DLP-printed GelMA-PMAA scaffold for bone regeneration through endochondral ossification

Jianpeng Gao, Hufei Wang, Ming Li, Zhongyang Liu, Junyao Cheng, Xiao Liu, Jianheng Liu, Xing Wang, Licheng Zhang

Article ID: 754
Vol 0, Issue 0, 2023, Article identifier:

VIEWS - 50 (Abstract) 35 (PDF) 11 (Supp.File)


Intramembranous ossification (IMO) and endochondral ossification (ECO) are two pathways of bone regeneration. The regeneration of most bone, such as limb bone, trunk bone, and skull base bone, mainly occurs in the form of endochondral ossification, which has also become one of the effective ways for bone tissue engineering. In this work, we prepared a well-structured and biocompatible methacrylated gelatin/polymethacrylic acid (GelMA/PMAA) hydrogel by digital light processing (DLP) printing technology, which could effectively chelate iron ions and continuously activate the hypoxia-inducible factor-1 alpha (HIF-1α) signaling pathway to promote the process of endochondral ossification and angiogenesis. The incorporation of PMAA endowed the hydrogel with remarkable viscoelasticity and high efficacy in chelation of iron ions, giving rise to the activation of HIF-1α signaling pathway, improving chondrogenic differentiation in the early stage, and facilitating vascularization in the later stage and bone remodeling. Therefore, the findings have significant implications on DLP printing technology of endochondral osteogenesis induced by the iron-chelating property of biological scaffold, which will provide an effective way in the development of novel bone regeneration.


Endochondral ossification; Digital light processing; Hydrogel; Bone tissue engineering

Included Database


Gillman CE, Jayasuriya AC, 2021, FDA-approved bone grafts and bone graft substitute devices in bone regeneration. Mater Sci Eng C Mater Biol Appl, 130: 112466. https://doi.org/10.1016/j.msec.2021.112466

Bose S, Sarkar N, 2020, Natural medicinal compounds in bone tissue engineering. Trends Biotechnol, 38(4): 404–417. https://doi.org/10.1016/j.tibtech.2019.11.005

Ghimire S, Miramini S, Edwards G, et al., 2021, The investigation of bone fracture healing under intramembranous and endochondral ossification. Bone Rep, 14: 100740. https://doi.org/10.1016/j.bonr.2020.100740

Galea GL, Zein MR, Allen S, et al., 2021, Making and shaping endochondral and intramembranous bosnes. Dev Dyn, 250(3): 414–449. https://doi.org/10.1002/dvdy.278

Chan WCW, Tan Z, To MKT, et al., 2021, Regulation and role of transcription factors in osteogenesis. I J Mol Sci, 22(11): 5445. https://doi.org/10.3390/ijms22115445

Weng Y, Wang H, Wu D, et al., 2022, A novel lineage of osteoprogenitor cells with dual epithelial and mesenchymal properties govern maxillofacial bone homeostasis and regeneration after MSFL. Cell Res, 32(9): 814–830. https://doi.org/10.1038/s41422-022-00687-x

He J, Yan J, Wang J, et al., 2021, Dissecting human embryonic skeletal stem cell ontogeny by single-cell transcriptomic and functional analyses. Cell Res, 31(7): 742–757. https://doi.org/10.1038/s41422-021-00467-z

Siddiqui Z, Sarkar B, Kim KK, et al., 2021, Self-assembling peptide hydrogels facilitate vascularization in two-component scaffolds. Chem Eng J, 422: 130145. https://doi.org/10.1016/j.cej.2021.130145

Bernhard JC, Marolt Presen D, Li M, et al., 2022, Effects of endochondral and intramembranous ossification pathways on bone tissue formation and vascularization in human tissue-engineered grafts. Cells, 11(19): 3070. https://doi.org/10.3390/cells11193070

Saul D, Khosla S, 2022, Fracture healing in the setting of endocrine diseases, aging, and cellular senescence. Endocr Rev, 43(6): 984–1002. https://doi.org/10.1210/endrev/bnac008

Ye X, He J, Wang S, et al., 2022, A hierarchical vascularized engineered bone inspired by intramembranous ossification for mandibular regeneration. Int J Oral Sci, 14(1): 31. https://doi.org/10.1038/s41368-022-00179-z

Fernández-Iglesias Á, Fuente R, Gil-Peña H, et al., 2021, The formation of the epiphyseal bone plate occurs via combined endochondral and intramembranous-like ossification. Int J Mol Sci, 22(2): 900. https://doi.org/10.3390/ijms22020900

Fu R, Liu C, Yan Y, et al., 2021, Bone defect reconstruction via endochondral ossification: A developmental engineering strategy. J Tissue Eng, 12: 20417314211004211. https://doi.org/10.1177/20417314211004211

Liu Y, Yang Z, Wang L, et al., 2021, Spatiotemporal immunomodulation using biomimetic scaffold promotes endochondral ossification-mediated bone healing. Adv Sci, 8(11): e2100143. https://doi.org/10.1002/advs.202100143

Wu L, Gu Y, Liu L, et al., 2020, Hierarchical micro/ nanofibrous membranes of sustained releasing VEGF for periosteal regeneration. Biomaterials, 227: 119555. https://doi.org/10.1016/j.biomaterials.2019.119555

Peng K, Zhuo M, Li M, et al., 2020, Histone demethylase JMJD2D activates HIF1 signaling pathway via multiple mechanisms to promote colorectal cancer glycolysis and progression. Oncogene, 39(47): 7076–7091. https://doi.org/10.1038/s41388-020-01483-w

Zhang S, Wang Y, Xu J, et al., 2021, HIFα regulates developmental myelination independent of autocrine Wnt signaling. J Neurosci, 41(2): 251–268. https://doi.org/10.1523/jneurosci.0731-20.2020

Wang P, Xiong X, Zhang J, et al., 2020, Icariin increases chondrocyte vitality by promoting hypoxia-inducible factor- 1α expression and anaerobic glycolysis, Knee, 27(1): 18–25. https://doi.org/10.1016/j.knee.2019.09.012

Fujii Y, Liu L, Yagasaki L, et al., 2022, Cartilage homeostasis and osteoarthritis. Int J Mol Sci, 23(11): 6316. https://doi.org/10.3390/ijms23116316

Ito Y, Matsuzaki T, Ayabe F, et al., 2021, Both microRNA- 455-5p and -3p repress hypoxia-inducible factor-2α expression and coordinately regulate cartilage homeostasis, Nat Commun, 12(1): 4148. https://doi.org/10.1038/s41467-021-24460-7

Jouan Y, Bouchemla Z, Bardèche-Trystram B, et al., 2022, Lin28a induces SOX9 and chondrocyte reprogramming via HMGA2 and blunts cartilage loss in mice. Sci Adv, 8(34): eabn3106. https://doi.org/10.1126/sciadv.abn3106

Haseeb A, Kc R, Angelozzi M, et al., 2021, SOX9 keeps growth plates and articular cartilage healthy by inhibiting chondrocyte dedifferentiation/osteoblastic redifferentiation. Proc Natl Acad Sci USA, 118(8): e2019152118. https://doi.org/10.1073/pnas.2019152118

Maes C, Carmeliet G, Schipani E, 2012, Hypoxia-driven pathways in bone development, regeneration and disease. Nat Rev Rheumatol, 8(6): 358–366. https://doi.org/10.1038/nrrheum.2012.36

Solanki AK, Lali FV, Autefage H, et al., 2021, Bioactive glasses and electrospun composites that release cobalt to stimulate the HIF pathway for wound healing applications. Biomater Res, 25(1): 1. https://doi.org/10.1186/s40824-020-00202-6

Peng Y, Wu S, Li Y, et al., 2020, Type H blood vessels in bone modeling and remodeling. Theranostics, 10(1): 426–436. https://doi.org/10.7150/thno.34126

Wan C, Gilbert SR, Wang Y, et al., 2008, Activation of the hypoxia-inducible factor-1alpha pathway accelerates bone regeneration. Proc Natl Acad Sci USA, 105(2): 686–691. https://doi.org/10.1073/pnas.0708474105

Voit RA, Sankaran VG, 2020, Stabilizing HIF to ameliorate anemia. Cell, 180: 6(1). https://doi.org/10.1016/j.cell.2019.12.010

Kaelin WG, Jr., Ratcliffe PJ, 2008, Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell, 30(4): 393–402. https://doi.org/10.1016/j.molcel.2008.04.009

Zheng X, Zhang X, Wang Y, et al., 2021, Hypoxia-mimicking 3D bioglass-nanoclay scaffolds promote endogenous bone regeneration. Bioact Mater, 6(10): 3485–3495. https://doi.org/10.1016/j.bioactmat.2021.03.011

Zhang J, Tong D, Song H, et al., 2022, Osteoimmunity-regulating biomimetically hierarchical scaffold for augmented bone regeneration. Adv Mater, 34(36): e2202044. https://doi.org/10.1002/adma.202202044

Cui J, Yu X, Yu B, et al., 2022, Coaxially fabricated dual-drug loading electrospinning fibrous mat with programmed releasing behavior to boost vascularized bone regeneration. Adv Healthc Mater, 11(16): e2200571. https://doi.org/10.1002/adhm.202200571

Han X, Sun M, Chen B, et al., 2021, Lotus seedpod-inspired internal vascularized 3D printed scaffold for bone tissue repair. Bioact Mater, 6(6): 1639–1652. https://doi.org/10.1016/j.bioactmat.2020.11.019

Donneys A, Yang Q, Forrest ML, et al., 2019, Implantable hyaluronic acid-deferoxamine conjugate prevents nonunions through stimulation of neovascularization. NPJ Regen Med, 4: 11. https://doi.org/10.1038/s41536-019-0072-9

Yao Q, Liu Y, Selvaratnam B, et al., 2018, Mesoporous silicate nanoparticles/3D nanofibrous scaffold-mediated dual-drug delivery for bone tissue engineering. J Control Release, 279: 69–78. https://doi.org/10.1016/j.jconrel.2018.04.011

Drager J, Sheikh Z, Zhang YL, et al., 2016, Local delivery of iron chelators reduces in vivo remodeling of a calcium phosphate bone graft substitute. Acta Biomater, 42: 411–419. https://doi.org/10.1016/j.actbio.2016.07.037

Liu Z, Zhang J, Fu C, et al., 2023, Osteoimmunity-regulating biomaterials promote bone regeneration. Asian J Pharm Sci, 18(1): 100774. https://doi.org/10.1016/j.ajps.2023.100774

Sun LL, Ma YF, Niu HY, et al., 2021, Recapitulation of in situ endochondral ossification using an injectable hypoxia-mimetic hydrogel. Adv Funct Mater, 31(5). https://doi.org/10.1002/adfm.202008515

Chen YC, Lin RZ, Qi H, et al., 2012, Functional human vascular network generated in photocrosslinkable gelatin methacrylate hydrogels. Adv Funct Mater, 22(10): 2027– 2039. https://doi.org/10.1002/adfm.201101662

Schuurman W, Levett PA, Pot MW, et al., 2013, Gelatin-methacrylamide hydrogels as potential biomaterials for fabrication of tissue-engineered cartilage constructs. Macromol Biosci, 13(5): 551–561. https://doi.org/10.1002/mabi.201200471

Kurian AG, Singh RK, Patel KD, et al., 2022, Multifunctional GelMA platforms with nanomaterials for advanced tissue therapeutics. Bioact Mater, 8: 267–295. https://doi.org/10.1016/j.bioactmat.2021.06.027

Hong Y, Zhou F, Hua Y, et al., 2019, A strongly adhesive hemostatic hydrogel for the repair of arterial and heart bleeds. Nat Commun, 10(1): 2060. https://doi.org/10.1038/s41467-019-10004-7

Gao Q, Niu X, Shao L, et al., 2019, 3D printing of complex GelMA-based scaffolds with nanoclay. Biofabrication, 11(3): 035006. https://doi.org/10.1088/1758-5090/ab0cf6

Ratheesh G, Vaquette C, Xiao Y, 2020, Patient-specific bone particles bioprinting for bone tissue engineering. Adv Healthc Mater, 9(23): e2001323. https://doi.org/10.1002/adhm.202001323

Gao J, Ding X, Yu X, et al., 2021, Cell-free bilayered porous scaffolds for osteochondral regeneration fabricated by continuous 3D-printing using nascent physical hydrogel as ink. Adv Healthc Mater, 10(3): e2001404. https://doi.org/10.1002/adhm.202001404

Zhu T, Cui Y, Zhang M, et al., 2020, Engineered three-dimensional scaffolds for enhanced bone regeneration in osteonecrosis. Bioact Mater, 5(3): 584–601. https://doi.org/10.1016/j.bioactmat.2020.04.008

Zhu T, Jiang M, Zhang M, et al., 2022, Construction and validation of steroid-induced rabbit osteonecrosis model. MethodsX, 9: 101713. https://doi.org/10.1016/j.mex.2022.101713

Zhu T, Jiang M, Zhang M, et al., 2022, Biofunctionalized composite scaffold to potentiate osteoconduction, angiogenesis, and favorable metabolic microenvironment for osteonecrosis therapy. Bioact Mater, 9: 446–460. https://doi.org/10.1016/j.bioactmat.2021.08.005

Zhao D, Zhu T, Li J, et al., 2021, Poly(lactic-co-glycolic acid)- based composite bone-substitute materials. Bioact Mater, 6 (2): 346–360. https://doi.org/10.1016/j.bioactmat.2020.08.016

Cui L, Zhang J, Zou J, et al., 2020, Electroactive composite scaffold with locally expressed osteoinductive factor for synergistic bone repair upon electrical stimulation. Biomaterials, 230: 119617. https://doi.org/10.1016/j.biomaterials.2019.119617

Sun LL, Ma YF, Niu HY, et al., 2021, Recapitulation of in situ endochondral ossification using an injectable hypoxia-mimetic hydrogel. Adv Funct Mater, 31(5): 2008515. https://doi.org/10.1002/adfm.202101589

DOI: http://dx.doi.org/10.18063/ijb.754


  • There are currently no refbacks.

Copyright (c) 2023 Author(s).

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.