Ratul Paper

Carbohydrate Polymers 348 (2025) 122838
Contents lists available at ScienceDirect
Carbohydrate Polymers
journal homepage: www.elsevier.com/locate/carbpol
Review
Cellulose nanocrystal based electrospun nanofiber for biomedical

applications–A review
Saifuddin Ahmed , Ratul Ahmed Khan , Taslim Ur Rashid *
Department Applied Chemistry and Chemical Engineering, Faculty of Engineering and Technology, University of Dhaka, Dhaka 1000, Bangladesh
A R T I C L E I N F O A B S T R A C T
Keywords: Electrospinning has become a revolutionized technique for nanofiber fabrication by offering versatile procedures
CNC to precisely regulate the nanofibers' properties suitable for a wide range of advanced applications. Nanofibers are
Electrospinning utilized as carriers for delivering medications and other health supplements as well as their ability to discharge
Nanofibers
their contents can be easily programmed and tailored in a specific manner, while serving as tissue engineering
Drug delivery
scaffolds or medical devices. Cellulose nanocrystals (CNC) are one of the most significant natural biopolymers
Tissue engineering
Wound healing incorporated as reinforcing agents for nanostructured fibrous frameworks. The integration of electrospinning
technology and CNC offers a viable method for manufacturing nanostructured porous substances with favorable
functionality, a high ratio of surface area to volume, a tunable crystal structure along with non-toxicity and
cytocompatibility, outstanding mechanical properties, flexibility, sustainability, and biodegradable properties.
This article offers a thorough summary of the latest progress in the application of CNC based electrospun
nanofibers in various biomedical fields such as drug delivery, tissue engineering, and wound healing. It covers
the techniques and parameters used for their fabrication, the different types of raw materials employed, and their
application criteria. The review concludes by discussing the prospects and challenges in this rapidly evolving
research domains.
1. Introduction applications employing electrospinning techniques has been very pop-

ular. The common bio-based polymers that are incorporated are chito-
Nanofibrous materials are hierarchical nanostructure having fiber san, gelatin, alginates, cellulose, collagen etc. (Furuno, Wang, Suzuki,
diameter ranging from 50 nm to 500 nm (Teixeira, Paiva, Amorim, & Nakahata, & Sakai, 2020; Khan, Arafat, Rashid, Haque, & Rahman,
Felgueiras, 2020). These materials have enormous potential to meet the 2024; Najafiasl, Osfouri, Azin, & Zaeri, 2020). These electrospun fibers
performance requirements of modern applications in food packaging can offer some unique properties that are important for biomedical
(Niu et al., 2020), energy storage (Senthilkumar, Ramasubramanian, applications. Some of the noteworthy advantages are high drug filling
Rao, Chellappan, & Ramakrishna, 2023), biomaterials (Barud & De and encapsulation performance, modulation of drug release behavior
Sousa, 2022) etc. One of the well-known techniques that is used and also during the moderate spinning process, the chemical structure
frequently to prepare nanofibers is electrospinning. Electrospinning of and functional properties of the drugs incorporated in the fibers remain
natural or synthetic polymer and composite systems can produce unaffected (Azimi et al., 2020). Appropriate biomechanical interactions
nanofibers with three dimensional interconnected porous structures of these fibers with different tissue cultures through mimicking the
having high surface area to volume ratio providing enhanced reactivity extracellular matrix can promote cell adhesion, proliferation and dif-
and unique performance characteristics (Kausar, 2021). Physical prop- ferentiation for various tissue engineering applications (Semnani et al.,
erties of the electrospun mats such as fiber diameter, geometrical 2017), wound dressings (Samadian et al., 2020), and medical implants
structure, porosity, surface area etc. can be modified by alternating the (Jia et al., 2021).
electrospinning solution composition, solvent, and applied voltage Among the natural biopolymers, cellulose nanocrystals (CNC), often
(Pelipenko, Kocbek, & Kristl, 2015). referred to as cellulose nanowhiskers, are cellulose derivatives which
Recently the use of natural biopolymers for medical field have drawn tremendous interest of biomedical researchers due to its
* Corresponding author.
E-mail address: [email protected] (T.U. Rashid).
https://doi.org/10.1016/j.carbpol.2024.122838
Received 5 July 2024; Received in revised form 4 October 2024; Accepted 6 October 2024
Available online 11 October 2024
0144-8617/© 2024 Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.
S. Ahmed et al. Carbohydrate Polymers 348 (2025) 122838
exceptional mechanical characteristics, biodegradability and biocom- Brown, Tsuzuki, & Rainey, 2016). CNCs can be used for a variety of
patibility. They are frequently employed in the fabrication of bio- applications, including fabrication of nanocomposites, where they can
composites as reinforcing agents (Chen et al., 2020). Nanostructured provide reinforcement with superior mechanical qualities to that of
fibrous frameworks reinforced with CNCs are favorable materials to be other synthetic materials (Trache et al., 2017). They are also used to
used in clinical fields like drug carriers (Chen et al., 2020a), wound anchor other nanoparticles to impart specific functions such enhanced
repair (Rashtchian, Hivechi, Bahrami, Milan, & Simorgh, 2020a), and hydrophobicity, dispersibility, and conductivity (Tang, Abdalkarim,
tissue regeneration (Unal et al., 2020) owing to the distinctive set of Dong, & Yu, 2023). They are affordable, ecologically friendly, biode-
characteristics, including a highly porous structure, a high ratio of sur- gradable, biocompatible and sustainable which lead to the rapid in-
face area to volume, tunable crystal structure along with non-toxicity crease in utilization of CNCs in numerous field of biomedical application
and cytocompatibility. (Garces, Aslanzadeh, Boluk, & Ayranci, 2020).
In this review, we attempt to elaborate the survey on the literatures
published on CNC based electrospun fibers as promising materials for 2.1. Synthesis of CNC
biomedical activity. The formulations, parameters, tunability and chal-
lenges affecting the preparation and application of electrospun fibers are 2.1.1. Physical methods of CNC preparation
also covered. The review emphasizes the significance of employing The physical method of CNC production primarily employs me-
CNCs in electrospun fibers for drug delivery, wound healing and chanical treatment and usually classified into four types: homogeniza-
advanced tissue engineering applications in addition to smart bio- tion under high pressure, microfluidization, fine grinding, and freezing
sensors. At the end, the future research directions and potential in this smashing (Geng, Chen, Peng, & Kuang, 2017).
field will be discussed. Homogenization is a one-step procedure that involves smashing the
solids to form a solution containing ultrafine particles and create a
2. Cellulose nanocrystals: synthesis, properties and applications suspension of high stability (Han et al., 2017). Homogenization under
high pressure can be a process of creating nanocellulose in industrial
CNCs are comprised of rod shaped or needle-like particles that can scale provided that the process temperature is maintained at 70–80 ◦ C
originate from various natural substances and have a high degree of for best production characteristics (Khiari, 2017). However, homoge-
crystallinity and specific surface area. These nanocrystals' size and nization under high pressure is an energy-intensive process and the
crystallinity vary depending on the source and how they were obtained valves get easily blocked by the long plant fibers in this method; hence,
(Trache, Hussin, Haafiz, & Thakur, 2017). In addition to lignocellulosic its performance is unreliable (Khalil et al., 2014).
biomass including materials like wood, cotton, and ramie, CNCs can also The microfluidization is another physical method for preparing
be obtained from sources such as tunicate cellulose, bacterial cellulose, nanomaterials (Villalobos-Castillejos et al., 2018). The raw slurry is
softwood kraft pulp, recycled pulp, waste biomass and others (Anwar, subjected to high pressure by the fluid pump and then forced into an
Bundjali, & Arcana, 2015; Filson, Dawson-Andoh, & Schwegler-Berry, interactive vessel of Y-shape with zigzag inner structure which results in
2009; Klemm et al., 2011). Using mechanical or chemical processes to a huge shear force as well as impaction occurring with the cavity walls
separate out the crystalline phase, CNCs may be readily extracted from and consequently smashing the nanoparticles further to obtain more
the majority of cellulose sources. Fig. 1 illustrates simplified extraction homogeneous CNC (Li, 2016). The drawback of microfluidization over
process of CNC from commonly used resources of cellulose. Pretreat- homogenization under high pressure is that longer fibers might easily
ment of these raw sources includes delignification with NaOH, bleaching jam the cavity and it consumes a lot of energy (Villalobos-Castillejos
with NaClO2 or H2O2 etc. Acid hydrolysis, which frequently uses sulfuric et al., 2018). Thus, this operation is difficult to implement in the in-
acid (Lusiana, Srihardyastutie, & Masruri, n.d.), chemical oxidation, dustrial sector.
enzymatic hydrolysis, mechanical grinding or disintegration, and ho- The preparation of microcrystalline cellulose by fine grinding was a
mogenization are the typically utilized procedures for CNC extraction revolutionary physical technique which could eventually produce
from the cellulose fibers obtained after pretreatment step (Filson & nanometer-sized cellulose by carefully adjusting the parameters of
Dawson-Andoh, 2009; Saito, Kimura, Nishiyama, & Isogai, 2007; Sofla, grinding. CNC having a diameter range of 10–40 nm can be obtained by
Fig. 1. Schematic representation of CNC preparation.
2
grinding the coniferous tree fibers after pretreatment (Song et al., 2013). distributed in water owing to the presence of carboxyl groups containing
CNC can also be produced by smashing the frozen cellulose using me- negative charge (Huang et al., 2020).
chanical force, called freezing smashing technique. In this technique The TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl)-mediated
typically liquid nitrogen is used to freeze the slurry of cellulose, which oxidation approach is usually employed for producing an oxidized
could cause the fibers to lose their toughness and become brittle at low nanocellulose because it can preferentially oxidize the primary hydroxyl
temperatures, increasing their internal stress producing nano sized cel- groups of cellulose structure into carboxyl groups (Isogai, Saito, &
lulose (Ma, Yu, & Wang, 2010). But this process is expensive, and the Fukuzumi, 2011; Oun & Rhim, 2018). TEMPO is a mild oxidizing agent.
performance achieved is too poor to be promoted. However, use of sodium hypochlorite changes this agent into a strong
one named nitrogen carbonyl cation (Carlsson, Lindh, Nyholm,
2.1.2. Chemical methods of CNC preparation Strømme, & Mihranyan, 2014). The TEMPO oxidation process uses little
energy, offers easy operation, and moderate reaction conditions.
2.1.2.1. Acid hydrolysis. Generally, chemical attacks on the bonds in the Nevertheless, since the TEMPO system contains hypohalite, it has the
disorganized amorphous segment are easier than those in the crystalline ability to produce chlorine, which is very detrimental to the environ-
region. Acid hydrolysis is one such process that takes place under ment (Wang, Liu, Jin, He, & Liu, 2019). An alternate oxidant called H2O2
controlled reaction time and temperature (Huang, Liu, Chang, & Wang, may break glycoside bonds by producing radicals of the hydroxyl and
2020). Glycosidic bond in the cellulose molecular chain contains oxygen hydroperoxyl groups, and subsequently change the hydroxyl group into
atom which is protonated by the action of hydronium ions (H3O+) a carboxyl group (Dias et al., 2011). CuSO4 as a catalyst can facilitate the
present in an acidic solution, causing the bond to weaken and eventually fabrication of CNCs with –COOH groups using H2O2 (Koshani, van de
break. In the meantime, (H3O+) also breaks the hydrogen bonds be- Ven, & Madadlou, 2018). Also, alkaline H2O2 treatment can effectively
tween the molecules of cellulose in the amorphous areas, which is driven generate CNCs (X. Huang et al., 2017).
by various secondary reactions (Chen, Tan, Lee, & Abd Hamid, 2017). Ammonium persulfate (APS) oxidation is an alternate technique to
Concentration of acid, process temperature, and duration of hydrolysis acid hydrolysis since it is a straightforward, inexpensive, one-time
can all have an impact on overall hydrolysis reaction (Mohomane, procedure with low toxicity, and high solubility. Also, it does not
Motloung, Koao, & Motaung, 2022). Numerous attempts have been require pretreatment to remove non-cellulosic materials and amorphous
made in recent years to explore an efficient acid solution for the hy- cellulose constituents (Zhang et al., 2020). Moreover, unlike TEMPO-
drolysis of cellulose into CNC (Camarero Espinosa, Kuhnt, Foster, & mediated oxidation, the oxidation of APS can produce cellulose nano-
Weder, 2013; Liu et al., 2014; Lorenz, Sattler, Reza, Bismarck, & Kont- crystals containing carboxyl groups (CNCs-COOH) straight from the
turi, 2017; Yu, Zhang, et al., 2017). cellulosic materials without involving any chemical treatment
For the preparation of CNC by acid hydrolysis method, mineral acids, (Khanjanzadeh & Park, 2021). The CNCs made using the APS-oxidation
such as H2SO4 (Beck-Candanedo, Roman, & Gray, 2005), HCl (Yu, Qin, method exhibited improved crystallinity, exceptional mechanical char-
Liang, et al., 2013), HNO3 (Rubleva, Voronova, Surov, Zakharov, & acteristics, and thermal properties in comparison to that obtained by the
Lebedeva, 2019), and H3PO4 (Camarero Espinosa et al., 2013) are found TEMPO-mediated oxidation method (Oun & Rhim, 2017; Zhang et al.,
to be used. In comparison among these four acids, maximum thermal 2016).
stability is exhibited by the CNC produced from HNO3 treatment (Dhar
& Katiyar, 2017). Moreover, the aqueous suspension of CNC produced 2.1.3. Enzymatic hydrolysis
by H2SO4 hydrolysis is more stable in comparison to the same obtained Enzymatic hydrolysis is a comparatively new technique that could be
using HCl (Chakrabarty & Teramoto, 2018). Basically, the acid hydro- a fascinating route to CNC production as this approach does not produce
lysis process is easy, and a variety of acids or acid combinations are hazardous residues like mineral acid hydrolysis does (Ribeiro, Pohl-
available. Yet, some difficulties, like the extensive use of acids, corrosion mann, Calado, Bojorge, & Pereira Jr, 2019). The conditions for enzy-
of equipment, and expensive purification methods need to be resolved matic hydrolysis are often maintained within moderate pressure and
(Li et al., 2022). temperature range, leading to a less energy consuming process. On top
of that, enzyme-produced CNC typically has relatively high-value ap-
2.1.2.2. Processing by ionic liquids. Ionic liquid, a liquid salt containing plications due to its morphological structures (Fritz et al., 2016).
organic cation and a nonpolar or organic anion, catalyzes the hydrolysis Enzymatic hydrolysis method for CNC production has not been explored
of cellulose to obtain nanocellulose where reaction temperature acts extensively in comparison to the other nonenzymatic processes till the
vital role in determining the diameter of the CNC (Kilpeläinen et al., date (Brinchi, Cotana, Fortunati, & Kenny, 2013). As a part of a greener
2007). Increasing the reaction temperature is found to decrease the approach to the CNC preparation, enzymatic hydrolysis can be a
diameter of the resultant CNC. Furthermore, the optimized temperature promising strategy because of its high efficiency (Chen, Deng, Shen, &
to obtain highly crystalline CNC has been stated to be 90 ◦ C (Tan, Abd Jia, 2018; Wang, Cheng, Li, Men, & Wu, 2020), excellent selectivity, low
Hamid, & Lai, 2015). The crystallinity of the cellulose fibers affects their expenditure of energy along with zero emission of harmful chemicals
solubility in ionic liquids which is also true for acid hydrolysis method and toxic substances (Mokhena & John, 2020; Salimi, Sotudeh-
(Lindman, Karlström, & Stigsson, 2010). Weakening these ordered re- Gharebagh, Zarghami, Chan, & Yuen, 2019).
gions is challenging because of their higher energy of stability (Lee, The catalytic enzymes that hydrolyze cellulosic biomass into CNC are
Hamid, & Zain, 2014). Ionic liquids have a high viscosity and separation known as cellulases. These enzymes, which include cellobiohydrolases,
of the products can be problematic. Another drawback is that they can exoglucanases, and endoglucanases, work in concert to achieve the
cause the cellulose chain to degrade due to excessive localized heating necessary level of hydrolysis to produce CNC with a high crystallinity
during dissolution (El Seoud, Koschella, Fidale, Dorn, & Heinze, 2007). index (Eriksson & Cavaco-Paulo, 1998). Exoglucanase targets the
polymeric chain of cellulose at the reducing or nonreducing ends,
2.1.2.3. Oxidation method. The oxidization process of CNC preparation shortening the chains, while endoglucanase acts to hydrolyze the
introduces anionic groups to cellulose molecules. The oxidation of –OH amorphous area of the cellulosic structure. The first one utilizes a pro-
groups and elimination of the amorphous area proceed concurrently in tein to produce cellobiose units by breaking down the short chains of
the first stage (Oun & Rhim, 2018). The end products contain carboxyl cellulose (Filson et al., 2009).
groups that are negatively charged (–COOH), which may be utilized to The main factors on which enzymatic hydrolysis depends are tem-
further modify the CNCs as well as help them disperse in aqueous so- perature, duration of hydrolysis and the concentration of cellulases used
lutions. The resulting CNCs showed good stability and could be freely with respect to the mass of cellulosic material being examined
(Zielińska, Szentner, Waśkiewicz, & Borysiak, 2021). Moreover, it is
3
highlighted that well-chosen cellulases, being able to work in harmony bonding between the cellulose chains, which leads to increased inter-
with one another, have a significant impact on the efficiency of enzy- molecular interactions and makes them suitable for reinforcing different
matic cellulose hydrolysis (Albornoz-Palma, Ching, Valerio, Mendonça, materials, such as polymers and elastomers (Yu, Qin, Liu, et al., 2013).
& Pereira, 2020; Arantes et al., 2020). However, the lengthy procedure Introduction of CNC into the composites altered mechanical character-
and expensive enzymes are still the drawbacks of the enzymatic hy- istics by improving the compatibility between filler substances and the
drolysis technique. Yet, the substantial potential of this method in matrix resulting in an excellent filler network (Tanpichai & Oksman,
fermentation and penetrability, associated with almost zero pollution 2016). On top of that, the ability of the composites to transfer the stress
level, has caught the attention of researchers and businesses recently to applied on them are found to be enhanced by the incorporation of CNCs
work on lowering the expenses related (Dashtban, Schraft, & Qin, 2009; as a reinforcing agent (Dhar, Tarafder, Kumar, & Katiyar, 2016). All of
Wang et al., 2011). Moreover, this environment friendly method is these properties of CNCs are extremely useful in a variety of function-
preferred for obtaining pure cellulosic material with good productivity, alization and applications.
appropriate for reinforcing high performance polymer composites and
biomedical uses (Karim, Afrin, Husain, & Danish, 2017). 2.3. Applications of CNC
2.1.4. Combined method CNCs are widely used as reinforcement in nanocomposites to

The most recent kind of CNC extraction method is referred to as a improve the mechanical, thermal and barrier properties. They are usu-
combined approach, in which physical, chemical or biological processes ally combined with a variety of polymers such as polyvinyl alcohol
are utilized in an integrated way to create nanocelluloses for diverse uses (PVA), polyethylene oxide (PEO), polypropylene (PP) and others to
(Squinca, Bilatto, Badino, & Farinas, 2020). Overall, all of the CNC produce nanocomposites with enhanced properties (Endo, Saito, &
preparation methods mentioned earlier, are associated with many issues Isogai, 2013; Zhou, Chu, Wu, & Wu, 2011). These nanocomposites have
that prevent the progress of these technologies, such as the extensive a potential to be used in a wide range of applications such as packaging
energy consumption, massive chemical pollution and toxicity, and the materials, biomedical devices, and building materials (Shojaeiarani,
difficulties in controlling the biological process etc. As a result, the CNC Bajwa, & Chanda, 2021). Because of the distinctive physiochemical
preparation is irresistibly embracing the trend of combining many ap- qualities, non-toxicity, and lack of flavor or color, CNCs are currently
proaches (Lu et al., 2018; Mishra, Manent, Chabot, & Daneault, 2012). becoming increasingly popular in the food sector (Mu et al., 2019). They
For instance, collaborative process of enzymatic treatment and H2SO4 are utilized in foods to perform various functions, such as an emulsifier,
hydrolysis has been resulted in a significant increase in yield along with thickening agent, and foam stabilizer having no impact on the quality of
reduction in reaction time and acid cost needed (Beltramino, Roncero, food (Li & Liu, 2021). Moreover, CNCs have the potential to improve the
Vidal, & Valls, 2018). mechanical, thermal, and gas barrier characteristics of many bio-based
materials, which would otherwise function poorly. This is especially
2.2. Properties of CNC true for food packaging materials (Angellier-Coussy, Guillard, Gastaldi,
Peyron, & Gontard, 2018).
Cellulose nanocrystals have attracted significant attention from re- The high mechanical strength of CNCs allow them to improve the
searchers in academic and industrial fields including bio resource en- properties of pulp and paper based products (Salam, Lucia, & Jameel,
gineering, materials science and engineering, and bio nanotechnology 2013). The addition of CNCs to paper products can improve their
because of their intriguing structural characteristics and distinctive strength, stiffness, and tear resistance (Yang, Tang, Wang, Kong, &
physicochemical properties (Rana, Frollini, & Thakur, 2021). CNCs are Zhang, 2014). CNCs can be used to fabricate filters and membranes with
nanoscale in size and have a rod-like shape with dimensions of around improved performance. They are able to provide a robust support
10–20 nm in diameter and up to hundreds of nanometers in length structure for filters and membranes, making them suitable water filtra-
(Habibi, Lucia, & Rojas, 2010). This unique size and shape give CNCs tion and separation of bio-molecules (Liu, Liu, & Shen, 2021; Smith,
unique properties compared to other cellulose derivatives (Eichhorn, Hendren, Haag Iv, Foster, & Martin, 2019). Nowadays 3D printing
2011). The surface of CNCs can be easily modified to change their technology has become very popular for fabricating CNC based com-
functional properties. This property makes them ideal for use in various posites to be used in medical applications (N'gatta et al., 2022). In the
applications, such as catalysts, sensors, and bioactive materials (Moreau, upcoming years, it's probable that the CNCs with fluorescent properties
Villares, Capron, & Cathala, 2016; Saidane, Perrin, Cherhal, Guellec, & will be extensively utilized for detection of metal ions and biosensors.
Capron, 2016). CNCs have good dispersion stability, which makes them CNCs have gained significant attention in the biomedical field due to
easy to process and handle. They can be dispersed in various solvents, their biocompatibility, biodegradability and non-toxic characteristics.
such as water, organic solvents, and polymers, making them compatible They are frequently utilized in biomedical field like as wound dressings,
with a wide range of processing methods. tissue engineering, and drug delivery (Afrin et al., 2022; Sharip et al.,
The excellent barrier properties of CNCs make them ideal for use in 2020). The biodegradable nature of CNCs makes them a promising
packaging materials, food packaging, and drug delivery systems (Nair, material for use in medical devices that need to be eliminated from the
Zhu, Deng, & Ragauskas, 2014). They prevent the migration of gases, system after a certain period. Despite the fact that many studies on the
liquids, and flavors, and they also help to avoid the ingress of moisture biocompatibility, long-term toxicity, and safety between biomaterials
and light (Ferrer, Pal, & Hubbe, 2017; Mariano, El Kissi, & Dufresne, based on CNCs and biological systems are still in the experimental stage,
2014). They have a high degree of transparency and a high refractive many findings point to a bright future (Randhawa et al., 2022).
index, making them useful in optical applications (Yao et al., 2017).
Biocompatibility and biodegradability of CNCs, make them suitable for 3. Electrospinning: fabrication techniques, properties and
use in biomedical applications (Jorfi & Foster, 2015). They decompose applications
into cellulose and other natural substances, which are not harmful to the
environment inside the human body. CNCs have been shown to have low 3.1. Fabrication techniques
toxicity and do not induce an immune response, making them an
attractive option for use in medical implants and devices (Lin & Electrospinning is a nanofiber fabrication technique comprised of
Dufresne, 2014). Most importantly, they possess excellent mechanical four major components: a syringe pump, a metallic needle or spinneret,
properties such as high tensile strength, toughness, and modulus, which a high voltage power supply, and a metallic collector with a variable
is ideal for use in high-performance composites (Aitomäki & Oksman, morphology (Rashid, Gorga, & Krause, 2021). It starts with the appli-
2014). The high tensile strength of CNCs is due to the strong hydrogen cation of a high voltage supply to the polymer solution or melt which is
4
continuously coming out of the tip of the needle from the syringe pump capillary clogging, solvent evaporation, non-aligned fiber production,
at a certain rate (Sill & Von Recum, 2008). The charged surface of the etc. (Cengiz, Krucińska, Gliścińska, Chrzanowski, & Goektepe, 2009).
polymer solution droplet is shaped through the reciprocating electro- The broad classification of the modifications can be multiple-needle
static repulsion of the same charge. At the same time, the opposite po- electrospinning (Fig. 2 (B)), needleless electrospinning (Fig. 2 (C, D
larity on the collector side draws the polymer droplet with coulombic and E)), coaxial-spinneret electrospinning, aligned fiber production
attraction. Both effects enable polymer solution layers to overcome the electrospinning, etc. (Davoodi, Gill, Wang, & Huang, 2021; Xue, Wu,
surface tension and slide past each other (uniaxial stretching). Thus, Dai, & Xia, 2019).
thinning of the polymer solution droplet starts creating a Taylor cone In a multiple-needle electrospinning technique (Fig. 2 (B)), multiple
(Haider, Haider, & Kang, 2018). Ultimately, nanofibers come out of the fiber jets are drawn from an array of nozzles mounted on the lower
syringe tip following the electric field with a whipping motion, dry out surface of a base (Lee, Jo, Go, & Chun, 2003; Zheng et al., 2020). The
along the way and get deposited on the collector surface (Doshi & upper surface of the base is provided with an inlet pipe supplying a
Reneker, 1995). pump's output to the base, which eventually reaches the nozzle array.
The nature and properties of the produced nanofibers depend on There is a collector underneath that has the opposite polarity of the
different parameters: distance between syringe and collector, electric drawn fibers, and it can move at a prescribed speed (Lee et al., 2003). A
field applied, flow rate, needle diameter, solution parameter; and single needle or multiple needles within each nozzle eject fiber jets
environmental parameter (Rashid et al., 2021). Solution parameters almost identically to the traditional electrospinning method, with the
include concentration, viscosity of the solution, solvent used, and con- exception of jet-to-jet coulombic repulsion of the same polarity, which
ductivity of the solution. Environmental parameters include relative adds up with the electric field force of attraction between the fiber jets
humidity and temperature inside the electrospinning system. To have a and the collector. This, along with some other factors, can cause diffi-
smooth and beadless nanofiber, all of these parameters should be tuned culty in precisely controlling the fiber morphology in this kind of setup
to the optimum level. Electrospinning of different materials requires of electrospinning (Xue et al., 2019). Further modifications and opti-
different critical values of the aforementioned parameters (Haider et al., mization of the nozzle array have been made and thoroughly analyzed
2018). (Xue et al., 2019). High throughput is one of the major pros of the
The traditional single-capillary needle or spinneret electrospinning multiple-needles electrospinning technique over the single-needle elec-
technique (Fig. 2 (A)) has gone through many, if not numerous, modi- trospinning technique (Xue et al., 2019).
fications to date to overcome problems like slow production rate, To talk about needleless electrospinning, two major types are – ball
Fig. 2. Schematic of two major types of electrospinning – needle electrospinning (A. single-needle electrospinning, and B. multiple-needle electrospinning) and
needleless electrospinning (C. plate-edge electrospinning, D. bowl-edge electrospinning, and E. ball electrospinning). Images A and D are reproduced with permission
from the reference (Thoppey, Bochinski, Clarke, & Gorga, 2011). Copyright © 2011 IOP publishing. Image B is reproduced with permission from the reference (Zheng
et al., 2020). Copyright © 2020 The Authors. Published by Elsevier Ltd. Image C is reproduced with permission from the reference (Thoppey, Bochinski, Clarke, &
Gorga, 2010). Copyright © 2010 Elsevier B.V.
5
electrospinning and edge electrospinning. Ball electrospinning is a chains) within the nanofiber. Electrospinning with suitable solvents and
needleless electrospinning technique that uses a moving spinneret of spinning parameters provides shear force, coulombic force, and relax-
preferably spherical shape (Fig. 2 (E)) (Smit & Sanderson, 2015; Yan, ation time to polymer chains that enhance crystallinity within the fiber
Niu, & Lin, 2019). One or more spheres of suitable materials, kept (Ojha, 2017). In this case, complete crystallization of polymer chains
partially submerged in polymer solution, are rotated to create an active before reaching the collector is a key to lamellar alignment (Lim, Tan, &
surface with a thin polymer solution layer on it (Smit & Sanderson, Ng, 2008). Otherwise, post-processing treatment such as annealing
2015). Multiple jets are drawn from the active surface by means of a might be required to increase the crystalline property of the electrospun
comparatively higher voltage difference than that of single-needle fiber (Rashid et al., 2021).
electrospinning, and the jets form from one end of the active surface, Generally, as a type of nanofiber, electrospun fibers have a high
move along with the ball's rotation, and terminate at the other end of the aspect ratio and a high surface-to-volume ratio, which in turn can cause
active surface (Willemse, 2013). Higher throughput of ball electro- them to exhibit properties different from those in the bulk state. For
spinning can often be met with problems like backbuilding of nanofibers example, they can show increased hydrophobicity, ease of functionali-
(Willemse, 2013; Yan et al., 2019). zation leading to properties like electrical conductivity etc. (Park &
On the other hand, edge electrospinning is a type of needleless Rutledge, 2017).
electrospinning that uses a motionless spinneret to spin a polymer so-
lution that falls off the edge of a plate (Fig. 2 (C)) or bowl (Fig. 2 (D))
3.3. Applications
(Thoppey et al., 2010; Thoppey, Bochinski, Clarke, & Gorga, 2011; Yan
et al., 2019). In general, this technique facilitates an electric field
Owing to their versatile properties, electrospun nanofibers have
gradient for an unconfined system of spinneret sites, and nearly identical
found numerous possibilities in different applications such as textile
fiber morphology with higher throughput is obtained (Thoppey et al.,
industry (Asmatulu & Khan, 2019b), water treatment (Sitab, Tujjohra,
2010, 2011). The bowl-edge electrospinning has an upper hand over
Rashid, & Rahman, 2023), air purification (Awad, Haghighat Mama-
plate-edge electrospinning in stable fiber electrospinning due to the
ghani, Boluk, & Hashisho, 2021), energy storage devices (Fang, Niu, Lin,
special source-collector geometry (Thoppey et al., 2011).
& Wang, 2008), sensors (Thenmozhi, Dharmaraj, Kadirvelu, & Kim,
2017), biomedical applications (Khan et al., 2024; Mwiiri & Daniels,
3.2. Properties 2020), food industry (Asmatulu & Khan, 2019a; Tamzid, Sakhawat, &
Rashid, 2024), pharmaceutical industry (G. Yang et al., 2018), use as
Tunable morphology of electrospun fibers (fiber diameter, fiber nanocomposites (Hsieh, 2018), etc. (Fig. 3).
diameter distribution (Nurwaha & Xjgjto, 2019), porous surface features In either case of water treatment or air purification, light weight,
(Nezarati, Eifert, & Cosgriff-Hernandez, 2013), beaded or bead-less high surface area, interconnected, porous structured nanofibrous
nanofibers (Fong, Chun, & Reneker, 1999), coaxial fibers (Han & membranes provide slip flow around the nanofibers that increases
Steckl, 2013), etc.) can dictate their mechanical, optical, thermal, diffusion, interception, and inertial impaction efficiencies (Fang et al.,
physicochemical or biological properties as a single fiber or as a whole 2008; Liu, Sui, & Dong, 2021). Making wearable electronics, smart
fiber mat (Rashid et al., 2021). textiles for defense or as fire retardant suits, etc. are some of the common
At the molecular level, electrospinning can facilitate the extended uses of electrospun fibers in the textile industry (Asmatulu & Khan,
chain crystal structure of a polymer (Kongkhlang, Tashiro, Kotaki, & 2019b). Electrospun nanofibers with a porous, interconnected structure
Chirachanchai, 2008). Here, each electrospun fiber is a bundle of are suitable candidates for use as a separator in a battery, an active
fibrillar structures, which in turn consist of crystalline polymer chain electrode in a photovoltaic cell, or as hydrogen storage (Fang et al.,
arrangements along the fiber axis (Kongkhlang et al., 2008). The crystal 2008). Again, the unmatched conspicuous properties of electrospun fi-
regions (crystallites) are connected through amorphous regions (tie bers have led to their application in different branches of biomedical
Fig. 3. Applications of electrospun nanofibers in different fields.
6
applications such as tissue engineering, drug delivery, wound healing, the loaded pharmaceuticals during moderate spinning (Sridhar et al.,
medical implants, membranes, etc. (Mwiiri & Daniels, 2020). Moreover, 2015). The distinctive structure of electrospun fibers can offer certain
use as catalysts, enzyme carriers, or catalytic supports is common for key benefits in drug delivery applications. High drug loading and
electrospun fibers (Xue, Xie, Liu, & Xia, 2017). encapsulation performance, optimal interactions of nanofibers with
various cell culture systems, the capacity to control drug release, the
4. CNC based electrospun nanofibers for biomedical material convenience of the procedure, and low expenditure are the most
prominent advantages exhibited (Sill & Von Recum, 2008). Most
4.1. Drug delivery notably, the nanofiber composition and the microstructure of mem-
branes may be controlled to effectively adjust the drug release process.
One of the most popular methods for creating drug-laden fibers is Moreover, the bioavailability of the drug molecules contained in the
electrospinning (Liu, Sui, & Dong, 2021). This method reduces in vitro nanofibers can be considerably increased (Hu, Prabhakaran, Tian, Ding,
drug burst release and can encapsulate a range of biomolecules while & Ramakrishna, 2015). These fiber matrixes can be used as frameworks
having essentially no effect on the molecular structure and bioactivity of to provide controlled release of a variety of medications since they have
Table 1
CNC based electrospun fibers for drug delivery applicationsa.
Material Electrospinning Model drug Key performance Drug delivery Reference
method performance
CNC-PHBV Needle Tetracycline • Enhanced hydrophilic, thermal and mechanical properties 86 % within 540 h (Cheng et al.,
electrospinning hydrochloride (TH) owing to the strong hydrogen bonding between CNC and 2017)
PHBV.
• Good cytocompatibility, high drug loading efficiency with
sustained long-term release of drug due to greater specific
surface area of the fibers and better compatibility with the
drug.
CNC-PEG-PLA Rotating collector Tetracycline • Reduced fiber diameter, increased fiber uniformity caused 95.7 % within (Yu, Wang, &
electrospinning hydrochloride (TH) improvement in hydrophilic properties with amplified 1032 h Abdalkarim,
thermal and mechanical properties. 2017)
• Excellent drug loading efficiency and sustained drug
release capability while maintaining good biocompatibility
with MG-63 cells.
Carboxylated CNC- Needle Tetracycline • Enhanced mechanical characteristics and thermal 94 % within 420 h (S. Hu et al.,
Cellulose acetate electrospinning hydrochloride (TH) properties with controlled long term drug release profile 2018)
originating from the strong interactions between CCNC and
CA matrix.
• Satisfactory homogeneous dispersion of composite, porous
structure and highly ordered chain alignment in the
nanofiber membrane.
CNC-PCL Needle Tetracycline • Enhanced biodegradability and mechanical performance – (Hivechi et al.,
electrospinning hydrochloride (TH) of nanofibers after incorporating CNC up to 1 wt%. 2019)
• Controlled release of drug and elevated drug detention
capacity arising from the intense hydrogen bond interaction
between CNC reinforced nanofiber mats and drug molecules
• CNC improved conductivity of the electrospinning
solution affecting the morphology and diameter of the
resulting nanofiber.
(CNC-g- Needle Tetracycline • Superior thermal and hydrophilic properties accompanied 81 % within 96 h (Chen,
PDMAEMA) - electrospinning hydrochloride (TH) by better fiber diameter uniformity and crystallization Abdalkarim,
PHBV potential obtained due to hydrogen bonding between the et al., 2020b)
two constituents.
• Smart and controlled drug release profile after
incorporation of CNC-g-PDMAEMA nanofillers
• Increased biocompatibility and cytocompatibility with the
human Hep-G2 cells than PHBV fiber alone.
• Novel material with tunable drug release and targeted
applications, for example cancer or tumor cells
Dendrimer Needle Tranexamic acid and • Modified CNC provided better mechanical support to the – (Mianehro, 2022)
modified CNC- electrospinning gatifloxacin scaffold
CA • Increased zeta potential resulted in enhanced distribution
of charge and better dispersion
• Antibacterial property was observed to be 99 % to both the
gram-positive and gram-negative bacteria.
• Controlled early release and ultimate release of drugs
• Biomedically safer drug carrier scaffold having no toxic
chemicals
Pectin-PEO-zein- Needle Hydroxychloroquine • CNC modified the morphology of the fibers and thus 85 % (w/w) HCQ (Zambuzi et al.,
HPMCAS-CNC electrospinning (HCQ) enhanced the sustained delivery profile release at 180 min 2024)
• The drug was uniformly distributed on the fibers and
interacted with polymer chains and CNCs mainly via
hydrogen bonds and electrostatic interaction
• Has the potential to continue drug release after 180 min
• Applicable for colon cancer treatment
a
CA: Cellulose acetate; CNC: Cellulose nanocrystal; HPMCAS: Hydroxypropyl methylcellulose acetate succinate; PCL: Polycaprolactone; PDMAEM: Poly[2
(Dimethylamino)ethyl Methacrylate]; PEG: Polyethylene glycol; PEO: Poly(ethylene oxide); PHBV: Poly(3-hydroxybutyrate-co-3-hydroxyvalerate); PLA: Polylactic
Acid.
7
substantial surface areas and the capacity to adsorb water (Torres-Giner, of the electrospun nanofiber matrixes followed by enhanced drug
Pérez-Masiá, & Lagaron, 2016). The electrospun matrix can offer loading and intelligent release performance (Hivechi, Bahrami, & Siegel,
controlled release, delayed dissolution, or quick and instantaneous 2019). Table 1 represents the research works conducted on electrospun
release, depending on the design that is chosen. The chemical compli- fibers reinforced with CNCs for drug delivery applications.
ance of the medications contained within the fiber microstructure Miao et al. first reported the use of CNCs into the electrospun
strongly influences the release profile. nanofibers of poly (3-hydroxybutyrate-co-3-hydroxyvalerate (PHVB) for
For producing controlled drug delivery vehicles, electrospinning of biomedical applications (Cheng et al., 2017). PHVB being not suitable
synthetic and biopolymers such as polylactic acid (PLA), poly- for biomedical application due to its hydrophobicity and low mechani-
caprolactone (PCL), polyethylene oxide (PEO), etc. has gained much cal strength, CNCs were introduced to enhance both the mechanical and
attention as their fiber size can be varied accordingly for the incorpo- hydrophilic properties of the produced nanofibers. CNC incorporation
ration of drug molecules and successfully delivering them in a designed with 6 wt% loading level successfully increased the tensile strength and
pattern (Galiano et al., 2018; Gao et al., 2019). However, the highly Young's modulus of the nanofibers by 125 % and 110 %, respectively
crystalline structure and hydrophobic nature of electrospun fibers from along with higher decomposition temperature owing to the hydrogen
these synthetic biopolymers limit their application as suitable carriers bonds among the molecules of PHBV and CNCs. Hydrophilic properties
for hydrophilic drugs as they inhibit the diffusion of drug molecules of the electrospun nanofibers were also excellent because of the presence
inside the fiber structure, and a lack of hydrophilic groups reduces in- of hydroxyl groups in CNC, and this hydrophilicity resulted in extraor-
teractions of the fibers with the drug molecules. So the drug molecules dinary drug loading and release performance of hydrophilic drugs which
appear on the fiber surfaces attached by weak bonding, thus, exhibiting could not be observed in the electrospun fibers of PHBV alone. Drug
initial burst release of drugs as well as poor drug loading capacity, very loading efficiency reached to >98 % while sustained long term release of
low sustained release of drugs and weak biocompatibility with cell drug was found from the improved hydrophilicity and specific surface
culture systems (Yu, Wang, & Abdalkarim, 2017). area of the carriers. It was reported that the prepared fiber mats with
These limitations are possible to overcome by introducing organic CNC loading of 5 wt% could release up to 86 % tetracycline hydro-
nanofillers which can regulate the water passage within nanofibrous chloride (TH) drug content within 540 h. Moreover, the biodegrad-
membranes and can modulate the drug release efficiency (Chou, Carson, ability and cytocompatibility test gave satisfactory results with 36 %
& Woodrow, 2015). Due to the high mechanical strength (Young's degradation of composite nanofiber achievable within 40 days. The
modulus of 150 GPa), excellent biodegradability with biocompatibility, physical properties along with accumulation and release capacity of
abundance of hydroxyl groups providing hydrophilic nature, and non- drug for electrospun fibers of PHBV are shown in Fig. 4 (a–c) (Cheng
toxic properties, CNCs have recently drawn greater interest as a novel et al., 2017). The figure depicts drug release, in vitro degradation
organic nanomaterial acting as a reinforcing agent to improve the behavior, morphological characteristics and hydrophilic properties of
properties of biodegradable electrospun polymeric matrixes (Liu, Sui, & different types of PHBV composite nanofibers associated with CNC. In
Dong, 2021). Low loading levels of CNCs have been shown to result in another work of electrospun nanofiber of PHBV for drug delivery
significant improvements in the mechanical and thermal characteristics application, CNC was functionalized by grafting with poly(N,N-
Fig. 4. (a) Representation of FE-SEM images and comparison of contact angle measurements for electrospun PHBV nanofibers and prepared composite membranes
with various level of drug loadings; (b) Accumulated drug release characteristic curve for PHBV fibers along with composite nanofibers loaded with 6 wt% CNC; (c) In
vitro degradation properties PHBV composite membranes with different CNC loadings; (d) Mechanism of TH drug release from host composite membranes of PHBV
(e) Profiles of in vitro drug delivery; f) comparison of contact angle data and fiber diameters for neat PHBV and PHBV/CNC-g-PDMAEMA (6 wt%) ternary composite
membranes containing various concentration of TH drug. Images a, b and c are reproduced with permission from the reference (Cheng et al., 2017). Copyright ©
2017 American Chemical Society. Images d, e and f are reproduced with permission from the reference (Chen, Abdalkarim, et al., 2020b). Copyright © 2020 Elsevier
B.V.
8
dimethylaminoethyl methacrylate (PDMAEMA) before incorporating it 4.2. Tissue engineering

into the composite system (Chen et al., 2020b). As the swelling property
and miscibility of the PDMAEMA is controlled by the pH and tempera- The process of tissue engineering involves implanting cells with
ture of the system, so the electrospun nanofiber obtained by using CNC- appropriate microenvironment, which are then transformed into new
g-PDMAEMA with PHBV resulted in stimuli-responsive smart and long tissues or part of organs being able to maintain the same functional and
term drug delivery vehicle where the drug release performance greatly structural qualities of the original tissues or organs (Kwon, Kwon, Lee,
depended on the human physiological conditions (Fig. 4 (d–f)) (Chen, Park, & Kim, 2018; Liu, Sui, & Dong, 2021). The biomaterials used in
Abdalkarim, et al., 2020b). As a result, the produced fiber mat is capable this technique require to have the ability to resemble the extracellular
of being used efficiently in targeted applications like treatment of cancer matrix (ECM) existing in natural systems so that cell transportation,
of tumor cells which possess different temperature and pH condition adhesion, differentiation, growth and smooth supply of necessary bio-
than the normal ones. Excellent biocompatibility of the composite macromolecules can promote new tissue regeneration uninterruptedly
membrane was proved by the exceptional cell attachment and growth (Bakhshandeh et al., 2017). This overall process depends on the
characteristics on the fiber structure and thus established itself as a biomechanical performance characteristics of the scaffold material used.
promising material to be used in biomedical applications. Electrospinning is a promising technique to be employed in tissue en-
Functionalized CNC was also reported to be used as reinforcement gineering systems, as it has the potential to produce highly porous
for electrospinning of cellulose acetate (S. Hu et al., 2018). The syner- nanometer scale fibers with larger surface area and strong inter-
gistic effect obtained from the hydrogen bonds between CA and connectivity (G. Yang et al., 2018). The surface topography of the
carboxylated CNC (CCNC) as well as the unique microstructure caused electrospun fibers helps to mimic the natural biological matrix systems
remarkable upgradation of thermal stability, physical properties along and thus makes them excellent substrate for cell attachment, prolifera-
with enhancement of drug delivery performance. The composite nano- tion and lost tissue regeneration (Jin et al., 2018). Incorporating CNC in
fiber exhibited an extended drug release profile of >86 % release within electrospun nanofibers for tissue engineering applications can be very
420 h while the drug loading capacity was >90 %. The presence of CCNC beneficial due to its excellent biocompatibility, degradability and low
reduced the contact angle by about 18◦ and thus increased the hydro- cytotoxicity characteristics (He et al., 2015; Rashad et al., 2019). It can
philicity of the prepared fiber mats which could promote cell adherence primarily reinforce the electrospun scaffold materials to provide suffi-
and growth on the surfaces. Hou-Yong et al. prepared a ternary com- cient mechanical strength required for tissue regeneration and also
posite fiber of CNC/polyethylene glycol-polylactic acid (CNC/PEG-PLA) introduce hydrophilicity that can accelerate the cell proliferation pro-
by electrospinning where CNC acted to reinforce the structure and cess. As a result, CNC based nanofibers have been explored in different
compatibility of the produced fiber mat was increased by PEG (Yu, sections of tissue engineering including bone/ligament tissue, skin tis-
Zhang, et al., 2017). PLA has highly hydrophobic characteristics with sue, tumors etc. (Domingues, Gomes, & Reis, 2014).
excessive crystallinity that induces poor drug loading and release The biomechanical performance of these electrospun scaffolds in
behavior. They successfully fabricated this composite electrospun fiber bone tissue engineering is found to be outstanding (Dutta et al., 2019a;
having increased drug loading capacity of 98 % and prolonged drug Patel, Dutta, Hexiu, Ganguly, & Lim, 2020; Zhang et al., 2015; Zhou
release behavior of 95.7 % within 1032 h owing to the extraordinary et al., 2013b). CNC was used as reinforcing agent for electrospinning
interaction between these three constituents. Improved hydrophilicity, polylactic acid (PLA) after some modification to improve the poor
satisfactory biocompatibility and sustained drug delivery of CNC/PEG- interaction compatibility between CNC and PLA. Grafting PLA with
PLA ternary nanofibrous membrane proved itself to be a promising maleic anhydride (MAH) before incorporating with CNC produced
drug delivery system. A very recent work on this topic investigated the MAH-g-PLA/CNC composite nanofiber where PLA-CNC interfacial
release behavior of hydroxychloroquine (HCQ) for the composite bonding properties were enhanced by hydrogen bonding leading to
nanofiber based on pectin, poly(ethylene oxide) (PEO), zein, and advanced mechanical strength (Zhou et al., 2013b). This composite
hydroxypropyl methylcellulose acetate succinate (HPMCAS) in presence proved to be an efficient scaffold material for bone tissue engineering
of CNC and CNF separately (Zambuzi et al., 2024). CNCs possess a high owing to non-toxicity, biocompatibility and hydrophilicity behavior that
surface area that facilitates robust interactions between the drug mole- can stimulate the growth of mesenchymal stem cells for osteoblast for-
cules and the polymer scaffold, resulting in enhanced HCQ retention. At mation. Similarly, Zhang et al. modified CNC with PEG before using it
180 min, fibers containing CNF released 95 % (w/w) HCQ and exhibited with PLA to produce nanofiber mats for bone tissue regeneration. The
an equilibrium point of release. CNC based fibers exhibited an 85 % (w/ composite mixture achieved well dispersion and stability due to pres-
w) release of HCQ within the same time having an increasing release ence of PEG which helped to solve the hydrophilic-hydrophobic inter-
curve which indicates the potential for sustained drug release. CNC has action complexities (Zhang et al., 2015). Along with satisfactory
more binding sites for interaction with drug molecules, illustrating the mechanical properties, this bio-scaffold was biocompatible enough to
prolonged drug release compared to the release profile reported in other allow osteogenic cell proliferation with addition of CNC-g-PEG up to 5
kinds of fibers. This reported electrospun fiber has enormous potential to wt% into the composite. Although the hydrophilicity of the prepared
be experimented with colon cancer treatment. nanofibers didn't improve which was attributed to the surface roughness
Electrospun nanofiber mats provide enlarged surface area and water of the fibers acting as a barrier for water penetration. The CNC-g-PEG
penetrability while the incorporation of CNCs into the electrospun ma- was assumed to exist inside the microstructure rather than on the sur-
trix can bring biodegradability, biocompatibility, mechanical strength face which could otherwise promote wettability. Fig. 5A describes the (i)
and thermal stability, high drug loading ability with intelligent and biomechanical performance, (ii) in vitro degradation behavior and (iii)
stimuli guided drug release behavior. Consequently, the development of morphology via SEM micrographs of MPLA and MPLA/CNC-5 scaffolds.
nanofibers reinforced by CNCs is projected to be helpful to boost Increasing amount of CNC improved reinforcement and osteogenic po-
nanomaterial-based drug delivery systems. However, the initial burst tential of the electrospun fibers while the stability against biodegrada-
release of medicines from the fiber surface over the first few hours poses tion was prolonged as well. Sayan et al. showed that (Fig. 5B) the
a particular barrier for researchers to overcome (Ding et al., 2019). combined effect of polycaprolactone (PCL) with CNC in the scaffold
Future research should involve investigating the cause of such burst could exhibit magnificent osteogenic potential and bone mineralization
release and finding ways to establish a completely controlled release capability. This highly porous structure with larger surface area can
profile of drug from the samples. Recently, coaxial electrospinning has mimic the appropriate extra cellular matrix viable for osteoblast cell
been considered to be an effective solution to this problem where the attachment and differentiation (Dutta et al., 2019a). They found that 2
produced nanofiber mat has core-shell structure and can present double % CNC content is optimum for cell differentiation and mineralization
phase drug delivery technique (Yu, Wang, Li, et al., 2013). process. The bone regeneration capability of PLA-2 scaffold prepared by
9
Fig. 5. (A) (i) Stress-strain curves of electrospun MPLA nanofibers and composite fibrous scaffolds of MPLA/CNC (ii) Degradation characteristics of MPLA and
MPLA/CNC-5 scaffolds, and illustration of in vitro degradation in one month using SEM images for (iii) neat MPLA and (iv) MPLA/CNC-5 scaffolds. Reproduced with
permission from the reference (Zhou et al., 2013a). Copyright © 2013 American Chemical Society. (B) Comparison of neat PCL fibers and their composite nanofibrous
scaffolds in terms of potential of hMSCs for osteogenic differentiation after treatment of 1 week and 2 weeks. (i) optical images of cultured hMSCs during ARS staining
to evaluate the effect of PCL and composite nanofibers. (ii) Mineralization study. Reproduced with permission from the reference (Dutta et al., 2019b). Copyright ©
2019 Sayan Deb Dutta et al. Published by Wiley. (C) (i) in vivo experimental procedure (above), and recovery of rat calvarial defect after 3 weeks treatment by μCT is
demonstrated (below), (ii) some pictures representing the conditions of Calvaria defect sites obtained by Hematoxylin and eosin (H&E) staining of collected tissues
after 3 weeks treatment (scale bar: 500 μm). PE means periosteum, NB means new bone formation. Reproduced with permission from the reference (Patel et al.,
2020). Copyright © 2020 Elsevier B.V.
Dinesh et. Al is presented in Fig. 5C shows that, (i) rat calvarial defect presence of CNCs in PCL/CHT nanofibrous structure resulted in a sub-
gets significantly healed after 3 weeks of treatment with this scaffold and stantial strengthening. Due to the load-supporting and elastic properties
(ii) no inflammation was observed from the histological analysis. of tendon tissues, it is essential to enhance the mechanical features of
Table 2 summarizes the trends of CNC based electrospun fibers in the tendon scaffolds while maintaining their ductility. The proposed tech-
field of tissue engineering. Nowadays CNC in electrospinning is utilized nique fulfills this criterion. The addition of small quantities of CNCs (3
for resolving different sensitive issues of tissue engineering like vascular wt%) greatly improved the mechanical properties of PCL/CHT nano-
tissue damage, tumor cell destruction etc. (He et al., 2014; Unal et al., fiber, resulting in the development of stronger tendons that were pre-
2020). Recurrence of glioblastoma tumor cells could not be prevented viously unachievable with these materials (Domingues et al., 2016). The
using 2D scaffolds which is why bacterial cellulose nanocrystal (BCNC) growth viability of human tendon cells was assessed on both the PCL/
with PLC-gelatin matrix structure was electrospun onto 3D nanofibrous CHT and PCL/CHT/CNC nanofiber and CNCs appeared to have negli-
scaffold eligible for improved cell adhesion by attracting proteins like gible effect on this cell growth viability as shown in Fig. 6 (j–l). The
fibronectin through surface hydroxyl groups (Unal et al., 2020). More- dynamic mechanical analysis of PLGA and CNC based electrospun fiber
over, the increased surface area connected more tumor cells to the depicted in Fig. 6 (k) states that the composite nanofiber obtained a
microenvironment through elongated axons to cause accelerated growth substantial increase in storage modulus compared to the pure PLGA
of these cells and thus prevented the repeated occurrence of glioblas- membranes. Compatibility analysis for skin tissue engineering in Fig. 6
toma tumors. The drawback of this material is that mechanical prop- (n) reported improved cell viability with the increment of CNC content
erties and water absorption ability of the nanofiber was poor due to the in PLGA membranes (Mo et al., 2015).
presence of BCNC. Fig. 6 (a–d) illustrates the swelling and hydrophilic Overall, the biomaterials typically designated for tissue engineering
properties of this composite nanofiber. Degree of swelling is important applications must prove to have specific qualifications which have been
for the model mimicking tumor matrix as it affects the transport of nu- prominently achieved by electrospun CNC reinforced composite fibers.
trients and signaling substances. Increasing BCNC percentage in the Their previous applications in this field give the testimony that CNC in
scaffold, decreased the water contact angle resulting in better electrospun form with tailored properties has great possibilities for
wettability. addressing the future demands of tissue engineering.
Attempts for preparing skin tissue substitutes from electrospun
nanofibers containing CNC were found to be efficient and considerable,
as the scaffolds could resemble the extracellular matrix to stimulate skin 4.3. Wound healing
tissue repair (Huang et al., 2018; Mo et al., 2015). Scaffolds of poly
(butylene succinate) (PBS) reinforced with CNC could provide a three- Wound, a discontinuity in the tissue, occurring in varying complexity
dimensional configuration with uniformly distributed interconnected and types, generally requires four stages of the healing process – he-
porous appearance which is a prerequisite for tissue regeneration stra- mostasis, inflammation, proliferation, and remodeling (Ambekar &
tegies (Huang et al., 2018). This extraordinary composite nanofiber with Kandasubramanian, 2019). To help in the healing process an ideal
controlled biodegradability and mechanical strength could successfully dressing should protect the wound from pain causing stress, resist mi-
transport cell nutrients and wastes during cell culture process ensuring crobial invasion, absorb excess exudates, fluids, and toxins, and at the
continuous adhesion and proliferation of 3T3 fibroblast cells. Excellent same time maintain a moist environment and enable oxygen permeation
mechanical characteristics of PCL/CHT/CNC nanofibrous scaffold at the injured site. Besides, it should be non-toxic or non-allergenic,
attempted for tendon tissue repair is represented in Fig. 6 (e–i). The lightweight, and should not promote any secondary trauma during
dressing change (Ambekar & Kandasubramanian, 2019; Teixeira et al.,
10
Table 2
CNC based electrospun fibers for tissue engineering applicationsa.
Material Electrospinning Target area Key performance Challenges Reference
method
MAH Needle electrospinning Bone tissue • Increased polarity on PLA surface followed by Initial rapid in vitro degradation (Zhou et al.,
grafted hydrogen bonding between PLA and CNC due to 2013b)
PLA/CNC MAH modification.
• This modification improved interfacial
interaction between CNC and PLA resulting in
increased hydrophilicity of the bio-scaffold.
• Zero toxicity with mesenchymal stem cells
(hASCs) and promotion of cell growth
• Advanced mechanical strength and in vitro
degradation stability
• Sufficient biocompatibility and physical
properties regarding bone tissue regeneration
application
Cellulose- Needle electrospinning Artificial • Unique morphology with uniaxial fiber In comparison to all-cellulose based (He et al., 2014)
CNC with rotating drum blood growth extended over long axis distance nanocomposites produced by film casting
collector vessels • Strong interaction between regenerated technique, tensile properties are inferior
cellulose and CNCs caused enhancement of
thermal properties.
• Increase of tensile strength by 101.7 % and
elastic modulus by 171.6 %
• No toxicity effects on human cells
• Cell growth over the surface as well as inside
the fiber structure
• Precise alignment of the fiber controls the
direction of cell growth orientation
• This controlled cell growth profile is suitable
for applications in artificial tissue such as blood
vessel, nerve, tendon etc.
CNC-g-PEG- Needle electrospinning Bone tissue • Poor interaction between hydrophilic CNC The hydrophilicity of the prepared nanofibers (C. Zhang et al.,
PLA and hydrophobic PLA matrix was solved by didn't improve, which was attributed to the 2015)
grafting PEG on CNC surface. surface roughness of the fibers acting as a
• Well dispersion of CNC in the matrix and barrier for water penetration. The CNC-g-PEG
enhanced colloidal stability achieved might have stayed inside the microstructure
• Ultimately excellent fiber reinforcement with rather than on the surface which could promote
improved ductility was observed. wettability.
• Sufficiently biocompatible for supporting
proliferation of human mesenchymal cells
leading osteoblast formation up to CNC-g-PEG
5 wt% addition.
PLGA-CNC Needle electrospinning Skin tissue • Best mechanical performance at 7 wt% CNC – (Mo et al., 2015)
loading
• Improved cytocompatibility, degradability
and thermal stability
• Mimics human skin tissue
• Promotes 3T3 fibroblast cell attachment,
differentiation and growth
PCL-CHT- Disk electrospinning Tendon/ • Eligible biomaterial for tendon/ligament Characteristic toe region in stress-strain curve is (R. M.
CNC ligament regeneration having relevant mechanical absent (Characteristic deformation behavior of Domingues et al.,
tissue characteristics tendon tissue at low strain level is not observed 2016)
• Enhanced toughness without compromising in the fabricated scaffold)
the biological performance
• Exhibits similar physical, biological,
functional and structural properties to that of
tendon tissues
• Can duplicate the extracellular matrix
presented by tendon tissue
• Promotes uniaxial growth of tenogenic cells
with desired phenotype due to anisotropic
alignment of fibers in fabricated scaffolds
PBS-CNC Skin tissue • Feasible cell growth and biocompatibility for Elongation at break decreased with increasing (A. Huang et al.,
skin tissue repair CNC content 2018)
• Adequate tensile strength, young's modulus
with better thermal stability up to CNC 3 wt%
addition
• Sufficient hydrophilicity with 3D porous
microstructure that can allow cell adhesion,
movement and proliferation on the surface as
well as inside the structure
• Better biodegradability
CNC-PCL Needle electrospinning Bone tissue • Incorporation of CNC resulted in improvement – (Dutta et al.,
of hydrophobic nature of PCL to hydrophilic 2019a)
followed by reinforcement of the prepared
scaffold.
(continued on next page)
11
Table 2 (continued )
Material Electrospinning Target area Key performance Challenges Reference
method
• Synergistic interaction between PCL and CNC

could successfully improve the mechanical
properties
• Osteogenic potential and bone mineralization
capability of the electrospun fibers were
enormous
• This highly porous structure with larger
surface area can mimic the appropriate extra
cellular matrix viable for osteoblast cell
attachment and differentiation
• Good biodegradability and no cytotoxicity
BCNC-PCL- Needle electrospinning Tumor • 3D platform for tumor tissue engineering with • Addition of BCNC degraded the mechanical (Unal et al., 2020)
Gelatin tissue ability to solve the discrepancy between in vivo performance of PCL-Gel matrix. The scaffold
and in vitro models. exhibited inferior tensile strength and
• Can provide microenvironment appropriate elongation at break.
for accelerating the tumor cell attachment, • Water absorption ability of the scaffold
differentiation and progress to avoid the decreased due to presence of BCNC.
recurrence of tumor after certain periods.
• Hydroxyl groups on the CNC surface enhances
cell adhesion capacity
• Gelatin empowers the structure by giving
three dimensional configurations.
PLA-CNC Rotating collector Bone tissue • Promising mechanical strength with greater – (Patel, Dutta,
electrospinning thermal durability Hexiu, Ganguly,
• Increased cell adhesion, multiplication and & Lim, 2020)
spreading capacity
• Outstanding biocompatibility with high
osteoconductivity
• Significant potential for supporting
osteogenesis
• Accelerated bone mineralization process
• Excellent bone regeneration observed in the
rat calvarial defect model
a
BCNC: Bacterial cellulose nanocrystal; CHT: Chitosan; MAH: Maleic anhydride; PBS: Polybutylene succinate; PCL: Polycaprolactone; PEG: Polyethylene glycol;
PLA: Polylactic acid; PLGA: Poly(lactic-co-glycolic acid).
2020). To meet these criteria, other than conventional wound dressings, good electrospinnability and improved fiber morphology. Besides,
modern wound dressings made of hydrocolloids, aerogels, etc. have a increased thermal stability along with water vapor transmission rate
major drawback of not being similar to extracellular matrix (ECM) (WVTR) and hydrophilicity were achieved with CNC incorporation
(Memic et al., 2019). Herein electrospun nanofibers, owing to their easy which are keys to better wound dressing performance.
tunability and processability from a wide variety of natural or synthetic Another common polymer matrix reinforced by CNC for wound
polymers, can mimic ECM very closely and thereby promote cell adhe- healing applications is poly(caprolactone) (Hivechi et al., 2021; Hivechi
sion, proliferation, and migration. Besides, their high surface area to et al., 2020; Rashtchian et al., 2020a). One study showed that crystal-
volume ratio and excellent porosity enables bioactive molecule incor- lization activation energy of this matrix increases with up to 1 % CNC
poration such as antimicrobial agents, anesthetics, anti-inflammatory incorporation using Ozawa-Flynn-Wall (OFW) methodology (Fig. 7A (i))
drugs, growth factors, etc. (Memic et al., 2019; Miguel et al., 2018). (Hivechi et al., 2021). Within the same study MTT cytotoxicity test
Finetuning the mechanical and physical properties of different resulted in PCL-CNC1.0 % (critical 1 % CNC incorporation) showing
polymeric electrospun nanofibers with CNC as reinforcing material for significantly higher absorbance than control group after 6 days as well
wound healing purposes has drawn the attention of researchers due to as absorbance increased significantly from day 1 indicating cell prolif-
its biodegradability, physical properties, biocompatibility, and low eration and viability (Fig. 7A (ii)). Rashitchian et al. showed in a study
toxicity (Hatch et al., 2019). Within the recent past, in 2014, Narges that CNC incorporation lead to higher hydrophilicity (lower water
et al. first gave a hint of using CNC along with an electrospinning so- contact angle) in the calcium alginate crosslinked poly (caprolactone)
lution for wound dressing preparation (Naseri, Mathew, Girandon, nanofiber mats (PCL-CaAlg+CNC) (Fig. 7B (i)) (Rashtchian et al.,
Fröhlich, & Oksman, 2015). In this study of CNC, irrespective of its 2020a). The lower water contact angle of sample fastens the hydrolysis
extraction process, along with the chitosan/poly(ethylene oxide) blend reaction and increases the degradation rate. (Fig. 7B (ii)). Hivechi et al.
resulted in an electrospun fiber mat that had better mechanical prop- took an interesting approach to combine the mechanical strength of
erties than just the chitosan/PEO matrix and had no cytotoxicity to- synthetic poly(caprolactone) with the biocompatibility of natural
wards adipose-derived stem cells. Later on, Ana et al. took a more robust gelatin (Hivechi et al., 2020). Their biaxially electrospun scaffold
approach with the same matrix from an antimicrobial perspective for showed increased biodegradability and biocompatibility after CNC
wound dressing applications (Ribeiro et al., 2021). The inclusion of incorporation than the CNC-less counterpart. Besides, just CNC inclusion
acacia plant-based extract to chitosan/poly(ethylene oxide)/1 % CNC led to faster full-thickness wound healing (well-organized collagen fi-
system led to lower minimum inhibitory concentration (MIC) as well as, bers appeared with sebaceous glands and hair follicles as shown in
lower minimum bactericidal concentration (MBC) and minimum Fig. 7C (i–ii) with lesser inflammation in Balb/c mice. These results can
fungicidal concentration (MFC) in the study against six bacteria species be attributed to CNC's mechanical properties, and surface charge which
(both gram-positive and gram-negative) and six fungi species. Besides, enable it to act as a stiff substrate for cell adhesion, growth, and
acacia release for 24 h from the system suggested its prolonged action migration (Hivechi et al., 2021; Rashtchian et al., 2020a).
and subsequent lower frequency of dressing change. On CNC's part, it Researchers conducted similar studies with other polymer-CNC sys-
increased spinning solutions' viscosity and conductivity resulting in tems as well, such as poly(vinyl alcohol) (Hussein et al., 2020; Teixeira
12
Fig. 6. Ratio of swelling for the scaffolds at various time periods (a) Demonstration of Water contact angle (WCA) experiment of different scaffolds of PCL/gel
containing (b) 0, (c) 0.5 and (d) 1.0 wt% BCNC. Mechanical characteristics evaluation of composite nanofibers PCL/CHT and PCL/CHT/CNC3. (e) Characteristic
stress-strain curves, (f) ultimate tensile strength, (g) Young's Modulus, (h) toughness, and (i) elongation at break. (j) Cell viability assessment by monitoring
mitochondrial activity of hTDCs (1 × 10 4 cells/sample) with the help of Alamar Blue assay. Confocal microscopy images showing the distribution of the hTDCs
seeded on (k) PCL/CHT and (l) PCL/CHT/CNC3 composite fibers (scale of the image is similar to image K) (Green: Calcein AM). (m) Dynamic mechanical analysis
and (n) fibroblast cell viability of PLGA nanofiber alone and PLGA nanofibers with CNC reinforcement of 1 wt%, 3 wt%, 5 wt% and 7 wt% denoted by a, b, c, d and e
respectively in the figure. Images a, b, c and d are reproduced with permission from the reference (Unal et al., 2020). Copyright © 2020 Elsevier B.V. Images e, f, g, h,
i, j, k and l are reproduced with permission from the reference (Domingues et al., 2016). Copyright © 2016 Wiley. Images m and n are reproduced with permission
from the reference (Mo et al., 2015). Copyright © 2015 Elsevier B.V.
et al., 2022), polylactide-polyglycolide (Zheng et al., 2018), poly(3-hy- biomedicine is biosensors. This field has not been extensively investi-
droxy-butyrate-co-3-hydroxy-valerate) (Abdalkarim, Yu, Wang, & Yao, gated yet using CNC-based electrospun fibers. The literature clearly in-
2017), gelatin-chitosan (Tabassum et al., 2024), etc. The Gelatin- dicates that biosensors constructed using electrospun fibers
chitosan-CNC system is a very recent inclusion to the field where 50 % strengthened with CNC exhibit promising potential. Zhu et al. developed
faster healing of wounds on the mice could be seen with the prepared sophisticated strain sensors that can detect human motion by integrating
nanofiber mat as a wound healing patch than the Gelatin-Chitosan carbon nanotube (CNT) and cellulose nanocrystal (CNC) fillers into a
counterpart (Tabassum et al., 2024). Other than these, Elsherbiny nanofiber membrane made of polyurethane (Zhu, Zhou, Liu, & Fu,
et al. took a completely different approach to CNC inclusion in wound 2019). The degree of sensitivity and broad range of strain that the strain
care patches where it acted as a coating-emulsion stabilizer rather than sensors can detect can be adjusted by altering the mass proportions of
direct incorporation in a spinning solution (Elsherbiny et al., 2023). CNT/CNC and the overall quantity of composite fillers in this sensor.
Here, poly(butylene succinate) nanofibers were coated with a ther- The power generator for sensors, made of a fibrous membrane composed
moresponsive eicosane/CNC o/w system loaded with bioactive α-ami- of polyvinylidene fluoride (PVDF) and CNC, achieved an ultimate
nophosphate derivatives. Owing to the amphiphilic character of voltage of 60 V when 2 wt% of CNCs were added to the PVDF nanofiber
cellulose materials CNC could successfully stabilize the eicosane o/w matrix (Fu et al., 2017). The excellent piezoelectric properties in PVDF
emulsion system even after water removal through lyophilization. This fibers were achieved due to both a high concentration of β phase and a
approach enabled a controlled release of drug from poly(butylene suc- high degree of crystallinity after blending CNC into the structure. The
cinate) nanofibers at a temperature range of 36–38 ◦ C and hurried results indicate that electrospun fibers based on CNCs are highly
release of drug is possible with the increased temperature at the wound promising materials for advanced biosensors.
site in case of microbial attack. Table 3 summarizes all the aforemen-
tioned works on CNC based electrospun fibers for wound healing 5. Challenges and future trends
application.
Despite the great potential of CNC-based electrospun nanofibers in The most significant problem regarding CNC based electrospun fiber
wound healing application current research greatly lack in vivo studies. production is preparing a stable dispersion of CNC in the solution matrix
Therapeutics release from smart wound dressings which will replace any using appropriate solvents which eventually determines the electro-
necessity of oral antibiotics can be one of the ultimate goals of future spinnability of the mixture followed by the quality and subsequent
research. application of the produced fibers. Initial burst release of drugs from
Another captivating and well-regarded topic in the field of electrospun scaffolds is one of the challenging issues associated with
13
Fig. 7. A) (i) Fitted results for crystallization activation energy using OFW method at 0.2 extent of conversion for PCL (■), PCL-CNC0.5 % (◆), PCL-CNC1.0 % (●),
PCL-CNC1.5 % (▴), PCL-CNC2.5 % (×), and PCL-CNC4.0 % (*). (ii) MTT cytotoxicity results for PCL nanofibers incorporated by different CNC contents; significantly
different groups are shown by *(p < 0.05) and ***(p < 0.001). Reproduced with permission from the reference (Hivechi et al., 2021). Copyright © 2021 Elsevier B.V.
B) (i) The water contact angle for (a) PCL-PVA/NaAlg, (b) PCL-PVA/NaAlg + CNC, (c) PCL-CaAlg, and (d) PCL-CaAlg + CNC nanofibers sheets. (ii) SEM images of
degraded nanofibers in 28 days. Reproduced with permission from the reference (Rashtchian et al., 2020a). Copyright © 2020 Elsevier B.V. C) (i) Photographs of
wounds in mice in which the wounds were treated with S1 (PCL/Gel nanofibers) and S2 (PCL/Gel nanofibers reinforced with cellulose nanocrystals). Control (Ctl)
corresponds to mice whose incisions were treated with sterile gauze. Images were taken at days 7 and 14 post surgery. (ii) Microscopic images of hematoxylin and
eosin (H&E) stained wounded tissue on Days 7, and 14 post-treatments: control without any treatment (Ctl), PCL/Gel wound dressing (S1), PCL/gel dressing
reinforced with CNC (S2). H&E staining demonstrates the presence of the epithelial layer in the S2 group (black arrow) at days 7. Skin appendices such as hair
follicles (green arrow) and sebaceous glands (red arrow) appeared in the S2 group 14 days post-treatment. The scale bar is 200 μm. Reproduced with permission from
the reference (Hivechi et al., 2020). Copyright © 2020 Springer Nature B.V. [Here, PCL = Poly(caprolactone), PCL-CNC X = Poly(caprolactone)/CNC composite
nanofibers where, X = CNC concentration, PCL-PVA/NaAlg = Sodium alginate crosslinked poly(caprolactone)/poly(vinyl alcohol) nanofiber mat, PCL-CaAlg =
Calcium alginate incorporated poly(caprolactone) nanofiber mat.]
drug delivery applications. Also the total percentage of drug release • Increasing the mechanical strength, and the thermal stability for
achieved from the fiber mats is not satisfactory yet and complete re- tissue engineering applications of CNC based electrospun fibers can
covery of drugs incorporated in the matrix is still a challenge (Chen, be achieved by making necessary polymer and/or CNC modification
Abdalkarim, et al., 2020b). In case of tissue engineering, the electrospun so that more interaction occurs between the polymer matrix and the
nanofibers reinforced with CNC do not always exhibit promising me- CNC. In this case, the mechanical strength of the nanofiber system
chanical performances (Huang et al., 2018; Unal et al., 2020). Moreover, should support cell adhesion, migration and proliferation as well as
modification of CNCs to be incorporated into polymer matrix for better suitable biodegradability. Other than surface modification of the
interaction characteristics with partner components sometimes inhibits nanofiber, CNCs (modified or unmodified) should be on the nano-
the thermal stability and hydrophilic properties of electrospun fibers fiber surface to overcome hydrophobicity problem in tissue engi-
(Zhang et al., 2015). On the wound healing side, lack of antimicrobial, in neering applications. Besides, spinning parameters should be as such
vivo studies, and lack of complete understanding of polymer matrix and to avoid any surface roughness on the nanofiber surface in this re-
CNC along with other therapeutics synergistically helping wound heal- gard. Complete degradation and metabolic excretion of the nanofiber
ing are key challenges (Elsherbiny et al., 2023; Ribeiro et al., 2021; system within physiological conditions without any host immuno-
Teixeira et al., 2022). Taking these facts into consideration, following logical response is a key aspect in tissue engineering. CNC based
topics should be addressed in the works of CNC based electrospun fibers electrospun fibers should go through sufficient in vivo studies to
for biomedical applications in future: meet this aspect. Fiber alignment needs to be either isotropic or
anisotropic as per performance criteria in individual tissue engi-
• Drug delivery from the CNC based electrospun fibers should be of neering applications. Future works should also conduct sufficient
good profile without any abrupt release characteristics. In this case, performance studies of the regenerated tissues within CNC based
attachment of drug molecules to the fiber system can be as such only electrospun fiber scaffolds.
certain indigenous or external stimuli will enable the release. This • There are probably concentration-wise or material-wise endless
will expedite targeted release characteristics given that drug release possible combination of polymer, CNC and therapeutics for wound
occurs within the stimuli magnitude imposed by human physiolog- healing applications. Any single combination must be tested for
ical conditions. Pharmacokinetics of the drug incorporated and drug antimicrobial activity, clotting aid, collagen deposition, re-
release kinetics from the nanofiber should be compatible with the epithelialization, anti-inflammation, gap closure efficiency and
fiber system degradation so that high release percentage and effi- healing capability, etc. Therefore, complete understanding of the
ciency can be achieved. mechanism for the synergistic effect from a possible combination is
14
Table 3
CNC based electrospun fibers for wound healing applicationsa.
Material Electrospinning Assessment Wound healing performance Key performance of CNC Challenges Reference
method type
PBS, Eicosan, CNC, Needleless In vitro • Thermal responsive Stabilizes eicosane o/w No antimicrobial activity (Elsherbiny
α-aminophosphonate electrospinning property at close to infected emulsion especially after before certain temperature; et al., 2023)
derivative human body temperature lyophilization when water is lacks any in-vivo studies
(39 ◦ C) removed; increases the
• Antimicrobial activity wettability of coated
against Bacillus subtilis, nanofibers
Staphylococcus aureus,
Escherichia coli, Klebsiella
pneumonia, and Candida
albicans
CNC, PVA, Tiger 17, Single-needle In vitro • Effective against Improves mats' surface Lacks knowledge of the (Teixeira et al.,
Cys-Pexiganan electrospinning Staphylococcus aureus and energy and structural stability conformational 2022)
Pseudomonas aeruginosa over time rearrangements undertaken
• Accelerates clotting by the peptides during
interactions with mat and
bacteria
CNC, PCL Single-needle In vivo and • Full-thickness wounds CNC incorporation up to 1 % No antimicrobial study is (Hivechi et al.,
electrospinning In vitro fade away more rapidly in increases the crystallization conducted 2021)
CNC containing samples activation energy and reduces
• Seeded cells on the the crystal volume
nanofiber scaffolds have
increased growth on the
samples containing CNC
Chitosan, PEO, CNC, Needle In vitro • Antibacterial effect Improves nanofibers' physical Exact mechanism of action (A. S. Ribeiro
Acacia plant-based electrospinning (against 6 bacteria species) integrity, morphology, of chitosan against et al., 2021)
extract and antifungal activity diameters, water vapor microorganisms is not fully
(against 6 fungi species) transmission rate and thermal understood; limited studies
• Continuous release of the properties regarding the mechanisms
acacia extract reduces the of action of acacia extracts
frequency of dressing's against bacteria
replacement
PVAHyaluronic acid, Needle In vitro • Exhibits excellent Improves mechanical and Antimicrobial mechanism of (Hussein et al.,
CNC, L-arginine, electrospinning hemocompatibility, high swelling properties; hyaluronic acid is not fully 2020)
Citric acid protein adsorption, contributes to cell understood
outstanding proliferative immobilization, proteins
and adhesive potential adhesion, high gap closure
• Antibacterial activity efficiency and healing
specially against Klebsiella capability
pneumonia
PCL, Gelatin, CNC Biaxial In vitro and • Shows faster wound Improves mechanical Some inconsistencies (Hivechi et al.,
electrospinning In vivo healing with lower properties and leads to fewer between the in vitro and in 2020)
inflammation phase than but larger crystallites in vivo studies; does not
control group nanofibers; increases guarantee the results from
biodegradability with faster cell culture will resemble in
generation of well-organized dynamical wound healing
collagen fibers, sebaceous scenarios
glands and hair follicles
CNC, PCL, Calcium Biaxial In vitro • More than 90 % cell Improves mechanical Single CNC concentration is (Rashtchian,
alginate electrospinning viability in the poly properties, hydrophilicity, studied; lacks antimicrobial Hivechi,
(caprolactone)-calcium biodegradability study Bahrami,
alginate-CNC sample Milan, &
Simorgh,
2020b)
CNC, PLGA, Needle In vivo • Increases collagen PLGA/CNC scaffold shows Reduction of inflammatory (Zheng et al.,
Neurotensin electrospinning deposition and re- better wound healing cytokines are discussed 2018)
epithelialization of diabetic performance than control skipping any antimicrobial
mice wounds group activity of the proposed
• Exhibits anti- material
inflammatory activities by
inhibiting IL-1β and IL-6
CNC-ZnO nanohybrid, Needle In vitro • Antibacterial activity of CNC-ZnO nanohybrid reduces Lacks the explanation of (Abdalkarim
PHBV electrospinning about 100 % against both nanofiber diameter, improves how the higher absorbency et al., 2017)
E. coli and S. aureus uniformity, mechanical of simulated fresh blood
strength, thermal stability, actively takes part in new
barrier property and tissue formation and normal
absorbency of simulated fresh wound healing
blood
Chitosan, PEO, CNC, Single needle In vitro • Non-cytotoxic impact on Improves spinnability of the Single concentration of CNC (Naseri et al.,
Genipin electrospinning adipose derived stem cells spinning solution; increases is explored; no antimicrobial 2015)
water vapor permeability and study is present
the O2/CO2 transmission
(continued on next page)
15
Table 3 (continued )
Material Electrospinning Assessment Wound healing performance Key performance of CNC Challenges Reference
method type
Gelatin, Chitosan, CNC, Needle In vivo • 50 % faster healing than Contributes to the ionic forces Role of individual (Tabassum
Hydroxyapatite, electrospinning the control group in the solution component is not clear; et al., 2024)
Glutaraldehyde separate presence of
hydroxyapatite and CNC is
not confirmed
a
PLGA: poly(lactic-co-glycolic) acid; PBS: Poly(butylene succinate); PVA: Poly(vinyl alcohol); PCL: Poly(caprolactone); PEO: Poly(ethylene oxide); PHBV: Poly(3-
hydroxy-butyrate-co-3-hydroxy-valerate).
required. This will help to reduce any inconsistencies between in viability, with no reported toxicity and capability of chemical modifi-
vitro and in vivo studies. Thereby future works on CNC based elec- cation for binding different biological molecules. However, it can be
trospun fibers for wound healing applications should focus on smart challenging to combine several materials into an electrospun fiber since
dressings which will enable little to no necessity for dressing there are restrictions related to their electrospinnability that must be
replacement with periodic and stimuli responsive therapeutics addressed. Effective biomaterials require an appropriate blend of poly-
release. mers, solvents, pre-treatments to make these precursors more soluble,
and the addition of new surface functional groups for enhanced per-
Electrospun fibers based on CNCs have outstanding mechanical formance. One of the common disadvantages of electrospinning is that
properties with biocompatibility, yet these have not been explored in the this process associates with lower production rates and further research
field of medical implants or bone implants. Application of CNC based should be focused on this matter to explore new solvent systems, com-
nanofibers in this area could be extremely beneficial. In general, posites and modification of CNCs for increased productivity. Previously
biomedical applications of CNC based electrospun fibers face a major reported works on biomedical application of CNC based electrospun fi-
challenge of commercialization of the product. Scale-up of existing bers mainly demonstrate the formulations and electrospinning condi-
electrospinning methods maintaining morphological and chemical tions while future research should concentrate on developing novel
characteristics for a particular application can be challenging. Exploring materials with unique structures by extensive investigation of structure-
new solvents or solvent systems and CNC derivatives, inventing novel property relationships so that desired functions can be performed effi-
methods of electrospinning with high throughput etc. can help to ciently. On top of that, there are many potential areas in this field which
overcome this challenge. are left to be explored with these nanofibers including medical implants,
membranes, biosensors, cancer treatment, antimicrobials, detection and
6. Concluding remarks diagnosis etc.
With this brief review, we hope to highlight many intriguing char-
Electrospinning is a straightforward and adaptable technology to acteristics of CNCs as reinforcing agent of nanofibers and their potential
fabricate highly porous 3D membranes and nanofibrous structures with in biomedical, while also serving as a catalyst for the development of
a large ratio of surface area to volume. These materials have a wide novel biomaterials with tailored properties for sensitive applications in
range of uses in biological tissues, drug delivery vehicles, medical im- this field.
plants and membranes, wound repair etc. In order to reinforce electro-
spun polymer nanofibers, CNCs with rod-like structures may be CRediT authorship contribution statement
produced from renewable resources which have excellent mechanical
strength, a high Young's modulus, low nanotoxicity, as well as large Saifuddin Ahmed: Writing – review & editing, Writing – original
aspect ratios. Electrospun nanofibers of CNCs show considerably draft, Visualization, Software, Methodology, Investigation, Formal
enhanced mechanical characteristics, a higher degree of crystallinity analysis, Data curation. Ratul Ahmed Khan: Writing – review & edit-
and hydrophilic properties, coupled with suitable biodegradability and ing, Writing – original draft, Visualization, Software, Methodology,
biocompatibility for their great applicability in biomedical applications. Investigation, Formal analysis, Data curation. Taslim Ur Rashid:
Recent developments in CNC-based electrospun nanofiber Writing – review & editing, Writing – original draft, Visualization, Su-
manufacturing and applications are outlined in this paper. Currently, pervision, Software, Resources, Project administration, Investigation,
research works in this topic concentrate on finding new solvents for CNC Funding acquisition, Conceptualization.
and CNC derivatives that are appropriate for electrospinning as well as
on developing electrospinning equipment to produce better fiber Declaration of competing interest
ensuring maximized utilization of these renewable, biodegradable, and
nontoxic interconnected porous structures in biomedical field. Addi- The authors declare that they have no known competing financial
tionally, the use of CNC based composites is advancing due to its highly interests or personal relationships that could have appeared to influence
accessible –OH groups, which are also in charge of resolving the limited the work reported in this paper.
solubility of conventional types of cellulose. These groups facilitate
interaction with a variety of biomolecules, such as proteins and en- Acknowledgements
zymes. The use of nanofiber mats of CNCs as drug carriers proved to be
feasible in previous works as these materials can depress unwanted The authors wish to acknowledge the financial support by University
initial release of drugs in high dosage, impose a negligible effect on Grants commission of Bangladesh Research Grant 2022–2023 (Ref. No.
loaded drugs and exhibits efficient drug loading along with sustained, Reg/Admin-3/63433).
smart and controlled release of drug molecules. Tissue engineering ap-
plications of these fibers are getting much more attention nowadays due Data availability
to their excellent outcome attributed to their biomechanical perfor-
mance and ability to mimic the extracellular matrix of targeted tissue No data was used for the research described in the article.
which can subsequently initiate cell attachment, proliferation and lost
tissue regeneration. Various forms of CNCs are incorporated in electro-
spinning for producing wound dressing materials having significant cell
16
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Cellulose nanocrystal based electrospun nanofiber for biomedical

1. Introduction applications employing electrospinning techniques has been very pop-

Fig. 1. Schematic representation of CNC preparation.

2.1.4. Combined method CNCs are widely used as reinforcement in nanocomposites to

Fig. 3. Applications of electrospun nanofibers in different fields.

dimethylaminoethyl methacrylate (PDMAEMA) before incorporating it 4.2. Tissue engineering

• Synergistic interaction between PCL and CNC

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