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Progress in the Development of Chitosan-Based Biomaterials for Tissue Engineering and Regenerative Medicine

Bolat Sultankulov, Dmitriy Berillo, Karina Sultankulova and 2 more

Biomolecules · 2019 · Review · CC BY

doi:10.3390/biom9090470

Abstract

Over the last few decades, chitosan has become a good candidate for tissue engineering applications. Derived from chitin, chitosan is a unique natural polysaccharide with outstanding properties in line with excellent biodegradability, biocompatibility, and antimicrobial activity. Due to the presence of free amine groups in its backbone chain, chitosan could be further chemically modified to possess additional functional properties useful for the development of different biomaterials in regenerative medicine. In the current review, we will highlight the progress made in the development of chitosan-containing bioscaffolds, such as gels, sponges, films, and fibers, and their possible applications in tissue repair and regeneration, as well as the use of chitosan as a component for drug delivery applications.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 21, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

Development of biomaterials is an active research field with the purpose of designing scaffolds for the regeneration of tissues and organs damaged by disease or injuries. Defining and designing appropriate material for tissue engineering is a critical step in tissue engineering and regenerative medicine. In the past few decades, significant attention has been given to natural polymers because of their biocompatibility and structural similarity to the extracellular matrix components. Abundant availability and unique biological activity of each natural polymer makes them a matching candidate for the development of novel natural or/and semi-synthetic materials closely resembling the natural structure and functionality of tissues required for successful regeneration. Starch, collagen, alginate, cellulose, hyaluronic acid, chitin, and chitosan (CS), are attractive natural polymers suitable for tissue regeneration. CS is a linear natural carbohydrate biopolymer derived from chitin with a structural similarity to glycosaminoglycans of the extracellular matrix (ECM) implicated in cell–cell adhesion. The hydrophilic structure of CS promotes cell adhesion, proliferation, and differentiation of different types of cells and the polycationic nature of CS at a mildly acidic condition allows immobilization of negatively charged enzymes, proteins, and DNA for gene delivery. CS for tissue engineering and regenerative medicine could be designed in various forms, such as hydrogels, sponges, fibers, sheets, films, and other structures.

2. Structure and Physico-Chemical Properties

Chitin is the second most abundant natural polymer and consists of 2-acetamido-2-deoxy-β-d-glucose through a β (1→4) linkage and is extracted from the shells of marine crustaceans, insects, or fungi. Chitin is insoluble in water and most organic solvents, and therefore its use in biomaterials fabrication is limited. CS is a linear polysaccharide derived from partial deacetylation of chitin, as shown in Figure 1. It is a copolymer of randomly located (1→4)-2-acetamido-2-deoxy-β-d-glucan (N-acetyl d-glucosamine) and (1→4)-2-amino-2-deoxy-β-d-glucan (d-glucosamine) units. The number of amino groups as a ratio between d-glucosamine to the sum of d-glucosamine and N-acetyl d-glucosamine is indicated as a deacetylation degree (DD) and should be at least 60% for CS. The deacetylation of chitin is conducted by chemical hydrolysis (alkaline conditions) or by enzymatic hydrolysis (chitin deacetylase). CS is soluble in dilute organic acids such as acetic acid, as well as diluted hydrochloric acid, and further modification of CS is accessible due to the availability of amino groups. The fungal source of CS is preferred at the industrial scale because of its narrower molecular mass distribution, all-year-round availability, more controlled and scalable production, and less immunogenicity in comparison to a seafood source, which could cause allergies and limit biomedical application.

The physical properties of CS depend on several factors, such as the molecular weight, DD, and purity of the product. CS solubility is pH dependent and it is soluble in diluted acids achieved by protonation of the amino groups of the d-glucosamine residues. Availability of protonated amino groups enables CS to form complexes with metal ions, natural or synthetic anionic (poly(acrylic acid)) polymers, lipids, proteins, and DNA. CS-based scaffolds can be chemically cross-linked by glutaraldehyde, oxidized dextran or other oxidized carbohydrates, 1,1,3,3-tetramethoxypropan, and genipin. It is important to note that CS is a unique semi-natural positively charged polysaccharide at acidic conditions. This property is used to develop CS-based polyelectrolytes for the preparation of films via a layer-by-layer deposition technique. The amino groups of CS could react with aldehyde groups through reductive amination. Hydroxyl groups along a CS chain enables etherification and esterification. In addition, CS possesses important properties, such as high biocompatibility, biodegradability, antibacterial activity, non-antigenicity, and high adsorption properties that make CS a good candidate for tissue engineering and other biomedical applications.

3.1. Chitosan for Wound Healing

Skin regeneration is a complex process that consists of four overlapping phases—hemostasis, inflammation, proliferation, and tissue remodeling. In other words, skin regeneration is a dynamic process involving blood elements, extracellular components, soluble factors, and cells. Therefore, the treatment of skin lesions requires dressing that not only ensures physical protection of the wound but also enhances the healing, provides antimicrobial protection, and reduces scar formation.

CS has very strong hemostatic activity which is not dependent on host coagulation pathway but depends on CS’s molecular weight and DD. The number of amine groups has a direct effect on blood coagulation, where moderate DD (68.36%) causes the formation of a mesh-like structure within CS, thus facilitating interaction with blood components, whereas higher DD results in stronger hydrogen bonds within CS causing the formation of a crystalline structure with limited ability to interact with red blood cells. Higher molecular weight could further increase the procoagulation effect due to higher interaction between polyelectrolytes. There are several CS containing hemostatic products available on the market and approved by the Food and Drug Administration of the United States (FDA), such as Celox®, HemCon®, Axiostat®, Chitoflex®, and Chitoseal®.

In addition to the hemostatic effect of CS, it was shown that CS affects all stages of healing in various ways. It was shown that CS induces migration of neutrophils, and neutrophil-like HL60 cells secrete IL-8, a potent neutrophil chemokine, in response to CS in direct correlation with the level of N-acetylation. CS has an immunomodulatory effect which is important for the wound healing process and depends on DD. It was shown that micro- and nano-sized CS particles induce inflammasome formation by macrophages. In contrast, macro-sized CS scaffolds inhibit the release of IL-1β and thus the formation of inflammasomes in mouse and human macrophages in vitro, making the use of macro-sized CS scaffolds rational when excessive inflammation is present. Moreover, CS also affects the expression of growth factors by increasing TGF-β1 expression in the early post-injury phase and decreasing it in later stages by binding to anionic growth factors. High DD CS stimulates proliferation of dermal fibroblasts allowing fibrous tissue formation and re-epithelialization. The polyelectrolyte complex-based cryogel of CS-gelatin-oxidized dextran (Ox.D) and different CS-oxidized dextran compositions showed elastic modulus in the range 2.7–14.3 + 0.4 kPa. The proliferation rate for cell culture of fibroblasts on CS-Ox.D-gelatin (1:1:1) increased significantly compared to the other CS compositions with Ox.D due to internal porosity of pore walls. CS containing scaffolds for wound healing could be made as 2D (films and fibers) and 3D (gels and sponges) with the properties required for wound management. The antimicrobial effect of CS could be enhanced by the addition of antimicrobial agents. In a recent study, a complex CS-cordycepin hydrogel with increased antimicrobial activity was developed without the addition of any cross-linking agents via a freeze-drying method where negatively charged cordycepin adhered to positively charged CS chains. In another study, textile polyethylene terephthalate composed of layer-by-layer coated CS was loaded with chlorhexidine and the mechanical stability of the composite was increased by thermal post-treatment which also increased the duration of chlorhexidine release up to 7 weeks. CS alone or in complex with other natural polymers is also used as a part of asymmetric membranes, usually in an underlying layer that is in contact with the damaged skin. Addition of nanoparticles (NPs) into hydrogels is another strategy used in biomaterial preparation. Shah and colleagues developed triple-component nanocomposite film that contained CS-silver-sericin and was loaded with moxifloxacin. The obtained films possess not only high antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA) strains (clinical isolates) but also support wound healing in a rat model, similar to commercial wound dressings. Most of the CS composite films containing collagen have intrinsic properties to induce healing, but the drawback is an allergic reaction to non-human collagen and therefore other safe substitutes are in demand. For example, human keratin-CS membrane with improved mechanical properties produced by the UV-crosslinking method shows potential as a wound dressing. CS-chondroitin sulfate-based polyelectrolyte complex shows an efficient antimicrobial effect and cytocompatibility suitable for wound healing applications. Furthermore, positively charged CS containing biomaterials could be loaded with growth factors and cytokines to improve their performance in the wound healing process. In a recent study, CS NPs prepared through ionotropic gelation with tripolyphosphate were loaded with granulocyte-macrophage colony-stimulating factor (GM-CSF) as a part of a nanocrystalline cellulose–hyaluronic acid composite prepared by a freeze-drying method. Loading efficiency of GM-CSF was as high as 97.4 ± 1.68% with sustained release of ~100% over 48 h and in vivo experiments have shown that composites loaded with encapsulated GM-CSF in CS NPs induce greater wound closure compared to the composite alone. Polycaprolactone nanofibers loaded with CS NPs containing GM-CSF also showed accelerated wound closure. Modification of CS with peptides also promotes wound closure, for example, CS hydrogels made from Ser-Ile-Lys-Val-Ala-Val-chitosan macromers when applied in vivo induces collagen expression, angiogenesis, expression of TGF-β1, and inhibits the expression of TNF-α, IL-1β, and IL-6 mRNA in a mouse skin wound model. CS could be further modified to increase affinity for the growth factors. For example, developed heparin-like polysaccharide (2-N, 6-O-sulfated CS) has a high affinity to the vascular endothelial growth factor in comparison to heparin due its higher sulfonation degree.

3.2. Bone and Cartilage Regeneration

During the development of biomaterials for bone and cartilage regeneration, it is necessary to not only create a scaffold that is biocompatible and biodegradable, but also contains suitable mechanical properties with interconnected pores that supports the differentiation status of cells, as well as the differentiation of stem cells into osteocytes and chondrocytes. It is sometimes not possible to prepare a biomaterial with these desired properties using only one polymer. Therefore, composite or hybrid materials are created where a supportive scaffold could be added to comply with the necessary mechanical properties. CS is used to create biomaterials for the regeneration of hard tissues such as bone and cartilage. In a hydrated state, CS scaffolds lack mechanical stability and therefore require extra modifications. CS induces apatite deposition and this phenomenon of the polymer has been used to enhance biomineralization of composite materials because CS favors calcium/phosphate ion accumulation and enhances the biomineralization potential of poly(ethylene glycol) diacrylate/CS-based hydrogel.

3.2.1. Bone

CS mechanical properties are usually increased by the addition of hydroxyapatite due to its biological similarity to bone inorganic component. In addition to hydroxyapatite, other composites, such as nano-zirconia/CS, nano-calcium zirconate/CS, and strontium-modified CS/montmorillonite composites with comparable mechanical properties were designed. It was shown that MC3T3-E1 pre-osteoblastic cells when cultured on a CS-graft-polycaprolactone copolymer surface, in comparison to a tissue culture-treated polystyrene surface, show significantly higher alkaline phosphatase activity, deposition of calcium, and ECM synthesis. For example, the addition of hydroxyapatite or bioglass to the matrix led to a compressive strength increase compared to CS alone. The polycationic nature of CS provides the possibility of designing polyelectrolyte complexes with polyanionic polymers to improve the mechanical properties of composite scaffolds. In one study, CS/chondroitin/nano-bioglass-based polyelectrolyte composite material was developed with improved bioactivity, such as accumulation of apatite and increased expression of type-1 collagen by MG63 osteoblast-like cells in vitro and with osteointegration of the scaffold in vivo. CS possesses active biomineralization properties and these could be further increased by introducing other polymers such as fucoidan and bioglass.

Freeze-dried CS/gelatin scaffolds crosslinked with either glutaraldehyde or genipin support bone regeneration in vivo in mice inducing ECM production with minimal inflammatory reactions. Thermosensitive hydrogel based on CS and beta-glycerophosphate was developed, however, it presented some biocompatibility issues due to an increased amount of substances required for gelation at body temperature. Recently, it was shown that the addition of TEMPO-oxidized cellulose nanofiber induced faster gelation and increased porosity with improved biocompatibility in vitro and in vivo in comparison to CS. CS could be layered on top of metal (e.g., titanium) implants to increase osteointegration. Composite materials based on polypyrrole/CS was synthesized through in situ electrochemical polymerization in oxalic acid medium and coated on 316L SS implants showing biocompatibility and protection against corrosion. Recently, CS has been utilized in 3D printing for various tissue engineering applications. CS-hydroxyapatite hydrogels were produced by a thermal cross-linking reaction using glycerol phosphate disodium salt and successfully printed on an extruder-based bioprinter. As a result, cells seeded on the printed scaffold increased osteogenic markers expression in comparison to 3D printed alginate and alginate-hydroxyapatite scaffolds.

3.2.2. Cartilage

Regeneration of cartilage damaged by injury, disease (osteoarthritis), and degeneration as a result of aging is an important task in modern orthopedics. The approaches used to regenerate cartilage are microfracture, mosaicplasty, autologous chondrocyte, and biomaterial implantation. An important limitation is the absence of blood vessels in the cartilage tissue, thus, the task of creating a biomaterial capable of stimulating the regeneration of cartilage under avascular conditions is the main goal of tissue engineering.

Designed biomaterials created for cartilage regeneration should be able to support cell proliferation and differentiation. Therefore, the use of cells and 3D scaffold together is a practical approach in tissue engineering. The microstructural architecture, physicochemical, and biochemical properties of the scaffold should be able to provide a temporary template for cells and support ECM synthesis required for the formation of cartilage tissue. This means that scaffolds, in addition to their biocompatibility and biodegradability, should be porous with interconnected pores. Three-dimensional scaffolds, such as hydrogels, fibrous materials, and foams/sponges, are common scaffolds used in cartilage regeneration research. Usually, scaffolds include cells (differentiated chondrocytes and stem cells) and bioactive molecules (peptides, growth factors, and cytokines). Hydrogels could offer high water content and support chondrogenesis potential, implantation without open surgery, and in situ scaffold formation. The low mechanical properties of hydrogels (E ≈ 200 kPa) can be overcome with the use of solid supporters which improve the mechanical stability of the hydrogel.

CS as a natural material with a structural similarity to sulfated glycosaminoglycans provides a compatible microenvironment for chondrocyte proliferation, ECM synthesis, and chondrogenesis. It was also demonstrated that chondrocytes cultured in CS-alginate beads reduce the expression of inflammatory cytokines (IL-6 and IL-8) and increase cartilage matrix components (hyaluronan and aggrecan) synthesis in vitro, in comparison to alginate beads alone. CS derivative carboxymethyl-CS in a dose-dependent manner reduced the inflammatory profile of primary rat chondrocytes by reducing iNOS expression and upregulating the anti-inflammatory cytokine IL-10 in vitro. In another study, the addition of hyaluronic acid-CS NPs to a pellet co-culture of the human infrapatellar fat pad (IPFP)-derived mesenchymal stem cells (MSCs) with osteoarthritic chondrocytes increased chondrogenic differentiation. Human IPFP-MSCs seeded on 3D-printed CS scaffolds in chondrogenic media containing TGF-β3 and BMP-6 attach, proliferate, and differentiate into chondrocyte-like cells modulating the formation of cartilaginous tissue in vitro.

CS also interacts with collagen via electrostatic interactions between abundant amino groups and sulfo groups, and freeze-dried type 2 collagen-CS hybrid scaffold possesses improved stiffness in comparison to single component scaffolds, with a good porous structure resembling cartilage. Moreover, type II collagen-CS scaffolds were also combined in the bi-layered scaffold with poly(lactic-co-glycolic acid) (PLGA) to further increase the mechanical and functional properties of biocomposites for cartilage regeneration. CS-silk fibroin blends have also shown potential in cartilage regeneration. One study found that bovine chondrocytes seeded on CS fibers made by an electrospinning method with a diameter of 300 nm have a 2-fold higher ratio of collagen II/collagen I in comparison to cells cultured on sponge-like scaffolds. It is also important to note that a new type of supermacroporous scaffold made by a cryogelation method (cryogel) is gaining attention. Supermacroporous (85–100 µm pore diameter) CS-agarose-gelatin scaffolds made by a cryogelation method (cryogel) possess good mechanical properties with an affable compression modulus of approximately 44 kPa of 5% cryogel at 15% deformation. In vivo experiments for the repair of subchondral cartilage defects in female New Zealand white rabbits using CS-agarose-gelatin cryogels have shown the formation of hyaline cartilage without any hypertrophy markers by the fourth week post-implantation. It is important to note that CS films induce human bone marrow MSCs to differentiate into chondrocyte-like spheroids in vitro via mTOR/S6K activation. The main advantages of CS for skin, bone, and cartilage regeneration are highlighted in Figure 2.

3.3. Chitosan for Drug Delivery

As a natural component, CS presents itself as an interesting substance for drug delivery applications. It is biodegradable and susceptible to degradation by lysozyme produced by mucosal tissue and chitinase produced by intestinal flora. CS solubility increases under acidic conditions which is useful for oral delivery of the drug. However, low solubility under physiological pH possesses some limitations. Due to its mucoadhesive nature, CS has been used as a vehicle to deliver drugs to nasal, ocular, buccal, and pulmonary tissues. For drug delivery purposes, CS is used in the form of nano/microparticles which is synthesized by emulsion, coacervation/precipitation, ionic gelation, reverse micellar methods, etc.. The problem of solubility of CS under physiological conditions, which is required for efficient delivery of drugs, is usually solved by chemical modification of CS and includes quaternization, alkylation, acetylation, carboxymethylation, CS/polyol salt combinations, synthesis of N-trimethyl CS, generation of sugar-bearing CS, conjugation with polyethylene oxide, generation of glycol-CS, etc.. For the encapsulation of hydrophobic substances, amphiphilic CS derivatives were synthesized. CS moiety is modified with a long chain alkyl group with hydrophobic function, and the addition of hydrophilic groups, such as succinyl, to the amino group enables CS derivative to form micelles in aqueous media. Micelle-forming N-succinyl-N′-octyl CS (SOC), N-octyl-N-trimethyl CS, and N-octyl-O-sulfate have been studied to deliver doxorubicin, hydroxycamptothecin (10-HCPT), and paclitaxel for tumor-targeted therapy with increased encapsulation.

CS NPs produced by an emulsion method is also used for the delivery of proteins and peptides. Its high loading efficiency and sustained release of proteins in CS particles have been reported. However, it includes sequential cross-linking with tripolyphosphate, glutaraldehyde, and genipin, which could affect the biological activity of loaded proteins. The emulsion method’s limitation could be prevented with the use of coacervation/precipitation, ionic gelation, polyelectrolyte formation, spray drying, and supercritical fluid drying methods. CS microspheres loaded with recombinant human interleukin-2 have been prepared by a coacervation/precipitation method without the use of cross-linking agents. The polycationic nature of CS is used to prepare polyelectrolyte complexes which spontaneously form upon mixing. For example, heparin is widely used with CS polyelectrolyte complex due to its ability to bind growth factors and cytokines. In a recent study, CS-heparin NPs were used for the delivery of siRNA against vascular endothelial growth factor in human retinal epithelial cells (ARPE-19) with a 2-fold higher transfection efficiency in comparison to carrying plasmid DNA alone. In addition to gene delivery, CS could be modified to deliver growth factors and cytokines. The addition of a sulfate group to CS mimics heparin and heparan sulfate and retains its intrinsic antimicrobial properties. Sulfated CS is able to bind fibroblast growth factor-2 and bone morphogenetic protein-2 and protects them from proteolytic cleavage. Moreover, it was shown that sulfated CS binds to the proteins better than heparin.

CS as a non-viral gene delivery system has also been explored. CS was used as a non-viral delivery system for plasmid transfection in 1995. The polycationic nature of CS interacts not only with negatively charged nucleic acid molecules forming a polyelectrolyte complex, but also with negatively charged cellular membranes, which results in increased uptake efficiency. Nowadays, CS is used to deliver siRNA and miRNA. A widely used method for the preparation of CS for gene delivery is ionic gelation and coacervation. Recent application of CS and its derivatives for drug delivery is summarized in Table 1.

4. Conclusions

CS, as a natural polymer, is actively used in tissue engineering and regenerative medicine as a biomaterial alone, as well as in combination with other polymers. In addition to its suitable mechanical physico-chemical properties, CS has a natural ability to stimulate tissue regeneration. Active research is underway in improving CS-containing scaffolds for wound healing, bone, and cartilage regeneration. In addition to this, CS-containing polymers are being actively studied for the delivery of drugs for targeted tumor therapy and nucleic acid delivery in genetic engineering applications. Further research on the preparation of CS-containing scaffolds via 3D printing and cryogelation methods will facilitate the application of CS in biomedicine. CS, as a part of any material, could introduce valuable properties such as antimicrobial activity, mucoadhesiveness, and biocompatibility, which are in demand for biomedical use. We believe that further research on CS and the search for new variations in its use with other polymers will reveal even greater prospects and properties of this unique polymer in biomedical applications.

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    Baxter R.M., Dai T., Kimball J., Wang E., Hamblin M.R., Wiesmann W.P., McCarthy S.J., Baker S.M. Chitosan dressing promotes healing in third degree burns in mice: Gene expression analysis shows biphasic effects for rapid tissue regeneration and decreased fibrotic signaling. J. Biomed. Mater. Res. A. 2013;101:340-348.

    Not in our library10.1002/jbm.a.34328

  39. 39.

    Tsai C.-W., Chiang I.-N., Wang J.-H., Young T.-H. Chitosan delaying human fibroblast senescence through downregulation of TGF-β signaling pathway. Artif. Cells Nanomed. Biotechnol. 2017;46:1-12.

    Not in our library10.1080/21691401.2017.1394873

  40. 40.

    Howling G.I., Dettmar P.W., Goddard P.A., Hampson F.C., Dornish M., Wood E.J. The effect of chitin and chitosan on the proliferation of human skin fibroblasts and keratinocytes in vitro. Biomaterials. 2001;22:2959-2966.

    Not in our library10.1016/s0142-9612(01)00042-4

  41. 41.

    Hamilton V., Yuan Y., Rigney D.A., Puckett A.D., Ong J.L., Yang Y., Elder S.H., Bumgardner J.D. Characterization of chitosan films and effects on fibroblast cell attachment and proliferation. J. Mater. Sci. Mater. Med. 2006;17:1373-1381.

    Not in our library10.1007/s10856-006-0613-9

  42. 42.

    Croisier F., Jérôme C. Chitosan-based biomaterials for tissue engineering. Eur. Polym. J. 2013;49:780-792.

    Not in our library10.1016/j.eurpolymj.2012.12.009

  43. 43.

    Song R., Zheng J., Liu Y., Tan Y., Yang Z., Song X., Yang S., Fan R., Zhang Y., Wang Y. A natural cordycepin/chitosan complex hydrogel with outstanding self-healable and wound healing properties. Int. J. Biol. Macromol. 2019;134:91-99.

    Not in our library10.1016/j.ijbiomac.2019.04.195

  44. 44.

    Aubert-Viard F., Mogrovejo-Valdivia A., Tabary N., Maton M., Chai F., Neut C., Martel B., Blanchemain N. Evaluation of antibacterial textile covered by layer-by-layer coating and loaded with chlorhexidine for wound dressing application. Mater. Sci. Eng. C. 2019;100:554-563.

    Not in our library10.1016/j.msec.2019.03.044

  45. 45.

    Alves P., Santos M., Mendes S., Miguel P.S., de Sá D.K., Cabral S.D.C., Correia J.I., Ferreira P., Alves P., Santos M., et al. Photocrosslinkable Nanofibrous Asymmetric Membrane Designed for Wound Dressing. Polymers. 2019;11:653.

    Not in our library10.3390/polym11040653

  46. 46.

    Shah A., Ali Buabeid M., Arafa E.-S.A., Hussain I., Li L., Murtaza G. The wound healing and antibacterial potential of triple-component nanocomposite (chitosan-silver-sericin) films loaded with moxifloxacin. Int. J. Pharm. 2019;564:22-38.

    Not in our library10.1016/j.ijpharm.2019.04.046

  47. 47.

    Lin C.-W., Chen Y.-K., Lu M., Lou K.-L., Yu J. Photo-Crosslinked Keratin/Chitosan Membranes as Potential Wound Dressing Materials. Polymers. 2018;10:987.

    Not in our library10.3390/polym10090987

  48. 48.

    Sharma S., Swetha K.L., Roy A. Chitosan-Chondroitin sulfate based polyelectrolyte complex for effective management of chronic wounds. Int. J. Biol. Macromol. 2019;132:97-108.

    Not in our library10.1016/j.ijbiomac.2019.03.186

  49. 49.

    Koukaras E.N., Papadimitriou S.A., Bikiaris D.N., Froudakis G.E. Insight on the Formation of Chitosan Nanoparticles through Ionotropic Gelation with Tripolyphosphate. Mol. Pharm. 2012;9:2856-2862.

    Not in our library10.1021/mp300162j

  50. 50.

    Karimi Dehkordi N., Minaiyan M., Talebi A., Akbari V., Taheri A. Nanocrystalline cellulose–hyaluronic acid composite enriched with GM-CSF loaded chitosan nanoparticles for enhanced wound healing. Biomed. Mater. 2019;14:035003.

    Not in our library10.1088/1748-605x/ab026c

  51. 51.

    Tanha S., Rafiee-Tehrani M., Abdollahi M., Vakilian S., Esmaili Z., Naraghi Z.S., Seyedjafari E., Javar H.A. G-CSF loaded nanofiber/nanoparticle composite coated with collagen promotes wound healing in vivo. J. Biomed. Mater. Res. Part A. 2017;105:2830-2842.

    Not in our library10.1002/jbm.a.36135

  52. 52.

    Chen X., Zhang M., Chen S., Wang X., Tian Z., Chen Y., Xu P., Zhang L., Zhang L., Zhang L. Peptide-Modified Chitosan Hydrogels Accelerate Skin Wound Healing by Promoting Fibroblast Proliferation, Migration, and Secretion. Cell Transplant. 2017;26:1331-1340.

    Not in our library10.1177/0963689717721216

  53. 53.

    Chen X., Fu W., Cao X., Jiang H., Che X., Xu X., Ma B., Zhang J. Peptide SIKVAV-modified chitosan hydrogels promote skin wound healing by accelerating angiogenesis and regulating cytokine secretion. Am. J. Transl. Res. 2018;10:4258-4268.

    Not in our library

  54. 54.

    Yu Y., Chen R., Sun Y., Pan Y., Tang W., Zhang S., Cao L., Yuan Y., Wang J., Liu C. Manipulation of VEGF-induced angiogenesis by 2-N, 6-O-sulfated chitosan. Acta Biomater. 2018;71:510-521.

    Not in our library10.1016/j.actbio.2018.02.031

  55. 55.

    Wang C., Yu Y., Chen H., Zhang S., Wang J., Liu C. Construction of cytokine reservoirs based on sulfated chitosan hydrogels for the capturing of VEGF in situ. J. Mater. Chem. B. 2019;7:1882-1892.

    Not in our library10.1039/c8tb02895h

  56. 56.

    Titorencu I., Albu M., Nemecz M., Jinga V. Natural Polymer-Cell Bioconstructs for Bone Tissue Engineering. Curr. Stem Cell Res. Ther. 2016;12:165-174.

    Not in our library10.2174/1574888x10666151102105659

  57. 57.

    Saravanan S., Leena R.S., Selvamurugan N. Chitosan based biocomposite scaffolds for bone tissue engineering. Int. J. Biol. Macromol. 2016;93:1354-1365.

    Not in our library10.1016/j.ijbiomac.2016.01.112

  58. 58.

    Deepthi S., Venkatesan J., Kim S.-K., Bumgardner J.D., Jayakumar R. An overview of chitin or chitosan/nano ceramic composite scaffolds for bone tissue engineering. Int. J. Biol. Macromol. 2016;93:1338-1353.

    Not in our library10.1016/j.ijbiomac.2016.03.041

  59. 59.

    He L.-H., Yao L., Xue R., Sun J., Song R. In-situ mineralization of chitosan/calcium phosphate composite and the effect of solvent on the structure. Front. Mater. Sci. 2011;5:282-292.

    Not in our library10.1007/s11706-011-0140-6

  60. 60.

    Tuzlakoglu K., Reis R.L. Formation of bone-like apatite layer on chitosan fiber mesh scaffolds by a biomimetic spraying process. J. Mater. Sci. Mater. Med. 2007;18:1279-1286.

    Not in our library10.1007/s10856-006-0063-4

  61. 61.

    Leonor I.B., Baran E.T., Kawashita M., Reis R.L., Kokubo T., Nakamura T. Growth of a bonelike apatite on chitosan microparticles after a calcium silicate treatment. Acta Biomater. 2008;4:1349-1359.

    Not in our library10.1016/j.actbio.2008.03.003

  62. 62.

    Elkholy S., Yahia S., Awad M., Elmessiery M. In vivo evaluation of β-CS/n-HA with different physical properties as a new bone graft material. Clin. Implant Dent. Relat. Res. 2018;20:416-423.

    Not in our library10.1111/cid.12599

  63. 63.

    Gaihre B., Jayasuriya A.C. Comparative investigation of porous nano-hydroxyapaptite/chitosan, nano-zirconia/chitosan and novel nano-calcium zirconate/chitosan composite scaffolds for their potential applications in bone regeneration. Mater. Sci. Eng. C. 2018;91:330-339.

    Not in our library10.1016/j.msec.2018.05.060

  64. 64.

    Koç Demir A., Elçin A.E., Elçin Y.M. Strontium-modified chitosan/montmorillonite composites as bone tissue engineering scaffold. Mater. Sci. Eng. C. 2018;89:8-14.

    Not in our library10.1016/j.msec.2018.03.021

  65. 65.

    Georgopoulou A., Kaliva M., Vamvakaki M., Chatzinikolaidou M. Osteogenic Potential of Pre-Osteoblastic Cells on a Chitosan-graft-Polycaprolactone Copolymer. Materials. 2018;11:490.

    Not in our library10.3390/ma11040490

  66. 66.

    Habibovic P., Barralet J.E. Bioinorganics and biomaterials: Bone repair. Acta Biomater. 2011;7:3013-3026.

    Not in our library10.1016/j.actbio.2011.03.027

  67. 67.

    Singh B.N., Veeresh V., Mallick S.P., Jain Y., Sinha S., Rastogi A., Srivastava P. Design and evaluation of chitosan/chondroitin sulfate/nano-bioglass based composite scaffold for bone tissue engineering. Int. J. Biol. Macromol. 2019;133:817-830.

    Not in our library10.1016/j.ijbiomac.2019.04.107

  68. 68.

    Lu H.-T., Lu T.-W., Chen C.-H., Mi F.-L. Development of genipin-crosslinked and fucoidan-adsorbed nano-hydroxyapatite/hydroxypropyl chitosan composite scaffolds for bone tissue engineering. Int. J. Biol. Macromol. 2019;128:973-984.

    Not in our library10.1016/j.ijbiomac.2019.02.010

  69. 69.

    Keller L., Regiel-Futyra A., Gimeno M., Eap S., Mendoza G., Andreu V., Wagner Q., Kyzioł A., Sebastian V., Stochel G., et al. Chitosan-based nanocomposites for the repair of bone defects. Nanomed. Nanotechnol. Biol. Med. 2017;13:2231-2240.

    Not in our library10.1016/j.nano.2017.06.007

  70. 70.

    Georgopoulou A., Papadogiannis F., Batsali A., Marakis J., Alpantaki K., Eliopoulos A.G., Pontikoglou C., Chatzinikolaidou M. Chitosan/gelatin scaffolds support bone regeneration. J. Mater. Sci. Mater. Med. 2018;29:59.

    Not in our library10.1007/s10856-018-6064-2

  71. 71.

    Nguyen T.H.M., Abueva C., Van Ho H., Lee S.-Y., Lee B.-T. In vitro and in vivo acute response towards injectable thermosensitive chitosan/TEMPO-oxidized cellulose nanofiber hydrogel. Carbohydr. Polym. 2018;180:246-255.

    Not in our library10.1016/j.carbpol.2017.10.032

  72. 72.

    Zhang L., Wu K., Song W., Xu H., An R., Zhao L., Liu B., Zhang Y. Chitosan/siCkip-1 biofunctionalized titanium implant for improved osseointegration in the osteoporotic condition. Sci. Rep. 2015;5:10860.

    Not in our library10.1038/srep10860

  73. 73.

    Dwivedi P., Narvi S.S., Tewari R.P. Application of polymer nanocomposites in the nanomedicine landscape: Envisaging strategies to combat implant associated infections. J. Appl. Biomater. Funct. Mater. 2013;11:129-142.

    Not in our library10.5301/jabfm.2013.11544

  74. 74.

    Kumar A.M., Suresh B., Das S., Obot I.B., Adesina A.Y., Ramakrishna S. Promising bio-composites of polypyrrole and chitosan: Surface protective and in vitro biocompatibility performance on 316L SS implants. Carbohydr. Polym. 2017;173:121-130.

    Not in our library10.1016/j.carbpol.2017.05.083

  75. 75.

    Liu J., Sun L., Xu W., Wang Q., Yu S., Sun J. Current advances and future perspectives of 3D printing natural-derived biopolymers. Carbohydr. Polym. 2019;207:297-316.

    Not in our library10.1016/j.carbpol.2018.11.077

  76. 76.

    Demirtaş T.T., Irmak G., Gümüşderelioğlu M. A bioprintable form of chitosan hydrogel for bone tissue engineering. Biofabrication. 2017;9:035003.

    Not in our library10.1088/1758-5090/aa7b1d

  77. 77.

    Liao I.-C., Moutos F.T., Estes B.T., Zhao X., Guilak F. Composite Three-Dimensional Woven Scaffolds with Interpenetrating Network Hydrogels to Create Functional Synthetic Articular Cartilage. Adv. Funct. Mater. 2013;23:5833-5839.

    Not in our library10.1002/adfm.201300483

  78. 78.

    Nettles D.L., Elder S.H., Gilbert J.A. Potential Use of Chitosan as a Cell Scaffold Material for Cartilage Tissue Engineering. Tissue Eng. 2002;8:1009-1016.

    Not in our library10.1089/107632702320934100

  79. 79.

    Freedman B.R., Mooney D.J. Biomaterials to Mimic and Heal Connective Tissues. Adv. Mater. 2019;31:1806695.

    Not in our library10.1002/adma.201806695

  80. 80.

    Jin R., Moreira Teixeira L.S., Dijkstra P.J., Karperien M., van Blitterswijk C.A., Zhong Z.Y., Feijen J. Injectable chitosan-based hydrogels for cartilage tissue engineering. Biomaterials. 2009;30:2544-2551.

    Not in our library10.1016/j.biomaterials.2009.01.020

  81. 81.
    Injectable hydrogels for cartilage and bone tissue engineering · 2017
    No notice
  82. 82.

    Huang H., Zhang X., Hu X., Dai L., Zhu J., Man Z., Chen H., Zhou C., Ao Y. Directing chondrogenic differentiation of mesenchymal stem cells with a solid-supported chitosan thermogel for cartilage tissue engineering. Biomed. Mater. 2014;9:035008.

    Not in our library10.1088/1748-6041/9/3/035008

  83. 83.

    Kuo C.-Y., Chen C.-H., Hsiao C.-Y., Chen J.-P. Incorporation of chitosan in biomimetic gelatin/chondroitin-6-sulfate/hyaluronan cryogel for cartilage tissue engineering. Carbohydr. Polym. 2015;117:722-730.

    Not in our library10.1016/j.carbpol.2014.10.056

  84. 84.

    VandeVord P.J., Matthew H.W.T., DeSilva S.P., Mayton L., Wu B., Wooley P.H. Evaluation of the biocompatibility of a chitosan scaffold in mice. J. Biomed. Mater. Res. 2002;59:585-590.

    Not in our library10.1002/jbm.1270

  85. 85.

    Choi B., Kim S., Lin B., Wu B.M., Lee M. Cartilaginous Extracellular Matrix-Modified Chitosan Hydrogels for Cartilage Tissue Engineering. ACS Appl. Mater. Interfaces. 2014;6:20110-20121.

    Not in our library10.1021/am505723k

  86. 86.
    Chitosan enriched three-dimensional matrix reduces inflammatory and catabolic mediators production by human chondrocytes. · 2015
    Not checked
  87. 87.

    Kong Y., Zhang Y., Zhao X., Wang G., Liu Q. Carboxymethyl-chitosan attenuates inducible nitric oxide synthase and promotes interleukin-10 production in rat chondrocytes. Exp. Ther. Med. 2017;14:5641-5646.

    Not in our library10.3892/etm.2017.5258

  88. 88.

    Huang S., Song X., Li T., Xiao J., Chen Y., Gong X., Zeng W., Yang L., Chen C. Pellet coculture of osteoarthritic chondrocytes and infrapatellar fat pad-derived mesenchymal stem cells with chitosan/hyaluronic acid nanoparticles promotes chondrogenic differentiation. Stem Cell Res. Ther. 2017;8:264.

    Not in our library10.1186/s13287-017-0719-7

  89. 89.

    Ye K., Felimban R., Traianedes K., Moulton S.E., Wallace G.G., Chung J., Quigley A., Choong P.F.M., Myers D.E. Chondrogenesis of infrapatellar fat pad derived adipose stem cells in 3D printed chitosan scaffold. PLoS ONE. 2014;9:e99410.

    Not in our library10.1371/journal.pone.0099410

  90. 90.

    Sionkowska A., Wisniewski M., Skopinska J., Kennedy C.J., Wess T.J. Molecular interactions in collagen and chitosan blends. Biomaterials. 2004;25:795-801.

    Not in our library10.1016/s0142-9612(03)00595-7

  91. 91.

    Haaparanta A.-M., Järvinen E., Cengiz I.F., Ellä V., Kokkonen H.T., Kiviranta I., Kellomäki M. Preparation and characterization of collagen/PLA, chitosan/PLA, and collagen/chitosan/PLA hybrid scaffolds for cartilage tissue engineering. J. Mater. Sci. Mater. Med. 2014;25:1129-1136.

    Not in our library10.1007/s10856-013-5129-5

  92. 92.

    Su J.-Y., Chen S.-H., Chen Y.-P., Chen W.-C. Evaluation of Magnetic Nanoparticle-Labeled Chondrocytes Cultivated on a Type II Collagen-Chitosan/Poly(Lactic-co-Glycolic) Acid Biphasic Scaffold. Int. J. Mol. Sci. 2017;18:87.

    Not in our library10.3390/ijms18010087

  93. 93.

    Bhardwaj N., Nguyen Q.T., Chen A.C., Kaplan D.L., Sah R.L., Kundu S.C. Potential of 3-D tissue constructs engineered from bovine chondrocytes/silk fibroin-chitosan for in vitro cartilage tissue engineering. Biomaterials. 2011;32:5773-5781.

    Not in our library10.1016/j.biomaterials.2011.04.061

  94. 94.

    Liu J., Fang Q., Yu X., Wan Y., Xiao B. Chitosan-Based Nanofibrous Membrane Unit with Gradient Compositional and Structural Features for Mimicking Calcified Layer in Osteochondral Matrix. Int. J. Mol. Sci. 2018;19:2330.

    Not in our library10.3390/ijms19082330

  95. 95.

    Noriega S.E., Hasanova G.I., Schneider M.J., Larsen G.F., Subramanian A. Effect of fiber diameter on the spreading, proliferation and differentiation of chondrocytes on electrospun chitosan matrices. Cells Tissues Organs. 2012;195:207-221.

    Not in our library10.1159/000325144

  96. 96.

    Bhat S., Tripathi A., Kumar A. Supermacroprous chitosan–agarose–gelatin cryogels: In vitro characterization and in vivo assessment for cartilage tissue engineering. J. R. Soc. Interface. 2011;8:540-554.

    Not in our library10.1098/rsif.2010.0455

  97. 97.

    Gupta A., Bhat S., Jagdale P.R., Chaudhari B.P., Lidgren L., Gupta K.C., Kumar A. Evaluation of three-dimensional chitosan-agarose-gelatin cryogel scaffold for the repair of subchondral cartilage defects: An in vivo study in a rabbit model. Tissue Eng. Part A. 2014;20:3101-3111.

    Not in our library10.1089/ten.tea.2013.0702

  98. 98.
    Chondrogenic Differentiation of Mesenchymal Stem Cells in Three-Dimensional Chitosan Film Culture · 2017
    Not checked
  99. 99.

    Vårum K.M., Holme H.K., Izume M., Stokke B.T., Smidsrød O. Determination of enzymatic hydrolysis specificity of partially N-acetylated chitosans. Biochim. Biophys. Acta. 1996;1291:5-15.

    Not in our library10.1016/0304-4165(96)00038-4

  100. 100.

    Rathore A.S., Gupta R.D. Chitinases from Bacteria to Human: Properties, Applications, and Future Perspectives. Enzyme Res. 2015;2015:791907.

    Not in our library10.1155/2015/791907

  101. 101.

    Sogias I.A., Williams A.C., Khutoryanskiy V.V. Why is Chitosan Mucoadhesive? Biomacromolecules. 2008;9:1837-1842.

    Not in our library10.1021/bm800276d

  102. 102.

    Casettari L., Illum L. Chitosan in nasal delivery systems for therapeutic drugs. J. Control. Release. 2014;190:189-200.

    Not in our library10.1016/j.jconrel.2014.05.003

  103. 103.

    Irimia T., Dinu-Pîrvu C.-E., Ghica M.V., Lupuleasa D., Muntean D.-L., Udeanu D.I., Popa L. Chitosan-Based in Situ Gels for Ocular Delivery of Therapeutics: A State-of-the-Art Review. Mar. Drugs. 2018;16:373.

    Not in our library10.3390/md16100373

  104. 104.

    Batista P., Castro P., Madureira A.R., Sarmento B., Pintado M. Development and Characterization of Chitosan Microparticles-in-Films for Buccal Delivery of Bioactive Peptides. Pharmaceuticals. 2019;12:32.

    Not in our library10.3390/ph12010032

  105. 105.

    Ortiz M., Jornada D.S., Pohlmann A.R., Guterres S.S. Development of Novel Chitosan Microcapsules for Pulmonary Delivery of Dapsone: Characterization, Aerosol Performance, and In Vivo Toxicity Evaluation. AAPS PharmSciTech. 2015;16:1033-1040.

    Not in our library10.1208/s12249-015-0283-3

  106. 106.

    Baranwal A., Kumar A., Priyadharshini A., Oggu G.S., Bhatnagar I., Srivastava A., Chandra P. Chitosan: An undisputed bio-fabrication material for tissue engineering and bio-sensing applications. Int. J. Biol. Macromol. 2018;110:110-123.

    Not in our library10.1016/j.ijbiomac.2018.01.006

  107. 107.

    Ahmed S., Ali A., Sheikh J. A review on chitosan centred scaffolds and their applications in tissue engineering. Int. J. Biol. Macromol. 2018;116:849-862.

    Not in our library10.1016/j.ijbiomac.2018.04.176

  108. 108.

    Xu X., Li L., Zhou J., Lu S., Yang J., Yin X., Ren J. Preparation and characterization of N-succinyl-N′-octyl chitosan micelles as doxorubicin carriers for effective anti-tumor activity. Colloids Surf. B Biointerfaces. 2007;55:222-228.

    Not in our library10.1016/j.colsurfb.2006.12.006

  109. 109.
    An Overview of Chitosan Nanoparticles and Its Application in Non-Parenteral Drug Delivery · 2017
    No notice
  110. 110.

    Chen K.-Y., Zeng S.-Y. Fabrication of Quaternized Chitosan Nanoparticles Using Tripolyphosphate/Genipin Dual Cross-Linkers as a Protein Delivery System. Polymers. 2018;10:1226.

    Not in our library10.3390/polym10111226

  111. 111.

    Divya K., Jisha M.S. Chitosan nanoparticles preparation and applications. Environ. Chem. Lett. 2018;16:101-112.

    Not in our library10.1007/s10311-017-0670-y

  112. 112.

    Özbaş-Turan S., Akbuǧa J., Aral C. Controlled Release of Interleukin-2 from Chitosan Microspheres. J. Pharm. Sci. 2002;91:1245-1251.

    Not in our library10.1002/jps.10122

  113. 113.

    Samorezov J.E., Alsberg E. Spatial regulation of controlled bioactive factor delivery for bone tissue engineering. Adv. Drug Deliv. Rev. 2015;84:45-67.

    Not in our library10.1016/j.addr.2014.11.018

  114. 114.

    Lin C., Romero R., Sorokina L.V., Ballinger K.R., Place L.W., Kipper M.J., Khetani S.R. A polyelectrolyte multilayer platform for investigating growth factor delivery modes in human liver cultures. J. Biomed. Mater. Res. A. 2018;106:971-984.

    Not in our library10.1002/jbm.a.36293

  115. 115.

    Tan Q., Tang H., Hu J., Hu Y., Zhou X., Tao Y., Wu Z. Controlled release of chitosan/heparin nanoparticle-delivered VEGF enhances regeneration of decellularized tissue-engineered scaffolds. Int. J. Nanomed. 2011;6:929-942.

    Not in our library10.2147/ijn.s18753

  116. 116.

    Liang Y., Kiick K.L. Heparin-functionalized polymeric biomaterials in tissue engineering and drug delivery applications. Acta Biomater. 2014;10:1588-1600.

    Not in our library10.1016/j.actbio.2013.07.031

  117. 117.

    Mansurov N., Chen W.C.W., Awada H., Huard J., Wang Y., Saparov A. A controlled release system for simultaneous delivery of three human perivascular stem cell-derived factors for tissue repair and regeneration. J. Tissue Eng. Regen. Med. 2018;12:e1164-e1172.

    Not in our library10.1002/term.2451

  118. 118.

    Pilipenko I., Korzhikov-Vlakh V., Sharoyko V., Zhang N., Schäfer-Korting M., Rühl E., Zoschke C., Tennikova T. pH-Sensitive Chitosan–Heparin Nanoparticles for Effective Delivery of Genetic Drugs into Epithelial Cells. Pharmaceutics. 2019;11:317.

    Not in our library10.3390/pharmaceutics11070317

  119. 119.

    Zeng K., Groth T., Zhang K. Recent Advances in Artificially Sulfated Polysaccharides for Applications in Cell Growth and Differentiation, Drug Delivery, and Tissue Engineering. ChemBioChem. 2019;20:737-746.

    Not in our library10.1002/cbic.201800569

  120. 120.

    Zhong Z., Li P., Xing R., Liu S. Antimicrobial activity of hydroxylbenzenesulfonailides derivatives of chitosan, chitosan sulfates and carboxymethyl chitosan. Int. J. Biol. Macromol. 2009;45:163-168.

    Not in our library10.1016/j.ijbiomac.2009.04.020

  121. 121.

    Ho Y.-C., Wu S.-J., Mi F.-L., Chiu Y.-L., Yu S.-H., Panda N., Sung H.-W. Thiol-Modified Chitosan Sulfate Nanoparticles for Protection and Release of Basic Fibroblast Growth Factor. Bioconj. Chem. 2010;21:28-38.

    Not in our library10.1021/bc900208t

  122. 122.

    Peschel D., Zhang K., Fischer S., Groth T. Modulation of osteogenic activity of BMP-2 by cellulose and chitosan derivatives. Acta Biomater. 2012;8:183-193.

    Not in our library10.1016/j.actbio.2011.08.012

  123. 123.

    Weltrowski A., da Silva Almeida M.-L., Peschel D., Zhang K., Fischer S., Groth T. Mitogenic Activity of Sulfated Chitosan and Cellulose Derivatives is Related to Protection of FGF-2 from Proteolytic Cleavage. Macromol. Biosci. 2012;12:740-750.

    Not in our library10.1002/mabi.201100518

  124. 124.

    Farrugia B.L., Mi Y., Kim H.N., Whitelock J.M., Baker S.M., Wiesmann W.P., Li Z., Maitz P., Lord M.S. Chitosan-Based Heparan Sulfate Mimetics Promote Epidermal Formation in a Human Organotypic Skin Model. Adv. Funct. Mater. 2018;28:1802818.

    Not in our library10.1002/adfm.201802818

  125. 125.

    Santos-Carballal B., Fernández Fernández E., Goycoolea F., Santos-Carballal B., Fernández Fernández E., Goycoolea F.M. Chitosan in Non-Viral Gene Delivery: Role of Structure, Characterization Methods, and Insights in Cancer and Rare Diseases Therapies. Polymers. 2018;10:444.

    Not in our library10.3390/polym10040444

  126. 126.

    Mumper R., Wang J., Claspell J., Rolland A. Novel polymeric condensing carriers for gene delivery. Proc. Control. Release Soc. 1995;22:178-179.

    Not in our library

  127. 127.

    Jayakumar R., Chennazhi K.P., Muzzarelli R.A.A., Tamura H., Nair S.V., Selvamurugan N. Chitosan conjugated DNA nanoparticles in gene therapy. Carbohydr. Polym. 2010;79:1-8.

    Not in our library10.1016/j.carbpol.2009.08.026

  128. 128.

    MacLaughlin F.C., Mumper R.J., Wang J., Tagliaferri J.M., Gill I., Hinchcliffe M., Rolland A.P. Chitosan and depolymerized chitosan oligomers as condensing carriers for in vivo plasmid delivery. J. Control. Release. 1998;56:259-272.

    Not in our library10.1016/s0168-3659(98)00097-2

  129. 129.

    Venkatesh S., Smith T.J. Chitosan-membrane interactions and their probable role in chitosan-mediated transfection. Biotechnol. Appl. Biochem. 1998;27:265-267.

    Not in our library

  130. 130.

    Vauthier C., Zandanel C., Ramon A.L. Chitosan-based nanoparticles for in vivo delivery of interfering agents including siRNA. Curr. Opin. Colloid Interface Sci. 2013;18:406-418.

    Not in our library10.1016/j.cocis.2013.06.005

  131. 131.

    Cryan S.-A., McKiernan P., Cunningham C.M., Greene C. Targeting miRNA-based medicines to cystic fibrosis airway epithelial cells using nanotechnology. Int. J. Nanomed. 2013;8:3907.

    Not in our library10.2147/ijn.s47551

  132. 132.

    Ban E., Kwon T.-H., Kim A. Delivery of therapeutic miRNA using polymer-based formulation. Drug Deliv. Transl. Res. 2019.

    Not in our library10.1007/s13346-019-00645-y

  133. 133.

    Csaba N., Köping-Höggård M., Alonso M.J. Ionically crosslinked chitosan/tripolyphosphate nanoparticles for oligonucleotide and plasmid DNA delivery. Int. J. Pharm. 2009;382:205-214.

    Not in our library10.1016/j.ijpharm.2009.07.028

  134. 134.

    Csaba N., Köping-Höggård M., Fernandez-Megia E., Novoa-Carballal R., Riguera R., Alonso M.J. Ionically crosslinked chitosan nanoparticles as gene delivery systems: Effect of PEGylation degree on in vitro and in vivo gene transfer. J. Biomed. Nanotechnol. 2009;5:162-171.

    Not in our library10.1166/jbn.2009.1017

  135. 135.

    Mao H.Q., Roy K., Troung-Le V.L., Janes K.A., Lin K.Y., Wang Y., August J.T., Leong K.W. Chitosan-DNA nanoparticles as gene carriers: Synthesis, characterization and transfection efficiency. J. Control. Release. 2001;70:399-421.

    Not in our library10.1016/s0168-3659(00)00361-8

  136. 136.

    Corsi K., Chellat F., Yahia L., Fernandes J.C. Mesenchymal stem cells, MG63 and HEK293 transfection using chitosan-DNA nanoparticles. Biomaterials. 2003;24:1255-1264.

    Not in our library10.1016/s0142-9612(02)00507-0

  137. 137.

    Zhu H., Cao J., Cui S., Qian Z., Gu Y. Enhanced Tumor Targeting and Antitumor Efficacy via Hydroxycamptothecin-Encapsulated Folate-Modified N-Succinyl-N′-Octyl Chitosan Micelles. J. Pharm. Sci. 2013;102:1318-1332.

    Not in our library10.1002/jps.23470

  138. 138.

    Gu Y., Li S., Feng S., Ding L., Liu Y., Zhu Q., Qian Z. Nanomedicine engulfed by macrophages for targeted tumor therapy. Int. J. Nanomed. 2016;11:4107-4124.

    Not in our library10.2147/ijn.s110146

  139. 139.

    Tu Z., Ma Y., Akers W., Achilefu S., Gu Y. Therapeutic effect of the treatment for colorectal cancer with adenoviral vectors mediated estrogen receptor β gene therapy combined with thermotherapy. J. Cancer Res. Clin. Oncol. 2014;140:623-632.

    Not in our library10.1007/s00432-014-1611-9

  140. 140.

    Woraphatphadung T., Sajomsang W., Rojanarata T., Ngawhirunpat T., Tonglairoum P., Opanasopit P. Development of Chitosan-Based pH-Sensitive Polymeric Micelles Containing Curcumin for Colon-Targeted Drug Delivery. AAPS PharmSciTech. 2018;19:991-1000.

    Not in our library10.1208/s12249-017-0906-y

  141. 141.

    Deng D., Qu L., Zhang J., Ma Y., Gu Y. Quaternary Zn–Ag–In–Se Quantum Dots for Biomedical Optical Imaging of RGD-Modified Micelles. ACS Appl. Mater. Interfaces. 2013;5:10858-10865.

    Not in our library10.1021/am403050s

  142. 142.

    Zhang C., Ding Y., Yu L., Ping Q. Polymeric micelle systems of hydroxycamptothecin based on amphiphilic N-alkyl-N-trimethyl chitosan derivatives. Colloids Surf. B Biointerfaces. 2007;55:192-199.

    Not in our library10.1016/j.colsurfb.2006.11.031

  143. 143.

    Zhang F., Fei J., Sun M., Ping Q. Heparin modification enhances the delivery and tumor targeting of paclitaxel-loaded N-octyl-N -trimethyl chitosan micelles. Int. J. Pharm. 2016;511:390-402.

    Not in our library10.1016/j.ijpharm.2016.07.020

  144. 144.

    Mo R., Jin X., Li N., Ju C., Sun M., Zhang C., Ping Q. The mechanism of enhancement on oral absorption of paclitaxel by N-octyl-O-sulfate chitosan micelles. Biomaterials. 2011;32:4609-4620.

    Not in our library10.1016/j.biomaterials.2011.03.005

  145. 145.

    Mo R., Xiao Y., Sun M., Zhang C., Ping Q. Enhancing effect of N-octyl-O-sulfate chitosan on etoposide absorption. Int. J. Pharm. 2011;409:38-45.

    Not in our library10.1016/j.ijpharm.2011.02.021

  146. 146.

    Jin X., Mo R., Ding Y., Zheng W., Zhang C. Paclitaxel-Loaded N-Octyl-O-sulfate Chitosan Micelles for Superior Cancer Therapeutic Efficacy and Overcoming Drug Resistance. Mol. Pharm. 2014;11:145-157.

    Not in our library10.1021/mp400340k

  147. 147.

    Ju C., Sun J., Zi P., Jin X., Zhang C. Thermosensitive Micelles–Hydrogel Hybrid System Based on Poloxamer 407 for Localized Delivery of Paclitaxel. J. Pharm. Sci. 2013;102:2707-2717.

    Not in our library10.1002/jps.23649

  148. 148.

    Qu G., Yao Z., Zhang C., Wu X., Ping Q. PEG conjugated N-octyl-O-sulfate chitosan micelles for delivery of paclitaxel: In vitro characterization and in vivo evaluation. Eur. J. Pharm. Sci. 2009;37:98-105.

    Not in our library10.1016/j.ejps.2009.01.004

  149. 149.

    Qu G., Wu X., Yin L., Zhang C. N-octyl-O-sulfate chitosan-modified liposomes for delivery of docetaxel: Preparation, characterization, and pharmacokinetics. Biomed. Pharmacother. 2012;66:46-51.

    Not in our library10.1016/j.biopha.2011.09.010

  150. 150.

    Zhong Z., Zhong Z., Xing R., Li P., Mo G. The preparation and antioxidant activity of 2-[phenylhydrazine (or hydrazine)-thiosemicarbazone]-chitosan. Int. J. Biol. Macromol. 2010;47:93-97.

    Not in our library10.1016/j.ijbiomac.2010.05.016

  151. 151.

    Chen X., Cao X., Jiang H., Che X., Xu X., Ma B., Zhang J., Huang T. SIKVAV-Modified Chitosan Hydrogel as a Skin Substitutes for Wound Closure in Mice. Molecules. 2018;23:2611.

    Not in our library10.3390/molecules23102611

  152. 152.

    Liu W., Wang F., Zhu Y., Li X., Liu X., Pang J., Pan W. Galactosylated Chitosan-Functionalized Mesoporous Silica Nanoparticle Loading by Calcium Leucovorin for Colon Cancer Cell-Targeted Drug Delivery. Molecules. 2018;23:3082.

    Not in our library10.3390/molecules23123082

  153. 153.

    Ning Q., Liu Y.-F., Ye P.-J., Gao P., Li Z.-P., Tang S.-Y., He D.-X., Tang S.-S., Wei H., Yu C.-Y. Delivery of Liver-Specific miRNA-122 Using a Targeted Macromolecular Prodrug toward Synergistic Therapy for Hepatocellular Carcinoma. ACS Appl. Mater. Interfaces. 2019;11:10578-10588.

    Not in our library10.1021/acsami.9b00634

  154. 154.

    Liu W., Zhu Y., Wang F., Li X., Liu X., Pang J., Pan W. Galactosylated chitosan-functionalized mesoporous silica nanoparticles for efficient colon cancer cell-targeted drug delivery. R. Soc. Open Sci. 2018;5:181027.

    Not in our library10.1098/rsos.181027

  155. 155.

    Yen H., Young Y., Tsai T., Cheng K., Chen X., Chen Y., Chen C., Young J., Hong P. Positively charged gold nanoparticles capped with folate quaternary chitosan: Synthesis, cytotoxicity, and uptake by cancer cells. Carbohydr. Polym. 2018;183:140-150.

    Not in our library10.1016/j.carbpol.2017.11.096

  156. 156.

    Huang Y., Guo J., Gui S. Orally targeted galactosylated chitosan poly(lactic-co-glycolic acid) nanoparticles loaded with TNF-a siRNA provide a novel strategy for the experimental treatment of ulcerative colitis. Eur. J. Pharm. Sci. 2018;125:232-243.

    Not in our library10.1016/j.ejps.2018.10.009

  157. 157.

    Xiao B., Chen Q., Zhang Z., Wang L., Kang Y., Denning T., Merlin D. TNFα gene silencing mediated by orally targeted nanoparticles combined with interleukin-22 for synergistic combination therapy of ulcerative colitis. J. Control. Release. 2018;287:235-246.

    Not in our library10.1016/j.jconrel.2018.08.021

  158. 158.
    Evaluation of Chitosan Derivative Microparticles Encapsulating Superparamagnetic Iron Oxide and Doxorubicin as a pH-Sensitive Delivery Carrier in Hepatic Carcinoma Treatment: An in vitro Comparison Study · 2018
    Not checked
  159. 159.

    Bin J., Xiao Y., Lin Z.T., Deng Y.L., Chen Y., Le D.E., Bin J., Li M., Liao Y., Liu Y., et al. High molecular weight chitosan derivative polymeric micelles encapsulating superparamagnetic iron oxide for tumor-targeted magnetic resonance imaging. Int. J. Nanomed. 2015;10:1155.

    Not in our library10.2147/ijn.s70022

  160. 160.

    Zariwala M.G., Bendre H., Markiv A., Farnaud S., Renshaw D., Taylor K.M., Somavarapu S. Hydrophobically modified chitosan nanoliposomes for intestinal drug delivery. Int. J. Nanomed. 2018;13:5837-5848.

    Not in our library10.2147/ijn.s166901

  161. 161.

    Chiesa E., Dorati R., Conti B., Modena T., Cova E., Meloni F., Genta I. Hyaluronic Acid-Decorated Chitosan Nanoparticles for CD44-Targeted Delivery of Everolimus. Int. J. Mol. Sci. 2018;19:2310.

    Not in our library10.3390/ijms19082310

  162. 162.

    Song Q., Jia J., Niu X., Zheng C., Zhao H., Sun L., Zhang H., Wang L., Zhang Z., Zhang Y. An oral drug delivery system with programmed drug release and imaging properties for orthotopic colon cancer therapy. Nanoscale. 2019.

    Not in our library10.1039/c9nr03802g

  163. 163.

    Feiz M.S., Meshkini A. Targeted delivery of adenosine 5′-triphosphate using chitosan-coated mesoporous hydroxyapatite: A theranostic pH-sensitive nanoplatform with enhanced anti-cancer effect. Int. J. Biol. Macromol. 2019;129:1090-1102.

    Not in our library10.1016/j.ijbiomac.2018.08.158

  164. 164.
    Selective delivery of PLXDC1 small interfering RNA to endothelial cells for anti-angiogenesis tumor therapy using CD44-targeted chitosan nanoparticles for epithelial ovarian cancer · 2018
    Not checked
  165. 165.

    Iglesias N., Galbis E., Díaz-Blanco M.J., Lucas R., Benito E., de-Paz M.-V. Nanostructured Chitosan-Based Biomaterials for Sustained and Colon-Specific Resveratrol Release. Int. J. Mol. Sci. 2019;20:398.

    Not in our library10.3390/ijms20020398

  166. 166.
    Development of dual-drug-loaded stealth nanocarriers for targeted and synergistic anti-lung cancer efficacy · 2018
    Not checked
  167. 167.

    Xie P., Du P., Li J., Liu P. Stimuli-responsive hybrid cluster bombs of PEGylated chitosan encapsulated DOX-loaded superparamagnetic nanoparticles enabling tumor-specific disassembly for on-demand drug delivery and enhanced MR imaging. Carbohydr. Polym. 2019;205:377-384.

    Not in our library10.1016/j.carbpol.2018.10.076

  168. 168.

    Wang K., Zhuang J., Liu Y., Xu M., Zhuang J., Chen Z., Wei Y., Zhang Y. PEGylated chitosan nanoparticles with embedded bismuth sulfide for dual-wavelength fluorescent imaging and photothermal therapy. Carbohydr. Polym. 2018;184:445-452.

    Not in our library10.1016/j.carbpol.2018.01.005

  169. 169.
    Mesenteric CD103+DCs Initiate Switched Coxsackievirus B3 VP1-Specific IgA Response to Intranasal Chitosan-DNA Vaccine Through Secreting BAFF/IL-6 and Promoting Th17/Tfh Differentiation · 2018
    Not checked
  170. 170.

    Sinani G., Sessevmez M., Gök M.K., Özgümüş S., Alpar H.O., Cevher E. Modified chitosan-based nanoadjuvants enhance immunogenicity of protein antigens after mucosal vaccination. Int. J. Pharm. 2019;569:118592.

    Not in our library10.1016/j.ijpharm.2019.118592

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