DNA-functionalized hyaluronic acid bioink in cartilage engineering: a perspective

Degenerative osteoarthritis, a common sequela of articular cartilage defect, significantly impacts the quality of life of millions of individuals worldwide. Three-dimensional (3D) bioprinting has emerged as an advanced tissue engineering strategy, offering precise spatial arrangements of cells, hydrogels, and bioactive cues. Hyaluronic acid (HA) is a crucial component of bioink designed for fabricating cartilage tissue. However, creating a bioink that closely mimics the cartilaginous extracellular matrix (ECM) still remains a challenge. HA hydrogels have limitations in recapitulating tunable mechanical properties, stimuli responsiveness, and flexibility in ligands’ adhesion akin to those of native tissues. In recent years, DNA has emerged as a smart biomaterial that endows hydrogels with tunable properties and allows for precise structural customization of the hydrogels due to its unique programmability. Integrating reversible DNA linkages, reconfigurable DNA architectures, DNA plasmid, and targeted DNA aptamers into HA hydrogels allows them to respond to the extracellular environment and express desired molecules, making them ideal artificial ECMs for 3D bioprinting of cartilage tissue. This review targets this challenge by highlighting the characteristics of DNA moieties designed as reversible crosslinkers, responsive units, and adhesion ligands to functionalize HA hydrogels. Furthermore, we offer perspectives on how DNA-functionalized HA hydrogels can be harnessed to create dynamic and biomimetic bioink capable of recapitulating the more complex functions required for cartilage tissue engineering.