Chitin and chitosan based polyurethanes: A review of recent advances and prospective biomedical applications

Accepted Manuscript Title: Chitin and chitosan based polyurethanes: A review of recent advances and prospective biomedical applications Author: Ali Usman Khalid Mahmood Zia Mohammad Zuber Shazia Tabasum Saima Rehman Fatima Zia PII: DOI: Reference:

S0141-8130(16)30134-9 http://dx.doi.org/doi:10.1016/j.ijbiomac.2016.02.004 BIOMAC 5813

To appear in:

International Journal of Biological Macromolecules

Received date: Revised date: Accepted date:

2-1-2016 28-1-2016 1-2-2016

Please cite this article as: Ali Usman, Khalid Mahmood Zia, Mohammad Zuber, Shazia Tabasum, Saima Rehman, Fatima Zia, Chitin and chitosan based polyurethanes: A review of recent advances and prospective biomedical applications, International Journal of Biological Macromolecules http://dx.doi.org/10.1016/j.ijbiomac.2016.02.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Chitin and chitosan based polyurethanes: A review of recent advances and prospective biomedical applications Ali Usman, Khalid Mahmood Zia, Mohammad Zuber*, Shazia Tabasum, Saima Rehman, Fatima Zia Institute of Chemistry, Government College University, Faisalabad, Pakistan

*

Corresponding author Prof Mohammad Zuber Phone: +92 321 6682375, Fax: +92 41 9200764 Email: [email protected]

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HIGHLIGHT 

Chitin and chitosan are amino polysaccharides having multidimensional properties.



Chitin gained wide spread acceptance in biomedical applications due to the presence of the acetamide group



Polyurethanes (PUs) are frequently used for various applications.



Review shed a light on chitin and chitosan based PUs with their potential applications.

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Abstract Chitin and chitosan are amino polysaccharides having massive structural propensities to produce bioactive materials with innovative properties, functions and diverse applications particularly in biomedical field. The specific physico-chemical, mechanical, biological and degradation properties offer efficient way to blend these biopolymers with synthetic ones. Polyurethane (PU) gained substantial attention owing to its structure-properties relationship. The immense activities of chitin/chitosan are successfully utilized to enhance the bioactive properties of polyurethanes. This review shed a light on chitin and chitosan based PU materials with their potential applications especially focusing the bio-medical field. All the technical scientific issues have been addressed highlighting the recent advancement in the biomedical field. Key words:

Chitin; chitosan; polyurethane; biomedical; recent advances

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1.

Introduction

Nature is gifted with numerous materials which could be obtained from various plant and animal resources. Starch, cellulose and chitin are naturally abundant, biodegradable and renewable polymers. After cellulose the second most abundant biopolymer, chitin found in various living organisms such as shrimps, crabs, insects and tortoise [1], as well as they found in cell wall of fungi, internal structures of invertebrates and exoskeleton of arthropods [2, 3, 4] and they can also be prepared by a non-biosynthetic pathway of a chitobiose oxazoline derivative by chitinase-catalyzed polymerization [5–7]. Chitin is a naturally occurring polysaccharide and is recognized by consisting of 2-acetamido-2-deoxy- D-glucose via a β (1–4) linkage [8]. In all their commercial forms, chitin and chitosan have potential array of wide ranging applications credited to their biocompatibility (nontoxic and low immunogenicity), biodegradability, antimicrobial properties, and environment friendly nature thus providing good opportunities for future progress [9-23]. The presence of acetamide group on the structured units of chitin (Figure1) makes chitin much easier to be modified by chemical reactions than cellulose. There are so many reviews which focused the application, modifications and properties of chitin and chitosan [24, 25]. Some reviews have also been reported on preparation, properties, modifications and applications of cellulose, starch and chitin nanocrystals [26-32]. Waste products of the crustacean shells (crabs, etc.) byproducts of food industry are commercially used for the production of chitin and chitosan [33]. It is believed that at least 1011 tons (1013kg) of chitin are synthesized and degraded, but only over 1, 50,000 tons of chitin is made available for commercial use [34]. Due the intractable molecular structures of chitin, it still remains primarily an underutilized resources despite its easy availability and huge annually production [30, 35]. It has become of great interest not only as an under-utilized resource but also as a potentially active

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biomaterial in different fields [36-38]. The non-solubility of chitin in almost all common solvents has been a stumbling block in its appropriate utilization [36, 39, 40]. Chitin fibers stand apart from all the others biodegradable natural fibers in many important properties i.e. biocompatibility, non-toxicity and low immunogenicity etc [30, 39, 41]. The incredible properties of chitin make it a suitable candidate for surgical sutures that form the largest groups of materials which are used in human body [39, 42]. It was reported that chitin sutures was absorbed in rat muscles about in 4 months [42]. 1.1

Structure of chitin and chitosan:

It is well known that the solubility problem of chitin results mainly from the highly extended hydrogen bonded semi-crystalline structure of chitin [43-45].Chitin is a unique structural biopolymer, which has a role similar to that of cellulose in terrestrial plants [46] and collagens in higher animal. Animals such as insects and crustaceans produce chitin in their shells, while plants produce cellulose in their cell walls. Chitin and cellulose are two main and structurally associated polysaccharides that provide protection to animals and plants, respectively and their structural integrity [47, 48]. Chitin structure is very much similar to cellulose, but the only difference of hydroxyl group at C-2 position by an acetamide group [49]. Chitin and chitosan are linear polysaccharides consisting of varying amounts of β-(1→4)-linked 2-amino-2-deoxy-β-Dglucopyranose (GlcN) and 2-acetamido-2-deoxy-β-D-glucopyranose (GlcNAc) residues [50]. Chitosan is a derivative of chitin, which is obtained by deacetylation of chitin (Fig. 1 (a)). Chitin mainly occurs in three different polymeric forms (α, β, γ) [51-54]. Later on it was found that third polymeric (γ- form) is a variant of α family [55]. Α chitin systematically comes from recrystallization from solution [56, 57], enzymatic polymerization [58] or in vitro biosynthesis [59, 60]. The rarer β-chitin is occurred in association with proteins in squid pens [61] and in the tubes

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prepared by vestimetiferan worms and pogonophoran [62, 63]. It also found in protozoa [64, 65] as well as Aphrodite chaetae [66] and a pure form of β-chitin is found in the mono-crystalline spines, which is obtained by the diatom Thalassiosira fluviatilis [67,68]. The chains are arranged in stacks or sheets in α-chitin and adjacent sheets along the c-axis have same direction as parallel arrangement .While in case of β-chitin the adjacent sheets along c-axis present in opposite direction as antiparallel arrangement. Every third sheet are in opposite direction to the preceding sheets in γ-chitin [69]. A schematic representation of the three structures is shown in Fig. 1(b). Fig. 1 (a)

Chemical structure of chitin and deacetylated chitin (chitosan) [8], (b) Three polymorphic configuration of chitin α–Chitin, b β–Chitin, c γ-Chitin [8]

Degree of acetylation (DA) of chitin is typically 0.90, which indicating the presence of some amino group during the course of extraction and purification. Chitin may also contain about 515% amino group [70, 71]. Thus the degree of N-acetylation, i.e. the ratio of 2-acetamido-2deoxy-d-glucopyranose to 2-amino-2-deoxy-d-glucopyranose structural units has a striking effect on chitin solubility and solution properties [71, 72]. 1.2

Reason for choosing chitin and chitosan:

Chitin and chitosan are highly functional polysaccharides among all other naturally occurring polysaccharides like cellulose, dextrin, pectin, alginic acid etc. because their antioxidant, hemostatic properties, solubility and structural characteristics are different in various media [7376]. Furthermore, chitin can be transformed into chitosan that has free amino groups, which is more beneficial for biomedical application. Due to rapidly growing interest in attractive biological properties of chitin and chitosan, a lot of research work has been reported to exploit them in many applications, mostly in the pharmaceutical and medical fields [77-85]. Generally,

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chitin is more appropriate than chitosan as biomaterial in the field of biomedical application due to the presence of the acetamide group (NHCOCH3) that is present in larger amount in its chain than in chitosan. This group is similar to the amide bond of the protein of the living tissue. Therefore we can say that chitin is basically a protein in nature, which is compatible with living (human or animal) ECM hence can be used in wound healing and tissue engineering applications [86, 87]. While in case of chitosan, amino group shares a higher percentage at C2 position, which imparts hemostatic characteristics to implanted devices [88]. 1.3

Application, development and Limitations:

Chitin and chitosan have a wide range of application in biomedical field such as wound healings, wound dressing, antibacterial coatings, tissue engineering scaffolds, separation membrane, stent coatings, sensor and drug delivery system [89-96]. Chitin and chitosan is also used for enzyme immobilization in the food industry and whole cells like that processing of milk when α- and βamylases are grafted on chitin and calcification of fruit juices [97]. Chitin has been used for the preparation of affinity column chromatography to determine the structure and to isolate lectins [98]. Further, more recently application of chitin as chitin film and fiber in the field of pharmaceutical and medical such as controlled drug released [99,100] and wound healing material [101-104]. Chitin and chitosan have a broad spectrum of food application such as preservation of foods from microbial deterioration [105-109], recovery of waste material from food processing discards [110-117], clarification and de-acidification of fruit juices [118-122], formation of biodegradable films [123-128] and purification of water [129-133]. Moreover, chitin and chitosan can be utilized in pharmaceutical adjuvant [134, 135], additives in cosmetics[136, 137], textile finishes, heavy metal chelating agent, photographic products, membrane, cements, hollow fiber and paper production [138-140]. For future development

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another form of chitin, i.e., chitin whisker has wide range of application. Chitin whiskers are attractive and promising material for both academic and medical/industrial fields, as renewable and biodegradable nanoparticles. However, recent studies primarily focused on the preparation and applications of nanocomposite based on chitin whiskers. Work has also been reported to prepare functional derivatives of chitosan by chemical modifications [141-143], in which a very few attained solubility in general organic solvents [144, 145] and some in binary solvent systems [146-148]. Many workers have reported that chemically modified chitin and chitosan exhibit improved solubility in specific organic solvents [149-157]. There has been a rising interest in the chemical modification of chitin and chitosan [158-161] not only to improve their solubility but also to enhance their applications [162, 163]. It is worth to mention that chitin has huge availability, but the utilization of chitin and chitosan has been limited by its insolubility and intractability. It should be noted that chitin is highly hydrophobic in nature and is insoluble in water and in most of the organic solvents. However, solubility is observed in specific solvents such as hexafluoroacetone, hexafluoro-2-propanol or N, N-dimethylacetamide [164,165]. The solubility pattern is important for the effective utilization of chitin/chitosan in biomedical applications. Chitin has found by far less attention than chitosan due to its highly hydrophobic character and uncreative material. 2.

Chitin and chitosan based materials:

Chitin and Chitosan is used for the preparation of films, sponges, fiber and hydrogels as explained earlier, most of the materials are used in the biomedical domain where biocompatibility is essential. In this regard cross linking reagents i.e. 1, 4-butanediol diglycidyl ether [166], epichlorohydrin [167], diisocyanate [168] are useful. Specific cross linking was performed on a blend of chitosan and starch, consequently starch was oxidized to generate a

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polyaldehyde that reacts with the –NH2 group of chitosan in the presence of a reducing agent [169]. A number of chitosan hydrogels are obtained through the action with multivalent anions: the case of glycerol phosphate is mentioned above [170] but tripolyphosphate and oxalic acid has also been used [171, 172, 173]. Hirano prepared blend and composite for chitin mentioned earlier [174]. In the literature different types of composites and blends are formed such as chitosan/cellulose fibers [175], chitosan/polyethylene glycol [176], chitosan/polyamide 6 [177], chitosan/cellulose using a common solvent [178], chitosan/polyvinyl pyrrolidone and chitosan/polyvinyl alcohol [179]. Among all the synthetic polymers, the use of PU for biomedical applications is quite interesting [180,181]. Relative to other polymeric materials like polyvinyl chloride [182], natural rubber [183], silicones [184] and polyethylene [185] polyurethanes offer good biocompatibility and cytotoxicity. They can also be easily injected, extruded, molded and recycled [186]. The low cost, easy modification and availability made polyurethane a useful material for diverse applications i.e. coatings, foams, adhesives, textile fishiness, sealants and elastomers [187-189] and for biomedical application [190,191]. Summary of various approaches in the synthesis and characterization of chitin and chitosan based materials have been presented in Table 1. Table 1 Different techniques for the synthesis and characterization of various chitin and chitosan based material and their perspective biomedical application [192-240] 2.1

Chitin and chitosan based PU materials

Functionalization of synthetic polymers by natural ones mainly polysaccharide like chitin and chitosan presents an appropriate process for biomaterials development [241-246]. Chitin and chitosan based polyurethanes are perhaps a more interesting option because they provide a

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unusual flexibility in both mechanical and biological properties in wide range of applications [247-250]. Molecular characterizations of PUEs have been presented in the published material citing below. The effect of the diisocyanate structure and length of chain extender (C.E.) using α, ω-alkane diols on the crystallinity, surface morphology and thermo-mechanical properties of PUEs have been investigated [251-253]. Much research has been conducted to functionalize biocompatible/biodegradable PU by chemical modification of final PU structure through the incorporation of chitin [206], chitosan [254, 255] and starch [256, 257]. Published work is also presented on the synthesis, characterization and application of chitin based PUs [258, 259]. In vitro biocompatibility and cytotoxicity of chitin/1, 4-butanediol blends based PUEs have been comprehensively presented [210,211]. Some documents are available on the structural characterization of chitin-based PUEs and their shape memory characteristics [205, 260]. XRD studies and surface characteristics of UV-irradiated and non-irradiated chitin-based PUEs have also been presented elsewhere [212-214, 261-263]. 2.2

Biomedical potential of chitin and chitosan based PU materials

Chitin and chitosan based PU have a range of biomedical application such as wound healings, tissue engineering scaffolds, separation membrane, stent coatings, sensor, sutures and drug delivery system. It is worth to mention that NHCOCH3, NH2, NHCOO groups present in chitin, chitosan and polyurethane are convincingly imparts bioactive properties beneficial for biomedical applications. It can be inferred that NHCOO group present in PU resembles with peptide linkage (NHCO) present in protein. Therefore incorporation of chitin or chitosan will definitely enhance the biocompatibility and reduce the cytotoxicity of the resultant material.

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3.

Chitin based PU materials

Synthesis of chitin based PU elastomers [264] have been comprehensively reported in the literature (Fig. 2). In order to declare a potential candidate as biomaterial, the material was characterized in order to check its cyto-toxicity/cyto-compatibility by using cell culture assay. Cells were visible on the surface of PU films which indicate that synthesized material had purely non-poisonous characteristics. In the culture method the performance of a cell is investigated through comparing it with control. A control (polystyrene tissue cell cultured) is a sample thoroughly compatible with cells & is cultured with the others test. If a material supports cell attachments & growth then it can be measure as biocompatible. Cell attachments & spreading after staining the fibroblast cells cultured on the surface of samples films were also examined. The attachments and growth of these cells were clearly visible on the PU films. Most of the cells are in active adhesion and flattened on the surface with more spindle morphology. Fig. 2 Chemical route for synthesis of chitin/1,4 butane diol based PU [264] In order to check the role of catalyst, a comprehensive study was conducted by varying the structure of diisocyanate in to the chitin based PU structure. It is worth to mention that catalyst dibutyl tin dilurate (DBTDL) is usually used in the polymerization of aliphatic diisocyanate (hexamethylene diisocyanate) based PU [265]. Thorough investigation of the material evaluated by cyto-toxicity/cyto-compatibility by using cell culture assay inferred that synthesized material had purely non-poisonous characteristics as the fibroblast cell interaction with samples films were visible on the surface of PU films. Further after staining the fibroblast cell cultured on the samples, spreading and cell attachments were also examined. The images showed the growth & attachments of these cells on PU film is very higher in samples based on aromatic character and

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chitin than the aliphatic/cyclo-aliphatic and BDO-based PU. The samples where polymerization was done by using a little quantity of catalyst have some poisonous behavior relative to the other samples where the polymerization was done in the absence of catalyst [266]. 3.1

Chitin-bentonite clay based PU composites

After evaluating the cyto-toxicity of the catalyst [266], another study was conducted to check the role of bentonite clay on the mechanical and cyto-compatibility of the material. For this purpose chitin-bentonite clay based PU bio-nanocomposites (PUBNC) have been reported [267]. The same cell assay was adopted as mentioned previously in order to check the viability of the material. It was observed that round shaped cells were visible on the surface of PU films which clearly indicate that synthesized material have purely poisonous characteristics and this poisonous character increase with increase in bentonite clay contents. The spreading and cell attachments images shown that that growth and cell attachment of these samples is much higher on the PU film, having zero bentonite nanoclay (PUBNC1) and most of the cells are in active adhesion and flattened on the surface with more spindle shaped morphology. The flat fibroblastic morphology shows that the cells are anchored well to the surface of the polymer. In most cases, as an example in this study, the PU bio- nanocomposites and their degradation products have higher cyto-toxicity than the control values. The results of this investigation are comparable with those from previous studies signifying that that organo-metallic character is highly toxic and leaves an unpleasant odor [268] which make the polymer film non biocompatible. 3.2

Chitin/Chitosan-PU network and blends

Matsui et al; 2012 discussed the behavior of chitin polyurethane in the forms of networks & blends in biological system. The most important use of biodegradable polymers is associated

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towards their medical application [269]. The chemical structures of the material are shown in Fig. 3. Fig. 3 Chemical structure of the materials used, polyurethane, chitin and a generic chemical pathway for the networks [269] In this study the biocompatibility of chitin /PU networks was evaluated by using protocol adapted from Sarasam and Sundararajan [270] using the MMT assay [271]. No toxic products were released in Vero cells. These results in vitro indicated that the materials were potentially biocompatible, with potential bio medical applications. The biocompatibility tests of the samples were also run using method adapted by Mosmann [272]. These results lead to the conclusions that the Vero cells show less adhesion to the networks than the positive control [219,223]. Kadnaim et al. [273] prepared PU and carboxymethyl chitosan (CMC) network using HAD crosslinker. The equilibrium water content increased with increase in amount of PU owing to hydrophobic nature of PU and formation of dense network structure in the presence of CMC. A slight increase in toughness properties was also observed. Cytotoxicity and biocompatibility results indicated the non-toxic nature of 30wt%PU /CMC so could be used as biomaterial. A good cell adhesion and proliferation was observed using L929 cell suspension on CMC-HAD and CMC-PU surfaces (Fig. 4).

Fig. 4 Biocompatibility tests of CMC-PU30wt% at 7 days(A) and 14 days(B) at 2000 magnification, optical micrograph of L929 cell in contact with CMC-HAD (C) and CMC-PU30wt% [273].

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3.3

Chitosan based waterborne PU

Xu et al [274] synthesized novel blood compatible waterborne PU by using chitosan as chain extenders through self emulsion polymerization following scheme shown in Fig. 5. Fig. 5 Synthesis of PU urea emulsion using chitosan as the chain extender [274] By adding chitosan content the size of the latex particles increase. By copolymerization polyurethane latex particles get more chitosan enwrapped, and the polyurethane make more cross linking points. The polydispersities of the latex particles increased with increased in particle size. Biocompatibility as well as anticoagulant property increase by increasing the amount of chitosan. Lin et al [275] synthesized waterborne polyurethane (WPU) based chitosan (CS) blend films. The thermo-mechanical properties and water absorption of WPU-CS films were assessed to estimate their properties like biocompatibility and mechanical strength for medical applications. By increasing the chitosan contents, tensile strength increased while elongation decreased accordingly. The presence of chitosan in the blend films promoted the thermal stability, water absorption and crystallinity. Biocompatibility test was performed using immortalized rat chondrocytes (IRC). After IRC were introduced onto the WPU-CS films for 1.5 and 120 h, it was observed that blends comprising 30 % chitosan had more cells attached initially, on the other hand blends having over 70 % chitosan seemed to promote the cell proliferation. On the whole, WPU-CS films with higher CS contents had better mechanical properties and biocompatibility. It was claimed that further investigation of WPU-CS films will permit their usage in cartilage repair [275].

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3.4

Chitosan based PU elastomers

Chitosan based PU elastomers by following two step synthesis processes [276]. For this investigation isocyanate (NCO) terminated polyurethane (PU) prepolymer was synthesized according to a recommended procedure [264] as laid in synthesis of chitin based PUEs. The PU prepolymer was transformed into the final PU in chain extension step. In this step the PU prepolymer was persuasively stirred by mechanical stirrer at 80 ˚C and then previously degassed chain extenders (i.e., blends of chitosan & 1, 4-butane diol, 2mole) was added. Prior to adding chitosan/1,4-BDO to the PU prepolymer, weighed amount of chitosan according to molar ratio was treated with volume ratio: 3/1 of distilled water and H2O2 followed by stirring at room temperature for 48 h. Resulting H2O2 treatment, the breakage of 1,4-β-D-glucoside bonds of chitosan leads to the fragmentation and formation of oligosaccharides. The resulting solution of oligosaccharides was added to the acetone as a non-solvent. The precipitated solid was collected and dried under vacuum overnight. The treated chitosan was dissolved in DMSO and used for preparation of PUEs. Schematic illustration of chemical route for synthesis of chitosan/1,4-BDO based polyurethane is shown in Fig. 6. All the prepared PU samples were then stored for 7 days at ambient temperature (25°C) and 40% relative humidity before testing. Results from the biocompatibility evaluation inferred that the material can be used as surgical thread (suture material) because of its unique mechanical properties, flexibility, ultimate tensile strength and non cyto-toxic character. Fig. 6 Chemical route for synthesis of chitosan/1,4-BDO based PUEs [276]

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3.5

Anionic PU nanoparticles coated with adsorbed chitosan

Xu et al, [277] prepared PU-c-CS nanoparticles by the ionic interactions between anionic PU and cationic chitosan (CS) in aqueous emulsions. The result from this investigation inferred that samples become more hydrophilic after the addition of chitosan. The water swelling ratio changed from 54.6 to 19.8% with an increased in CS content from 0 to 12.7% (wt %). By electrostatic interactions, the partially ionized CS and PU could form compact +H3N-COO− layers which showed the PU-c-CS nanoparticles with core-shell structure formed. Hence, the thicker compact +H3N-COO− layers could induce the films more difficult to swell in water as increase in CS contents. The TEM analysis showed that the synthesized nano particles were spherical in shape. By ionic interactions between cationic chitosan and anionic polyurethane, the PU-c-CS nano-particles were produced as the spherical surface of PU [278] and the PU-c-CS interface complex layer prevented more CS solution diffuse into the core-shell structure. The surface morphology of PU and PU-c-CS were also examined by AFM technique in tapping mode. The AFM results revealed that the PU film was very smooth and drop height of the surface was 12.7 nm, while the PU-c-CS films were rougher than PU films and the drop height was 2.3 nm. As the chitosan was used in the chain extension step so it acts as hard segment of the final PU structure. Resultantly, by the addition of CS contents the hard segments rich domains of PU-c-CS would be higher. Hence the average size of hard domains increased correspondingly. The dark area correspond the soft segment rich domains, while the light area correspond hard segment domains. So these big light regions could be assigned to the domains of PU coated by CS. In order to check its biocompatibility, cell attachment and proliferation was studied using umbilical vein endothelial cells (HUVEC, ECV304). Inverted microscopy (ECLIPSE TE2000, Nikon Co.) was used to take photos of randomly selected areas of the

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cultured cells every 12 h after ECV304 cells were plated. Blank Petri dish and PU film were used as control groups. Cell adhesion for artificial substrate was mainly affected by surface charge, the molecular aggregation form on the surface and biological & chemical properties of the substrate surface etc. [279,280]. The results of experiments showed that chitosan film with positive charge and PU film with negative charge was not favorable for cell attachments and spreading. It was suggested that hydrophilic domain and hydrophobic domain on the surface of PU-c-CS films, which could support/facilitate the proliferation and cell adhesion. Hence endothelium regeneration of vascular scaffold was possible by CS immobilization onto the surface of PU [281]. This study showed that after PU film was modified by CS, the (activated partial thromboplastin time) APTT of PU-c-CS film increased with increase of CS content, which indicated that better anticoagulant activity of PU-c-CS films. This change occurs because CS shows some haemostatic effect and exhibit the anticoagulation property of the whole blood. It can be concluded that blood compatibility increased with increase in CS contents [282-286]. 3.6

SPEO Coupling-PU in chitosan as coating material

Wang et al., [287] prepared the blends of stearyl poly(ethylene oxide) coupling (SPEO coupling)-polymer in chitosan as coating materials for PU intravascular catheters and scheme has been presented in Fig.7 (a). In this study the blood compatibility of the coated catheters under a shear rate of blood flow was performed by the dynamic experiment through a closed-loop tubular system with the shear rate of 1500 s-1 [288-291]. The FTIR spectra confirmed the polymerization of the proposed structure. The results of in vitro testing of static clotting time, platelet rectification time (PRT), platelet time (PT) and thrombin time (TT) were evaluated and interpreted. The intrinsic coagulation pathway is started, as the result of Ca2+ (Factor IV) is complemented into the anticoagulated

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human plasma. The prothrombin (Factor II) is activated and converted into thrombin. Thrombin initiates the fibrinogen (Factor I) in plasma to convert into insoluble fibrin (frame work of thrombus). The time of this phenomenon was measured as PRT. Extrinsic coagulation was started on the addition of tissue thromboplastin (Factor III contain Ca2+) to the tissue system, which is measured as PT. The TT is the duration from the addition of thrombin to the conformation of the insoluble fibrin. The presence of the chitosan MSPEO coating may be extending the PRT and PT, while hardly affect the TT. Hence it can be seen that both exo-gentic conformation of thrombin and endo-gentic are deferred from coatings anti-thrombogenic effect. Once the thrombin is formed, the coating is little effective. In another study different blood samples were taken out during the experiment. The difference of platelet’s concentration from that of original blood sample was evaluated and interpreted. The count of RBC, WBC, and the measurement of HGB (hemoglobin) were also evaluated and interpreted. The samples PU-org (original-for blank matrix) and Chi-con (for controlled sample coated with chitosan) have shown much less variation and little hemolysis than the others samples. Further the photographs under optical microscope of organ showed little hemolysis, indicated in vitro blood compatibility of the coatings. At the end of the convalescence, no aberrant response was found due to slight infection generated during the blood collection on the tail and on the main organs no pathologic variation was found related to the intravenation of MSPEO. Yang et al. [292] prepared chitosan and poly(vinyl alcohol) (PVA) hydrogel via a four step surface modification method i.e. oxidation of the PU surface, functionalities modification, carbodiimide reaction, coupling, and hydrogel crosslinking. This chitosan/PVA hydrogel was applied as thin layer on segmented PU catheter that showed significant antibacterial effects along with reduced protein absorption due to increased hydrophilicity and slippery surface. Shortly, the

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four-step modification method offered easy and effective mode to coat the surface of PU catheters with a lubricious layer of chitosan/PVA hydrogel that could assist to lessen the chances of complications (encrustation, trauma, catheter obstruction, bacterial infection or colonization etc.) associated to the usage of urethral catheters. 3.7

Thermoplastic

PU

membrane

immobilized

with

water

soluble

chitosan

(WSC)/dextran sulfate Blood compatibility of thermoplastic polyurethane membrane immobilized with water-soluble chitosan/dextran sulfate has also been comprehensively discussed and reported [293]. For this investigation Lin et al, [293] prepared WSC by using N-carboxypropylation of chitosan. Sodium salt of dextran sulfate (DS) was formed by careful purification by sulfating a recommended fraction of dextran and general structure of dextran sulfate. In the dextran chain, each glucose unit has approximately two sulfate groups. The sulfated polysaccharide DS is a polyanion and will interact with cations or polycations. After ozone grafted polymerization of poly (acrylic acid) (PAA), surface immobilization onto the thermoplastic PU membrane with WSC/DS was carried (Fig. 7 (b)). Fig. 7 (a) Polymerization of SPED and synthesis of MESPEO [287]; (b) Chemical scheme of surfaceimmobilized TPU membranes [293] The results revealed that the adsorption of albumin (Alb) and fibrinogen onto the surfacemodified TPU membranes was lowest probably due to electrostatic repulsion. It is well known that protein adsorption is effected by surface characteristics i.e. hydrophilicity, roughness, charge, and chemistry. These results are consistent with those of other researchers [294,295].

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Winterton et al. [294] showed reduced adsorption of plasma proteins such as fibrinogen and albumin onto heparin-immobilized surfaces. They showed that both albumin and fibrinogen had no binding affinity to heparin at physiological pH. On the other hand, adsorption on surface modified (TPU-C16) increased compared to the unmodified TPU surface. Moreover, the adsorption of human plasma fibrinogen (HPF) on the native and surface–modified TPU membranes were examined at pH 7.4 and concentration of 0.3 mg/ml and surface modification effect of TPU membranes on HPF was estimated by using Langmuir isotherm. The results revealed that the adsorbed amount of HPF on the TPU-WSC/ DS membranes was extensively lesser than on the native TPU- membrane, because chitosan is a weak base and value of PKa is 6.5 at pH 7.4 and TPU- chitosan carries a positive charge (-NH3+). Adsorption of protein was promoted on this surface due to electrostatic attraction. But, when TPU-chitosan treated with DS, the adsorption was reduced probably by electrostatic repulsive interactions between negative charge on HPF and SO3− groups of DS. By increasing the length of the spacer chitosan, the bound amount of DS increase, which is mention earlier. Hence such composition showed lowest adsorption of HPF. It is likely that the improved protein anti fouling effect may be ascribed to synergism between the negatively charged sulfonate groups of DS and dynamic mobility of high molecular weight WSC. Park et al [295] also reported similar results that the bioactivity of immobilized heparin depended on the length of PEO spacer. Han et al [296] also investigated that preparation of PU grafted with different molecular weight of PEO and reported that a significant increase in surface mobility and hydrophilicity by an increase in the chain length of PEO. It is worth to mention that plasma proteins are always adsorbed on to the material surface, when blood contacts with a foreign material, i.e. hemodialyzer, angioaccess device or catheter and they provoke attachment of platelet, some red blood cells and white blood cells on

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to the plasma protein layer. Materials such as ADP, ATP are released by adherent aggregated platelets, inducing more platelet aggregation on the surface. An insoluble fibrin network or thrombus is formed in the final phase [297-299]. Hence protein adsorption and platelet adhesion are very important for determining blood compatibility of artificial surfaces [298,299]. Platelet adhesion was even higher on chitosan grafted membrane than on the native TPU membrane. Platelet adhesion increased slightly with incubation time and is reduced by electrostatic repulsion between platelet and negative charged functional groups i.e. acrylic and heparin. However, due to electrostatic attraction the immobilization of positive charges of chitosan would increase the platelet adhesion [299-301]. Surface modification of chitosan membrane by complexinterpenetration of dextran sulfate and showed similar results as reported by Amiji et al [302]. Dextran sulfate coated chitosan membrane reduced the number of platelet adherent 70% compared to chitosan membrane. The albumin/fibrinogen ratio is important for assessing the adhesion of platelets to artificial surface, which is proposed by Dion et al [303] and the number of adherent platelet is lower, as ratio is increased. The ratio obtained in this study is 2.9 for modified TPU. Lee et al [304] observed the degree of platelet adhesion on wetability gradient surface in the presence or absence of plasma proteins. Platelet adhesion increased with increasing wetability in the absence of plasma protein. While in contrast platelet adhesion was suppressed on hydrophilic surfaces in the presence of plasma proteins. From the discussion it was concluded that platelet adhesion promoting proteins are not presented at hydrophilic surfaces due to the socalled Vroman effect, by which fibrinogen initially adsorbed from plasma is displaced from the surface by other proteins [305]. Kang et al [297, 306] also suggested that platelet adhesion was significantly suppressed on heparin-immobilized PUs and reported that the bioactivity of immobilized heparin depended on the length of PEO spacer [307].

21

The clotting times of the native, PAA and WSC-grafted TPU membranes were efficiently the same as those of human plasma with no surface (the negative control) whereas the clotting times of modified TPU by direct approach (TPU-D membrane) were much longer relative to native TPU. This shows that dextran sulfate should be an effective agent in the increasing blood clotting time and thereby it can be exert an anti-coagulant effect. The result showed that increase in hydrophilicity and surface mobility, as the result of longer WSC spacer for binding DS, and thus, increasing the blood compatibility. Activated partial thromboplastin time (APTT) of various free sulfated polysaccharides i.e. chondroitin-6-sulfate, heparin (HEP) and dextran sulfate (DS) were evaluated at various concentrations. Blood coagulation times are not likely to prolong by all polysaccharides which have sulfate groups. In another experiment of Lin et al. [308] surface treatment of TPU was done via low temperature plasma (LTP) surface treatment rather than ozone with subsequent grafting of PAA followed by WSC and HEP grafting. After 90 seconds of LTP, results showed that surface densities of peroxide and PAA reached a maximum leading to higher graft densities of WSC and HEP. The WSC/HEP immobilized TPU membrane showed no cytotoxicity with reduced platelet adhesion, thrombin inactivation and prolonged blood coagulation period. Thus the WSC/HEP/TPU membranes have improved in vitro blood compatibility and can be usefully employed as medical materials. Neville et al. [309] have suggested that dextran sulfate keeps thrombin inactivation instead of anti-factor Xa activity. Magnani et al. [310] reported the bioactivity of differently sulfated hyaluronic acid derivatives-HyalS and heparin immobilized on PUPA (PUPA consists of poly(amido-amine) connected with PU chains via hexamethylene diisocyanate (HMDI) surface) and concluded that thrombin inactivation increases with increasing degree of sulfation.

22

In short, the role of WSC may be explained by properties like that the excluded volume on the surface and its spacer arm effect in binding anionic chain of DS and the hydrophilic in such a way that it repels adhesion and proteins. Moreover the surface grafted with WSC/DS show higher blood compatibility. The reason is that the synergism between the negatively charged of the sulfate groups and dynamic mobility of DS chains [311]. From the results of L929 fibroblast, the MMT values on TPU-WSC/DS were enhanced compared with TPU-C and native TPU membrane. Chatelet et al. [312] reported that chitosan looks to be cytostatic toward fibroblasts, i.e., it inhibits cell proliferation but it is not cytotoxic. Chitosan seems to be cytostatic towards L929 cells, due to strong electrostatic interactions between the negative charges on the surfaces of cell membranes and the cationic sites on chitosan of the surface of the cell membranes. Uchida et al. [313] reported that extremely high adhesion of fibroblasts on CS-based materials would alter their growth. Hence, it inhibits cell proliferation due to inhibition of L929 cell migration. Positive charge of the amino group of chitosan was shielded by negatively charged sulfate of DS. Thus, in vitro L929 cell cultivation, only chitosan cannot be considered as a suitable for biomaterial, while the WSC/DS immobilized TPU membranes are more suitable for L929 cell proliferation. Janik et al. [314] synthesized PU derived from HDI, PCL and BDO and modified it with chitosan (DD 72 wt%) in the amount of 0.1-0.5wt% as a part of hard segment content. Surface prolilometry and contact angle measurement explained the increase in hydrophilicity after chitosan modification and the trend is observed to be stronger when compared to in the case of collagen modification. Incorporation of chitosan into PU backbone was also in focus of Janik et al. They obtained PU derived from IPDI, PCL, and BDO to get a chitosan modified crosslinked system. No change in contact angle was found after chitosan modification. This system was stable under sterilization conditions and in

23

the range of Farmacopea demands. Thus the better extensibility and peer tensile strength of chitosan modified PU in comparison to unmodified PU could be usefully employed as material for heart valves [314- 316]. 3.8

Chitosan-PUNIPAAm thermosensitive membranes

Thermosensitive chitosan-PUNIPAAm membranes were potentially exhibited low cytotoxicity and could promote cell adhesion and growth. The morphology of 3T3 fibroblast cells on membrane was quite similar to control i.e. polystyrene. Not only cell viability of 3T3 fibroblast cells remained while proliferation was also seen on the surface of chitosan-PU/NIPAAm membranes. The result revealed that chitosan-PUNIPAAm- membranes could support the growth of 3T3 fibroblasts and can be easily stripped off from the skin owing to thermosensitive behavior of poly(N-isopropylacrylamide). The antibacterial ability and the values of water vapor transmission rate and permeability of the chitosan-PUNIPAAm membranes are comparable to the commercially available products so may be considered as wound dressing [317]. 3.9

Superfine chitosan-PU blend membranes

Zuo et al. [318] formulated superfine chitosan powder (SCP) and biomedical polyurethane (BPU) based novel asymmetrical membranes through immersion precipitation phase inversion process. Increment in SCP content led to increase in pore diameter and porosities of blend membranes firstly, which decreased afterward. However, the strong hydrophilicity of SCP enhanced the water absorption rate and the water vapor transmission rate remarkably that increased with increase in SCP content. WAXD results determined that the aggregated structure of SCP persisted while the amorphous region of BPU increased. The results of mechanical testing indicated that with increase in the ratio of SCP to BPU, mechanical properties decreased, although all blend membranes presented the good elasticity. Later on Zuo et al. [319] also

24

studied the role of polyvinylpyrrolidone (PVP), a pore forming agent, on the structure and functioning of the SCP-BPU composite scaffolds. SEM, XRD and porosity measurements were used to study the morphology and structure of the SCP-BPU composite scaffolds. The result indicated that composite scaffolds were asymmetric with a skin layer near the top surface and a porous supporting solid matrix. The maximum value of porosity and average pore size of SCPBPU scaffolds was at 5 wt. % of PVP whereas crystallinity, tensile properties, degradation rates and the lamellar thickness of scaffolds reduced with rising PVP content from 0 to 8 wt. %. Thus, SCP-BPU scaffolds made via immersion precipitation phase transformation could be a promising material to be applied in skin tissue engineering just by adjusting the ratio of PVP. 3.10

Chitosan gel based PU

Habib et al.[320] synthesized a novel tissue adhesive comprised of urethane prepolymer and chitosan gel. The IPDI and castor oil derived biomedical PU offered good adhesion while chitosan gel provide biocompatibility and tissue healing (regeneration) properties to prepared adhesives. Chitosan/PU tissue adhesive unlike cyanoacrylate adhesives does not produce any degraded toxic product and unlike fibrin-based glues, it showed acceptable adhesion strength to the tissue even in the presence of water. Effect of tissue adhesives on the viability of Caco-2, T47D, HT-29, and NIH-3T3 cell lines ensured no significant cytotoxic effect that will optimize the use of this adhesive to be used internally and externally in future. 4.

Conclusion

Chitin and chitosan are amino polysaccharides having multidimensional properties. Polyurethanes on the other hand are frequently used for various applications as they offered in wide-ranging of compositions, properties and complex structures. Combination of both these polymers will definitely lead to road map for the advancement in the related areas. Various

25

schematic ways have been presented to synthesize chitin/chitosan based PU membrane, films, coatings etc. following their biomedical applications. Cell proliferation and cell adhesion data suggested them as non-toxic, biocompatible, biodegradable implantable materials. Actually, the acetamide, amino and carbamate linkages groups present in chitin, chitosan and PU, respectively are responsible for biomedical application. Therefore chitin or chitosan based materials either implanted externally or internally will definitely enhance the biocompatibility and reduce the cyto-toxicity. This scientific diagnostic character will provide an opportunity for further advancements in this specific area. Recently a promising approach is the development and exploration of polysaccharide based functional nano-materials in diverse field of applications. Chitin and chitosan whiskers, nanofibers etc. grasped the attention of researchers to use their exceptional properties to the fullest with the combination of research in multidisciplinary areas.

26

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[311] Y.H. Kim, D.K. Han, K.D. Park, S.H. Kim, Biomaterials. 24 (2003) 2213-2223. [312] C. Chatelet, O. Damour, A. Domard, Biomaterials. 22 (2001) 261-268. [313] Y. Uchida, M. Izume, A. Ohtakara, Chitin and Chitosan, Elsevier Applied Science, London/New York, 1988, p. 373.

45

[314] PL Pat. Appl. A1 391 140 (2010). [315] I. Gibas, M. Szypcio, H. Janik, in: R. Steller, D. Zochowska, (Eds.), The Proc. After Conference on Modified Polymers — State and perspectives Wroclaw University of Technology, Wroclaw 2009, pp. 179-182. [316] P. Litwa, H. Janik , I. Gibas, Cast segmented polyurethanes modified with chitosan for medical application”, Bio Med Tech Conference, Silesia 2011, Zabrze 18.03.2011. [317] J. M. Yang, S. J. Yang, H. T. Lin, T. H. Wu, H. J. Chen, Mater. Sci. Engin C, 28(2008) 150-156. [318] D. Y. Zuo, Y. Z. Tao, Y. B. Chen, W. L. Xu, Polym. Bull. 62(2009) 713-725. [319] D. Y. Zuo, W. L. Xu, H. T. Liu, Adv. Polym. TechnoL. 31(2012) 310-318. [320] F.N. Habib, S.S. Kordestani, F. Afshar-Taromi, Z. Shariatinia, Int. J. Polym. Anal. Charact. 16(2011), 609-618.

46

(A)

(B) Figure 1 (A) (B)

Chemical structure of chitin and and deacetylated chitin (chitosan) [8] Three polymorphic configuration of chitin α–Chitin, b β–Chitin, c γ-Chitin [8]

47

Figure 2 Chemical route for synthesis of chitin/1,4 butane diol based PU [264]

48

Figure 3 Chemical structure of the materials used, polyurethane, chitin and a generic chemical pathway for the networks [269]

49

Figure 4 Biocompatibility tests of CMC-PU30wt% at 7 days(A) and 14 days(B) at 2000 magnification, optical micrograph of L929 cell in contact with CMC-HAD (C) and CMC-PU30wt% [273].

50

Figure 5 Synthesis of PU urea emulsion using chitosan as the chain extender [274]

51

Figure 6 Chemical route for synthesis of chitosan/1,4-BDO based PUEs [276]

52

(a)

(b) Figure 7 (a) Polymerization of SPED and synthesis of MESPEO [287]; (b) Chemical scheme of surface-immobilized TPU membranes [293]

53

Table 1 Different techniques for the synthesis and characterization of various chitin and chitosan based material and their perspective biomedical application Sr no

Name

Techniques using for Characterization

1

Methotrexate (MTX) /LaF3:Tb3/chitosan nanoparticles

SEM , XRD

2

waterborne PU-carboxy methyl chitin blend

FTIR, SEM, TGA, DMA, WAXD

3

Chitosan–alginate

DLS, SEM, FT-IR

Potential application Potentially used in targeted drug delivery applications and bioconjugation of the anticancer drug Pharmacy, Personal care, Agriculture Potentially used for oral insulin delivery

Ref

192

193 194

Antimicrobial activity for Carboxymethyl chitosan/organic 4

rectorite/alginate

fibrous mats and Potential FT-IR, FESEM, XRD

used for controlling wound

195

infection and bleeding in medical fields. 5

Chitin –PU

FTIR, DSC, DMTA

6

PU –chitosan

DLS,IR,TEM

7

chitosan/PVA hydrogel nanofiber

FTIR, XPS

8

PEG-O-chitosan nanoparticles

SEM, DLS, TEM, AFM, FTIR, 1 HNMR

9

PU –chitin/1,4-butane diol blends

XRD

11

PU elastomers based on chitosan and poly(e-caprolactone ) Chitin-PU

FTIR, DMTA, TGA, 1 HNMR,13CNMR XRD

12

Chitin-PU Bionanocomposites

XRD, OM

13

PU Nanoparticles coated with Adsorbed chitosan

IR, XPS, DLS, TEM, AFM

14

Chitin-PU blends (thesis)

XRD

10

15 16

Novel β-chitin/nanosilver composite Biomimetic LBL structured nanofibrous matrices assembled

SEM, FTIR, XRD, TGA SEM

Biomedical, self-repairing, aerospace material Used to provide anticoagulative property Potential application in wound healing Potential application for delivery of drug release. Drug release from pegylated chitosan nanoparticles is remarkably slower than chitosan Biodegradable elastomers with tunable hydrophobicity Biomedical &industrial uses For shape memory PU Bionanocomposites formulation Cardiovascular biomaterials For biomedical field of application Scaffolds for wound dressing Manily used for wound healing and functional

196 197 198

199

200 201 202 203 204 205 206 207

54

17 18

19 20

by chitosan/collagen Chitin-PU

FTIR, DSC, XRD

Chitin whisker- waterborne PU nanocomposite

FTIR, XRD, DSC, AFM, SEM, DMA

Folate-PEG coated cationic modified chitosan – Cholesterol liposomes Chitin/poly(3-hydroxybutyrateco-3-hydroxyvalerate) hydrogel

208 209

HNMR, TEM, DLS

For targeted drug delivery system

210

HDF

Skin tissue engineering

211

21

Glycol chitin as thermo gelling polymer

Fast gelation kinetics

22

Chitin-poly(caprolactone) composite

FTIR, SEM, TG/DTA

Chitosan/alginate nano-layered

SEM, DSC, TGA, water

PET film

contact angles

23

properties of wounded skin For biodegradability Useful in bionanocomposites formation

Thermo gelling biomaterials for drug delivery and injectable tissue engineering Biomedical used for Drug delivery Multilayer films, coating

212

213

for biomedical appliances or multilayer edible

214

coatings 24

Chitin butyrate/poly(€caprolactone) blends

ATR-FTIR

25

N-halamine /chitin nanofiber

FTIR, UV-VIS, XRD, TGA

Facile fabrication of mesoporous 26

poly(ethylene-co-vinyl

TIPS , SEM, FTIR

alcohol)/chitosan blend monoliths poly(3-hydroxybutyrate-co-327

hydroxyvalerate)/chitin nanocrystals composite

28

29

Fabrication of chitin– chitosan/nano ZrO2 composite Fabrication of chitin– chitosan/nano TiO2-cscaffolds

30

protein-loaded chitosan

XPS, Static water contact angle,

Scaffolds for tissue

TIPS

engineering

SEM, FTIR, XRD, TGA

SEM, XRD, FTIR, TGA.

chitosan-g-poly acrylonitrile/silver nanocomposite

216

217

218

Scaffolds used in tissue engineering

219

Tissue engineering scaffolds

220

Potential bifunctional CLSM, SEM, TGA

scaffolds for bone tissue

221

engineering.

microspheres 31

biomedical related

215

applications.

GRGDSPC-modified poly(lactide-co-glycolide acid)-

Tissue engineering applications For antibacterial and antifungal activities Waste water purification or

FTIR, TGA, TEM

Useful to provide antimicrobial material

222

Composite films of poly(vinyl 32

alcohol)–chitosan–bacterial

FTIR,XRD,TEM

For controlled drug release

223

cellulose

55

synthesis of chitosan-g33

FTIR, XRD,TEM, SEM,

poly(acrylamide)/ZnS

EDX,TGA

nanocomposite

34

35

36

37

For controlled drug delivery with antimicrobial

224

activity. Antimicrobial activity

N-quaternized chitosan/poly(vinyl

FTIR, XRD, SEM, TGA

alcohol) hydrogels

towards bacteria and fungi

225

and metal ions uptake

poly(glycolic acid) grafted

FTIR, XPS, X-Ray

chitosan Gamma irradiated chitosan/

FTIR

poly(vinyl alcohol) blends PMAA–chitosan–PEG

SEM, XRD, TEM, DSC

nanoparticles

Applicable for biomedical field

226

Used as strong antimicrobial reagent.

227

For oral controlled drug delivery

228

Poly(vinylphosphonic acid) 38

immobilized on chitosan: A

FTIR,XRD

glycosaminoglycan-inspired

For bone tissue engineering application

229

matrix Chitosan-graft-poly(ɛ39

caprolactone) amphiphilic

1

HNMR, FTIR, DLS,TEM

copolymer micelles

40

alginate, chitosan and cellulose nanocrystals

chitosan/hydroxyapatite/β-

FTIR

SEM

Electrospinning of carboxymethyl chitin/poly(vinyl alcohol)

SEM

nanofibrous 43 44

45

46

47

N-hexoyl chitosan derivatives poly(l-glutamic acid)/chitosan microcapsules Chitosan/cellulose micro crystals (CMC)

FTIR, DSC, AFM FTIR, TGA, SEM, TEM, CLSM

TGA, XRD, SEM

alcohol)/silk fibroin nanoparticles

pharmaceutical

231

Scaffolds for bone tissue engineering

232

Scaffolds for tissue engineering application For pharmaceutical field

233

234

For drug delivery applications

235

Useful as antimicrobial films

236

For skin tissue

chitosan/poly(caprolactone) carboxyethyl chitosan/poly(vinyl

230

applications.

tricalcium phosphate composite

42

delivery For medical and

squid pen 41

For 5-fluorouracil drug

engineering. SEM, XRD, DSC

237

Electro spun matrix used as potential wound

238

56

dressing for skin regeneration. 48

49

Chitosan/hyaluronan hydrogels Acetylsalicylic acid-acylated chitosan

FTIR 1

HNMR, FTIR

For soft tissue engineering applications. For controlled drug release

239

240

57