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. 2026 Jul 22;8(16):4474–4479. doi: 10.1039/d6na00083e

3D bioprinted coverage-type lung patch for postoperative wound sealing and prevention of pulmonary air leakage

Fengyi Han a,b,†, Xiaopei Zhang b,†, Ke Sun a,b,†, Huaxin Song a,b, Guohua Wang a, Yuanfei Wang c,✉, Tong Wu b,✉, Wenjie Jiao a,✉
PMCID: PMC13390821  PMID: 42488784

Abstract

Postoperative pulmonary air leakage is a common complication after thoracic surgery. We developed a 3D-bioprinted hydrogel patch using a PLMA/PEGNB/XG bioink via PTPC. In both ex vivo and in vivo models, the patch effectively sealed lung injuries and reduced air leakage compared with conventional methods.

A 3D-printed PLMA/PEGNB/XG-based self-adhesive lung patch was developed as a translationally relevant solution for sealing postoperative pulmonary air leaks.graphic file with name d6na00083e-ga.jpg

Postoperative pulmonary air leakage is a common complication following thoracic surgery.1,2 It is primarily induced by inevitable lung tissue injury caused by surgical manipulations such as incision, suturing, and traction, leading to air leakage into the pleural cavity. It has been reported that up to 60% of patients undergoing lung surgery experience postoperative air leakage.3 More importantly, approximately 10–20% of patients undergoing pulmonary resection develop prolonged air leakage,4 which increases the risk of pulmonary infection and extends the average hospital stay of patients.5

Significant limitations exist in commonly used clinical strategies for managing pulmonary air leakage.6 A continuous chest tube can alleviate mild air leakage.7 However, indwelling chest tubes increase the risk of infection and induce severe pain associated with pleural irritation.8 For severe postoperative pulmonary air leakage, further surgical intervention is required.9 Given the lack of standardization in existing protocols and their inability to balance efficacy and safety, biomaterials have emerged as a potential solution.10–12

Clinically applied biomaterials for pulmonary air-leakage management mainly include sealants and patch-based products. Although these materials have provided useful options for clinical practice, further improvement is still needed in mechanical adaptability, sealing durability, and operational convenience. For instance, some conventional or commercially available sealants may exhibit mechanical mismatch with soft and dynamic lung tissue, which limits their ability to accommodate repeated expansion and contraction during respiration and may compromise long-term sealing stability.13 In contrast, patch-based products offer more direct clinical applicability. A prospective randomized clinical study has shown that Neoveil, a bioabsorbable polyglycolic acid sheet, may provide more favorable air-leak control than TachoSil, a collagen sponge coated with human fibrinogen and thrombin, after open lung surgery.14 Therefore, to improve the clinical applicability of patch-based materials and enhance their performance in preventing pulmonary air leakage, this study focused on optimizing biocompatible materials, simplifying the fabrication process, and reinforcing coverage performance compatible with native lung tissue.

Biomaterials have been widely applied in tissue repair owing to their excellent biocompatibility.15–18 Extrusion-based 3D bioprinting technology enables the fabrication of customized, complex spatial structures due to its versatility and operational convenience.19,20 The selection of bioink is a critical factor determining printing performance, scaffold mechanical strength, and biocompatibility.21 ε-Poly-l-lysine (ε-PL) is a natural homopolyamide polymer composed of l-lysine, with cationic character, water solubility, biodegradability, and reported non-toxicity.22 PEG is a synthetic polymer approved by the FDA for human injection and is known for its non-toxicity, low irritancy, and low immunogenicity.23,24 PEG-containing systems have also been used in 3D printing. For example, a PEG-PLA/Gelatin composite system was applied as a printing ink to fabricate scaffolds for cartilage regeneration.25 In another study involving 3D-printed bone-regeneration scaffolds, increasing the PEG content in the ink to 20% significantly improved scaffold hydrophilicity.26 Xanthan gum (XG) is a high-molecular-weight microbial polysaccharide obtained from the fermentation of Xanthomonas campestris.27,28 Its shear-thinning behavior and stability across broad temperature and pH ranges make it useful for improving the rheological and mechanical performance of bioinks.29–31 In food-related 3D printing, XG has been combined with sodium alginate to prepare pseudoplastic starch-based gels with relatively good extrudability and shape retention.32 A chitosan/XG-based ink has been used in extrusion-based 3D printing to fabricate wound-healing patches.33 A GelMA/XG bioink containing N-halamine/TiO2 has also been reported for 3D-printed antibacterial wound dressings, which inhibited bacterial biofilm formation and showed an appropriate swelling ratio and high water absorption efficiency.34

In the present study, a biomimetic hydrogel has been developed via extrusion-based 3D bioprinting technology. Specifically, the hydrogel serves as the main matrix of the patch and is crosslinked through a phototriggered transient-radical and persistent-radical coupling (PTPC) reaction between methacrylated poly-l-lysine (PLMA) and o-nitrobenzyl alcohol-modified four-arm polyethylene glycol (PEGNB). When the aqueous solution containing PLMA, PEGNB, and the photoinitiator lithium phenyl(2,4,6-trimethylbenzoyl) phosphinate (LAP) was irradiated with 395 nm ultraviolet light, PLMA rapidly underwent polymerization to form highly crosslinked hard-phase particles. Meanwhile, the PEGNB terminal NB groups were photolyzed with LAP catalysis, generating nitroso groups. These groups captured free radicals to form stable nitroxide radicals, subsequently coupling with carbon-centered radicals on PLMA hard-phase particles. This ultimately formed covalent bonds between ε-PL hard-phase particles and the PEG soft-phase matrix, constructing a stable composite network. Notably, the entire reaction was completed in seconds,35 significantly improving the efficiency of material preparation and the convenience of clinical application.

Considering the rheological requirements of bioinks for extrusion-based 3D bioprinting, XG was incorporated into the hydrogel system to develop a multicomponent bioink with pseudoplastic characteristics. The addition of XG optimized the shear-thinning behavior of the bioink while maintaining morphological fidelity during printing. Finally, square sheet-shaped composite hydrogels were successfully fabricated via 3D bioprinting. After lyophilization, they can be directly converted into clinically applicable patches for the repair of pulmonary air leakage.

Fig. 1A illustrates the preparation of the bioink and the 3D bioprinting process, in which PLMA, PEGNB, and XG were physically mixed in LAP solution to yield the printing bioink (Fig. 1A(i)). During the printing process, under 395 nm ultraviolet light irradiation, the PTPC reaction could be completed within a few seconds (Fig. 1A(iii)). To investigate the effect of different printing rotation angles on patch porosity, three printing rotation angles (30°, 60°, and 90°) were set (Fig. 1A(ii)). In a previous study on the rapid preparation of hydrogels through PTPC, the hard-phase content was found to largely determine the gel properties. Based on the mass ratio of the hard phase to the soft phase (Rw), the gels were classified as tough gels with Rw values of 0.04–0.10 and strong gels with Rw values of 0.16–0.30.35 Inspired by this design principle, two bioinks with different PLMA/PEGNB mass ratios were prepared to further investigate the effect of hard-phase proportion on patch performance, namely group I (2% PLMA/5% PEGNB/10% XG) and group II (2% PLMA/10% PEGNB/10% XG).

Fig. 1. (A) (i) PLMA/PEGNB/XG were physically mixed in LAP solution to prepare bioink. (ii) The bioink was printed via an extrusion-based 3D printer at printing angles of 30°, 60°, and 90° under 395 nm ultraviolet light irradiation. (iii) The mechanism of interfacial bonding and covalent integration between PLMA and PEGNB molecules. (B) Representative SEM micrographs of the printed patch surfaces under different printing angles and PLMA/PEGNB ratios. (C) Comparison of porosity among patches in each group. n = 4, ns P > 0.05, when compared with groups I and II in 30°, ***P < 0.001, when compared with groups I and II in 60°, ***P < 0.001, when compared with groups I and II in 90°. (D) Comparison of nominal strain at break among patches in each group. n = 4, *P < 0.05, when compared with groups I and II. (E) Oscillatory strain amplitude sweep of groups I (2% PLMA/5% PEGNB/10% XG), showing the storage modulus (G′) and loss modulus (G″) as functions of strain. (F) Oscillatory strain amplitude sweep of groups II (2% PLMA/10% PEGNB/10% XG), showing the storage modulus (G′) and loss modulus (G″) as functions of strain.

Fig. 1

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SEM images (Fig. 1B) reveal that, under identical PLMA/PEGNB ratios, patch structures exhibit no significant differences across varying printing angles. In contrast, at a fixed printing angle, the porous structure of group I appears more continuous and uniform. Photographs of the 3D-printed patches are shown in Fig. S1. Fig. 1C and S2A show that group I had higher porosities and larger pore diameters at 60° and 90°, both of which were significantly higher than those of group II (at the same rotation angles) (P < 0.001). However, no significant structural differences were observed in the 30° group. The calculated porosity represents the two-dimensional apparent porosity based on SEM image analysis rather than the three-dimensional bulk porosity. This might be due to the irregular relative movement trajectory between the nozzle and the substrate at a 30° printing rotation angle, or to large fluctuations in the bioink extrusion shear force, which masked the influence of differences in component ratios on the surface-mount structure.

Fig. 1D shows that the fracture nominal strain (εtb) of group I is significantly lower than that of group II (P < 0.05). Therefore, it was inferred that reducing the proportion of PEGNB could enhance the impact resistance of the patches, increasing their likelihood of adhering to the visceral pleura and reducing their tendency to undergo plastic deformation. Meanwhile, airflow impact was observed at the lung air-leakage sites, and this characteristic showed advantages for lung air-leakage applications. The Young's modulus of the patches in all groups displayed in Fig. S2B shows no significant difference (P > 0.05), and all values fall within the range of human lung elastic modulus, which is 5 to 10 kPa.36,37 Its mechanical properties are always compatible with human lung tissue.

To examine how bioink composition affected extrusion-based 3D printability, five formulations were tested by oscillatory strain amplitude sweep at a fixed temperature and frequency: 2% PLMA/5% PEGNB, 2% PLMA/10% PEGNB, 10% XG, group I (2% PLMA/5% PEGNB/10% XG), and group II (2% PLMA/10% PEGNB/10% XG). Fig. S2C and S2D show that, for the PLMA/PEGNB formulations without XG, the loss modulus (G″) remained higher than the storage modulus (G′), and the phase angle was close to 90°. These results indicate a viscous, liquid-like state with limited structural stability for shape retention after extrusion. Fig. S2E shows that the 10% XG formulation exhibited a clear linear viscoelastic region, with a storage modulus of 1265 Pa, a critical strain of 8.888%, indicating stable structural characteristics and yield behavior. Fig. 1E shows that group I had a transition similar to that of pure XG, with G′ > G″ at low strain and G″ > G′ after the critical strain was exceeded. This pattern suggests that group I could retain its structure under low-strain conditions and flow under higher deformation, which is consistent with the extrusion and post-deposition shape-retention requirements of 3D-printing bioinks. Fig. 1F shows that, by contrast, group II maintained G″ > G′ throughout the tested strain range, indicating a predominantly viscous response and no clear elastic-dominated region. Although this formulation showed some shear-thinning behavior that may aid extrusion, its weaker structural support may reduce shape retention after printing and make stable, uniform construct formation more difficult. These rheological results indicate that XG improved the structural stability and printing suitability of the PLMA/PEGNB system, with group I showing better adaptability for extrusion-based 3D printing.

Therefore, the patch with a PLMA/PEGNB mass ratio of 0.4 and a printing angle of 60° was selected for subsequent experiments. Subsequently, the in vitro degradation behavior of the hydrogel patches printed using this optimized formulation was evaluated. The patches were immersed in PBS for 0, 3, 6, 9, and 12 days, after which the changes in their lyophilized dry weight were measured and the degradation ratio was calculated. As shown in Fig. S2F, the degradation ratio of the patches increased rapidly during the first 3 days, with no obvious further increase observed from day 6 to day 12. This degradation behavior may help the patches retain most of their structure during the early stage of pulmonary air leak repair, thereby maintaining short-term sealing function.

The in vitro cytocompatibility of the patches was evaluated using RLE-6TN cells. As shown in Fig. 2A, we compared the morphology of RLE-6TN cells cultured for 24 hours in complete medium (control) with that of cells cultured in extracts from days 1, 3, and 5 of the patches. RLE-6 TN cells in both the control and experimental groups maintained a flat and well-spread morphology with clear. This indicates the patch extracts did not release cytotoxic substances that could disrupt cellular structural integrity or impair adherence. RLE-6 TN cells were cultured for 24 hours with patch extracts from days 1, 3, and 5, followed by live/dead staining and microscopic observation (Fig. 2B). The stained cells showed that their viability was comparable to that of the control group, with no obvious increase in dead cells observed in the extract-cultured groups. Furthermore, RLE-6TN were co-cultured with patches (group II, 60°), and cell proliferation was assessed using the CCK-8 assay. In Fig. 2C, RLE-6TN cells in both groups showed similar proliferation rates. These results demonstrate that the patches exhibit good biocompatibility and support normal cell proliferation.

Fig. 2. (A) RLE-6TN cells were co-cultured with patch extracts (1-day, 3-day, and 5-day leaching) or blank complete medium (control group) for 24 hours. Actin cytoskeletons were stained with Phalloidin-Fluor 488 (green), and cell nuclei were stained with DAPI (blue). (B) Live/dead cell staining of RLE-6TN cells after 24 hours of co-culture with patch extracts (1-day, 3-day, and 5-day leaching) or blank complete medium. (C) Cell viability of RLE-6TN cells in the patch group and the blank control group was assessed using CCK-8. n = 4, **P < 0.01, when compared with the patch and control groups on day 1, ns P > 0.05, when compared with the patch and control groups on day 3, ns P > 0.05, when compared with the patch and control groups on day 5.

Fig. 2

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To evaluate the sealing effect of patches on pulmonary air-leakage sites in rats, an isolated lung air-leakage model was first established in Sprague-Dawley rats. Three sealing methods (Fig. 3A) were applied to the model: traditional surgical nylon suture (suture group), commercial n-butyl cyanoacrylate animal tissue adhesive (TA group), and patch combined with a small amount of TA (patch + TA group). The physical morphological characteristics of these three repair methods are shown in Fig. S3. The airway pressure of each group of lung tissues in the normal state, leakage state, after repair, and when the tidal volume increased after repair was measured using a precision digital pressure gauge (Fig. S4), and the re-expansion of the lung tissues was observed simultaneously. Rat lungs repaired through suture and the TA group showed only moderate re-expansion at baseline tidal volume, whereas those repaired with the patch + TA exhibited better re-expansion. This preliminary indication suggests that the patch enhances sealing of pulmonary air leakage through the combined effects of physical support and adhesion.

Fig. 3. (A) Timeline of the in vitro animal experiment. (B) The maximum tolerable tidal volume was determined by increasing it until air leakage occurred. n = 3, **P < 0.01, when compared with patch + TA and other groups. Auxiliary line, basic tidal volume of 10 mL. (C) The maximum tolerable airway pressure was reached by increasing tidal volume until airway leakage occurred. n = 3, **P < 0.01, when compared with suture and patch + TA; ***P < 0.001, when compared with TA and patch + TA.

Fig. 3

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Airway pressure and tidal volume were further quantified to assess repair stability. After repair, the tidal volume was gradually increased until bubbles reappeared in the PBS solution at the site of lung leakage. The tidal volume at this point was recorded as the maximum tidal volume, and the corresponding airway pressure was recorded as the maximum airway pressure. Fig. 3B shows that the patch + TA group tolerated a maximum tidal volume of 15 mL. In the suture group, a small number of bubbles were still observed at the baseline tidal volume of 10 mL, whereas the maximum tidal volume in the TA group was 11 mL. Fig. 3C shows that the maximum airway pressure in the patch + TA group reached 25.58 ± 0.26 kPa, which was significantly higher than that in the suture group (19.26 ± 0.81 kPa) and the TA group (18.20 ± 1.01 kPa). These data indicate that the patch provided additional structural support and sealing at the repaired site, allowing the lung tissue to tolerate higher tidal volumes and airway pressures and reducing recurrent air leakage from increased intrapulmonary pressure.

It should be noted that the TA used in this study was an animal-use n-butyl cyanoacrylate tissue adhesive. Its role was not to simulate a clinically standard sealant for pulmonary air-leakage management, but rather to serve as a rapid adhesive control. When used alone, TA could form a local adhesive layer on the lung surface. However, under repeated lung collapse–re-expansion and air-flow impact at the leakage site, its coverage area, flexible adaptability, and structural support may be limited. This may explain why no significant difference was observed between the TA group and the conventional suture group. In contrast, in the patch + TA group, TA was primarily used for initial patch fixation, while the patch itself provided broad physical coverage and flexible structural support over the leakage site, thereby improving the repaired region's tolerance to higher tidal volumes and airway pressures. These results suggest that the patch may enhance sealing stability in a dynamic pulmonary air-leakage environment through the combined effects of structural coverage and mechanical support.

To further verify the effectiveness of patches in practical applications, an in vivo lung air-leakage model was established in Sprague-Dawley rats. Rats with right lung air leakage repaired with patches were designated the experimental (patch) group, while those without repair served as the control group. Cross-sectional CT scans were performed 24 hours post-operation to assess air leakage volume. As illustrated in Fig. 4A, the patch was stably adhered to the air-leakage site on the upper lobe of the right lung in the rats. In the lung window image of Fig. 4C, the pure black area within the thoracic cavity, circled by the red dotted line, was identified as the range of air leakage after lung surface injury. This intuitively revealed that the area of air leakage in the patch group was significantly smaller than that in the control group. The proportions of the pneumothorax area relative to the right hemithorax area in cross-sectional CT scans (Fig. 4B) were shown to indicate that the pneumothorax area of rats without thoracotomy was 0, and the pneumothorax area ratios in the patch group and the control group were 14.51 ± 4.88% and 41.90 ± 1.87%, respectively. The pneumothorax area was significantly reduced after patch repair under the necessary auxiliary fixation conditions used in this study. These findings further support the patch's potential to reduce pulmonary air leakage in a living, dynamic physiological environment.

Fig. 4. (A) Patches were used to repair the air-leaking right upper lung lobe of rats. (B) Statistical analysis of the pneumothorax area ratio in normal (non-thoracotomy), control (thoracotomy without repair) and patch (thoracotomy with patch repair), n = 4, **P < 0.001, compared with the patch and control. (C) Cross-sectional CT lung window images of rats at 24 hours after survival. Proximal-head end and distal-head end pictures were selected for each group.

Fig. 4

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Conclusions

Hydrogel-based sealants and adhesive patches have been investigated for the repair of pulmonary air leakage and other dynamic soft-tissue defects. Progel is currently the only sealant approved for treating intraoperative air leaks after lung resection, but its sealing performance in clinical use still leaves room for improvement. To address the mechanical mismatch between sealants and respiratory lung tissue, several hydrogel systems have been developed. ALG-MA-DA and Gel-MA-DA sealants showed adhesive and air-leak prevention effects in ex vivo lung injury models and in small-animal pleural and tracheal injury models, and their tissue compatibility was observed in vivo over two weeks to one month.38 A gelatin-, tannic acid-, and transglutaminase-based sealant was also reported, in which micron-sized air bubbles were introduced to form alveolus-like aerated pores, contributing to the recovery of lung mechanical properties and reparative cellular responses.3 An elastic hydrogel sealant based on methacryloyl-substituted tropoelastin (MeTro) can adhere to soft tissues after photocrosslinking and shows elasticity and burst pressure suitable for sealing tissues such as the lung and blood vessels.39 Another study developed a body fluid-triggered adhesive hydrogel composed of PEG-SG and PL, which rapidly sealed femoral artery and cardiac wounds in large animals and closed lung injuries in both rat and large-animal models.40 These reports show that hydrogel materials for leakage repair are no longer limited to passive physical barriers but are increasingly designed to combine tissue adhesion, elasticity, biocompatibility, and mechanical behavior that more closely match native tissue. Nevertheless, many of these systems are still used mainly as in situ-forming gels or sprayable sealants. Their ability to control patch geometry, porous architecture, and preformed structural support remains limited. On this basis, a printable hydrogel patch with adjustable structure, lung-matched mechanical properties, and stable coverage performance may provide a useful strategy for postoperative pulmonary air-leakage repair.

In this study, a 3D-bioprinted hydrogel patch was prepared from a PLMA/PEGNB/XG composite bioink, and its structure could be adjusted by changing the printing angle and bioink composition. The optimized patch showed a Young's modulus within the range reported for native lung tissue. Cytocompatibility assays using RLE-6TN cells showed no obvious adverse effects on cell morphology, viability, or proliferation after exposure to patch extracts. In both ex vivo and in vivo SD rat lung air-leakage models, the patch covered the injured lung surface and reduced air leakage, most likely by providing a flexible physical barrier against local air-flow impact. Compared with conventional suturing and TA treatment, the patch + TA group showed improved sealing performance. Several limitations should also be noted. Although the bioink components were selected with the expectation of possible interfacial interactions, the adhesive mechanical properties of the final printed patch on wet lung tissue were not quantitatively measured. The ex vivo model also did not include a patch-only group, which limited direct evaluation of the patch's independent capacity for fixation and sealing. Future work should therefore include standardized wet-lung tissue adhesion tests and comparisons of patches fabricated with different printing paths or rotation angles. The patch's ability to remain fixed to lung tissue without auxiliary adhesive also needs to be examined. In addition, patch-only groups and clinically relevant pulmonary sealant controls should be included in more-refined wet-lung models. The in vivo degradation profile, degradation mechanism, and safety of the degradation products also require further investigation. Finally, large-animal studies will be necessary to assess the patch's performance and safety under conditions more closely reflecting clinical pulmonary air-leakage repair.

Author contributions

Fengyi Han: data curation, formal analysis, methodology, writing – original draft. Xiaopei Zhang: data curation, methodology. Ke Sun: formal analysis, investigation. Huaxin Song: investigation. Guohua Wang: investigation. Yuanfei Wang: funding acquisition, supervision, writing – review and editing. Tong Wu: conceptualization, methodology, supervision, writing – review and editing. Wenjie Jiao: funding acquisition, supervision, writing – review and editing.

Conflicts of interest

The authors declare no competing financial interest.

Supplementary Material

NA-008-D6NA00083E-s001

Acknowledgments

This research was supported by Natural Science Foundation of Shandong Province (ZR2020MH234), Qingdao Key Health Discipline Development Fund (2025-2027) and Shandong Provincial Key Medical and Health Discipline of Oral Medicine (2025-2027). The authors also gratefully acknowledge the support provided by the Youth Science and Technology Innovation Team of the Shandong Provincial Health Commission.

Data availability

The datasets used in this study are available from the corresponding author upon reasonable request.

Supplementary information (SI) is available. See DOI: https://doi.org/10.1039/d6na00083e.

Notes and references

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

NA-008-D6NA00083E-s001
NA-008-D6NA00083E-s001.pdf (772.4KB, pdf)

Data Availability Statement

The datasets used in this study are available from the corresponding author upon reasonable request.

Supplementary information (SI) is available. See DOI: https://doi.org/10.1039/d6na00083e.

Articles from Nanoscale Advances are provided here courtesy of Royal Society of Chemistry

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