches the maximum displacement value, the limit switch is actuated and the rotation of the camshaft (7''') stops.

[0031] Figure 5 also shows a blister holder (8) or a support part including the blister body (1).

[0032] To consider the optimal design of the five pushers P02 to P05 presented in FIGS. 2 to 4, it is necessary to clarify the optimal conditions regarding the rotational speed and angle of the header (2) (hereinafter also referred to as the pusher) for applying a pressing force to the blister body (1). This is because these two variables are related to the displacement of the pusher in the blister (1). Conditions related to pusher performance were examined in blister bodies (1) of 50 μl and 100 μl. Starting from 3 revolutions per minute (rpm) and up to 21 rpm, various speeds were tested within the operating range of the blister operating device. The pusher P01 (FIG. 1) was used for standardization, and the rotation angle of the camshaft (7’’’) was set to 360° (maximum piston displacement, 5 mm).

[0033] FIGS. 6(a) to 6(b) show schematic diagrams of the blister measurement device (9) after testing the P01 blister (FIG. 1) with the experimental device of FIG. 5. The blister measurement device (9) functioning as a microfluidic circuit is used to quantify (quantify) the amount of fluid discharged and the amount of air injected corresponding to the rotational speed of the camshaft (7’’’), as detailed below. As an example, the blister measurement device (9) may be arranged in the blister holder (8). During the liquid discharge test, microscopic images were acquired. Thereby, further quantification of the filled cavity (9’) or chamber and channels (9’’) of the blister measurement device (9) by image analysis becomes possible. Thus, the blister body (1) is arranged in the cavity or the blister pedestal (9’’’), and a pressing force is applied to the blister body (1) by the mechanical device in FIG. 5. Next, by fluidly connecting the fluid outlet channel (4) to the blister measurement device (9), it becomes possible to measure the amount of liquid and air bubbles discharged through the fluid outlet channel (4) during the crushing of the blister body (1). For visualization purposes, the blister may be filled with dyed water, which makes it easier to observe the discharged liquid in the microscopic images of the cavity (9') and channel (9'') of the blister measurement device (9). In the case shown in FIG. 6(b), since air bubbles are detected in the chamber closest to the blister pedestal (9'''), most of the air is discharged at the end of the test. Thus, it can be seen that the complete crushing of the blister aimed at discharging the maximum amount of liquid is not preferable in terms of functionality because air bubbles are also injected into the microfluidic circuit through the fluid outlet channel (4).

[0034] The results of quantifying (numerically quantifying) the discharge amounts (volume amounts) of liquid and air corresponding to the camshaft rotation speed are shown in FIG. 7. FIG. 7(a) shows the results for the case of 50 μl, and FIG. 7(b) shows the results for the case of 100 μl. In both cases, the amount of air injected into the microfluidic channel can be minimized when the camshaft rotation speed varies between 12 rpm and 18 rpm.

[0035] Also, it is important to consider the volume amounts of liquid and air discharged according to the pusher displacement controlled by the rotation angle of the camshaft (7''') (as described in FIG. 5). For blisters of 100 μl (FIG. 8(a)) and 200 μl (FIG. 8(b)), rotation angles between 210° and 330° are considered. Regarding the test in FIG. 7, the camshaft rotation speed is set to 15 rpm. As the volume of the blister increases, the height of the blister body also increases. When the initial distance between the blister and the pusher is kept constant, as the blister volume increases, it is necessary to make the rotation angle of the camshaft (7''') smaller to achieve the same displacement. Therefore, the angle range selected for each blister volume is slightly modified.

[0036] From the results obtained, it is possible to determine the maximum pusher displacement (given by the rotation angle of the camshaft (7’’’)) to avoid air injection into the microfluidic circuit for blister volumes of 100 μl and 200 μl. This displacement corresponds to 3.3 mm (at 240°) and 3.75 mm (at 270°) respectively. Similarly, it has been shown that it is preferable to keep the pusher in the lower position until the end of the procedure once the camshaft (7’’’) has rotated to a fixed angle (which means pusher displacement). When the pressing force of the header (2) (pusher) is released, the structure of the blister body (1) returns very slightly to its original shape due to the elasticity of the material that constitutes it. This may cause a slight undesired backflow towards the blister body (1).

[0037] As shown in FIGS. 7 to 8, when the optimal conditions (angle and rotation speed) for the functionality of the pusher are obtained for the P01 pusher, as summarized in FIG. 9, other pusher shapes P02 to P05 are tested under the same conditions. The selected camshaft rotation speed is 15 rpm. The rotation angle selected for each blister volume to be tested is the maximum value determined in the preliminary tests according to FIGS. 7 to 8. In the worst-case scenario, a blister having the largest available volume (200 μl) is used. The design of the propulsion surface (2’) and / or the main surface (6) (the contact area between the pusher and the blister) is important to avoid air bubble ejection. In a preferred pusher design (as the preferred embodiment P02), when the blister is actuated, it is possible to store all the air inside the blister body (1).

[0038] Considering the total amount of liquid that can be removed from the blister, P01 is the least efficient. Furthermore, for the shapes of P03, P04 and P05, the amount of air injected into the microfluidic circuit through the fluid outlet channel (4) is greater. For this reason, the optimal pusher design is P02, according to which it was possible to increase the average liquid discharge volume by 35 μl compared to P01 and at the same time avoid the accompanying air injection.

[0039] The most significant difference between P02 and the other pushers under consideration (P03, P04, and P05) is that the pusher has its maximum height (H) (see FIGS. 3 - 4) closer to the fluid outlet channel (4), thereby enabling the pushing of air and liquid in opposite directions. For verification purposes, the form of this pusher P02 is designed to have a certain angle (α). However, this is merely a specific embodiment of the present invention, and more complex topologies, including pushers with multiple angles or free - form pusher propulsion surfaces (2’), are also effective.

[0040] In summary, to overcome the limitations of the prior - art dome - shaped pushers, the present invention provides a novel header (2) (pusher) design. In particular, the pusher shape P02 is advantageous with respect to the amount of liquid (reagent) discharged without air bubbles. As shown in FIG. 2, the pusher height should be maximum (H) on the side adjacent to the fluid outlet channel (4) and minimum (h) on the opposite side. The notch prevents the fluid outlet channel (4) from being crushed when the pusher crushes the blister body (1) and the liquid flows out towards the microfluidic circuit. The notch is advantageous for avoiding the crushing of the fluid outlet channel (4) until most of the liquid volume stored in the blister is discharged and for minimizing the back - flow of fluid towards the blister body (1). In this way, the blister does not completely crush when the fluid outlet channel (4) is blocked, thereby enabling a portion of the blister body (1) to be configured to store the formed air bubbles.

Claims

1. A blister opening system, wherein the blister opening system ● a blister body (1) disposed on a support surface (1’’’), the blister body (1) being crushable by a pressing force and configured to store a liquid volume (1’), the blister body (1); ● a header (2) having a propulsion surface (2’), the header (2) being relatively movable with respect to the blister body (1), and configured to transmit a pressing force to the blister body (1) through the propulsion surface (2’) in a pressing direction (3) by the relative movement, the header (2); ● a fluid outlet channel (4) fluidly connected to the blister body (1) and configured such that when a pressing force is exerted on the blister body (1) by the header (2), the liquid volume (1’) can flow from the blister body (1) toward the fluid outlet channel (4) and comprising wherein in the blister opening system, the propulsion surface (2’) of the header (2) forms a relative angle (5) that is substantially different from 90° with the pressing direction (3) and the support surface (1’’’) at least at a relative position between the header (2) and the blister body (1), the pressing force of the propulsion surface (2’) against the blister body (1) forms a gas - enclosed volume (1’’) in the blister body (1), and the gas - enclosed volume (1’’) is disposed substantially on the opposite side of the blister body (1) with respect to the fluid outlet channel (4) and is arranged as such, the header (2) comprises a notch (2’’), a protrusion or a depression disposed adjacent to the fluid outlet channel (4), characterized in that it is a blister opening system.

2. The propulsion surface (2') of the header (2) is configured to press the blister body (1) and discharge at least 80% of the liquid volume (1') stored in the blister body (1) through the fluid outlet channel (4). The blister opening system according to claim 1.

3. The propulsion surface (2') of the header (2) is substantially inclined with respect to the support surface (1''') at the complementary angle of the relative angle (5). The blister opening system according to claim 1.

4. The propulsion surface (2') of the header (2) is substantially parallel to the support surface (1'''). The blister opening system according to claim 1.

5. The blister body (1) includes a blister surface (6) configured to contact the propulsion surface (2') of the header (2), and the blister surface (6) is substantially inclined with respect to the support surface (1''') at the complementary angle of the relative angle (5). The blister opening system according to claim 1.

6. The header (2) includes a plunger or a pusher. The blister opening system according to claim 1.

7. The propulsion surface (2') of the header (2) is substantially flat. The blister opening system according to claim 1.

8. The propulsion surface (2') of the header (2) includes one or more depressions and / or recesses. The blister opening system according to claim 1.

9. The propulsion surface (2') of the header (2) closes the fluid outlet channel (4) at least at the position where the header (2) exerts a pressing force on the blister body (1), while at least a part of the blister body (1) stores the gas volume (1') within the gas enclosure volume (1''), The blister opening system according to any one of claims 1 to 8.

10. The header (2) is configured to be switchable between at least two positions. In the first position, the propulsion surface (2') closes the fluid outlet channel (4), and in the second position, the propulsion surface (2') keeps the fluid outlet channel (4) open. The blister opening system according to claim 9.

11. A holder (8) configured to have at least a blister pedestal (9''') for arranging the blister body (1), and further comprising actuating means (7). The actuating means (7) - A mechanical device comprising a piston (7') and a spiral cam (7'') connected to a rotary camshaft (7'''), - A stepper motor for actuating the rotary camshaft (7''') and thereby causing displacement of the piston (7'), and is provided with The piston (7') transmits a pressing force to the header (2) according to the direction, angle, and speed of rotation of the camshaft (7'''). The blister opening system according to any one of claims 1 to 8.

12. In the following cases, namely when the piston (7') reaches a predetermined maximum movement amount or a predetermined position, when the header (2) comes into contact with the blister body (1), a switch configured to stop the rotation of the mechanical device in one of them. further comprising The blister opening system according to claim 11.

13. further comprising a blister measurement device (9) fluidly connected to the fluid outlet channel (4), the blister measurement device (9) being configured to measure the liquid volume (1') and the gas volume discharged through the fluid outlet channel (4) The blister opening system according to claim 11.

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