Chitosan has a number of commercial and possible biomedical uses. It can be used inagriculture as a seed treatment andbiopesticide, helping plants to fight off fungal infections. Inwinemaking, it can be used as afining agent, also helping to prevent spoilage. In industry, it can be used in a self-healingpolyurethanepaint coating. Inmedicine, it is useful inbandages to reduce bleeding and as an antibacterial agent; it can also be used to help deliver drugs through the skin.
In 1799, British chemistCharles Hatchett experimented withdecalcifying the shells of various crustaceans, finding that a soft, yellow and cartilage-like substance was left behind that we now know to be chitin. In 1859, French physiologistCharles Marie Benjamin Rouget found that boiling chitin in potassium hydroxide solution could deacetylate it to produce a substance that was soluble in dilute organic acids, that he calledchitine modifiée. In 1894, German chemistFelix Hoppe-Seyler named the substance chitosan. From 1894 to 1930 there was a period of debate and confusion over the exact composition of chitin and particularly whether animal and fungal forms were the same chemicals. In 1930 the first chitosan films and fibres were patented but competition from petroleum-derived polymers limited their uptake. It was not until the 1970s that there was renewed interest in the compound, spurred partly by laws that prevented the dumping of untreated shellfish waste.[1]
Forming chitosan by partial deacetylation of chitinCommercial chitosan is derived from the shells of shrimp and other sea crustaceans, includingPandalus borealis, pictured here.[2]
Chitosan is produced commercially bydeacetylation ofchitin, which is the structuralelement in theexoskeleton ofcrustaceans (such as crabs and shrimp) and cell walls offungi.[3][4][5] A common method for obtaining chitosan is the deacetylation of chitin using sodium hydroxide in excess as a reagent and water as a solvent. The reaction followsfirst-order kinetics though it occurs in two steps; theactivation energy barrier for the first stage is estimated at 48.8 kJ·mol−1 at 25–120 °C (77–248 °F) and is higher than the barrier to the second stage.[6][7][8]
Diagrammatic representation of chitosan preparation from natural source in which natural and chemical processing are utilised.
The degree of deacetylation (%) can be determined byNMR spectroscopy and the degree of deacetylation in commercially available chitosan ranges from 60 to 100%.[9][10] On average, the molecular weight of commercially produced chitosan is 3800–20,000 daltons.
Chitosan contains the following three functional groups: C2-NH2, C3-OH, and C6-OH. C3-OH has a large spatial site resistance and therefore is relatively difficult tomodify. C2-NH2 is highly reactive for fine modifications and is the most common modifying group in chitosan.[12] In chitosan, althoughamino groups are more prone tonucleophilic reactions thanhydroxyl groups, both can react non-selectively withelectrophilic reagents such as acids, chlorides, andhaloalkanes tofunctionalize them.[13] Since chitosan contains a variety of functional groups, it can be functionalized in different ways such as phosphorylation, thiolation, and quaternization to adapt it to specific purposes.
Water-soluble phosphorylated chitosan can be obtained by the reaction ofphosphorus pentoxide and chitosan under low-temperature conditions usingmethane sulfonic acid as the catalyst; phosphorylated chitosan with good antibacterial activity and ionic properties can be prepared by graft copolymerization of chitosan monophosphate.[14][15]
In tissue engineering, phosphorylated chitosan exhibits improved swelling and ionic conductivity. Although itscrystallinity is reduced, itstensile strength remains largely unchanged. These properties make it useful for creating scaffolds that can support bone tissue regeneration by binding growth factors and promoting stem cell differentiation into bone-forming cells.[19] Additionally, to enhance the solubility of chitosan-basedhydrogels at neutral or alkaline pH, the derivativeN-methylene phosphonic acid chitosan (NMPC-GLU) has been developed. This material maintains goodmechanical strength and improvecell proliferation, making it valuable for biomedical applications.[20]
Thiolated chitosan is produced by attaching thiol groups to the amino groups of chitosan using a thiol-containingcoupling agent.[21][22] The primary site for this modification is the amino group at the 2nd position of chitosan's glucosamine units. During this process, thioglycolic acid and cysteine mediate the reaction, forming anamide bond between the thiol group and chitosan. At a pH below 5, thiol activity is reduced, which limits disulfide bond formation.[23]
The modified chitosan exhibits improved adhesive properties and stability due to the covalent attachment of the thiol groups. Lower pH reduces oxidation, enhancing its adhesion properties.[24][25][26] Additionally, thiolated chitosan can interact with cell membrane receptors, improvingmembrane permeability[27] and showing potential for applications inbacterial adhesion prevention, for example for coating stainless steel.[28][29]
There are two main methods of chitosan quaternization: direct quaternization and indirect quaternization.
The directquaternization of chitosan amino acids treats chitosan withhaloalkanes under alkaline conditions. Another method is the reaction of chitosan withaldehydes first, followed by reduction, and finally with haloalkanes to obtain quaternized chitosan.[30][31]
The indirect quaternization method refers to introducing small molecules containing quaternary ammonium groups into chitosan, such as glycidyl trimethyl ammonium chloride, (5-bromopentyl) trimethyl ammonium bromide, etc.[32][33] Quaternary ammonium groups can further be introduced into the chitosan backbone viaazide-alkyne cycloaddition,[34] or by dissolving chitosan in alkali andurea and then reacting it with 3-chloro-2-hydroxypropyl trimethylammonium chloride,[35] which provides a simple andgreen solution to achieve chitosan functionalization.
Cationic derivatives of chitosan have important roles in bioadhesion, absorption enhancement, anti-inflammatory, antibacterial and anti-tumor applications. Chitosan modified with quaternary ammonium groups is one of the most common cationic chitosan derivatives. Quaternized chitosan with a permanent positive charge has increased antimicrobial activity and solubility compared to normal chitosan.[36]
Chitosan commonly dissolves via three methods—acidic solutions, ionic liquids, or aqueous CO2.[37] Theamino group in chitosan has apKb value of ~6.5, which leads to significant protonation in neutral solution, increasing with increased acidity (decreased pH) and the %DA-value. This makes chitosan water-soluble and a bioadhesive which readily binds to negatively charged surfaces[38][39][40] such as mucosal membranes. Also, chitosan can effectively bind to other surface via hydrophobic interaction and/or cation-π interaction (chitosan as a cation source) in aqueous solution.[41][42] The free amine groups on chitosan chains can makecrosslinked polymeric networks withdicarboxylic acids to improve chitosan's mechanical properties.[43] Chitosan enhances the transport of polardrugs across epithelial surfaces, and isbiocompatible andbiodegradable. However, it is not approved by the FDA for drug delivery. Purified quantities of chitosan are available forbiomedical applications.[4][3]
Chitosan has biological properties, such asbiodegradability andbiocompatibility.[44] The biological properties of chitosan are closely related to its physicochemical structure, which includes the degree of deacetylation, water content, and molecular weight. Deacetylation refers to the process of removing the acetyl group from chitosan, and this process determines the content of free amine groups in chitosan. Studies have shown that chitosan has good solubility only when the degree of deacetylation is above 85%. The enhanced chitosan uptake is mainly due to the interaction of positively charged chitosan with cell membranes, activation of chlorine–bicarbonate exchange channels, and reorganization of proteins associated withepithelial tight junctions, thus opening epithelial tight junctions.[45][better source needed] Chitosan inhibits the growth of different bacteria and fungi by mechanisms involving several factors, including the degree of deacetylation, pH, divalent cations, and solvent type.[citation needed]
The agricultural and horticultural uses for chitosan, primarily for plant defense and yield increase, are based on how this glucosamine polymer influences the biochemistry and molecular biology of the plant cell. The cellular targets are the plasma membrane and nuclear chromatin. Subsequent changes occur in cell membranes, chromatin, DNA, calcium,MAP kinase, oxidative burst, reactive oxygen species, callose pathogenesis-related (PR) genes, and phytoalexins.[46]
Chitosan was first registered as an active ingredient (licensed for sale) in 1986.[47]
Inagriculture, chitosan is typically used as a natural seed treatment and plant growth enhancer, and as an ecologically friendlybiopesticide substance that boosts the innate ability of plants to defend themselves against fungal infections.[48]
Degraded molecules of chitin/chitosan exist in soil and water. Chitosan applications for plants and crops are regulated in the USA by theEnvironmental Protection Agency, and the USDANational Organic Program regulates its use on organic certified farms and crops.[49] EPA-approved, biodegradable chitosan products are allowed for use outdoors and indoors on plants and crops grown commercially and by consumers.[50]
In the European Union and United Kingdom, chitosan is registered as a "basic substance" for use as a biologicalfungicide andbactericide on a wide range of crops.[51][52]
The natural biocontrol ability of chitosan should not be confused with the effects of fertilizers or pesticides upon plants or the environment. Chitosan active biopesticides represent a new tier of cost-effective biological control of crops for agriculture and horticulture.[53] The biocontrol mode of action of chitosan elicits natural innate defense responses within plant to resist insects, pathogens, and soil-borne diseases when applied to foliage or the soil.[54] Chitosan increases photosynthesis, promotes and enhances plant growth, stimulates nutrient uptake, increases germination and sprouting, and boosts plant vigor. When used as a seed treatment or seed coating on cotton, corn, seed potatoes, soybeans, sugar beets, tomatoes, wheat, and many other seeds, it elicits aninnate immunity response in developing roots which destroys parasitic cyst nematodes without harming beneficialnematodes and organisms.[55]
Agricultural applications of chitosan can reduce environmental stress due to drought and soil deficiencies, strengthen seed vitality, improve stand quality, increase yields, and reduce fruit decay of vegetables, fruits and citrus crops .[56] Horticultural application of chitosan increases blooms and extends the life of cut flowers and Christmas trees. TheUS Forest Service has conducted research on chitosan to control pathogens in pine trees[57][58] and increase resin pitch outflow which resists pine beetle infestation.[59]
Chitosan has been studied for applications in agriculture and horticulture dating back to the 1980s.[60] By 1989, chitosan salt solutions were applied to crops for improved freeze protection or to crop seed for seed priming.[61] Shortly thereafter, chitosan salt received the first everbiopesticide label from the EPA, then followed by otherintellectual property applications.
Chitosan has been used to protect plants in space, as well, exemplified byNASA's experiment to protect adzuki beans grown aboard the space shuttle andMir space station in 1997.[62] NASA results revealed chitosan induces increased growth (biomass) and pathogen resistance due to elevated levels of β-(1→3)-glucanase enzymes within plant cells. NASA confirmed chitosan elicits the same effect in plants on earth.[63]
In 2008, the EPA approved natural broad-spectrum elicitor status for an ultralow molecular active ingredient of 0.25% chitosan.[64] A natural chitosan elicitor solution for agriculture and horticultural uses was granted an amended label for foliar and irrigation applications by the EPA in 2009.[56] Given its low potential for toxicity and abundance in the natural environment, chitosan does not harm people, pets, wildlife, or the environment when used according to label directions.[65][66][67] Chitosan blends do not work againstbark beetles when put on a tree's leaves or in its soil.[68]
Chitosan can be used inhydrology as a part of afiltration process.[69] Chitosan causes the fine sediment particles to bind together, and is subsequently removed with the sediment during sand filtration. It also removesheavy minerals,dyes, and oils from the water.[69] As an additive in water filtration, chitosan combined with sand filtration removes up to 99% ofturbidity.[70] Chitosan is among the biological adsorbents used for heavy metals removal without negative environmental impacts.[69]
Chitosan has a long history for use as afining agent in winemaking.[72][73] Fungal source chitosan has shown an increase in settling activity, reduction of oxidized polyphenolics in juice and wine, chelation and removal of copper (post-racking) and control of the spoilageyeastBrettanomyces.[citation needed] These products and uses are approved for European use by the EU andOIV standards.[74][failed verification]
Chitosan-based wound dressings have been widely explored for a variety of acute and chronic wounds. Chitosan has the ability to adhere tofibrinogen, which produces increasedplatelet adhesion, causing clotting of blood and hemostasis.[3][75][76] Chitosanhemostatic agents are salts made from mixing chitosan with an organic acid (such as succinic or lactic acid).[77][78] Chitosan may have other properties conducive to wound healing, including antibacterial and antifungal activity, which remain under preliminary research.[3][79]
Chitosan is used within some wound dressings to decrease bleeding.[80] Upon contact with blood, the bandage becomes sticky, effectively sealing the laceration.[81] Chitosan hydrogel-based wound dressings have also been found useful as burn dressings, and for the treatment of chronic diabetic wounds and hydrofluoric acid burns.[3][80]
Chitosan-containing wound dressings received approval for medical use in the United States in 2003.[80]
Chitosan is dissolved in dilute organic acid solutions but is insoluble in high concentrations of hydrogen ions at pH 6.5 and is precipitated as a gel-like compound.[82] Chitosan is positively charged by amine groups, making it suitable for binding to negatively charged molecules. However, it has disadvantages such as low mechanical strength and low-temperature response rate; it must be combined with other gelling agents to improve its properties.[82] Using glycerolphosphate salts (possessing a single anionic head) without chemical modification or cross-linking, the pH-dependent gelation properties can be converted to temperature-sensitive gelation properties. In the year 2000, Chenite was the first to design the temperature-sensitive chitosan hydrogels drug delivery system using chitosan and β-glycerol phosphate. This new system can remain in the liquid state at room temperature, while becoming gel with increasing temperature above the physiological temperature (37 °C). Phosphate salts cause a particular behaviour in chitosan solutions, thereby allowing these solutions to remain soluble in the physiological pH range (pH 7), and they will be gel only at body temperature. When the liquid solution of chitosan-glycerol phosphate, containing the drug, enters the body through a syringe injection, it becomes a water-insoluble gel at 37 °C. The entrapped drug particles between the hydrogel chains will be gradually released.[82]
Pigmented chitosan objects can be recycled,[95] with the option of reintroducing or discarding the dye at each recycling step, enabling reuse of the polymer independently of colorants.[96][97] Unlike other plant-basedbioplastics (e.g.cellulose,starch), the main natural sources of chitosan come from marine environments and do not compete for land or other human resources.[85][98]
Chitosan is marketed in a tablet form as a "fat binder".[101] Although the effect of chitosan on loweringcholesterol and body weight has been evaluated, the effect appears to have no or low clinical importance.[102][103] Reviews from 2016 and 2008 found there was no significant effect, and no justification for overweight people to use chitosan supplements.[102][104] In 2015, the U.S.Food and Drug Administration issued a public advisory about supplement retailers who made exaggerated claims concerning the supposed weight loss benefit of various products.[105]
Microbial contamination of food products accelerates the deterioration process and increases the risk of foodborne illness caused by potentially life-threatening pathogens.[106] Ordinarily, food contamination originates superficially, requiring surface treatment and packaging as crucial factors to assure food quality and safety.[106] Biodegradable chitosan films have potential for preserving various food products, retaining their firmness and restricting weight loss due to dehydration. In addition, composite biodegradable films containing chitosan and antimicrobial agents are in development as safe alternatives to preserve food products.[106]
Chitosan is being investigated as anelectrolyte forrechargeable batteries with good performance and lowenvironmental impact due to rapidbiodegradability, leavingrecycleable zinc. The electrolyte has excellent physical stability up to 50 °C, electrochemical stability up to 2 V with zinc electrodes, and accommodatesredox reactions involved in the Zn-MnO2 alkaline system. As of 2022[update] results were promising, but the battery needed testing on a larger scale and under actual use conditions.[107][108][109]
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