Molecular engineering of glycosaminoglycan chemistry for biomolecule delivery

Abstract

Glycosaminoglycans (GAGs) are linear, negatively charged polysaccharid es that interact with a variety of positively-charged growth factors. In this review article, the effects of engineering GAG chemistry for molecular delivery applications in regenerative medicine are presented. Three major areas of focus at the structure-function-property interface are discussed: 1) macromolecular properties of GAGs, 2) effects of chemical modifications on protein binding, and 3) degradation mechanisms of GAGs. GAG-protein interactions can be based on 1) GAG sulfation pattern, 2) GAG carbohydrate conformation, and 3) GAG polyelectrolyte behavior. Chemical modifications of GAGs, which are commonly performed to engineer molecular delivery systems, affect protein binding and are highly dependent on the site of modification on the GAG molecules. The rate and mode of degradation can determine the release of molecules as well as the length of GAG fragments to which the cargo is electrostatically coupled and eventually released from the delivery system. Overall, GAG-based polymers are a versatile biomaterial platform offering novel means to engineer molecular delivery systems with a high degree of control in order to better treat a range of degenerate or injured tissues.

Plasma and urinary glycosaminoglycans in the course of juvenile idiopathic arthritis

“…The latter process occur probably much earlier in children, even before manifestation of clinical symptoms of JIA. Increased degradation of tissue CS, which is not compensated by the rate of synthesis process, results in disturbances of the cell signaling process which involves interactions with cytokines, growth factors or ROS [2,3,30]. As a result, the JIA can manifest itself.…”

“…It is known that these glycans, due to a high density of negative electric charge, interact with many types of molecules, including enzymes, growth factors, transcription factors or extracellular matrix structural proteins [3]. Although in physiological conditions GAGs are components of a dynamic structure of ECM, which is continually being remodeled, the disturbances of synthesis, modification or degradation of these polysaccharides contribute to development of connective tissue-related disorders, including rheumatoid arthritis [2,5]. Probably, these disorders are also observed in the course of juvenile idiopathic arthritis (JIA).…”

“…GAGs are classified into five classes, and they include chondroitin sulfate (CS), dermatan sulfate (DS), heparan sulfate/heparin (HS/H), keratan sulfate (KS) and nonsulfated hyaluronic acid (HA). They are linear polysaccharide chains that consist of repeated disaccharide units composed of amino sugar and uronic acid or galactose residues [2,3]. It is known that these glycans, due to a high density of negative electric charge, interact with many types of molecules, including enzymes, growth factors, transcription factors or extracellular matrix structural proteins [3].…”

Dual Affinity Heparin-Based Hydrogels Achieve Pro-Regenerative Immunomodulation and Microvascular Remodeling

“…Heparin is a glycosaminoglycan that binds cationic proteins such as SDF-1α and protects them from denaturing conditions. 23–25 We have previously demonstrated that matrices functionalized with a heparin derivative protect proteins against denaturation to maximize bioactivity and lower the payload requirement for in vivo efficacy. 24,26 To reduce the anticoagulant activity of heparin for safe use in vivo, we incorporated a cross-linkable heparin derivative that was selectively desulfated at the -N position (Hep −N ) 24 within a poly(ethylene glycol) diacrylate (PEG-DA) network.…”

Heparin microparticle effects on presentation and bioactivity of bone morphogenetic protein-2

“…Glycosaminoglycans (GAGs) are linear polysaccharide chains that bind positively charged growth factors primarily through their negatively charged sulfate groups and exist both as free chains and covalently-linked components of glycosylated proteins known as proteoglycans [9, 10]. GAGs such as heparin, heparan sulfate, and chondroitin sulfate are ubiquitous components of natural extracellular matrices (ECM) that are involved in sequestering and immobilizing growth factors within the cellular microenvironment [11–13].…”