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.

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Stress-induced fibroblast senescence is thought to contribute to skin aging. Ultraviolet light (UV) radiation is the most potent environmental risk factor in these processes. An Epilobium angustifolium (EA) extract was evaluated for its capacity to reverse the senescent response of normal human dermal fibroblasts (NHDF) in vitro and to exhibit skin photo-protection in vivo. The HPLC-UV-MS analysis of the EA preparation identified three major polyphenol groups: tannins (oenothein B), phenolic acids (gallic and chlorogenic acids) and flavonoids. EA extract increased the cell viability of senescent NHDF induced by serum deprivation. It diminished connective tissue growth factor and fibronectin gene expressions in senescent NHDF. Down-regulation of the UV-induced release of both matrix metalloproteinase-1 and -3 and the tissue inhibitor of matrix metalloproteinases-1 and -2, and also down-regulation of the gene expression of hyaluronidase 2 were observed in repeatedly UV-irradiated NHDF after EA extract treatment. Interestingly, EA extract diminished the down-regulation of sirtuin 1 dampened by UV-irradiation. The application of EA extract using a sub-irritating dose protected skin against UV-induced erythema formation in vivo. In summary, EA extract diminished stress-induced effects on NHDF, particularly on connective tissue growth factor, fibronectin and matrix metalloproteinases. These results collectively suggest that EA extract may possess anti-aging properties and that the EA polyphenols might account for these benefits.

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Injectable hydrogels that aim to mechanically stabilise the weakened left ventricle (LV) wall to restore cardiac function or to deliver stem cells in cardiac regenerative therapy have shown promising data. However, the clinical translation of hydrogel-based therapies has been limited due to difficulties injecting them through catheters. We have engineered a novel catheter (AMCath) that overcomes translational hurdles associated with delivering fast-gelling covalently cross-linked hyaluronic acid hydrogels to the myocardium. We developed an experimental technique to measure the force required to inject such hydrogels and determined the mechanical/ viscoelastic properties of the resulting hydrogels. The preliminary in vivo feasibility of delivering fast-gelling hydrogels through AMCath was demonstrated by accessing the porcine LV and showing that the hydrogel was retained in the myocardium postinjection (three 200μL injections delivered, 192, 204 and 183μL measured). However, the mechanical properties of the hydrogels were reduced by passage through AMCath (≤20.62% reduction). We have also shown AMCath can be used to deliver c-ADSC loaded hydrogels without compromising the viability (80% viability) of the c-ADSCs in vitro. Therefore, we show that hydrogel/catheter compatibility issues can be overcome as we have demonstrated the minimally invasive delivery of a fast gelling covalently cross-linked hydrogel to the beating myocardium.

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Due to its native origin, excellent biocompatibility and biodegradability, hyaluronan (HA) represents an attractive polymer for superparamagnetic iron oxide nanoparticles (SPION) coating. Herein, we report HA polymeric micelles encapsulating oleic acid coated SPIONs, having a hydrodynamic size of about 100 nm and SPION loading capacity of 1-2 wt %. The HA-SPION polymeric micelles were found to be selectively cytotoxic toward a number of human cancer cell lines, mainly those of colon adenocarcinoma (HT-29). The selective inhibition of cell growth was even observed when the SPION loaded HA polymeric micelles were incubated with a mixture of control and cancer cells. The selective in vitro inhibition could not be connected with an enhanced CD44 uptake or radical oxygen species formation and was rather connected with a different way of SPION intracellular release. While aggregated iron particles were visualized in control cells, nonaggregated solubilized iron oxide particles were detected in cancer cells. In vivo SPION accumulation in intramuscular tumor following an intravenous micelle administration was confirmed by magnetic resonance (MR) imaging and histological analysis. Having a suitable hydrodynamic size, high magnetic relaxivity, and being cancer specific and able to accumulate in vivo in tumors, SPION-loaded HA micelles represent a promising platform for theranostic applications.

This review shows the steps toward material selection focalized on the design and development of medical devices based on hyaluronan (HA). The selection is based on chemical and mechanical properties, biocompatibility, sterilization, safety, and scale-up costs. These facts play a vital role in the industrialization process. Approved medical devices containing-HA are illustrated to identify key parameters. The first part of this work involves the steps toward a complete characterization of chemical and mechanical aspects, reproducibility of the processes and scale up. In a second stage, we aimed to describe the preclinical in vitro and in vivo assays and selected examples of clinical trials. Furthermore, it is important to keep in mind the regulatory affairs during the research and development (R&D) using standardization (ISO standards) to achieve the main goal, which is the functionality and safety of the final device. To keep reproducible experimental data to prepare an efficient master file for the device, based on quality and recorded manufacturing data, and a rigorous R&D process may help toward clinical translation. A strong debate is still going on because the denominated basic research in HA field does not pay attention to the purity and quality of the raw materials used during the development. So that, to achieve the next generation of devices is needed to overcome the limitations of state of art in terms of efficacy, biodegradability, and non-toxicity.