**15. Tissue Therapeutic Interventions Involving CS**

With the recent publication of the first draft of the GAG Interactome, the GAG–protein interactive properties previously investigated [116,233] have now been extensively catalogued [235]. There are two major areas of therapeutic application involving CS: (i) use of CS as a drug to treat OA cartilage depleted of proteoglycans; and (ii) therapeutic use of CS-depolymerising enzymes to remove the CS side chains of CS-PGs that are laid down in scar tissues, which stabilise spinal cord defects, neural damage in the PNS and neural damage following brain trauma [243,258,259]. While CS-PGs are laid down in neural scar tissues to stabilise the neural defects to prevent further mechanical damage at the defect site, the CS side chains of these PGs inhibit neural outgrowth through the scar tissue, thus functional recovery of the spinal cord or other traumatised neural tissues is prevented [260]. Chondroitinase ABC, ACII and hyaluronidase-4 (HYAL4) [261], which is a CS hydrolase despite its misnaming, have all been evaluated in models of spinal cord injury [262]. Removal of CS from the defect site by these enzymes resulted in recovery of neural functional properties [260,263–265]. Acute trauma to the brain and upper limbs resulting in neural damage have also been treated using chondroitinase ABC [266,267], resulting in neural sprouting through the defect site [268] and functional recovery [269].

Chondroitin sulphate has been of interest as a therapeutic agent for the treatment of OA for at least the last decade. A biochemical study in 2008 showed that CS interfered with progressive degenerative structural changes in joint tissues and thus showed promise in the treatment of OA [270]. A review of several CS preparations subsequently shows variable but generally positive responses in the treatment of OA but emphasises the need for highly purified CS preparations to provide unequivocal results [271]. A further study with pharmaceutical grade CS subsequently confirmed that highly purified CS had beneficial effects in the treatment of OA [272]. Continued assessment of highly purified pharmaceutical grade CS and other CS preparations confirmed safety data on the use of pharmaceutical grade CS for the treatment of OA and set down some guidelines for its use but indicated these were not applicable to lower grade CS preparations [273]. A further study raised doubts on some therapeutic CS preparations primarily focussing on the beneficial functions of CS-based therapeutic supplements and potential harmful effects of some fucosylated CS preparations which may contaminate these in a similar manner to the oversulphated CS species which have previously been identified, as contaminants in some

heparin preparations [274]. A current study on highly purified therapeutic commercially available CS (Condrosulf®, IBSA, Biochimique, Lugano, Switzerland) and a literature review on its clinical efficacy confirmed the reduced pain and improvements in joint function afforded by this preparation of CS to OA patients [275]. Condrosulf® is a cost-effective and safe treatment for OA, efficacious after 30 days of administration and has beneficial properties for at least the months after the drug is discontinued. Full safety reports analyses confirmed the safety profile for CS. It has almost no side effects and shows better gastrointestinal tolerance compared to conventional non-steroidal anti-inflammatory drugs used to treat OA [275]. The beneficial properties of CS may explain the resurgence in the use of PGs, recombinant PG sub-domains, GAG and PG mimetic, and the development of neo-PGs [276] for therapeutic repair procedures. CS can also be used to stimulate stem cells and promote the attainment of defined pluripotent stem cell lineages [277]. GAGs also have generalised properties which are useful in tissue repair [278] and have been incorporated into a number of bioscaffolds to promote stem cell regulation and to develop potential new tissue repair strategies (reviewed in [279]).
