Besides biocompatibility and nontoxicity, biodegradability is another requirement for materials with applications in pharmaceutical and biomedical fields [229]. Generally, biodegradability is the property of a material to decompose into simple molecules under the action of biological elements (e.g., enzymes) [230]. 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 [231]. 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 [232].

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 [233]. 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 [234]. 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 [235].

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 [229]. For instance, as demonstrated in an earlier study [236], 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 [162].

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 [237,238].

The oxidation process, using various chemicals, including metaperiodate, hypochlorite, dichromate, nitrogen dioxide, or TEMPO (2,2,6,6-tetramethylpiperidn-1-yl)oxyl) [239,240,241,242,243], 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 [242].

2,3-dialdehyde celluloses (DAC), obtained via periodate oxidation, have been considered degradable, although only at a slow rate [244]. 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%) [245]. If the chemical oxidation by is coupled with γ-irradiation, as observed with bacterial cellulose used in soft tissue repair [242], 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 [242]. 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 [246]. 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 [247]. 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 [143].

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 [133]. 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 [248]. 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%) [249].

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.