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Hyaluronic Acid and its Derivatives for Biomedical Applications

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 August 2019) | Viewed by 31196

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Special Issue Editor

Prof. Dr. Silvia Arpicco

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Guest Editor

Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, Via P. Giuria 9, 10125 Torino, Italy
Interests: liposomes; actively targeted drug delivery systems; hyaluronic acid; anticancer drugs
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In the last few decades, hyaluronic acid (HA) has been widely used in the biomedical and pharmaceutical field. Thanks to its favorable physicochemical and biological properties, including biocompatibility, biodegradability, nonimmunogenicity, HA has been employed as such or as a starting material for different purposes and in several therapeutic fields, such as fabrication of matrices and devices for tissue engineering, drug delivery, imaging, or surgical applications. The use of HA continues to grow; thus, this Special Issue aims to provide the state of the art and the dissemination of the latest information on new approaches and methods dealing with the preparation, characterization, and use of HA-based materials. I encourage authors to submit research papers and comprehensive reviews for this Special Issue.

Prof. Dr. Silvia Arpicco
Guest Editor

Manuscript Submission Information

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Keywords

Hyaluronic acid
Drug delivery systems
Bioconjugates
Theranostic agents
Active targeting
Hydrogel
Topical drug delivery
Tissue engineering
Implantable biomaterials

Published Papers (6 papers)

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Research

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15 pages, 2965 KiB

Open AccessArticle

Hyaluronic Acid–Decorated Liposomes as Innovative Targeted Delivery System for Lung Fibrotic Cells

by Laura Pandolfi, Vanessa Frangipane, Claudia Bocca, Alessandro Marengo, Erika Tarro Genta, Sara Bozzini, Monica Morosini, Maura D’Amato, Simone Vitulo, Manuela Monti, Giuditta Comolli, Maria Teresa Scupoli, Elias Fattal, Silvia Arpicco and Federica Meloni

Molecules 2019, 24(18), 3291; https://doi.org/10.3390/molecules24183291 - 10 Sep 2019

Cited by 36 | Viewed by 4317

Abstract

Collagen Tissue Disease–associated Interstitial Lung Fibrosis (CTD-ILDs) and Bronchiolitis Obliterans Syndrome (BOS) represent severe lung fibrogenic disorders, characterized by fibro-proliferation with uncontrolled extracellular matrix deposition. Hyaluronic acid (HA) plays a key role in fibrosis with its specific receptor, CD44, overexpressed by CTD-ILD and BOS cells. The aim is to use HA-liposomes to develop an inhalatory treatment for these diseases. Liposomes with HA of two molecular weights were prepared and characterized. Targeting efficiency was assessed toward CTD-ILD and BOS cells by flow cytometry and confocal microscopy and immune modulation by RT-PCR and ELISA techniques. HA-liposomes were internalized by CTD-ILD and BOS cells expressing CD44, and this effect increased with higher HA MW. In THP-1 cells, HA-liposomes decreased pro-inflammatory cytokines IL-1β, IL-12, and anti-fibrotic VEGF transcripts but increased TGF-β mRNA. However, upon analyzing TGF-β release from healthy donors-derived monocytes, we found liposomes did not alter the release of active pro-fibrotic cytokine. All liposomes induced mild activation of neutrophils regardless of the presence of HA. HA liposomes could be also applied for lung fibrotic diseases, being endowed with low pro-inflammatory activity, and results confirmed that higher MW HA are associated to an increased targeting efficiency for CD44 expressing LFs-derived from BOS and CTD-ILD patients. Full article

(This article belongs to the Special Issue Hyaluronic Acid and its Derivatives for Biomedical Applications)

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14 pages, 4824 KiB

Open AccessArticle

High Molecular Weight Hyaluronan Suppresses Macrophage M1 Polarization and Enhances IL-10 Production in PM_2.5-Induced Lung Inflammation

by Qiwen Shi, Lan Zhao, Chenming Xu, Leifang Zhang and Hang Zhao

Molecules 2019, 24(9), 1766; https://doi.org/10.3390/molecules24091766 - 07 May 2019

Cited by 42 | Viewed by 5116

Abstract

PM_2.5 is particulate matter with a diameter of 2.5 μm or less. Airway macrophages are the key players regulating PM_2.5-induced inflammation. High molecular weight hyaluronan (HMW-HA) has previously been shown to exert protective effects on PM_2.5-induced acute lung injury and inflammation. However, little is known about the detailed mechanism. In this study, we aimed to determine whether HMW-HA alleviates PM_2.5-induced pulmonary inflammation by modulating macrophage polarization. The levels of M1 biomarkers TNF-α, IL-1β, IL-6, CXCL1, CXCL2, NOS2 and CD86, as well as M2 biomarkers IL-10, MRC1, and Arg-1 produced by macrophages were measured by ELISA, qPCR, and flow cytometry. In addition, the amount of M1 macrophages in lung tissues was examined by immunofluorescence of CD68 and NOS2. We observed a decline in PM_2.5-induced M1 polarization both in macrophages and lung tissues when HMW-HA was administered simultaneously. Meanwhile, western blot analysis revealed that PM_2.5-induced JNK and p38 phosphorylation was suppressed by HMW-HA. Furthermore, in vitro and in vivo studies showed that co-stimulation with HMW-HA and PM_2.5 promoted the expression and release of IL-10, but exhibited limited effects on the transcription of MRC1 and ARG1. In conclusion, our results demonstrated that HMW-HA ameliorates PM_2.5-induced lung inflammation by repressing M1 polarization through JNK and p38 pathways and promoting the production of pro-resolving cytokine IL-10. Full article

(This article belongs to the Special Issue Hyaluronic Acid and its Derivatives for Biomedical Applications)

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13 pages, 5739 KiB

Open AccessArticle

Charge-Controlled Synthetic Hyaluronan-Based Cell Matrices

by Patricia S. Hegger, Julia Kupka, Burcu Baykal Minsky, Sabine Laschat and Heike Boehm

Molecules 2018, 23(4), 769; https://doi.org/10.3390/molecules23040769 - 27 Mar 2018

Cited by 5 | Viewed by 4223

Abstract

The extracellular matrix (ECM) represents a highly charged and hydrated network in which different cells in vertebrate tissues are embedded. Hydrogels as minimal ECM mimetics with a controlled chemistry offer the opportunity to vary material properties by varying the negative network charge. In this paper, a synthetic biology model of the ECM based on natural and highly negatively charged polyelectrolyte hyaluronic acid (HA) is characterized with specific emphasis on its charge-related bioactivity. Therefore, the thiol-Michael addition click reaction is used to produce HA hydrogels with defined network structure and charge density. The presented hydrogels show enzymatic degradability and cell attachment. These properties depend on both covalent and electrostatic interactions within the hydrogel network. Furthermore, no unspecific or specific attachment of proteins to the presented hydrogels is observed. In addition, these fundamental insights into charge-related ECM behavior and the influence of electrostatic properties could also lead to innovations in existing biomedical products. Full article

(This article belongs to the Special Issue Hyaluronic Acid and its Derivatives for Biomedical Applications)

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2240 KiB

Open AccessArticle

Thymosin α1 Interacts with Hyaluronic Acid Electrostatically by Its Terminal Sequence LKEKK

by Walter Mandaliti, Ridvan Nepravishta, Francesca Pica, Paola Sinibaldi Vallebona, Enrico Garaci and Maurizio Paci

Molecules 2017, 22(11), 1843; https://doi.org/10.3390/molecules22111843 - 27 Oct 2017

Cited by 12 | Viewed by 5679

Abstract

Thymosin α1 (Tα1), is a peptidic hormone, whose immune regulatory properties have been demonstrated both in vitro and in vivo and approved in different countries for treatment of several viral infections and cancers. Tα1 assumes a conformation in negative membranes upon insertion into the phosphatidylserine exposure as found in several pathologies and in apoptosis. These findings are in agreement with the pleiotropy of Tα1, which targets both normal and tumor cells, interacting with multiple cellular components, and have generated renewed interest in the topic. Hyaluronan (HA) occurs ubiquitously in the extracellular matrix and on cell surfaces and has been related to a variety of diseases, and developmental and physiological processes. Proteins binding HA, among them CD44 and the Receptor for HA-mediated motility (RHAMM) receptors, mediate its biological effects. NMR spectroscopy indicated preliminarily that an interaction of Tα1 with HA occurs specifically around lysine residues of the sequence LKEKK of Tα1 and is suggestive of a possible interference of Tα1 in the binding of HA with CD44 and RHAMM. Further studies are needed to deepen these observations because Tα1 is known to potentiate the T-cell immunity and anti-tumor effect. The binding inhibitory activity of Tα1 on HA-CD44 or HA-RHAMM interactions can suppress both T-cell reactivity and tumor progression. Full article

(This article belongs to the Special Issue Hyaluronic Acid and its Derivatives for Biomedical Applications)

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10122 KiB

Open AccessArticle

Molecular Dynamic Analysis of Hyaluronic Acid and Phospholipid Interaction in Tribological Surgical Adjuvant Design for Osteoarthritis

by Jacek Siódmiak, Piotr Bełdowski, Wayne K. Augé II, Damian Ledziński, Sandra Śmigiel and Adam Gadomski

Molecules 2017, 22(9), 1436; https://doi.org/10.3390/molecules22091436 - 04 Sep 2017

Cited by 27 | Viewed by 5776

Abstract

Tribological surgical adjuvants constitute a therapeutic discipline made possible by surgical advances in the treatment of damaged articular cartilage beyond palliative care. The purpose of this study is to analyze interactions between hyaluronic acid and phospholipid molecules, and the formation of geometric forms, that play a role in the facilitated lubrication of synovial joint organ systems. The analysis includes an evaluation of the pathologic state to detail conditions that may be encountered by adjuvants during surgical convalescence. The synovial fluid changes in pH, hyaluronic acid polydispersity, and phospholipid concentration associated with osteoarthritis are presented as features that influence the lubricating properties of adjuvant candidates. Molecular dynamic simulation studies are presented, and the Rouse model is deployed, to rationalize low molecular weight hyaluronic acid behavior in an osteoarthritic environment of increased pH and phospholipid concentration. The results indicate that the hyaluronic acid radius of gyration time evolution is both pH- and phospholipid concentration-dependent. Specifically, dipalmitoylphosphatidylcholine induces hydrophobic interactions in the system, causing low molecular weight hyaluronic acid to shrink and at high concentration be absorbed into phospholipid vesicles. Low molecular weight hyaluronic acid appears to be insufficient for use as a tribological surgical adjuvant because an increased pH and phospholipid concentration induces decreased crosslinking that prevents the formation of supramolecular lubricating forms. Dipalmitoylphosphatidylcholine remains an adjuvant candidate for certain clinical situations. The need to reconcile osteoarthritic phenotypes is a prerequisite that should serve as a framework for future adjuvant design and subsequent tribological testing. Full article

(This article belongs to the Special Issue Hyaluronic Acid and its Derivatives for Biomedical Applications)

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Review

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18 pages, 1740 KiB

Open AccessReview

Pursuing Intracellular Pathogens with Hyaluronan. From a ‘Pro-Infection’ Polymer to a Biomaterial for ‘Trojan Horse’ Systems

by Elita Montanari, Chiara Di Meo, Angela Oates, Tommasina Coviello and Pietro Matricardi

Molecules 2018, 23(4), 939; https://doi.org/10.3390/molecules23040939 - 18 Apr 2018

Cited by 12 | Viewed by 4939

Abstract

Hyaluronan (HA) is among the most important bioactive polymers in mammals, playing a key role in a number of biological functions. In the last decades, it has been increasingly studied as a biomaterial for drug delivery systems, thanks to its physico-chemical features and ability to target and enter certain cells. The most important receptor of HA is ‘Cluster of Differentiation 44’ (CD44), a cell surface glycoprotein over-expressed by a number of cancers and heavily involved in HA endocytosis. Moreover, CD44 is highly expressed by keratinocytes, activated macrophages and fibroblasts, all of which can act as ‘reservoirs’ for intracellular pathogens. Interestingly, both CD44 and HA appear to play a key role for the invasion and persistence of such microorganisms within the cells. As such, HA is increasingly recognised as a potential target for nano-carriers development, to pursuit and target intracellular pathogens, acting as a ‘Trojan Horse’. This review describes the biological relationship between HA, CD44 and the entry and survival of a number of pathogens within the cells and the subsequent development of HA-based nano-carriers for enhancing the intracellular activity of antimicrobials. Full article

(This article belongs to the Special Issue Hyaluronic Acid and its Derivatives for Biomedical Applications)

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