Ionically cross-linkable hyaluronate-based hydrogels for injectable cell delivery

Abstract

Although hyaluronate is an attractive biomaterial for many biomedical applications, hyaluronate hydrogels are generally formed using chemical cross-linking reagents that may cause unwanted side effects, including toxicity. We thus propose to design and prepare ionically cross-linkable hyaluronate compounds that can form gels in the presence of counter-ions. This study is based on the hypothesis that introduction of alginate to hyaluronate backbones (hyaluronate-g-alginate) could allow for gel formation in the presence of calcium ions. Here, we demonstrated ease of formation of cross-linked structures with calcium ions without additional chemical cross-linking reagents in hyaluronate-g-alginate (HGA) gels. The mechanical properties of HGA gels were regulated through changes in polymer composition and calcium concentration. We also confirmed that HGA gels could be useful in regenerating cartilage in a mouse model following subcutaneous injection into the dorsal region with primary chondrocytes. This finding was supported by histological and immunohistochemical analyses, glycosaminoglycan quantification and chondrogenic marker gene expression. This approach to the design and tailoring of ionically cross-linkable biomedical polymers may be broadly applicable to the development of biomaterials, especially in the drug delivery and tissue engineering fields.