Application of Chitosan and Hyaluronan in Medicine

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Nanomedicine and Nanotechnology".

Deadline for manuscript submissions: closed (20 January 2022) | Viewed by 46809

Special Issue Editor

Centre of Experimental Medicine of Slovak Academy of Sciences, Dubravska cesta 9, 84104 Bratislava, Slovakia
Interests: hyaluronan; reactive oxygen species; drugs; antioxidants; biopolymers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We are pleased to invite you to submit original research papers and reviews in numerous fields of medicine.

This Special Issue aims to publish papers concerning applications of chitosan and hyaluronan in medicine. Chitosan is synthesized by the alkaline N-deacetylation of chitin (β-N-acetyl-glucosamine polymer). Chitosan has several advantageous properties, such as degradability, biocompatibility, physiological inertness, absence of toxicity, remarkable affinity to proteins, hemostaticity, lack of allergenicity, and antibacterial activity. Chitosan and its derivatives have been widely used in cosmetics and in the field of medicine, including biomaterials for tissue-engineered scaffolds and tissue repair, wound dressings, and biochemical separation systems. Hyaluronan, another β-polymer, is one of the major structural components of the extracellular matrix in vertebrates. HA is widely distributed in both prokaryotic and eukaryotic cells. Adult humans contain about 12–15 g of HA, most of which occurs in skin, vitreous body of the eye, umbilical cord, synovial fluid of articular joints. The HA biopolymer provides a wide range of pharmacological activities, including anti-inflammatory, wound healing and tissue regenerating, immunomodulatory, anti-cancer, anti-proliferative, anti-diabetic, anti-aging, skin repairing, and cosmetic properties.

In this Special Issue, original research articles and reviews are welcome. Research areas may include (but are not limited to) the following: osteoarthritis, skin wound healing, tissue engineering, gene delivery, ophthalmology, dentistry, cancer.

I look forward to receiving your contributions.

Dr. Katarína Valachová
Guest Editor

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Keywords

  • polysaccharides
  • reactive oxygen species
  • skin wound healing
  • tissue engineering
  • ophthalmology
  • dentistry
  • gene delivery
  • cancer

Published Papers (20 papers)

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17 pages, 7254 KiB  
Article
Chitosan Scaffolds as Microcarriers for Dynamic Culture of Human Neural Stem Cells
by Yoshiki Ando, Fei-Chien Chang, Matthew James, Yang Zhou and Miqin Zhang
Pharmaceutics 2023, 15(7), 1957; https://doi.org/10.3390/pharmaceutics15071957 - 15 Jul 2023
Viewed by 1144
Abstract
Human neural stem cells (hNSCs) possess remarkable potential for regenerative medicine in the treatment of presently incurable diseases. However, a key challenge lies in producing sufficient quantities of hNSCs, which is necessary for effective treatment. Dynamic culture systems are recognized as a powerful [...] Read more.
Human neural stem cells (hNSCs) possess remarkable potential for regenerative medicine in the treatment of presently incurable diseases. However, a key challenge lies in producing sufficient quantities of hNSCs, which is necessary for effective treatment. Dynamic culture systems are recognized as a powerful approach to producing large quantities of hNSCs required, where microcarriers play a critical role in supporting cell expansion. Nevertheless, the currently available microcarriers have limitations, including a lack of appropriate surface chemistry to promote cell adhesion, inadequate mechanical properties to protect cells from dynamic forces, and poor suitability for mass production. Here, we present the development of three-dimensional (3D) chitosan scaffolds as microcarriers for hNSC expansion under defined conditions in bioreactors. We demonstrate that chitosan scaffolds with a concentration of 4 wt% (4CS scaffolds) exhibit desirable microstructural characteristics and mechanical properties suited for hNSC expansion. Furthermore, they could also withstand degradation in dynamic conditions. The 4CS scaffold condition yields optimal metabolic activity, cell adhesion, and protein expression, enabling sustained hNSC expansion for up to three weeks in a dynamic culture. Our study introduces an effective microcarrier approach for prolonged expansion of hNSCs, which has the potential for mass production in a three-dimensional setting. Full article
(This article belongs to the Special Issue Application of Chitosan and Hyaluronan in Medicine)
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15 pages, 3160 KiB  
Article
3D Porous Scaffold-Based High-Throughput Platform for Cancer Drug Screening
by Yang Zhou, Gillian Pereira, Yuanzhang Tang, Matthew James and Miqin Zhang
Pharmaceutics 2023, 15(6), 1691; https://doi.org/10.3390/pharmaceutics15061691 - 09 Jun 2023
Viewed by 1317
Abstract
Natural polymer-based porous scaffolds have been investigated to serve as three-dimensional (3D) tumor models for drug screening owing to their structural properties with better resemblance to human tumor microenvironments than two-dimensional (2D) cell cultures. In this study, a 3D chitosan–hyaluronic acid (CHA) composite [...] Read more.
Natural polymer-based porous scaffolds have been investigated to serve as three-dimensional (3D) tumor models for drug screening owing to their structural properties with better resemblance to human tumor microenvironments than two-dimensional (2D) cell cultures. In this study, a 3D chitosan–hyaluronic acid (CHA) composite porous scaffold with tunable pore size (60, 120 and 180 µm) was produced by freeze-drying and fabricated into a 96-array platform for high-throughput screening (HTS) of cancer therapeutics. We adopted a self-designed rapid dispensing system to handle the highly viscous CHA polymer mixture and achieved a fast and cost-effective large-batch production of the 3D HTS platform. In addition, the adjustable pore size of the scaffold can accommodate cancer cells from different sources to better mimic the in vivo malignancy. Three human glioblastoma multiforme (GBM) cell lines were tested on the scaffolds to reveal the influence of pore size on cell growth kinetics, tumor spheroid morphology, gene expression and dose-dependent drug response. Our results showed that the three GBM cell lines showed different trends of drug resistance on CHA scaffolds of varying pore size, which reflects the intertumoral heterogeneity across patients in clinical practice. Our results also demonstrated the necessity to have a tunable 3D porous scaffold for adapting the heterogeneous tumor to generate the optimal HTS outcomes. It was also found that CHA scaffolds can produce a uniform cellular response (CV < 0.15) and a wide drug screening window (Z′ > 0.5) on par with commercialized tissue culture plates, and therefore, can serve as a qualified HTS platform. This CHA scaffold-based HTS platform may provide an improved alternative to traditional 2D-cell-based HTS for future cancer study and novel drug discovery. Full article
(This article belongs to the Special Issue Application of Chitosan and Hyaluronan in Medicine)
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16 pages, 7564 KiB  
Article
Chitosan-Based Membranes for Skin Wound Repair in a Dorsal Fold Chamber Rat Model
by Maria Helena Casimiro, Luís M. Ferreira, Pedro M. P. Santos, João P. Leal, Gabriela Rodrigues, Inês Iria, Sara Alves, Diogo Pais and Diogo Casal
Pharmaceutics 2022, 14(12), 2736; https://doi.org/10.3390/pharmaceutics14122736 - 07 Dec 2022
Cited by 2 | Viewed by 1172
Abstract
Frequently, deep partial and full-thickness skin wounds do not spontaneously regenerate. To restore the normal function of skin, epidermal and dermal components have to be supplied to the wound bed by grafting various substrates. Available options are limited and frequently costly. Herein, authors [...] Read more.
Frequently, deep partial and full-thickness skin wounds do not spontaneously regenerate. To restore the normal function of skin, epidermal and dermal components have to be supplied to the wound bed by grafting various substrates. Available options are limited and frequently costly. Herein, authors present a possible approach using 3D skin scaffolds capable of mimicking structure and biological functions of the extracellular matrix, providing, in parallel, a good environment for cell attachment, proliferation and differentiation. Low-molecular weight chitosan-based membranes were prepared by freeze-drying and ionizing radiation techniques to be used as skin scaffolds. Poly (vinyl alcohol), PVA, vinyl pyrrolidone, VP, and gelatin from cold water fish were incorporated. Information regarding membranes’ physical-chemical properties from SEM analysis, swelling and weight loss, together with biological response through in vitro assays (using Human Caucasian Fetal Foreskin Fibroblast) allowed the selection of an optimized batch of membranes that was used as skin scaffold in a dorsal rat model wound. The in vivo implantation assays (in Wistar rats) resulted in very promising results: (i) healing process faster than control; (ii) good vascularization; (iii) viable new tissues morphologically functional. Full article
(This article belongs to the Special Issue Application of Chitosan and Hyaluronan in Medicine)
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13 pages, 2138 KiB  
Article
Protective Abilities of an Inhaled DPI Formulation Based on Sodium Hyaluronate against Environmental Hazards Targeting the Upper Respiratory Tract
by Juhura G. Almazi, Dina M. Silva, Valentina Trotta, Walter Fiore, Hui X. Ong and Daniela Traini
Pharmaceutics 2022, 14(7), 1323; https://doi.org/10.3390/pharmaceutics14071323 - 22 Jun 2022
Cited by 2 | Viewed by 1910
Abstract
The exposure of lung epithelium to environmental hazards is linked to several chronic respiratory diseases. We assessed the ability of an inhaled dry powder (DPI) medical device product (PolmonYDEFENCE/DYFESATM, SOFAR SpA, Trezzano Rosa, Italy), using a formulation of sodium hyaluronate (Na-Hya) [...] Read more.
The exposure of lung epithelium to environmental hazards is linked to several chronic respiratory diseases. We assessed the ability of an inhaled dry powder (DPI) medical device product (PolmonYDEFENCE/DYFESATM, SOFAR SpA, Trezzano Rosa, Italy), using a formulation of sodium hyaluronate (Na-Hya) as the key ingredient as a defensive barrier to protect the upper respiratory tract. Specifically, it was evaluated if the presence of the barrier formed by sodium hyaluronate present on the cells, reducing direct contact of the urban dust (UD) with the surface of cells can protect them in an indirect manner by the inflammatory and oxidative process started in the presence of the UD. Cytotoxicity and the protection capability against the oxidative stress of the product were tested in vitro using Calu-3 cells exposure to UD as a trigger for oxidative stress. Inflammation and wound healing were assessed using an air-liquid interface (ALI) culture model of the Calu-3 cells. Deposition studies of the formulation were conducted using a modified Anderson cascade impactor (ACI) and the monodose PillHaler® dry powder inhaler (DPI) device, Na-Hya was detected and quantified using high-performance-liquid-chromatography (HPLC). Solubilised PolmonYDEFENCE/DYFESATM gives protection against oxidative stress in Calu-3 cells in the short term (2 h) without any cytotoxic effects. ALI culture experiments, testing the barrier-forming (non-solubilised) capabilities of PolmonYDEFENCE/DYFESATM, showed that the barrier layer reduced inflammation triggered by UD and the time for wound closure compared to Na-Hya alone. Deposition experiments using the ACI and the PillHaler® DPI device showed that the majority of the product was deposited in the upper part of the respiratory tract. Finally, the protective effect of the product was efficacious for up to 24 h without affecting mucus production. We demonstrated the potential of PolmonYDEFENCE/DYFESATM as a preventative barrier against UD, which may aid in protecting the upper respiratory tract against environmental hazards and help with chronic respiratory diseases. Full article
(This article belongs to the Special Issue Application of Chitosan and Hyaluronan in Medicine)
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14 pages, 2006 KiB  
Article
Chitooligosaccharides Improve the Efficacy of Checkpoint Inhibitors in a Mouse Model of Lung Cancer
by Astrid Zedlitz Johansen, Marco Carretta, Marie-Louise Thorseth, Shawez Khan, Klaire Yixin Fjæstad, Christian Beltoft Brøchner, Hannes Linder, Christina Ankjærgaard, Marco Donia, Inna Chen, Dorte Lisbet Nielsen, Claus Preibisch Behrens and Daniel Hargbøl Madsen
Pharmaceutics 2022, 14(5), 1046; https://doi.org/10.3390/pharmaceutics14051046 - 12 May 2022
Cited by 4 | Viewed by 2518
Abstract
YKL-40 (also named chitinase 3 like-1 protein [CHI3L1]) is a secreted chitinase-like protein which is upregulated in cancers and suggested to have pro-tumorigenic activity. YKL-40 lacks enzymatic function, but it can bind carbohydrates such as chitin. Chitooligosaccharides (COS) derived from deacetylation and hydrolysis [...] Read more.
YKL-40 (also named chitinase 3 like-1 protein [CHI3L1]) is a secreted chitinase-like protein which is upregulated in cancers and suggested to have pro-tumorigenic activity. YKL-40 lacks enzymatic function, but it can bind carbohydrates such as chitin. Chitooligosaccharides (COS) derived from deacetylation and hydrolysis of chitin might be used for the blockade of YKL-40 function. Here, public single-cell RNA sequencing datasets were used to elucidate the cellular source of YKL-40 gene expression in human tumors. Fibroblasts and myeloid cells were the primary sources of YKL-40. Screening of YKL-40 gene expression in syngeneic mouse cancer models showed the highest expression in the Lewis lung carcinoma (LL2) model. LL2 was used to investigate COS monotherapy and combinations with immune checkpoint inhibitors (anti-PD-L1 and anti-CTLA-4) (ICIs) and radiotherapy (8 Gy × 3) (RT). COS tended to reduce plasma YKL-40 levels, but it did not affect tumor growth. LL2 showed minimal responses to ICIs, or to RT alone. Interestingly, ICIs combined with COS led to delayed tumor growth. RT also enhanced the efficacy of ICIs; however, the addition of COS did not further delay the tumor growth. COS may exert their anti-tumorigenic effects through the inhibition of YKL-40, but additional functions of COS should be investigated. Full article
(This article belongs to the Special Issue Application of Chitosan and Hyaluronan in Medicine)
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19 pages, 2868 KiB  
Article
Thiolated Chitosan Conjugated Liposomes for Oral Delivery of Selenium Nanoparticles
by Atiđa Selmani, Elisabeth Seibert, Carolin Tetyczka, Doris Kuehnelt, Ivan Vidakovic, Karin Kornmueller, Markus Absenger-Novak, Borna Radatović, Ivana Vinković Vrček, Gerd Leitinger, Eleonore Fröhlich, Andreas Bernkop-Schnürch, Eva Roblegg and Ruth Prassl
Pharmaceutics 2022, 14(4), 803; https://doi.org/10.3390/pharmaceutics14040803 - 06 Apr 2022
Cited by 6 | Viewed by 2699
Abstract
This study aimed to design a hybrid oral liposomal delivery system for selenium nanoparticles (Lip-SeNPs) to improve the bioavailability of selenium. Thiolated chitosan, a multifunctional polymer with mucoadhesive properties, was used for surface functionalization of Lip-SeNPs. Selenium nanoparticle (SeNP)-loaded liposomes were manufactured by [...] Read more.
This study aimed to design a hybrid oral liposomal delivery system for selenium nanoparticles (Lip-SeNPs) to improve the bioavailability of selenium. Thiolated chitosan, a multifunctional polymer with mucoadhesive properties, was used for surface functionalization of Lip-SeNPs. Selenium nanoparticle (SeNP)-loaded liposomes were manufactured by a single step microfluidics-assisted chemical reduction and assembling process. Subsequently, chitosan-N-acetylcysteine was covalently conjugated to the preformed Lip-SeNPs. The Lip-SeNPs were characterized in terms of composition, morphology, size, zeta potential, lipid organization, loading efficiency and radical scavenging activity. A co-culture system (Caco-2:HT29-MTX) that integrates mucus secreting and enterocyte-like cell types was used as a model of the human intestinal epithelium to determine adsorption, mucus penetration, release and transport properties of Lip-SeNPs in vitro. Thiolated Lip-SeNPs were positively charged with an average size of about 250 nm. Thiolated Lip-SeNPs tightly adhered to the mucus layer without penetrating the enterocytes. This finding was consistent with ex vivo adsorption studies using freshly excised porcine small intestinal tissues. Due to the improved mucoadhesion and retention in a simulated microenvironment of the small intestine, thiolated Lip-SeNPs might be a promising tool for oral selenium delivery. Full article
(This article belongs to the Special Issue Application of Chitosan and Hyaluronan in Medicine)
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19 pages, 8793 KiB  
Article
Bio-C (Modified Hyaluronic Acid-Coated-Collagen Tube) Implants Enable Functional Recovery after Complete Spinal Cord Injury
by Changhong Zheng, Huina Zhang, Yanling Cui, Yuchen Mu, Kun Jiang, Liqiang Zhou, Junbang Wang, Jiping Liu, Yaxuan Deng, Chunxue Zhang, Wenmin Zhu, Kongyan Wu and Yi Eve Sun
Pharmaceutics 2022, 14(3), 596; https://doi.org/10.3390/pharmaceutics14030596 - 09 Mar 2022
Cited by 1 | Viewed by 2215
Abstract
Neural repair within the central nervous system (CNS) has been extremely challenging due to limited abilities of adult CNS neurons to regenerate, particularly in a highly inflammatory injury environment that is also filled with myelin debris. Spinal cord injury (SCI) is a serious [...] Read more.
Neural repair within the central nervous system (CNS) has been extremely challenging due to limited abilities of adult CNS neurons to regenerate, particularly in a highly inflammatory injury environment that is also filled with myelin debris. Spinal cord injury (SCI) is a serious medical condition that often leads to paralysis and currently has no effective treatment. Here we report the construction of a novel biocompatible and biodegradable material, Bio-C, through coating of acid-desalted-collagen (ADC) tube with pre-modified hyaluronic acid, which, after implantation, can elicit quite robust neural regeneration and functional recovery after complete spinal-cord transection with a 2 mm–spinal-cord-segment removal in mice. We combined morphological, electrophysiological, and objective transcriptomic analyses, in addition to behavioral analyses, to demonstrate neural tissue regeneration and functional recovery through the establishment of Bio-C-induced anti-inflammatory, neurogenic, and neurotrophic microenvironment. Through this study, we unveiled the underlying logic for CNS neural repair. Full article
(This article belongs to the Special Issue Application of Chitosan and Hyaluronan in Medicine)
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13 pages, 2593 KiB  
Article
A Randomized Placebo-Controlled Phase 2 Study of Gemcitabine and Capecitabine with or without T-ChOS as Adjuvant Therapy in Patients with Resected Pancreatic Cancer (CHIPAC)
by Susann Theile, Julia Sidenius Johansen, Dorte Lisbet Nielsen, Benny Vittrup Jensen, Carsten Palnæs Hansen, Jane Preuss Hasselby, Sverrir Vídalín Eiríksson and Inna Markovna Chen
Pharmaceutics 2022, 14(3), 509; https://doi.org/10.3390/pharmaceutics14030509 - 25 Feb 2022
Cited by 2 | Viewed by 1435
Abstract
The antitumor activity of chitooligosaccharides has been suggested. This phase 2 trial evaluated the efficacy and safety of T-ChOS™, in addition to adjuvant chemotherapy, in patients after resection of pancreatic ductal adenocarcinoma (PDAC). In this single-center, randomized, double-blind, placebo-controlled trial using patients ≥18 [...] Read more.
The antitumor activity of chitooligosaccharides has been suggested. This phase 2 trial evaluated the efficacy and safety of T-ChOS™, in addition to adjuvant chemotherapy, in patients after resection of pancreatic ductal adenocarcinoma (PDAC). In this single-center, randomized, double-blind, placebo-controlled trial using patients ≥18 years of age after complete macroscopic resection for PDAC, patients were randomly assigned (1:1) to either a continuous oral T-ChOS group or a placebo group, in combination with gemcitabine (GEM) and oral capecitabine (CAP), for a maximum of six cycles. The primary endpoint was disease-free survival (DFS). Recruitment was stopped prematurely in July 2018, with 21 of planned 180 patients included, due to poor accrual and because modified FOLFIRINOX replaced GEM/CAP for the target population. Nine patients received T-ChOS and twelve received the placebo. The median DFS was 10.8 months (95% CI 5.9–15.7) for the T-ChOS arm and 8.4 months (95% CI 0–21.5) in the placebo arm. Overall, seven patients (78%) in the T-ChOS arm and eight patients (67%) in the placebo arm experienced at least one grade 3–4 treatment-related adverse event, most frequently neutropenia. Altogether, the addition of T-ChOS to chemotherapy in patients after resection of PDAC seems safe. However, the clinical benefit cannot be assessed due to the premature cessation of the trial. Full article
(This article belongs to the Special Issue Application of Chitosan and Hyaluronan in Medicine)
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13 pages, 22569 KiB  
Article
A Non-thermal Biocompatible Plasma-Modified Chitosan Scaffold Enhances Osteogenic Differentiation in Bone Marrow Stem Cells
by Ihn Han, Juie Nahushkumar Rana, Ji-Hye Kim, Eun Ha Choi and Youngsun Kim
Pharmaceutics 2022, 14(2), 465; https://doi.org/10.3390/pharmaceutics14020465 - 21 Feb 2022
Cited by 8 | Viewed by 1766
Abstract
Non-thermal biocompatible plasma (NBP) was considered as an efficient tool in tissue engineering to modify the surface of biomaterials. Three-dimensional chitosan scaffolds have been extensively used in different ways because it holds some remarkable properties, including biodegradability and biocompatibility. In this study, we [...] Read more.
Non-thermal biocompatible plasma (NBP) was considered as an efficient tool in tissue engineering to modify the surface of biomaterials. Three-dimensional chitosan scaffolds have been extensively used in different ways because it holds some remarkable properties, including biodegradability and biocompatibility. In this study, we evaluated the osteogenic potential of NBP-treated chitosan scaffolds using two different plasma sources: a dielectric barrier discharge (NBP-DBD) and a soft jet (NBP-J). The surface modification of the scaffold was evaluated using scanning electron microscopy. For osteogenic differentiation of cells, proliferation and differentiation were tested by using bone marrow-derived stem cells (BMSCs). We observed that cell viability using NBP-DBD and NBP-J treated chitosan scaffolds yielded significant improvements in cell viability and differentiation. The results obtained with MTT and live/dead assays showed that NBP-modified scaffold increases cell metabolic by MTT assay and live/dead assay. It also observed that the NBP treatment is more effective at 5 min with DBD and was selected for further investigations. Enhanced osteogenic differentiation was observed using NBP-treated scaffolds, as reflected by increased alkaline phosphatase activity. Our findings showed that NBP is an innovative and beneficial tool for modifying chitosan scaffolds to increase their activity, making them suitable as biocompatible materials and for bone tissue engineering. Full article
(This article belongs to the Special Issue Application of Chitosan and Hyaluronan in Medicine)
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27 pages, 12947 KiB  
Article
Genipin-Crosslinked, Proteosaccharide Scaffolds for Potential Neural Tissue Engineering Applications
by Henna Cassimjee, Pradeep Kumar, Philemon Ubanako and Yahya E. Choonara
Pharmaceutics 2022, 14(2), 441; https://doi.org/10.3390/pharmaceutics14020441 - 18 Feb 2022
Cited by 9 | Viewed by 2740
Abstract
Traumatic brain injuries (TBIs) are still a challenge for the field of modern medicine. Many treatment options such as autologous grafts and stem cells show limited promise for the treatment and the reversibility of damage caused by TBIs. Injury beyond the critical size [...] Read more.
Traumatic brain injuries (TBIs) are still a challenge for the field of modern medicine. Many treatment options such as autologous grafts and stem cells show limited promise for the treatment and the reversibility of damage caused by TBIs. Injury beyond the critical size necessitates the implementation of scaffolds that function as surrogate extracellular matrices. Two scaffolds were synthesised utilising polysaccharides, chitosan and hyaluronic acid in conjunction with gelatin. Both scaffolds were chemically crosslinked using a naturally derived crosslinker, Genipin. The polysaccharides increased the mechanical strength of each scaffold, while gelatin provided the bioactive sequence, which promoted cellular interactions. The effect of crosslinking was investigated, and the crosslinked hydrogels showed higher thermal decomposition temperatures, increased resistance to degradation, and pore sizes ranging from 72.789 ± 16.85 µm for the full interpenetrating polymer networks (IPNs) and 84.289 ± 7.658 μm for the semi-IPN. The scaffolds were loaded with Dexamethasone-21-phosphate to investigate their efficacy as a drug delivery vehicle, and the full IPN showed a 100% release in 10 days, while the semi-IPN showed a burst release in 6 h. Both scaffolds stimulated the proliferation of rat pheochromocytoma (PC12) and human glioblastoma multiforme (A172) cell cultures and also provided signals for A172 cell migration. Both scaffolds can be used as potential drug delivery vehicles and as artificial extracellular matrices for potential neural regeneration. Full article
(This article belongs to the Special Issue Application of Chitosan and Hyaluronan in Medicine)
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18 pages, 2743 KiB  
Article
PEGylated Chitosan Nanoparticles Encapsulating Ascorbic Acid and Oxaliplatin Exhibit Dramatic Apoptotic Effects against Breast Cancer Cells
by Sherif Ashraf Fahmy, Asmaa Ramzy, Asmaa A. Mandour, Soad Nasr, Anwar Abdelnaser, Udo Bakowsky and Hassan Mohamed El-Said Azzazy
Pharmaceutics 2022, 14(2), 407; https://doi.org/10.3390/pharmaceutics14020407 - 13 Feb 2022
Cited by 29 | Viewed by 2758
Abstract
This study aims to design a pH-responsive dual-loaded nanosystem based on PEGylated chitosan nanoparticles loaded with ascorbic acid (AA) and oxaliplatin (OX) for the effective treatment of breast cancer. In this regard, non-PEGylated and PEGylated chitosan nanoparticles (CS NPs) loaded with either ascorbic [...] Read more.
This study aims to design a pH-responsive dual-loaded nanosystem based on PEGylated chitosan nanoparticles loaded with ascorbic acid (AA) and oxaliplatin (OX) for the effective treatment of breast cancer. In this regard, non-PEGylated and PEGylated chitosan nanoparticles (CS NPs) loaded with either ascorbic acid (AA), oxaliplatin (OX), or dual-loaded with AA-OX were fabricated using the ionotropic gelation method. The hydrodynamic diameters of the fabricated AA/CS NPs, OX/CS NPs, and AA-OX/CS NPs were 157.20 ± 2.40, 188.10 ± 9.70, and 261.10 ± 9.19 nm, respectively. While the hydrodynamic diameters of the designed AA/PEG-CS NPs, OX/PEG-CS NPs, and AA-OX/PEG-CS NPs were 152.20 ± 2.40, 156.60 ± 4.82, and 176.00 ± 4.21 nm, respectively. The ζ-potential of the prepared nanoparticles demonstrated high positive surface charges of +22.02 ± 1.50, +22.58 ± 1.85 and +40.4 ± 2.71 mV for AA/CS NPs, OX/CS NPs, and AA-OX/CS NPs, respectively. The ζ-potential of the PEGylated CS NPs was reduced owing to the shielding of the positive charges by the PEG chains. Additionally, all the prepared nanoparticles exhibited high entrapment efficiencies (EE%) and spherical-shaped morphology. The chemical features of the prepared nanoparticles were investigated using Fourier transform infrared (FTIR) spectroscopy. Release studies showed the capability of the prepared non-PEGylated and PEGylated chitosan NPs to release their cargo in the acidic environment of cancer tissue (pH 5.5). Furthermore, the AA/CS NPs, AA/PEG-CS NPs, OX/CS NPs, OX/PEG-CS NPs, AA-OX/CS NPs and AA-OX/PEG-CS NPs exhibited remarkable cytotoxic activities against breast adenocarcinoma (MCF-7) cells with IC50 values of 44.87 ± 11.49, 23.3 ± 3.73, 23.88 ± 6.29, 17.98 ± 3.99, 18.69 ± 2.22, and 7.5 ± 0.69 µg/mL, respectively; as compared to free AA and OX (IC50 of 150.80 ± 26.50 and 147.70 ± 63.91 µg/mL, respectively). Additionally, treatment of MCF-7 cells with IC50 concentrations of AA, AA/CS NPs, AA/PEG-CS NPs, OX, OX/CS NPs, OX/PEG-CS NPs, AA-OX/CS NPs or AA-OX/PEG-CS NPs increased the percentages of early apoptotic cells to 5.28%, 9.53%, 11.20%, 5.27%, 13.80%, 8.43%, 2.32%, and 10.10%, respectively, and increased the percentages of late apoptotic cells to 0.98%, 0.37%, 2.41%, 2.06%, 0.97%, 9.66%, 56%, and 81.50%, respectively. These results clearly indicate that PEGylation enhances the apoptotic effect of AA and OX alone, in addition to potentiating the apoptotic effect of AA and OX when combined on MCF-7 cells. In conclusion, PEGylated chitosan nanoparticles encapsulating AA, OX, or AA and OX represent an effective formula for induction of apoptosis in MCF-7 cells. Full article
(This article belongs to the Special Issue Application of Chitosan and Hyaluronan in Medicine)
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16 pages, 2259 KiB  
Article
Design of Bio-Responsive Hyaluronic Acid–Doxorubicin Conjugates for the Local Treatment of Glioblastoma
by Alessio Malfanti, Giuseppina Catania, Quentin Degros, Mingchao Wang, Mathilde Bausart and Véronique Préat
Pharmaceutics 2022, 14(1), 124; https://doi.org/10.3390/pharmaceutics14010124 - 05 Jan 2022
Cited by 16 | Viewed by 2347
Abstract
Glioblastoma is an unmet clinical need. Local treatment strategies offer advantages, such as the possibility to bypass the blood–brain barrier, achieving high drug concentrations at the glioblastoma site, and consequently reducing systemic toxicity. In this study, we evaluated the feasibility of using hyaluronic [...] Read more.
Glioblastoma is an unmet clinical need. Local treatment strategies offer advantages, such as the possibility to bypass the blood–brain barrier, achieving high drug concentrations at the glioblastoma site, and consequently reducing systemic toxicity. In this study, we evaluated the feasibility of using hyaluronic acid (HA) for the local treatment of glioblastoma. HA was conjugated to doxorubicin (DOX) with distinct bio-responsive linkers (direct amide conjugation HA-NH-DOX), direct hydrazone conjugation (HA-Hz-DOX), and adipic hydrazone (HA-AdpHz-DOX). All HA-DOX conjugates displayed a small size (less than 30 nm), suitable for brain diffusion. HA-Hz-DOX showed the best performance in killing GBM cells in both 2D and 3D in vitro models and displayed superior activity in a subcutaneous GL261 tumor model in vivo compared to free DOX and other HA-DOX conjugates. Altogether, these results demonstrate the feasibility of HA as a polymeric platform for the local treatment of glioblastoma and the importance of rationally designing conjugates. Full article
(This article belongs to the Special Issue Application of Chitosan and Hyaluronan in Medicine)
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15 pages, 5067 KiB  
Article
Combination of Two Kinds of Medicated Microparticles Based on Hyaluronic Acid or Chitosan for a Wound Healing Spray Patch
by Angela Fabiano, Chiara Migone, Luca Cerri, Anna Maria Piras, Andrea Mezzetta, Giuseppantonio Maisetta, Semih Esin, Giovanna Batoni, Rossella Di Stefano and Ylenia Zambito
Pharmaceutics 2021, 13(12), 2195; https://doi.org/10.3390/pharmaceutics13122195 - 18 Dec 2021
Cited by 9 | Viewed by 2741
Abstract
Olive leaves extract (OLE) has been extensively studied as antioxidant and antibiotic and these characteristics make it particularly interesting for use on wounds. For this reason, the aim of this study was to introduce OLE in microparticles (MP) of hyaluronic acid (MPHA-OLE) or [...] Read more.
Olive leaves extract (OLE) has been extensively studied as antioxidant and antibiotic and these characteristics make it particularly interesting for use on wounds. For this reason, the aim of this study was to introduce OLE in microparticles (MP) of hyaluronic acid (MPHA-OLE) or chitosan (MPCs-OLE) to obtain a spray patch for the treatment of wounds in anatomical areas that are difficult to protect with traditional patches. The MP were characterized for particle size and ability to protect OLE from degradation, to absorb water from wound exudate, to control OLE release from MP. The MPHA and MPCs medicated or not and mixtures of the two types in different proportions were studied in vitro on fibroblasts by the scratch wound healing assay. The MP size was always less than 5 µm, and therefore, suitable for a spray patch. The MPCs-OLE could slow down the release of OLE therefore only about 60% of the polyphenols contained in it were released after 4 h. Both MPHA and MPCs could accelerate wound healing. A 50% MPHA-OLE-50% MPCs-OLE blend was the most suitable for accelerating wound healing. The MPHA-OLE-MPCs-OLE blends studied in this work were shown to have the characteristics suitable for a spray patch, thus giving a second life to the waste products of olive growers. Full article
(This article belongs to the Special Issue Application of Chitosan and Hyaluronan in Medicine)
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10 pages, 2206 KiB  
Article
Comparative Study of Chitosan and Oligochitosan Coatings on Mucoadhesion of Curcumin Nanosuspensions
by Gye Hwa Shin and Jun Tae Kim
Pharmaceutics 2021, 13(12), 2154; https://doi.org/10.3390/pharmaceutics13122154 - 14 Dec 2021
Cited by 10 | Viewed by 2396
Abstract
Curcumin nanosuspensions (Cur-NSs), chitosan-coated Cur-NSs (CS-Cur-NSs), and oligochitosan-coated Cur-NSs (OCS-Cur-NSs) were prepared by using an ultrasonic homogenization technique. The mean particle size of Cur-NSs was 210.9 nm and significantly (p < 0.05) increased to 368.8 nm by CS coating and decreased to [...] Read more.
Curcumin nanosuspensions (Cur-NSs), chitosan-coated Cur-NSs (CS-Cur-NSs), and oligochitosan-coated Cur-NSs (OCS-Cur-NSs) were prepared by using an ultrasonic homogenization technique. The mean particle size of Cur-NSs was 210.9 nm and significantly (p < 0.05) increased to 368.8 nm by CS coating and decreased to 172.8 nm by OCS coating. Encapsulation efficiencies of Cur-NSs, CS-Cur-NSs, and OCS-Cur-NSs were 80.6%, 91.4%, and 88.5%, respectively. The mucin adsorption of Cur-NSs was steeply increased about 3–4 times by CS and OCS coating. Morphological changes of these NSs were studied using circular dichroism spectroscopy, Fourier-transform infrared (FT-IR) spectroscopy, and transmission electron microscopy (TEM). Thus, CS-Cur-NSs and OCS-Cur-NSs showed great potential as mucoadhesive nano-carriers for the efficient delivery of water insoluble compounds like curcumin to the gastrointestinal system. Full article
(This article belongs to the Special Issue Application of Chitosan and Hyaluronan in Medicine)
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16 pages, 3598 KiB  
Article
Chitosan–Platelet-Rich Plasma Implants Improve Rotator Cuff Repair in a Large Animal Model: Pivotal Study
by Anik Chevrier, Mark B. Hurtig and Marc Lavertu
Pharmaceutics 2021, 13(11), 1955; https://doi.org/10.3390/pharmaceutics13111955 - 18 Nov 2021
Cited by 3 | Viewed by 1683
Abstract
The purpose of this study was to assess the safety and efficacy of chitosan–platelet-rich plasma (PRP) hybrid implants used as an adjunct to surgical rotator cuff repair in a pivotal Good Laboratory Practice (GLP)-compliant study. The infraspinatus tendon was transected in 48 skeletally [...] Read more.
The purpose of this study was to assess the safety and efficacy of chitosan–platelet-rich plasma (PRP) hybrid implants used as an adjunct to surgical rotator cuff repair in a pivotal Good Laboratory Practice (GLP)-compliant study. The infraspinatus tendon was transected in 48 skeletally mature ewes and repaired with a transosseous-equivalent (TOE) technique. In the two treatment groups, a chitosan–PRP solution was injected at the footprint between the tendon and the bone and on top of the repaired site (2 mL or 3 mL doses, n = 12 per group). To further assess chitosan safety, a chitosan–water solution was injected at the same sites (3 mL, n = 12). Outcome measures included Magnetic Resonance Imaging (MRI) assessment and clinical pathology at 3 months and 6 months and histopathology at 6 months. The tendon gap was decreased at 3 months on MRI images and certain histopathological features were improved at 6 months by chitosan–PRP treatment compared to controls. The group treated with chitosan–water was not different from controls. Chitosan–PRP treatment induced no negative effects in the sheep, which suggests high safety. This study provides further evidence on the safety and efficacy of chitosan–PRP for rotator cuff repair augmentation, which could eventually be used in a clinical setting. Full article
(This article belongs to the Special Issue Application of Chitosan and Hyaluronan in Medicine)
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12 pages, 6065 KiB  
Article
Towards the Development of a Female Animal Model of T1DM Using Hyaluronic Acid Nanocoated Cell Transplantation: Refinements and Considerations for Future Protocols
by Fernanda Zamboni, Ibrahim F. Cengiz, Ana M. Barbosa, Antonio G. Castro, Rui L. Reis, Joaquim M. Oliveira and Maurice N. Collins
Pharmaceutics 2021, 13(11), 1925; https://doi.org/10.3390/pharmaceutics13111925 - 13 Nov 2021
Cited by 12 | Viewed by 1919
Abstract
Female mice (Black 6 strain) (C57BL/6) aged 6 weeks were subject to low dose streptozotocin (STZ) treatment for five consecutive days to mimic type 1 diabetes mellitus (T1DM) with insulitis. At two weeks after STZ injections, evaluation of the elevated glucose levels was [...] Read more.
Female mice (Black 6 strain) (C57BL/6) aged 6 weeks were subject to low dose streptozotocin (STZ) treatment for five consecutive days to mimic type 1 diabetes mellitus (T1DM) with insulitis. At two weeks after STZ injections, evaluation of the elevated glucose levels was used to confirm diabetes. The diabetic mice were then subject to the transplantation of pancreatic β-cells (MIN-6 line). Four groups of mice were studied. The first group was injected with saline-only acting as the placebo surgery control, also known as SHAM group, the second and third groups were injected with MIN-6 single cells and polyethylene glycol-modified dipalmitoyl-glycerol-phosphatidyl ethanolamine (PEG-DPPE) modified MIN-6 single cells (500 µg per 1.106 cells), respectively, while the fourth group was injected with hyaluronic acid (HA)-coated MIN-6 single cells (5 bilayers). At seven- and fourteen-days following transplantation, the mice were euthanised. The renal and pancreatic tissues were then collected and histologically analysed. The induction of diabetes in female mice, through five-consecutive daily STZ injections resulted in inconsistent glycaemic levels. Interestingly, this shows an incomplete diabetes induction in female mice, of which we attribute to sex dimorphism and hormonal interferences. Transplantation failure of free-floating encapsulated cells was unable to decrease blood glucose hyperglycaemia to physiological ranges. The result is attributed to deprived cell–cell interactions, leading to decreased β-cells functionality. Overall, we highlight the necessity of refining T1DM disease models in female subjects when using multiple low-dose STZ injections together with transplantation protocols. Considerations need to be made regarding the different developmental stages of female mice and oestrogen load interfering with pancreatic β-cells susceptibility to STZ. The use of pseudo islets, cell aggregates and spheroids are sought to improve transplantation outcome in comparison to free-floating single cells. Full article
(This article belongs to the Special Issue Application of Chitosan and Hyaluronan in Medicine)
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17 pages, 3794 KiB  
Article
Design, Synthesis, Characterization, and In Vitro Evaluation of a New Cross-Linked Hyaluronic Acid for Pharmaceutical and Cosmetic Applications
by Sabrina Sciabica, Giovanni Tafuro, Alessandra Semenzato, Daniela Traini, Dina M. Silva, Larissa Gomes Dos Reis, Luisa Canilli, Massimo Terno, Elisa Durini, Silvia Vertuani, Anna Baldisserotto and Stefano Manfredini
Pharmaceutics 2021, 13(10), 1672; https://doi.org/10.3390/pharmaceutics13101672 - 13 Oct 2021
Cited by 7 | Viewed by 2524
Abstract
Hyaluronic acid (HA), an excellent biomaterial with unique bio properties, is currently one of the most interesting polymers for many biomedical and cosmetic applications. However, several of its potential benefits are limited as it is rapidly degraded by hyaluronidase enzymes. To improve the [...] Read more.
Hyaluronic acid (HA), an excellent biomaterial with unique bio properties, is currently one of the most interesting polymers for many biomedical and cosmetic applications. However, several of its potential benefits are limited as it is rapidly degraded by hyaluronidase enzymes. To improve the half-life and consequently increase performance, native HA has been modified through cross-linking reactions with a natural and biocompatible amino acid, Ornithine, to overcome the potential toxicity commonly associated with traditional linkers. 2-chloro-dimethoxy-1,3,5-triazine/4-methylmorpholine (CDMT/NMM) was used as an activating agent. The new product (HA–Orn) was extensively characterized to confirm the chemical modification, and rheological analysis showed a gel-like profile. In vitro degradation experiments showed an improved resistance profile against enzymatic digestions. Furthermore, in vitro cytotoxicity studies were performed on lung cell lines (Calu-3 and H441), which showed no cytotoxicity. Full article
(This article belongs to the Special Issue Application of Chitosan and Hyaluronan in Medicine)
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Review

Jump to: Research

35 pages, 13391 KiB  
Review
Hyaluronic Acid: Known for Almost a Century, but Still in Vogue
by Anna Lierova, Jitka Kasparova, Alzbeta Filipova, Jana Cizkova, Lenka Pekarova, Lucie Korecka, Nikola Mannova, Zuzana Bilkova and Zuzana Sinkorova
Pharmaceutics 2022, 14(4), 838; https://doi.org/10.3390/pharmaceutics14040838 - 11 Apr 2022
Cited by 23 | Viewed by 4698
Abstract
Hyaluronic acid (HA) has a special position among glycosaminoglycans. As a major component of the extracellular matrix (ECM). This simple, unbranched polysaccharide is involved in the regulation of various biological cell processes, whether under physiological conditions or in cases of cell damage. This [...] Read more.
Hyaluronic acid (HA) has a special position among glycosaminoglycans. As a major component of the extracellular matrix (ECM). This simple, unbranched polysaccharide is involved in the regulation of various biological cell processes, whether under physiological conditions or in cases of cell damage. This review summarizes the history of this molecule’s study, its distinctive metabolic pathway in the body, its unique properties, and current information regarding its interaction partners. Our main goal, however, is to intensively investigate whether this relatively simple polymer may find applications in protecting against ionizing radiation (IR) or for therapy in cases of radiation-induced damage. After exposure to IR, acute and belated damage develops in each tissue depending upon the dose received and the cellular composition of a given organ. A common feature of all organ damage is a distinct change in composition and structure of the ECM. In particular, the important role of HA was shown in lung tissue and the variability of this flexible molecule in the complex mechanism of radiation-induced lung injuries. Moreover, HA is also involved in intermediating cell behavior during morphogenesis and in tissue repair during inflammation, injury, and would healing. The possibility of using the HA polymer to affect or treat radiation tissue damage may point to the missing gaps in the responsible mechanisms in the onset of this disease. Therefore, in this article, we will also focus on obtaining answers from current knowledge and the results of studies as to whether hyaluronic acid can also find application in radiation science. Full article
(This article belongs to the Special Issue Application of Chitosan and Hyaluronan in Medicine)
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18 pages, 3025 KiB  
Review
General Characteristics, Biomedical and Dental Application, and Usage of Chitosan in the Treatment of Temporomandibular Joint Disorders: A Narrative Review
by Marcin Derwich, Lukasz Lassmann, Katarzyna Machut, Agata Zoltowska and Elzbieta Pawlowska
Pharmaceutics 2022, 14(2), 305; https://doi.org/10.3390/pharmaceutics14020305 - 27 Jan 2022
Cited by 5 | Viewed by 3318
Abstract
The aim of this narrative review was to present research investigating chitosan, including its general characteristics, properties, and medical and dental applications, and finally to present the current state of knowledge regarding the efficacy of chitosan in the treatment of temporomandibular disorders (TMDs) [...] Read more.
The aim of this narrative review was to present research investigating chitosan, including its general characteristics, properties, and medical and dental applications, and finally to present the current state of knowledge regarding the efficacy of chitosan in the treatment of temporomandibular disorders (TMDs) based on the literature. The PICO approach was used for the literature search strategy. The PubMed database was analyzed with the following keywords: (“chitosan”[MeSH Terms] OR “chitosan”[All Fields] OR “chitosans”[All Fields] OR “chitosan s”[All Fields] OR “chitosane”[All Fields]) AND (“temporomandibular joint”[MeSH Terms] OR (“tem-poromandibular”[All Fields] AND “joint”[All Fields]) OR “temporomandibular joint”[All Fields] OR (“temporomandibular”[All Fields] AND “joints”[All Fields]) OR “temporo-mandibular joints”[All Fields]). After screening 8 results, 5 studies were included in this review. Chitosan presents many biological properties and therefore it can be widely used in several branches of medicine and dentistry. Chitosan promotes wound healing, helps to control bleeding, and is used in wound dressings, such as sutures and artificial skin. Apart from its antibacterial property, chitosan has many other properties, such as antifungal, mucoadhesive, anti-inflammatory, analgesic, antioxidant, antihyperglycemic, and antitumoral properties. Further clinical studies assessing the efficacy of chitosan in the treatment of TMD are required. According to only one clinical study, chitosan was effective in the treatment of TMD; however, better clinical results were obtained with platelet-rich plasma. Full article
(This article belongs to the Special Issue Application of Chitosan and Hyaluronan in Medicine)
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13 pages, 1407 KiB  
Review
Assessment of the Substance Antioxidative Profile by Hyaluronan, Cu(II) and Ascorbate
by Katarína Valachová and Ladislav Šoltés
Pharmaceutics 2021, 13(11), 1815; https://doi.org/10.3390/pharmaceutics13111815 - 31 Oct 2021
Cited by 3 | Viewed by 1476
Abstract
In the minireview presented here, the authors discuss the evaluation of inhibitory effect of substances in the phases of initiation and propagation of high-molar-mass hyaluronan oxidative degradation. The experimental approach should be considered as original since on using a simple experimental assay it [...] Read more.
In the minireview presented here, the authors discuss the evaluation of inhibitory effect of substances in the phases of initiation and propagation of high-molar-mass hyaluronan oxidative degradation. The experimental approach should be considered as original since on using a simple experimental assay it is possible to prove both the so-called “preventive” and “chain-breaking” antioxidant activity of investigated water-soluble endo- or exogenous substances. Full article
(This article belongs to the Special Issue Application of Chitosan and Hyaluronan in Medicine)
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