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Hyaluronan and synovial joint: function, distribution and healing

Tamer Mahmoud Tamer

Interdisciplinary Toxicology · 2013 · Review

doi:10.2478/intox-2013-0019

Abstract

Synovial fluid is a viscous solution found in the cavities of synovial joints. The principal role of synovial fluid is to reduce friction between the articular cartilages of synovial joints during movement. The presence of high molar mass hyaluronan (HA) in this fluid gives it the required viscosity for its function as lubricant solution. Inflammation oxidation stress enhances normal degradation of hyaluronan causing several diseases related to joints. This review describes hyaluronan properties and distribution, applications and its function in synovial joints, with short review for using thiol compounds as antioxidants preventing HA degradations under inflammation conditions.

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Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 20, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

The human skeleton consists of both fused and individual bones supported and supplemented by ligaments, tendons, and skeletal muscles. Articular ligaments and tendons are the main parts holding together the joint(s). In respect of movement, there are freely moveable, partially moveable, and immovable joints. Synovial joints (Figure 1), the freely moveable ones, allow for a large range of motion and encompass wrists, knees, ankles, shoulders, and hips (Kogan, ).

Cartilage

In a healthy synovial joint, heads of the bones are encased in a smooth (hyaline) cartilage layer. These tough slippery layers – e.g. those covering the bone ends in the knee joint – belong to mechanically highly stressed tissues in the human body. At walking, running, or sprinting the strokes frequency attain approximately 0.5, 2.5 or up to 10 Hz.

Cartilage functions also as a shock absorber. This property is derived from its high water entrapping capacity as well as from the structure and intermolecular interactions among polymeric components that constitute the cartilage tissue (Servaty et al., ). Figure 2 sketches a section of the cartilage – a chondrocyte cell that permanently restructures/rebuilds its extracellular matrix. Three classes of proteins exist in articular cartilage: collagens (mostly type II collagen); proteoglycans (primarily aggrecan); and other noncollagenous proteins (including link protein, fibronectin, COMP – cartilage oligomeric matrix protein) and the smaller proteoglycans (biglycan, decorin, and fibromodulin). The interaction between highly negatively charged cartilage proteoglycans and type II collagen fibrils is responsible for the compressive and tensile strength of the tissue, which resists applied load in vivo.

Synovium/synovial membrane

Each synovial joint is surrounded by a fibrous, highly vascular capsule/envelope called synovium, whose internal surface layer is lined with a synovial membrane. Inside this membrane, type B synoviocytes (fibroblast-like cell lines) are localized/embedded. Their primary function is to continuously extrude high-molar-mass hyaluronans (HAs) into synovial fluid.

Synovial fluid

The synovial fluid (SF) of natural joints normally functions as a biological lubricant as well as a biochemical pool through which nutrients and regulatory cytokines traverse. SF contains molecules that provide low-friction and low-wear properties to articulating cartilage surfaces.

Molecules postulated to play a key role in lubrication alone or in combination, are proteoglycan 4 (PRG4) (Swann et al., ) present in SF at a concentration of 0.05–0.35 mg/ml (Schmid et al., 2001), hyaluronan (HA) (Ogston & Stanier, ) at 1–4 mg/ml (Mazzucco et al., ), and surface-active phospholipids (SAPL) (Schwarz & Hills, ) at 0.1 mg/ml (Mazzucco et al., ). Synoviocytes secrete PRG4 (Jay et al.,; Schumacher et al., ) and are the major source of SAPL (Dobbie et al.,; Hills & Crawford,; Schwarz & Hills, ), as well as HA (Haubeck et al.,; Momberger et al., ) in SF. Other cells also secrete PRG4, including chondrocytes in the superficial layer of articular cartilage (Schmid et al.,; Schumacher et al., ) and, to a much lesser extent, cells in the meniscus (Schumacher et al., ).

As a biochemical depot, SF is an ultra filtrate of blood plasma that is concentrated by virtue of its filtration through the synovial membrane. The synovium is a thin lining (∼50 µm in humans) comprised of tissue macrophage A cells, fibroblast-like B cells (Athanasou & Quinn,; Revell,; Wilkinson et al., ), and fenestrated capillaries (Knight & Levick, ). It is backed by a thicker layer (∼100 µm) of loose connective tissue called the subsynovium (SUB) that includes an extensive system of lymphatics for clearance of transported molecules. The cells in the synovium form a discontinuous layer separated by intercellular gaps of several microns in width (Knight & Levick,; McDonald & Levick, ). The extracellular matrix in these gaps contains collagen types I, III, and V (Ashhurst et al.,; Rittig et al., ), hyaluronan (Worrall et al., ), chondroitin sulphate (Price et al.,; Worrall et al., ), biglycan and decorin proteoglycans (Coleman et al., ), and fibronectin (Poli et al., ). The synovial matrix provides the permeable pathway through which exchange of molecules occurs (Levick, ), but also offers sufficient outflow resistance (Coleman et al.,; Scott et al., ) to retain large solutes of SF within the joint cavity. Together, the appropriate reflection of secreted lubricants by the synovial membrane and the appropriate lubricant secretion by cells are necessary for development of a mechanically functional SF (Blewis et al., ).

In the joint, HA plays an important role in the protection of articular cartilage and the transport of nutrients to cartilage. In patients with rheumatoid arthritis (RA), (Figure 3) it has been reported that HA acts as an anti inflammatory substance by inhibiting the adherence of immune complexes to neutrophils through the Fc receptor (Brandt, ), or by protecting the synovial tissues from the attachment of inflammatory mediators (Miyazaki et al.,, Mendichi & Soltes, ).

Reactive oxygen species (ROS) (O2 •–, H2O2, •OH) are generated in abundance by synovial neutrophils from RA patients, as compared with synovial neutrophils of osteoarthritis (OA) patients and peripheral neutrophils of both RA and OA patients (Niwa et al., ).

McCord demonstrated that HA was susceptible to degradation by ROS In vitro, and that this could be protected by superoxide dismutase (SOD) and/or catalase, which suggests the possibility that there is pathologic oxidative damage to synovial fluid components in RA patients. Dahl et al. reported that there are reduced HA concentrations in synovial fluids from RA patients. It has also been reported that ROS scavengers inhibit the degradation of HA by ROS (Soltes,; Blake et al.,; Betts & Cleland,; Soltes et al., ).

These findings appear to support the hypothesis that ROS are responsible for the accelerated degradation of HA in the rheumatoid joint. In the study of Juranek and Soltes the oxygen radical scavenging activities of synovial fluids from both RA and OA patients were assessed, and the antioxidant activities of these synovial fluids were analyzed by separately examining HA, d-glucuronic acid, and N-acetyl-d-glucosamine.

Hyaluronan

In 1934, Karl Meyer and his colleague John Palmer isolated a previously unknown chemical substance from the vitreous body of cows’ eyes. They found that the substance contained two sugar molecules, one of which was uronic acid. For convenience, therefore, they proposed the name “hyaluronic acid”. The popular name is derived from “hyalos”, which is the Greek word for glass + uronic acid (Meyer & Palmer, ). At the time, they did not know that the substance which they had discovered would prove to be one of the most interesting and useful natural macromolecules. HA was first used commercially in 1942 when Endre Balazs applied for a patent to use it as a substitute for egg white in bakery products (Necas et al., ).

The term “hyaluronan” was introduced in 1986 to conform to the international nomenclature of polysaccharides and is attributed to Endre Balazs (Balazs et al., ) who coined it to encompass the different forms the molecule can take, e.g, the acid form, hyaluronic acid, and the salts, such as sodium hyaluronate, which forms at physiological pH (Laurent, ). HA was subsequently isolated from many other sources and the physicochemical structure properties and biological role of this polysaccharide were studied in numerous laboratories (Kreil, ). This work has been summarized in a Ciba Foundation Symposium (Laurent, ) and a recent review (Laurent & Fraser,; Chabrecek et al.,; Orvisky et al., ).

Hyaluronan (Figure 4) is a unique biopolymer composed of repeating disaccharide units formed by N-acetyl-d-glucosamine and d-glucuronic acid. Both sugars are spatially related to glucose which in the β-configuration allows all of its bulky groups (the hydroxyls, the carboxylate moiety, and the anomeric carbon on the adjacent sugar) to be in sterically favorable equatorial positions while all of the small hydrogen atoms occupy the less sterically favorable axial positions. Thus, the structure of the disaccharide is energetically very stable. HA is also unique in its size, reaching up to several million Daltons and is synthesized at the plasma membrane rather than in the Golgi, where sulfated glycosaminoglycans are added to protein cores (Itano & Kimata,; Weigel et al.,; Kogan et al., ).

In a physiological solution, the backbone of a HA molecule is stiffened by a combination of the chemical structure of the disaccharide, internal hydrogen bonds, and interactions with the solvent. The axial hydrogen atoms form a non-polar, relatively hydrophobic face while the equatorial side chains form a more polar, hydrophilic face, thereby creating a twisting ribbon structure. Solutions of hyaluronan manifest very unusual rheological properties and are exceedingly lubricious and very hydrophilic. In solution, the hyaluronan polymer chain takes on the form of an expanded, random coil. These chains entangle with each other at very low concentrations, which may contribute to the unusual rheological properties. At higher concentrations, solutions have an extremely high but shear-dependent viscosity. A 1% solution is like jelly, but when it is put under pressure it moves easily and can be administered through a small-bore needle. It has therefore been called a “pseudo-plastic” material. The extraordinary rheological properties of hyaluronan solutions make them ideal as lubricants. There is evidence that hyaluronan separates most tissue surfaces that slide along each other. The extremely lubricious properties of hyaluronan have been shown to reduce postoperative adhesion formation following abdominal and orthopedic surgery. As mentioned, the polymer in solution assumes a stiffened helical configuration, which can be attributed to hydrogen bonding between the hydroxyl groups along the chain. As a result, a coil structure is formed that traps approximately 1000 times its weight in water (Chabrecek et al.,; Cowman & Matsuoka,; Schiller et al., )

Hyaluronan networks

The physico-chemical properties of hyaluronan were studied in detail from 1950 onwards (Comper & Laurent, ).

The molecules behave in solution as highly hydrated randomly kinked coils, which start to entangle at concentrations of less than 1 mg/mL. The entanglement point can be seen both by sedimentation analysis (Laurent et al., ) and viscosity (Morris et al., ). More recently Scott and his group have given evidence that the chains when entangling also interact with each other and form stretches of double helices so that the network becomes mechanically more firm (Scott et al., ).

Rheological properties

Solutions of hyaluronan are viscoelastic and the viscosity is markedly shearing dependent (Morris et al.,; Gibbs et al., ). Above the entanglement point the viscosity increases rapidly and exponentially with concentration (∼c3.3) (Morris et al., ) and a solution of 10 g/l may have a viscosity at low shear of ∼106 times the viscosity of the solvent. At high shear the viscosity may drop as much as ∼103 times (Gibbs et al., ). The elasticity of the system increases with increasing molecular weight and concentration of hyaluronan as expected for a molecular network. The rheological properties of hyaluronan have been connected with lubrication of joints and tissues and hyaluronan is commonly found in the body between surfaces that move along each other, for example cartilage surfaces and muscle bundles (Bothner & Wik, ).

Water homeostasis

A fixed polysaccharide network offers a high resistance to bulk flow of solvent (Comper & Laurent, ). This was demonstrated by Day (1950) who showed that hyaluronidase treatment removes a strong hindrance to water flow through a fascia. Thus HA and other polysaccharides prevent excessive fluid fluxes through tissue compartments. Furthermore, the osmotic pressure of a hyaluronan solution is non-ideal and increases exponentially with the concentration. In spite of the high molecular weight of the polymer the osmotic pressure of a 10 g/l hyaluronan solution is of the same order as an l0 g/l albumin solution. The exponential relationship makes hyaluronan and other polysaccharides excellent osmotic buffering substances – moderate changes in concentration lead to marked changes in osmotic pressure. Flow resistance together with osmotic buffering makes hyaluronan an ideal regulator of the water homeostasis in the body.

Network interactions with other macromolecules

The hyaluronan network retards the diffusion of other molecules (Comper & Laurent,; Simkovic et al., ). It can be shown that it is the steric hindrance which restricts the movements and not the viscosity of the solution. The larger the molecule the more it will be hindered. In vivo hyaluronan will therefore act as a diffusion barrier and regulate the transport of other substances through the intercellular spaces. Furthermore, the network will exclude a certain volume of solvent for other molecules; the larger the molecule the less space will be available to it (Comper & Laurent, ). A solution of 10 g/l of hyaluronan will exclude about half of the solvent to serum albumin. Hyaluronan and other polysaccharides therefore take part in the partition of plasma proteins between the vascular and extravascular spaces. The excluded volume phenomenon will also affect the solubility of other macromolecules in the interstitium, change chemical equilibria and stabilize the structure of, for example, collagen fibers.

Medical applications of hyaluronic acid

The viscoelastic matrix of HA can act as a strong biocompatible support material and is therefore commonly used as growth scaffold in surgery, wound healing and embryology. In addition, administration of purified high molecular weight HA into orthopaedic joints can restore the desirable rheological properties and alleviate some of the symptoms of osteoarthritis (Balazs & Denlinger,; Balazs & Denlinger,; Kogan et al., ). The success of the medical applications of HA has led to the production of several successful commercial products, which have been extensively reviewed previously.

Table 1 summarizes both the medical applications and the commonly used commercial preparations containing HA used within this field. HA has also been extensively studied in ophthalmic, nasal and parenteral drug delivery. In addition, more novel applications including pulmonary, implantation and gene delivery have also been suggested. Generally, HA is thought to act as either a mucoadhesive and retain the drug at its site of action/absorption or to modify the in vivo release/absorption rate of the therapeutic agent. A summary of the drug delivery applications of HA is shown in Table 2.

Cosmetic uses of hyaluronic acid

HA has been extensively utilized in cosmetic products because of its viscoelastic properties and excellent biocompatibility. Application of HA containing cosmetic products to the skin is reported to moisturize and restore elasticity, thereby achieving an antiwrinkle effect, albeit so far no rigorous scientific proof exists to substantiate this claim. HA-based cosmetic formulations or sunscreens may also be capable of protecting the skin against ultraviolet irradiation due to the free radical scavenging properties of HA (Manuskiatti & Maibach, ).

HA, either in a stabilized form or in combination with other polymers, is used as a component of commercial dermal fillers (e.g. Hylaform®, Restylane® and Dermalive®) in cosmetic surgery. It is reported that injection of such products into the dermis, can reduce facial lines and wrinkles in the long term with fewer side-effects and better tolerability compared with the use of collagen (Duranti et al.,; Bergeret-Galley et al.,; Leyden et al., ). The main side-effect may be an allergic reaction, possibly due to impurities present in HA (Schartz,; Glogau, ).

Biological function of hyaluronan

Naturally, hyaluronan has essential roles in body functions according to organ type in which it is distributed (Laurent et al., ).

Space filler

The specific functions of hyaluronan in joints are still essentially unknown. The simplest explanation for its presence would be that a flow of hyaluronan through the joint is needed to keep the joint cavity open and thereby allow extended movements of the joint. Hyaluronan is constantly secreted into the joint and removed by the synovium. The total amount of hyaluronan in the joint cavity is determined by these two processes. The half-life of the polysaccharide at steady-state is in the order of 0.5–1 day in rabbit and sheep (Brown et al.,; Fraser et al., ). The volume of the cavity is determined by the pressure conditions (hydrostatic and osmotic) in the cavity and its surroundings. Hyaluronan could, by its osmotic contributions and its formation of flow barriers in the limiting layers, be a regulator of the pressure and flow rate (McDonald & Leviek, ). It is interesting that in fetal development the formation of joint cavities is parallel with a local increase in hyaluronan (Edwards et al., ).

Lubrication

Hyaluronan has been regarded as an ideal lubricant in the joints due to its shear-dependent viscosity (Ogston & Stanier, ) but its role in lubrication has been refuted by others (Radin et al., ). However, there are now reasons to believe that the function of hyaluronan is to form a film between the cartilage surfaces. The load on the joints may press out water and low-molecular solutes from the hyaluronan layer into the cartilage matrix. As a result, the concentration of hyaluronan increases and a gel structure of micrometric thickness is formed which protects the cartilage surfaces from frictional damage (Hlavacek, ). This mechanism to form a protective layer is much less effective in arthritis when the synovial hyaluronan has both a lower concentration and a lower molecular weight than normal. Another change in the arthritic joint is the protein composition of the synovial fluid. Fraser et al. showed more than 40 years ago that addition of various serum proteins to hyaluronan substantially increased the viscosity and this has received a renewed interest in view of recently discovered hyaladherins (see above). TSG-6 and inter-α-trypsin inhibitor and other acute phase reactants such as haptoglobin are concentrated to arthritic synovial fluid (Hutadilok et al., ). It is not known to what extent these are affecting the rheology and lubricating properties.

Scavenger functions

Hyaluronan has also been assigned scavenger functions in the joints. It has been known since the 1940s that hyaluronan is degraded by various oxidizing systems and ionizing irradiation and we know today that the common denominator is a chain cleavage induced by free radicals, essentially hydroxy radicals (Myint et al., ). Through this reaction hyaluronan acts as a very efficient scavenger of free radicals. Whether this has any biological importance in protecting the joint against free radicals is unknown. The rapid turnover of hyaluronan in the joints has led to the suggestion that it also acts as a scavenger for cellular debris (Laurent et al., ). Cellular material could be caught in the hyaluronan network and removed at the same rate as the polysaccharide (Stankovska et al.,; Rapta, et al., ).

Regulation of cellular activities

As discussed above, more recently proposed functions of hyaluronan are based on its specific interactions with hyaladherins. One interesting aspect is the fact that hyaluronan influences angiogenesis but the effect is different depending on its concentration and molecular weight (Sattar et al., ). High molecular weight and high concentrations of the polymer inhibit the formation of capillaries, while oligosaccharides can induce angiogenesis. There are also reports of hyaluronan receptors on vascular endothelial cells by which hyaluronan could act on the cells (Edwards et al., ). The avascularity of the joint cavity could be a result of hyaluronan inhibition of angiogenesis.

Another interaction of some interest in the joint is the binding of hyaluronan to cell surface proteins. Lymphocytes and other cells may find their way to joints through this interaction. Injection of high doses of hyaluronan intra-articularly could attract cells expressing these proteins. Cells can also change their expression of hyaluronan-binding proteins in states of disease, whereby hyaluronan may influence immunological reactions and cellular traffic in the path of physiological processes in cells (Edwards et al., ). The observation often reported that intra-articular injections of hyaluronan alleviate pain in joint disease (Adams, ) may indicate a direct or indirect interaction with pain receptors.

Hyaluronan and synovial fluid

In normal/healthy joint, the synovial fluid, which consists of an ultrafiltrate of blood plasma and glycoproteins contains HA macromolecules of molar mass ranging between 6–10 mega Daltons (Praest et al., ). SF serves also as a lubricating and shock absorbing boundary layer between moving parts of synovial joints. SF reduces friction and wear and tear of the synovial joint playing thus a vital role in the lubrication and protection of the joint tissues from damage during motion (Oates et al., ).

As SF of healthy humans exhibits no activity of hyaluronidase, it has been inferred that oxygen-derived free radicals are involved in a self-perpetuating process of HA catabolism within the joint (Grootveld et al.,; Stankovska et al.,; Rychly et al., ). This radical-mediated process is considered to account for ca. twelve-hour half-life of native HA macromolecules in SF.

Acceleration of degradation of high-molecular-weight HA occurring under inflammation and/or oxidative stress is accompanied by impairment and loss of its viscoelastic properties (Parsons et al.,; Soltes et al.,; Stankovska et al.,; Lath et al.,; Hrabarova et al.,; Valachova & Soltes,; Valachova et al., ). Low-molecular weight HA was found to exert different biological activities compared to the native high-molecular-weight biopolymer. HA chains of 25–50 disaccharide units are inflammatory, immune-stimulatory, and highly angiogenic. HA fragments of this size appear to function as endogenous danger signals, reflecting tissues under stress (Noble,; West et al.,; Soltes et al.,; Stern et al.,; Soltes & Kogan, ). Figure 5 describes the fragmentation mechanism of HA under free radical stress.Initiation phase: the intact hyaluronan macromolecule entering the reaction with the HO• radical formed via the Fenton-like reaction:Cu+ + H2O2 → Cu2+ + HO• + OH– H2O2 has its origin due to the oxidative action of the Weissberger system (see Figure 6)Formation of an alkyl radical (C-centered hyaluronan macroradical) initiated by the HO• radical attack.Propagation phase: formation of a peroxy-type C-macroradical of hyaluronan in a process of oxygenation after entrapping a molecule of O2.Formation of a hyaluronan-derived hydroperoxide via the reaction with another hyaluronan macromolecule.Formation of highly unstable alkoxy-type C-macroradical of hyaluronan on undergoing a redox reaction with a transition metal ion in a reduced state.Termination phase: quick formation of alkoxy-type C-fragments and the fragments with a terminal C=O group due to the glycosidic bond scission of hyaluronan. Alkoxy-type C fragments may continue the propagation phase of the free-radical hyaluronan degradation reaction. Both fragments are represented by reduced molar masses (Kogan, 2011; Rychly et al.,; Hrabarova et al.,; Surovcikova et al.,; Valachova et al.,; Banasova et al., ).

Initiation phase: the intact hyaluronan macromolecule entering the reaction with the HO• radical formed via the Fenton-like reaction:

Cu+ + H2O2 → Cu2+ + HO• + OH–

H2O2 has its origin due to the oxidative action of the Weissberger system (see Figure 6)

Formation of an alkyl radical (C-centered hyaluronan macroradical) initiated by the HO• radical attack.

Propagation phase: formation of a peroxy-type C-macroradical of hyaluronan in a process of oxygenation after entrapping a molecule of O2.

Formation of a hyaluronan-derived hydroperoxide via the reaction with another hyaluronan macromolecule.

Formation of highly unstable alkoxy-type C-macroradical of hyaluronan on undergoing a redox reaction with a transition metal ion in a reduced state.

Termination phase: quick formation of alkoxy-type C-fragments and the fragments with a terminal C=O group due to the glycosidic bond scission of hyaluronan. Alkoxy-type C fragments may continue the propagation phase of the free-radical hyaluronan degradation reaction. Both fragments are represented by reduced molar masses (Kogan, 2011; Rychly et al.,; Hrabarova et al.,; Surovcikova et al.,; Valachova et al.,; Banasova et al., ).

Several thiol compounds have attracted much attention from pharmacologists because of their reactivity toward endobiotics such as hydroxyl radical-derived species. Thiols play an important role as biological reductants (antioxidants) preserving the redox status of cells and protecting tissues against damage caused by the elevated reactive oxygen/nitrogen species (ROS/RNS) levels, by which oxidative stress might be indicated.

Soltes and his coworkers examined the effect of several thiol compounds on inhibition of the degradation kinetics of a high-molecular-weight HA In vitro. High molecular weight hyaluronan samples were exposed to free-radical chain degradation reactions induced by ascorbate in the presence of Cu(II) ions, the so called Weissberger's oxidative system. The concentrations of both reactants [ascorbate, Cu(II)] were comparable to those that may occur during an early stage of the acute phase of joint inflammation (see Figure 6) (Banasova et al.,; Valachova et al.,; Soltes et al.,; Soltes et al.,; Stankovska et al.,; Soltes et al.,; Soltes et al.,; Valachova et al.,; 2009; 2010;; 2013; Hrabarova et al.,,; Rapta et al.,;; Surovcikova-Machova et al., 2012; Banasova et al.,; Drafi et al.,; Fisher & Naughton, ).

Figure 7 illustrates the dynamic viscosity of hyaluronan solution in the presence and absence of bucillamine, d-penicillamine and l-cysteine as inhibitors for free radical degradation of HA. The study showed that bucillamine to be both a preventive and chain-breaking antioxidant. On the other hand, d-penicillamine and l-cysteine dose dependently act as scavenger of •OH radicals within the first 60 min. Then, however, the inhibition activity is lost and degradation of hyaluronan takes place (Valachova et al.,; Valachova et al.,;; Hrabarova et al., ).

l-Glutathione (GSH; l-γ-glutamyl-l-cysteinyl-glycine; a ubiquitous endogenous thiol, maintains the intracellular reduction-oxidation (redox) balance and regulates signaling pathways during oxidative stress/conditions. GSH is mainly cytosolic in the concentration range of ca. 1–10 mM; however, in the plasma as well as in SF, the range is only 1–3 µM (Haddad & Harb, ). This unique thiol plays a crucial role in antioxidant defense, nutrient metabolism, and in regulation of pathways essential for the whole body homeostasis. Depletion of GSH results in an increased vulnerability of the cells to oxidative stress (Hultberg & Hultberg, ).

It was found that l-glutathione exhibited the most significant protective and chain-breaking antioxidative effect against hyaluronan degradation. Thiol antioxidative activity, in general, can be influenced by many factors such as various molecule geometry, type of functional groups, radical attack accessibility, redox potential, thiol concentration and pKa, pH, ionic strength of solution, as well as different ability to interact with transition metals (Hrabarova et al., ).

Figure 8 shows the dynamic viscosity versus time profiles of HA solution stressed to degradation with Weissberger's oxidative system. As evident, addition of different concentrations of GSH resulted in a marked protection of the HA macromolecules against degradation. The greater the GSH concentration used, the longer was the observed stationary interval in the sample viscosity values. At the lowest GSH concentration used, i.e. 1.0 µM (Figure 8), the time-dependent course of the HA degradation was more rapid than that of the reference experiment with the zero thiol concentration. Thus, one could classify GSH traces as functioning as a pro-oxidant.

The effectiveness of antioxidant activity of 1,4-dithioerythritol expressed as the radical scavenging capacity was studied by a rotational viscometry method (Hrabarova et al., ). 1,4-dithioerythritol, widely accepted and used as an effective antioxidant in the field of enzyme and protein oxidation, is a new potential antioxidant standard exhibiting very good solubility in a variety of solvents. Figure 9 describes the effect of 1,4-dithioerythritol on degradation of HA solution under free radical stress (Hrabarova et al., ).

N-Acetyl-l-cysteine (NAC), another significant precursor of the GSH biosynthesis, has broadly been used as effective antioxidant in a form of nutritional supplement (Soloveva et al.,; Thibodeau et al., ). At low concentrations, it is a powerful protector of α1-antiproteinase against the enzyme inactivation by HOCl. NAC reacts with HO• radicals and slowly with H2O2; however, no reaction of this endobiotic with superoxide anion radical was detected (Aruoma et al., ).

Investigation of the antioxidative effect of N-Acetyl-l-cysteine. Unlike l-glutathione, N-acetyl-l-cysteine was found to have preferential tendency to reduce Cu(II) ions to Cu(I), forming N-acetyl-l-cysteinyl radical that may subsequently react with molecular O2 to give O2 •– (Soloveva et al.,; Thibodeau et al., ). Contrary to l-cysteine, NAC (25 and 50 µM), when added at the beginning of the reaction, exhibited a clear antioxidative effect within ca. 60 and 80 min, respectively (Figure 10A). Subsequently, NAC exerted a modest pro-oxidative effect, more profound at 25-µM than at 100-µM concentration (Figure 10A). Application of NAC 1 h after the onset of the reaction (Figure 10B) revealed its partial inhibitory effect against formation of the peroxy-type radicals, independently from the concentration applied (Hrabarova et al., ).

An endogenous amine, cysteamine (CAM) is a cystine-depleting compound with antioxidative and anti-inflammatory properties; it is used for treatment of cystinosis – a metabolic disorder caused by deficiency of the lysosomal cystine carrier. CAM is widely distributed in organisms and considered to be a key regulator of essential metabolic pathways (Kessler et al., ).

Investigation of the antioxidative effect of cysteamine. Cysteamine (100 µM), when added before the onset of the reaction, exhibited an antioxidative effect very similar to that of GSH (Figure 8A and Figure 11A). Moreover, the same may be concluded when applied 1 h after the onset of the reaction (Figure 11B) at the two concentrations (50 and 100 µM), suggesting that CAM may be an excellent scavenger of peroxy radicals generated during the peroxidative degradation of HA (Hrabarova et al., ).

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    Banasova M, Valachova K, Rychly J, Priesolova E, Nagy M, Juranek I, Soltes L. Scavenging and chain breaking activity of bucillamine on free-radical mediated degradation of high molar mass hyaluronan. ChemZi. 2011;7:205-206.

    Not in our library

  14. 14.

    Banasová M, Valachová K, Hrabárová E, Priesolová E, Nagy M, Juránek I, Šoltés L. Early stage of the acute phase of joint inflammation. In vitro testing of bucillamine and its oxidized metabolite SA981 in the function of antioxidants. 16th Interdisciplinary Czech-Slovak Toxicological Conference in Prague. Interdiscip Toxicol. 2011;4(2):22.

    Not in our library

  15. 15.

    Barrett JP, Siviero P. Retrospective study of outcomes in Hyalgan(R)-treated patients with osteoarthritis of the knee. Clin Drug Invest. 2002;22:87-97.

    Not in our library10.2165/00044011-200222020-00003

  16. 16.

    Bergeret-Galley C, Latouche X, Illouz YG. The value of a new filler material in corrective and cosmetic surgery: DermaLive and DermaDeep. Aesthetic Plast Surg. 2001;25:249-255.

    Not in our library10.1007/s002660010131

  17. 17.

    Bernatchez SF, Tabatabay C, Gurny R. Sodium hyaluronate 0.25-percent used as a vehicle increases the bioavailability of topically administered gentamicin. Graefes Arch Clin Exp Ophthalmol. 1993;231:157-161.

    Not in our library10.1007/bf00920939

  18. 18.

    Betts WH, Cleland LG. Effect of metal chelators and antiinflammatory drugs on the degradation of hyaluronic acid. Arthritis Rheum. 1982;25:1469-1476.

    Not in our library10.1002/art.1780251213

  19. 19.

    Blake DR, Hall ND, Treby DA. Protection against superoxide and hydrogen peroxide in synovial fluid from rheumatoid patients. Clin Sci. 1981;61:483-486.

    Not in our library10.1042/cs0610483

  20. 20.

    Blewis ME, Nugent-Derfus GE, Schmidt TA, Schumacher BL, Sah RL. A model of synovial fluid lubricant composition in normal and injured. European cells and materials. 2007;13:26-39.

    Not in our library10.22203/ecm.v013a03

  21. 21.

    Bothner H, Wik O. Rheology of hyaluronate. Acta Otolaryngol Suppl. 1987;442:25-30.

    Not in our library10.3109/00016488709102834

  22. 22.

    Brandt K. Modification of chemotaxis by synovial fluid hyaluronate. Arthritis Rheum. 1970;13:308-309.

    Not in our library

  23. 23.

    Brown MB, Jones SA. Hyaluronic acid: a unique topical vehicle for the localized delivery of drugs to the skin. J Eur Acad Dermatol Venereol. 2005;19:308-318.

    Not in our library10.1111/j.1468-3083.2004.01180.x

  24. 24.

    Brown TJ, Laurent UBG, Fraser JRE. Turnover of hyaluronan in synovial joints: elimination of labelled hyaluronan from the knee joints of the rabbit. Exp Physiol. 1991;76:125-34.

    Not in our library10.1113/expphysiol.1991.sp003474

  25. 25.

    Bucolo C, Mangiafico P. Pharmacological profile of a new topical pilocarpine formulation. J Ocul Pharmacol Ther. 1999;15:567-573.

    Not in our library10.1089/jop.1999.15.567

  26. 26.

    Bucolo C, Spadaro A, Mangiafico S. Pharmacological evaluation of a new timolol/pilocarpine formulation. Ophthalmic Res. 1998;30:101-106.

    Not in our library10.1159/000055461

  27. 27.

    Camber O, Edman P, Gurny R. Influence of sodium hyaluronate on the meiotic effect of pilocarpine in rabbits. Curr Eye Res. 1987;6:779-784.

    Not in our library10.3109/02713688709034844

  28. 28.

    Camber O, Edman P. Sodium hyaluronate as an ophthalmic vehicle – some factors governing its effect on the ocular absorption of pilocarpine. Curr Eye Res. 1989;8:563-567.

    Not in our library10.3109/02713688908995755

  29. 29.

    Cantor JO, Cerreta JM, Armand G, Turino GM. Aerosolized hyaluronic acid decreases alveolar injury induced by human neutrophil elastase. Proc Soc Exp Biol Med. 1998;217:471-475.

    Not in our library10.3181/00379727-217-44260

  30. 30.

    Chabrecek P, Soltes L, Kallay Z, Fugedi A. Isolation and characterization of high molecular weight (3H) hyaluronic acid. J Label Compd Radiopharm. 1990;28:1121-1125.

    Not in our library

  31. 31.

    Chabrecek P, Soltes L, Kallay Z, Novak I. Gel permeation chromatographic characterization of sodium hyaluronate and its reactions prepared by ultrasonic degradation. Chromatographia. 1990;30:201-204.

    Not in our library

  32. 32.

    Chen FH, Rousche KT, Tuan RS. Technology Insight: adult stem cells in cartilage regeneration and tissue engineering. Nat Clin Pract Rheumatol. 2006;2(7):373-82.

    Not in our library10.1038/ncprheum0216

  33. 33.

    Coleman P, Kavanagh E, Mason RM, Levick JR, Ashhurst DE. The proteoglycans and glycosaminoglycan chains of rabbit synovium. Histochem J. 1998;30:519-524.

    Not in our library10.1023/a:1003291303380

  34. 34.

    Comper WD, Laurent TC. Physiological function of connective tissue polysaccharidcs. Physiol Rev. 1978;58:255-315.

    Not in our library10.1152/physrev.1978.58.1.255

  35. 35.

    Cowman MK, Matsuoka S. Experimental approaches to hyaluronan structure. Carbohydrate Research. 2005;340:791-809.

    Not in our library10.1016/j.carres.2005.01.022

  36. 36.

    Dahl LB, Dahl IM, Engstrom-Laurent A, Granath K. Concentration and molecular weight of sodium hyaluronate in synovial fluid from patients with rheumatoid arthritis and other arthropathies. Ann Rheum Dis. 1985;44:817-822.

    Not in our library10.1136/ard.44.12.817

  37. 37.

    Dobbie JW, Hind C, Meijers P, Bodart C, Tasiaux N, Perret J, Anderson JD. Lamellar body secretion: ultrastructural analysis of an unexplored function of synoviocytes. Br J Rheumatol. 1995;34:13-23.

    Not in our library10.1093/rheumatology/34.1.13

  38. 38.

    Dougados M. Sodium hyaluronate therapy in osteoarthritis: arguments for a potential beneficial structural effect. Semin Arthritis Rheum. 2000;30:19-25.

    Not in our library10.1053/sarh.2000.0246

  39. 39.

    Dráfi F, Valachová K, Hrabárová E, Juránek I, Bauerová K, Šoltés L. Study of methotrexate and β-alanyl-L-histidine in comparison with L-glutathione on high-molar-mass hyaluronan degradation induced by ascorbate plus Cu (II) ions via rotational viscometry. 60th Pharmacological Days in Hradec Králové. Acta Medica. 2010;53(3):170.

    Not in our library

  40. 40.

    Drobnik J. Hyaluronan in drug delivery. Adv Drug Dev Rev. 1991;7:295-308.

    Not in our library

  41. 41.

    Duranti F, Salti G, Bovani B, Calandra M, Rosati ML. Injectable hyaluronic acid gel for soft tissue augmentation – a clinical and histological study. Dermatol Surg. 1998;24:1317-1325.

    Not in our library10.1111/j.1524-4725.1998.tb00007.x

  42. 42.

    Edwards JCW, Wilkinson LS, Jones HM. The formation of human synovial cavities: a possible role for hyaluronan and CD44 in altered interzone cohesion. J Anat. 1994;185:355-67.

    Not in our library

  43. 43.

    Edwards JCW. Consensus statement. Second international meeting on synovium. Cell biology, physiology and pathology. Ann Rheum Dis. 1995;54:389-91.

    Not in our library10.1136/ard.54.5.389

  44. 44.

    Eliaz RE, Szoka FC. Liposome-encapsulated doxorubicin targeted to CD44: a strategy to kill CD44-overexpressing tumor cells. Cancer Res. 2001;61:2592-2601.

    Not in our library

  45. 45.

    Figueiredo F, Jones GM, Thouas GA, Trounson AO. The effect of extracellular matrix molecules on mouse preimplantation embryo development In vitro. Reprod Fertil Dev. 2002;14:443-451.

    Not in our library10.1071/rd02007

  46. 46.

    Fisher AE, Naughton ODP. Therapeutic chelators for the twenty first century: new treatments for iron and copper mediated inflammatory and neurological disorders. Curr Drug Delivery. 2005;2:261-268.

    Not in our library10.2174/1567201054367940

  47. 47.

    Fraser JRE, Foo WK, Maritz JS. Viscous interactions of hyaluronic acid with some proteins and neutral saccharides. Ann Rheum Dis. 1972;31:513-20.

    Not in our library10.1136/ard.31.6.513

  48. 48.

    Fraser JRE, Kimpton WG, Pierscionek BK, Cahill RNP. The kinetics of hyaluronan in normal and acutely inflamed synovial joints – observations with experimental arthritis in sheep. Semin Arthritis Rheum. 1993;22:9-17.

    Not in our library10.1016/s0049-0172(10)80015-0

  49. 49.

    Furnus CC, de Matos DG, Martinez AG. Effect of hyaluronic acid on development of in vitro produced bovine embryos. Theriogenology. 1998;49:1489-99.

    Not in our library10.1016/s0093-691x(98)00095-8

  50. 50.

    Gandolfi SA, Massari A, Orsoni JG. Low-molecular-weight sodium hyaluronate in the treatment of bacterial corneal ulcers. Graefes Arch Clin Exp Ophthalmol. 1992;230:20-23.

    Not in our library10.1007/bf00166757

  51. 51.

    Gardner DK, Lane M, Stevens J, Schoolcraft WB. Changing the start temperature and cooling rate in a slow-freezing protocol increases human blastocyst viability. Fertil Steril. 2003;79:407-410.

    Not in our library10.1016/s0015-0282(02)04576-4

  52. 52.

    Gardner DK, Rodriegez-Martinez H, Lane M. Fetal development after transfer is increased by replacing protein with the glycosaminoglycan hyaluronan for mouse embryo culture and transfer. Hum Reprod. 1999;14:2575-2580.

    Not in our library10.1093/humrep/14.10.2575

  53. 53.

    Ghosh P, Guidolin D. Potential mechanism of action of intraarticular hyaluronan therapy in osteoarthritis: are the effects molecular weight dependent? Semin Arthritis Rheum. 2002;32:10-37.

    Not in our library10.1053/sarh.2002.33720

  54. 54.

    Ghosh S, Jassal M. Use of polysaccharide fibres for modem wound dressings. Indian J Fibre Textile Res. 2002;27:434-450.

    Not in our library

  55. 55.

    Gibbs DA, Merrill EW, Smith KA, Balazs EA. Rheology of hyaluronic acid. Biopolymers. 1968;6:777-91.

    Not in our library10.1002/bip.1968.360060603

  56. 56.

    Glogau RG. The risk of progression to invasive disease. J Am Acad Dermatol. 2000;42:S23-S24.

    Not in our library10.1067/mjd.2000.103339

  57. 57.

    Grootveld M, Henderson EB, Farrell A, Blake DR, Parkes HG, Haycock P. Oxidative damage to hyaluronate and glucose in synovial fluid during exercise of the inflamed rheumatoid joint. Detection of abnormal low-molecular-mass metabolites by proton-N.M.R. spectroscopy. Biochem J. 1991;273:459-467.

    Not in our library10.1042/bj2730459

  58. 58.

    Guidolin DD, Ronchetti IP, Lini E. Morphological analysis of articular cartilage biopsies from a randomized. clinical study comparing the effects of 500–730 kDa sodium hyaluronate Hyalgan(R) and methylprednisolone acetate on primary osteoarthritis of the knee. Osteoarthritis Cartilage. 2001;9:371-381.

    Not in our library10.1053/joca.2000.0398

  59. 59.

    Gurny R, Ibrahim H, Aebi A. Design and evaluation of controlled release systems for the eye. J Control Release. 1987;6:367-373.

    Not in our library

  60. 60.

    Haddad JJ, Harb HL. L-gamma-Glutamyl-L-cysteinyl-glycine (glutathione; GSH) and GSH-related enzymes in the regulation of pro- and anti-inflammatory cytokines: a signaling transcriptional scenario for redox(y) immunologic sensor(s). Mol Immunol. 2005;42:987-1014.

    Not in our library10.1016/j.molimm.2004.09.029

  61. 61.

    Hamburger MI, Lakhanpal S, Mooar PA, Oster D. Intra-articular hyaluronans: a review of product-specific safety profiles. Semin Arthritis Rheum. 2003;32:296-309.

    Not in our library10.1053/sarh.2002.50008

  62. 62.

    Haubeck HD, Kock R, Fischer DC, van de Leur E, Hoffmeister K, Greiling H. Transforming growth factor ß1, a major stimulator of hyaluronan synthesis in human synovial lining cells. Arthritis Rheum. 1995;38:669-677.

    Not in our library10.1002/art.1780380515

  63. 63.

    Herrero-Vanrell R, Fernandez-Carballido A, Frutos G, Cadorniga R. Enhancement of the mydriatic response to tropicamide by bioadhesive polymers. J Ocul Pharmacol Ther. 2000;16:419-428.

    Not in our library10.1089/jop.2000.16.419

  64. 64.

    Hills BA, Crawford RW. Normal and prosthetic synovial joints are lubricated by surface-active phospholipid: a hypothesis. J Arthroplasty. 2003;18:499-505.

    Not in our library10.1016/s0883-5403(03)00072-x

  65. 65.

    Hlavacek M. The role of synovial fluid filtration by cartilage in lubrication of synovial joints. J Biomech. 1993;26(10):1145-50.

    Not in our library10.1016/0021-9290(93)90062-j

  66. 66.

    Hochberg MC. Role of intra-articular hyaluronic acid preparations in medical management of osteoarthritis of the knee. Semin Arthritis Rheum. 2000;30:2-10.

    Not in our library10.1053/sarh.2000.0245

  67. 67.

    Hrabarova E, Valachova K, Rapta P, Soltes L. An alternative standard for trolox-equivalent antioxidant-capacity estimation based on thiol antioxidants. Comparative 2,2’-azinobis[3-ethylbenzothiazoline-6-sulfonic acid] decolorization and rotational viscometry study regarding hyaluronan degradation. Chemistry & Biodiversity. 2010;7(9):2191-2200.

    Not in our library10.1002/cbdv.201000019

  68. 68.

    Hrabarova E, Valachova K, Rychly J, Rapta P, Sasinkova V, Malikova M, Soltes L. High-molar-mass hyaluronan degradation by Weissberger's system: Pro- and anti-oxidative effects of some thiol compounds. Polymer Degradation and Stability. 2009;94:1867-1875.

    Not in our library

  69. 69.

    Hrabarova E, Valachova K, Juranek I, Soltes L. Free-radical degradation of high-molar-mass hyaluronan induced by ascorbate plus cupric ions: evaluation of antioxidative effect of cysteine-derived compounds. Chemistry & Biodiversity. 2012;9:309-317.

    Not in our library10.1002/cbdv.201100046

  70. 70.

    Hrabarova E, Gemeiner P, Soltes L. Peroxynitrite: In vivo and in vitro synthesis and oxidant degradative action on biological systems regarding biomolecular injury and inflammatory processes. Chem Pap. 2007;61:417-437.

    Not in our library

  71. 71.

    Hrabárová E, Valachová K, Juránek I, Šoltés L, Zaikov G. E. Free-radical degradation of high-molar-mass hyaluronan induced by ascorbate plus cupric ions. Anti-oxidative properties of the Pieštany-spa curative waters from healing peloid and maturation pool. Kinetics, Catalysis and Mechanism of Chemical Reactions. 2011;29-36.

    Not in our library

  72. 72.

    Hrabárová E, Valachová K, Rychlý J, Rapta P, Sasinková V, Gemeiner P, Šoltés L. High-molar-mass hyaluronan degradation by the Weissberger′s system: pro- and antioxidative effects of some thiol compounds. Polym Degrad Stab. 2009;94:1867-1875.

    Not in our library

  73. 73.

    Hultberg M, Hultberg B. The effect of different antioxidants on glutathione turnover in human cell lines and their interaction with hydrogen peroxide. Chem Biol Interact. 2006;163(3):192-198.

    Not in our library10.1016/j.cbi.2006.08.001

  74. 74.

    Hutadilok N, Ghosh P, Brooks PM. Binding of haptoglobin. inter-α-trypsin inhibitor, and l proteinase inhibitor to synovial fluid hyaluronate and the influence of these proteins on its degradation byoxygen derived free radicals. Ann Rheum Dis. 1988;47:377-85.

    Not in our library10.1136/ard.47.5.377

  75. 75.

    Inoue M, Katakami C. The effect of hyaluronic-acid on corneal epithelial-cell proliferation. Invest Ophthalmol Vis Sci. 1993;34:2313-2315.

    Not in our library

  76. 76.

    Itano N, Kimata K. Mammalian hyaluronan synthases. IUBMB Life. 2002;54:195-199.

    Not in our library10.1080/15216540214929

  77. 77.

    Jaakma U, Zhang BR, Larsson B. Effects of sperm treatments on the in vitro development of bovine oocytes in semidefined and defined media. Theriogenology. 1997;48:711-720.

    Not in our library10.1016/s0093-691x(97)00295-1

  78. 78.

    Jang G, Lee BC, Kang SK, Hwang WS. Effect of glycosaminoglycans on the preimplantation development of embryos derived from in vitro fertilization and somatic cell nuclear transfer. Reprod Fertil Dev. 2003;15:179-185.

    Not in our library10.1071/rd02054

  79. 79.

    Jarvinen K, Jarvinen T, Urtti A. Ocular absorption following topical delivery. Adv Drug Dev Rev. 1995;16:3-19.

    Not in our library

  80. 80.

    Jay GD, Britt DE, Cha DJ. Lubricin is a product of megakaryocyte stimulating factor gene expression by human synovial fibroblasts. J Rheumatol. 2000;27:594-600.

    Not in our library

  81. 81.

    Joly T, Nibart M, Thibier M. Hyaluronic-acid as a substitute for proteins in the deep-freezing of embryos from mice and sheep – an In vitro investigation. Theriogenology. 1992;37:473-480.

    Not in our library

  82. 82.

    Juranek I, Soltes L, Islamova R.M, Kolesov S.V, Zaikov G.E. Reactive oxygen species in joint physiology: Possible mechanism of maintaining hypoxia to protect chondrocytes from oxygen excess via synovial fluid hyaluronan peroxidation. Kinetics, Catalysis and Mechanism of Chemical Reactions: From Pure to Applied Science. Volume 2 – Tomorrow and Perspectives. 2012;1-10.

    Not in our library

  83. 83.

    Kano K, Miyano T, Kato S. Effects of glycosaminoglycans on the development of in vitro matured and fertilized porcine oocytes to the blastocyst stage In vitro. Biol Reprod. 1998;58:1226-1232.

    Not in our library10.1095/biolreprod58.5.1226

  84. 84.

    Kelly MA, Goldberg VM, Healy WL. Osteoarthritis and beyond: a consensus on the past, present, and future of hyaluronans in orthopedics. Orthopedics. 2003;26:1064-1079.

    Not in our library10.3928/0147-7447-20031001-19

  85. 85.

    Kemmann E. Creutzfeldt-Jakob disease (CJD) and assisted reproductive technology (ART) – quantification of risks as part of informed consent. Hum Reprod. 1998;13:1777.

    Not in our library10.1093/humrep/13.7.1777

  86. 86.

    Kessler A, Biasibetti M, da Silva Melo DA, Wajner M, Dutra-Filho CS, de Souza Wyse AT, Wannmacher CMD. Antioxidant effect of cysteamine in brain cortex of young rats. Neurochem Res. 2008;33:737-44.

    Not in our library10.1007/s11064-007-9486-7

  87. 87.

    Kim A, Checkla DM, Dehazya P, Chen WL. Characterization of DNA-hyaluronan matrix for sustained gene transfer. J Control Release. 2003;90:81-95.

    Not in our library10.1016/s0168-3659(03)00175-5

  88. 88.

    Kirwan J. Is there a place for intra-articular hyaluronate in osteoarthritis of the knee? Knee. 2001;8:93-101.

    Not in our library10.1016/s0968-0160(01)00075-8

  89. 89.

    Knight AD, Levick JR. Morphometry of the ultrastructure of the blood-joint barrier in the rabbit knee. Q J Exp Physiol. 1984;69:271-288.

    Not in our library10.1113/expphysiol.1984.sp002805

  90. 90.

    Kogan G. Hyaluronan – A High Molar mass messenger reporting on the status of synovial joints: part 1. Physiological status. New Steps in Chemical and Biochemical Physics. 2010;121-133.

    Not in our library

  91. 91.

    Kogan G, Soltes L, Stern R, Mendichi R, Pethrick R. A, Ballada, Zaikov G. E. Hyaluronic acid: A biopolymer with versatile physico-chemical and biological properties. Chapter 31. Handbook of Polymer Research: Monomers, Oligomers, Polymers and Composites. 2007a;393-439.

    Not in our library

  92. 92.

    Kogan G, Soltes L, Stern R, Gemeiner P. Hyaluronic acid: A natural biopolymer with a broad range of biomedical and industrial applications. Biotechnol Lett. 2007;29:17-25.

    Not in our library10.1007/s10529-006-9219-z

  93. 93.

    Kreil G. Hyaluronidases-A group of neglected enzymes. Protein Sciences. 1995;4:1666-1669.

    Not in our library10.1002/pro.5560040902

  94. 94.

    Lane M, Maybach JM, Hooper K. Cryo-survival and development of bovine blastocysts are enhanced by culture with recombinant albumin and hyaluronan. Mol Reprod Dev. 2003;64:70-78.

    Not in our library10.1002/mrd.10210

  95. 95.

    Langer K, Mutschler E, Lambrecht G. Methylmethacrylate sulfopropylmethacrylate copolymer nanoparticles for drug delivery – Part III. Evaluation as drug delivery system for ophthalmic applications. Int J Pharm. 1997;158:219-231.

    Not in our library

  96. 96.

    Lath D, Csomorova K, Kollarikova G, Stankovska M, Soltes L. Molar mass-intrinsic viscosity relationship of high-molar-mass yaluronans: Involvement of shear rate. Chem Pap. 2005;59:291-293.

    Not in our library

  97. 97.

    Laurent TC, Laurent UBG, Fraser JRE. The structure and function of hyaluronan: An over view. Immunology and Cell Biology. 1996;74:A1-A7.

    Not in our library10.1038/icb.1996.32

  98. 98.

    Laurent TC. The biology of hyaluronan. Ciba Foundation Symposium. 1989;1-298.

    Not in our library

  99. 99.

    Laurent TC, Fraser JRE. Hyaluronan. FASEB J. 1992;6:2397-2404.

    Not in our library

  100. 100.

    Laurent TC, Laurent UBG, Fraser JRE. Functions of hyaluronan. Ann Rheum Dis. 1995;54:429-32.

    Not in our library10.1136/ard.54.5.429

  101. 101.

    Laurent TC, Ryan M, Pictruszkiewicz A. Fractionation of hyaluronic acid. The polydispersity of hyaluronic acid from the vitreous body. Biochim Biophys Acta. 1960;42:476-85.

    Not in our library10.1016/0006-3002(60)90826-x

  102. 102.

    Levick JR. An analysis of the interaction between interstitial plasma protein, interstitial flow, and fenestral filtration and its application to synovium. Microvasc Res. 1994;47:90-125.

    Not in our library10.1006/mvre.1994.1007

  103. 103.

    Leyden J, Narins RS, Brandt F. A randomized, double-blind, multicenter comparison of the efficacy and tolerability of Restylane versus Zyplast for the correction of nasolabial folds. Dermatol Surg. 2003;29:588-595.

    Not in our library10.1046/j.1524-4725.2003.29150.x

  104. 104.

    Lim ST, Forbes B, Berry DJ, Martin GP, Brown MB. In vivo evaluation of novel hyaluronan/chitosan microparticulate delivery systems for the nasal delivery of gentamicin in rabbits. Int J Pharm. 2002;231:73-82.

    Not in our library10.1016/s0378-5173(01)00873-0

  105. 105.

    Luo Y, Prestwich GD. Synthesis and selective cytotoxicity of a hyaluronic acid-antitumor bioconjugate. Bioconjug Chem. 1999;10:755-763.

    Not in our library10.1021/bc9900338

  106. 106.

    Luo Y, Ziebell MR, Prestwich GD. A hyaluronic acid-taxol antitumor bioconjugate targeted to cancer cells. Biomacromolecules. 2000;1:208-218.

    Not in our library10.1021/bm000283n

  107. 107.

    Maheu E, Ayral X, Dougados M. A hyaluronan preparation (500– 730 kDa) in the treatment of osteoarthritis: a review of clinical trials with Hyalgan(R). Int J Clin Pract. 2002;56:804-813.

    Not in our library

  108. 108.

    Manuskiatti W, Maibach HI. Hyaluronic acid and skin: wound healing and aging. Int J Dermatol. 1996;35:539-544.

    Not in our library10.1111/j.1365-4362.1996.tb03650.x

  109. 109.

    Mazzucco D, Scott R, Spector M. Composition of joint fluid in patients undergoing total knee replacement and revision arthroplasty: correlation with flow properties. Biomaterials. 2004;25:4433-4445.

    Not in our library10.1016/j.biomaterials.2003.11.023

  110. 110.

    McCord JM. Free radicals and inflammation: protection of synovial fluid by superoxide dismutase. Science. 1974;185:529-531.

    Not in our library10.1126/science.185.4150.529

  111. 111.

    McDonald JN, Levick JR. Morphology of surface synoviocytes in situ at normal and raised joint pressure, studied by scanning electron microscopy. Ann Rheum Dis. 1988;47:232-240.

    Not in our library10.1136/ard.47.3.232

  112. 112.

    McDonald JN, Leviek JR. Effect of intra-articular hyaluronan on pressure-flow relation across synovium in anaesthetized rabbits. J Physiol. 1995;485(Pt.1):179-93.

    Not in our library10.1113/jphysiol.1995.sp020722

  113. 113.

    Mendichi R, Soltes L. Hyaluronan molecular weight and polydispersity in some commercial intra-articular injectable preparations and in synovial fluid. Inflamm Res. 2002;51:115-116.

    Not in our library10.1007/pl00012388

  114. 114.

    Meyer K, Palmer JW. The polysaccharide of the vitreous humor. Journal of Biology and Chemistry. 1934;107:629-634.

    Not in our library

  115. 115.

    Miltner O, Schneider U, Siebert CH. Efficacy of intraarticular hyaluronic acid in patients with osteoarthritis–a prospective clinical trial. Osteoarthritis Cartilage. 2002;10:680-686.

    Not in our library10.1053/joca.2002.0815

  116. 116.

    Miyano T, Hirooka RE, Kano K. Effects of hyaluronic-acid on the development of 1-cell and 2-cell porcine embryos to the blastocyst stage in-vitro. Theriogenology. 1994;41:1299-1305.

    Not in our library10.1016/0093-691x(94)90488-5

  117. 117.

    Miyazaki M, Sato S, Yamaguchi T. Analgesic and antiinflammatory action of hyaluronic sodium. 1983.

    Not in our library

  118. 118.

    Miyazaki T, Miyauchi S, Nakamura T. The effect of sodium hyaluronate on the growth of rabbit cornea epithelial cells In vitro. J Ocul Pharmacol Ther. 1996;12:409-415.

    Not in our library10.1089/jop.1996.12.409

  119. 119.

    Momberger TS, Levick JR, Mason RM. Hyaluronan secretion by synoviocytes is mechanosensitive. Matrix Biol. 2005;24:510-519.

    Not in our library10.1016/j.matbio.2005.08.006

  120. 120.

    Moreira CA, Armstrong DK, Jelliffe RW. Sodium hyaluronate as a carrier for intravitreal gentamicin – an experimental study. Acta Ophthalmol (Copenh). 1991;69:45-49.

    Not in our library10.1111/j.1755-3768.1991.tb01989.x

  121. 121.

    Moreira CA, Moreira AT, Armstrong DK. In vitro and in vivo studies with sodium hyaluronate as a carrier for intraocular gentamicin. Acta Ophthalmol (Copenh). 1991;69:50-56.

    Not in our library10.1111/j.1755-3768.1991.tb01990.x

  122. 122.

    Morimoto K, Metsugi K, Katsumata H. Effects of lowviscosity sodium hyaluronate preparation on the pulmonary absorption of rh-insulin in rats. Drug Dev Ind Pharm. 2001;27:365-371.

    Not in our library10.1081/ddc-100103737

  123. 123.

    Morimoto K, Yamaguchi H, Iwakura Y. Effects of viscous hyaluronate-sodium solutions on the nasal absorption of vasopressin and an analog. Pharmacol Res. 1991;8:471-474.

    Not in our library10.1023/a:1015894910416

  124. 124.

    Morris ER, Rees DA, Welsh EJ. Conformation and dynamic interactions in hyaluronate solutions. J Mol Biol. 1980;138:383-400.

    Not in our library10.1016/0022-2836(80)90294-6

  125. 125.

    Myint P. The reactivity of various free radicals with hyaluronic acid steady-state and pulse radiolysis studies. Biochim Biophys-Aeta. 1987;925:194-202.

    Not in our library10.1016/0304-4165(87)90109-7

  126. 126.

    Necas J, Bartosikova L, Brauner P, Kolar J. Hyaluronic acid (hyaluronan): a review. Veterinarni Medicina. 2008;53(8):397-411.

    Not in our library

  127. 127.

    Niwa Y, Sakane T, Shingu M, Yokoyama MM. Effect of stimulated neutrophils from the synovial fluid of patients with rheumatoid arthritis on lymphocytes: a possible role of increased oxygen radicals generated by the neutrophils. J Clin Immunol. 1983;3:228-240.

    Not in our library10.1007/bf00915347

  128. 128.

    Noble PW. Hyaluronan and its catabolic products in tissue injury and repair. Matrix Biol. 2002;21:25-29.

    Not in our library10.1016/s0945-053x(01)00184-6

  129. 129.

    Oates KMN, Krause WE, Colby RH. Using rheology to probe the mechanism of joint lubrication: polyelectrolyte/protein interactions in synovial fluid. Mat Res Soc Syrnp Proc. 2002;711:53-58.

    Not in our library

  130. 130.

    Ogston AG, Stanier JE. The physiological function of hyaluronic acid in synovial fluid viscous, elastic and lubricant properties. J Physiol. 1953;199:244-52.

    Not in our library10.1113/jphysiol.1953.sp004842

  131. 131.

    Ortonne JP. A controlled study of the activity of hyaluronic acid in the treatment of venous leg ulcers. J Dermatol Treatment. 1996;7:75-81.

    Not in our library

  132. 132.

    Orvisky E, Soltes L, Chabrecek P, Novak I, Kery V, Stancikova M, Vins I. The determination of hyaluronan molecular weight distribution by means of high perfeormance size exclusion chromatography. J Liq Chromatogr. 1992;15:3203-3218.

    Not in our library

  133. 133.

    Parsons BJ, Al-Assaf S, Navaratnam S, Phillips GO, Kennedy JF, Phillips GO, Williams, Hascall VC. Comparison of the reactivity of different oxidative species (ROS) towards hyaluronan. Hyaluronan: Chemical, Biochemical and Biological Aspects. 2002;141-150.

    Not in our library

  134. 134.

    Peer D, Florentin A, Margalit R. Hyaluronan is a key component in cryoprotection and formulation of targeted unilamellar liposomes. Biochim Biophys Acta-Biomembranes. 2003;1612:76-82.

    Not in our library10.1016/s0005-2736(03)00106-8

  135. 135.

    Peer D, Margalit R. Physicochemical evaluation of a stability-driven approach to drug entrapment in regular and in surface-modified liposomes. Arch Biochem Biophys. 2000;383:185-190.

    Not in our library10.1006/abbi.2000.2046

  136. 136.

    Poli A, Mason RM, Levick JR. Effects of Arg- Gly-Asp sequence peptide and hyperosmolarity on the permeability of interstitial matrix and fenestrated endothelium in joints. Microcirculation. 2004;11:463-476.

    Not in our library10.1080/10739680490476024

  137. 137.

    Praest BM, Greiling H, Kock R. Effects of oxygen-derived free radicals on the molecular weight and the polydispersity of hyaluronan solutions. Carbohydr Res. 1997;303:153-157.

    Not in our library

  138. 138.

    Price FM, Levick JR, Mason RM. Glycosaminoglycan concentration in synovium and other tissues of rabbit knee in relation to synovial hydraulic resistance. J Physiol (Lond). 1996;495:803-820.

    Not in our library10.1113/jphysiol.1996.sp021634

  139. 139.

    Prisell PT, Camber O, Hiselius J, Norstedt G. Evaluation of hyaluronan as a vehicle for peptide growth factors. Int J Pharm. 1992;85:51-56.

    Not in our library

  140. 140.

    Radin EL, Swann DA, Weisser PA. Separation of a hyaluronate-frec lubricating fraction from synovial fluid. Nature. 1970;228:377-8.

    Not in our library10.1038/228377a0

  141. 141.

    Rapta P, Valachova K, Gemeiner P, Soltes L. High-molar-mass hyaluronan behavior during testing its radical scavenging capacity in organic and aqueous media: Effects of the presence of Manganese (II) ions. Chem Biodivers. 2009;6:162-169.

    Not in our library10.1002/cbdv.200800075

  142. 142.

    Rapta P, Valachová K, Gemeiner P, Šoltés L. High-molar-mass hyaluronan behavior during testing its antioxidant properties in organic and aqueous media: effects of the presence of Mn(II) ions. Chem Biodivers. 2009;6:162-169.

    Not in our library10.1002/cbdv.200800075

  143. 143.

    Rapta P, Valachová K, Zalibera M, Šnirc V, Šoltés L, Pethrick R. A, Petkov P, Zlatarov A, Zaikov G. E, Rakovsky S. K. Hyaluronan degradation by reactive oxygen species: scavenging eggect of the hexapyridoindole stobadine and two of its derivatives. Monomers, Oligomers, Polymers, Composites, and Nanocomposites. 2010;113-126.

    Not in our library

  144. 144.

    Rees MD, Kennett EC, Whitelock JM, Davies MJ. Oxidative damage to extracellular matrix and its role in human pathologies. Free Radical Biol. Med. 2008;44:1973-2001.

    Not in our library10.1016/j.freeradbiomed.2008.03.016

  145. 145.

    Revell PA. Synovial lining cells. Rheumatol Int. 1989;9:49-51.

    Not in our library10.1007/bf00270244

  146. 146.

    Risberg B. Adhesions: preventive strategies. Eur J Surg. 1997;163:32-39.

    Not in our library

  147. 147.

    Rittig M, Tittor F, Lutjen-Drecoll E, Mollenhauer J, Rauterberg J. Immunohistochemical study of extracellular material in the aged human synovial membrane. Mech Ageing Dev. 1992;64:219-234.

    Not in our library10.1016/0047-6374(92)90080-w

  148. 148.

    Rychly J, Soltes L, Stankovska M, Janigova I, Csomorova K, Sasinkova V, Kogan G, Gemeiner P. Unexplored capabilities of chemiluminescence and thermoanalytical methods in characterization of intact and degraded hyaluronans. Polym Degrad Stab. 2006;91(12):3174-3184.

    Not in our library

  149. 149.

    Saettone MF, Giannaccini B, Chetoni P, et al. Evaluation of highmolecular-weight and low-molecular-weight fractions of sodium hyaluronate and an ionic complex as adjuvants for topical ophthalmic vehicles containing pilocarpine. Int J Pharm. 1991;72:131-139.

    Not in our library

  150. 150.

    Saettone MF, Monti D, Torracca MT, Chetoni P. Mucoadhesive ophthalmic vehicles – evaluation polymeric low-viscosity formulations. J Ocul Pharmacol. 1994;10:83-92.

    Not in our library10.1089/jop.1994.10.83

  151. 151.

    Sakurai K, Miyazaki K, Kodera Y. Anti-inflammatory activity of superoxide dismutase conjugated with sodium hyaluronate. Glycoconj J. 1997;14:723-728.

    Not in our library10.1023/a:1018521501289

  152. 152.

    Sasaki H, Yamamura K, Nishida K. Delivery of drugs to the eye by topical application. Prog Retinal Eye Res. 1996;15:583-620.

    Not in our library

  153. 153.

    Sattar A, Kumar S, West DC. Does hyaluronan have a role in endothelial cell proliferation ofthe synovium. Semin. Arthritis Rheum. 1992;22:37-43.

    Not in our library10.1016/0049-0172(92)90047-h

  154. 154.

    Schartz RA. The actinic keratoses. A perspective and update. Dermatol Surg. 1997;23:1009-1019.

    Not in our library10.1111/j.1524-4725.1997.tb00438.x

  155. 155.

    Schiller J, Volpi N, Hrabarova E, Soltes L, Kalia S, Averous L. Hyaluronic acid: a natural biopolymer. Handbook of Biopolymers and Their Applications. 2011;3-34.

    Not in our library

  156. 156.

    Schmid T, Lindley K, Su J, Soloveychik V, Block J, Kuettner K, Schumacher B. Superficial zone protein (SZP) is an abundant glycoprotein in human synovial fluid and serum. Trans Orthop Res Soc. 2001a;26:82.

    Not in our library

  157. 157.

    Schmid T, Soloveychik V, Kuettner K, Schumacher B. Superficial zone protein (SZP) from human cartilage has lubrication activity. Trans Orthop Res Soc. 2001b;26:178.

    Not in our library

  158. 158.

    Schumacher BL, Block JA, Schmid TM, Aydelotte MB, Kuettner KE. A novel proteoglycan synthesized and secreted by chondrocytes of the superficial zone of articular cartilage. Arch Biochem Biophys. 1994;311:144-152.

    Not in our library10.1006/abbi.1994.1219

  159. 159.

    Schumacher BL, Hughes CE, Kuettner KE, Caterson B, Aydelotte MB. Immunodetection and partial c DNA sequence of the proteoglycan, superficial zone protein, synthesized by cells lining synovial joints. J Orthop Res. 1999;17:110-120.

    Not in our library10.1002/jor.1100170117

  160. 160.

    Schumacher BL, Schmidt TA, Voegtline MS, Chen AC, Sah RL. Proteoglycan 4 (PRG4) synthesis and immunolocalization in bovine meniscus. J Orthop Res. 2005;23:562-568.

    Not in our library10.1016/j.orthres.2004.11.011

  161. 161.

    Schwarz IM, Hills BA. Synovial surfactant: lamellar bodies in type B synoviocytes and proteolipid in synovial fluid and the articular lining. Br J Rheumatol. 1996;35:821-827.

    Not in our library10.1093/rheumatology/35.9.821

  162. 162.

    Schwarz IM, Hills BA. Surface-active phospholipids as the lubricating component of lubricin. Br J Rheumatol. 1998;37:21-26.

    Not in our library10.1093/rheumatology/37.1.21

  163. 163.

    Scott DL, Shipley M, Dawson A, Edwards S, Symmons DP, Woolf AD. The clinical management of rheumatoid arthritis and osteoarthritis: strategies for improving clinical effectiveness. Br J Rheumatol. 1998;37:546-554.

    Not in our library10.1093/rheumatology/37.5.546

  164. 164.

    Scott JE, Cummings C, Brass A, Chen Y. Secondary and tertiary structures of hyaluronan in aqueous solution, investigated by rotary shadowing-electron microscopy and computer simulation. Biochem J. 1991;274:600-705.

    Not in our library10.1042/bj2740699

  165. 165.

    Servaty R, Schiller J, Binder H, Arnold K. Hydration of polymeric components of the cartilage – An infrared spectroscopic study on hyaluronic acid and chondroitin sulfate. Int J Biol Macromol. 2000;28:123-129.

    Not in our library10.1016/s0141-8130(00)00161-6

  166. 166.

    Simkovic I, Hricovini M, Soltes L, Mendichi R, Cosentino C. Preparation of water soluble/insoluble derivatives of Hyaluronic acid by cross linking with epichlorohydrin in aqueous NaOH/NH4OH solution. Carbohydr Polym. 2000;41:9-14.

    Not in our library

  167. 167.

    Simon A, Safran A, Revel A. Hyaluronic acid can successfully replace albumin as the sole macromolecule in a human embryo transfer medium. Fertil Steril. 2003;79:1434-1438.

    Not in our library10.1016/s0015-0282(03)00349-2

  168. 168.

    Soldati D, Rahm F, Pasche P. Mucosal wound healing after nasal surgery. A controlled clinical trial on the efficacy of hyaluronic acid containing cream. Drugs Exp Clin Res. 1999;25:253-261.

    Not in our library

  169. 169.

    Soloveva ME, Solovev VV, Faskhutdinova AA, Kudryavtsev AA, Akatov VS. Prooxidant and cytotoxic action of N-acetylcysteine and glutathione in combinations with vitamin B12b. Cell Tissue Biol. 2007;1:40-49.

    Not in our library

  170. 170.

    Soltes L, Kogan G, Pearce E. M, Zaikov G. E, Kirshenbaum G. Impact of transition metals in the free-radical degradation of hyaluronan biopolymer. Kinetics & Thermodynamics for Chemistry & Biochemistry: Vol. 2. 2009;181-199.

    Not in our library

  171. 171.

    Soltes L, Mendichi R, Kogan G, Mach M. Associating Hyaluronan Derivatives: A Novel Horizon in Viscosupplementation of Osteoarthritic Joints. Chem Biodivers. 2004;1:468-472.

    Not in our library10.1002/cbdv.200490040

  172. 172.

    Soltes L, Brezova V, Stankovska M, Kogan G, Gemeiner P. Degradation of high-molecular-weight hyaluronan by hydrogen peroxide in the presence of cupric ions. Carbohydr Res. 2006a;341:639-644.

    Not in our library10.1016/j.carres.2006.01.014

  173. 173.

    Soltes L, Mendichi R, Kogan G, Schiller J, Stankovska M, Arnhold J. Degradative action of reactive oxygen species on hyaluronan. Biomacromolecules. 2006b;7:659-668.

    Not in our library10.1021/bm050867v

  174. 174.

    Soltes L, Stankovska M, Brezova V, Schiller J, Arnhold J, Kogan G, Gemeiner P. Hyaluronan degradation by copper (II) chloride and ascorbate: rotational viscometric, EPR spin-trapping, and MALDI-TOF mass spectrometric investigations. Carbohydr Res. 2006c;341:2826-2834.

    Not in our library10.1016/j.carres.2006.09.019

  175. 175.

    Soltes L, Stankovska M, Kogan G, Germeiner P, Stern R. Contribution of oxidative reductive reations to high molecular weight hyaluronan catabolism. Chem Biodivers. 2005;2:1242-1245.

    Not in our library10.1002/cbdv.200590094

  176. 176.

    Soltes L, Valachova K, Mendichi R, Kogan G, Arnhold J, Gemeiner P. Solution properties of high-molar-mass hyaluronans: the biopolymer degradation by ascorbate. Carbohydr Res. 2007;342:1071-1077.

    Not in our library10.1016/j.carres.2007.02.018

  177. 177.

    Soltes L, Pearce E. M, Kirshenbaum G, Zaikov G. E. Hyaluronan – A High-Molar-Mass Messenger Reporting on the Status of Synovial Joints: Part II. Pathophysiological Status. New Steps in Chemical and Biochemical Physics. Pure and Applied Science. 2010;137-152.

    Not in our library

  178. 178.

    Stankovska M, Arnhold J, Rychly J, Spalteholz H, Gemeiner P, Soltes L. In vitro screening of the action of non-steroidal anti-inflammatory drugs on hypochlorous acid-induced hyaluronan degradation. Polym Degrad Stabil. 2007;92:644-652.

    Not in our library

  179. 179.

    Stankovska M, Soltes L, Vikartovska A, Mendichi R, Lath D, Molnarova M, Gemeiner P. Study of hyaluronan degradation by means of rotational Viscometry: Contribution of the material of viscometer. Chem Pap. 2004;58:348-352.

    Not in our library

  180. 180.

    Stankovska M, Hrabarova E, Valachova K, Molnarova M, Gemeiner P, Soltes L. The degradative action of peroxynitrite on high-molecular-weight hyaluronan. Neuroendocrinol Lett. 2006;27(Suppl. 2):31-34.

    Not in our library

  181. 181.

    Stankovska M, Soltes L, Vikartovska A, Gemeiner P, Kogan G, Bakos D. Degradation of high-molecular-weight hyaluronan: a rotational viscometry study. Biologia. 2005;60(Suppl. 17):149-152.

    Not in our library

  182. 182.

    Stern R, Kogan G, Jedrzejas M. J, Soltes L. The many ways to cleave hyaluronan. Biotechnol Adv. 2007;25:537-557.

    Not in our library10.1016/j.biotechadv.2007.07.001

  183. 183.

    Stiebel-Kalish H, Gaton DD, Weinberger D. A comparison of the effect of hyaluronic acid versus gentamicin on corneal epithelial healing. Eye. 1998;12:829-833.

    Not in our library10.1038/eye.1998.213

  184. 184.

    Suchanek E, Simunic V, Juretic D, Grizelj V. Follicular-fluid contents of hyaluronic-acid, follicle-stimulating-hormone and steroids relative to the success of in-vitro fertilization of human oocytes. Fertil Steril. 1994;62:347-352.

    Not in our library10.1016/s0015-0282(16)56890-3

  185. 185.

    Surendrakumar K, Martyn GP, Hodgers ECM. Sustained release of insulin from sodium hyaluronate based dry powder formulations after pulmonary delivery to beagle dogs. J Control Release. 2003;91:385-394.

    Not in our library10.1016/s0168-3659(03)00263-3

  186. 186.

    Surini S, Akiyama H, Morishita M. Polyion complex of chitosan and sodium hyaluronate as an implant device for insulin delivery. STP Pharm Sci. 2003;13:265-268.

    Not in our library10.1016/s0168-3659(03)00196-2

  187. 187.

    Surovcikova L, Valachova K, Banasova M, Snirc V, Priesolova E, Nagy M, Juranek I, Soltes L. Free-radical degradation of high-molar-mass hyaluronan induced by ascorbate plus cupric ions: Testing of stobadine and its two derivatives in function as antioxidants. General Physiol Biophys. 2012;31:57-64.

    Not in our library10.4149/gpb_2012_006

  188. 188.

    Swann DA, Silver FH, Slayter HS, Stafford W, Shore E. The molecular structure and lubricating activity of lubricin isolated from bovine and human synovial fluids. Biochem J. 1985;225:195-201.

    Not in our library10.1042/bj2250195

  189. 189.

    Takayama K, Hirata M, Machida Y. Effect of interpolymer complex-formation on bioadhesive property and drug release phenomenon of compressed tablet consisting of chitosan and sodium hyaluronate. Chem Pharmaceut Bull. 1990;38:1993-1997.

    Not in our library10.1248/cpb.38.1993

  190. 190.

    Tani E, Katakami C, Negi A. Effects of various eye drops on corneal wound healing after superficial keratectomy in rabbits. Jpn J Ophthalmol. 2002;46:488-495.

    Not in our library10.1016/s0021-5155(02)00541-5

  191. 191.

    Tascioglu F, Oner C. Efficacy of intra-articular sodium hyaluronate in the treatment of knee osteoarthritis. Clin Rheumatol. 2003;22:112-117.

    Not in our library10.1007/s10067-002-0690-1

  192. 192.

    Thibodeau PA, Kocsis-Bedard S, Courteau J, Niyonsenga T, Paquette B. Thiols can either enhance or suppress DNA damage induction by catecholestrogens. Free Radic Biol Med. 2001;30:62-73.

    Not in our library10.1016/s0891-5849(00)00446-9

  193. 193.

    Turino GM, Cantor JO. Hyaluronan in respiratory injury and repair. Am J Respir Crit Care Med. 2003;167:1169-1175.

    Not in our library10.1164/rccm.200205-449pp

  194. 194.

    Uthman I, Raynauld JP, Haraoui B. Intra-articular therapy in osteoarthritis. Postgrad Med J. 2003;79:449-453.

    Not in our library10.1136/pmj.79.934.449

  195. 195.

    Valachova K, Vargova A, Rapta P, Hrabarova E, Drafi F, Bauerova K, Juranek I, Soltes L. Aurothiomalate as preventive and chain-breaking antioxidant in radical degradation of high-molar-mass hyaluronan. Chemistry & Biodiversity. 2011;8:1274-1283.

    Not in our library10.1002/cbdv.201000351

  196. 196.

    Valachova K, Banasova M, Machova L, Juranek I, Bezek S, Soltes L. Antioxidant activity of various hexahydropyridoindoles. Journal of Information Intelligence and Knowledge. 2013b;5:15-32.

    Not in our library

  197. 197.

    Valachova K, Hrabarova E, Priesolova E, Nagy M, Banasova M, Juranek I, Soltes L. Free-radical degradation of high-molecular-weight hyaluronan induced by ascorbate plus cupric ions. Testing of bucillamine and its SA981-metabolite as antioxidants. J Pharma & Biomedical Analysis. 2011;56:664-670.

    Not in our library10.1016/j.jpba.2011.06.015

  198. 198.

    Valachová K, Hrabárová E, Dráfi F, Juránek I, Bauerová K, Priesolová E, Nagy M, Šoltés L. Ascorbate and Cu(II) induced oxidative degradation of high-molar-mass hyaluronan. Pro- and antioxidative effects of some thiols. Neuroendocrinol Lett. 2010a;31(2):101-104.

    Not in our library

  199. 199.

    Valachová K, Hrabárová E, Gemeiner P, Šoltés L. Study of pro- and anti-oxidative properties of d-penicillamine in a system comprising high-molar-mass hyaluronan, ascorbate, and cupric ions. Neuroendocrinol Lett. 2008;29:697-701.

    Not in our library

  200. 200.

    Valachová K, Hrabárová E, Juránek I, Šoltés L. Radical degradation of high-molar-mass hyaluronan induced by Weissberger oxidative system. Testing of thiol compounds in the function of antioxidants. 16th Interdisciplinary Slovak-Czech Toxicological Conference in Prague. Interdiscip Toxicol. 2011b;4(2):65.

    Not in our library

  201. 201.

    Valachová K, Kogan G, Gemeiner P, Šoltés L. Hyaluronan degradation by ascorbate: Protective effects of manganese (II). Cellulose Chem. Technol. 2008b;42(9–10):473-483.

    Not in our library

  202. 202.

    Valachová K, Kogan G, Gemeiner P, Šoltés L. Hyaluronan degradation by ascorbate: protective effects of manganese (II) chloride. Progress in Chemistry and Biochemistry. Kinetics, Thermodynamics, Synthesis, Properties and Application. 2009b;201-215.

    Not in our library

  203. 203.

    Valachová K, Mendichi R, Šoltés L, Pethrick R. A, Petkov P, Zlatarov A, Zaikov G. E, Rakovsky S. K. Effect of l-glutathione on high-molar-mass hyaluronan degradation by oxidative system Cu(II) plus ascorbate. Monomers, Oligomers, Polymers, Composites, and Nanocomposites. 2010c;101-111.

    Not in our library

  204. 204.

    Valachová K, Rapta P, Kogan G, Hrabárová E, Gemeiner P, Šoltés L. Degradation of high-molar-mass hyaluronan by ascorbate plus cupric ions: effects of d-penicillamine addition. Chem Biodivers. 2009a;6:389-395.

    Not in our library10.1002/cbdv.200800261

  205. 205.

    Valachová K, Rapta P, Slováková M, Priesolová E, Nagy M, Mislovicová D, Dráfi F, Bauerová K, Šoltés L, Zaikov G. E, Valente A. J. M, Iordanskii A. L. Radical degradation of high-molar-mass hyaluronan induced by ascorbate plus cupric ions. Testing of arbutin in the function of antioxidant. Advances in Kinetics and Mechanism of Chemical Reactions. 2013a;1-19.

    Not in our library

  206. 206.

    Valachová K, Šoltés L, Pearce E. M, Kirshenbaum G, Zaikov G.E. Effects of biogenic transition metal ions Zn(II) and Mn(II) on hyaluronan degradation by action of ascorbate plus Cu(II) ions. New Steps in Chemical and Biochemical Physics. Pure and Applied Science, Nova Science Publishers. 2010b;153-160.

    Not in our library

  207. 207.

    Valachová K, Vargová A, Rapta P, Hrabárová E, Dráfi F, Bauerová K, Juránek I, Šoltés L. Aurothiomalate in function of preventive and chain-breaking antioxidant at radical degradation of high-molar-mass hyaluronan. Chem Biodivers. 2011a;8:1274-1283.

    Not in our library10.1002/cbdv.201000351

  208. 208.

    Vanos HC, Drogendijk AC, Fetter WPF. The influence of contamination of culture-medium with hepatitis-B virus on the outcome of in vitro fertilization pregnancies. Am J Obstet Gynecol. 1991;165:152-159.

    Not in our library10.1016/0002-9378(91)90244-l

  209. 209.

    Vazquez JR, Short B, Findlow AH. Outcomes of hyaluronan therapy in diabetic foot wounds. Diabetes Res Clin Pract. 2003;59:123-127.

    Not in our library10.1016/s0168-8227(02)00197-3

  210. 210.

    Weigel PH, Hascall VC, Tammi M. Hyaluronan synthases. J Biol Chem. 1997;272:13997-14000.

    Not in our library10.1074/jbc.272.22.13997

  211. 211.

    West DC, Hampson IN, Arnold F, Kumar S. Angiogenesis induced by degradation products of hyaluronic acid. Science. 1985;228:1324-1326.

    Not in our library10.1126/science.2408340

  212. 212.

    Wilkinson LS, Pitsillides AA, Worrall JG, Edwards JC. Light microscopic characterization of the fibroblastlike synovial intimal cell (synoviocyte). Arthritis Rheum. 1992;35:1179-1184.

    Not in our library10.1002/art.1780351010

  213. 213.

    Worrall JG, Bayliss MT, Edwards JC. Morphological localization of hyaluronan in normal and diseased synovium. J Rheumatol. 1991;18:1466-1472.

    Not in our library

  214. 214.

    Worrall JG, Wilkinson LS, Bayliss MT, Edwards JC. Zonal distribution of chondroitin-4-sulphate/dermatan sulphate and chondroitin-6-sulphate in normal and diseased human synovium. Ann Rheum Dis. 1994;53:35-38.

    Not in our library10.1136/ard.53.1.35

  215. 215.

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