A highly adhesive hydrogel suitable for lung parenchymal resection wounds and methods of use thereof
Patent Information
- Application Number
- CN202611078833.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2026-07-20
- Publication Date
- 2026-10-20
AI Technical Summary
虽然现有的纤维蛋白胶或化学合成胶在一定程度上能够辅助封闭创面，但针对湿性生理环境下的肺组织（持续呼吸运动导致组织形变、表面渗血渗液）仍存在诸多局限：（1）粘附力不足；传统生物蛋白胶在湿润组织表面的粘接强度有限，难以抵抗呼吸运动带来的持续张力；（2）膨胀与压迫风险；部分合成材料吸水后过度膨胀，可能压迫肺组织或支气管，影响术后恢复；（3）操作便捷性差：部分产品需复杂配制或固化时间长，难以在微创手术中精准喷涂
3.水凝胶制备过程中均采用降解材料制成，能够保证后期在体内降解，降低临床风险。
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Abstract
Description
Technical Field
[0001] This invention relates to the field of biomedical materials technology, specifically to a highly adhesive hydrogel suitable for lung parenchymal resection wounds and its application method. This hydrogel exhibits good biocompatibility, biodegradability, and excellent adhesion properties, making it suitable for lung surgery and the treatment of air leaks. Background Technology
[0002] Pulmonary resection (such as lobectomy and wedge resection) is a major surgical procedure for treating lung cancer, pulmonary nodules, and various benign lesions. Regardless of whether traditional surgical instruments or manual suturing are used, postoperative air leakage (PAL) is one of the most common and challenging complications in thoracic surgery. Statistics show that the incidence of persistent air leakage after pulmonary resection is approximately 15% to 25%. Even mild leaks (grade II or lower) can, if not properly managed, prolong the time of chest drainage tube placement, increase hospital stay, and potentially lead to serious complications such as empyema and pleural infection, exacerbating patient suffering and financial burden.
[0003] Currently, the main clinical treatments for lung parenchymal resection wounds include mechanical suturing, electrocoagulation hemostasis, bioadhesive bonding, and autologous tissue covering. Although existing fibrin glue or chemically synthesized glue can assist in wound closure to some extent, there are still many limitations for lung tissue in a moist physiological environment (continuous respiratory movement leads to tissue deformation and surface bleeding and exudation): (1) Insufficient adhesion; traditional bioadhesive glue has limited adhesion strength on moist tissue surfaces and is difficult to resist the continuous tension brought about by respiratory movement; (2) Risk of expansion and compression; some synthetic materials expand excessively after absorbing water, which may compress lung tissue or bronchi and affect postoperative recovery; (3) Poor ease of operation: some products require complex preparation or have long curing time, making it difficult to spray accurately in minimally invasive surgery. Therefore, there is an urgent clinical need for a sealant product that combines strong wet surface adhesion, moderate expansion rate, good biocompatibility, and ease of operation, specifically for the closure of grade II or lower air leakage after lung parenchymal resection. Summary of the Invention
[0004] The purpose of this invention is to provide a highly adhesive hydrogel suitable for treating lung parenchymal resection wounds. This hydrogel exhibits excellent adhesion, mechanical strength, and biocompatibility, making it suitable for treating air leaks during lung surgery.
[0005] To achieve the above objectives, the present invention adopts the following technical solution.
[0006] A highly adhesive, tensile-resistant in-situ molding hydrogel suitable for lung parenchyma resection wounds, comprising a first component, a second component, a first component liquid, and a second component liquid; In this solution, by weight ratio, 1 part of the first component is dissolved in 1 part of the first component liquid to form a first component solution; 0.1-1.3 parts of the second component are dissolved in 1 part of the second component liquid to form a second component solution. The first component solution and the second component solution are mixed in a volume ratio of 1:1 and react to form a hydrogel. The first component is either 8-arm-PEG-SG or DA-8-arm-PEG-SG; the second component is either trilysine, polyethyleneimine, or 8-arm-PEG-NH2 (HCl) or a combination thereof; the first component liquid is either phosphate buffer or water; the second component liquid is either borate buffer or water.
[0007] Furthermore, the molecular weight of 8-arm-PEG-SG, which is the first component, is between 4 and 20 kDa, and the molecular weight of DA-8-arm-PEG-SG is between 4 and 20 kDa.
[0008] Furthermore, the molecular weight of the second component, 8-arm-PEG-NH2(HCl), is between 4 and 20 kDa.
[0009] Furthermore, the molecular weight of trilysine is between 1 and 5 kDa.
[0010] Furthermore, the molecular weight of polyethyleneimine is between 1 and 5 kDa.
[0011] When the first component liquid is phosphate buffer, the concentration of phosphate buffer is 10-40 mmol / L.
[0012] When the second component liquid is borate buffer, the concentration of borate buffer is 35-85 mmol / L.
[0013] It should be noted that the preparation method of DA-8-arm-PEG-SG here is as follows: 1 M 8-arm-PEG-SG and 1 M dopamine (DA) hydrochloride are pre-dissolved and mixed in a sample tube. Grafting reaction is carried out through the spontaneous reaction of the amino group of DA with 8-arm-PEG-SG. After an appropriate reaction time, the mixture is dried to obtain the DA-8-arm-PEG-SG polymer.
[0014] A method for using a highly adhesive hydrogel suitable for lung parenchymal resection wounds. Includes the following steps: S1, dissolve the first component uniformly in the first component liquid; S2, dissolve the second component uniformly in the second component liquid; S3 involves spraying the first and second components alternately and evenly onto the tissue in a 1:1 ratio to form a sheet-like hydrated and sealing hydrogel, thereby preventing lung leakage.
[0015] Compared with the prior art, the beneficial effects of the present invention are as follows.
[0016] 1. The eight-arm polyethylene glycol cross-linked hydrogel can perfectly conform to various complex wound shapes, such as irregular shapes, different sizes, and even multiple micro-wounds, achieving ideal all-round sealing.
[0017] 2. Despite the traction and friction caused by continuous respiratory movements of the lungs, the hydrogel's adhesive force can maintain a sealed state for a long time without any recurrence of leakage, demonstrating excellent sealing performance. 3. The hydrogels are made of degradable materials during preparation, which ensures that they degrade in vivo and reduces clinical risks. Attached Figure Description
[0018] Figure 1 Images showing hydrogel sprayed on an intact lung and a damaged lung.
[0019] Figure 2 is Scanning electron microscope image of the hydrogel.
[0020] Figure 3 Images of hemolysis in hydrogels.
[0021] Figure 4 Image of hydrogel co-cultured with 293 T cells for 3 days. Detailed Implementation
[0022] The present invention will now be described in detail with reference to the accompanying drawings and embodiments.
[0023] First, the ratio and concentration of different components were adjusted to obtain the preparation effect of hydrogels in different embodiments, and their performance was studied.
[0024] Example 1: Weigh 1 gram of 8-arm-PEG-SG (molecular weight 20 kDa) and dissolve it in 1 ml of sterile water to prepare a first component solution; weigh 0.3 gram of trilysine (molecular weight 0.4 kDa) and dissolve it in 1 ml of sterile water to prepare a second component solution. Mix the liquid containing the first component and the liquid containing the second component in equal proportions.
[0025] Example 2: Weigh 1 gram of DA-8-arm-PEG-SG (molecular weight 20 kDa) and dissolve it in 1 ml of sterile water to prepare a first component solution; weigh 0.3 gram of trilysine (molecular weight 0.4 kDa) and dissolve it in 1 ml of sterile water to prepare a second component solution. Mix the liquid containing the first component and the liquid containing the second component in equal proportions.
[0026] Example 3: Weigh 1 gram of 8-arm-PEG-SG (molecular weight 20 kDa) and dissolve it in 1 ml of sterile water to prepare a first component solution; weigh 1.3 grams of 8-arm-PEG-NH2(HCl) (molecular weight 20 kDa) and dissolve it in 1 ml of sterile water to prepare a second component solution. Mix the liquid containing the first component and the liquid containing the second component in equal proportions.
[0027] Example 4: Weigh 1 gram of DA-8-arm-PEG-SG (molecular weight 20 kDa) and dissolve it in 1 ml of sterile water to prepare a first component solution; weigh 1.3 grams of 8-arm-PEG-NH2(HCl) (molecular weight 20 kDa) and dissolve it in 1 ml of sterile water to prepare a second component solution. Mix the liquid containing the first component and the liquid containing the second component in equal proportions.
[0028] Example 5: 1 gram of 8-arm-PEG-SG (molecular weight 20 kDa) was dissolved in 1 ml of sterile water to prepare a first component solution; 0.1 gram of polyethyleneimine (molecular weight 1 kDa) was dissolved in 1 ml of sterile water to prepare a second component solution. The liquids containing the first and second components were mixed in equal proportions to form a sheet-like hydrated sealing hydrogel, thereby preventing lung leakage.
[0029] Example 6: 1 gram of DA-8-arm-PEG-SG (molecular weight 20 kDa) was dissolved in 1 ml of sterile water to prepare a first component solution; 0.1 gram of polyethyleneimine (molecular weight 1 kDa) was dissolved in 1 ml of sterile water to prepare a second component solution. The liquids containing the first and second components were mixed in equal proportions to form a sheet-like hydrated sealing hydrogel, thereby preventing lung leakage.
[0030] Example 7: 1 gram of 8-arm-PEG-SG (molecular weight 20 kDa) was dissolved in 1 ml of sterile water to prepare a first component solution; 0.1 gram of trilysine (molecular weight 0.4 kDa) and 0.1 gram of polyethyleneimine (molecular weight 1 kDa) were dissolved in 1 ml of sterile water to prepare a second component solution. The liquids containing the first and second components were mixed in equal proportions to form a sheet-like hydrated sealing hydrogel, thereby preventing lung leakage.
[0031] Example 8: 1 gram of DA-8-arm-PEG-SG (molecular weight 20 kDa) was dissolved in 1 ml of sterile water to prepare a first component solution; 0.1 gram of trilysine (molecular weight 0.4 kDa) and 0.1 gram of polyethyleneimine (molecular weight 1 kDa) were dissolved in 1 ml of sterile water to prepare a second component solution. The liquids containing the first and second components were mixed in equal proportions to form a sheet-like hydrated sealing hydrogel, thereby preventing lung leakage.
[0032] Example 9: 1 gram of 8-arm-PEG-SG (molecular weight 20 kDa) was dissolved in 1 ml of phosphate buffer (15 mmol / L) to prepare the first component solution; 1.3 grams of 8-arm-PEG-NH2(HCl) (molecular weight 20 kDa) was dissolved in 1 ml of borate buffer (75 mmol / L) to prepare the second component solution. The liquids containing the first and second components were mixed in equal proportions to form a sheet-like hydrated and sealing hydrogel, thereby preventing lung leakage.
[0033] Example 10: 1 gram of DA-8-arm-PEG-SG (molecular weight 20 kDa) was dissolved in 1 ml of phosphate buffer (10 mmol / L) to prepare the first component solution; 1.3 grams of 8-arm-PEG-NH2(HCl) (molecular weight 20 kDa) was dissolved in 1 ml of borate buffer (35 mmol / L) to prepare the second component solution. The liquids containing the first and second components were mixed in equal proportions to form a sheet-like hydrated and sealing hydrogel, thereby preventing lung leakage.
[0034] Example 11: 1 gram of DA-8-arm-PEG-SG (molecular weight 20 kDa) was dissolved in 1 ml of phosphate buffer (40 mmol / L) to prepare the first component solution; 0.3 gram of trilysine (molecular weight 0.4 kDa) was dissolved in 1 ml of borate buffer (85 mmol / L) to prepare the second component solution. The liquids containing the first and second components were mixed in equal proportions to form a sheet-like hydrated and sealing hydrogel, thereby preventing pulmonary leakage.
[0035] Example 12: 1 gram of DA-8-arm-PEG-SG (molecular weight 20 kDa) was dissolved in 1 ml of phosphate buffer (10 mmol / L) to prepare a first-component solution; 0.1 gram of polyethyleneimine (molecular weight 1 kDa) was dissolved in 1 ml of borate buffer (35 mmol / L) to prepare a second-component solution. The liquids containing the first and second components were mixed in equal proportions to form a sheet-like hydrated sealing hydrogel, thereby preventing lung leakage.
[0036] Example 13: 1 gram of DA-8-arm-PEG-SG (molecular weight 20 kDa) was dissolved in 1 ml of phosphate buffer (10 mmol / L) to prepare a first-component solution; 0.1 gram of trilysine (molecular weight 0.4 kDa) and 0.1 gram of polyethyleneimine (molecular weight 1 kDa) were dissolved in 1 ml of borate buffer (35 mmol / L) to prepare a second-component solution. The solutions containing the first and second components were mixed in equal proportions to form a sheet-like hydrated sealing hydrogel, thereby preventing lung leakage.
[0037] Example 14: 1 gram of DA-8-arm-PEG-SG (molecular weight 20 kDa) was dissolved in 1 ml of phosphate buffer (10 mmol / L) to prepare a first-component solution; 0.1 gram of trilysine (molecular weight 0.4 kDa) and 0.1 gram of polyethyleneimine (molecular weight 2 kDa) were dissolved in 1 ml of borate buffer (35 mmol / L) to prepare a second-component solution. The solutions containing the first and second components were mixed in equal proportions to form a sheet-like hydrated sealing hydrogel, thereby preventing lung leakage.
[0038] Example 15: 1 gram of DA-8-arm-PEG-SG (molecular weight 15 kDa) was dissolved in 1 ml of phosphate buffer (10 mmol / L) to prepare a first-component solution; 0.1 gram of trilysine (molecular weight 0.4 kDa) and 0.1 gram of polyethyleneimine (molecular weight 1 kDa) were dissolved in 1 ml of borate buffer (85 mmol / L) to prepare a second-component solution. The solutions containing the first and second components were mixed in equal proportions to form a sheet-like hydrated sealing hydrogel, thereby preventing lung leakage.
[0039] Example 16: 1 gram of DA-8-arm-PEG-SG (molecular weight 10 kDa) was dissolved in 1 ml of phosphate buffer (10 mmol / L) to prepare a first-component solution; 0.1 gram of trilysine (molecular weight 0.4 kDa) and 0.1 gram of polyethyleneimine (molecular weight 1 kDa) were dissolved in 1 ml of borate buffer (35 mmol / L) to prepare a second-component solution. The liquids containing the first and second components were mixed in equal proportions to form a sheet-like hydrated and sealing hydrogel, thereby preventing lung leakage.
[0040] Performance analysis of the above embodiments 1. Hydrogel degradation cycle test Take 0.5g of hydrogel, dry the sample to constant weight under room temperature and vacuum conditions before degradation, then immerse it in the degradation solution, and record the quality test of the process using an electronic balance at fixed times (2, 4, 8, 12, 16 weeks).
[0041] 2. Hydrogel swelling performance test Swelling studies were performed in phosphate-buffered saline (PBS) buffer (pH 7.4). After gelation, the initial weight of the hydrogel was determined and defined as W. b The hydrogel was then immersed in PBS for 24 hours. After removing excess water from the surface, the sample was removed and weighed; the latter weight is defined as W. a The swelling ratio is calculated using Formula 1: ×100% (1) 3. Hydrogel fracture strength test A hole approximately 0.16 cm (+0.02 cm) in diameter was punched in a fresh pig casing. The gel product of this invention was applied to this hole to form a hydrogel of a specified thickness. Pressure was applied from below the casing using a phosphate buffer solution with a pH of 7.4 until the gel ruptured. The maximum pressure reading was recorded using a digital reader connected to a sensor. The rupture strength results are shown in Table 1. The data shows that the rupture strength of this sealing gel far exceeds the physiological pressure of holding one's breath or coughing, indicating that it possesses excellent mechanical properties and can be applied to the lungs.
[0042] 4. Hydrogel impermeability test Take a fresh pigskin and make a hole with a diameter of about 0.16 cm (+0.02 cm). Apply the gel product of this invention to the hole, add sterile water under the pigskin and apply pressure until the gel breaks. Record the maximum pressure.
[0043] 5. Gel formation time test Mix the liquid containing the first component and the liquid containing the second component in equal proportions and spray them into a small bottle. Pour the bottle over and observe its flow. Record the hydrogel formation time.
[0044] The experimental data are shown in Table 1. For cell and animal experiments, the precursor solution was sterilized by filtration through a 0.2 μm filter.
[0045] Hydrogel morphology analysis and animal experimental characterization data are illustrated in Example 13. Weigh 1 part of DA-8-arm-PEG-SG (molecular weight 20 kDa) and dissolve it in 1 ml of phosphate buffer to prepare the first component solution; weigh 0.1 part of trilysine (molecular weight 0.4 kDa) and 0.1 part of polyethyleneimine (molecular weight 1 kDa) and dissolve them in 1 ml of borate buffer to prepare the second component solution. Mix the solutions containing the first and second components in equal proportions. 6. Hydrogel morphology analysis After the hydrogel formed by spraying is dehydrated with alcohol (30%-100%), it is then photographed with a scanning electron microscope.
[0046] 7. In vitro hemolysis test Rabbit whole blood was centrifuged at 1200 rpm for 10 minutes, and the supernatant was removed to obtain a red blood cell (RBC) solution. The RBC solution was diluted to 10% with PBS. Positive control: 200 μL of red blood cell suspension and 3.8 ml of deionized water were added to each group. Negative control: 2 ml of red blood cell suspension and 2 ml of PBS were added to each group. After incubation, the cells were centrifuged at 3000 rpm for 10 minutes, and the absorbance was measured at 545 nm using a microplate reader. The hemolysis rate of the hydrogel was calculated using Equation 2.
[0047] (2) 8. Cytotoxicity test Cell compatibility analysis of the hydrogel was performed using 293 T cells.
[0048] Table 1. Mechanical Strength Data of Hydrogels
Claims
1. A highly adhesive hydrogel suitable for lung parenchymal resection wounds, characterized in that: It includes a first component, a second component, a first component liquid, and a second component liquid; In this solution, by weight ratio, 1 part of the first component is dissolved in 1 part of the first component liquid to form a first component solution; 0.1-1.3 parts of the second component are dissolved in 1 part of the second component liquid to form a second component solution. The first component solution and the second component solution are mixed in a volume ratio of 1:1 and react to form a hydrogel. The first component is either 8-arm-PEG-SG or DA-8-arm-PEG-SG; the second component is either trilysine, polyethyleneimine, or 8-arm-PEG-NH2 (HCl) or a combination thereof; the first component liquid is either phosphate buffer or water; the second component liquid is either borate buffer or water.
2. The highly adhesive hydrogel suitable for lung parenchymal resection wounds according to claim 1, characterized in that: The molecular weight of 8-arm-PEG-SG, which is the first component, is between 4 and 20 kDa, and the molecular weight of DA-8-arm-PEG-SG is between 4 and 20 kDa.
3. The highly adhesive hydrogel suitable for lung parenchymal resection wounds according to claim 1, characterized in that: The molecular weight of 8-arm-PEG-NH2(HCl), which is the second component, is between 4 and 20 kDa.
4. The highly adhesive hydrogel suitable for lung parenchymal resection wounds according to claim 1, characterized in that: The molecular weight of trilysine is between 1 and 5 kDa.
5. The highly adhesive hydrogel suitable for lung parenchymal resection wounds according to claim 1, characterized in that: The molecular weight of polyethyleneimine is between 1 and 5 kDa.
6. The highly adhesive hydrogel suitable for lung parenchymal resection wounds according to claim 1, characterized in that: When the first component liquid is phosphate buffer, the concentration of phosphate buffer is 10-40 mmol / L.
7. The highly adhesive hydrogel suitable for lung parenchymal resection wounds according to claim 1, characterized in that: When the second component liquid is borate buffer, the concentration of borate buffer is 35-85 mmol / L.
8. A method of using the highly adhesive hydrogel for lung parenchymal resection wounds as described in any one of claims 1-7, characterized in that: Includes the following steps: S1, dissolve the first component uniformly in the first component liquid; S2, dissolve the second component uniformly in the second component liquid; S3 involves spraying the first and second components alternately and evenly onto the tissue in a 1:1 ratio to form a sheet-like hydrated and sealing hydrogel, thereby preventing lung leakage.