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Hyaluronic Acid: Basic and Clinical Aspects

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A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (31 October 2020) | Viewed by 59928

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Prof. Dr. Giovanni Abatangelo

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Guest Editor

Faculty of Medicine, University of Padova, 35100 Padova, Italy
Interests: hyaluronan; tissue repair
Special Issues, Collections and Topics in MDPI journals

Prof. Jeffrey M Davidson

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Guest Editor

Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
Interests: extracellular matrix; collagen; elastin; hyaluronan; wound healing; biomaterials; gene delivery

Special Issue Information

Dear Colleagues,

Hyaluronic acid (HA) is a linear polysaccharide made by repeating units of glucuronic acid and N-acetyl glucosamine with a variable molecular weight ranging from 2 × 10³ to 2 × 10⁶ Daltons. It is present in all connective tissues where the charged macromolecule avidly binds water while enabling the organization of huge complexes of proteoglycans, such as in a cartilage matrix. In the past, HA was considered to be simply a structural component mainly of skin and cartilage, where HA exerts exceptional rheological, hygroscopic, and viscoelastic properties. The biomechanical role of HA has also been shown to be important for the normal function of the eye and joints. However, appreciation of the roles of HA were dramatically changed when deeper investigation identified its importance also in numerous cell functions: multiple cell receptors specifically recognize HA; small HA fragments stimulate angiogenesis; HA can initiate a signal transduction cascade in many cell types while inducing modifications in cell behavior; and certain cell types will respond to HA as a functions of its molecular mass. The biosynthesis of HA is also unusual, since it is synthesized at cell surface and extruded directly into the extracellular matrix. More recently, novel approaches have developed from the chemical modification of HA. Its esterification with benzyl alcohol has enabled the production of medical biomaterials in different forms, such as membranes, nonwoven tissues, gauzes, and tubes. It has also been possible to seed esterified HA materials with multiple human cell types in vitro to obtain human tissue equivalents such as dermis, epidermis, and cartilage. These in vitro reconstructed tissues can be useful as tissue substitutes in wound healing and cartilage repair. Recently tubular structures (with a diameter of 2 mm) of esterified HA have been used as a temporary guide for the regeneration of small vessels in rats and pigs.
Apart from the extensive promotion of HA for cosmetic applications, the clinical development of HA and HA derivatives is expanding particularly in the fields of articular pathology, ophthalmology, and cutaneous repair and aging.
The great potential of this polysaccharide has stimulated the interest of pharmaceutical industries, which has provided new strategies for the production of HA and the formulation of numerous new derivatives.

Prof. Giovanni Abatangelo
Prof. Jeffrey M Davidson
Guest Editors

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Keywords

hyaluronan
drug delivery
skin
hydrogel
inflammation
nanoparticle
wound healing
scaffolds
cancer
osteoarthritis

Published Papers (9 papers)

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Research

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25 pages, 7921 KiB

Open AccessArticle

Addition of High Molecular Weight Hyaluronic Acid to Fibroblast-Like Stromal Cells Modulates Endogenous Hyaluronic Acid Metabolism and Enhances Proteolytic Processing and Secretion of Versican

by Jiapeng Xue, Jinnan Chen, Quan Shen, Deva Chan, Jun Li, Adam P. Tanguay, Tannin A. Schmidt, Faizan Niazi and Anna Plaas

Cells 2020, 9(7), 1681; https://doi.org/10.3390/cells9071681 - 13 Jul 2020

Cited by 8 | Viewed by 4536

Abstract

We have examined the effect of exogenous linear chain high molecular weight hyaluronic acid (HMW HA) on endogenously synthesized hyaluronic acid (HA) and associated binding proteins in primary cultures of fibroblast-like stromal cells that were obtained by collagenase digestion of the murine peripatellar fat pad. The cultures were expanded in DMEM that was supplemented with fetal bovine serum and basic fibroblast growth factor (bFGF) then exposed to macrophage-colony-stimulating factor (MCSF) to induce macrophage properties, before activation of inflammatory pathways using E. coli lipopolysaccharide (LPS). Under all culture conditions, a significant amount of endogenously synthesized HA localized in LAMP1-positive lysosomal vesicles. However, this intracellular pool was depleted after the addition of exogenous HMW HA and was accompanied by enhanced proteolytic processing and secretion of de novo synthesized versican, much of which was associated with endosomal compartments. No changes were detected in synthesis, secretion, or proteolytic processing of aggrecan or lubricin (PRG4). The addition of HMW HA also modulated a range of LPS-affected genes in the TLR signaling and phagocytosis pathways, as well as endogenous HA metabolism genes, such as Has1, Hyal1, Hyal2, and Tmem2. However, there was no evidence for association of endogenous or exogenous HMW HA with cell surface CD44, TLR2 or TLR4 protein, suggesting that its physiochemical effects on pericelluar pH and/or ionic strength might be the primary modulators of signal transduction and vesicular trafficking by this cell type. We discuss the implications of these findings in terms of a potential in vivo effect of therapeutically applied HMW HA on the modification of osteoarthritis-related joint pathologies, such as pro-inflammatory and degradative responses of multipotent mesenchymal cells residing in the synovial membrane, the underlying adipose tissue, and the articular cartilage surface. Full article

(This article belongs to the Special Issue Hyaluronic Acid: Basic and Clinical Aspects)

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15 pages, 4226 KiB

Open AccessArticle

The Role of Hyaluronic Acid in Cartilage Boundary Lubrication

by Weifeng Lin, Zhang Liu, Nir Kampf and Jacob Klein

Cells 2020, 9(7), 1606; https://doi.org/10.3390/cells9071606 - 2 Jul 2020

Cited by 67 | Viewed by 6060

Abstract

Hydration lubrication has emerged as a new paradigm for lubrication in aqueous and biological media, accounting especially for the extremely low friction (friction coefficients down to 0.001) of articular cartilage lubrication in joints. Among the ensemble of molecules acting in the joint, phosphatidylcholine (PC) lipids have been proposed as the key molecules forming, in a complex with other molecules including hyaluronic acid (HA), a robust layer on the outer surface of the cartilage. HA, ubiquitous in synovial joints, is not in itself a good boundary lubricant, but binds the PC lipids at the cartilage surface; these, in turn, massively reduce the friction via hydration lubrication at their exposed, highly hydrated phosphocholine headgroups. An important unresolved issue in this scenario is why the free HA molecules in the synovial fluid do not suppress the lubricity by adsorbing simultaneously to the opposing lipid layers, i.e., forming an adhesive, dissipative bridge between them, as they slide past each other during joint articulation. To address this question, we directly examined the friction between two hydrogenated soy PC (HSPC) lipid layers (in the form of liposomes) immersed in HA solution or two palmitoyl–oleoyl PC (POPC) lipid layers across HA–POPC solution using a surface force balance (SFB). The results show, clearly and surprisingly, that HA addition does not affect the outstanding lubrication provided by the PC lipid layers. A possible mechanism indicated by our data that may account for this is that multiple lipid layers form on each cartilage surface, so that the slip plane may move from the midplane between the opposing surfaces, which is bridged by the HA, to an HA-free interface within a multilayer, where hydration lubrication is freely active. Another possibility suggested by our model experiments is that lipids in synovial fluid may complex with HA, thereby inhibiting the HA molecules from adhering to the lipids on the cartilage surfaces. Full article

(This article belongs to the Special Issue Hyaluronic Acid: Basic and Clinical Aspects)

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16 pages, 5386 KiB

Open AccessArticle

Boosting the Intra-Articular Efficacy of Low Dose Corticosteroid through a Biopolymeric Matrix: An In Vivo Model of Osteoarthritis

by Matilde Tschon, Francesca Salamanna, Lucia Martini, Gianluca Giavaresi, Luca Lorenzini, Laura Calzà and Milena Fini

Cells 2020, 9(7), 1571; https://doi.org/10.3390/cells9071571 - 28 Jun 2020

Cited by 14 | Viewed by 2569

Abstract

The purpose of this study was to verify the efficacy of a single intra-articular (i.a.) injection of a hyaluronic acid-chitlac (HY-CTL) enriched with two low dosages of triamcinolone acetonide (TA, 2.0 mg/mL and 4.5 mg/mL), in comparison with HY-CTL alone, with a clinical control (TA 40 mg/mL) and with saline solution (NaCl) in an in vivo osteoarthritis (OA) model. Seven days after chemical induction of OA, 80 Sprague Dawley male rats were grouped into five arms (n = 16) and received a single i.a. injection of: 40 mg/mL TA, HY-CTL alone, HY-CTL with 2.0 mg/mL TA (RV2), HY-CTL with 4.5 mg/mL TA (RV4.5) and 0.9% NaCl. Pain sensitivity and Catwalk were performed at baseline and at 7, 14 and 21 days after the i.a. treatments. The histopathology of the joint, meniscus and synovial reaction, type II collagen expression and aggrecan expression were assessed 21 days after treatments. RV4.5 improved the local pain sensitivity in comparison with TA and NaCl. RV4.5 and TA exerted similar beneficial effects in all gait parameters. Histopathological analyses, measured by Osteoarthritis Research Society International (OARSI) and Kumar scores and by immunohistochemistry, evidenced that RV4.5 and TA reduced OA features in the same manner and showed a stronger type II collagen and aggrecan expression; both treatments reduced synovitis, as measured by Krenn score and, at the meniscus level, RV4.5 improved degenerative signs as evaluated by Pauli score. TA or RV4.5 treatments limited the local articular cartilage deterioration in knee OA with an improvement of the physical structure of articular cartilage, gait parameters, the sensitivity to local pain and a reduction of the synovial inflammation. Full article

(This article belongs to the Special Issue Hyaluronic Acid: Basic and Clinical Aspects)

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14 pages, 3919 KiB

Open AccessArticle

Hyaluronic Acid (HA) Receptors and the Motility of Schwann Cell(-Like) Phenotypes

by Sihem Ouasti, Alessandro Faroni, Paul J. Kingham, Matilde Ghibaudi, Adam J. Reid and Nicola Tirelli

Cells 2020, 9(6), 1477; https://doi.org/10.3390/cells9061477 - 17 Jun 2020

Cited by 6 | Viewed by 3202

Abstract

The cluster of differentiation 44 (CD44) and the hyaluronan-mediated motility receptor (RHAMM), also known as CD168, are perhaps the most studied receptors for hyaluronic acid (HA); among their various functions, both are known to play a role in the motility of a number of cell types. In peripheral nerve regeneration, the stimulation of glial cell motility has potential to lead to better therapeutic outcomes, thus this study aimed to ascertain the presence of these receptors in Schwann cells (rat adult aSCs and neonatal nSCs) and to confirm their influence on motility. We included also a Schwann-like phenotype (dAD-MSCs) derived from adipose-derived mesenchymal stem cells (uAD-MSCs), as a possible basis for an autologous cell therapy. CD44 was expressed similarly in all cell types. Interestingly, uAD-MSCs were RHAMM(low), whereas both Schwann cells and dASCs turned out to be similarly RHAMM(high), and indeed antibody blockage of RHAMM effectively immobilized (in vitro scratch wound assay) all the RHAMM(high) Schwann(-like) types, but not the RHAMM(low) uAD-MSCs. Blocking CD44, on the other hand, affected considerably more uAD-MSCs than the Schwann(-like) cells, while the combined blockage of the two receptors immobilized all cells. The results therefore indicate that Schwann-like cells have a specifically RHAMM-sensitive motility, where the motility of precursor cells such as uAD-MSCs is CD44- but not RHAMM-sensitive; our data also suggest that CD44 and RHAMM may be using complementary motility-controlling circuits. Full article

(This article belongs to the Special Issue Hyaluronic Acid: Basic and Clinical Aspects)

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14 pages, 3050 KiB

Open AccessArticle

Anti-Inflammatory Performance of Lactose-Modified Chitosan and Hyaluronic Acid Mixtures in an In Vitro Macrophage-Mediated Inflammation Osteoarthritis Model

by Elena Tarricone, Elena Mattiuzzo, Elisa Belluzzi, Rossella Elia, Andrea Benetti, Rina Venerando, Vincenzo Vindigni, Pietro Ruggieri and Paola Brun

Cells 2020, 9(6), 1328; https://doi.org/10.3390/cells9061328 - 26 May 2020

Cited by 32 | Viewed by 3776

Abstract

The development and progression of osteoarthritis (OA) is associated with macrophage-mediated inflammation that generates a broad spectrum of cytokines and reactive oxygen species (ROS). This study investigates the effects of mid-MW hyaluronic acid (HA) in combination with a lactose-modified chitosan (CTL), on pro-inflammatory molecules and metalloproteinases (MMPs) expression, using an in vitro model of macrophage-mediated inflammation. Methods. To assess chondrocyte response to HA and CTL in the presence of macrophage derived inflammatory mediators, cells were exposed to the conditioned medium (CM) of U937 activated monocytes and changes in cell viability, pro-inflammatory mediators and MMPs expression or ROS generation were analysed. Results. CTL induced changes in chondrocyte viability that are reduced by the presence of HA. The CM of activated U937 monocytes (macrophages) significantly increased gene expression of pro-inflammatory molecules and MMPs and intracellular ROS generation in human chondrocyte cultures. HA, CTL and their combinations counteracted the oxidative damage and restored gene transcription for IL-1β, TNF-α, Gal-1, MMP-3 and MMP-13 to near baseline values. Conclusions. This study suggests that HA-CTL mixture attenuated macrophage-induced inflammation, inhibited MMPs expression and exhibited anti-oxidative effects. This evidence provides an initial step toward the development of an early stage OA therapeutic treatment Full article

(This article belongs to the Special Issue Hyaluronic Acid: Basic and Clinical Aspects)

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Review

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18 pages, 2974 KiB

Open AccessReview

Hyaluronic Acid Injection Laryngoplasty for Unilateral Vocal Fold Paralysis—A Systematic Review and Meta-Analysis

by Chen-Chi Wang, Shang-Heng Wu, Yu-Kang Tu, Wen-Jiun Lin and Shih-An Liu

Cells 2020, 9(11), 2417; https://doi.org/10.3390/cells9112417 - 5 Nov 2020

Cited by 31 | Viewed by 5669

Abstract

Unilateral vocal fold paralysis (UVFP) is a common disorder that may cause glottal closure insufficiency and then hoarseness of voice and aspiration during swallowing. We conducted a systematic review and meta-analysis to evaluate whether hyaluronic acid (HA) injection laryngoplasty (IL) is an effective treatment for patients with UVFP. Comprehensive systematic searches were undertaken using PubMed, EBSCO Medline, and Cochrane Library databases. We appraised the quality of studies according to preset inclusion and exclusion criteria. The lengths of follow-up were divided into “short-term” (3 months or shorter), “medium-term” (6 months), and “long-term” (12 months or longer). We performed random-effect meta-analysis to estimate the changes in voice-related quality of life, perceptual evaluation by grading systems, voice lab analysis of maximal phonation time, and normalized glottal gap area, before and after HA IL. Fourteen studies were eligible for the final analysis. The results showed that patients’ glottal closure insufficiency could be improved; maximal phonation time could be prolonged; perceptual evaluations of the voice and quality of life were better after HA IL, but the duration of treatment effect varied among different studies. In conclusion, HA IL is an effective treatment for UVFP, which may achieve a long-term effect and therefore reduce the likelihood of requiring permanent medialization thyroplasty. Full article

(This article belongs to the Special Issue Hyaluronic Acid: Basic and Clinical Aspects)

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18 pages, 811 KiB

Open AccessReview

Use of Hyaluronic Acid (HA) in Chronic Airway Diseases

by Luis Máiz Carro and Miguel A. Martínez-García

Cells 2020, 9(10), 2210; https://doi.org/10.3390/cells9102210 - 29 Sep 2020

Cited by 28 | Viewed by 6607

Abstract

Hyaluronic acid (HA) is a key component of the extracellular matrix of the lungs. A unique attribute of HA is its water-retaining properties, so HA has a major role in the regulation of fluid balance in the lung interstitium. Hyaluronic acid has been widely used in the treatment of eyes, ears, joints and skin disorders, but in the last years, it has been also proposed in the treatment of certain lung diseases, including airway diseases, due to its anti-inflammatory and water-binding capacities. Hyaluronic acid aerosol decreases the severity of elastase-induced emphysema in murine models, prevents bronchoconstriction in asthmatics and improves some functional parameters in chronic obstructive pulmonary disease (COPD) patients. Due to the protection of HA against bronchoconstriction and its hydration properties, inhaled HA would increase the volume of airway surface liquid, resulting in mucus hydration, increased mucous transport and less mucous plugging of the airways. In addition, it has been seen in human studies that the treatment with nebulised HA improves the tolerability of nebulised hypertonic saline (even at 6% or 7% of concentration), which has been demonstrated to be an effective treatment in bronchial secretion management in patients with cystic fibrosis and bronchiectasis. Our objective is to review the role of HA treatment in the management of chronic airway diseases. Full article

(This article belongs to the Special Issue Hyaluronic Acid: Basic and Clinical Aspects)

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17 pages, 1334 KiB

Open AccessReview

Hyaluronic Acid Biomaterials for Central Nervous System Regenerative Medicine

by Gregory Jensen, Julianne L. Holloway and Sarah E. Stabenfeldt

Cells 2020, 9(9), 2113; https://doi.org/10.3390/cells9092113 - 17 Sep 2020

Cited by 56 | Viewed by 6531

Abstract

Hyaluronic acid (HA) is a primary component of the brain extracellular matrix and functions through cellular receptors to regulate cell behavior within the central nervous system (CNS). These behaviors, such as migration, proliferation, differentiation, and inflammation contribute to maintenance and homeostasis of the CNS. However, such equilibrium is disrupted following injury or disease leading to significantly altered extracellular matrix milieu and cell functions. This imbalance thereby inhibits inherent homeostatic processes that support critical tissue health and functionality in the CNS. To mitigate the damage sustained by injury/disease, HA-based tissue engineering constructs have been investigated for CNS regenerative medicine applications. HA’s effectiveness in tissue healing and regeneration is primarily attributed to its impact on cell signaling and the ease of customizing chemical and mechanical properties. This review focuses on recent findings to highlight the applications of HA-based materials in CNS regenerative medicine. Full article

(This article belongs to the Special Issue Hyaluronic Acid: Basic and Clinical Aspects)

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19 pages, 369 KiB

Open AccessFeature PaperReview

Hyaluronic Acid: Redefining Its Role

by G. Abatangelo, V. Vindigni, G. Avruscio, L. Pandis and P. Brun

Cells 2020, 9(7), 1743; https://doi.org/10.3390/cells9071743 - 21 Jul 2020

Cited by 229 | Viewed by 19924

Abstract

The discovery of several unexpected complex biological roles of hyaluronic acid (HA) has promoted new research impetus for biologists and, the clinical interest in several fields of medicine, such as ophthalmology, articular pathologies, cutaneous repair, skin remodeling, vascular prosthesis, adipose tissue engineering, nerve reconstruction and cancer therapy. In addition, the great potential of HA in medicine has stimulated the interest of pharmaceutical companies which, by means of new technologies can produce HA and several new derivatives in order to increase both the residence time in a variety of human tissues and the anti-inflammatory properties. Minor chemical modifications of the molecule, such as the esterification with benzyl alcohol (Hyaff-11^® biomaterials), have made possible the production of water-insoluble polymers that have been manufactured in various forms: membranes, gauzes, nonwoven meshes, gels, tubes. All these biomaterials are used as wound-covering, anti-adhesive devices and as scaffolds for tissue engineering, such as epidermis, dermis, micro-vascularized skin, cartilage and bone. In this review, the essential biological functions of HA and the applications of its derivatives for pharmaceutical and tissue regeneration purposes are reviewed. Full article

(This article belongs to the Special Issue Hyaluronic Acid: Basic and Clinical Aspects)

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