Injectable hydrogels with pH-responsiveness and self-healing ability have great potential for anti-cancer drug delivery. Herein, we developed a series of polysaccharide-based self-healing hydrogels ...with pH-sensitivity as drug delivery vehicles for hepatocellular carcinoma therapy. The hydrogels were prepared by using N-carboxyethyl chitosan (CEC) synthesized via Michael reaction in aqueous solution and dibenzaldehyde-terminated poly(ethylene glycol) (PEGDA). Doxorubicin (Dox), as a model of water-soluble small molecule anti-cancer drug was encapsulated into the hydrogel in situ. Self-healing behavior of the hydrogels was investigated at microscopic and macroscopic levels, and the hydrogels showed rapid self-healing performance without any external stimulus owing to the dynamic covalent Schiff-base linkage between amine groups from CEC and benzaldehyde groups from PEGDA. The chemical structures, rheological property, in vitro gel degradation, morphology, gelation time and in vitro Dox release behavior from the hydrogels were characterized. Injectability was verified by in vitro injection and in vivo subcutaneous injection in a rat. pH-responsive behavior was verified by in vitro Dox release from hydrogels in PBS solutions with different pH values. Furthermore, the activity of Dox released from hydrogel matrix was evaluated by employing human hepatocellular liver carcinoma (HepG2). Cytotoxicity test of the hydrogels using L929 cells confirmed their good cytocompatibility. Together, these pH-responsive self-healing injectable hydrogels are excellent candidates as drug delivery vehicles for liver cancer treatment. STATEMENT OF SIGNIFICANCE: pH-responsive drug delivery system could release drug efficiently in targeted acid environment and minimalize the amount of drug release in normal physiological environment. pH-sensitive injectable hydrogels as smart anti-cancer drug delivery carriers show great potential application for cancer therapy. The hydrogels with self-healing property could prolong their lifetime during implantation and provide the advantage of minimally invasive surgery and high drug-loading ratio. This work reported the design of a series of pH-responsive self-healing injectable hydrogels based on N-carboxyethyl chitosan synthesized in aqueous solution and dibenzaldehyde-terminated poly(ethylene glycol) via a green approach, and demonstrated their potential as intelligent delivery vehicle of doxorubicin for hepatocellular carcinoma therapy via the pH-responsive nature of dynamic Schiff base.
Recent advancements in the synthesis, properties, and applications of chitosan as the second after cellulose available biopolymer in nature were discussed in this review. A general overview of ...processing and production procedures from A to Z was highlighted. Chitosan exists in three polymorphic forms which differ in degree of crystallinity (α, β, and γ). Thus, the degree of deacetylation, crystallinity, surface area, and molecular mass significantly affect most applications. Otherwise, the synthesis of chitosan nanofibers is suffering from many drawbacks that were recently treated by co-electrospun with other polymers such as polyvinyl alcohol (PVA), polyethylene oxide (PEO), and polycaprolactone (PCL). Ultimately, this review focuses on the area of new trend utilization of chitosan nanoparticles as nanospheres and nanocapsules, in cartilage and bone regenerative medicine. Owing to its biocompatibility, bioavailability, biodegradability, and costless synthesis, chitosan is a promising biopolymeric structure for water remediation, drug delivery, antimicrobials, and tissue engineering.
Many by-products that are harmful to the environment and human health are generated during food processing. However, these wastes are often potential resources with high-added value. For example, ...crustacean waste contains large amounts of chitin. Chitin is one of the most abundant polysaccharides in natural macromolecules, and is a typical component of crustaceans, mollusks, insect exoskeleton and fungal cell walls. Chitosan is prepared by deacetylation of chitin and a copolymer of D-glucosamine and N-acetyl-D-glucosamine through β-(1 → 4)-glycosidic bonds. Chitosan has better solubility, biocompatibility and degradability compared with chitin. This review introduces the preparation, physicochemical properties, chemical and physical modification methods of chitosan, which could help us understand its biological activities and applications. According to the latest reports, the antibacterial activity, antioxidant, immune and antitumor activities of chitosan and its derivatives are summarized. Simultaneously, the various applications of chitosan and its derivatives are reviewed, including food, chemical, textile, medical and health, and functional materials. Finally, some insights into its future potential are provided, including novel modification methods, directional modification according to structure-activity relationship, activity and application development direction, etc.
•The utilization of chitosan is effective solution to improve the value of waste.•The physicochemical properties and modification of chitosan were reviewed.•Chitosan and its derivatives have many biological activities.•Chitosan and its derivatives can be used in various industrial fields.
•Microstructure conferred by 3D printing is critical for cell growth on chitosan scaffolds.•Demonstration of biocompatibility of 3D printed chitosan scaffolds.•Comparison of fibroblast and ...keratinocyte cell growth on 2D and 3D surfaces.•Efficacy of 3D chitosan scaffolds for treatment of wounds in a diabetic rat model.
The fabrication of porous 3D printed chitosan (CH) scaffolds for skin tissue regeneration and their behavior in terms of biocompatibility, cytocompatibility and toxicity toward human fibroblasts (Nhdf) and keratinocytes (HaCaT), are presented and discussed. 3D cell cultures achieved after 20 and 35 days of incubation showed significant in vitro qualitative and quantitative cell growth as measured by neutral red staining and MTT assays and confirmed by scanning electron microphotographs. The best cell growth was obtained after 35 days on 3D scaffolds when the Nhdf and HaCaT cells, seeded together, filled the pores in the scaffolds. An early skin-like layer consisting of a mass of fibroblast and keratinocyte cells growing together was observed. The tests of 3D printed scaffolds in wound healing carried out on streptozotocin-induced diabetic rats demonstrate that 3D printed scaffolds improve the quality of the restored tissue with respect to both commercial patch and spontaneous healing.
Chitosan oligosaccharide (COS) is an oligomer of β-(1➔4)-linked d-glucosamine. COS can be prepared from the deacetylation and hydrolysis of chitin, which is commonly found in the exoskeletons of ...arthropods and insects and the cell walls of fungi. COS is water soluble, non-cytotoxic, readily absorbed through the intestine and mainly excreted in the urine. Of particular importance, COS and its derivatives have been demonstrated to possess several biological activities including anti-inflammation, immunostimulation, anti-tumor, anti-obesity, anti-hypertension, anti-Alzheimer's disease, tissue regeneration promotion, drug and DNA delivery enhancement, anti-microbial, anti-oxidation and calcium-absorption enhancement. The mechanisms of actions of COS have been found to involve the modulation of several important pathways including the suppression of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPK) and the activation of AMP-activated protein kinase (AMPK). This review summarizes the current knowledge of the preparation methods, pharmacokinetic profiles, biological activities, potential therapeutic applications and safety profiles of COS and its derivatives. In addition, future research directions are discussed.
Advanced development of chitosan hydrogels has led to new drug delivery systems that can release their active ingredients in response to environmental stimuli. This review considers more recent ...investigation of chitosan hydrogel preparations and the application of these preparations for drug delivery in wound dressings. Applications and structural characteristics of different types of active ingredients, such as growth factors, nanoparticles, nanostructures, and drug loaded chitosan hydrogels are summarized.
•This review presents the application of chitosan as an effective material for biomedical applications.•Various preparation methods of chitosan hydrogels have been reviewed.•Chitosan hydrogels incorporated with growth factors accelerate treating chronic wounds.•Nanostructure drugs as a new growing field have significant effect on wound healing.•Essential oils and other chemical drugs are also reviewed in this paper.
Chitosan is the second abundant biopolymer present on earth after cellulose. Chitosan is extracted from the shells of shrimp and other crustaceans. Several methods were reported for its extraction, ...but the most commercial is the deacetylation of chitin. Chitosan as a biopolymer has numerous applications and uses. But, its mechanical, chemical and biological characteristics can be enhanced by modification of its chemical structures. Several modification methods and derivatives were reviewed in the literatures, and several were collected in this review. The reviewed modified chitosan derivatives herein were five types of derivatives. The first is substituted chitosan derivatives including thiolated, phosphorylated, and N-phthaloylated derivatives. The second is crosslinked chitosan derivatives including chitosan-glutaraldehyde, chitosan-ethylene diamine tetraacetic acid, and chitosan-epichlorohydrin derivatives. The third is carboxylic acid derivatives of chitosan obtained from carboxyalkylation, acrylation, methacrylation, and benzoylation of chitosan. The fourth is ionic chitosan derivatives including highly cationic and sulfated derivatives. The last is bounded chitosan to specific molecules including cyclodextrin, thiosemicarbazone, dioxime, and crown ether precursors. The review also highlights the reported advantages and applications of the modified chitosan and the synthetic routes of the biopolymer modification.
•Chitosan biopolymer can be functionalized by numerous function groups.•Functionalization can be addition, coupling, and crosslinking.•Modification of chitosan upgrades its potential applications.
•Guanidinylated chitosan derivatives were synthesized utilizing two different protecting groups.•Reactions in organic medium enabled quantitative conversion.•100% N-modification and good control of ...the degree of substitution was achieved.•The derivatives were well characterized using 1H and COSY NMR and IR spectroscopy.•Structure–activity relationship was developed against S. aureus and E. coli.
A new synthetic approach employing two types of protecting groups, tertiarybutyldimethylsilyl (TBDMS) and tertiarybutyloxycarbonyl (Boc) was developed to obtain a series of guanidinylated chitosan derivatives. The synthesis was carried out in organic solvents which allowed quantitative reaction, a good control on the degree of substitution, and 100% substitution of the chitosan amino groups. Similar derivatives carrying the trimethylammonium group were also synthesized as reference compounds. All the derivatives were characterized using 1H and COSY NMR and IR spectroscopy. The antibacterial effect against clinically relevant strains of S. aureus and E. coli was found to increase with increase in the degree of substitution and decrease in the spacer length of the derivatives in both the series. An optimum activity could be obtained at a degree of substitution above 0.5 for most derivatives. The trimethylammonium derivatives showed slightly higher activity than the corresponding guanidinium derivatives but a similar structure–activity relationship was obtained.
Chitosan (CS) is an abundant and renewable polysaccharide that is reported to exhibit a great variety of beneficial properties. However, the poor solubility of chitosan in water limits its ...applications. In this paper, we successfully synthesized single
-quaternized (QCS) and double
-diquaternized (DQCS) chitosan derivatives, and the resulting quaternized materials were water-soluble. The degree of quaternization (DQ) of QCS and DQCS was 0.8 and 1.3, respectively. These derivatives were characterized by FTIR, ¹H NMR,
C NMR, TGA, and SEM. Moreover, the antioxidant activity of the chitosan was evaluated by free radical scavenging ability (against DPPH-radical, hydroxyl-radical, and superoxide-radical) and ferric reducing power. Our results suggested that the antioxidant abilities were in the order of DQCS > QCS > CS, which was consistent with the number of quaternized groups. These data demonstrate that the number of quaternized groups of chitosan derivatives contributes to their antioxidant activity. Therefore, DQCS, with a higher number of quaternized groups and higher positive charge density, is endowed with high antioxidant activity, and can be used as a candidate material in food and pharmaceutical industries.
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