Advancements and Frontiers in the High Performance of Natural Hydrogels for Cartilage Tissue Engineering

Abstract

Cartilage injury originating from trauma or osteoarthritis is a common joint disease that can bring about an increasing social and economic burden in modern society. On account of its avascular, neural, and lymphatic characteristics, the poor migration ability of chondrocytes, and a low number of progenitor cells, the self-healing ability of cartilage defects has been significantly limited. Natural hydrogels, occurring abundantly with characteristics such as high water absorption, biodegradation, adjustable porosity, and biocompatibility like that of the natural extracellular matrix (ECM), have been developed into one of the most suitable scaffold biomaterials for the regeneration of cartilage in material science and tissue engineering. Notably, natural hydrogels derived from sources such as animal or human cadaver tissues possess the bionic mechanical behaviors of physiological cartilage that are required for usage as articular cartilage substitutes, by which the enhanced chondrogenic phenotype ability may be achieved by facilely embedding living cells, controlling degradation profiles, and releasing stimulatory growth factors. Hence, we summarize an overview of strategies and developments of the various kinds and functions of natural hydrogels for cartilage tissue engineering in this review. The main concepts and recent essential research found that great challenges like vascularity, clinically relevant size, and mechanical performances were still difficult to overcome because the current limitations of technologies need to be severely addressed in practical settings, particularly in unpredictable preclinical trials and during future forays into cartilage regeneration using natural hydrogel scaffolds with high mechanical properties. Therefore, the grand aim of this current review is to underpin the importance of preparation, modification, and application for the high performance of natural hydrogels for cartilage tissue engineering, which has been achieved by presenting a promising avenue in various fields and postulating real-world respective potentials.

Keywords: cartilage tissue engineering; hydrogel scaffolds; mechanical property; natural hydrogel; regenerative medicine.

Figure 1

Some natural biopolymers, derived from renewable resources, and their respective chemical structures: silk fibroin, alginate, and chitin. Reproduced from Mano et al. (2007) with permission from Copyright 2007 Royal Society.

Figure 2

Schematic illustration of (A) preparation process of BC-DN hydrogels, bilayered hydrogel scaffolds, and the structure of bilayer hydrogel. (B) Schematic depiction of the preparation of bilayer hydrogel scaffolds. (C) Schematic illustration of the structure of the bilayer hydrogel. (D) SEM image of bilayer hydrogel scaffolds. Reproduced from Zhu X. B. et al. (2018) with permission from Copyright 2018 American Chemical Society.

Figure 3

(A) Representative images of BMMSCs attachment, viability, and distribution in composite scaffolds. Blue fluorescence represents the contours of scaffolds; merged images include bright field views to show the scaffold pores. CLSM images of Live/Dead staining demonstrated cell viability of after 72 h of culture in growth medium. (Red represents the dead cells; green represents the live cells; Scale bar = 250 μm). CCK-8 assay showed that the number of cells in the three groups increased over time (B). DNA content in the various scaffolds during osteogenic culture indicating slow proliferation while MSCs differentiating into osteoblasts. Results are expressed as mean ± SD (n = 3, ^*,#P < 0.05, ^**,##P < 0.01; ^#compared to PCL group in (B), and compared to day 1 in (C)). Reproduced from Dong et al. (2017) with permission from Copyright 2017 Springer Nature.

Figure 4

(A) Schematic illustration for fabricating natural-synthetic GelMA-PAM biohybrid hydrogel via the photo-initiating polymerization. (B) Molecular crosslinking structures: covalent crosslinking between GelMA-PAM, covalent crosslinking between PAM-PAM, and covalent/physical crosslinking between GelMA-GelMA. Reproduced from Han et al. (2017) with permission from Copyright 2017 Royal Society of Chemistry.

Figure 5

Schematic illustration of the biohybrid gradient scaffolds for osteochondral repair by 3D printing technology. (A) The compositions of bio-ink A and bio-ink B and 3D-printing method of hybrid gradient scaffolds assisted with a low-temperature receiver. (B) Formation of hydrogel scaffold after UV light-initiated polymerization with hydrogen bonding interactions. (C) Osteochondral repair treated with the biohybrid gradient PACG-GelMA scaffold, with Mn²⁺ and BG being loaded on the top and bottom layers, respectively. Reproduced from Gao et al. (2019) with permission from Copyright 2019 Wiley.

Figure 6

Schematic illustration of the overall design of three-phase hybrid hydrogels. Allogeneic chondrocytes are encapsulated with a CCH hybrid hydrogel, forming the ectopic cartilage with a diffusion chamber system for cartilage repair. Reproduced from Jiang et al. (2018) with permission from Copyright 2018 Royal Society of Chemistry.

Figure 7

Schematic illustration of the fabrication process and implementation of CGN nanocomposite hydrogels. Reproduced from Lu et al. (2019) with permission from Copyright 2019 Elsevier.

Figure 8

Schematic illustration of preparation and utilization of USPIO-labeled Dex/CNC/USPIO-KGN hydrogels for artificial cartilage repair. Reproduced from Yang et al. (2019) with permission from Copyright 2019 American Chemical Society.

Figure 9

Live/Dead staining of ALG-hBMSCs, ALG-Gel-hBMSCs, and ALG-Gel-hBMSCs/3D-printed PCL scaffold with 2D well plate culture and ALG-Gel-hBMSCs with 3D bioreactor culture on day 0, 3, 7, and 14, respectively. Scale bar = 200 μm. Reproduced from Xu et al. (2019) with permission from Copyright 2019 Elsevier.

Figure 10

ALG hydrogel aiding cartilage defect repair in a rabbit model: (A) photographs of knee joints in the control group and the ALG hydrogel group at the 0, 2, and 4 weeks after post-operation. (B) H&E staining of cartilage defect. Reproduced from Ma et al. (2019) with permission from Copyright 2019 Royal Society of Chemistry.