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RESEARCH ARTICLE

Composite bacterial cellulose–psoralen– polycaprolactone scaffold for enhanced bone regeneration and infection prevention in open bone defects

Bo Jiang1 ,  Tianming Wang2 ,  Fengyong Mao1 ,  Xiao Zhao2 ,  Qingqiang Yao2 ,  Jiayi Li2* ,  Yang Huang3* ,  Jianchao Gui4*
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1 Department of Orthopedics, Children’s Hospital of Nanjing Medical University, Nanjing, China
2 Department of Orthopedic Surgery, Institute of Digital Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
3 International Innovation Center for Forest Chemicals & Materials and Jiangsu Co-Innovation Center of Efficient Processing & Utilization of Forest Resources, Nanjing Forestry University, Nanjing, China
4 Sports Medicine and Joint Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
IJB 2025, 11(2), 370–386; https://doi.org/10.36922/ijb.8357
Submitted: 1 January 2025 | Accepted: 7 February 2025 | Published: 7 February 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/ )
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Abstract

This study aimed to improve the treatment of open bone defects by developing a hybrid scaffold that enhances bone regeneration and prevents infections. Polycaprolactone (PCL) scaffolds were incorporated for mechanical support, while bacterial cellulose (BC) membranes facilitated psoralen (Pso) delivery. PCL scaffolds were fabricated via three-dimensional (3D) printing, and BC was extracted from fungi to prepare three types of scaffolds as follows: PCL, BC–PCL, and BC–Pso–PCL. The scaffolds were characterized through scanning electron microscopy, contact angle measurement, and infrared spectroscopy. Biocompatibility was assessed by cytotoxicity (CCK-8) assay, cell migration assay, live/dead cell staining, and cell proliferation experiments. Antibacterial effects were tested under a simulated bacterial environment. Osteogenic performance was evaluated by alkaline phosphatase (ALP) activity, Alizarin red staining (ARS), and immunofluorescence after osteogenic induction. Quantitative reverse transcriptase PCR (qRT-PCR) and Western blotting were performed to analyze bone regeneration and angiogenesis markers. Bone regeneration efficacy was assessed in vivo using a 5 mm critical-sized cranial bone defect model in rats. Biocompatibility studies demonstrated that all three scaffolds showed good biocompatibility. BC–Pso–PCL scaffold effectively inhibited Staphylococcus aureus growth. The ALP staining and ARS following osteogenic induction indicated that the BC–Pso–PCL group exhibited superior ALP activity and mineralized nodule formation compared to other groups. Subsequent immunofluorescence, qRT-PCR, and Western blot further confirmed the superior osteogenic performance of the BC–Pso–PCL scaffold. In vivo experiments demonstrated that the BC–Pso–PCL scaffold achieved the highest level of new bone formation in rat cranial defects. In conclusion, the BC–Pso–PCL scaffold demonstrated superior biocompatibility in cytotoxicity, cell migration, live/dead staining, and proliferation assays, while also promoting bone regeneration and angiogenesis. The in vivo study further confirmed its superior potential in bone formation. These findings highlight the BC–Pso– PCL hybrid scaffold as a promising implantable scaffold for treating open bone defects, with potential for future clinical applications.

Graphical abstract
Keywords
Composite scaffold
Bone infection
Bone regeneration
Drug delivery
Psoralen
Funding
This study was supported by the National Key Research and Development Program of China (2023YFB3813000), the Science and Technology Project of Jiangsu Province (BE2022718), Nanjing International Joint Research and Development Project (202201028), and the National Natural Science Foundation of China (82102567).
Conflict of interest
The authors declare they have no competing interests
References
  1. Wang J, Zhang Y, Tang Q, Zhang Y, Yin Y, Chen L. Application of antioxidant compounds in bone defect repair. Antioxidants (Basel). 2024;13(7):789. doi: 10.3390/antiox13070789
  2. Masters EA, Ricciardi BF, Bentley KLM, Moriarty TF, Schwarz EM, Muthukrishnan G. Skeletal infections: microbial pathogenesis, immunity and clinical management. Nat Rev Microbiol. 2022;20(7):385-400. doi: 10.1038/s41579-022-00686-0
  3. Lázár V, Snitser O, Barkan D, Kishony R. Antibiotic combinations reduce Staphylococcus aureus clearance. Nature. 2022;610(7932):540-546. doi: 10.1038/s41586-022-05260-5
  4. He Y, Liu X, Lei J, et al. Bioactive VS4-based sonosensitizer for robust chemodynamic, sonodynamic and osteogenic therapy of infected bone defects. J Nanobiotechnology. 2024;22(1):31. doi: 10.1186/s12951-023-02283-6
  5. Ma L, Cheng Y, Feng X, et al. A Janus-ROS healing system promoting infectious bone regeneration via sono-epigenetic modulation. Adv Mater. 2024;36(2): e2307846. doi: 10.1002/adma.202307846
  6. Yuan X, Zhu W, Yang Z, et al. Recent advances in 3D printing of smart scaffolds for bone tissue engineering and regeneration. Adv Mater. 2024;36(34):e2403641. doi: 10.1002/adma.202403641
  7. Wang J, Wu Y, Li G, et al. Engineering large-scale self-mineralizing bone organoids with bone matrix-inspired hydroxyapatite hybrid bioinks. Adv Mater. 2024;36(30):e2309875. doi: 10.1002/adma.202309875
  8. Lee H, Han G, Na Y, et al. 3D-printed tissue-specific nanospike-based adhesive materials for time-regulated synergistic tumor therapy and tissue regeneration in vivo. Adv Funct Mater. 2024;34(48):2406237. doi: 10.1002/adfm.202406237
  9. Xue Y, Niu W, Wang M, Chen M, Guo Y, Lei B. Engineering a biodegradable multifunctional antibacterial bioactive nanosystem for enhancing tumor photothermo-chemotherapy and bone regeneration. ACS Nano. 2020;14(1):442-453. doi: 10.1021/acsnano.9b06145
  10. Fang L, Liu Z, Wang C, et al. Vascular restoration through local delivery of angiogenic factors stimulates bone regeneration in critical size defects. Bioact Mater. 2024;36:580-594. doi: 10.1016/j.bioactmat.2024.07.003
  11. Shim JH, Yoon MC, Jeong CM, et al. Efficacy of rhBMP-2 loaded PCL/PLGA/β-TCP guided bone regeneration membrane fabricated by 3D printing technology for reconstruction of calvaria defects in rabbit. Biomed Mater. 2014;9(6):065006. doi: 10.1088/1748-6041/9/6/065006
  12. Wang J, Tavakoli J, Tang Y. Bacterial cellulose production, properties and applications with different culture methods - a review. Carbohydr Polym. 2019;219:63-76. doi: 10.1016/j.carbpol.2019.05.008
  13. Ren Y, Song X, Tan L, et al. A review of the pharmacological properties of psoralen. Front Pharmacol. 2020;11: 571535. doi: 10.3389/fphar.2020.571535
  14. An J, Yang H, Zhang Q, et al. Natural products for treatment of osteoporosis: the effects and mechanisms on promoting osteoblast-mediated bone formation. Life Sci. 2016;147:46-58. doi: 10.1016/j.lfs.2016.01.024
  15. Zhang T, Han W, Zhao K, et al. Psoralen accelerates bone fracture healing by activating both osteoclasts and osteoblasts. FASEB J. 2019;33(4):5399-5410. doi: 10.1096/fj.201801797R
  16. Liu L, Zhang L, Cui ZX, Liu XY, Xu W, Yang XW. Transformation of psoralen and isopsoralen by human intestinal microbial in vitro, and the biological activities of its metabolites. Molecules. 2019;24(22):4080. doi: 10.3390/molecules24224080
  17. Thakur A, Sharma R, Jaswal VS, Nepovimova E, Chaudhary A, Kuca K. Psoralen: a biologically important coumarin with emerging applications. Mini Rev Med Chem. 2020;20(18):1838-1845. doi: 10.2174/1389557520666200429101053
  18. Galiatsatos P, Maydan DD, Macalpine E, et al. Psoralen: a narrative review of current and future therapeutic uses. J Cancer Res Clin Oncol. 2024;150(3):130. doi: 10.1007/s00432-024-05648-y
  19. Huang K, Wu B, Hou Z, et al. Psoralen downregulates osteoarthritis chondrocyte inflammation via an estrogen-like effect and attenuates osteoarthritis. Aging (Albany NY). 2022;14(16):6716-6726. doi: 10.18632/aging.204245
  20. Yin BF, Li ZL, Yan ZQ, et al. Psoralen alleviates radiation-induced bone injury by rescuing skeletal stem cell stemness through AKT-mediated upregulation of GSK-3β and NRF2. Stem Cell Res Ther. 2022;13(1):241. doi: 10.1186/s13287-022-02911-2
  21. Huang Y, Liao L, Su H, et al. Psoralen accelerates osteogenic differentiation of human bone marrow mesenchymal stem cells by activating the TGF-β/Smad3 pathway. Exp Ther Med. 2021;22(3):940. doi: 10.3892/etm.2021.10372
  22. Huang K, Sun YQ, Chen XF, et al. Psoralen, a natural phytoestrogen, improves diaphyseal fracture healing in ovariectomized mice: a preliminary study. Exp Ther Med. 2021;21(4):368. doi: 10.3892/etm.2021.9799
  23. Li JP, Xie BP, Zhang WJ, et al. [Psoralen inhibits RAW264.7 differentiation into osteoclasts and bone resorption by regulating CD4+T cell differentiation]. Zhongguo Zhong Yao Za Zhi. 2018;43(6):1228-1234. doi: 10.19540/j.cnki.cjcmm.20180104.017
  24. Chai L, Zhou K, Wang S, et al. Psoralen and bakuchiol ameliorate M-CSF plus RANKL-induced osteoclast differentiation and bone resorption via inhibition of AKT and AP-1 pathways in vitro. Cell Physiol Biochem. 2018;48(5):2123-2133. doi: 10.1159/000492554
  25. Białczyk A, Wełniak A, Kamińska B, Czajkowski R. Oxidative stress and potential antioxidant therapies in vitiligo: a narrative review. Mol Diagn Ther. 2023;27(6):723-739. doi: 10.1007/s40291-023-00672-z
  26. Ma Q, Bian M, Gong G, et al. Synthesis and evaluation of bakuchiol derivatives as potent anti-inflammatory agents in vitro and in vivo. J Nat Prod. 2022;85(1):15-24. doi: 10.1021/acs.jnatprod.1c00377
  27. Guo Z, Li P, Wang C, et al. Five constituents contributed to the psoraleae fructus-induced hepatotoxicity via mitochondrial dysfunction and apoptosis. Front Pharmacol. 2021;12:682823. doi: 10.3389/fphar.2021.682823
  28. Zhang R, Shi W, Li L, Huang X, Xu D, Wu L. Biological activity and health promoting effects of psoralidin. Pharmazie. 2019;74(2):67-72. doi: 10.1691/ph.2019.8619
  29. Chiou WF, Don MJ, Liao JF, Wei BL. Psoralidin inhibits LPS-induced iNOS expression via repressing Syk-mediated activation of PI3K-IKK-IκB signaling pathways. Eur J Pharmacol. 2011;650(1):102-109. doi: 10.1016/j.ejphar.2010.10.004
  30. Kong L, Ma R, Yang X, et al. Psoralidin suppresses osteoclastogenesis in BMMs and attenuates LPS-mediated osteolysis by inhibiting inflammatory cytokines. Int Immunopharmacol. 2017;51:31-39. doi: 10.1016/j.intimp.2017.07.003
  31. Wang X, Yang X, Xiao X, Li X, Chen C, Sun D. Biomimetic design of platelet-rich plasma controlled release bacterial cellulose/hydroxyapatite composite hydrogel for bone tissue engineering. Int J Biol Macromol. 2024;269(Pt 2):132124. doi: 10.1016/j.ijbiomac.2024.132124
  32. Rivero-Buceta V, Aguilar MR, Hernández-Arriaga AM, et al. Anti-staphylococcal hydrogels based on bacterial cellulose and the antimicrobial biopolyester poly(3- hydroxy-acetylthioalkanoate-co-3-hydroxyalkanoate). Int J Biol Macromol. 2020;162:1869-1879. doi: 10.1016/j.ijbiomac.2020.07.289
  33. Cao Z, Wang H, Chen J, et al. Silk-based hydrogel incorporated with metal-organic framework nanozymes for enhanced osteochondral regeneration. Bioact Mater. 2022;20:221-242. doi: 10.1016/j.bioactmat.2022.05.025
  34. Yuan S, Zheng B, Zheng K, et al. Immunoregulation in skull defect repair with a smart hydrogel loaded with mesoporous bioactive glasses. Biomater Res. 2024;28:0074. doi: 10.34133/bmr.0074
  35. Wasti S, Adhikari S. Use of biomaterials for 3d printing by fused deposition modeling technique: a review. Front Chem. 2020;8:315. doi: 10.3389/fchem.2020.00315
  36. Xie Y, Zheng Y, Fan J, Wang Y, Yue L, Zhang N. Novel electronic-ionic hybrid conductive composites for multifunctional flexible bioelectrode based on in situ synthesis of poly(dopamine) on bacterial cellulose. ACS Appl Mater Interfaces. 2018;10(26):22692-22702. doi: 10.1021/acsami.8b05345
  37. Nie R, Zhang QY, Feng ZY, et al. Hydrogel-based immunoregulation of macrophages for tissue repair and regeneration. Int J Biol Macromol. 2024;268(Pt 1):131643. doi: 10.1016/j.ijbiomac.2024.131643
  38. Duda GN, Geissler S, Checa S, Tsitsilonis S, Petersen A, Schmidt-Bleek K. The decisive early phase of bone regeneration. Nat Rev Rheumatol. 2023;19(2):78-95. doi: 10.1038/s41584-022-00887-0
  39. Yang N, Liu Y. The role of the immune microenvironment in bone regeneration. Int J Med Sci. 2021;18(16):3697-3707. doi: 10.7150/ijms.61080
  40. Riegger J, Schoppa A, Ruths L, Haffner-Luntzer M, Ignatius A. Oxidative stress as a key modulator of cell fate decision in osteoarthritis and osteoporosis: a narrative review. Cell Mol Biol Lett. 2023;28(1):76. doi: 10.1186/s11658-023-00489-y
  41. Iantomasi T, Romagnoli C, Palmini G, et al. Oxidative stress and inflammation in osteoporosis: molecular mechanisms involved and the relationship with microRNAs. Int J Mol Sci. 2023;24(4):3772. doi: 10.3390/ijms24043772
  42. Zaidi M, Yuen T, Kim SM. Pituitary crosstalk with bone, adipose tissue and brain. Nat Rev Endocrinol. 2023;19(12):708-721. doi: 10.1038/s41574-023-00894-5
  43. Wang T, Ye J, Zhang Y, et al. Role of oxytocin in bone. Front Endocrinol (Lausanne). 2024;15:1450007.

doi: 10.3389/fendo.2024.1450007

  1. Liu M, Banerjee R, Rossa C Jr, D’Silva NJ. RAP1-RAC1 signaling has an important role in adhesion and migration in HNSCC. J Dent Res. 2020;99(8):959-968. doi: 10.1177/0022034520917058
  2. Peña OA, Martin P. Cellular and molecular mechanisms of skin wound healing. Nat Rev Mol Cell Biol. 2024;25(8):599-616. doi: 10.1038/s41580-024-00715-1
  3. Wang T, Ouyang H, Luo Y, et al. Rehabilitation exercise-driven symbiotic electrical stimulation system accelerating bone regeneration. Sci Adv. 2024;10(1):eadi6799. doi: 10.1126/sciadv.adi6799
  4. Sun H, Xu J, Wang Y, et al. Bone microenvironment regulative hydrogels with ROS scavenging and prolonged oxygen-generating for enhancing bone repair. Bioact Mater. 2023;24:477-496. doi: 10.1016/j.bioactmat.2022.12.021
  5. Gao Z, Song Z, Guo R, et al. Mn single-atom nanozyme functionalized 3D-printed bioceramic scaffolds for enhanced antibacterial activity and bone regeneration. Adv Healthc Mater. 2024;13(13):e2303182. doi: 10.1002/adhm.202303182
  6. Zhang Q, Jing Y, Gong Q, et al. Endorepellin downregulation promotes angiogenesis after experimental traumatic brain injury. Neural Regen Res. 2024;19(5):1092-1097. doi: 10.4103/1673-5374.382861
  7. Lin J, Shi Y, Men Y, Wang X, Ye J, Zhang C. Mechanical roles in formation of oriented collagen fibers. Tissue Eng Part B Rev. 2020;26(2):116-128. doi: 10.1089/ten.TEB.2019.0243
  8. Wang H, Hsu YC, Wang C, et al. Conductive and enhanced mechanical strength of Mo2Ti2C3 MXene-based hydrogel promotes neurogenesis and bone regeneration in bone defect repair. ACS Appl Mater Interfaces. 2024;16(14):17208-17218. doi: 10.1021/acsami.3c19410
  9. Zhao Z, Xia X, Liu J, et al. Cartilage-inspired self-assembly glycopeptide hydrogels for cartilage regeneration via ROS scavenging. Bioact Mater. 2023;32:319-332. doi: 10.1016/j.bioactmat.2023.10.013
  10. Shaw P, Dwivedi SKD, Bhattacharya R, Mukherjee P, Rao G. VEGF signaling: role in angiogenesis and beyond. Biochim Biophys Acta Rev Cancer. 2024;1879(2):189079. doi: 10.1016/j.bbcan.2024.189079
  11. Portais A, Gallouche M, Pavese P, et al. Staphylococcus aureus screening and preoperative decolonisation with Mupirocin and Chlorhexidine to reduce the risk of surgical site infections in orthopaedic surgery: a pre-post study. Antimicrob Resist Infect Control. 2024;13(1):75. doi: 10.1186/s13756-024-01432-2
  12. Cheung GYC, Bae JS, Otto M. Pathogenicity and virulence of Staphylococcus aureus. Virulence. 2021;12(1):547-569. doi: 10.1080/21505594.2021.1878688

 

 

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