Functional Materials Based on Nanocellulose for Pharmaceutical/Medical Applications

Functional Materials Based on Nanocellulose for Pharmaceutical/Medical Applications: Comparison

Please note this is a comparison between Version 3 by Peter Tang and Version 4 by Peter Tang.

Nanocelluloses (NCs), with their remarkable characteristics, have proven to be one of the most promising “green” materials of our times and have received special attention from researchers in nanomaterials. A diversity of new functional materials with a wide range of biomedical applications has been designed based on the most desirable properties of NCs, such as biocompatibility, biodegradability, and their special physicochemical properties.

nanocellulose
nanocrystalline cellulose
nanofibrillated cellulose
bacterial cellulose
hydrogels
nanogels
nanocomposites
drug delivery
wound healing
tissue engineering

1. Introduction

Science and technology continue to move toward the use of renewable raw materials, more environmentally friendly and sustainable resources as a result of their potential to manufacture numerous high-value products with low environmental impact ^[1][2][3].

Nanocellulosic materials derived from abundant and inexhaustible cellulose are an important component of this vital movement ^[4][5]. The immense interest generated by these nanomaterials during several decades is mainly related to their exciting properties and possibilities of producing from a multitude of sustainable resources ^[6].

Generally, cellulose nanomaterials include all cellulose-based materials that are at least one size in nanometer scale, with various shapes, physical properties, or surface chemistry. Depending on the origin of the cellulose, the processing conditions, and the methods of their preparation, nanocelluloses are classified into three main categories (Figure 1): (i) cellulose nanocrystals (CNC), which are short and rigid; (ii) cellulose nanofibers (CNF), long and flexible; and (iii) bacterial nanocellulose (BNC), with high purity and very crystalline ^{[1][7][8][9][10]}. Even though these types of nanocelluloses have a relatively similar chemical composition, there are major differences in their degrees of crystallinity and particle size, as well as in their morphological characteristics ^[11].

Figure 1. Preparation scheme and dimensions of different types of nanocelluloses: nanocrystalline cellulose, nanofibrilar cellulose, and bacterial nanocellulose.

Cellulose nanocrystals (CNC), also known as nanocrystalline cellulose (NCC), cellulose nanowhiskers (CNW), or cellulose crystallites, are obtained by acid hydrolysis of wood or various non-wood materials (cotton, hemp, flax, wheat straw, mulberry bark, ramie, Avicel, tunicin, algae or bacteria), which consists in the chemical removal of lignin, hemicellulose and of amorphous regions within cellulose ^[12]. Cellulose nanofibrils (CNFs), also called microfibrillated cellulose, nanofibrils, and microfibrils, or nanofibrillated cellulose (NFC), are extracted from wood, sugar beet, potato tuber, hemp, flax by delamination of pulp by mechanical pressure before and/or after chemical or enzymatic treatment ^[9]. Bacterial nanocellulose (BNC) or microbial cellulose is produced by some bacterial genera, such as Gram-negative bacteria: Acetobacter, Rhizobium, Pseudomonas, Salmonella, etc. or Gram-positive bacteria: Sarcina ventriculi, in fermentation processes of sugars and vegetable carbohydrates. This has a large specific surface area, higher water retention value, is considered chemically pure cellulose, and does not contain lignin or hemicellulose ^[13].

All types of nanocelluloses (NCs) are chemically similar but have different organizational forms and consequently different physical characteristics. As entities, CNFs are micrometer-long fibrils having highly entangled networks of nanofibers with both crystalline and amorphous domains. CNCs are stiffer and highly crystalline rods (ca. 90%), while BNCs are secreted as a ribbon-shaped fibril composed of a bundle of much finer nanofibers.

Beyond possessing the advantageous performances of nanomaterials, the natural nanocellulose (NC) is low cost, completely renewable, highly biocompatible, having low ecological toxicity risk and low cytotoxicity to a range of animal and human cell types compared to the synthetic ones ^[14][15]. These excellent properties provide NCs an important place in interdisciplinary studies and an increased interest in their applications as biomedical materials.

To date, there has been a strong focus of researchers on the design, manufacture, and processing of nanocellulose-based materials for their potential use in biomedicine, as well as a tremendous increase in the number of scientific publications, from 2015 to 2020, with topic keywords “tissue engineering”, “drug delivery”, and “wound healing”, respectively ^[16][17].

2. Advanced Functional Materials Based on Nanocellulose—General Characteristics

2.1. Hydrogels

With the progress of nanotechnology, hydrogels have received much more attention due to their particular and excellent characteristics. Hydrogels were the first biomaterials to be conceived for use in humans. They have moved forward to now mimic basic physiological processes and are essentials as bioactive implants in the sense of “in vivo” scaffolds. The use of hydrogels as biomaterials is strongly related to their properties. Hydrogels are three-dimensional network colloidal gels from hydrophilic polymer crosslinked able by swelling to absorb and retain large volumes of water in an aqueous environment ^{[18][19][20][21][22][23]}. In the swollen state, they have a soft and rubbery structure that mimics the behavior of extracellular matrix (ECM) in biological tissues ^[24]. Furthermore, hydrogels are conformable to different kinds of surfaces on which they are placed. These properties, in combination with their mucoadhesive nature, elasticity, swelling, and deswelling characteristics in response to environmental stimuli, make hydrogels potential candidates for biomedical applications ^[18][25]. Thus, hydrogels have found applications to produce different types of materials such as contact lenses ^[26], blood-contacting hydrogels ^[27], wound-healing bioadhesives ^[28], artificial kidney membranes ^[29], artificial skin ^[30], vocal cord replacement ^[31][32], and artificial tendons ^[33]. Depending on the size of the obtained particles, hydrogels may be classified as macro-, micro-, or nanogels. When they have particle sizes bigger than 100 m, they are usually called macrogels, while gels with particle sizes up to the micrometer range are called microgels. Finally, if these gels are smaller than 100 nm, they are usually considered nanogels ^[34][35].

2.2. Nanogels

Nanogels, also called “hydrogel nanoparticles”, “nanoscalar polymer networks”, “gel nanoparticles”, or “nanoscale hydrogels”, are combine the properties of gels with those of colloids ^[18]. Generally, they have a spherical shape and size between 20 and 200 nm ^[36]. Hydrogels, at the nanometer scale, have a great potential in the field of biomedical applications, e.g., as drug-delivery systems, as they combine the characteristics of hydrogels with the advantages of nanoparticles ^[36][37]. Reducing the size of hydrogel particles in the nano range is reflected in increasing the solubility of hydrophobic drugs, improving the accumulation of drugs in tumors, but also by reducing cytotoxic side effects and increasing the stability of therapeutic agents against enzymatic and chemical degradation ^[34]. The nanogels also possess some desirable properties, such as high drug-loading capacities, chemical stability, and mechanical properties to avoid the disassembly or fracture during transport, and sensitive response behavior to ensure rapid drug release in response to the relevant stimuli ^[38]. In addition to their excellent applicability in the drug delivery field, nanogels have also found applications in other biomedical fields, such as chemotherapy ^[39][40], diagnosis of diseases ^[41], vaccines delivery ^[42], biocatalysis ^[43], and generation of bioactive scaffolds in regenerative medicine ^[34]. They have also been studied for use in diabetes treatments ^[44] and gene and protein delivery ^[41][45]. Nanohydrogels prepared from natural sources have drawn huge attention due to their vast applications in pharmacy, medicine, tissue engineering, cancer therapy, and drug delivery ^[46]. The use of nanocellulosic materials in obtaining hydrogels from renewable materials has been a much-desired goal that has been achieved for many hydrogel types ^[47][48][49]. Several smart hydrogels such as injectable hydrogels ^[33][50][51], shape memory ^[52][53], supramolecular hydrogels ^[54][55], double-membrane hydrogels ^[56], temperature-sensitive hydrogels ^[57], and many other hydrogels types based on nanocellulose with potential for biomedical applications have been developed. However, on their own, nanocellulose materials do not gel ^[58]. Different ways are used to perform, for example, for the gelation of CNC suspensions: by simply increasing the concentration of suspension due to a decrease in the electrostatic double-layer distance ^[59]; by modifying the solvent conditions through ionic strength increase ^[60]; by addition of polymers ^[58]; by sonication ^[61]; and by hydrothermal treatment at elevated temperature ^[47]. Nanocrystalline cellulose, with their high rigidity and relatively low anisotropy, are well-suited to act as templates for aligned structures (e.g., artificial muscle-like materials) while providing toughness and flexibility. With collagen, for instance, this afforded networks with mechanical properties similar to tendon and ligaments and excellent biocompatibility ^[62]. Nanofibrillated cellulose (CNFs) is the type of nanocellulose most likely to form hydrogels due to the length of the nanofibrils. CNFs form gels with much higher elasticity than those resulting from CNCs. CNF suspensions exhibit gelation (G′ > G″, G′ ∝ ω⁰, and G″ ∝ ω⁰, where, G′ is the storage modulus, G″ is the loss modulus, ω is the frequency) even down to a concentration near to 0.1 wt.%, i.e., the critical gelation concentration, above which the nanofibrils form interconnected networks ^[63]. CNFs will afford such structures at concentration ranges of 0.05–6 wt.% ^[62]. The simplest case is offered by pristine CNFs, which spontaneously form hydrogels, probably promoted by their length and interacting entanglements ^[64].

2.3. Nanocomposites

Currently, research is also progressing in the field of nanocomposite hydrogels, including functionalized nanomaterials ^[18]. In general, in order to improve or modify certain properties, polymeric matrices of nanocomposites are reinforced with nanoparticles/nanofillers ^[65]. In particular, hydrogels are reinforced with nanoscale materials to obtain nanocomposites with high mechanical strength characteristics or are combined with nanoparticles that confer antibacterial or magnetic properties ^[34].

2.3.1. Nanocellulose Materials as “Reinforcing Agents” into Polymer Matrices

Over the past decade, composite materials have attracted a great deal of interest, and particular attention has been focused on the use of nanocellulose as an alternative to inorganic reinforcing agents in polymer matrices for the production of fully “green” composites ^[66][67][68]. Nanocellulose, owing to its exceptionally high mechanical properties (high specific strength and modulus), high surface area, high aspect ratio, and low environmental impact, has greater advantages as reinforcing filler in comparison to glass fibers, silica, carbon black, and other expensive nanosized fillers ^[65]. Thus, composite materials with natural fillers have not only met the environmental appeal but also contributed to developing low-density materials with improved properties ^[69]. Hydrogels entirely made of biopolymers and reinforced with nanocellulose can be classified as “green” nanocomposite materials because of their renewable and biodegradable design ^[70]. The design of cellulose-based biocomposites is a pathway with many alternatives due to the wide variety of cellulose fibers with specific geometries, the diversity of polymers and manufacturing processes, the multitude of types of reinforcements, and the possibilities of orientation and arrangement of fibers ^[17]. Nanocrystalline cellulose has been investigated as reinforcing agents for a variety of polymeric systems due to their large aspect ratio, high specific strength and modulus, low density, high surface area, and unique optical properties ^{[51][62][65][71][72]}. CNCs have been used as reinforcing agents in a wide range of polymer matrices, from the most common to the most unusual, such as: poly(vinyl alcohol), poly(oxyethylene), polyethylene glycol, poly(N-isopropylacrylamide), starch, natural rubber, or polyurethane ^{[67][73][74][75][76]}. Nanofibrillated cellulose (NFC) has excellent properties for mechanical reinforcement due to its special morphology that combines the advantages of the length of the fibers in the micrometers range with those of their width in the nanometers range ^[69]. The use of CNF networks as reinforcing elements together with a suitable matrix polymer is an efficient reinforcement solution for high-quality, specialized applications of bio-based composites. The combination of nanofiber flexibility, aspect ratio, and strength is the main advantage of CNFs in various applications ^[77]. For instance, comparing the reinforcement capacity of CNC and NFC (at the same addition) using poly(ethylene oxide) (PEO) as the polymer matrix, Xu and coworkers ^[75] reported that the nanocomposites reinforced with NFC demonstrated higher-strength and elastic modulus than nanocomposites with CNC. However, CNC-based nanocomposites presented a higher strain of failure. The higher strength values of NFC-based nanocomposites are the effect of their high aspect ratio of cellulose nanofibrils that favors more entanglement and network percolation. By comparison, bacterial nanocellulose (BNC), having the highest purity of all nanocellulose materials, doubled by high crystallinity and excellent biological affinity, is the ideal reinforcing component for biopolymer composites ^[78].

2.3.2. Nanocellulose Materials as “Matrices” for Different Reinforcing Agents

The inclusion of biocompatible and/or bioactive compounds as components of the composite is the proper way to overcome certain limitations of nanocellulose materials, improving their biocompatibility, antimicrobial activity, or water-holding capacity ^[79]. Generally, nanocellulose can be reinforced with different polymers with specific properties, obtaining a material with different characteristics from those of starting materials ^[65]. Nanocellulose can also be used as a substrate for the incorporation of inorganic nanoparticles, such as carbon nanotubes, graphene, and graphene oxide to obtain hydrogels with antibacterial, antiviral, antifungal, magnetic, electrical, and mechanical properties. The high specific surface area, the presence of reducing functional groups, and the ability to form aqueous suspensions are the main arguments for the use of nanocelluloses as a support for metal/metal oxide nanoparticles ^[80]. The process of composite formation is performed through physicochemical interactions or by mechanical capture of nanoparticles in the structural matrix of nanocellulose ^[81]. Nanocellulose-based compounds have found applications in various biomedical areas, from dressings to drug administration and even as a basis for scaffolding in regenerative medicine ^[82]. Silver particles have been used as potential agents with a broad antibacterial activity and low presumed toxicity to coat cellulosic materials for biomedical applications. The composite was prepared by immersing BNC in a silver ammonium solution and showed to be effective as dressing in wound-healing applications by decreasing inflammation and promoting wound-healing ^[30]. The silver nanoparticles were incorporated in crystalline nanocellulose by microwave-assisted synthesis, and the composites proved to have high antibacterial properties against E. coli (Gram-negative bacteria) and S. aureus (Gram-positive bacteria) ^[83]. Barua and coworkers ^[84] prepare copper-copper oxide nanoparticles (Cu–CuO) NP-coated CNFs through a green reductive technique, which exhibited promising antimicrobial activity against Gram-positive and Gram-negative bacteria and fungal species.

3. Nanocellulose-Based Materials in Pharmaceutical/Medical Applications

The nanocellulose materials, used as independent functional material or as reinforcement units in composite materials, have received tremendous attention in a wide variety of applications, including foods, packaging, cosmetics, biomedical implants, optics, water filtration, hygienic applications, and so forth ^[3][14][17]. However, especially in biomedical fields, they appear to have significant advantages due to their intrinsic biodegradability and biocompatibility ^[14]. However, other interesting features should also be considered, such as mechanical properties, low risk of cytotoxicity, its three-dimensional (3D) nanofibrous network, and last but not least, its natural source ^[62][85][86].

3.1. Nanocellulose-Based Materials in Drug-Delivery Systems (DDS)

An ideal drug carrier should be nontoxic, non-immunogenic, biocompatible, and biodegradable; enhance drug solubility and stability and have high drug-loading capacity; and be capable of reaching correct concentrations at a proper rate determined by an optimal ^[36]. Other equally important criteria to be met are related to its size and surface characteristics because these two parameters control the residence time in the bloodstream and the target site. More exactly, the size needs to be sufficiently large enough to prevent rapid penetration into fenestrated blood vessels, yet sufficiently small to avoid phagocytosis. The surface nature also decides the duration and destination of the drug carrier in the circulatory system. For instance, a hydrophilic surface will most likely make the carrier avoid phagocytosis by macrophages, and this hydrophilicity can be accomplished either by covering the surface with a hydrophilic polymer (i.e., PEG) or by using block copolymers with hydrophilic and hydrophobic areas ^[62]. Being a natural nanosized material, nanocellulose features meet the necessary criteria mentioned above regarding its function as a vehicle for DDS: its horizontal measurements extend from 5 to 20 nm, and the longitudinal measurement ranges from 10 nm to a few microns; each of its monomers bears three hydroxyl groups with the ability to form hydrogen bonds, which plays a major role in the surface hydrophilicity. Of course, the nanocellulose unique properties should not be overlooked because they make this material play an important role among drug-delivery vectors, such as high crystallinity, biocompatibility, biodegradability, high surface area, unique mechanical and rheological properties, liquid absorption capacity, and porosity ^{[36][85][87][88]}. The three types of nanocellulose are quite similar to each other, yet there are distinct differences that set them apart. These differences make each type of nanocellulose better suited for a certain drug-delivery system compared to the others ^[87]. The researchers summarize the recent reports on nanocellulose-based drug-delivery systems in Table 1.

Table 1. Nanocellulose hydrogels/nanocomposites in drug-delivery applications.

NCs Type

Drug Delivery

System

Drug

Drug-Release Conditions

Drug Release

Cytotoxicity evaluations in in vitro studies induced by CNC- and CNC-based materials.

Material

Cellulose Source

Material

Toxicological

Experiment

Mechanism

Ref.

Cells

Lines

Cellulose Source

Toxicological

Experiment

Toxicological Results

Cells

Lines

Toxicological Results

Results and Possible Application

Results and

Ref.

Possible

Application

Abbreviations: PBMNC—Human peripheral blood mononuclear cells; HEK—Human epidermal keratinocytes; NHDF—Normal human dermal fibroblasts; A549—Human lung alveolar epithelial cells; HDF—Human dermal fibroblasts; MRC-5—Human lung fibroblast cell line; THP-1—Human monocytic leukemia cell line; A549—Human alveolar epithelial cell line; Caco-2—Human epithelial colorectal adenocarcinoma cells; BEAS-2B—Transformed human bronchial epithelial cells; hDF—Adult human dermal fibroblasts; MSCs—Mesenchymal stem cells; L929—Mouse fibroblast cells; GSH—Levels of glutathione (marker of oxidative stress); GIT—Gastrointestinal tract; MTT—Methylthiazolyldiphenyl-tetrazolium bromide; AB assay—Alamar blue assay; MTS assay—CellTiter-Glo luminescent cell viability assay; PB assay—Presto blue assay; AB assay—Alamar blue cell viability assay; U-NFC—Unmodified NFC; A-NFC—Carboxymethylated-NFC; C-NFC—Hydroxypropyltrimethylammonium-NFC; P-NFC—Phosphorylated NFC; S-NFC—Sulfoethylated NFC; C-NFC—Carboxymethylated-NFC; H-NFC—Hydroxypropyltrimethylammonium-NFC; c-CNF—Carboxylated CNF; cys-CNF—Cysteine-functionalized CNF; L-CNC—Lignin-coated-CNC; L-CNF—Lignin-coated-CNF.

Table 5. Cytotoxicity evaluations in in vitro studies induced by BNC- and BNC-based materials.

Material	Cellulose Source	Toxicological Experiment	Cells Lines	Toxicological Results		Ref.
	Results and		Possible		Application	Ref.
CNC
	CNC							cCNC/SA double-membrane hydrogels	CH, EGF	PBS, pH 7.4, 37 °C; t_90% = 3 days (CH); t_90% = 4 to 8 days (EGF).	Swelling/erosion
	BNC							^[	⁸⁹	^]
	CNF							TEMPO-oxidized CNC/CSos	PrHy, IMI
	CNC	Breast cancer	Cotton (Whatman 1 filter paper) PBS, pH 7.4, room temp.; t_40% ^[50]
		MTS assay;	= 12 min (PrHy); t _80% = 2 h (IMI).	-	ATP assay.	BEAS 2B hMDMs ^[90]
		Cytotoxicity at 100 mg/mL;
BNC scaffolds	G. xylinus	CCk-8 assay	HUVECs, SMCs,	No micronuclei induction after exposure to 2.5–100 mg/mL; No induction of proinflammatory cytokines in hMDMs.	Toxicity impact on lungs or bone marrow	^[135]	Fibroblasts	CNC-HDQ complex	HDQ	Double crosslinking 3D-printed CNF hydrogels	Skin TE
		BC tubes have no toxic or side effects on vessel-related cells cultured on their surface;		the surface of BC tubes was beneficial for cell attachment, proliferation, and ingrowth.	CNC CNC- carboxyl groups dH ^[	Softwood cellulose pulp₂O, room temp., in the dark; t_40% = 1 h; t_80% = 4 h.	^111]
		MTS assay	-	CaCO-2, HeLa, MDCK, J774 ^[91]
	Vascular		TE			^[166]		CNC not exhibit any significant cytotoxicity; can exert stress on cells if they possess a high charge density; Charge-dependent decrease in mitochondrial activity (charge contents > 3.9 mmol/g).	Drug delivery	^[136]	CS/CNC nanocomposite hydrogels	CNF/PVA bilayer scaffold C
c-CNCs	Skin TE	SGF, pH 1.2, 37	t-CNCs ^[	Cotton Tunicate from °C; ¹¹⁵120 min: 65% (0.5% CS/CNC); 50% (2.5% CS/CNC).	^] Ritger–Peppas model; n = 0.61–0.66; Non-Fickian diffusion.	^[92]

Stuela clava		LDH assay	A549 MDM MDDC	The aspect ratio in combination with CNCs dose influences the uptake by the 3D co-culture system of the human epithelial airway barrier system.	Toxicity impact on lungs	^[137]	QC/cCNC/β-GP nanocomposite hydrogels	CNF/Gel/ApA DOX		Bone TE PBS, pH 7.4, 37 °C; t_90% = 4 days (0% cCNC); t_90% = 7 days (1% cCNC); t_90% = 17 days (2.5% cCNC).	Swelling/erosion	^[93]
	^[
CNC	¹¹⁶	^]
	Wood pulp	TB assay	A549	CNC were nontoxic to A549 cells; CNC induced a robust inflammatory response; CNC particles induced a more robust inflammatory response compared to NCF.	Comparable toxicity of CNC with CNF	^[138]	Gel/CNC nanocomposite hydrogels	TPh	SGF, pH 1.2, 37 °C; 24 h: 90% (5% CNC); 85% (10% CNC); 60% (25% CNC).	CNC	-		^[94]

CNCgel CNCdry	CNC/PVA nanocomposites	Wood pulp Skin TE	LDH assay ^[117]
	MH-S			Low conc. (1.5 and 5 μg/cm²) induce no cytotoxicity; A high dose of CNCdry induced a decrease in cell viability; CNC exposure further altered the secretion of cytokines.	Toxicity impact on lungs	^[139]	m-CNC/Alg hydrogels	Gel/HA/CNC hydrogels	Skin wound repair		^[118]
CNC	Ibu	PBS, pH 7.4, 37 °C; t = 0–30 min; 45%–60% burst release; t = 30–330 min; sustained release.		Wheat bran Fickian diffusion	MTT assay	Caco-2 ^[95]
	Dose-dependent decrease in cell viability, but only with significant results above 1000 μg/mL;		The cell viability decreased significantly upon contact with CNC90 (88.09%) at 2000 μg/mL, although CNC30 (92.81%) and CNC60 (93.11%) did not significantly decrease the cell viability.		Biocompatible nanocomposites	^[140]	CNF	Col/CNC/GMs PDA/TEMPO-CNF composite hydrogels	TCH		PBS; “On-off” drug release under NIR irradiation; 120 min: 60% (pH 5.0); 30% (pH 7.4); 15 h: 70% (pH 5.0); 55% (pH 7.4).			Blood vessel Korsmeyer–Peppas model; Non-Fickian diffusion.	^[119[96]
^]		CNF/HPMC nanocomposites
PEG-grafted CNC nanocomposites	Bone TE	^[120]
CNC/PVA hybrid hydrogels	Soft TE	^[121]
CNC/PAAm composite hydrogels	TE	^[122]
	KT	a-CNC/Gel hydrogels composite	Breast cancer	^[123]
TEMPO-CNC reinforced PVA hydrogels	Corneal implant	^[124]
BNC	BNC/Fibrin composites	New blood vessel	^[78]
	BNC-Gel/HAp nanocomposites	Bone TE	^[125]
	Alg/BNC/Col composite	TE	^[126]
	3D BNC/PMS scaffolds	TE; soft tissues regeneration	^[127]
	DBC/Col-p	TE; tissues regeneration	^[128]
	BNC/PA/Gel/HAp	Bone repair	^[129]
	(BNC-Col)-Ap/OGP peptides	Bone TE	^[130]
	BNC-CNTs composites	Bone regeneration
								K-CNC R-CNC	Rubberwood fiber Kenaf-bast fiber	MTT assay	RAW 264.7 HaCaT	Cytotoxicity of K-CNC and R-CNC is not significant up to 700 μg/mL; K-CNC and R-CNC induced the formation of ROS in RAW264.7 macrophages.	Biocompatible nanocomposites	^[141]
	CNC CNC-FL CNC-HM	Cellulose pulp	MTT assay	ATCC PCS201012, A375	No cytotoxicity in direct and indirect contact assays.	Drug delivery	^[142]
	CNC in nanocomposites
Collagen/CNCs/ GMs scaffolds	MCC	MTT assay	HUVECs	No cytotoxicity; Excellent biocompatibility.	Vascular TE	^[143]
CNC CNC-AEM CNC-AEMA	Softwood pulp	ATP assay	J774 A.1 PBMNC	One cationic CNC induced secretion of proinflammatory cytokine IL-1b associated with increase mitochondrial-derived ROS and extracellular ATP levels.	Drug and DNA delivery systems	^[144]
PLA/CNCg-PEG nanocomposites	Southern pine	Live/dead assays	hMSCs	Suitable biocompatibility; Nontoxic effect on hMSCs proliferation.	Bone TE	^[145]
TEMPO-CNC reinforced PVA hydrogels	MCC	AB assay	HCE-2cells	Nontoxicity; Excellent biocompatibility; The HCE-2 cells viability above the 70%.	Ophthalmic applications	^[146]

CNF	Bleached dissolving pulp Norway spruce (Picea bies)	MTT assay [³H]-thymidine uptake assay	L929; Thymocytes PBMNCs	CNFs were not cytotoxic; CNC has non-inflammatory and on-immunogenic properties.	Implantable biomaterials TE	^[151]
CNF	Pinus radiata pulp	LDH assay MTT assay	HEK NHDF	No toxic effect for keratinocytes and fibroblasts; Non-immunotoxic.
Octenidine-loaded BNC	K. xylinus	ATP assay	HaCaT		Wound dressings		Pure BNC has no influence on HaCaT viability; OCT/BNC extracts exhibited time and concentration-dependent toxicity; cell-damaging effects were observed at extract conc >10% and longer incubation times (24 and 48 h).	Active wound dressing ^[152]
	^[	¹⁶⁷	^]		CNF CNC	Wood pulp	TB assay
BNC	Sugar cane molasses		A549	CNF caused a significant decrease in cell viability, at 72 h; Decrease in GSH levels after exposure to CNF.	CNC toxicity		LDH activity	HepG2/C3A	BC is not cytotoxic (conc. < 170 μg/mL); BNC has a protective effect against CP-induced myelotoxicity and enotoxicity.	Biomaterial TE ^[138]
	^[	¹⁶⁸	^]		U-NFC A-NFC C-NFC
Vaccarin- loaded BNC	Never-dried bleached sulfite softwood dissolving pulp		G. xylinusAB assay LDH assays	HDF	Toxicity impacts on dermal, lung, and macrophage cells		MTT assay MRC-5 THP-1	^[153]
	L929			No cytotoxicity for treated NFC; HDF and MRC-5 cells: the metabolic activity of the treated cells was comparable to that of the negative control; THP-1 cells: a higher metabolic activity of the NFC-treated; U-CNF has an inflammatory response, which was suppressed when surface charges were introduced on the CNFs.	BNC-Vac has lower toxicity and better biocompatibility than BNC; RGR for both BNC and BNC-Vac was above 74%.	Wound dressing	^[169]	CNF	Bleached Eucalyptus Globulus kraft pulp	MTT assay	A549 THP-1
Gentamycin-loaded BNC		Cytotoxic effect at the highest dose tested;		Genotoxic effects in A549 cells in the co-cultures; No oxidative DNA damages.	TE	K. xylinus	NR assay	U2-OS	No cytotoxicity on osteoblast culture after 24 h; gentamycin released from G-BNC after 8 h (400 mg/L) and 16 h (600 mg/L) is enough to eliminate S. aureus and P. aeruginosa biofilms. ^[	Bone regeneration TE^154]
		^[	¹⁷⁰	^]		CNF
Curcumin- loaded BNC	Curauá fibers (Ananas erectifolius L. B. Smith)	K. xylinus Cytotoxicity assays ISO 10993-5	MTS assay Vero		HNDF CNF shows no cytotoxicity and suitable biocompatibility; The morphology and basic functions of the cells are not affected by the direct contact with the tested materials.	The cytotoxic effect on the cells depended on the conc. of curcumin; at 0.5 mg/mL C, a strong cytotoxicity for BNC-C and BNC-DC180; BNC-DC300 suitable cytotoxicity, even at higher extract conc. Scaffold TE	^[	Wound dressing ^155]		PBS, pH 7.4; 8 h: 95% (5% CNF), 62% (0.5% CNF), 56% (0.75% CNF), 37% (1% CNF).
	^[	¹⁷¹	^]		CNF
BNC-GTMAC	Softwood bleached kraft fiber	BNC-GHDE LDH	G. xylinus assay	AB assay Caco-2, HT-29MTX Raji B		HaCaT Minimal or no cytotoxicity in a cellular model of the intestinal epithelium (for CNC-25 at 0.75% and 1.5% w/w, as well as for CNF-50 at 0.75% w/w).	No cytotoxicity; Suitable wound closure rates in the presence of the samples, with complete coverage of the scratched area after 5 days. Biocompatible material		Non-Fickian diffusion; n = 0.52–0.61.	^[97]
CNF/Alg hydrogels	MH	SGF, pH 1.2; SIF, pH 7.4, 37 °C; T_40% = 90 min (CNF/Alg-50/50, SGF) t_80% = 145 min (CNF/Alg-50/50, SIF).	Fickian diffusion mechanism	^[98]
BNC	BNC-SA hybrid hydrogels	Ibu	PBS, pH 1.5, 7.0 and 11.8; 37 °C; 24 h: 90% (pH 11.8); 80% (pH 7.0); and 60% (pH 1.5); PBS, pH 7.4; 0.15 V, 0.3 V, 0.5 V; 24 h: 95% (0.5 V); 85% (0.3 V and 0.15 V); 80% (0 V).	Korsmeyer–Peppas model; Non-Fickian diffusion; pH; n = 0.498–0.772; E-field; n = 0.700–0.491.	^[99]
	TCH-loaded BNC composites	TCH	HEPES buffers, pH 7, 37 °C; 3 h: ~100% (free TCH); 90% (0.5% TCH); 60% (0.3% TCH); 20% (0.1% TCH); 10% (0.05% TCH);	-	^[100]
	OCT-loaded BNC	OCT	PBS, pH 7.4, 32 °C; 8 h: 82.7% ± 2.6% in first; 24 h 91.8% ± 2.0% after	Ritger–Peppas model; n = 0.51–0.55; Non-Fickian diffusion.	^[101]
	PI-loaded BNC	PI	PI buffer, 32 °C; t_84% = 48 h.	Ritger–Peppas model; n = 0.608–0.612	^[102]
	PHMB-loaded BNC	PHMB	PHMB buffer, 32 °C; t_87% = 48 h.	Ritger–Peppas model; n = 0.863–0.871	^[102]

Abbreviations: cCNC—Cationic cellulose nanocrystals; SA—Sodium alginate; CH—Ceftazidime hydrate; EGF—Epidermal growth factor human; PBS—Phosphate-buffered saline; CSos—Chitosan oligosaccharide; PrHy—Procaine hydrochloride; IMI—Imipramine hydrochloride; HDQ—Hydroquinone; C—Curcumin; CS—Chitosan; QC—Quaternized cellulose; β-GP—β-glycerophosphate; DOX—Doxorubicin; Gel—Gelatin; TPh—Theophylline; m-CNC—Magnetic cellulose nanocrystals; NIR—Near-infrared spectroscopy; PDA—Polydopamine; HPMC—Hydroxypropylmethyl cellulose; KT—Ketorolac tromethamine; Alg—Alginate; MH—Metformin hydrochloride; SGF—Simulated gastric fluid; SIF—Simulated intestinal fluid; HEPES—(4-(2-hydroxyethyl)-1-piperazine- ethanesulfonic acid); TCH—Tetracycline hydrochloride; AM—Acrylamide; Ibu—Ibupofren; OCT—Octenidine; PI—Povidone-iodine; PHMB—Polihexanide; dH₂O—Distilled water.

3.2. Nanocellulose-Based Materials in Wound-Healing Applications

Human skin is the largest organ in the human body, with the primary function of acting as a vital barrier to provide protection against adverse effects of the surrounding environment (microorganisms, mechanical impacts, hazardous substances, and radiation). In addition, it is an organ of protection, sensation, and regulation (e.g., body temperature, moisture) ^[27][103]. A break in the skin affects all the functions of the organ, and therefore, any wound must be rapidly and efficiently repaired. Wound healing represents a series of biological processes in monocytes, and macrophages play a vital role in order to restore skin functions ^[104] to prevent dehydration and minimize the risk of bacterial infections: shortly after injury, monocytes reach the wound site, differentiate into macrophages, and participate in the phagocytosis of necrotic tissue and secretion of cytokines and growth factors; macrophages release a wide spectrum of soluble mediators that recruit and activate fibroblasts and promote angiogenesis and epithelialization ^[27]. Most of the skin lesions that result in minimal tissue damage heal efficiently within a week or two. However, severe injuries require outside intervention to minimize the risk of infection or dehydration of the wound bed ^[27], such as different types of wound dressings based on natural or synthetic polymers, as well as their combinations. The wound dressing could have different forms (films, foams, membranes, and hydrogels), and most of the time, they contain bioactive substances such as drugs, growth factors, peptides, and others, which can accelerate wound healing ^[79].

The requirements of an “ideal wound dressing” are quite challenging: must provide a moist environment, oxygen circulation, ensure liquid drainage, absorb the excess of fluids that exudes from the wound, and provide wound protection from infections. In addition, it must be easy to apply and painless to remove. It should be biocompatible, have enough mechanical strength to avoid undesirable fracture, could accelerate the healing process, and restore the structure and function of the skin ^{[38][79][105][106]}. Among different wound-dressing materials, hydrogels have received special attention owing to their unique characteristics such as super-high absorbability, ability to provide hydration for healing, suitable oxygen permeability, easy replacement, and controlled drug release ^[24][107].

Hydrogels match most of the challenging features mentioned above, being the most appropriate material for wounded patients. In addition, the hydrogel can encapsulate actives substances (i.e., antibiotics) in their molecular network during gelling and release them in a controlled manner at the wounded site ^[18]. However, the mechanical properties are essential in wound dressing, and therefore, the inherent mechanical weakness of many hydrogels remains the major drawback in such applications. Several approaches have been employed in order to improve the mechanical properties of hydrogels, and one of them would be the use of hydrogels with nanosized particles (i.e., cellulose nanoparticles) or incorporation of cellulosic polymers to the hydrogel’s network for preparing versatile and robust wound dressings ^[38][108].

Nanocellulosic materials have superior mechanical properties and a high water absorption capacity, which allows the skin to maintain its natural moisture and to absorb the exudate from wounds, where appropriate, properties that show the resemblance to the nanoscale architecture of the extracellular matrix (ECM) ^[103]. Last but not least, nanocellulose contains numerous hydroxyl groups, which facilitate the mucoadhesion with epithelial tissues and also facilitate the formation of composites hydrogel with other polymers or small molecules, which can inhibit the propagation of bacteria on the surface of a wound ^[38].

3.3. Nanocellulose-Based Materials in Tissue Engineering Applications

Tissue engineering is another area of exciting potential applications for nanocellulose materials ^[16]. These applications include skin, bone, and cartilage tissue, engineering of blood vessels and soft tissues, repairing congenital heart defects, or ophthalmologic applications ^[103]. An ideal scaffold for tissue engineering is a material with high porosity, interconnected pores with adequate size, the presence of functional groups for cell adherence, and a high surface-to-volume ratio. Furthermore, tissue engineering scaffolds should possess suitable mechanical properties and should be nontoxic for cells. All these physicochemical properties are essential for cells growth and proliferation, vascularization, and nutrient transfer ^[109][110]. Cellulose-based materials have been shown to have great biomedical potential in the construction of ECM-mimicking scaffolds owing to their intrinsic characteristics, such as biocompatibility, lack of cytotoxicity, tunable 3D architecture and porous microstructures, and desired mechanical properties, although in vivo degradability still remains under discussion due to lack of the relevant enzyme in the human body ^{[48][62][111][112]}. In particular, the use of cellulose nanoparticles to improve the performance of other polymers used as scaffolds is another topic of interest for the researchers. Nanocellulose is considered one of the most promising nano-reinforcement materials of composites due to its nanoscale size, high aspect ratio, and excellent mechanical strength. Compared to other nanofillers, the incorporation of nanocellulose from natural sources could greatly improve the mechanical property of the polymer matrix, but without the sacrifice of its biocompatibility and biodegradability. Last but not least, the presence of surface hydroxyl groups in nanocellulose not only makes the chemical modification easy but also enhances the hydrophilicity of the materials, which is beneficial to the growth and proliferation of cells ^[113][114]. Nanocellulose-based materials applications in tissue engineering are vast and varied, and Table 2 presents some examples, from the multitude of applications in this field, for each type of nanocellulosic material.

Table 2. Nanocellulose hydrogels/nanocomposites in tissue engineering applications.

NCs Type	TE Systems	Applications	References
CNF	CNF/CS nanocomposites	Artificial skin	^[30]
	CNF-based thixotropic gels
	^[


Wound dressing
¹⁵⁶
^]
		^[	¹⁷²	^]		CNF	Banana peel bran
BNC in nanocomposites								MTT assay							Caco-2	CNF conc. < 500 mg/mL are not cytotoxic to Caco-2 cells; Viability of Caco-2 decreased with increasing CNF conc.	Biocompatible material	^[157]
U-NFC A-NFC C-NFC P-NFC S-NFC	Never-dried bleached sulfite softwood dissolving pulp	Resazurin Assay	Caco-2	None of the NFCs inducing cytotoxic effects in the intestinal cells;
BNC/ALG bilayer composites		The differences in physics-chemical properties of the studied NFCs were not reflected in the Caco-2 response in terms of metabolic activity and cell membrane integrity.			Drug release in gastrointestinal tract (GIT)	G. xylinus	ISO10993-5:2009	hNCs hMNC	The composites were found to be noncytotoxic, with a cell viability of 98% and a uniform distribution of cells on the entire porous layer.	Neocartilage TE ^[158]
PVA/CNC

nanocomposites	Sugarcane bagasse	MTT assay	L929
	^[	¹⁷³	^]		U-NFC C-NFC H-NFC P-NFC S-NFC	Never-dried bleached sulfite softwood dissolving pulp	MTS Assay	BEAS-2B
BNC-COL-Ap composites	G. xylinus	MTT assay	No cytotoxicity for the highest tested dose (500 μg/mL) for any of the NFCs;	None of the NFCs induced genotoxic effects;	Osteoblastic cells All samples were able to increase intracellular formation of ROS.	The composites did not exhibit cytotoxicity effects. In vitro toxicity of NFCs		Bone regeneration TE ^[159]
	^[	¹⁷⁴	^]		c-CNF cys-CNF	Never-dried bleached sulfite softwood dissolving pulp	PB assay	hDF	cys-CNF did not induce toxic effects on hDF when tested at a concentration up to 0.5 mg/mL, nor did the starting material c-NF cys-CNF presented a dual action in vitro: inhibition of metalloproteinase and radical scavenging activity.
ALG/BCN/COL composite	Wound dressing		A. xylinum		CCk-8 assay	^[	MC3T3-E1 hAMS	MC3T3-E1 and hams cells were viable and proliferate well, after 2 and 5 days of incubation—suitable cytocompatibility.	TE ^160]
	^[	¹⁷⁵	^]	CNF in nanocomposites

BC-PHEMA composites	A. xylinum	AB assay	rMSCs	BC-PHEMA composites are nontoxic and biocompatible; did not influence the morphology and proliferation of the rMSCs.	Wound dressing	^[176]	CNF L-CNF CNC L-CNC
BC/COL composites	Dissolving pulp	AB assay		G. xylinus A549	Live/ Dead assay THP-1	Cytotoxic and inflammatory responses were dependent on type, size, and hydrophobicity Low or inexistent toxicity of all CNMs in A549 cells Dose-dependent cytotoxic and inflammatory responses in THP-1 cells.	TE	UCBMSCs	No cytotoxicity; Provide advanced microenvironment for UCB-MSCs viability and in vitro proliferation; Significantly elevated proteins and calcium deposition. ^[161]
		Bone regeneration		TE		^[177]	Noncytotoxic effect; Strong attachment and proliferation of human fibroblast skin cells on the scaffold.	CNF /GEL/ApA TE scaffolds		Bleached birch pulp	MTT assay	MSCs
GEL/BNC nanocomposite		CNFs and CNF-COOHs have no cytotoxicity;		CNF-COOH-ApA cells expressed a low level of stress, visible through lower cell density and the cell inclusions.	Bone TE	A. xylinum	MTT assay ^[	HEK293 ¹⁶²	BNG showed negligible cytotoxicity. ^]
	Wound dressing		^[	¹⁴⁷	^]
	^[	¹⁷⁸	^]		GA-HA-CNC hydrogels	NFC hydrogels crosslinked with Ca MCC	CCK-8 assay	²⁺	Bleached sulfite softwood pulp NIH-3T3		AB assay Cell viability, at 1, 4, and 7 days, higher than 70% limit; No foreign body response.	hDF
BNC-GEL nanocomposite		Cell viability about 78% indicates no toxic effects.		No inflammatory response of blood-derived mononuclear cells was observed in relation to the cytokines secretion.	Skin TE	Wound healing		-	MTS assay	MRC-5	The samples have no cytotoxicity, and the cells retained their morphology in direct contact with the membrane, The cells attaching to the GEL porous site, while not attaching to the GEL thin-coated BC side. ^[148]
	Bone regeneration		^[	¹⁶³	^]
TE			^[	¹⁷⁹	^]		CS/Gel/NCC/CP nanocomposites	TEMPO-CNF hydrogel Soft wood cellulose fibers	MTT assay		Bleached birch kraft pulp	MTT assay Fibroblast cell	hDF	Nontoxicity effect and great hDF cells viability.
Chitosan-BNC	K. xylinus	MTT assay		Lack of cytotoxicity after 3 days of increasing the cells’ viability.	Wound healing	^[149]
	Wound healing			GM07492	No cytotoxicity for the BC group and BC-Chi-Cip group; Ciprofloxacin-loaded BC-Chi samples exhibited a significant but slight decrease in the metabolic activity of cells (moderate cytotoxicity).	^[164]
	Wound dressing			^[	¹⁸⁰	CNC/PVA	MCC	^[131]
^]	AB assay		HCE-2	Nontoxic and cytocompatible profile of the CNC-PVA hydrogel; Suitable biocompatibility toward HCE-2.	Ophthalmic applications	^[150]	BNC	Ear cartilage TE	^[132]
BNC/Alg bilayer composite	Neocartilage formation	^[133]
BNC/CS composites	Cartilage tissue regeneration	^[134]

Abbreviations: CS—Chitosan; PVA—Poly(vinyl) alcohol; Gel—Gelatin; ApA—Phosphonate; HA—Hyaluronic acid; Col—Collagen; GMs—Gelatin microspheres; PEG—Poly(ethylene glycol); PAAm—Polyacrylamide; a-CNC—Anionic CNC; HAp—Hydroxyapatite; Alg—Alginate; PMS—Paraffin microspheres; DBC—Dialdehyde bacterial cellulose; Col-p—Collagen peptide; PA—Procyanidin; Ap—Carbonate apatite; OGP—Osteogenic growth peptide; CNTs—Carbon nanotubes.

4. Toxicological Evaluation and Potential Limitations of NCs-Based Materials

4.1. Toxicological Evaluation of NC-Based Materials

Toxicological studies aim to provide data that predict the possible effects on the human health of people exposed to a particular substance, thus reducing the risk of disease.

Limited data on the toxic effects of NCs-based materials (single NCs or NCs in nanocomposites) on human health and important issues such as their biodurability and high aspect ratios make the toxicological assessment of these materials particularly important and at the same time highly necessary. Toxicological testing of NC materials has proved to be particularly difficult, given that there are a wide variety of raw materials, different methods for obtaining each type of nanocellulose, as well as various processes for the preparation of NCs-based materials (hydrogels, films, particles, composites, etc.). All these aspects show the particularly wide range of physicochemical properties of NC-based materials, which must be taken into account when evaluating the toxicological properties. Toxicological data to date show contradictory results related to cytotoxic and genotoxic effects, of NC-based materials, both in vitro and in vivo.

Toxicological data to date show contradictory results related to cytotoxic and genotoxic effects, of NC-based materials, both in vitro and in vivo (Tables 3, 4 and 5).

Table 3.

Abbreviations: BEAS 2B—Human bronchial epithelial cells; hMDMs—Monocyte-derived macrophages; Caco-2—Human colon carcinoma cells; HeLa—Human cervix; MDCK—Dog kidney; J774—Mouse macrophages; A549—Epithelial cells; MDM—Human blood monocyte-derived macrophages; MDDC—Dendritic cells; MH-S—Murine alveolar macrophages; RAW 264.7—Macrophages; ATCC PCS201012—Primary human fibroblasts; A375—Malignant melanoma cells; J774A.1—Mouse monocyte/macrophage; PBMNC—Peripheral blood mononuclear cells; hMSCs—Human mesenchymal stem cells; L929—Mouse fibroblast; NIH-3T3—Fibroblast; HCE-2—Human corneal epithelial cells; LDH assay—Lactate dehydrogenase cytotoxicity assay; MTT assay—(3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay; TB assay—Trypan blue exclusion staining cell viability assay; MTS assay—CellTiter-Glo luminescent cell viability assay; MCC—Microcrystalline cellulose.

Table 4. Cytotoxicity evaluations in in vitro studies induced by CNF- and CNF-based materials.





NFC/QCRs nanocomposites


Brown algae


MTT assay

GO/n-HAp/BNC/b-glucan biocomposite		-	NR assay L929	Cells viability is higher than 80% (for 5 to 1000 μg/mL CNFs/QCRs), indicating that there is no cytotoxicity.	Wound healing	^[165]

MC3T3-E1


All samples had suitable potential for cell adhesion and proliferation with very low cytotoxicity

The order of the cell viability: BgC-1.4 (93%) > BgC-1.3 (79.8%) > BgC-1.2 (71.4%) > BgC-1.1 (68.9%).


Bone regeneration

TE

	^[	¹⁸¹	^]

Abbreviations: HUVECs—Human umbilical vein endothelial cells; SMCs—Smooth muscle cells; HaCaT—Human keratinocytes cells; HepG2/C3A—Human C3A hepatoma cells; L929—Mouse skin fibroblast cells; U2-OS—Osteoblast cell; HNDF—Human neonatal dermal fibroblasts; MC3T3-E1—Mouse osteoblastic cells; rMSCs—Mouse mesenchymal stem cells; UCBMSCs—Human umbilical cord blood-derived mesenchymal stem cells; MRC-5—Normal lung tissues cells; GM07492—Human fibroblast cells; CCk-8 assay—Cholecystokinin-octopeptide proliferation assay; ATP assay—Adenosine triphosphate assay; LDH assay—Lactate dehydrogenase assay; NR assay—Neutral red assay; MTS assay—CellTiter 96^® Aqueous Non-Radioactive Cell Proliferation assay; AB assay—Alamar blue assay; G. xylinus—Gluconacetobacter xylinus; K. xylinus—Komagataeibacter xylinus; A. xylinum—Acetobacter xylinum; BNC- GTMAC—BNC functionalized with glycidyl trime-thylammonium chloride (GTMAC); BNC-GHDE—BNC functionalized with glycidyl hexadecyl ether (GHDE).

4.2. In Vivo Degradability of Nanocellulose-Based Materials

Besides biocompatibility and nontoxicity, biodegradability is another requirement for materials with applications in pharmaceutical and biomedical fields ^[182]. Generally, biodegradability is the property of a material to decompose into simple molecules under the action of biological elements (e.g., enzymes) ^[183]. Biodegradation is controlled by the material properties (e.g., molecular weight, crystallinity), and thus the biodegradation time can vary from months to years depending on its amorphous/crystalline or hydrophilic/hydrophobic behaviors ^[184]. For some biomedical applications (e.g., artificial heart valves or menisci), nonbiodegradable materials may be acceptable, whereas, for other applications (e.g., tissue regeneration), the bioresorbable materials that enable tissue regeneration at rates appropriate to their degradation are preferable, biodegradation being an essential property in this regard ^[185]. NCs are considered to be generally biodegradable because it derives from its natural sources—cellulose. However, there are some distinct differences between cellulose and industrially-obtained NC in terms of their size, morphology, surface characteristics, or physicochemical properties, so it cannot be entirely assumed that nanocellulose has the same biodegradability as cellulose in its native state ^[186]. Indeed, the studies performed to evaluate the in vivo degradability of nanocellulose showed that its biodegradation still remains a challenge given that NC itself does not undergo complete degradation in the human body due to the lack of specific enzymes ^[187]. The biodegradation of nanocellulose is usually performed by cellulolytic microorganisms, which produce enzymes (endoglucanases, cellobiohydrolases, and β-glucosidases) that act synergistically, leading to depolymerization of cellulose. In typical enzymatic hydrolysis, endoglucanases and cellobiohydrolases are responsible for the degradation of cellulose to cellobiosis, followed by its hydrolysis to free glucose molecules ^[188]. Given the facts mentioned above, some efforts have been made to find ways to improve the cellulose fibers’ biodegradation, making them resorbable by the organism ^[182]. For instance, as demonstrated in an earlier study ^[189], the incorporation of cellulase enzymes in bacterial cellulose and especially the conjunction of these enzymes with β-glucosidase led to a loss of integrity of almost 80% of tested materials after 2 days. A more recent study showed that the incorporation of the proteinase K, a kind of serine proteases, into scaffolds based on poly(butylene succinate) (PBS)/poly (lactic acid) (PLA) reinforced with NFCs, accelerated the degradation of the NFC-based scaffolds, acting mainly on the C=O bond of PLA. It showed promising prospects in improving the biodegradability of nanocellulose-based scaffolds by incorporating degradable polymers or related enzymes ^[190]. The introduction of N-acetyl-glucosamine residues (GlcNAc) into bacterial cellulose (BC) molecule during its synthesis by metabolically engineered Gluconacetobacter xylinus is another attempt that renders the cellulosic biopolymers susceptible to in vivo degradation. It was noticed that the modified-BC with high content of GlcNAc became more susceptible to biodegradation (e.g., to lysozyme and cellulase) compared with BC produced by the control strain. The susceptibility of modified-BC to in vivo degradation was evaluated by its subcutaneous implantation in the female BALB/c mice backs. Visual inspection of implant sites, after 10- and 20-days post-implantation, respectively, indicated little to no degradation of the cellulose produced by the control strain, while the modified-BC was almost entirely degraded after 10 days and completely undetectable after 20 days ^[191][192]. The oxidation process, using various chemicals, including metaperiodate, hypochlorite, dichromate, nitrogen dioxide, or TEMPO (2,2,6,6-tetramethylpiperidn-1-yl)oxyl) ^{[193][194][195][196][197]}, makes cellulose materials more vulnerable to hydrolysis and therefore potentially degradable by the human body. The only impediment of this process is that it can significantly alter the structure of cellulose, disturbing the unique, medically desirable properties of cellulose, such as its high tensile strength and conformability. However, this “disadvantage” becomes an “advantage” in soft tissue applications where the material often needs to readily conform to the various contours of the body and to have adequate strength for tissue support and allow easy handling ^[196]. 2,3-dialdehyde celluloses (DAC), obtained via periodate oxidation, have been considered degradable, although only at a slow rate ^[198]. In tissue engineering applications, cellulose acetate (acetyl cellulose) and ethyl cellulose have hardly been considered as scaffold materials since they are known to degrade very slowly or are practically non-resorbable in vivo. By oxidation with periodate, which has a regioselective action at the C2 and C3 atoms in the glucopyranose units, a structure with two aldehyde groups is formed that is less stable at physiological conditions. Thus, oxidized acetyl cellulose sponges, implanted subcutaneously into Wistar rats in vivo, showed a partial degradation of about 47% after 60 weeks, while for ethyl cellulose the proportion was only 18%) ^[199]. If the chemical oxidation by is coupled with γ-irradiation, as observed with bacterial cellulose used in soft tissue repair ^[196], resorbable and fully conformable materials are obtained. In vivo, these oxidized materials showed degradation as early as 2 weeks and continued to be slowly degraded until 26 weeks. A potential mechanism of oxidized-BNC resorption was considered, consisting of two steps: initial rapid resorption via hydrolysis of oxidized domains resulting in degradation of about 70%–80%, followed by the formation of short oligosaccharides that are further cleared by phagocytosis. In this last stage, the action of macrophages and giant cells breaks down the short glucan chains to the point where they can be consumed by the cells ^[196]. Oxidized bacterial cellulose (OBC) coupled with two degradable polymers, such as chitosan (CS) and collagen (COL), leads to nanocomposites (OBC/COL/CS) with excellent biodegradation. In vivo degradation performance of nanocomposites was evaluated by subcutaneous implantation using male Sprague–Dawley rats and was compared with oxidized regenerated plant cellulose (ORC), which is among the most widely used absorbable topical hemostatic agents for internal bleeding control. ORC has relatively poor biodegradability in vivo. Its complete absorption requires as long as 8 weeks ^[200]. After implantation for 7 days, sample residues stained purple-brown can be seen on the majority of sections. However, after 30 days, neither residual fragments of samples remaining in the subcutaneous tissue nor an evident pathological response of the implanted sites were observed in nanocomposites groups with oxidized-BC (OBC, OBC/CS, and OBC/COL/CS). In contrast, in the ORC group, even though the fiber diameter decreased markedly compared with that observed after the first 7 days, residual fragments were still found after 30 days ^[201]. Unlike oxidized-BC, unmodified BC shows poor degradation when is used, for instance, as porous scaffolds for bone tissue engineering, alone or in combination with gelatin via different crosslinking techniques and coating hydroxyapatite. At six weeks after implantation in the nude mice model, the results of the histological analysis showed clearly visible fibers in all scaffolds, suggesting poor degradation of the bacterial cellulose that unfortunately partly inhibited the new bone formation ^[129]. Similar to bacterial cellulose, the biodegradability of nanocrystalline cellulose (CNCs) and nanofiber cellulose (CNFs), respectively, also evaluated in various studies, is improved by modification (e.g., TEMPO-oxidation) or in combination with other biodegradable polymers. For instance, cellulose nanocrystals combined with biodegradable collagen and gelatin microspheres containing basic fibroblast growth factor (bFGF) were evaluated as a biodegradable platform for long-term release and consequent angiogenic boosting. The scaffolds were implanted into the subcutaneous tissue of the rat backs, and their biodegradability was assessed at 3, 7, and 10 days. With prolonged times, the gross views revealed that scaffolds size was reduced following implantation. On the 3rd day, all of the implanted scaffolds maintained their shape. On the 7th day, the scaffolds based on collagen/CNCs appeared to be smaller in size than other groups. Following that, on the 10th day, no residue of these scaffolds was observed, which may have been caused by degradation in vivo ^[119]. On the other hand, injectable hydrogels based on TEMPO-oxidized cellulose nanofiber (TOCNFs), methyl cellulose, carboxymethyl cellulose, and polyethylene glycol, with different concentrations (0.2% and 1% w/v) of TOCNFs were tested regarding their degradation in vivo. The biodegradability was evaluated using male rats by direct dorsal administration of 0.5 mL of injectable hydrogels and observation after two weeks by opening the injection site. Degradation studies revealed that nanocellulose fibers do not undergo complete degradation after 14 days. Moreover, the TOCNFs concentration in the hydrogel was inversely proportional to hydrolytic degradation rate: a higher concentration of TOCNFs in the hydrogel determines a lower degradation capacity, as evidenced by the much smaller size of the hydrogels with 0.2% TOCNFs after 2 weeks ^[202]. Last but not least, cellulose fibers derived from Styela clava tunics (SCT-CF) are also considered slowly degradable compared with wood pulp cellulose fibers (WP-CF). The biodegradability was evaluated by film subcutaneous implantation into Sprague–Dawley (SD) rats for various lengths of time. The weight loss was greater in cellulose films from Styela clava (almost 24% of their initial weight) than in films prepared from wood pulp cellulose (less than 10%). It was considered that the higher susceptibility of SCT-CF to degradation would be due to its content of about 98% α-cellulose and very low concentrations of ββ-cellulose and, additionally, a lower crystallinity index of SCT-CF (10.71%) unlike WP-CF (33.78%) ^[203]. Thereby, it can be concluded that, in terms of biodegradation, the cellulose fibers may be considered nonbiodegradable in vivo or, at best, slowly degradable, but their susceptibility to the action of biological agents can be improved, to a greater or lesser degree, by various methods, i.e., by chemical modification, by association with different well-known degradable polymers or by incorporating of related enzymes. Moreover, biodegradability is a complex characteristic that not only depends on cellulose fiber nature and obtaining methodology but also on its crystallinity form, degree of polymerization, morphology, chemical derivatization, swelling, etc.

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