Bionic cilia system, drug delivery system and preparation method and application thereof

Abstract

The invention provides a bionic cilia system, a drug delivery system and a preparation method and application of the bionic cilia system and the drug delivery system. The bionic cilia system comprises a bionic cilia array and a sound wave stimulation system and / or a sound production control system, and the bionic cilia array comprises bionic cilia existing in an array form; and the length-diameter ratio of the bionic cilia is 1-1000. The bionic cilia system can directly respond to sound wave signals. The drug delivery system provided by the invention can realize controlled drug release with sound frequency selectivity, is simple and convenient to operate, and is particularly suitable for prevention and treatment which can generate a prevention or treatment effect through subcutaneous absorption.

Description

Technical Field

[0001] The invention relates to a bionic cilia system, a drug delivery system, and a preparation method and application thereof. Background Art

[0002] Language plays a unique and valuable role in human communication. People have been committed to the advancement of automatic speech recognition technology. Voice assistants represented by Apple Siri have completely changed the function of voice-controlled smart devices and provided a large number of application scenarios, such as smart homes and smart medical care. However, current speech recognition technology relies heavily on artificial intelligence algorithms and smart electronic devices, that is, first collecting human voice signals, and then extracting and identifying signal features through signal processing technology and artificial intelligence algorithms, and finally converting them into control signals for subsequent electronic devices. In the absence of intelligent electronic devices or algorithm support, existing speech recognition technology is greatly limited. At present, there is no physical sound decoding device that does not rely on algorithms or electronic devices, nor has there been any report on voice-controlled drug release.

[0003] The human auditory system senses sound through the hair cells in the cochlea. Sound waves in the frequency range of 20-20,000Hz are transmitted to the inner ear through the ear canal, causing resonance of the basilar membrane of the human cochlea. The hair cells in the cochlea convert mechanical sound wave vibrations into electrical excitation of lower-level neurons through the back-and-forth swinging of their ciliary bundles, which are then transmitted to the brain to form auditory perception. So far, inspired by natural cilia in nature, many bionic artificial cilia devices driven by magnetic fields, electric fields, light and air pressure have been developed for particle / droplet transport manipulation, flow sensing, fluid mixing, microfluidic pumping and micro-robotics. At present, there are no bionic artificial cilia devices and systems that directly respond to sound wave signals. Summary of the invention

[0004] The technical problem to be solved by the present invention is to overcome the defects that the bionic cilia system of the prior art cannot respond to sound wave signals, the drug administration method in the current prior art cannot achieve on-demand controlled drug release, and the drug administration is limited in an environment where it is inconvenient to drip the drug or the time period is limited. A bionic cilia system, a drug delivery system, and a preparation method and application thereof are provided. The bionic cilia system of the present invention can directly respond to sound wave signals. The drug delivery system of the present invention applies the resonance characteristics of sound wave stimulation to drug delivery, which can achieve on-demand drug release controlled by sound frequency, and is easy to operate.

[0005] The present invention solves the above technical problems through the following technical solutions:

[0006] The present invention provides a bionic cilia system, which comprises a bionic cilia array, and an acoustic wave stimulation system and / or a sound control system. The bionic cilia array comprises bionic cilia in an array form; the aspect ratio of the bionic cilia is 1-1000.

[0007] In the present invention, the aspect ratio of the bionic ciliary array is preferably 10-200, more preferably 30-100, for example 30, 35, 40, 45 or 50.

[0008] In the present invention, the sound frequency range of the sound wave stimulation system and / or the sound control system is preferably 20 Hz-20 KHz.

[0009] The inventors have found that the aspect ratio of the bionic cilia is 1-1000, and the sound frequency range of the sound wave stimulation system and / or sound control system that can respond is 20-20KHz. The larger the aspect ratio, the lower the corresponding frequency.

[0010] In the present invention, preferably, the aspect ratio of the bionic cilia is 30-50, and the sound frequency range of the sound wave stimulation system and / or the sound control system is preferably 500-2200 Hz.

[0011] More preferably, the aspect ratio of the bionic cilia is 30, and the sound frequency range of the sound wave stimulation system and / or the sound control system is 2100-2300 Hz, for example, 2200 Hz.

[0012] More preferably, the aspect ratio of the bionic cilia is 35, and the sound frequency range of the sound wave stimulation system and / or the sound control system is 1400-1600 Hz, for example, 1500 Hz.

[0013] More preferably, the aspect ratio of the bionic cilia is 40, and the sound frequency range of the sound wave stimulation system and / or the sound control system is 1100-1300 Hz, for example, 1200 Hz.

[0014] More preferably, the aspect ratio of the bionic cilia is 45, and the sound frequency range of the sound wave stimulation system and / or the sound control system is 700-900 Hz, for example, 800 Hz.

[0015] More preferably, the aspect ratio of the bionic cilia is 50, and the sound frequency range of the sound wave stimulation system and / or the sound control system is 400-600 Hz, for example, 500 Hz.

[0016] In the present invention, the elongation at break of the bionic cilia is preferably 1%-100%, more preferably 1%-50%, for example 2.2%.

[0017] In the present invention, the tensile strength of the bionic cilia can be 10-100 MPa, preferably 20-100 MPa, more preferably 50-100 MPa, for example 79.3 MPa.

[0018] In the present invention, the tensile modulus of the bionic cilium may be 0.1-10 GPa, preferably 1-5 GPa, more preferably 2-5 GPa, such as 4.2 GPa.

[0019] In the present invention, the bending strength of the bionic cilia can be 1-500 MPa, preferably 10-200 MPa, more preferably 500-200 MPa, such as 120 MPa.

[0020] In the present invention, the bending modulus of the bionic cilium may be 0.1-10 GPa, preferably 1-5 GPa, more preferably 2-5 GPa, such as 4 GPa.

[0021] In the present invention, the material source of the bionic cilia can be selected from conventional bionic cilia materials in the art, for example, selected from synthetic polymer materials and / or natural animal hair, and the synthetic polymer materials may include but are not limited to one or more of polyethylene, polypropylene, polyvinyl chloride, polystyrene, acrylonitrile-butadiene-styrene copolymer (ABS), polyester and nylon; wherein the polyester is preferably silicone-modified polyester; the synthetic polymer material is preferably in the form of resin, and the synthetic polymer material is more preferably silicone polyester-modified resin, such as HTL resin.

[0022] In a specific embodiment of the present invention, the bionic cilia are made of high temperature resistant resin material, the elongation at break of the bionic cilia is 2.2%, the tensile strength of the bionic cilia is 79.3 MPa, the tensile modulus of the bionic cilia is 4.2 GPa, the bending strength of the bionic cilia is 120 MPa, and the bending modulus of the bionic cilia is 4 GPa.

[0023] In the present invention, the cross-sectional area of ​​the bionic cilia can be circular or polygonal, preferably circular; the polygon can be triangular or square.

[0024] In the present invention, the diameter of the bionic cilia may be 1 nm-10 mm, preferably 1 μm-1 mm, more preferably 50 μm-200 μm, for example 100 μm.

[0025] In the present invention, the spacing between the bionic cilia can be 10 nm-10 cm, preferably 100 μm-10 mm, more preferably 500 μm-5 mm, such as 1 mm.

[0026] In the present invention, the number of cilia distributed on the bionic cilia array can be 1-100,000, preferably 10-1,000, more preferably 50-500, such as 100.

[0027] In the present invention, the array density of the bionic cilia array can be 1-100 / mm2 (the number of bionic cilia per unit area), preferably 1-50 / mm2, more preferably 1-10 / mm2, for example 4 / mm2.

[0028] In the present invention, those skilled in the art know that the biomimetic cilia array generally includes a substrate, and the shape of the substrate can be circular, triangular, rectangular, polygonal, etc., preferably circular. The equivalent width of the substrate can be 10nm-100cm, preferably 1mm-10cm, more preferably 5mm-10mm, for example 8mm. When the substrate is rectangular, the equivalent width refers to the width of the rectangle. When the substrate is circular, the equivalent width refers to the diameter of the circle.

[0029] In the present invention, the manufacturing method of the bionic artificial cilia array can be prepared according to existing methods, such as 3D printing, micro-nano processing, mold manufacturing, thermal processing or wire drawing; preferably, it is a 3D printing method; the 3D printing method is preferably a projection light-curing 3D printing method.

[0030] The precision of the 3D printing is preferably 5-15 μm, for example, 10 μm. The exposure wavelength of the 3D printing is preferably 380-420 nm, for example, 405 nm. The exposure time of the 3D printing is preferably 1-3 s. The exposure intensity of the printing is preferably 50-60 mW / cm 2 The exposure waiting time of the 3D printing is preferably 300-500s. The model of the printer used for the 3D printing may be Shenzhen Magic Cube nanoArch S130.

[0031] In the present invention, the acoustic wave stimulation system is used to emit sound waves to stimulate the bionic cilia to resonate. The sound intensity of the acoustic wave stimulation system is preferably 60-140dB, for example 100dB. In the present invention, the acoustic wave stimulation system can be a piezoelectric transducer, a buzzer, a speaker, a horn or a sound.

[0032] In the present invention, the sound control system can be used to achieve the following control purpose: control the sound wave stimulation system included in the bionic cilia system, or the sound-generating device outside the bionic cilia system to emit sound waves, thereby causing the resonance of the bionic cilia. Specifically, the sound control system can control various parameters of the sound waves, such as controlling one or more of the intensity, frequency, sound frequency, sound duration, and sound interval duration, so as to simulate different sound wave environments according to actual scenarios.

[0033] Preferably, the sound control system can be a virtual system including a control module, and the control module can achieve the above-mentioned control purpose, such as a program that can be installed on an electronic device, and more specifically, an APP program that can be installed on a mobile phone to control the sound of a mobile phone, television or speaker.

[0034] Preferably, the sound control system includes a computer-readable storage medium storing logic instructions, and the logic instructions are executed by a processor to achieve the above control purpose, such as a USB flash drive or an optical disk. More preferably, the sound control system also includes a processor, and the processor executes the logic instructions to achieve the control purpose; the sound control system can be a function signal generator.

[0035] The function signal generator can be electrically connected to the sound wave stimulation system to control one or more of the intensity, frequency, occurrence frequency, duration and interval duration of the sound waves to achieve the control purpose. For example, the function signal generator is electrically connected to the buzzer.

[0036] In the present invention, the bionic cilia system preferably further comprises a shell device, in which the bionic cilia array, the sound wave stimulation system and / or the sound control system are arranged. The shell device may be a conventional shell device in the art, such as a capsule device.

[0037] In a preferred embodiment of the present invention, the bionic cilia system comprises the bionic cilia array, the sound control system and a capsule device, wherein the bionic cilia array and the sound control system are arranged in the capsule device. The sound control system is preferably a piezoelectric transducer.

[0038] The present invention also provides a drug delivery system, which includes a drug-carrying unit and the above-mentioned bionic cilium system, wherein the drug-carrying unit is adsorbed on the bionic cilium of the bionic cilium system, the drug-carrying unit includes a drug and a carrier, and the carrier includes a hydrogel.

[0039] The drug delivery system of the present invention achieves controlled drug release through the following process: when subjected to acoustic stimulation emitted by an acoustic stimulation system or controlled by a sound control system, the bionic cilia vibrate under the acoustic stimulation, causing the adsorbed drug-loaded solution to fall off the bionic cilia, thereby achieving sound-controlled drug release.

[0040] Wherein, the hydrogel can be selected from gelatin, polyvinyl alcohol, polyacrylamide, sodium polyacrylate, chitosan or hyaluronic acid, preferably selected from gelatin. The material of the gelatin can be methacrylated gelatin (GelMA). The mass concentration of the hydrogel is preferably 10%-30%, for example 20%. The mass concentration of the hydrogel refers to the ratio of the mass of the hydrogel to the total mass of the carrier.

[0041] Wherein, the carrier preferably further includes a photoinitiator, and the photoinitiator may be conventional in the art, for example, lithium phenyl (2,4,6-trimethylbenzoyl) phosphate (also known as LAP). When the carrier includes a hydrogel and a photoinitiator, the preparation method of the carrier preferably includes mixing the hydrogel and the photoinitiator. The mixing temperature is preferably 50-80°C, for example 70°C. The mixing time is preferably 10-60min, for example 20min.

[0042] Wherein, the drug preferably includes macromolecular drugs and / or small molecule drugs, the macromolecular drugs are preferably polypeptide drugs, protein drugs, antibody drugs, polysaccharide drugs or nucleic acid drugs, more preferably protein drugs, and the protein drugs are preferably insulin and / or glucagon.

[0043] The drug concentration of the drug-carrying unit can be conventionally selected according to the required dosage of the drug, for example, 10 mg / mL. The drug concentration of the drug-carrying unit refers to the mass of the drug contained in 1 mL of the drug-carrying unit. For example, each 1 mL of the drug-carrying unit contains a total of 10 mg of insulin and glucagon, that is, the drug concentration is 10 mg / mL.

[0044] The present invention also provides a method for preparing the above-mentioned drug delivery system, which comprises the following steps: preparing a drug-carrying unit, and adsorbing the drug-carrying unit on bionic cilia.

[0045] Wherein, the method for adsorbing the drug-carrying unit on the bionic cilium can be prepared according to the existing method, generally including the modification method, and the modification method may include direct application, natural curing, photocuring or freeze-drying, preferably photocuring. The photocuring method can be conventional photocuring methods in the art, such as ultraviolet light curing. The photocuring time is preferably 10-600s, such as 30s, 60s or 120s. The wavelength of the light for photocuring is preferably 250-420nm, such as 255nm.

[0046] In a preferred embodiment of the present invention, the method of adsorbing the drug-carrying unit on the bionic cilia preferably includes applying the drug-carrying solution on the bionic cilia and curing it with ultraviolet light.

[0047] The drug-carrying unit can be prepared according to existing methods. The drug-carrying unit can exist in the form of a solution.

[0048] In a preferred embodiment of the present invention, the preparation method of the drug-carrying unit comprises the following steps: mixing the drug and the carrier.

[0049] In this example, the carrier preferably includes a hydrogel and a photoinitiator, and the photoinitiator can be conventional in the art, such as lithium phenyl (2,4,6-trimethylbenzoyl) phosphate (also known as LAP). The preparation of the drug-carrying unit preferably includes mixing the carrier and the drug. The mixing temperature is preferably 50-80° C., such as 70° C. The mixing time is preferably 10-60 min, such as 20 min.

[0050] The present invention also provides the use of the above-mentioned drug delivery system in the preparation of drugs for preventing or treating diseases, wherein the diseases are preferably endocrine diseases, respiratory diseases, gastrointestinal diseases, cardiovascular diseases or tumors, and the endocrine diseases are preferably diabetes.

[0051] The positive and progressive effects of the present invention are:

[0052] The bionic cilia system of the present invention can directly respond to sound wave signals.

[0053] The drug delivery system of the present invention provides a new controlled drug release method, which delivers drugs adsorbed on bionic cilia through the resonance characteristics of the bionic cilia system to sound wave stimulation. The drug delivery system of the present invention can realize the controlled release of drugs selective to sound frequency, is easy to operate, and is particularly suitable for prevention and treatment that can produce preventive or therapeutic effects through subcutaneous absorption. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Figure 1 Schematic diagram of the bionic cilia system inspired by cochlear hair cells in Example 1.

[0055] Figure 2 This is a real picture of the cochlear hair cell structure and the manufactured bionic cilia array of Example 1.

[0056] Figure 3 This is the bionic cilia array of Example 2 and its vibration diagram under sound wave stimulation.

[0057] Figure 4 This is a test effect diagram of the mechanical properties, resonance frequency and displacement characterization under resonance conditions of the bionic ciliary array of Example 1.

[0058] Figure 5 This is a diagram of the drug-loaded bionic ciliary array of Effect Example 1 and its release test in solution.

[0059] Figure 6 This is a graph showing the insulin concentration measurement results of Effect Example 2.

[0060] Figure 7 This is the in vitro release curve of insulin and glucagon in Effect Example 2.

[0061] Figure 8 It is a SEM comparison picture of the insulin-loaded bionic ciliary array of Effect Example 2 before and after resonance release.

[0062] Fig. 9 Schematic diagram of the preparation of the drug delivery system in Example 12.

[0063] Fig.10 The figure shows a drug delivery system including a capsule device according to Effect Example 3 and vibration diagrams of different ciliary arrays.

[0064] Fig.11 This is a graph showing the test results of using the insulin-loaded bionic cilia array of Effect Example 3 for blood sugar regulation in diabetic mice.

[0065] Fig.12 This is another test result diagram of the insulin-loaded bionic ciliary array of Effect Example 3 for blood glucose regulation in diabetic mice.

[0066] Fig.13 This is a graph showing the test results of using the bionic cilia array loaded with glucagon in Effect Example 3 for blood glucose regulation in diabetic mice.

[0067] Fig.14 This is a graph showing the test results of using the insulin-loaded bionic cilia array of Effect Example 3 for pulsed blood glucose regulation in diabetic mice. DETAILED DESCRIPTION

[0068] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. Those skilled in the art may make various changes or modifications to these embodiments without departing from the principles and essence of the present invention, but these changes and modifications all fall within the scope of protection of the present invention.

[0069] Example 1 Preparation of a bionic cilia array of bionic cochlear hair cell structures

[0070] This embodiment provides a bionic cilia array that mimics the structure of cochlear hair cells. The cochlear structure of newborn rats was isolated in vitro, and the cochlear tissue was extracted for scanning electron microscopy. The typical morphological structure of cochlear hair cells is shown in Figure 2. Figure 1 As shown in part a of the figure, it usually includes three rows of outer hair cells and inner hair cells. The top is composed of cilia of different lengths. The diameter of a single cilia is about 100nm. The outer hair cells show a typical V-shaped structure. Using Solidworks software, a cilia array composed of bionic cilia of different heights was designed. The cilia diameter was 100μm, the cilia aspect ratio was 20-80, and the material of the bionic cilia was selected from HTL resin material. The bionic cilia array was made using a high-precision projection light-curing 3D printer. Its physical picture and local detailed structure are shown in the figure. Figure 2 As shown in b in the figure, the printing parameters of the 3D printer used are: printer model: Shenzhen Mofang nanoArch S130; printing accuracy: 10μm; exposure wavelength: 405nm; exposure time: 1-3s; exposure intensity: 50-60; exposure waiting time 300-500s.

[0071] Example 2

[0072] This embodiment 2 provides a bionic cilia system, which includes a bionic cilia array and a piezoelectric transducer, wherein the bionic cilia array includes bionic cilia in the form of an array. The method for preparing a bionic cilia array is the same as that of embodiment 1, and a bionic cilia array with a diameter of 100 μm and a length of 5 mm (aspect ratio of 50) is prepared on the same substrate (circular in shape and 8 mm in diameter). Among them, the cross-sectional area of ​​the bionic cilia is circular, the spacing between the bionic cilia is 1 mm, and the array density of the bionic cilia array is 4 strands per square millimeter. The material of the bionic cilia is HTL resin, with a tensile strength of 79.3 MPa, a tensile modulus of 4.2 GPa, an elongation at break of 2.2%, a bending strength of 120 MPa, and a bending modulus of 4 GPa. The actual picture is as follows Figure 3 As shown in part a of the figure, a piezoelectric transducer is integrated at the bottom of the bionic cilia array to simulate the function of amplifying acoustic wave signals of the basilar membrane of the cochlea.

[0073] Example 3

[0074] This embodiment provides a bionic cilia system, which includes a bionic cilia array and a piezoelectric transducer. The difference between this embodiment and embodiment 2 is that the aspect ratio of the bionic cilia is 30.

[0075] Example 4

[0076] This embodiment provides a bionic cilia system, which includes a bionic cilia array and a piezoelectric transducer. The difference between this embodiment and embodiment 2 is that the aspect ratio of the bionic cilia is 35.

[0077] Example 5

[0078] This embodiment provides a bionic cilia system, which includes a bionic cilia array and a piezoelectric transducer. The difference between this embodiment and embodiment 2 is that the aspect ratio of the bionic cilia is 40.

[0079] Example 6

[0080] This embodiment provides a bionic cilia system, which includes a bionic cilia array and a piezoelectric transducer. The difference between this embodiment and embodiment 2 is that the aspect ratio of the bionic cilia is 45.

[0081] Effect Example 1

[0082] The bionic cilia of the bionic cilia system of Example 2-6 were observed to vibrate under external acoustic stimulation. Figure 3 b. The prepared artificial cilia have good mechanical properties and maintain integrity and inherent resonance frequency during vibration ( Figure 4 (a) in the

[0083] The bionic cilia of the bionic cilia system of Examples 2-6 were vibrated under external acoustic stimulation, and the displacement of the bionic cilia with different aspect ratios under different acoustic stimulations was measured. It was found that the resonance frequency of the bionic cilia was inversely proportional to its aspect ratio (e.g. Figure 4 As shown in part c of the figure, when the diameter is the same, the longer the length, the lower the natural frequency. Figure 4 As shown in part b, the vibration amplitude of the bionic cilia of Example 2 reaches a maximum value at its resonant frequency (about 500 Hz); the vibration amplitude of the bionic cilia of Example 3 reaches a maximum value at its resonant frequency (about 2200 Hz); the vibration amplitude of the bionic cilia of Example 4 reaches a maximum value at its resonant frequency (about 1500 Hz); the vibration amplitude of the bionic cilia of Example 5 reaches a maximum value at its resonant frequency (about 1200 Hz); the vibration amplitude of the bionic cilia of Example 6 reaches a maximum value at its resonant frequency (about 800 Hz).

[0084] The bionic cilia of the bionic cilia system of Example 2 are vibrated under external acoustic stimulation, and the relationship between the voltage value on the piezoelectric transducer and the vibration amplitude of the bionic cilia is observed. Figure 4 As shown in part d in FIG, the vibration amplitude of the bionic cilia induced by the external acoustic stimulation applied by the piezoelectric transducer is proportional to the voltage value applied to the piezoelectric transducer.

[0085] The bionic cilia surface of the bionic cilia system of Example 2 is coated with rhodamine B dye ( Figure 5 The diffusion of the dye in the water environment was tested under vibration and non-vibration conditions. The results show that under external acoustic stimulation, the vibration of the ciliary array accelerates the diffusion of the dye in the solution (e.g. Figure 5 (as shown in part b of the figure).

[0086] Example 7

[0087] This embodiment provides a method for preparing a drug delivery system, which comprises the following steps:

[0088] S1. Prepare drugs: dissolve 20 mg insulin and glucagon in 1 ml PBS solution respectively, and stir to mix to prepare drug solutions.

[0089] S2. Prepare the carrier: weigh 0.2 g of GelMA-90 (methacrylated gelatin), add 1 ml of photoinitiator LAP (phenyl (2,4,6-trimethylbenzoyl) lithium phosphate), heat and dissolve in a 70° C. water bath for 20 min to prepare a 20% mass fraction of GelMA-90 solution.

[0090] S3. Preparation of drug loading unit: 500 μL of drug solution and 500 μL of GelMA-90 solution were mixed in a 1:1 (volume ratio).

[0091] S4, adsorbing the drug-carrying unit on the bionic cilia of the bionic cilia system of Example 2: applying the drug-carrying unit on the surface of the cilia array, and curing it by ultraviolet light (λ=255nm) for 120s. Then assembling the piezoelectric transducer at the bottom of the bionic cilia array.

[0092] This embodiment provides a drug delivery system obtained by the above-mentioned drug delivery system preparation method, which includes the bionic ciliary system of Example 2 and the above-mentioned drug-carrying unit, and the drug-carrying unit is adsorbed on the bionic cilia of the bionic ciliary system.

[0093] Example 8

[0094] This embodiment provides a method for preparing a drug delivery system, which is different from Embodiment 7 only in that the curing time by ultraviolet light (λ=255 nm) irradiation is 30 s.

[0095] This embodiment provides a drug delivery system prepared by the preparation method of the drug delivery system.

[0096] Example 9

[0097] This embodiment provides a method for preparing a drug delivery system, which is different from Embodiment 7 only in that the curing time by ultraviolet light (λ=255 nm) irradiation is 60 s.

[0098] This embodiment provides a drug delivery system prepared by the preparation method of the drug delivery system.

[0099] Example 10

[0100] This embodiment provides a drug delivery system, which is different from Embodiment 7 only in that the material of the hydrogel is GelMA-30.

[0101] This embodiment provides a preparation method of the drug delivery system, and its preparation method is the same as that of Example 7.

[0102] Embodiment 11

[0103] This embodiment provides a drug delivery system, which is different from Embodiment 7 only in that the material of the hydrogel is GelMA-60.

[0104] This embodiment provides a preparation method of the drug delivery system, and its preparation method is the same as that of Example 7.

[0105] Effect Example 2

[0106] In order to verify that GelMA hydrogel does not affect insulin concentration, the inventors tested the drug-loaded unit of Example 7 and the GelMA hydrogel without insulin loading (control group), and found that the GelMA hydrogel without insulin loading did not interfere with the measurement of insulin concentration. Figure 6 As shown in part a of FIG.

[0107] The bionic cilia of the drug delivery system of Examples 7-9 were vibrated for one hour under external acoustic stimulation at 500 Hz, and the control group without external acoustic stimulation was used to measure the amount of insulin released by the artificial cilia using a Branford detection kit. Figure 6 From part b, it can be seen that the amount of insulin in the control group did not change. After the experimental group was stimulated by 500 Hz vibration, the rate of insulin release from the GelMA using 120 s UV cross-linking in Example 7 was significantly accelerated, indicating that when the aspect ratio of the bionic cilium is 50, the resonance effect is better when the sound frequency range of the acoustic wave stimulation is 500 Hz, and the effect of drug release is also better.

[0108] The bionic cilia of the drug delivery system of Examples 7, 10 and 11 were vibrated for two hours under external acoustic stimulation at 500 Hz, and the amount of insulin released by the artificial cilia was measured. The control group was a control group in which the bionic cilia were not stimulated by the sound stimulation system to cause resonance. Figure 6 As shown in part c, the artificial cilia coated with GelMA hydrogels (GelMA-30, GelMA-60, GelMA-90) with different grafting degrees in Examples 7, 10 and 11 released insulin rapidly after two hours of acoustic stimulation. Compared with the control group, the insulin release of the cilia array of Example 7 increased by 109%. Compared with the control group, the insulin release of the cilia array of Example 10 increased by 91% relative to the control group. Compared with the control group, the insulin release of the cilia array of Example 11 increased by 56% relative to the control group.

[0109] The in vitro release curves of insulin and glucagon in Example 7 were measured. The release amounts of both drugs under external sound stimulation were significantly higher than those of the control group. Figure 7 As shown in parts a and b in Figure 1, artificial cilia exhibit pulse release characteristics under multi-segment stimulation mode ( Figure 7 Part c in the figure). After vibration stimulation, the surface of the cilia became rough and the amount of gel on the cilia was significantly reduced ( Figure 8 ).

[0110] Example 12

[0111] This embodiment provides a drug delivery system, which includes a bionic cilia array and a piezoelectric transducer, and a capsule device; wherein the bionic cilia array is different from that of embodiment 7 only in that the diameter of the bionic cilia is 100 μm, and the aspect ratio of the bionic cilia includes two groups of different aspect ratios, which are 50 and 40 respectively. The two groups of bionic cilia arrays with different aspect ratios are assembled on both sides of the circular piezoelectric transducer device and encapsulated in a capsule device with a semi-permeable membrane window (such as Fig.10 The preparation method of the drug delivery system is the same as that of Example 7.

[0112] Effect Example 3

[0113] The drug delivery system in Example 12 was applied to blood glucose regulation in type 1 diabetic mice. Fig. 9 Specifically, the blood sugar regulating drugs insulin and glucagon were modified on two bionic cilia arrays (diameter 100 μm, aspect ratio 50 and 40, respectively) with different natural frequencies (500 and 1200 Hz) by the method in Example 3. When an external acoustic stimulus of 500 or 1200 Hz was applied, the bionic cilia array that matched the input frequency vibrated violently due to resonance, while the bionic cilia that did not match the input frequency hardly vibrated ( Fig.10(part b of the ).

[0114] The entire capsule device was implanted subcutaneously into diabetic mice for blood sugar regulation. The mice were fasted during the experiment until the designated meal time. After applying 500 Hz acoustic stimulation for 10 minutes every hour, the blood sugar levels of the mice gradually dropped to the normal range (less than 200 mg / dL) and could be maintained until 8 hours after treatment until they started eating ( Fig.11 ). The control group was not stimulated by external sound to induce resonance.

[0115] In addition, the blood glucose status of mice was observed, e.g. Fig.12 As shown in the figure, under acoustic stimulation, the hypoglycemic effect of the bionic cilia array loaded with modified insulin is improved, and normal blood sugar can be maintained for about 10 hours. When insulin is injected intraperitoneally into mice to induce hypoglycemia, the 1200Hz acoustic stimulation applied every half an hour can restore their blood sugar levels faster than those of the control group mice, indicating that acoustic stimulation promotes the release of glucagon, such as Fig.13 shown.

[0116] Mice were tested without fasting and had free access to food during the experiment, e.g. Fig.14 As shown, 2 hours after the first acoustic stimulation, the blood glucose levels of diabetic mice dropped to 200 mg / dL, and returned to a hyperglycemic state after another 2 hours. In contrast, the blood glucose levels of mice without acoustic stimulation (control group) did not return to normal. After the second stimulation, the blood glucose levels of diabetic mice dropped again to about 260 mg / dL, and then rose again. The third stimulation showed a similar decline-rise result, but the reduction in blood glucose levels was less due to the decrease in the amount of insulin on the cilia. From the above, it can be seen that the feasibility of bionic cilia arrays to achieve acoustic frequency-selective on-demand drug release has been verified in type 1 diabetic mice.

[0117] Although the specific embodiments of the present invention are described above, it should be understood by those skilled in the art that this is only for illustration and the protection scope of the present invention is defined by the appended claims. Those skilled in the art may make various changes or modifications to these embodiments without departing from the principles and essence of the present invention, but these changes and modifications all fall within the protection scope of the present invention.

Claims

1. A bionic cilia system, characterized in that: It comprises a bionic cilia array, and an acoustic wave stimulation system and / or a sound control system. The bionic cilia array comprises bionic cilia in an array form; the aspect ratio of the bionic cilia is 1-1000.

2. The bionic cilia system according to claim 1, characterized in that: The bionic cilia system meets one or more of the following conditions: (1) The aspect ratio of the bionic ciliary array is 10-200, preferably 30-100, for example 30, 35, 40, 45 or 50; (2) The elongation at break of the bionic cilia is 1%-100%, preferably 1%-50%, for example 2.2%; (3) The tensile strength of the bionic cilia is 10-100 MPa, preferably 20-100 MPa, more preferably 50-100 MPa, for example 79.3 MPa; (4) The tensile modulus of the bionic cilia is 0.1-10 GPa, preferably 1-5 GPa, more preferably 2-5 GPa, for example 4.2 GPa; (5) The bending strength of the bionic cilia is 1-500 MPa, preferably 10-200 MPa, more preferably 500-200 MPa, for example 120 MPa; (6) The bending modulus of the bionic cilium is 0.1-10 GPa, preferably 1-5 GPa, more preferably 2-5 GPa, for example 4 GPa; and, (7) The sound frequency range of the sound wave stimulation system and / or the sound control system is 20 Hz-20 KHz.

3. The bionic cilia system according to claim 1, characterized in that: The aspect ratio of the bionic cilia is 30-50, and the sound frequency range of the sound wave stimulation system and / or the sound control system is 500Hz-2200Hz; Preferably, the aspect ratio of the bionic cilia is 30, and the sound frequency range of the sound wave stimulation system and / or the sound control system is 2100-2300 Hz, for example, 2200 Hz; Preferably, the aspect ratio of the bionic cilia is 35, and the sound frequency range of the sound wave stimulation system and / or the sound control system is 1400-1600 Hz, for example, 1500 Hz; Preferably, the aspect ratio of the bionic cilia is 40, and the sound frequency range of the sound wave stimulation system and / or the sound control system is 1100-1300 Hz, for example, 1200 Hz; Preferably, the aspect ratio of the bionic cilia is 45, and the sound frequency range of the sound wave stimulation system and / or the sound control system is 700-900 Hz, for example, 800 Hz; Preferably, the aspect ratio of the bionic cilia is 50, and the sound frequency range of the sound wave stimulation system and / or the sound control system is 400-600 Hz, for example, 500 Hz.

4. The bionic cilia system according to claim 1, characterized in that: The bionic cilia system meets one or more of the following conditions: (1) The diameter of the bionic cilia is 1 nm-10 mm, preferably 1 μm-1 mm, more preferably 50 μm-200 μm, for example 100 μm; (2) The distance between two adjacent bionic cilia is 10 nm-10 cm, preferably 100 μm-10 mm, more preferably 500 μm-5 mm, for example 1 mm; (3) The number of bionic cilia distributed on the bionic cilia array is 1-100,000, preferably 10-1,000, more preferably 50-500, for example 100; (4) The array density of the bionic cilia array is 1-100 hairs / mm2, preferably 1-50 hairs / mm2, more preferably 1-10 hairs / mm2, for example 4 hairs / mm2; (5) The material of the bionic cilia is selected from synthetic polymer materials and / or natural animal hair, and the synthetic polymer material is preferably one or more of polyethylene, polypropylene, polyvinyl chloride, polystyrene, acrylonitrile-butadiene-styrene copolymer, polyester and nylon; wherein the polyester is preferably silicone-modified polyester; the synthetic polymer material is preferably in the form of resin; the synthetic polymer material is more preferably silicone-modified polyester, such as HTL resin; (6) The bionic cilia array further comprises a substrate, wherein the equivalent width of the substrate is 10 nm-100 cm, preferably 1 mm-10 cm, more preferably 5 mm-10 mm, for example 8 mm; and, (7) The bionic ciliary system further comprises a shell device, wherein the bionic ciliary array, the acoustic wave stimulation system and / or the sound control system are arranged in the shell device; the shell device is preferably a capsule device.

5. The bionic cilia system according to claim 1, characterized in that: The manufacturing method of the bionic cilia array is 3D printing, micro-nano processing, mold manufacturing, thermal processing or wire drawing; preferably, it is a 3D printing method; the 3D printing method is preferably a projection light-curing 3D printing method; The precision of the 3D printing is preferably 5-15 μm, for example, 10 μm; the exposure wavelength of the 3D printing is preferably 380-420 nm, for example, 405 nm; the exposure time of the 3D printing is preferably 1-3 s; the exposure intensity of the 3D printing is preferably 50-60 mW / cm 2 ; The exposure waiting time of the 3D printing is preferably 300-500s.

6. The bionic cilia system according to claim 1, characterized in that: The bionic cilia system meets one or more of the following conditions: (1) The sound frequency range of the sound wave stimulation system is 500Hz-2200Hz; (2) The sound intensity of the sound wave stimulation system is 60-140 dB, for example, 100 dB; (3) The acoustic wave stimulation system is a piezoelectric transducer, a buzzer, a speaker, a horn or a sound.

7. The bionic cilia system according to claim 1, characterized in that: The sound control system is used to achieve the following control purpose: control the sound wave stimulation system included in the bionic cilia system, or the sound generating device outside the bionic cilia system to emit sound waves, thereby causing the resonance of the bionic cilia; Preferably, the sound control system controls various parameters of the sound waves, such as one or more of intensity, frequency, sound frequency, sound duration and sound interval duration; Preferably, the sound control system is any one of the following: The sound control system is a virtual system including a control module, and the control module realizes the above control purpose, such as a program installed on an electronic device, and more specifically, an APP program installed on a mobile phone, which is used to control the sound of a mobile phone, a television or a stereo; And, the sound control system includes a computer-readable storage medium storing logic instructions, and the logic instructions achieve the control purpose when executed by a processor; preferably, the sound control system also includes a processor, and the processor achieves the control purpose when executing the logic instructions; the sound control system is more preferably a function signal generator.

8. A drug delivery system, characterized in that It comprises a drug-carrying unit, and the bionic cilium system according to any one of claims 1 to 7, wherein the drug-carrying unit is adsorbed on the bionic cilium of the bionic cilium system, the drug-carrying unit comprises a drug and a carrier, and the carrier comprises a hydrogel; Wherein, the hydrogel is preferably selected from gelatin, polyvinyl alcohol, polyacrylamide, sodium polyacrylate, chitosan or hyaluronic acid, and more preferably selected from gelatin; the material of the gelatin is preferably methacrylated gelatin; the model of the methacrylated gelatin is preferably GelMA-90, GelMA-30 or GelMA-60; Wherein, the carrier preferably further comprises a photoinitiator, and the photoinitiator is preferably phenyl (2,4,6-trimethylbenzoyl) lithium phosphate; Wherein, the drug preferably includes macromolecular drugs and / or small molecule drugs, the macromolecular drugs are preferably polypeptide drugs, protein drugs, antibody drugs, polysaccharide drugs or nucleic acid drugs, more preferably protein drugs, and the protein drugs are preferably insulin and / or glucagon.

9. A method for preparing the drug delivery system according to claim 8, characterized in that: The method comprises the following steps: preparing a drug-carrying unit, and adsorbing the drug-carrying unit onto bionic cilia; Among them, the method of adsorbing the drug-carrying unit on the bionic cilium includes a modification method, and the modification method is preferably direct application, natural curing, photocuring or freeze-drying, and more preferably photocuring; the photocuring time is preferably 10-600s, for example, 30s, 60s or 120s; the wavelength of the light for photocuring is preferably 250-420nm, for example, 255nm.

10. Use of the drug delivery system as claimed in claim 8 in preparing a drug for preventing or treating a disease, wherein the disease is preferably an endocrine disease, a respiratory disease, a gastrointestinal disease, a cardiovascular disease or a tumor, and the endocrine disease is preferably diabetes.

Images