ReviewApplications and emerging trends of hyaluronic acid 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
References (154)
- et al.
In situ crosslinkable hyaluronan hydrogels for tissue engineering
Biomaterials
(2004) - et al.
Crosslinked hyaluronic acid hydrogels: a strategy to functionalize and pattern
Biomaterials
(2005) - et al.
Intralymphatic chemotherapy using a hyaluronan–cisplatin conjugate
J Surg Res
(2008) - et al.
Hyaluronan scaffolds—a balance between backbone functionalization and bioactivity
Acta Biomater
(2010) - et al.
Bone regeneration using hyaluronic acid-based hydrogel with bone morphogenic protein-2 and human mesenchymal stem cells
Biomaterials
(2007) - et al.
Cross-linked hyaluronic acid hydrogel films: new biomaterials for drug delivery
J Controlled Release
(2000) - et al.
Hydrogels for tissue engineering: scaffold design variables and applications
Biomaterials
(2003) - et al.
Hyaluronic acid and chondroitin-4-sulphate treatment reduces damage in carbon tetrachloride-induced acute rat liver injury
Life Sci
(2004) - et al.
Buccal drug delivery: a challenge already won?
Drug Discov Today Technol
(2005) - et al.
Hydrogel nanoparticles in drug delivery
Adv Drug Deliv Rev
(2008)
Effect of the cations sodium, potassium and calcium on the interaction of hyaluronate chains: a light scattering and viscometric study
Int J Biol Macromol
Hyaluronan in morphogenesis
Semin Cell Dev Biol
Hyaluronan–cell interactions in cancer and vascular disease
J Biol Chem
Hyaluronan and its catabolic products in tissue injury and repair
Matrix Biol
Signaling properties of hyaluronan receptors
J Biol Chem
Glial hyaluronate-binding protein (GHAP) optic nerve and retina
Brain Res
Effect of diagnostic hydrodistension and four intravesical hyaluronic acid instillations on bladder ICAM-1 intensity and association of ICAM-1 intensity with clinical response in patients with interstitial cystitis
Urology
The hyaluronan receptor for endocytosis (HARE) is not CD44 or CD54 (ICAM-1)
Biochem Biophys Res Commun
The lymphatics revisited: new perspectives from the hyaluronan receptor LYVE-1
Trends Cardiovasc Med
Mouse LYVE-1 is an endocytic receptor for hyaluronan in lymphatic endothelium
J Biol Chem
Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components
Immunity
Detachment variants of Chinese hamster cells: hyaluronic acid as a modulator of cell detachment
Exp Cell Res
Biocompatibility and stability of disulfide-crosslinked hyaluronan films
Biomaterials
Cell detachment mediated by hyaluronic acid
Exp Cell Res
Ras-transformed cells express both CD44 and RHAMM hyaluronan receptors: only RHAMM is essential for hyaluronan-promoted locomotion
Exp Cell Res
Migration of cranial neural crest cells in a cell-free hyaluronate-rich matrix
Dev Biol
Hyaluronan-binding proteins and receptors
Adv Drug Deliv Rev
The effect of hyaluronate and its oligosaccharides on endothelial cell proliferation and monolayer integrity
Exp Cell Res
Application of angiogenic oligosaccharides of hyaluronan increases blood vessel numbers in rat skin
J Invest Dermatol
Tumour hyaluronan in relation to angiogenesis and metastasis
Wenner Gren Int Ser
Localization of epidermal hyaluronic acid using the hyaluronate binding region of cartilage proteoglycan as a specific probe
J Invest Dermatol
Hyaluronate accumulation in human epidermis treated with retinoic acid in skin organ culture
J Invest Dermatol
Fibrotic healing of adult and late gestation fetal wounds correlates with increased hyaluronidase activity and removal of hyaluronan
Int J Biochem Cell Biol
Hyaluronan: a multifunctional, megaDalton, stealth molecule
Curr Opin Cell Biol
Evaluation of the matrix-synthesis potential of crosslinked hyaluronan gels for tissue engineering of aortic heart valves
Biomaterials
Experimental approaches to hyaluronan structure
Carbohydr Res
The many ways to cleave hyaluronan
Biotechnol Adv
Hyaluronans in the treatment of osteoarthritis of the knee: evidence for disease-modifying activity
Osteoarthritis Cartilage
Injectable biodegradable hydrogels composed of hyaluronic acid–tyramine conjugates for drug delivery and tissue engineering
Chem Commun
Chemistry and biology of hyaluronan
New trends in face rejuvenation by hyaluronic acid injections
J Cosmet Dermatol
Hyaluronic acid (hyaluronan): a review
Vet Med
Biomedical applications of hyaluronic acid
Glycosaminoglycans of human bone tissue
Calcif Tissue Int
Polymeric biomaterials
Hyaluronan: from extracellular glue to pericellular cue
Nat Rev Cancer
CD44: the hyaluronan receptor
J Cell Sci
Hydrogels for tissue engineering
Chem Rev
Hyaluronic acid hydrogels for biomedical applications
Adv Mater
An insight on hyaluronic acid in drug targeting and drug delivery
J Drug Target
Cited by (397)
Advancements in drug-loaded hydrogel systems for bone defect repair
2024, Regenerative TherapyResistance to enzymatic degradation and efficacy evaluation of crosslinked hyaluronic acid based commercial viscosupplements for knee osteoarthritis treatment
2023, Carbohydrate Polymer Technologies and Applications