Solvent-Free Synthesis and Characterization of Allyl Chitosan Derivatives PDF

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RSC Advances This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online PAPER View Journal | View Issue Solvent-free synthesis and characterization of allyl Cite this: RSC Adv., 2019, 9, 20968 chitosan derivatives† Open Access Article. Published on 04 July 2019. Downloaded on 11/6/2024 10:49:20 PM. Tatiana A. Akopova, *a Tatiana S. Demina, ab Georgii V. Cherkaev,a Mukhamed A. Khavpachev,a Kseniya N. Bardakova,bc Andrey V. Grachev,d Leonid V. Vladimirov,d Alexander N. Zelenetskiia and Petr S. Timashev bcd The solvent-free synthesis of allyl-substituted chitosan derivatives through reactive co-extrusion of chitosan powder with allyl bromide at shear deformation was performed. For the structural characterization, FTIR and NMR methods were employed. The results were confirmed by chemical analysis. The total content of allyl substituents from 5 to 50 per 100 chitosan units as a function of the component ratio in the reactive mixtures was revealed. Carrying out the reaction without any additives leads to the selective formation of N-alkylated derivatives, whereas in the presence of alkali the ethers of chitosan were preferentially formed. The results suggest that the proposed approach allows significantly Received 21st May 2019 Accepted 26th June 2019 higher yield of products to be obtained at high process speeds and significantly lower reagent consumption as compared with the liquid-phase synthesis in organic medium. The synthesized DOI: 10.1039/c9ra03830b unsaturated derivatives are promising photosensitive components for use in laser stereolithography for rsc.li/rsc-advances fabrication of three-dimensional biocompatible structures with well-defined architectonics. its derivatives, can be successfully used to create similar struc- Introduction tures due to their high cellular affinity and ability to control Polysaccharide chitosan and its derivatives are prospective bioresorption.15,16 materials for the creation of biomedical materials in the form of To obtain the materials with a high degree of reproduction of hydrogels, microgranules, nanoparticles, nanobers, etc.1–4 The a given morphology with a resolution of up to 200–400 nm the presence of primary amine groups in the structure of chitosan laser stereolithography technology was used.17–19 It is based on determines its solubility in diluted aqueous organic and the principle of initiating spatial cross-linking of material at mineral acids and its unique complex-forming properties. two-photon absorption in the highly focused eld of femto- Chitosan exhibits bacteriostatic and antiviral activity, and second laser radiation in UV region of spectrum. In order to effectively binds heavy metal ions, proteins and fatty acids.5–7 A increase the reactivity of functional groups of polymers in cross- number of chitosan derivatives and composites based on it are linking reactions when exposed to laser radiation, unsaturated proposed to produce materials with enhanced solubility, sorp- groups were introduced into their structure.20,21 tion capacity, physical mechanical characteristics and ability to There is a relatively few data in literature on attempts to form lms, bres and cross-linked structures.8–11 Recently much obtain the unsaturated chitosan derivatives. They are mainly attention has been paid to three-dimensional models of combined with the introduction of vinyl groups into its struc- different cell cultures formed in the volume of polymer matrices ture, carried out in an organic solvent medium. For example, Qi of specied architectonics and offered as biomimetic et al.22 had obtained the methacrylic derivatives, capable of implants.12–14 Natural polysaccharides, including chitosan and crosslinking with hydrogels formation under UV radiation. The synthesis of crosslinkable photosensitive product by incorpo- ration of methacrylate groups to prefabricated N-succinyl chi- a Enikolopov Institute of Synthetic Polymeric Materials, Russian Academy of Sciences, tosan was performed by Kufelt et al.23 Shitrit and Bianco-Peled24 70 Profsoyuznaya st., Moscow 117393, Russia. E-mail: [email protected] had studied the possibility to obtain the acrylated chitosan at its b Institute for Regenerative Medicine, Sechenov University, 8-2 Trubetskaya st., Moscow interaction with polyethylene glycol diacrylate (PEGDA) for 119991, Russia using as a mucoadhesive drug delivery systems. Photo- c Institute on Photon Technologies, Federal Scientic Research Centre “Crystallography and Photonics”, Russian Academy of Sciences, 2 Pionerskaya st., Troitsk, Moscow crosslinkable chitosan carrying vinyl carboxylic acid groups was 142190, Russia also synthesized by interaction with maleic anhydride under d Semenov Institute of Chemical Physics, Russian Academy of Sciences, 4 Kosygina st., mild conditions.25 However, the vinyl groups are very active in Moscow 119991, Russia the processes of chitosan cross-linking via the Michael type † Electronic supplementary information (ESI) available. See DOI: reaction, which can lead to decrease in the yield of target 10.1039/c9ra03830b 20968 | RSC Adv., 2019, 9, 20968–20975 This journal is © The Royal Society of Chemistry 2019  View Article Online Paper RSC Advances products.26 The reactions of chitosan amine groups with anhy- many cases.41 A series of solvent-free mechanochemical organic drides of unsaturated fatty acids lead mainly to production of reactions have been performed by using ball milling process.42 insoluble derivatives both in aqueous and common organic Since organic substances, polymers especially, have low thermal solvents, as marked by Zhang and Hirano.27 All the above leads stability and large strain relaxation times, the most appropriate This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. to difficulty of removing the uncrosslinked material from the technique for their solid-state modication is twin-screw obtained well-dened 3D structures based on acrylated chitosan extrusion, which is capable of ne temperature control at slow derivatives. The groups active in the spatial cross-linking continuous deformation of solids.43,44 Shear deformation exclusively in sharply focused laser radiation eld are repre- provides numerous possibilities to circumvent many processing sented to us as allyl groups. The side reaction with the free obstacles typical for interaction of hydrophilic polymers and amine groups of the chitosan chain is not typical for their hydrophobic organic reagents.45,46 According to classical theory double bond. It is also important that when the amino groups of of mechanochemistry, the shear deformation of solid reagents Open Access Article. Published on 04 July 2019. Downloaded on 11/6/2024 10:49:20 PM. the polymer are involved in the alkylation reaction, the resulting is accompanied by the formation of active states in the bulk of product is a secondary amine which is capable of protonation in substance, by disordering of its structure and polarization of the presence of acids as the primary amino group of chitosan. molecules.47–50 The consequence is, for example, the intensive Therefore, the solubility in aqueous media, which is charac- polymerization of solid vinyl and cyclic monomers,51 the high teristic for the initial polymer, will not be signicantly reduced mobility of the end functional groups and the ability of heter- if the degree of substitution (DS) by hydrophobic moieties is not oceptive links of synthetic polymers and monomers to direc- too high.28 tional reactions with functional groups of polysaccharides.52,53 It is known a method for alkylation of chitosan with allyl Mechanochemical processes, which currently receiving bromide in PriOH in presence of large excess of alkali,29,30 per- a great deal of interest, are important not only for their high formed similarly to heterogeneous processes for allyl cellulose efficiency but also for their simplicity and cleanness. The reac- derivatives. The authors note the diffusively complicated type of tions in these conditions oen proceed without the need for any the process due to bad swelling of chitosan both in alkali and initiators and catalysts, therefore their products are more PriOH. Homogeneous allylation of cellulose by reacting with compatible with human health and the environment. As was allyl bromide was performed in LiCl/DMAc solution containing shown in our earlier studies, chitosan with high degree of NaOH powder, and an allyl DS per anhydroglucose unit of 2.80 deacetylation,54 its salts and complexes with bioactive organic was found.31 Illy et al.28 carried out the allylation of chitosan in compounds,55 the acylated and carboxymethylated deriva- aqueous medium by interaction of water-soluble chitosan tives56–58 can be produced via the solid-state extrusion. A series oligomers (polymerization degree of 12 units, approx.) with allyl of polysaccharide-based new materials have been obtained by glycidyl ether, and DS was found to be 0.33 in presence of application of solid-state co-extrusion to mixtures of poly- double molar excess of alkylation agent to amine groups. The saccharides like chitosan, chitin or cellulose with synthetic main disadvantage of homogeneous solution methods is the polymers or monomers.59–64 limited solubility of polymers and, consequently, the low In this study, we developed mechanochemical synthesis of productivity of the processes for obtaining derivatives. allyl-substituted chitosan derivatives capable of crosslinking Generally, the production of derivatives of natural poly- with three-dimensional scaffolds formation under UV radia- saccharides, as well as the alkaline deacetylation of chitin with tion. For this purpose, regularities of the chitosan reactions in chitosan formation, is always accompanied by preliminary solid state with allyl bromide under shear deformation were activation of polysaccharides in order to destroy their highly revealed. Experiments were performed using solvent-free reac- organized supramolecular structure with a complex system of tive co-extrusion that may be regarded as more economical and hydrogen bonds preventing their dissolution and melting ecologically favorable procedure in chemistry. Techniques such without decomposition.32 These processes require the use of as Nuclear Magnetic Resonance (NMR), Fourier Transform a large excess of aggressive reagents and solvents followed by Infrared Spectroscopy (FTIR) and bromometric titration were their expensive regeneration and oen begin as heterogeneous used for characterization. reactions.33–35 Therefore, the development of efficient environ- mentally friendly methods allowing to increase the availability of polysaccharide functional groups in the processes of their chemical modication is an urgent task. Experimental Mechanochemical synthesis based on joint action of high pressure and shear strains onto solid mixture of reagents, Materials including polymers,36,37 can serve as an alternative method to Chitosan (molecular weight of 80 000; degree of acetylation (DA) produce the polysaccharide derivatives. The method allows to of 0.15) was prepared from crab chitin (moisture 4.3%, ash avoid any solvents, does not involve the melting of reactive content 1.8%, Xiamen Fine Chemical Import & Export Co., LTD, mixtures and, therefore, is a convenient and effective way of China) through solid-state synthesis in accordance with pub- target chemical modication of infusible polysaccharides.38–40 lished procedure.54 Allyl bromide (AB; 99%) of synthetic grade Organic solid-state reactions have numerous advantages since was purchased from Acros Organics (PubChem CID: 7841). they are innitely high-concentration reactions and proceed Sodium hydroxide of analytical grade (microprills, 99%) was much more efficiently and faster than solution reactions in purchased from Merck KGaA (Germany). This journal is © The Royal Society of Chemistry 2019 RSC Adv., 2019, 9, 20968–20975 | 20969  View Article Online RSC Advances Paper Preparation of chitosan and its allyl-substituted derivatives equipped with diamond crystal (n ¼ 2.4; angle of incidence 45 deg.). The obtained ATR spectra were converted into IR- The synthesis was carried out in a pilot twin-screw extruder absorbance mode. All the spectra presented in this work were (Berstorff, Germany) with parallel rotation of screws (d ¼ 40 recorded and treated using a set of programs: Bruker Opus mm) and controlled heating (4 zones). The extruder is equipped This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. (version 6.1). with force elements of screws capable to realize the compres- The degree of substitution (DS) per glucosamine unit was sion and shear deformation of solid mixtures of reagents. determined by titrating the allyl chitosan with bromine in Reagents were fed manually at screw rotation speed of 60 rpm. With a residence time of ca. 2–3 minutes, feed rate of 30 g min1 chloroform solution according to standard analysis of the bromine number determination by Knopp method.66 was achieved. The DS was calculated by the equation: As a starting component for synthesis of allyl chitosan derivatives the chitin was used. At rst stage by means of Open Access Article. Published on 04 July 2019. Downloaded on 11/6/2024 10:49:20 PM. Br (%) ¼ 15984x/(167 + 41x), alkaline deacetylation of chitin at 3-fold molar excess of NaOH and the heating temperature of cylinder body of extruder of where 15 984 – molecular weight of Br2 molecule, multiplied by 160  C we obtained chitosan and used it for the synthesis as an 100; 167 – molecular weight of monomer link of allyl chitosan intermediate (Sample 1). With this method of carrying out the with DA ¼ 0.15; 41 – molecular weight of allyl group; x – degree process it becomes possible to use the chitosan in the most of substitution (in parts of unit). When multiplied by 100, the disordered nonequilibrium state, which increases the reactivity degree of substitution per 100 glucosamine units is obtained. of its functional groups under conditions of solid-state synthesis (see Fig. S1†).53 The reactive mixture aer chitin deacetylation contained: chitosan 52  2%; sodium hydroxide 25  2%; sodium acetate 23  2%. Results and discussion The allyl-substituted chitosan derivatives were obtained by NMR analysis repeated treatment of the reactive mixtures aer adding of allyl 1 H NMR spectra of the prepared allyl chitosan samples are bromide at different ratios during cooling of the extruder presented in Fig. 1, and DS parameters calculated from the working zones to 0–5  C. The sample of allyl chitosan we had spectra are summarized in Table 1. In the gure are marked the obtained earlier under similar conditions of mechanical action spectral ranges used to determine the content of allyl groups in but in the absence of alkali medium65 was used as a reference modied chitosan by measuring and comparing the integral sample (Sample 2). The molar ratios of allyl bromide (AB) per intensities of proton signals in structural fragments: H2C]CH– chitosan unit were 0.5 (for Samples 2 and 3), 1.0 (Sample 4), 1.5 CH2–O– and H2C]CH–CH2–NR– (total signal at 5.8 ppm), R ¼ (Sample 5), and 2.0 (Sample 6). Molar content of alkali in H or All (I); H2C]CH–CH2–NR– from 5.3 to 5.6 ppm (II); H2C] reactive mixtures (at preparation of Samples 3–6) was 2 mol of CH–CH2–O– from 5.0 to 5.2 ppm (III); pCH–NH2 at 3.0–3.1 ppm NaOH per chitosan unit. The products were puried with PriOH followed by dialysis against deionized water (DW) to remove completely the unreacted monomer and alkaline impurities. Aer 48 h of dialysis the samples were dissolved in 0.1 M HCL and then precipitated with 1 M NaOH. The residues were rinsed with DW up to the absence of a qualitative reaction of ushing waters to chlorine ions and freeze-dried to produce the nal product in powder form. To record the NMR spectra, samples were dried in the form of chitosan hydrochloride in vacuum chamber at RT to ensure the dissolution in D2O at measurement. Characterization of allyl-chitosan samples 1 H NMR (300 MHz, D2O) spectra were recorded on a Bruker- Avance II-300 spectrometer at 90  C. The suppression of the solvent signal was carried out by the standard for spectrometers of this type pulse sequence “zgpr”. To calibrate the scale of chemical shis the signal of DMSO-d6 (d ¼ 2.5 ppm) was used. The data of 1H NMR analysis was used to reveal the features of the structure and to calculate the ratio of chitosan and allyl constituents in the synthesized derivatives. FT-IR spectra were recorded on a Bruker Vertex 70 spec- trometer (USA). All spectra were initially collected in ATR mode Fig. 1 Proposed chemical composition of allyl-modified chitosan at resolution of 2 or 4 cm1 by employing an ATR-mono- chains, and 1H NMR spectra of initial chitosan (1) and a number of allyl reection Gladi ATR (Pike Technologies, USA) accessory chitosan samples (Samples 2–6 in Table 1). 20970 | RSC Adv., 2019, 9, 20968–20975 This journal is © The Royal Society of Chemistry 2019  View Article Online Paper RSC Advances Table 1 Degree of substitution (DS) of chitosan functional groups with allyl fragments according to NMR spectroscopy and bromometric titrationa P Ratio of integral intensity of DS proton signals in structural fragments I Bromine number Ratio of N- This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. Samples and V (%) By NMR By titration and O-substituted groups 2 0.7 7.5 0.10 0.08 — 3 0.3 5.7 0.05 0.06 1:2 4 1.1 9.3 0.17 0.10 1 : 1.8 5 1.4 20.8 0.21 0.23 1 : 1.7 6 3.3 41.2 0.50 0.47 1 : 1.5 Open Access Article. Published on 04 July 2019. Downloaded on 11/6/2024 10:49:20 PM. a Sample 1 (initial chitosan) according to NMR analysis contains 15% of N-acetylated units (the remains of chitin), the content of which does not change in the chosen conditions of synthesis of derivatives. Ratio of N- and O-substituted groups was calculated by proportion of integral intensity of proton signals in structural fragments II and III. (IV); H3C–CONH– at 1.9 ppm (V); H-OD – residual signal (when in O- and N-allyl fragments do not overlap and have been suppressing) the protons of water. correctly used for quantitative analysis of ratio of these frag- The results of NMR analysis show that in the absence of ments in the modied chitosan. NaOH the reaction of allylation proceeds exclusively with amino The estimation of the number of allyl substituents included groups of chitosan (Fig. 2, path 1). Conducting of the process in in the structure of chitosan, based on determination of the alkaline medium leads to non-selective formation of O- and N- mass of bromine joining to 100 g of polymer during titration, substituted derivatives of chitosan, meanwhile the content of O- showed a good convergence of results obtained by spectral and substituted fragments is 1.5–2 times higher. The alkali not only chemical methods (Table 1). activates the hydroxyl groups of polymer in the nucleophilic substitution reaction, but also binds the halogen ions formed during the reaction (path 2). In the absence of NaOH, the FT-IR analysis exuded bromine ions can be bound by any of amino groups of Fig. 4 presents the IR-spectra of initial chitosan as well as of the chitosan macromolecule, as shown, for example, in Fig. 2, path products of its reaction with allyl bromide under conditions of 1. The total DS of chitosan functional groups is symbatically solid state synthesis in presence of NaOH. The high-frequency dependent on the AB content in the reactive mixtures and rea- part (3700–2500 cm1) of the overview IR-spectrum contains ches 0.50 at a double molar excess of alkylation agent with a strong broad band of the stretching vibrations of O–H groups, regard to the polymer units. which overlaps both the doublets of NH2 and CH2 stretching To conrm the correctness of the signal assignments in 1H vibrations. As a result, the bands 3356 and 3295 cm1 of NMR spectra of the products, a model mixture consisting of asymmetric and symmetric N–H stretching peaks appear in the initial chitosan, allyl alcohol and allyl amine with a 5-fold molar spectrum as weak shoulders; whereas the doublet of C–H excess of chitosan with regard to low-molecular-weight stretching vibrations can be clearly seen with maximum at 2870 components was prepared. Fig. 3 shows the mixture spec- and its high-frequency shoulder at approx. 2997 cm1. The trum, on which the ascriptions of signals of characteristic analysis of the high-frequency region that the relative intensity protons are shown. D[OH]/D[CH] in the spectra of the reaction products consis- The comparison of 1H NMR spectra of the modied chitosan tently decreases with increase of AB evidencing the participa- samples and the model mixture (Fig. 1 and 3) shows that the tion of O–H groups in reaction as well as the appearance of position of groups of characteristic signals (selected regions) is additional alkyl groups (the increase of intensity of the almost unchanged. The signal groups of terminal vinyl protons stretching vibrations of C–H bonds). Simultaneously with this effect the intensity of the ]C–H stretching band of allyl groups (see: peak at 3085 cm1)67 noticeably increases. At the same time very little (if any) changes could be observed for the stretching vibrations of NH2 groups. To other typical IR-bands of allyl groups are attributed 1645 cm1 of stretching vibrations of double bonds as well as the 922 cm1 of ]C–H deformation.68 Since in the systems under consideration the position of 1645 cm1 band practically coincides with the Amide-I vibrations of the residual acetamide groups of chitin as well as the intensity of 922 cm1 band is strong enough and thus is a better match for evaluation of the Fig. 2 Schemes of reactions occurring at solid-state synthesis in content of the graed allyl groups. An analogous band in the mixtures of chitosan and allyl bromide in the absence of NaOH (1) and spectrum of initial allyl bromide is observed at 927 cm1.67 The in alkaline medium (2). comparison of curves 2 and 3 in this region of spectra shows This journal is © The Royal Society of Chemistry 2019 RSC Adv., 2019, 9, 20968–20975 | 20971  View Article Online RSC Advances Paper This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. Open Access Article. Published on 04 July 2019. Downloaded on 11/6/2024 10:49:20 PM. 1 Fig. 3 H NMR spectrum of the model mixture of chitosan with allyl alcohol and allyl amine. The water signal is partially suppressed. comparison of the ratio of the relative intensities D[C–O]/D[OH], where D[C–O] is the sum (envelope) of the bands with maximum at 1030 cm1 of the stretching vibrations of C–O(H) groups as well as other C–O bonds including stretching vibrations of glycosidic bonds in the structure of chitosan macromolecule. The band of deformation vibrations of NH2 groups in the spectrum of initial chitosan is observed at 1590 cm1, i.e., in- between the Amide-I and Amide-II bands. The participation of NH2 groups in reaction with AB nonetheless could be seen due to broadening and low-frequency shi towards the Amide-II band (down to 1574 cm1). An approximate estimation of the amount of NH2 groups depleted in the reaction with allyl bromide was evaluated by using the ratio D[NH2]/D, where 1375 cm1 band was employed as the internal standard band according to the liter- ature68 is attributed to overlayed bands of C–N stretching and Fig. 4 IR-spectra of initial chitosan (1) and allyl chitosan with degree of CH2 deformation vibrations. This well coincides with our substitution of 0.2 (2) and 0.5 (3) (Samples 5 and 6 in Table 1, conclusion about the character of allylation of chitosan with respectively). preferential substitution of hydroxyl groups if the reaction is carried out in the alkaline medium under the above synthesis conditions. that the change in molar ratio between AB and chitosan from For greater clarity, in the present work we have shown only 1.5 to 2.0 (Samples 5 and 6, respectively) at least doubled the the IR spectra of samples obtained at high content of allyl total yield of AB graing. A very close estimate of the yield of bromide in the initial medium (Samples 5 and 6). It should be reaction as a function of the components ratio follows from the 20972 | RSC Adv., 2019, 9, 20968–20975 This journal is © The Royal Society of Chemistry 2019  View Article Online Paper RSC Advances noted that the observed changes in the IR spectra were char- data showed that the total content of allyl substitutes up to 50 acteristic for all the samples studied. per 100 chitosan units can be achieved. The use of allyl-substituted derivatives in laser-induced processes allows to avoid the undesirable polymer cross- This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. Application aspects linking in non-irradiated areas and to ensure the complete In comparison with the heterogeneous synthesis in organic removal of the unnecessary material for formation of the medium,29 the solid-state synthesis of allyl-substituted deriva- desired structure of polymer scaffold. The obtained materials tives of chitosan is characterized by a signicantly lower reagent can be used as the polymer implants with specied internal consumption and a high process speed (few minutes). For structure for regenerative medicine purposes, which expands introduction in the structure of chitosan of 8–10 unsaturated both the eld of practical application of chitosan and the range groups per 100 parts of polymer in conditions of solid-state of biocompatible polymers suitable for structuring with the use Open Access Article. Published on 04 July 2019. Downloaded on 11/6/2024 10:49:20 PM. synthesis it is possible to avoid the use of alkali, while in the of laser technologies. liquid-phase process its content should not be less than 0.75 Thus, the proposed solvent-free extrusion process to obtain moles per link (PriOH, 70  C, 4 hours). With the ratio chito- chitosan derivatives differs from typical liquid-phase methods san : NaOH : AB equal to 1 : 3 : 2 in the liquid-phase process, by high efficiency, simplicity and cleanness. The allyl chitosan the total DS equal to 0.21 against 0.50 in solid-state synthesis is derivatives synthesized in this work are effective components achieved (Table 1, Sample 6). And only the use of reprecipitated for the laser-induced formation of the well-dened polymer chitosan with the maximum disordered structure allowed to scaffolds. increase DS of the product of the liquid-phase synthesis to 0.47. Thus, mechanical activation of the reactive systems under solid- state twin-screw extrusion provide disordering of supramolec- Conflicts of interest ular structure of polymer comparable to specially selected There are no conicts to declare. conditions of precipitating from a solution to achieve enhanced accessibility of the chitosan functional groups. It is important for practical use, that all obtained derivatives Acknowledgements did not lose the solubility in acidic aqueous media in compar- This work was supported by the Russian Foundation for Basic ison with the initial polymer. The preliminary studies on usage Research (grant no. 18-29-17050-mk). NMR spectra registration of obtained unsaturated chitosan derivatives for biomedical was performed with the nancial support from Ministry of application, in particular for fabrication of polymer scaffolds by Science and Higher Education of the Russian Federation using laser stereolithography, have shown that allyl-substituted the equipment of Collaborative Access Center “Center for derivatives are reactive in the processes of spatial cross- Polymer Research” of ISPM RAS. linking under UV radiation (see Fig. S2†).69 At the same time, the introduction of allyl fragments into the structure of chitosan does not change its ability to maintain the adhesion, the Notes and references spreading and proliferative activity of human mesenchymal stem cells, which was determined by metabolic activity of cells 1 R. A. A. Muzzarelli, Carbohydr. Polym., 2009, 76, 167–182. of NCTC L929 line with the use of MTT test.70,71 2 M. Prabaharan, J. Biomater. Appl., 2008, 23, 5–36. 3 S. K. Shukla, A. K. 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