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Abbreviation (ISO4): Prog Chem      Editor in chief: Jincai ZHAO

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Progress in Chemistry >

2023 , Vol. 35 >Issue 10: 1450 - 1460

DOI: https://doi.org/10.7536/PC230303

Review

New Dressings Based on Chitosan and Its Application

  • Quan Zhang ,
  • Siyu Duan ,
  • Zhongyuan Huo ,
  • Xinwang Meng ,
  • Jun Wang ,
  • Guohe Xu , *
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  • College of Science and Engineering, Hebei Agricultural University, Cangzhou 061100, China
*Corresponding author e-mail:

Received date: 2023-03-09

  Revised date: 2023-05-20

  Online published: 2023-07-18

Supported by

Basic Scientific Research Funds for Universities Affiliated to Hebei Province(KY2022056)

Innovation and Entrepreneurship Training Program for Undergraduate Students of Hebei Agricultural University(2023114)

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Abstract

Chitosan has great potential in the fields of materials science and biomedicine because of its advantages such as coagulation, antibacterial, biocompatibility and biodegradation. This paper introduces the coagulation and bacteriostatic mechanism of chitosan, and lists the research progress of new dressings based on chitosan. According to the different morphology, the new dressings can be divided into the following types: fabric dressings based on chitosan, hydrogel dressings based on chitosan, spongy dressings based on chitosan, hydrocolloid dressings based on chitosan, asymmetric wettable dressings based on chitosan and frozen gel dressings based on chitosan. The experimental results of the new dressings based on chitosan in terms of antibacterial properties, in vitro coagulation properties, waterproof properties, breathable properties and mechanical properties were summarized. The application of new dressings based on chitosan in the treatment of diabetic foot ulcer, burn wound, inferior vena cava injury and endoscopic sinus surgery was summarized in detail. Finally, based on some problems existing in the new dressings based on chitosan (for example, the preparation process is greatly affected by the external environment conditions, some working mechanism of chitosan is still in the preliminary stage), the future development of the new dressings and their application are prospected.

Contents

1 Introduction

2 Working mechanism of new dressings based on chitosan

2.1 Hemostasis effect of chitosan

2.2 Bacteriostatic effect of chitosan

3 Research progress of new dressings based on chitosan

3.1 Fabric dressing based on chitosan

3.2 Hydrogel dressing based on chitosan

3.3 Spongy dressing based on chitosan

3.4 Hydrocolloidal dressing based on chitosan

3.5 Asymmetric wettability dressing based on chitosan

3.6 Frozen gel dressing based on chitosan

4 Application of new dressing based on chitosan

4.1 Diabetic foot ulcer

4.2 Burn wound

4.3 Inferior vena cava injury

4.4 Endoscopic sinus surgery

5 Conclusion and outlook

Key words： chitosan; new dressings; application

Cite this article

Quan Zhang , Siyu Duan , Zhongyuan Huo , Xinwang Meng , Jun Wang , Guohe Xu . New Dressings Based on Chitosan and Its Application[J]. Progress in Chemistry, 2023 , 35(10) : 1450 -1460 . DOI: 10.7536/PC230303

1 Introduction

Skin is the largest organ of the human body, which plays an important role in maintaining homeostasis and preventing microbial invasion, and its healing is a complex process[1]. Skin trauma is the destruction of the normal structure and function of skin tissue, which is caused by different factors, such as the damage caused by sharp tools, light, heat, chemicals and other external injury factors, and may also be caused by other pathological factors. Skin wounds are often treated with wound dressings to protect the wound from re-invasion and accelerate healing. Traditional dressings to protect wound healing include band-aids, gauze, bandages and other items, which can be used for open surgical wounds and chronic wounds, but are only suitable for emergency treatment of small areas of trauma, and are difficult to use for larger areas of trauma. Traditional dressings have poor air permeability and water resistance. Once they are soaked by wound exudate or external liquid, they will lose the function of wound dressings. Therefore, too long adhesion time will lead to secondary bacterial infection and even wound deterioration. In order to solve these drawbacks, scientists began to explore new dressings[1]. In 1962, Winter first proposed the concept of wet healing, which holds that the healing rate of wounds in wet environment is significantly higher than that in dry environment (2 to 4 times higher), because wound dehydration will disturb the microenvironment needed for wound healing, thus hindering the healing process[2][3]. Therefore, an ideal non-toxic, non-allergic, non-adhesive skin wound dressing is very important in daily life, which can absorb excess exudate and maintain a moist environment on the wound surface. At the same time, it should have good antibacterial and biocompatibility properties to promote wound healing, as well as self-cleaning ability to prevent contamination[4].
Chitosan (CTS) is a natural polymer material, as shown in Figure 1, which has been widely prepared from chitin as a raw material since 1859[5]. Chitosan has excellent film-forming properties, biocompatibility, hemostatic activity, anti-infective properties and biodegradability, which shows good application prospects in water treatment, biomedicine, agriculture, food and other fields[6,7][8,9][10⇓⇓~13][14⇓~16][17,18][19⇓~21][22⇓⇓~25]. In addition, it was also found that chitosan could promote wound healing, which provided a new choice for the production of new dressings[26,27]. Moreover, chitosan is rich in amino and hydroxyl groups, which is a highly hydrophilic natural substance with high charge and polar group density and super moisturizing ability, which can well meet the "moist healing" theory[2]. To date, chitosan-based hemostatic materials have been studied for nearly 30 years. In 2002, the Food and Drug Administration (FDA) approved the first commercially available chitosan hemostatic bandage, HemCon, which was widely used in the Iraq War in 2003. According to statistics, the hemostatic effect of HemCon is significantly better than that of ordinary gauze. However, the degradation time in vivo is slow, which can cause more serious chronic inflammation[28]. In 2007, another modified chitosan hemostatic powder, Celox, approved by the FDA, was launched to make up for HemCon's shortcomings to some extent. This product is not acidic, which greatly reduces the risk of inflammation, but it has poor hemostatic effect on severe bleeding, high hemolysis rate and easy to cause thrombosis[29]. Up to now, the new dressing based on chitosan has become a widely concerned hemostatic dressing, which has made great progress in degradation, hemostatic effect and bacteriostasis through continuous improvement by researchers.
图1 壳聚糖结构式

Fig.1 Structural formula for chitosan

In this paper, the hemostatic and bacteriostatic mechanisms of chitosan were described in detail.The new chitosan-based dressings (chitosan-based fabric dressings, chitosan-based hydrogel dressings, chitosan-based spongy dressings, chitosan based hydrocolloid dressing, chitosan based asymmetric wetting dressing and chitosan based frozen gel dressing) were introduced and reviewed.The advantages of the new chitosan-based dressing, such as good biocompatibility, strong hemostatic effect, waterproof and breathable, were reviewed, and the application of the new chitosan-based dressing in the treatment of diabetic foot ulcer, burn wound, inferior vena cava injury and endoscopic sinus surgery was summarized. Finally, based on some problems of the new chitosan dressing (such as the preparation process is greatly affected by the external environmental conditions, and part of the working mechanism of chitosan dressing is still in the preliminary stage), the development of the new chitosan dressing is prospected, which provides a reference for its further development and improvement.

2 Working Mechanism of Chitosan-based New Dressing

The new dressing based on chitosan is a kind of dressing with the functions of ventilation, waterproof and disinfection. With the excellent properties of chitosan itself, it can inhibit some microorganisms from entering the body. Compared with the traditional wound dressing, the new dressing based on chitosan has good biocompatibility, coagulability and bacteriostasis. In order to enhance the bacteriostatic effect of chitosan, scientists add some special substances to it.Uch as oxidized carboxymethyl cellulose, cellulose nanofibers, silver nanoparticles and the like, or a carrier is used for conveying anti-inflammatory and bactericidal drugs into the liquid dressing, thereby obtaining excellent blood coagulation and bacteriostatic effects[30][31][32].

2.1 Hemostatic effect of chitosan

Chitosan has good effects of promoting erythrocyte aggregation and platelet adhesion and aggregation in blood, so that it has good effect of promoting blood coagulation and achieving good hemostasis. The agglutination effect of chitosan on erythrocytes depends not only on its own structure and molecular weight, but also on its cationic effect at low pH, which can promote platelet aggregation and agglutinate negatively charged platelets to achieve hemostasis[33]. Okamoto et al pointed out that the reason why platelets can strongly adhere to the surface of chitosan is the aggregation of special chemical groups, N H 3 +, on platelets[34]. Various metabolites released during platelet adhesion and aggregation also accelerate platelet adsorption and aggregation during blood coagulation, thereby accelerating blood coagulation, as shown in Figure 2.
图2 壳聚糖促进血小板聚合示意图

Fig.2 Schematic diagram of chitosan’s promotion of platelet polymerization

2.2 Bacteriostasis of Chitosan

Chitosan has a good inhibitory effect on bacteria and other microorganisms, and has a significant inhibitory effect on common bacteria existing on the surface of the human body, such as Staphylococcus epidermidis, Escherichia coli, and Staphylococcus aureus, which are prone to occur in burn wounds[35]. The bacteriostatic mechanism of chitosan can be divided into the following four types: (1) Chitosan molecules can selectively bind metal ions and their coenzymes to inhibit the absorption of nutrients and trace elements by bacteria; (2) The positive charge carried by chitosan interacts with the negative charge of the bacterial cell membrane, resulting in the destruction of the cell membrane and the leakage of proteins and other components, thus causing the death of bacteria; (3) activating and combining the components of the bacterial cell wall to cause the death of the bacteria due to the decomposition of the cell wall; (4) Chitosan with lower molecular weight can enter the nucleus of bacteria and bind to their DNA, thus interfering with and hindering the synthesis of their proteins and blocking the metabolism of pathogenic bacteria, as shown in Figure 3[36⇓~38].
图3 壳聚糖的抑菌机制

Fig.3 Antibacterial mechanism of chitosan

3 Research Progress of New Dressing Based on Chitosan

Chitosan-based novel dressings can be divided into chitosan-based moist dressings and chitosan-based dry dressings according to the state. The greatest advantage of wet dressing is that it is more in line with the "wet healing theory" and can better promote wound healing. Dry dressings have also attracted the attention of scholars because of their more convenient storage conditions[39]. In this part, the new chitosan-based moist dressings (chitosan-based hydrogel dressings, chitosan-based hydrocolloid dressings, chitosan-based asymmetric moist dressings, chitosan based frozen gel dressings) and dry dressings (chitosan based fabric dressings and chitosan based sponge dressings) are introduced respectively.

3.1 Chitosan-based textile dressing

Chitosan-based fabric dressings are one of the most common and widely used new wound dressings, which are mostly used to treat bleeding wounds by pressing with gauze, cotton or other fabric materials[40,41][42]. Chitosan-based fabric dressings only need to be fully soaked in chitosan solution. Therefore, chitosan-based fabric dressings play an important role in new hemostatic materials because of their good softness, cuttability, simple preparation method and excellent biocompatibility after adding chitosan[43].
In 2022, Anbazhagan et al. Prepared a bimetallic silver and platinum nanoparticle chitosan cotton gauze (AgPt NPs-CS/CG) with citric acid as a reducing agent[44]. Compared with common gauze, the antibacterial efficiency of AgPt NPs-CS/CG against bacteria, yeast and filamentous fungi was significantly improved by UV-Vis spectroscopy, FE-TEM and elemental mapping analysis. In addition, Ag Pt NPs-CS/CG showed obvious hydrophobicity and better antibacterial and antioxidant activities, and the treatment promoted the wound healing of mouse embryonic fibroblast (NIH3T3) in vitro. AgPt NPs-CS/CG greatly improved the antibacterial and wound healing effects.
In 2020, Fang et al. Established a chitosan-valine dressing (CVG) made by covering chitosan and vaseline on a sterile coating and then drying[45]. The cytotoxicity test of the material was performed in vitro, and the reliability extended water standard was in the range of 8% to 12% after two hours of CVG application. Moreover, CVG also shows great antibacterial activity against Gram-positive and Gram-negative microorganisms. Wound healing and tissue similarity examinations were completed over a period of 14 days. CVG showed a faster rate in treating injuries compared to the control group.

3.2 Chitosan-based hydrogel dressing

Chitosan-based hydrogel dressings are composed of one or more hydrophilic polymers combined by one or more cross-linking methods, which have a three-dimensional network structure inside. Chitosan-based hydrogels can swell and retain a large amount of water due to the presence of a crosslinked network, and the amount of water absorbed is closely related to the degree of crosslinking. The higher the degree of crosslinking, the lower the water absorption, similar to the elasticity of soft tissue, which can support tissue regeneration. They provide a tissue-like environment for wound healing and keep the wound moist. In addition, bioactive molecules and drugs can be entrapped in the hydrogel and released by diffusion, further improving the therapeutic efficacy[46]. Chitosan hydrogel dressings can be synthesized by crosslinking chitosan with positive charges and ions and polymers with negative charges[47]. In general, chitosan-based hydrogels are ideal candidates for drug delivery and moisture protection in wound dressing applications, and have ultra-stretchability, rapid self-healing, and good antibacterial activity, which are in great demand especially in skin wound healing[48].
In 2022, in order to study the treatment of infectious bleeding wounds, Yang et al. Crosslinked dopamine methacrylate anhydride (DAMA) and zinc-doped calcite nanoparticles (Zn-nWH) with quaternized chitosan methacrylate anhydride (QCSMA) to obtain multifunctional chitosan hydrogel dressing (QCSMA/DAMA/Zn-nWH).The multifunctional chitosan hydrogel dressing has the effects of hemostasis, disinfection and wound healing promotion, and shows good adhesion (0.031 MPa) and clearance capacity (94%), good biocompatibility (hemolysis rate < 2%, no cytotoxicity), low in vitro coagulation BCI value (< 13%) and can activate the coagulation pathway[49]. At the same time, it showed excellent antibacterial properties (antibacterial rate against Staphylococcus aureus and Escherichia coli > 90%). All these results indicate that this chitosan hydrogel dressing has faster gelation, stronger skin wound adsorption for tissue adhesion, excellent biocompatibility and blood compatibility, good antibacterial properties and free radical scavenging ability,It can effectively promote hemostasis and wound healing, and has great potential in clinical hemostasis and anti-infection healing.
In 2023, Tannaz et al. Prepared a hydrogel wound dressing with biocompatibility and biodegradability by using chitosan and agarose as raw materials[50]. At the same time, based on the fact that the hydrogel material can efficiently deliver drugs, ciprofloxacin was incorporated into the hydrogel through polydopamine-modified silk fibroin nanoparticles, and the drug loading was measured to be as high as 80.74%, and it could show more drug release, and the released antibiotic retained more than 80% of its biological activity, effectively inhibiting the growth of Pseudomonas aeruginosa. In addition, the physical and chemical properties of the prepared chitosan hydrogel wound dressing and the cell reaction show that the prepared chitosan hydrogel wound dressing can support the proliferation and growth of fibroblasts.
In 2023, Lu et al., aiming at the characteristics of poor water retention, brittleness and weak skin adhesion of hydrogel as an independent wound dressing, selected macromolecular crosslinked chitosan and polyacrylamide double network hydrogel as the functional layer (C-A).Another robust poly (vinyl alcohol) -polyacrylamide/glycerol protective layer was designed to cover its surface (P-A), and the interfacial reaction just connects the two layers tightly to achieve functional synergy[51]. In the double-layer chitosan hydrogel dressing, the surface P-a layer with strong water-locking ability can keep the wound surface moist for a long time,The high strength and toughness enable the dressing to maintain integrity under large deformation and stress to enhance wound protection, while the C-A layer with moderate adhesion ensures that the dressing fits the skin, and the synergistic swelling ability can ensure the rapid absorption of wound exudate. In in vitro and in vivo tests, the chitosan hydrogel dressing showed excellent antibacterial and cytocompatibility, and it could significantly accelerate skin tissue regeneration and wound closure compared with commercially available hydrogel dressings.
In 2023, Suneetha et al. Developed a fungal carboxymethyl chitosan-impregnated bacterial cellulose hydrogel as a wound dressing using bacterial cellulose and carboxymethyl chitosan produced by Gluconacetobacter[52]. Carboxymethyl chitosan is produced by chitosan and chloroacetic acid under alkaline conditions, in which carboxymethyl can be substituted on hydroxyl and amino groups to form O-carboxymethyl and N-carboxymethyl chitosan, respectively, thereby increasing the water solubility and pH sensitivity of carboxymethyl chitosan. The modified carboxymethyl chitosan was characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), water contact angle test, thermogravimetric analysis (TGA) and scanning electron microscopy (SEM).The experimental results showed that the modified carboxymethyl chitosan greatly improved the hydrophilicity of bacterial cellulose, which is essential for wound healing applications. In addition, the biocompatibility, antibacterial activity, cell adhesion and spreading ability were also significantly better than those of the control group. Therefore, this fungal carboxymethyl chitosan-impregnated bacterial cellulose hydrogel can be considered suitable for antimicrobial wound dressing applications.

3.3 Chitosan-based sponge dressing

Chitosan-based sponge dressing is a soft hemostatic material with a well-interconnected microporous structure[53,54]. With its unique structure, sponges have excellent fluid absorption capacity, which provides support for cell interaction and promotes cell proliferation. At the same time, it has the advantages of good air permeability, isolation of bacteria, soft material, and reduction of wound damage[55]. When preparing the chitosan-based sponge dressing, the chitosan solution can be stirred in an acidic environment to foam it, and after crosslinking, it can be transformed into a chitosan-based sponge dressing by freeze-drying technology, as shown in Figure 4[56]. The sponge can greatly retain the original performance of the hydrogel, and the most remarkable excellent performance of the sponge compared with the hydrogel dressing based on chitosan is that the sponge can be stored for a longer time and is more convenient to carry.
图4 基于壳聚糖的海绵状敷料的制备示意图

Fig.4 Schematic diagram of the preparation of spongy dressing based on chitosan

In 2023, Shi et al. Constructed a chitosan-polyethylene glycol (CS-PG) expanded sponge with interpenetrating network by using chitosan and Ca2+[57]. At the same time, various activated coagulation factors in the plasma are also loaded into the pore structure of the chitosan sponge. The prepared CS-PG sponge can rapidly seal and adhere, catalyze and activate automatic coagulation by thrombin, and provide a simpler and more efficient method for treating high-pressure arterial bleeding wounds. As a next-generation bioactive material, CS-PG sponge showed excellent hemostatic properties compared with traditional hemostatic materials in both rabbit femoral artery injury and rat liver injury models.
In 2018, Zhao et al. Developed a composite sponge (QCSG/CNT) based on carbon nanotube (CNT) and glycidyl methacrylate functionalized quaternized chitosan (QCSG)[28]. The quaternized chitosan is modified on the basis of chitosan, and the chitosan is reacted with a modifying reagent with a quaternary ammonium group to make the chitosan have the property of a quaternized salt. Due to the addition of amine groups on the modified quaternized chitosan, the hydrophilicity and electropositivity of the modified quaternized chitosan are enhanced. When the CNT content was 4 mg/mL (QCSG/CNT4), it had better hemostatic effect than the hemostatic sponge without chitosan in the mouse liver injury model, and the hemostatic time was reduced from 101 s to 73 s, which could be used for hemostasis and healing of incompressible fatal wounds.

3.4 Chitosan-based hydrocolloid dressing

Chitosan-based hydrocolloid dressing is a new type of dressing developed in recent years, which is mainly composed of a covering layer (usually polyurethane film or non-woven fabric), a hydrocolloid layer and an elastomer or adhesive layer.It has good water vapor permeability, and its external polyurethane waterproof layer has a certain physical barrier to microorganisms, which can prevent bacterial infection of the wound surface to a certain extent, and is mainly suitable for the treatment of mild and moderate wounds with a small amount of exudate[58][59]. Chitosan-based hydrocolloid dressings are usually prepared by heating the polymer elastomer and chitosan together, and adding plasticizers, tackifying resins, antioxidants, and crosslinking agents to make them fully crosslinked[58].
In 2018, Hiranpattanakul et al. Prepared a chitin/chitosan hydrocolloid (CCH) wound dressing by embedding chitosan microspheres prepared by crosslinking chitosan with tripolyphosphate into chitin matrix in a certain proportion, and evaluated its enzymatic degradation effect (gradual surface degradation by 1.4 G/mL lysozyme,After 7 days, the water adsorption decreased from 231% ± 22% of the initial dry weight to 55.3% ± 2.9% of the wet weight), the antibacterial activity against Escherichia coli and the biocompatibility with L929 cells were measured, and the data were significantly better than those of the traditional dressing[60]. The effective antibacterial activity and good enzymatic degradation effect indicate the potential of chitosan hydrocolloid dressings as wound healing dressings in the medical field.
In 2022, in order to test the effect of chitosan-based hydrogel dressings, Liu et al. Used chitosan-based hydrocolloid dressings made of hydrocarbon resin, styrene-isoprene block copolymer, sodium hydroxymethylcellulose and adipic acid to test 80 patients with chronic refractory wounds[61]. Among them, 40 people used the hydrocolloid dressing based on chitosan, while the other 40 people used the general dressing to form a comparative study of clinical treatment, and the itching and pain score of the dressing, the cost and frequency of dressing change, the healing efficiency of the wound, and the change of the area were studied. Through the comparison between the study group and the control group, it was found that the wound healing rate, wound healing area change, itching and pain degree, cost and frequency of the study group with chitosan-based hydrocolloid dressing were significantly better than those of the control group. This indicates that the chitosan-based hydrocolloid has the characteristics of relieving pain, accelerating healing, being economical and practical, and has good clinical efficacy.

3.5 Chitosan-based asymmetric wettability dressing.

Chitosan-based asymmetric wettability dressing means that two sides of the same material show different wettability, such as a material with one hydrophobic side and the other hydrophilic side. The hydrophobic surface can effectively prevent external liquid contamination, including water, blood and bacteria. The hydrophilic surface can maintain a comfortable, moist environment and promote wound healing[62,63]. As one of the special wettability materials, chitosan-based asymmetric wettability interfacial materials have great potential applications in unidirectional fluid transport, microfluidic systems, oil-water separation, wound dressings and so on. For the production of chitosan-based asymmetric wetting dressings, a variety of different technologies have been explored to produce asymmetric interfaces, such as wet phase inversion method, dry/wet method, supercritical CO2(scCO2) assisted phase inversion technology, electrospinning technology, bio-printing technology, and their advantages and disadvantages and preparation methods are shown in Table 1[64].
表1 基于壳聚糖的不对称膜的制备和优缺点

Table 1 Preparation, advantages and disadvantages of asymmetric membranes based on chitosan

Preparation method Preparation Advantages Disadvantages
Wet-phase inversion method The casting polymer is soaked in a non-solvent coagulant bath to promote the polymer to precipitate, thus forming a film. Easy to operate The top layer of the asymmetric membrane thickness reduction(<1 μm)
Dry/wet-phase
inversion method		 Membrane production is initiated by a pre-evaporation process before the cast polymer is immersed in the coagulation bath. Producing a denser top layer The evaporation process uses a volatile solvent; Time-consuming
scCO2-phase inversion method Under the supercritical condition of CO2, the precipitation of polymer solution is promoted to produce an asymmetric membrane. Simple; fast; eco-friendly Professional high-pressure equipment is required.
Electrospinning method A polymer solution is loaded into a syringe and subjected to a high-voltage electric field, which promotes the polymer to be sprayed toward the collector, resulting in nanofibers. The operation is simple; the asymmetric membrane based on chitosan can be optimized by adjusting the parameters; a variety of polymers can be used. A professional DC power supply and injection pump are required, and the control requirements for processing variables and environmental conditions are demanding.
Bioprinting method Asymmetric membranes can be produced by printing different layers containing the respective skin cells (keratinocytes om top, fibroblasts on bottom). Asymmetric membranes based on chitosan can be customized to the specific needs of the patient. A professional 3D printer is required; a sterile environment is required; The number of polymers and solvents available is limited.
In 2020, Wang et al. Prepared modified cotton fabric dressings with asymmetric wettability using a quick and simple spraying strategy, in which one side of the fabric was sprayed with chitosan solution to achieve hydrophilicity (contact angle 0 °), while the other side was treated with paraffin wax to achieve hydrophobicity (contact angle 152 °)[65]. The asymmetric wettable chitosan cotton fabric dressing showed better hemostatic ability and lower clotting index than ordinary cotton fabric dressing in in vitro coagulation experiments. In addition, the hemostatic performance in the rat liver animal model was better than that of the common cotton fabric dressing, which prolonged the survival time of rats in the carotid artery animal model.
Liang et al. Reported a nanosilver (AgNPs)/chitosan composite dressing with an asymmetric wetting surface as a wound healing material[66]. The addition of AgNPs to chitosan dressing improved its bacteriostatic activity against drug-sensitive and drug-resistant pathogens. The asymmetric surface modification gives the dressing a high degree of hydrophobicity and inherent hydrophilicity of chitosan. The asymmetric wetting AgNPs/chitosan composite dressing has better moisturizing properties and clotting ability compared with the unmodified dressing. Cytocompatibility tests evaluated in vitro and in wound infection models have also demonstrated that composite dressings are non-toxic to the body. In addition, the in vivo wound healing model in mice showed that the asymmetric moist AgNPs/chitosan dressing promoted wound healing and accelerated reepithelialization and collagen deposition. This indicates that asymmetric wetting chitosan dressings have great potential in promoting wound healing.
In 2022, Liu et al. Reported a biomimetic bilayer asymmetric wettable wound dressing prepared by low-temperature 3D printing combined with electrospinning[67]. The hydrophilic bottom layer of the dressing, consisting of chitosan and copper ions, is used to kill bacteria and accelerate wound healing. In addition, the composite dressing also has good cytocompatibility and antibacterial properties in vitro. The results of cell scratch assay showed that the migration area of human umbilical vein endothelial cells increased by about 48.19% compared with the control group. In addition, in vivo experiments in rats showed that the wound closure of this chitosan dressing reached 98.24% after 12 days, which was much higher than the data of the control group.

3.6 Chitosan-based cryogel dressing

Chitosan-based frozen gel dressing is inspired by the morphology of frozen soil and the phenomenon of seawater freezing in nature, which can form porous crosslinked networks with different pore sizes at low temperature under the action of crosslinking agents.With its special pore-forming mechanism, it shows the advantage of rapid absorption, in which ice crystals act as pore-forming agents in the frozen gel, and the interconnected macroporous structure produced by the sublimation of ice crystals allows water molecules to enter freely, allowing it to absorb blood quickly and aggregate red blood cells and platelets effectively[68][69][61][70⇓~72][70,73,74]. These unique properties make cryogel valuable for research in hemostasis, coagulation, etc. Chitosan-based cryogel is mainly prepared with water as the solvent. In the environment below zero, most of the water becomes ice crystals, and a small part remains in the liquid phase. Chitosan and other polymers in the liquid phase are concentrated and crosslinked to form a polymer network, and when the ice crystals melt, the chitosan cryogel with a highly intercommunicating macroporous structure can be obtained, as shown in Figure 5[75].
图5 基于壳聚糖的冷冻凝胶的制备示意图

Fig.5 Schematic of the preparation of frozen gel dressing based on chitosan

In 2022, Shi et al. Prepared a series of polyacrylic acid/chitosan (PAA/CS) cryogel dressings by cryo-structuring technique[76]. These cryogels have high porosity (> 94%), rapid water absorption (< 3 seconds), high blood-sucking capacity (> 2000%), excellent mechanical strength, and fatigue resistance. The PAA/CS showed the highest mechanical strength of 65.05 kPa and retained its full shape after 100 compression cycles. Mouse femoral artery bleeding model and liver injury model experiments showed that compared with commercial hemostatic dressings (gauze, gelatin sponge and CS sponge), PAA/CS low-temperature gel dressings showed higher whole blood coagulation ability and red blood cell and platelet adhesion ability. The hemostatic properties of PAA/CS cryogel were greatly improved by the synergistic effect of rapid blood sucking property, platelet adhesion enhancing behavior, and negative charge activating endogenous hemostatic pathway behavior. Therefore, PAA/CS cryogel dressings show potential application in preventing massive bleeding from arteries and visceral organs, and will be of practical value in rapid hemostasis for clinical application.
In 2023, Xuan et al. Used a one-step method to prepare an antibacterial, shape memory reduced graphene/chitosan (rGO-CTS) cryogel with high blood absorption, incompressibility, and rapid wound recovery[77]. The rGO-CTS cryogel exhibited good mechanical properties, antibacterial activity, and biocompatibility. The rGO-CTS cryogel showed good coagulation and hemostasis in a mouse liver trauma model. Therefore, this chitosan cryogel has great potential as a new hemostatic material applied to incompressible wounds, showing potential applications in preventing massive bleeding in arteries and visceral organs, and will be of practical value in rapid hemostasis for clinical applications.
The preparation and main advantages of the novel chitosan-based dressing are summarized in Table 2.
表2 基于壳聚糖的新型敷料的对比

Table 2 Comparison of novel dressing based on chitosan

Type of dressing Preparation technology Advantages ref
Fabric dressing The fabric is thoroughly soaked in a chitosan solution. It is easy to prepare, soft, tailoring and biocompatibility. 39⇓⇓~42
Hydrogel dressing Cross-linking of positively charged chitosan with negatively charged ions, and polymers can be used to synthesize chitosan-based hydrogel dressings. The treatment effect is good, with super stretching, fast self-healing and good antibacterial activity. 45⇓~47
Spongy dressing The chitosan solution is stirred in an acidic environment to foam, then cross-linked and transformed into a chitosan-based spongy dressing by freeze-drying technology. With excellent permeability and fluid absorption capacity, the material is soft and can be stored for a longer time, and is easier to carry. 53,54
Hydrocolloidal dressing The polymer elastomer and chitosan are heated together. Plasticizer, viscosifying resin, antioxidant and crosslinking agent are added to make it fully crosslinked. It has good water vapor permeability, effective antibacterial activity and a good enzymatic degradation effect. 57,58
Asymmetric wettability dressing Wet-phase inversion method; dry/wet-phase inversion method; scCO2-phrase inversion method; Electrospinning method; Bioprinting method It has lower clotting index, high hydrophobic and hydrophilic activity and antibacterial activity, and can effectively protect against water, blood and bacterial contamination. 63
Frozen gel dressing Using water as the solvent, in a sub-zero environment, most of the water turns into ice crystals and a small part remains in the liquid phase. Chitosan and other polymers in the liquid phase are concentrated and cross-linked to form polymer networks. When the ice crystals melt, frozen gels with highly intercommunicating microporous structures can be obtained. It has high porosity, rapid water absorption, high blood-sucking ability, excellent mechanical strength and fatigue resistance, whole blood coagulation ability and red blood cell and platelet adhesion ability 69,72,73

4 Application of novel chitosan-based dressing

4.1 Application in diabetic foot ulcer

Diabetic foot is a common, complex and chronic complication in diabetic patients, which results mainly in ulcers, amputations and death. The lifetime risk of diabetic foot ulcer (DFU) in diabetic patients can reach 34%, and the recurrence rate is high, which increases the disability rate, mortality rate and treatment costs, and seriously affects the quality of life of patients[78][79][80]. In order to shorten the treatment time and reduce the recurrence rate, a new dressing based on chitosan has been paid attention to by researchers as a highly effective dressing, and it has been found to have a good effect on diabetic foot ulcers.
In 2022, Wang et al. Used chitosan-based cotton fabric to treat diabetic foot ulcers, and used carboxymethyl chitosan (CMC)/sodium alginate (ALg) composite film (CMC/ALg-GSNO) and traditional medical gauze to compare diabetic mice in vitro.The results showed that the chitosan wound dressing could effectively promote the healing of diabetic wounds in the rat model compared with gauze[81].

4.2 Application in burn wound

Burn is a common skin trauma in daily life. If it is not treated early and timely, complications such as scar or deformity will occur, and even lead to death. Timely treatment for burn patients is not only to save lives, but also to alleviate pain, promote wound healing and restore self-care ability as soon as possible[82]. Because of the particularity of burn wound, higher requirements are put forward for covering materials[83,84]. The early treatment of burn wound is mainly through debridement and external application to prevent infection, promote cell migration, proliferation and differentiation, and repair the epidermis[85]. The biggest disadvantage of traditional dressing is that the necrotic scab of the wound adheres to the dressing, which is easy to cause secondary injury and aggravate the pain of patients when the dressing is removed[86,87]. The new dressing based on chitosan has good biocompatibility, non-irritation, coagulability, and can inhibit the excessive proliferation of fibroblasts[88,89].
In 2017, Massand et al., in order to solve the problem that the traditional burn dressing showed a bad tendency to shrink when wet and could not maintain its integrity during manipulation, tried to use a chitosan hydrocolloid dressing with silver sulfadiazine and carboxymethyl fiber bundles as the main raw materials to observe the clinical characteristics and healing ability of burn wounds in pediatric centers[87]. A sample of 12 patients with partial burns, with an average proportion of burns to total body surface area (TBSA) of 6.8%, involving the trunk and extremities, were treated with chitosan-based silver-loaded hydrocolloid dressings. It was found that the wound healed mostly or completely in an average of 3 days. The dressing maintains its size when wet and its integrity when removed. No burns were found to be infected at any time during the study. Based on the results of this pilot study, chitosan-based dressings warrant further investigation as an alternative to conventional burn dressings.

4.3 Application in inferior vena cava injury

Inferior vena cava injury is a rare complication of laparoscopic surgery, but it is highly lethal. According to incomplete statistics, the mortality rate during operation is as high as 31.8%, and 30% of postoperative deaths are due to multiple organ failure and other causes[90]. Because the inferior vena cava is directly connected to the heart, it is the thickest and largest vein in the human body. Once it is injured during the operation, it will bleed heavily. Whether it has a dressing that can stop bleeding quickly is the main factor to reduce the mortality rate of inferior vena cava trauma.
Xie et al. Attempted to use chitosan-based hemostatic gauze for the treatment of inferior vena cava injury during laparoscopic surgery[91]. A circumferential incision of 5 to 30 mm was created in the inferior vena cava of four domestic pigs and repaired laparoscopically with this hemostatic gauze. Animals were killed 2 min and 4 weeks after surgery for histopathological analysis. The results showed that all IVC injuries were successfully repaired by laparoscopy with single chitosan dressing without recurrent bleeding. The mean operation time was 55 min, and the blood loss was about 1 mL. There was no evidence of clot formation in the repaired vessel. Histology showed that the chitosan-based hemostatic gauze partially degenerated into small particles with a moderate chronic inflammatory reaction 4 weeks after repair. Therefore, chitosan-based hemostatic dressings are a simple and reliable technique for the control of severe bleeding from IVC injury during laparoscopic surgery.
In 2022, Sun et al. Prepared chitosan/microparticle rapamycin-based hemostatic gel to treat inferior vena cava injury in rats[92]. They used a rat model of inferior vena cava patch venoplasty to take scanning electron microscopy photographs and measure water contact angles. Patches were harvested on day 14 for immunohistochemistry and immunofluorescence. There were fewer proliferating cell nuclear antigen-positive cells and fewer macrophages than in the control group. The results showed that the chitosan-based gel dressing with dual anticoagulant and antiproliferative functions could effectively inhibit neointimal hyperplasia of inferior vena cava and play a good hemostatic effect. Therefore, chitosan-based hemostatic dressing is a simple and reliable technique to control severe bleeding from IVC injury during laparoscopic surgery.

4.4 Application of endoscopic sinus surgery

Sinusitis is a common disease with clinical manifestations of nasal obstruction, headache, dysosmia and other symptoms. Its etiology is complex and difficult to cure. Relevant studies have shown that the incidence of chronic sinusitis accounts for the eighth place in chronic diseases, seriously affecting the quality of life of patients[93,94][95]. Endoscopic sinus surgery is a commonly used medical method, which can effectively remove the diseased tissue of patients and restore the normal physiological function of paranasal sinuses[96]. However, because the nasal cavity is close to the skull and orbit, patients may have intracranial complications such as meningitis and cerebrospinal fluid rhinorrhea, or orbital complications such as periorbital congestion and orbital hematoma after endoscopic sinus surgery. Because of the special location of bleeding, it is difficult for traditional medical dressings to achieve good hemostatic effect.
In 2017, Zhou et al. Conducted a randomized controlled trial on 268 patients in order to confirm that chitosan-based hydrogel dressings could be used for the recovery of endoscopic sinus surgery[97]. Overall, the hydrogel dressing significantly reduced adhesions and promoted hemostasis after endoscopic sinus surgery compared with the control intervention. Compared with the control intervention group, the chitosan-based hydrogel dressing significantly reduced edema and infection, improved hemostasis, and had no effect on granuloma, mucosal edema, and crusting.

5 Summary and Prospect

Chitosan-based dressing, as an efficient dressing, has become a hot area of concern in recent years, and has made important achievements in basic and applied research.Including the proposal of moist healing theory, the exploration of hemostatic and bacteriostatic mechanisms of chitosan, the preparation and characterization of different types of new chitosan-based dressings, and their specific applications in wound healing. At present, scientists have begun to explore the preparation of new dressings based on chitosan: to improve the effect of new dressings by adding new substances, changing the structure of chitosan or delivering drugs through chitosan microspheres.Especially after adding oxidized carboxymethyl cellulose, cellulose nanofibers, hemp oil and other substances, the effect of sterilization and hemostasis has been significantly improved.
Chitosan can be widely used in medical dressings, nano-drugs, drug delivery, artificial skin, ultrafine fibers and antibacterial drug films because of its excellent hemostasis, permeability, fibrogenicity and biocompatibility. In terms of drug delivery, various preparation methods of drug-loaded microspheres, such as spray drying, emulsion crosslinking and ionic crosslinking, also provide new choices for the raw materials of chitosan dressings. In 2019, Zhou et al. Developed chitosan microspheres of levofloxacin as a sustained-release drug for ophthalmic infections, showing great potential in the biomedical field[98].
However, the new dressings based on chitosan still face a series of challenges: (1) Some new dressings based on chitosan are greatly affected by external conditions in the preparation process, such as temperature, pH, reagent types and stirring rate, and how to accurately control the best external conditions and raw materials to achieve better results needs further exploration by researchers. (2) Due to the wet healing theory, the new dressings based on chitosan are mainly wet dressings, but because of the particularity of the liquid, it is not suitable for long-term dry and muggy environment.Therefore, it is necessary to select and develop more heat-resistant raw materials, study new polymerization methods to construct new polymer materials with new structures and new properties, reduce the difficulty of their preservation, and reduce the evaporation of water. (3) At present, the new dressing based on chitosan is not highly recognized, and even some doctors and nurses do not understand it. In 2007, Longtai Medical successfully developed hydrocolloid, becoming the first enterprise in Asia that can independently develop hydrocolloid. However, 80% of the company's new dressings are foreign trade, and the domestic sales are not ideal. In addition, the cost of the new dressings based on chitosan is much higher than that of traditional hemostatic dressings, which makes it difficult for them to appear in the public eye. Therefore, in order to make the new dressing based on chitosan gradually mature, it needs to be recognized by the public, prove its superior characteristics through theory and practice, and further reduce the production cost. (4) Chitosan was discovered as early as 1859, but in recent years, it has been analyzed by scientists, and many theories of coagulation mechanism have not been fully confirmed, so the research on new dressings based on chitosan is still in the preliminary stage, and more relevant personnel need to continue to explore.
Finally, it is expected that the new dressing based on chitosan will be recognized by the public as soon as possible. Based on the hemostatic and bacteriostatic mechanism of chitosan, the different effects of the new dressing based on chitosan in different environments will be compared unremittingly.And then explore the best preparation conditions, and expand its application in the fields of biomedicine and materials science, and provide new ideas and new directions for people's future choice.

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