Smart responsive in situ hydrogel systems applied in bone tissue engineering

Abstract

The repair of irregular bone tissue suffers severe clinical problems due to the scarcity of an appropriate therapeutic carrier that can match dynamic and complex bone damage. Fortunately, stimuli-responsive in situ hydrogel systems that are triggered by a special microenvironment could be an ideal method of regenerating bone tissue because of the injectability, in situ gelatin, and spatiotemporally tunable drug release. Herein, we introduce the two main stimulus-response approaches, exogenous and endogenous, to forming in situ hydrogels in bone tissue engineering. First, we summarize specific and distinct responses to an extensive range of external stimuli (e.g., ultraviolet, near-infrared, ultrasound, etc.) to form in situ hydrogels created from biocompatible materials modified by various functional groups or hybrid functional nanoparticles. Furthermore, "smart" hydrogels, which respond to endogenous physiological or environmental stimuli (e.g., temperature, pH, enzyme, etc.), can achieve in situ gelation by one injection in vivo without additional intervention. Moreover, the mild chemistry response-mediated in situ hydrogel systems also offer fascinating prospects in bone tissue engineering, such as a Diels-Alder, Michael addition, thiol-Michael addition, and Schiff reactions, etc. The recent developments and challenges of various smart in situ hydrogels and their application to drug administration and bone tissue engineering are discussed in this review. It is anticipated that advanced strategies and innovative ideas of in situ hydrogels will be exploited in the clinical field and increase the quality of life for patients with bone damage.

Keywords: bone tissue engineering; endogenous stimulus; exogenous stimulus; in situ hydrogels; smart hydrogels.

FIGURE 1

Different stimulus-responsive in situ hydrogel systems based on biomaterials were explored to obtain excellent treatment in bone tissue engineering. Exogenous stimulus-responsive systems form in situ hydrogels in response to triggers such as UV, NIR, US, etc. Endogenous stimulus-responsive systems form in situ hydrogels in response to internal triggers such as temperature, enzyme, etc.

FIGURE 2

Schematic diagram of bone tissue structure. (A) Bone hierarchical structure (Zhu et al., 2021). HAP, hydroxyapatite; GAGs, glycosaminoglycans; NCPs, non-collagenous proteins. Copyright 2021, Elsevier. (B) Schematic diagram of cartilage and subchondral bone.

FIGURE 3

Scheme of various exogenous stimulus strategies for in situ hydrogel triggering in bone tissue engineering.

FIGURE 4

Photo-crosslinking in situ hydrogel applied to bone tissue engineering. (A) Schematic representation of GelMA-c-OGP hydrogel construction and its mechanical properties (Qiao et al., 2020). Copyright 2020, Wiley-VCH. (B) Schematic illustration of bone regeneration in vivo at the time of injection of this hydrogel modeled with cholesterol-modified miR-26a at the site of bone malformation (Gan et al., 2021). Copyright 2021, Elsevier. (C) Schematic diagram of the IGF-1bsn functioning as activators for promoting cell proliferation and inhibiting apoptosis (Wu H. et al., 2023). Copyright 2023, Elsevier. (D) Schematic illustration of therapeutic sEVs released from GelMA/nanoclay hydrogel for cartilage regeneration (Hu et al., 2020). Copyright 2020, Taylor & Francis Group.

FIGURE 5

NIR-responsive in situ hydrogel in tissue engineering. (A) In situ gelation in vitro and in vivo of PNAM–MoS₂ (Lee et al., 2021). Copyright 2021, Wiley-VCH. (B) The controllable in situ synthesis of a CuS/¹³¹I -PEGDA hydrogel (Meng et al., 2018). Copyright 2018, American Chemical Society. (C) Schematic illustration of NIR light-induced angiogenesis in a photoactivatable hydrogel with embedded UCNP-PMAOs (Zheng et al., 2020). Copyright 2021, RSC.

FIGURE 6

Schematic illustration of the design of in situ nanocomposite hydrogels with a controlled release of KGN and ultrasonic stimuli ROS production for irregular cartilage repair (Wu S. et al., 2023). Copyright 2023, RSC.

FIGURE 7

Temperature stimulus-responsive in situ hydrogel applied in bone tissue engineering. (A) Graphical representation of the injectable in situ hydrogel experimental strategy in vivo or in vitro (Muscolino et al., 2021). Copyright 2021, Elsevier. (B) Schematic representation of PF127-based copolymer temperature stimulus-responsive in situ hydrogel in chondral regeneration (Madry et al., 2020). Copyright 2020, Wiley-VCH. (C) Schematic diagram of one-time injection of the TePN hydrogel system for long-term osteoarthritis treatment (Seo et al., 2022). Copyright 2022, Elsevier. (D) Preparation of DFO-GMs hydrogel complex for repairing a critical-sized femoral defect (Zeng et al., 2022). Copyright 2022, Elsevier.

FIGURE 8

Various enzyme stimulus-responsive in situ hydrogel schemes. Enzyme response mechanisms of horseradish peroxidase (A), transglutaminase (B), and thrombin (C).

FIGURE 9

Peroxidase enzymatically crosslinking injectable in situ hydrogels. (A) Overall scheme of enzymatically cross-linked injectable hydrogels for delivery of cells and TGF-β1 for cartilage tissue engineering (Arora et al., 2017). Copyright 2017, Europe PMC. (B) Preparation of the BMSC-laden injectable Col-HA hydrogel for cartilage regeneration (Zhang et al., 2020). Copyright 2020, RSC.

FIGURE 10

Fabrication of hydrogel Gel/TG/TA-MPs-His6-T4L-BMP2 (Hydrogel/MPs-His6-T4L-BMP2), which was applied to bone defects (Chen X. et al., 2021). Copyright 2021, Elsevier.

FIGURE 11

Fibrin-thrombin-based in situ hydrogels were applied in bone tissue disease. (A) Schematic illustration of rhBMP-2@SCS NPs to induce therapeutic osteogenesis (Chen et al., 2022). Copyright 2022, Elsevier. (B) Scheme of the gelation process of Fb/F127/PMMA hydrogel through a dual-syringe device while filling the meniscal defect region (An et al., 2021). Copyright 2021, SAGE Publications Ltd. (C) The schematic representation describes the overall procedure during the injection. The fibrinogen and thrombin (Tb) solutions were injected, and the semi-interpenetrated polymer network was subsequently formed (Kim et al., 2021). Copyright 2021, American Orthopaedic Society for Sports Medicine.

FIGURE 12

Glucose oxidase-based in situ hydrogels were applied in bone tissue engineering. (A) Scheme of pH and glucose dual-responsive injectable hydrogels with insulin and fibroblasts as bioactive dressings for diabetic wound healing (Zhao et al., 2017). Copyright 2017, American Chemical Society. (B) Schematic illustrations of gelation mechanisms by O₂ oxidation, direct addition of H₂O₂ solution, and the indirect H₂O₂ supplement method via GOD-catalyzed glucose oxidation and glucose-triggered in situ forming keratin hydrogel as a drug depot for the treatment of diabetic wounds (Chen Y. et al., 2021). Copyright 2021, Elsevier. (C) Fabrication of the CS-DMAA hydrogel. The molecular structures of the acryloylated-CS and the poly (DMAA) are given. This hydrogel is used as a tissue filler via in situ injection and glucose-responsive hydrogenation (Zhang Q. et al., 2021). Copyright 2021, Wiley-VCH.

FIGURE 13

Chemical reaction crosslinking stimulus-responsive in situ hydrogel. (A) Oligomeric polyhedral oligomeric alkyne-azide cycloaddition (SPAAC) system (Liu et al., 2021). Copyright 2021, Elsevier. (B) Schematic illustration of the in situ hydrogel formed by a Diels–Alder click-crosslinking reaction. (Park et al., 2020). Copyright 2020, Elsevier. (C) Thiol-Michael addition reaction (Gilchrist et al., 2021). Copyright 2021, Elsevier. (D) Schematic representation of the formation of injectable hydrogels chemically cross-linked by a Schiff’s base reaction between aqueous solutions of GC and poly(EO-co-Gly)-CHO (Cao et al., 2015). Copyright 2015, RSC.