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Cited by 64Bone Tissue Engineering MaterialsHydrogels: synthesis, properties, applications3D Printing in Biomedical Research

The DOI matches its Crossref record; 121 of the 122 references it cites were found in a registry or an index, and 1 are not checked yet.

Nanoclay-Composite Hydrogels for Bone Tissue Engineering

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Hwang, Hee Sook, Lee, Chung-Sung·2024·Gels
DOI 10.3390/gels10080513PMC PMC11353637
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Abstract

Nanoclay-composite hydrogels represent a promising avenue for advancing bone tissue engineering. Traditional hydrogels face challenges in providing mechanical strength, biocompatibility, and bioactivity necessary for successful bone regeneration. The incorporation of nanoclay into hydrogel matrices offers a potential unique solution to these challenges. This review provides a comprehensive overview of the fabrication, physico-chemical/biological performance, and applications of nanoclay-composite hydrogels in bone tissue engineering. Various fabrication techniques, including in situ polymerization, physical blending, and 3D printing, are discussed. In vitro and in vivo studies evaluating biocompatibility and bioactivity have demonstrated the potential of these hydrogels for promoting cell adhesion, proliferation, and differentiation. Their applications in bone defect repair, osteochondral tissue engineering and drug delivery are also explored. Despite their potential in bone tissue engineering, nanoclay-composite hydrogels face challenges such as optimal dispersion, scalability, biocompatibility, long-term stability, regulatory approval, and integration with emerging technologies to achieve clinical application. Future research directions need to focus on refining fabrication techniques, enhancing understanding of biological interactions, and advancing towards clinical translation and commercialization. Overall, nanoclay-composite hydrogels offer exciting opportunities for improving bone regeneration strategies.

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Figure 1 Properties of hydrogels for bone tissue engineering.
Figure 1 Properties of hydrogels for bone tissue engineering.CC BY · PubMed Central
Figure 2 Considerations and benefits of nanoclay reinforcement in hydrogels for bone tissue engineering.
Figure 2 Considerations and benefits of nanoclay reinforcement in hydrogels for bone tissue engineering.CC BY · PubMed Central
Figure 3 Nanoclay-composite hydrogel for 3D printing biomaterial ink. (A) Synthesis process and representative images of a nanoclay sol-like mixture, a nanoclay-methacrylated hyaluronic acid mixture, and a nanoclay-methacrylated hyaluronic acid-alginate gel-like mixture. (B) Representative images of a straight filament and straight filament rotating around the collecting rod. (C) Optical images of straight filaments with diameters of 100, 200, and 300 µm, respectively. (D) Filaments can be formed into spiral shapes to endure extensive stretching, subsequently used to create a handmade clover. (E) 3D printing of complex architectures based on hydrogels. (F) Macroscopic and fluorescence images of the non-porous scaffold and 3D printed porous scaffold based on hydrogels. (G) In vivo micro-CT reconstructed images of calvarial defects at 4 weeks and 8 weeks after implantation. Reproduced with permission from Guo et al. [97].
Figure 3 Nanoclay-composite hydrogel for 3D printing biomaterial ink. (A) Synthesis process and representative images of a nanoclay sol-like mixture, a nanoclay-methacrylated hyaluronic acid mixture, and a nanoclay-methacrylated hyaluronic acid-alginate gel-like mixture. (B) Representative images of a straight filament and straight filament rotating around the collecting rod. (C) Optical images of straight filaments with diameters of 100, 200, and 300 µm, respectively. (D) Filaments can be formed into spiral shapes to endure extensive stretching, subsequently used to create a handmade clover. (E) 3D printing of complex architectures based on hydrogels. (F) Macroscopic and fluorescence images of the non-porous scaffold and 3D printed porous scaffold based on hydrogels. (G) In vivo micro-CT reconstructed images of calvarial defects at 4 weeks and 8 weeks after implantation. Reproduced with permission from Guo et al. [97].CC BY · PubMed Central
Figure 4 Dual nanoengineered DNA hydrogel (DAC) hydrogel for vascularized bone regeneration. (A) Schematic illustration of preparation of DAC hydrogel. (B) Schematics of the extrusion 3D printing process, scale bar: 5 mm. (C) Stability of 3D-printed DAC hydrogels at different pH values. (D) Reaction scheme of QK peptide-conjugated amyloid fibrils (AF-QK). (E) Stimulation effects of various hydrogels on HUVEC migration (Left). Quantitative migration ratio after HUVECs being cultured for 24 h (Right). (F) qRT–PCR analysis of angiogenesis-related gene (VEGF, PDGF-B, CD31, and VWF) expression in HUVECs cultured for 3 days. (G) Mineralized matrix determined by Alizarin red staining for 7 and 14 days. (H) Representative micro-CT images with cross-section and longitudinal section of skull defects implanted with hydrogels. (I) Quantitative analysis of OCN, CD31, and VEGF expression at 4, 8, and 12 weeks. *, p < 0.05; **, p < 0.01; ***, p < 0.001. AF = amyloid fibrils, DA = DNA/AF hydrogel, DAC1.0 = DNA/AF/nanoclay hydrogel. Reproduced with permission from Yang et al. [98].
Figure 4 Dual nanoengineered DNA hydrogel (DAC) hydrogel for vascularized bone regeneration. (A) Schematic illustration of preparation of DAC hydrogel. (B) Schematics of the extrusion 3D printing process, scale bar: 5 mm. (C) Stability of 3D-printed DAC hydrogels at different pH values. (D) Reaction scheme of QK peptide-conjugated amyloid fibrils (AF-QK). (E) Stimulation effects of various hydrogels on HUVEC migration (Left). Quantitative migration ratio after HUVECs being cultured for 24 h (Right). (F) qRT–PCR analysis of angiogenesis-related gene (VEGF, PDGF-B, CD31, and VWF) expression in HUVECs cultured for 3 days. (G) Mineralized matrix determined by Alizarin red staining for 7 and 14 days. (H) Representative micro-CT images with cross-section and longitudinal section of skull defects implanted with hydrogels. (I) Quantitative analysis of OCN, CD31, and VEGF expression at 4, 8, and 12 weeks. *, p < 0.05; **, p < 0.01; ***, p < 0.001. AF = amyloid fibrils, DA = DNA/AF hydrogel, DAC1.0 = DNA/AF/nanoclay hydrogel. Reproduced with permission from Yang et al. [98].CC BY · PubMed Central
Figure 5 Gelatin–Sumecton composite hydrogels. (A) Macroscopical images of lyophilized hydrogels. Scale bar = 5 mm. (B) Swelling ratio after 24 h of hydration. Statistical significance: *** p < 0.001. (C) Scanning electron microscopy (SEM) representative images. Scale bar = 200 μm. (D) Compressive stress–strain curves of hydrogels. (E) Histomorphometric analysis showing the percentage of repair among all experimental groups. Same letters displayed in different histograms denote significant differences (p < 0.001) among these groups. (F) Cross-sectional representative images stained with VOF trichrome dye of the defect site. SUM0: gelatin hydrogel without Sumecton, SUM0.5: gelatin–Sumecton composite hydrogel with Sumecton 0.5%, SUM1: gelatin–Sumecton composite hydrogel with Sumecton 1%, SUM2: gelatin–Sumecton composite hydrogel with Sumecton 2%, CT: Connective tissue, DS: Defect site, NB: Newly formed bone. Scale bar is 500 μm in (F). Reproduced with permission from Lukin et al. [114].
Figure 5 Gelatin–Sumecton composite hydrogels. (A) Macroscopical images of lyophilized hydrogels. Scale bar = 5 mm. (B) Swelling ratio after 24 h of hydration. Statistical significance: *** p < 0.001. (C) Scanning electron microscopy (SEM) representative images. Scale bar = 200 μm. (D) Compressive stress–strain curves of hydrogels. (E) Histomorphometric analysis showing the percentage of repair among all experimental groups. Same letters displayed in different histograms denote significant differences (p < 0.001) among these groups. (F) Cross-sectional representative images stained with VOF trichrome dye of the defect site. SUM0: gelatin hydrogel without Sumecton, SUM0.5: gelatin–Sumecton composite hydrogel with Sumecton 0.5%, SUM1: gelatin–Sumecton composite hydrogel with Sumecton 1%, SUM2: gelatin–Sumecton composite hydrogel with Sumecton 2%, CT: Connective tissue, DS: Defect site, NB: Newly formed bone. Scale bar is 500 μm in (F). Reproduced with permission from Lukin et al. [114].CC BY · PubMed Central
Figure 6 Halloysite nanotube-composite chitosan hydrogels. In vitro biocompatibility of scaffolds: (A) OD values; and (B) live/dead staining of free (control) and encapsulated hASCs in different hydrogels on days 1, 3, and 5 of culture. In vitro osteogenic differentiation of free (control) and encapsulated hASCs in normal medium (NM) and osteogenic medium (OM): (C) ALP activity on days 7 and 14 of culture; and (D) Alizarin red staining on day 21 of culture; scaffolds: (a) CS/GP = chitosan/β-glycerophosphate hydrogel, (b) mHNT2CS/GP = chitosan/β-glycerophosphate hydrogel with chitosan-modified HNTs, and (c) IC@mHNT2CS/GP = chitosan/β-glycerophosphate hydrogel with chitosan-modified HNTs and Icariin. * p < 0.03, ** p < 0.002, *** p < 0.001. Reproduced with permission from Aghdam et al. [119].
Figure 6 Halloysite nanotube-composite chitosan hydrogels. In vitro biocompatibility of scaffolds: (A) OD values; and (B) live/dead staining of free (control) and encapsulated hASCs in different hydrogels on days 1, 3, and 5 of culture. In vitro osteogenic differentiation of free (control) and encapsulated hASCs in normal medium (NM) and osteogenic medium (OM): (C) ALP activity on days 7 and 14 of culture; and (D) Alizarin red staining on day 21 of culture; scaffolds: (a) CS/GP = chitosan/β-glycerophosphate hydrogel, (b) mHNT2CS/GP = chitosan/β-glycerophosphate hydrogel with chitosan-modified HNTs, and (c) IC@mHNT2CS/GP = chitosan/β-glycerophosphate hydrogel with chitosan-modified HNTs and Icariin. * p < 0.03, ** p < 0.002, *** p < 0.001. Reproduced with permission from Aghdam et al. [119].CC BY · PubMed Central

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  1. Wang, A., and Wang, W. (2019). Nanomaterials from Clay Minerals: A New Approach to Green Functional Materials, Elsevier.

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Metadata

Authors
Hwang, H. S., & Lee, C.-S.
Affiliations
  • Dankook University (KR)
  • Soonchunhyang University (KR)
Corresponding author
  • Hwang, Hee Sook
  • Lee, Chung-Sung
ORCID
Venue
Gels
Publisher
MDPI AG
Published
2024-08-03
Volume
10
Issue
8
Pages
513
ISSN
2310-2861 (ISSN-L)
DOI
10.3390/gels10080513
PMC
PMC11353637
OpenAlex
W4401323500
Cited by
60
References
122
Citations by year
2026: 36 · 2025: 21 · 2024: 3
FWCI
2.15
Type
journal article
Language
en
Open access
Licence
Locations
  • Gels (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
Soonchunhyang University Research Fund
Topics
  • Physical Sciences › Engineering › Biomedical Engineering › Bone Tissue Engineering Materials
  • Physical Sciences › Materials Science › Biomaterials › Hydrogels: synthesis, properties, applications
  • Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
Keywords
nanoclay, composite hydrogels, bone tissue engineering, bone regeneration, hydrogel synthesis, in situ polymerization, physical blending, 3D printing, biocompatibility, bioactivity (biomaterials), cell adhesion and differentiation, bone defect repair, osteochondral tissue engineering, drug delivery, nanoclay dispersion

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