Functional Cellulose-Based Hydrogels As Extracellu

Dutta et al.
Journal of Biological Engineering (2019) 13:55

https://doi.org/10.1186/s13036-019-0177-0
REVIEW Open Access
Functional cellulose-based hydrogels as

extracellular matrices for tissue engineering
Sayan Deb Dutta1, Dinesh K. Patel2 and Ki-Taek Lim1*
Abstract
Cellulose-based hydrogels are immensely important for tissue engineering. In this review, we attempt to document
the source, nature, and application of cellulose-based hydrogels as an extracellular matrix for tissue growth and
regeneration. Hydrogels can be prepared either from native cellulose, including both bacterial and plant sources or
from cellulose derivatives, such as methyl cellulose, carboxymethylcellulose, and hydroxypropylmethylcellulose or
even metal ions such as silver. Cellulose-polymer composite (polymers that include natural sources including
chitosan, starch, alginates, collagen, hyaluronic acid, and chitin) are an attractive, inexpensive, and advantageous
structural material that is easy to use. Cellulose-based scaffolding materials are widely used in the regeneration of
various tissues, such as bone, cartilage, heart, blood vessel, nerve, and liver, among others. In this review, we discuss
the most important applications of cellulosic hydrogels in tissue engineering based on their structural
compositions.
Keywords: Cellulose, Hydrogels, Scaffolds, Extracellular matrices, Tissue engineering
Introduction materials contributes to their biocompatibility. Thus,

Cells communicate with each other either directly via hydrogels can be used as membranes for biosensors
molecular interactions or through the secretion of differ- [10, 11], in artificial heart and skin [12, 13], contact
ent hormones or mediators which systematically regulate lenses [14, 15], and drug delivery [3, 6, 16]. Cross-
various cell functions. Growth factors are also secreted linking synthetic polymer-based hydrogels have been
during cellular crosstalk and may be pro-proliferative or reported, including poly (ethylene glycol) [17, 18],
anti-proliferative in nature, being mainly involved in cell poly (vinyl alcohol) [18, 19], poly (amido-amine) [20],
differentiation, migration, adhesion, and gene expression. poly (N-isopropylacrylamide) [21], polyacrylamide [18,
Natural and synthetic materials may be used as bulking 22], and poly (acrylic acid) [18, 23].
agents for the binding of various growth factors by mim- In tissue engineering, hydrogels are the most extensively
icking natural extracellular matrix (ECM) molecular used biopolymer due to their highly swollen three- dimen-
self-assembly via secondary forces, such as ionic or sional (3D) environment, which is very similar to soft tis-
hydrogen bonds, whereas chemical gels are result of co- sues and allows for the diffusion of nutrients, growth
valent bonds [1–5]. factors and cellular waste through the elastic network and
Hydrogels have potential applications in various fields for the regeneration of damaged tissues [13, 18, 24, 25]. In
such as agriculture, food, biomaterials, water purification, regenerative medicine, hydrogel used to repair and assist
biomedicine, and pharmaceuticals, among others. [6–8]. regeneration of various soft and hard tissues, such as cartil-
Hydrogels are primarily made up of natural living tissue age, bone and vascular tissues [26–28]. Natural hydrogels
rather than synthetic biomaterials, as a result have a high include the bioprocessing of natural polymer-based mate-
water content and a soft consistency similar to natural tis- rials such as proteins, including collagen, gelatin, and fibrin,
sues [9]. Moreover, the high water content of these and polysaccharides, including alginate chitosan, hyaluronic
acid, dextran, and cellulose which are used as extracellular
matrices (ECM).
* Correspondence: [email protected]
1
Biorobotics Laboratory, Department of Biosystems Engineering, Kangwon Cellulose is a fibrous, tough, water-insoluble substance,
National University, Chuncheon, Republic of Korea found in the protective cell walls of plants, particularly in
Full list of author information is available at the end of the article
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Dutta et al. Journal of Biological Engineering (2019) 13:55 Page 2 of 19
stalks, stems, trunks, and all woody portions. However, it biomass (Additional file 1: Figure S1) [33]. In addition,
is also produced by some animals (e.g., tunicates), fungi some fungi and green algae produce cellulose (e.g. Valonia
and a few bacteria [29–31]. Due to the presence of abun- ventricular, Glaucocystis) and some marine ascidians con-
dant hydroxyl groups in the cellulose molecule, cellulose tain cellulose in their outer cell membrane. Some bacterial
can be used to prepare hydrogels with varying structures genera, such as, Gluconacetobacter, Agrobacterium, Pseudo-
and properties to act as a platform for advanced tissue en- monas, Rhizobium, and Sarcina are able to synthesize bac-
gineering and regenerative medicine. Cellulose-based mate- terial cellulose either from glucose or other carbon sources
rials represents a naturally occurring ‘nanomaterial’, and has [34–36]. Purified bacterial cellulose is highly crystalline and
attracted the attention of researchers all over the world, as possess a high degree of polymerization (DP). One of the
shown by the increasing number of annual publications crucial features of cellulose is its micro-crystalline structure
appearing in ‘Science Direct’ with ‘cellulose-based hydrogels and its synthesis in nature as individual molecules (linear
for tissue engineering’ (Fig. 1) as the search item. However, chain of glucosyl residues) which undergo self-assembly at
furthur studies are needed for the development and appli- the site of biosynthesis [37].
cation of cellulose-based hydrogels. This review highlights
the recent development and use of various cellulose-based Molecular structure of cellulose
hydrogels as an ECM and their structural properties for ap- Cellulose mainly consist of D-glucopyranose ring units in
plications in advanced tissue engineering. a 4C1 configuration, which exhibits the lowest energy con-
formation [38]. Each unit is linked by β-1, 4-glycosidic
Structure of cellulosic biomass linkage that results in an alternate turning of the cellulose
Cellulose is the most abundant biopolymer and is distrib- chain axis by 180° [39–41]. Within the cellulose chain,
uted throughout nature in plants, animals, algae, fungi, and three reactive hydroxyl groups (−OH) exist in each anhy-
minerals. A major source of cellulose is plant fiber. Cellu- droglucose unit (AGU). The –OH groups of the AGU, the
lose is the main structural component of plants that pro- oxygen atoms of the D-glucopyranose ring, and the glyco-
vides them with their mechanical as well as structural sidic linkage interacts with each other within the chain or
integrity as it contributes approximately 40% to the carbon another cellulose chain by intermolecular and intramo-
fraction in plants (Additional file 1: Table S1). Cellulose can lecular hydrogen bonds [42]. The presence of hydrogen
be found in its pure form in plants with hemicelluloses, lig- bond provides stability to the cellulose molecule and al-
nins, and other components [32]. Surprisingly, a large frac- lows it to be a functionally active biomolecule (Additional
tion of cellulose is produced from trees (wood fiber) with a file 1: Figure S2).
global production of approximately 1,750,000 kt. Annual X-ray diffraction studies revealed the crystalline struc-
plants such as bamboo, cotton linters, jute, flax, sisal, hemp, ture of cellulose, and NMR experiments have confirmed
and ramie also produces significant amount of cellulosic its dimorphic and polymorphic nature [43, 44]. Different
Fig. 1 Publications related to cellulose-based hydrogels for tissue engineering (science direct search system; ‘cellulose based hydrogel for tissue
engineering’ as search term; https://www.sciencedirect.com)

polymorphs of cellulose are listed in Table 1. Solid-state (S1, S2, and S3) of which S2 is the thickest e (approximately
13
C-NMR was used to identify different polymorphs, de- 3–5 μm thickness) as shown in Additional file 1: Figure
noted as cellulose Iα and Iβ. Cellulose Iβ is naturally oc- S3d. The S2 layer contains microfibrils arranged in parallel
curring in plants, whereas cellulose produced by [58–60].
primitive organisms crystallizes in the Iα form [55].
Cellulose chains are arranged in a basic fibrillary unit Structure of bacterial cellulose (BC)
or elementary fibrils with a length of 0.1 to 0.2 μm and Bacterial cellulose (BC) can be obtained in pure form.
have a characteristic lateral dimension of 0.0015 μm to Compared to PC, BC contains no hemicellulose or lignin
0.0035 μm [56, 57]. Such fibrils are known as cellulose fi- and only a very small amount of carbonyl and carboxyl
brils. These fibrils are further assembled into microfibrils moieties are present [61]. BC possesses a high degree of
with a width of 0.1 μm and a length of 0.1 to 1 μm (Fig. crystallinity (above 80%) with a good water retention
2a). This fibrillary architecture can be found in both na- capacity, and an extraordinary mechanical strength, par-
tive and man-made fibers [39]. ticularly under wet conditions. One important advantage
of using BC is its in-situ molding ability, i.e. shaping
Structure of plant cellulose (PC) during biosynthesis [62]. The culturing and production
In the case of plant cell walls, a sheath of amorphous cellu- of BC is the most important part, although it is also im-
lose surrounded by a hemicellulose layer covers the micro- portant to maintain the pH of the culture medium, since
fibrils [33]. Fibers from different plants vary in morphology a low pH can often led to the accumulation by-products,
and dimension. Additional file 1: Figure S3 clearly shows such as of gluconic, acetic, or lactic acids [63]. Figure 2b
the variations in the fiber morphologies of cotton (S3a), clearly shows the structure and formation of bacterial
spruce wood (S3b), and ramie plant (S3c). Surprisingly, all cellulose in Acetobacter xylinum.
three plants share a common internal structure made up of
multiple cell wall layers [58]. During the early growth Role of extracellular matrix (ECM)
phase, plant fibers develop a primary cell wall (P layer) that ECMs are used in tissue engineering and regenerative
is much thinner than the secondary wall (S layer) formed medicine as a natural model for bioactive modifications.
on its inner side. Inside the S wall, a tertiary cell wall (T Compared to other ECMs, hydrogels have provided op-
layer) is present, which is typically an open, hollow area or portunities for the use of a natural ECM as a model for
lumen-like structure. The cell wall thickness and length of designing biomimetic scaffolds.
the plant fiber are approximately 4–630 μm and 15–30 μm,
respectively. The swelling characteristics as well as their Structure and composition of ECM
physical and chemical properties are strongly influenced by The tissues of the human body contain a significant
the configuration, composition, and structure of the P layer, amount of extracellular space, into which ECM molecules
which contains microfibrils crisscrossed onto each other to are secreted by cells to form a large and complex network.
make a net-like helical structure (S3d-e). The secondary The ECM of the extracellular space provides tissue with
layer is 3–5 μm in thickness and comprises three sublayers mechanical strength, organizes cells into specific tissues,
Table 1 Polymorphs of cellulose

Source Cellulose Features References
polymorphs
Valonia ventricosa1 Cellulose I Native cellulose, found in nature, interconvertible, stable. Crystalline forms are Marchessault
(bubble algae) termed as Iα and Iβ. Iα considered as primitive type, while higher plants possess Iβ. and Sarko, 1967
Acetobacter xylinum [45]
(bacteria) [46]
Microdictyon (green algae) [47]
Halocynthia (tunicates) [48]
Halicystis (green algae)2 Cellulose II Obtained from cellulose I, interconvertible, also found in nature. [49]
Mutant strain of A. xylinum [50]
[51]
Kuga et al.,
1993 [52]
Chemical conversion of Valonia Cellulose III Interconvertible and not found in nature. Two crystalline forms isolated as IIII and [49]
cellulose I and cellulose II IIIII respectively. [50]
Chemical conversion and Cellulose IV Interconvertible and not found in nature. Two crystalline forms isolated as IVI and [53]
heating of cellulose IIII and IIIII IVII respectively. [54]
highly crystalline cellulose obtained from Valonia
1
2
naturally occurring cellulose II

Fig. 2 Structure of cellulose and bacterial cellulose. a structure of cellulose fibrils (0.2 μm) and microfibrils (1 μm); b SEM images of Acetobacter
xylinum and formation of bacterial cellulose [53] SEM: Scanning electron micrograph
and controls cell behavior and cell differentiation. Two trigger complex cascades of intracellular enzymatic reac-
crucial components of the ECM are proteins and glycans, tions that regulate gene and protein expression and de-
in particular fibrous proteins (e.g., collagen, laminin, and fine the fate of a cell in a specific tissue [18, 66]. Cell can
elastin) and glycosaminoglycans (GAGs) [64, 65]. Fibrous also transmits a signal to actively construct and degrade
proteins act as a scaffold and provide adhesion to matrix their microenvironment. Thus, the ECMs acts as both a
structure that are initially embedded in GAGs [65]. Thus, space-filling mechanical scaffold and a bioactive and
cell-matrix adhesions mediate various physiological re- dynamic environment to mediate cellular functions
sponses including cell growth, migration, differentiation, [64, 65]. However, natural ECMs also provide cellular
survival, tissue organization and matrix remodeling [66]. adhesion, proteolytic degradation and growth factor
(GF)- binding [18].
Function of ECM
The ECM components undergo self-assembly to form a Basic properties of hydrogels
complex 3D network [18]. Figure 3 shows the role of Hydrogels are a type of polymer biomaterials with vari-
ECMs in various cellular responses. Cell receptors bind ous properties. In the field of pharmaceutical and bio-
both soluble and tethered signaling cues from the ECM medical engineering, hydrogels are very important due
environment. In turn, these receptor-ligand interactions to their in-vivo swelling properties, mechanical strength

Fig. 3 Schematic representation of the extracellular matrix (ECM). In a natural environment, cells (green) use specific markers (pink) to bind to a
mechanical support matrix of polysaccharides or hydrogel (yellow) and fibrous proteins (blue). Dissolved proteins like growth factors (purple)
enable communication between the cells and matrix-degrading enzymes (black), thus remodeling the matrix [67]
and compatibility with biological tissues, facilitating rate for a predetermined time. The optimum degree of
binding (Fig. 4) [68–70]. cross-linking may lead to a hydrogel with a suitable mech-
anical strength. However, by increasing the degree of
Mechanical properties cross-linking, a stronger form of the hydrogel can be pre-
The mechanical properties of hydrogels are significant from pared, such as brittle hydrogel that exhibits a decreased
both a pharmaceutical and biomedical point of view [68]. percentage of elongation [68, 71].
The optimum mechanical strength of a hydrogel is an es-
sential requirement for its successful implementation as a Swelling properties
drug delivery system. The excellent mechanical properties Hydrogels are polymer-based biomaterials developed by the
of hydrogels allows its physical integrity to be maintained physical or chemical linking of polymers. When hydrogels
until the cargo molecules are released at a predetermined are exposed to water, they can absorb the water or aqueous
Fig. 4 Advantages of the use of cellulose-based hydrogels for tissue engineering

fluids without dissolving. This swelling continues until more effective than the static culture method; due to the
there is an equilibrium between the water and the polymer increased growth of bacteria and the high cellulose yield
is established. On the other hand, the elasticity of this bio- (Fig. 5) [90]. One of the essential features of bacterial
material results from the polymer-polymer interactions that cellulose (BC) is the presence of a fine microfibrillar
prevent the water flux inside the hydrogel resulting in a structure that is entirely responsible for its high tensile
state known as “equilibrium swelling” [72]. strength, high crystallinity index, and high degree of
polymerization. A previous study found that a hydrogel
Biocompatibility obtained from BC (0.8%) had a good biocompatibility
In the case of tissue engineering and regenerative medicine, for use in tissue remodeling[91]. The study also showed
hydrogels must be compatible and non-toxic. Biocompati- the high degree of crystallinity of BC around 89% [92], a
bility is a process that deals with the ability of a hydrogel to high degree of polymerization [93], and a high specific
perform an appropriate host response in a specific applica- surface area (37 m2/g) [94]. Again, BC also showed a
tion. Biosafety and bio-functionality are the two keys factors large surface area, high aspect ratio, and low bulk dens-
regulating biocompatibility [73]. Polysaccharide-based ity, as well as hydrophilicity [76]. For this reason, BC is
hydrogels are strikingly important among the polymer widely used in healthcare and medicinal research [95].
hydrogels due to the variety of chemical structures and
functional properties [74, 75]. Hydrogels also act as revers- Processing of cellulose-based hydrogels
ible gels with enlargements, such as ionic, H-bonding, or Various methods have been employed for the production
hydrophobic forces which play a crucial role in forming the and processing of hydrogels based on cellulosic mate-
network [76–78]. The extensive use of hydrogels in the bio- rials. Hydrogels can be obtained either directly from na-
medical field is a direct result of their capacity to hold high tive cellulose or from cellulose derivatives [96]. A list of
amount of water, elasticity, biocompatibility, and non-toxi- cellulose derivatives, and their solvents, and processing
city, among others. The swelling properties of hydrogels re- methods is presented in Table 3.
sults from the presence of hydrophilic groups, such as,
−OH, −COOH, −CONH2, and -SO3H in polymer chains Hydrogels obtained from native cellulose
[79]. Swelling is a crucial property of hydrogels for use in A cellulose-based hydrogel can be obtained from a cellu-
biomedical applications, such as in wound dressings [80]. lose solution through physical cross-linking. Due to the
presence of hydroxyl groups in cellulose, it can easily form
Cellulose-based hydrogel production cross-linking through hydrogen bonding. The highly ex-
The production of cellulose and cellulose-based hydrogel tended hydrogen-bonded structure of cellulose results in a
has many advantages in the biomedical and pharmaceut- compact such that it is not easily dissolved in common
ical industries [76]. In addition to plant cellulose (PC) solvents [113]. Various solvents have been used to dissolve
production, microbial cellulose (MC; also known as bac- cellulose. Nowadays, new solvents, such as N-methylmor-
terial cellulose or BC) production is of great importance pholine-N-oxide (NMMO), ionic liquids (ILs), and alkali/
and is normally carried out using Gram-negative bac- urea (or thiourea) aqueous systems have been developed
teria, such as Acetobacter xylinum [81]. Other bacteria to dissolve cellulose, with important applications in hydro-
used to produces cellulose are listed in Table 2. Bacterial gel research. However, certain bacterial species are in-
cellulose is produced using either static or shaking cul- volved in the processing of nearly-pure cellulose hydrogels
ture methods. However, the shaking culture method is [96]. Many solvent systems are used to obtain hydrogels
Table 2 List of some bacteria producing cellulose

Type of bacteria Example Application References
Gram-negative Acetobacter xylinum Tissue repair material, human tissue substitute or artificial skins; wound dressing [81]; [82]; [83]; [84]
Gluconacetobacter hansenii Medical pads, artificial skins [85]
Acetobacter pasteurianus Medical pads, membranes [86]; [87]
Rhizobium sp. Tissue repair material [82]; [88]
Agrobacterium sp. Tissue repair material [82]; [88]
Aerobacter sp. Tissue repair material [88]
Azotobacter sp. Tissue repair material [88]
Salmonella sp. Tissue repair material [88]
Achromobacter sp. Tissue repair material [88]
Gram-positive Sarcina ventriculi Cell culture, tissue engineering, regenerative medicine [82]; [88]; [89]

Fig. 5 Schematic representation of strategy for BC production [73] BC: bacterial cellulose
from native cellulose. One such systems involves the use cellulose concentration has been determined to be 7 wt%.
of LiCl/DMAc which consists of a mixture of 3 to 15% The presence of water in the cellulose solution is a critical
lithium chloride/LiCl (w/w), dimethylacetamide/DMAc, factor for hydrogel production [96]. There have been re-
and 1-methyl-2-pyrrolidinone under specific temperature ports of the rapid dissolution of cellulose at room
conditions (normally less than 150 °C) [114]. Cellulose is temperature (around 25 °C) using solvent system with a
then dissolved in amide and LiCl in the absence of any mixture of dimethylsulfoxide/tertrabutylaluminium fluor-
polar medium other than amide to obtain hydrogels. ide trihydrate (DMSO/TBAF) [116]. Due to its ability to
However, [99] described the processing of cellulose hydro- form hydrated dipoles in aqueous solution, TBAF is con-
gels in bead form via the dropwise addition of cellulose so- sidered as a suitable solvents for cellulose.
lution into DMAc and LiCl to azeotropic methanol or The NMMO solvent system also provides a method
isopropanol as a non-solvent (Fig. 6a). The size of the for the production of regenerated cellulose fibers, films,
beaded hydrogels obtained from this method may varies food casings, membranes, sponges, and beads, among
from 100 to 1500 μm [99]. In the LiCl/DMAc system, the others without the formation of hazardous byproducts
Table 3 Summary of some cellulose derivatives and its corresponding hydrogel processing methods
Cellulose/cellulose derivatives Nature of solvents Solvent Corresponding hydrogels preparation methods References
systems
Cellulose form wood Polar solvents NMMO Solution polymerization at 85 °C [97]
Cellulose from cotton pulp Polar solvents LiCl/DMAc Solution polymerization at 75–90 °C [98]; [99]; [100]
Filter paper Ionic solvents [Amim]Cl Solution polymerization at 70 °C, 2 h ([101]; [102])
Tunicate cellulose Alkali aqueous Alkali/urea Polymerization at −12 to −10 °C, 5–10 min [103]
systems
Cotton linter Alkali aqueous Alkali/ Polymerization at −5 °C, 2–10 min [104]
systems thiourea
Carboxymethylcellulose Polar solvents H2O Solution polymerization, In situ polymerization [105]; [106];
(CMC) [107]
Methyl cellulose (MC) Polar solvents DCM/DMSO Solution polymerization, In situ polymerization [106]; [108];
[109]
Hydroxyethyl cellulose (HEC) Polar solvents H2O Solution polymerization, cryogenic treatment [106]; [110]
Hydroxypropyl methyl cellulose Polar solvents H2O/ethanol Solution polymerization, inverse-phase suspension [106]; [111]
(HEMP) polymerization
Cellulose acetate (CA) Polar solvents Acetone/H2O Chemical cross-linking [112]
NMMO N-methylmorpholine-N-oxide, LiCl/DMAc Lithium chloride/dimethylacetamide, [Amim] Cl 1-allyl-3-methylimidazolium chloride, H2O water, DCM/DMSO
Dichloromethane/dimethyl sulfoxide

Fig. 6 a Cellulose hydrogel beads with an average size of 467 μm [99], b NMMO fibers, c Viscose fibers [115]
NMMO: N-methylmorpholine-N-oxide
from cellulose solution [115]. Fiber formation occurs in additives in the food, pharmaceutical, and cosmetic indus-
a dry jet-wet spinning process, taking into account sev- tries. Selective cellulose derivatives, including methyl
eral physical factors (e.g. nozzle and air-gap dimensions, cellulose (MC), hydroxypropyl cellulose (HPC), hydroxy-
drew-down ratio, take-up speed) and dopinge character- propylmethyl cellulose (HPMC), and carboxymethyl cellu-
istics (cellulose DP and concentration, temperature, lose (CMC) have been used to fabricate cellulose-based
modifiers) which influence the shaping process and the hydrogels through physical and chemical cross-linking. In
final fibers properties. Tertiary amine oxides are also the case of physically cross-linked gels, no covalent bond-
capable of dissolving up to 10% cellulose [117]. A novel ing formation or breakage takes place, and the cross-
method has been developed which produces highly con- linked network is formed through ionic bonding, hydro-
centrated cellulose, up to 23%, by treating cellulose with gen bonding, or an associative polymer- polymer inter-
NMMO and water [118]. The cellulose fibers generated action [96]. On the other hand, chemical cross-linked
using the NMMO system are of two types: NMMO fiber hydrogels are prepared through cross-linking two or more
and viscose fiber. The NMMO fiber is typically round/ kinds of polymer chains either with a functionalized
oval, homogenous/dense, highly amorphous, and crystal- cross-linker [124] or under UV irradiation [125]. Physic-
line, as shown in Fig. 6b. On the other hand, viscose fi- ally cross-linked hydrogels are widely used in different
bers are lobate, less homogenous, and more or less biomedical fields, including as scaffolds for cell cultures,
amorphous, as indicated in Fig. 6c [119]. in cartilage models, and as implants in bone defects [126].
Ionic liquids (ILs) also served as a suitable solvent for Silated-hydroxypropylmethyl cellulose (Si-HPMC)
cellulose and cellulosic materials. Hydrophilic ILs, such as hydrogels are generally developed for use as scaffold in
1-butyl-3-methylimidazolium chloride (BMIMCl) and 3D cultures of osteogenic cells, and are suitable for both
1-allyl-3-methylimidazolium chloride (AMIMCl) are com- in vivo injection and in vitro culturing. However, a previ-
monly used to dissolve cellulose at room temperature ous study presented the use of Si-HPMC hydrogels in
(around 25 °C) [120, 121]. After treatment with AMIMCl, osteoblastic survival, proliferation, and differentiation
regenerated cellulose exhibited excellent mechanical prop- when used as a new scaffold and provided a new treat-
erties. Thus, room temperature ILs represents a new and ment technique after bone replacement surgery [127].
versatile platform for the comprehensive utilization of cel- MC hydrogels are widely used to mount the surface of
lulose resources and the manufacturing of novel polystyrene dishes and are used to cultivate human em-
cellulose-based materials with unique properties [121]. bryonic stem cells (hESCs) for the formation of embry-
Similar to ILs, a cellulose solvent with fast dissolution onic bodies (EBs) in liquid suspension cultures [96, 128,
was developed using a mixture of precooled (− 12 °C) 7 129]. The EBs developed from the hESCs are shown to
wt% NaOH and 12 wt% urea aqueous solution [[103, express molecular markers specific for representative
122, 123] in]. Native cellulose dissolved within 2 min in cells from the three embryonic germ layers, indicating
NaOH/urea solution. Thus, this alkali/urea solvent sys- the use of MC-coated dish for the large-scale production
tem provides a rapid and convenient method for the of EBs from hESCs as shown in Fig. 7a-c.
rapid-rate dissolution of cellulose.
Mixed hydrogels
Hydrogels obtained from cellulose derivatives The mixing or blending of different polymers, such as, a
Water-soluble cellulose derivatives are generally biocom- cellulose-polymer composite is a desirable, inexpensive
patible, and can therefore be used as thickening agents, and advantageous method for obtaining novel structural
binding agents, emulsifiers, film formers, suspension aids, materials [6]. Cellulose (or its derivatives) blended with
surfactants, lubricants, and stabilizers, and in particular as natural biodegradable polymers, such as chitin, chitosan

[130], starch [131, 132], alginates [133, 134], and hyalur- microscopy (SEM), rheological measurement, dynamic
onic acid [135], has been used to created novel materials mechanical analysis (DMA), and swelling test analyses
for specific applications. Some examples include the to evaluate the structure and morphology of the hydro-
blending of a cellulose-polymer composite with chitosan gels (Fig. 8a-c) [138].
for the removal of heavy metals, with starch for the food Currently, polymeric-inorganic hybrid compounds
industry, and with alginates for tissue engineering have been widely used in various fields, such as elec-
[Chang, 2011]. trical, optical, magnetic, and biological fields, among
Cellulose-chitosan hydrogel beads areprepared by others [138]. A novel method for the incorporation of
blending cellulose powder to chitosan solution [136]. inorganic materials and cellulose hydrogels has been
Chitosan is perviously blended with a highly concen- studied in New Zealand white rabbits with critically-
trated carboxymethylated cellulose solution to form sized bone defects in the distal femoral epiphyses [139].
physical hydrogels, which is then cross-linked by irradi- In the experimental process, the researchers used an in-
ation [137]. This cellulose-chitosan duplex has been jectable and self-cross-linkable bone substitute (IBS2)
shown to exert non-diffusible antibacterial properties composed of Si-HPMC viscous solution (3 wt%) in alka-
[128, 129]. A novel microporous hydrogel produced by line medium, supplemented with biphasic calcium phos-
mixing of cellulose with sodium alginate (SA) solution phate (BCP) ceramic particles. The diameter of the BCP
and then cross linking with epichlorohydrin. The final particles ranged from 40 to 80 μm. After a number of
cellulose/SA hydrogels were characterized by solid-- weeks, centripetal bone formation was observed near the
state, 13C NMR, wide-angle X-ray diffraction (WXRD), defects, with a yield strength that was significantly
thermo-gravimetric analysis (TGA), scanning electron higher than that of the host trabecular bone tissue.
Fig. 7 MC-coated hydrogel dishes for hESCs differentiation. a Original photograph s of the MC Hydrogel-coated in a polystyrene dish at distinct
temperatures; b Photograph of a water drop on the surface of the MC hydrogel coated in a polystyrene dish in the dried or hydrated state; c
Photomicrographs of the hESCs cultivated by different methods for distinct periods (magnification 40x). MC: methyl cellulose; hESCs: human
embryonic stem cells; HDC: hanging drop culture; LSC-PS: liquid suspension culture in polystyrene dish; LSC-ULAP: liquid suspension culture in
the Corning Ultralow Attachment plate; LSC-MC/PS: liquid suspension culture in the MC-coated polystyrene dish. Scale bars, 1.0 mm [124, 134]

Fig. 8 Original photograph (a), SEM image (b), and compressive stress-strain curve (c) of cellulose/SA hydrogel [139] SEM: scanning electron
microscopy; SA: sodium alginate
Figure 9a-c shows how bone regeneration occurs after (HEC) and carboxymethyl cellulose sodium salt (CMCNa)
the application of Si-HPMC/BCP materials. The use of cross-linked with hyaluronic acid allow for the prolifera-
BC from Gluconacetobacter hansenii along with a novel tion of keratinocytes in an in vitro culture [144]. Bacterial
composite material composed of calcium-deficient hy- nanocellulose (BNC) has great potential for use as a scaf-
droxyapatite (CdHAP) for orthopedic use has been well fold in tissue engineering, since BC is more effective than
characterized and described by [140]. On the other hand, PC, which accounts for BC being the first choice in med-
[141] reported the use of heparin/cellulose/charcoal ical and tissue engineering applications.
composites to understand the mechanism and crosstalk
among cells. To study intracellular drug delivery systems BC hydrogels in biomedical applications
and cellular proliferation, single-walled carbon nano- BC has promising features due to the similar of its nano-
tubes (SWCNTs) wrapped with cellulose have been ob- structure and morphology to collagen making BC an at-
served in HeLa cells [101, 102]. Researchers developed tractive choice for use in the support and immobilization
SWCNTs with a cellulose solution, dissolved in ionic li- of cells. The architecture of BC materials can be engi-
quid 1-butyl-3-methylimidazolium bromide (Fig. 9d-e). neered at range of scales, ranging from the nano to mac-
Another study showed that long cellulose/SWCNT scaf- roscale by controlling the biofabrication process. BC fibers
folds could promote the growth of HeLa cells, whereas are solid and, when used in combination with other bio-
short cellulose/SWCNT were found to only have a small compatible materials, produce nanocomposites particu-
effect on cell proliferation of HeLa cells (Fig. 9f-h). larly suitable for use in human and veterinary medicine
Healthy cells have a green nucleus, uniform chromatin, [76]. The applications of BC composite hydrogels in bio-
and an intact cell membrane, whereas necrotic cells or medicine and tissue engineering are listed in Table 4. BC
late apoptotic cells have red nuclei with damaged cell composites can also be used in cornea formation after cor-
membranes. Cells cultured on a composite scaffold and nea surgical treatment, as well as heart and vascular tissue
a glass slide are healthy with a green nucleus (Fig. 9f and regeneration [148].
h), however, some cells culture on purified SWCNTs are
in the late apoptotic stage (Fig. 9g). Thus, inorganic- Bioactive cartilage implantation
based cellulosic hydrogels provide a wide range of appli- Since, BC gels are free from the action of proteolytic en-
cations in the biomedical and tissue engineering field. zymes and reactive oxygen species (ROS), they protects
the body from carcinogenesis and prevents the appearance
Application of cellulose hydrogels in tissue of inflammation. Some examples of cartilage implants
engineering composed of BC are septum implants, ear implants, and
Cellulose-based hydrogels are used in different fields re- intervertebral discs, among others [176]. Now a days, the
lated to tissue engineering. Patterned macroporous (PM) use of bio-mimicking scaffolds has led to the exploration
with a diameter larger than 100 μm were introduced to of BC as a potential scaffolding material. A previous study
pristine 3D nanofibrous BC scaffolds using infrared (IR) showed that BC did not induce the activation of pro- in-
micromachining techniques to create an in vitro culture flammatory cytokines during in vitro macrophage screen-
model for breast cancer cells (BCs) [142]. PM-BC scaffolds ing, but rather stimulated the biogenesis of collagen type
were found to be promote cellular adhesion, growth, pro- II with chondrocytes seeded on BC membranes, indicating
liferation, and infiltration of BCs. A. xylinum BC also pro- the suitability of BC as bio-mimicking scaffold [177]. An-
motes wound healing as it maintains the wound moist by other more recent study showed the synthesis of
controlling the wound exudates and also heals severe modified bacterial cellulose (MBC) from metabolically
second-degree burns [143, 144]. Hydroxyethylcellulose engineered Gluconacetobacter xylinus with a high

Fig. 9 TEM of IBS2-filled bone defects after 8 weeks (a-c). a The image clearly showed the mature bone tissue (B) containing the osteocytes (Os);
b The vacuole containing the Si-HPMC polymer solution (H) around the microporous BPC granules (G) are visible; c The precipitation of the
biological apatite (Ap) between the BPC crystals, collagen fibers (C), and the nucleus of osteoblastic cells can also be observed. [135]; d FE-SEM
image of purified SWCNTs; e IR spectra of purified SWCNTs, cellulose and C/S-C; f-h. FM images of HeLa cells cultured for 24 h on the C/S-C (f),
the SWCNTs (g), and a glass slide (h) [100, 138]. TEM: transmission electron microscopy; Si-HPMC: silated-hydroxypropylmethyl cellulose; BPC:
biphasic calcium phosphate; FE-SEM: scanning electron microscopy; SWCNTs: single-walled carbon nanotubes; IR: infrared spectra; C/S-C:
cellulose/SWCNTs complex
proliferation level of human mesenchymal stem cells Wound dressing materials

(hMSCs) compared to native cellulose. This material BC has been successfully used as wound dressing ma-
was reported to be a novel in vivo degradable scaffold terial since the 1980s. BC composite materials are
for chondrogenesis [178, 179]. used in medicine due to their biocompatible, sterile,
porous, and flexible nature. The use of BC sheets al-
Blood vessel prototypes lows for wounds to breathe, and prevent the forma-
Artificial blood vessel-like structures composed of BC tion of scabs and scars. On the other hand, the use
are almost 5–25 cm long, which are stable, mechanic- of BC in dressing materials also reduces the amount
ally strong and resistant to water, aqueous liquids, ions, of pain, protects the skin from infections, and reduces
and small particles, among others. Such vessel-like the loss of body fluids. As such, BC composite mate-
structure are often used as main platforms for neuro- rials are an ideal candidate for the treatment of
transmitters. Natural BNC has promising mechanical wounds and burns [180]. Some examples of commer-
properties, including tear resistance and shape- cially available BC composite gels are listed in Table 5.
retention properties, such that it is better suited for use A novel type of BC-based wound dressing, which is
as biological vessels [176]. impregnated with superoxide dismutase and poviargol,

Table 4 Uses of plant cellulose (PC), microbial cellulose (MC) and bacterial cellulose (BC) composite hydrogels in tissue engineering
Sl. Hydrogel composite Applications References
No.
1 Plant cellulose (PC) purified Tissue engineering and regenerative medicine [145]; Liu et al., 2014 [146]
2 Algal cellulose (AC) Bone tissue and cartilage engineering [147]
3 Bacterial cellulose (BC) purified Bone tissue engineering, cornea treatment, heart and vascular muscle [148]
regeneration
4 Carboxymethyl cellulose (CMC) Drug loading and controlled release of drugs, nucleus pulposus [149]; [148]
5 Polyvinylpyrrolidone (PVP) Soft-tissue replacement wound management [149]
6 Gelatin Wound dressing, tissue regeneration [80]; [150], [151]
7 Starch Reinforcement agent for bionanocomposites [152]
8 Alginate, sodium alginate High strength hydrogel preparation [153]
9 Acrylic acid Burn wound healing [154]
10 Graphene oxide (GO) Biomedicine [155]
11 Vaccarin Cell growth carrier wound dressing [156]
12 Hyaluronic acid (HA) Wound dressing, tissue engineering [157]
13 Chondroitin sulfate (CS) Dental material scaffold Opera et al., 102
14 Calcium phosphate (CP) Bone substitute [158]
15 Ca2+ activated cellulose, cellulose/ Bone tissue engineering [148]
lactide
16 2-hydroxyethyl methacrylate Contact lenses and optic component for biosensors [159]
(PHEMA)
17 Polyacrylamide Cartilage replacement [160] & [161]
18 Gellan gum High strength hydrogel for synthetic connective tissue [153]
19 L-carrageenan High strength hydrogel for synthetic connective tissue [153]
20 Hydroxyapatite Bone scaffold substitute, bone tissue engineering [162]; [163]; [164]; [165];
[166]
21 Nanohydroxyapatite Bone tissue engineering
22 Polyvinyl alcohol (PVA) Cardiovascular soft tissue replacement, artificial cornea biomaterials ([167]; [168]); [169]; ([170];
[171])
23 Polylacitide and glycidyl Skin repair material [172]
methacrylate
24 Collagen Wound dressing for skin regeneration [173]; [148]
20 Silver Antimicrobial wound dressing [174]; [175]
was found to stimulate the healing of thermal skin Surgical implants

burns resulting from acute radiation disease [183]. BCs and BNCs can be used in the form of tracheotomy
Surprisingly, BC/collagen type I composite was found tubes for reconstructive surgery, such as for artificial heart
to promote the reduction of protease, interleukins, valves, and as blood vessels in the form of nanotubes or
and ROS activity in an in vitro culture study [184]. neurotubes for the regeneration of coronary blood vessel
Table 5 Commercially available hydrogel wound dressing contains cellulose or its sodium salt. Most dressings are available in two
forms, either as sheets or as amorphous gels. Products containing silver ions show antimicrobial property
The hydrogel wound dressing (producer) Composition References
IntraSite™ Gel (Smith and Nephew) Carboxymethycellulose sodium (CMCNa), propylene glycol and water
GranuGel™ (ConvaTec) Carboxymethycellulose sodium (CMCNa), Propylene glycol, pectin and water [181], [182]
Purilon Gel™ (ColoPlast) Carboxymethycellulose (CMC), calcium alginate and water
Aquacel Ag™ (ConvaTec) Carboxymethycellulose sodium (CMCNa) and silver ions (1.2%)
Silvercel™ (Johnson and Johnson) Carboxymethycellulose (CMC), silver ions (8%) and calcium alginate

and nerves. Previous studies have found new epithelial cell Other applications
layers to form over these artificial BC tubes, demonstrat- Biomimetic scaffolds are of great interest to tissue engin-
ing the successful application of BC in tissue implantation eering as they supports essential cell functions. BNC
[185]. The use of PVA/BC nanocomposites for the re- scaffolds in combination with soluble collagen-I stimu-
placement of cardiovascular tissues has also been re- late estrogenic differentiation of mesenchymal stem cells
ported, since these would mimic the role of natural (MSCs) [Vielreicher et al., 2018]. The use of cell-derived
collagen and elastin (a connective tissue protein that helps ECM collagen-I holds good potential, particularly for the
skin to return to its original position [167, 168] tissue engineering of mechanically-challenged tissues.
An optimized method for the purification of nano- fibril-
Potential drug delivery material lated cellulose (NFC) and hydrogel production from
Transdermal systems can act as an entry gate for BCs into wood cellulose was described for the development of a
the domain of drug delivery systems [186]. BC dry films wound dressing material [192]. Inflammation, autolytic
have been obtained after the successful immersion of debridement, granulated tissue formation, and re- epi-
these in benzalkonium chloride (an antimicrobial agent). thelialization are the processes that generally occur dur-
Their subsequent drug loading capacity was found to be ing wound healing. Wound dressings are designed to
0.116 mg/cm2 (per unit surface area), and the effect of promote healing while protecting the wounds from in-
drug was found to last for at least 24 h against Staphylo- fection. This is particularly important in cases of chronic
coccus aureus and Bacillus subtilis applied to the wounded wounds (e.g., ulcers), which fail to heal properly. Since a
area [187]. Silver nanoparticle-coated BC fibers showed moist environment encourages rapid healing, hydrogels
99.99% antimicrobial activity against Escherichia coli and are optimal candidates for the development of wound
S. aureus [164]. Despite these promising results, the appli- dressings, either as sheets or in an amorphous form
cation of BC hydrogels involves certain clinical and [193]. Various types of hydrogel dressings have been pat-
pharmacological limitations. However, despite these limi- ented so far and are currently commercially available
tations, the complex nanofibrillar structure of BC repre- (Table 5), based on synthetic or natural polymers, or a
sents a suitable macromolecular support for the inclusion combination of these. Among the most recent patents, it
of drugs, i.e. for use as a drug carrier [188]. is worth citing those describing in situ forming gels (e.g.,
based on sprayable formulations [194] and on coalescing
Artificial grafting of cornea nanoparticles [195]), and those exploring radiation
Corneal disease is a serious health problem that can lead crosslinking as a stabilization technique, which allows to
to partial or complete blindness. An estimated 10 mil- obtain sterile and cross-linked hydrogel films in a sin-
lion people have lost their eyesight due to corneal infec- gle-step process [196, 197].
tion or similar diseases. With this in mind, researchers Scaffold attempts to mimic natural ECMs. The most
around the world have developed biomaterials for the common method of tissue engineering includes the use of
treatment of defective corneas. The properties of bacter- biodegradable scaffolds to support the growth and develop-
ial cellulose, including its nanoporous structure, and ex- ment of cells into tissues or by injecting the isolated single
cellent mechanical properties, make it an ideal candidate cell suspensions [5]. Cellulose-based scaffolding materials
for use as an artificial cornea to help maintain the intra- are widely used to regenerate various tissues, such as bone,
ocular pressure of the eye and re-establish ocular pellu- cartilage, heart, blood vessel, nerve, and liver, among others.
cidity. The BC/polyvinyl alcohol (BC/PVA) hydrogel has However, the design of scaffolds often involves issues related
a water content and light transmittance comparable to to the need requirement for adequate cell-cell adhesion,
that of natural cornea and was successfully synthesized cell-cell communication, and cell-ECM communication,
and described by Wang et al. for this end. which are crucial features of tissue functioning [198]. To
overcome these problems, biodegradable scaffolds have
been developed. Since, natural polymers are biocompatible,
Dental implants their use allows us to avoid stimulating chronic inflamma-
BC composite hydrogels were prepared from Acetobacter tion or immunological reactions or toxicity. Therefore,
hansenii by [189] for used in dental root canal treatment hydrogels are used extensively in tissue engineering due to
(RCT) due to intracanal asepsis. Dental RCT is required their high swelling properties and their biocompatibility. As
when dental caries progress to infection of the dental a result, they can be incorporated the cells of soft tissues
pulp. From a materials point of view, BC has superior and bioactive molecules via gelling process [199].
properties compared to plant cellulose (paper points) for
the use in dental RCT. Moreover, research has demon- Conclusion and future directions
strated the tissue regeneration of periodontal cells after The current review clearly shows that based explicitly on
the application of BC hydrogels [190, 191]. cellulose biopolymers, hydrogels are a diverse class of

materials that have widespread applications in the field Cellulose-based hydrogels have been recently modified
of tissue engineering and regenerative medicine. In these using a nontoxic cross-linking agent or cross-linking treat-
areas, scaffolds played a significant role and have been ments, to improve the yield of both the final product and
developed to form temporary, artificial ECMs to support the manufacturing processes. However, further research is
cell attachment and three-dimensional (3D) tissue for- needed to develop more advanced cellulose-based hydro-
mation. Due to their high mechanical strength and ther- gels for use in healthcare and medicine.
mostability, bacterial cellulose derivatives are widely used
for wound dressing and healing, providing a novel method Additional file
for the treatment of epidermal burns. Most interestingly,
the work of researchers across the globe in the fields of Additional file 1: Table S1. α-Cellulose content of some plant products
cellulose hydrogel development and characterization seem [197–204]. Figure S1: Source of some naturally occurring cellulose. a.
hard wood (beech tree); b. cotton tree; c. bamboo; d. Gluconacetobacter
to indicate that hydrogels based on cellulosic biomaterials xylinum; e. ascidians. Figure S2. Hydrogen bonding pattern in cellulose
could be potential candidates for applications in the field molecule. The hydrogen bonding within or between cellulose molecules
of tissue engineering. However, the research outcomes ap- represents its crystalline nature while studying through X-ray diffraction
or NMR technique. Figure S3. Microphotograph showing variation in
pear somewhat different from the promising predictions. morphology of different fibers. a. twisted cotton fibers; b. tracheids of
For example, while using hydrogels in bioengineering ap- spruce wood; c. straight fibers of ramie. Copyright permission from [205];
plications, researchers have encountered a number of simplified model of plant cell wall. d. structure of S1-S3 layer; e-f. Cellulose
assembly with pectin, hemicellulose, and lignin. Copyright permission
problems. These include difficulties in the handling, main- from ([49]; [206–208]). (DOCX 312 kb)
tenance, storage of hydrogels, for example, for hydrogels
designed using bioprinters, which are not as much mech- Abbreviations
anically strong as was theoretically determined. During in 3D: Three-dimensional; AMIMCl: 1-allyl-3-methylimidazolium chloride;
vitro experiments it was more difficult to sterilize scaffold- BC: Bacterial cellulose; BCP: Biphasic calcium phosphate; BMIMCl: 1-butyl-3-
methylimidazolium chloride; BNC: Bacterial nanocellulose; CdHAP: Calcium-
ing structures than, for example, the cell culture media. deficient hydroxyapatite; CMC: Carboxymethyl cellulose;
Sterilizing by means of autoclaving can cause the func- CMCNa: Carboxymethylcellulose sodium salt; DMA: Dynamic mechanical
tional properties of cellulose-based hydrogels to change. analysis; DMAc: Dimethylacetamide; DMSO/TBAF: Dimethysulfoxide/
tertrabutylaluminium fluoride trihydrate; DP: Dope characteristics;
However, their sterilization is necessary since the use of EBs: Embryonic bodies; ECM: Extracellular matrix; GAGs: Glycosaminglycans;
hydrogels without proper sterilization could be a large HEC: Hydroxyethylcellulose; hESCs: Human embryonic stem cells;
source of contamination during in vivo and in vitro exper- HPC: Hydroxypropyl cellulose; HPMC: Hydroxypropylmethyl cellulose;
ILs: Ionic liquids; IR: Infrared; LiCl: Lithium chloride; MBC: Modified bacterial
iments in laboratory. Researchers have also often encoun- cellulose; MC: Methyl cellulose; MSCs: Mesenchymal stem cells;
tered difficulties while loading hydrogels with drugs or NaOH: Sodium hydroxide; NFC: Nano-fibrillated cellulose; NMMO: N-
cells for controlled drug delivery. Further research into methylmorpholine-N-oxide; NMR: Nuclear magnetic resonance; PC: Plant
cellulose; PM: Patterned macroporous; ROS: Reactive oxygen species;
hydrogels will be required for the development of new SA: Sodium alginate; SEM: Scanning electron microscopy; Si-HPMC: Silated-
methods and protocols in order to overcome these limita- hydroxypropylmethyl cellulose; SWCNTs: Single-walled carbon nanotubes;
tions. Despite these issues, the use of BC hydrogels TGA: Thermo-gravimetric analysis; UV: Ultra-violet; WXRD: Wide-angle X-ray
diffraction
compared to plant-derived or manmade hydrogels is cur-
rently on the rise due to the cost-effective production of Acknowledgements
BC hydrogels using stirred-tank or static bioreactors. The authors would like to thank Prof. Lim for his continuous support to write
the manuscript.
However, more needs to be done to improve plant-derived
cellulosic gel production (PC hydrogels). The use of Funding
cellulose-based hydrogels in tissue engineering has both This research was supported by ‘Co-operative Research Program for
advantages and disadvantages, the latter of which will Agriculture Science and Technology Development (No. PJ012854012017)’,
Rural Development Administration, Republic of Korea and ‘Basic Science
need to be resolved before cellulosic hydrogels can be Research Program’ through the ‘National Research Foundation of Korea’
more widely applied. funded by the Ministry of Education (No. 2018R1A6A1A03025582) and the
Researchers are also working to improve our under- ‘National Research Foundation of Korea’ (NRF-2016R1D1 A3B03932921).
standing of the mechanism behind the molecular inter- Availability of data and materials
action involved in cellulose ECM materials so that, in Not applicable.
the future, materials that mimic natural ECMs in terms
of their composition, structural characteristics, and Authors’ contributions
SDD wrote the manuscript. DKP and KTL reviewed the manuscript, edited,
mechanical properties can be developed. The proper and provided feedback. KTL read and approved the final manuscript.
development of 3D scaffolding materials could be used
to replace conventional tissue engineering techniques to Ethics approval and consent to participate
Not applicable.
a great extent. Cellulose- based hydrogels have import-
ant applications in tissue engineering due to their high Consent for publication
biocompatibility and environment- friendly properties. Not applicable.

Competing interests 19. Martens PJ, Bryant SJ, Anseth KS. Tailoring the degradation of hydrogels
The authors declare no competing interests. formed from multivinyl poly (ethylene glycol) and poly (vinyl alcohol)
macromers for cartilage tissue engineering. Biomacromolecules. 2003.
https://doi.org/10.1021/bm025666v.
Publisher’s Note 20. Ferruti P, Bianchi S, Ranucci E, Chiellini F, Piras AM. Novel agmatine-
Springer Nature remains neutral with regard to jurisdictional claims in containing poly (amidoamine) hydrogel as scaffolds for tissue engineering.
published maps and institutional affiliations. Biomacromolecules. 2005. https://doi.org/10.1021/bm050210+.
21. Nayak S, Lee H, Chmielewski J, Lyon LA. Folate-mediated cell targeting and
Author details cytotoxicity using thermoresponsive microgels. J Am Chem Soc. 2004.
1 https://doi.org/10.1021/ja0474143.
Biorobotics Laboratory, Department of Biosystems Engineering, Kangwon
National University, Chuncheon, Republic of Korea. 2The Institute of Forest 22. Gao D, Xu H, Philbert MA, Kopelman R. Ultrafine hydrogel nanoparticles:
Science, Kangwon National University, Chuncheon 24341, Republic of Korea. synthetic approach and therapeutic application in living cells. Angewandate
Chemie Int Edn. 2007. https://doi.org/10.1002/ange.200603927.
Received: 24 February 2019 Accepted: 10 May 2019 23. Tomatsu I, Hashidzume A, Harada A. Contrast viscosity changes upon
photoirradiation for mixtures of poly(acrylic acid)-based α-cyclodextrin and
azobenzene polymers. J Am Chem Soc. 2006. https://doi.org/10.1021/
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Functional cellulose-based hydrogels as

Introduction materials contributes to their biocompatibility. Thus,

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Table 1 Polymorphs of cellulose

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Fig. 4 Advantages of the use of cellulose-based hydrogels for tissue engineering

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Table 2 List of some bacteria producing cellulose

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proliferation level of human mesenchymal stem cells Wound dressing materials

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was found to stimulate the healing of thermal skin Surgical implants

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185. Baptista A, Ferreira I, Borges J. Cellulose-Based Bioelectronic Devices. InTech.

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