Stimulus-responsive hydrogel-based variable-stiffness chest drainage tube and its preparation method

Abstract

This application relates to the field of biomedical polymer materials technology, and discloses a variable-rigidity chest drainage tube based on a stimulus-responsive hydrogel and its preparation method. The variable-rigidity chest drainage tube comprises an interpenetrating network hydrogel, which includes: a chitin first network, prepared by phase inversion from a chitin solution with a mass percentage concentration of 1.5-4.0%; and a polyacrylamide second network, formed by polymerizing a second network precursor solution in the first network. The second network precursor solution comprises: 15-30% w / v acrylamide; 0.1-1.0% w / AAm N,N'-methylenebisacrylamide; and 0.5-2.0% w / AAm ammonium persulfate. This invention utilizes the reversible reconstruction mechanism of hydrogen bonds between the chitin and polyacrylamide networks to maintain high rigidity of the drainage tube before insertion and transform it into high flexibility after placement in body fluid, thus solving the patient discomfort and tissue damage risks caused by excessive rigidity of silicone tubes.

Description

Technical Field

[0001] This invention relates to the field of biomedical polymer materials technology, specifically to a variable-hardness chest drainage tube based on stimulus-responsive hydrogel and its preparation method. Background Technology

[0002] A chest drainage tube is an essential medical device used after thoracic surgery. It is inserted into the patient's chest cavity to drain postoperative fluid and air, helping the lungs to re-expand. Successful insertion and subsequent placement of the drainage tube directly impact the patient's recovery process. However, there is an inherent contradiction in the physical requirements of drainage tubes in clinical practice: sufficient rigidity is needed during insertion, while sufficient flexibility is required when left in place.

[0003] Currently, silicone drainage tubes are mainly used in clinical practice. Silicone material possesses excellent chemical stability and mechanical strength. This high strength and rigidity provide the necessary support for the doctor's insertion operation, ensuring that the tube can overcome tissue resistance, be accurately placed in the intended position, and maintain patency of the lumen. On the other hand, traditional hydrogel materials are also being studied due to their high water content and tissue-like softness, which give them excellent biocompatibility.

[0004] The limitation of existing technologies lies in their inability to reconcile the aforementioned contradictions. The constant high rigidity of silicone tubing is both an advantage and a disadvantage. Once inserted into the body, this rigidity continuously compresses and rubs against the pleura and intercostal tissues, causing severe pain, especially when the patient breathes or coughs, and may even lead to tissue damage. Traditional soft hydrogels, while offering high comfort, have insufficient mechanical strength to withstand the axial pressure during insertion, making them prone to bending and causing operational failure. To address this issue, while there have been attempts to develop stimulus-responsive hydrogels (such as alginate systems), the hardness transformation rate of these materials is limited. Either the stiffness in the hard state is insufficient to support insertion, or the soft state remains too rigid, resulting in minimal improvement in comfort and failing to truly resolve the clinical dilemma. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention provides a variable-hardness chest drainage tube based on stimulus-responsive hydrogel and its preparation method, thereby resolving the technical contradiction in existing technologies where the insertion rigidity of the drainage tube material cannot be balanced with the flexibility and comfort of in-vivo placement, as well as the problem of insufficient hardness transformation ratio of existing stimulus-responsive materials.

[0006] To achieve the above objectives, the present invention provides the following technical solution:

[0007] In a first aspect, the present invention provides a variable-stiffness chest drainage tube based on a stimulus-responsive hydrogel, the variable-stiffness chest drainage tube comprising an interpenetrating network hydrogel, the interpenetrating network hydrogel comprising:

[0008] A first chitin network, which is prepared by phase inversion from a chitin solution with a mass percentage concentration of 1.5-4.0%;

[0009] A second polyacrylamide network, formed by polymerizing a second network precursor solution in a first network, the second network precursor solution comprising:

[0010] Acrylamide at 15-30% w / v;

[0011] 0.1-1.0% w / AAm of N,N'-methylenebisacrylamide;

[0012] Ammonium persulfate of 0.5-2.0% w / AAm.

[0013] By employing the above technical solution, this invention constructs an interpenetrating network hydrogel based on reversible hydrogen bond reconstruction. The principle behind its variable hardness lies in:

[0014] Network composition: The interpenetrating network hydrogel consists of hydrogen-rich donors and acceptors (such as hydroxyl groups). amino The first network of chitin and rich in amide groups () It consists of a second network of polyacrylamide.

[0015] Rigid State (Pre-Intubation): During pretreatment in specific solvent environments (such as ethanol-water solutions), the solvent induces the formation of strong hydrogen bonds between polymer chains, mainly manifested as polymer-polymer hydrogen bonds between chitosan and chitosan-polyacrylamide. These dense hydrogen bonds act as strong physical cross-linking points, greatly restricting the movement of polymer chains, giving the hydrogel tubing a rigid state with high modulus and high hardness, thus meeting the stiffness required for clinical insertion procedures.

[0016] Flexible state (post-insertion): After the drainage tube is inserted into the human thoracic cavity, it comes into contact with body fluids (mainly water), and the environment changes. Water molecules, as strong hydrogen bond competitors, will quickly penetrate into the interior of the hydrogel network.

[0017] Hydrogen bond reconstruction: After water molecules penetrate, they competitively break the original polymer-polymer hydrogen bonds and form polymer-water hydrogen bonds instead. This hydrogen bond reconstruction process releases the original physical cross-linking constraints, releases the mobility of polymer chain segments, causes the hydrogel network to swell, and transforms the tube from a rigid state to a soft state with low modulus and high flexibility, thereby significantly improving patient comfort during drainage and reducing tissue damage.

[0018] Therefore, this invention utilizes an interpenetrating network constructed from chitin and polyacrylamide, and a solvent-induced reversible hydrogen bond reconstruction mechanism, to enable the drainage tube to possess both rigidity during insertion and flexibility within the body.

[0019] Preferably, the first network is prepared from a chitin solution with a mass percentage concentration of 2.0%; the second network precursor solution comprises: 20% w / v acrylamide; 0.5% w / AAm N,N'-methylenebisacrylamide; and 1.0% w / AAm ammonium persulfate. This formulation allows the hydrogel to achieve balanced mechanical properties and rapid response characteristics.

[0020] Preferably, the chitin solution uses a 1-butyl-3-methylimidazolium chloride ionic liquid as a solvent. This ionic liquid has excellent solubility for chitin and is the basis for preparing a uniform, high-strength chitin first network.

[0021] Preferably, the wall thickness of the variable stiffness chest drainage tube is 1.0-3.0 mm. This thickness range provides sufficient structural support for the tube and ensures rapid and complete stimulus response.

[0022] Secondly, the present invention provides a method for preparing a variable-stiffness chest drainage tube based on stimulus-responsive hydrogel, using the following technical solution:

[0023] A method for preparing a variable-stiffness chest drainage tube based on stimulus-responsive hydrogel includes the following steps:

[0024] S1. Dissolve chitin powder in an ionic liquid to obtain a chitin solution;

[0025] S2. The chitin solution is injected into a mold and phase-inverted in deionized water to obtain chitin hydrogel tubes, i.e., the first network.

[0026] S3. Prepare an impregnation solution containing acrylamide, N,N'-methylenebisacrylamide and ammonium persulfate;

[0027] S4. The first network is immersed in the impregnation liquid, and then thermal polymerization is carried out to form a second polyacrylamide network in the first network;

[0028] S5. The polymerized product is washed to obtain the variable stiffness chest drainage tube.

[0029] By employing the above technical solution, this invention provides a clear and controllable two-step method for constructing interpenetrating networks. First, through steps S1 and S2, a chitin first network with a stable three-dimensional network structure is prepared using a phase inversion method. Then, through steps S3 and S4, the precursor solution of the second network permeates into the framework of the first network and initiates polymerization in situ, forming an interpenetrating network structure with interwoven polymer chains and topological interlocking. The cleaning step in S5 ensures the biocompatibility of the final product. This method has clear process steps and controllable conditions, and can reliably prepare dual-network hydrogel tubing with the aforementioned stimulus-responsive characteristics.

[0030] Preferably, in step S1, the dissolution temperature is 80-110℃, and the dissolution time is 4-12 hours. By adopting the above technical solution, this combination of temperature and time range can effectively destroy the crystal structure of chitin while ensuring that the chitin polymer chain does not undergo significant degradation, thereby achieving its dissolution in ionic liquid and laying the foundation for the formation of a uniform first network.

[0031] Preferably, in step S1, the dissolution is carried out under mechanical stirring conditions at a stirring speed of 200-600 rpm. Chitosan forms a high-viscosity solution in ionic liquids. Mechanical stirring within this speed range provides sufficient shear force to overcome mass transfer resistance, ensuring uniform dispersion and complete dissolution of the chitosan powder, preventing local aggregation, and thus obtaining a homogeneous, defect-free chitosan solution.

[0032] Preferably, in step S2, the phase transformation time is 24-72 hours. This time range ensures that the exchange process between the ionic liquid solvent and the deionized water non-solvent is completed, allowing the chitin polymer chains to fully rearrange and form a stable physical cross-linked network structure. At the same time, it ensures that the ionic liquid in the mold is fully replaced, ensuring that the first network is completely formed.

[0033] Preferably, in step S4, the immersion is carried out at 4°C for 24-48 hours. By adopting the above technical solution, the low temperature environment of 4°C can effectively inhibit the activity of the initiator and prevent premature polymerization of the second network precursor solution during the immersion process; at the same time, the immersion time of 24-48 hours ensures that the components (monomer, crosslinking agent, initiator) in the impregnation solution can be uniformly diffused and distributed in the internal pores of the chitin first network.

[0034] Preferably, in step S4, the thermal polymerization is carried out at a temperature of 60-80°C for 3-6 hours. This temperature range is within the effective activity range of the ammonium persulfate thermal initiator, ensuring a stable polymerization reaction; the polymerization time of 3-6 hours ensures the complete reaction and cross-linking of acrylamide monomers within the first network, while avoiding damage to the hydrogel structure of the first network that may be caused by prolonged heating.

[0035] This invention provides a variable-stiffness chest drainage tube based on stimulus-responsive hydrogel and its preparation method. It has the following beneficial effects:

[0036] 1. This invention utilizes the reversible reconstruction mechanism of hydrogen bonds between chitin and polyacrylamide networks to maintain high rigidity of the drainage tube before insertion and transform it into high flexibility after being placed in body fluid. Unlike traditional silicone tubes, which have constant hardness and are prone to compressing tissues in the body, this invention solves the problem of patient discomfort and tissue damage risk caused by excessive rigidity of silicone tubes.

[0037] 2. This invention uses a specific combination of chitin and polyacrylamide. This interpenetrating network structure achieves a significant modulus change. Compared with the existing technology that uses calcium alginate-polyacrylamide network, the hardness change is limited. This invention solves the technical problems of insufficient response rate and insignificant stiffness-flexibility transition effect of existing stimulus-responsive hydrogels.

[0038] 3. This invention constructs a topologically interlocked double-network hydrogel through a two-step method. Chitosan provides skeletal support, and polyacrylamide provides interpenetrating reinforcement, giving the pipe excellent comprehensive mechanical properties. The single-network hydrogel in the prior art has a simple structure, low mechanical strength, and brittle texture. This invention overcomes the defects of single-network hydrogels, such as poor mechanical properties and inability to be used as molded pipes. Detailed Implementation

[0039] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments.

[0040] The main raw materials and reagents used in the following examples and comparative examples have the following sources and specifications. Reagents not specifically mentioned are all commercially available analytical grade or higher grade products.

[0041] Chitosan, CAS No.: 1398-61-4, is a natural linear polysaccharide, which is a white or pale yellow powder with a degree of deacetylation (DD) of less than 10% and a particle size that passes through a 100-mesh sieve.

[0042] 1-Butyl-3-methylimidazolium chloride, CAS No.: 79917-90-1, is used as a non-derivative solvent for chitin.

[0043] Acrylamide, CAS No.: 79-06-1.

[0044] N,N'-Methylenebisacrylamide, CAS No.: 110-26-9.

[0045] Ammonium persulfate, also known as APS, CAS number: 7727-54-0.

[0046] Example 1:

[0047] This embodiment provides a variable-stiffness chest drainage tube based on a stimulus-responsive hydrogel and its preparation method, including the following steps:

[0048] (1) Preparation of chitin solution: Weigh 2.0g of chitin powder and add it to 98.0g of 1-butyl-3-methylimidazolium chloride ionic liquid. The mixture is heated for 6 hours under mechanical stirring at 90℃ and 300rpm until a uniform, transparent viscous solution is formed, and a chitin solution with a mass percentage concentration of 2.0% is obtained.

[0049] (2) First network formation: The chitin solution prepared in step (1) is injected into a concentric cylindrical mold (the gap between the mold jackets, i.e. the wall thickness, is 2.0 mm). Then the whole mold is immersed in a large amount of deionized water and left to stand for 24 hours to carry out phase transformation.

[0050] (3) Demolding and cleaning: Remove the formed tubular hydrogel from the mold and soak it in deionized water for 48 hours. Replace the deionized water every 6 hours during this period to fully remove the ionic liquid and obtain chitin hydrogel tubes (first network).

[0051] (4) Preparation of impregnation solution: Using deionized water as solvent, prepare an impregnation solution containing 20% ​​(w / v) acrylamide, 0.5% (w / AAm) N,N'-methylenebisacrylamide and 1.0% (w / AAm) ammonium persulfate.

[0052] (5) Impregnation and polymerization: Immerse the chitin hydrogel tube prepared in step (3) in the impregnation solution prepared in step (4) and soak it at 4°C in the dark for 24 hours. Take out the fully soaked hydrogel tube, remove the excess liquid on the surface and seal it quickly. Place it in a constant temperature water bath at 70°C for thermal polymerization for 4 hours (this step forms a second network in the first network).

[0053] (6) Preparation of finished product: After the polymerization reaction is completed, the sample is taken out and soaked in deionized water for 48 hours. During this period, the water is changed several times to remove residual monomers and initiators, and the variable hardness chest drainage tube based on stimulus-responsive hydrogel of Example 1 is obtained.

[0054] Example 2:

[0055] This embodiment provides a variable-stiffness chest drainage tube based on a stimulus-responsive hydrogel and its preparation method, including the following steps:

[0056] (1) Preparation of chitin solution: Weigh 1.5g of chitin powder and add it to 98.5g of 1-butyl-3-methylimidazolium chloride ionic liquid. The mixture is heated at 80℃ and 200rpm for 12 hours to obtain a chitin solution with a mass percentage concentration of 1.5%.

[0057] (2) First network forming: The chitin solution prepared in step (1) is injected into a concentric cylindrical mold (the wall thickness is 1.0 mm), and then the whole mold is immersed in a large amount of deionized water and left to stand for 72 hours.

[0058] (3) Demolding and cleaning: Remove the formed tubular hydrogel from the mold and soak it in deionized water for 48 hours, changing the deionized water every 6 hours to obtain chitin hydrogel tubes.

[0059] (4) Preparation of impregnation solution: Using deionized water as solvent, prepare an impregnation solution containing 15% (w / v) acrylamide, 0.1% (w / AAm) N,N'-methylenebisacrylamide and 0.5% (w / AAm) ammonium persulfate.

[0060] (5) Impregnation and polymerization: Immerse the chitin hydrogel tube prepared in step (3) in the impregnation solution prepared in step (4) and soak it at 4°C in the dark for 36 hours. Take out the fully soaked hydrogel tube, remove the excess liquid on the surface and seal it quickly. Then place it in a constant temperature water bath at 60°C for thermal polymerization for 6 hours.

[0061] (6) Preparation of finished product: After the polymerization reaction is completed, the sample is taken out and soaked in deionized water for 48 hours, during which the water is changed several times to obtain the variable hardness chest drainage tube based on stimulus-responsive hydrogel in Example 2.

[0062] Example 3:

[0063] This embodiment provides a variable-stiffness chest drainage tube based on a stimulus-responsive hydrogel and its preparation method, including the following steps:

[0064] (1) Preparation of chitin solution: Weigh 4.0g of chitin powder and add it to 96.0g of 1-butyl-3-methylimidazolium chloride ionic liquid. The mixture is heated for 4 hours under mechanical stirring at 110℃ and 600rpm to obtain a chitin solution with a mass percentage concentration of 4.0%.

[0065] (2) First network forming: The chitin solution prepared in step (1) is injected into a concentric cylindrical mold (the wall thickness is 3.0 mm), and then the whole mold is immersed in a large amount of deionized water and left to stand for 24 hours.

[0066] (3) Demolding and cleaning: Remove the formed tubular hydrogel from the mold and soak it in deionized water for 48 hours, changing the deionized water every 6 hours to obtain chitin hydrogel tubes.

[0067] (4) Preparation of impregnation solution: Using deionized water as solvent, prepare an impregnation solution containing 30% (w / v) acrylamide, 1.0% (w / AAm) N,N'-methylenebisacrylamide and 2.0% (w / AAm) ammonium persulfate.

[0068] (5) Impregnation and polymerization: Immerse the chitin hydrogel tubes prepared in step (3) in the impregnation solution prepared in step (4) and soak them at 4°C in the dark for 48 hours. Take out the fully soaked hydrogel tubes, remove the excess liquid from the surface, seal them quickly, and place them in an 80°C constant temperature water bath for thermal polymerization for 3 hours.

[0069] (6) Preparation of finished product: After the polymerization reaction is completed, the sample is taken out and soaked in deionized water for 48 hours, during which the water is changed several times to obtain the variable hardness chest drainage tube based on stimulus-responsive hydrogel in Example 3.

[0070] Example 4:

[0071] This embodiment provides a variable-stiffness chest drainage tube based on a stimulus-responsive hydrogel and its preparation method, including the following steps:

[0072] (1) Preparation of chitin solution: Same as step (1) in Example 1, to obtain a chitin solution with a mass percentage concentration of 2.0%.

[0073] (2) First network forming: Same as step (2) in Example 1.

[0074] (3) Demolding and cleaning: Same as step (3) in Example 1.

[0075] (4) Preparation of impregnation solution: Using deionized water as solvent, prepare an impregnation solution containing 15% (w / v) acrylamide, 0.5% (w / AAm) N,N'-methylenebisacrylamide and 1.0% (w / AAm) ammonium persulfate.

[0076] (5) Impregnation and polymerization: Same as step (5) in Example 1.

[0077] (6) Preparation of finished product: Same as step (6) of Example 1, to obtain the variable hardness chest drainage tube based on stimulus-responsive hydrogel of Example 4.

[0078] Example 5:

[0079] This embodiment provides a variable-stiffness chest drainage tube based on a stimulus-responsive hydrogel and its preparation method, including the following steps:

[0080] (1) Preparation of chitin solution: Same as step (1) in Example 1, to obtain a chitin solution with a mass percentage concentration of 2.0%.

[0081] (2) First network forming: Same as step (2) in Example 1.

[0082] (3) Demolding and cleaning: Same as step (3) in Example 1.

[0083] (4) Preparation of impregnation solution: Using deionized water as solvent, prepare an impregnation solution containing 20% ​​(w / v) acrylamide, 1.0% (w / AAm) N,N'-methylenebisacrylamide and 1.0% (w / AAm) ammonium persulfate.

[0084] (5) Impregnation and polymerization: Same as step (5) in Example 1.

[0085] (6) Preparation of finished product: Same as step (6) of Example 1, to obtain the variable hardness chest drainage tube based on stimulus-responsive hydrogel of Example 5.

[0086] Comparative Example 1:

[0087] The difference between this comparative example and Example 1 is that only steps (1) (preparation of chitin solution), (2) (first network molding) and (3) (demolding and cleaning) of Example 1 are performed, and subsequent steps (4), (5) and (6) are omitted to obtain the chitin hydrogel tube of Comparative Example 1.

[0088] Comparative Example 2:

[0089] The difference between this comparative example and Example 1 is that steps (1), (2) and (3) are omitted; the impregnation solution prepared in step (4) of Example 1 is directly injected into the concentric cylindrical mold used in step (2) of Example 1, and the thermal polymerization in step (5) and the finished product preparation in step (6) are directly performed to obtain the pure polyacrylamide hydrogel tube of Comparative Example 2.

[0090] Comparative Example 3:

[0091] This comparative example is a comparison with existing technology. The sample used was a commercially available medical-grade silicone chest drainage tube, whose diameter and wall thickness were basically the same as those of the drainage tube sample prepared in Example 1.

[0092] Comparative Example 4:

[0093] The difference between this comparative example and Example 1 is that steps (1) and (2) are not performed, but are replaced with the following steps: a 2.0% (w / v) sodium alginate aqueous solution is prepared and injected into the concentric cylindrical mold used in step (2) of Example 1. The mold is then immersed in a 1.0M calcium chloride solution for crosslinking for 2 hours to obtain a calcium alginate hydrogel tube. The remaining subsequent steps (3) to (6) are the same as in Example 1.

[0094] Test Example 1:

[0095] This test example verifies the reversible change in the elastic modulus of the thoracic drainage tube sample prepared in Example 1 under different solvent environments. The test used a universal testing machine (equipped with a compression testing module), physiological saline (0.9% NaCl solution), and 75% (v / v) ethanol aqueous solution.

[0096] Experimental steps:

[0097] 1. Take the drainage tube sample prepared in Example 1 and stored in deionized water, and use a cutting mold to prepare 5 cylindrical test samples of the same size (e.g., 10 mm in diameter and 5 mm in height), numbered S1-1, S1-2, S1-3, S1-4, and S1-5.

[0098] 2. Immerse five samples in physiological saline and equilibrate at a constant temperature of 25°C for 24 hours to allow them to reach a fully swollen initial soft state. Remove each sample individually, wipe off surface moisture with a non-woven fabric, and place them on the platform of a universal testing machine. Set the compression rate (e.g., 1 mm / min), apply a strain of 0-10%, record the stress-strain curve, and calculate the elastic modulus within the strain range of 0-5%, which is recorded as the initial soft-state elastic modulus.

[0099] 3. Subsequently, the above samples were immersed in a 75% (v / v) ethanol aqueous solution and treated at 25°C for 10 minutes to convert them into a hard state. Each sample was removed and immediately placed on the platform of a universal testing machine. A compression test was performed using the same parameters as the initial soft state test, and its elastic modulus was calculated and recorded as the hard state elastic modulus.

[0100] 4. Finally, the hardened samples after testing were re-immersed in a large amount of fresh physiological saline and equilibrated at a constant temperature of 25°C for 24 hours to allow them to recover to a soft state. Each sample was then removed and subjected to compression testing using the same parameters as the initial soft-state test. The elastic modulus was calculated and recorded as the recovered soft-state elastic modulus.

[0101] The experimental data are shown in Table 1 below.

[0102] Table 1: Elastic modulus test data of the sample in Example 1 under different treatment conditions

[0103]

[0104] Conclusion: The data from Test Example 1 (as shown in Table 1) verified the reversible hardness adjustment function of the material prepared in Example 1.

[0105] The material exhibits an average elastic modulus of approximately 75.5 MPa in its initial soft state (immersed in physiological saline). This state corresponds to full hydration of the material, where the chitin and polyacrylamide polymer chains form a dynamic hydrogen bond network with water molecules, resulting in high chain segment freedom of movement and the material's flexibility.

[0106] When the material was treated with a 75% ethanol solution, its elastic modulus increased to approximately 302.4 MPa, the average value in the hard state, an increase of nearly four times. The mechanism behind this phenomenon is that ethanol, as a poor solvent, disrupts the hydration between the polymer chains and water molecules, promoting the formation of dense intermolecular hydrogen bonds between the hydroxyl groups on the chitin chains and the amide groups on the polyacrylamide chains. This reconstruction of the supramolecular network restricts chain segment movement, thus increasing the material's stiffness.

[0107] When the hard material was placed back into saline solution, its elastic modulus recovered to 75.3 MPa (mean), which is essentially consistent with the initial soft state value. This demonstrates the non-covalent and reversible nature of the process: water molecules permeate and competitively disrupt the hydrogen bonds between polymers, restoring the material to its hydrated and flexible state. This test data confirms that the present invention (Example 1), through solvent replacement, enables the material to achieve a wide range of reversible switching between soft and hard states.

[0108] Test Example 2:

[0109] This test example was used to examine the rate of hardness change of the thoracic drainage tube prepared in Example 1 under varying solvent conditions, i.e., the hardening rate and softening rate. The elastic modulus of the sample at different treatment time points was measured using a universal testing machine.

[0110] Experimental steps:

[0111] 1. Take the soft hydrogel tube prepared in Example 1 and cut it into test strips of the same specifications (size as in Example 1). Randomly divide them into two groups, A and B. Group A is used for hardening kinetics test, and the initial state is a soft state after physiological saline equilibrium; Group B is used for softening kinetics test, and is pre-soaked in 75% ethanol solution for 24 hours to ensure that it reaches a completely hardened equilibrium state.

[0112] 2. For Group A tests, the samples were simultaneously immersed in a 75% (v / v) ethanol aqueous solution. One sample was removed at immersion times of 1 minute, 2 minutes, 5 minutes, and 10 minutes, the surface liquid was immediately wiped dry, and a compression test was performed. The elastic modulus was recorded. The data at 0 minutes was taken as the initial soft-state average value from Test Example 1.

[0113] 3. For Group B tests, the fully hardened samples were simultaneously immersed in physiological saline at 37°C (simulating body temperature). One sample was removed at immersion times of 1 minute, 5 minutes, 10 minutes, and 30 minutes for compression testing, and the elastic modulus was recorded. The data at 0 minutes was taken as the average value of the hardened state in Test Example 1.

[0114] The experimental data are shown in Table 2 below.

[0115] Table 2: Data on the change of elastic modulus of the sample in Example 1 during solvent conversion process over time.

[0116]

[0117] Note: "-" indicates that no sampling test was set at this time point.

[0118] Conclusion: The data in Table 2 show the response kinetics of the material of the present invention under solvent stimulation.

[0119] During the hardening process (Group A), the material exhibited rapid response characteristics. After immersion in a 75% ethanol solution, the elastic modulus jumped from 75.5 MPa to 182.3 MPa within 1 minute, an increase of over 140%; at 2 minutes, the modulus reached 245.1 MPa, providing sufficient stiffness for surgical puncture; and after 5 minutes, the modulus approached its equilibrium value. This rapid hardening characteristic is attributed to the rapid diffusion of small ethanol molecules within the gel network. Ethanol quickly replaces free water in the network, inducing the formation of high-density hydrogen bonds between chitin and polyacrylamide segments, leading to a denser network structure. In clinical practice, medical staff only need to perform a short preoperative immersion to complete the hardening preparation.

[0120] During the softening process (Group B), the material exhibited a gradual decrease in modulus in 37°C saline. The modulus decrease was relatively small in the first minute (approximately 4.2%), maintaining high stiffness; at 5 minutes, the modulus dropped to 210.4 MPa, still retaining some support; by 30 minutes, the modulus had decreased to 78.5 MPa, essentially returning to its initial soft state. The phenomenon of the softening rate being lower than the hardening rate is due to the energy barrier that external water molecules need to overcome to disrupt the already formed dense hydrogen bond network, and the dense structure hindering water molecule penetration. This kinetic characteristic has practical application value: in the initial stage of drainage tube insertion into the pleural cavity (within 1-5 minutes), the tube can maintain sufficient rigidity to resist tissue resistance, preventing kinking or curling; as the insertion time increases, the tube gradually softens to conform to the tissue, reducing mechanical stimulation to the pleura and lung tissue.

[0121] Test Example 3:

[0122] This test case is used to evaluate whether the elastic modulus of the chest drainage tube sample prepared in Example 1 remains stable after undergoing multiple transitions between a soft state (physiological saline) and a hard state (ethanol solution).

[0123] Experimental steps:

[0124] 1. Take the sample prepared in Example 1 (specifications same as in Test Example 1) and perform cyclic treatment. The cyclic steps are as follows: First, equilibrate the sample in physiological saline for 24 hours and test its soft elastic modulus using a universal testing machine; then, treat the same batch of samples in 75% (v / v) ethanol aqueous solution for 10 minutes and test its hard elastic modulus. This process is counted as one cycle.

[0125] 2. Repeat the above cycle 10 times. Record the soft and hard elastic modulus data measured in the 1st, 5th, and 10th cycles.

[0126] The experimental data are shown in Table 3 below.

[0127] Table 3: Data on the change of elastic modulus of the sample in Example 1 during cyclic testing

[0128]

[0129] Note: The data for the first iteration is taken from the mean of test case 1.

[0130] Conclusion: The cyclic test data in Table 3 show that the material in Example 1 has high performance stability.

[0131] After the 10th cycle, the retention rate of the soft elastic modulus (73.9 MPa) compared to the first cycle (75.5 MPa) was approximately 97.9%; the retention rate of the hard elastic modulus (295.5 MPa) compared to the first cycle (302.4 MPa) was approximately 97.7%. The data indicate that the material's fundamental modulus and response amplitude did not significantly decrease after multiple solvent-induced conversions.

[0132] This stability stems from the technical mechanism of this invention. The change in hardness depends on the formation and breaking of intermolecular hydrogen bonds between chitin and polyacrylamide segments, which is a physically reversible process. The interpenetrating network (IPN) structure formed by the underlying chitin first network and polyacrylamide second network is chemically stable and does not degrade or structurally break down during cycling.

[0133] Therefore, the hardness reversibility of this material is not an instantaneous function, but rather an ability to maintain its function through repeated use or environmental fluctuations, demonstrating its durability as a medical device material.

[0134] Test Example 4:

[0135] This test example is used to compare the performance differences in hardness (elastic modulus) and stimulus response range between the samples of Examples 1-5 of the present invention and the samples of Comparative Examples 1-4.

[0136] Experimental steps:

[0137] 1. Sample preparation: Hydrogel tubes were prepared according to the preparation methods of Examples 1-5, Comparative Examples 1, 2 and 4. Comparative Example 3 (silicone tube) used a commercially available medical-grade product.

[0138] 2. Sample preparation: Cut all samples (including Comparative Example 3) into cylindrical test samples of the same size (size same as Test Example 1).

[0139] 3. Soft state test: Place all samples in physiological saline (0.9% NaCl) and equilibrate at 25°C for 24 hours. Remove them and test their elastic modulus using a universal testing machine according to the parameters of Test Example 1. Record this as the soft state elastic modulus.

[0140] 4. Hardness Test: Place all the above samples in a 75% (v / v) ethanol aqueous solution and treat at 25°C for 10 minutes. Remove them and test their elastic modulus using a universal testing machine according to the parameters of Test Example 1. Record this as the hardness elastic modulus.

[0141] 5. Data Calculation: Calculate the ratio of the hard modulus to the soft modulus of each sample, and record it as the hardness change factor.

[0142] The experimental data are shown in Table 4 below.

[0143] Table 4: Comparison of soft / hard elastic modulus and change factor between the examples and comparative samples

[0144]

[0145] Conclusion: The data in Table 4 compare the performance differences between the proposed solution and different control groups.

[0146] The samples from Examples 1-5 of this invention all exhibited low elastic modulus (61.4-88.9 MPa) in the soft state (physiological saline solution) and high elastic modulus (203.5-452.7 MPa) in the hard state (ethanol solution). The change in hardness was greater than 3.3 times, with Example 3 reaching 5.09 times. This indicates that the dual-network structure of this invention effectively combines high-stiffness hard state and high-flexibility soft state.

[0147] The data from Comparative Example 1 (chitosan network only) (15.8 MPa) show that the mechanical strength of the single chitosan network is insufficient and there is no obvious hardening response in ethanol (magnification 1.35), demonstrating the necessity of the second network (polyacrylamide) for high strength and responsiveness.

[0148] Comparative Example 2 (polyacrylamide network only) had a modulus of only 103.8 MPa in the hard state, significantly lower than that of the Example. Although it also exhibited some hardening due to dehydration shrinkage in ethanol (magnification ratio 1.99), its stiffness in the hard state was insufficient to meet the requirements for catheter insertion. This demonstrates the importance of the first network (chitosan) as a key framework and hydrogen bonding site.

[0149] The modulus of Comparative Example 3 (silicone tubing) remained almost unchanged in both solvents (magnification 1.00), and its modulus (approximately 152 MPa) was constant. This is a typical non-responsive material that cannot be transformed into a soft state after implantation to improve patient comfort.

[0150] Comparative Example 4 (calcium alginate-polyacrylamide network), although also employing a dual-network structure and exhibiting responsiveness (rate of change 2.78), had significantly lower hard modulus (180.6 MPa) and rate of change compared to the embodiments of the present invention (such as 305.1 MPa and 4.00 times that of Example 1). This confirms the hydrogen bond reconstruction-based response mechanism between the chitin first network and the polyacrylamide second network, which possesses advantages not found in the calcium alginate-polyacrylamide system.

[0151] In summary, comparative tests have demonstrated that the chitosan-polyacrylamide interpenetrating network structure used in this invention is a necessary technical combination to achieve a wide range of hardness variations (hard-state stiffness and soft-state flexibility).

[0152] Test Example 5:

[0153] This test case is used to evaluate the in vitro cytotoxicity and blood compatibility of the material prepared in Example 1.

[0154] Experimental steps:

[0155] 1. In vitro cytotoxicity test (MTT method): The extraction method was used according to ISO 10993-5. The soft hydrogel tubes (sterilized) prepared in Example 1 were placed in DMEM cell culture medium and incubated at 37°C in a 5% CO2 incubator for 24 hours to prepare the material extract. L929 mouse fibroblasts were seeded at a certain density in 96-well plates and cultured for 24 hours. The original culture medium was discarded, and the medium was replaced with culture medium containing the material extract, a negative control (DMEM medium), and a positive control (DMEM medium containing phenol), respectively, and cultured for another 24 hours. Subsequently, MTT solution was added to each well, and cultured for another 4 hours. The supernatant was discarded, and formazan crystals were dissolved in dimethyl sulfoxide (DMSO). The absorbance (OD value) at 490 nm was measured using a microplate reader, and the relative cell proliferation rate (RGR) was calculated. RGR(%) = (OD_sample group / OD_negative control group) × 100%.

[0156] 2. Hemolysis rate test: Refer to ISO 10993-4 standard. Prepare anticoagulated whole blood from rabbits and dilute it with physiological saline. Take the soft hydrogel tubes (sterilized) from Example 1 and incubate them with the diluted rabbit blood in a constant temperature water bath at 37°C for 60 minutes. A negative control (physiological saline) and a positive control (distilled water) are also provided. After incubation, centrifuge immediately and collect the supernatant. Measure the absorbance (OD value) of the supernatant at 545 nm using a spectrophotometer and calculate the hemolysis rate. Hemolysis rate (%) = [(OD_sample group - OD_negative control group) / (OD_positive control group - OD_negative control group)] × 100%.

[0157] The experimental data are shown in Table 5 below.

[0158] Table 5: In vitro biocompatibility evaluation data of the samples from Example 1

[0159]

[0160] Conclusion: The data in Table 5 show that the material in Example 1 has good biocompatibility.

[0161] In the cytotoxicity test, the mean relative growth rate (RGR) of L929 cells treated with the extract of Example 1 was 96.0%, significantly higher than the non-toxic threshold of 75% RGR in the medical material standard. The positive control group (7.1%) demonstrated the effectiveness of the test system.

[0162] In the hemolysis test, the average hemolysis rate of the material in Example 1 was 1.35%, which is far lower than the 5% hemolysis standard for medical materials.

[0163] The above data confirms the biocompatibility of the material. This biocompatibility is attributed to the material system of this invention: chitin, as a natural polysaccharide, has a known biocompatibility basis; the polyacrylamide hydrogel network is chemically stable and highly bioinert. This invention physically entangles and fixes polyacrylamide within the chitin backbone through an interpenetrating network structure, combined with thorough soaking and cleaning during the preparation process (as in step 6 of Example 1), effectively reducing the potential dissolution risk of residual monomers or initiators, ensuring the material's cell compatibility and blood compatibility, and meeting the biocompatibility requirements for medical device applications.

Claims

1. An application of stimulus-responsive hydrogels in the fabrication of variable-stiffness chest drainage tubes, characterized in that, The variable-stiffness chest drainage tube comprises an interpenetrating hydrogel network capable of reversibly changing between a rigid and flexible state. The interpenetrating hydrogel network includes: A first chitin network, which is prepared by phase inversion from a chitin solution with a mass percentage concentration of 1.5-4.0%; A second polyacrylamide network, formed by polymerizing a second network precursor solution in a first network, the second network precursor solution comprising: Acrylamide at 15-30% w / v; 0.1-1.0% w / AAm of N,N'-methylenebisacrylamide; Ammonium persulfate at a concentration of 0.5-2.0% w / AAm; The method for preparing the variable stiffness chest drainage tube includes the following steps: S1. Dissolve chitin powder in an ionic liquid to obtain a chitin solution; S2. The chitin solution is injected into a mold and phase-inverted in deionized water to obtain chitin hydrogel tubes, i.e., the first network. S3. Prepare an impregnation solution containing acrylamide, N,N'-methylenebisacrylamide and ammonium persulfate; S4. The first network is immersed in the impregnation liquid, and then thermal polymerization is carried out to form a second polyacrylamide network in the first network; S5. The polymerized product is washed to obtain the variable stiffness chest drainage tube.

2. The application according to claim 1, characterized in that, The first network was prepared from a chitin solution with a mass percentage concentration of 2.0%; the second network precursor solution contained: 20% w / v acrylamide; 0.5% w / AAm of N,N'-methylenebisacrylamide; 1.0% w / AAm of ammonium persulfate.

3. The application according to claim 1, characterized in that, The chitin solution uses 1-butyl-3-methylimidazolium chloride ionic liquid as a solvent.

4. The application according to claim 1, characterized in that, The wall thickness of the variable stiffness chest drainage tube is 1.0-3.0 mm.

5. The application according to claim 1, characterized in that, In step S1, the dissolution temperature is 80-110℃ and the dissolution time is 4-12 hours.

6. The application according to claim 1, characterized in that, In step S1, the dissolution is carried out under mechanical stirring conditions, with a stirring speed of 200-600 rpm.

7. The application according to claim 1, characterized in that, In step S2, the phase transformation time is 24-72 hours.

8. The application according to claim 1, characterized in that, In step S4, the immersion is carried out at 4°C for 24-48 hours.

9. The application according to claim 1, characterized in that, In step S4, the thermal polymerization is carried out at a temperature of 60-80°C for 3-6 hours.

Images