Post-Implantation Stiffening by a Bioinspired, Double-Network, Self-Healing Hydrogel Facilitates Minimally Invasive Cell Delivery for Cartilage Regeneration

Abstract

Injectable hydrogels have demonstrated advantages in cartilage repair by enabling the delivery of cells through a minimally invasive approach. However, several injectable hydrogels suffer from rapid degradation and low mechanical strength. Moreover, higher mechanical stiffness in hydrogels can have a detrimental effect on post-implantation cell viability. To address these challenges, we developed an in situ forming bioinspired double network hydrogel (BDNH) that exhibits temperature-dependent stiffening after implantation. The BDNH mimics the microarchitecture of aggrecan, with hyaluronic acid-conjugated poly(N-isopropylacrylamide) providing rigidity and Schiff base crosslinked polymers serving as the ductile counterpart. BDNHs exhibited self-healing property and enhanced stiffness at physiological temperature. Excellent cell viability, long time cell proliferation, and cartilage specific matrix production were observed in the chondrocytes cultured in the BDNH hydrogel. Evidence of cartilage regeneration in a rabbit cartilage defect model using chondrocyte-laden BDNH has suggested it to be a potential candidate for cartilage tissue engineering.

Polysaccharide-Based Double-Network Hydrogels: Polysaccharide Effect, Strengthening Mechanisms, and Applications

“…Tough polysaccharide-based DN hydrogels have been applied in cartilage repair, such as the HA-furan/GG, PDA-CS/PAAm (Figure B), GG/HPAAm, and CMCD/PAAm . Recently, a HA-furan/GG DN hydrogel has been fabricated to support chondrocyte proliferation, new ECM deposition, and cartilage regeneration (Figure C) .…”

“…Recently, a polysaccharide-based DN hydrogel with temperature-dependent stiffening has been developed to combine injectability, degradation resistance, and bioactivity (named the BDNH hydrogel) . The adipic acid dihydrazide grafted CS and oxidized dextran were prepared as the flexible network cross-linked by Schiff base cross-linking between the amine and aldehyde groups.…”

Hemostatic Tranexamic Acid-Induced Fast Gelation and Mechanical Reinforcement of Polydimethylacrylamide/Carboxymethyl Chitosan Hydrogel for Hemostasis and Wound Healing

“…Injectable hydrogel is a kind of hydrogel material that can be injected in vitro and rapidly gelate in vivo , possessing the unique advantages of filling irregular wounds, enabling minimally invasive transplantation, and encapsulating cells, drugs, and bioactive molecules. − As such, it has broad application prospects in rapid hemostasis, wound dressings, 3D cell culture, and targeted drug delivery . Particularly, many injectable hydrogels have been developed for hemorrhage control and wound healing, , which are essential for traumatic or surgical injuries to reduce life-threatening complications.…”