Chitosan nanocomposites based on distinct inorganic fillers for biomedical applications

Figures & data

Figure 1. Main biomedical applications of chitosan nanocomposites.

Figure 2. Representation of the basic units (a) Si-O tetrahedron and Al-O or Al-O octahedron present on the clay minerals [43]. (b) Representation of the different structures resulted from different clay dispersion in the polymeric matrix. (i) Tactoid structures, (ii) intercalated structures and (iii) exfoliated structures [39].

Figure 3. Schematic representation of (a) graphene and (b) graphene oxide sheet [86].

Table 1. Overview of CHI nanocomposites with different fillers.

Filler	Aim	Nanocomposite properties	Ref.
Layered silicates
MMT	Study the influence of molecular weight and deacetylation degree of CHI	Intercalated CHI between the MMT layers, independently of the CHI molecular weight	[49]
	Develop porous structured scaffolds from MMT and CHI	Thermal property improved for 80:20 weight ratio MTT:CHI, decomposition onset increasing by 25°C. Silicate well dispersed in the polymer. Interlayer spacing increase from 1.2 to 1.5 nm for MMT:CHI wt ratio 20:80	[50]
	Develop nacre-like structures	CHI/MTT films densely stacked with a well-defined layered structure. Elastic modulus increase; good interfacial stress transfer ability	[51]
Ceramic nanoparticles
BG NPs	Study of CHI/BG NPs potential for periodontal regeneration	Membranes with higher modulus. Ability to promote the deposition of an apatite layer upon immersion in SBF	[103]
	Produce nanocomposite coatings of BG and BG NPs with CHI	A hydroxyapatite (HA) layer was formed on all coatings; BG NPs showed higher ability to form HA	[104]
HA NPs	Study the effect of micro and nano HA for bone graft substitutes	Independently of the HA size cortical bone formation was achieved, reaching higher yield for HA NPs	[105]
	Study the mechanical properties of CHI/ HA NPs cross-linked with genipin	Tensile strength increase ~100% for HA NPs concentration up to 10 wt%, decreasing at higher HA NPs wt%	[106]
Metallic nanoparticles
Ag NPs	Study the antibacterial activity of CHI/Ag NPs	Both components act synergistically against two strains of Gram-positive Staphylococcus aureus	[63]
Au NPs	Investigate the use of CHI matrix for glucose biosensing applications	Film characteristics were tuned by control of CHI and Ag NPs deposition conditions, achieving a biosensor with detection limit near 13 μM	[64]
ZnO NPs	Characterize the CHI/ ZnO NPs nanocomposites membranes	Achieved antibacterial activity against Bacillus subtilis, E. coli and Gram-positive bacterium S. aureus at 6–10 wt% ZnO NPs. Tensile strength increase (~24% for at 6 wt% ZnO NPs)	[65]
Carbon materials
CNTs	Develop CHI/aligned MWNTs for neural tissue regeneration	Increase of 35.7% in Young’s modulus. Electrical conductivity increased by ${10}^5$ S m^–1	[33]
	Coating of CHI on the CNTs surface	Increase of tensile strength for 50:50 wt% CHI/CNTs, decrease of surface electrical resistivity to 16 Ω sq^–1	[107]
GO	Study the influence of GO on the thermal stability and mechanical properties of CHI films	Storage modulus maximized at 0.5 wt% GO and a nacre-like structure was obtained. Tg increased from 186.6°C to 192.5°C	[36]
	Study the mechanical behavior of CHI/graphene films	0.1–0.3 wt% of GO increased the elastic modulus over 200%	[108]
	Study the dye adsorption properties of GO/CHI composite fibers	The adsorption capacity of fuchsin acid dye onto the fibers dependent on pH	[37]
	Develop GO genipin cross-linked CHI films	Mechanical reinforcement (tensile strength); increase of resistance to enzymatic degradation; addition of GO reported to be non-toxic	[109]
	Study mechanical behavior of CHI/GO nanocomposite films in the wet state	The presence of an aqueous medium increased the tensile strength (three times higher compared to dry state)	[38]

Abbreviation: SBF, simulated body fluid.

Figure 4. (a) Schematic representation of the procedure to obtain a membrane/film using the solvent casting method. (b) Comparison between the surface of a (i) CHI membrane and (ii) CHI/bioactive glass membrane.[115]

Figure 5. Representation of (a) three main LbL methods: (i) dip coating; (ii) spin coating and (iii) spray coating; and (b) image of a chitosan/alginate free-standing membrane, where (i) represents the membrane obtained by dip coating a polypropylene substrate after 100 cycles and (ii) its respective cross-section scanning electron microscopy (SEM) picture.[129]

Figure 6. Schematic illustration of the different structures resulted from the different building blocks and substrates used in the LbL process.[130]

Figure 7. (a) Representation of the different electrospinning approaches, namely (i) wet–dry spinning, (ii) wet–wet spinning and (iii) co-axial electrospinning. (b) Representation of a (i) macroscopic electrospun chitosan fiber mat and (ii) chitosan/hydroxyapatite nanoparticles fibers morphology obtained by SEM with respective insert image at lower magnification.[136]

Figure 8. Representation of a possible application of CHI nanocomposite for bone regeneration. CHI/BG-NPs scaffolds were used to fill the pig femur bone defect when this was hydrated.[148]

Table 2. Chitosan based nanocomposites for different biomedical applications.

Application	Composition	Processing technique	Shape	Ref.
Biosensing	CHI/DNA/MWNTs	Spin coating	Film	[149]
	CHI/GO bond to 5’amine single strand DNA	Spin coating	Film	[150]
	CHI/Au NPs/hemoglobin	Dip coating	Membrane	[151]
	CHI/Au NPs linked to cytochrome c and glucose oxidase	Electrodeposition	Film	[152]
Bone regeneration	CHI/HA NPs loaded with icariin	Solvent casting	3D scaffold	[153]
	CHI/HA NPs/ collagen	Freeze drying	3D scaffold	[154]
	CHI/HA NPs/SWNTs	Freeze drying	3D scaffold	[155]
	CHI/BG NPs	Freeze drying	3D scaffold	[148]
	CHI/GO	Freeze drying	3D scaffold	[156]
Drug delivery	CHI/layered silicate loaded with doxorubicin	Freeze drying	3D scaffold	[157]
	ALG/CHI/ HA NPs loaded with doxorubicin	Solvent casting	Hydrogel	[158]
	CHI/GO loaded with fluorescein sodium	Solvent casting	Membrane	[159]
	CHI/MMT loaded with oxytetracycline	Freeze drying	Scaffold	[160]
Tissue engineering	CHI/CNTs	Freeze drying	3D scaffold	[161]
	CHI/graphene	Solvent casting	Hydrogels	[162]
	CHI/HA NPs	Electrospinning	Membrane	[163,164]
	CHI/CNTs	Solvent casting	Hydrogel	[165]
	CHI/carbon nanofibers	Freeze drying	3D scaffold	[166]
	CHI/TiO2 NPs	Solvent casting	Membrane	[167]
Wound healing	CHI/poly(ethylene glycol)/ZnO/Ag NPs	Solvent casting	Film	[168]
	CHI/PVA/graphene	Electrospinning	Membrane	[169]
	CHI/MMT loaded with silver sulfadiazine	Solvent casting	Membrane	[170]
	CHI/Ag NPs	Solvent casting	Membrane	[171]
	CHI/Ag-MMT	Solvent casting	Film	[172]
	CHI/reduced GO	Solvent casting	Film	[173]

Abbreviation: PVA, poly(vinyl alcohol).

Zhu W, Lu C, Chang F, et al. Supramolecular ionic strength-modulating microstuctures and properties of nacre-like biomimetic nanocomposites containing high loading clay. RSC Adv. 2012;2:6295–6305. 10.1039/c2ra20523h

 Web of Science ®Google Scholar

Alexandre M, Dubois P. Polymer-layered silicate nanocomposites: preparation, properties and uses of a new class of materials. Mater Sci Eng R. 2000;28:1–63. 10.1016/S0927-796X(00)00012-7

 Web of Science ®Google Scholar

Bitounis D, Ali-Boucetta H, Hong BH, et al. Prospects and challenges of graphene in biomedical applications. Adv Mater. 2013;25:2258–2268. 10.1002/adma.201203700

 PubMed Web of Science ®Google Scholar

Lertsutthiwong P, Noomun K, Khunthon S, et al. Influence of chitosan characteristics on the properties of biopolymeric chitosan-montmorillonite. Prog. Nat. Sci.-Mater Int. 2012;22:502–508. 10.1016/j.pnsc.2012.07.008

 Web of Science ®Google Scholar

Ennajih H, Bouhfid R, Essassi EM, et al. Chitosan-montmorillonite bio-based aerogel hybrid microspheres. Micropor Mesopor Mat. 2012;152:208–213. 10.1016/j.micromeso.2011.11.032

 Web of Science ®Google Scholar

Wang SS, Shu YQ, Liang BL, et al. Nacre-inspired green artificial bionanocomposite films from the layerby-layer assembly of montmorillonite and chitosan. Chinese J Polym Sci. 2014;32:675–680. 10.1007/s10118-014-1455-4

 Web of Science ®Google Scholar

Mota J, Yu N, Caridade SG, et al. Chitosan/bioactive glass nanoparticle composite membranes for periodontal regeneration. Acta Biomater. 2012;8:4173–4180. 10.1016/j.actbio.2012.06.040

 PubMed Web of Science ®Google Scholar

Seuss S, Lehmann M, Boccaccini AR. Alternating current electrophoretic deposition of antibacterial bioactive glass-chitosan composite coatings. Int. J. Mol. Sci. 2014;15:12231–12242. 10.3390/ijms150712231

 PubMed Web of Science ®Google Scholar

Lee JS, Baek SD, Venkatesan J, et al. In vivo study of chitosan-natural nano hydroxyapatite scaffolds for bone tissue regeneration. Int. J. Biol. Macromolec. 2014;67:360–366. 10.1016/j.ijbiomac.2014.03.053

 PubMed Web of Science ®Google Scholar

Li XY, Nan KH, Shi S, et al. Preparation and characterization of nano-hydroxyapatite/chitosan cross-linking composite membrane intended for tissue engineering. Int. J. Biol. Macromolec. 2012;50:43–49. 10.1016/j.ijbiomac.2011.09.021

 PubMed Web of Science ®Google Scholar

Potara M, Jakab E, Damert A, et al. Synergistic antibacterial activity of chitosan-silver nanocomposites on Staphylococcus aureus. Nanotechnology. 2011;22:135101–135110.

 PubMed Web of Science ®Google Scholar

Du Y, Luo XL, Xu JJ, et al. A simple method to fabricate a chitosan-gold nanoparticles film and its application in glucose biosensor. Bioelectrochemistry. 2007;70:342–347. 10.1016/j.bioelechem.2006.05.002

 PubMed Web of Science ®Google Scholar

Li LH, Deng JC, Deng HR, et al. Synthesis and characterization of chitosan/ZnO nanoparticle composite membranes. Carbohydr. Res. 2010;345:994–998. 10.1016/j.carres.2010.03.019

 PubMed Web of Science ®Google Scholar

Gupta P, Sharan S, Roy P, et al. Aligned carbon nanotube reinforced polymeric scaffolds with electrical cues for neural tissue regeneration. Carbon. 2015;95:715–724. 10.1016/j.carbon.2015.08.107

 Web of Science ®Google Scholar

Hwang JY, Kim HS, Kim JH, et al. Carbon nanotube nanocomposites with highly enhanced strength and conductivity for flexible electric circuits. Langmuir. 2015;31:7844–7851. 10.1021/acs.langmuir.5b00845

 PubMed Web of Science ®Google Scholar

He LH, Wang HF, Xia GM, et al. Chitosan/graphene oxide nanocomposite films with enhanced interfacial interaction and their electrochemical applications. Appl Surf Sci. 2014;314:510–515. 10.1016/j.apsusc.2014.07.033

 Web of Science ®Google Scholar

Fan HL, Wang LL, Zhao KK, et al. Fabrication, mechanical properties, and biocompatibility of graphene-reinforced chitosan composites. Biomacromolecules. 2010;11:2345–2351. 10.1021/bm100470q

 PubMed Web of Science ®Google Scholar

Li YH, Sun JK, Du QJ, et al. Mechanical and dye adsorption properties of graphene oxide/chitosan composite fibers prepared by wet spinning. Carbohydr. Polym. 2014;102:755–761. 10.1016/j.carbpol.2013.10.094

 PubMed Web of Science ®Google Scholar

Liu Hong, Li Jianhua, Ren Na, et al. Graphene oxide-reinforced biodegradable genipin-cross-linked chitosan fluorescent biocomposite film and its cytocompatibility. Int J Nanomedicine. 2013;8:3415–3426. 10.2147/IJN

 PubMed Web of Science ®Google Scholar

Han DL, Yan LF, Chen WF, et al. Preparation of chitosan/graphene oxide composite film with enhanced mechanical strength in the wet state. Carbohydr. Polym. 2011;83:653–658. 10.1016/j.carbpol.2010.08.038

 Web of Science ®Google Scholar

Caridade SG, Merino EG, Alves NM, et al. Bioactivity and viscoelastic characterization of chitosan/bioglass (R) composite membranes. Macromol Biosci. 2012;12:1106–1113.10.1002/mabi.v12.8

 PubMed Web of Science ®Google Scholar

Costa RR, Mano JF. Polyelectrolyte multilayered assemblies in biomedical technologies. Chem Soc Rev. 2014;43:3453–3479. 10.1039/c3cs60393h

 PubMed Web of Science ®Google Scholar

Yang GJ, Yang XY, Zhang L, et al. Counterionic biopolymers-reinforced bioactive glass scaffolds with improved mechanical properties in wet state. Mater Lett. 2012;75:80–83. 10.1016/j.matlet.2012.01.122

 Web of Science ®Google Scholar

Silva CSR, Luz GM, Gamboa-martÍnez TC, et al. Poly(e-caprolactone) Electrospun scaffolds filled with nanoparticles. production and optimization according to Taguchi’s methodology. J. Macromol Sci Part B-Phys. 2014;53:781–799. 10.1080/00222348.2013.861304

 Web of Science ®Google Scholar

Van Thu V, Dung PT, Tam LT, et al. Biosensor based on nanocomposite material for pathogenic virus detection. Colloids Surf. B: Biointerfaces. 2014;115:176–181. 10.1016/j.colsurfb.2013.11.016

 PubMed Web of Science ®Google Scholar

Singh A, Sinsinbar G, Choudhary M, et al. Graphene oxide-chitosan nanocomposite based electrochemical DNA biosensor for detection of typhoid. Sens. Actuator B-Chemc. 2013;185:675–684. 10.1016/j.snb.2013.05.014

 Web of Science ®Google Scholar

Zhang LL, Han GQ, Liu Y, et al. Immobilizing haemoglobin on gold/graphene-chitosan nanocomposite as efficient hydrogen peroxide biosensor. Sens. Actuator B-Chem. 2014;197:164–171.

 Web of Science ®Google Scholar

Song YH, Liu HY, Wang Y, et al. A glucose biosensor based on cytochrome c and glucose oxidase co-entrapped in chitosan- gold nanoparticles modified electrode. Anal. Methods. 2013;5:4165–4171. 10.1039/c3ay40399h

 Web of Science ®Google Scholar

Fan JJ, Bi L, Wu T, et al. A combined chitosan/nano-size hydroxyapatite system for the controlled release of icariin. J. Mater. Sci. Mater. Med. 2012;23:399–407. 10.1007/s10856-011-4491-4

 PubMed Web of Science ®Google Scholar

Pallela R, Venkatesan J, Janapala VR, et al. Biophysicochemical evaluation of chitosan-hydroxyapatite-marine sponge collagen composite for bone tissue engineering. J. Biomed. Mater. Res Part A. 2012;100A:486–495. 10.1002/jbm.a.v100a.2

 Web of Science ®Google Scholar

Im O, Li J, Wang M, et al. Biomimetic three-dimensional nanocrystalline hydroxyapatite and magnetically synthesized single-walled carbon nanotube chitosan nanocomposite for bone regeneration. Int J Nanomedicine. 2012;7:2087–2099.

 PubMed Web of Science ®Google Scholar

Depan D, Girase B, Shah JS, et al. Structure-process-property relationship of the polar graphene oxide-mediated cellular response and stimulated growth of osteoblasts on hybrid chitosan network structure nanocomposite scaffolds. Acta Biomater. 2011;7:3432–3445. 10.1016/j.actbio.2011.05.019

 PubMed Web of Science ®Google Scholar

Yuan Q, Shah J, Hein S, et al. Controlled and extended drug release behavior of chitosan-based nanoparticle carrier. Acta Biomater. 2010;6:1140–1148. 10.1016/j.actbio.2009.08.027

 PubMed Web of Science ®Google Scholar

Abou Taleb MF. Alkahtani A, Mohamed SK. Radiation synthesis and characterization of sodium alginate/chitosan/hydroxyapatite nanocomposite hydrogels: a drug delivery system for liver cancer. Polym Bull. 2015;72:725–742.

 Web of Science ®Google Scholar

Justin R, Chen BQ. Strong and conductive chitosan-reduced graphene oxide nanocomposites for transdermal drug delivery. J Mater Chem B. 2014;2:3759–3770. 10.1039/c4tb00390j

 PubMed Web of Science ®Google Scholar

Salcedo I, Sandri G, Aguzzi C, et al. Intestinal permeability of oxytetracycline from chitosan-montmorillonite nanocomposites. Colloids Surf B-Biointerfaces. 2014;117:441–448. 10.1016/j.colsurfb.2013.11.009

 PubMed Web of Science ®Google Scholar

Axpe E, Bugnicourt L, Merida D, et al. Sub-nanoscale free volume and local elastic modulus of chitosan-carbon nanotube biomimetic nanocomposite scaffold-materials. J. Mater Chem B. 2015;3:3169–3176. 10.1039/C5TB00154D

 PubMed Web of Science ®Google Scholar

Sayyar S, Murray E, Thompson BC, et al. Processable conducting graphene/chitosan hydrogels for tissue engineering. J Mater Chem B. 2015;3:481–490. 10.1039/C4TB01636J

 PubMed Web of Science ®Google Scholar

Liverani L, Abbruzzese F, Mozetic P, et al. Electrospinning of hydroxyapatite-chitosan nanofibers for tissue engineering applications. Asia-Pacific J Chem Eng. 2014;9:407–414. 10.1002/apj.v9.3

 Web of Science ®Google Scholar

Martins AM, Eng G, Caridade SG, et al. Electrically conductive chitosan/carbon scaffolds for cardiac tissue engineering. Biomacromolecules. 2014;15:635–643. 10.1021/bm401679q

 PubMed Web of Science ®Google Scholar

Peng CC, Yang MH, Chiu WT, et al. Composite nano-titanium oxide–chitosan artificial skin exhibits strong wound-healing effect—an approach with anti-inflammatory and bactericidal kinetics. Macromol Biosci. 2008;8:316–327. 10.1002/(ISSN)1616-5195

 PubMed Web of Science ®Google Scholar

Liu Y, Kim HI. Characterization and antibacterial properties of genipin-crosslinked chitosan/poly(ethylene glycol)/ZnO/Ag nanocomposites. Carbohydr. Polym. 2012;89:111–116.

 PubMed Web of Science ®Google Scholar

Lu BG, Li T, Zhao HT, et al. Graphene-based composite materials beneficial to wound healing. Nanoscale. 2012;4:2978–2982. 10.1039/c2nr11958g

 PubMed Web of Science ®Google Scholar

Aguzzi C, Sandri G, Bonferoni C, et al. Solid state characterisation of silver sulfadiazine loaded on montmorillonite/chitosan nanocomposite for wound healing. Colloids Surf B-Biointerfaces. 2014;113:152–157. 10.1016/j.colsurfb.2013.08.043

 PubMed Web of Science ®Google Scholar

González-Campos JB, Mota-Morales JD, Kumar S, et al. New insights into the bactericidal activity of chitosan-Ag bionanocomposite: the role of the electrical conductivity. Colloids Surf B-Biointerfaces. 2013;111:741–746. 10.1016/j.colsurfb.2013.07.003

 PubMed Web of Science ®Google Scholar

Lavorgna M, Attianese I, Buonocore GG, et al. MMT-supported Ag nanoparticles for chitosan nanocomposites: structural properties and antibacterial activity. Carbohydr. Polym. 2014;102:385–392. 10.1016/j.carbpol.2013.11.026

 PubMed Web of Science ®Google Scholar

Lim HN, Huang NM, Loo CH. Facile preparation of graphene-based chitosan films: enhanced thermal, mechanical and antibacterial properties. J. Non-Cryst. Solids. 2012;358:525–530. 10.1016/j.jnoncrysol.2011.11.007

 Web of Science ®Google Scholar

Sahoo NG, Pan YZ, Li L, et al. Nanocomposites for bone tissue regeneration. Nanomedicine. 2013;8:639–653. 10.2217/nnm.13.44

 PubMed Web of Science ®Google Scholar