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10 Hyaluronic Acid and Chondroitin Sulfate (Polysaccharides of Human Origin): Biodegradable Polymers as Biomaterials

10 Hyaluronic Acid and Chondroitin Sulfate (Polysaccharides of Human Origin): Biodegradable Polymers as Biomaterials

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1.10 Hyaluronic Acid and Chondroitin Sulfate (Polysaccharides of Human Origin):…



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degradation within the body by free radicals e.g. nitric oxide and MMPs found in

the extracellular matrix, trailed by endocytosis. It can also experience digestion

by lysosomal enzymes to form mono and disaccharides, which can be subsequently transformed into ammonia, carbon dioxide and water via the Krebs cycle

[41]. In previous investigations, HA was considered to be a passive structural

component of connective tissues; nevertheless, later investigations shown it to be

energetically elaborate various biological procedures e.g. modulating cell migration and differentiation during embryogenesis, regulating extra cellular matrix

organization and metabolism, in addition playing significant roles in wound healing, metastasis, and inflammation [42]. Since HA is synthesized by cells while

initial wound healing, this polymer has been widely studied for wound dressing

applications. Additional distinctive features of HA include its capability to

encourage angiogenesis, to control wound site inflammation by acting as a free

radical scavenger, and to be identified by receptors on a diversity of cells related

with tissue repair. Owing to the high functionality and charge density of HA, it

can be cross-linked by a different physical and chemical methods [43]. Improved

HA, e.g. esterified derivatives like ethyl/benzyl esters (HYAFFs) and crosslinked hyaluronic acid gels have been broadly studied for wound dressing application. These chemical alterations have also been found to significantly minimize

the degradation rate of the polymer. The benzyl esters (HYAFFs) experience

hydrolytic degradation via ester bonds in the absence of enzymatic activity with

degradation time’s varying from 1–2 weeks to 2–3 months, depending on the

degree of esterification. The de-esterified polymers are more hydrated and soluble and resemble native HA [44, 45]. HA also plays an important role in tissue

repair by encouraging mesenchymal and epithelial cell migration and differentiation, thus improving collagen deposition and angiogenesis. This character, in

addition to its immunoneutrality makes HA an ideal biomaterial for tissue engineering and drug delivery applications. Its aqueous solubility permits HA to be

synthesized into various kinds of porous and three-dimensional structures for

these applications. Therefore a viscous formulation of HA containing fibroblast

growth factor (OSSIGELs) is experiencing late stage clinical trial as a synthetic

bone graft to hasten bone fracture healing. Likewise HYAFFs 11 is presently

been utilized as a carrier vehicle for a different growth factors and morphogens

as well as bone marrow stromal cells. In an investigation that associated HYAFFs

11 with an absorbable collagen sponge as a carrier vehicle for osteoinductive

protein, recombinant human bone morphogenetic protein-2 (rhBMP-2) shown a

well healing response with HYAFFs11 carrier than collagen [46]. HA-based

materials have also replaced collagen-based materials as injectable soft tissue

fillers [47]. High molecular weight viscous HA solutions (AMVISCs and

AMVISCs PLUS) are being used as a vitreous humor substitute as well as to

shield the sensitive eye tissue through cataract extraction, corneal transplantation

and glaucoma surgery. Viscous HA solutions (SYNVISCs, ORTHOVISCs) are

clinically utilized as a synovial fluid substitute to relieve pain and improve join

mobility in osteoarthritis patients [48]. A recent animal investigation established

the merits of exogenous HA in treating vascular diseases [49].



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1.10.2



Mammalian Polysaccharides and Its Nanomaterials



Chondroitin Sulfate



Reports have shown that a significant phase of wound healing includes the secretion of glycosaminoglycans by fibroblast cells to form a hydrophilic matrix

appropriate for remodeling while healing. A current investigation expending rat

embryonic fibroblast cells showed that the most of the glycosaminoglycan chains

produced were chondroitin sulfate, signifying the implication of this natural

polymer for its utilization in biomedical applications [50]. Chondroitin sulfate is

the main component of aggrecan, the most plentiful glycosaminoglycan found in

the proteoglycans of articular cartilage. Reports have revealed that CS can trigger the metabolic response of cartilage tissue and has antiinflammatory features

[51]. It is also elaborate cell recognition, intracellular signaling, and the connection of extracellular matrix components to cell-surface glycoproteins [52].

Chondroitin sulfate entails repeating unit formed by N-acetyl galactosamine

(GalNAc) and glucuronic acid (GlcA) modified by sulfation, where the location

of sulfation differs with the kind of CS [53]. In mammals chondroitin sulfate

disaccharides have been found to be monosulfated in the fourth or sixth position

of the GalNAc residue or disulfated in the second and sixth position of the GlcA

and GalNAcor in the four and six positions of GalNAc residue [54]. The enzymes

accountable for these alterations are chondroitin sulfotransferases. Owing to its

biocompatibility, non-immunogenicity and pliability, CS hydrogels have been

broadly studied for wound dressing applications [55]. Alike to HA, numerous

physical and chemical crosslinking techniques have been established for CS to

form hydrogels for biomedical applications [56]. As CS plays a significant role

in controlling the expression of the chondrocyte phenotype, it has been broadly

studied as a scaffolding material for cartilage tissue engineering. This is mainly

significant since investigations have revealed that effective cartilage regeneration

can be attained via the use of a tissue engineered implant, simply if the seeded

cells experience normal proliferation and phenotype development within the biodegradable scaffold together with the fabrication of a novel cartilage-specific

extracellular matrix. Numerous investigations have examined the efficiency of

utilizing composite scaffolds composed of CS and other biopolymers, e.g. collagen or synthetic biodegradable polymers, as scaffolds for cartilage tissue engineering. These investigations have explored a strong correlation between the use

of CS and the bioactivity of the seeded chondrocytes [57]. Additional natural

bioactive polysaccharides that are being acknowledged as potential biomaterials

for different biomedical applications comprise heparin sulfate, keratin sulfate

and dermatan sulfate.



1.11



Natural–Origin Polymers as Carriers and Scaffolds for Biomolecules and Cell…



1.11



1.11.1



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Natural–Origin Polymers as Carriers and Scaffolds

for Biomolecules and Cell Delivery in Tissue

Engineering Applications

Hyaluronan



Hyaluronic acid is most often called as hyaluronan owing to the information that it

exists in vivo as a polyanion and not in the protonated acid form [58]. Hyaluronan

is a naturally occurring non-sulfated glycosaminoglycan and a main macromolecular component of the intercellular matrix of most connective tissues e.g. cartilage,

vitreous of the human eye, umbilical cord and synovial fluid [58]. Hyaluronic acid

is a linear polysaccharide that comprised of alternating disaccharide units of α-1,4Dglucuronic acid and β-1,3-N-acetyl-D-glucosamine, connected by β(1→3) bonds

[59]. Hyaluronan and its linked networks have various physiological functions that

comprise tissue and matrix water regulation, structural and space-filling properties,

lubrication, and a number of macromolecular functions [58]. Particularly for its

enhanced viscoelastic features, hyaluronan function as a lubricant and shock

absorber in synovial fluid. Hyaluronan has been extensively investigated for drug

delivery, for dermal, nasal, pulmonary, parenteral, liposome-modified, implantable

delivery devices and for gene delivery (reviewed in Liao et al. [58]). Hyaluronan

for tissue engineering has been intensive on cartilage, bone and osteochondral

applications, most probable owing to the information that it is a major macromolecular component of the extracellular matrix. Industrially available hyaluronan is

derived from various sources, chiefly by isolation from rooster comb, umbilical

cord, synovial fluid, or vitreous humor. In addition, hyaluronic acid can be simply

and controllably fabricated in large scales via microbial fermentation, from strains

of bacteria such as Streptococci [58], enabling the scale-up of derived products and

avoiding the risk of animal-derived pathogens. Hyaluronan is accessible for numerous applications, for lubrication and mechanical support for the joints in osteoarthritis (Artz® from Seikagaku Corporation in Japan; Hyalgan® and Hyalubrix®

from Fidia in Italy) as a viscoelastic gel for surgery and wound healing (Jossalind®

from Hexal in Germany; Bionect® from CSC Pharmaceutical in USA), for implantation of artificial intraocular lens (Healon® from OVD from Advanced Medical

Optics in USA, Opegan R® from Seikagaku in Japan, Opelead® from Shiseido in

Japan, Orthovisc® from Anika in USA) and as culture media for use in in vitro

fertilization (EmbryoGlue® from Vitrolife, USA) [58]. Hyaff® commercialized by

Fidia in Italy has been extensively employed as a biomaterial for biomedical applications. From a chemical viewpoint, Hyaff® is a benzyl ester of hyaluronic acid

and its key features are that HYAFF® preserves the biological features of the natural molecule from which it originates, the natural degradation of Hyaff® releases

hyaluronic acid, which is then degraded via well-known metabolic pathways and

that depends on the extent of esterification, it is likely to obtain polymers with various levels of hydrophobicity.



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1



Mammalian Polysaccharides and Its Nanomaterials



Fig. 1.5 HA cryogels and hydrogen bonding between –COOH groups



The word hydrogel explains 3-D network structures derived from a class of

synthetic and/or natural polymers which can absorb and retain considerable

amount of water or biological fluids (Fig. 1.5). Polysaccharides that are employed

to produce physical cryogels: carboxymethylated cellulose, xanthan, hyaluronan,

carboxymethylated curdlan, starch (amylose, amylopectin and their mixtures),

β-glucan, locust bean gum, maltodextrins and agarose. A variety of physically

crosslinked cryogels from polysaccharides with tunable mechanical, structural,

biological features as well as numerous applications is considered and the studies

of the fabrication mechanism for these cryogels are also explored. The accurate

forming method of HA cryogel has not been completely understood. The complication in gel formation method of HA cryogel might be primarily obtained from

its chemical structure, which includes not only massive –OH groups as in PVA

and galactomannan, but also –COO and –NHCH3 groups along with potential

hydrophobic regions. The intermolecular and intramolecular hydrogen bonding

induced from –COOH in HA chains may play a significant role in respect to the

network formation and stabilization of HA gel, and the probable example is

revealed in Fig. 1.5.



1.11.2



Chondroitin Sulphate



Extracellular matrix components are appreciated building elements for the fabrication of biomaterials involved in tissue engineering, particularly if their biological,

chemical and physical features can be regulated. An instance is chondroitin sulfate,

one of the best physiologically vital glycosaminoglycans. Glycosaminoglycans

(GAGs) are present in the lubricating fluid of the joints and as components of



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