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Review

Nanocellulose as an Avenue for Drug Delivery Applications: A Mini-Review

by
Rini Thresia Varghese
1,2,*,
Reeba Mary Cherian
1,2,
Cintil Jose Chirayil
1,*,
Tijo Antony
1,2,3,
Hanieh Kargarzadeh
4,* and
Sabu Thomas
2
1
Department of Chemistry, Newman College, Thodupuzha 685585, Kerala, India
2
School of Chemical Sciences, Mahatma Gandhi University, Priyadarshini Hills, Kottayam 6865560, Kerala, India
3
Department of Chemistry, Pavanathma College, SH40, Murickassery 685604, Kerala, India
4
Center of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Lodz, Poland
*
Authors to whom correspondence should be addressed.
J. Compos. Sci. 2023, 7(6), 210; https://doi.org/10.3390/jcs7060210
Submission received: 31 March 2023 / Revised: 11 May 2023 / Accepted: 16 May 2023 / Published: 23 May 2023
Browse Figures
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Abstract

:
A controlled and sustained release of an accurate dose of medications into a system can cure diseases associated with the human body. Different potential drug delivery vehicles, which are biocompatible and non-toxic, have been synthesized and developed for the controlled release of drugs targeting specific organs or areas. A delivery agent procured from sustainable sources with less or no side effects is more advantageous in terms of compatibility and toxicity. Among a few bioresources, one such material obtained is the nanocellulose-based drug delivery vehicle. They are ideal for the transport and release of drugs since they are biocompatible and possess good mechanical properties. A major characteristic feature of nanocellulose is that different surface modifications are possible due to the presence of a large number of hydroxyl groups, which can strengthen the interactions required with the therapeutic drug for delivery. Pharmaceutical drugs can strongly bind to the nanocellulose material through electrostatic interactions, and the release can occur in a sustained manner to the target within a few minutes to several days. In this mini-review, we have tried to summarize some of the most important works carried out in the field of nanocellulose-based drug delivery, different types of nanocellulose, its surface modification possibilities, and delivery of medications through three main routes, oral, transdermal, and topical, that have been reported to be effective.

1. Introduction

The world has been inclined to use non-renewable sources to meet all its demands in every aspect of life for so long, 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. That is when the people realized the impacts of the constant exploitation of these non-renewable or petroleum-based products causing environmental pollution, health problems, climatic change, and the depletion of fossil fuel reserves. 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, gelatin, collagen, elastin, and cellulose for developing more sustainable biomaterials [1]. 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 the utilizing these biopolymers for various applications [2]. 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 1010 tons [3,4]. 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-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 [5]. 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 fibers. 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 [6,7]. Nishiyama et al. studied the crystalline nature of cellulose and concluded that the native cellulose is a mixture of two crystalline polymorphs, namely Iα and Iβ [8,9]. 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 [6]. 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 into cells is mostly low, which does not induce obvious oxidative stress and does not cause other obvious cytotoxic and genotoxic effects [10].
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. [10], Sanga Pachuau [11], Gumrah Dumanli [12], Salimi et al. [13], Khine and Stenzel [14], and Raghva et al. [1] on nanocellulose for drug delivery application.

2. Nanocellulose

Cellulose-based particles with at least any one dimension in the nanometer scale are given the generic name “Nanocellulose”. They have a diameter of less than 100 nm and several micrometers in length [5,15]. The inter- or intra-molecular hydrogen bonding between the elementary fibers 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 fiber, a strength-to-weight ratio higher than stainless steel, and a tensile strength greater than cast iron [16,17,18].
Nanocellulose can be derived from different sources, such as plants, agricultural residues, aquatic animals, and microorganisms [2,19]. Among agromass, nanocellulose has been reported to synthesize from corncob, banana leaves, cotton, rice husk, sugarcane bagasse, wheat straw, coconut husk, and wood [20]. However, there are also reports for the extraction of nanocellulose from ginger [21], coffee grounds [22], durian rind waste [23], lemon seeds [24], pea hull [25], rubber wood [26], etc. Nanocellulose can also be obtained from aquatic organisms such as tunicates and microorganisms such as fungi, algae, and bacteria [6,27]. 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 [18]. 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) (Figure 1). They all have the same chemical composition but differ in structure, particle size, purity, crystallinity, and other physicochemical properties [4,28,29].

2.1. 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 [34]. They are obtained via acid hydrolysis of the native nanocellulose. The acid hydrolysis procedure breaks down the amorphous regions of the nanocellulose chains hydrolyzing 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, H2SO4, 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 [34,35]. The type and the concentration of acid influence the crystallinity, morphology, physicochemical properties, and dispersibility of nanocellulose [13]. The sulphuric acid hydrolysis produces nanocellulose with sulphonic groups on it, causing good dispersibility in aqueous media but with lower thermal stability. The use of mineral acid is a matter of concern when it comes to corrosion of the reactors and safety concerns [19]. 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 (AmimCl), tetrabutylammonium acetate, 2-hydroxyethyl ammonium hydrogen sulphate [36,37]. Transition metal salt catalyst also acts as a catalyst to remove the amorphous regions of cellulose [38].

2.2. Cellulose Nanofibrils (CNF)

Cellulose nanofibrils (CNF/NCF) are long entangled nanocellulose fibers with sizes ranging from 1–100 nm in diameter and 100 nm to several micrometers in length [5]. 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 [39]. They are commonly prepared using mechanical approaches such as ultrasonication, high-pressure homogenization, steam explosion, grinding, micro fluidization, or cryocrushing, in which the pressure acts as the center of fiber causing the defibrillation of the microfibers to nanofibers leaving the amorphous region behind, along with the crystalline region [13,34,40]. The greater the number of cycles of mechanical disintegration, the smaller will be the size of the nanofibers [6]. 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 [5,6,41,42]. 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 [43]. Although TEMPO CNFs have higher fibrillation, their use is not always the best and depends on the final application. For instance, an extensive application is to improve the mechanical properties of paper and cardboard. In that case, mechanical pretreatments have better properties than TEMPO [44]. Nevertheless, for other applications, such as optical applications, TEMPO produces a more fibrillated sample.

2.3. Bacterial Nanocellulose (BNC)

Bacterial nanocellulose (BNC) is produced by certain bacteria through a metabolic pathway involving the fermentation of carbohydrates [5]. The most common bacteria reported for the synthesis of bacterial nanocellulose are Acetobacter xylinum, Pseudomonas, Azotobacter, Aerobacter, Rhizobium, and Xanthococcus [1]. 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 [45]. 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 cultivation area [46,47]. 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 [48]. 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 [49,50,51]. 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 [1]. All the biomedical applications related to using nanocellulose materials center 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 [52,53,54].

3. Surface Modification of Nanocellulose for Drug Delivery

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 [55]. Common forms of nanocellulose used for drug delivery applications include nanoparticles, hydrogels, aerogels, membranes, and films [49]. 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 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 [56].
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 [57]. In this case, surface modifications can induce steric and electrostatic effects along with decreasing its moisture sensitivity and increasing thermal stability [34]. 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.

4. Applications of Nanocellulose in Drug Delivery

The unique characteristics of nanocellulose make it a suitable candidate for drug delivery applications in the pharmaceutical field. Nanocellulose is one the apt candidate 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]. The advantages and disadvantages of the three routes have been included in Table 1.

4.1. Oral Drug Delivery

Various reports have been published on the oral administration route of drugs by nanocellulose-based membranes. 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.
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].
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].

4.2. Local Application

Herein, 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].

4.3. Transdermal Delivery

Transdermal drug delivery involves the delivery through the skin into the systemic circulation to attain therapeutic concentrations. Transdermal films utilized for drug release should possess excellent drug-loading efficiency. Transdermal films should be capable of loading the drug effectively with a balance between the minimum effective dose and the toxic threshold dose. This mode of delivery is designed so that the drawbacks of oral and parenteral drug delivery, such as avoiding the pre-metabolism of GI and hepatic systems.
Bacterial nanocellulose, due to their intrinsic biocompatibility and 3D nanoporous structure, can house both hydrophilic and lipophilic pharmaceutical ingredients under different temperatures and humidity levels, and this was studied by Silva and co-workers [87] by investigating the long-term storage capability of caffeine, lidocaine, ibuprofen, and diclofenac. The in vivo cutaneous compatibility studies were carried out for caffeine-loaded membranes in the form of patches. The active pharmaceutical ingredient (API)-loaded BNC membranes revealed good storage results and cutaneous compatibility, which make them ideal dermal delivery systems. Various applications of bacterial nanocellulose and its other variants in the field of skin tissue engineering and wound healing have been discussed, and these have been summarized in a review by Bacakova et al. [88].
Abba et al. [89] reported the use of BNC membranes for the transdermal administration of crocin. Results indicated a gradual release of crocin within seven hours, which is attributed to the 3D network of BNC. In addition, the surface morphology of croc in loaded BNC membrane was intact without any further fiber damage. Further studies prove that this BNC membrane can be utilized for carrying other water-soluble active compounds as well.
Preparation of a transdermal drug delivery vehicle suitable for the controlled release of ketorolac tromethamine (KT), a non-steroidal analgesic, was reported by Sarkar et al. [90] that comprises cellulose nanofibers extracted from raw jute and chitosan. The CNF/chitosan transdermal film showed a sustained drug release rate making it a suitable candidate for transdermal drug delivery. KT, when administered transdermally, would help to reduce its side effects in the gastrointestinal tract and also control the therapeutic dosage. In order to treat chronic skin wounds, Alkhatib et al. also recommended administering the antiseptic named octenidine over the course of 8 days using a ready-to-use BNC/Poloxamer hybrid system [91]. Biodegradable Microneedle (MN) technology utilized for transdermal drug delivery has been experimented with by Medhi et al. [92] for the transdermal delivery of Lidocaine, a numbing anesthetic. Fish scale biopolymer and bacterial CNF that had been loaded with lidocaine were combined to produce the MN arrays. The results suggest that the loaded MN arrays penetrate the stratum corneum and dissolve in the skin, releasing lidocaine. It was reported that after 36 h, the MNs loaded with 7.5% (w/w) lidocaine exhibited improved drug penetration rates of 2.5 to 7.5% (w/w) through the skin.
A study by Plappert and group [93] reported the use of cellulose nanofibre-based patches for the sustained release of a non-steroidal anti-inflammatory drug (NSAID), Piroxicam. The extent of loading is dependent on surface charge density and carboxylate group content. A prolonged release of Piroxicam for several hours was observed on exposure to simulated human skin fluid. Different types of nanocellulose used for the delivery of various therapeutic agents have been tabulated in Table 2.

5. Conclusions

Nanocellulose has emerged as an excellent material for various biomedical and biotechnological applications in terms of its properties, such as biocompatibility, biodegradability, and low to no cytotoxicity. Biocompatible nanocellulose materials with controlled properties and tuning surface functionalization can pave the way for innovative applications in the field of drug delivery, wound dressing, and medical implants [98]. In the present review, nanocellulose-based drug delivery systems utilized both for internal and external applications have been discussed. The drug delivery method uses nanocellulose as aerogels, cryogels, hydrogels, microparticles, nanoparticles, and membranes. All the different forms of nanocellulose have applications in drug delivery, which were made possible through different surface modification techniques, both hydrophilic and most hydrophobic drugs are transported at the required dose to the target site. As reported in all the previous cases, nanocellulose-based drug delivery systems showed a controlled and sustained release rate, which can be attributed to the high porosity and H-bonding interactions between drug molecules and nanocellulose –OH groups. However, more studies on the nanocellulose-based drug delivery vehicle cytotoxicity need to be emphasized more in the coming years. Healing applications and other biomedical applications of nanocellulose have to be broadly studied and researched. In addition, the commercialization of value-added products from nanocellulose needs to be further investigated for other biomedical applications such as wound dressing and organ replacement. Commercial wound dressing materials made from bacterial nanocellulose, similar to the one Biofilm used for chronic ulcers, intense burns, and wound skin grafting, are available in the market, paving the way to the commercial applications of nanocellulose in the market [54]. In the future, the use of such a biocompatible and biodegradable material for varying biomedical applications would be of utmost importance. However, for the commercialization of these applications, various in vitro and in vivo studies and clinical trials have to be conducted to carefully study and observe the functionality and applicability of these highly promising nanocellulose-based drug delivery materials.

Author Contributions

Conceptualization, C.J.C., H.K. and S.T.; validation, C.J.C., H.K. and S.T.; investigation, R.T.V., R.M.C. and T.A.; writing—original draft preparation, R.T.V., R.M.C. and T.A.; writing—review and editing, C.J.C., H.K. and S.T.; supervision, C.J.C., H.K. and S.T.; project administration, C.J.C., H.K. and S.T. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

Data sharing is not applicable to this article.

Conflicts of Interest

All authors (Rini Thresia Varghese, Reeba Mary Cherian, Cintil Jose Chirayil, Tijo Antony, Hanieh Kargarzadeh, Sabu Thomas) declare that they have no conflicts of interest.

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Jcs 07 00210 g001 550
Figure 1. Different forms of nanocellulose based on morphology and source [30,31,32,33].
Figure 1. Different forms of nanocellulose based on morphology and source [30,31,32,33].
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Jcs 07 00210 g002 550
Figure 2. Injectable hydrogel from CNC. Reprinted with permission from [86]. Copyright © 2019, American Chemical Society.
Figure 2. Injectable hydrogel from CNC. Reprinted with permission from [86]. Copyright © 2019, American Chemical Society.
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Table
Table 1. Advantages and disadvantages of different drug delivery routes.
Table 1. Advantages and disadvantages of different drug delivery routes.
Nanocellulose in Drug Delivery
RouteAdvantagesDisadvantagesReferences
Oral
  • Preferred route
  • Simple, comfortable
  • Economic
  • Non-invasive
  • Harsh gastric conditions
  • Slow onset of action
  • Subject to first-pass metabolism
  • Not suitable if vomiting, unconscious
[66,67]
Transdermal
  • Evades the gastrointestinal tract and liver metabolism
  • Offers therapeutic effect at lower doses
  • Unable to deliver large medications
  • Only fine molecules capable of passing through the skin are delivered.
[68]
Topical/Local
  • Increased effectiveness
  • Lower dose required
  • Reduced toxicity
  • Only local effect
  • Mild problems only resolved
[69,70]
Table
Table 2. Selected examples of nanocellulose used for the delivery of therapeutic drugs.
Table 2. Selected examples of nanocellulose used for the delivery of therapeutic drugs.
Type of NanocelluloseDelivery MethodDelivery RouteDrugReferences
Spray-dried CNFEncapsulation
Drug release		OralAcetaminophen[81]
Magnetic CNCColonic releaseOralIbuprofen[78]
CNFColon-specific drug deliveryOralMethotrexate[63]
CNFPseudo-Fickian diffusionTopicalChloramphenicol[94]
BNCControlled drug releaseTopicalOctenidine[91]
BNCControlled cutaneous drug releaseTransdermalCaffeine, Ibuprofen, Lidocaine, Diclofenac[87]
BNCControlled pH-responsive drug releaseLocalized drug deliveryCisplatin[95]
BNCControlled pH-sensitive drug deliveryTransdermal, oral deliveryDiclofenac[96]
CNFpH-sensitive controlled drug deliveryTransdermalDoxorubicin[97]
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Varghese, R.T.; Cherian, R.M.; Chirayil, C.J.; Antony, T.; Kargarzadeh, H.; Thomas, S. Nanocellulose as an Avenue for Drug Delivery Applications: A Mini-Review. J. Compos. Sci. 2023, 7, 210. https://doi.org/10.3390/jcs7060210

AMA Style

Varghese RT, Cherian RM, Chirayil CJ, Antony T, Kargarzadeh H, Thomas S. Nanocellulose as an Avenue for Drug Delivery Applications: A Mini-Review. Journal of Composites Science. 2023; 7(6):210. https://doi.org/10.3390/jcs7060210

Chicago/Turabian Style

Varghese, Rini Thresia, Reeba Mary Cherian, Cintil Jose Chirayil, Tijo Antony, Hanieh Kargarzadeh, and Sabu Thomas. 2023. "Nanocellulose as an Avenue for Drug Delivery Applications: A Mini-Review" Journal of Composites Science 7, no. 6: 210. https://doi.org/10.3390/jcs7060210

APA Style

Varghese, R. T., Cherian, R. M., Chirayil, C. J., Antony, T., Kargarzadeh, H., & Thomas, S. (2023). Nanocellulose as an Avenue for Drug Delivery Applications: A Mini-Review. Journal of Composites Science, 7(6), 210. https://doi.org/10.3390/jcs7060210

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