3D-printed core–shell scaffolds with a biphasic calcium phosphate core and GelMA hydrogel shell for bone tissue engineering

Alg:

Alginate

β-TCP:

Beta-tricalcium phosphate

BCP:

Biphasic calcium phosphate

BTE:

Bone tissue engineering

ECM:

Extracellular matrix

FESEM:

Field emission scanning electron microscopy

HA:

Hydroxyapatite

PBS:

Phosphate-buffered saline

SBF:

Simulated body fluid

3D:

Three-dimensional

1. Lanza, R., et al., Principles of tissue engineering. 2020: Academic press.

2. Valdoz, J. C. et al. The ECM: To scaffold, or not to scaffold, that is the question. Int. J. Mol. Sci. 22(23), 12690 (2021).

   Google Scholar 

3. Beheshtizadeh, N. et al. The stability and self-assembly of tri-calcium silicate and hydroxyapatite scaffolds in bone tissue engineering applications. J. Biol. Eng. 19(1), 16 (2025).

   Google Scholar 

4. Mohammadzadeh, M. et al. Promoting osteogenesis and bone regeneration employing icariin-loaded nanoplatforms. J. Biol. Eng. 18(1), 29 (2024).

   Google Scholar 

5. Sakkas, A. et al. Autogenous bone grafts in oral implantology—is it still a “gold standard”? A consecutive review of 279 patients with 456 clinical procedures. Int. J. Implant Dent. 3(1), 23 (2017).

   Google Scholar 

6. Vaezi, M. et al. Extrusion-based 3D printing technologies for 3D scaffold engineering. In Functional 3D tissue engineering scaffolds 235–254 (Elsevier, 2018).

   Google Scholar 

7. Janning, K. et al. Development of an end-to-end automated production concept for extrusion-based additive manufacturing of personalized medical scaffolds. Front. Manuf. Technol. 5, 1572842 (2025).

   Google Scholar 

8. Beheshtizadeh, N. et al. 3D printing of complicated GelMA-coated alginate/tri-calcium silicate scaffold for accelerated bone regeneration. Int. J. Biol. Macromol. 229, 636–653 (2023).

   Google Scholar 

9. Fatimi, A. et al. Natural hydrogel-based bio-inks for 3D bioprinting in tissue engineering: A review. Gels 8(3), 179 (2022).

   Google Scholar 

10. Tavoni, M. et al. Bioactive calcium phosphate-based composites for bone regeneration. J. Compos. Sci. 5(9), 227 (2021).

    Google Scholar 

11. Miramond, T. et al. Osteoinduction of biphasic calcium phosphate scaffolds in a nude mouse model. J. Biomater. Appl. 29(4), 595–604 (2014).

    Google Scholar 

12. Beheshtizadeh, N. et al. Applying extrusion-based 3D printing technique accelerates fabricating complex biphasic calcium phosphate-based scaffolds for bone tissue regeneration. J. Adv. Res. 40, 69–94 (2022).

    Google Scholar 

13. White, E. & Shors, E. C. Biomaterial aspects of Interpore-200 porous hydroxyapatite. Dent. Clin. North Am. 30(1), 49–67 (1986).

    Google Scholar 

14. Cho, D.-Y. et al. Cage containing a biphasic calcium phosphate ceramic (Triosite) for the treatment of cervical spondylosis. Surg. Neurol. 63(6), 497–503 (2005).

    Google Scholar 

15. Hurtado, A. et al. Alginate: Enhancement strategies for advanced applications. Int. J. Mol. Sci. 23(9), 4486 (2022).

    Google Scholar 

16. Gogoi, D., et al., Applications and formulation of bio-ink in the development of tissue scaffold: A review. Bioimplants Manufacturing, 2024: p. 71–95.

17. Wang, Y. et al. Innovative polymer-based composite materials in additive manufacturing: A review of methods, materials, and applications. Polym. Compos. 45(17), 15389–15420 (2024).

    Google Scholar 

18. Xue, X. et al. Recent advances in design of functional biocompatible hydrogels for bone tissue engineering. Adv. Funct. Mater. 31(19), 2009432 (2021).

    Google Scholar 

19. Mamidi, N., Ijadi, F. & Norahan, M. H. Leveraging the recent advancements in GelMA scaffolds for bone tissue engineering: An assessment of challenges and opportunities. Biomacromol 25(4), 2075–2113 (2023).

    Google Scholar 

20. Wang, L. et al. 3D printing of reduced glutathione grafted gelatine methacrylate hydrogel scaffold promotes diabetic bone regeneration by activating PI3K/Akt signaling pathway. Int. J. Biol. Macromol. 222, 1175–1191 (2022).

    Google Scholar 

21. Ferraris, S. et al. Bioactive materials: In vitro investigation of different mechanisms of hydroxyapatite precipitation. Acta Biomater. 102, 468–480 (2020).

    Google Scholar 

22. Vadillo, J. et al. Enhancing the mechanical properties of 3D-printed waterborne polyurethane-urea and cellulose nanocrystal scaffolds through crosslinking. Polymers https://doi.org/10.3390/polym14224999 (2022).

    Google Scholar 

23. Bupphathong, S. et al. Gelatin methacrylate hydrogel for tissue engineering applications-A review on material modifications. Pharmaceuticals (Basel) https://doi.org/10.3390/ph15020171 (2022).

    Google Scholar 

24. Lores, N. J. et al. Gelatin methacrylate coating on 3D-printed poly(esterurethane) scaffolds improves cell adhesion and proliferation. ChemBioChem 26(23), e202500317 (2025).

    Google Scholar 

25. Yang, R. et al. Functional gelatin hydrogel scaffold with degraded-release of glutamine to enhance cellular energy metabolism for cartilage repair. Int. J. Biol. Macromol. 221, 923–933 (2022).

    Google Scholar 

26. Zhu, Y. et al. Strategies of functionalized GelMA-based bioinks for bone regeneration: Recent advances and future perspectives. Bioact. Mater. 38, 346–373 (2024).

    Google Scholar 

27. Yue, K. et al. Synthesis, properties, and biomedical applications of gelatin methacryloyl (GelMA) hydrogels. Biomaterials 73, 254–271 (2015).

    Google Scholar 

28. Mohammadzadeh, M. et al. Smart biomaterials for cardiovascular, bone, and skin tissue engineering: Mechanisms, applications, and future prospects. J. Biol. Eng. https://doi.org/10.1186/s13036-025-00607-8 (2026).

    Google Scholar 

29. Sonowal, L. et al. Advancements of bioceramics in biomedical applications. Next Materials 9, 101010 (2025).

    Google Scholar 

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Authors and Affiliations

1. Faculty of Mechanical Engineering, University of Tabriz, Tabriz, Iran

   Amir Shadi, Amir Mostafapour & Behzad Asghari

2. Department of Tissue Engineering, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran

   Nima Beheshtizadeh

Contributions

Amir Shadi: Conceptualization, Investigation, Methodology, Resources, Visualization, Formal analysis, Data curation, Writing—original draft,—Amir Mostafapour: Resources, Formal analysis, Writing – review & editing, Funding acquisition, and Supervision.—Behzad Asghari: Conceptualization, Data curation, Software, Visualization, and Writing—original draft.—Nima Beheshtizadeh: Investigation, Conceptualization, Methodology, Validation, Writing—original draft, Writing – review & editing, Funding acquisition, Supervision, and Project administration.

Corresponding authors

Correspondence to Amir Mostafapour or Nima Beheshtizadeh.

Competing interests

The authors declare no competing interests.

Ethical approval and consent to participate

Research was approved by Tabriz University of Medical Sciences’ Ethical Committee (IR.TBZMED.VCR.REC.1404.103). We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Consent for publication

Not applicable.

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