Recent advance in bioactive hydrogels for repairing spinal cord injury: material design, biofunctional regulation, and applications

Abstract

Functional hydrogels show potential application in repairing spinal cord injury (SCI) due to their unique chemical, physical, and biological properties and functions. In this comprehensive review, we present recent advance in the material design, functional regulation, and SCI repair applications of bioactive hydrogels. Different from previously released reviews on hydrogels and three-dimensional scaffolds for the SCI repair, this work focuses on the strategies for material design and biologically functional regulation of hydrogels, specifically aiming to show how these significant efforts can promoting the repairing performance of SCI. We demonstrate various methods and techniques for the fabrication of bioactive hydrogels with the biological components such as DNA, proteins, peptides, biomass polysaccharides, and biopolymers to obtain unique biological properties of hydrogels, including the cell biocompatibility, self-healing, anti-bacterial activity, injectability, bio-adhesion, bio-degradation, and other multi-functions for repairing SCI. The functional regulation of bioactive hydrogels with drugs/growth factors, polymers, nanoparticles, one-dimensional materials, and two-dimensional materials for highly effective treating SCI are introduced and discussed in detail. This work shows new viewpoints and ideas on the design and synthesis of bioactive hydrogels with the state-of-the-art knowledges of materials science and nanotechnology, and will bridge the connection of materials science and biomedicine, and further inspire clinical potential of bioactive hydrogels in biomedical fields.

Keywords: Bioactivity; Biomedical engineering; Functional regulation; Hydrogels; Spinal cord injury.

Scheme 1.

Model on the design and functional regulation of bioactive hydrogels for the SCI repair

Fig. 1

Hydrogels for tissue engineering applications: a Diagram of hydrogels treatment of central neuropathy (brain, spinal cord). b Cell behavior of injectable hydrogels. Reprinted from Ref [50], Copyright 2021, Royal Society of Chemistry

Fig. 2

Unique physical, chemical, and biological properties of hydrogels for cell and drug delivery in SCI repairing. Reprinted from Ref [14], Copyright 2022, Elsevier

Fig. 3

The preparation process and structure diagram of bioactive DNA hydrogels: a DNA-nSi hydrogels. Reprinted from Ref. [63], Copyright 2018, American Chemical Society. b DNA-OA-nSi hydrogels. Reprinted from Ref. [64], Copyright 2020, Elsevier. c AuNS-DNA and AuNR-DNA hydrogels. Reprinted from Ref. [65], Copyright 2017, Elsevier. d CPT-DNA hydrogels. Reprinted from Ref. [66], Copyright 2020, American Chemical Society

Fig. 4

Synthesis and structures of bioactive protein hydrogels: a SF-collagen composite hydrogels. Reprinted from Ref. [73], Copyright 2017, Elsevier b Metal sulfide-protein hybrid hydrogels. Reprinted from Ref. [75], Copyright 2017, Wiley–VCH. c TA-PVA/BSA hydrogels. Reprinted from Ref. [76], Copyright 2018, American Chemical Society. d Mfp3 hydrogels formed by photochemical gelation. Reprinted from Ref. [78], Copyright 2018, American Chemical Society

Fig. 5

Synthesis and structures of bioactive peptide hydrogels: a KK-BSA hydrogels formed by Ag–S coordination. Reprinted from Ref. [81], Copyright 2020, Wiley–VCH. b Photosensitive peptide hydrogel via self-assembly. Reprinted from Ref. [82], Copyright·2023, American Chemical Society. c ECM protein-mimic peptide hydrogel. Reprinted from Ref. [83], Copyright 2018, American Chemical Society. d Self-assembly and gelation pathways of β-sheet forming peptides. Reprinted from Ref [84], Copyright 2022, Royal Society of Chemistry

Fig. 6

Synthesis and structure of bioactive polysaccharide hydrogels: a 3D printed Alg/Gel/CNCs hydrogel. Reprinted from Ref. [87], Copyright· 2021, Elsevier. b CaP-TOCNF hybrid hydrogel. Reprinted from Ref. [88], Copyright·2021, MDPI. c CM/ZnO-MCM-41/TC hybrid hydrogel for drug delivery. Reprinted from Ref. [90], Copyright 2017, Elsevier

Fig. 7

Synthesis and structure of other biopolymer hydrogels: a PDA/Cu-CS composite hydrogel. Reprinted from Ref. [93], Copyright 2020, American Chemical Society. b PEG/CTS hydrogels loaded with TiO₂ NPs. Reprinted from Ref. [94], Copyright·2018, Elsevier. c Self-healing HA nanocomposite hydrogel. Reprinted from Ref. [95], Copyright·2022, American Chemical Society. d GelMA-PAM hybrid hydrogel. Reprinted from Ref. [96], Copyright 2017, Royal Society of Chemistry

Fig. 8

Cell biocompatibility of bioactive hydrogels: a GHNbBG hydrogel for osteogenesis. Reprinted from Ref. [99], Copyright 2023, Elsevier. b EGF and BFGF-loaded peptide hydrogels for SCI. Reprinted from Ref. [26], Copyright 2023, Elsevier. c GelMA hydrogel loaded BMSCs and NSCs for SCI repair. Reprinted from Ref. [103], Copyright 2020, Elsevier

Fig. 9

Self-healing hydrogels for SCI repair: a XG-PEG self-healing hydrogel. Reprinted from Ref. [108], Copyright 2018, American Chemical Society. b Self-healing FC/FI-Cur hydrogel for treating SCI. Reprinted from Ref. [109], Copyright 2021, Elsevier. c Self-healing AHA/DTP hydrogel for repairing SCI. Reprinted from Ref. [110], Copyright 2022, Elsevier

Fig. 10

Anti-bacterial and anti-inflammatory properties of hydrogels: a nAg/HNTs/GelMA for preventing bacterial infection and promoting bone tissue regeneration. Reprinted from Ref. [115], Copyright 2020, Elsevier. b ADSCs-loaded CaNeu hydrogel for the formation of anti-inflammatory microenvironment. Reprinted from Ref. [116], Copyright 2021, Elsevier

Fig. 11

Injectable ability of hydrogels: a Injectable thermosensitive PLEL/EVs hydrogel for SCI repair. Reprinted from Ref. [8], Copyright 2022, Elsevier. b Injectable SF/DA hydrogel for SCI repair. Reprinted from Ref. [123], Copyright 2020, Elsevier

Fig. 12

Biological adhesion of hydrogels: a SF-GMA/LM-AC hydrogel with high adhesion for SCI repair. Reprinted from Ref. [130], Copyright 2023, Elsevier. b Col-FB hydrogel for SCI repair. Reprinted from Ref. [131], Copyright 2022, American Chemistry Society. c SF-RGD hydrogel for the SCI adhesion and osteogenic differentiation. Reprinted from Ref. [132], Copyright 2019, Wiley–VCH

Fig. 13

Multi-functions of bioactive hydrogels: a Biodegradable hydrogel Cab-M/H gels for healing injured site. Reprinted from Ref. [140], Copyright 2019, Elsevier. b Multifunctional conductive ICH/NSCs hydrogel for SCI repair. Reprinted from Ref. [142], Copyright 2023, American Chemistry Society. c Multifunctional FE/EVs hydrogel for promoting neuronal differentiation and axon formation. Reprinted from Ref. [25], Copyright 2021, Elsevier. d PMEAC hydrogel scaffold for regulating the microenvironment motor function recovery. Reprinted from Ref. [146], Copyright 2022, Elsevier

Fig. 14

Growth factor/drug-hydrogel for SCI treatment: a PDGF-MPHM + NSCs hydrogel for SCI repair, Reprinted from Ref. [152], Copyright 2023, American Chemical Society. b Dual-drug NSCs-cfGel system for repairing SCI. Reprinted from Ref. [10], Copyright 2022, Elsevier

Fig. 15

Polymer hydrogels for SCI repair: a 3D bioprinted conductive composite hydrogel for SCI repair. Reprinted from Ref. [169], Copyright 2023, Elsevier. b PLL hydrogel and its potential application in SCI repair. Reprinted from Ref. [174], Copyright 2023, Elsevier

Fig. 16

NP-functionalized bioactive hydrogels for SCI repair: a CeNP-Gel hydrogel for repairing SCI. Reprinted from Ref. [181], Copyright 2021, Wiley–VCH. b PPy NP-embedded collagen-HAMA hybrid hydrogel for in vivo SCI repair. Reprinted from Ref. [188], Copyright 2021, American Chemical Society

Fig. 17.

1DM-incorporated hydrogels for SCI repair applications: a electrospun MAL-PCL fiber-doped PEG-HA hydrogel for SCI repair. Reprinted from Ref. [193], Copyright 2020, Elsevier. b CNT-doped conductive PEG hydrogels for SCI repair. Reprinted from Ref. [195], Copyright 2018, Royal Society of Chemistry. c NGF-functionalized SFN hydrogels for scarless spinal cord repair. Reprinted from Ref. [200], Copyright 2022, American Chemical Society. d peptide nanofiber (PNF)-PEO AFG for spinal cord regeneration. Reprinted from Ref. [204], Copyright 2021, Elsevier

Fig. 18.

2DM-incorporated hydrogels for SCI repair applications: a MoS₂/GO/PVA hydrogel for repairing SCI. Reprinted from Ref. [207], Copyright 2022, Springer Nature. b rGO/XG gel for repairing SCI. Reprinted from Ref. [209], Copyright 2022, Elsevier. c MXene and AuNPs-modified GelMA hydrogel for the recovery of SCI. Reprinted from Ref. [212], Copyright 2023, Elsevier. d 2D GeP@PDA-doped HA-DA hydrogel for enhanced repair of SCI. Reprinted from Ref. [11], Copyright 2021, Wiley–VCH