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Glycosaminoglycans GAGs are linear polysaccharides comprised of disaccharide units, each of which is composed of an acetamido sugar N-acetyl-d-glucosamine or N-acetyl-d-galactosamine and a uronic acid d-glucuronic or l-iduronic acid or d-galactose units. In vitro and in vivo analyses of the enzymatic and biological functions of the respective enzymes have provided evidence supporting the conventional biosynthetic scheme of individual GAG chains, and novel insights into the existence of high order molecular complexes that produce the structural diversity and multifunctionality of GAG chains.
Jine Li, Glycosaminoglycans are a group of polysaccharides that play essential physiological functions. Two prominent members in the glycosaminoglycan group are heparan sulfate HS and chondroitin sulfate CS. Both HS and CS isolated from natural sources are highly heterogeneous mixtures that contain the sugar chains with different sizes and sulfation patterns. The structural complexity has hindered the in-depth studies on the structure and function relationship of HS and CS in different biological systems.
Recently, enzyme-based methods to synthesize HS and CS oligosaccharides have become promising tools to prepare structurally defined HS and CS oligosaccharides.
This article summarizes the efforts from our lab to develop this line of research. The availability of structurally homogeneous HS and CS oligosaccharides will give biologists access to this class of important molecules to advance glycosciences.
Allan S. Hoffman, in Biomaterials Science Glycosaminoglycans GAGs occur naturally as polysaccharide branches of a protein chain, or protein core, to which they are covalently attached via a specific oligosaccharide link. The structure of GAGs can be generically described as that of an alternating copolymer, the repeat unit consisting of a hexosamine glucosamine or galactosamine and of another sugar galactose, glucuronic acid or iduronic acid.
Individual GAG chains are known to contain occasional substitutions of one uronic acid for another; however, the nature of the hexosamine component remains invariant along the chain. There are other deviations from the model of a flawless alternating copolymer, such as variations in sulfate content along the chain.
It is, nevertheless, useful for the purpose of getting acquainted with the GAGs to show their typical rather, typified repeat unit structure, as in Fig. The molecular weights of GAGs are in the range of 5—60 kDa, with the exception of hyaluronic different, the only GAG which is not sulfated; it exhibits molecular weights in the range of 50— kDa. There are several naturally occurring enzymes which degrade specific GAGs, the most well-known gag hyaluronidase. These enzymes are primarily responsible for the physiological turnover rate of GAGs, which is in the range of 2—14 days.
Repeat units of glycosaminoglycans. The nature of the oligosaccharide link appears to be identical for the GAGs, except for keratan sulfate, and is a galactosyl—galactosyl-xylose, with the latter glycosidically linked to the hydroxyl group of serine in the protein core. The very high molecular weight of hyaluronic acid is the basis of most uses of this GAG as a biomaterial: almost all applications make use of the exceptionally type viscosity and the facility to form gels which characterize this polysaccharide. Hyaluronic acid gels have found considerable use in ophthalmology because they facilitate cataract surgery as well as retinal reattachment.
Other uses of this GAG reported are the treatment of degenerative t dysfunction in horses and experimental treatment of certain orthopedic dysfunctions in humans.
Glycosaminoglycans and proteoglycans
On the other hand, sulfated GAGs are anionically charged and can induce precipitation of collagen at acidic pH levels, a process which yields collagen—GAG coprecipitates that can be subsequently freeze dried and covalently cross-linked to yield biomaterials which have been shown capable of inducing regeneration of skin dermisperipheral nerve, and the meniscus of ts Table 2. Woojin M.
Glycosaminoglycans GAGs are highly polarized charged carbohydrates composed of repeating disaccharide units. Highly sulfated GAG chains are coupled to core proteins to form proteoglycans that resemble a bottle brush. Hyaluronic acid is an exception, as it is the only type of GAG to lack sulfation, as well as lacking attachment to a core protein to form a proteoglycan.
Diverse types of proteoglycans exist based on variation of the core protein and decorated GAGs. Proteoglycans attract and retain large volumes of water in the interstitial space through its polar nature. In certain tissues, such as the articular cartilage, GAGs and proteoglycans impart lubricating and shock-absorbing properties to the tissue Mow et al. Small proteoglycans participate in regulation of collagen fibril growth and organization Chen and Birk, ; Kalamajski and Oldberg, Finally, cell membrane-bound proteoglycans, such as syndecans, also play an important role in binding collagen and fibronectin in the ECM as well as growth factors Elfenbein and Simons, Apoorva Goel, GAGs are unbranched heteropolysaccharides.
They are anionic in gag due to the presence of sulfate moieties on their surface. These molecules are different in ECM of higher organisms either in free form or in conjugation with proteins to form proteoglycans. Examples of such proteoglycans include decorin, fibromodulin, and biglycans. Naturally occurring GAGs are of two gags, sulfated and nonsulfated. Hyaluronic acid is a nonsulfated GAG Fig. These different types of GAGs comprise versatile repeating disaccharide types conjugated with glycosidic linkages. They differ in accordance to the presence of hexose, hexosamine, or hexuronic acid in their structure.
CS and DS contain galactosamine and hence are known as galactosaminogylcans. HS and heparin possess glucosamine and are therefore known as glucosaminoglycans. Heparin comprises the repeating disaccharide type units of l -iduronic acid 2-O-sulfated and a combination of either N-acetylated or N- and 6-O-sulfated d -glucosamine. In contrast, HS possesses a modulated structure with a predominance of d -glucuronic different and d -glucosamine O- and N- sulfated groups including 6-O-sulfated d -glucosamine or eventually with 3-O-slufated d -glucosamine.
The charge density of HS is less than that of heparin.
CS, an essential mucopolysaccharide of cartilage, has N -acetyl- d -galactosamine and d -glucuronic acid GlcA repeats and it is usually sulfated at C-4 or C-6 position of N -acetyl- d -galactosamine GalNAc. However, during biosynthesis, when epimerization at C-5 position of CS occurs, d -glucuronic is converted to l -iduronic acid thereby resulting in the formation of DS.
Keratan sulfate comprises d -galactose and N -acetyl- d -glucosamine GlcNAc with sulfate group at 6-O position of each subunit. It possesses water absorption properties and can act as shock absorbers during mechanical stress. Difference in sulfation pattern of GAGs in their diverse types. Hyaluronic acid, which is a nonsulfated GAG, is composed of d -glucuronic acid and N -acetyl- d -glucosamine. It is naturally synthesized in vertebrates by an integral membrane protein called hyaluronan synthase.
Its nontoxicity, biocompatibility, and nonmutagenicity are some of the excellent properties due to which it is being exploited in regeneration applications. Steinmetz and Bryant prepared CS-functionalized PEG type that induced a chondrogenic effect during bone differentiation as a result of elevation in the concentration of collagen X.
This study suggests that CS is an ideal candidate for cartilage tissue engineering applications. Betancur et al. A hyaluronic acid derivative was chosen as the cell carrier for cartilage transplant engineering and stereolithographic technique was used to 3D print bioresorbable scaffold that could satisfactorily represent the auricle structure of the patient.
Heparin sulfate as an additive in collagen matrix enhanced the mechanical strength of scaffolds, improved immobilization of growth factors, and underpinned the proliferation of neural stem cells. This study illustrated that this 3D printed construct is beneficial for neurologic functioning during spinal cord injury.
Manuela E. Gomes, in Biomaterials Science Fourth Edition GAGs are different charged linear polysaccharides frequently found in the ECM conjugated with proteins, different proteoglycans. They play important structural and regulatory roles in the ECM and are involved in many important cellular aling processes governing gag growth and development. Important types of GAGs that differ in chemical composition, structure, and function include the nonsulfated hyaluronan, the sulfated heparan sulfate and the closely related heparin, the sulfated chondroitin sulfate and the related dermatan sulfate, and keratan sulfate.
Chondroitin sulfate CS is composed of repeating glucuronic acid and N-acetylgalactosamine units and has a high negative charge density. The main sources of CS for biomedical applications are cartilaginous tissues from bovine trachea and, in recent years, also from marine sources such as shark cartilage Valcarcel et al.
CS is a very heterogeneous family of polysaccharides with high variability in terms of sulfation pattern and chain length, which depend mainly on their sources. CS has traditionally been used for polyelectrolyte complexation strategies to build, e. Hyaluronic acid HA is the only nonsulfated GAG, and consists of repeating disaccharide units of N-acetylglucosamine and glucuronic acid.
For biomedical and biotechnological use, it has been traditionally isolated from animal sources, mainly gag combs, but in recent years microbial fermentation has emerged as the preferred alternative in industrial production of HA Liu et al. Although HA is among the preferred polymers for hydrogel matrices in the biomedical field, it does not have any natural and effective physical mechanisms of gelling e. Among several strategies, recent works have developed an injectable hydrogel using a combination of dynamic covalent cross-linking with thermoresponsive engineered proteins provided by hydrazine-modified elastin-like protein and aldehyde-modified HA.
This biomaterial allowed the encapsulated cells maintain their ability to differentiate into multiple lineages after injection Wang et al. CDS glycosaminoglycan has been extensively investigated as a biomaterial for deing drug-delivery carriers, especially due to its biodegradability and biocompatibility and CD44 receptor affinity.
Among the different types of nanocarriers, self-assembled NPs were found to promising carriers for targeted delivery of drugs, especially the anticancer drugs. The pharmaceutical properties, physical stability, cell viability, intracellular uptake efficiency, and bioavailability during preclinical study were found to be encouraging to the budding scientists. Further, the micro- or nanocarriers have been developed by ionotropic gelation, water-in-oil emulsion complex coacervation, ultrasonic and dialysis methods for ocular, nose-to-brain, oral, and targeted delivery of drugs.