Biomaterials and tissue engineering approaches using glycosaminoglycans for tissue repair: Lessons learned from the native extracellular matrix

The extracellular matrix (ECM) is vital to tissue repair, regeneration, and homeostasis. It imparts physical cues, including mechanical stimuli, which influence cell behavior, and biochemical cues, such as growth factor and cytokine sequestration and signaling, resulting in cell growth, migration, differentiation, and apoptosis [6,7]. The major component of the ECM consists of proteins such as collagen, elastin, fibronectin, laminin, and proteoglycans. Glycosaminoglycans (GAGs), which are polysaccharides, are also present in the ECM. Sulfated GAGs are covalently bound to proteins forming proteoglycans. Hyaluronan or hyaluronic acid, a non-sulfated GAG, has non-covalently linked complexes with proteoglycans. GAGs interact with water and other molecules, providing a hydrated macromolecular network in the ECM [6,7] that results in providing both biochemical and mechanical signals to cells.

GAGs have gained significant interest in the field of tissue engineering due to their role in modulating cell behavior [10]. Recent reviews have focused on specific GAGs and their use alone or as blends in biomaterials for various tissue engineering applications [11,12]. More generally, GAGs have been incorporated in biomaterials as medical devices with significant advances in skin, ligament, tendon, cartilage, and bone tissue repair [13], [14], [15], [16], [17], [18], [19]. Native GAGs, specifically hyaluronic acid, chondroitin sulfate, and heparin, have been the most widely explored and have been used as coatings, for growth factor delivery, and incorporated into hydrogels or in other biomaterial formulations. This review provides an overview of native GAGs and their role in the ECM and focuses on their application in tissue repair and replacement. Biomaterials and tissue engineering approaches, specifically in orthopaedic applications and wound healing, are discussed. Emphasis in this review is placed on the application of GAGs in bone, cartilage, tendon/ligament, and wound healing where the basic biology of the GAGs in these tissues is described and studies that have shown promise leading to preclinical studies in vivo and/or human use are summarized.

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