Elsevier

Acta Biomaterialia

Volume 9, Issue 7, July 2013, Pages 7081-7092
Acta Biomaterialia

Review
Applications and emerging trends of hyaluronic acid in tissue engineering, as a dermal filler and in osteoarthritis treatment

https://doi.org/10.1016/j.actbio.2013.03.005Get rights and content

Abstract

Hyaluronic acid (HA) is a naturally occurring biodegradable polymer with a variety of applications in medicine, including scaffolding for tissue engineering, dermatological fillers and viscosupplementation for osteoarthritis treatment. HA is available in most connective tissues in body fluids such as synovial fluid and the vitreous humor of the eye. HA is responsible for several structural properties of tissues as a component of extracellular matrix and is involved in cellular signaling. Degradation of HA is a stepwise process that can occur via enzymatic or non-enzymatic reactions. A reduction in HA mass or molecular weight via degradation or slowing of synthesis affects physical and chemical properties such as tissue volume, viscosity and elasticity. This review addresses the distribution, turnover and tissue-specific properties of HA. This information is used as the context for considering recent products and strategies for modifying the viscoelastic properties of HA in tissue engineering, as a dermal filler and in osteoarthritis treatment.

Section snippets

Introduction to hyaluronic acid

Hyaluronic acid (HA), also named hyaluronan, is a high molecular weight (105–107 Da), naturally occurring biodegradable polymer. HA is an unbranched non-sulfated glycosaminoglycan (GAG) composed of repeating disaccharides (β-1,4-d-glucuronic acid (known as uronic acid) and β-1,3-N-acetyl-d-glucosamide) (Fig. 1) [1], [2], [3]. HA can include several thousand sugar molecules in the backbone. HA is a polyanion that can self-associate and can also bind to water molecules (when not bound to other

History of HA

In 1934, Karl Meyer and his colleague John Palmer were the first investigators who discovered and isolated HA from the vitreous body of cows’ eyes [2], [4]. In the 1950s, the chemical structure of HA was solved by this group. They found that HA is composed of two sugar molecules (d-glucuronic acid (known as uronic acid) and d-N-acetyl glucosamine) and called it hyaluronic acid (hyaluronan). This name is derived from “hyalos” (the Greek word for glass + uronic acid). Initially, they isolated HA as

Chemical properties of HA

Structural studies showed that the two sugar molecules, d-glucuronic acid and d-N-acetyl glucosamine, in the HA disaccharide structure are connected together through alternative β-1,4 and β-1,3 glycosidic bonds (Fig. 1) [2], [4]. The HA backbone is stiffened in physiological solution via a combination of internal hydrogen bonds, interactions with solvents and the chemical structure of the disaccharide. HA molecular investigations suggested that the axial hydrogen atoms form a non-polar face

Synthesis of HA

HA is a natural polymer biologically synthesized by cells in the body via an enzymatic process. HA production is a unique, highly controlled and continuous process, HA is produced and secreted by cells including fibroblasts, keratinocytes or chondrocytes. The Golgi network is the production site for most GAG. In tissues such as skin and cartilage, where HA composes a large portion of the tissue mass, the level of HA synthesis is very high. HA is naturally synthesized by hyaluronan synthases

Degradation of HA

Degradation of HA is a stepwise process that can occur via enzymatic or non-enzymatic reactions. Three types of enzymes (hyaluronidase, β-d-glucuronidase and β-N-acetyl-hexosaminidase) are involved in enzymatic degradation of HA. These enzymes are found in various forms, in the intercellular space and in serum. Hyaluronidase cleaves high molecular weight HA into smaller fragments, while the other two enzymes degrade the fragments by removing non-reducing terminal sugars [4], [91], [92]. It was

Turnover and possible pathways for elimination of HA

Studies showed that the concentration of HA in the human body varies from a high concentration of 4 g kg−1 in umbilical cord, 2–4 g l−1 in synovial fluid, 0.2 g kg−1 in dermis, and ∼10 mg l−1 in thoracic lymph, to a low concentration of 0.1–0.01 mg l−1 in normal serum. In an average human body (70 kg), the total HA content is ∼15 g [2], [4]. From this 15 g, the largest amount was found in the ECM of skin and musculoskeletal tissue. Depending on the location in the body, most of the HA is catabolized within

Application of HA in tissue engineering

Since HA is one of the main components of body tissues, its potential for tissue engineering applications has been highly touted. HA is highly soluble at room temperature and has a high rate of elimination and turnover, depending on its molecular weight and location in the body. Each of these properties could be a barrier for HA scaffold fabrication and structural integrity. To overcome these limitations, modification and crosslinking of HA have been proposed [5], [98], [99]. To chemically

Conclusion

HA is a naturally occurring biomolecule, abundantly available in body tissues and fluids. Owing to the prevalence of HA in the body and its desirable properties, HA has been used in several types of biomedical products. This paper reviewed the physical and chemical characteristics of HA as applied to tissue engineering, dermal filling and viscosupplementation. In each application, difficulties such as potential toxicity of crosslinking techniques, high viscosity of HA solutions and rapid

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