AccScience Publishing / IJB / Online First / DOI: 10.36922/ijb.4243
Submit to IJB
Cite this article
48
Download
701
Views
Journal Browser
Volume | Year
Issue
Search
Forthcoming Issue
Current Issue
View All
News and Announcements
View All
RESEARCH ARTICLE

3D-printed zinc/magnesium-doped hydroxyapatite-polycaprolactone composite scaffolds for angiogenesis and osteogenesis

Lei Qiang1,2,3,4 ,  Hao Huang2 ,  Jing Shan5 ,  Guanlu Shen6 ,  Quan Zhang6 ,  Weize Kong4 ,  Ya Fang6 ,  Yiwei Zhang4 ,  Jinwu Wang4 ,  Yihao Liu4* ,  Chengwei Wang4* ,  Pengfei Zheng3,6* ,  Jie Weng1,2*
Show Less
1 Institute of Biomedical Engineering, College of Medicine, Southwest Jiaotong University, Chengdu, Sichuan, China
2 Key Laboratory of Advanced Technologies of Materials (MOE), School of Materials Science and Engineering, College of Medicine, Southwest Jiaotong University, Chengdu, Sichuan, China
3 Department of Orthopaedic Surgery, Children’s Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
4 Shanghai Key Laboratory of Orthopedic Implant, Department of Orthopedic Surgery Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
5 Faculty of Medicine and Health, School of Pharmacy, The University of Sydney, Sydney, Australia
6 Jiangsu Key Laboratory of Marine Bioresources and Environment, Co-Innovation Center of Jiangsu Marine Bio-industry Technology, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, Jiangsu Ocean University, Lianyungang, Jiangsu, China
IJB 2024, 10(6), 4243 https://doi.org/10.36922/ijb.4243
Submitted: 15 July 2024 | Accepted: 3 September 2024 | Published: 4 September 2024
© 2024 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/ )
Download PDF
Cite
XML
Abstract

Critical-sized bone defect repair remains a major clinical challenge that requires scaffolds with angiogenesis and osteogenesis potential. Herein, we synthesized zinc (Zn)-doped and zinc/magnesium (Zn/Mg)-co-doped hydroxyapatite (HA) via the hydrothermal method and subsequently mixed them with polycaprolactone (PCL) as ink to fabricate composite scaffolds through 3D printing. We explored the potential of composite scaffolds in promoting angiogenesis and osteogenesis. In vitro experiments demonstrated that Zn/Mg-co-doped composite scaffolds can promote angiogenesis. In addition, Zn/Mg-co-doped scaffolds could promote osteogenesis and were superior to Zn-doped composite scaffolds. Furthermore, in vivo studies using a rat femoral defect model confirmed that the Zn/Mg-co-doped scaffolds repaired bone defects. Thus, the Zn/Mg-co-doped composite scaffolds developed in this study were effective in promoting angiogenesis and bone defect repairs, providing an excellent solution for the design and development of clinical materials.

Graphical abstract
Keywords
Zinc/magnesium-doped hydroxyapatite-polycaprolactone scaffolds
3D printing
Angiogenesis
Osteogenesis
Bone regeneration
Funding
This work was supported by the National Key Research and Development Program of China (2023YFC2411300); National Natural Science Foundation of China (82072412/92048205/ 52071277); Biomaterials and Regenerative Medicine Institute Cooperative Research Project by Shanghai Jiao Tong University School of Medicine (2022LHB08); Project of Shanghai Science and Technology Commission (22015820100); China Postdoctoral Science Foundation (2022M721685/2022M722121); and the China Postdoctoral Science Foundation Special Grant Program (2023T160331).
Conflict of interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper
References
  1. Li Y, Xu JK, Mi J, et al. Biodegradable magnesium combined with distraction osteogenesis synergistically stimulates bone tissue regeneration via CGRP-FAK-VEGF signaling axis. Biomaterials. 2021;275:120984. doi: 10.1016/j.biomaterials.2021.120984
  2. Wang Q, Xia QQ, Wu Y, et al. 3D-printed atsttrin-incorporated alginate/hydroxyapatite scaffold promotes bone defect regeneration with TNF/TNFR signaling involvement. Adv Healthc Mater. 2015;4:1701-1708. doi: 10.1002/adhm.201500211
  3. Hasani-Sadrabadi MM, Sarrion P, Pouraghaei S, et al. An engineered cell-laden adhesive hydrogel promotes craniofacial bone tissue regeneration in rats. Sci Transl Med. 2020;12:eaay6853. doi: 10.1126/scitranslmed.aay6853
  4. Possolli NM, Raupp-Pereira F, Montedo ORK, et al. LZS bioactive glass-ceramic scaffolds: colloidal processing, foam replication technique and mechanical properties to bone tissue engineering. Open Ceram. 2022;9:100219. doi: 10.1016/j.oceram.2022.100219
  5. Ren Y, Kong WQ, Liu YH, et al. Photocurable 3D-printed PMBG/TCP scaffold coordinated with PTH (1-34) bidirectionally regulates bone homeostasis to accelerate bone regeneration. Adv Healthc Mater. 2023;12:e202300292. doi: 10.1002/adhm.202300292
  6. Wu YG, Xing ZY, Zhao R, et al. Engineered cell-laden armor unit-mimicking bioceramic granules for bone regeneration. Adv Funct Mater. 2024;34:10331. doi: 10.1002/adfm.202310331
  7. Zhao R, Chen SY, Zhao WL, et al. A bioceramic scaffold composed of strontium-doped three-dimensional hydroxyapatite whiskers for enhanced bone regeneration in osteoporotic defects. Theranostics. 2020;10: 1572-1589. doi: 10.7150/thno.40103
  8. Xu JK, Hu PJ, Zhang XT, et al. Magnesium implantation or supplementation ameliorates bone disorder in CFTR-mutant mice through an ATF4-dependent Wnt/β-catenin signaling. Bioact Mater. 2022;8:95-108. doi: 10.1016/j.bioactmat.2021.06.034
  9. Li WT, Miao WQ, Liu YH, et al. Bioprinted constructs that mimic the ossification center microenvironment for targeted innervation in bone regeneration. Adv Funct Mater. 2022;32:2109871. doi: 10.1002/adfm.202109871
  10. Gu JN, Zhang QQ, Geng MR, et al. Construction of nanofibrous scaffolds with interconnected perfusable microchannel networks for engineering of vascularized bone tissue. Bioact Mater. 2021;6:3254-3268. doi: 10.1016/j.bioactmat.2021.02.033
  11. Dorozhkin SV. Multiphasic calcium orthophosphate (CaPO) bioceramics and their biomedical applications. Ceram Int. 2016;42:6529-6554. doi: 10.1016/j.ceramint.2016.01.062
  12. Thompson JB, Kindt JH, Drake B, et al. Bone indentation recovery time correlates with bond reforming time. Nature. 2001;414:773-776. doi: 10.1038/414773a
  13. Lim KT, Patel DK, Dutta SD, et al. Human teeth-derived bioceramics for improved bone regeneration. Nanomaterials Basel. 2020;10:2396. doi: 10.3390/nano10122396
  14. Zhang H, Huang HF, Hao GR, et al. 3D printing hydrogel scaffolds with nanohydroxyapatite gradient to effectively repair osteochondral defects in rats. Adv Funct Mater. 2021;31:2006697. doi: 10.1002/adfm.202006697
  15. Huang H, Yang AC, Li JS, et al. Preparation of multigradient hydroxyapatite scaffolds and evaluation of their osteoinduction properties. Regen Biomater. 2022;9:001. doi: 10.1093/rb/rbac001
  16. Supova M. Substituted hydroxyapatites for biomedical applications: a review. Ceram Int. 2015;41:9203-9231. doi: 10.1016/j.ceramint.2015.03.316
  17. Lakhkar NJ, Lee IH, Kim HW, et al. Bone formation controlled by biologically relevant inorganic ions: role and controlled delivery from phosphate-based glasses. Adv Drug Deliver Rev. 2013;65:405-420. doi: 10.1016/j.addr.2012.05.015
  18. Li SJ, Zhang LY, Liu CY, et al. Spontaneous immuno-modulation and regulation of angiogenesis and osteogenesis by Sr/Cu-borosilicate glass (BSG) bone cement to repair critical bone defects. Bioact Mater. 2023;23:101-117. doi: 10.1016/j.bioactmat.2022.10.021
  19. D’Mello S, Elangovan S, Hong L, et al. Incorporation of copper into chitosan scaffolds promotes bone regeneration in rat calvarial defects. J Biomed Mater Res B. 2015;103: 1044-1049. doi: 10.1002/jbm.b.33290
  20. Wang Y, Wang XY, Pang YY, et al. Ion-engineered microcryogels via osteogenesis-angiogenesis coupling and inflammation reversing augment vascularized bone regeneration. Adv Funct Mater. 2024;34(34):2400745. doi: 10.1002/adfm.202400745
  21. Ghorbani FM, Kaffashi B, Shokrollahi P, et al. PCL/ chitosan/Zn-doped nHA electrospun nanocomposite scaffold promotes adipose derived stem cells adhesion and proliferation. Carbohyd Polym. 2015;118:133-142. doi: 10.1016/j.carbpol.2014.10.071
  22. Kulanthaivel S, Mishra U, Agarwal T, et al. Improving the osteogenic and angiogenic properties of synthetic hydroxyapatite by dual doping of bivalent cobalt and magnesium ion. Ceram Int. 2015;41:11323-11333. doi: 10.1016/j.ceramint.2015.05.090
  23. Xiao DQ, Yang F, Zhao Q, et al. Fabrication of a Cu/Zn co-incorporated calcium phosphate scaffold-derived GDF-5 sustained release system with enhanced angiogenesis and osteogenesis properties. RSC Adv. 2018;8:29526-29534. doi: 10.1039/c8ra05441j
  24. Elrayah A, Zhi W, Feng S, et al. Preparation of micro/nano-structure copper-substituted hydroxyapatite scaffolds with improved angiogenesis capacity for bone regeneration. Materials. 2018;11:1516. doi: 10.3390/ma11091516
  25. Shoaib M, Bahadur A, Iqbal S, et al. Magnesium doped mesoporous bioactive glass nanoparticles: a promising material for apatite formation and mitomycin c delivery to the MG-63 cancer cells. J Alloy Compd. 2021;866:159013. doi: 10.1016/j.jallcom.2021.159013
  26. Castiglioni S, Cazzaniga A, Albisetti W, et al. Magnesium and osteoporosis: current state of knowledge and future research directions. Nutrients. 2013;5:3022-3033. doi: 10.3390/nu5083022
  27. Rude RK, Singer FR, and Gruber HE. Skeletal and hormonal effects of magnesium deficiency. J Am Coll Nutr. 2009;28:131-141. doi: 10.1080/07315724.2009.10719764
  28. Shrestha S, Lee SY, Shrestha D, et al. Micro/nanometer-sized porous structure of zinc phosphate incorporated Ti (HPO4) hydrate bioceramic induces osteogenic gene expression and enhances osteoporotic bone regeneration. Chem Eng J. 2022;450:138360. doi: 10.1016/j.cej.2022.138360
  29. Yin S, Lin SH, Xu JY, et al. Dominoes with interlocking consequences triggered by zinc: involvement of microelement-stimulated MSC-derived exosomes in senile osteogenesis and osteoclast dialogue. J Nanobiotechnol. 2023;21:346. doi: 10.1186/s12951-023-02085-w
  30. Shahed CA, Ahmad F, Günister E, et al. Antibacterial mechanism with consequent cytotoxicity of different reinforcements in biodegradable magnesium and zinc alloys: a review. J Magnes Alloy. 2023;11:3038-3058. doi: 10.1016/j.jma.2023.08.018
  31. Matsunaga K. First-principles study of substitutional magnesium and zinc in hydroxyapatite and octacalcium phosphate. J Chem Phys. 2008;128:245101. doi: 10.1063/1.2940337
  32. Naing MW, Chua CK, Leong KF, et al. Fabrication of customised scaffolds using computer-aided design and rapid prototyping techniques. Rapid Prototyping J. 2005;11(4):249-259. doi: 10.1108/13552540510612938
  33. Chua CK, Leong KF, Cheah CM, et al. Development of a tissue engineering scaffold structure library for rapid prototyping. part 1: investigation and classification. Int J Adv Manuf Technol. 2003;21:291-301. doi: 10.1007/s001700300034
  34. Chua CK, Leong KF, Cheah CM, et al. Development of a tissue engineering scaffold structure library for rapid prototyping. Part 2: Parametric library and assembly program. Int J Adv Manuf Technol. 2003;21:302-312. doi: 10.1007/s001700300035
  35. Dong C, Wei H, Zhang XN, et al. 3D printed hydrogel/ wesselsite-PCL composite scaffold with structural change from core/shell fibers to microchannels for enhanced bone regeneration. Compos B: Eng. 2022;246:110264. doi: 10.1016/j.compositesb.2022.110264
  36. Xiao DQ, Tan Z, Fu YK, et al. Hydrothermal synthesis of hollow hydroxyapatite microspheres with nano-structured surface assisted by inositol hexakisphosphate. Ceram Int. 2014;40:10183-10188. doi: 10.1016/j.ceramint.2014.02.057
  37. Huang H, Qiang L, Fan MJ, et al. 3D-printed tri-element-doped hydroxyapatite/ polycaprolactone composite scaffolds with antibacterial potential for osteosarcoma therapy and bone regeneration. Bioact Mater. 2024;31:18-37. doi: 10.1016/j.bioactmat.2023.07.004
  38. Kim H, Mondal S, Bharathiraja S, et al. Optimized Zn-doped hydroxyapatite/doxorubicin bioceramics system for efficient drug delivery and tissue engineering application. Ceram Int. 2018;44:6062-6071. doi: 10.1016/j.ceramint.2017.12.235
  39. Fleet ME, Liu X. Coupled substitution of type A and B carbonate in sodium-bearing apatite. Biomaterials. 2007;28:916-926. doi: 10.1016/j.biomaterials.2006.11.003
  40. Karunakaran G, Kumar GS, Cho EB, et al. Microwave-assisted hydrothermal synthesis of mesoporous carbonated hydroxyapatite with tunable nanoscale characteristics for biomedical applications. Ceram Int. 2019;45:970-977. doi: 10.1016/j.ceramint.2018.09.273
  41. Kundu K, Afshar A, Katti DR, et al. Composite nanoclay-hydroxyapatite-polymer fiber scaffolds for bone tissue engineering manufactured using pressurized gyration. Compos Sci Technol. 2021;202:108598. doi: 10.1016/j.compscitech.2020.108598
  42. Karageorgiou V, Kaplan D. Porosity of 3D biomaterial scaffolds and osteogenesis. Biomaterials. 2005;26:5474-5491. doi: 10.1016/j.biomaterials.2005.02.002
  43. Zhao FL, Gao A, Liao Q, et al. Balancing the anti-bacterial and pro-osteogenic properties of Ti-based implants by partial conversion of ZNO nanorods into hybrid zinc phosphate nanostructures. Adv Funct Mater. 2024;34:2311812. doi: 10.1002/adfm.202311812
  44. Li Y, Xiong W, Zhang CC, et al. Enhanced osseointegration and antibacterial action of zinc-loaded titania-nanotube-coated titanium substrates: and studies. J Biomed Mater Res A. 2014;102:3939-3950. doi: 10.1002/jbm.a.35060
  45. Rasmussen JW, Martinez E, Louka P, et al. Zinc oxide nanoparticles for selective destruction of tumor cells and potential for drug delivery applications. Expert Opin Drug Del. 2010;7:1063-1077. doi: 10.1517/17425247.2010.502560
  46. Xu L, Willumeit-Römer R, Luthringer-Feyerabend BJC. Effect of magnesium-degradation products and hypoxia on the angiogenesis of human umbilical vein endothelial cells. Acta Biomater. 2019;98:269-283. doi: 10.1016/j.actbio.2019.02.018
  47. Hung CC, Chaya A, Liu K, et al. The role of magnesium ions in bone regeneration involves the canonical Wnt signaling pathway. Acta Biomater. 2019;98:246-255. doi: 10.1016/j.actbio.2019.06.001

 

 

 

 

Share
Back to top
International Journal of Bioprinting, Electronic ISSN: 2424-8002 Print ISSN: 2424-7723, Published by AccScience Publishing
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here
Accept