WO2020027751A2

WO2020027751A2 - Hydraulic interface apparatus and operation method for microfluidic systems

Info

Publication number: WO2020027751A2
Application number: PCT/TR2019/050142
Authority: WO
Inventors: Barbaros CETIN; Ender YILDIRIM; Utku HATIPOGLU
Original assignee: Ihsan Dogramaci Bilkent Universitesi; Cankaya Universitesi
Priority date: 2018-03-09
Filing date: 2019-03-06
Publication date: 2020-02-06
Also published as: WO2020027751A3; WO2020027751A9; DE112019001246T5

Abstract

The invention concerns a new hydraulic interface device (1) and the operation method (100) of the device that has been designed to be used to transmit valuable fluids to micro-fluidic systems and to move these fluids within these systems.

Description

HYDRAULIC INTERFACE APPARATUS AND OPERATION METHOD

FOR MICROFLUIDIC SYSTEMS

The technical field of the invention:

The invention relates to a novel hydraulic interface apparatus and the operation method thereof that has been designed to generate flow of valuable liquids such as suspension, drug and biological samples within microfluidic systems and to ensure the minimisation of the loss of the loaded valuable liquids.

State of the art:

Today, microfluidics technology is used extensively. Simply, microfluidic technology is based on the forming microchannels on or within any given substrate. By the aforementioned technique, it is possible to prepare and/or easily analyse biological liquid samples and particles (cells, fat globules, molecules, even organisms) flowing through microchannels at a certain speed

Microfluidic systems are used with the present art in the fields that involve biological and/or chemical samples and in general, the work involves minute volume of liquids. The aforementioned volume is generally around 10-500 mΐ . Therefore, the transport minute amount of liquid volume should be carried out delicately and the loss of liquid that occurs during the transport should be kept at minimum levels. However, the loss of fluid that occurs during the implementation of microfluidic systems employing the present art is higher than the desired level.

Since liquids used in microfluidic systems are generally of valuable characteristic meaning that losses occurring during operation may result in serious problems. Especially, the samples that is used in minute amounts and contains very valuable chemical agents creates serious cost issues. The primary reason for these losses is the the liquid loading/transport techniques in the microfluidics system.

The current state of the art employs syringe pumps to transport liquids in the microfluidic systems. The main reason of the liquid loss in the use of syringe pumps is due to necessity of loading of the valuable sample in the syringe and connecting tubing without any air bubble. Considering the volume of the syringes, the volume of the valuable sample needs to be in the range of 0.5-5mL. The entire volume loaded in the syringe pump cannot be transferred into the microfluidic system. The main reason for this issue is the dead volume occurring within the syringe and the interconnect tubing. In current practice, dead volume occurring in the syringe causes loss of the valuable liquid in microfluidic systems.

Special low volume interconnect tubing or integrated micro pumps have been developed to reduce the losses in microfluidics systems. However, integrated micro pumps cause an increase in cost and impose design constraints on the microfluidic system due to the fact that they are integrated. The use of low volume interconnect tubing has not achieved the desired reduction in the level of loss. Therefore, these components have not been ideal solutions for the elimination of the aforementioned loss of liquid.

A design which is similar to the syringe pump and has been designed to regulate the flow of liquids in microfluidic systems is mentioned in patent application number US2006159564A1 in the state of the art. The design in question is an alternative flow controller that is substantially similar to the commonly used syringe pumps, and contains dead volumes as in the current state of the art. This fluid flow controller that contains dead volume, which is one of the largest problems encountered, is not a sufficient alternative for the valuable liquids to be transported without loss.

Object of the Invention:

The object of the invention is to facilitate the movement of valuable liquids within microfluidic systems with minimal loss and to minimize the amount of the loss of samples and financial loss .

The object of the invention is to put forth a new interface apparatus that ensures the transport of valuable liquids within microfluidic systems at the desired speed.

An additional object of the invention is to put forth a new interface apparatus that ensures the transport of valuable liquids within microfluidic systems with minimal loss.

An additional object of the invention is to put forth a new interface apparatus that ensures the transport of valuable fluids within microfluidic systems without any possibility of contamination .

Description of the Figures :

Figure 1. illustrates the general view of the hydraulic interface apparatus

Figure 2. illustrates the exploded view of the hydraulic interface apparatus

Figure 3. illustrates a sectional view of the hydraulic interface apparatus prior to use Figure 4. illustrates a sectional view of the hydraulic interface apparatus during use

Figure 5. illustrates the integrated state of the hydraulic interface apparatus with the control system and the microfluidic system

Figure 6. illustrates the operation method of the hydraulic interface apparatus

The components shown in the figures have been individually numerated and the names of the components that correspond to these numbers are as follows:

1. Hydraulic Interface Apparatus

2. Body

2.1. Upper base

2.2. O-ring seat

e. Wall thickness

3. Membrane

4. Seal

5. Cap

6. Bolt

7. Nut

8. Hydraulic intake hole

9. Fluid outlet hole

10. Hydraulic liquid chamber

11. Valuable liquid chamber

12. Controller

13. Fluidic Interconnect tubing

14. Connection hole

15. Microfluidic system

16. Microfluidic system intake hole

100. The operation method of the hydraulic interface apparatus 101. the filling/ feeding of the valuable liquid chamber with valuable liquid

102. the feeding of the fluid/semi fluid into the hydraulic liquid chamber

103. the increase in liquid pressure level on the membrane and the deformation of the elastic membrane

104. the injection of the valuable liquid through the liquid outlet hole to the microfluidic system or to any chamber/ system

105. the integration to the microfluidic system or to any system

106. the connection of the microfluidic system to the hydraulic interface apparatus

Description of the Invention:

The invention concerns a hydraulic interface apparatus (1) that has been developed to ensure the transport of suspensions, drug and biological samples that are used in lab-on-a-chip and microfluidic systems in minute quantities without any loss and at the desired amount and to ensure loading of precise amount of the sample into the system to which it has been connected.

Two chambers/partitions, the hydraulic liquid chamber (10) and the valuable liquid chamber (11), have been built in hydraulic interface apparatus (1) to transport the valuable liquids in the system to which they are to be loaded. The membrane (3) that is not liquid or gas permeable and that has an elastic texture divides the hydraulic liquid chamber (10) and the valuable liquid chamber (11) .

The hydraulic liquid chamber (10) is the chamber in which any given fluid/semi fluid is to be placed is located in the empty cylindrical body (2) of the hydraulic interface apparatus (1) of which the upper base (2.1) is closed. The diameter of the hydraulic liquid chamber (10) must always be smaller than the diameter of the body.

The membrane (3) is placed over the open end of the body (2) and the cap (5) is placed over the membrane. Thus, the hydraulic liquid chamber (10) has been built in the body (2), of which the open end has been closed with the membrane (3), and the valuable liquid chamber (11) has been formed between the membrane (3) and the cap (5) .

With the placement of the membrane (3) on the body (2), the cylindrical body (2) with an open base has been made into a cylindrical structure that contains the hydraulic liquid chamber

(10) with both the upper base (2.1) and the other base having been closed (both bases closed) .

One of the most significant characteristics of the hydraulic interface apparatus (1), which is the subject of the invention, is the fact that the valuable liquid in the valuable liquid chamber (11) does not come into contact with the fluid/semi fluid in the hydraulic liquid chamber (10) and the fact that there is no diffusion between them. To ensure sealing and separation of the hydraulic liquid chamber (10) and the valuable liquid chamber

(11), an O-ring seat (2.2) has been formed on the open end of the body (2) prior to the placement of the membrane. The O-ring seat (2.2) is in the form of a groove that is located within the body (2) along the cylindrical wall of the body (2) . The sealing element (4) has been carefully placed in the o-ring seat (2.2) to prevent any leak of the fluid/semi fluid within the hydraulic liquid chamber from the inner wall of the body (2), (10) . Therefore, the hydraulic interface apparatus (1) that has been illustrated in Figure 2, consists of in order; the body (2), the seal (4) placed on the o-ring seat (2.2) that is located in the inner wall of the body, the membrane (3) that has been placed on the body (2) bearing the seal (4), and the cap (5) that has been placed on the membrane (3) .

The body (2), in which a sealing element is placed to its inner wall to ensure unmixing of the fluid/semi fluid in the hydraulic liquid chamber (10) formed between the membrane (3) and the body (2) and the valuable liquid in the valuable liquid chamber (11) formed between the cap (5) and the membrane (3), and the cap (5) are assembled such that the membrane (3) is placed in between.

The assembly of the body (2) and the cap (5), that are placed over each other with the seal (4) and the membrane (3) between them, is carried out by use of the bolt (6) and nut (7) in this embodiment of the apparatus.

There are multiple connection holes (14) on the cap (5) and the body (2) wall thickness (e) due to the difference between the diameters of the hydraulic liquid chamber (10) and the body (2) . Once the body (2) and the cap (5) have been placed on top of each other with the membrane (3) between them, the cap (5) and the body (2) should be adjusted to ensure that the connection holes (14) are aligned. Once the connection holes (14) on the body (2) are aligned with the connection holes (14) on the cap

(5), the assembly of the body (2) and the cap (5) is carried out by inserting bolts (6) through the aligned connection holes (14) .

When nuts (7) are affixed to the protruding end of each bolt

(6), and the cap (5) and body (2) have been securely fitted so as to have a membrane (3), and a hydraulic liquid chamber (10) and valuable liquid chamber (11) divided by a membrane (3) between them, the final form of the hydraulic interface apparatus (1) will have been assembled as shown in Figure 1. In alternative embodiments of the invention, it is possible for the cylindrical body (2) to have a structure that is preferably a square, a rectangle or a polygon with a closed base and containing a hydraulic liquid chamber (10) . The membrane (3), seal (4) and cap (5) that is to be used in keeping with the shape of the body (2) could be designed to fit the shape of the body (2) . The aforementioned cap (5) and body (2) can either be in one piece or it may consist of multiple pieces that may be assembled and disassembled.

In alternative embodiments of the invention, the cap (5) and body (2), containing the membrane (3) and the hydraulic liquid chamber (10) and the valuable liquid chamber (11) divided by the membrane (3), may be attached without bolts (6) and nuts (7), by adhesive or by ultrasonic welding so as to provide sealing.

A hydraulic intake hole (8) is located anywhere on the closed upper base (2.1) of the body (2) of the hydraulic interface apparatus (1) that is the subject of the invention. The fluid/semi fluid is fed to the hydraulic liquid chamber (10) between the membrane (3) and the closed body (2) by way of the hydraulic intake hole (8) .

A liquid outlet hole (9) is located anywhere on the cap (5) of the hydraulic interface apparatus (1) that is the subject of the invention. The transport of the valuable fluid that has collected in the valuable liquid chamber (11) between the cap (5) and the membrane (3) to the desired system is carried out via the liquid outlet hole ( 9 ) .

In this embodiment of the invention, it is possible to access and/or intervene in the inside of the hydraulic interface apparatus (1) from outside, via the hydraulic intake hole (8) and the fluid outlet hole (9) . The present invention is used to establish control over the flow of fluids within microfluidic devices. In the hydraulic interface apparatus (1), the hydraulic liquid chamber (10) containing the fluid/semi fluid and the valuable liquid chamber (11) containing the valuable liquid, that are separated by the membrane (3) and are independent of each other, are shown in Figure 4.

The fundamental function of the hydraulic interface apparatus (1) is to generate flow of micro volumes of valuable liquids in desired volumes without any loss and to transport exactly the desired volume to the system to which it is attached. For utilisation, the hydraulic interface apparatus (1) is integrated to the desired microfluidic system (15) or to any relevant system which is compatible with direct transport through the fluid outlet hole (9) . A hydraulic interface apparatus (1) that has been integrated to a microfluidic system (15) and has been connected to a controller (12) is illustrated in Figure 5.

The controller (12), is the system that injects the fluid/semi fluid into the hydraulic liquid chamber (10) of the hydraulic interface apparatus (1) . One end of the fluidic interconnect tubing (13) is connected to the controller (12) and the other end is connected to/inserted in the hydraulic intake hole (8) . The fluid/semi fluid that is fed by the controller (12) is transport to the hydraulic liquid chamber (10) by using the fluidic interconnect tubing (13) .

The microfluidic system (15) is the system to which the valuable liquid exiting the valuable liquid chamber (11) of the hydraulic interface apparatus (1) is loaded. The microfluidic system intake hole (16) comprised in the microfluidic system (15), which is connected to the hydraulic interface apparatus (1) right underneath the cap (5), is connected/mounted to the fluid outlet hole (9) that is located on the cap (5) and is extending to the valuable liquid chamber (11) .

The connection/mounting of the fluidic interconnect tubing (13) to the hydraulic intake hole (8) and the connection/mounting of the microfluidic system intake hole (16) to the fluid outlet hole (9) can be established by adhesive bonding or mechanical connection with fasteners.

In another embodiment of the invention, the valuable liquid exiting the valuable liquid chamber (11) of the hydraulic interface apparatus (1) can be transported to/loaded into any chamber/system without physical reliance on any system.

The general operation method (100) of the hydraulic interface apparatus (1), that enables the flow of micro volumes of valuable liquids without loss at the desired volumes and that enables transport of valuable liquids to the system to which it is attached at exactly the desired volume, includes the following steps ;

• the loading/feeding (101) of the valuable liquid chamber (11) with valuable liquid when the volume of the hydraulic liquid chamber (10) of the hydraulic interface apparatus (1) that has no fluid/semi fluid or any liquid in it is maximum and the volume of the valuable liquid chamber (11) is minimum,

• the feeding of fluid/semi fluid (102) into the hydraulic liquid chamber (10) of the hydraulic interface apparatus (1) from the controller (12),

• the deflection (103) of the elastic membrane (3) as the liquid pressure on the membrane (3) increases due to loading of the fluid/semi fluid in the hydraulic liquid chamber (10), • the injection of the valuable liquid (104) through the fluid outlet hole (9) to a microfluidic system (15) or to any chamber/system, as the membrane (3) deflects and exerts pressure on the valuable liquid within the valuable liquid chamber (11) .

In accordance with the hydraulic interface apparatus operation method (100), if required, the following procedures may be carried out before utilisation;

• the hydraulic interface apparatus (1) may be integrated (105) to a microfluidic system (15) or any system with which it is to be used,

• the microfluidic system (15) may be connected (106) to the hydraulic interface apparatus (1) right underneath the cap (5) of the body (2) . This would allow the hydraulic interface apparatus (1) to be physically integrated to different systems.

The section view of the standard structure of the hydraulic interface apparatus (1) while it is not in use is shown in Figure 3. When the hydraulic interface apparatus (1) is empty, or when the pressures in the hydraulic liquid chamber (10) and the valuable liquid chamber (11) on either side of the membrane (3) are equal, the volume of the hydraulic liquid chamber (10) is at its maximum level and the volume of the valuable liquid chamber (11) is at its minimum level. The primary reason for this is that the membrane (3) is located between the body (2) and the cap (5) , such that it is touching the cap (5) . Because of the way the membrane (3) is located in the hydraulic interface apparatus (1), the volume of the empty valuable liquid chamber (11) within the hydraulic interface apparatus (1) is almost zero.

The volume of the valuable liquid chamber (11) increases due to the elastic membrane (3) after the valuable liquid chamber (11) is filled with valuable liquid. The fluid/semi fluid located in the controller (12) is transported to the hydraulic liquid chamber (10) by passing through the hydraulic intake hole (8) of the hydraulic interface apparatus (1) via the fluidic interconnect tubing (13) . As the fluid/semi fluid is loaded into the hydraulic liquid chamber

(10), the elastic membrane (3) begins to deflect. As the fluid/semi fluid is continued to be injected from the controller

(12) via the fluidic interconnect tubing (13), the volume of the hydraulic liquid chamber (10) increases and the volume of the valuable liquid chamber (11) decreases at the same rate.

The liquid pressure on the membrane (3) increases as the process of the feeding of the hydraulic liquid chamber (10) continues. As the pressure in the hydraulic liquid chamber (10) exceeds the pressure in the valuable liquid chamber (11) , the membrane begins to deflect towards the valuable liquid chamber (11) and the fluid outlet hole (9) . Thus, the valuable liquid in the valuable liquid chamber (11) is injected through the fluid outlet hole (9) into the microfluidic system (15) or any other chamber due to the pressure exerted by the membrane (3) .

By means of the hydraulic interface apparatus (1) explained above, any valueless fluid/semi fluid with has been utilised as driving force. The problem of the loss of the valuable fluid that remained within the fluidic interconnect tubing (13), that is the subject of the invention and that is one of the biggest problems of the state of the art, has been minimised by the use of valueless fluid/semi fluid in the fluidic interconnect tubing

(13) in the hydraulic interface apparatus (1) and by ensuring that the volume of liquid transported is equal to the valuable liquid loaded in the valuable liquid chamber (11) . Thus, the process of transporting the liquid to the microfluidic system (15) without leaving any liquid in the hydraulic interface apparatus (1) is completed with ease.

The injection of the full volume or the desired volume of the valuable liquid to the microfluidic system (15), depends on the rate at which the hydraulic liquid chamber (10) is fed with the fluid/semi fluid.

The fluid/semi fluid that is fed from the controller (12) into the hydraulic liquid chamber (10) may vary based on the preferences of the user, provided that it is incompressible. Since the said fluid/semi fluid does not need to have any property other than being incompressible, it is possible to use insignificant fluids/semi fluids. Thus, the hydraulic interface apparatus (1) enables the process of the transfer of valuable fluids to microfluidic systems (15) without loss of valuable fluids, at lower costs.

As the membrane (3) in the hydraulic interface apparatus (1), that is the subject of the invention, is not liquid- or gas- permeable, it is not possible for the fluid in the hydraulic liquid chamber (10) to mix with the valuable liquid in the valuable liquid chamber (11) . This situation enables ideal transfer of valuable liquid for the purposes of the targeted goal .

The location of the membrane (3) in the hydraulic interface apparatus (1) is of paramount importance for the present invention. Due to the fact that there is no space or element to create volume between the membrane (3) and the cap (5), and due to the fact that the geometric shapes of the membrane (3) and the cap (5) are the same, the membrane (3) is unloaded when the valuable liquid chamber (11) is empty and this enables the volume of the valuable liquid chamber (11) to be zero. This situation allows the volume of the valuable liquid chamber

(11) to be minimised to zero when the valuable liquid is to be injected and when the fluid/semi fluid within the controller

(12) completely fills the hydraulic liquid chamber (10) . Therefore, as a result of the volume of the valuable liquid chamber (11) being minimised to zero the possibility of any liquid remaining in the hydraulic interface apparatus (1) after transferring valuable liquid entirely to the microfluidic system (15) . The location of the membrane (3) prevents the formation of dead volume for the valuable liquid within the hydraulic interface apparatus (1) .

The hydraulic interface apparatus (1) that is the subject of the invention has enabled the transfer of valuable liquids without any loss, to microfluidic systems (15) . Due to the structure of the present hydraulic interface apparatus (1), no dead volumes are built within the hydraulic interface apparatus (1) and the loss of valuable liquids is eliminated. Especially due to the fact that fluid/semi fluid fed by the controller (12) is separated from the valuable fluid, the need for the hydraulic interface apparatus (1) being loaded fully with valuable liquid has been eliminated. When the hydraulic interface apparatus (1) is used, this situation minimises the loss of valuable liquids containing valuable biological sample liquids and/or biological particles, and virtually eliminates sample losses and reduces financial losses.

Claims

1. Hydraulic interface apparatus (1) characterised by;

comprising a valuable liquid chamber (11) in which the valuable liquid that is to be injected into a microfluidic system (15) is located, between the membrane (3) and the cap (5) that has zero volume when empty, such that the volume can be increased by placing valuable liquid inside of it; a preferably elastic membrane (3) that separates the hydraulic liquid chamber (10) and the valuable liquid chamber (11) between which it is located, that is not liquid- or gas-permeable, that is located on the body (2), that remains adjacent to the cap (5) when unloaded and therefore ensures that the volume of the valuable liquid chamber (11) is zero, that is able to deform and increase the volume of the valuable liquid chamber (11) when it is filled with valuable liquid; a hydraulic liquid chamber (10) that is located between the membrane (3) and the body (2), that enables the elastic membrane (3) to deform as a result of the increase of liquid pressure exerted by any fluid/semi fluid, when any fluid/semi fluid with which it is filled is used as driving force.

2. Hydraulic interface apparatus (1) of Claim 1, characterised in that the body (2) in which the hydraulic liquid chamber (10) is located is in the shape of a hollow cylinder and has a closed upper base (2.1) .

3. Hydraulic interface apparatus (1) of Claim 1, characterised in that it comprises a hydraulic intake hole (8) placed in any location on the upper base (2.1) of its body (2) that enables the passage of fluid/semi fluid.

4. Hydraulic interface apparatus (1) of Claim 1, characterised in that the body (2) comprises an o-ring seat (2.2) on which the seal (4) on the inner wall of the body (2) is to be fitted so as to prevent any leakage of fluid/semi fluid in the hydraulic liquid chamber (10) from the inner wall of the body ( 2 ) .

5. Hydraulic interface apparatus (1) of Claim 1, characterised in that the seal is located on the o-ring seat (2.2) on the inner wall of the body (2) .

6. Hydraulic interface apparatus (1) of Claim 1, characterised in that it comprises a fluid outlet hole (9) placed in any location on the cap (5) that enables the release of valuable fluid .

7. Hydraulic interface apparatus (1) of Claim 1, characterised in that it comprises multiple connection holes (14) placed in any location along the wall thickness (e) of the body (2) .

8. Hydraulic interface apparatus (1) of Claim 1, characterised in that it comprises multiple connection holes (14) placed in any location along the cap (5) .

9. Hydraulic interface apparatus (1) of Claim 1, characterised in that it comprises nuts (7) and bolts (6) that are used to join the cap (5) to the body (2), that houses the seal (4) on its inner wall, such that the membrane (3) is located between them.

10. Hydraulic interface apparatus operation method (100) that enables movement of micro volumes of valuable liquids without loss at the desired amounts and the transmission of precise volumes of such liquids to any system, characterised by;

• the filling/feeding (101) of the valuable liquid chamber (11) with valuable liquid when the volume of the hydraulic liquid chamber (10) of the hydraulic interface apparatus (1) that has no fluid/semi fluid or liquid of any type in it is at maximum and the volume of the valuable liquid chamber (11) is at minimum,

• the deformation (103) of the elastic membrane (3) as the liquid pressure on the membrane increases (3) due to the fluid/semi fluid filling the hydraulic liquid chamber (10),

• the injection of the valuable liquid (104) through the fluid outlet hole (9) to a microfluidic system (15) or to any chamber/system, as the membrane (3) deforms and exerts pressure on the valuable liquid within the valuable liquid chamber (11).

11. Hydraulic interface apparatus operation method (100) of

Claim 10, that enables movement of micro volumes of valuable liquids without loss at the desired volumes and the transmission of precise volumes of such liquids to a system to which it is connected characterised by; comprising the following procedural steps for the fluid/semi fluid or any non-fluid within the hydraulic interface apparatus (1) for the purpose of the transmission of the valuable liquid into any system,

• the initial integration with a microfluidic system (15) or any system with which it is to be utilised, • the connection (106) of the microfluidic system (15) to the hydraulic interface apparatus (1) from underside of the body (2) cap (5) .

12. Hydraulic interface apparatus operation method (100) of Claim 10, characterised by; the transfer of the fluid/semi fluid located in the controller (12) through the fluid outlet hole (9) of the hydraulic interface apparatus (1) to the hydraulic liquid chamber (10) by way of the fluidic interconnect tubing (13) during the process of the feeding of the fluid/semi fluid to the hydraulic liquid chamber

(10) .