Hydrogel-based vascularization strategy in the field of bone tissue engineering_West China Medical Journal

Authors：

JIANG Jiabao ¹ , ZHE Man ² , XING Fei ¹ , LUO Rong ¹ , CHEN Zhao ¹ , HUANG Fuguo ¹ , XIANG Zhou ¹ ,  LIU Ming ¹

1. Department of Orthopaedics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
2. Animal Experiment Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

LIU Ming, Email: liuming15@qq.com

Keywords：

Hydrogel; vascularization; bone repair; bone defect; endothelial cell

DOI：

10.7507/1002-0179.202112137

Video：

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Bone tissue regeneration and blood vessel formation are inseparable. How to realize the vascularization of bone repair scaffolds is an urgent problem in bone tissue engineering. The growth and development, mineralization maturity, reconstruction and remodeling, and tissue regeneration of bone are all based on forming an excellent vascularization network. In recent years, more and more researchers have used hydrogels to carry different cells, cytokines, metal ions and small molecules for in vitro vascularization and application in bone regeneration. Based on this background, this article reviews the hydrogel-based vascularization strategies in bone tissue engineering.

Citation： JIANG Jiabao, ZHE Man, XING Fei, LUO Rong, CHEN Zhao, HUANG Fuguo, XIANG Zhou, LIU Ming. Hydrogel-based vascularization strategy in the field of bone tissue engineering. West China Medical Journal, 2023, 38(4): 608-615. doi: 10.7507/1002-0179.202112137 Copy

1.	Schemitsch EH. Size Matters: defining critical in bone defect size!. J Orthop Trauma, 2017, 31(Suppl 5): S20-S22.
2.	Fröhlich M, Grayson WL, Wan LQ, et al. Tissue engineered bone grafts: biological requirements, tissue culture and clinical relevance. Curr Stem Cell Res Ther, 2008, 3(4): 254-264.
3.	Carano RA, Filvaroff EH. Angiogenesis and bone repair. Drug Discov Today, 2003, 8(21): 980-989.
4.	Tomlinson RE, Silva MJ. Skeletal blood flow in bone repair and maintenance. Bone Res, 2013, 1(4): 311-322.
5.	Simunovic F, Finkenzeller G. Vascularization strategies in bone tissue engineering. Cells, 2021, 10(7): 1749.
6.	Percival CJ, Richtsmeier JT. Angiogenesis and intramembranous osteogenesis. Dev Dyn, 2013, 242(8): 909-922.
7.	Salhotra A, Shah HN, Levi B, et al. Mechanisms of bone development and repair. Nat Rev Mol Cell Biol, 2020, 21(11): 696-711.
8.	Vailhé B, Vittet D, Feige JJ. In vitro models of vasculogenesis and angiogenesis. Lab Invest, 2001, 81(4): 439-452.
9.	Hu K, Olsen BR. The roles of vascular endothelial growth factor in bone repair and regeneration. Bone, 2016, 91: 30-38.
10.	Yue S, He H, Li B, et al. Hydrogel as a biomaterial for bone tissue engineering: a review. Nanomaterials (Basel), 2020, 10(8): 1511.
11.	Crosby CO, Zoldan J. Mimicking the physical cues of the ECM in angiogenic biomaterials. Regen Biomater, 2019, 6(2): 61-73.
12.	Giraudo MV, Di Francesco D, Catoira MC, et al. Angiogenic potential in biological hydrogels. Biomedicines, 2020, 8(10): 436.
13.	Buwalda SJ, Vermonden T, Hennink WE. Hydrogels for therapeutic delivery: current developments and future directions. Biomacromolecules, 2017, 18(2): 316-330.
14.	Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science, 1997, 275(5302): 964-967.
15.	Chen YW, Shen YF, Ho CC, et al. Osteogenic and angiogenic potentials of the cell-laden hydrogel/mussel-inspired calcium silicate complex hierarchical porous scaffold fabricated by 3D bioprinting. Mater Sci Eng C Mater Biol Appl, 2018, 91: 679-687.
16.	Thébaud NB, Pierron D, Bareille R, et al. Human endothelial progenitor cell attachment to polysaccharide-based hydrogels: a pre-requisite for vascular tissue engineering. J Mater Sci Mater Med, 2007, 18(2): 339-345.
17.	Mihaila SM, Popa EG, Reis RL, et al. Fabrication of endothelial cell-laden carrageenan microfibers for microvascularized bone tissue engineering applications. Biomacromolecules, 2014, 15(8): 2849-2860.
18.	Santos L, Fuhrmann G, Juenet M, et al. Extracellular stiffness modulates the expression of functional proteins and growth factors in endothelial cells. Adv Healthc Mater, 2015, 4(14): 2056-2063.
19.	Zhao Z, Wang M, Shao F, et al. Porous tantalum-composited gelatin nanoparticles hydrogel integrated with mesenchymal stem cell-derived endothelial cells to construct vascularized tissue in vivo. Regen Biomater, 2021, 8(6): rbab051.
20.	Paschos NK, Brown WE, Eswaramoorthy R, et al. Advances in tissue engineering through stem cell-based co-culture. J Tissue Eng Regen Med, 2015, 9(5): 488-503.
21.	Caplan AI. All MSCs are pericytes?. Cell Stem Cell, 2008, 3(3): 229-230.
22.	Chen W, Thein-Han W, Weir MD, et al. Prevascularization of biofunctional calcium phosphate cement for dental and craniofacial repairs. Dent Mater, 2014, 30(5): 535-544.
23.	Wenz A, Tjoeng I, Schneider I, et al. Improved vasculogenesis and bone matrix formation through coculture of endothelial cells and stem cells in tissue-specific methacryloyl gelatin-based hydrogels. Biotechnol Bioeng, 2018, 115(10): 2643-2653.
24.	Barre A, Naudot M, Colin F, et al. An alginate-based hydrogel with a high angiogenic capacity and a high osteogenic potential. Biores Open Access, 2020, 9(1): 174-182.
25.	Liu J, Chuah YJ, Fu J, et al. Co-culture of human umbilical vein endothelial cells and human bone marrow stromal cells into a micro-cavitary gelatin-methacrylate hydrogel system to enhance angiogenesis. Mater Sci Eng C Mater Biol Appl, 2019, 102: 906-916.
26.	Yang C, Han B, Cao C, et al. An injectable double-network hydrogel for the co-culture of vascular endothelial cells and bone marrow mesenchymal stem cells for simultaneously enhancing vascularization and osteogenesis. J Mater Chem B, 2018, 6(47): 7811-7821.
27.	Bai Y, Bai L, Zhou J, et al. Sequential delivery of VEGF, FGF-2 and PDGF from the polymeric system enhance HUVECs angiogenesis in vitro and CAM angiogenesis. Cell Immunol, 2018, 323: 19-32.
28.	Wang C, Wang X, Dong K, et al. Injectable and responsively degradable hydrogel for personalized photothermal therapy. Biomaterials, 2016, 104: 129-137.
29.	Juhl O, Zhao N, Merife AB, et al. Aptamer-functionalized fibrin hydrogel improves vascular endothelial growth factor release kinetics and enhances angiogenesis and osteogenesis in critically sized cranial defects. ACS Biomater Sci Eng, 2019, 5(11): 6152-6160.
30.	Zhang R, Liu Y, Qi Y, et al. Self-assembled peptide hydrogel scaffolds with VEGF and BMP-2 enhanced in vitro angiogenesis and osteogenesis. Oral Dis, 2022, 28(3): 723-733.
31.	Divband B, Aghazadeh M, Al-Qaim ZH, et al. Bioactive chitosan biguanidine-based injectable hydrogels as a novel BMP-2 and VEGF carrier for osteogenesis of dental pulp stem cells. Carbohydr Polym, 2021, 273: 118589.
32.	Lee SS, Kim JH, Jeong J, et al. Sequential growth factor releasing double cryogel system for enhanced bone regeneration. Biomaterials, 2020, 257: 120223.
33.	Liu C, Yang G, Zhou M, et al. Magnesium ammonium phosphate composite cell-laden hydrogel promotes osteogenesis and angiogenesis in vitro. ACS Omega, 2021, 6(14): 9449-9459.
34.	Zhang X, Huang P, Jiang G, et al. A novel magnesium ion-incorporating dual-crosslinked hydrogel to improve bone scaffold-mediated osteogenesis and angiogenesis. Mater Sci Eng C Mater Biol Appl, 2021, 121: 111868.
35.	Wu J, Zheng K, Huang X, et al. Thermally triggered injectable chitosan/silk fibroin/bioactive glass nanoparticle hydrogels for in-situ bone formation in rat calvarial bone defects. Acta Biomater, 2019, 91: 60-71.
36.	Perez RA, Kim JH, Buitrago JO, et al. Novel therapeutic core-shell hydrogel scaffolds with sequential delivery of cobalt and bone morphogenetic protein-2 for synergistic bone regeneration. Acta Biomater, 2015, 23: 295-308.
37.	Wolf FI, Cittadini A. Chemistry and biochemistry of magnesium. Mol Aspects Med, 2003, 24(1/2/3): 3-9.
38.	Gu Y, Zhang J, Zhang X, et al. Three-dimensional printed Mg-doped β-TCP bone tissue engineering scaffolds: effects of magnesium ion concentration on osteogenesis and angiogenesis in vitro. Tissue Eng Regen Med, 2019, 16(4): 415-429.
39.	Jomova K, Valko M. Advances in metal-induced oxidative stress and human disease. Toxicology, 2011, 283(2/3): 65-87.
40.	Wu C, Zhou Y, Xu M, et al. Copper-containing mesoporous bioactive glass scaffolds with multifunctional properties of angiogenesis capacity, osteostimulation and antibacterial activity. Biomaterials, 2013, 34(2): 422-433.
41.	Dai Q, Li Q, Gao H, et al. 3D printing of Cu-doped bioactive glass composite scaffolds promotes bone regeneration through activating the HIF-1α and TNF-α pathway of hUVECs. Biomater Sci, 2021, 9(16): 5519-5532.
42.	Yuan Y, Hilliard G, Ferguson T, et al. Cobalt inhibits the interaction between hypoxia-inducible factor-alpha and von Hippel-Lindau protein by direct binding to hypoxia-inducible factor-alpha. J Biol Chem, 2003, 278(18): 15911-15916.
43.	Solanki AK, Lali FV, Autefage H, et al. Bioactive glasses and electrospun composites that release cobalt to stimulate the HIF pathway for wound healing applications. Biomater Res, 2021, 25(1): 1.
44.	Cheng W, Ding Z, Zheng X, et al. Injectable hydrogel systems with multiple biophysical and biochemical cues for bone regeneration. Biomater Sci, 2020, 8(9): 2537-2548.
45.	Wu C, Zhou Y, Chang J, et al. Delivery of dimethyloxallyl glycine in mesoporous bioactive glass scaffolds to improve angiogenesis and osteogenesis of human bone marrow stromal cells. Acta Biomater, 2013, 9(11): 9159-9168.
46.	Yegappan R, Selvaprithiviraj V, Amirthalingam S, et al. Injectable angiogenic and osteogenic carrageenan nanocomposite hydrogel for bone tissue engineering. Int J Biol Macromol, 2019, 122: 320-328.
47.	Smart N, Rossdeutsch A, Riley PR. Thymosin beta4 and angiogenesis: modes of action and therapeutic potential. Angiogenesis, 2007, 10(4): 229-241.
48.	Kraehenbuehl TP, Ferreira LS, Zammaretti P, et al. Cell-responsive hydrogel for encapsulation of vascular cells. Biomaterials, 2009, 30(26): 4318-4324.
49.	Ikeda Y, Tajima S, Yoshida S, et al. Deferoxamine promotes angiogenesis via the activation of vascular endothelial cell function. Atherosclerosis, 2011, 215(2): 339-347.
50.	Wang K, Cheng W, Ding Z, et al. Injectable silk/hydroxyapatite nanocomposite hydrogels with vascularization capacity for bone regeneration. J Mater Sci Tech, 2021, 63: 172-181.
51.	Ostrovidov S, Salehi S, Costantini M, et al. 3D bioprinting in skeletal muscle tissue engineering. Small, 2019, 15(24): e1805530.
52.	Heinrich MA, Liu W, Jimenez A, et al. 3D bioprinting: from benches to translational applications. Small, 2019, 15(23): e1805510.
53.	Mei Q, Rao J, Bei HP, et al. 3D bioprinting photo-crosslinkable hydrogels for bone and cartilage repair. Int J Bioprint, 2021, 7(3): 367.
54.	Anada T, Pan CC, Stahl AM, et al. Vascularized bone-mimetic hydrogel constructs by 3D bioprinting to promote osteogenesis and angiogenesis. Int J Mol Sci, 2019, 20(5): 1096.

1. Schemitsch EH. Size Matters: defining critical in bone defect size!. J Orthop Trauma, 2017, 31(Suppl 5): S20-S22.
2. Fröhlich M, Grayson WL, Wan LQ, et al. Tissue engineered bone grafts: biological requirements, tissue culture and clinical relevance. Curr Stem Cell Res Ther, 2008, 3(4): 254-264.
3. Carano RA, Filvaroff EH. Angiogenesis and bone repair. Drug Discov Today, 2003, 8(21): 980-989.
4. Tomlinson RE, Silva MJ. Skeletal blood flow in bone repair and maintenance. Bone Res, 2013, 1(4): 311-322.
5. Simunovic F, Finkenzeller G. Vascularization strategies in bone tissue engineering. Cells, 2021, 10(7): 1749.
6. Percival CJ, Richtsmeier JT. Angiogenesis and intramembranous osteogenesis. Dev Dyn, 2013, 242(8): 909-922.
7. Salhotra A, Shah HN, Levi B, et al. Mechanisms of bone development and repair. Nat Rev Mol Cell Biol, 2020, 21(11): 696-711.
8. Vailhé B, Vittet D, Feige JJ. In vitro models of vasculogenesis and angiogenesis. Lab Invest, 2001, 81(4): 439-452.
9. Hu K, Olsen BR. The roles of vascular endothelial growth factor in bone repair and regeneration. Bone, 2016, 91: 30-38.
10. Yue S, He H, Li B, et al. Hydrogel as a biomaterial for bone tissue engineering: a review. Nanomaterials (Basel), 2020, 10(8): 1511.
11. Crosby CO, Zoldan J. Mimicking the physical cues of the ECM in angiogenic biomaterials. Regen Biomater, 2019, 6(2): 61-73.
12. Giraudo MV, Di Francesco D, Catoira MC, et al. Angiogenic potential in biological hydrogels. Biomedicines, 2020, 8(10): 436.
13. Buwalda SJ, Vermonden T, Hennink WE. Hydrogels for therapeutic delivery: current developments and future directions. Biomacromolecules, 2017, 18(2): 316-330.
14. Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science, 1997, 275(5302): 964-967.
15. Chen YW, Shen YF, Ho CC, et al. Osteogenic and angiogenic potentials of the cell-laden hydrogel/mussel-inspired calcium silicate complex hierarchical porous scaffold fabricated by 3D bioprinting. Mater Sci Eng C Mater Biol Appl, 2018, 91: 679-687.
16. Thébaud NB, Pierron D, Bareille R, et al. Human endothelial progenitor cell attachment to polysaccharide-based hydrogels: a pre-requisite for vascular tissue engineering. J Mater Sci Mater Med, 2007, 18(2): 339-345.
17. Mihaila SM, Popa EG, Reis RL, et al. Fabrication of endothelial cell-laden carrageenan microfibers for microvascularized bone tissue engineering applications. Biomacromolecules, 2014, 15(8): 2849-2860.
18. Santos L, Fuhrmann G, Juenet M, et al. Extracellular stiffness modulates the expression of functional proteins and growth factors in endothelial cells. Adv Healthc Mater, 2015, 4(14): 2056-2063.
19. Zhao Z, Wang M, Shao F, et al. Porous tantalum-composited gelatin nanoparticles hydrogel integrated with mesenchymal stem cell-derived endothelial cells to construct vascularized tissue in vivo. Regen Biomater, 2021, 8(6): rbab051.
20. Paschos NK, Brown WE, Eswaramoorthy R, et al. Advances in tissue engineering through stem cell-based co-culture. J Tissue Eng Regen Med, 2015, 9(5): 488-503.
21. Caplan AI. All MSCs are pericytes?. Cell Stem Cell, 2008, 3(3): 229-230.
22. Chen W, Thein-Han W, Weir MD, et al. Prevascularization of biofunctional calcium phosphate cement for dental and craniofacial repairs. Dent Mater, 2014, 30(5): 535-544.
23. Wenz A, Tjoeng I, Schneider I, et al. Improved vasculogenesis and bone matrix formation through coculture of endothelial cells and stem cells in tissue-specific methacryloyl gelatin-based hydrogels. Biotechnol Bioeng, 2018, 115(10): 2643-2653.
24. Barre A, Naudot M, Colin F, et al. An alginate-based hydrogel with a high angiogenic capacity and a high osteogenic potential. Biores Open Access, 2020, 9(1): 174-182.
25. Liu J, Chuah YJ, Fu J, et al. Co-culture of human umbilical vein endothelial cells and human bone marrow stromal cells into a micro-cavitary gelatin-methacrylate hydrogel system to enhance angiogenesis. Mater Sci Eng C Mater Biol Appl, 2019, 102: 906-916.
26. Yang C, Han B, Cao C, et al. An injectable double-network hydrogel for the co-culture of vascular endothelial cells and bone marrow mesenchymal stem cells for simultaneously enhancing vascularization and osteogenesis. J Mater Chem B, 2018, 6(47): 7811-7821.
27. Bai Y, Bai L, Zhou J, et al. Sequential delivery of VEGF, FGF-2 and PDGF from the polymeric system enhance HUVECs angiogenesis in vitro and CAM angiogenesis. Cell Immunol, 2018, 323: 19-32.
28. Wang C, Wang X, Dong K, et al. Injectable and responsively degradable hydrogel for personalized photothermal therapy. Biomaterials, 2016, 104: 129-137.
29. Juhl O, Zhao N, Merife AB, et al. Aptamer-functionalized fibrin hydrogel improves vascular endothelial growth factor release kinetics and enhances angiogenesis and osteogenesis in critically sized cranial defects. ACS Biomater Sci Eng, 2019, 5(11): 6152-6160.
30. Zhang R, Liu Y, Qi Y, et al. Self-assembled peptide hydrogel scaffolds with VEGF and BMP-2 enhanced in vitro angiogenesis and osteogenesis. Oral Dis, 2022, 28(3): 723-733.
31. Divband B, Aghazadeh M, Al-Qaim ZH, et al. Bioactive chitosan biguanidine-based injectable hydrogels as a novel BMP-2 and VEGF carrier for osteogenesis of dental pulp stem cells. Carbohydr Polym, 2021, 273: 118589.
32. Lee SS, Kim JH, Jeong J, et al. Sequential growth factor releasing double cryogel system for enhanced bone regeneration. Biomaterials, 2020, 257: 120223.
33. Liu C, Yang G, Zhou M, et al. Magnesium ammonium phosphate composite cell-laden hydrogel promotes osteogenesis and angiogenesis in vitro. ACS Omega, 2021, 6(14): 9449-9459.
34. Zhang X, Huang P, Jiang G, et al. A novel magnesium ion-incorporating dual-crosslinked hydrogel to improve bone scaffold-mediated osteogenesis and angiogenesis. Mater Sci Eng C Mater Biol Appl, 2021, 121: 111868.
35. Wu J, Zheng K, Huang X, et al. Thermally triggered injectable chitosan/silk fibroin/bioactive glass nanoparticle hydrogels for in-situ bone formation in rat calvarial bone defects. Acta Biomater, 2019, 91: 60-71.
36. Perez RA, Kim JH, Buitrago JO, et al. Novel therapeutic core-shell hydrogel scaffolds with sequential delivery of cobalt and bone morphogenetic protein-2 for synergistic bone regeneration. Acta Biomater, 2015, 23: 295-308.
37. Wolf FI, Cittadini A. Chemistry and biochemistry of magnesium. Mol Aspects Med, 2003, 24(1/2/3): 3-9.
38. Gu Y, Zhang J, Zhang X, et al. Three-dimensional printed Mg-doped β-TCP bone tissue engineering scaffolds: effects of magnesium ion concentration on osteogenesis and angiogenesis in vitro. Tissue Eng Regen Med, 2019, 16(4): 415-429.
39. Jomova K, Valko M. Advances in metal-induced oxidative stress and human disease. Toxicology, 2011, 283(2/3): 65-87.
40. Wu C, Zhou Y, Xu M, et al. Copper-containing mesoporous bioactive glass scaffolds with multifunctional properties of angiogenesis capacity, osteostimulation and antibacterial activity. Biomaterials, 2013, 34(2): 422-433.
41. Dai Q, Li Q, Gao H, et al. 3D printing of Cu-doped bioactive glass composite scaffolds promotes bone regeneration through activating the HIF-1α and TNF-α pathway of hUVECs. Biomater Sci, 2021, 9(16): 5519-5532.
42. Yuan Y, Hilliard G, Ferguson T, et al. Cobalt inhibits the interaction between hypoxia-inducible factor-alpha and von Hippel-Lindau protein by direct binding to hypoxia-inducible factor-alpha. J Biol Chem, 2003, 278(18): 15911-15916.
43. Solanki AK, Lali FV, Autefage H, et al. Bioactive glasses and electrospun composites that release cobalt to stimulate the HIF pathway for wound healing applications. Biomater Res, 2021, 25(1): 1.
44. Cheng W, Ding Z, Zheng X, et al. Injectable hydrogel systems with multiple biophysical and biochemical cues for bone regeneration. Biomater Sci, 2020, 8(9): 2537-2548.
45. Wu C, Zhou Y, Chang J, et al. Delivery of dimethyloxallyl glycine in mesoporous bioactive glass scaffolds to improve angiogenesis and osteogenesis of human bone marrow stromal cells. Acta Biomater, 2013, 9(11): 9159-9168.
46. Yegappan R, Selvaprithiviraj V, Amirthalingam S, et al. Injectable angiogenic and osteogenic carrageenan nanocomposite hydrogel for bone tissue engineering. Int J Biol Macromol, 2019, 122: 320-328.
47. Smart N, Rossdeutsch A, Riley PR. Thymosin beta4 and angiogenesis: modes of action and therapeutic potential. Angiogenesis, 2007, 10(4): 229-241.
48. Kraehenbuehl TP, Ferreira LS, Zammaretti P, et al. Cell-responsive hydrogel for encapsulation of vascular cells. Biomaterials, 2009, 30(26): 4318-4324.
49. Ikeda Y, Tajima S, Yoshida S, et al. Deferoxamine promotes angiogenesis via the activation of vascular endothelial cell function. Atherosclerosis, 2011, 215(2): 339-347.
50. Wang K, Cheng W, Ding Z, et al. Injectable silk/hydroxyapatite nanocomposite hydrogels with vascularization capacity for bone regeneration. J Mater Sci Tech, 2021, 63: 172-181.
51. Ostrovidov S, Salehi S, Costantini M, et al. 3D bioprinting in skeletal muscle tissue engineering. Small, 2019, 15(24): e1805530.
52. Heinrich MA, Liu W, Jimenez A, et al. 3D bioprinting: from benches to translational applications. Small, 2019, 15(23): e1805510.
53. Mei Q, Rao J, Bei HP, et al. 3D bioprinting photo-crosslinkable hydrogels for bone and cartilage repair. Int J Bioprint, 2021, 7(3): 367.
54. Anada T, Pan CC, Stahl AM, et al. Vascularized bone-mimetic hydrogel constructs by 3D bioprinting to promote osteogenesis and angiogenesis. Int J Mol Sci, 2019, 20(5): 1096.

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