Temperature and pH dual-response pulmonary nodule positioning injection gel, preparation method thereof and injection device

Abstract

The invention belongs to the technical field of pulmonary nodule positioning, and particularly relates to temperature and pH dual-response pulmonary nodule positioning injection gel, a preparation method thereof and an injection device. Specifically, the preparation method of the pulmonary nodule positioning injection gel comprises the following steps: dissolving a water-soluble macromolecular protein containing a dopamine group, an amino group and a carboxyl group in water under a dark condition to obtain a solution I; under a dark condition, dissolving a water-soluble high-molecular polymer containing an aldehyde group in water to obtain a solution II; under a dark condition, mixing the solution I and the solution II, pouring the mixture into a columnar mold with a recognition line, then performing freeze drying, and finally demolding to obtain the pulmonary nodule positioning injection gel. Wherein the identification line is divided into a built-in section and an exposed section, the built-in section is embedded in the pulmonary nodule positioning injection gel, the exposed section is exposed out of the pulmonary nodule positioning injection gel, and the exposed section is used for positioning identification. The pulmonary nodule positioning injection gel is a hard gel material, has heat and acid response capability, and is used for pulmonary nodule positioning.

Description

Technical Field

[0001] The present invention belongs to the technical field of pulmonary nodule localization, and particularly relates to a temperature- and pH-responsive pulmonary nodule localization injection gel, a preparation method thereof, and an injection device. Background Art

[0002] Pulmonary nodules refer to various round or oval lesions that appear in the lungs. The causes are due to various factors. For example, pulmonary nodules caused by inflammation, autoimmune diseases, etc. do not need to be removed, while malignant pulmonary nodules caused by lung cancer need to be surgically removed. During the process of removing pulmonary nodules, it is necessary to localize the pulmonary nodules.

[0003] There are various methods for preoperative localization of pulmonary nodules, including CT-guided puncture localization, fluorescence staining localization, and virtual navigation bronchoscopy VBN localization, etc. Among them, CT-guided puncture localization is to place a positioning needle, hook wire, or staining agent (such as methylene blue) near the nodule under the guidance of CT to help find the nodule position during the operation. However, the lung tissue may be damaged during the puncture process, resulting in pneumothorax, and in severe cases, thoracic drainage may be required; and the puncture may damage blood vessels, resulting in bleeding, especially for nodules close to the pleura or blood vessels. Fluorescence staining localization is to inject a fluorescent dye (such as indocyanine green, ICG) before the operation, and the nodule is localized through a fluorescence imaging device during the operation. However, the dye may spread to the surrounding tissues, affecting the localization accuracy, and special fluorescence imaging equipment is required, increasing the surgical cost. Virtual navigation bronchoscopy VBN localization is to reach near the nodule through three-dimensional reconstruction and virtual navigation technology, combined with a bronchoscope for marking. However, this localization method is complex in operation and high in equipment cost, increasing the economic burden on patients.

[0004] Malignant pulmonary nodule sites usually accumulate lactic acid and generate a large amount of heat due to the glycolysis of malignant tumor cells, resulting in an environment that is slightly acidic and higher than physiological temperature; in addition, the pulmonary nodule site is a moist environment, and common adhesive materials will fail in a moist environment. Therefore, there is an urgent need in the art to develop a pulmonary nodule localization material that is not restricted by the surrounding environment of the pulmonary nodule to help visually identify the pulmonary nodule site during the operation. The pulmonary nodule localization material needs to meet the following requirements: (1) It has the properties of dual response to heat and acid and adhesion under moist conditions, and will not cause the localization function to fail due to the special environment of the pulmonary nodule; (2) The localization is accurate and has good intuitiveness, will not be displaced or fall off due to the patient's breathing, movement, etc., and the doctor can directly find the pulmonary nodule site by visual inspection during the operation; (3) It has high biological safety, and even if the patient does not receive surgery after pulmonary nodule localization, it can be absorbed by tissue ablation by itself; (4) The preparation method is simple and the cost is low, reducing the economic burden on patients and hospitals. Summary of the Invention

[0005] Based on the above-mentioned disadvantages and deficiencies existing in the prior art, one of the objectives of the present invention is to at least solve one or more of the above-mentioned problems existing in the prior art. In other words, one of the objectives of the present invention is to provide a temperature and pH dual-responsive lung nodule localization injection gel, its preparation method, and injection device that meet one or more of the foregoing requirements.

[0006] In order to achieve the above-mentioned invention objectives, the present invention adopts the following technical solutions:

[0007] A preparation method of a temperature and pH dual-responsive lung nodule localization injection gel, comprising the following steps:

[0008] Under light-shielding conditions, a water-soluble macromolecular protein containing dopamine groups, amino groups, and carboxyl groups is dissolved in water to obtain Solution 1;

[0009] Under light-shielding conditions, a water-soluble polymer containing aldehyde groups is dissolved in water to obtain Solution 2;

[0010] Under light-shielding conditions, Solution 1 and Solution 2 are mixed and then poured into a columnar mold with a recognition line placed therein, followed by freeze-drying, and finally demolded to obtain the lung nodule localization injection gel;

[0011] Among them, the recognition line is divided into an embedded section and an exposed section. The embedded section is embedded in the lung nodule localization injection gel, and the exposed section is exposed outside the lung nodule localization injection gel. The exposed section is used for positioning and recognition.

[0012] As a preferred solution, the water-soluble macromolecular protein containing dopamine groups, amino groups, and carboxyl groups is selected from one of mussel adhesive protein, dopamine-modified silk fibroin, dopamine-modified collagen, dopamine-modified polylysine, and dopamine-modified acellular porcine skin matrix.

[0013] As a preferred solution, the water-soluble macromolecular protein containing dopamine groups, amino groups, and carboxyl groups is selected from one of dopamine-modified silk fibroin, dopamine-modified collagen, dopamine-modified polylysine, and dopamine-modified acellular porcine skin matrix; among them, the grafting rate of dopamine modification is 10-30%.

[0014] As a preferred solution, the water-soluble polymer containing aldehyde groups is selected from one of aldehyde-modified hyaluronic acid, oxidized hyaluronic acid, oxidized sodium alginate, and oxidized dextran.

[0015] As a preferred solution, the recognition line is a degradable collagen thread.

[0016] As a preferred solution, the pressure of the freeze-drying is 0.1-0.5 mbar, the temperature is -70 to -50 °C, and the time is 20-30 h.

[0017] As a preferred embodiment, the inner diameter of the columnar mold is 0.5 to 2 mm, and the height is 10 to 50 mm.

[0018] The present invention also provides a pulmonary nodule positioning injection gel prepared by the preparation method described in any one of the above embodiments.

[0019] As a preferred embodiment, the exposed segment length of the identification line is 10 to 90% of the length of the identification line.

[0020] The present invention also provides an injection device for the pulmonary nodule positioning injection gel described in any one of the above embodiments, including a trocar and an injection piston and a positioning rod disposed in the inner cavity of the trocar. The injection piston is used to drive the positioning rod to move toward the outlet end of the trocar. The outlet end of the trocar has a bayonet, and the pulmonary nodule positioning injection gel is disposed in the bayonet; wherein, one end of the positioning rod adjacent to the bayonet has a card slot, and the exposed segment of the identification line of the pulmonary nodule positioning injection gel is embedded in the card slot.

[0021] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0022] (1) The pulmonary nodule positioning injection gel of the present invention is a rigid gel material with thermal and acid response capabilities. In an acidic environment, the carboxylic acid groups can be protonated (the negative charge is reduced or positively charged), resulting in weakened electrostatic interactions between molecular chains, causing the crosslinked network to relax. It can also hydrolyze the imine bond and acylhydrazone bond in the dynamic Schiff base bond, reducing the gel crosslinking degree, and then rapidly swelling; at the same time, the pulmonary nodule positioning injection gel absorbs tissue fluid at the pulmonary nodule site. When the tissue fluid enters the relaxed crosslinked network, it will further expand the crosslinked network space, causing the gel to rapidly swell. The swelling causes the molecular chains to unfold, exposing more sticky groups (such as dopamine groups, hydroxyl groups, carboxyl groups, and amino groups, etc.), and the adhesion increases in a moist environment; the thermal environment can not only gradually relax the triple helix structure of proteins in the gel, resulting in a decrease in its physical properties (such as strength and elasticity), making its surface sticky, but also accelerate the hydrolysis rate of the Schiff base bond, further accelerating the swelling; the adhesion ability of the catechol group in dopamine mimics the adhesion mechanism of the byssus protein of shellfish (such as mussels) in nature; through hydrogen bond interaction, metal coordination bond interaction, and covalent bond interaction, it can firmly adhere to tissues even in a moist environment; through the gel material with dual thermal and acid response, it can rapidly swell, and the gel will quickly fill the injection channel formed by the injection needle and contact with the tissue, and the unfolded molecular chains and the sticky surface make it firmly adhere to the tissue;

[0023] (2) The pulmonary nodule positioning injection gel of the present invention has excellent biosecurity, hydrophilicity, anti-inflammatory and antioxidant capabilities. As time goes by, it can be gradually absorbed, metabolized, and excreted by the body, without obvious immune and inflammatory reactions, reducing the risk of potential long-term adverse reactions and complications, and no need for secondary removal, reducing the workload of doctors and the pain of patients;

[0024] (3) The injection device of the lung nodule positioning injection gel of the present invention uses an injection needle with an inner and outer sleeve structure to pierce the lung surface and deliver the gel to the lung nodule site, leaving a recognizable identification line mark that allows doctors to find the lung nodule site by direct visual inspection with the naked eye;

[0025] (4) Compared with the traditional positioning device, the metal anchor needle, it may scratch the lung tissue, cause pneumothorax, and may also cause infection, inflammation and the generation of body resistance; the injection gel materials of the present invention are all made of functional biopolymers, making them have excellent biological safety; good biodegradability; anti-inflammatory and antioxidant effects; in addition, these materials can promote cell proliferation, differentiation and tissue regeneration, and help repair the postoperative wound surface after being absorbed by the body;

[0026] (5) The present invention only locates by the way that the positioning material absorbs the tissue fluid at the lung nodule site and swells to fill the puncture tract, which is largely limited by the liquid absorption capacity of the positioning material and the amount of tissue fluid at the lung nodule site; the temperature and pH dual-responsive positioning gel material provided by the present invention can not only make the gel swell rapidly by making full use of the special environment around the lung nodule, exposing more adhesion groups, but also introduce dopamine groups into the material, which can adhere to tissues in a humid environment and further enhance its adhesion ability;

[0027] (6) The preparation method of the lung nodule positioning injection gel of the present invention is simple. The positioning material can be obtained by simple mixing and stirring and finally freeze-drying. It can not only be adjusted according to clinical needs, that is, customized according to actual surgical requirements, but also can be prepared in large quantities and stored in a low-temperature sealed manner for immediate use, reducing the preparation time and improving the treatment efficiency. Description of the Drawings

[0028] Figure 1 It is the SEM photograph of the lung nodule positioning injection gel of Example 1 of the present invention;

[0029] Figure 2 It is the physical photograph of the lung nodule positioning injection gel of Example 1 of the present invention;

[0030] Figure 3 It is the tensile force change diagram of the lung nodule positioning injection gel of Example 1 of the present invention and wet tissue;

[0031] Figure 4 It is the adhesion strength diagram of the lung nodule positioning injection gel of Example 1 of the present invention and wet tissue;

[0032] Figure 5 It is the structural schematic diagram of the injection device of the lung nodule positioning injection gel of Example 1 of the present invention;

[0033] Figure 6 It is a schematic enlarged view of the outlet end of the trocar in Embodiment 1 of the present invention. Detailed implementation manners

[0034] To more clearly illustrate the embodiments of the present invention, the specific implementation manners of the present invention will be described below with reference to the accompanying drawings. Obviously, the accompanying drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can be obtained based on these drawings, and other implementation manners can also be obtained.

[0035] Embodiment 1:

[0036] For the temperature- and pH-responsive pulmonary nodule localization injection gel of this embodiment, the decellularized porcine skin matrix solution grafted with dopamine groups and the oxidized hyaluronic acid solution are mixed in equal proportions, and stirred thoroughly in the dark until no particles remain. Subsequently, it is injected into a mold with a recognition line and freeze-dried.

[0037] Specifically, the preparation process of the decellularized porcine skin matrix grafted with dopamine groups is as follows:

[0038] Purchase the dry hard porcine skin matrix sold online. Take 1.0 g and cut it into small pieces and place it in 9 mL of PBS. Place it under high temperature and high pressure conditions for 30 min, and then freeze-dry to obtain the treated decellularized porcine skin matrix for standby; to obtain the dopamine-modified decellularized porcine skin matrix, immerse the decellularized porcine skin matrix in 10 mmol / L Tris-HCl (pH = 8.5) containing hydrochloric acid dopamine (2 mg / mL), and stir at 40 rpm at room temperature for 12 h. Then, ultrasonically rinse it with deionized water 10 times (5 min each time), and freeze-dry it in a freeze-dryer for 48 h to obtain the decellularized porcine skin matrix grafted with dopamine groups; among them, the grafting rate of the decellularized porcine skin matrix grafted with dopamine groups is 15%;

[0039] The oxidized hyaluronic acid is purchased from Guangzhou Carbohydrate Technology Co., Ltd.;

[0040] The preparation method of the temperature- and pH-responsive pulmonary nodule localization injection gel of this embodiment includes the following steps:

[0041] S1: Dissolve 0.15 g of the decellularized porcine skin matrix grafted with dopamine groups in 5 mL of deionized water, and stir evenly in the dark until no residual particles, to obtain Solution A, and the solution concentration is 30 mg / mL;

[0042] S2: Dissolve 0.10 g of oxidized hyaluronic acid in 5 mL of deionized water, and stir and mix evenly in the dark until no residual particles, to obtain Solution B, and the solution concentration is 20 mg / mL;

[0043] S3: Mix solution A and B in equal volumes and stir them evenly under dark conditions to obtain solution C;

[0044] S4: Inject the solution C obtained in step S3 into a columnar mold (inner diameter 0.5 mm, height 10 mm) with an identification line placed therein; wherein, the identification line is a degradable collagen thread;

[0045] S5: Freeze-dry the gel obtained in step S4 at -50 °C and 0.2 mbar for 24 h to remove moisture. The dried bulk solid obtained after demolding is the temperature and pH dual-responsive pulmonary nodule localization injection gel required.

[0046] As Figure 1 shown, the SEM image of the pulmonary nodule localization injection gel of this embodiment shows that the prepared injection gel is a porous structure, which can well absorb the tissue fluid at the pulmonary nodule, and also proves the formation of the gel cross-linking network.

[0047] As Figure 2 shown, the physical photo of the pulmonary nodule localization injection gel of this embodiment shows that the pulmonary nodule localization injection gel is successfully prepared; the identification line is divided into an internal segment and an external segment. The internal segment is embedded in the pulmonary nodule localization injection gel, and the external segment is exposed outside the pulmonary nodule localization injection gel. The external segment is used for positioning and identification. The length of the external segment of the identification line is 60% of the length of the identification line, and it can be specifically determined between 10% and 90% according to actual application requirements.

[0048] Figure 3 shows the tensile force-displacement change curve of the pulmonary nodule localization injection gel and the moist tissue obtained through the lap shear experiment. The highest point in the figure is the fracture stress point, representing the maximum tensile force (F max ) and displacement when the gel material is pulled away from the lung tissue.

[0049] As Figure 4 shown, the adhesion strength of the pulmonary nodule localization injection gel of this embodiment is calculated by the maximum tensile stress F max / the contact area S between the gel and the lung tissue, and the result shows that its adhesion strength is as high as 46.51667 KPa.

[0050] The injection device of the pulmonary nodule localization injection gel of this embodiment is used to deliver the pulmonary nodule localization injection gel to the pulmonary nodule site; specifically, as Figure 5 and Figure 6As shown in the figure, the injection device includes a trocar 1, a positioning rod 2, and an injection piston handle 6. There is a scale 4 outside the trocar 1. The injection piston handle 6 is connected to the positioning rod 2 and is used to drive the positioning rod 2 to move towards the outlet end of the trocar 1. Among them, the cooperation structure between the injection piston handle 6 and the trocar 1 is similar to that of an existing syringe and will not be elaborated here; there is a bayonet 3 at the outlet end of the trocar 1, and there is a slot 7 at one end of the positioning rod 2 adjacent to the bayonet 3. The pulmonary nodule positioning injection gel 8 is placed in the bayonet 3 of the trocar 1, and the exposed section 9 of the identification line of the pulmonary nodule positioning injection gel 8 is embedded in the slot 7. Among them, the overall length of the trocar 1 is 10 - 20 cm, and the inner diameter is 1.0 - 3.0 mm. Preferably, a positioning rod knob 5 is provided outside the trocar 1 for cooperating with the scale 4 to indicate the injection stroke.

[0051] The usage method of the injection device in this embodiment is as follows: The trocar 1 is first punctured into the pulmonary nodule site, and then the positioning rod 2 injects and embeds the pulmonary nodule positioning injection gel into the pulmonary nodule site. After completing the pulmonary nodule injection positioning, the trocar 1 and the positioning rod 2 are pulled out together, and the gel with the identification line is positioned at the pulmonary nodule site.

[0052] Comparative Example 1:

[0053] The difference in the preparation method of the pulmonary nodule positioning injection gel in this comparative example from that of Example 1 is that no oxidized hyaluronic acid is added;

[0054] Specifically, steps S2 and S3 are omitted in the corresponding preparation method, that is, solution A is directly injected into a placed cylindrical mold with identification (inner diameter 0.5 mm, height 10 mm);

[0055] Other steps can refer to Example 1.

[0056] By performing compression tests and lap shear tests on the pulmonary nodule positioning injection gels of Comparative Example 1 and Example 1 respectively, it is obtained that the compression stresses of the pulmonary nodule positioning injection gels of Comparative Example 1 and Example 1 are 77.56 KPa and 257.13 KPa respectively, and the bonding strengths are 32.97431 KPa and 46.51667 KPa respectively. It can be seen that the mechanical properties and bonding strength of the pulmonary nodule positioning injection gel of Example 1 are significantly improved, which can not only prevent the pulmonary nodule positioning injection gel from breaking or deforming during injection and affecting pulmonary nodule positioning, but also improve the bonding with the pulmonary nodule to ensure the positioning accuracy.

[0057] Example 2:

[0058] The temperature and pH dual-responsive pulmonary nodule positioning injection gel in this embodiment is prepared by mixing dopamine-grafted silk fibroin and oxidized sodium alginate in different proportions, and stirring thoroughly in the dark until there are no particle residues, and then injecting it into a mold with an identification line for freeze-drying.

[0059] Specifically, the preparation process of dopamine-grafted silk fibroin is as follows:

[0060] Take 15 mg of dopamine hydrochloride and place it in 10 mL of sodium periodate solution (1 mg / mL), stir evenly to obtain a 1.5 mg / mL dopamine hydrochloride solution; then, add 200 mg of commercially available silk fibroin powder and stir and react at 40 °C for 2 h; after the reaction, extract the mixture, and dry the residue in an oven at 60 °C to obtain dopamine-grafted silk fibroin powder with a grafting rate of 20%;

[0061] The process for oxidizing sodium alginate is as follows:

[0062] First, dissolve 8 g of sodium alginate completely in 400 mL of pure water, and then obtain a 2.0% (w / v) ammonium alginate solution under vigorous stirring. Then, add a certain amount of NaIO4 and start the oxidation reaction at 25 °C to obtain oxidized sodium alginate. After the reaction lasts for 24 h, add an equimolar amount of ethylene glycol and stir for 0.5 h to reduce the excess periodate, thereby stopping the reaction. Then, put them into a dialysis bag with a molecular weight cut-off of 3500 and dialyze with deionized water for 3 days. Finally, obtain dry oxidized sodium alginate by freeze-drying;

[0063] The preparation method of the temperature- and pH-responsive lung nodule localization injection gel in this example includes the following steps:

[0064] S1: Dissolve 1.0 g of silk fibroin grafted with dopamine groups in 9 mL of deionized water, stir evenly in the dark without residual particles to obtain solution A, and the concentration of dopamine-grafted silk fibroin is 10 wt%;

[0065] S2: Dissolve 1.0 g of oxidized sodium alginate in 9 mL of deionized water, stir evenly in the dark without residual particles to obtain solution B, and the concentration of oxidized ammonium alginate solution is 10 wt%;

[0066] S3: Mix solution A and B in a ratio of 1:2, 2:1 or 1:1, stir evenly to obtain solution C;

[0067] S4: Inject the solution C obtained in step S3 into a columnar mold (inner diameter 0.5 mm, height 15 mm) placed with an identification line; among them, the identification line is a degradable collagen thread;

[0068] S5: Freeze-dry the gel obtained in step S4 at -70 °C and 0.1 mbar for 20 h to remove moisture, and the dry block solid obtained after demolding is the required injection material.

[0069] Example 3:

[0070] The temperature- and pH-responsive lung nodule positioning injection gel of this example is prepared by mixing mussel adhesive protein and aldehyde-modified hyaluronic acid in equal proportions, and stirring thoroughly in the dark until there are no particle residues, and then injecting it into a mold with an identification line for freeze-drying.

[0071] Among them, the mussel adhesive protein is purchased from Guangdong Yuantai Chemical Co., Ltd.

[0072] Specifically, the preparation process of aldehyde-modified hyaluronic acid is as follows:

[0073] Dissolve 2 g of hyaluronic acid in 100 mL of PBS solution (pH value 6), then add 2 mL of ethylene glycol and continue stirring for 3 h; finally, dialyze the mixture for three days (molecular weight: 3500), and then freeze-dry to obtain aldehyde-modified hyaluronic acid.

[0074] The preparation method of the temperature- and pH-responsive lung nodule positioning injection gel of this example includes the following steps:

[0075] S1: Dissolve 4.0 g of mussel adhesive protein in 6 mL of deionized water, stir evenly in the dark until there are no residue particles to obtain solution A, and the concentration of mussel adhesive protein is 40 wt%.

[0076] S2: Dissolve 1.0 g of aldehyde-modified hyaluronic acid in 9 mL of deionized water, stir evenly in the dark until there are no residue particles to obtain solution B, and the concentration of aldehyde-modified hyaluronic acid solution is 10 wt%.

[0077] S3: Mix solution A and B in a 1:1 ratio, and stir until uniform to obtain solution C.

[0078] S4: Inject the solution C obtained in step S3 into a columnar mold (inner diameter 1.0 mm, height 15 mm) with an identification line placed in it; among them, the identification line is a degradable collagen thread.

[0079] S5: Freeze-dry the gel obtained in step S4 at -60 °C and 0.3 mbar for 22 h to remove moisture, and the dry block solid obtained after demolding is the required lung nodule positioning injection gel.

[0080] Example 4:

[0081] The temperature- and pH-responsive lung nodule positioning injection gel of this example is prepared by mixing dopamine-modified collagen and aldehyde-modified hyaluronic acid in different proportions, and stirring thoroughly in the dark until there are no particle residues, and then injecting it into a mold with an identification line for freeze-drying.

[0082] Among them, the preparation method of dopamine-modified collagen is as follows:

[0083] After dissolving dopamine hydrochloride (2 mg / mL) in 10 mM Tris-HCl (pH 8.5), collagen was immersed in the oxygen-containing solution to be modified in a horizontal rotation mode (50 rpm, 12 h) at room temperature. Then, the sample was ultrasonically rinsed with deionized water 10 times (5 min each time), and the irradiated and sterilized clean pDA-CSS was sealed and stored in phosphate buffer saline PBS, and then freeze-dried in a freeze dryer for 48 h to obtain dopamine-grafted modified collagen.

[0084] The preparation process of aldehyde-modified hyaluronic acid can refer to Example 3;

[0085] The preparation method of the temperature- and pH-responsive lung nodule positioning injection gel in this example includes the following steps:

[0086] S1: Dissolve 1.0 g of dopamine-modified collagen in 9 mL of deionized water, stir evenly in the dark without residual particles to obtain Solution A, and the concentration of dopamine-modified collagen is 10 wt%;

[0087] S2: Dissolve 1.0 g of aldehyde-modified hyaluronic acid in 9 mL of deionized water, stir and mix evenly in the dark without residual particles to obtain Solution B, and the concentration of aldehyde-modified hyaluronic acid is 10 wt%;

[0088] S3: Mix Solution A and B in a 1:1 ratio and stir until uniform to obtain Solution C;

[0089] S4: Inject Solution C obtained in Step S3 into a columnar mold (inner diameter 1.5 mm, height 20 mm) placed with an identification line; among them, the identification line is a degradable collagen thread;

[0090] S5: Freeze-dry the gel obtained in Step S4 at -65 °C and 0.5 mbar for 30 h to remove moisture, and the dried block solid obtained after demolding is the required lung nodule positioning injection gel.

[0091] Example 5:

[0092] The temperature- and pH-responsive lung nodule positioning injection gel in this example is prepared by mixing mussel adhesive protein and oxidized hyaluronic acid in equal proportions, stirring thoroughly in the dark until there are no particle residues, and then injecting them into a mold with an identification line for freeze-drying.

[0093] Among them, mussel adhesive protein is purchased from Guangdong Yuantai Chemical Co., Ltd., and oxidized hyaluronic acid is purchased from Guangzhou Carbohydrate Technology Co., Ltd.;

[0094] The preparation method of the temperature- and pH-responsive lung nodule positioning injection gel in this example includes the following steps:

[0095] S1: Dissolve 3.0 g of mussel adhesive protein in 7 mL of deionized water, stir evenly in the dark without residual particles to obtain solution A, and the concentration of mussel adhesive protein is 30%;

[0096] S2: Dissolve 1.0 g of oxidized hyaluronic acid in 9 mL of deionized water, stir evenly in the dark without residual particles to obtain solution B, and the concentration of oxidized hyaluronic acid is 10 wt%;

[0097] S3: Mix solution A and B in a ratio of 1:1, and stir until homogeneous to obtain solution C;

[0098] S4: Inject solution C obtained in step S3 into a cylindrical mold (inner diameter 1.5 mm, height 20 mm) with an identification line; among them, the identification line is a degradable collagen thread;

[0099] S5: Freeze-dry the gel obtained in step S4 at -55 °C and 0.4 mbar for 25 h to remove moisture, and the dried block solid obtained after demolding is the required lung nodule localization injection gel.

[0100] In view of the large number of embodiments of the present invention, the raw materials and dosages involved can be selected according to actual needs within the limited range. The experimental data of each embodiment are huge and numerous, and it is not suitable to list them one by one here. However, the content to be verified and the final conclusions obtained in each embodiment are similar. Therefore, the verification content of each embodiment will not be described one by one here.

[0101] The above is only a detailed description of the preferred embodiments and principles of the present invention. For those of ordinary skill in the art, according to the idea provided by the present invention, there will be changes in the specific implementation manners, and these changes should also be regarded as the protection scope of the present invention.

Claims

1. A method for preparing a temperature and pH dual-responsive pulmonary nodule localization injection gel, characterized in that: The following steps are involved: Under light-proof conditions, a water-soluble macromolecular protein containing a dopamine group, an amino group and a carboxyl group is dissolved in water to obtain a solution 1; Under light-proof conditions, dissolving the aldehyde-containing water-soluble high molecular polymer in water to obtain solution 2; Under light-proof conditions, solution 1 and solution 2 were mixed and poured into a columnar mold with identification lines, followed by freeze drying and demolding to obtain a pulmonary nodule localization injection gel; Among them, the identification line is divided into an embedded segment and an exposed segment. The embedded segment is embedded in the lung nodule positioning injection gel, and the exposed segment is exposed outside the lung nodule positioning injection gel. The exposed segment is used for positioning and identification.

2. The preparation method according to claim 1, characterized in that: The water-soluble macromolecular protein containing dopamine groups, amino groups and carboxyl groups is selected from mussel mucin, dopamine-modified silk protein, dopamine-modified collagen, dopamine-modified polylysine and dopamine-modified decellularized pig skin matrix.

3. The preparation method according to claim 2, characterized in that: The water-soluble macromolecular protein containing dopamine groups, amino groups and carboxyl groups is selected from dopamine-modified silk fibroin, dopamine-modified collagen, dopamine-modified polylysine and dopamine-modified decellularized pig skin matrix; wherein the grafting rate of dopamine modification is 10-30%.

4. The preparation method according to claim 1, characterized in that: The aldehyde-containing water-soluble high molecular polymer is selected from one of aldehyde-modified hyaluronic acid, oxidized hyaluronic acid, oxidized sodium alginate and oxidized dextran.

5. The preparation method according to claim 1, characterized in that: The identification line is a degradable collagen line.

6. The preparation method according to any one of claims 1 to 5, characterized in that: The freeze drying process is performed at a pressure of 0.1 to 0.5 mbar, a temperature of -70 to -50°C, and a time of 20 to 30 hours.

7. The preparation method according to any one of claims 1 to 5, characterized in that: The inner diameter of the columnar mold is 0.5-2 mm, and the height is 10-50 mm.

8. The pulmonary nodule localization injection gel obtained by the preparation method according to any one of claims 1 to 7.

9. The pulmonary nodule localization injection gel according to claim 7, characterized in that: The length of the exposed section of the identification line is 10 to 90% of the length of the identification line.

10. The injection device for locating and injecting gel for lung nodules according to claim 8 or 9, characterized in that: The invention comprises a trocar and an injection piston and a positioning rod arranged in the inner cavity of the trocar. The injection piston is used to drive the positioning rod to move toward the outlet end of the trocar. The outlet end of the trocar has a bayonet, and a lung nodule positioning injection gel is arranged in the bayonet. The positioning rod has a slot at one end adjacent to the bayonet, and the exposed section of the identification line of the lung nodule positioning injection gel is embedded in the slot.

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