A bio-adaptive physical hydrogel enables dynamic tissue engineering for tracheal reconstruction

1. Etienne, H. et al. Tracheal replacement. Eur. Respir. J. 51, 1702211 (2018).

   Google Scholar 

2. Wright, C. D. et al. Postintubation tracheal stenosis: management and results 1993 to 2017. Ann. Thorac. Surg. 108, 1471–1477 (2019).

   Google Scholar 

3. Guibert, N. et al. Treatment of post-transplant complex airway stenosis with a three-dimensional, computer-assisted customized airway stent. Am. J. Respir. Crit. Care Med. 195, e31–e33 (2017).

   Google Scholar 

4. Ali, S. R. & Mehta, A. C. Alive in the airways: live endobronchial foreign bodies. Chest 151, 481–491 (2017).

   Google Scholar 

5. Oliveira, J. F. D. et al. In Tracheostomy 11–22 (Springer, 2018).

6. Hollenhorst, M. I. et al. Bitter taste signaling in tracheal epithelial brush cells elicits innate immune responses to bacterial infection. J. Clin. Invest. 132, e150951 (2022).

7. Tang, H. et al. A bioengineered trachea-like structure improves survival in a rabbit tracheal defect model. Sci. Transl. Med. 15, eabo4272 (2023).

   Google Scholar 

8. Xu, Y. et al. Biomimetic trachea engineering via a modular ring strategy based on bone-marrow stem cells and atelocollagen for use in extensive tracheal reconstruction. Adv. Mater. 34, 2106755 (2022).

   Google Scholar 

9. Yang, S. et al. Morphogens enable interacting supracellular phases that generate organ architecture. Science 382, eadg5579 (2023).

   Google Scholar 

10. Duda, G. N. et al. The decisive early phase of bone regeneration. Nat. Rev. Rheumatol. 19, 78–95 (2023).

    Google Scholar 

11. Laufer, E., Nelson, C. E., Johnson, R. L., Morgan, B. A. & Tabin, C. Sonic hedgehog and Fgf-4 act through a signaling cascade and feedback loop to integrate growth and patterning of the developing limb bud. Cell 79, 993–1003 (1994).

    Google Scholar 

12. Liu, Z., Wan, X., Wang, Z. L. & Li, L. Electroactive biomaterials and systems for cell fate determination and tissue regeneration: design and applications. Adv. Mater. 33, e2007429 (2021).

    Google Scholar 

13. Huang, G. et al. Functional and biomimetic materials for engineering of the three-dimensional cell microenvironment. Chem. Rev. 117, 12764–12850 (2017).

    Google Scholar 

14. Moroni, L. et al. Biofabrication strategies for 3D in vitro models and regenerative medicine. Nat. Rev. Mater. 3, 21–37 (2018).

    Google Scholar 

15. Tang, H., Sun, W., Chen, Y., She, Y. & Chen, C. Future directions for research on tissue-engineered trachea. Bio-Des. Manuf. 5, 627–632 (2022).

16. Yu, L. & Ding, J. Injectable hydrogels as unique biomedical materials. Chem. Soc. Rev. 37, 1473–1481 (2008).

    Google Scholar 

17. Shi, J., Yu, L. & Ding, J. PEG-based thermosensitive and biodegradable hydrogels. Acta Biomater. 128, 42–59 (2021).

    Google Scholar 

18. Chen, X. et al. An injectable and active hydrogel induces mutually enhanced mild magnetic hyperthermia and ferroptosis. Biomaterials 298, 122139 (2023).

19. Patel, M., Lee, H. J., Park, S., Kim, Y. & Jeong, B. Injectable thermogel for 3D culture of stem cells. Biomaterials 159, 91–107 (2018).

    Google Scholar 

20. Yu, J. et al. Single-dose physically cross-linked hyaluronic acid and lipid hybrid nanoparticles containing cyclic guanosine monophosphate-adenosine monophosphate eliminate established tumors. ACS Nano 18, 29942–29955 (2024).

    Google Scholar 

21. Sarmah, D. & Karak, N. Physically cross-linked starch/hydrophobically-associated poly(acrylamide) self-healing mechanically strong hydrogel. Carbohydr. Polym. 289, 119428 (2022).

    Google Scholar 

22. Tong, X. & Yang, F. Sliding hydrogels with mobile molecular ligands and crosslinks as 3D stem cell niche. Adv. Mater. 28, 7257 (2016).

    Google Scholar 

23. Ruscitto, A. et al. Lgr5-expressing secretory cells form a Wnt inhibitory niche in cartilage critical for chondrocyte identity. Cell Stem Cell 30, 1179–1198.e1177 (2023).

    Google Scholar 

24. Dai, M. et al. A well defect-suitable and high-strength biomimetic squid type II gelatin hydrogel promoted in situ costal cartilage regeneration via dynamic immunomodulation and direct induction manners. Biomaterials 240, 119841 (2020).

    Google Scholar 

25. Hou, M. et al. Dominant role of in situ native cartilage niche for determining the cartilage type regenerated by BMSCs. Bioact. Mater. 13, 149–160 (2022).

    Google Scholar 

26. Xiang, L. et al. Motion lubrication suppressed mechanical activation via hydrated fibrous gene patch for tendon healing. Sci. Adv. 9, eadc9375 (2023).

    Google Scholar 

27. Yu, L. et al. Comparative studies of thermogels in preventing post-operative adhesions and corresponding mechanisms. Biomater. Sci. 2, 1100–1109 (2014).

    Google Scholar 

28. Deng, J. et al. Versatile hypoxic extracellular vesicles laden in an injectable and bioactive hydrogel for accelerated bone regeneration. Adv. Funct. Mater. 33, 2211664 (2023).

29. Zhang, H. et al. Maintaining hypoxia environment of subchondral bone alleviates osteoarthritis progression. Sci. Adv. 9, eabo7868 (2023).

    Google Scholar 

30. Zhang, Y. et al. Dual functions of microRNA-17 in maintaining cartilage homeostasis and protection against osteoarthritis. Nat. Commun. 13, 2447 (2022).

    Google Scholar 

31. Castilho, M., Mouser, V., Chen, M., Malda, J. & Ito, K. Bi-layered micro-fibre reinforced hydrogels for articular cartilage regeneration. Acta Biomater. 95, 297–306 (2019).

    Google Scholar 

32. de Roy, L. et al. Structure-function of cartilage in osteoarthritis: an ex-vivo correlation analysis between its structural, viscoelastic and frictional properties. Acta Biomater. 190, 293–302 (2024).

    Google Scholar 

33. Nilssen, Y. et al. Tracheal cancer: a rare and deadly but potentially curable disease that also affects younger people. Eur. J. Cardiothorac. Surg. 64, ezad244 (2023).

34. Boogaard, R. et al. Tracheomalacia and bronchomalacia in children: incidence and patient characteristics. Chest 128, 3391–3397 (2005).

    Google Scholar 

35. Furlow, P. W. & Mathisen, D. J. Surgical anatomy of the trachea. Ann. Cardiothorac. Surg. 7, 255 (2018).

    Google Scholar 

36. Samat, A. A., Hamid, Z. A. A., Yahaya, B. H. & Mariatti Jaafar, M. In Advances in Experimental Medicine and Biology (2022).

37. Xia, D. et al. Tissue-engineered trachea from a 3D-printed scaffold enhances whole-segment tracheal repair in a goat model. J. Tissue Eng. Regen. Med. 13, 694–703 (2019).

    Google Scholar 

38. Xu, Y. et al. Photocrosslinked natural hydrogel composed of hyaluronic acid and gelatin enhances cartilage regeneration of decellularized trachea matrix. Mater. Sci. Eng. C 120, 111628 (2021).

39. van Gastel, N. et al. Lipid availability determines fate of skeletal progenitor cells via SOX9. Nature 579, 111–117 (2020).

    Google Scholar 

40. Li, D. et al. Stable subcutaneous cartilage regeneration of bone marrow stromal cells directed by chondrocyte sheet. Acta Biomater. 54, 321–332 (2017).

    Google Scholar 

41. Daly, A. C. & Kelly, D. J. Biofabrication of spatially organised tissues by directing the growth of cellular spheroids within 3D printed polymeric microchambers. Biomaterials 197, 194–206 (2019).

    Google Scholar 

42. Decker, R. S., Koyama, E. & Pacifici, M. Articular cartilage: structural and developmental intricacies and questions. Curr. Osteoporos. Rep. 13, 407–414 (2015).

    Google Scholar 

43. Bhattacharjee, M. et al. Tissue engineering strategies to study cartilage development, degeneration and regeneration. Adv. Drug Deliv. Rev. 84, 107–122 (2015).

    Google Scholar 

44. Yang, B. et al. Recapitulating hypoxic metabolism in cartilaginous organoids via adaptive cell-matrix interactions enhances histone lactylation and cartilage regeneration. Nat. Commun. 16, 2711 (2025).

    Google Scholar 

45. Yang, W. & Lefebvre, V. PTPN11 in cartilage development, adult homeostasis, and diseases. Bone Res. 13, 53 (2025).

    Google Scholar 

46. Woods, J. P., Rackley, A., Kwon, H. R. & Olson, L. E. PDGFRα signaling regulates cartilage and fibrous tissue differentiation during synovial joint development. Nat. Commun. 16, 4041 (2025).

    Google Scholar 

47. Minamoto, K. & Pinsky, D. J. Recipient iNOS but not eNOS deficiency reduces luminal narrowing in tracheal allografts. J. Exp. Med. 196, 1321–1333 (2002).

    Google Scholar 

48. Liu, S. et al. A tissue injury sensing and repair pathway distinct from host pathogen defense. Cell 186, 2127–2143.e2122 (2023).

    Google Scholar 

49. Griffin, D. R. et al. Activating an adaptive immune response from a hydrogel scaffold imparts regenerative wound healing. Nat. Mater. 20, 560–569 (2021).

    Google Scholar 

50. Yu, L., Chang, G., Zhang, H. & Ding, J. Temperature-induced spontaneous sol–gel transitions of poly(D,L-lactic acid-co-glycolic acid)-b-poly(ethylene glycol)-b-poly(D,L-lactic acid-co-glycolic acid) triblock copolymers and their end-capped derivatives in water. J. Polym. Sci. Part A: Polym. Chem. 45, 1122–1133 (2007).

    Google Scholar 

Download references

Author notes

1. These authors contributed equally: Hai Tang, Hanchen Wang, Weiyan Sun, Yi Chen.

Authors and Affiliations

1. Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China

   Hai Tang, Weiyan Sun, Yi Chen, Ziyin Pan, Qingfeng Bai, Weikang Lin, Yulong Hu, Lei Wang, Lei Zhang, Yunlang She, Xuefei Hu & Chang Chen

2. Shanghai Engineering Research Center of Lung Transplantation, Shanghai, China

   Hai Tang, Weiyan Sun, Yi Chen, Ziyin Pan, Qingfeng Bai, Weikang Lin, Yulong Hu, Lei Wang, Lei Zhang, Yunlang She, Xuefei Hu & Chang Chen

3. State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Fudan University, Shanghai, China

   Hanchen Wang, Yaoben Wang, Jiandong Ding & Lin Yu

4. Department of Cardiothoracic Surgery, Ningbo No.2 Hospital, Ningbo, Zhejiang, China

   Minglei Yang & Guofang Zhao

5. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA

   Kewen Lei

Contributions

H.T., H.W., and W.S. designed the study and conducted data curation and analysis. H.T. oversaw all experiments and contributed to cell experiments, animal surgery, sample collection, histological analysis, mechanical and biochemical testing. H.W. and W.S. contributed to cell experiments, animal surgery and sample collection. Y.C. contributed to RNA sequencing, data curation and analysis. H.W. and Y.W. contributed to experimental material fabrication, characterization, data collation and analysis. Z.P., Q.B., W.L., and L.W. contributed to cell experiments, animal studies and data analysis. Z.P., Q.B., Y.H., M.Y., G.Z., and L.Z. contributed to animal surgery, data collation and validation. Y.S. and X.H. contributed to data validation and writing and review of the manuscript. J.D. and K.L. contributed to the manuscript’s writing and review. C.C. and L.Y. supervised the study and contributed to the manuscript’s design, writing and review.

Corresponding authors

Correspondence to Weiyan Sun, Lin Yu or Chang Chen.

Competing interests

The authors declare no competing interests.

Peer review information

Nature Communications thanks Tendy Chiang, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. A peer review file is available.

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Reprints and permissions