**8. Alginate**

tissue injury. Current model of hyaluronic acid appear in the early stages of wound healing is to physically make room for white blood cells, which mediate the immune re‐ sponse and at least in part, reduce collagen deposition and therefore lead to reduced scarring [86]. This hypothesis is in agreement with the research of West and coworkers, who have showed that in adult and late gestation fetal wound healing process, removal

HA can be modified through several different ways, such as chemically esterify its car‐ boxylic groups with some types of alcohol. The physico-chemical properties of the new biopolymers allow the preparation of many biomaterials with different biocompatibilities for various medical applications [88]. Shen and coworkers implanted hyaluronan hydro‐ gel and periodate oxidated hyaluronan hydrogel in ischemic myocardium and found rapid degradation rates, low quantity of inflammation-mediating cells, thin fibrous cap‐ sules with dense blood vessels around the hydrogels at week 2 [89]. Praveen and cow‐ orkers used HA/polyvinyl alcohol (PVA) coating membrane to minimize the problems related to protein deposition and fibrous tissue formation on an implanted glucose sen‐ sor [90]. HA hydrogels modified with laminin could support cell infiltration, angiogene‐ sis, and simultaneously inhibit the formation of glial scar after being implanted into the lesion of the cortex [91]. Compared with pure gelatin hydrogen, HA/gelatin composite has a better compatibility and contiguity with the surrounding brain tissue with no in‐ flammatory reaction and fibrous encapsulation [92]. Intravitreal implants of hyaluronic acid esters represent useful biocompatible and biodegradable properties for a potential drug delivery system in the treatment of posterior segment ocular diseases [93]. A crosslinked HA hydrogel that contained a covalently bound derivative of the anti-prolifera‐ tive drug MMC was synthesized and evaluated *in vitro* and *in vivo*. This hydrogel has strong potential as anti-fibrotic barriers for the prevention of post-surgical adhesions [94]. Two injectable thiolated HA derivatives were coupled to four alpha, beta-unsaturat‐ ed ester and amide derivatives of poly(ethylene glycol) (PEG) 3400 and were found that the encapsulated cells can retained their original fibroblast phenotype and secreted ECM in vivo [95]. A fibrin/HA composite gel with autologous chondrocytes has been synthe‐ sized for tracheal reconstruction. Histologically, the grafts showed no signs of inflamma‐

of HA results in fibrotic scarring [87].

120 Advances in Biomaterials Science and Biomedical Applications

tory reaction and were covered with ciliated epithelium [96].

Heparin (from Ancient Greek ηπαρ (hepar), liver), a highly sulfated glycosaminoglycan, is widely used as an injectable anticoagulant, and has the highest negative charge densi‐ ty of any known biological molecule [97]. Heparins are involved in different pathways of the coagulation cascade with anticoagulant, antithrombotic, profibrinolytic, anti-aggre‐ gative, as well as anti-inflammatory effects [98]. As stated in the fibrin section, the pri‐ mary anticoagulant effect of heparin is through the suppression of thrombin-dependent amplification of the coagulation cascade, and inhibition of thrombin-mediated conversion

**7. Heparin**

of fibrinogen to fibrin [99].

Alginate, is a salt of alginic acid ( medical-dictionary.thefreedictionary.com), and an anionic polysaccharide distributed widely in the cell walls of brown algae, where it, through bind‐ ing water, forms a viscous gum (Wikipedia, the free encyclopedia). Sodium alginate (com‐ posed of mannuronic and guluronic (G) dimmers) is a biocompatible and biodegradable polymer, and has been widely used in cell encapsulation technology, though the biocompat‐ ibility of the alginates in relation to their composition is a matter of debate [113]. In the mol‐ ecules of sodium alginate the primary block guluronic acid contains available carboxylic acid groups that allow the alginate to be reversibly crosslinked by divalent cations, such as Ca+2 and Mg+2, to form a relatively stable hydrogel [114,115]. Clinically, water-soluble algi‐ nates are useful as materials for dental impressions. Calcium alginates have been widely used as a base material to encapsulate glucose-sensing pancreatic islets that secrete insulin into the lymphatic system to reverse the effects of insulin-dependent diabetics [116]. Some investigators have utilized alginates to promote the viability of encapsulated cells [117]. Al‐ ginate-poly-L-lysine-alginate (APA) microcapsules continue to be the most widely studied device for the immuno-protection of transplanted therapeutic cells [118]. Alginate-chitosanalginate (ACA) microcapsules have been developed as a device for the transplantation of living cells with protein adsorption onto the surface of microcapsules immediately upon im‐ plantation [119].

**Figure 4.** Model of pathogenesis of heparin-induced thrombocytopenia (HIT). Heparin binds with Platelet factor 4 (PF4), which exposes neoepitopes on PF4 and leads to antibody production (1). Heparin-PF4-IgG immune complexes form (2), and IgG in multimolecular complex triggers platelet activation via binding to Fc receptors (3). Activated pla‐ telet releases additional PF4 (4a) and prothrombotic platelet microparticles (4b). Thrombotic risk is further promoted by binding of PF4 to heparin-like molecules on endothelial cells (EC), contributing to immune system–mediated endo‐ thelial damage (5) [112].
