An implantable drug release chip based on acoustofluidics and a manufacturing method thereof

Abstract

This invention discloses an implantable drug delivery chip based on acoustic flow control, comprising a biocompatible substrate, a sharp-edged cantilever micropump, and a drug. The biocompatible substrate has a chamber for containing the drug and an output channel communicating with the chamber. The output channel is used for the output of a liquid containing the drug. The sharp-edged cantilever micropump is disposed in the output channel and includes at least one sharp-edged cantilever unit extending inward into the output channel. The sharp-edged cantilever unit controls the delivery of the liquid containing the drug through acoustic flow effect under ultrasonic excitation. This invention also discloses its fabrication method. This invention enables wirelessly programmable selective drug release from implantable devices, isolates the drug carrier from direct contact with the in vivo environment, and achieves high-precision drug release from the implanted drug delivery device.

Description

Technical Field

[0001] This invention belongs to the field of microfluidic drug delivery technology, specifically relating to an implantable drug delivery chip based on acoustic fluid control and its fabrication method. Background Technology

[0002] In the medical field, effective drug delivery is crucial for drugs to exert their therapeutic effects. Traditional drug delivery methods, such as oral, intravenous, and intramuscular injections, present challenges such as systemic transmission, rapid degradation and excretion, and widespread adverse reactions. For diseases requiring long-term drug treatment (such as hypertension and diabetes), patients are required to perform long-term self-monitoring, repeated medication, and multiple injections, which may lead to decreased patient compliance and thus weaken the actual therapeutic effect of the drug.

[0003] In recent years, various implantable devices have been developed, all aimed at improving patient compliance for complex medical conditions requiring repetitive and long-term medication, further promoting the development of personalized medicine. However, for implantable devices, challenges remain regarding biocompatibility, precise drug dosage control, drug storage, and overall device miniaturization.

[0004] Current implantation methods mostly utilize various hydrogels to carry drugs. After implantation, the drug is released through hydrogel decomposition, concentration gradient, or external field stimulation. While these methods can successfully place drugs into the body and achieve in vivo drug release, several problems remain. For example, the drug-carrying hydrogel is directly exposed in the body, limiting the ability to carry high concentrations of drugs and restricting the use of certain medications. Drug release through hydrogel decomposition or concentration gradient is a passive release method, which cannot achieve high precision. While external field stimulation allows for effective control, the preparation of drug carriers is complex and the types of drugs that can be carried are limited. Summary of the Invention

[0005] This invention addresses the shortcomings of existing technologies by providing an implantable drug delivery chip based on acoustic fluid control and its manufacturing method, which enables controllable and precise drug delivery while also isolating the drug carrier from direct contact with the in vivo environment.

[0006] To achieve the above objectives, the technical solution of the present invention is as follows:

[0007] An implantable drug delivery chip based on acoustic flow control includes a biocompatible matrix, a sharp-edged cantilever micropump, and a drug. The biocompatible matrix has a chamber for containing the drug and an output channel communicating with the chamber. The output channel is used for the output of a liquid containing the drug. The sharp-edged cantilever micropump is disposed in the output channel and includes at least one sharp-edged cantilever unit. The sharp-edged cantilever unit controls the delivery of the liquid containing the drug through the acoustic flow effect under ultrasonic excitation.

[0008] The output channel is connected to the external environment. The chip uses ultrasound for wireless excitation. Under ultrasound excitation, each sharp-edged cantilever unit will exhibit an acoustic flow effect, thereby producing a liquid delivery effect to deliver the drug to the external environment.

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

[0010] Optionally, the drug is carried in a drug storage module and placed in the chamber, the drug storage module being a solid or a gel; the drug storage module is provided with microchannels, and the biocompatible matrix further includes an input channel for introducing liquid, the two ends of the microchannel being connected to the input channel and the output channel respectively.

[0011] Optionally, as the liquid flows through the microchannel, the drug storage module releases the loaded drug into the liquid to form the drug-containing liquid.

[0012] Optionally, the sharp-edge cantilever unit is connected to the side wall of the output channel, with its free end extending in the output direction of the output channel and its end forming a sharp angle with an acute angle.

[0013] Optionally, several sharp-edged cantilever units are arranged at intervals on opposite sides of the output channel along the extension direction, and the sharp-edged cantilever units on both sides are staggered.

[0014] Optionally, the biocompatible matrix has multiple independent chambers, each chamber is connected to an output channel, each output channel is equipped with a sharp-edged cantilever micropump, and each chamber is used to contain different drugs.

[0015] Optionally, the lengths of the sharp-edged cantilever units within each of the output channels may differ to achieve selective response to ultrasonic waves.

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

[0017] A method for fabricating the above-mentioned acoustic fluid control-based implantable drug delivery chip includes:

[0018] Fabricate the sharp-edged cantilever micropump;

[0019] The encapsulation cap, loading substrate, and pumping module are fabricated using biocompatible materials. The loading substrate has a receiving groove and an output port connected to the receiving groove. The pumping module has an output microchannel and a connecting groove connected to the output microchannel.

[0020] A sharp-edged cantilever micropump is installed in a connecting groove, and the drug is placed in a receiving groove. The loading substrate is bonded to the pumping module and the encapsulation cap respectively. The loading substrate and the pumping module are bonded to enclose and seal the connecting groove, and the output port is connected to the output microchannel to form the output channel. The loading substrate and the cap are bonded to enclose and seal the receiving groove to form the chamber. The encapsulation cap, the loading substrate and the pumping module are combined to form the biocompatible matrix.

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

[0022] The beneficial effects of this invention are as follows:

[0023] 1) Drugs embedded in biocompatible substrates avoid direct contact with the in vivo environment, increasing the variety of drugs available.

[0024] 2) Solid or gel-packaged drugs can be directly encapsulated into a biocompatible matrix, eliminating the need for complex drug carrier preparation processes;

[0025] 3) The overall device is small in size, enabling minimally invasive surgery;

[0026] 4) Active control via ultrasound enables precise fluid control at the microfluidic scale, achieving accurate drug release;

[0027] 5) It can achieve different controls on the release of various drugs. Attached Figure Description

[0028] Figure 1 This is an exploded structural diagram of an implantable drug delivery chip based on acoustic fluid control, as shown in the embodiment.

[0029] Figure 2 This is a schematic diagram of the overall structure of an implantable drug delivery chip based on acoustic fluid control, as shown in the embodiment. Part of the structure is shown in perspective to illustrate the liquid flow path.

[0030] Figure 3(a) is a front view of the structure of the sharp-edged cantilever micropump of the embodiment;

[0031] Figure 3(b) is a three-dimensional structural schematic diagram of the sharp-edged cantilever micropump of the embodiment;

[0032] Figure 3(c) is a schematic diagram of the principle of liquid conveying effect achieved by the sharp-edged cantilever unit in the embodiment;

[0033] Figure 4 A three-dimensional structural diagram of the drug storage module in this embodiment;

[0034] Figure 5 This is a schematic diagram of the pumping module in an embodiment. Detailed Implementation

[0035] The present invention will be further explained below with reference to the accompanying drawings and specific embodiments. The accompanying drawings are merely illustrative to facilitate understanding of the invention, and their specific proportions can be adjusted according to design requirements. The vertical relationships of relative elements and the definitions of front / back in the graphics described herein should be understood by those skilled in the art to refer to the relative positions of the components; therefore, they can all be flipped to present the same component, and all of this should fall within the scope disclosed in this specification.

[0036] refer to Figure 1 and Figure 2 This embodiment uses an acoustic fluid control-based implantable drug delivery chip for the sustained release of two drugs as an example. Its biocompatible substrate is disassembled into two encapsulation caps 1, a loading substrate 5, and two pumping modules 4. The two encapsulation caps 1 and the pumping modules 4 are symmetrically arranged on both sides of the loading substrate 5 to form a structure for the sustained release of two drugs. The following describes the structure for the sustained release of one drug in detail. The encapsulation caps 1, the loading substrate 5, and the pumping modules 4 cooperate to form a chamber A, and an input channel a and an output channel b communicating with chamber A. A drug storage module 21 is provided within chamber A. The drug storage module 21 is a solid or gel, and it has microchannels 21a within it. The two ends of the microchannels 21a are connected to the input channel a and the output channel b, respectively. Liquid enters from the input channel a, and as it flows through the microchannels 21a, the drug storage module 21 releases the loaded drug into the liquid, forming a drug-containing liquid. The output channel b is used for the output of the drug-containing liquid. Referring to Figures 3(a) and 3(b), the sharp-edged cantilever micropump 3 is disposed in the output channel b, including at least one sharp-edged cantilever unit 31. The sharp-edged cantilever unit 31 can control the delivery of drug-containing liquid through the acoustic flow effect under ultrasonic excitation, thereby achieving sustained drug release by controlling the action of ultrasound on the sharp-edged cantilever micropump 3. The drug storage module 21 gradually consumes the drug stored therein as the liquid flows in the microchannel 21a.

[0037] The sharp-edged cantilever micropump 3 also includes a flow channel 3b forming part of the output channel b, and a boss 32 for positioning and indicating direction. The sharp-edged cantilever unit 31 is connected to the sidewall of the flow channel 3b, with its free end extending in the output direction of the output channel b and its end forming a sharp angle. For example, referring to Figure 3(c), in a 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 obliquely into the flow channel from the sidewall, while the parallel line segment 312 is relatively far from the sidewall and parallel to it. Its other end is connected to the sidewall via an arc line segment 313. Several sharp-edged cantilever units 31 of the above shape are spaced apart on opposite sides of the flow channel 3b along the extending direction, with the sharp-edged cantilever units 31 on both sides staggered. When ultrasound waves irradiate the sharp-edged cantilever unit, the tip of the unit vibrates rapidly, creating two vortices rotating in opposite directions around it. This is known as the acoustic flow effect. Through the combined action of the two vortices, liquid is pumped out along the sharp-edged tip. Alternatively, the sharp-edged cantilever unit 31 can also be of other shapes, as long as the sharp-edged acoustic flow effect is achieved under ultrasound and the pumping direction is consistent.

[0038] The structure for another drug sustained release is the same as the structure described above. Its chamber A is equipped with a drug storage module 22. The drug storage module 22 and the drug storage module 21 can have similar microchannel 22a structures, but the drugs they carry are different. The sharp-edged cantilever micropumps 3 corresponding to the two drugs can achieve specific responses to different ultrasound waves through differences in shape, length and other settings, thereby achieving independent sustained release control.

[0039] The following example illustrates the preparation method when the drug storage module 21 is a drug-loaded gel, which has microchannels 21a with a height of 300 micrometers. The microchannels 21a are preferably meandering to provide a longer contact path for drug release. For example... Figure 4 As shown. The overall dimensions are 11 mm × 11 mm × 600 micrometers. The drug storage module 21 was fabricated using 3D printing and molding processes. The fabrication method is as follows:

[0040] Step 1.1: Print the drug storage module mold using 3D modeling software and a 3D printer. The flow channel mold has a height of 300 micrometers, the mold groove has a height of 600 micrometers, and the bottom layer has a thickness of 1 millimeter. Print multiple molds for later use.

[0041] Step 1.2: Prepare the precursors required for the drug-loaded gel;

[0042] Step 1.3: Place the mold in a petri dish, pour in the drug-loaded gel precursor solution until it covers the mold, and remove air bubbles by suction.

[0043] Step 1.4: Add the gelling agent to the precursor after removing air bubbles, and incubate for 24 hours.

[0044] Step 1.5: Use a blade to remove excess gel from outside the mold and remove the gel. This completes the preparation of the drug-loaded gel.

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

[0046] In this embodiment, the pumping module 4 and the sharp-edged cantilever micropump 3 are assembled in a nested configuration. The pumping module 4 is a polydimethylsiloxane elastic polymer with an output microchannel 4b having a width and height of 100 micrometers and a connecting groove 41 that matches the sharp-edged cantilever micropump 3. Figure 5 As shown, it is fabricated using a molding process. The sharp-edged cantilever micropump 3 is fabricated using two-photon 3D printing technology. The specific steps are as follows:

[0047] Step 2.1: The pumping module mold is made using 3D printing technology. The output microchannel mold is a rectangular cross-section mold with a height of 100 micrometers and a width of 100 micrometers. The connecting groove mold matches the external dimensions of the designed sharp-edged cantilever micropump 3. Multiple molds are printed at the same time for backup.

[0048] Step 2.2: Place the pumping module mold in a petri dish, pour in the pre-prepared polydimethylsiloxane solution, remove air bubbles by suction, and bake at 80°C for 1 hour to produce an elastic polymer with output microchannel 4b and connecting groove 41.

[0049] Step 2.3: Use a punch with a diameter of 1 mm to punch a hole at one end of the flow channel outlet of the elastic polymer obtained in step 2.2;

[0050] Step 2.4: Fabricate the sharp-edged cantilever micropump 3 using two-photon 3D printing technology;

[0051] Step 2.5: Under a microscope, the sharp-edged cantilever micropump 3 is nested into the connecting groove 41, thereby assembling the pumping module 4 and the sharp-edged cantilever micropump 3. The output microchannel 4b and the channel 3b form part of the output channel b.

[0052] Furthermore, the loading substrate 5 is prepared by molding polydimethylsiloxane using a mold to create a receiving groove 51, and a connecting microchannel is punched out using a punch to form an output port 5b. Similarly, the encapsulation cap 1 is prepared using polydimethylsiloxane, and an input channel a is punched out using a punch as a liquid inlet. During assembly, the surfaces of the loading substrate 5 with the receiving groove 51 and the encapsulation cap 1 are cleaned using a plasma cleaner. The drug storage module 21 is placed in the receiving groove 51 and bonded to the encapsulation cap 1, thereby forming a chamber A by the groove 51 and the encapsulation cap 1, and a closed channel by the microchannel 21a and the surface of the encapsulation cap 1. The input channel a connects to the inlet of the microchannel 21a of the drug storage module 21 in chamber A. The above steps are repeated to encapsulate another drug storage module 22. The pumping module 4, which is assembled with a sharp-edged cantilever micropump 3, is bonded to the bonding surface of the loading substrate 5 using a plasma cleaner, so that the connecting groove 41 is closed and the output port 5b connects to the input end of the output microchannel 4b to form an output channel b.

[0053] In practical applications, there are no restrictions on the form or type of drug carried in each drug storage module; 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 receiving groove 51, and the encapsulation cover 1 does not need to be set with an input channel a and a liquid inlet. The liquid drug itself can flow in the output channel b and be controlled by the sharp-edged cantilever micropump 3.

[0054] In practical applications, the number of drug types that can be released by an acoustic fluid control-based implantable drug delivery chip is not fixed. The number of drug types can be expanded by connecting multiple integrated devices, changing the size and shape of the drug-loading chamber of the substrate, and changing the liquid flow channel design in the integrated device. When increasing the number of drug types, different sizes and shapes of sharp-edged cantilever micropumps should be designed to achieve independent control of multiple drugs.

[0055] The above embodiments are only used to further illustrate the implantable drug delivery chip based on acoustic flow control and its manufacturing method according to the present invention. However, the present invention is not limited to the embodiments. Any simple modifications, equivalent changes and alterations made to the above embodiments based on the technical essence of the present invention shall fall within the protection scope of the technical solution of the present invention.

Claims

1. A method for fabricating an implantable drug delivery chip based on acoustic fluid control, characterized in that, include: A sharp-edged cantilever micropump is fabricated, wherein the sharp-edged cantilever micropump includes at least one sharp-edged cantilever unit. The encapsulation cap, loading substrate, and pumping module are fabricated using biocompatible materials. The loading substrate has a receiving groove and an output port connected to the receiving groove. The pumping module has an output microchannel and a connecting groove connected to the output microchannel. The sharp-edged cantilever micropump is installed in the connecting groove, the drug is placed in the receiving groove, and the loading substrate is bonded to the pumping module and the encapsulation cap respectively. The loading substrate is bonded to the pumping module to enclose and seal the connecting groove, and the output port is connected to the output microchannel to form an output channel; the loading substrate is bonded to the cover plate to enclose and seal the receiving groove to form a chamber; the encapsulation cover, loading substrate and pumping module are combined to form a biocompatible matrix; The fabricated acoustic flow-based implantable drug delivery chip includes a biocompatible matrix, a sharp-edged cantilever micropump, and a drug. The biocompatible matrix has a chamber for containing the drug and an output channel connected to the chamber. The output channel is used for the output of liquid containing the drug. The sharp-edged cantilever micropump is located in the output channel. The sharp-edged cantilever unit controls the delivery of liquid containing the drug through the acoustic flow effect under ultrasonic excitation.

2. The method for fabricating an implantable drug delivery chip based on acoustic fluid control according to claim 1, characterized in that: The drug is a liquid drug.

3. The method for fabricating an implantable drug delivery chip based on acoustic fluid control according to claim 1, characterized in that: The drug is carried in a drug storage module and placed in the chamber. The drug storage module is solid or gel. The drug storage module is provided with microchannels. The biocompatible matrix also includes an input channel for introducing liquid. The two ends of the microchannel are respectively connected to the input channel and the output channel.

4. The method for fabricating an implantable drug delivery chip based on acoustic fluid control according to claim 3, characterized in that: When the liquid flows through the microchannel, the drug storage module releases the drug it carries into the liquid, forming the drug-containing liquid.

5. The method for fabricating an implantable drug delivery chip based on acoustic fluid control according to claim 1, characterized in that: The sharp-edged cantilever unit is connected to the side wall of the output channel, with its free end extending in the output direction of the output channel and its end forming a sharp angle.

6. The method for fabricating an implantable drug delivery chip based on acoustic fluid control according to claim 1, characterized in that: The output channel has several sharp-edged cantilever units arranged at intervals on both sides of the opposite side along the extension direction, and the sharp-edged cantilever units on both sides are staggered.

7. The method for fabricating an implantable drug delivery chip based on acoustic fluid control according to claim 1, characterized in that: The biocompatible matrix has multiple independent chambers, each chamber is connected to an output channel, each output channel is equipped with a sharp-edged cantilever micropump, and each chamber is used to contain different drugs.

8. The method for fabricating an implantable drug delivery chip based on acoustic fluid control according to claim 7, characterized in that: The lengths of the sharp-edged cantilever units within each output channel are different to achieve selective response to ultrasonic waves.

9. The method for fabricating an implantable drug delivery chip based on acoustic fluid control according to claim 1, characterized in that: The sharp-edged cantilever micropump is manufactured using 3D printing technology.

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