AccScience Publishing / IJB / Online First / DOI: 10.36922/IJB025160146
RESEARCH ARTICLE

Converging Pvt1 signaling and 3D bioprinting technology for next-generation biodegradable tracheal replacement constructs

Wei Zuo1 Shao-Xiao Qiu2 Jian Cui1 Wen-Jian Liao1 Jun-Tao Zou1 Qing Jie Chen3* Fei Xu2*
Show Less
1 Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
2 Department of Respiratory and Critical Care Medicine, Shenzhen Bao’an People’s Hospital, Shenzhen, Guangdong, China
3 Department of Nuclear Medicine, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
Received: 14 April 2025 | Accepted: 8 September 2025 | Published online: 8 September 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
Abstract

Tracheal reconstruction remains a major clinical challenge due to persistent limitations in graft vascularization, epithelialization, and long-term mechanical compatibility. Conventional synthetic scaffolds and autologous grafts often fail to achieve durable integration, underscoring the need for innovative biofabrication strategies. In the present study, we elucidate the mechanoregulatory role of the long non-coding (lnc) RNA Pvt1 in controlling endothelial cell proliferation and focal adhesion dynamics during tracheal regeneration. Patient-specific tracheal stents were fabricated using extrusion-based three-dimensional bioprinting with hierarchically optimized architectures that combined polycaprolactone (PCL) copolymers with endothelial progenitor cell (EPC)-recruiting motifs. Computational fluid dynamics-guided nozzle path planning and in situ piezoelectric characterization enabled sub- 200 μm resolution in replicating native tracheal microtopography while maintaining 94% EPC viability after printing. Pvt1-enriched bioinks significantly enhanced vascularization, yielding a 2.3-fold increase in neovascularization compared with controls in rat tracheal defect models, alongside a 38% reduction in fibrotic markers. The constructs exhibited a dual-stage biodegradation profile (30% mass loss at eight weeks), providing mechanical compatibility with tissue ingrowth patterns as confirmed by micro-computed tomography-based strain mapping. Collectively, these findings demonstrate the convergence of lncRNA biology and precision bioprinting, delivering an off-the-shelf solution for complex tracheal reconstruction that addresses current barriers in graft epithelialization and immunomodulatory response. The study advances the translational potential of bioengineered airway substitutes through molecularly informed design principles.  

Graphical abstract
Keywords
Biodegradable materials
Endothelial cells
Personalized treatment
Pvt1
Tracheal repair
Three-dimensional printing
Funding
This study was supported by the National Natural Science Foundation of China (82260015), Jiangxi Key Research and Development Plan (No.20243BBI91018), the Jiangxi Provincial Health Commission Science and Technology Project (No.202410200), the Jiangxi Province Traditional Chinese Medicine Science and Technology Project (No.2023A0302), the Shenzhen Baoan People’s Hospital academic leader research start-up fund (No.202400120201), and the Shenzhen Baoan District Medical Health Research Project (No.BAGZL2024036).
Conflict of interest
The author(s) declared no potential conflicts of interest concerning the research, authorship, and/or publication of this article.
References
  1. Aydin S, Oz G, Dumanli A, Dongel I, Camas HE. Management of life-threatening tracheal emergencies. Ann Ital Chir. 2022;93:626-632.
  2. Wang H. Chronic adenoiditis. J Int Med Res. 2020;48(11):300060520971458. doi: 10.1177/0300060520971458
  3. Filip C, Socolov DG, Albu E, Filip C, Serban R, Popa RF. Serological parameters and vascular investigation for a better assessment in DVT during pregnancy—a systematic review. Medicina (Kaunas). 2021;57(2):160. doi: 10.3390/medicina57020160
  4. Sawamoto K, Alvarez Gonzalez J, Piechnik M, et al. Mucopolysaccharidosis IVA: diagnosis, treatment, and management. Int J Mol Sci. 2020;21(4):1517. doi: 10.3390/ijms21041517
  5. Cetrano E, Trezzi M, Secinaro A, et al. Bronchial mismatch as a predictor of respiratory failure after congenital tracheal stenosis repair. Ann Thorac Surg. 2018;105(4):1264-1271. doi: 10.1016/j.athoracsur.2017.10.046
  6. Ren J, Xu Y, Zhiyi G, et al. Reconstruction of the trachea and carina: surgical reconstruction, autologous tissue transplantation, allograft transplantation, and bioengineering. Thorac Cancer. 2022;13(3):284-295. doi: 10.1111/1759-7714.14315
  7. Richardson CM, Hart CK, Johnson KE, Gerber ME. Slide tracheoplasty. Otolaryngol Clin North Am. 2022;55(6):1253-1270. doi: 10.1016/j.otc.2022.07.014
  8. Zhang S, Xiao G, Peng R, Zhang P, Hong J. Clinical consequences of herpes simplex virus DNA in donor corneas: different prognosis and management of endothelial keratoplasty and deep anterior lamellar keratoplasty. J Clin Virol. 2020;129:104508. doi: 10.1016/j.jcv.2020.104508
  9. Broersen LHA, Andela CD, Dekkers OM, Pereira AM, Biermasz NR. Improvement but no normalization of quality of life and cognitive functioning after treatment for Cushing’s syndrome. J Clin Endocrinol Metab. 2019;104(10):4501-4512. doi: 10.1210/jc.2019-01054
  10. Wei G, Wang Y, Yang G, Wang Y, Ju R. Recent progress in nanomedicine for enhanced cancer chemotherapy. Theranostics. 2021;11(13):6370-6392. doi: 10.7150/thno.57828
  11. Shai SE, Lai YL, Hung YW, et al. De novo cartilage growth after implantation of a 3-D-printed tracheal graft in a porcine model. Am J Transl Res. 2020;12(7):3728-3740.
  12. Raguram A, Banskota S, Liu DR. Therapeutic in vivo delivery of gene editing agents. Cell. 2022;185(15):2806-2827. doi: 10.1016/j.cell.2022.03.045
  13. Perez RE, Santiago JC, Lopez MC, et al. Behavior of calcium, phosphorus, and parathormone before transplantation and in months 1, 3, 6, 9, and 12 after transplantation. Transplant Proc. 2020;52(4):1152-1156. doi: 10.1016/j.transproceed.2020.01.065
  14. Bertolin J, Sanchez V, Ribera A, et al. Treatment of skeletal and non-skeletal alterations of mucopolysaccharidosis type IVA by AAV-mediated gene therapy. Nat Commun. 2021;12(1):4944. doi: 10.1038/s41467-021-25697-y
  15. Chang NW, Dai HJ, Shih YY, et al. Biomarker identification of hepatocellular carcinoma using a methodical literature mining strategy. Database (Oxford). 2017;2017:bax082. doi: 10.1093/database/bax082
  16. Wu J, Lee B, Saha P, Kumta PN. A feasibility study of biodegradable magnesium–aluminum–zinc–calcium– manganese (AZXM) alloys for tracheal stent application. J Biomater Appl. 2019;33(8):1080-1093. doi: 10.1177/0885328218824775
  17. Luffy SA, Wu J, Kumta PN, Gilbert TW. Evaluation of magnesium alloys for use as an intraluminal tracheal for pediatric applications in a rat tracheal bypass model. J Biomed Mater Res B Appl Biomater. 2019;107(6):1844-1853. doi: 10.1002/jbm.b.34277
  18. Wu DT, Munguia-Lopez JG, Cho YW, et al. Polymeric scaffolds for dental, oral, and craniofacial regenerative medicine. Molecules. 2021;26(22):7043. doi: 10.3390/molecules26227043
  19. Gao C, Lu C, Jian Z, et al. 3D bioprinting for fabricating artificial skin tissue. Colloids Surf B Biointerfaces. 2021;208:112041. doi: 10.1016/j.colsurfb.2021.112041
  20. Stramiello JA, Mohammadzadeh A, Ryan J, Brigger MT. The role of bioresorbable intraluminal airway stents in pediatric tracheobronchial obstruction: a systematic review. Int J Pediatr Otorhinolaryngol. 2020;139:110405. doi: 10.1016/j.ijporl.2020.110405
  21. Feuerbach T, Kock S, Thommes M. Slicing parameter optimization for 3D printing of biodegradable drug-eluting tracheal stents. Pharm Dev Technol. 2020;25(6):650-658. doi: 10.1080/10837450.2020.1727921
  22. Yao W, Li S, Liu R, et al. Long non-coding RNA PVT1: a promising chemotherapy and radiotherapy sensitizer. Front Oncol. 2022;12:959208. doi: 10.3389/fonc.2022.959208
  23. Dvorak P, Leupen S, Soucek P. Functionally significant features in the 5ʹ untranslated region of the ABCA1 gene and their comparison in vertebrates. Cells. 2019; 8(6):623. doi: 10.3390/cells8060623
  24. Shi Y, Yang F, Wei S, Xu G. Identification of key genes affecting results of hyperthermia in osteosarcoma based on integrative ChIP-seq/TargetScan analysis. Med Sci Monit. 2017;23:2042-2048. doi: 10.12659/msm.901191
  25. Zhou C, Yi C, Yi Y, et al. LncRNA PVT1 promotes gemcitabine resistance of pancreatic cancer via activating Wnt/β-catenin and autophagy pathway through modulating the miR-619-5p/Pygo2 and miR-619-5p/ATG14 axes. Mol Cancer. 2020;19(1):118. doi: 10.1186/s12943-020-01237-y
  26. Chen S, Shen X. Long noncoding RNAs: functions and mechanisms in colon cancer. Mol Cancer. 2020;19(1):167. doi: 10.1186/s12943-020-01287-2
  27. Zhang M, Zhang L, Fu L, et al. Positive feedback regulation of lncRNA PVT1 and HIF2α contributes to clear cell renal cell carcinoma tumorigenesis and metastasis. Oncogene. 2021;40(37):5639-5650. doi: 10.1038/s41388-021-01971-7
  28. Shang R, Lal N, Lee CS, et al. Cardiac-specific VEGFB overexpression reduces lipoprotein lipase activity and improves insulin action in rat heart. Am J Physiol Endocrinol Metab. 2021;321(6):E753-E765. doi: 10.1152/ajpendo.00219.2021
  29. Ma L, Zhang Q, Hao J, Wang J, Wang C. LncRNA PVT1 exacerbates the inflammation and cell-barrier injury during asthma by regulating miR-149. J Biochem Mol Toxicol. 2020;34(11):e22563. doi: 10.1002/jbt.22563
  30. Lu X, Yu Y, Yin F, et al. Knockdown of PVT1 inhibits IL-1β- induced injury in chondrocytes by regulating miR-27b-3p/ TRAF3 axis. Int Immunopharmacol. 2020;79:106052. doi: 10.1016/j.intimp.2019.106052
  31. Gao B, Jing H, Gao M, et al. Long-segmental tracheal reconstruction in rabbits with pedicled tissue-engineered trachea based on a 3D-printed scaffold. Acta Biomater. 2019;97:177-186. doi: 10.1016/j.actbio.2019.07.043
  32. Gao M, Zhang H, Dong W, et al. Tissue-engineered trachea from a 3D-printed scaffold enhances whole-segment tracheal repair. Sci Rep. 2017;7(1):5246. doi: 10.1038/s41598-017-05518-3
  33. Park HS, Lee JS, Jung H, et al. An omentum-cultured 3D-printed artificial trachea: in vivo bioreactor. Artif Cells Nanomed Biotechnol. 2018;46(suppl 3):1131-1140. doi: 10.1080/21691401.2018.1533844
  34. Ahn CB, Son KH, Yu YS, Kim TH, Lee JI, Lee JW. Development of a flexible 3D printed scaffold with a cell-adhesive surface for artificial trachea. Biomed Mater. 2019;14(5):055001. doi: 10.1088/1748-605X/ab2a6c
  35. Bae SW, Lee KW, Park JH, et al. 3D bioprinted artificial trachea with epithelial cells and chondrogenic-differentiated bone marrow-derived mesenchymal stem cells. Int J Mol Sci. 2018;19(6):1624. doi: 10.3390/ijms19061624
  36. Park JH, Yoon JK, Lee JB, et al. Experimental tracheal replacement using 3-dimensional bioprinted artificial trachea with autologous epithelial cells and chondrocytes. Sci Rep. 2019;9(1):2103. doi: 10.1038/s41598-019-38565-z
  37. Taniguchi D, Matsumoto K, Tsuchiya T, et al. Scaffold-free trachea regeneration by tissue engineering with bio-3D printing. Interact Cardiovasc Thorac Surg. 2018;26(5):745-752. doi: 10.1093/icvts/ivx444
  38. Jensen EC. Quantitative analysis of histological staining and fluorescence using ImageJ. Anat Rec (Hoboken). 2013;296(3):378-381. doi: 10.1002/ar.22641
  39. Kaye R, Goldstein T, Grande DA, Zeltsman D, Smith LP. A 3-dimensional bioprinted tracheal segment implant pilot study: rabbit tracheal resection with graft implantation. Int J Pediatr Otorhinolaryngol. 2019;117: 175-178. doi: 10.1016/j.ijporl.2018.11.010
  40. Lee KY, Mooney DJ. Alginate: properties and biomedical applications. Prog Polym Sci. 2012;37(1):106-126. doi: 10.1016/j.progpolymsci.2011.06.003
  41. Liu M, Liu Z, Chen Y, et al. Dendritic epidermal T cells secreting exosomes promote the proliferation of epidermal stem cells to enhance wound re-epithelialization. Stem Cell Res Ther. 2022;13(1):438. doi: 10.1186/s13287-022-02783-6
  42. Zheng J, Hu L, Cheng J, et al. lncRNA PVT1 promotes the angiogenesis of vascular endothelial cell by targeting miR-26b to activate CTGF/ANGPT2. Int J Mol Med. 2018;41(3):1742-1752. doi: 10.3892/ijmm.2018.3595
  43. Schober A, Nazari-Jahantigh M, Wei Y, et al. MicroRNA- 126-5p promotes endothelial proliferation and limits atherosclerosis by suppressing Dlk1. Nat Med. 2014;20(4):368-376. doi: 10.1038/nm.3487
  44. Shirodkar AV, St Bernard R, Gavryushova A, et al. A mechanistic role for DNA methylation in endothelial cell-enriched gene expression: relationship with DNA replication timing. Blood. 2013;121(17): 3531-3540. doi: 10.1182/blood-2013-01-479170
  45. Herman AB, Tsitsipatis D, Gorospe M. Integrated lncRNA function upon genomic and epigenomic regulation. Mol Cell. 2022;82(12):2252-2266. doi: 10.1016/j.molcel.2022.05.027
  46. Welter S, Essaleh W. Management of tracheobronchial injuries. J Thorac Dis. 2020;12(10):6143-6151. doi: 10.21037/jtd-2019-as-05
  47. Frauenfelder C, Maughan E, Kenth J, et al. Tracheal resection for critical airway obstruction in Morquio A syndrome. Case Rep Pediatr. 2023;2023:7976780. doi: 10.1155/2023/7976780
  48. Leivaditis V, Skevis K, Mulita F, et al. Advancements in the management of postoperative air leak following thoracic surgery: from traditional practices to innovative therapies. Medicina (Kaunas). 2024;60(5):802. doi: 10.3390/medicina60050802
  49. Genden EM, Laitman BM. Human tracheal transplantation. Transplantation. 2023;107(8):1698-1705. doi: 10.1097/TP.0000000000004509
  50. Delaere P, Meulemans J, Vranckx J, Vos R, Poorten VV. Tracheal transplantation. Thorac Surg Clin. 2025;35(1):131-141. doi: 10.1016/j.thorsurg.2024.07.002
  51. Samat AA, Hamid ZAA, Yahaya BH. Tissue engineering for tracheal replacement: strategies and challenges. Adv Exp Med Biol. 2022;137:137-163. doi: 10.1007/5584_2022_707
  52. Tracy T, Wu L, Liu X, Cheng S, Li X. 3D printing: Innovative solutions for patients and pharmaceutical industry. Int J Pharm. 2023;631:122480. doi: 10.1016/j.ijpharm.2022.122480
  53. Uchida DT, Bruschi ML. 3D printing as a technological strategy for the personalized treatment of wound healing. AAPS PharmSciTech. 2023;24(1):25. doi: 10.1208/s12249-023-02503-0
  54. Serrano DR, Kara A, Yuste I, et al. 3D printing technologies in personalized medicine, nanomedicines, and biopharmaceuticals. Pharmaceutics. 2023;15(2):313. doi: 10.3390/pharmaceutics15020313
  55. Wang P, Sun Y, Shi X, Shen H, Ning H, Liu H. 3D printing of tissue engineering scaffolds: a focus on vascular regeneration. Bio-Des Manuf. 2021;4(2):344-378. doi: 10.1007/s42242-020-00109-0
  56. Guerra AJ, Cano P, Rabionet M, Puig T, Ciurana J. 3D-printed PCL/PLA composite stents: towards a new solution to cardiovascular problems. Materials (Basel). 2018;11(9):1679. doi: 10.3390/ma11091679
  57. Townsend JM, Hukill ME, Fung KM, et al. Biodegradable electrospun patch containing cell adhesion or antimicrobial compounds for trachea repair in vivo. Biomed Mater. 2020;15(2):025003. doi: 10.1088/1748-605X/ab5e1b
  58. Genden EM, Miles BA, Harkin TJ, et al. Single-stage long-segment tracheal transplantation. Am J Transplant. 2021;21(10):3421-3427. doi: 10.1111/ajt.16752
  59. Park JH, Ahn M, Park SH, et al. 3D bioprinting of a trachea-mimetic cellular construct of a clinically relevant size. Biomaterials. 2021;279:121246. doi: 10.1016/j.biomaterials.2021.121246
  60. Wahbeh JM, Lama J, Park S, Ebramzadeh E, Hollister SJ, Sangiorgio SN. Degradation and fatigue behavior of 3D-printed bioresorbable tracheal splints. J Biomed Mater Res B Appl Biomater. 2024;112(12):e35501. doi: 10.1002/jbm.b.35501
  61. Ji K, Zhang Q, Song W, et al. LncRNA PVT1 promotes cell proliferation, invasion, and migration and inhibits cell apoptosis by phosphorylating YAP. Can J Gastroenterol Hepatol. 2022;2022:5332129. doi: 10.1155/2022/5332129
  62. Li X, Ren H. Long noncoding RNA PVT1 promotes tumor cell proliferation, invasion, migration and inhibits apoptosis in oral squamous cell carcinoma by regulating miR-150-5p/ GLUT-1. Oncol Rep. 2020;44(3):1101-1112. doi: 10.3892/or.2020.7706
  63. Cui M, Chang Y, Fang QG, et al. Non-coding RNA Pvt1 promotes cancer stem cell–like traits in nasopharyngeal cancer via inhibiting miR-1207. Pathol Oncol Res. 2019;25(4):1411-1422. doi: 10.1007/s12253-018-0453-1
  64. Du J, Zheng L, Gao P, et al. A small-molecule cocktail promotes mammalian cardiomyocyte proliferation and heart regeneration. Cell Stem Cell. 2022;29(4):545-558.e13. doi: 10.1016/j.stem.2022.03.009

 

 

 



Share
Back to top
International Journal of Bioprinting, Electronic ISSN: 2424-8002 Print ISSN: 2424-7723, Published by AccScience Publishing