epithelial, connective, and nerve tissues of vertebrates. It is designated as a glycosaminoglycan. [1] Glycosaminoglycans are composed of disaccharide blocks of N-acetylgalactosamine or N-acetylglucosamine, (amino sugars) and uronic sugars such as glucuronic acid, iduronic acid or galactose. This group of heteropolysaccharides comprises HA, chondroitin sulfates, dermatan sulfate, heparin and heparin sulfates whose sulfation degree is less than that of heparin. Unlike other glycosaminoglycans, hyaluronan is not sulfated and it is self-standing, i.e. without an association with a core protein. [2] It was isolated in 1934 by Meyer and Palmer from bovine vitreous humor. [3] The polymer chain of hyaluronan comprises repeating disaccharide units where the pyranose rings are connected by β-1,3 bonds. The repeating units are bonded with a β-1,4 glycosidic bond within the chain between N-acetyl-D-glucosamine and D-glucuronic acid. At physiological pH each glucuronate unit, associated with its carboxylate group, carries an anionic charge. The hundreds of negative charges are fixed to each chain. These anionic groups are balanced with mobile cations such as Na + , K + , Ca 2+ and Mg 2+ . During ionization of D-glucuronic acid with the carboxylic groups, the charges influence the organization of the chains and their interactions with their surroundings. In turn, they are affected by pH and ionic strength. The chain organization and charge directly affect the solubility in water, since hyaluronan is water-insoluble when convertedAs an Extracellular Matrix (ECM) component, Hyaluronic acid (HA) plays a multi-faceted role in cell migration, proliferation and differentiation at micro level and system level events such as tissue water homeostasis. Among its biological functions, it is known to interact with cytokines and contribute to their retention in ECM microenvironment. In addition to its biological functions, it has advantageous physical properties which result in the industrial endeavors in the synthesis and extraction of HA for variety of applications ranging from medical to cosmetic. Recently, HA and its derivatives have been the focus of active research for applications in biomedical device coatings, drug delivery systems and in the form of scaffolds or cell-laden hydrogels for tissue engineering. A specific reason for the increase in use of HA based structures is their immunomodulatory and regeneration inducing capacities. In this context, this article reviews recent literature on modulation of the implantable biomaterial microenvironment by systems based on HA and its derivatives, particularly hydrogels and microscale coatings that are able to deliver cytokines in order to reduce the adverse immune reactions and promote tissue healing.

Hydrogel scaffolds which bridge the lesion, together with stem cell therapy represent a promising approach for spinal cord injury (SCI) repair. In this study, a hydroxyphenyl derivative of hyaluronic acid (HA-PH) was modified with the integrin-binding peptide arginine-glycine-aspartic acid (RGD), and enzymatically crosslinked to obtain a soft injectable hydrogel. Moreover, addition of fibrinogen was used to enhance proliferation of human Wharton's jelly-derived mesenchymal stem cells (hWJ-MSCs) on HA-PH-RGD hydrogel. The neuroregenerative potential of HA-PH-RGD hydrogel was evaluated in vivo in acute and subacute models of SCI. Both HA-PH-RGD hydrogel injection and implantation into the acute spinal cord hemisection cavity resulted in the same axonal and blood vessel density in the lesion area after 2 and 8 weeks. HA-PH-RGD hydrogel alone or combined with fibrinogen (HA-PH-RGD/F) and seeded with hWJ-MSCs was then injected into subacute SCI and evaluated after 8 weeks using behavioural, histological and gene expression analysis. A subacute injection of both HA-PH-RGD and HA-PH-RGD/F hydrogels similarly promoted axonal ingrowth into the lesion and this effect was further enhanced when the HA-PH-RGD/F was combined with hWJ-MSCs. On the other hand, no effect was found on locomotor recovery or the blood vessel ingrowth and density of glial scar around the lesion. In conclusion, we have developed and characterized injectable HA-PH-RGD based hydrogel, which represents a suitable material for further combinatorial therapies in neural tissue engineering. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1129-1140, 2018.

(2016) Immunomodulation with self-crosslinked polyelectrolyte multilayer-based coatings. Biomacromolecules, 17 (6). pp. 2189 -2198 . ISSN 1525 Access from the University of Nottingham repository: http://eprints.nottingham.ac.uk/34683/1/Knopf-Marques%20et%20al%202016%20Revised %20final.pdf Copyright and reuse:The Nottingham ePrints service makes this work by researchers of the University of Nottingham available open access under the following conditions. This article is made available under the Creative Commons Attribution Non-commercial licence and may be reused according to the conditions of the licence. For more details see: http://creativecommons.org/licenses/by-nc/2.5/ A note on versions:The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher's version. Please see the repository url above for details on accessing the published version and note that access may require a subscription. . Moreover, we demonstrate that crosslinking PLL/HA film using HA-aldehyde is already effective by itself to limit inflammatory processes.Finally, this functionalized self-crosslinked PLL/HA-aldehyde films constitutes an innovative and efficient candidate for immunomodulation of any kind of implants of various architecture and properties.

Recent studies undoubtedly show that the mammalian target of rapamycin (mTOR) and the Hippo–Yes-associated protein 1 (YAP) pathways are important mediators of mechanical cues. The crosstalk between these pathways as well as de-regulation of their signaling has been implicated in multiple tumor types, including liver tumors. Additionally, physical cues from 3D microenvironments have been identified to alter gene expression and differentiation of different cell lineages. However, it remains incompletely understood how physical constraints originated in 3D cultures affect cell plasticity and what the key mediators are of such process. In this work, we use collagen scaffolds as a model of a soft 3D microenvironment to alter cellular size and study the mechanotransduction that regulates that process. We show that the YAP-mTOR axis is a downstream effector of 3D cellular culture-driven mechanotransduction. Indeed, we found that cell mechanics, dictated by the physical constraints of 3D collagen scaffolds, profoundly affect cellular proliferation in a YAP–mTOR-mediated manner. Functionally, the YAP–mTOR connection is key to mediate cell plasticity in hepatic tumor cell lines. These findings expand the role of YAP–mTOR-driven mechanotransduction to the control hepatic tumor cellular responses under physical constraints in 3D cultures. We suggest a tentative mechanism, which coordinates signaling rewiring with cytoplasmic restructuring during cell growth in 3D microenvironments.