Drug-carrying microsphere in-situ attachment method and system for drug storage cavity

Abstract

The invention relates to a drug-loading microsphere in-situ attachment method and system.The method comprises the steps that S1, a drug storage runner is designed in a titanium jaw bone implant, 3D printing is conducted on the titanium jaw bone implant with the drug storage runner, a sample is obtained, and the drug storage runner is the drug storage cavity used for drug storage and drug release; s2, carrying out atomized silicone oil treatment and laser etching on the inner wall of the medicine storage cavity in the sample; s3, carrying out microsphere type selection on the sample subjected to atomized silicone oil treatment and laser etching, and realizing in-situ attachment of microspheres by using a vacuum drying method; and S4, testing the in-situ attachment of the microspheres to judge whether the in-situ attachment of the microspheres is effective or not. According to the invention, in-situ attachment of the drug-loaded microspheres in the drug storage cavity can be realized, and slow release, controlled release and delayed release of the drug can be effectively controlled.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medicine, in particular to a method and system for in-situ attachment of drug-loaded microspheres in a drug storage cavity. BACKGROUND

[0002] The mandible is the largest and strongest mobile load-bearing bone in the lower 1 / 3 of the human head, and is essential for human speech, mastication, and facial movement. The incidence of mandibular injury, tumor, inflammation, or congenital dysplasia is gradually increasing. Although the human skeleton has certain self-healing and regenerative capacity, the self-repairing capacity is limited for bone defects of 4 cm or more in length defined clinically. Treatment of such defects mainly relies on bone transplantation, which can use the patient's own bone tissue or artificial bone implantation to repair the defect and promote new bone growth, improving the patient's appearance, psychological state, and quality of life. Autologous bone transplantation has good tissue compatibility and osteoinductive activity, but is limited by the amount of available bone tissue and the complexity of the surgery. Artificial bone implantation faces the challenge of biocompatibility, such as modulus mismatch that can cause stress shielding, and the implant body becomes a bacterial attachment site, increasing the risk of inflammation or foreign body reaction.

[0003] Implantable local drug delivery can prevent or treat rejection, reduce the need for secondary surgery, and reduce the toxic and side effects on other parts. Common drug loading methods include titanium nanotube drug loading, drug coating, and 3D printed implant drug loading, but each has its own limitations. The mandible bears special physiological functions of the human body, and conventional drug loading methods cannot meet its functional requirements. Therefore, attaching drug-loaded microspheres to the inner wall of the drug storage cavity for drug release to achieve sustained, controlled, and delayed drug release provides a new solution to the difficulty of stable, appropriate, and continuous drug release for local drug delivery.

[0004] In the prior art, microspheres are often attached to the surface of materials by physical adsorption, electrostatic adsorption, and other methods. However, such attachment methods generally have weak binding force and poor stability, and the microspheres are prone to fall off in actual application. At the same time, it is difficult to achieve precise positioning of the microspheres during the attachment process, and they are usually randomly distributed, which cannot meet the functional requirements of strict spatial distribution. In addition, these technologies are mostly limited to the surface treatment of soft tissues, organic materials, or composite materials, and are difficult to apply to the functional modification of inert metals such as titanium alloys. Some methods rely on heat treatment or chemical cross-linking processes, which not only complicate the operation, but also may cause structural damage and loss of activity of the drugs or bioactive factors loaded in the microspheres. In summary, existing technologies cannot achieve in-situ attachment of drug-loaded microspheres in drug storage cavities or complex structures, and cannot control the "sustained release", "controlled release", and "delayed release" of drugs. Therefore, there is an urgent need for a simple, green, low-cost, and efficient method to achieve in-situ attachment of drug-loaded microspheres to the inner wall of the drug storage cavity for drug release. SUMMARY

[0005] To this end, the technical problem to be solved by the present application is to overcome the problem that it is difficult to achieve in-situ attachment of drug-loaded microspheres in the drug storage cavity in the prior art, and it is impossible to control the "sustained release", "controlled release" and "delayed release" of drugs.

[0006] To solve the above technical problems, the present application provides a method for in-situ attachment of drug-loaded microspheres in a drug storage cavity, comprising:

[0007] Step S1: design a drug storage flow channel inside a titanium jaw implant, and 3D print the titanium jaw implant with the drug storage flow channel to obtain a sample, wherein the drug storage flow channel is a drug storage cavity for storing and releasing drugs;

[0008] Step S2: perform misted silicon oil treatment and laser etching on the inner wall of the drug storage cavity in the sample;

[0009] Step S3: select the type of microspheres for the sample after misted silicon oil treatment and laser etching, and use a vacuum drying method to achieve in-situ attachment of the microspheres;

[0010] Step S4: test the in-situ attachment of the microspheres to determine whether the in-situ attachment of the microspheres is effective.

[0011] In an embodiment of the present application, the method of designing a drug storage flow channel inside a titanium jaw implant in step S1 comprises:

[0012] Obtain the concentration C of the osmotic active particles in the cells in the inflammatory lesion area cell and the concentration C of the osmotic active particles outside the healthy environment cells cavity , and establish a liquid level-osmotic pressure balance equation:

[0013] ΔΠ=Π cell -Π cavity =(C cell -C cavity )RT a

[0014] In combination with the liquid level-osmotic pressure balance equation ΔΠ, derive the liquid level rising height H of the drug storage cavity, and the formula is:

[0015] H=βΔΠt response

[0016] h1=max H

[0017] Wherein, Π cell is the intracellular osmotic pressure, Π cavity is the extracellular osmotic pressure, C cell , C cavity are the numbers of intracellular and extracellular osmotic active particles, R is the gas constant, T a is the absolute temperature, and t responseh1 is the depth of the drug storage cavity, and β is a liquid level response adjustment factor;

[0018] V single = V total / num, wherein V single is the required mass of pH-sensitive microspheres attached to a single drug storage cavity, V total is the required mass of pH-sensitive microspheres attached to all drug storage cavities, and num is the number of drug storage cavities.

[0019] According to the pH value of the lesion area, the pH-sensitive microspheres are divided into pH-low-sensitive drug-loaded microspheres and pH-high-sensitive drug-loaded microspheres, and a pH-low-sensitive drug-loaded microsphere coverage area and a pH-high-sensitive drug-loaded microsphere coverage area are designed in the drug storage cavity, wherein

[0020] The height of the pH-low-sensitive drug-loaded microsphere coverage area is Δh1 = (V1 / V single )h1, wherein V1 = 0.3V single , and V1 is the total amount of microspheres in the pH-low-sensitive drug-loaded microsphere coverage area.

[0021] The height of the pH-high-sensitive drug-loaded microsphere coverage area is Δh2 = h1-Δh1, and h1 is the depth of the drug storage cavity.

[0022] In an embodiment of the present application, the drug storage cavity is a funnel-shaped drug storage cavity, which includes a conical region for carrying microspheres and a rectangular region for buffering the rising speed of the liquid level from the lesion area.

[0023] In an embodiment of the present application, the method for performing the step S2 of performing misted silicon oil treatment on the inner wall of the drug storage cavity in the sample includes:

[0024] S21, connect a first air compressor with an exhaust pressure of P1 to the inlet of the micro lubrication device, and connect the outlet of the micro lubrication device and a second air compressor with an exhaust pressure of P2 to the inlet of the vortex tube, connect the input end of the nozzle to the cold end outlet of the vortex tube, the vortex tube is used to provide cold air for the nozzle, and the micro lubrication device is used to provide air flow and silicon oil for the nozzle; the nozzle is used to perform misted silicon oil treatment on the inner wall of the drug storage cavity.

[0025] Obtain the temperature reduction amplitude ΔT of the vortex tube:

[0026]

[0027] wherein K is the efficiency of the vortex tube, D p is the diameter of the inlet of the vortex tube, D v is the inner diameter of the vortex tube, and D ois the diameter of the cold end outlet, P is the inlet pressure of the vortex tube, P0 is the atmospheric pressure, and n is an index coefficient;

[0028] S22, if the temperature reduction amplitude ΔT = T1-T2<25℃, then proceed to S22; otherwise, proceed to S23; wherein, T1 is the ambient temperature measured at a distance L from the nozzle, and T2 is the low-temperature atomization temperature measured at a distance L from the nozzle;

[0029] S22, the second air compressor connected to the micro-lubrication device is turned off, and the first air compressor connected to the micro-lubrication device is used to provide air pressure for the micro-lubrication device and the vortex tube, so that the inlet pressure of the vortex tube is P;

[0030] S23, the first air compressor is controlled to provide air pressure for the micro-lubrication device and the vortex tube, the second air compressor is used to supplement the air pressure lacking in the vortex tube, so that the inlet pressure of the vortex tube is P; and the low-temperature atomization temperature of the vortex tube is set to T2, and the air pressure of the nozzle is adjusted to P a so that the cold air flow and the silicone oil are mixed at the nozzle to perform low-temperature atomization;

[0031] S24, under the low-temperature atomization condition, the average diameter D of the atomized droplets is obtained and expressed as:

[0032]

[0033] wherein C is a proportional coefficient, n is an index coefficient, Q1 is the liquid flow of the silicone oil, Q2 is the air flow, and P a is the spray pressure of the air pressure valve used to control the nozzle; and A is the diameter of the nozzle;

[0034] S25, according to the average diameter D of the atomized droplets, the speed v0 of the atomized droplets sprayed from the nozzle, the Weber number We, the Reynolds number Re, and the capillary number Ca are obtained, so as to measure the atomization effect, and are expressed as:

[0035]

[0036] wherein η is the viscosity of the silicone oil, ρ is the density of the silicone oil, and σ is the surface tension of the silicone oil;

[0037] If We≥10, Re≥4000, and Ca≥1, then the droplets are easy to form a liquid film; otherwise, the droplets are not easy to form a liquid film.

[0038] In an embodiment of the present application, the step S2 of laser etching the inner wall of the drug storage cavity in the sample includes:

[0039] S26, laser etching is performed on the sample treated by the atomized silicone oil, laser scanning interval d=d a is used in the pH high-sensitive drug-loaded microsphere coverage area where height Δh2 is located b , and d a is greater than d b ;

[0040] The laser scanning speed is set as v, the processing times is N, the laser power is E, the frequency is , the pulse width is τ, the spot size is w, the size of the convex bottom formed by laser etching is b, the size of the convex top formed by laser etching is a, the distance between the convex top and the concave bottom formed by laser etching is h, the etching correction coefficient is k, and the Hamker constant is A H , the closest distance between the microspheres and the sample surface is H0, the microsphere radius is r, and the microsphere density is ρ r , the solid surface roughness ε and the microsphere adhesion force F ab are respectively represented as:

[0041]

[0042] If the microsphere adhesion force F ab reaches a preset adhesion force range, it indicates that the laser etching and the silicone oil atomization treatment are effective, otherwise the laser etching parameters need to be adjusted;

[0043] After the sample is cleaned and dried, the wettability of the sample is tested: the static contact angle α of the sample surface is measured; if α < 150°, the laser scanning speed v and the laser scanning interval d a , d b are reduced, and the laser etching step is repeated until α ≥ 150°;

[0044] The adhesion of the sample is tested again: the contact angle hysteresis Δα of the sample surface is measured; the contact angle hysteresis Δα is judged, if Δα < 30°, the silicone oil viscosity η is increased, and the laser etching step is repeated until Δα ≥ 30°.

[0045] In an embodiment of the present application, the step S3 of selecting the microspheres for the sample treated by the atomized silicone oil and the laser etching, and using the vacuum drying method to realize the in-situ adhesion of the microspheres comprises:

[0046] S31, the pH low-sensitive drug-loaded microspheres with a particle size of d1 are selected to match the scanning interval d a in the pH low-sensitive drug-loaded microsphere coverage area where height Δh1 is located, and the pH high-sensitive drug-loaded microspheres with a particle size of d2 are selected to match the scanning interval d b in the pH high-sensitive drug-loaded microsphere coverage area where height Δh2 is located, and d1 > d2.

[0047] S32, a first and a second test tube with a volume of V of the drug solution are obtained, and the pH low-sensitive drug-loaded microspheres with a particle size of d1 are weighed into the first test tube, and the pH high-sensitive drug-loaded microspheres with a particle size of d2 are weighed into the second test tube to obtain respective microsphere mixtures;

[0048] S33, the microsphere mixture in the first test tube is transferred to the pH low-sensitive drug-loaded microsphere covering area, and the microsphere mixture in the second test tube is transferred to the pH high-sensitive drug-loaded microsphere covering area; if the microsphere mixture slides along the surface of the drug release port of the drug storage cavity, the volume V of the drug solution is reduced; otherwise, the microsphere mixture is completed.

[0049] S34, the sample is placed in a vacuum drying oven for drying treatment, the pressure of the vacuum drying oven is set to P, the temperature is set to T, and the drying time is set to t, so that the drug solution is volatilized and the microspheres are adhered to the inner wall of the drug storage cavity.

[0050] In an embodiment of the present application, the step S3 further comprises judging whether the in-situ adhesion of the microspheres is successful, and the method comprises:

[0051] S35, the sample is scanned to obtain a sample spectrum, and it is judged whether there is a hydroxyl characteristic peak in the sample spectrum; if not, it indicates that the in-situ adhesion of the microspheres fails, and the particle sizes d1 and d2 of the microspheres and the laser scanning interval d are adjusted to match the particle size of the microspheres and the laser scanning interval; if so, it indicates that the in-situ adhesion of the microspheres is successful, and the in-situ adhesion of the microspheres is tested. a 、d b

[0052] In an embodiment of the present application, the method for testing the in-situ adhesion of the microspheres in step S4 comprises:

[0053] S41, a microsyringe is used to release a quantitative droplet suspended at the bottom end of the needle tip of the syringe, the movable platform is used to drive the sample to move upwards until the microspheres on the surface of the sample are in full contact with the droplet, and finally the movable platform is used to drive the sample to move downwards.

[0054] S42, during the upward or downward movement of the sample, if the droplet adheres to the surface of the microspheres or the droplet separates from the surface of the microspheres, the pressure P, the temperature T and the drying time t under the vacuum drying condition are modified, and the test is re-performed until the microspheres separate from the surface of the sample with the droplet; otherwise, it indicates that the in-situ adhesion of the microspheres is effective.

[0055] In an embodiment of the present application, the method for laser etching the inner wall of the drug storage cavity in step S2 is ring-radiation laser etching, which comprises:

[0056] ring texture is etched on the inner wall of the drug storage cavity by laser etching;

[0057] ​The radial texture is etched on the inner wall of the medicine storage cavity by laser.

[0058] To solve the above technical problems, the application provides a drug-loaded microsphere in-situ attachment system for a medicine storage cavity, comprising:

[0059] A design module is configured to design a medicine storage flow channel in a titanium jaw implant and perform 3D printing on the titanium jaw implant with the medicine storage flow channel to obtain a sample, wherein the medicine storage flow channel is a medicine storage cavity for drug release.

[0060] A pretreatment module is configured to perform atomized silicon oil treatment and laser etching on the inner wall of the medicine storage cavity in the sample.

[0061] An in-situ attachment module is configured to select a type of microspheres for the sample after the atomized silicon oil treatment and laser etching and realize in-situ attachment of the microspheres by using a vacuum drying method.

[0062] A test module is configured to test the in-situ attachment of the microspheres to determine whether the in-situ attachment of the microspheres is effective.

[0063] The above technical solution of the application has the following advantages compared with the prior art:

[0064] The application realizes in-situ attachment of drug-loaded microspheres by designing a medicine storage flow channel (medicine storage cavity) in a titanium jaw implant and performing low-temperature silicon oil treatment and micro-level laser etching treatment on the surface of the medicine storage cavity and by using a vacuum drying method.

[0065] The titanium jaw implant of the application is simple to manufacture, has low cost and is easy to popularize on a large scale. BRIEF DESCRIPTION OF DRAWINGS

[0066] In order to make the content of the application more easily understood, the application will be further described in detail below according to specific embodiments of the application and in conjunction with the drawings.

[0067] Figure 1 is a method flowchart in the embodiments of the application;

[0068] Figure 2 is a schematic diagram of in-situ attachment of pH low-sensitive drug-loaded microspheres and pH high-sensitive drug-loaded microspheres in the embodiments of the application;

[0069] Figure 3 is a schematic diagram of a medicine storage cavity structure in the titanium jaw implant in the embodiments of the application;

[0070] Figure 4 is a schematic diagram of a cross section of the medicine storage cavity in the embodiments of the application;

[0071] Figure 5 is a structure diagram of a low-temperature atomized silicone oil treatment device in an embodiment of the present application;

[0072] Figure 6 is a schematic diagram of a ring-radiation laser etching process in an embodiment of the present application;

[0073] Figure 7 is a schematic diagram of an atomized silicone oil treatment zone and a texture modification zone in an embodiment of the present application;

[0074] Figure 8 is a schematic diagram of a test on in-situ attachment of microspheres in an embodiment of the present application. DETAILED DESCRIPTION

[0075] The present application will be further described below in conjunction with the drawings and specific embodiments so that those skilled in the art can better understand the present application and implement it. The embodiments are not intended to limit the present application.

[0076] Embodiment One

[0077] Referring to Figure 1 the present application relates to a method for in-situ attachment of drug-loaded microspheres to a drug storage cavity, comprising:

[0078] Step S1: design a drug storage flow channel inside a titanium jaw implant, and 3D print the titanium jaw implant with the drug storage flow channel to obtain a sample, wherein the drug storage flow channel is a drug storage cavity 1 for drug storage and drug release;

[0079] Step S2: perform atomized silicone oil treatment and laser etching on the inner wall of the drug storage cavity 1 in the sample;

[0080] Step S3: select microspheres (in this embodiment, the microspheres are pH-sensitive drug-loaded microspheres, including pH low-sensitive drug-loaded microspheres 4 and pH high-sensitive drug-loaded microspheres 5) for the sample after atomized silicone oil treatment and laser etching, and use a vacuum drying method to realize in-situ attachment of the microspheres;

[0081] Step S4: test the in-situ attachment of the microspheres to determine whether the in-situ attachment of the microspheres is effective.

[0082] It should be noted that in-situ attachment of microspheres refers to making drug-loaded or functional microspheres form a firm bond on the surface of a material (such as metal, polymer or composite structure) through physical, chemical or composite means, and realizing a fixed mode with controllable spatial positioning and low shedding rate. For in-situ attachment of the pH low-sensitive drug-loaded microspheres 4 and the pH high-sensitive drug-loaded microspheres 5 in this embodiment, please refer to Figure 2 .

[0083] The present embodiment will be described in detail as follows:

[0084] Step S1, the sample material of this embodiment is titanium alloy (TC4), and a drug storage cavity 1 for storing and releasing drugs is designed on the surface of the sample:

[0085] S11, according to the pathological characteristics of the patient, the drug ciprofloxacin hydrochloride (CIP, molecular weight 331.34 g / mol) is selected as a small molecule drug. The total amount of drug-loaded microspheres V required by the matrix is determined total = 3.4 g. Since the pH-sensitive microspheres in this embodiment are divided into pH-low-sensitive drug-loaded microspheres 4 and pH-high-sensitive drug-loaded microspheres 5, the pH trigger threshold of the pH-low-sensitive drug-loaded microspheres 4 is defined as 6.5, and the pH trigger threshold of the pH-high-sensitive drug-loaded microspheres 5 is 5.5.

[0086] According to the depth distribution of the longitudinal section of the jaw lesion area, the drug storage cavity 1 is configured by geometric parameters, which specifically includes: obtaining the intracellular osmotic active particle concentration C cell and the extracellular osmotic active particle concentration C cavity of the lesion area in the inflammation period

[0087] ΔΠ=Π cell -Π cavity =(C cell -C cavity )RT a

[0088] H=βΔΠt response

[0089] Wherein, Π cell is the intracellular osmotic pressure, and Π cavity is the extracellular osmotic pressure.

[0090] Then, according to the liquid level rising height H of the drug storage cavity 1, the depth h1 of the drug storage cavity 1 is determined as maxH = 3 mm, wherein C cavity and C cell are the intracellular osmotic active particle concentration of the lesion area in the inflammation period and the extracellular osmotic active particle concentration of the healthy environment respectively, R is the gas constant, T a is the absolute temperature, t response is the response time of the drug release system, and β is the liquid level response adjustment factor. In practice, ΔΠ will be affected by proteins, inorganic salts and other substances produced by inflammation, and β is used to modify the liquid level-osmotic pressure balance equation ΔΠ.

[0091] Please refer to Figure 3 and Figure 4The base longitudinal section of the medicine storage cavity 1 in the embodiment is funnel-shaped, and the funnel-shaped medicine storage cavity 1 includes a tapered region and a rectangular region. The tapered region is used to carry the pH-sensitive drug-loaded microspheres. In the embodiment, the medicine storage space of the medicine storage cavity 1 is actually the space in the tapered region. The rectangular region (which is not attached with the pH-sensitive drug-loaded microspheres) is used to buffer the liquid level rising speed from the lesion region, and can also define the cross section of the drug release channel and regulate the drug outflow rate, so as to realize the precise and controllable drug delayed release.

[0092] Please refer to Figure 4 The outer orifice diameter D1 of the drug release port of the medicine storage cavity 1 is 9.6 mm, the inner orifice diameter D2 is 3.6 mm, the depth h1 of the medicine storage cavity 1 is 3 mm, and the number num of the medicine storage cavities 1 is 10. The required mass of the pH-sensitive drug-loaded microspheres attached to each medicine storage cavity 1 is obtained from V single = V total / num, and each medicine storage cavity 1 is loaded with 0.34 g of drug-loaded microspheres.

[0093] Please refer to Figure 4 In the embodiment, the coverage area of the pH low-sensitive drug-loaded microspheres 4 and the coverage area of the pH high-sensitive drug-loaded microspheres 5 are designed in the medicine storage cavity 1, wherein,

[0094] The height of the coverage area of the pH low-sensitive drug-loaded microspheres 4 is Ah1=(V1 / V single )h1=0.9 mm (V1=0.3V single =0.102 g, and V1 is the total amount of the microspheres in the coverage area of the pH low-sensitive drug-loaded microspheres 4).

[0095] The height of the coverage area of the pH high-sensitive drug-loaded microspheres 5 is Ah2=h1-Ah1=2.1 mm (h1 is the depth of the medicine storage cavity, which refers to the depth of the tapered region in the funnel-shaped medicine storage cavity), and V2=0.7V single =0.238 g, and V2 is the total amount of the microspheres in the coverage area of the pH high-sensitive drug-loaded microspheres 5).

[0096] S12, perform tomography on the craniofacial jaw site to be transplanted of the patient and construct a three-dimensional graph, open the medicine storage cavity 1 for medicine storage and drug release in the three-dimensional graph according to the design in step S11, generate a printing model, import the printing model into a 3D printer, and obtain a printed part; and sequentially perform heat treatment, support removal, polishing and sand blasting treatment on the printed part, and finally obtain a 3D printed finished product sample.

[0097] Step S2, perform atomized silicon oil treatment and laser etching on the inner wall of the medicine storage cavity 1 of the finished product sample

[0098] It should be noted that the entire titanium alloy sample can be subjected to atomized silicon oil treatment (which is also beneficial for sterilization), and the purpose of the atomized silicon oil treatment of the sample is to facilitate the release of the pH-sensitive drug-loaded microspheres.

[0099] S21, please refer to Figure 5 Assemble the low-temperature atomizing silicone oil treatment device. Connect the first air compressor 15 with an exhaust pressure of P1 to the minimal lubrication device 13, connect the outlet of the minimal lubrication device 13 and the second air compressor 21 with an exhaust pressure of P2 to the air inlet of the vortex tube 10 through the T-tube 14, connect the input end of the nozzle 7 to the cold end outlet of the vortex tube 10, use raw tape to maintain the air tightness of the air inlet and cold end outlet of the vortex tube 10, check whether the hot end outlet of the vortex tube 10 (normal temperature gas enters the vortex tube 10, the hot end outlet is used to discharge hot air, and the cold end outlet discharges low-temperature cold air) is blocked; connect the one-way valve 20 between the second air compressor 21 and the T-tube 14 to prevent the gas from flowing back from the minimal lubrication device 13, and turn the first pressure gauge and the first pressure knob (the first pressure gauge and the first pressure knob are located at Figure 5 Component I in the embodiment is connected between the first air compressor 15 and the minimal lubrication device 13 to detect and control the intake pressure of the minimal lubrication device 13;

[0100] Place the second pressure gauge and the second pressure knob (the second pressure gauge and the second pressure knob are located at Figure 5 Component II) is connected between the T-tube 14 and the vortex tube 10 to detect and control the inlet pressure of the vortex tube 10; the pressure gauge 8 and the pressure valve 9 are connected between the cold end outlet of the vortex tube 10 and the nozzle 7 to detect and control the spray pressure; a thermocouple thermometer is placed at a radial distance L from the nozzle 7 to detect the ambient temperature T1 and the low-temperature atomization temperature T2.

[0101] The minimal lubrication device 13 of this embodiment further includes a frequency-regulating generator 17 and a gas diverter 18. The gas diverter 18 receives airflow from the first air compressor 15 and diverts the gas provided by the first air compressor 15. A portion of the airflow from the gas diverter 18 enters the frequency-regulating generator 17, which controls the delivery rate of the silicone oil in the oil tank 11. The other portion of the airflow from the gas diverter 18 enters the combination pump 16. The amount of air delivered to the combination pump 16 by the gas diverter 18 is controlled by adjusting the air flow control valve 19. In the combination pump 16, the gas and silicone oil are initially mixed.

[0102] In this embodiment, an air compressor with a rated exhaust pressure of 0.8 MPa is used as the air source. The MQL device 13 used is a FS-type quasi-dry external oil supply device produced by Fuji BC Technology Research Institute Co., Ltd., which has a maximum pressure tolerance of 0.8 MPa. By observing the first pressure gauge and controlling the first pressure knob, the inlet pressure of the MQL device 13 is kept within the range of 0.7 MPa-0.8 MPa, and the MQL device 13 is debugged. The viscosity η is 20 cSt and the density ρ is 0.95 g / cm3 and a silicone oil (polydimethylsiloxane) with a surface tension σ of 21 mN / m is filled into the oil tank 11 of the micro-lubrication device 13, the liquid flow Q1 of the micro-lubrication device 13 is set to be between 4-8 ml / min, the air flow Q2 is set to be between 60-70 L / min, the spray pressure P of the air pressure valve 9 is set to be between 0.4-0.5 MPa. a between 0.4-0.5 MPa.

[0103] The average diameter D of the atomized droplets is obtained according to an empirical formula: wherein C is a proportional coefficient (C=1.15), n is an index coefficient (n=0.5), Q1 is the liquid flow of the silicone oil, Q2 is the air flow, P is the spray pressure of the air pressure valve for controlling the nozzle, and A is the diameter of the nozzle. a The average diameter D of the atomized droplets is adjusted by controlling the relevant parameters.

[0104] The spray pressure P is controlled by observing the air pressure gauge 8 and adjusting the air pressure valve 9. a The liquid flow knob 12 is adjusted to set the oil consumption to be 4-8 ml / min, the air flow control valve 19 is adjusted to control the air flow to be 60-70 L / min, the sample 6 is fixed, the diameter A of the round nozzle 7 is selected to be 3.2 mm, and the distance L between the nozzle 7 and the surface of the sample 6 is adjusted to be 30 mm. The room temperature is measured by a thermocouple thermometer to be 34℃, and the room temperature atomization is performed. However, due to the evaporation or diffusion phenomenon of the droplet atomization, the surface droplet deposition uniformity is decreased. To this end, the low-temperature atomization is performed to improve the atomization effect.

[0105] S22, the required temperature for the low-temperature atomization is 4-6℃, the temperature reduction amplitude is ΔT according to the following formula, a suitable vortex tube 10 is selected for the test, specifically, a vortex tube 10 produced by Jiangsu Sirui Pneumatic Equipment Technology Co., Ltd. with a model of SR-WLG02 is used, the efficiency of the vortex tube 10 is 0.3, the inlet of the vortex tube 10 is a one-eighth screw thread, the inner diameter of the vortex tube 10 is 27 mm, the outlet of the cold end of the vortex tube 10 is a two-eighth screw thread, the index parameter is 3, and the atmospheric pressure is 0.1 MPa, which indicates that the vortex tube 10 can effectively perform the low-temperature atomization. ΔT is expressed as:

[0106]

[0107] wherein the vortex tube 10 is connected with the nozzle 7, the vortex tube 10 is used to provide cold air for the nozzle 7, K is the efficiency of the vortex tube, D is the diameter of the inlet of the vortex tube, D is the inner diameter of the vortex tube, D is the diameter of the outlet of the cold end, P is the inlet pressure of the vortex tube, P0 is the atmospheric pressure, and n is the index coefficient. p The average diameter D of the atomized droplets is adjusted by controlling the relevant parameters. v The average diameter D of the atomized droplets is adjusted by controlling the relevant parameters. o The average diameter D of the atomized droplets is adjusted by controlling the relevant parameters.

[0108] When the temperature reduction amplitude satisfies ΔT = T1-T2 < 25℃, then the second air compressor 21 is turned off, the pressure knob I is controlled, the first air compressor 15 with an exhaust pressure of P1 is used to provide the air pressure for the trace lubrication device 13 and the MCF 10, the pressure knob II is controlled, the air inlet pressure of the MCF 10 is P.

[0109] When the temperature reduction amplitude does not satisfy ΔT = T1-T2 < 25℃, the pressure knob I is controlled, the first air compressor 15 with an exhaust pressure of P1 is used to provide the air pressure for the trace lubrication device 13 and the MCF 10, the second air compressor 21 with an exhaust pressure of P2 is used to supplement the air pressure for the MCF 10, the pressure knob II is controlled, the air inlet pressure of the MCF 10 is P, and the temperature adjusting valve of the MCF 10 is adjusted to set the low-temperature atomization temperature to T2. Due to the air pressure loss at the hot end outlet of the MCF 10, the spray pressure is P' a , the air pressure valve 9 is adjusted to adjust the air pressure to P a , the atomization pressure is maintained, the cold air flow and the silicone oil are mixed at the nozzle 7 to perform low-temperature atomization.

[0110] Specifically, the temperature reduction amplitude ΔT of the embodiment is between 28-30℃, which is greater than 25℃, at this time, the required air inlet pressure of the MCF 10 is 0.9MP, which exceeds the air inlet pressure bearing range of the trace lubrication device 13, the MCF 10 is supplied in parallel, and the first air compressor 15 with an exhaust pressure of 0.8MPa is used to provide the air pressure for the trace lubrication device 13.

[0111] The first pressure gauge and the first pressure knob are observed to control the air inlet pressure of the trace lubrication device 13 to be within the range of 0.7MPa-0.8MPa, the liquid flow knob 12 is adjusted to set the oil consumption to be 5-9ml / min, the air flow control valve 19 is adjusted to control the air flow to be 70-80L / min, the second air compressor 21 with an exhaust pressure of 0.4MPa is used to supplement the air pressure for the MCF 10, the two kinds of gases are mixed in the T-shaped pipe 14, the second pressure gauge and the second pressure knob are observed to control the air inlet pressure of the MCF 10 to be 0.9MPa, the temperature adjusting valve of the MCF 10 is rotated, the temperature at 30mm in the radial direction of the nozzle 7 is measured by using a thermocouple thermometer to be 4℃, and the branch only provides the cold air flow. The air pressure gauge 8 and the air pressure valve 9 are connected at the nozzle 7, the spray pressure is controlled to be 0.4-0.5MPa, the trace lubrication device 13 switch is turned on to perform low-temperature atomization. The atomization time t1 is 1min, a high-speed camera is used to shoot the spray field, the recorded video is decomposed into single-frame images, the images are imported into an image processing software ImageJ, an edge detection algorithm is used to identify the droplet contour, the diameter of each droplet is calculated, the size of all droplets is counted, data analysis is performed, and the average diameter D of the atomized droplets is obtained to be between 30-60μm.

[0112] S23, the velocity v0 of the atomized liquid droplets ejected from the nozzle 7, the Weber number We, the Reynolds number Re, and the capillary number Ca are obtained according to the following formula, so as to measure the atomization effect:

[0113]

[0114] wherein η is the viscosity of the silicone oil, ρ is the density of the silicone oil, and σ is the surface tension of the silicone oil. If We≥10, Re≥4000, and Ca≥1, the liquid droplets are easy to break and spread, and a thin liquid film is formed on the surface of the sample (which is required in this embodiment); otherwise, the liquid droplets are not easy to form a liquid film and are difficult to break.

[0115] The calculation results of this embodiment are as follows: the Weber number We is between 9250 and 14550, the Reynolds number Re is between 117900 and 147690, and the capillary number Ca is between 74.9 and 93.7, which indicates that the behaviors of the liquid droplets in the low-temperature atomization process, such as flow, breaking, and deformation, are very significant, and a thin liquid film can be formed on the surface.

[0116] S24, referring to Figure 6 The annular-radial laser etching process is performed Figure 6 The left side of the middle is an annular texture, Figure 6 The right side of the middle is a radial texture). The titanium alloy sample treated with atomized silicone oil is fixed on the laser processing platform, and the computer-aided design software is used to accurately plan the annular laser scanning path. The inclined laser etching technology is adopted, the laser beam is perpendicular to the horizontal plane and the normal line of the sample surface at an angle θ, after completing the etching of each annular texture, the laser focal length is adjusted through the precision optical system until all the annular textures are etched, and a plurality of annular rings are formed on the inner wall of the drug storage cavity 1. Then the titanium alloy sample is fixed on the 45° special angle positioning pad to ensure that the processing surface (the inner wall of the drug storage cavity 1) is perpendicular to the laser beam. In this embodiment, the annular drug release orifice surface is evenly divided into 8 regions (360° in total). The vertical laser etching technology is adopted to etch the radial texture in each region in turn. After completing the processing of each region, the sample is rotated by 45° through the precision rotating platform, and the etching of the next region is continued until all the radial textures are etched, and a plurality of straight lines are formed on the inner wall of the drug storage cavity 1.

[0117] It should be noted that the laser etching in this embodiment can increase the adhesion of the inner wall of the drug storage cavity 1 to the microspheres, so that the microspheres are better adhered to the inner wall of the drug storage cavity 1. Preferably, the annular-radial laser etching process makes the effective etching area of the inner wall reach 100%, and the inner wall is etched all over, which can increase the number of microspheres deployed, and thus greatly improve the utilization rate of the inner wall of the drug storage cavity 1.

[0118] Please refer to Figure 7, the inside wall of the drug storage cavity 1 can be seen atomized silicone oil treatment area 2 and texture modification area 3, wherein the atomized silicone oil treatment area 2 is the area of the inside wall of the drug storage cavity 1 after the atomized silicone oil treatment, and the atomized silicone oil treatment area 2 can avoid the released microspheres from adhering to the inside wall of the drug storage cavity 1 again; the texture modification area 3 is the area where the annular texture and the radial texture formed by laser etching are located, and the texture modification area 3 can improve the adhesion of the microspheres.

[0119] Further, the relatively sparse scanning interval d a = 200 μm is used in the pH low-sensitive drug-loaded microsphere coverage area at the height Δh1 near the drug release port of the drug storage cavity 1, and the relatively dense scanning interval d b = 100 μm is used in the pH high-sensitive drug-loaded microsphere coverage area at the height Δh2 far from the drug release port of the drug storage cavity 1. By selecting appropriate laser scanning speed v, processing times N, laser power E, frequency pulse width τ and spot diameter w, the convex bottom size b formed by laser etching, the convex top size a formed by laser etching, and the distance h between the convex top and the concave bottom are adjusted, and then the solid surface roughness ε and the microsphere adhesion force F ab are respectively represented as:

[0120]

[0121] Finally, the laser scanning parameters are set as: laser scanning speed v = 50 mm / s, processing times N = 4, laser power E = 5 W, frequency pulse width τ = 35 ns, spot size w = 50 μm, and etching correction coefficient k = 1. The calculated microsphere adhesion force F ab is 43.2 μN. If the microsphere adhesion force F ab reaches the preset adhesion force range (34.6 μN < F ab < 67.7 μN), it indicates that the laser etching and the atomized silicone oil treatment are effective, otherwise the laser etching parameters need to be adjusted.

[0122] S25, most of the silicone oil on the surface of the laser processed sample (drug storage cavity 1), the black substance generated by the laser processing of the silicone oil, and the cutting chips generated by the laser processing of the sample are cleaned with deionized water; then the sample is placed in an ultrasonic cleaner and cleaned with anhydrous ethanol as a solvent for 5 min, and at the same time, a clean fine hair brush is used to remove the remaining residual silicone oil, the black substance generated by the laser processing of the silicone oil, and the cutting chips generated by the laser processing of the sample on the surface of the sample. After cleaning, a drying box is used to dry the surface of the sample for 1 min.

[0123] After drying, the sample is subjected to wettability test, and the surface static contact angle a is measured by a contact angle measuring instrument. The sample is subjected to adhesion test, and the contact angle hysteresis Da is measured. The size of the static contact angle a is determined; if a < 150°, the laser scanning speed v and the laser scanning pitch d are reduced a , d b , the laser etching step S24 is repeated until a ≥ 150°. The size of the contact angle hysteresis Da is determined, and if Da < 30°, the silicone oil viscosity η is increased, and the laser etching step S24 is repeated until Da ≥ 30°.

[0124] S26, the dried sample is placed on the test platform, and a 5 μl water droplet is obtained by squeezing the syringe. The sample gradually approaches the droplet as the test platform rises, and continues to squeeze 0.2 mm after contact to make full contact. Then the test platform is lowered to separate the droplet from the syringe, and the surface contact angle of the sample is measured by SDC-100 contact angle measuring instrument, and the surface static contact angle a is 155.0°. Then the sample is placed on the test platform, and a 5 μl water droplet is obtained by squeezing the syringe. After contact, continue to squeeze 0.2 mm to make full contact, and then move the platform horizontally at a speed of 5 mm / s to make the bottom of the droplet move continuously on the sample. The two different contact angles on both sides of the three-phase contact line are measured, which are the advancing contact angle a A and the receding contact angle a R , the difference between the two contact angles is the contact angle hysteresis Da, which is 70.5°. Since the contact angle hysteresis Da is greater than 30°, it indicates that the surface has high adhesion.

[0125] Step S3, selection of microspheres and use of vacuum drying method for in-situ adhesion

[0126] S31, the annular surface morphology of the drug storage cavity 1 orifice is observed by scanning electron microscope, and the depth and profile of the annular surface texture are characterized by super-depth microscope. Then, in the pH low-sensitive drug-loaded microsphere coverage area near the release port height Dh1, large particle size pH low-sensitive drug-loaded microspheres 4 with particle size d1 = 100 μm and scanning pitch d a = 200 μm are selected, and in the pH high-sensitive drug-loaded microsphere coverage area away from the release port height Dh2, small particle size pH high-sensitive drug-loaded microspheres 5 with particle size d2 = 50 μm and scanning pitch d b = 100 μm are selected, and the microsphere selection is completed.

[0127] S32, first with glue head pipette 5 ml of liquid medicine, respectively, into the first, second test tube, weighing 0.102 g particle size of 100 μm pH low sensitivity drug-loaded microspheres 4 into the first test tube, weighing 0.238 g particle size of 50 μm pH high sensitivity drug-loaded microspheres 5 into the second test tube, so that it is dispersed in 5 ml of liquid, and shake, so that the microspheres are fully dispersed in the liquid. Take a drop of liquid on the glass slide, then use an optical microscope to observe. Observation of microspheres in the liquid evenly distributed, no obvious agglomeration or precipitation, then the microspheres are fully dispersed in the liquid.

[0128] S33, using a micro-syringe to transfer the first test tube microspheres mixed liquid to the Δh1 outside the conical region near the release port, the second test tube microspheres mixed liquid to the Δh2 inside the conical region away from the release port, if the microspheres mixed liquid along the drug storage cavity 1 release port surface slip, then reduce the liquid volume V, the purpose is to let the liquid thick some, prevent the microspheres mixed liquid slip; otherwise complete the drug-loaded microspheres mixed liquid production. It should be noted that the purpose of using the liquid in this embodiment is to stick the microspheres on the inner wall of the drug storage cavity 1.

[0129] The titanium alloy sample is placed in a vacuum drying oven, and a single-stage vacuum pump is used to draw the vacuum drying oven to a vacuum condition. The vacuum drying oven is set to a pressure of -0.1 MPa, a temperature of 28°C, and a drying time of 2 hours. After drying, the sample is taken out by wearing a temperature-insulating glove, and it is allowed to cool to room temperature. In this way, the liquid evaporates, and the microspheres stick to the inner wall of the drug storage cavity 1.

[0130] S34, place the sample on the ATR crystal (attenuated total reflection crystal) and apply pressure to ensure close contact. Set the number of scans n to 32, the resolution p to 4 cm -1 , and the scan range Δ to 4000-400 cm -1 , and collect the sample spectrum. Analyze the sample spectrum, focusing on the hydroxyl characteristic peaks: free -OH (a broad peak appears at 3200-3600 cm -1 ), hydrogen-bonded -OH (a peak that is wider and moves to lower wavenumbers 3200-3400 cm -1 ), and intermolecular strong hydrogen bonds (split into two peaks, 3400 cm -1 and 3250 cm -1 ). Determine whether the sample spectrum contains hydroxyl characteristic peaks. If there are no hydroxyl characteristic peaks, it indicates that the microspheres have failed to adhere in situ, and the microsphere particle size d1, d2 and laser scanning pitch d a , d b (adjust the microsphere particle size and laser scanning pitch to match) should be adjusted. If there are hydroxyl characteristic peaks, it indicates that the microspheres have successfully adhered in situ, and step S4 is executed.

[0131] Step S4, in-situ adhesion of microspheres is tested (whether the microspheres adhered to the inner wall of the medicine storage cavity 1 will be taken down by water droplets is tested by water droplet test)

[0132] In this embodiment, the in-situ adhesion of microspheres is defined as: the drug-loaded microspheres adhere to the sample surface, the microspheres adhered to the sample surface are dried by vacuum drying method, and based on the interaction of titanium alloy-microsphere-liquid droplet, the microspheres are realized to be separated from the sample surface with liquid droplets in the wetting state.

[0133] S41, place the sample on the movable platform of the optical contact angle tester, use the microsyringe to release 5 μl liquid droplets at the bottom end (needle tip) of the syringe, and move the movable platform upward at a constant speed until the drug-loaded microspheres on the sample surface are in full contact with the liquid droplets. Finally, the sample is moved downward by the movable platform, and in this process, the state between them is observed;

[0134] S42, if the liquid droplets adhere to the surface of the microspheres or the liquid droplets are separated from the surface of the drug-loaded microspheres with the needle tip, the pressure P, temperature T and drying time t under vacuum drying conditions need to be modified, and the test is performed again until the drug-loaded microspheres are separated from the sample surface with the liquid droplets, which indicates that the drug-loaded microspheres in the titanium alloy sample can be driven by liquid and then reach the affected area for drug release.

[0135] As shown in Figure 8 , (a) in Figure 8 indicates that the liquid droplets adhere to the surface of the drug-loaded microspheres (invalid), Figure 8 (b) in Figure 8 indicates that the liquid droplets are separated from the surface of the drug-loaded microspheres with the needle tip (invalid), Figure 8 (c) in Figure 8 indicates that the drug-loaded microspheres are separated from the sample surface with the liquid droplets (valid).

[0136] As a further step:

[0137] Step S5: evaluation of antibacterial performance

[0138] S51, after dilution, the staphylococcus aureus is uniformly coated on the agar plate, and the drug-loaded sample and the non-drug-loaded sample are respectively closely attached to the surface of different agar plates for dynamic culture;

[0139] S52, for the drug-loaded group, the transparent inhibition zone diameter is measured at different time points 0, 12, 24, 36, 48 and 60 h, and the diameter is 10, 43.8, 36.5, 40.2, 32.1 and 10.2 mm. According to D = (D n -D0) / 2, the inhibition zone width is calculated as 0, 16.9, 13.2, 15.1, 11.05 and 0.1. D nDiameter of the inhibition zone, D0 is the diameter of the sample. From 60h, the width of the inhibition zone no longer changes. That is, the antibacterial time is 60h; and the number of bacteria in the non-drug-loaded group increases slowly from 0-12h; the number of bacteria increases exponentially from 12-36h; after 36h, the culture medium surface is completely covered by colonies, and the color gradually changes from light yellow to dark yellow.

[0140] Experiments show that the application has good antibacterial properties.

[0141] Example two

[0142] The embodiment provides a drug-loaded microsphere in-situ attachment system for a drug storage cavity, comprising:

[0143] A design module is used for designing a drug storage flow channel in a titanium jaw implant body, and performing 3D printing on the titanium jaw implant body with the drug storage flow channel to obtain a sample, wherein the drug storage flow channel is a drug storage cavity for drug release.

[0144] A pretreatment module is used for performing atomized silicon oil treatment and laser etching on the inner wall of the drug storage cavity in the sample.

[0145] An in-situ attachment module is used for selecting a microsphere for the sample after the atomized silicon oil treatment and the laser etching, and realizing in-situ attachment of the microsphere by using a vacuum drying method.

[0146] A test module is used for testing the in-situ attachment of the microsphere to determine whether the in-situ attachment of the microsphere is effective.

[0147] Example three

[0148] The embodiment provides an electronic device, comprising a memory, a processor and a computer program stored in the memory and capable of running on the processor, and the processor implements the steps of the in-situ attachment method of the drug-loaded microsphere for the drug storage cavity.

[0149] Example four

[0150] The embodiment provides a computer readable storage medium, which stores a computer program, and the computer program is executed by a processor to implement the steps of the in-situ attachment method of the drug-loaded microsphere for the drug storage cavity.

[0151] Those skilled in the art will appreciate that embodiments of the application can be readily used as software, hardware, or a combination of software and hardware. In one embodiment, the application can be implemented in software and / or firmware. In addition, those skilled in the art will further appreciate that the application can be implemented as a method, apparatus, or computer program product. Therefore, embodiments of the application can take the form of an entirely hardware embodiment, an entirely software embodiment or an embodiment combining software and hardware aspects all generally referred to herein as a "circuit" or "module." Furthermore, embodiments of the application can take the form of a computer program product on a computer-readable storage medium having computer program code embodied in the storage medium. The computer program code can cause a computer, processor, or other programmable data processing apparatus to effect the steps in the embodiments of the application as set forth in the description below.

[0152] The computer program instructions can also be loaded onto a computer, other programmable data processing apparatus, or other devices to cause a series of operational steps to be performed on the computer, other programmable apparatus or other devices to produce a computer implemented process such that the instructions which execute on the computer or other programmable apparatus provide processes for implementing the functions specified in the flowchart block or blocks. Figure 1 The computer program instructions can also be loaded onto a computer, other programmable data processing apparatus, or other devices to cause a series of operational steps to be performed on the computer, other programmable apparatus or other devices to produce a computer implemented process such that the instructions which execute on the computer or other programmable apparatus provide processes for implementing the functions specified in the flowchart block or blocks. Figure 1 The computer program instructions can also be loaded onto a computer, other programmable data processing apparatus, or other devices to cause a series of operational steps to be performed on the computer, other programmable apparatus or other devices to produce a computer implemented process such that the instructions which execute on the computer or other programmable apparatus provide processes for implementing the functions specified in the flowchart block or blocks. The computer program instructions can also be loaded onto a computer, other programmable data processing apparatus, or other devices to cause a series of operational steps to be performed on the computer, other programmable apparatus or other devices to produce a computer implemented process such that the instructions which execute on the computer or other programmable apparatus provide processes for implementing the functions specified in the flowchart block or blocks.

[0153] The computer program instructions can also be loaded onto a computer, other programmable data processing apparatus, or other devices to cause a series of operational steps to be performed on the computer, other programmable apparatus or other devices to produce a computer implemented process such that the instructions which execute on the computer or other programmable apparatus provide processes for implementing the functions specified in the flowchart block or blocks. Figure 1 The computer program instructions can also be loaded onto a computer, other programmable data processing apparatus, or other devices to cause a series of operational steps to be performed on the computer, other programmable apparatus or other devices to produce a computer implemented process such that the instructions which execute on the computer or other programmable apparatus provide processes for implementing the functions specified in the flowchart block or blocks. Figure 1 The computer program instructions can also be loaded onto a computer, other programmable data processing apparatus, or other devices to cause a series of operational steps to be performed on the computer, other programmable apparatus or other devices to produce a computer implemented process such that the instructions which execute on the computer or other programmable apparatus provide processes for implementing the functions specified in the flowchart block or blocks. The computer program instructions can also be loaded onto a computer, other programmable data processing apparatus, or other devices to cause a series of operational steps to be performed on the computer, other programmable apparatus or other devices to produce a computer implemented process such that the instructions which execute on the computer or other programmable apparatus provide processes for implementing the functions specified in the flowchart block or blocks.

[0154] The computer program instructions can also be loaded onto a computer, other programmable data processing apparatus, or other devices to cause a series of operational steps to be performed on the computer, other programmable apparatus or other devices to produce a computer implemented process such that the instructions which execute on the computer or other programmable apparatus provide processes for implementing the functions specified in the flowchart block or blocks. Figure 1 The computer program instructions can also be loaded onto a computer, other programmable data processing apparatus, or other devices to cause a series of operational steps to be performed on the computer, other programmable apparatus or other devices to produce a computer implemented process such that the instructions which execute on the computer or other programmable apparatus provide processes for implementing the functions specified in the flowchart block or blocks. Figure 1 The computer program instructions can also be loaded onto a computer, other programmable data processing apparatus, or other devices to cause a series of operational steps to be performed on the computer, other programmable apparatus or other devices to produce a computer implemented process such that the instructions which execute on the computer or other programmable apparatus provide processes for implementing the functions specified in the flowchart block or blocks. The computer program instructions can also be loaded onto a computer, other programmable data processing apparatus, or other devices to cause a series of operational steps to be performed on the computer, other programmable apparatus or other devices to produce a computer implemented process such that the instructions which execute on the computer or other programmable apparatus provide processes for implementing the functions specified in the flowchart block or blocks.

[0155] Although preferred embodiments of the application have been described herein, those skilled in the art will readily devise numerous other variations of these preferred embodiments that will fall within the scope of the present application. Accordingly, the attached claims are intended to embrace all such variations.

[0156] Obviously, the above-mentioned embodiments are only examples for clearly illustrating the present application, and are not intended to limit the present application. Based on the above description, other different forms of changes or variations can be made by those skilled in the art. Here, it is not necessary and also impossible to enumerate all the embodiments. The obvious changes or variations derived from the above description are still within the protection scope of the present application.

Claims

1. An in-situ attachment method of drug-loaded microspheres for a drug storage cavity, characterized by: The application relates to a method for designing a drug storage flow channel in a titanium jawbone implant, and the method comprises the following steps: Step S1: a drug storage flow channel is designed in a titanium jawbone implant, and the titanium jawbone implant with the drug storage flow channel is subjected to 3D printing to obtain a sample, wherein the drug storage flow channel is a drug storage cavity for drug storage and release; Step S2: the inner wall of the drug storage cavity in the sample is subjected to atomized silicon oil treatment and laser etching; Step S3: the sample after the atomized silicon oil treatment and the laser etching is subjected to microsphere selection, and vacuum drying is used to realize in-situ adhesion of the microspheres; Step S4: the in-situ adhesion of the microspheres is tested to determine whether the in-situ adhesion of the microspheres is effective.

2. The method for in-situ attachment of drug loaded microspheres to drug reservoirs as claimed in claim 1, wherein: The method for designing the drug storage flow channel in the titanium jawbone implant in the step S1 comprises the following steps: Obtaining the concentration C of the intracellular osmotic active particles in the inflammation stage lesion area cell And the concentration C of the extracellular osmotic active particles in the healthy environment cavity Establishing the liquid level-osmotic pressure balance equation: ΔΠ = Π cell -Π cavity = (C cell -C cavity )RT a The liquid level rising height H of the drug storage cavity is derived according to the liquid level-permeability pressure balance equation Delta Pi, and the formula is as follows: H = βΔ∏t response h1 = max H Wherein, ∑ cell is the intracellular osmotic pressure, ∑ cavity is the extracellular osmotic pressure, C cell , C cavity are the intracellular and extracellular osmotic active particle numbers, R is the gas constant, T a is the absolute temperature, t response is the response time of the drug release system, h1 is the depth of the drug storage cavity, and β is the liquid level response adjustment factor; V single = V total / num, wherein V single is the mass of pH-sensitive microspheres required to be attached to a single drug storage cavity, V total is the mass of pH-sensitive microspheres required to be attached to all drug storage cavities, and num is the number of drug storage cavities. According to the pH value of the lesion area, the pH-sensitive microspheres are divided into pH low-sensitive drug-loaded microspheres and pH high-sensitive drug-loaded microspheres, and the pH low-sensitive drug-loaded microspheres and the pH high-sensitive drug-loaded microspheres are designed to cover the pH low-sensitive drug-loaded microspheres and the pH high-sensitive drug-loaded microspheres in the drug storage cavity, wherein pH low-sensitive drug-loaded microspheres coverage area height, Δh1 = (V1 / V single )h1, wherein V1 = 0.3V single , V1 is the total amount of pH low-sensitive drug-loaded microspheres in the coverage area; The height Delta h2 of the pH high-sensitive drug-loaded microsphere covering area is h1- Delta h1, and h1 is the depth of the drug storage cavity.

3. The method for in-situ attachment of drug loaded microspheres to drug reservoirs as claimed in claim 1, wherein: The drug storage cavity is a funnel-shaped drug storage cavity, which comprises a conical region and a rectangular region, the conical region is used for bearing the microspheres, and the rectangular region is used for buffering the liquid level rising speed from the lesion area.

4. The method for in-situ attachment of drug loaded microspheres to drug reservoirs as claimed in claim 1, wherein: The method for atomizing silicon oil treatment on the inner wall of the drug storage cavity in the sample in the step S2 comprises the following steps: S21, a first air compressor with an exhaust pressure P1 is connected with an inlet of a micro-lubrication device, an outlet of the micro-lubrication device and a second air compressor with an exhaust pressure P2 are jointly connected to an inlet of a vortex tube, an input end of a nozzle is connected with a cold end outlet of the vortex tube, the vortex tube is used for providing cold air for the nozzle, the micro-lubrication device is used for providing air flow and silicon oil for the nozzle, and the nozzle is used for atomizing silicon oil treatment on the inner wall of the drug storage cavity; The temperature reduction amplitude Delta T of the vortex tube is obtained: where K is the efficiency of the vortex tube, D p is the diameter of the vortex tube inlet, D v is the inner diameter of the vortex tube, D o is the cold end outlet diameter, P is the vortex tube inlet pressure, P0 is the atmospheric pressure, and n is an index coefficient; The temperature reduction amplitude Delta T of the vortex tube is reduced to improve the atomization effect, when the temperature reduction amplitude Delta T = T1-T2 < 25 DEG C, S22 is performed; otherwise, S23 is performed; wherein T1 is the ambient temperature measured at a distance L from the nozzle, and T2 is the low-temperature atomization temperature measured at the distance L from the nozzle; S22, the second air compressor connected with the micro-lubrication device is closed, and the first air compressor connected with the micro-lubrication device is used to provide air pressure for the micro-lubrication device and the vortex tube, so that the inlet pressure of the vortex tube is P; S23, control the first air compressor to provide trace lubrication device and vortex tube gas pressure, using the second air compressor to supplement the vortex tube missing gas pressure, so that the inlet pressure of vortex tube is P; at the same time, set the low temperature atomization temperature of vortex tube as T2, because of the gas pressure loss of vortex tube hot end outlet, and adjust the gas pressure of nozzle to P a Mix the cold air flow and silicone oil at the nozzle to carry out low temperature atomization; S24, under the condition of low-temperature atomization, the average diameter D of the atomized liquid droplets is obtained, which is expressed as: where C is a proportionality coefficient, n is an exponent coefficient, Q1 is the flow rate of the silicone oil liquid, Q2 is the flow rate of the air, P a is the spray pressure of the air pressure valve for controlling the nozzle; A is the nozzle diameter; S25, according to the average diameter D of the atomized liquid droplets, the speed v0 of the atomized liquid droplets sprayed from the nozzle, the Weber number We, the Reynolds number Re and the capillary number Ca are obtained, so as to measure the atomization effect, which is expressed as: Wherein, eta is the viscosity of silicon oil, rho is the density of silicon oil, and sigma is the surface tension of silicon oil; If We >= 10, Re >= 4000 and Ca >= 1, the liquid droplets are easy to form a liquid film; otherwise, the liquid droplets are not easy to form a liquid film.

5. The method for in-situ attachment of drug loaded microspheres to drug reservoirs as claimed in claim 2, wherein: The method for laser etching on the inner wall of the drug storage cavity in the sample in the step S2 comprises the following steps: S26, the sample treated with atomized silicone oil is subjected to laser etching, and the laser scanning interval d=d a is used in the pH high-sensitive drug-loaded microsphere covered area with height Δh2 b , and d a is greater than d b ; The laser scanning speed is v, the processing number is N, the laser power is E, the frequency is f The pulse width is τ, the spot size is w, the raised bottom size formed by laser etching is b, the raised top size formed by laser etching is a, the distance between the raised top and the pit bottom formed by laser etching is h, the etching correction coefficient is k, and the Hamker constant is A H The closest distance between the microspheres and the sample surface is H0, the microsphere radius is r, and the microsphere density is ρ r The solid surface roughness ε and the microsphere adhesion force F ab are respectively represented as: If the microsphere adhesion force F ab If the microsphere adhesion force F reaches the preset adhesion force range, it indicates that the laser etching and silicone oil atomization treatment are effective, otherwise the laser etching parameters need to be adjusted. After the sample is cleaned and dried, the sample is subjected to a wettability test: the static contact angle a of the sample surface is measured; if a < 150°, the laser scanning speed v and the laser scanning interval d are reduced a , d b , the laser etching step is repeated until a ≥ 150°; Then the adhesion of the sample is tested: the contact angle hysteresis Δα of the sample surface is measured; the contact angle hysteresis Δα is determined, if Δα < 30°, the viscosity η of the silicone oil is increased, the laser etching step is repeated until Δα ≥ 30°.

6. The method for in-situ attachment of drug loaded microspheres to drug reservoirs as claimed in claim 5, wherein: The step S3 includes: S31, in the pH low-sensitive drug-loaded microspheres coverage area where height Δh1 is located, pH low-sensitive drug-loaded microspheres with particle size d1 are selected and the scanning interval d is matched a Matching, in the pH high-sensitive drug-loaded microspheres coverage area where height Δh2 is located, pH high-sensitive drug-loaded microspheres with particle size d2 are selected and the scanning interval d is matched b Matching, and d1>d2; S32, a first and a second test tube with a volume of V of the drug solution are obtained, the pH low-sensitive drug-loaded microspheres with a particle size of d1 are weighed and put into the first test tube, and the pH high-sensitive drug-loaded microspheres with a particle size of d2 are weighed and put into the second test tube, to obtain the respective microsphere mixtures; S33, the microsphere mixture in the first test tube is transferred to the pH low-sensitive drug-loaded microsphere covering area, and the microsphere mixture in the second test tube is transferred to the pH high-sensitive drug-loaded microsphere covering area; if the microsphere mixture slides along the surface of the drug release port of the drug storage cavity, the volume V of the drug solution is reduced; otherwise, the microsphere mixture is completed; S34, the sample is placed in a vacuum drying oven for drying treatment, the pressure P, the temperature T and the drying time t of the vacuum drying oven are set, and the drug solution is volatilized to make the microspheres adhere to the inner wall of the drug storage cavity.

7. The method for in-situ attachment of drug loaded microspheres to drug reservoirs as claimed in claim 1, wherein: The step S3 further includes determining whether the in-situ adhesion of the microspheres is successful, and the method includes: S35, scanning the sample to obtain a sample spectrum, judging whether there is a hydroxyl characteristic peak in the sample spectrum, if not, indicating that the in-situ adhesion of the microspheres fails, then adjusting the microsphere particle size d1, d2 and the laser scanning interval d a b , so that the microsphere particle size and the laser scanning interval are matched; if there is, indicating that the in-situ adhesion of the microspheres succeeds, then testing the in-situ adhesion of the microspheres.​ 8. The method for in-situ attachment of drug loaded microspheres to drug reservoir according to claim 1, wherein: The method for testing the in-situ adhesion of the microspheres in the step S4 includes: S41, a microsyringe is used to release a quantitative droplet suspended at the bottom end of the needle tip of the syringe, the movable platform is used to drive the sample to move upwards until the microspheres on the surface of the sample are in full contact with the droplet, and finally the movable platform is used to drive the sample to move downwards; S42, during the upward or downward movement of the sample, if the droplet adheres to the surface of the microspheres or the droplet separates from the surface of the microspheres, the pressure P, the temperature T and the drying time t under the vacuum drying condition are modified, and the test is performed again until the microspheres separate from the surface of the sample with the droplet; otherwise, it indicates that the in-situ adhesion of the microspheres is effective.

9. The method for in-situ attachment of drug loaded microspheres to drug reservoirs as claimed in claim 1, wherein: The method for laser etching the inner wall of the drug storage cavity in the step S2 is ring-radiation laser etching, which includes: a ring structure is etched on the inner wall of the drug storage cavity by laser etching; a radiation structure is etched on the inner wall of the drug storage cavity by laser etching.

10. An in-situ attachment system for drug-loaded microspheres for a drug reservoir, characterized by: The method includes: a design module for designing a drug storage flow channel in a titanium jaw implant and 3D printing the titanium jaw implant with the drug storage flow channel to obtain a sample, wherein the drug storage flow channel is a drug storage cavity for drug release; a pretreatment module for atomizing silicone oil treatment and laser etching of the inner wall of the drug storage cavity in the sample; an in-situ adhesion module for selecting microspheres for the sample after the atomized silicone oil treatment and laser etching, and realizing in-situ adhesion of the microspheres by using a vacuum drying method; a test module for testing the in-situ adhesion of the microspheres to determine whether the in-situ adhesion of the microspheres is effective.

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