Exploring the extracellular matrix: Engineering native glycosaminoglycans to modulate host responses

The extracellular matrix (ECM) is composed of a group of naturally derived biomacromolecules and soluble factors refined from harvested tissues and organs, with growing clinical attention and efficacy in repair, regeneration, and tissue engineering. The four main components of the ECM are fibrous proteins, glycoproteins, glycosaminoglycans (GAGs), and proteoglycans (PGs). These components undergo tissue-specific post-translational modifications and cell-mediated hierarchical assembly, resulting in the formation of macromolecular structures such as collagen fibrils. These structures exhibit a spectrum of biomolecular, biomechanical, and biophysical properties, ranging from soft, translucent hydrogels to rigid, mineralized tissues. GAGs are cell-secreted linear polysaccharides that contribute to several crucial physiological processes via molecular interactions with various proteins. An increasing number of studies have focused on the synthesis of chemically modified GAGs. These engineered GAGs, capable of incorporating various bio-functional elements, offer superior alternatives to their native counterparts in tissue engineering and cell-based therapeutic approaches. The versatility and enhanced functionality of these modified GAGs render them particularly valuable for various applications. This review discusses several chemical methods for preparing chemically engineered GAGs with different functional groups and highlights the significance of these chemically engineered GAGs in guiding important biological functions. Moreover, the most recent findings related to GAG modifications in modulating host responses are critically discussed. In an unbiased manner, the prospects for current advances in the development of chemically engineered GAGs and their clinical applications in the field of tissue engineering are also discussed in this review, suggesting intriguing paths toward feasible translational studies that have yet to be explored.