Sulfated Glycosaminoglycans As Promising Artificial Extracellular Matrix Components to Improve the Regeneration of Tissues

Abstract

Glycosaminoglycans (GAG) such as hyaluronan (HA) or chondroitin/dermatan sulfate (CS/DS) occur in many connective tissues, for instance, in bone, cartilage and skin. Due to their significant water-binding capacity, GAG are essential for the biomechanical properties of these tissues. However, there is also increasing evidence that the sulfation of GAG does not occur at random, but a "sulfation code" exists that mediates the physiological functions of GAG. Thus, the biological properties of these biomacromolecules are strongly influenced by the degree of sulfation (ds) and the sulfate group distribution along the polymer. Therefore, certain GAG might also have interesting pharmacological properties. It is, thus, commonly accepted that GAG represent promising biomaterials in the field of tissue engineering as well as to design new bioactive materials for tissue repair and reconstruction. In this review we will focus on chemically sulfated GAG and provide a survey of these compounds on four different levels. First, we will provide an overview on chemical functionalization strategies of naturally occurring HA and CS/DS with special emphasis on regioselective methods to introduce a defined number of sulfate residues into the carbohydrate backbone. Second, chemical and biochemical methods to characterize the synthesized compounds will be introduced with the focus on methods based on nuclear magnetic resonance (NMR) and mass spectrometry (MS). In the third part, we will discuss the interaction of natural and chemically sulfated GAG with proteins and other biomolecules with regulatory functions. Additionally, biological consequences of these interactions regarding healing processes of skin and bone will be presented by discussing selected cell culture experiments. Finally, in vivo effects of GAG as components of artificial extracellular matrices will be discussed.

Molecular and bioenergetic differences between cells with African versus European inherited mitochondrial DNA haplogroups: Implications for population susceptibility to diseases

“…All five enzymes are sulfotransferases, which catalyze the transfer of sulfate onto DS, CS or keratan sulfate (KS). This may be significant for cellular behavior because the degree of sulfation of GAGs can mediate biological functions [33], which include cellular proliferation, migration, differentiation, angiogenesis and activation of cytokine/growth factors.…”

Improvement of the Digestibility of Sulfated Hyaluronans by Bovine Testicular Hyaluronidase: A UV Spectroscopic and Mass Spectrometric Study

“…The sulfated HA derivatives with ds s  = 1.2 (sHA1) and 1.8 (sHA2) are digested (within the experimental error range) to the same extents; however, only about 20% of the effect that is detectable in the case of the native HA can be achieved. That is, the extent of digestion is significantly reduced when sulfated HA samples are used as substrates [5, 14]. Considering the accuracy of the applied method, the very low absorbance detected in the case of the highly sulfated derivative (sHA3, ds s  = 3) suggests that no significant degradation has taken place.…”

“…Motivated by the discovery of the “sulfation code” [4], the interest in chemically (over)sulfated GAGs has also significantly increased because these compounds were shown to possess many beneficial properties and improve, for instance, the incorporation of metal implants into the corresponding tissue such as bone [5]. However, there are also negative aspects: chemically sulfated GAGs may be toxic, as evidenced by the lethal contamination of heparin with a chemically oversulfated CS [6], so caution is advised prior to the in vivo use of any chemically sulfated GAGs, including sulfated HA.…”

“…Even though mass spectrometry (MS) is an additional powerful method of structure elucidation (particularly when combined with MS/MS and/or chromatographic separation) [5], the application of MS to polysaccharides is difficult and this particularly applies if polymers with charged functional groups such as sulfate (i.e., strong electrolytes) are of interest: while native dextran (with a molecular weight of about 67 kDa but without any charged groups) [8] is detectable by MS, the strongly sulfated heparin was not detectable in a mass higher than about 4 kDa [5]. …”

Glycosaminoglycans in Tendon Physiology, Pathophysiology, and Therapy

“…67,109 GAG composition may also be linked with the individuals' physical activity, as immobilization has been shown to be associated with reduction of GAG content. 110 The turnover of mature collagen and cross-links increases with heavy exercise; 111 collagen fibrils thicken and GAGs with galactosamine content increase, 112 resulting in an associated increase in tendon stiffness. 113 However, collagen turnover in response to exercise is much higher in immature tendon and is associated with a reduction in collagen maturation 111 and altered concentrations of HA.…”