Double - network hydrogel based on exopolysaccharides as a biomimetic extracellular matrix to augment articular cartilage regeneration

Abstract

Cartilage regeneration remains a current challenge with no satisfactory strategy in surgery. Hydrogels with structurally and biochemically biomimicking characteristics have been regarded as a promising approach for the success of cartilage regeneration. Naturally sourced hydrogels from exopolysaccharides are ideal candidates for the construction of biomimetic extracellular matrix (ECM) because of their biomimetic networks, high water content, cytocompatibility, and biodegradability. Here, an approach that integrates covalent and ionic bonds in a hydrogel system is shown to form a natural polymeric hydrogel double network (DN) for promoting the adhesion and proliferation of chondrocytes and supporting the formation of matured cartilage tissue. DN hydrogels comprised of chemically crosslinked hyaluronan (HA) and physically crosslinked gellan gum (GG) were developed for potential scaffold fabrication. Compared with HA single network (SN) hydrogel and GG SN hydrogel, the obtained HA/GG DN hydrogel with Young's modulus of 28.6 kPa exhibited adequate compressive strength (208.9 kPa) and high toughness (dissipated energy 2837 J/m³) and thus can be used as a biomimetic extracellular matrix for minimal invasively repairing cartilage. In vitro studies showed that HA/GG DN hydrogel-based ECM promoted the proliferation of chondrocytes. The HA/GG DN hydrogel significantly supported the deposition of cartilage ECM-specific sulfated glycosaminoglycan and type II collagen and facilitated the formation of cartilage tissues. In a rabbit osteochondral defect model, HA/GG DN hydrogel significantly improved cartilage regeneration. The HA/GG DN hydrogel as a biomimetic ECM is a promising candidate as a biomaterial scaffold for cartilage regeneration and repair. STATEMENT OF SIGNIFICANCE: The fabrication of a biomaterial scaffold as an artificial extracellular matrix (ECM) for cartilage regeneration remains a big challenge. In this work, we fabricated a double-network (DN) hydrogel based on hyaluronan and gellan gum (HA/GG) through a sequential chemical and physical cross-linking process. The HA/GG DN hydrogel exhibited high compressive strength, high toughness, stiffness, and good self-recovery property. The HA/GG DN hydrogel can support chondrocyte proliferation and new ECM deposition correlated with the enhanced mechanical properties, good cytocompatibility, and biodegradability. In vivo animal experiments demonstrated that this HA/GG DN hydrogel facilitates hyaline-like cartilage regeneration. These findings imply that the developed HA/GG DN hydrogel as a biomimetic ECM offers a hopeful new platform for cartilage tissue engineering.

Keywords: Articular cartilage regeneration; Biomimetic extracellular matrix; Double network hydrogel; Hyaluronic acid; Mechanical property.