Implantable drug release chip based on acoustic flow control and manufacturing method thereof

Abstract

The invention discloses an implantable drug release chip based on acoustic flow control. The implantable drug release chip comprises a biocompatible matrix, a sharp-edge cantilever micropump and a drug, the biocompatible base body is provided with a cavity for containing medicine and an output channel communicated with the cavity, and the output channel is used for outputting liquid containing the medicine; the sharp-edge cantilever micropump is arranged in the output channel and comprises at least one sharp-edge cantilever unit extending towards the inner side of the output channel, and the sharp-edge cantilever unit controls conveying of liquid containing medicine through the acoustic streaming effect under ultrasonic excitation. The invention further discloses a manufacturing method of the composite material. According to the invention, wireless programmable selective drug release of the implanted device can be realized, direct contact between a drug carrier and an in-vivo environment is isolated, and high-precision drug release of the implanted drug release device is realized.

Description

Technical Field

[0001] The invention belongs to the technical field of microfluidic drug release, and in particular relates to an implantable drug release chip based on acoustic fluidics and a manufacturing method thereof. Background Art

[0002] In the medical field, effective drug delivery is crucial for the drug to be effective. Traditional drug delivery methods, such as oral, intravenous, and intramuscular injections, have challenges such as rapid degradation and excretion throughout the body, and widespread adverse reactions. For long-term medication for diseases such as hypertension and diabetes, patients are required to perform long-term self-monitoring, repeated medication, and multiple injections, which may reduce patient compliance and thus weaken the actual therapeutic effect of the drug.

[0003] In recent years, a variety of implantable devices have been developed to improve patient compliance, treat complex medical treatments that require repeated and long-term medication, and further promote the development of personalized medicine. However, for implantable devices, it is necessary to solve the problems of biocompatibility, precise control of drug dosage, drug storage, and overall device miniaturization.

[0004] Currently, most existing implantable methods use various hydrogels to carry drugs. After implantation, the drugs carried can be released by relying on the decomposition of the hydrogel, concentration difference, or external field stimulation. The aforementioned methods can successfully put drugs into the body and achieve in vivo release of drugs, but there are still some problems, such as: the hydrogel carrying drugs is directly exposed to the body and cannot carry high-concentration drugs, which limits the use of some drugs; the method of releasing drugs through the decomposition or concentration difference of hydrogel is a passive release method, and its drug release accuracy cannot reach a very high precision; while the external field stimulation method can achieve effective control, the preparation of its drug carrier is complicated and the types of drugs that can be carried are limited. Summary of the invention

[0005] In view of the deficiencies in the prior art, the present invention provides an implantable drug release chip based on acoustic fluidics and a manufacturing method thereof, which can achieve controlled and precise drug release and isolate the drug carrier from direct contact with the internal environment.

[0006] In order to achieve the above purpose, the technical solution of the present invention is:

[0007] An implantable drug release chip based on acoustic fluidics comprises a biocompatible matrix, a sharp-edge cantilever micropump and a drug; the biocompatible matrix has a chamber for accommodating the drug and an output channel connected to the chamber, the output channel is used for outputting a liquid containing the drug; the sharp-edge cantilever micropump is arranged in the output channel, and comprises at least one sharp-edge cantilever unit, and the sharp-edge cantilever unit controls the delivery of the liquid containing the drug through the acoustic fluidic effect under ultrasonic excitation.

[0008] Among them, the output channel is connected to the external environment, and the chip uses ultrasound for wireless excitation. Under ultrasonic excitation, each sharp-edge cantilever unit will have an acoustic streaming effect to produce a liquid transport effect, so as to transport the drug to the external environment.

[0009] Optionally, the medicine is a liquid medicine.

[0010] Optionally, the drug is carried in a drug storage module and placed in the chamber, and the drug storage module is solid or gel; a microfluidic channel is provided in the drug storage module, and the biocompatible matrix also includes an input channel for inputting liquid, and two ends of the microfluidic channel are respectively connected to the input channel and the output channel.

[0011] Optionally, when the liquid flows through the microfluidic channel, the drug storage module releases the loaded drug into the liquid to form the liquid containing the drug.

[0012] Optionally, the sharp-edge cantilever unit is connected to a side wall of the output channel, and a free end extends toward an output direction of the output channel and a tip end forms an acute angle.

[0013] Optionally, a plurality of the sharp-edge cantilever units are arranged at intervals on two opposite sides of the output channel along the extension direction, and the sharp-edge cantilever units on the two sides are staggered.

[0014] Optionally, the biocompatible matrix has a plurality of independent chambers, each chamber is connected to the output channel, each output channel is provided with the sharp-edge cantilever micropump, and each chamber is used to contain different drugs.

[0015] Optionally, the lengths of the sharp-edge cantilever units in the output channels are different to achieve selective response to ultrasound.

[0016] Optionally, the biocompatible matrix has a thickness of 2 to 4 mm, and the width of each channel and microfluidic channel is 0.05 to 0.15 mm.

[0017] A method for manufacturing the above-mentioned implantable drug release chip based on acoustic fluidics comprises:

[0018] manufacturing the sharp-edge cantilever micropump;

[0019] The packaging cover, the loading substrate and the pumping module are respectively made of biocompatible materials, the loading substrate has a receiving groove and an output port connected to the receiving groove, and the pumping module has an output microchannel and a connecting groove connected to the output microchannel;

[0020] The sharp-edge cantilever micropump is installed in the connecting groove, the drug is placed in the containing groove, and the loading substrate is bonded to the pumping module and the packaging cover respectively; the loading substrate is bonded to the pumping module so that the connecting groove is enclosed and sealed, and the output port is connected to the output microchannel to form the output channel; the loading substrate is bonded to the cover plate so that the containing groove is enclosed and sealed to form the chamber; the packaging cover, the loading substrate and the pumping module are combined to form the biocompatible matrix.

[0021] Optionally, the sharp-edge cantilever micropump is manufactured using 3D printing technology.

[0022] The beneficial effects of the present invention are:

[0023] 1) Drugs embedded in biocompatible substrates avoid direct contact with the in vivo environment, increasing the number of drug options;

[0024] 2) Solid or gel-packed drugs are directly encapsulated into biocompatible matrices, eliminating the need for complex drug carrier preparation processes;

[0025] 3) The overall device is small in size and can achieve minimally invasive surgery;

[0026] 4) Active control through ultrasound can achieve precise fluid control at the microfluidic scale and achieve precise drug release;

[0027] 5) Different control of the release of multiple drugs can be achieved. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 Schematic diagram of the exploded structure of an implantable drug release chip based on acoustic fluidics in an embodiment;

[0029] Figure 2 This is a schematic diagram of the overall structure of an implantable drug release chip based on acoustic fluidics in an embodiment, in which part of the structure is perspective to reflect the liquid flow path;

[0030] FIG3( a ) is a schematic front view of the structure of the sharp-edge cantilever micropump of the embodiment;

[0031] FIG3( b ) is a schematic diagram of the three-dimensional structure of the sharp-edge cantilever micropump of the embodiment;

[0032] FIG3( c ) is a schematic diagram showing the principle of the sharp-edged cantilever unit of the embodiment to achieve the liquid conveying effect;

[0033] Figure 4 is a schematic diagram of the three-dimensional structure of a drug storage module of an embodiment;

[0034] Figure 5 It is a schematic structural diagram of a pumping module of an embodiment. DETAILED DESCRIPTION

[0035] The present invention is further explained below in conjunction with the accompanying drawings and specific embodiments. The various drawings of the present invention are only for illustration to make it easier to understand the present invention, and the specific proportions can be adjusted according to design requirements. The upper and lower relationships of the relative elements and the definitions of the front / back in the figures described in the text should be understood by those skilled in the art to refer to the relative positions of the components, so they can all be flipped to present the same components, which should all fall within the scope disclosed in this specification.

[0036] refer to Figure 1 and Figure 2 , the embodiment takes an implantable drug release chip based on acoustic fluidics for sustained release of two drugs as an example, and its biocompatible matrix is ​​disassembled into two packaging covers 1, a loading substrate 5 and two pumping modules 4. The two packaging covers 1 and the pumping modules 4 are symmetrically arranged on both sides of the loading substrate 5 to form a structure for sustained release of two drugs. The following is a specific description of the structure for sustained release of one drug. The packaging cover 1, the loading substrate 5 and the pumping module 4 form a chamber A and an input channel a and an output channel b connected to the chamber A. A drug storage module 21 is arranged in the chamber A. The drug storage module 21 is solid or gel, and a microchannel 21a is arranged therein. The two ends of the microchannel 21a are connected to the input channel a and the output channel b respectively. When the liquid enters from the input channel a and flows through the microchannel 21a, the drug storage module 21 releases the loaded drug in the liquid to form a liquid containing the drug. The output channel b is used for the output of the liquid containing the drug. 3(a) and 3(b), the sharp-edged cantilever micropump 3 is disposed in the output channel b, and includes at least one sharp-edged cantilever unit 31. The sharp-edged cantilever unit 31 can control the delivery of the liquid containing the drug through the acoustic streaming effect under ultrasonic excitation, thereby achieving the sustained release of the drug by controlling the effect of ultrasonic waves on the sharp-edged cantilever micropump 3. The drug storage module 21 will gradually consume the drug stored therein as the liquid in the microchannel 21a flows.

[0037] The sharp-edged cantilever micropump 3 as a whole also includes a flow channel 3b for forming a part of the output channel b, and a boss 32 for positioning and indicating the direction. The sharp-edged cantilever unit 31 is connected to the side wall of the flow channel 3b, and the free end extends in the output direction of the output channel b and the end forms a sharp angle with an acute angle. For example, referring to Figure 3 (c), from the longitudinal section parallel to the liquid flow direction, the two line segments forming the sharp angle of the sharp-edged cantilever unit 31 include an inclined line segment 311 and a parallel line segment 312, the inclined line segment 311 extends from the flow channel side wall obliquely into the flow channel, the parallel line segment 312 is relatively far away from the flow channel side wall and is arranged parallel to the flow channel side wall, and the other end is connected to the flow channel side wall through an arc segment 313. A plurality of sharp-edged cantilever units 31 of the above-mentioned shape are arranged at intervals on both sides of the flow channel 3b opposite to each other along the extension direction, and the sharp-edged cantilever units 31 on both sides are staggered. When the ultrasonic wave is irradiated to the sharp-edged cantilever unit, the tip of the sharp-edged cantilever unit will vibrate rapidly, and two eddies rotating in opposite directions will appear around it, which is called the acoustic streaming effect. Through the joint action of the two eddies, the liquid is pumped out along the direction of the sharp-edged tip. In addition, the sharp-edged cantilever unit 31 can also be other shapes that can realize the sharp-edged acoustic streaming effect under ultrasound, and the direction of the pumping effect generated is consistent.

[0038] The structure for sustained-release of another drug refers to the aforementioned structure, in which a drug storage module 22 is provided in chamber A. The drug storage module 22 and the drug storage module 21 may have a similar microfluidic channel 22a structure but carry different drugs. The sharp-edged cantilever micropumps 3 corresponding to the two drugs may achieve specific responses to different ultrasonic waves through differences in shape, length, and other settings, thereby achieving independent sustained-release control.

[0039] The following example illustrates a method for preparing a drug storage module 21 that is a drug-loaded gel, which has a microchannel 21a with a height of 300 microns. The microchannel 21a is preferably arranged in a serpentine manner to have a longer contact path for easy release of the drug, for example Figure 4 The overall size is 11 mm × 11 mm × 600 μm, and the drug storage module 21 is prepared by 3D printing and reverse molding process. The preparation method of the drug storage module 21 is as follows:

[0040] Step 1.1, printing a drug storage module mold using 3D modeling software and a 3D printer, wherein the flow channel mold height is 300 microns, the mold groove height is 600 microns, the bottom layer thickness is 1 mm, and multiple molds are printed for backup;

[0041] Step 1.2, preparing the precursors required for the drug-loaded gel;

[0042] Step 1.3, place the mold in a culture dish, pour the drug-loaded gel precursor solution into the mold until it covers the mold, and remove bubbles by suction;

[0043] In step 1.4, the gelling agent is added to the precursor after the bubbles are removed, and the precursor is incubated for 24 hours.

[0044] In step 1.5, use a blade to remove the excess gel outside the mold and take out the gel. This completes the drug-loaded gel configuration.

[0045] The drug storage module 22 can be made in a similar manner. Alternatively, it can also be solid and made in other molding methods.

[0046] The pumping module 4 and the sharp-edge cantilever micropump 3 in this embodiment are assembled by nesting, wherein the pumping module 4 is a polydimethylsiloxane elastic polymer with an output microchannel 4b with a width and height of 100 microns and a connecting groove 41 matching the sharp-edge cantilever micropump 3, such as Figure 5 As shown, it is prepared by the reverse molding process. The sharp edge cantilever micropump 3 is prepared by two-photon 3D printing technology. The specific steps are as follows:

[0047] Step 2.1, making a pumping module mold by 3D printing technology, wherein the output microchannel mold is a rectangular cross-section channel mold with a height of 100 microns and a width of 100 microns, and the connecting groove mold matches the outer dimensions of the designed sharp-edge cantilever micropump 3, and multiple molds are printed at the same time for backup;

[0048] Step 2.2, placing the pumping module mold in a culture dish, pouring the pre-configured polydimethylsiloxane solution, exhausting the bubbles by suction, and baking at 80° C. for 1 hour to manufacture an elastic polymer with an output microchannel 4 b and a connecting groove 41;

[0049] Step 2.3, punching a hole at one end of the flow channel outlet of the elastic polymer obtained in step 2.2 using a puncher with a diameter of 1 mm;

[0050] Step 2.4, preparing a sharp-edge cantilever micropump 3 by two-photon 3D printing technology;

[0051] Step 2.5, embed the sharp-edge cantilever micropump 3 into the connecting groove 41 under a microscope, thereby assembling the pumping module 4 and the sharp-edge cantilever micropump 3, and the output microchannel 4b and the channel 3b form a part of the output channel b.

[0052] In addition, the loading substrate 5 is prepared by mold-reversing polydimethylsiloxane so that it has a receiving groove 51, and a connected microfluidic channel is punched out by a puncher to form an output port 5b. Similarly, the packaging cover 1 is prepared by polydimethylsiloxane, and an input channel a is punched out by a puncher as a liquid inlet. During assembly, a plasma cleaner is used to clean the surface of the loading substrate 5 having the receiving groove 51 and the surface of the packaging cover 1, and the drug storage module 21 is placed in the receiving groove 51 and bonded to the packaging cover 1, so that the groove 51 and the packaging cover 1 are enclosed to form a chamber A, and the microfluidic channel 21a and the surface of the packaging cover 1 are enclosed to form a closed channel, and the input channel a is connected to the inlet of the microfluidic channel 21a of the drug storage module 21 in the chamber A. Repeat the above steps to encapsulate another drug storage module 22. The pumping module 4 assembled with the sharp-edged cantilever micropump 3 is bonded to the surface to be bonded of the loading substrate 5 by a plasma cleaner, so that the connecting groove 41 is enclosed and closed, and the output port 5b is connected to the input end of the output microfluidic channel 4b to form an output channel b.

[0053] In practical applications, the form and type of drugs carried in each drug storage module are not restricted; the drug storage module can be a solid drug, a drug-loaded gel or a liquid drug, etc.; when the drug is a liquid drug, the liquid drug can be directly placed in the accommodating groove 51, and the packaging cover 1 does not need to be provided with an input channel a and a liquid inlet, and the liquid drug itself can flow in the output channel b and be controlled by the sharp-edge cantilever micropump 3.

[0054] In practical applications, the number of drug types that can be released by implantable drug release chips based on acoustic fluidics is not fixed. The number of drug types can be expanded by connecting multiple integral devices, changing the size and shape of the drug-loading chamber of the loading substrate, and changing the design of the liquid flow channel in the integral device. When increasing the number of drug types, the size and shape of different sharp-edge cantilever micropumps should be designed at the same time to achieve independent control of multiple drugs.

[0055] The above embodiments are only used to further illustrate an implantable drug release chip based on acoustic fluidics and a method for manufacturing the same, but the present invention is not limited to the embodiments. Any simple modifications, equivalent changes and modifications made to the above embodiments based on the technical essence of the present invention fall within the protection scope of the technical solution of the present invention.

Claims

1. An implantable drug release chip based on acoustic fluidics, characterized in that: The invention comprises a biocompatible matrix, a sharp-edge cantilever micropump and a drug; the biocompatible matrix has a chamber for accommodating the drug and an output channel connected to the chamber, and the output channel is used for outputting a liquid containing the drug; the sharp-edge cantilever micropump is arranged in the output channel, and comprises at least one sharp-edge cantilever unit, and the sharp-edge cantilever unit controls the delivery of the liquid containing the drug through the acoustic flow effect under ultrasonic excitation.

2. The implantable drug release chip based on acoustic fluidics according to claim 1, characterized in that: The medicine is a liquid medicine.

3. The implantable drug release chip based on acoustic fluidics according to claim 1, characterized in that: The drug is carried in a drug storage module and placed in the chamber, and the drug storage module is solid or gel; a microfluidic channel is provided in the drug storage module, and the biocompatible matrix also includes an input channel for inputting liquid, and the two ends of the microfluidic channel are respectively connected to the input channel and the output channel.

4. The implantable drug release chip based on acoustic fluidics according to claim 3, characterized in that: When the liquid flows through the microchannel, the drug storage module releases the loaded drug into the liquid to form the liquid containing the drug.

5. The implantable drug release chip based on acoustic fluidics according to claim 1, characterized in that: The sharp-edge cantilever unit is connected to the side wall of the output channel, and the free end extends toward the output direction of the output channel and the end forms a sharp angle.

6. The implantable drug release chip based on acoustic fluidics according to claim 1, characterized in that: A plurality of the sharp-edge cantilever units are arranged at intervals on two opposite sides of the output channel along the extension direction, and the sharp-edge cantilever units on the two sides are staggered.

7. The implantable drug release chip based on acoustic fluidics according to claim 1, characterized in that: The biocompatible matrix has a plurality of independent chambers, each chamber is connected to the output channel, each output channel is provided with the sharp-edge cantilever micropump, and each chamber is used to contain different drugs.

8. The implantable drug release chip based on acoustic fluidics according to claim 7, characterized in that: The lengths of the sharp-edge cantilever units in the output channels are different to achieve selective response to ultrasound.

9. A method for manufacturing an implantable drug release chip based on acoustic fluidics according to any one of claims 1 to 8, characterized in that: include: manufacturing the sharp-edge cantilever micropump; The packaging cover, the loading substrate and the pumping module are respectively made of biocompatible materials, the loading substrate has a receiving groove and an output port connected to the receiving groove, and the pumping module has an output microchannel and a connecting groove connected to the output microchannel; The sharp-edge cantilever micropump is installed in the connecting groove, the drug is placed in the containing groove, and the loading substrate is bonded to the pumping module and the packaging cover respectively; The loading base is bonded to the pumping module so that the connecting groove is enclosed and closed, and the output port is connected to the output microchannel to form the output channel; the loading base is bonded to the cover plate so that the accommodating groove is enclosed and closed to form the chamber; the packaging cover, the loading base and the pumping module are combined to form the biocompatible matrix.

10. The method for manufacturing an implantable drug release chip based on acoustic fluidics according to claim 9, characterized in that: The sharp-edge cantilever micropump is manufactured using 3D printing technology.

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