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Carboxymethyl cellulose-based materials for infection control and

wound healing: A review

Vimala Kanikireddy, Kokkarachedu Varaprasad, Tippabattini

Jayaramudu, Chandrasekaran Karthikeyan, Rotimi Sadiku

PII: S0141-8130(20)33919-2
DOI: https://doi.org/10.1016/j.ijbiomac.2020.07.160
Reference: BIOMAC 16208

To appear in: International Journal of Biological Macromolecules

Received date: 15 April 2020

Revised date: 3 July 2020
Accepted date: 14 July 2020

Please cite this article as: V. Kanikireddy, K. Varaprasad, T. Jayaramudu, et al.,

Carboxymethyl cellulose-based materials for infection control and wound healing: A
review, International Journal of Biological Macromolecules (2020), https://doi.org/
10.1016/j.ijbiomac.2020.07.160

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© 2020 Published by Elsevier.

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Carboxymethyl cellulose-based materials for infection control

and wound healing: A review
Vimala Kanikireddya*, Kokkarachedu Varaprasadb*, Tippabattini Jayaramuduc,
Chandrasekaran Karthikeyanb, Rotimi Sadikud
a
Department of Chemistry, Osmania University, Hyderabad, 500 007, Telangana, India
b
Centro de Investigaciòn dePolìmeros Avanzados (CIPA), Edificio de Laboratorios, Avenida
Collao 1202, Concepciòn, Chile
c
Laboratory of Materials Science, Instituto de Química de Recursos Naturales, Universidad
deTalca, 747, Talca, Chile
d
Institute of NanoEngineering Research (INER), Department of Chemical, Metallurgical &

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Materials Engineering (Polymer Division), Tshwane University of Technology,
Pretoria West Campus, Staatsarillerie Rd, Pretoria, 1083, South Africa

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* Corresponding author: prasad@cipachile.cl, varmaindian@gmail.com
Abstract:
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The development of ideal wound dressing materials with excellent characteristics is currently
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a major demand in wound therapy. In recent years, carboxymethyl cellulose (CMC)-based
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wound dressing materials have been of immense attraction due to their noble properties, such

as: biocompatibility, biodegradability, tissue resembling, low cost and non-toxic. It is used
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extensively, in a variety of applications in the biomedical and pharmaceutical fields. The

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hydrophilic nature of CMC, makes it possible to blend and cross-link with other materials,

such as: synthetic polymers, natural polymers and inorganic materials and it enables the
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preparation of innovative wound dressing biomaterials. Hence, this review, focuses on the

intrinsic characteristics of CMC-based wound dressing materials, including hydrogels, films,

3D printing, fibres, gauzes and their recent advancements in chronic wound healing.

Keywords: Carboxymethyl cellulose, Wound dressing, Biomedical, Antimicrobial

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Contents
1. Introduction ........................................................................................................................ 3
1.1. Carboxymethyl cellulose (CMC) synthesis and applications ..................................... 4
2. Characteristics of an ideal wound dressing materials ......................................................... 7
3. CMC based wound dressing biomaterials .......................................................................... 8
3.1. CMC Hydrogels .......................................................................................................... 9
3.2. CMC films ................................................................................................................. 12
3.3. CMC fibres, Gauzes and Wafers ............................................................................... 13
3.4. CMC Nanoparticles ................................................................................................... 15

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3.5. Salt CMC derivatives ................................................................................................ 16
3.6. CMC in 3D bio-printing ............................................................................................ 17

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3.7. CMC-based antimicrobials materials ........................................................................ 19
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4. CMC-based drug delivery systems for wound infections ................................................ 24
5. CMC materials for chronic wounds.................................................................................. 24
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5.1. Ulcer Wounds ............................................................................................................ 25
5.2. Burn Wounds............................................................................................................. 26
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6. CMC-based systems in the wound healing process.......................................................... 28

7. Commercially available CMC wound dressing materials ................................................ 31
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8. Conclusion and future prospects....................................................................................... 32

9. Acknowledgements .......................................................................................................... 33
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10. References ..................................................................................................................... 34

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1. Introduction

A wound is a type of injury that occurs following the breakage of alignment of body cells due

to the external violence. Many of the chronic wounds, which can occur by accidents, burns,

trauma and diseases, affect public life and the economy [1]. Chronic non-healing wounds, not

only affect the quality of life, but can have an attendant huge financial burden to the society

(e.g., healthcare cost, productivity loss), owing to pain and inability to perform daily living

activities [1,2]. For instance, the incidence of chronic non-healing wounds, such as: diabetic,

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ulcers, continues to increase and they have become a serious problem in the medical field,

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since approximately 20% of diabetic scars are likely to develop into chronic non-healing foot

wounds [1,2]. In addition, wound care is an enormous concern to countries’ economies.

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Recent studies reported that ~2% of US citizens, annually suffer from chronic wounds and
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such sufferers spend, between $28.1 billion-$96.8 billion US dollars in order to cure such
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wounds [3]. Therefore, there is a growing interest to develop better wound care materials,

which can support faster healing and low cost.

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In general, wound healing process involves four phases, i.e., Hemostasis, Inflammation,
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Proliferation and Maturation. Hemostatic phase is the first phase of the injury and the primary
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objective is to stop bleeding. In the inflammatory phase, there is the need to destroy the

bacteria and create a wound bed. Proliferative phase needs to fill the wound and cover the

wound and in the maturation phase, there is a slow collagen fibers regeneration and the tissue

fibre gains strength. However, wound healing process depends on several factors, i.e.,

moisture, infection, age and body type. Kim et. al., [4] prepared a nonwoven calcium

carboxymethyl cellulose/chitosan blend as hemostatic agents. Similarly, Basu et. al., [5]

prepared carboxymethyl cellulose-based films with full thickness, for normal and chronic

wound healing applications. The films showed excellent hemolytic and cytocompatibility

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with fibroblast cells, which enhanced the efficiency of wound healing process, in normal and

diabetic rats, for wound closure and tissue regeneration.

Wound dressing materials play crucial roles, which include the protection and fast-cure of the

wound. However, the process of wound curing involves three steps, viz: i) washing of wound,

ii) applying dressings and iii) bandaging the wound [6]. In ancient times, honey, resins, gums

and herbal extracts, were used in wound care applications. In the middle of the 19th century, a

large number of textile fibres and gauges with different structures (knitted, non-woven and

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composites), were developed and used as traditional wound dressing materials. Later on,

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Winter et. al., revealed that by keeping the wound environment moist, it would enhance the

healing and fast-curing of the wound when compared to keeping the wound environment dry
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[7]. In recent years, cell culture and cell biology greatly expanded and a better understanding
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of the biological processes and tissue regeneration in the wound healing process, emerged
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[8]. In addition, great interest has been growing in the development of new wound care

products, which incorporate the latest understandings that are involved in the dynamic and
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complex process of wound healing [2]. The main goal of the innovations is to reduce the
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wound healing time periods, resolve the chronic wound healing problems and render some

relief from severe pain [2].

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1.1. Carboxymethyl cellulose (CMC) synthesis and applications

Recently, biopolymer-based wound dressing materials have drawn some critical attention due

to their biocompatibility, biodegradability, non-toxicity and their cost-effectiveness.

Especially so, CMC based wound dressing materials are very attractive due to their

physicochemical properties. CMC is a one of the most important polysaccharides and it is a

chemical modification of cellulose. In their chemical structure, the carboxymethyl groups (-

CH2-COOH) are bound to the hydroxyl groups of the glucopyranose chain of cellulose.

According to the Williamson ether synthesis, the preparation of CMC consists of two steps,

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i.e., i) Alkali cellulose treatment and ii) Esterification reaction. Firstly, cellulose is treated

with sodium hydroxide, which leads to activated alkali cellulose and then this is reacted with

monochloroacetic acid [9]. In this step, the carboxymethyl groups are substituted to cellulose

molecules in the place of three hydroxyl groups and the degree of substitution, varying

between 0.4-1.5 [9,10]. Due to this degree of substitution, the CMC is available with different

molecular weights, ranging between 90,000-2,000,000 g/mol [10]. Figure 1 shows the

synthesis reaction and the chemical structure of CMC.

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Figure 1. Synthesis and chemical structure of CMC
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Concerning their potential applications, CMC have been explored in different

applications and this is exemplified in Figure 2. Among these applications, CMC has been
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widely used in pharmaceuticals (drug delivery, antimicrobial) and biomedical (wound

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dressing) applications [2]. In addition, CMC wound dressings are recognized for being

flexible, capable of absorbing exudate, promoting angiogenesis and autolytic debridement.

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To the extent that CMC is non-toxic to humans, water-soluble and it is also abundant in

nature [1]. It has served as the basis for many medications and materials implanted or

installed in the human body. Owing to these advantages CMC-based biomaterials (hydrogels,

films, nanocomposites) are widely used for wound dressing and drug delivery applications

[5,10–12]. Liuyun et. al., prepared and studied the biological properties of a novel composite

scaffold of nano-hydroxyapatite/chitosan/CMC for bone tissue engineering [13]. The

compressive strength of n-HA/CS/CMC scaffold was tested by using a universal testing

machine. The wide range of applications of CMC, include: chronic wound healing (foot

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ulcers, diabetic) and acute wound healing, such as: abrasion, first and second-degree burns

[6]. AquaRite and Extra CMC™ are soft, non-woven, highly absorbent CMC-based wound

dressings and are currently available in the market [14].

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Figure 2. Various applications of CMC

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Pristine CMC can be used for wound healing and skin regeneration applications due to CMC

physiological properties, such as: non-toxicity and compatibility with mucous membrane,

bone and skin [5,15]. Furthermore, it can maintain a moist environment at the wound

surrounding areas, which will help in the growth of extracellular matrix and re-

epithelialization. However, there is not enough evidence on the application of pristine CMC

to treat chronic wounds, such as: diabetes and diabetic foot ulcers. Recently, Wong et. al.,

developed non-crosslinked and without antibacterial agent-based CMC films, for bacterial

wound infection control and healing applications. However, the films developed have high

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degradation rate and needed to be changed every 6 h [10]. Similarly, Poulami et. al.,

developed CMC and poly(ethylene glycol) blended films for wound healing of full-thickness

wounds in normal and diabetic rats. They suggested that the material prepared was used as a

template for tissue regeneration in skin tissue engineering application. However, most of the

available products are not clinically accepted due to the limitations of their physicochemical

characteristics. Therefore, the fabrication of bioactive wound dressing materials play

important role in wound healing applications and they should have the capacity of

biomolecules (antibiotics and growth factors) delivery. Subsequently, the combination of

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antibacterial agents with delivery systems is required to control and prolong the release of

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bioactive molecules (antibacterial agents) in order to prevent wound infected area during the
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healing process.
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In the literature, there are several reports available on antibacterial agents e.g., organic and
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inorganic-based materials for wound dressing applications [16]. Amongst, these inorganic

materials, metal nanoparticles have been broadly studied for wound dressing applications due
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to their physicochemical properties [17–19]. It is worth noting that metal nanoparticles,

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showed excellent antibacterial activities against human pathogens [18–21]. However, the

combination of metal nanoparticle with biopolymers can tune the chemical and medical
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properties of the starting material, which improved the applicability of clinical applications.

However, the present review delivers on wide-ranging information on CMC-based wound

dressings, such as: hydrogels, films, 3D printing, fibres, gauzes, antimicrobials and it also

discusses the current advancements in chronic wound healing.

2. Characteristics of an ideal wound dressing materials

Ideal wound dressing material requirements, are: i) ability to provide a moist environment

and promote wound healing, ii) capable of absorbing excess fluids and enhance epidermal

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migration, iii) promotes wound healing, iv) provides mechanical protection, v) good

antimicrobial properties, vi) good gaseous exchange, vii) not to adhere to the wound and viii)

must be cost-effective [6]. Moisture vapour transmission rate and permeability of gases play

important roles in the wound healing process. High transition rate wound, becomes too dry

and delays the healing process. Low, excess exudate can lead to infections of wounds. Hence,

maintaining the optimal wound dressing conditions are necessary for ideal wound dressing

materials [22].

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In recent studies, CMC-based materials have been actively studied in wound dressing

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technology due to their high ability to absorb the exudates and maintaining the optimum

conditions. However, CMC has been used in the preparation of ideal wound dressing
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materials owing to low-cost, biocompatibility, biodegradability, low toxicity, non-
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immunogenicity and amiable processes and good film-forming capacity. Additionally, it can
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activate macrophages and increase cytokine levels in wounds [23].

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3. CMC based wound dressing biomaterials

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CMC (known as carmellose) has good binding capacity to ocular surface cells, excellent

compatibility with mucous membrane, bone, skin and capability to blend with other water-
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soluble polymers, e.g., poly(ethylene glycol) and poly(vinyl alcohol) [24,25]. In addition, it

has strong hydrophilicity (due to the hydroxyl and carboxyl groups) and it has a stable

internal network structure [26,27]. Therefore, it has been reported to improve wound dressing

materials characteristics in clinical applications. Namazi et. al., [15] prepared antibiotic-

loaded carboxymethyl cellulose/MCM-41 nanocomposite hydrogel films, as potential wound

dressing products. Likewise, Paladini et. al., prepared antimicrobial cotton gauzes for the

prevention of wound infections [28]. Oliveira et. al., prepared PVA-Na CMC hydrogels for

Propolis drug delivery to wounds [29]. The hydrogels developed showed good mechanical

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strength, high water uptake, flexibility and of course, the good antimicrobial characteristics of

Propolis. Fig. 3 shows the various types of CMC-based wound dressing materials.

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Figure 3. CMC-based wound dressing materials A) Hydrogels [12], B) Fibers [30], C)
Gauzes [31], D) Nanoparticles [32], E) Wafers [33] and F) Films [1]
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3.1. CMC Hydrogels

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Hydrogels are three-dimensional structures hydrophilic in nature, which are formed by

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crosslinking of polymeric materials and they can hold large amount of water in their networks

[34,35]. The high water-absorbing capacity and tissue-like structure, make them ideal
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materials for wound dressing and drug delivery applications [36]. An ideal wound dressing
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agent, protects the wound against external contamination, reduces the healing process time

and decreases scar formation [6]. CMC-based hydrogels help to heal wounds because they

maintain moist environment at the wound surrounding area, which helps in the proliferation

and migration of fibroblast and keratinocytes. Furthermore, the moisture could serve to

accentuate cell growth, enzymes, growth factors and hormone. Moreover, these hydrogels

provide superior characteristics that are autolytic debridement of slough and necrotic tissue

and they do not allow bacteria growth.

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Generally, CMC-based hydrogels were prepared via chemical-crosslinking or physical-

crosslinking techniques, as agents for wound dressing applications [37]. Saputra et. al.,

prepared CMC hydrogels from water hyacinth with silver nanoparticles by using citric acid

crosslinker for antimicrobial activity [38]. Capanema et. al., developed carboxymethyl

cellulose–PEG superabsorbent hydrogels, through chemical crosslinking technique by using

the citric acid. The materials prepared were kept at 80±2 oC for 24 h in order to obtain good

level of crosslinks. During, this step, an esterification reaction was made possible between the

hydroxyl groups and acid groups of the citric acid by elimination of water molecules. The

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materials developed showed high absorption capacity and it was suggested that they can be

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used as the next generation skin substitutes for the treatment of chronic wounds [12]. Fekete
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et. al., synthesized CMC-starch based crosslinking hydrogels, which was achieved by gamma
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irradiation without the use of any crosslinking agents or other additives. The hydrogels

prepared could offer a cheaper, superior alternative when compared to pure cellulose
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derivative-based gels. The radiation generates free radicals in both CMC and starch, which
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leads to chemical crosslinking, instead of degradation [39]. Likewise, Sunaryono et. al.,

reported on CMC-PVA matrix ferrogel-based hydrogel in order to achieve an artificial

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muscle [40]. Mishra et. al., [41] prepared CMC/PVA/gelatin and crosslinked it with
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polyacrylamide (PAM) hydrogels and loaded with povidone-iodine drug for wound dressing

applications [42]. Bayindir Bilgic et. al., developed α-tocopherol-loaded CMC/chitosan

hydrogels via the free-radical polymerization method for wound dressing applications [43].

The authors reported the non-toxicity of α-tocopherol-loaded CMC/chitosan on L929

fibroblast cell (cytotoxicity analysis, according to ISO 10,993-5 standards). Besides, this

hydrogel is believed to be capable of promoting wound healing, by enhancing cell

proliferation.

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For wound applications, an ideal wound dressing materials with suitable pore size,

transmittance, mechanical property, a simple preparation technology and biocompatibility,

are challenges to be considered. Recently, Li and co-workers formulated porous sponge-like

PVA-CMC-PEG hydrogels with pH sensitivity by using the simple phase separation/a one-

step thawing-freezing method without adding any toxic chemicals for wound dressing

[13,44]. The authors explained that the porous size of the materials was controlled by the

varying, of the PVA concentration. The cytotoxicity test showed that the hydrogel developed

was non-toxic on L929 cells growth and the full-thickness skin defect experiment, illustrated

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the fact that hydrogel greatly promoted the wound healing process. In addition, a bi-layer

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hydrogel, has good mechanical properties, suitable water vapor permeability, bacteria
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resistance ability and low adhesion to wound. Therefore, this porous hydrogel has an
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effective wound dressing characteristics, making it suitable for use in clinical applications.
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Overall, CMC has been used for the development of bioactive hydrogels by employing

several methods in order to enhance their applicability in wound dressing. In 1989, several
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hydrogels were prepared and sterilized by using radiation method [45]. From this method,
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several commercial wound dressing hydrogels, such as: Vigilon, Ivalon, Aqua gel and Kik

gel, Burn caring, P-Chitosan and Hiezel, were produced [45]. Recently, Lima et. al.,
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fabricated polyvinylpyrrolidone/CMC/agar hydrogel with silver nanoparticles for wound

healing applications [46]. In this work, the hydrogels were developed by using gamma

irradiation technique, which can improve the antibacterial properties of the dressings.

Hydrogel does not has a sign of toxicity and in-vivo results explained that silver hydrogel

composite can rapidly heal rabbit wounds.

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3.2. CMC films

Among the biodegradable films, CMC-based films are the most promising for antimicrobial,

wound dressing and other (e.g. food packaging) applications, due to their water-soluble, film-

forming and hydrocolloidal behaviours [47]. Usually, the CMC-based films were developed

by the solution casting method [48,49]. Briefly, certain amounts of polymers were dissolved

in solvents (distilled water) under stirring conditions. After obtaining the homogeneous

solution, depending on the requirement, different materials, such as: other polymers for

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making blend films, cross-linkers and plasticizers were added, with constant stirring

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conditions. Thereafter, the solution was poured into a petridish and dried at the desired

temperature [49]. Tufan et. al., prepared and characterized CMC films, which were
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synthesized from sunflower stalk [50]. Previous studies reported that CMC and
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polysaccharide blend films exhibited a strong barrier against gases and lipids and outstanding
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mechanical properties. Additionally, cellulose and their derivatives were used as

reinforcement materials in composites of polymer matrix. They enhanced the mechanical,

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barrier and thermal properties of the film [51]. Li et. al., developed some edible, eco-
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friendly, mechanically strong CMC films, incorporated with chitin nanofibres extracted from

crab shells as reinforcing and antimicrobial agent that can be used for active food packaging
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applications [11]. Likewise, Basu and his group, fabricated CMC/PEG blend films as wound

dressing materials for full-thickness normal and chronic (diabetic) wound healing [5]. Lan et.

al., prepared some novel food packaging materials with CMC/SA/CS composite film, by the

casting method and the films produced, exhibited very advantageous mechanical strength and

good antibacterial rate against E.coli and S.aureus [27]. Recently, Azarifar et. al., optimized

gelatin-CMC-based nanocomposite films containing chitin nanofiber and Trachyspermum

Ammi essential oil by response surface methodology [48]. Similarly, Abdollahi developed

CMC–agar biocomposite films with summer savoury essential oil as an antimicrobial agent

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and the results showed maximum antimicrobial properties on gram-positive bacteria [26].

They concluded that by using savory essential oil in the films, water vapor permeability and

antibacterial property, were increased and hence, reduced the water barrier properties and

tensile strength of the films. However, the search to develop ideal materials, is still a

challenging issue and there is, need to investigate and improve biomaterials characteristics

that are essential in healthcare.

3.3. CMC fibres, Gauzes and Wafers

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Wound healing is a complex and dynamic process, which involves so many phases. The

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selection of a wound dressing material depends on the type of wounds and the stage of the

healing process. Wounds with excess fluids require high absorptive dressings and also still
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maintain the appropriate moisture in order to promote fast healing. Fibres and gauzes are very
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significant materials in wound care. They have high absorbency, are non-adherent, can be cut
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and used according to the sizes of the wounds in the wound beds and they have low infection

rates. Non-woven fabrics are more advantageous because of their characteristics, such as:
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high fluid absorption, porosity, lightweight and flexibility [52]. Lately, Liu et al group
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prepared CMC hydrogel fibers with aluminium sulphate cross-linker, via a solution spinning

method [44]. The CMC hydrogel fibres obtained, had excellent moisture absorption capacity,
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making them well-suited for wound dressing applications. CMC viscose non-woven fibres

with high absorbency and moist conditions that showed good vapour permeability, were

successfully synthesized in an aqueous medium. They can be used as high performance and

low-cost medical dressings [53]. Zhao et. al., developed carboxymethyl cotton knitted fabrics

for wound dressings with different solvents, such as: water, ethanol-water and isopropanol-

water [54]. They found out that isopropanol-water is the best solvent to prepare

carboxymethyl cotton fabrics. These outcomes play a significant role on a large scale in the

industry, especially for the preparation of CMC dressing.

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Similarly, gauzes also have several advantages, such as in the maintenance of moisture

environment, reduction of blood loss, promotion and protection from dirt and bacteria, in

wound healing. It is the most important component in first aid kit and serves certain

functions, e.g., pads before bandaging the wound. Xue et. al., (2016) fabricated CMC gauze

inserted in AgNPs for antibacterial wound dressing [55]. AgNPs were formed on the surface

of the gauze, which exhibited strong antimicrobial activity that promoted wound healing.

SUNTOUGH topical hemostatic gauze is a sodium carboxymethyl cellulose gauze, currently

available in the market. It has unique properties, such as: soft, very easy to use, immediate

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hemostatic nature and the maintenance of moist healing environments [56]. Wu et. al.

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developed silver nanoparticles/carboxymethylated cotton gauze via carboxymethylation
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process [31]. In this process, in order to obtain small size (5-20 nm) nanoparticles, they used
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polyvinylpyrrolidone as a reducing agent. Due to this modification, they improved water

absorption capacity, exceeding 2000% of the initial value of the Ag/carboxymethylated gauze
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(0.4% w/v) and it did not show any cytotoxic tendency on L929 cells. In addition, they did
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wound healing studies on rabbit model and their studies explained the fact that silver

nanoparticles/carboxymethylated (0.4% w/v), showed a complete wound healing capacity

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within 15 days, on a rabbit model.

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In recent times, Platelet-rich plasma was used in wound healing due to their platelet-rich

content that helps in the acceleration of tissue regeneration. However, due to their short

biological half-life, their utility is decreased. In order to solve this concern, Yassin et. al.,

(2019) formulated CMC-based platelet-rich plasma wafers by using the lyophilisation process

[57]. Lyophilized CMC wafers were prepared in order to improve the platelet-rich plasma

stability, which can help in the acceleration of wound healing. In this work, in-vivo wound

test, explained the fact that the platelet-rich plasma-based CMC-wafers, completely healed

wound within 10 days and histopathological test also clarified the fact that the platelet-rich

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plasma-based CMC-wafers healed wounds, faster than the neat CMC-wafers. Chen et. al.,

prepared haemostatic sponges from CMC and N-acryloyl-2-glycine by the thermos-initiation

polymerization process [33]. In this polymerization, CMC and N-acryloyl-2-glycine were

bonded via hydrogen bonding, which can strength the sponge. CMC mainly, can stabilize the

air bubbles during the thermos-initiation polymerization process. In conclusion, they stated

that the CMC-based sponge developed, can reduce the bleeding time and blood loss when

compared with gauze and the commercial gelation sponges, due to the high blood absorption

capacity and the concentration influence of blood coagulation factors. Lately, Shabnam et.

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al., prepared CMC-based wafers incorporated with resveratrol (RSV)-loaded cellulose acetate

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butyrate (CAB) NPs. The RSV-CAB NPs were synthesized by using the solvent evaporation
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technique and the reaction parameters (polymer content, surfactant concentration and W/O
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volume ratio) were optimized according to the Box-Behnken design. They suggested that the

optimum condition for the CAB polymer content, is 20 mg, PVA surfactant is 1.8% and the
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W/O volume ratio of 7. Then, the formulated NPs were successfully incorporated into the
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CMC and their blend wafers (CMC-HPMC and CMC-chitosan). Finally, they concluded that

the CMC-HPMC wafer showed superior wound healing activity than the CMC and CMC-
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chitosan, in terms of porosity, hydration capacity and adhesive strength [58]. These wafers
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have the capability to uptake wound fluids and guard the moisture environment in order to

promote wound healing. Overall, wafers offer an effective pharmaceutical delivery system,

for the platelet-rich plasma to target the wound sites.

3.4. CMC Nanoparticles

Since the last decade, CMC has been used for the modification of nanoparticles. In addition,

CMC-based nanoparticles are widely used in biomedical applications. The carboxylate ions

in the CMC chain, permit the physical adsorption of nanoparticles on the surface, which

yields better, stable and water-soluble targeted nanoparticles [59]. Aguilera et al developed

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CMC-coated magnetic nanoparticles that are targeted, specifically, for drug delivery in order

to treat neurological disorders through the human lung microvascular endothelial cell model

of the blood-brain barrier [60]. In addition, Kawasaki et al prepared a mixed film of chitosan

and CMC nanofibers and they reported that the fibres obtained were tough enough to protect

a substrate from non-specific cell adhesion and that the resulting complex of chitosan and

CMC nanofibers are promising, as functional biomaterials [61]. Liu et al prepared CMC-

Ursolic acid/hydroxycamptothecin nanoparticles by a nanoprecipitation method for anti-

cancer combination therapy [62]. The resulting polymer nanoparticles exhibited a higher

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drug-loading capacity and eliminated bulk tumor growth in a 4T1 orthotopic tumor murine

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mode. Garza-Navarro et al prepared AgNPs from polysaccharides, which is an eco-friendly
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process [63]. CMC was used as a reducing and stabilizing media, which is an
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environmentally benign method and it is industrially scalable for bulk production of AgNPs.

Koneru et. al., developed grapefruit seed extract, incorporated in sodium

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CMC/hydroxypropyl methylcellulose materials via the solution casting method, for potential
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wound healing applications. In the hydrogel matrix, the grapefruit seed extract (GFSE),

created micelles nanoparticles. It believed that it was formed due to the presence of
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hydrophobic glycerides in GFSE with NaCMC. Furthermore, these glycerides create polymer
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aggregation and this was confirmed from the FETEM analysis. The materials developed were

studied for their antimicrobial activities and these studies showed an excellent activity on

gram-negative bacteria than that of the gram-positive bacteria. Finally, they concluded that

they could be useful in wound healing and drug delivery applications [32].

3.5. Salt CMC derivatives

CMC derivatives, such as: sodium carboxymethyl cellulose (Na-CMC) and calcium

carboxymethyl cellulose (Ca-CMC) were also used as wound dressing materials and for drug

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delivery applications. Na-CMC displays a high film-forming capacity with excellent

compatibility with the human skin [64]. Wong et. al., prepared Na-CMC films in order to

investigate their antimicrobial activity and wound-healing capacity and their study, proved

that Na-CMC films can effectively remove the microbes from wound beds through a polymer

microbe adhesion and hence, promote wound healing [10]. Unlike Na-CMC, Ca-CMC is not

completely soluble in water, however, it swells in water several times their original volume.

In here, the ions can increase the blood viscosity and enhance coagulation through platelet

aggregation. Therefore, the calcium-based wound dressing materials could amplify the blood

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clotting and works as a hemostatic agent [4]. Ospanova et. al., prepared chitosan and Na-

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CMC thin films on triclosan, chlorhexidine, silver ions and iodine plates as potential
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antibacterial agents for medical and biological implants. The results obtained, confirmed the
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fact that the multilayer on silicon plates, exhibited good antimicrobial activity [65]. Namazi

et. al., prepared a CMC hydrogel, which incorporated silica MCM-41 nanocomposites [66].
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Their results demonstrated the fact that CMC/MCM-41 hydrogel films showed good
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antimicrobial activity and can be beneficial for wound healing.

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3.6. CMC in 3D bio-printing

In recent years, there have been worldwide demands for organ and tissue regenerations. 3D
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bioprinting is an emerging technology to mimic a 3D functional live tissue scaffold for tissue

engineering and wound therapy [67]. Bioink is the main component needed to fabricate 3D

structures of functional organs or tissues. Bioink contains live cells and biomaterial, which

can fabricate 3D tissue structures [68]. Cellulose and their derivatives are potential materials

needed for 3D bio-printing structures due to their biocompatibility and good mechanical

strength. Habib et. al., prepared alginate-carboxymethyl cellulose 3D bioprinting hydrogel in

order to fabricate large scale tissue scaffolds and they concluded that these hydrogels are

potential biomaterials that can be used in 3D processes [69]. Aizada et. al., studied the novel

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3-D scaffolds, filled with CMC hydrogel and examined the anti-proliferative activity of

Centella asiatica leaves extract [70]. Gopinathan and Noh reviewed the recent trends in

bioinks for 3D printing [71], while Sultan et. al., reviewed the 3D printing of nanocellulosic

inks and their recent research developments for biomedical applications [68]. Markstedt et.

al., reported on a novel bioink, composed of nanocellulose and alginate 3D bioprint human

chondrocytes for cartilage tissue engineering applications [72]. Kageyama et. al., examined

the in-situ cross-linkable gelatin-CMC hydrogels, used to fabricate perfusable vasculatures

[73]. Ávila et. al., prepared 3D bioprinting of human chondrocyte-laden nanocellulose

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hydrogels for patient-specific auricular cartilage regeneration [74]. Recently, Maver et. al.,

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employed alginate and CMC biopolymers for the development of wound dressing materials
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by using a spin-assisted layer-by-layer coating process [75]. They used, in principle, the films
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produced for the delivery of analgesic (diclofenac and lidocaine) drugs. They reported the

fact that it was necessary to investigate the cytotoxicity characters of the films on human skin
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cells in order to utilise the products for wound dressing applications. In addition to the results
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obtained, they used the product for the development of real wound dressing materials via the

three-dimensional (3D) bioprinting processes. Maver et al (2018) prepared CMC-based

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scaffold with stable porosity by using the 3D printing and electrospinning methods for
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potential clinical application in the alleviation of pain in wound care [76]. In this scaffold,

they loaded pain killer drug, such as: nonsteroidal anti-inflammatory diclofenac sodium and it

was combined to anesthetics lidocaine drug (LID) filled CMC/PEO material (via

electrospinning) as a first layer to contact the wound site. In this combination the 3D printed

layer enhanced the drug-releasing and could be prolonged pain relief until the change of the

dressing material after approximately 2 days. Fig. 4 shows the combined release profiles of

the CMC/PEO/LID (first layer) and ALG/CMC/DCS (second layer) [76]. However, several

biomaterials have been printed by using the 3D bioprinting methods. The resulting

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biomaterial structures, are static, inanimate and unable to transform with dynamic changes in

the internal environment of the body [77]. In order to overcome this problem, a four-

dimensional (4D) printing method was implemented as an option, suitable for biomaterials

for the regeneration process of human tissues [78]. Lately, Oladapo et. al., used CMC in

order to prepare a nanostructured hydrogel composite by the four-dimensional (4D) printing

method [79]. However, the 3D and 4D printing technologies need to be simple enough to use

on biopolymer for wound dressing application.

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Figure 4. A) CMC-based wound dressing material, prepared by 3D printing and

electrospinning method and B) Combined release profiles of CMC/PEO/LID (first layer) and
ALG/CMC/DCS (second layer) [76]
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3.7. CMC-based antimicrobials materials

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CMC is a very important derivative of cellulose; it is nontoxic and has high chemical

stability. However, due to it poor antimicrobial activity and low mechanical strength, it does

not serve as an effective wound dressing agent. Hence, the combination of CMC hydrogels

and films with antimicrobial agents and drugs is essential to control and sustain the release of

antimicrobial agents that prevent bacterial growth in wounds and enhances the healing

efficiency [26]. Amongst the materials in such combination, are: metals and metal

nanoparticles with cellulose derivative combinations, which exhibit good antimicrobial

activity as well as good mechanical strength [41]. Rakhshaei et. al., (2017) developed

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bioactive wound dressing CMC/ZnO impregnated MCM-41 nanocomposite hydrogels [15].

The nanocomposite hydrogels prepared, showed excellent drug delivery efficiency and

antimicrobial activity against gram-positive Staphylococcus aureus and gram-negative

Escherichia coli. Lately, silver nanoparticles-based wound dressing materials are gaining

increased popularity due to their extensive antimicrobial effect against gram-positive, gram-

negative, fungi and viruses. Lustosa et. al. research group, synthesized silver nanoparticles in

CMC with cashew gum hydrogels in order to accelerate wound healing and antimicrobial

activity [80]. In addition, the anionic nature of CMC can lead to the preparation of a wide

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range of pH-sensitive hydrogels for drug delivery. Salama et al (2016) prepared CMC-grafted

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poly (dimethylaminoethyl methacrylate)/calcium phosphate, a three-dimensional hybrid
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materials, for sustained release of protein drugs [81]. They proved that these hybrids are
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capable of sustained release of bovine serum albumin (BSA) and that they are favourable

materials for bone tissue regeneration. Quadros, et al (2013) prepared chitosan/CMC/Ionic

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liquid/Ago nanoparticles with antimicrobial activity form a membrane [82]. The combination
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of CS/CMC/IL/Ago nanoparticles exhibits an excellent synergistic effect that demonstrates

high antimicrobial activity for Staphylococcus aureus and Escherichia coli bacteria. Table 1
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explains various CMC wound dressing products and their usage against different bacteria in
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wound dressing/healing applications.

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Table 1: CMC-based wound dressing material agents for different bacteria

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Name of the Materials Preparation Name of the Bacteria Applications References
technique
Pseudomonas aeruginosa, Staphylococcus
CMC films Solvent Casting aureus Wound dressing [10]

Silver nanoparticles, CMC In-situ Staphylococcus aureus and Escherichia Antimicrobial [55]
activity
CMC, reduced graphene oxide Solution mixing (Biofilms formation) Staphylococcus aureus Infected wounds [83]
(reduced 81-84%) and Pseudomonas
aeruginosa (50-62%)
o f
o
CMC, Silver nanoparticles Photoreduction Staphylococcus epidermidis and Candida Antimicrobial [84]

CMC, chitosan Freeze-drying

albicans

p r
Staphylococcus aureus and Escherichia coli
activity
Wound [85]
CMC (from Bamboo), Silver nanoparticles In-situ
e -
Escherichia coli, Bacillus subtilis Wound dressing [86]
CMC nanofibres–silver nanoparticles Electrospinning

P r
Escherichia coli and Staphylococcus aureus Antimicrobial
dressing
[87]

CMC, polyoxyethylene nanofiber, silver Electrospinning

nanoparticles
a l Escherichia coli Wound dressing [88]

CMC, Polylactic acid, Collagen boosters Spry

(maintain acidic environment at the wound
r n Staphylococcus aureus Wound dressing [89]

area)
CMC, chitosan
o u
Freeze-drying Escherichia coli In-vitro drug [90]

J delivery
antimicrobial
study
and

Tet-O-CMC nanoparticles, Tetracycline Staphylococcus aureus and Escherichia coli Post- [91]
loaded O-carboxymethyl chitosan freeze-drying surgical/traumatic
nanoparticles, wound dressing
CMC-ethanolic Eucalyptus camaldulensis Blending Streptococcus pyogenes, Pseudomonas Antimicrobial [92]
L. leaves extract aeruginosa and Staphylococcus epidermidis activity

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CMC- PVP hydrogels without and with Physical Staphylococcus aureus and Escherichia coli Wound dressing [93]
boric acid stimulation
technique
CMC, Mixed micelles solution of PEG-b- Electrostatic Escherichia coli and Staphylococcus aureus Wound dressing [94]
PCL and PCL-b-PHMG-b-PCL interactions
CMC, Clindamycin loaded human hair Freeze-drying Staphylococcus aureus Antibacterial [95]
keratin hydrogel wound dressing
CMC/ Polyurethane nanofibers containing Electrospinning
Malva sylvestris extract
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Escherichia coli, Staphylococcus aureus Diabetic wound
healing
[96]

CMC, PVA, Cu NPs Crosslinking

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Escherichia coli, Staphylococcus aureus Antibacterial
Wound Dressing
[97]

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n a
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4. CMC-based drug delivery systems for wound infections

Wound management has become more complicated due to increased and stubborn microbial

infections, which is a major public health issue [98]. Wounds are classified as acute and

chronic. Acute wounds are caused by traumas, which heals within a predicted time period (8-

12 weeks). In contrast, wounds can lead to chronic infections and associated diseases, such

as: diabetics, venous ulcers, etc. The healing time of chronic wounds can be prolonged for an

upward of 12 weeks or more [99]. In order to accelerate wound curing/healing as well as

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inhibit wound infections, antibiotics-loaded CMC materials are most important. The

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antimicrobial drug, loaded in CMC materials, has already proven, to prevent bacteria as well

as wound infections. Recently, Okoye et. al., (2015) developed the product, ciprofloxacin,
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inserted in gelatin and Na-CMC for wound dressing applications [99]. Ciprofloxacin was
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used as an antibiotic, which prevents gram-positive and gram-negative bacteria. Cai et. al.,
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(2015) prepared Na-CMC/chitosan sponge and investigated their drug loading as well as

antimicrobial activities [90]. Gentamicin (GEN), ibuprofen (IBU) and roxithromycin (ROX)
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are known and used as model drugs. They concluded that Gentamicin showed a superior
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inhibition of E.coli than the other two drugs. Similarly, Gupta et. al., (2014) [100] developed

PVA/PEO/CMC/aloe vera and PVA/PEO/CMC/curcumin-based wound dressing materials,

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loaded with Tetracycline hydrochloride (TC), as a model drug. The results demonstrated the

fact that the resultant wound dressings, showed superior antimicrobial activity against E.coli

and S. aureus and the drug diffusion on the wound bed prevented the wound from infections.

5. CMC materials for chronic wounds

The repair of a chronic wound is one of the most complex processes in human life. In

addition, is to stop fluid loss and the recovery of the skin from chronic wound infections,

which are challenging issues [12]. However, in order to control chronic wounds, several

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materials have been developed for clinical applications. Amongst them, CMC and their

derivative materials have their own importance, in clinical applications [12]. In this report,

we present the recent CMC-based wound dressing materials that are useful for the control of

most chronic wounds, such as ulcers and burn wounds.

5.1. Ulcer Wounds

CMC-based hydrogels have been used for ulcer wound treatment. According to literature,

CMC can easily be cross-linked via radiation techniques and form biomaterials without using

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any cross-linkers and initiators [101]. Nho et. al., developed CMC hydrogels, which were

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crosslinked with antibacterial Propolis honey via radiation method for diabetic ulcer [102]. In

this work, honey can accelerate the debridement of necrotic tissue in order to promote wound
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healing due to their high osmotic activity, high acidity and antibacterial activity (hydrogen
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peroxide content). In the hydrogel, CMC provided the moisture environment and helped to
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heal the wound. In addition, these materials have significant biodegradability,

biocompatibility and nontoxicity properties. However, honey has been used to cure wounds,
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since thousands of years [103]. Lately, Park et. al., prepared chestnut honey-impregnated
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CMC hydrogel for diabetic ulcer wound healing. In this study, they used CMC for the

increase of moisture and viscosity of the hydrogels [104]. However, for the development of
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theses hydrogels, they did not use any toxic materials. The materials, however, exhibited vital

antibacterial activity towards Staphylococcus aureus and Escherichia coli. In addition, in-

vivo wound healing studies on db/db mice, explained that chestnut honey-CMC hydrogel can

effectively heal wounds within 21 days.

Another advantage of CMC, is their film formation as an individual material and with other

polymers via blending by solution casting method [56]. Of course, the blending process can

improve the films structure, mechanical strength, fluid absorption and degradability. Basu et

al prepared CMC and CMC/PEG blend films via solution casting method for wound healing

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applications [5]. In this work, they reported the fact that these films have significant

functional and mechanical properties. The cell cytotoxicity test indicated that the films are

noncytotoxic and they support fibroblast cell proliferation. Wound healing test, illustrated the

fact that CMC and CMC blended films, can heal normal wounds within 16 days (complete

skin), however, they cannot completely, cure a diabetic rat wound. The authors reported

further that pure CMC films are more effective in healing wounds when compared to blended

films. However, films can also cure normal and diabetic wounds, effectively. Hence, in

general, CMC films have potential in skin regeneration in wound healing applications. In

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order to enhance the antimicrobial property of wound dressing materials, several antibiotics

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are introduced into the wound dressing systems. Lately, in order to achieve effective
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antimicrobial wound dressing hydrogels, Huber et al (2017) used cellobiose dehydrogenase
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in succinyl chitosan-CMC hydrogel for continuous production of hydrogen peroxide, which

can provide antimicrobial property [105]. They specified that the CMC hydrogel network was
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converted in-situ, by limited hydrolysis via cellulose, into substrates that are accepted by
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cellobiose dehydrogenase for the continuous production of hydrogen peroxide. In addition,

chitosan-CMC hydrogel exhibits non-toxic nature on the NIH 3T3 mouse fibroblast cell (this
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study was carried out by using the ViCell instruments). However, they specified the fact that
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hydrogel needs to overcome the associated dosage issues for wound treatments and hence, it

can constitute a promising wound healing approach in the future.

5.2. Burn Wounds

According to recent reports, a high molecular weight of CMC biomaterial heals burn wound

faster than the lower molecular biomaterial counterparts [64]. Because CMC biomaterials can

reduce moisture loss without extreme retention at the wound site, they can, therefore,

promote burn wound healing [106]. In addition, their molecular weights, greatly affect the

regulation of trans epidermal water loss in the biomaterials. However, in order to protect burn

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wounds from antibiotics resistant bacteria, many researchers have invented several new

wound dressing materials. In these inventions, antibiotics (Xylitol,

Ethylenediaminetetraacetic acid and gentamicin) encapsulated CMC hydrogels, were used to

control biofilms (coherent cluster of viable bacteria) formation of chronic wound sites.

However, Ali et. al., controlled the wound biofilm infection by employing a reduced

graphene oxide to encapsulate CMC hydrogel, which was formulated by using a simple

solution mixing method [83]. In this study, the cell viability test, illustrated the fact that

reduced graphene oxide encapsulated CMC hydrogel, has low cytotoxicity on primary human

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dermal fibroblast cells. Finally, the authors suggested that if NaOH was used for the synthesis

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of reduced graphene oxide, it can reduce the toxicity level of the reduced graphene oxide and
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it can be used for wound dressing applications. Similarly, Percival et. al., had prepared
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silver-ionic polymer-based wound dressing materials for burn wound [107]. They specified

the fact that the CMC-based wound dressing materials can protect the wounds from drug-
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resistant bacteria. In addition, when there is a change in the pH of the material, from 8.5 to
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5.5, the materials antibacterial properties are highly increased. Overall, the study explained

the fact that pH affected the activity of wound dressings on antibiotic-resistant bacteria.
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Furthermore, it helps to protect burn wounds, which present big issues in clinical
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applications. This is so, owing to the long healing time, large size and irregular shape, pain

and re-injury during wound dressing changes, in addition to possible scarring. In this regards,

ideal materials were developed to speed-up healing and improve burn patient outcomes and

minimize any associated unpleasant issues. Liang et. al., integrated self-regulating/anti-

adhesive hydrogels by utilising CMC/sodium alginate/chitosan for burn wound healing

treatments [108]. In this investigation, it was reported that 1% of propanediol improved the

moisture retention ability of the wound dressing hydrogels. These anti-adhesive hydrogels

can self-regulate the moisture levels that are required for wound healing. Additionally, these

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hydrogels have excellent water vapor permeability characteristics, which can improve the

healing of deep second-degree burn wounds. Ultimately, the authors clarified the fact that this

hydrogel exhibited better-wound healing and inflammatory characteristics than the

commercially available (DuoDERMTM) wound dressing material.

Huang et. al., (2018) developed injectable nanocomposite self-healing hydrogel for deep and

partially-thick burn wounds [109]. The authors specified the fact that the amine groups of

CMC can react with aldehyde groups of polymers (cellulose nanocrystal, functionalized with

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aldehyde groups) and form self-healing hydrogels in order to cure burn wounds and eliminate

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pains during wound dressing changes and prevent scar formation. Cytotoxicity studies (three-

dimensional cell culture) explained that these hydrogels are biocompatible and render support
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to the cell growth (human primary dermal fibroblasts). In-vivo (deep partial thickness) burn
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wound healing, studied on rat, explained the fact that the self-healing hydrogel developed,
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can heal burn wounds within 14 days and can allow very fast skin regeneration. In addition,

these injectable hydrogels are able to, completely, cover large and irregularly-shaped wounds
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in order to maintain a moist environment and they can easily be removed from the wound.
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6. CMC-based systems in the wound healing process

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Biofilm (skin, oral cavity and gut or from the external environment, to

forming polymicrobial communities, known as biofilms) wound infections usually require

potent antibiotics and wound dressing materials in order to control the infection and

accelerate wound healing. Lately, antibiotics-loaded CMC materials are gaining significant

interest due to their drug loading efficacy, exudates absorption capacity and antimicrobial

characteristics, which enhance wound healing. This type of dressings, when applied to wound

surface, it absorbs the exudates and allows the diffusion of drug on the wound bed and

protect the wound against infection. Amant et al., prepared a CMC-based wafer, loaded with

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anti-inflammatory, anti-oxidant resveratrol-loaded nanomaterials for wound healing [58]. In

this regards, researchers have developed antimicrobial resistant CMC-based wound dressing

materials by encapsulating a potent antimicrobial, which can control the bacterial infection

and heal the wound [110]. In addition, several antibiotic nanomaterials can accentuate fast

wound healing processes, in different stages, such as: hemostasis (helps blood coagulation

and prevents the microbial infections), inflammation, proliferation and remodelling.

However, extensive evidence, collectively indicate the fact that antibiotics impregnated CMC

polymeric materials have significant wound healing capacity [46,110]. The mechanism of

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antibiotics impregnated CMC dressing materials, can involve in antimicrobial activity in

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different ways, such as: (a) direct interaction with the membrane cell wall of microbes, (b)
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generation and the control of reactive oxygen species (ROS), (c) induction of intracellular
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effects (e.g., interactions with macromolecules, such as DNA and/or proteins) and (d)

stabilization and control delivery of antibiotics. A schematic diagram of antibiotic/CMC

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nanomaterials and the mechanisms of antibacterial dressing materials, are as shown in Fig. 5.
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ROS play an important role in wound repair via a redox signalling [111]. However, ROS in

excessive amounts, have a deleterious effect, inducing lipid peroxidation, protein

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modification and DNA damage, hence, leading to apoptosis and senescence. High levels of
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ROS occur if either their production is increased, or their detoxification is impaired. The

majority of ROS during wound repair are most likely being produced by neutrophils and

macrophages, during the inflammatory phase. The low-concentration level hydrogen

peroxide (between 10−8 to 10−6 molar), can show a positive effect in acute wound repair and

also stimulating fibroblast proliferation. However, the continuous production of reactive

oxygen species, can induce matrix metalloproteinase generation, damage protein and lipid

peroxidation and DNA damage, leading to cell disruption, tissue damage and cell death

[112,113]. Therefore, in order to reduce the toxicity of the metal nanoparticles and to enhance

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their applicability in wound dressing applications, it is often, prepared with several types of

organic compounds and biopolymer encapsulated metal nanoparticles in order to control

bacterial infection and achieve fast wound healing [114–116].

CMC plays a potentially important role in the reduction (control) of active free radicals

(ROS) against antibiotics (metal oxides, nanoparticles, drugs) production, due to the different

functional groups. The CMC polymers act as a stabilizing or capping agent in forming a

quasi-monolayer on the surface of the nanomaterials. As a result, antibiotics physical

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properties need to be redesigned and also in order to improve the quality and safety without

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changes of their properties. This approach can be achieved by coating or encapsulating with a

CMC biopolymer for the modification of the metal oxide surface matrix. In addition, CMC
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maintains moist environment around the wound for extracellular matrix formation, rapid
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epithelialisation and healing. Lately, Saladino et. al., prepared CMC composites containing
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exfoliated grapheme oxide (GO) for infected wound dressing applications. They reported that

the composites developed, showed good antimicrobial activity and did not exhibit
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cytotoxicity on normal fibroblasts and haemolytic activity, which is suitable for use in wound
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dressing applications [110]. De Lima et. al., synthesized PVP/CMC/Agar hydrogel

membrane with silver nanoparticles for wound healing applications. They reported the fact
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that CMC enhanced the swelling capacity of hydrogel membrane, with intense formation of

re-epithelialization and neovascularisation [46]. The authors dwelled on the synthesis and in-

vivo behaviour of PVP/CMC/Agar hydrogel membranes impregnated with silver

nanoparticles for wound healing applications [46].

However, cytocompatibility of CMC/ZnO impregnated MCM-41 nanocomposite hydrogel

films, can increase the biocompatibility of adipose tissue-derived stem cells [15]. Silver

alginate/CMC nanocomposites can significantly, improve healing, as indicated by a reduction

in the surface area of the wound [117]. Biodegradable CMC/graphene oxide nanocomposite

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hydrogel beads have no significant toxicity against colon cancer cells [118]. CMC/MCM-41

nanocomposite hydrogel films enhanced the swelling and permeability properties of wound

healing and dressing systems [66]. Superabsorbent crosslinked CMC-PEG hydrogels are

cytocompatible, when considering the in-vitro cell viability responses of more than 95%,

towards human embryonic kidney cells [12].

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Figure 5. Antimicrobial action of antibiotics (metal oxides, nanoparticles, drugs) with CMC
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on pathogenic bacteria wound cell

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7. Commercially available CMC wound dressing materials

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CMC-based wound dressing materials are commercially available in the market [28,29]. Few
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CMC wound dressing materials are only used to cover wounds for healing, without the

seeding of the skin cells. According to the literature, cell migration properties of the dressing

material can improve wound healing [119]. In this regards, fibrin protein was used on the

wound dressing materials and this can enhance cell migration and the hemostatic property of

the materials. Bacakova et al (2018) reported on an improved Hcel® NaT (commercially

available CMC-based wound dressing material) with good cell adhesion and proliferation

characteristics on human dermal fibroblasts cells, by the use of fibrin [119]. The authors

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specified the fact that the porous forms of Hcel® NaT, have better cell adhesion and

proliferation characteristics than the homogeneous forms of Hcel® NaT.

In addition, the commercially available wound dressing materials are used to control the

delivery of drugs in order to accelerate wound healing. Maver et. al., (2015) used Aquacel®

in order to deliver the non-steroid anti-inflammatory pain-killing drugs [2]. The drug-loaded

substances cannot reduce the water holding and air permeability characteristics of the wound

dressing materials. This wound dressing material is biocompatible with the human skin cell.

Besides, the authors reported that the drug-releasing capacity of wound dressing materials, is

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principally dependent on the environmental conditions, such as pH and temperature [120].

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Finally, they concluded that in the future, a wound dressing drug-loaded material can solve
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several wound-related problems and improve the wound treatment.
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8. Conclusion and future prospects
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Active wound dressing materials should absorb wound fluids and pus, control the bacterial
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infection, improve functional adhesion (not only the wound tissue, but healthy tissue also)

and be easily removable. In recent years, various advanced concepts have been developed for
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the preparation of superior wound healing and biocompatible materials. The potential
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applications of CMC biopolymer, in wound healing, have received great attention over the

past few decades. This approach is an eco-friendly concept that keeps a moist wound

environment, minimises wound healing time and avoids (or considerably reduces) infections.

This review has highlighted and discussed CMC-based different types of wound dressing

materials, i.e. hydrogels, nanoparticles, films, fibres, antimicrobial composites and 3-D

printing materials that are useful in wound care. In addition, commercially available CMC-

based dressing materials and their relevant therapeutic performances are presented. However,

there are still challenges in controlling the need for: speedy wound healing capacity,

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biocompatibility, biodegradability and desirable mechanical properties of CMC. The review

has revealed the importance and desirable characteristics that have been highlighted earlier on

and the shortcomings (e.g. a non-crosslinked and without antibacterial agent-based type of

CMC) associated with wound healing capacity and wound healing process of CMC, from a

fundamental point of view and this is also an important future research topic. Furthermore,

environmentally-friendly and green synthetic methods should also be taken into account and

seriously considered in order to meet the strong demands on sustainable development of

CMCs. Nevertheless, the exploration and fabrication of CMC-based materials and their

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extended developments, will no doubt, remain one of the key focuses of future research.

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9. Acknowledgements
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The authors wish to acknowledge the Fondecyt Postdoctoral No 3190029 (KC and KVP),

CONICYT Regional project R17A10003 and GORE BIO-BIO.

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Conflicts of interest
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There are no conflicts of interest to declare.

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10. References

[1] L. Vinklárková, R. Masteiková, G. Foltýnová, J. Muselík, S. Pavloková, J.

Bernatonienė, D. Vetchý, Film wound dressing with local anesthetic based on
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doi:10.1016/j.jab.2017.08.002.
[2] T. Maver, S. Hribernik, T. Mohan, D.M. Smrke, U. Maver, K. Stana-Kleinschek,
Functional wound dressing materials with highly tunable drug release properties, RSC
Adv. 5 (2015) 77873–77884. doi:10.1039/C5RA11972C.
[3] M. Olsson, K. Järbrink, U. Divakar, R. Bajpai, Z. Upton, A. Schmidtchen, J. Car, The
humanistic and economic burden of chronic wounds: A systematic review, Wound
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[4] G.H. Kim, J.N. Im, T.H. Kim, G.D. Lee, J.H. Youk, S.J. Doh, Preparation and
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[5] P. Basu, U. Narendrakumar, R. Arunachalam, S. Devi, I. Manjubala, Characterization
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Thickness Wounds in Normal and Diabetic Rats, ACS Omega. 3 (2018) 12622–12632.
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[6] M. Uzun, A review of wound management materials, J. Text. Eng. Fash. Technol. 4
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[7] G.D. Winter, Formation of the Scab and the Rate of Epithelization of Superficial
Wounds in the Skin of the Young Domestic Pig, Nature. 193 (1962) 293–294.
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[8] I. Orlando, I. Roy, Cellulose-Based Hydrogels for Wound Healing, in: M.I.H. Mondal
(Ed.), Springer International Publishing, Cham, 2018: pp. 1–18. doi:10.1007/978-3-
319-76573-0_38-1.
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[9] A. Pettignano, A. Charlot, E. Fleury, Carboxyl-functionalized derivatives of

carboxymethyl cellulose: towards advanced biomedical applications, Polym. Rev. 59
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Graphical abstract

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Highlights

 CMC utilization for the preparation of wound dressing materials are reviewed

 The wound healing process of antibiotic-loaded CMC wound dressing materials are
discussed

 The review presents various types of CMC-based wound healing materials

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