Heparin-based and heparin-inspired hydrogels: size-effect, gelation and biomedical applications.

Heparin is the highest negatively charged biomolecule, which is a polysaccharide belonging to the glycosaminoglycan family, and its role as a regulator of various proteins, cells and tissues in the human body makes it an indispensable macromolecule. Heparin-based hydrogels are widely investigated in various applications including implantation, tissue engineering, biosensors, and drug-controlled release due to the 3D-constructs of hydrogels. However, heparin has supply and safety problems because it is usually derived from animal sources, and has the clinical limitations of bleeding and thrombocytopenia. Therefore, analogous heparin-mimicking polymers and hydrogels derived from non-animal and/or totally synthetic sources have been widely studied in recent years. In this review, the progress and potential biomedical applications of heparin-based and heparin-inspired hydrogels are highlighted. We classify the forms of these hydrogels by their size including macro-hydrogels, injectable hydrogels, and nano-hydrogels. Then, we summarize the various fabrication strategies for these hydrogels including chemical covalent bonding, physical conjugation, and the combination of chemical and physical interactions. Covalent bonding includes free radical polymerization of vinyl-containing components, amide bond formation reaction, Michael-type addition reaction, click-chemistry, divinyl sulfone crosslinking, and mussel-inspired coating. Hydrogels physically conjugated via host-guest interaction, electrostatic interaction, hydrogen bonding, and hydrophobic interaction are also discussed. Finally, we conclude with the challenges and future directions for the fabrication and the industrialization of heparin-based and heparin-inspired hydrogels. We believe that this review will attract more attention toward the design of heparin-based and heparin-inspired hydrogels, leading to future advancements in this emerging research field.