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Chitosan Biomedical Applications: Opportunities and Challenges

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A special issue of Pharmaceutics (ISSN 1999-4923).

Deadline for manuscript submissions: closed (15 November 2018) | Viewed by 52185

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Special Issue Editors

Prof. Dr. Carla Marcella Caramella

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Guest Editor

Department of Drug Sciences, University of Pavia, 27100 Pavia, Italy
Interests: mucosal delivery; mucoadhesion; nanosystems

Prof. Dr. Silvia Rossi

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Guest Editor

Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy
Interests: rheology and viscosimetry; mucoadhesion; in situ gelling polymers; micro- and nanoparticulate systems; statistical optimization techniques; wound dressings, nervous tissue repair
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Giuseppina Sandri

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Guest Editor

Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy
Interests: nanoparticles; nanofibers; in situ gelling systems; scaffolds; tissue engineering
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Chitosans represent a family of polymers of natural origin that possess unique physico-chemical, pharmaceutical and biological properties. In particular they offer the advantages of biocompatibility and biodegradability, which favour their applications in medical fields, chemical versatility and technological versatility,which make them ideal ingredients for a variety of formulations (hydrogels, xerogels, powders, films, sponges, scaffolds, nanostructures).

Chitosans also possess a variety of biological properties like hemostatic and angiogenic activity, antimicrobial properties, radical scavenging and antioxidant activity. All these properties, coupled with the ability of stimulating granulation process, facilitate the proliferative remodelling phase of wound healing sequence.

Due to their unique polycationic nature, chitosans are among the most popular mucoadhesive agents and known to promote transmucosal and transepithelial drug absorption. They also inhibit intestinal fat absorption and improve intestinal microflora.

Because of their versatility, chitosan and chitosan derivatives have been studied for a number of biomedical applications, ranging from medicinals to medical devices and combination (drug plus device) products and are largely available on the market as nutraceuticals.

Pharmaceutical applications likely include the development of drug products, for both small and complex molecules, intended for nasal, ophtalmic, intestinal and cutaneous administration, as well as the employment in immunological medicinal products (vaccines, ..) and in advanced therapy products (tissue engineering, gene delivery). In the field of medical devices and combination products, chitosans are already used in tissue repair as adsorbent, hemostatic, antimicrobial and dental dressings, and proposed for tissue regeneration as, for example, hydrogel scaffolding for cell proliferation, bone graft substitutes, dental fillers.

Despite this favourable scenario, there are many issues that need to be addessed attentively even in the early research and developmen phases, namely the quality of both native and semisyntehtic chitosans, primarily the characterization and stardardization of chemical and physico-chemical properties, but also the safety issues linked to their natural origin, extraction or semisynthetic processes, or even intrinsic biological activities that may trigger unwanted effects. Failure to look at these aspects would delay the translation of the research products into the clinic and ultimately compromise the regulatory approval.

Besides these difficulties, we want to deliver a positive message on the future of the developmental research on chitosans biomedical products, in particular in certain challenging therapeutic areas. As an example, in the area of wound healing and tissue repair there are still important unmet medical needs (e.g. the treatment of chronic lesions ), which, together with the increasing demand of such products due to population aging and on behalf of new emerging countries, allow an encouraging message to be conveyed to the researchers engaged in these challenges.

This special issue is dedicated to recent novel and innovative contributions in the field of biomedical applications of chitosans and derivatives. These may concern both medicated and unmedicated (medical device) products, both formulation development and manufacturing processes, both native chitosans and their derivatives. Contributions from PhD students, post-doc and and young investigators will be welcome.

We invite the researchers to contribute their original research work, but also review articles that are related to the topic will be considered.

Prof. Dr. Carla M. Caramella
Prof. Dr. Silvia Rossi
Prof. Dr. Giuseppina Sandri
Guest Editors

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Keywords

Chitosan
Chitosan derivatives
Wound healing
Tissue repair
Medical devices
Tissue engineering
Chitosan regulatory status

Published Papers (10 papers)

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Research

10 pages, 1955 KiB

Open AccessArticle

Design and Evaluation of An Extended-Release Olmesartan Tablet Using Chitosan/Cyclodextrin Composites

by Makoto Anraku, Ryo Tabuchi, Miwa Goto, Daisuke Iohara, Yasuyuki Mizukai, Yuji Maezaki, Akihiro Michihara, Daisuke Kadowaki, Masaki Otagiri and Fumitoshi Hirayama

Pharmaceutics 2019, 11(2), 82; https://doi.org/10.3390/pharmaceutics11020082 - 15 Feb 2019

Cited by 5 | Viewed by 3495

Abstract

Sustained-release olmesartan tablets (OLM) were prepared by the simple, direct compression of composites of anionic sulfobutyl ether-β-cyclodextrin (SBE-β-CD) and cationic spray-dried chitosan (SD-CS), and were evaluated for use as a sustained release preparation for the treatment of hypertension. An investigation of the interaction between OLM and SBE-β-CD by the solubility method indicated that the phase diagram of the OLM/SBE-β-CD system was the A_L type, indicating the formation of a 1:1 inclusion complex. The release of OLM from tablets composed of the SD-CS/SBE-β-CD composite was slow in media at both pH 1.2 and at 6.8. The in vitro slow release characteristics of the SD-CS/SBE-β-CD composite were reflected in the in vivo absorption of the drug after normal rats were given an oral administration of the preparation. Furthermore, the SD-CS/SBE-β-CD composite continuously increased the antihypertensive effect of OLM in hypertensive rats, compared with that of the drug itself. These results suggest that a simple mixing of SD-CS and SBE-β-CD can be potentially useful for the controlled release of a drug for the continuous treatments of hypertension. Full article

(This article belongs to the Special Issue Chitosan Biomedical Applications: Opportunities and Challenges)

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19 pages, 4527 KiB

Open AccessArticle

Chitosan-Based Mucoadhesive Vaginal Tablets for Controlled Release of the Anti-HIV Drug Tenofovir

by Raúl Cazorla-Luna, Fernando Notario-Pérez, Araceli Martín-Illana, Roberto Ruiz-Caro, Aitana Tamayo, Juan Rubio and María Dolores Veiga

Pharmaceutics 2019, 11(1), 20; https://doi.org/10.3390/pharmaceutics11010020 - 05 Jan 2019

Cited by 41 | Viewed by 5862

Abstract

Vaginal microbicides have the potential to give women at high risk of contracting HIV the option of self-protection by preventing the sexual transmission of the virus. In this paper, mucoadhesive vaginal tablets based on chitosan, alone and in combination with pectin and locust bean gum, were developed for the sustained release of tenofovir (an antiretroviral drug). The formulations were placed in simulant vaginal fluid (SVF) to swell, and Hg porosity and SEM microscopy were used for the microstructural characterization of the swelling witnesses. The results show that the association of pectin and chitosan generated polyelectrolyte complexes and produced a robust system able to maintain its structure during the swelling process, when small pores are formed. Drug release and bovine vaginal mucoadhesion studies were performed in SVF showing that tenofovir-controlled dissolution profiles and adhesion to the mucosa were conditioned by the swelling processes of the polymer/s in each formulation. Tablets based on chitosan/pectin have the most homogeneous tenofovir dissolution profiles and last up to 96 h, remaining attached to the vaginal mucosa for the same period. These formulations can therefore be considered a good option for the self-protection of women from the sexual transmission of HIV. Full article

(This article belongs to the Special Issue Chitosan Biomedical Applications: Opportunities and Challenges)

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11 pages, 3292 KiB

Open AccessArticle

Sequential Photodynamic Therapy with Phthalocyanine Encapsulated Chitosan-Tripolyphosphate Nanoparticles and Flucytosine Treatment against Candida tropicalis

by Yi-Hsuan Hsieh, Wen-Ching Chuang, Kun-Hua Yu, Cheng-Ping Jheng and Cheng-I Lee

Pharmaceutics 2019, 11(1), 16; https://doi.org/10.3390/pharmaceutics11010016 - 04 Jan 2019

Cited by 19 | Viewed by 3665

Abstract

Antibiotic resistance has become a crisis. Candida tropicalis (C. tropicalis) is one of the most highly virulent and drug-resistant pathogens. An alternative antimicrobial therapy to eradicate C. tropicalis effectively, without the risk of developing drug-resistance, is needed. Photodynamic therapy (PDT) is an alternative therapy that does not carry the risk of undesired drug resistance. To target the pathogens and to enhance the cellular penetration of the applied photosensitizer, we fabricated cationic chitosan/tripolyphosphate nanoparticles to encapsulate phthalocyanine. Our strategy promotes the uptake of phthalocyanine four-fold. This enhanced PDT can effectively inhibit planktonic C. tropicalis, such that only ~20% of C. tropicalis in the test survived; but it has a limited ability to inhibit adherent C. tropicalis. Further tests with adherent C. tropicalis indicated that sequential treatment with PDT and flucytosine significantly eliminates pseudohyphae and yeast-like C. tropicalis cells. The cell viability is only ~10% after this sequential treatment. This study provides evidence of an effective therapy against drug resistant C. tropicalis, and this strategy can be potentially applied to other pathogens. Full article

(This article belongs to the Special Issue Chitosan Biomedical Applications: Opportunities and Challenges)

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14 pages, 2747 KiB

Open AccessArticle

Chitosan-Polylactide/Hyaluronic Acid Complex Microspheres as Carriers for Controlled Release of Bioactive Transforming Growth Factor-β1

by Qing Min, Jiaoyan Liu, Jing Li, Ying Wan and Jiliang Wu

Pharmaceutics 2018, 10(4), 239; https://doi.org/10.3390/pharmaceutics10040239 - 17 Nov 2018

Cited by 7 | Viewed by 4799

Abstract

Chitosan(CH)-polylactide(PLA) copolymers containing varied PLA percentages were synthesized using a group-protection method and one of them with solubility in water-based solvents was used to prepare CH-PLA/hyaluronic acid (HA) complex microspheres for the delivery of transforming growth factor-β1 (TGF-β1). An emulsification processing method was developed for producing TGF-β1-loaded CH-PLA/HA microspheres using sodium tripolyphosphate (TPP) as ionic crosslinker and the size of the microspheres was devised to the micron level in order to achieve high encapsulating efficiency. The encapsulating efficiency, swelling property and release administration of the microspheres could be synergistically regulated by PLA component, the applied TPP dose and the incorporated HA amount. In comparison to CH/HA microspheres, the CH-PLA/HA microspheres had greatly reduced TGF-β1 release rates and were able to administrate the TGF-β1 release at controlled rates over a significant longer period of time. The released TGF-β1 was detected to be bioactive when compared to the free TGF-β1. These results suggest that the presently developed CH-PLA/HA complex microspheres have promising potential in delivering TGF-β1 for cartilage repair applications where the applied TGF-β1 amount in the early stage needs to be low whilst the sustained TGF-β1 release at an appropriate dose in the later stage has to be maintained Full article

(This article belongs to the Special Issue Chitosan Biomedical Applications: Opportunities and Challenges)

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16 pages, 3032 KiB

Open AccessArticle

Optimized Chitosan/Anion Polyelectrolyte Complex Based Inserts for Vaginal Delivery of Fluconazole: In Vitro/In Vivo Evaluation

by Bayan Darwesh, Hibah M. Aldawsari and Shaimaa M. Badr-Eldin

Pharmaceutics 2018, 10(4), 227; https://doi.org/10.3390/pharmaceutics10040227 - 12 Nov 2018

Cited by 28 | Viewed by 3579

Abstract

(1) Background: Fluconazole, used orally for vaginal candidiasis, has reported gastrointestinal side effects. Therefore, researchers directed towards the drug vaginal delivery. However, vaginal delivery is limited by poor retention and leakage. Thus, this work aimed at exploring chitosan/anion polyelectrolyte complex (PEC) for the formulation of fluconazole vaginal inserts with controlled release and appreciable mucoadhesion. (2) Methods: PECs were prepared and assessed for interactions. Fluconazole PEC based vaginal inserts were prepared by lyophilization using mannitol. 3¹5¹ factorial design was applied to investigate the effect of the anion type and Chitosan/anion ratio on the inserts mucoadhesion and release properties. The optimized insert [based on 5:5 chitosan: anionic polymer (sodium alginate)] release was modulated by the release retardant; Compritol^® 888. The selected formulation was subjected to microbiological and histological evaluation. (3) Results: Fluconazole inserts showed satisfactory drug content, acceptable friability percentages and highest swelling indices at six hours. Statistical analysis showed significant effect of the studied factors on detachment force and release properties. Microbiological assays revealed significantly higher antifungal activity of inserts compared to fluconazole solution. Reduced inflammatory cells were confirmed by histological evaluation. (4) Conclusion: CH/Alg based vaginal insert could be a promising platform for vaginal delivery of antifungal drugs used for vaginal candidiasis treatment. Full article

(This article belongs to the Special Issue Chitosan Biomedical Applications: Opportunities and Challenges)

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8 pages, 25021 KiB

Open AccessArticle

Skull Bone Regeneration Using Chitosan–Siloxane Porous Hybrids—Long-Term Implantation

by Yuki Shirosaki, Motomasa Furuse, Takuji Asano, Yoshihiko Kinoshita and Toshihiko Kuroiwa

Pharmaceutics 2018, 10(2), 70; https://doi.org/10.3390/pharmaceutics10020070 - 08 Jun 2018

Cited by 5 | Viewed by 4374

Abstract

Burr holes in craniotomy are not self-repairing bone defects. To regenerate new bone at the sites of these defects, a good scaffold is required. Biodegradable hybrids including silica or siloxane networks have been investigated as bone tissue scaffolds. This study examined skull bone regeneration using chitosan-siloxane hybrids after long-term implantation (two and three years). After implantation of the hybrids, the surrounding cells migrated and formed fibrous tissues and blood vessels. Then, bone formation occurred from the surrounding blood vessels. Addition of calcium ions and coating with hydroxyapatite improved bone regeneration. Finally, the regenerated tissue area became smaller than the initial hole, and some areas changed to completed bone tissues. Full article

(This article belongs to the Special Issue Chitosan Biomedical Applications: Opportunities and Challenges)

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12 pages, 8773 KiB

Open AccessFeature PaperArticle

Acyclovir-Loaded Chitosan Nanospheres from Nano-Emulsion Templating for the Topical Treatment of Herpesviruses Infections

by Manuela Donalisio, Federica Leone, Andrea Civra, Rita Spagnolo, Ozgen Ozer, David Lembo and Roberta Cavalli

Pharmaceutics 2018, 10(2), 46; https://doi.org/10.3390/pharmaceutics10020046 - 10 Apr 2018

Cited by 64 | Viewed by 6710

Abstract

Acyclovir is not a good candidate for passive permeation since its polarity and solubility limit is partitioning into the stratum corneum. This work aims to develop a new topical formulation for the acyclovir delivery. New chitosan nanospheres (NS) were prepared by a modified nano-emulsion template method. Chitosan NS were characterized by Dynamic Light Scattering (DLS), Transmission Electron Microscopy (TEM), and an in vitro release study. The in vitro skin permeation experiment was carried out using Franz cells and was equipped with porcine skin. Biological studies were performed on the Vero cell line infected by HSV-1 and HSV-2 strains. The acyclovir loaded chitosan NS appeared with a spherical shape, a size of about 200 nm, and a negative zeta potential of about 40.0 mV. The loading capacity of the drug was about 8.5%. In vitro release demonstrated that the percentage of acyclovir delivered from the nanospheres was approximately 30% after six hours. The in vitro skin permeation studies confirmed an improved amount of permeated acyclovir. The acyclovir-NS complex displayed a higher antiviral activity than that of free acyclovir against both the HSV-1 and the HSV-2 strain. The acyclovir-loaded NS showed no anti-proliferative activity and no signs of cytotoxicity induced by NS was detected. Confocal laser scanning microscopy confirmed that the NS are taken up by the cells. Full article

(This article belongs to the Special Issue Chitosan Biomedical Applications: Opportunities and Challenges)

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15 pages, 1462 KiB

Open AccessArticle

Chitosan Loaded into a Hydrogel Delivery System as a Strategy to Treat Vaginal Co-Infection

by Diego R. Perinelli, Raffaella Campana, Athanasios Skouras, Giulia Bonacucina, Marco Cespi, Francesca Mastrotto, Wally Baffone and Luca Casettari

Pharmaceutics 2018, 10(1), 23; https://doi.org/10.3390/pharmaceutics10010023 - 03 Feb 2018

Cited by 38 | Viewed by 7150

Abstract

Polymeric hydrogels are common dosage forms designed for the topical administration of antimicrobial drugs to treat vaginal infections. One of the major advantages of using chitosan in these formulations is related to the intrinsic and broad antimicrobial activity exerted on bacteria and fungi by this natural polymer. Most vaginal yeast infections are caused by the pathogenic fungus Candida albicans. However, despite the anti-Candida activity towards and strains susceptibility to low molecular weight chitosan being documented, no information is available regarding the antimicrobial efficacy of mixed hydrogels in which chitosan is dispersed in a polymeric matrix. Therefore, the aim of the study is to evaluate the anti-Candida activity against eight different albicans and non-albicans strains of a mixed hydroxypropyl methylcellulose (HPMC)/chitosan hydrogel. Importantly, chitosan was dispersed in HPMC matrix either assembled in nanoparticles or in a monomolecular state to eventually correlate any variation in terms of rheological and mucoadhesive properties, as well as anti-Candida activity, with the chitosan form. Hydrogels containing 1% w/w chitosan, either as free polymer chain or assembled in nanoparticles, showed an improved mucoadhesiveness and an anti-Candida effect against all tested albicans and non-albicans strains. Overall, the results demonstrate the feasibility of preparing HPMC/CS mixed hydrogels intended for the prevention and treatment of Candida infections after vaginal administration. Full article

(This article belongs to the Special Issue Chitosan Biomedical Applications: Opportunities and Challenges)

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8 pages, 1898 KiB

Open AccessArticle

Chitosan Gel to Treat Pressure Ulcers: A Clinical Pilot Study

by Virginia Campani, Eliana Pagnozzi, Ilaria Mataro, Laura Mayol, Alessandra Perna, Floriana D’Urso, Antonietta Carillo, Maria Cammarota, Maria Chiara Maiuri and Giuseppe De Rosa

Pharmaceutics 2018, 10(1), 15; https://doi.org/10.3390/pharmaceutics10010015 - 17 Jan 2018

Cited by 13 | Viewed by 5168

Abstract

Chitosan is biopolymer with promising properties in wound healing. Chronic wounds represent a significant burden to both the patient and the medical system. Among chronic wounds, pressure ulcers are one of the most common types of complex wound. The efficacy and the tolerability of chitosan gel formulation, prepared into the hospital pharmacy, in the treatment of pressure ulcers of moderate severity were evaluated. The endpoint of this phase II study was the reduction of the area of the lesion by at least 20% after four weeks of treatment. Thus, 20 adult volunteers with pressure ulcers within predetermined parameters were involved in a 30 days study. Dressing change was performed twice a week at outpatient clinic upon chronic wounds management. In the 90% of patients involved in the study, the treatment was effective, with a reduction of the area of the lesion and wound healing progress. The study demonstrated the efficacy of the gel formulation for treatment of pressure ulcers, also providing a strong reduction of patient management costs. Full article

(This article belongs to the Special Issue Chitosan Biomedical Applications: Opportunities and Challenges)

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1615 KiB

Open AccessArticle

A Chitosan—Based Liposome Formulation Enhances the In Vitro Wound Healing Efficacy of Substance P Neuropeptide

by Tamara Mengoni, Manuela Adrian, Susana Pereira, Beatriz Santos-Carballal, Mathias Kaiser and Francisco M. Goycoolea

Pharmaceutics 2017, 9(4), 56; https://doi.org/10.3390/pharmaceutics9040056 - 06 Dec 2017

Cited by 50 | Viewed by 6378

Abstract

Currently, there is considerable interest in developing innovative biodegradable nanoformulations for controlled administration of therapeutic proteins and peptides. Substance P (SP) is a neuropeptide of 11 amino acids that belongs to the tachykinins family and it plays an important role in wound healing. However, SP is easily degradable in vivo and has a very short half-life, so the use of chitosan-based nanocarriers could enhance its pharmaceutical properties. In light of the above, the aim of this work was to produce and characterize chitosan-coated liposomes loaded with SP (SP-CH-LP) as novel biomaterials with potential application in mucosal wound healing. The loaded system’s biophysical properties were characterized by dynamic light scattering with non-invasive back scattering (DLS-NIBS), mixed mode measurements and phase analysis light scattering (M3-PALS) and high performance liquid chromatography with ultraviolet/visible light detection (HPLC-UV/VIS). Then, the efficacy of the obtained nanoformulations was examined via proof-of-principle experiments using in vitro cell assays. These assays showed an increment on cell motility and proliferation after treatment with free and encapsulated neuropeptides. Additionally, the effect of SP on wound healing was enhanced by the entrapment on CH-LP. Overall, the amenability of chitosan-based nanomaterials to encapsulate peptides and proteins constitutes a promising approach towards potential novel therapies to treat difficult wounds. Full article

(This article belongs to the Special Issue Chitosan Biomedical Applications: Opportunities and Challenges)

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