Cellulose, a linear polysaccharide, is the most common and renewable biopolymer in nature.
1. Introduction
The most prevalent and renewable biopolymer in nature is cellulose, which is a linear polysaccharide. Cellulose is an organic molecule with a formula comprising a polysaccharide composed of a linear polymer of hundreds or even thousands of connected
D-glucose units. Cellulose is a structural component of the major cell wall of plants, many types of algae, and oomycetes
[1][2][3]. This natural polymer cannot be melted (heated) or dissolved (in common organic solvents). By derivatized chemical modification or direct dissolving, cellulose can be converted into a processible liquid state
[4]. As adsorbents, cellulose and cellulose derivatives have been utilized in the form of hydrogels
[5][6], films
[7][8], beads
[9][10], microfibers
[11], and microcrystals
[12][13]. In all these applications, cellulose as a solid phase provides a large surface area that may separate chemicals from flowing liquids due to cellulose active functional groups. In chromatography
[14], protein purification
[15], and drug delivery
[16][17][18][19], cellulose beads can be utilized as the stationary phase. Papermaking and the synthesis of micro fibrillated cellulose have both employed partially or considerably fibrillated cellulose. Micro fibrillated cellulose was created from wood using a high-pressure homogenization process
[20] and has since been utilized as a filter aid as well as an excellent thickener
[21]. In general, considerable energy consumption is unavoidable for the nanoscale fibrillation of wood or other cellulosed source items that need cleaves of interfibrillar hydrogen bonds
[22].
Cellulose nanocrystals (CNCs) receive more research attention than their CNC counterparts (in this case micro fibrillated cellulose)
[23][24]. The reason for this is because nanoparticles with their nanosized (higher surface area) have superior characteristics. The popularity of nanocellulose materials is continuously increasing. CNCs and nano fibrillated cellulose (CNF) (or alternatively cellulose nanofibrils) can be used in applications ranging from small-scale medical-grade items to larger-scale sorbent products. For instance, CNF shows promise for applications that need flexibility, such as possibly wearable electrochemical applications
[25]. CNF-based aerogels are reasonably simple to make using freeze drying or critical point drying and have received a lot of attention
[26]. To research material/cell interactions using CNFs, CNF-based nanocomposite hydrogels can be employed as sophisticated origami actuators. Artificial tissue, medical devices, diagnostics, and biosensors have all used these actuators
[27]. Because of their ionic connections, CNF and poly ethylene glycol (PEG) can undergo a reversible sol gel transition when subjected to strain or temperature ramping
[28].
The key attribute that cellulose-based goods provide to a matrix due to their elongated structure is their capacity to enhance mechanical capabilities
[29][30]. For instance, enhancing mechanical properties of polymers
[31][32][33][34][35], ceramics
[36][37], etc. Aerogels made of chemically cross-linked nanostructured materials based on cellulose can be employed as flexible substrates for a variety of functional nanoparticles, including hydrophobic nutritional supplements and nanoparticles
[38][39]. CNC aerogel nanostructures’ porous structure enables rapid water absorption and swelling via macropores and the macropillary action of mesopores; that makes this substrate ideal for separation and extraction
[40]. CNCs have been linked with biopolymers using cross-linking chemistries to generate a reinforced hydrogel structure, a process that involves, for instance, borax
[41]. Basic fibroblast growth factor was loaded into disposable gelatin microspheres, which were then integrated into porous collagen/CNC scaffolds, according to Li et al.
[42]. Cotton nanofibrils on their own are more amenable to hydrogel production than CNCs. Dried CNC films with a helix inner structure are usually formed, for example, by depositing a suspension
[43] onto a substrate and then drying it. The drying may be separated into many parts that are governed by geometry, the atmospheric partial pressure of water, and temperature. CNC division into liquid crystalline domains depends on aspect ratio and concentration of CNC based on Onsager theory
[44][45]. Having stated that, specific applications based on CNC and CNF literature have been identified; there have previously been reviews on the individual subjects of CNF
[46], micro fibrillated cellulose
[47][48][49][50], cellulose nanocrystals
[46][51][52], and cellulose nanocrystals in polymers
[47][53][54] and prospective readers are recommended to study the reviews of these references (refs.).
Cellulose has a wide range of characteristics, including, but not limited to, gas barrier ability
[55], as liquid crystal assembled structures
[56][57][58][59], hydrogel-based templates
[60], aerogels
[61][62][63], and inks
[64][65][66], and the ability to provide Pickering emulsion capability
[67][68][69][70][71][72][73][74][75][76][77][78]. Moreover, additional modification such as the hydrophilization of cellulose-based aerogels has piqued the interest of researchers due to its potential in oil/water separations and organic pollutant entrapment
[79]. It should be noted that several of the studies given can be classified as belonging to the same category, for example, inks can be classified as belonging to the hydrogel-based templates category.
Microfluidics is the science and technology of systems that are microscale integrated channels through which small quantities of liquid may flow and during which the flow and the material within can be controlled or altered in tandem
[80][81]. The history of microfluidics may be traced back to an attempt to perform miniature biochemical analyses
[82]. At the microfluidics scale, because the dimensions are small, the specific effects are augmented, resulting in behaviour that differs from that of macroscopic fluids. This causes viscous to inertial forces to become dominant
[83], surface effects to become significant, and mass and heat transfer to become efficient
[84]. For instance, the size of the particles being focused, a topic that will be covered later, is impacted heavily by inertial forces
[85]. This size dependency can be advantageous for biological sample cleanup since smaller particles are sucked out, enhancing final sample purity, or minimizing bacterial contamination
[86].
The use of microfluidics simplifies the existence and varied interaction of several phase fluids in a single “lab on chip”
[87]. As a result of the characteristics listed, this intriguing subject has led the way for multidisciplined study in the physical, biological, chemical, and medical disciplines. In the production of nanoparticles, super control over reaction kinetics
[88], as well as tuning and modifying thermodynamic parameters, can provide nanoparticles with customizable size and crystal structure.
Microfluidic devices can be used for causing the flow-induced orientation of cellulose, as a mixing zone
[89], for emulsification (can come under the category of mixing), as a reactor such as acting as a glucose assay
[90], and as an analytical tool, or cellulose itself can be used to make a microfluidic device
[91]. The microcapsule emulsification approach includes mechanically shearing the system to generate a polydisperse mixture of droplets from the mixing of oil and water. This droplet creation has received much attention in recent decades since it allows for the generation of microparticles. Water-in-oil droplet microfluidics is used to create consistent spherical CNC droplets in a nontoxic and environmentally friendly manner. Following the evaporation of the water within the droplets, the molecular cross-linking of surface modified CNCs is accelerated. On the other hand, on a microfluidic chip, emulsification can occur through three broad designs of co-flow, fluid-focused flow, or the T- or Y-junction meeting of multiple flows
[89][92][93][94][95].
2. Design of Cellulose with Microfluidics
In the literature, microfluidic technology has been employed to enhance the fabrication of cellulose-based parts. Figure 1 shows how microfluidics may be used to generate distinct shapes in cellulose products.
Figure 1. Cellulose shape formation using flow modulation of microfluidics
[96][97][98][99]. (
a) CNC–CNF joint orientation along channels of a microfluidic chip for particle production with optimized qualities. Adapted with permission from Ref.
[99]. Copyright 2018 Wiley-VCH. (
b) The assembly process of regenerated silk fibroin (RSF) fibrils suspended in RSF/CNF passing via a microfluidic channel is depicted. RSF and CNF are distributed; the majority of RSF molecules are in random-coil form. Adapted with permission from Ref.
[96]. Copyright 2019 American Chemical Society. (
c) The nanofibrils are focused in the channels, and a gelation agent (NaCl) is injected along the route to help the cellulose rods stay in place as they exit the channel. Adapted from Ref.
[98]. (
d) Microfluidics-based microparticle manufacturing with customizable final sizes. The setup for the experiment is shown at the bottom. Adapted from Ref.
[97].
To create strong fibres from CNF and CNC, a continuous wet spinning technique based on microfluidic flow focusing has been devised. For the first time, fibres with an average breaking tenacity of 29.5 centi Newton per tex have been recorded. CNCs are an appealing building element for producing lightweight yet robust and flexible textiles due to their high strength and modulus. When CNCs are added to CNFs alone, the concentration of dope can be increased by 4 to 5 times
[99] (See
Figure 1a).
In Lu et al.
[96], cellulose hydrogel was utilized to create a microfluidic device using a 3D printer. Indeed, silk fibroin and CNF hybrid fibres were dry-spun via a microfluidic chip that resembled the structure of a spider’s main
ampullate gland in this work
[96]. Many researchers have used nano-scale innovations, such as the use of titanium dioxide
[100], graphene oxide
[101], carbon nanotubes
[102], and CNC, to improve the mechanical qualities of artificial silk. The authors’ research in Lu et al.
[96] revealed that CNF may easily be used to enhance the mechanical properties of silk fibres. Stress at break of RSF/CNF with 0.1 wt% CNF was determined to be about 485 ± 106 MPa, representing a 58 percent increase over RSF fibres spun from silkworm (maximum recorder was 686 MPa). The method of integration of the two ingredients is depicted in
Figure 1b. Spider silks have amazing mechanical qualities; hence, one of the areas of research in the field of biomimetic fibres has been the construction of high-performance artificial silk fibres as waveguides
[103]. Strong fibres such as the one introduced here might be useful in biological media, bio-photonics, and central nervous system interfaces
[104]. Similarly, in other refs., the direction and alignment of silk-spinning through microfluidic chips have been optimized through flow analysis
[105][106][107]. This finding sets the path for further research into the demystification of the enigma of the natural spinning process. It offers a complete and methodical look at the process of creating highly oriented artificial fibres for biological applications
[108]. In the development, regeneration and characterization of a blended system combining
Bombyx Mori silk fibroin protein and cellulose acetate, a cellulose derivative, silk may be mixed with cellulose derivatives
[109]. Many studies on the combination of silk and cellulose acetate for filament/fibre manufacturing may be found in the literature
[96][104][108][110][111][112][113][114][115][116][117][118].
CNF, which has a lot of potential as a building component for biobased products, might need to have hydrodynamic alignment (alignment due to fluid-induced orientation) and a dispersion–gel transition involved in its process. Gelation can occur due to the introduction of NaCl, a coagulant that acts as a charge screener
[2]. Knowing these two concepts, alignment and gradual gelation, led the author to design the microfluidic channel in
Figure 1c. Based on mechanical examination, the filaments generated were shown to be more durable and stiffer than the precursor material, CNF, and equivalent CNF-based polymer nanocomposites in the literature
[2]. The generated fibres are equally as tough and strong as cellulose pulp fibres when equal fibril orientation is used.
Figure 1c depicts the assembly process for the design of this durable fiber. The cross section of the fibres is also represented as a diffractogram. The orientation of fibres as a function of residence time and shearing in the microfluidic channel was employed in all three studies listed above. It would have been ideal to assess the level of orientation using the plot introduced by Pignon et al.
[119]; small-angle light scattering and small-angle X-ray scattering were used in this experiment. Cluster breakup may also be studied using a confocal setup because gelation is involved. Furthermore, utilizing rheology and theoretical models, the Folgar–Tucker orientation of fibres along the boundaries of the microfluidic setup and at the centre may be determined
[31].
By merging microfluidic and flash-freezing methods
[97], porous cellulose acetate microspheres with variable particle sizes and pore characteristics were effectively manufactured. These particles exhibited a large specific surface area and good adsorption properties. The diameter of the microspheres may be precisely adjusted by modifying the microfluidic settings. For oil, the developed porous structures were able to adsorb up to 30 times their weight, while for Congo red, they were able to adsorb up to 23.9 mg·g
−1. A pictograph of the procedure is shown in
Figure 1d. The setup for the experiment is also shown at the bottom. Staying on the subject of using the microsphere as a way of extraction/separation, paclitaxel, one of the natural anticancer drugs that can be isolated from the bark of
pacific yew tree, was recognized, and separated in Wu et al.
[120] using a sophisticated design of microspheres
[120]. These examples demonstrate how microfluidics may be used to design structures that are entirely adjustable and suited for specific applications such as separation.
The highlights of recent research utilizing microfluidics in the development of cellulose-based goods are shown in Table 1.
Table 1. Presentation of research involving microfluidics in the creation of cellulose-based goods, as well as their highlights.
Table 1 displays a presentation of research involving microfluidics in the creation of cellulose-based goods, as well as their highlights. As a recap of
Table 1, a study of silk-spinning through microfluidic chips has uncovered the secrets of the natural spinning process
[104], a study easily extendable to cellulose. Paper as a substrate aids in reducing existing stiff wastes and inevitable pollution
[90]. Polysaccharides have been shown to be useful in medication encapsulation and delivery. Using
E. coli as a biocatalyst, a paper fuel cell can generate 11.8 W·cm
−2 of electricity using paper cells
[123]. Membrane-less Microfluidic Paper Fuel Cells are promising technologies for harvesting energy. H
2O
2 is used as both fuel and oxidant in a paper-based microfluidic fuel cell for portable electronics. The fuel cell does not require precious-metal catalysts, and the fuel utilized is carbon free and environmentally friendly
[148], with a peak energy capacity of 0.88 mW·cm
−2.
A 3D-printed microfluidic chip allows for nucleic acid extraction without the need of vortexes or centrifuges
[149]. Inside the chip’s microgeometries, magnetic, interfacial, and viscous drag forces are defined. Cavitating flow patterns have the potential to be utilized to promote a wide range of industrial and technological applications. In a coagulation bath, cellulose nanocrystals were wet spun
[141]. The effect of sodium alginate on the properties of the micro composite filament was investigated. Bioimaging experiments demonstrated that solid cellulose deposits may be recognized in their spatial location
[142].
3. Cellulose as a Microfluidic Building Block
We offered a generalization on the issue of microfluidics and cellulose in the preceding section. The use of cellulose as a microfluidics building component will be discussed here. Paper, elastomer, thermosets, silicon/glass, thermoplastics, and hydrogels are some of the materials that may be used to make microfluidics chips
[150]. Here, we focus on paper-based microfluidics.
Paper-based microfluidics, often known as “lab on paper,” is a revolutionary fluid management and analysis technology. The system is said to be low-cost, simple to use, disposable, and requires no equipment. Indeed, paper is an appealing substrate for these devices since it is omnipresent, ubiquitous, and incredibly inexpensive. As a result, the material is also compatible with a wide range of additional chemical, biomedical, biomedical, biochemical, and medicinal applications. It transfers liquid through capillary forces without the help of any external forces. Microfluidic paper-based analytical devices, for example, may be utilized to measure the concentration of various analytes in a solution while also serving as an excellent platform for point-of-care diagnostics (dubbed as POC). Furthermore, it has found use in water quality analysis, as water pollution is harmful to human health. In Chen et al.
[151], a layered multilayer electrostatic printing approach for manufacturing nanofiber-based microfluidic chips for water quality analysis was created. Devices provide easy fabrication techniques, flexible prototyping, mass production possibilities, and multi-material integration.
As stated earlier, cellulose is a plentiful natural solid carbohydrate biopolymer that is vital to the biosphere and plays an important role in the global carbon budget
[152]. The use of cellulose-derived nanoparticles for cell imaging, material science, sensors, and other medical applications is gaining popularity
[152]. One application for cellulose is as a component in the manufacture of microfluidic chips. Overall, few procedures for developing microfluidic devices, photolithography
[153][154][155], plotting using a plotter
[156], etching
[157][158][159], plasma
[160], cutting
[161][162] and wax printing
[163][164][165], flexography printing
[166], screen printing
[167], and laser treatment
[168] have been documented. These approaches can be utilized to make microfluidic devices; to classify them, photolithography, etching, spraying, screen printing, and dipping wax are examples of indirect patterning processes, whereas wax priming, plotting, flexography, writing, stamping, and inkjet printing are examples of direct patterning methods.
Figure 2 shows the technology involved in patterning a PAD, including 3D printing, wax printing, flexography printing, cutting, photolithography, and plotting.
Figure 2. Methods of patterning a PAD
[169][170][171][172][173]: (
a) 3D printing; Adapted from Ref.
[169]. (
b) wax printing; Adapted from Ref.
[170]. (
c) flexography printing; Adapted with permission from Ref.
[172]. Copyright 2019 Elsevier. (
d) cutting; Adapted with permission from Ref.
[171]. Copyright 2015 Wiley-VCH. (
e) photo-lithography; Adapted with permission from Ref.
[171]. Copyright 2015 Wiley-VCH. (
f) plotting; Adapted with permission from Ref.
[173]. Copyright 2016 Springer-Verlag. These strategies are described in detail in the main text.
To explain some of the methods briefly: Wax printing uses a basic printer to design wax on paper, after which the wax is melted to produce channels. This process is quick but offers limited resolution due to the isotropy of melted wax
[164]. A wax layer creates the hydrophobic boundaries that are needed to guide the flow of a hydrophilic liquid. Inkjet printing involves coating paper with a hydrophobic polymer and then applying an ink that selectively etches the polymer to allow the paper to emerge
[171]. Photolithography is comparable to inkjet printing in that etching is accomplished using a photomask and a photoresist polymer
[155]. Using a hydrophilizing agents such as fluorocarbon plasma polymerization, the paper first becomes hydrophobic, and then oxygen plasma etching is used to form hydrophilic patterns onto the paper
[174]. In flexographic printing, the process involves the usage of conventional graphic printing, functional inks, and a substrate such as paper. Flexography, inkjet printing, wax printing, and 3D printing all have striking parallels in this regard. Filling the vacuum with a hydrophobic substance, such as a solid melted at a certain temperature or a hydrophobic polymer immersed in an organic solvent, is another approach for creating hydrophilic structures on paper. These materials may easily penetrate the porous network in their liquid state and form a barrier once solidified. For applications that demand portable yet small fluid handling, microfluidics parts made by 3D printing with paper as part of the operation is of great use. A 3D printer can also be used to produce hybrid channels. This technology is inexpensive and suited for household usage because it offers accurate fluid handling abilities, functionality (versatile), and user-friendliness
[169]. A depiction of 3D-printed microfluidics is shown in
Figure 2a. Some examples of other methods mentioned earlier are also depicted in
Figure 2b–f.
Aside from selecting a good technique for microfluidic paper-based manufacturing, it is also critical to pick a material that can go through the process. Cellulose and cellulose derivatives are suitable materials for 3D printing; nevertheless, finding strong cellulose solvents is crucial for their efficient use because cellulose cannot be melted (processed). However, due to strong hydrogen bonding, cellulose is also insoluble in water and other organic solvents. Only a few effective solvent systems capable of dissolving cellulose have been discovered thus far. As a result, researchers discovered functionalization processes such as xanthation
[175], esterification
[176], and etherification
[177] on the cellulose hydroxyl group as a method of disrupting hydrogen bonds and breaking cellulose’s tenacity to dissolve. However, non-derivatizing solvents such as ionic liquid
[178] can also dissolve cellulose without requiring chemical changes, which is advantageous in many instances
[179].
The most significant cellulose derivatives are cellulose ethers and esters
[177]. These are found in a variety of goods, including thickeners, binders
[180], emulsifiers, coatings, and membranes. The esterification of cellulose allows for the transformation of cellulose into different forms
[181]. Cellulose ethers are plentiful, low-cost, environmentally friendly compounds with exceptional characteristics. They have several uses in food, medicines, cosmetics, and other commercial items. They are also commonly employed in 3D printing, where they serve several purposes
[182][183]. The properties of ink are vital in 3D printing; specifically, 3D printing ink requires a well-regulated viscoelastic response (such as high viscosity and shear thinning behaviour)
[184]. The shear thinning properties of polymer solutions are frequently used to achieve this objective
[185][186]. These expected rheological behaviours can be obtained using cellulose ethers. Cellulose ether has been used to change the viscosity of a variety of industrial products
[187]. However, when an external force is applied, the mixing energy will break the hydrogen bonds between the cellulose chains, causing the chain to align in the low direction, as seen by the shear thinning of the pseudoplastic behaviour
[188]. The qualities of cellulose ether solution are thus sought since they are low at greater shear rates and high when the flow is halted. Furthermore, these materials are thixotropic
[182], which is advantageous for becoming an ink since it necessitates the rehabilitation of the structure following fracture via the nozzle.
Table 2 contains a substantial amount of the literature devoted to the development of cellulose-based microfluidic devices that can showcase the objective behind developing such systems.
Table 2. Presentation of research in which cellulose was employed as a chip-building material.
As a recap of
Table 2, PADs have been developed for sub-microliter surface area/volume analysis. The wax-printing technology that was previously used to design paper substrates has been improved to make high-resolution designs patterned in filter paper. In recent years, paper-based microfluidics used for analytical purposes, also known as PADs, have attracted a lot of interest for carrying out a variety of traditional analytical activities. PADs’ appealing characteristics are mostly due to them being made of paper (cellulose), which is inexpensive, readily disposable, and environmentally benign. Three-dimensional paper-based microfluidics with three layer channels made from a paper-made substrate demonstrates the enzymatic detection of biomarkers such as glucose, lactate and uric acid
[192]. According to the ISI Web of Knowledge data collection, the market for these types of devices has been steadily growing, as seen by 942 publications published under the title microfluidic paper-based between the years 2018 and 2022. Clearly, the trend indicates the future growth of PADs.
Figure 3 depicts a brief overview of the use of cellulose in the creation of microfluidic chips of varying scale, size, shape, and design. The technique of transport depends on hydrophilic cellulose or nitrocellulose fibres to transfer liquid from an input guided through a porous medium via capillary action. The benefit of paper-based microfluidics is their passively controlled activity, which distinguishes them from more sophisticated microfluidic designs. The following regions are found in paper-based devices: an inlet in a substrate that is commonly constructed of cellulose where liquid is manually dispersed, a channel in which a hydrophilic network controls liquid transport, and a flow amplifier in which flow velocity is impacted to impart a controlled velocity to flowing liquid. A flow resistor is a capillary element that imparts a lowered flow velocity to control residence time, a barrier is a wall that prevents liquid from penetrating out of the channels, and an outlet is a location where a chemical or biological reaction occurs. For instance, in Figure 3a,c, the μPAD is divided into three parts: sensing, substrate, and water addition. The distance between the regions of addition of water and substrate was designed to be 12 mm, while the area of sensing was estimated to be 11 mm.
Figure 3. (
a) Photolithographic devices for measuring glucose and protein. Adapted with permission from Ref.
[190]. Copyright 2010 American Chemical Society. (
b) As a supporting material embedding for the microchannels, cellulose nanofibrils hydrogel, a 3D structuring ultrathin film, was employed. Adapted with permission from Ref.
[204]. Copyright 2017 American Chemical Society. (
c) The μPAD is divided into three parts: sensing (6.5 mm diameter), substrate (6.5 mm diameter), and water addition (11 mm diameter). The distance between the regions of addition of water and substrate was calculated to be 12 mm, while the area of sensing was estimated to be 11 mm. Adapted with permission from Ref.
[197]. Copyright 2018 American Chemical Society. (
d) Scanning electron microscopy (SEM) photos of white wood microchannels are shown, as well as high magnification SEM photographs of individual microchannels, to demonstrate the presence of pits with an average diameter of 2.5 μm in addition to obstructed mass transmission that these designs can offer. Adapted with permissions from Ref.
[196]. Copyright 2018 American Chemical Society.