Heparan sulfate as a central modulator of growth factor dynamics in tissue regeneration

Growth factors (GFs) are potent regenerative proteins that modulate biological responses and stimulate tissue repair by activating cell signaling pathways to enhance proliferation, differentiation, and migration. However, the rapid degradation and diffusion characteristics of GFs necessitate the use of supraphysiological doses and/or frequent administrations to maintain therapeutic effects, which can result in reduced efficacy and an increased risk of adverse events. To address these challenges, novel GF delivery systems seek to preserve bioactivity and modulate GF release, ultimately promoting more effective tissue regeneration. Heparan sulfate (HS) is an essential regulator of GF activity, executing molecular recognition and information storage for controlling extracellular matrix remodeling and cellular behavior during tissue development. In this perspective, we summarize the diverse roles of HS in tissue repair, focusing on its interactions with GFs. These include protective functions, the tonic release of GFs, promoting the complexation of GFs with their cognate receptors, and enhancing the activation of intracellular signaling. Finally, we provide perspectives on using HS as a component of novel biomaterials and medical devices for improving tissue regeneration.