**1. Introduction**

Glycosaminoglycans (GAGs) are long, unbranched polysaccharide chains made up primarily of repeating disaccharide units. These disaccharide subunits are composed of one hexuronic acid and one amino sugar linked by glycosidic bonds [1] and these variations in disaccharide composition are used to distinguish the major classes of GAGs: Hyaluronic Acid (HA), Chondroitin Sulfate (CS), Dermatan Sulfate (DS), Keratan Sulfate (KS), and Heparan Sulfate (HS). GAGs are sulfated to varying degrees, with the exception of Hyaluronic Acid (HA), which is unsulfated. The different hexuronic acids and amino sugars found in each GAG are summarized in Table 1 and a structural diagram of the repeating disaccharide unit of each GAG is provided in Figure 1. CS, DS, and HS range in molecular mass between 10,000 and 50,000 Daltons and KS and Heparin (a GAG similar to but distinguished from HS) range between 5000 and 15,000 Daltons. In contrast, HA is generally a very high molecular weight GAG, ranging between approximately 100,000 and 10,000,000 Daltons [2]. The presence of the ionizable groups (sulfates and carboxylates on hexuronic acids) confers GAGs with polyionic properties that are responsible for their key abilities such as water retention, cell binding, control of ion fluxes and neuronal signaling [3–5].

**Table 1.** The hexuronic acid and amino sugar constituents of each glycosaminoglycan.


**Citation:** Sodhi, H.; Panitch, A. Glycosaminoglycans in Tissue Engineering: A Review. *Biomolecules* **2021**, *11*, 29. https://doi.org/10.33 90/biom11010029

Received: 7 December 2020 Accepted: 23 December 2020 Published: 29 December 2020

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

**Figure 1.** Repeating disaccharide unit of each glycosaminoglycan. "R" indicates a potential sulfation point.

The first reference to GAGs can be found in electronically available published literature dating back to the late 1930s when Karl Meyer summarized GAG chemical properties and biological relevance known at the time. Then, they were referred to as mucopolysaccharides and were classified primary as "containing iduronic acid", with sub-divisions of sulfate-free and sulfate-containing, or "neutral" [6]. Even at this time, knowledge of their general localization within the body was growing. It was known, for example, that "chondroitinsulfuric acid" could be isolated from cartilage, the aorta, and the sclera and also that its presence was decreased in "rachitic" (weak) bones [6]. Fast forward to the 1950s and researchers had identified that cell excretion of mucopolysaccharides could be used to determine the differentiation of fibroblasts in culture [7]. Research in this time period focused on isolating and characterizing new GAGs and elucidating the expression patterns and purpose of GAGs in the body [8], during development [9] and disease [10–12]. Foreshadowing the discovery of the importance of GAGs in tissue remodeling and applications in tissue engineering, in 1958, Bollet et al. analyzed the GAG content of granulation tissue formed when polyvinyl sponges were implanted under the dorsal skin of guinea pigs [13].

The first research using GAGs in tissue engineering scaffolds arose in the 1980s, with scientists investigating hyaluronic acid as a component of scaffolds for regeneration of tissues. Since then, all GAGs, with the exception of Keratan sulfate, have seen increased utilization in tissue engineering constructs for the treatment of a myriad of diseases such as osteoarthritis, neuropathy, and bone defects, to name a few. This review aims to summarize the use of each GAG in the advancement of tissue engineering in the last five years, depicted pictorially in Figure 2, and project how, as GAGs become more thoroughly understood, their utility and ubiquity in the tissue engineering field will expand.

**Figure 2.** Each GAG and their aforementioned tissue engineering applications. This figure was made using BioRender.
