Introduction

The usage of non-renewable sources to meet all the demands in every aspect of life, to such a

degree that the whole balance of the system comprising of the living and non-living species

starts to get imbalanced, causing environmental instability. Health problems, climatic change,

and the depletion of fossil fuel reserves when people realized the impacts of the constant

exploitation of these non-renewable or petroleum-based products causing environmental

pollution. This happens when the rate of consumption of fossil reserves outruns the rate of

regeneration of fossil reserves. Then, the scientific community started to look for an

alternative source where they met the advantageous applicability of sustainable renewable

products. From the beginning of the 21st century, the scientific community has put their trust

in a group of different biopolymers such as starch, pectin, hemicellulose, chitosan, alginate,

gelatine, collagen, elastin, and cellulose for developing more sustainable biomaterials. Since

then, a vast number of scientific studies exploiting these biomaterials in every discipline of

applications ranging from biomedical to material engineering applications have been

elucidated. The high degree of biodegradability, biocompatibility, and bio-availability, along

with promising mechanical, structural, chemical, and biological properties, enlightens the

need of utilizing these biopolymers for various applications [1]. Among these biopolymers,

cellulosic materials have received tremendous attention in the research and scientific

community.

Cellulose forms the principal component of the plant cell wall. The cellulose comprises 40% of all

organic matter and constitutes 40–50%, which is nearly half of the total biomass of a plant with an

annual production of approximately 10 10 tons [2, 3]. The plant cell wall is composed of a primary and

secondary wall, and the secondary wall, in turn, is composed of three layers. The middle layer of the

secondary cell wall has cellulose in the form of cellulose microfibres (CMFs). Each microfibre is

composed of elementary nanofibrils, which are bound together helically with inter- and intra-

1
molecular hydrogen bonding forming microfibres. Cellulose in the plant cell wall is present in the

form of a composite material along with hemicellulose and lignin. The cellulose microfibres act as a

reinforcement in the matrix composed of hemicellulose, lignin, pectin, and other organic compounds.

Lignin acts as a binder between cellulose and hemicellulose [4]. The cellulose (C6H10O5)n molecule is

a homopolymer of anhydrous-D-glucose units in chair conformation linked by β-1,4-glycosidic

linkages.

The extensive presence of the hydroxyl groups in the cellulose molecule helps in hydrogen bonding

formation resulting in the fibrillar structure. Another consequence of this hydrogen bonding might

include the formation of crystalline and amorphous regions in the cellulose fibres. The intense inter-

and intra-molecular hydrogen bonding cause the crystallinity, good physicochemical properties,

rigidity, and un-reactiveness towards the water and other chemical reagents, whereas the weak

hydrogen bonds cause the formation of amorphous domains with increased hydrophilicity, flexibility,

and accessibility,[5]. Nishiyama et al. studied the crystalline nature of cellulose and concluded that

the native cellulose is a mixture of two crystalline polymorphs, namely I α and Iβ ,[6]. The structure

and properties of the nanocellulose largely depend on the source and method of extraction. Higher

plants contain a high amount of cellulose with greater crystallinity and mechanical properties,

whereas lower plants or agricultural residues have a lesser amount of cellulose with decreased

crystallinity and mechanical properties [7]. Being biocompatible is necessary for the delivery of drugs

in vivo. Many studies conducted have reported that nanocellulose in all pure forms does not exhibit

any cytotoxicity in vivo. Mostly, Bacterial nanocellulose-based drug delivery systems possess no

toxicity. However, the biocompatibility of nanocellulose depends on its structural characteristics,

applied concentrations, cell type, exposure time, and the research models. The nanocellulose uptake

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into cells is mostly low, which does not induce obvious oxidative stress and does not cause other

obvious cytotoxic and genotoxic effects [8].In the present work, we summarized the most important

recent works carried out in the field of nanocellulose being used as a drug delivery vehicle, with the

delivery of medications through three main routes, oral, transdermal, and topical, that have been

reported to be effective. This review compiled is other than that covered by Huo et al. [8], Sanga

Pachuau ,[9] Gumrah Dumanli ,[10] Salimi et al.[11], Khine and Stenzel [12], and Raghva et al.[13]

on nanocellulose for drug delivery application.

Bacterial Cellulose and its properties

Cellulose is the most liberal and viable sustainable polymer, and it is the one that is

predominantly utilized. Though cellulose is considered a plant-based product, several

fermentation techniques showed positive results in producing alternative sources of cellulose

from bacterial genera. Though the BC and plant fiber have different physical and

chemical properties, they have a similar structure with two discrete cellulosic subunits I and

II [14]. The polymerization degree of cellulose varies from 2000–6000 in BC to 13,000–14,000

in plan cellulose. The 3D mesh-like structure of the cellulose prevents microbial attack.

The b-1 4 glycosidic linkage is responsible for the free surface hydroxyl group in the

surface area of the cellulose. BC is 10–50 nm in diameter with 100–1000 nm in length [15].

Hydrogen bonds are plentiful within cellulose due to the presence of a

large number of oxygen atoms and hydroxyl groups [16]. Parallel stacking is observed

within cellulose due to the presence of van derWaals force and in the development of crystalline

nanofibers[17]

3
Fig:Inter and intramolecular hydrogen bonding between bacterial cellulose[18]

Source of bacterial cellulose

Very few bacterial species can synthesize cellulose, among which is Gram-negative

bacterium Gluconacetobacter xylinus (conventionally known as Acetobacter xylinum) [19].

Researchers discovered the bacterium responsible for the production of cellulose as microfibrils

on a large scale. This group of Gram-negative, rod-shaped aerobic bacteria,

due to the high yield of cellulose, is considered to be a model organism for the production

of BC [20] for commercial fermentation. Apart from this group, BC can be synthesized by other

bacterial genera such as Agrobacterium spp., Acetobacter spp., Azotobacter, Rhizobium spp., Sarcina,

Alcaligenes, and Pseudomonas [20]. Acetobacter, a common vinegar bacterium, is a non-

photosynthetic advanced purple bacterium that can convert glucose, glycerol, sugar, or any other

organic substances into pure cellulose [21]. In the growth medium, microfibrils are merged

from each synthetic site to form large-ribboned cellulose, which is non-motile due to the

formation of floating pellicles with the entangled associated cells. Apart from plant host

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cells, tumor[19]-forming bacterium Agrobacterium tumefaciens also secretes cellulose fibrils

which surround the cell in order to promote cell attachment and virulence [22]. Both

Agrobacterium tumefaciens and Gluconacetobacter xylinus can be grown widely in a suitable

medium, whereas mutants of both species are impaired in cellulose biosynthesis. The

genus Komagataeibacter has also been found to be noteworthy for its cellulose producing

ability[23].The production of cellulose take place under the presence of various types of precursors,

including hexanoates, hexoses, the three carbon compounds pyruvate, dihydroxyacetone,

pyruvate, and glycerol, along with the presence of four-carbon compounds such as dicarboxylic

acid, which is associated with citrate cycle. The rate of synthesis of the BC remains

unaffected by the inhibitors that are associated with protein synthesis at the resting stage

of the bacterial cells. It has been observed that bacteria similar to A. xylinum retain the

cytoplasmic enzymes when incubated with UDP-[14C] glucose in the presence of bis-(30,50)-

cyclic diguanylic acid (c-di-GMP) or GTP. A. xylinum is the model organism in which the

entire phenomenon of the development of BC can be observed fromglucose. Themechanisms

of phosphorylation of glucose in the presence of glucokinase followed by the process of

isomerization of glucose-6-phosphate to glucose-1-phosphate in the presence of the enzyme

phosphoglucomutase act as important steps in the synthesis of BC.

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Figure: Biosynthesis of cellulose I and cellulose II from glucose and fructose in bacterial cell .

Nanocellulose

Cellulose-based particles with at least any one dimension in the nanometre scale are given the generic

name “Nanocellulose”. They have a diameter of less than 100 nm and several micrometres in length

[4, 24]. The inter- or intra-molecular hydrogen bonding between the elementary fibres of microfiber is

broken down via any chemical or mechanical treatment to yield nanocellulose. They are

biodegradable, lightweight, have a large specific area, low density, and with stiffness greater than

Kevlar fibre, a strength-to-weight ratio higher than stainless steel, and a tensile strength greater than

cast iron [25-27].Nanocellulose can be derived from different sources, such as plants, agricultural

residues, aquatic animals, and microorganisms.Among agromass, nanocellulose has been reported to

synthesize from corncob, banana leaves, cotton, rice husk, sugarcane bagasse, wheat straw, coconut

husk, and wood [28]. However, there are also reports for the extraction of nanocellulose from ginger

[29], coffee grounds [30], durian rind waste [31], lemon seeds [32], pea hull [33], rubber wood [34],

etc. Nanocellulose can also be obtained from aquatic organisms such as tunicates and microorganisms

such as fungi, algae, and bacteria.[6, 35]. The source and extraction methods determine the degree of

polymerization, polymer chain length, and the properties of the nanocellulose; for example, the degree

of polymerization of cellulose obtained from wood and cotton, respectively, are 10,000 and 15,000

anhydrous glucose units [28]. Depending on the source and morphological characteristics,

nanocellulose can be divided into three main forms: Cellulose nanocrystals (CNC/NCC), Cellulose

Nanofibrils (CNF), and Bacterial nanocellulose (BNC). They all have same chemical composition but

differ in structure, particle size, purity, crystallinity, and other physicochemical properties [36, 37].

6
11.4 Preparation
methods/nanocellulose
synthesis
methods
11.4.1 Pretreatment methods
Nanocellulose Synthesis Methods

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. Enzyme hydrolysis
Enzymes with the ability of selective hydrolysis, such as laccase, can degrade or

modify the lignin and hemicellulose contents without disturbing cellulose content

[5,47]. Since cellulosic fibers contain many different organic compounds as a com-

posite structure, a single specific enzyme cannot degrade the fiber. The following set

of enzymes are required to decay extra cellulose compound [48]:

1. Cellobiohydrolases: A & B type cellulases—attack greatly on crystalline cellulose

2. Endoglucanases: C & D type cellulases—attack disordered structure of cellulose

Pääkkö and Ankerfors [43] produced NFC from bleached softwood pulp. In this

method a mild enzymatic hydrolysis was applied followed by refining and homog-

enization. It was observed that the mild hydrolysis using endoglucanase increased

the aspect ratio without a harsh reaction compared to acid hydrolysis. An additional

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advantage of enzyme pretreatment is that it increases the solids level, which allows

a smooth pass during HPH processing [49].

Alkaline–acid
Alkaline–acid pretreatment is the most common method used for lignin, hemicel-

lulose, and pectin solubilization before mechanical isolation of NFC [10,11,51]. This

method included the following steps [52]:

1. Sodium hydroxides (NaOH). Soaking fibers in 12–17.5 wt% solution for 2 hours. This raises

the surface area of cellulosic fibers and eases the hydrolysis.

2. Hydrochloric acid (HCL). Soaking fibers in 1 M solution at 60–80°C. This solubilizes the

hemicelluloses.

3. Sodium hydroxides (NaOH). Treating with 2 wt% solution for 2 hours at 60–80°C. This

disrupts the lignin structure, and breaks the linkages between carbohydrate and lignin.

Alkaline pretreatment is an effective method that can improve cellulose yield from

43% to 84% [53]. It also helps to removed lignin and hemicelluloses partially from

soy hull fibers and wheat straw.

3.Ionic liquids
Ionic liquids (ILs) are organic salts having special properties such as nonflammabil-

ity, thermal and chemical stability, and infinitely low vapor pressure [54,55]. It is an

increasing interest of researchers to study as solvents of cellulosic materials. Li, Wei

[56] treated sugarcane bagasse with 1-butyl-3-methylimidazolium chloride [(Bmim)

Cl] as ionic liquid and followed the high-pressure homogenization (HPH) technique

to prepare NFC. The pulp passed through homogenizer without clogging; these fibers

were then precipitated in water solution and regenerated by freeze-drying.

Mechanical process
Cellulosic materials are required to go through mechanical treatment for defibril-

lation. Pretreatment processing, either by chemicals or enzymes, is done before

mechanical fibrillation to ease the process [57]. Chemical treatments help in widening

9
the space between hydroxyl groups, increasing the inner surface, altering crystal-

linity, and breaking cellulose hydrogen bonds, thus enhancing surface areas, which

helps boost the reactivity of the fibers [58]. There are many mechanical methods for

converting cellulosic fiber to nanocellulose, such as homogenizing [59–61], microflu-

idization [62,63], grinding [64], cryocrushing [65], and high-intensity ultrasonication

(HIUS) [66–68].

High-pressure homogenization
High-pressure homogenization (HPH) is an efficient method for refining of cellulosic

fibers. It was introduced in 1983, to use nanofibril cellulose from wood pulp [69,70].

This procedure is very simple and does not involve addition of any organic solvents

[71]. In this process, cellulosic pulp is passed through a very small nozzle at high

pressure. There are many types of forces that can be applied on cellulose pulp such as

high velocity and pressure, as well as impact and shear forces, which influence fluid

Cellulose-Reinforced Nanofibre Composites268

to generate shear rates in the stream and decrease the size of fibers to the nanoscale

[66]. Many researchers have used HPH for many other raw materials, such as bleached

sugar beet by Leitner etal. [72], extraction of prickly pear by Habibi etal. [73], etc.

There are some drawbacks in HPH, such as fiber clogging. Cellulosic fibers must be

chopped very small and passed through HPH to avoid this problem. Mechanical pre-

treatments are before HPH to produce nanofibers from kenaf bast fiber [74].

Micro fluidization
Microfluidizers work similar to HPH in the production of nanocellulose fiber.

Grinding
Grinding is another strategy to break up cellulose into nanosize fibers. In this process,

pulp passes through a couple of stones, where one stone is fixed while the other stone

rotates. This mechanism provides shear forces to break down the hydrogen bond and

cell wall structure of fibers and convert pulp into nanoscale fibers [59]. Wang and

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Drzal [76] used a commercial stone grinder to produce NFC from bleached eucalyp-

tus pulp, which helps to study the relation between energy consumption and fibril-

lation time as a function of crystallinity. Friction of stones generates heat due to the

fibrillation process, which helps to evaporate water content and raise solid content,

which takes 11 hours to boost specific fibrillation energy.

Cryocrushing
Cryocrushing is another mechanical method used to break the cellulose wall into

nanosize fibers. In this method, fibers are kept in water and cellulose absorbs water

in its cavity. Water-soaked cellulose is immersed in liquid nitrogen, which solidifies

the water content, and is subsequently crushed by mortar and pestle [78]. Applying

high-impact force on frozen cellulosic fibers leads to rupture due to applied pressure

through ice crystals resulting in conversion to nanocellulose [59]. Wang and Sain [51]

studied the HPH and cryocrushing processes to produce nanofibers from soybean

stock and observed the diameter of nanofibers in the range of 50–100 nm through

transmission electron microscopy (TEM).

Nanocellulose: Preparation methods and applications 269

High-intensity ultrasonication

The HIUS process uses hydrodynamic forces of ultrasound with oscillation power

to isolate cellulose fibrils [79]. In this process, cavities in cells of cellulose convert

into powerful mechanical oscillating power. Molecules absorb the ultrasonic energy

of high-intensity waves and consist of formation, expansion, and implosion of micro-

scopic gas bubbles [80]. Various studies have been reported dealing with the synthesis

of nanocellulose fiber from cellulose through HIUS and oscillating power [66–68].

Wang and Cheng [81] studied the effect of temperature, concentration, power, size,

time, and distance from probe tip on degree of fibrillation of some cellulose fibers

using HIUS. It was concluded that high temperature, high power, and short fiber size

11
are required to make better fibrillation. It is also reported that a combination of HPH

and HIUS increased the fibrillation and provided uniformity in nanofibers compared

to HIUS alone.

Ball milling process

Ball milling is a mechanical process in which cellulose suspension is placed in a hol-

low cylindrical container for the production of CNF. This hollow cylindrical container

is partially filled with balls made up of ceramic, zirconia, or metal; the container

rotates and breaks cellulose cell walls through the high-energy collision between

the balls. Zhang, Tsuzuki [82] studied various factors affecting production of CNF

such as ball size, ball-to-cellulose weight ratio, grinding time, moisture content, and

carboxylic charge. Maintaining homogeneity of the produced CNF is always a major

challenge in this method.

Chemical hydrolysis

The NFCs produced by mechanical methods consist of alternating crystalline and

amorphous regions within the single cellulose domains [19]. In order to dissolve

the amorphous domain and permit longitudinal cutting of microfibrils, strong but

controlled acid hydrolysis treatment is performed. The obtained nanocellulose, as an

aqueous suspension exhibits crystallinity greater than 90%, are termed as CNCs. In

the acid hydrolysis process, the hydronium ion enters the amorphous regions of cellu-

lose chains and promotes the hydrolytic cleavage of the glycosidic bonds. A mechani-

cal treatment for nanocellulose dispersion, such as sonication, is required to prevent

agglomeration.

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Cellulose Nanocrystals (CNC)

Cellulose nanocrystals are rod- or needle-shaped nanocellulose which are mainly composed of

crystalline regions with particle sizes ranging from 2–20 nm in diameter and 100–500 nm in length

[38]. They are obtained via acid hydrolysis of the native nanocellulose. The acid hydrolysis procedure

breaks down the amorphous regions of the nanocellulose chains hydrolysing weak hydrogen bonds

and glycosidic bonds, leaving behind the crystalline portion of the nanocellulose in reduced sizes.

Different types of acids are employed for acid hydrolysis, which includes HCl, H 2SO4, HBr, H3PO4,

H2C2O4, ionic liquid, metal salt catalysts, and solid or gaseous acids. Some types of pre-treatment

procedures are also conducted before the hydrolysis step. The alkaline treatment is conducted for the

removal of hemicellulose, and delignification or bleaching is conducted for the removal of lignin [38,

39]. The type and the concentration of acid influence crystallinity, morphology, physicochemical

properties, and dispersibility of nanocellulose [11].The use of mineral acid is a matter of concern

when it comes to corrosion of the reactors and safety concerns [40]. The ionic liquid treatment

removes the amorphous regions, hemicellulose, and lignin from the cellulose yielding high-quality

CNCs. The well-known ionic liquids include 1-butyl-3-methylimidazolium hydrogen sulphate

(bmimH2SO4), 1-allyl-3-methilimidazolium chloride , tetrabutylammonium acetate, 2-hydroxyethyl

ammonium hydrogen sulphate [41, 42]. Transition metal salt catalyst also acts as a catalyst to remove

the amorphous regions of cellulose [43].

Cellulose Nanofibrils (CNF)

Cellulose nanofibrils (CNF/NCF) are long entangled nanocellulose fibres with sizes ranging from 1–

100 nm in diameter and 100 nm to several micrometres in length [4]. The CNF contains both the

amorphous as well as crystalline regions. They are longer in length, hydrophilic, flexible with a high

aspect ratio, and have good accessibility for chemical modification [44]. They are commonly prepared

using mechanical approaches such as ultrasonication, high-pressure homogenization, steam explosion,

13
grinding, micro fluidization, or cryocrushing, in which the pressure acts as the centre of fibre causing

the defibrillation of the microfibers to nanofibers leaving the amorphous region behind, along with the

crystalline region [11, 38, 45]. The greater the number of cycles of mechanical disintegration, the

smaller will be the size of the nanofibers [7]. The main drawback of mechanical disintegration is the

high-energy consumption and clogging of the equipment. Certain chemical approaches, such as

TEMPO (2,2,6,6- tetramethylpiperidine-1-oxyl) mediated oxidation, organosolv treatments, partial

carboxymethylation, and enzymatic hydrolysis, are also employed before the mechanical

defibrillation procedure to make the extraction process simpler and obtain nanofibres [4, 7, 46, 47].

TEMPO-oxidized CNF has high aqueous dispersibility due to the profound number of carboxyl

groups present, high morphological stability, and crystallinity, and the approach is simple and

profitable [48]. Although TEMPO CNFs have higher fibrillation, their use is not always the best and

depends on the final application. Mechanical pretreatments have better properties than TEMPO [49].

Bacterial Nanocellulose (BNC)

Bacterial nanocellulose (BNC) is produced by certain bacteria through a metabolic pathway involving

the fermentation of carbohydrates[4]. The most common bacteria reported for the synthesis of

bacterial nanocellulose are Acetobacter xylinum, Pseudomonas, Azotobacter, Aerobacter, Rhizobium,

and Xanthococcus . They are characterized by high crystallinity, high purity, higher

specific area, higher mechanical properties, higher liquid absorption capacity, and good

biocompatibility. The high purity of BNC is because of the absence of other organic compounds such

as hemicellulose, pectin, lignin, etc. The bacterial pathway for the synthesis of BNC involves two

steps: polymerization and crystallization in two modes of culture: static and dynamic approaches. The

glucose units produced get polymerized to form β-1,4 linear glucan chains, which are secreted

extracellularly and later then crystallize to produce nanoribbons of nanocellulose [50]. The physical,

mechanical properties and morphological characteristics of the BNC depend on the type of approach

followed, and the type can be decided as per the application of the nanocellulose. The mechanical

properties of the static culture-derived BNC are low, and it needs a longer duration time and a large

14
cultivation area [51, 52]. An optimum condition of pH ranging between 3 and 7 and temperature

between 25 and 30 °C should be maintained with saccharides as the carbon source . The high purity

and good biocompatibility make the bacterial nanocellulose to be used in applications related to the

biomedical field, such as tissue engineering applications, wound dressing, shape-memory, sensing,

drug delivery systems, protein delivery systems, or plasma delivery systems.

Nanocellulose has been the best platform for drug delivery applications in different forms, such

as nanoparticles, tablets, aerogels, hydrogels, and membranes, because of its high surface area,

mechanical strength, aspect ratio, non-immunogenic and superior bio-compatibility [53, 54]. The

nanocellulose effectively transports and aids in the controlled release of the incorporated drug locally.

The high surface-to-volume ratio helps in better cell adhesion and absorption. For drug delivery

systems, biocompatibility, biodegradability, and bio-availability are all important factors with critical

significance. All the biomedical applications related to using nanocellulose materials centre on their

properties of low cost, easy availability, biocompatibility, outstanding mechanical properties, and low

cytotoxicity. CNFs and CNCs have been regarded to be an alternative to other carbon-based

nanofillers being utilized in drug delivery applications. BNC has been commercially utilized for

wound dressing and other skin-related diseases [55].

Surface moderation

The nanocellulose, with wide advantages such as nano dimensions, recyclability, biocompatibility,

low cytotoxicity, biodegradability, low ecological toxicity, and high surface area, finds application in

drug delivery systems [56]. Common forms of nanocellulose used for drug delivery applications

include nanoparticles, hydrogels, aerogels, membranes, and films. They are administered either

externally or internally. The external administration includes the oral supplement, while the internal

includes transdermal administration. The biocompatibility, surface charge, particle size, and

modification determine effective drug delivery systems. The profound presence of surface hydroxyl

groups on nanocellulose paves the way for the modification of the biopolymer for its application as

15
per the nature of the drug. The hydrophilic nature and high surface area of the nanocellulose help in

the adherence of the hydrophilic drugs on it and the constant release of the drug [57].The surface

chemistry of the nanocellulose can be adequately tuned as per the type of drug. The hydrophobic drug

finds it difficult to adhere to the nanocellulose since the biopolymer is hydrophilic. Hence, the

hydrophobization of the nanocellulose has to be carried out via appropriate chemical modifications.

The aggregation of the nanoparticle due to its nano-size, sensitivity to moisture, and low thermal

stability of the nanocellulose causes adverse effects on its use as a delivery system [58]. In this case,

surface modifications can induce steric and electrostatic effects along with decreasing its moisture

sensitivity and increasing thermal stability.

Two types of surface modifications can be carried out: (a) covalent modifications including

esterification, etherification, oxidation, silylation, amination, amidation, polymer grafting,

carbamation, sulphonation, phosphorylation [13,54,58], (b) coating of CNC with the cationic

surfactants, such as CTAB (cetyltrimethylammonium bromide), which helps in the adherence of the

hydrophobic drugs and later the sustained controlled release of these hydrophobic drugs such as

curcumin, non-steroidal inflammatory drugs, etc. [59,60,61]. Apart from these, natural surfactants can

also be used to hydrophobized the CNCs. The modification approach greatly influences the stability

of the delivery systems [62]. The type of modification varies the hydrophobic interactions and

covalent binding for the drug release.

16
Implementation

The unique characteristics of nanocellulose make it suitable candidate for drug delivery applications

in the pharmaceutical field. Nanocellulose is one of the apt candidates for drug delivery systems due

to its inherent properties such as biocompatibility, biodegradability, low toxicity, and easy availability.

Mostly drug delivery systems in nano forms can enhance release in a sustained fashion, loading

hydrophobic drugs and increasing drug half-life. The release time of drugs can vary from several

minutes to days. It depends on the type of nanocellulose used and its properties, the active

pharmaceutical ingredient, and the properties of the membrane product. Different forms of

nanocellulose-based drug delivery systems have been studied, and they have been categorized into

microparticles, hydrogels, beads, membranes, and films. In addition, the administration routes can be

classified into two types, internal and external. Internal routes include the oral route, and external

routes include transdermal and topical/local routes of administration [63]. Several reviews have been

published and discussed the various applications of nanocellulose in drug delivery and other

biomedical applications [1,13,64,65].

17
Oral Drug Delivery

Nanocellulose-based membranes served as oral administration routes for various drugs. A

nanocellulose (NCC)-based oral administration system for the delivery of anti-cancer drugs, such as

docetaxel, paclitaxel, and etoposide, was reported by Jackson et al. [71]. The loading of the drug was

achieved by modification of the NCC surface by binding a cationic surfactant CTAB that resulted in

an increase in the zeta potential of NCC in a concentration-dependent manner. All the results revealed

a controlled release of drugs over several days [60,61,71,72].Thin films of nanoporous morphology

comprising chitosan and nanocrystalline cellulose were fabricated for the release of the anti-cancer

drug, doxorubicin hydrochloride, and hydrophobic drug, curcumin. The electrostatic and hydrogen

bonding interactions made the assembly strong enough to load the two drugs for sustained delivery

under physiological conditions. The interactions were studied using molecular docking studies, and

they found that these films are good carriers for other lipophilic drugs also [ 73]. Based on different

studies carried out by Emara et al., it was found that nanocellulose-based systems were suitable

supports for the delivery of poorly water-soluble drugs wherein the solubility increases with an

increase in nanocellulose content [74]. Zheng et al. [75] prepared CNF/alginate and MCC/alginate

beads which were utilized for the release of metformin hydrochloride drug. The incorporation of CNF

provided improved swelling and mechanical properties, whereas alginate served as a drug delivery

vehicle. However, based on the reports, the cumulative release through CNF/alginate beads was 10%

greater than that of MCC/alginate beads, and a sustained release occurred over 240 min.

18
 Controlled drug release systems based on sustainable feedstock were developed by Patil et al.

[76] employing nanocomposites of cellulose nanofibers obtained from waste sugarcane bagasse onto

starch urea-formaldehyde granules for applications in the agricultural field. The presence of CNF

inhibited the initial release of the model encapsulant, dimethyl phthalate (DMP); however, the overall

release rate is enhanced, thereby paving the way for a controlled-release drug carrier.

A study by Thomas et al. revealed that polymer nanoparticles could serve as efficient oral drug

delivery carriers as they decrease the problems associated with harsh gastric conditions and provide

controlled release of the drug in the target area. They have synthesized alginate/cellulose hybrid

polymer nanoparticles for the delivery of rifampicin drugs. The mucoadhesive nature of alginate

beads and the small size of cellulose nanoparticles combined make it an efficient oral drug delivery

system. Studies show that only 15% of the drug is released within 2 h, confirming that the system

protects the drug from harsh gastric conditions [77].

Nanocellulose-based beads are also reported to act as a delivery vehicle which is reported by

Supramanian et al., where they produced magnetic nanocellulose alginate hydrogel beads for the

transport of the drug Ibuprofen. They prepared magnetic nanocellulose m-CNC from rice husk, then

modified it with iron oxide by co-precipitation method, which, on incorporation into the beads,

increases the integrity and swelling percentage of the beads while also decreasing the drug release rate

[78].

Hivechi et al. in 2019 reported the preparation of NCC-reinforced polycaprolactone nanofibers

(PCL) and studied the controlled release of tetracycline hydrochloride (TCH) drug. It was reported

that increasing the amount of NCC in the PCL nanofibers was responsible for the slow release of the

drug [79].

Targeted drug delivery of curcumin was studied using a novel nanocellulose-based system for

controlled release of the drug at pH-5.5 at a loading capacity of 83%. The nanocellulose was

conjugated with folic acid and better cross-linked with polymers, glycidyl methacrylate (GMA), and

hydroxyethyl methacrylate (HEMA). From the studies, it was established that the loaded NC system

with curcumin was an efficient killer of cancer cells. The increased loading efficiency was explained

due to the hydrogen bonding interactions between curcumin and polymeric system [80].

19
 Bacterial nanocellulose composite materials have also been used as drug delivery carriers. In a

work reported by Valo et al. [81], they prepared nanocellulose aerogel scaffolds from bacterial

nanocellulose, which showed good, sustained drug release character. Additionally, in another work

reported by Shi et al. group, BNC sodium alginate composites (BC/SA) cross-linked by calcium

chloride [82] were suitable for the delivery of ibuprofen drug via dual-stimuli responsive, controlled

drug delivery by pH- and electro-response. Ahmad et al. prepared biocompatible and mucoadhesive

BNC-g-poly (acrylic acid) hydrogels as enteric-coated systems and revealed a pH-responsive swelling

behavior of the prepared hydrogels with controlled delivery of albumin at increased pH of 6.8 [83].

Local Application

The active pharmaceutical ingredient is delivered at or near the target site. Biodegradable, non-toxic

films comprising CNC/AFNC polymers with good mucoadhesive properties have been prepared by

Lauren and co-workers, which are suitable options for periodontic applications where a high local

dose is required. Bioadhesive activator agents such as mucin and pectin have been used for the rapid

release of metronidazole drugs. Studies showed that there is a rapid release rate that ensures inactivity

after the detachment of the patch [84]. Injectable hydrogels (Figure 2) from cellulose nanocrystals

were obtained by salt-induced charge screening. These pH-responsive drug carriers were found

suitable for the in vitro release of a model protein (BSA), readily water-soluble doxorubicin (DOX),

poorly water-soluble tetracycline (TC), where TC

showed a burst release rate within 2 days, and the

latter two had a sustained release for 2 weeks.

However, only DOX was found to be released fully

from the hydrogel [85].

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