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Cited by 113Silk-based biomaterials and applicationsBone Tissue Engineering MaterialsOsteoarthritis Treatment and Mechanisms

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Marginal sealing around integral bilayer scaffolds for repairing osteochondral defects based on photocurable silk hydrogels

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Wu, Xiaolin, Zhou, Mingliang, Jiang, Fei, Yin, Shi, Lin, Sihan, Yang, Guangzheng, Lu, Yuezhi, Zhang, Wenjie, Jiang, Xinquan·2021·Bioactive Materials
DOI 10.1016/j.bioactmat.2021.04.005PMC PMC8081879
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Abstract

Osteochondral repair remains a major challenge in current clinical practice despite significant advances in tissue engineering. In particular, the lateral integration of neocartilage into surrounding native cartilage is a difficult and inadequately addressed problem that determines the success of tissue repair. Here, a novel design of an integral bilayer scaffold combined with a photocurable silk sealant for osteochondral repair is reported. First, we fabricated a bilayer silk scaffold with a cartilage layer resembling native cartilage in surface morphology and mechanical strength and a BMP-2-loaded porous subchondral bone layer that facilitated the osteogenic differentiation of BMSCs. Second, a TGF-β3-loaded methacrylated silk fibroin sealant (Sil-MA) exhibiting biocompatibility and good adhesive properties was developed and confirmed to promote chondrocyte migration and differentiation. Importantly, this TGF-β3-loaded Sil-MA hydrogel provided a bridge between the cartilage layer of the scaffold and the surrounding cartilage and then guided new cartilage to grow towards and replace the degraded cartilage layer from the surrounding native cartilage in the early stage of knee repair. Thus, osteochondral regeneration and superior lateral integration were achieved in vivo by using this composite. These results demonstrate that the new approach of marginal sealing around the cartilage layer of bilayer scaffolds with Sil-MA hydrogel has tremendous potential for clinical use in osteochondral regeneration.

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Crossref · 10.1016/j.bioactmat.2021.04.005

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Graphical abstract CC BY-NC-ND · PubMed Central
Fig. 1 Schematic illustration of the integral bilayer silk scaffold combined with Sil-MA hydrogel in osteochondral repair.
Fig. 1 Schematic illustration of the integral bilayer silk scaffold combined with Sil-MA hydrogel in osteochondral repair.CC BY-NC-ND · PubMed Central
Fig. 2 Bilayer silk scaffold preparation and characterization. A) Illustration of bilayer silk scaffold preparation. B) Morphological observation of all samples, including 10–30% D/S and 10–30% P/S materials. C) Stress-strain curves and elastic modulus of 10–30% D/S and 10–30% P/S materials. D) Surface roughness of native cartilage and 10–30% D/S materials; the value of the representative roughness parameter Ra was quantified. E) Live/dead staining of BMSCs on P/S materials and chondrocytes on D/S materials after 7 d of culture. F) After stimulation with TGF-β3 for 4, 7, and 14 d, the expression of cartilage-related genes (Sox9, Acan, and Col II) in chondrocytes on D/S materials was evaluated by q-PCR. G) The expression of bone-related genes (Alp, Osx, and Col I) was examined by q-PCR when BMSCs on P/S materials were cocultured with BMP-2 for 4, 7, and 14 d. H) Stereomicroscopic and SEM images of bilayer silk scaffolds. I) Cumulative release curve of BMP-2 from the subchondral bone layer of the bilayer scaffold.
Fig. 2 Bilayer silk scaffold preparation and characterization. A) Illustration of bilayer silk scaffold preparation. B) Morphological observation of all samples, including 10–30% D/S and 10–30% P/S materials. C) Stress-strain curves and elastic modulus of 10–30% D/S and 10–30% P/S materials. D) Surface roughness of native cartilage and 10–30% D/S materials; the value of the representative roughness parameter Ra was quantified. E) Live/dead staining of BMSCs on P/S materials and chondrocytes on D/S materials after 7 d of culture. F) After stimulation with TGF-β3 for 4, 7, and 14 d, the expression of cartilage-related genes (Sox9, Acan, and Col II) in chondrocytes on D/S materials was evaluated by q-PCR. G) The expression of bone-related genes (Alp, Osx, and Col I) was examined by q-PCR when BMSCs on P/S materials were cocultured with BMP-2 for 4, 7, and 14 d. H) Stereomicroscopic and SEM images of bilayer silk scaffolds. I) Cumulative release curve of BMP-2 from the subchondral bone layer of the bilayer scaffold.CC BY-NC-ND · PubMed Central
Fig. 3 Synthesis and characterization of the Sil-MA hydrogel. A) Illustration of Sil-MA hydrogel preparation. B) 1H-NMR spectra of SF and Sil-MA. C) Cell viability of chondrocytes on 10–30% Sil-MA compared with primary chondrocytes cultured in normal medium. D) Schematic of the measurement procedure for the strength property relative to lap shear and its representative stress/strain curve of 10% SF, 10–30% Sil-MA. E) Adhesion interface of 20% Sil-MA bonded between native cartilage and the C layer of the bilayer scaffold. Green, red and blue symbols represent the distributions of native cartilage, 20% Sil-MA, and the C layer of the scaffold, respectively. F) Cumulative release curve of TGF-β3 from 20% Sil-MA. G) Transwell assay to test the migration effect of TGF-β3 released from 20% Sil-MA on chondrocytes. H) Migrated cells were quantified by counting.
Fig. 3 Synthesis and characterization of the Sil-MA hydrogel. A) Illustration of Sil-MA hydrogel preparation. B) 1H-NMR spectra of SF and Sil-MA. C) Cell viability of chondrocytes on 10–30% Sil-MA compared with primary chondrocytes cultured in normal medium. D) Schematic of the measurement procedure for the strength property relative to lap shear and its representative stress/strain curve of 10% SF, 10–30% Sil-MA. E) Adhesion interface of 20% Sil-MA bonded between native cartilage and the C layer of the bilayer scaffold. Green, red and blue symbols represent the distributions of native cartilage, 20% Sil-MA, and the C layer of the scaffold, respectively. F) Cumulative release curve of TGF-β3 from 20% Sil-MA. G) Transwell assay to test the migration effect of TGF-β3 released from 20% Sil-MA on chondrocytes. H) Migrated cells were quantified by counting.CC BY-NC-ND · PubMed Central
Fig. 4 Marginal sealing effect of the Sil-MA hydrogel in vivo. A) Procedures for Sil-MA hydrogel application. B) Surgical procedures for the use of bilayer silk scaffolds combined with Sil-MA hydrogel in osteochondral repair: a) defect preparation; b) scaffold implantation; c) bleeding; d) 20% Sil-MA hydrogel injection; e) UV irradiation; f) stopped bleeding and completion. The red arrow indicates blood flowing from the defect after scaffold implantation. The blue arrow shows that the bleeding stopped after Sil-MA hydrogel application. C) Immediate implantation conditions at 0 weeks and repair conditions at 3 weeks were observed to evaluate the effect of the Sil-MA hydrogel. The blue arrow represents the gap between the C layer and native cartilage. The red arrow indicates the tight link between the C layer and native cartilage sealed by the 20% Sil-MA hydrogel. Green irregular shapes point to the undegraded C layer material that is replaced with neocartilage.
Fig. 4 Marginal sealing effect of the Sil-MA hydrogel in vivo. A) Procedures for Sil-MA hydrogel application. B) Surgical procedures for the use of bilayer silk scaffolds combined with Sil-MA hydrogel in osteochondral repair: a) defect preparation; b) scaffold implantation; c) bleeding; d) 20% Sil-MA hydrogel injection; e) UV irradiation; f) stopped bleeding and completion. The red arrow indicates blood flowing from the defect after scaffold implantation. The blue arrow shows that the bleeding stopped after Sil-MA hydrogel application. C) Immediate implantation conditions at 0 weeks and repair conditions at 3 weeks were observed to evaluate the effect of the Sil-MA hydrogel. The blue arrow represents the gap between the C layer and native cartilage. The red arrow indicates the tight link between the C layer and native cartilage sealed by the 20% Sil-MA hydrogel. Green irregular shapes point to the undegraded C layer material that is replaced with neocartilage.CC BY-NC-ND · PubMed Central
Fig. 5 Osteochondral engineering using the all-silk-derived composite. A) a, e, i, m, q, Gross images of different groups. c, g, k, o, s, Micro-CT 3D images of different groups. The dark yellow, green and brown colors in the 3D reconstruction images represent the primary bone, new bone and 3D reconstructed new bone, respectively, within the selected ROI. b, f, j, n, r, d, h, l, p, t, Histological analysis of different groups by safranin-O/fast-green staining. The green arrows in Fig. 5A–j, n, and r indicate lateral integration between neocartilage and adjacent cartilage. B) The ICRS macroscopic repair scores were quantified. C) BMD (g/cm3), D) BV/TV (%) and E) Th (μm) values of micro-CT bone remodeling were quantitatively measured.
Fig. 5 Osteochondral engineering using the all-silk-derived composite. A) a, e, i, m, q, Gross images of different groups. c, g, k, o, s, Micro-CT 3D images of different groups. The dark yellow, green and brown colors in the 3D reconstruction images represent the primary bone, new bone and 3D reconstructed new bone, respectively, within the selected ROI. b, f, j, n, r, d, h, l, p, t, Histological analysis of different groups by safranin-O/fast-green staining. The green arrows in Fig. 5A–j, n, and r indicate lateral integration between neocartilage and adjacent cartilage. B) The ICRS macroscopic repair scores were quantified. C) BMD (g/cm3), D) BV/TV (%) and E) Th (μm) values of micro-CT bone remodeling were quantitatively measured.CC BY-NC-ND · PubMed Central

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Metadata

Authors
Wu, X., Zhou, M., Jiang, F., Yin, S., Lin, S., Yang, G., Lu, Y., Zhang, W., & Jiang, X.
Affiliations
Shanghai Jiao Tong University (CN)
Corresponding author
  • Jiang, Fei
  • Zhang, Wenjie
  • Jiang, Xinquan
ORCID
Venue
Bioactive Materials
Publisher
Elsevier BV
Published
2021-11
Volume
6
Issue
11
Pages
3976-3986
ISSN
  • 2097-1192 (ISSN-L)
  • 2452-199X
DOI
10.1016/j.bioactmat.2021.04.005
PMC
PMC8081879
OpenAlex
W3158673470
Cited by
113
References
52
Citations by year
2026: 10 · 2025: 26 · 2024: 20 · 2023: 24 · 2022: 30 · 2021: 3
FWCI
5.03
Type
journal article
Language
en
Open access
Licence
Locations
  • Bioactive Materials (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (31700848, 81620108006, 81921002, 81991505)
  • National Key Research and Development Program of China (2016YFC1102900)
Topics
  • Physical Sciences › Materials Science › Biomaterials › Silk-based biomaterials and applications
  • Physical Sciences › Engineering › Biomedical Engineering › Bone Tissue Engineering Materials
  • Health Sciences › Medicine › Rheumatology › Osteoarthritis Treatment and Mechanisms
Keywords
osteochondral regeneration, marginal sealing, bilayer scaffold, silk fibroin hydrogel, TGF-beta3, BMP-2, mesenchymal stem cells, chondrogenic differentiation, cartilage integration, knee cartilage repair, subchondral bone regeneration

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