Strategies of Functionalized GelMA-based Bioinks for Bone Regeneration: Recent Advances and Future Perspectives

Overview

Journal Bioact Mater

Specialty Biomedical Engineering

Date 2024 May 20

PMID 38764449

Authors

Yaru Zhu

Xingge Yu

Hao Liu

Junjun Li

Mazaher Gholipourmalekabadi

Kaili Lin

Changyong Yuan

Penglai Wang

Affiliations

Soon will be listed here.

Abstract

Gelatin methacryloyl (GelMA) hydrogels is a widely used bioink because of its good biological properties and tunable physicochemical properties, which has been widely used in a variety of tissue engineering and tissue regeneration. However, pure GelMA is limited by the weak mechanical strength and the lack of continuous osteogenic induction environment, which is difficult to meet the needs of bone repair. Moreover, GelMA hydrogels are unable to respond to complex stimuli and therefore are unable to adapt to physiological and pathological microenvironments. This review focused on the functionalization strategies of GelMA hydrogel based bioinks for bone regeneration. The synthesis process of GelMA hydrogel was described in details, and various functional methods to meet the requirements of bone regeneration, including mechanical strength, porosity, vascularization, osteogenic differentiation, and immunoregulation for patient specific repair, etc. In addition, the response strategies of smart GelMA-based bioinks to external physical stimulation and internal pathological microenvironment stimulation, as well as the functionalization strategies of GelMA hydrogel to achieve both disease treatment and bone regeneration in the presence of various common diseases (such as inflammation, infection, tumor) are also briefly reviewed. Finally, we emphasized the current challenges and possible exploration directions of GelMA-based bioinks for bone regeneration.

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References

Yin J, Han Q, Zhang J, Liu Y, Gan X, Xie K . MXene-Based Hydrogels Endow Polyetheretherketone with Effective Osteogenicity and Combined Treatment of Osteosarcoma and Bacterial Infection. ACS Appl Mater Interfaces. 2020; 12(41):45891-45903. DOI: 10.1021/acsami.0c14752. View

Kim J, Raja N, Choi Y, Gal C, Sung A, Park H . Enhancement of properties of a cell-laden GelMA hydrogel-based bioink via calcium phosphate phase transition. Biofabrication. 2023; 16(1). DOI: 10.1088/1758-5090/ad05e2. View

Suo H, Zhang D, Yin J, Qian J, Wu Z, Fu J . Interpenetrating polymer network hydrogels composed of chitosan and photocrosslinkable gelatin with enhanced mechanical properties for tissue engineering. Mater Sci Eng C Mater Biol Appl. 2018; 92:612-620. DOI: 10.1016/j.msec.2018.07.016. View

Zhang J, Wehrle E, Rubert M, Muller R . 3D Bioprinting of Human Tissues: Biofabrication, Bioinks, and Bioreactors. Int J Mol Sci. 2021; 22(8). PMC: 8069718. DOI: 10.3390/ijms22083971. View

Ahmadi S, Rabiee N, Bagherzadeh M, Elmi F, Fatahi Y, Farjadian F . Stimulus-Responsive Sequential Release Systems for Drug and Gene Delivery. Nano Today. 2020; 34. PMC: 7416836. DOI: 10.1016/j.nantod.2020.100914. View

Zhou X, Chen J, Sun H, Wang F, Wang Y, Zhang Z . Spatiotemporal regulation of angiogenesis/osteogenesis emulating natural bone healing cascade for vascularized bone formation. J Nanobiotechnology. 2021; 19(1):420. PMC: 8670285. DOI: 10.1186/s12951-021-01173-z. View

Li D, Chen K, Tang H, Hu S, Xin L, Jing X . A Logic-Based Diagnostic and Therapeutic Hydrogel with Multistimuli Responsiveness to Orchestrate Diabetic Bone Regeneration. Adv Mater. 2021; 34(11):e2108430. DOI: 10.1002/adma.202108430. View

Jin Q, Jin G, Ju J, Xu L, Tang L, Fu Y . Bioprinting small-diameter vascular vessel with endothelium and smooth muscle by the approach of two-step crosslinking process. Biotechnol Bioeng. 2022; 119(6):1673-1684. PMC: 9314886. DOI: 10.1002/bit.28075. View

Wang M, Li W, Hao J, Gonzales 3rd A, Zhao Z, Sanchez Flores R . Molecularly cleavable bioinks facilitate high-performance digital light processing-based bioprinting of functional volumetric soft tissues. Nat Commun. 2022; 13(1):3317. PMC: 9184597. DOI: 10.1038/s41467-022-31002-2. View

10.

Yin J, Yan M, Wang Y, Fu J, Suo H . 3D Bioprinting of Low-Concentration Cell-Laden Gelatin Methacrylate (GelMA) Bioinks with a Two-Step Cross-linking Strategy. ACS Appl Mater Interfaces. 2018; 10(8):6849-6857. DOI: 10.1021/acsami.7b16059. View

11.

Wang B, Diaz-Payno P, Browe D, Freeman F, Nulty J, Burdis R . Affinity-bound growth factor within sulfated interpenetrating network bioinks for bioprinting cartilaginous tissues. Acta Biomater. 2021; 128:130-142. DOI: 10.1016/j.actbio.2021.04.016. View

12.

Xu C, Chang Y, Xu Y, Wu P, Mu C, Nie A . Silicon-Phosphorus-Nanosheets-Integrated 3D-Printable Hydrogel as a Bioactive and Biodegradable Scaffold for Vascularized Bone Regeneration. Adv Healthc Mater. 2021; 11(6):e2101911. DOI: 10.1002/adhm.202101911. View

13.

Zhang J, Yang H, Abali B, Li M, Xia Y, Haag R . Dynamic Mechanics-Modulated Hydrogels to Regulate the Differentiation of Stem-Cell Spheroids in Soft Microniches and Modeling of the Nonlinear Behavior. Small. 2019; 15(30):e1901920. DOI: 10.1002/smll.201901920. View

14.

Purcell B, Elser J, Mu A, Margulies K, Burdick J . Synergistic effects of SDF-1α chemokine and hyaluronic acid release from degradable hydrogels on directing bone marrow derived cell homing to the myocardium. Biomaterials. 2012; 33(31):7849-57. PMC: 3449064. DOI: 10.1016/j.biomaterials.2012.07.005. View

15.

Donaldson A, Tanase C, Awuah D, Vasanthi Bathrinarayanan P, Hall L, Nikkhah M . Photocrosslinkable Gelatin Hydrogels Modulate the Production of the Major Pro-inflammatory Cytokine, TNF-α, by Human Mononuclear Cells. Front Bioeng Biotechnol. 2018; 6:116. PMC: 6156527. DOI: 10.3389/fbioe.2018.00116. View

16.

Ribeiro J, Bordini E, Ferreira J, Mei L, Dubey N, Fenno J . Injectable MMP-Responsive Nanotube-Modified Gelatin Hydrogel for Dental Infection Ablation. ACS Appl Mater Interfaces. 2020; 12(14):16006-16017. PMC: 7370252. DOI: 10.1021/acsami.9b22964. View

17.

Tournier P, Guicheux J, Pare A, Maltezeanu A, Blondy T, Veziers J . A partially demineralized allogeneic bone graft: in vitro osteogenic potential and preclinical evaluation in two different intramembranous bone healing models. Sci Rep. 2021; 11(1):4907. PMC: 7921404. DOI: 10.1038/s41598-021-84039-6. View

18.

Xu Y, Xu C, He L, Zhou J, Chen T, Ouyang L . Stratified-structural hydrogel incorporated with magnesium-ion-modified black phosphorus nanosheets for promoting neuro-vascularized bone regeneration. Bioact Mater. 2022; 16:271-284. PMC: 8965728. DOI: 10.1016/j.bioactmat.2022.02.024. View

19.

Liu L, Yu F, Li L, Zhou L, Zhou T, Xu Y . Bone marrow stromal cells stimulated by strontium-substituted calcium silicate ceramics: release of exosomal miR-146a regulates osteogenesis and angiogenesis. Acta Biomater. 2020; 119:444-457. DOI: 10.1016/j.actbio.2020.10.038. View

20.

Choi E, Kim D, Kang D, Yang G, Jung B, Yeo M . 3D-printed gelatin methacrylate (GelMA)/silanated silica scaffold assisted by two-stage cooling system for hard tissue regeneration. Regen Biomater. 2021; 8(2):rbab001. PMC: 7955716. DOI: 10.1093/rb/rbab001. View