Bacterial nanocellulose as a versatile scaffold for biomedical applications: synthesis, functionalization, and future prospects

Bacterial nanocellulose as a versatile scaffold for biomedical applications: Synthesis, functionalization, and future prospects Liliana Melro a,* , C´ atia Alves a , Marta Fernandes a , Sofia Rocha a,b,c , Behnaz Mehravani a , Ana Isabel Ribeiro a , Sara Azevedo a,b,c , Vanessa F. Cardoso b,c , ´ Oscar Carvalho b,c , Nuno Dourado b,c , Ant´ onio J. Salgado d,e , Andrea Zille a , Jorge Padr˜ ao a,* a Centre for Textile Science and Technology (2C2T), Department of Textile Engineering, University of Minho, Campus of Azur´ em, 4800-058 Guimar˜ aes, Portugal b Center for MicroElectroMechanical Systems (CMEMS), University of Minho, Campus Azur´ em, 4800-058 Guimar˜ aes, Portugal c LABBELS – Associate Laboratory, University of Minho, 4800-058 Guimar˜ aes, Portugal d Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar 4710-057 Braga, Portugal e ICVS/3B’s – PT Government Associate Laboratory, 4710-057 Braga Portugal ARTICLE INFO Keywords: Bacterial nanocellulose Bioactive compounds, Cancer therapy Composites Implants Wound dressings ABSTRACT Bacterial nanocellulose (BNC) consists of nanofibres of cellulose randomly entangled during their synthesis by particular bacterium cells during fermentation. Thus, it may be regarded as a unique three-dimensional of pure cellulose that is consolidated during the generation of the fibres by their microbiological factories. The metabolic synthesis and purification processes are approached, underscoring its potential as an ideal template for the production of biomedical composite solutions, based on its inherent nano-driven assets. Also, BNC properties can be greatly enhanced by the incorporation of bioactive substances, which may be inorganic or organic, leading to the formulation of superior wound dressings and implants. In wound dressings, the most relevant agents encompass silver and copper nanoparticles, curcumin, and hyaluronic acid. BNC implants cover several organs such as blood vessels, heart valves, nerve scaffolds, cornea, tympanic membranes, vocal cords, bone, cartilage, dental structures, contrast and drug delivery agents. The functionalization of BNC with iron oxide nanoparticles, graphene, alginate, chitosan, silk fibroin, or bone morphogenetic protein 2 human in implants allows the enhancement or mimicking of mechanical properties, cell migration, proliferation, differentiation, and biocompatibility. This highlights the potential of using BNC as a scaffold for biomedical applications, offering a compelling alternative to petrochemical-based biomaterials. 1. Introduction Bacterial nanocellulose (BNC) is a versatile polysaccharide excreted by bacteria that has gained interest in the biomedical field due to its intrinsic physicochemical properties. This biopolymer presents high purity and flexibility, high water retention (>90 %), high degree of polymerization (2,000–6,000) and crystallinity (70–90 %). Its entangled nanofibrous structure results in a very porous material similar to the extracellular matrix (ECM). In addition, the BNC hydrogel possesses excellent mechanical properties, namely high tensile strength and elastic modulus [1–3]. Such properties endow BNC with a broad spectrum of possible applications in the biomedical field. Hydrogels are some of the most promising biomaterials because they are prone to chemical modifications with bioactive chemicals, genes, and cells, thus opening an array for a variety of applications in dental care, wound dressing, and controlled drug delivery. Tissue engineering has considerably invested in the regeneration and reconstruction of damaged tissues. Three-dimensional (3D) structural scaffolds have led to the development of functional engineered tissues for mechanical support during in vivo implantation, such as cartilage, bone, skin, heart valves, nerves, and tendons [4]. A variety of inorganic nanoparticles (NPs) are used in healthcare applications: silver (Ag), gold (Au), copper (Cu), platinum (Pt), titanium (Ti), and their oxide derivatives. Their size ranges from about 1 to 100 nm and vary in shape, e.g., nanodisks, nanowires (Nws), nanotubes, and nanorods (NRs). These intrinsic physicochemical properties remarkably revolutionize healthcare, including therapeutics, optoelectronics, drug discovery, diagnostic biological probes, catalysis, display instruments, * Corresponding authors. E-mail addresses: [email protected] (L. Melro), [email protected] (J. Padr˜ ao). Contents lists available at ScienceDirect Applied Materials Today journal homepage: www.elsevier.com/locate/apmt https://doi.org/10.1016/j.apmt.2025.102858 Received 7 April 2025; Received in revised form 3 July 2025; Accepted 13 July 2025 Applied Materials Today 46 (2025) 102858 2352-9407/© 2025 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ ). biological sensors, and the detection of environmental toxic metals or reagents and medicines. Metal or bare NPs are known to potentially induce toxicity by directly interacting with cells, or through the release of toxic metal ions, hindering their use in biomedical applications. Thus, biological processes are taking over the production of NPs, due to its safer and eco-friendlier approach. These processes include the use of distinct biological resources such as plants, bacteria, actinomycetes, fungi and yeasts, viruses, and a wide variety of marine and freshwater algae [5]. Another aspect to consider regarding metal NPs is their high surface energy and van der Waals forces that facilitate aggregation, hindering their effectiveness. Aggregation may be mitigated through the use of a substrate able to stabilize the NPs [6]. Hyaluronic acid, bone morphogenic protein 2, gelatine, chitosan, lignin, and polylactic acid (PLA), are some examples of biocompatible organic fillers used in biomedical applications. These fillers are less likely to cause an immune response or other adverse reactions. However, similar to inorganic NPs, their synthesis can be both laborious and hazardous. Added features include improved strength, flexibility, promotion of cell growth, and antimicrobial properties [7–11]. This review provides a detailed description of the synthesis of BNC and its mechanical properties according to the physical state of the biopolymer. In addition, it focuses on the various applications of BNC when functionalized or in combination with inorganic or organic compounds, and its significance in wound dressings, implants, and cancer therapy. 2. Bacterial nanocellulose 2.1. Synthesis Different genera of fermentation bacteria are recognized as possessing the required genes for BNC production such as Rhizobium, Azotobacter, Agrobacterium, Aerobacter, Salmonella, Escherichia, among others. Nevertheless, the most prominent belong to the Acetobacteraceae family, namely: Novacetimonas and Komagataeibacter [12]. The biosynthesis of BNC corresponds to an extremely complex and highly regulated metabolic process that undergoes several steps and involves a series of genes responsible for the encoding of both enzymes and different Fig. 1. Schematic representation of the biosynthetic pathway for BNC and organization of the various subunits in the bacterial cellulose synthase complex. Adapted from Ref. [14], under the Licence CC BY 4.0, 2021, Nanjing Medical University. L. Melro et al. Applied Materials Today 46 (2025) 102858 2 catalytic complexes [13,14]. BNC is produced as fibres that intertwine with each other. As their concentration increases, a 3D network is developed thus creating a floating macroscopic porous membrane. This structure is formed by the bacterial cells entrapped between the produced cellulosic ribbons, which allows for these non-motile, strictly aerobic bacteria to grow at the interface of the culture medium [12,15]. This process can use multiple carbon sources for the BNC building blocks such as glucose, fructose, and galactose. Therefore, it is important to note that BNC will vary depending not only on the carbon source used, but also on the bacterial strain. Different carbon sources and different metabolic profiles will govern BNC properties such as the mechanical properties, crystallinity, and thickness of the produced BNC [15,16]. BNC biosynthesis (Fig. 1) using glucose as the main carbon source is the most common and straightforward metabolic pathway. It may be broken down into four main enzymatic steps: (i) phosphorylation of glucose into glucose-6-phosphate via glucokinase; which is followed by the (ii) preparation of linear glucan chains, meaning the isomerization of glucose-6-phosphate by phosphoglucomutase into glucose-1-phosphate; (iii) uridine diphosphate glucose (UDP-Glc), a direct precursor of cellulose, is synthesized by UDPG-pyrophosphorylase, which translates into the assembly and crystallization of glucan chains into hierarchically structured cellulose ribbons; lastly, (iv) UDP-Glc polymerizes into cellulose by a membrane protein complex called cellulose synthase, and it is secreted to the extracellular environment [13,14,17–20]. It should be underscored that for BNC synthesis using disaccharides, such as sucrose, lactose, and maltose, the initial metabolic process is different. The disaccharides must first be converted into their respective monosaccharides through an additional hydrolysis step and only then undergo the cycle referred above [16,17]. As for the genes involved in this process, it is important to highlight those belonging to the BNC synthase operon (bcs), namely bcsA, bcsB, bcsC, and bcsD [12,13,17]. BcsA has a catalytic role in cellulose production and its activity can be regulated through the cyclic di-GMP (di-guanosine monophosphate) messenger. It is embedded in the inner membrane as eight transmembrane helices and consists of two cytoplasmatic domains: a catalytic β-1,4-glycosyltransferase domain conserved between transmembrane helices four and five and a C-terminus containing a PilZ domain. The binding of cyclic di-GMP to BcsA occurs in its PilZ domain and induces a conformational change that allows UDP-Glc access to the catalytic site. Once activated, this catalytic domain promotes the polymerization of UDP-Glc monomers into β-1,4-glucan chains [14,17]. BcsB is a large periplasmic protein anchored to the inner membrane through a single transmembrane helix. This protein interacts with BcsA, being responsible for the BcsA stabilization and enabling its catalytic activity. It is assumed that BcsB also has an important function in the transportation of the synthesized glucan chain through the periplasm into the outer membrane [14,17]. BcsC is a β-barrel type outer membrane porin protein. It is suggested that BcsC leads to the formation of membrane pores that allow cellulose secretion into the extracellular environment. In periplasmic domain of BcsC there is a tetratricopeptide repetition [13,14,17]. BcsD is a periplasmic protein that assists in the association and crystallization processes of the glucan chain. Moreover, the hierarchical cellulose assembly process is also largely controlled by the BcsD-driven arrangement of linear terminal complex arrays and their orientation longitudinal to the axis of the cell. It also prepares the glucan chain for secretion through BcsC protein; however, the mechanism of its function is not fully described yet. Nevertheless, it is evident that this protein is essential for the optimal production of BNC [13,14,16,17]. The up regulation of carboxymethyl cellulase has been suggested as an additional factor for BNC enhanced production. This enzyme catalyses the hydrolysis of endo-β-1,4-glycosidic bonds of cellulose chains. However, its activity has been correlated with higher production of BNC due to its potential as cellulose error correction enzyme. This enzyme is expressed by the cmcAx gene [14]. Other proteins with a hypothesized relevant role in BNC production are ccpAx protein and ß-glucosidase. CcpAx protein possibly assists BNC production during the crystallization phase. It interacts with the BcsD subunit and is also able to facilitate protein-protein interactions during the assembly of the cellulose synthase complex [12,14]. Finally, ß-glucosidase (expressed by bglxAx gene), is envisioned to modify and affect the degree of polymerization of the newly synthesized glucan chains. However, the details of its actual role have not been unveiled yet [14,17]. Initially, sub-fibrils are formed, then they crystallize and organize themselves to form fibrils, which in turn combine to form cellulose nanoor microfibres, consisting of about 1,000 individual glucan chains [13,14,20]. Thus, BNC consists of an ultra-thin 3D network developed and stabilized through interand intramolecular hydrogen bonds. The high amount of hydrogen bonds endow the material with its remarkable water-holding capacity (about 200 times its dry weight) [14] and also the formation of its hierarchical structure. The nanofibrous structure of BNC is able to mimic the fibrous architecture of the ECM (e.g. collagen, elastin and fibrin fibres that are components of connective tissues), and its resistance, flexibility, and porosity are important in the support of tissues that undergo constant stress and deformation like skin, muscle and cartilage, and the porosity and permeability that allows diffusion of gases or nutrients [13,14,16–18] [16,19]. The morphology of BNC can vary depending on the culture methods used, ranging from uniform membranes to spherical or irregular pelletshaped hydrogels. There are two main types of bacterial culture used to obtain BNC: static and agitated culture. Fig. 2 displays some examples of BNC produced from different strains, obtained from static and agitated cultures. This distinction influences not only the supramolecular structure of the obtained product but also its mechanical characteristics and physical properties [14]. Due to its simplicity, static culture represents the most commonly used technique for the production of BNC as a flat membrane with a homogeneous supramolecular structure [13,14,18,20, 21]. This approach allows the use of containers of any shape, which in turn, will dictate the shape of the membrane formed [17,18]. In this technique, BNC producing bacterium are incubated for 2 to 20 days at temperatures between 25 and 30 ◦C [13,14]. The most commonly used culture medium is the Hestrin-Schramm medium, which uses glucose as the main carbon source, yeast extract as a source of nitrogen and growth factors, peptone as a nitrogen source, and citrate-phosphate buffer to prevent pH reduction caused by gluconic acid during the bacteria aerobic growth [16,21]. It should be noted that the variation of any of these parameters affects the final product, making the incubation time the most critical factor. It is relevant to mention that the membrane is generated at the air-liquid interface, where there is more oxygen available. As the membrane produced on the medium grows downwards and entangles the bacteria, it limits the oxygen supply, resulting in reduced oxygenation and overall lower productivity. Incubation time is the main factor that governs the thickness of the BNC membrane produced [13,14,16–18,20,22]. However, historically, static culture is characterized as incompatible with industry. The most common arguments are the high costs associated with culture medium and the assurance of aseptic conditions in a large area. An established strategy to reduce costs is the use of alternative culture media based on agricultural and industrial wastes particularly rich in carbon sources, such as sugar cane processing industries and fruit juice production plants [14]. The agitated or dynamic culture comprises agitation or mixing of the culture medium to enhance the dissolved oxygen and improve the availability of nutrients concentration, consequently increasing the rate of BNC biosynthesis [14,16–18,21]. The shape and size of BNC is governed by the applied rotational speed. It usually presents itself with a spherical, cocoon-shaped, pellet-shaped, or even irregular clump-shaped morphology, therefore its applications are generally different from the membranes obtained through static culture [13,17,18,22]. Furthermore, BNC from dynamic culture possesses higher water absorptivity and higher suspension viscosity. The dynamic culture increases the amount of dissolved oxygen [21,22]. Furthermore, in dynamic culture, BNC usually possesses lower crystallinity and inferior mechanical properties such as lower Young’s modulus, due to the decreased degree of L. Melro et al. Applied Materials Today 46 (2025) 102858 3 polymerization and organization of the BNC nanofibres [13,14,16,21]. Bioreactors are able to ensure a suitable control of media flow and aeration which aids in the proper growth of microorganisms and animal cells. It is thus expected that they should be able to overcome those previously identified disadvantages. However, despite several types of bioreactors being tested for the scale-up production of BNC, the ideal automated process for industrial-scale production of this material has not yet been achieved [13,19,20]. There are a series of bioreactors that have been studied in this process, including the stirred, airlift, membrane, and rotating disc reactors, as illustrated in Fig. 3. The most appealing property of stirred-type bioreactors for the industrial production of BNC is their high volumetric mass transfer coefficient for the transfer of oxygen. However, the agitation associated with this type of bioreactor can harm the productivity of BNC by the same principles of the agitated culture. In addition, this process is energy-intensive when compared to other bioreactors, especially airlift bioreactors [17,24]. Airlift bioreactors are particularly interesting due to their simple design and facile maintenance. Besides, they have proved to be an energy-efficient method that involves less shear stress on the membranes than the one felt in typical agitated methods. Normally, airlift produced BNC bioreactor is characterized by either a fibrous or pellet shape, with higher water-holding capacity. Its mechanical properties can be altered by changing the number of separating plates [14,17,18]. Membrane reactors, on the other hand, often use oxygen-permeable silicone Fig. 2. Optical images of BNC produced by five strains of K. xylinus, (a-e) in static condition, and (f-j) in agitated condition. Reproduced from Ref. [23] with permission, Copyright 2018, Spinger Nature. Fig. 3. Schematic representation of bacterial cellulose production in (a) static and agitated reactors (b) rotating disc reactors (c) silicon membrane reactors (d) stirred type reactors (e) airlift reactors, their components and shape of BNC produced. Reproduced from Ref. [17] with permission, copyright 2022, IPO Science. L. Melro et al. Applied Materials Today 46 (2025) 102858 4 membranes so that a BNC membrane can be formed on its surface. The degree of roughness of this membrane directly correlates with the rate of BNC that can be produced. These bioreactors are characterized by their high oxygen permeability and large surface area but they are associated with high operating costs and difficulties in the harvesting of the BNC [17,20]. A different option is the rotating disc reactors, which are designed so that half of the disc’s surface is in contact with the air, while the other half is submerged in the culture medium. This particular configuration allows for better access of the bacterium attached to the disc to oxygen and nutrients present in the reactor, which increases the yield of the process at low rotation speeds. The production rate can be altered by changing either the rotational speed of the discs or the distance between them. Despite this, it has been shown that the yield of BNC is not that higher than the one obtained from static culture [17,20, 24]. Although all these bioreactors offer slightly improved yields compared to conventional static and agitated methods [20]. One possible explanation for the absence of higher BNC yields through dynamic culture may be correlated to the shear stress of dynamic cultures which is reflected by the presence of a higher concentration of negative cellulose producing mutants [13,14,17,20–22]. 2.2. Purification Ubiquitously BNC is embedded with bacterium cells and culture medium containing secondary metabolites [25]. Living bacterium cells and other impurities represent potential safety hazards and will impact the quality and characteristics of the BNC fibres. Thus, BNC must be submitted to different purification steps. Typical purification procedures are described in Table 1 [26]. Pure BNC displays improved mechanical strength, biocompatibility, and enhanced functional characteristics, such as water-holding capacity. In addition, if BNC contains a low thickness, it becomes more transparent, becoming more adequate for optics and electronics applications [27]. Commonly, the purification protocols displayed in Table 1 are sufficient to meet biomedical applications requirements, such as physicochemical, cytotoxicity, hemocompatibility, and biocompatibility [28]. Numerous industries are exploring the potentialities of BNC, and as this field of study develops, so do novel methods for purification and functionalization. As observable in Table 1, all purification methodologies comprise the use of an alkali solution (NaOH or KOH). Thus, all purification processes involve the mercerization of BNC. Mercerization will simultaneously degrade amorphous regions of cellulose and will convert cellulose I polymorphs to cellulose II. Cellulose II polymorph contains one additional hydrogen bond per cellulose monomer; thus, it is a more thermodynamically stable polymorph. Therefore, purified BNC exhibits enhanced properties in comparison to unpurified BNC [38]. 2.3. Properties for biomedical applications Considering the various applications in biosensing, immunotherapy, drug delivery, tissue engineering and regeneration, implants, and medical devices, it is of utmost significance that the materials potentiate a favourable environment for the growth and differentiation of cells. Non-toxicity, biocompatibility, mechanical, and physical requirements are also mandatory when classifying a biomaterial as ideal. Naturally occurring polymers, such as: chitosan, alginate, gelatine, starch, cellulose, and silk fibroin (SF), present enhanced biocompatibility. It is hypothesized that their similarity with ECM prevents immunological reactions and inhibits chronic inflammatory response. Their degradation within the human body may or may not be desirable, depending on the proposed application [39,40]. BNC is highly biocompatible and has been tested in animals and humans as long-term implants for up to one year. Furthermore, the literature supports this statement through tests performed with BNCbased implants that showed no severe signs of inflammation, no formation of fibrotic capsule, nor did it present toxicity according to genetic and cellular assays [2]. This proves that BNC can be an excellent material for wound dressing, hard and soft tissue engineering (e.g. skin regeneration, artificial dura mater membrane, facial nerve regeneration, prosthetic hernioplasty, cancer diagnosis, drug delivery, tissue-engineered cornea stroma, and neuroendovascular applications) [40–42]. Relating to its in vivo degradation, that is, degradation under Table 1 Purification methods applied to different bacteria and the carbon source used throughout their fermentation. Bacterium Carbon Source Purification Method Ref Bacillus sp. strain SEE3Glucose •Distilled water (wash and boil) [25] •0.1 M NaOH (3 h, 80 ◦C) •Distilled water (until neutral pH) Komagataeibacter europaeus SGP37 Glucose •Tap water (wash) [29] •0.5 M NaOH (1 h, boil) •Distilled water (30 min, boil) •Distilled water (until neutral pH) Starkeya sp. strain N1B Naphthalene •0.5 % aqueous KOH solution [30] •Water (until neutral pH) Komagataeibacter sp. High fructose corn syrup (Hungrasweet F50) •1 or 4 M NaOH (depending on the thickness, 10 to 30 times) [31] •Distilled water (until neutral pH) Komagataeibacter pasteurianus ATCC 23760 Glucose •Tap water (24 h, wash) [32] •0.1 % solution of NaOH (15 min, 70 ◦C) •Distilled water (until neutral pH) •Sterilized by Gamma irradiation (20 kGy) Komagataeibacter hansenii Glucose, mannitol, fructose, sucrose, and glycerol •1 M KOH solution (48 h) [33]•0.5 M HCl bath (1 h) •Distilled water (until neutral pH) Komagataeibacter sucrofermentans DSM15973 Glucose, pure glycerol, and crude glycerol (20 %) •0.1 M NaOH solution (2 h, 80 ◦C) [34] •Distilled water (until neutral pH) Komagataeibacter xylinus ATCC 23770 Glucose •0.5 % (w/v) aqueous NaOH solution (6 h, 80 ◦C) [28] •Deionized water (until neutral pH) Komagataeibacter sucrofermentans ATCC 700178 Fructose •0.5 M NaOH solution (3 days, solution replaced twice a day) [35] •Deionized water (until neutral pH) Taonella mepensis Glucose •Distilled water (12 h, water changed hourly) [36] •1 % NaOH solution (1 h, 80 ◦C) •Distilled water (until neutral pH) Komagataeibacter hansenii ATCC 53582 Glucose •2 % sodium dodecyl sulphate (SDS) solution (magnetic stirrer, overnight) [37] •Distilled water (until SDS removal) •1 M NaOH solution (50 rpm, 90 min, 60 ◦C) •Distilled water (until neutral pH) L. Melro et al. Applied Materials Today 46 (2025) 102858 5 physiological conditions, BNC is known to be principally degraded by cellulase, an enzyme that is not produced by the human body. So, in principle, this is beneficial for long-term implants. But it also limits its applications, for instance, to achieve a drug delivery system, BNC should be degraded within a short period [2,40]. Factors affecting biodegradation are the mechanical stress of bodily movements or inflammatory cellular response, that contribute to changes in crystallinity and molecular weight. In addition, several other mechanisms that contribute to BNC degradation have been identified: hydrolysis, enzymatic degradation, oxidation, and physical degradation. The chemical structure of BNC is composed of linear glucose units, each with one primary hydroxyl (OH) group and two secondary OH groups. These acting sites form glycosides that can be chemically attacked by body fluids constituents forming oligomers, and consequently monomers. During hydrolysis, the biomaterial absorbs the body fluids, leading to swelling and degradation. Enzymatic degradation occurs due to the presence of endogenous hydrolase enzymes present in plasma and interstitium that accelerate the hydrolysis of the glycosidic linkages. Oxidative degradation occurs as a result of hydrogen removal from the polymer chains by oxidants produced by tissues. Physical and chemical scission of bonds in the polymer chain can be due to swelling and wearing, which accelerate the damaging of the amorphous region by environmental stress [40]. If desired, a biomaterial can be tailored to become biodegradable through modification with metal NPs or bioactive molecules [40]. Considering the fibrous nanosized 3D network, high OH content, and water retention capacity, it is expected that BNC can retain considerable concentrations of drugs, either small (e.g., diclofenac, octenidine, and lidocaine) or large molecules (polymeric drugs, peptides, or proteins) relevant for drug delivery. Specific applications include dermal/- transdermal, oral, and dental administrations [2]. A drug-loaded BNC for dental therapies was reported by Weyell and co-workers [43] and demonstrated slow partial degradability under physiological conditions in the mouth, showing potential as an innovative wound dressing and drug delivery systems. A hydrolytic degradable BNC-based hydrogel scaffold incorporating calcium phosphate for bone tissue regeneration was developed by Basu et al. [44]. The mechanical strength of BNC is equivalent to synthetic polymers, resulting from the complex interlaced nanofibres that develop into a porous matrix. The arrangement of BNC microfilaments within the 3D nanofibrillar network gives rise to a thin, extremely fluid, and hydrophilic structure. In addition, the crucial mechanical strength of BNC is attributable to its linear cellulose chains and high cohesion between macromolecules [45]. The Young’s modulus and stiffness are significantly higher in dry samples compared to hydrated BNC [46]. Drying at atmospheric pressure and temperature leads to a higher density of cellulose fibrils due to its smaller volume (thickness), reflected in less porosity, more homogeneous structure, higher quantity and stronger hydrogen bonds and higher crystallinity, ultimately improving strength and Young’s modulus. The freeze-drying method maintains the cavities between the layered structure leading to lower crystallinity and less quantity and weaker hydrogen bonds between the cellulose molecules, impacting Young’s modulus [47]. If on the one hand, the typical behaviour of brittle materials was evidenced by oven-dried BNC, freeze-dried BNC on the other hand, exhibited low Young’s modulus and higher elongation before fracture [48]. A summary of the different values obtained in the literature is presented in Table 2. 3. Bioactive substances and antimicrobial agents and their applications Bioactive substances promote tissue growth by interacting with and integrating into damaged tissue, thus exhibiting biological activity. The incorporation of bioactive molecules within BNC, such as natural polymers (e.g., proteins: collagen, silk, gelatine, and fibrin; polysaccharides: starch, chitosan, cellulose, and alginate; polynucleotides: DNA, RNA) and inorganic compounds (e.g., metal NPs: Cu, Ag, Ti, and Au; minerals: hydroxyapatite, calcium phosphate, and silica (Si)) instil very desirable properties to the polymeric scaffold. These may include structural, regenerative, and/or antimicrobial properties, or act as cancer treatment agents. Some of these properties can be achieved through the application of external stimuli like radiation and ultrasound. Internal stimuli include pH, enzymes, and redox [54,55]. Hyaluronic acid is often used in ligament tissue engineering, osteochondral defects, and vascular grafts. Chitosan applicability can be found in bone formation and cartilage tissue engineering. Proteins like collagen or gelatine are largely used in drug delivery and tissue engineering scaffolds, and silk can be Table 2 Mechanical properties of BNC produced under static mode, according to the physical state of the sample. Sample Size (cm) Thickness ( μ m) Load (kN) Strain rate (mm min - 1 ) Young’s modulus (GPa) Tensile strength (MPa) Elongation at break (%) Ref Vacuum dry n.d. n.d. n.d. n.d. 5.13 n.d. n.d. [47] Dry n.d. n.d. n.d. n.d. 13.02 n.d. n.d. [47] Oven dried 2.0 × 6.0 22.7 1.0 5.0 5.6±0.76 37.2±3.3 2.20±0.06 [48] Dry (25 ◦C) 1.5 ×10 300–500 n.d. 10 n.d. 17.38±7.23 6.63±1.55 [49] Dry (25 ◦C) - rehydrated 1.5 ×10 300–500 n.d. 10 n.d. 17.40±3.68 11.04±3.68 [49] Dry (40 ◦C) 6.5 ×2 2670±670 10 2–4 0.139±0.022 10.34±3.69 7.94±3.39 [46] Dry (80 ◦C) 1.5 ×10 300–500 n.d. 10 n.d. 12.94±1.80 6.40±1.61 [49] Dry (80 ◦C) - rehydrated 1.5 ×10 300–500 n.d. 10 n.d. 8.49±5.47 11.08±2.75 [49] Hydrated 0.6 × 3.5 800 0.005 10 0.0056±0.0030 n.d. n.d. [50] Hydrated 0.6 × 3.5 800 0.005 10 0.0011±0.0004 n.d. n.d. [50] Hydrated 1.0 ×10 300–500 n.d. n.d. 9.14 112.4 0.6 [51] Hydrated 1.5 ×10 300–500 n.d. 10 n.d. 1.18±1.01 12.80±2.17 [49] Moist (1.82 %) 1.5 ×10 280 n.d. 4.8 1.044 20.76 2.28 [52] Moist 6.5 × 2.0 2670±670 10 2–4 0.02638±15.22 4.64±0.32 21.74±6.25 [46] Freeze dried 2.0 × 6.0 34.9 1.0 5.0 0.18±0.06 7.2±1.1 4.92±1.2 [48] Freeze dried 6.0 × 1.0 n.d. n.d. n.d. 2.68±0.73 n.d. n.d. [53] n.d. – not defined L. Melro et al. Applied Materials Today 46 (2025) 102858 6 found in drug delivery applications. Biopolymers, for example PLA or poly-(γ-glutamic acid) (PGA), are found in implant and suture [39]. A more thorough description and examples of the applicability of such bioactive molecules within the BNC matrix are described below. 3.1. Wound healing and wound dressing Skin disorders, including wounds, can profoundly affect the wellbeing, resulting in a noticeable decrease in overall quality of life [56]. Despite the availability of several therapeutic strategies, the ongoing demand for developing and enhancing new wound healing methods remains crucial [57,58]. As part of the treatment for skin wounds, the application of wound dressings plays a pivotal role. These wound dressings are designed to foster an optimal healing environment, enhance patient comfort, and offer mechanical properties that simplify their application for enhanced efficacy [59]. To establish an optimal environment for wound healing, it is required to uphold moisture retention, improve exudate absorption, facilitate oxygen exchange, and promote re-epithelialization, minimizing wound exposure duration and preventing infections. These essential elements contribute to an effective and accelerated wound healing process [57]. Being a biopolymer endowed with remarkable characteristics, BNC fulfils the fundamental requirements for promoting an exceptional and accelerated wound healing process, either through its incorporation as a skin substitute or direct application as a wound dressing (see Fig. 4) [60,61]. Extensive evidence indicates that BNC exhibits superior properties to traditional gauze-based wound dressings or synthetic products, making it an outstanding choice for wound healing applications [26]. The biocompatibility of BNC is attributed to its structural similarity to collagen, which facilitates both epithelialization and angiogenesis. This remarkable property enables its effective application in treating diverse wound types, including ulcers, burns, skin grafts, lacerations, and skin substitutes. Its wide-ranging efficacy in managing diverse types of wounds further accentuates its promising prospects for applications in wound healing [20,62]. Furthermore, high water retention enhances moisture retention and contributes to minimizing the adherence of the wound dressing to the affected area, particularly in burn cases [63]. Consequently, removing the wound dressing considerably reduces pain and discomfort, ensuring patients a more comfortable and less distressing wound healing experience [64]. The remarkable flexibility of BNC wound dressings allows for full adaptation and coverage of the affected area, making them a highly versatile and optimal choice for treating various wound types, including chronic, acute, and burns. This adaptability provides consistent wound support throughout the healing process, leading to better patient outcomes and enhanced healing potential [61]. Due to its exceptional intrinsic properties, this biopolymer has led to the commercialization of various wound dressings. These wound dressings show exceptional effectiveness, leading to positive and notable outcomes [24]. Table 3 provides examples of commercialized BNC-based products specifically developed for wound dressing and wound healing. Modification of BNC with active compounds (e.g., antibiotics, antiinflammatory drugs, peptides, proteins, and inorganic NPs) facilitates the healing process by quickly enhancing it, thus minimizing exposure to the inflammatory phase [57,71]. The BNC structure’s abundance of OH groups provide exceptional capacity for modifications. This intrinsic versatility empowers the production of BNC as a versatile material with potential application in several biomedical fields, including wound healing, drug delivery, and tissue engineering [13,72–74]. 3.1.1. Inorganic compounds in wound dressings The large surface-to-volume ratio of inorganic NPs, together with their heat resistance and long-term stability, are interesting and effective characteristics that demonstrate therapeutic potential against infections. This is especially important considering the substantial increase in antimicrobial resistance. In fact, multidrug-resistant pathogens are responsible for the death of 700,000 people yearly, according to the World Health Organization (WHO) [75]. Metal NPs can improve the antibacterial properties of wound dressing materials by killing the bacteria, thereby controlling the infections and promoting wound healing processes. They can stimulate the cellular and molecular process to maintain the wound microenvironment such that the healing process is facilitated by inducing antibacterial, antimicrobial, anti-inflammatory, and angiogenic effects [76]. Several attempts were made to improve the antibacterial properties of wound dressing materials and enhance wound healing by incorporating metal NPs such as AgNPs, CuNPs, zinc oxide (ZnONPs), and magnesium oxide NPs (MgONPs) [77–81]. Effective against bacteria, fungi, and viruses, the mechanism of action of AgNPs can be based on Ag + ion release that interacts with the cell membrane of bacteria leading to cell death. In addition, these ions generate reactive oxygen species (ROS), thus targeting the bacterial cell envelope causing DNA damage [75]. The shape and size of AgNPs are other factors that influence their antibacterial effectiveness. This can be controlled with the synthesis methodology, and the application fields vary [82]. The use of AgNPs in wound dressings is known to promote wound healing due to decreased inflammatory response. However, there is evidence of significant transdermal penetration of AgNPs into Prevents the entry of microorganisms Flexible and non-abrasive structure Promotion of oxygen transport Trapping of active agents High water content Biocompatible Biodegradable High purity High porosity Hypoallergenic Capability for controlled release of drugs Reduced loss of electrolytes and proteins Preserves the required wound moisture level Softness Transparency Cell adhesion Water vapour permeability Promotes tissue granulation Conformity to the specific wound area Easy removal, reducing pain caused on user Acceleration of the granulation process Prevents dehydration of the wound Excellent mechanical properties Reduced wound adhesion Ability to absorb exudate Non-carcinogenic Easily modified Injury BNC Fig. 4. Properties that classify BNC as an ideal scaffold for wound healing. L. Melro et al. Applied Materials Today 46 (2025) 102858 7 capillaries during the use of surgical dressings. In fact, dose-dependent histopathological abnormalities in the skin have been reported [83]. Despite some negative views and facts over the use of AgNPs, films of AgNws with BNC prepared by Wan et al. (2020) were able to provide biophysical cues that facilitated cell proliferation and progressed the wound-repairing process, along with the expected antibacterial effect and excellent stretchability and flexibility, as illustrated in Fig. 5 [84]. Ag, in the form of nanoprisms (AgNPrs), were prepared using a light-induced transformation reaction with light-emitting diodes (LED) to reduce their inherent toxicity to mammalian cells. Cell viability of the films using human dermal fibroblasts (HDFa) was in the range of 68.86–124.19 % for direct cytotoxicity test and 89–118 % for indirect cytotoxicity test, indicating that the films can be considered non-toxic. The composite also demonstrated good antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, Enterococcus faecalis, and Staphylococcus aureus [85]. Xie and co-workers (2019) used polydopamine (PDA) as a reducing agent to produce AgNPs to reduce their toxicity and enhance the biological compatibility of the BNC composites. The chelation between PDA and Ag and the 3D network of BNC plays a crucial role in the stable release of Ag + ions. The samples showed good Table 3 Examples of commercialized BNC-based products specifically developed for wound dressing and wound healing. Commercial name (producing bacteria) Company/distributor Active compound Properties Wound type Ref Biofill® (Acetobacter xylinum) BioFill Produtos Bioetecnologicos, Curitiba, Brazil None Reduced risk of infection Facilitates the healing process Pain relief Water vapor permeability Durable Burns Abrasions Ulcers [24, 65] Bioprocess® (n.d.) BioFill Produtos Bioetecnologicos, Curitiba, Brazil None Acceleration of the healing process Burns Abrasions Ulcers [66] Dermafill TM (Acetobacter xylinum) Cellulose Solutions ltd, Georgia, USA None Pain relief Acceleration of the healing process Burns Abrasions Lacerations Ulcers [65] Nanoskin® (Komagataeibacter xylinum) Innovatec None Non-toxic Biocompatible Hypoallergenic Maintenance of a humid environment Facilitates oxygen exchange Promotes granulation and epitilisation Ulcers Skin cancers Amputations [57, 67] Membracel® (Komagataeibacter xylinum) Vuelo Pharma, Curitiba, Brazil None Rapid skin regeneration Maintenance of wound moisture Pain relief Facilitates oxygen exchange Ulcers Burns Lacerations [57] CelMat® (n.d.) Bowil Biotech Sp., Władysławowo, Poland None Hypoallergenic Non-toxic Promotes cell regeneration Protects against entry of microorganisms Burn wounds [57] EpiProtect®2117 (n.d.) S2Medical AB, Link¨ oping, Sweden None Permeable to water vapour and air Impermeable to liquids Bacterial barrier Facilitates evaporation of exudate Burn wounds [68] Bionext® (Komagataeibacter xylinum) Bionext Produtos Biotecnol´ ogicos, Curitiba, PR Brazil None Pain relief Reduced risk of infection Facilitates the healing process Ulcers Burns Lacerations [69] Prima Cell TM (n.d.) Xylos Corporation, US None Pain relief Facilitates the healing process Ulcers [65] Nanoderm TM (n.d.) Axcelon Biopolymers Corporation, Ontario, Canada None Prevents infections Pain relief Reduces bacterial proliferation Minimises hydroelectrolytic loss Infected wounds [57] Nanoderm TM Ag (n.d.) Axcelon Biopolymers Corporation, Montreal, Canada Ag Controlled release of Ag Sustained antimicrobial activity Flexible Economical Infected wounds [26, 57] Suprasorb X® (n.d.) Lohmann & Rauscher International, Neuwied, Germany Polyhexamethylene biguanide (PHMB) Maintenance of wound moisture High exudate absorption Comfortable Reduced risk of infection Antimicrobial activity Ulcers Burns Post-surgical wounds Skin grafts Abrasions Lacerations [26] Xcell® (n.d.) Xylos Corporation, US PHMB Pain relief Accelerates the granulation process Antimicrobial activity Maintenance of wound moisture Ulcers [70] n.d. – not defined L. Melro et al. Applied Materials Today 46 (2025) 102858 8 cytocompatibility against normal human dermal fibroblasts, demonstrating that PDA supported cell growth and eased the stable release of Ag + [86]. The reducing properties of the catechol groups of PDA were similarly explored by Jiji et al. (2020). Cell viability was tested using NIH/3T3 cells and found that the BNC/PDA/AgNPs composite showed cell viability, a non-toxic nature, and improved cell proliferation. A synergistic effect of AgNPs and PDA has assisted in promoting fibroblast proliferation, granulation tissue formation, angiogenesis, and re-epithelialization. AgNPs eliminate the infection from pathogens and lead to an effective healing process. The antimicrobial activity Fig. 5. (a) Digital images showing the robustness and excellent stretchability and flexibility of the BNC/AgNws dressings, (b) water vapour permeability (WVP), (c) water uptake, (d) water retention rate, of BNC/AgNws dressings, (e) Scanning Electron Microscopy (SEM) images of bacteria on BNC/Ag dressings (scale bars: 1 μ m), (f) release profiles of Ag + from BNC/AgNws dressings (*p <0.05, n =4, NS means insignificant, p >0.05), (g) wound healing rate (WHR) after in vivo animal experiment (h) viability of NIH/3T3 cells cultured on BNC/AgNws dressings. Adapted from Ref. [84] with permission, Copyright 2020, Elsevier. L. Melro et al. Applied Materials Today 46 (2025) 102858 9 (72.4±3.1 %) on human keratinocytes (HaCaT). Thus, this composite presents promising attributes for potential application in diabetic or burn wound dressings due to its ultraviolet (UV) protection, non-cytotoxicity, transparency, and antifungal activity [141]. Table 5 summarizes examples of BNC functionalized with organic compounds for application in dressings and wound healing. 3.1.3. Combination of organic and inorganic compounds in wound dressings Combining organic and inorganic compounds holds important potential for producing nanocomposites for wound healing. Third-degree burns can be treated by applying a bioadhesive nanocomposite composed of BNC, PDA, and AgNPs. BNC serves as an exceptional ECM and a scaffold for in situ incorporation of AgNPs. Applying PDA coating facilitates the reduction of silver nitrate, leading to the formation of AgNPs. Moreover, the distinctive adhesive properties of PDA and its surface functionalization capabilities contribute to its intriguing and versatile role in wound dressing materials [87]. Chronic wounds are difficult to treat due to the elevated number of microorganisms, and to the significant increase in antibiotic resistance. Ag is a broad-spectrum natural antimicrobial that has attracted attention in wound management. The incorporation of AgNPs onto BNC showed considerable efficacy against the wound-infecting pathogenic microbes like S. aureus, P. aeruginosa, and Candida auris, according to a work presented by Gupta and co-workers (2020). In a development of their previous work [127], the complex curcumin:hydroxypropyl-β-cyclodextrin was in this case used as reducing agent of AgNO 3 to prepare AgNPs. The loading of both AgNPs and curcumin proved to be cytocompatible demonstrating potential to be used in wound dressing applications [142]. Similarly, Zhao et al. (2022) have produced films using BNC, AgNPs, PDA, and chitosan to improve the antibacterial action and protect wounds from infections caused by bacteria. A synergistic effect was observed with improved antibacterial action against S. aureus and P. aeruginosa. The tensile strength of the film increased due to increase of hydrogen bonds by the presence of chitosan. The films that were tested exhibited the absence of cytotoxicity using NIH/3T3 cells. However, the presence of AgNPs showed a slight inhibition of NIH/3T3 cell growth, below 5 % [109]. The significant increase in antibiotic resistance poses a major global health challenge [143]. A multifunctional nanocomposite based on BNC, gelatine (1 wt.%), and selenium NPs (SeNPs) (30 mmol L -1 ) has also been developed to address the antibiotic resistance issue. SeNPs can recognize and distinguish between bacteria and healthy mammalian cells in addition to being non-toxic. In a work by Mao and co-workers (2021), SeNPs are used along with gelatine to functionalize BNC hydrogel. The incorporation of SeNPs has shown antibacterial effect. The presence of SeNPs has facilitated ROS generation and induced oxidative stress to destroy the bacteria. The coating with gelatine reduced the porosity of the hydrogel which helps in the control release of SeNPs. Cytotoxicity was tested using NIH/3T3 cells, and the samples prepared using concentrations of H 2 SeO 3 below 0.06 mol L −1 were found to be non-toxic. These accelerated the wound healing process by promoting granulation tissue formation, collagen deposition, and angiogenesis, by reducing the inflammatory response. The mechanical results suggested that the tensile strength and Young´s modulus improved with the addition of gel due to the formation of hydrogen bonds and even more with the addition of an optimized amount of SeNPs. This composite meets a wide range of requirements for wound dressing applications. Biocompatibility, biodegradability, hemocompatibility, excellent mechanical properties, high swelling capacity, flexibility, remarkable wound healing, as well as antioxidant, anti-inflammatory, and antimicrobial activities, are among the achieved features. A synergistic effect between gelatine and SeNPs has been established [144]. Schizophyllan (SPG) is an extracellular polysaccharide obtained from fungus Schizophyllum commune with good antimicrobial, antioxidant, anti-wrinkle, and moisturizing effects and can also promote cell proliferation and regeneration. Hence, aminoalkylsilane groups and SPG were simultaneously used by Hamedi et al. (2021) to modify the BNC hydrogel. Thereafter, ZnONPs were loaded on functionalized BNC. The obtained samples were tested against E. coli and S. aureus and showed inhibition effect. Suppression of the respiratory chain enzymes by the released Zn 2+ ions and additionally generation of a huge amount of ROS can be the factors leading to the death of bacteria. Considering the cell viability of more than 70 % from cytotoxic tests, it can be understood that the samples are non-toxic to fibroblasts and the presence of SPG can lead to cell proliferation and thus promote a smooth wound healing process. The swelling behaviour of the samples with SPG improved in comparison with BNC due to the hydrophilic nature of SPG and the formation of hydrogen bonds with water molecules. However, the addition of ZnONPs reduced the swelling ratio due to the chelation of ZnONPs with the hydrophilic sites of the polymer. Nevertheless, the swelling ratio remained higher than that of the pristine BNC. The hydrogen bonding between the OH groups in the polymer and oxygen bonds in the NPs resulted in improved tensile strength of the hydrogel [110]. Nanozymes are able to regulate ROS levels to provide good antibacterial effect. Hence, a study investigating the effects of enzyme-based wound dressing was conducted by Zhang et al (2022). In this study, a nanocomposite was developed using polypropylene (PP) enveloped BNC and hollow mesoporous nanocatalyst iron (Fe@HCMS) together with glucose oxidase (GluO x ). The antibacterial results indicated that BNC/ PP/Fe@HCMS/GluO x has good antibacterial activity against S. aureus and E. coli. Noticeable hemocompatibility with rabbit red blood cells with the hemolysis ratio below 1.5 %. The composite was able to reduce the bleeding. The cell viability was 81 %. The formation of new epithermal layers in combination with a good antibacterial effect due to the conversion of glucose to a hydroxyl radical (•OH) at the wound sites has promoted wound healing of BNC/PP/Fe@HCMS/GluO x [116]. Hydrogels consisting of alginate, casein, BNC and Fe 3 O 4 NPs synthesized by co-precipitation were prepared by Patwa et al. (2020). The FeO 3 NPs promoted a rough surface necessary for cell adhesion. The swelling properties of the hydrogel improved with the addition of both BNC and Fe 3 O 4 NPs at large concentrations. This can be attributed to the increase of irregular porous size that facilitated more water take-up. The antibacterial activity was observed in all the hydrogels and the inhibition zone is higher against S. aureus in comparison with E. coli. Cell viability over 80 % was found for all samples when tested against murine embryonic fibroblasts [111]. In a different study, Luo and co-workers (2020) modified BNC with maleic anhydride. Thereafter it was used to synthesize spherical-shaped NPs, since maleic anhydride enhances the bonding between the BNC and the ZnNPs. The antibacterial properties of the sample were greater against S. aureus in comparison with E. coli. The incorporation of ZnO has maintained adequate pore size and porosity of the sample and enhanced the water vapor permeability. The water vapor transmission rate was observed to be 2856.60 g m -2 and this value is well within the limit of a desired value (2500–3000 g m -2 ) for a wound dressing material. The cytotoxicity results have suggested that at lower concentrations (5 wt.%) of ZnO, it was non-toxic to the mouse fibroblast cells. No irritation on the skin for 5 wt.% ZnONPs but at 20 wt.% ZnONPs exhibited irritation and crust formation. The sample also showed a good wound healing process due to the improved re-epithelialization and wound contraction. The tensile strength and Young´s modulus increased with the addition of ZnONPs and the properties indicate that the membranes were flexible, comfortable, and resilient [115]. Any potential cytotoxic effect of ZnONPs seems to have been overcome by functionalizing BNC with botulin diphosphate (BDP). An antioxidant, anti-burn, and antitumor compound that, according to Melnikova et al. (2021), when in combination with ZnO demonstrated good values of cell availability (L929 mouse fibroblasts) and no significant difference compared to pristine BNC. Furthermore, it presented good wound healing properties due regulation of oxygenation and microcirculation, L. Melro et al. Applied Materials Today 46 (2025) 102858 16 Table 5 Examples of BNC functionalized with organic compounds for wound dressings and wound healing applications. Application Compounds Incorporation method Properties Ref. NPs or complex (size; shape) Drugs or other components Wound healing Commercial α -13 ′ -COOH (n.d.) n.d. Ex situ – impregnation Controlled release of α -13 ′ -COOH (24 h) [120] Preservation of a moist environment Enhancement of compression strength Collagen deposition (10 days) Facilitates dermal thickness (~150 %) Wound healing Commercial Collagen/chitosan (n.d.) n.d. Ex situ – immersion High swelling capacity: 166 %, 15 min [122] Tensile strength: 128.6±4.7 kPa Young’s modulus: 382.3±6.7 kPa Elongation rates: 4.8±1.1 % Density: 5.9±0.3 mg cm -3 Antimicrobial activity: E. coli (97.6 %) S. aureus (98.3 %) K. xylinus (97.4 %) Non-cytotoxic Hemostatic Degradable: 86 %, 30 days Promotes fibroblast production and reduces inflammatory response (in vivo) Wound healing Commercial Hyaluronic acid (n.d.) n.d. Ex situ – impregnation Tensile strength: ~0.54–0.9 MPa [130] Young’s modulus: ~1.25–2 MPa Strain at break: ~30–45 % High water retention capacity Non-cytotoxic: Cell viability (L929) >80 % Wound healing Keratin (n.d., 83.73 nm) n.d. In situ: 3 % w/v keratin under static fermentation In situ: non-cytotoxic (L929 fibroblasts and HS2 keratinocytes) [133] Ex situ –impregnation Ex situ: non-cytotoxic. Cell viability (L929, except for the 1:1 ratio BNC: keratin; HS2 keratinocytes) Waound healing Commercial Gelatine (n.d.) n.d. Ex situ – immersion Stress-strain: ~200–800 MPa [135] Tensile strength: ~110–785 MPa Young’s modulus: ~20–35 GPa) Transparent: >75 % transmittance Moderate wettability: <90º Non-cytotoxic: Cell viability (NIH/3T3) >87 %, 5 days Hemocompatible: ~0.3–1.1 % Good wound healing ability Inhibits scar formation Promotes angiogenesis Biocompatible (TNFα , IL-6, and IL-1β) Wound dressing Curcumin (n.d.) n.d. Ex situ – immersion Moderate water absorption capacity: ~190–300 % [126] Sustained release (initial burst in the first 8 h, maximum of 64 %) Antimicrobial activity (Log reduction): S. aureus (1.42–2.63) E. coli (0.36–0.91) Wound dressing Curcumin (n.d.) hydroxypropylβ-cyclodextrin as encapsulating agent Ex situ – immersion Humidity absorption: 97.63±0.057 % [127] Transparency: 66.13±2.36 % transmittance Water vapour permeability: 2258.53–2460.63 g m -2 /24 h Biocompatible Hemocompatible: <0.20 % (in vitro) Non-cytotoxic: Cell viability (A549) 60 % Controlled release of curcumin: ~77 % at 6 h and 82 % at 48 h Antimicrobial activity: S. aureus (11.08±0.90 mm) Antioxidant activity: IC50=1087.49 ±6.47 µg mL -1 Wound dressing Chitosan/ ciprofloxacin (n.d.) n.d. Ex situ – immersion Water vapor permeable: 12.34±0.10 g m -2 h [135] Sustained antibiotic release: ~74 %, 6 h Antimicrobial activity: P. aeruginosa (4.3 mm) S. aureus (5.5 mm) (continued on next page) L. Melro et al. Applied Materials Today 46 (2025) 102858 17 Table 5 (continued) Application Compounds Incorporation method Properties Ref. NPs or complex (size; shape) Drugs or other components Non-cytotoxic: Cell viability (GM07492) 84.2 % Wound dressing Chitosan NPs (n.d., 339–700 nm) n.d. Ex situ – immersion BNC/chitosan 2 %: [137] Young’s modulus: 2.06 MPa Tensile strength: 0.95 MPa Elongation at break: 68 % Antimicrobial activity: <99 % reduction against S. aureus and E. coli Non-cytotoxic Promotes cell adhesion and proliferation Biocompatible Stimulates collagen production Acceptable inflammatory response Wound dressing Commercial Poly ([2-(methacryloyloxy) ethyl] trimethylammonium chloride) (10 and 40 wt.%) (n.d.) n.d. In situ – mixing and polymerization UV-A and UV-B resistance [141] High water absorption capacity: 225–873 %, 48 h Storage modulus: >1.7 GPa Young’s modulus: ≥2.4 GPa Elongation at break: >2.4 % Non-cytotoxic: Cell viability (HaCaT) 72.4–81.4 % Antifungal activity (Log reduction): C. albicans (3.4–5.5) Burn wound dressing Commercial Collagen/chitosan (n.d.) n.d. In situ – mixing of collagen in culture medium Ex situ – immersion in chitosan Moisture content: 95.5±0.10 % [121] Hemocompatible: 1.51±0.01 % Facilitates oxygen exchange: 76.8±0.07 % porosity Flexible: tensile strength of ~0.8 MPa Microbial reduction Non-cytotoxic: Cell viability (mammalian cells) 90 % Reduced healing process time (in vivo) Burn wound dressing Curcumin (n.d.) n.d. Ex situ – immersion Non-cytotoxic [122,125] Enhances cellular adhesion Antimicrobial activity: E. coli (15±0 mm) P. aeruginosa (16.3±0.4 mm) S. typhimutium (16±0 mm) S. aureus (15.5±0.4 mm) Improves wound healing process: 64.25 %, 15 days Reduces scar formation Increases cell proliferation and collagen production Burn wound dressing Acrylic acid/ keratinocytes/ fibroblasts (n. d.) n.d. Ex situ – mixing Enhances wound healing: 77.34±6.21 %, 13 days [125,138] Increases collagen deposition Facilitates reepithelialization process Burn wound dressing (third degree) Commercial Timol (n.d.) n.d. Ex situ – immersion High water absorption capacity: >400 g m -2 d -1 [129,139] Antimicrobial activity: S. aureus (40.33±1.15 mm) E. coli (18.33±1.15 mm) P. aeruginosa (20.67±0.57 mm) K. pneumoniae (41.33±1.15 mm) Non-cytotoxic: Cell viability (NIH/3T3) 88.81 % Facilitates cell proliferation Enhances wound healing process: 90.7 %, 20 days Reduction in scar formation Chronic wound healing Dehydrogenative polymer of coniferyl alcohol (n.d.) n.d. Ex situ – immersion High swelling: ~74–97 % [129,131] Controlled and sustained release for 72 h (initial burst of 34 % in 1 h) Antimicrobial activity Chronic wound dressing Commercial Hyaluronic acid (n.d.) n.d. Ex situ – impregnation High swelling capacity: 3334.21 ±353.54 %, 24 h [131,133] Non-cytotoxic n.d. – not defined. L. Melro et al. Applied Materials Today 46 (2025) 102858 18 reduction of oxidative stress, and hypoxia in a burn wound [96]. The enhancement of the mechanical properties with the incorporation of AgNPs was also verified by Song et al. (2021), who produced a hydrogel based on PVA/BNC/AgNPs. Both the stress at break and elongation at break improved, but only at an optimized concentration of AgNPs. This was due to AgNPs agglomeration at higher concentrations that disturb the formation of the hydrogel network, contributing to the decline in properties. These hydrogels were tested for antibacterial activity against E. coli and S. aureus showing significant antibacterial effects. Good cytocompatibility using L929 cells was verified. The addition of AgNPs increased the re-epithelialization due to the anti-inflammatory activities, improved angiogenesis and formation of a hair follicle [114]. Table 6 Examples of BNC functionalized with organic and inorganic compounds for wound dressings and wound healing applications. Application Compounds Incorporation method Properties Ref. NPs or complex (size; shape) Drugs or other components Burn wound healing (third degree) AgNPs (n.d.) PDA In situ – polymerization Antimicrobial activity: [87] S. aureus (22.33±0.57 mm) E. coli (12.00±1.00 mm) P. aeruginosa (15.67±0.57 mm) K. pneumoniae (15.00±0.00 mm) Non-cytotoxic: Cell viability (NIH/3T3) >70 % Water vapor permeability: ~400 g m -2 d -1 Promotes cell proliferation, reepithelialization, and collagen deposition (IL-1 α , IL-6, Il-10, VEGF-A, VEGF-B, bFGF, TGFβ1, TGF-β3, and SMAD-3) Effective in wound healing: 94.35 % healing rate at 20 days and 100 % after 25 days No scar formation Wound healing AgNPs (n.d., 42.71±17.97 nm) /Curcumin-Cyclodextrins n.d. In situ – immersion Non-cytotoxic: Cell viability (U251, MSTO and Panc 1) >80 % [142] Hemolysis: 6.85±1.12 % Antimicrobial activity: significant for P. aeruginosa, S. aureus, and C. auris Antioxidant activity Wound dressing Gelatine/SeNPs (n.d., 75 nm) n.d. In situ – immersion and reduction Tensile strength: ~0.74–0.85 MPa [144] Young’s modulus: ~2.77–3.08 MPa Failure strain: ~33.4–40 % High swelling: >2000 % Antioxidant activity: ~25–80 % 24 h Degradable: 100 %, 180 min Controlled release of SeNPs: ~20.4–25.2 %, 3 days Antimicrobial activity against E. coli, MDR E. coli, S. aureus, and MDR S. aureus Non-cytotoxic at concentrations below 60 mmol L -1 Hemocompatible: hemolysis rate <2 % Facilitates wound healing (96 %, 14 days) Anti-inflammatory activity (TNFα and IL-6) Promotes fibroblast and collagen production Promotes angiogenesis Biocompatible (in vivo, TNFα , IL-6, and IL-1) Wound dressing Ag/graphitic carbon nitride(gCN)/ eucalyptus extract(EE) Electrospinning (with PVA) PVA Immersion (without PVA) Release profile: [145] – BC/Ag/gCN/EE after 30 h: 61% of Ag and 67% of EE – PVA/BC/Ag/gCN/EE after 12 h: 62% of Ag and 74% of EE Biodegradability: – PVA/BC/Ag/gCN/EE ~44 % – uncrosslinked PVA/BC/Ag/gCN/EE 79 % – crosslinked PVA/BC/Ag/gCN/EE improved dissolvability significantly Mechanical properties: – BC/Ag/gCN/EE tensile strength 6.99 MPa Young Modulus 121.37 MPa – uncrosslinked PVA/BC/Ag/gCN/EE tensile strength 6.56 MPa Young Modulus 412.88 MPa – PVA/BC/Ag/gCN/EE tensile strength 8.44 MPa Young Modulus 564.84 MPa Antibacterial: strong antibacterial activity against E. coli and S. aureus Viability: – BC/Ag/gCN/EE 89 ±2.31 % – PVA/BC/Ag/gCN/EE 96 ±3.28 % Scratch area reduction: – BC/Ag/gCN/EE 18.69% – PVA/BC/Ag/gCN/EE 23.97 % n.d. – not defined. L. Melro et al. Applied Materials Today 46 (2025) 102858 19 Table 6 summarizes examples of BNC functionalized with organic and inorganic compounds for application in wound dressings and wound healing. 3.2. Implants Implants assist as support, or as replacement of damaged body parts, and can also function as delivery agents or for monitoring of physiological activity. Once introduced into the body, medical implants can remain permanently or serve their purpose for a temporary term. Examples of implants are artificial joints, surgical meshes, breast implants, cochlear implants, intraocular lenses, pacemakers, or other cardiac implants, and intrauterine contraceptive devices. Medical body implants can be made of metal, plastic, ceramic, skin, bone, or other tissues [146]. Biocompatibility and lack of toxicity are two essential features for 3D scaffolds, in association with the ability to promote cell adhesion, proliferation, and differentiation. Another essential property is its porosity, which should enable cell infiltration, vascularization, nutrient exchange, and possess adequate mechanical properties. It has been found that the implant morphology should resemble that of the ECM [147]. BNC is a biomaterial applied in several biomedical applications (see Table 7), attributed to its outstanding mechanical, physical, and chemical properties. Furthermore, different sizes can be achieved by regulating its biosynthesis [148]. Nevertheless, the lack of antimicrobial, anti-inflammatory, and antioxidant properties limits its application. BNC modification adaptability is advantageous to mitigate this limitation, facilitated by its abundance of OH groups and a neutral electrostatic charge [65]. Therefore, the risk of infection or rejection after implantation can be easily mitigated or even overcome if the right antimicrobial agents are incorporated within the implant matrix, avoiding the need for a second surgery. An extensive array of positively/negatively charged organic/inorganic compounds can be introduced using various methods (in situ and ex situ), resulting in composites that fulfil the requisites of the biomedical field [149,150]. BNC-based functional composites have been applied in the development of wound dressings, cancer therapy, drug delivery, biosensors, and implants [40, 151]. Some examples of implants are displayed in Fig. 7. Their application has been prioritized over synthetic products due to their hemocompatibility, biocompatibility, ease of sterilization, and lack of cytotoxicity [13]. Another notable property is the degradability of BNC [152]. In specific contexts, a sought-after attribute involves the degradation and absorption of materials within the body upon implantation, particularly within tissue engineering. This property enhances cellular production, growth, and adhesion, facilitating the gradual replacement of the implant with newly regenerated tissue [153]. Nonetheless, it can be easily modified to increase degradability (e.g., oxidation processes [122], cellulase treatment, and radiation [154]). 3.2.1. Soft tissue implants BNC can be applied in the replacement of synthetic soft implants, namely, cardiovascular systems (e.g., artificial blood vessels and heart valve replacement), nervous system (e.g., nerve scaffold and dura mater replacement), ophthalmic applications (e.g., artificial cornea and contact lenses), urinary conduits, and skeletal system (e.g., cartilage regeneration, meniscus implant, artificial ligament/tendon, tympanic membranes, and vocal cords) [150,157,158]. 3.2.1.1. Inorganic compounds in soft tissue implants. According to several studies, the treatment for neurological disorders like Parkinson’s and Alzheimer’s disease, or cervical spinal cord injury, can potentially rely on cell-based therapy based on neural stem cells (NSC) to protect and restore damaged neurons. However, there is an urgent need to regulate the growth and differentiation of these cells and to ensure the successful integration of implanted tissues essentially, transitioning from the laboratory to clinical application. Neurogenesis, as with any cell culture, is very particular regarding the surrounding physiological conditions. The surface in which they differentiate and grow is of particular importance, therefore significant efforts have been made to develop a scaffold able to provide the microenvironment to develop NSC. An example is a work developed by Guo et al. (2021), who developed an electrically conductive scaffold by making use of the conductivity of 3D-graphene (3D-G). Despite de biocompatibility of this inorganic foam, the large pores of 100–300 µm signifie that cells tendentially attach, proliferate and differentiate along the walls and not on the inside. To simulate a more realistic environment, BNC was added to the 3D-G by culturing K. xylinum on its surface. The resulting superior surface area and reduced pore size provided a broad array of oxygen groups that increased biocompatibility, proliferation, and differentiation. In fact, primary cortical neurons cultured on this composite formed an intense neuronal network with greater network activity than the one formed on the graphene foam alone. RNA-Seq analysis suggest that the composite offers a more promising 3D conductive substrate for neural tissue engineering. Furthermore, the incorporation of BNC onto the 3D-G surface lowers the Young’s modulus of the biopolymer to levels similar to softtissue membranes, since the inorganic matrix presents approximately 1,000–2,000 MPa [159]. Endothelial cells are important constituents of the blood vessels and the lymphatic system, operating as a selective barrier for the transport of molecules between blood/lymph and tissues. The blood vessel endothelium layer is extremely important in vascular integrity therefore, an intact endothelium ensures the normal working of blood vessels. It regulates blood flow, vascular tone, angiogenesis, monocyte/leukocyte Table 7 Examples of commercialized BNC-based products specifically developed for medical implants. Commercial name (producing bacteria) Company/distributor Active compound Properties Wound type Ref SYnthesized Cellulose (BASYC®) (n.d.) University Jena and Polymer Jena, Germany None High mechanical strength Blood vessel repair [24]    High water retention      Low roughness of inner tube surface   Xylos ® Porous Surgical Mesh (n.d.) Xylos Corporation ®None Reinforcement Abdominal and thoratic deffects [155] Xylos ® Vessel Guard (n.d.) Xylos Corporation ®None Protection Cover for vessels during anterior vertebral surgery [155] Gore-Tex® membranes Gore-Tex®n.d. Periodontal tissue improvement Dental implant [156] Securian n.d. n.d. Tissue Tendon repair [156]    Reinforcement matrix   Gelfoam™Pharmacia & Upjohn Company LLC n.d. Tympanic membrane perforations Tissue repair [156] n.d. – not defined. L. Melro et al. Applied Materials Today 46 (2025) 102858 20 adhesion, platelet aggregation, and facilitates normal functions of tissues or organs. Malfunction may result in different pathologies such as aneurysms, stroke and heart disease, diabetes, among others. In tissue engineered vascular grafts (TEVG), autologous saphenous vein and synthetic vascular grafts are used to circumvent these issues [160,161]. Modified synthetic nondegradable polymers, biodegradable synthetic or natural polymers have been used for constructing vascular grafts, among them polytetrafluoroethylene (e-PTFE) or polyethylene terephthalate (PET). Nonetheless, problems in seeding endothelial cells onto prosthetic grafts via physical forces (gravitational or hydrostatic seeding) could not fulfil the preclinical requirements. In addition, surface hydrophobicity or hydrophilicity are another major issue. Hydrophobic surfaces tendentially adsorb non-specific proteins, leading to platelet adhesion and thrombus formation, whilst highly hydrophilic materials can hinder adhesion thus full coverage of endothelial cells, disabling long-term applications of vascular grafts [161]. Biologically active cells are able to achieve tissue remodelling and regrowth of injured blood vessels, but it is a lengthy process since cellular denudation occurs due to the high dynamic shear stress at the damaged site, impairing tissue growth. A magnetic field gradient can potentially target magnetic NPs-loaded cells locally to the BNC surface and be a retention platform to increase cell homing at damaged vasculature. The incorporation of magnetite (Fe 3 O 4 ) within BNC was possible through in situ precipitation of Fe 3+ and Fe 2+ . To avoid oxidation, dextran was used to protect the iron oxide NPs and improve cytocompatibility. The characterization of this magnetic hydrogel showed a superparamagnetic behaviour since no hysteresis loop was formed. The Young’s modulus of the composite for all the experimental samples (200–380 KPa) was higher than that reported for healthy carotid walls during the cardiac cycle (130±15 KPa in systole and 80±10 KPa in diastole) and with no significant differences to the untreated BNC membrane (320.51±149.58 KPa). This shows the mechanical suitability of the hydrogel as vascular graft. The release of weakly bonded metal NPs was verified for 100 mM and 50 mM Fe 3+ containing BNC, whilst the 25 mM sample remained almost invariant throughout the 8 days of experiment. Cell viability via live/dead and MTT assays presented 90.56 % live cells and 9.43 % dead cells of a total of 339 cells for the 25 mM Fe 3+ BNC, similar to pristine BNC (98 % live cells of a total of 227 cells). The other concentrations of Fe 3+ , 50 mM and 100 mM showed poor results of viability. Cultured human aortic smooth muscle cells (HASMC) showed an extended morphology and were well adhered to all the substrates, seemingly proliferating faster in pristine BNC and 25 mM magnetic BNC. Cell targeting was achieved at low iron oxide NPs concentration (25 mM), but the cell coverage in the magnetic BNC was lower than the systems based on magnetized steel stents. The reason can be due to the coating of the NPs with dextran, which is known to resist cell adhesion [160]. Zhang et al. (2020) demonstrated a non-invasive and convenient method to remotely regulate the adhesion of endothelial cells based on an oscillating magnetic field. BNC membranes were modified using PEG-coated iron oxide NPs with grafted Arg-Gly-Asp peptide used as cell anchors. Seeded murine endothelial cells were subjected to a magnetic field at different frequencies (0 Hz, 0.1 Hz, 2 Hz), and adhesion and growth of endothelial cells showed to be significantly oscillation frequency dependent, with cell growth promotion under lower frequency, leading to successful endothelialization on the modified BNC membranes. The magnetic BNC composite demonstrated high mechanical strength with Young’s modulus of 1.75±0.3 MPa, only slightly lower than pristine BNC (2.21±0.4 MPa). Similar tensile strength and elongation at break to BNC were also verified. Cell viability, illustrated in Fig. 8, was analysed by the CCK-8 assay using murine endothelial C166 cells. The results showed no reduction of the composite (1 mg mL -1 for 24 h) viability by more than 20 %. Increased incubation for up to 7 days (at concentrations higher than 125 μ g mL -1 ) caused some toxic effects, however, not enough to label it as non-biocompatible. Release of iron oxide NPs was less than 0.1 % after Fig. 7. Examples of soft (blue boxes) and hard (grey boxes) BNC-based implants. Created with BioRender.com. L. Melro et al. Applied Materials Today 46 (2025) 102858 21 incubation for 14 days. C166 cells show higher coverage on peptide-modified membranes than pristine BNC, irrespective of the applied magnetic field. The former showed higher cell seeding density and more extended cellular morphology. The reason could be due to the peptide’s ability to interact with the integrin receptors on the cell membrane and enhance cell adhesion and affinity [161]. Different applications of magnetic NPs include actuators. These materials produce mechanical motion or force in response to an external stimulus. These can be applied into various medical devices or implantable systems for specific purposes. Superparamagnetic iron oxide NPs (SPIONs) are a good example since their applicability in biomedicine includes: drug delivery, making use of their targeting through an external magnetic field [162], contrast agents for magnetic resonance imaging to enhance the visibility of specific tissues [163], and hyperthermia therapy due to the ability of SPIONs to generate heat when exposed to an alternating magnetic field [164]. The incorporation of these NPs within BNC to be potentially used as actuators was reported by Roig-Sanchez and co-workers (2021), who tested a static and agitated culture of BNC in the presence of SPIONs. Magnetic actuation is conferred by SPIONs. The combination of platinum NPs (PtNPs) or AuNPs with SPIONs allows the controlled motion of the hydrogels by a magnetic field and an H 2 O 2 oxidation reaction. These Janus Pt/SPIONs structures increased by five times the directionality and movement [165]. Table 8 summarizes examples of BNC functionalized with inorganic compounds for soft tissue implant applications. 3.2.1.2. Organic compounds in soft tissue implants. Loss of function of articulation and muscles due to cartilage damage constitutes a problem. Such injuries are frequent in the aging population and athletes. The human body’s capacity for self-regeneration faces limitations due to the restricted proliferation of chondrocytes, the absence of blood vessels and nerves, and the relatively low metabolic rate [158,166]. The predominant treatment method involves autografting chondrocytes, specialized cells that stimulate the generation of new cartilage tissue. Nonetheless, the demand for dual surgeries and an extended recovery period has prompted exploring a biomaterial-based approach to cartilage transplantation [158]. Implants require high porosity to support chondrocyte migration and ECM production. However, BNC presents different sizes Fig. 8. (a) Immunofluorescence staining micrographs of vinculin (green), F-actin (red), and nuclei (blue) after incubation of C166 cells on BNC/magnetic BNC/ peptide-grafted magnetic BNC for 24 h under “stationary”, “slow”, and “fast” conditions by applying various oscillation frequencies (0, 0.1, and 2 Hz) of a magnetic field. The untreated cells on each type of membrane are control groups. Scale bars represent 50 μ m. (b,c) Corresponding quantifications of adhered cell density and area. Data are shown as mean ±standard errors (n =30). The statistical significance of the results was determined using one-way ANOVA, *, **, ***, and **** represent the significance at p <0.05, p <0.01, p <0.005, and p <0.001. Reproduced from Ref. [161] with permission, Copyright 2020, American Chemical Society. L. Melro et al. Applied Materials Today 46 (2025) 102858 22 and interconnectivity that may inhibit chondrocyte proliferation [167]. Numerous approaches have been developed to adjust pore size, similar to the ECM dimensions (ranging from 100 to 500 µm) [168]. These methodologies include laser drilling, photoreticulation, freeze-drying, and incorporating NPs/microparticles during synthesis [123,169,170]. Photoreticulation of a BNC/methacrylate gelatine hydrogel decreased the pore size from 200 to 10 µm, attributed to hydrogen bonding. Notwithstanding the reduced pore size, chondrocyte growth and proliferation were successful [171]. To increase the number of pores in BNC, freeze-drying becomes a practical and cost-effective method to achieve this attribute. Li et al. (2017) developed a BNC-chitosan composite (1 wt.%). The combination of the freeze-drying process and the viscosity enhancement, resulting from the presence of chitosan, contributed to a substantial 50 % increase in pore size [172]. Healthy cartilage has a high-water content of about 80 %, so the replacement implant must maintain this property [154]. BNC exhibits a notable inert water retention capacity, rendering it suitable for cartilage replacement applications. Incorporating BNC into cartilage implants must facilitate the progression of new tissue development, a phenomenon referred to as chondrogenesis [173]. Furthermore, BNC hydrogels were modified with alginate and/or hyaluronic acid to achieve this property. The composite BNC/chitosan/alginate/gelatine (80:20 % w/w) was evaluated, promoting cell adhesion, proliferation, and cell differentiation of chondrocytes [174]. The production of printable a 3D hydrogel of BNC and methacryloyl gelatine, demonstrated in Fig. 9 a-g, enhanced mechanical properties. After 24 weeks of in vivo implantation, the ear cartilage implant exhibited Young’s modulus (1.33±0.13 MPa) similar to the modulus of elasticity of human ear cartilage (1.41±0.67 MPa). Cell viability displayed promising results, with values exceeding 97 % following a 7-day testing [175]. The in situ polymerization modification with an additional organic compound, PGA, resulted in a biomaterial that exhibited improved mechanical properties. This modification enhanced bond interactions, amplifying elastic recovery after compression, fracture strength, and tenacity. The composite shows promising properties in cartilage application, including excellent cell viability [176]. Moreover, the application of natural proteins was also analysed for mechanical improvement. The integration of SF into BNC, followed by the freeze-drying procedure, revealed an enhancement in compressive strength and deformation. This improvement can be attributed to the crosslinking interaction between BNC and SF [177]. All the exemplified examples indicate that utilizing these organic materials did not compromise the non-cytotoxicity of the final composites. The high viability can be attributed to the similarity of BNC to the ECM of hyaline cartilage [168]. Severe cardiovascular conditions require a vascular transplant to replace obstructed pathways. These replacements may involve applying alternative body tissues (from oneself or a donor) or using artificial vascular grafts (e.g., blood vessels or cardiac valves) [178]. Surgically, synthetic materials are employed to replace large-diameter blood vessels (ranging from 6 to 10 mm in diameter), commonly utilizing PTFE and e-PTFE. Nevertheless, these materials are inadequate for replacing small-diameter vessels (with diameters less than 6 mm) due to their susceptibility to clotting and restenosis. This inherent limitation constitutes the main obstacle preventing commercially accessible prostheses designed for this type of vessel [179]. BNC hemocompatibility makes it a promising choice for adequately replacing both types of implants [180]. BASYC® (BActerial SYnthesized Cellulose) is a commercially available BNC-based product that replaces artificial blood vessels. It features a tubular configuration and mechanical properties resembling natural blood vessels [24]. Applying this biomaterial as a cardiovascular tube necessitates the preservation of blood vessel characteristics, including internal roughness and pressure resistance [13]. Furthermore, issues related to limited elasticity and anti-thrombogenic properties must be addressed to establish BNC as a viable product. For this purpose, a crucial modification is required [178]. Fig. 9h illustrates a PVA-modified BNC for application in artificial blood vessels. The D-BNC tube possesses a bigger external diameter and more homogeneous character along the diametric direction and the S-BNC tube possesses denser nano-cellulose close to the inner wall. The hydrogen bonds are notably reduced within the BNC matrix increasing the elasticity/stretch at break. The mechanical properties are displayed in Fig. 9i-m. Higher Young’s modulus, tensile strength, and elongation at break are verified Table 8 Examples of BNC functionalized with inorganic compounds for soft tissue implants applications. Compounds Incorporation method Properties Ref. Application NPs or complex (size; shape) Drugs or other components Neural tissue engineering 3D-G (n.d.) n.d. In situ – culturing of K. xylinum on the 3D-G surface Non-toxic: Cell viability >99 % [159] Kept physiological levels of stemness Young’s modulus similar to softtissue membranes Vascular grafts Fe 3 O 4 (n.d., 49.81 ±20.77 nm) n.d. In situ – mixing and reduction Superparamagnetic behaviour [160] Young’s modulus: 200 – 380 KPa Non-toxic: Cell viability (Human aortic smooth muscle cells) 98 % Cell targeting achieved at low iron oxide NPs concentration (25 mM) Vascular grafts Iron oxide core (~10 nm) PEG-coated iron oxide (~26 nm) n.d. Ex situ – mixing Young’s modulus: 1.75 ±0.3 MPa [161] Tensile strength: 2.22 ±0.4 MPa Elongation at break: 3.59 ±0.3 % Non-toxic: Cell viability (murine endothelial C166 ) >80 % Release of iron oxide NPs: <0.1 %, 14 days Cargo-delivery systems, theragnostic, tissue engineering SPIONs (spherical, 7.1 ± 1.5 nm) AuNPs (spherical, 19 – 47 nm) PtNPs (n.d., 3 nm) n.d. In situ – mixing NPs in culture medium Superparamagnetic behaviour [165] Magnetic response in water toward a magnetic field at 10 mm was directly proportional to the SPIONs concentration: [SPIONs] =2.50 mg mL -1 – speed of 13.5 ±1.7 mm s -1 n.d. – not defined. L. Melro et al. Applied Materials Today 46 (2025) 102858 23 Fig. 9. Printability test of bacterial nanocellulose (BNC)/gelatin methacryloyl (GelMA) hydrogel of (a) PSH characters printed with BNC/GelMA hydrogel, (b) cuboid structure at different layers printed with BNC/GelMA hydrogel, (c) human mandibular model printed with BNC/GelMA hydrogel, (d) human nose model printed with BNC/GelMA hydrogel (e) Young’s modulus of regenerated cartilage (n =3), (f) glycosaminoglycan (GAG) content of regenerated cartilage (n =3), (g) Total collagen content of regenerated cartilage (n =3). **P <0.01, ***P <0.001, ****P <0.0001. (h) Macro-morphology of the (h.a) S-BNC tube, (h.b) D-BNC tube, (h.c) S-BNC/ PVA composite tube, (h.d) D-BNC/PVA composite tube and (h.e) PVA tube, (i-l) axial stretch mechanical properties of the PVA tube (a), S-BNC tube (b), D-BNC tube (c), S-BNC/PVA composite tube (d) and D-BNC/PVA composite tube (e). Significant differences between groups are indicated (*p <0.05), (m) circumferential dynamic compliance of the S-BNC tube (red), D-BNC tube (blue), S-BNC/PVA tube (dashed red), D-BNC/PVA tube (dashed blue) and PVA tube (black). Significant differences between groups are indicated (*p <0.05). Adapted from Ref. [175,181], under the Licence CC BY 4.0, 2023, ACCSCIENCE Publishing and with permission, Copyright 2015, Royal Society of Chemistry, respectively. L. Melro et al. Applied Materials Today 46 (2025) 102858 24 for the D-BNC tube as a result of the thicker fibres and a denser nano-fibre network. Permeability attainment was also successful, as no water leakage was detected, and there was an enhancement in burst pressure without any cytotoxic effects [181]. Moreover, ensuring the migration and proliferation of endothelial cells on the implant surface holds extreme importance in achieving biocompatibility. The BNC/chitosan/heparin composites significantly facilitated the adhesion and growth of human saphenous vein endothelial cells (SVEC) and endothelial progenitor cells (EPC). Conversely, the BNC/heparin composite exclusively exhibited these effects in the second cell type, EPC. Both variants hold promise for application in small-diameter vascular grafts, effectively minimizing the potential for thrombogenicity and augmenting biocompatibility [182]. In addition, a chemical crosslinking process was employed to incorporate heparin into BNC, functionalized with SFNPs. The proliferation of endothelial cells, rapid endothelialization, minimal presence of inflammatory cells, and absence of degradability for 4 weeks were observed [183]. Incorporating 1 % w/v fish gelatine resulted in rapid endothelialization, with hemolysis rates remaining below 1 % (demonstrating hemocompatibility) and an enhanced level of biocompatibility [184]. Replacing blood vessels or vascular grafts smaller than 6 mm in diameter presents challenges. However, several multifunctional BNC composites exhibit promising properties. BNC/chitosan composites demonstrated no allergic reactions and effectively suppressed inflammatory responses or excessive growth of regenerated muscle tissue. This fulfils the criteria for biocompatibility and non-cytotoxicity [185]. In vivo, blood vessel regeneration was swiftly accomplished through in situ modification of BNC with potato starch. Potato starch particles at higher concentrations (2% w/v) expanded during the fermentation process, resulting in an increase in pore size (~28±6 μ m) [186]. Corneal dysfunction culminates in vision loss, prompting the adoption of an artificial cornea as the optimal treatment approach. The demand for synthetic alternatives arises from donor scarcity. This transplantation technique demonstrates heightened efficacy owing to its non-vascular nature [187]. The artificial cornea should satisfy the following pre-requisites: biocompatibility, mechanical stability, comfort, rigid structure, transparency, and the ability to enhance cell adhesion and proliferation [188]. In this context, hyaluronic acid can be applied in corneal implants. Anisotropic properties and high transparency (40 % higher than BNC) were achieved due to the incorporation of this agent. The chemically crosslinked BNC/hyaluronic acid composite demonstrated considerable cytocompatibility towards corneal stromal cells and suture strength comparable to the human eye [189]. The integration of this composite into BNC, without requiring a crosslinking agent, displayed several encouraging attributes. Mechanical properties and elasticity, high porosity, and excellent transmittance are some of the characteristics of the composite [190]. Beyond hyaluronic acid, incorporating PVA improves the optical properties through the expansion of interstitial spaces of BNC, promoting increased light transmission. Moreover, this inclusion supports the diffusion of oxygen and essential nutrients crucial for cellular growth while demonstrating minimal immunogenicity [191]. Therefore, the excellent ability to promote light transmission, high water content combined with UV protection establishes PVA as a viable option to replace non-biocompatible polymethyl methacrylate in corneal implants and contact lenses [13]. PP-based implants are applied surgically for the treatment of hernias. Nonetheless, a reduction in physicochemical properties, accelerated degradation in the human body, and its non-inert nature that fosters infections and inflammation decrease the efficacy of employing these synthetic polymers [192]. To mitigate associated biological risks, an inventive biomaterial, BNC, was combined with chitosan and applied to a PP mesh. After 3 months of implantation, the composite favoured tissue remodelling and demonstrated a distinct absence of cytotoxicity. Unlike PP-based hernia meshes, this includes minimal irritation and no allergic reactions [193]. In addition to treating hernias, BNC can serve as a substitute for a perforated tympanic membrane because of its flexibility, biocompatibility, and transparency. However, no necessity for modifying BNC for this specific application was identified. PVA emerges as a plausible choice for modification to enhance light transmission [147]. Different alternatives have been explored to promote the regeneration of urological tissues, such as the case of urinary conduits - a critical component in managing bladder cancer treatment [147]. Keratocytes were cultured on a BNC/SF bi-layer scaffold. SF encouraged cell proliferation and migration, while BNC supported preserving epithelial cells, which play a crucial role in urethral reconstruction [194]. Repairing nerve injuries is a complex and crucial process characterized by the challenges of limited regenerative potential. An up-andcoming solution lies in applying neural implants, particularly highlighted by the BNC favourable compatibility with Schwann cells [195]. In addition to biological properties, nerve regeneration implants need effective electrical conductivity to facilitate nerve impulses. Thus, Wu et al. (2021) developed a 3D bioprinting scaffolds of BNC (0.3 %)/alginate (5 %)/gelatine methacrylate (5 %) loaded with RSC96 cells that showed a good electrical conductivity (6 ×10 -7 S m -1 ). The effect of introducing RSC96 cells on neural regeneration was assessed, confirming the expression of numerous mRNA genes associated with axon growth, proliferation regulation, migration control, Schwann cell maturation, and myelination. Following 21 days of in vivo implantation, no indications of inflammation or toxicity were observed [196]. From a different perspective, rat sciatic nerve regeneration was assessed using an oxidized BNC composite functionalized with chitosan NPs (in situ) containing nerve growth factors. The microporous composite exhibited a notable reduction of microbial proliferation, while the oxidation of BNC improved its biodegradability. Schwann cell adhesion and proliferation demonstrated similar results to commercial grafts, and nerve growth factors were responsible for evident nerve repair (10 mm in 4 weeks) [197]. The electrical signal between cells plays an important part in tissue regeneration. As a conductive material, nerve conduits are able to transmit electrical signals between cells in electroactive tissue, thus allowing nerve repair through the promotion of Schwann cells adhesion and proliferation to construct the connected belt when the Wallerian degeneration occurs. In peripheral nerve injury, this is especially important since it allows the bridge between the two ends of damaged nerves. Poly(3,4-ethylenedioxythiophene) (PEDOT), a conductive polymer that has gained a significant interest in tissue engineering due to its biocompatibility and electrical properties, has been used in combination with sulfonated nanofibres (SNFs) and BNC to create a transparent conductive membrane. This composite showed great biocompatibility, high conductivity, and appropriate mechanical strength to be used for peripheral nerve repair, according to in vivo tests on Sprague Dawley rats [198]. Overall, composites based on BNC modified with organic compounds present promising physicochemical and biological properties for replacing synthetic soft implants. Table 9 summarizes examples of BNC functionalized with organic compounds for application in soft implants. 3.2.2. Hard tissue implants Hard tissue implants are medical devices used to support, replace, or repair either bone, cartilage, or dental structures. Typically, biocompatible ceramics and metals are used for this purpose, increasingly allied to biopolymers due to their excellent biocompatibility, adequate mechanical properties, porous structure, and enhanced osteogenic activity [200,201]. Furthermore, BNC is similar to the ECM, having a broad spectrum of applications, including bone in periodontal surgery, cartilage in the temporomandibular joint, skin and oral mucosa, dentin and dental pulp, and has the ability to be engineered into bone tissue. The ability of nanocellulose scaffolds to transfer cells and growth factors to damaged sites is under study. In addition, surface modification to promote the bioactivity of cellulose-based grafts is another area of interest, in which bioactive compounds are linked to BNC to promote bone cell L. Melro et al. Applied Materials Today 46 (2025) 102858 25 Fig. 11. (a) H&E staining analysis of newly formed bone values: (left) Comparison of newly formed bone values between different groups, analyzed by One-way analysis of variance and LSD-t test. * p <0.05; NS: no significance. Error bars indicate standard deviations. (right) Comparison of newly formed bone values between four and eight weeks, analyzed by independent-samples t-test; * p <0.05; NS: no significance. Error bars indicate standard deviations. Cytotoxic effects and attachment of mice MC3T3-E1 cells on BNC, collagen, and collagen/BNC porous microspheres (b) cell viability, (c) adhesion rate, (d) SEM images of cell attachment. Adapted from Ref. [8,219], with permission, Copyright 2020, Elsevier and under the Licence CC BY 4.0, 2019, MDPI, respectively. L. Melro et al. Applied Materials Today 46 (2025) 102858 32 cells. Moreover, an in vivo study performed on CT-26 cells subcutaneously implanted in female Balb/c mice evidenced a significant reduction in the tumour volume after 10 days, validating the high potential of the novel magnetic BNC-based scaffolds for cancer chemotherapy treatment [227]. Photothermal therapy (PTT) and photodynamic therapy (PDT) are alternative treatments that have considerably enhanced the effectiveness of bacterial infections and cancer treatment, overcoming the resistance of antibiotics and anticancer drugs [228]. In PTT, the treatment is based on the local heat generated by photothermal agents under irradiation at a specific wavelength. The increase in the temperature can inhibit the bacteria by destroying the cell membrane, evaporating the cellular fluid, or denaturing proteins and enzymes [229]. The effect of PTT in cancer cells is protein denaturation and temporary cells inactivation, when the tissue temperature increases up to 42 ◦C, long-term cells inactivation (43–45 ◦C), rapid cell necrosis (45–48 ◦C), and microvascular thrombosis and ischemia (48–60 ◦C) [230]. In PDT, photochemical reactions occur involving molecular oxygen and specific light wavelengths that stimulate a photosensitizer agent, generating ROS which can destroy target bacteria or cancer cells [231,232]. For example, Ni et al. (2021) reported the development of a hybrid material that integrates photodynamic, photothermal, and Ag-ion releasing effects. Porous Coordination Network-224 (PCN-224) metal-organic frameworks (MOFs) NPs were in situ grown on the surface of Ti 3 C 2 MXene nanosheets and then filtered onto BNC scaffolds, followed by the sputtering of nanosilver using the magnetron sputtering method. The photothermal performance, shown in Fig. 13e, demonstrates that PCN@Ti 3 C 2 -BNC reached up to 58.9 ◦C after 300 s illumination, which was higher than for PCN-BNC (38.3 ◦C) and Ti 3 C 2 -BNC (53.6 ◦C). These results suggest that the nanosilver covered on the surface of Ti 3 C 2 and Table 11 Examples of BNC functionalized with organic compounds for hard tissue implants applications. Application NPs (size; shape) Source Incorporation Properties Ref. Bone tissue BMP-2 (n.d.) Collagen Ex situ – Immersion Proliferation rate: 105–130 % [8]Good adhesion rate: 90.7 % Normal bone differentiation behaviour Bone tissue Hydroxyapatite (n.d.) n.d. Ex situ – Mixing Porosity: 314.14±23.2 µm [218] Tensile strength: 1.58±0.19 MPa Strain at break: 3.97±2.27 % Excellent cell viability Bone regeneration BMP-2 (n.d.) n.d. Ex situ –Loading Healing and bone regeneration remarkably accelerated [219] n.d. – not defined. Fig. 12. Representation of the mechanism of drug delivery, phototherapy (PTT and PDT), and diagnosis (SERS) BNC-based implants for cancer therapy. L. Melro et al. Applied Materials Today 46 (2025) 102858 33 Fig. 13. (a) Representative FESEM images of oxidized BNC, TB/oxidized BNC, ⍺PD-1@AuNCs/oxidized BNC, and TB/⍺PD-1@AuNCs/oxidized BNC. (b) Photothermal infrared images of ⍺PD-1@AuNCs. (c) The temperature variation curve of ⍺PD-1@AuNCs. (d) Cytotoxicity of ⍺PD-1@AuNCs at different concentrations. (e) Surface thermal images and (f) temperature change of PCN-BNC, Ti 3 C 2 -BNC, PCN@Ti 3 C 2 -BNC and Ag-PCN@Ti 3 C 2 -BNC recorded by an infrared camera and illuminated by a 500 W Xe lamp with a 420 nm filter (31.45 W cm -2 , 15 cm distance). (g) Photothermal heating curves of Ag-PCN@Ti 3 C 2 -BNC for 5 circles. Adapted from Ref. [233,238], with permission, Copyright 2021, Elsevier and with permission, Copyright 2022, Springer Nature, respectively. L. Melro et al. Applied Materials Today 46 (2025) 102858 34 PCN-224, weakened the photon absorption ability of Ti 3 C 2 nanosheets. The photothermal stability of Ag-PCN@Ti 3 C 2 -BNC (Fig. 13g) showed no relevant changes in elevating and declining temperature in 5 circles. Furthermore, they found that under visible light illumination for two rounds of 30 min (Xe lamp, 31.45 W cm -2 ), the antibacterial efficiency, both against Gram positive and Gram negative, was enhanced due to the synergy between PCN-224 and Ti 3 C 2 , by generating 1O 2 and photothermal heat, respectively, which in turn boosts the nanosilver oxidation and accelerates Ag + ions release. With this sterilization process, it was obtained a 6-log unit and 99.99 % bacteria inactivation which lasted for 6 months of room preservation [233]. In another work, to increase the photodynamic activity of MOFs, carbon quantum dots (CQDs) (energy donors) were encapsulated in the PCN-224 porphyrin-based MOFs (acceptor) during a solvothermal reaction process to construct fluorescence resonance energy transfer (FRET) pairs. Then, the synthesized CQDs@PCN-224 NPs were immobilized into the BNC membrane using an eco-friendly in situ biosynthetic approach where a compact sandwich-like structure of the BNC/MOFs membrane was formed by its inversion during the cultivation process. This method prevents MOFs leakage during use as shown by a <1.5 % leaching. The obtained BNC/CQDs@PCN-224 composite showed excellent antibacterial efficacy when exposed to light for 30 min, >99.99 % for both S. aureus and E. coli, good hemocompatibility (rabbit red blood cells), and low cytotoxicity (L929 cells) [234]. Li et al. (2021) incorporated AuNRs into BNC membranes as a photothermal agent, to achieve nearinfrared (NIR)-- activated bactericidal properties, and further coated with phase-transitioned bovine serum albumin (PTB) film, to improve the blocking efficiency against biofoulings, obtaining a dual-functional BNC composite. The resulting BNC scaffold presented antifouling properties against the adsorption of proteins and the attachment of bacteria and mammalian fibroblasts. Moreover, with 5 min of NIR irradiation light, both Gram positive and Gram negative bacterium could be fully eliminated due to the heat generated from the incorporated AuNRs. In vitro biocompatibility evaluation showed negligible cytotoxicity and in vivo tests using an infected full-thickness skin wound model in Sprague-Dawley rats showed good histocompatibility with the wound being almost fully closed on day 12 post-treatment [235]. Zhang et al. (2019) designed a transdermal drug targeting system for breast cancer therapy based on BNC and laser-sensitized magnetic NPs (LMNs). Fe 3 O 4 NPs, which served as the magnetic core, were first coated with hydrogels loaded with Dox and hematoporphyrin monomethyl ether (HMME). Then, the LMNs were grafted with folic acid to promote cell-specific recognition and binding. Finally, the NPs complex was loaded onto the BNC scaffold. When irradiated (633 nm laser), this multifunctional theragnostic scaffold produces repeatedly singlet oxygen (O − ) and releases the anticancer drug Dox, thus combining both photodynamic therapy and chemotherapy. The performance of this system was evaluated in vitro using human breast carcinoma (MCF-7) and human skin fibroblasts (HSF) cells, and in vivo using Balb/c mice bearing MCF-7 cells. For the treatment, cells were irradiated with static magnetic field (100 mT) for 6 h and He-Ne laser (633 nm, 100 mW cm -2 ) for 10 min. In vitro results showed that the MCF-7 cells growth was delayed 50 % in comparison with the non-treated control group and in a scratch/wound healing test the monolayer restoration was delayed by 82 % (24 h). Meanwhile, viability tests indicated no inhibition in the growth of HSF cells. Moreover, in vivo chemotherapy and PDT measured on Balb/c mice bearing MCF7 cells with tumour volumes of 100 mm 3 showed, on the 14 th day, a decrease of the tumour volume to 40.8±5.4 mm 3 and tumour growth inhibition rates of 80.38 %, while no evidence of leukopenia or associated toxicity was observed [236]. Chu et al. (2018) took advantage of the ability of C 60 isotopes to generate abundant ROS when exposed to light, to use them in scaffolds for PDT to treat skin cancer. Fullerene C 60 NPs suspension was first prepared by a solvent exchange method, being afterward incorporated into the BNC by vacuum filtration. Results showed that C 60 particles of diameters less than 100 nm were uniformly distributed in the ultrafine BNC network and, when exposed to light, the scaffold exhibited excellent antibacterial performance due to the high destructive power of ROS against bacteria. Moreover, in vitro cell experiments showed a high rate of cell death (80 %) toward human epidermoid carcinoma cells A-143, giving rise to a great potential of BNC/C 60 scaffolds for treating skin cancer [237]. Recently, Zhou et al. (2023) reported a multifunctional therapeutic system to be used as a versatile implant for avoiding the recurrence of head and neck squamous cell carcinoma (HNSCC) after resection, where PTT was used to boost the immunotherapy mediated by the anti-programmed death 1 (PD-1) antibody. The scaffold was prepared by first encapsulating PD-1 into gold nanocages (AuNCs) and then, together with thrombin (TB), they were incorporated into oxidized BNC. The photothermal treatment (Fig. 13b,c), consisting of consecutive NIR laser irradiation (808 nm, 1.0 W cm -2 ) for 5 min, on SCC7 cells was first evaluated in vitro, revealing a noticeable reduction in the cell proliferation (Fig. 13d). The immunotherapeutic system was further evaluated in vivo using SCC7 tumour-bearing mice where a tumour was resected after reaching 100 mm 3 , leaving a small amount of tumour behind. Likewise, the NIR laser irradiation treatment inhibited the tumour growth and suppressed the residual tumour recurrence, with no apparent toxicity. This effect is a consequence of the increased intracellular ROS levels that triggered tumour pyroptosis, a type of programmed cell death, induced by the inflammatory Caspase-1 cleavage of gasdermin D protein, the increase in T-cell infiltration, and the decrease in the number of immunosuppressive cells. Field Emission Scanning Electron Microscopy (FESEM) images in Fig. 13a suggest that the properties of the oxidized BNC were maintained since no alterations in its structure were verified after coating with TB. Furthermore, the loading of TB and ⍺PD-1@AuNCs was confirmed [238]. The early diagnosis of cancer offers a superior chance for a successful treatment. Surface-enhanced Raman scattering (SERS) is an imaging technique with ultrahigh sensitivity, stability, low cost, repeatability, and ease of use. It has the ability to identify with high sensitivity and reliability the main biomarkers which involve different biomolecules, such as proteins, nucleic acids, and lipids, distinguishing tumour cells from normal cells through fingerprint signals [239–241]. In a study on cancer diagnosis, Ferreira et al. (2019) developed a low-cost hybrid substrate based on BNC and in situ grown AgNPs for direct SERS analysis of exosomes. Statistical principal component analysis (PCA) was used to classify exosome-derived SERS signals obtained from PBS solutions of exosomes isolated from nontumorigenic breast epithelium (MCF-10A) and breast cancer (MDA-MB-231) cell cultures. This label-free diagnostic method allowed a tumoral and nontumoral exosomes discrimination with a 95 % confidence [242]. Similarly, Li et al. (2024) reported the development of a SERS substrate based on BNC and in situ synthesis of AgNPs, but for detection of glutathione in serum. The monitoring of glutathione can be used in cancer detection as the levels of this tripeptide small molecule are higher in the serum of cancer patients. For SERS measurements, Ellman’s reagent (DTNB) was added to colon cancer, gastric cancer, and normal serum diluted with PBS. Higher contents of glutathione were detected in cancer serum when compared with normal serum, being 2.6 times higher in colon cancer and 2.8 times higher in gastric cancer [243]. These works show the feasibility and great potential of BNC/AgNPs substrate for SERS application in real-time and early cancer diagnosis. Table 10 presents examples of the various applications of BNC in cancer therapy. Table 12 4. Conclusions and future perspectives The current state of the art regarding BNC in the biomedical field, especially its use as wound dressings and body implants, is described above. According to the literature, the growing interest in BNC is due to its notable intrinsic properties such as excellent mechanical properties, high water retention, easy functionalization, high purity. In fact, the importance of BNC as a substitute for petrochemical-based polymers, L. Melro et al. Applied Materials Today 46 (2025) 102858 35 Table 12 BNC composites in cancer therapy applications. Application NPs (or complex) (size; shape) Drugs or other components Incorporation method Properties Ref. Drug delivery for breast cancer treatment NLCs (spherical, ~150 nm) Doxorubicin (Dox) Ex situ – Immersion Dox release: 50 % after 24 h and sustained over time [223] In vivo antitumor efficacy (MDA-MB-231 cells) Treatment of skin cancer and soft tissues infected by bacterial pathogens Ag complex with 4-aminobenzoic acid (AgpABA) (n.d.) n.d. Ex situ – Immersion Antiproliferative activity against eight human tumor cell lines (U251, MCF-7, NCI-ADR/RES, 786-0, NCI-H460, PC-3, HT-29, and K562) [224] Sustained release of Ag-pABA up to 120 h Treatment of skin cancer Ag complex with nimesulide (AgNMS) (n. d.) n.d. Ex situ – Immersion Antiproliferative activity against adenocarcinoma (MCF-7, TGI =26.3 µM, PC-3, TGI =22.8 µM, OVCAR-03, TGI =22.5 µM, and HT-29, TGI =41.1 µM) cell lines [225] Antiproliferative effect at AgNMS concentrations higher than 70 µM for the other cell lines Inactive free NMS for all human tumors (TGI > 200 µM) Proliferation of immortalized human keratinocytes HaCaT unaffected by AgNMS complex and NMS Selective inhibition of SCC of SCC15 (TGI =67.3 µM) and UACC-62 (TGI =2.8 µM) Less active against SCC of FaDu (TGI =107.2 µM) and SCC4 (TGI >400) Sustained release of AgNMS complex for up to 216 h Antitumoral efficacy of the BNC scaffold containing AgNMS (Balb/c mice with induced SSCC cells) Drug carrier system with antibacterial, anticancer, and larvicidal activities CuO NPs (spherical, ~ 48 nm) n.d. Ex situ – Solution mixing and casting Antibacterial activity (S. aureus, S. mutans, S. typhimurium, E. coli, and P. fluorescens) [226]Anticancer: Caco-2, HepG-2, and MDA Antilarvicidal activity: A. aegypti mosquito in all stages of larval and pupal instar Chemotherapy (colon cancer) Fe 3 O 4 NPs (spherical, 8–15 nm) n.d. Ex situ – Co-precipitation Antibacterial (8 strains) [227]Non-cytotoxic Anticancer Photodynamic and photothermal therapy for microbial disinfection PCN-224 MOFs@Ti 3 C 2 MXene (n.d.) Nanosilver Ex situ – Filtration and sputtering Antibacterial activity: [233] S. aureus and E. coli (>99.99 %, 2 h of NIR light exposure Cytotoxicity: Cell viability (L929 cells) 75.84 and 69.75 %, after 12 and 24 h Photodynamic therapy for microbial disinfection CQDs@PCN-224 MOFs (spherical, 99.1 ±18.1 nm) n.d. In situ – mixing in culture medium +sonication Thermally stable at 265 ◦C [234] Breaking stress: 12.5 MPa Elongation at break: 27 % Antibacterial activity: S. aureus and E. coli (> 99.99 %, 30 min of NIR light exposure) Good hemocompatibility: hemolysis rates <5 % (rabbit red blood cells) Non-cytotoxic. Cell viability (L929 cells) 88 % Photothermal therapy for microbial disinfection AuNRs (rod-like, 51 ±7x15±3 nm;) PTB Ex situ – Immersion Antifouling (FITC-BSA protein, E. coli DH5 α - pBADDs bacteria, and L929 cells) [235] Antibacterial activity: S. aureus and E. coli (~100 %, 5 min of irradiation of NIR light exposure) Good biocompatibility with negligible cytotoxicity in vitro (L929 cells) Skin wound healing performance in vivo (Sprague-Dawley rats) Drug delivery and photodynamic therapy for breast cancer treatment Magnetic-hydrogel (Fe 3 O 4 -FA-NIPAm-AA) NPs (MHNP) (n.d., ~106 nm Dox and HMME Ex situ – Immersion In vitro – cell growth delayed 50 % (MCF-7 cells) and 82 % in a scratch/wound healing test [236] No inhibition in the growth of HSF cells In vivo – tumour growth inhibition rates of 80.38 % (MCF7 cells) No evidence of leukopenia or associated toxicity Photodynamic therapy for skin cancer treatment Fullerene C60 (n.d., <100 nm) n.d. Ex situ – Vacuum filtration Antibacterial activity against E. coli and S. aureus [237] Anti-cancer (human-derived epidermoid carcinoma A-431 cells) Photothermal therapy and immunotherapy AuNCs (cubic, 89.0 nm) PD-1 antibody and thrombin Ex situ – Immersion In vitro – marked reduction in cell proliferation (SCC7 cells) [238] In vivo – tumour recurrence inhibited without toxicity (continued on next page) L. Melro et al. Applied Materials Today 46 (2025) 102858 36 such as polyethylene, polypropylene, polyurethane, polytetrafluoroethylene, and polyether ether ketone, which are prevalent in established biomedical materials, is clear. These polymers often suffer from poor biocompatibility, both shortand long-term, contrary to BNC, which can lead to chronic inflammatory responses and the formation of fibrous collagen capsules around them. This, in turn, can result in pain, restricted movement, and even necrosis. In turn, the physical characteristics of the BNC’s fibrous network are particularly well-suited for wound dressings and implants because they closely resemble the extracellular matrix, especially its component, collagen. As a result, its use in blood vessels and biosensors is, also, of particular interest. In addition, the potential for extensive modifications, functionalization processes, and carrier applications enhances its diverse biomedical uses. In fact, since specific properties can be easily endowed to BNC, tissue engineering seems to be one of the most interesting areas, e.g. by the incorporation of bioactive molecules that promote cell growth leading to tissue repair and regeneration. The major number of studies found are focused on wound dressings and wound healing, highlighting the continued development of BNC for these applications, due to its relevant properties of biocompatibility, high porosity, water holding capacity, and nontoxicity. For soft implant area, cartilage, vascular grafts/blood vessels, and cornea are the most common applications, based on the favourable mechanical properties. Hard tissue implants are majorly based on bone tissue regeneration, that take advantage of its nano scaffold architecture. Inorganic nanoparticles/ complexes still play an important role in the functionalization of BNC, despite the growing efforts on using organic nanoparticles/complexes. The displayed separation between inorganic and organic nanoparticles/ complexes should assist in highlighting its influence towards BNC and its application goal, envisaging a tendency of the most effective and or less detrimental. Nevertheless, due to non-consistent characterization methodology displayed in the references, it is extremely precarious the establishment of a comparison. Thus, for the development of future applications, for both inorganic and organic nanoparticles/complexes a coherent set of characterizations should be promoted to allow a robust comparison between these two approaches. Again, despite the intriguing physicochemical properties of BNC, there is no clear consensus on testing methodology, especially regarding parameters and assay types. Variations assays, such as whether they are conducted on never-dried, lyophilized, or dried samples, and whether temperature or vacuum conditions are used, are also significant. Therefore, improving the standardization of methodology vs physicochemical properties should focus on defining the applications requirements and treat the material architecture as a nano non-woven material. Furthermore, although cellulases capable of degrading cellulose are not present in the human body, BNC is still exposed to mechanical stress, oxidation, and other factors that could affect its long-term use. Therefore, further investigation is needed to understand and correlate all these concepts in order to take advantage of the excellent properties of this sustainable material. In conclusion, BNC functionalized with inorganic and organic nanoparticles/complexes clearly display a wide set of relevant functions and activities, that may and should be explored in other areas. Its fibrous nature clearly drives its use towards the textile industry, in particular for the development of advanced multifunctional technical textiles, that comprise a plethora of applications. The main factor impairing this shift is its recalcitrant high production cost. However, the available funding for the implementation of sustainable industries, should press the development of novel BNC production methodologies and further lead to low-cost culture media use bio-based on waste products. A lower cost BNC will promptly permeate within fibre-based industries such as packaging, automotive, and construction. CRediT authorship contribution statement Liliana Melro: Writing – review & editing, Writing – original draft, Visualization, Validation, Methodology, Investigation, Conceptualization. C´ atia Alves: Writing – review & editing, Writing – original draft, Visualization, Validation, Methodology, Investigation, Conceptualization. Marta Fernandes: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Methodology, Investigation, Conceptualization. Sofia Rocha: Writing – review & editing, Writing – original draft, Visualization, Validation, Methodology, Investigation. Behnaz Mehravani: Writing – review & editing, Writing – original draft, Validation, Methodology, Investigation. Ana Isabel Ribeiro: Writing – review & editing, Writing – original draft, Validation, Methodology, Investigation. Sara Azevedo: Writing – original draft, Validation, Methodology, Investigation. Vanessa F. Cardoso: Writing – review & editing, Visualization, Validation. ´ Oscar Carvalho: Validation. Nuno Dourado: Validation. Ant´ onio J. Salgado: Validation. Andrea Zille: Writing – review & editing, Visualization, Validation, Supervision. Jorge Padr˜ ao: Writing – review & editing, Visualization, Validation, Supervision, Conceptualization. Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Acknowledgements This work was funded by the European Regional Development Fund through the Operational Competitiveness Program and the National Foundation for Science and Technology of Portugal (FCT) under the projects UID/CTM/00264/2020 of Centre for Textile Science and Technology (2C2T) on its components Base (10.54499/UIDB/00264/ 2020) and programmatic (10.54499/UIDP/00264/2020). The authors Liliana Melro, C´ atia Alves, Behnaz Mehravani and Vanessa Cardoso also acknowledge the grants supported by MCTES, FSE, UE and FCT, I.P. 2020.04919.BD (https://doi.org/10.54499/2020.04919.BD), 2022.10 454.BD (https://doi.org/10.54499/2022.10454.BD), 2022.13094.BD (https://doi.org/10.54499/2022.13094.BD), and 2020.02304.CEECIND (https://doi.org/10.54499/2020.02304.CEECIND/CP1600/CT0 025), respectively. Table 12 (continued) Application NPs (or complex) (size; shape) Drugs or other components Incorporation method Properties Ref. Cancer diagnosis (SERS) AgNPs (n.d., 92.1±51.57 nm) n.d. Ex situ – Microwave in situ AgNPs synthesis into BNC Enhancement factors (EF): 10 4 to 10 5 (rhodamine 6G, 10 −11 M) [242]Differentiation of tumoral and non-tumoral exosomes: MCF-10A and MDA-MB-231 with 95 % confidence Cancer diagnosis (SERS) AgNPs (n.d., 65±10 nm) n.d. Ex situ – Soaking in ammonia followed by in situ reduction in silver trifluoroacetate (CF3COOAg) solution EF: 3.8 ±10 7 (glutathione in serum of cancer (gastric and colon), 2.9 ±10 –8 M) [243] n.d. – not defined. L. Melro et al. Applied Materials Today 46 (2025) 102858 37 Data availability No data was used for the research described in the article. References [1] R.K. Mishra, A. Sabu, S.K. Tiwari, Materials chemistry and the futurist ecofriendly applications of nanocellulose: Status and prospect, Journal of Saudi Chemical Society 22 (2018) 949–978, https://doi.org/10.1016/j. jscs.2018.02.005. [2] Y. P¨ otzinger, D. Kralisch, D. Fischer, Bacterial Nanocellulose: The Future of Controlled Drug Delivery? Ther Deliv 8 (2017) 753–761, https://doi.org/ 10.4155/tde-2017-0059. [3] P. Pandit, T.N. Gayatri, Introduction to Green Nanomaterials. Green Nanomaterials, 2020, pp. 1–21. [4] K. Chojnacka, K. Moustakas, M. Mikulewicz, Multifunctional cellulose-based biomaterials for dental applications: A sustainable approach to oral health and regeneration, Ind Crops Prod 203 (2023), https://doi.org/10.1016/j. indcrop.2023.117142. [5] S. Mahmood Ansari, Q. Saquib, V. De Matteis, et al., Marine Macroalgae Display Bioreductant Efficacy for Fabricating Metallic Nanoparticles: Intra/Extracellular Mechanism and Potential Biomedical Applications, Bioinorg Chem Appl 2021 (2021) 1–26, https://doi.org/10.1155/2021/5985377. [6] L. Song, L. Shu, Y. Wang, et al., Metal nanoparticle-embedded bacterial cellulose aerogels via swelling-induced adsorption for nitrophenol reduction, Int. J. Biol. Macromol. 143 (2020) 922–927, https://doi.org/10.1016/j. ijbiomac.2019.09.152. [7] A. Yasin, Y. Ren, J. Li, et al., Advances in Hyaluronic Acid for Biomedical Applications, Front Bioeng Biotechnol 10 (2022), https://doi.org/10.3389/ fbioe.2022.910290. [8] W. Zhang, X.-c. Wang, X.-y. Li, et al., A 3D porous microsphere with multistage structure and component based on bacterial cellulose and collagen for bone tissue engineering, Carbohydr Polym 236 (2020), https://doi.org/10.1016/j. carbpol.2020.116043. [9] R. Rodríguez-Rodríguez, H. Espinosa-Andrews, C. Velasquillo-Martínez, et al., Composite hydrogels based on gelatin, chitosan and polyvinyl alcohol to biomedical applications: a review, International Journal of Polymeric Materials and Polymeric Biomaterials 69 (2019) 1–20, https://doi.org/10.1080/ 00914037.2019.1581780. [10] I. Ullah, Z. Chen, Y. Xie, et al., Recent advances in biological activities of lignin and emerging biomedical applications: A short review, Int. J. Biol. Macromol. 208 (2022) 819–832, https://doi.org/10.1016/j.ijbiomac.2022.03.182. [11] F. Ebrahimi, H. Ramezani Dana, Poly lactic acid (PLA) polymers: from properties to biomedical applications, International Journal of Polymeric Materials and Polymeric Biomaterials 71 (2021) 1117–1130, https://doi.org/10.1080/ 00914037.2021.1944140. [12] S. Mishra, P.K. Singh, R. Pattnaik, et al., Biochemistry, Synthesis, and Applications of Bacterial Cellulose: A Review, Front Bioeng Biotechnol 10 (2022), https://doi.org/10.3389/fbioe.2022.780409. [13] P. Samyn, A. Meftahi, S.A. Geravand, et al., Opportunities for bacterial nanocellulose in biomedical applications: Review on biosynthesis, modification and challenges, Int. J. Biol. Macromol. 231 (2023), https://doi.org/10.1016/j. ijbiomac.2023.123316. [14] F. Barja, Bacterial nanocellulose production and biomedical applications, The Journal of Biomedical Research 35 (2021), https://doi.org/10.7555/ jbr.35.20210036. [15] A. Randhawa, S.D. Dutta, K. Ganguly, et al., A Review of Properties of Nanocellulose, Its Synthesis, and Potential in Biomedical Applications, Applied Sciences 12 (2022), https://doi.org/10.3390/app12147090. [16] S. Sandhu, A. Arpa, X. Chen, et al., Engineering Bacterial Cellulose for Diverse Biomedical Applications, Recent. Prog. Mater. 1 (2019) 1, https://doi.org/ 10.21926/rpm.1904006. -1. [17] R. Rai, P. Dhar, Biomedical engineering aspects of nanocellulose: a review, Nanotechnology. 33 (2022), https://doi.org/10.1088/1361-6528/ac6fef. [18] P.V. Navya, V. Gayathri, D. Samanta, et al., Bacterial cellulose: A promising biopolymer with interesting properties and applications, Int. J. Biol. Macromol. 220 (2022) 435–461, https://doi.org/10.1016/j.ijbiomac.2022.08.056. [19] W. Liu, H. Du, M. Zhang, et al., Bacterial Cellulose-Based Composite Scaffolds for Biomedical Applications: A Review, ACS Sustain Chem Eng 8 (2020) 7536–7562, https://doi.org/10.1021/acssuschemeng.0c00125. [20] C. Sharma, N.K. Bhardwaj, Bacterial nanocellulose: Present status, biomedical applications and future perspectives, Materials Science and Engineering: C 104 (2019), https://doi.org/10.1016/j.msec.2019.109963. [21] Raghavendran, V., Asare, E., Roy, I., Bacterial cellulose: Biosynthesis, production, and applications. (2020), pp 89-138. [22] M. Skoˇ caj, Bacterial nanocellulose in papermaking, Cellulose 26 (2019) 6477–6488, https://doi.org/10.1007/s10570-019-02566-y. [23] P. Singhsa, R. Narain, H. Manuspiya, Physical structure variations of bacterial cellulose produced by different Komagataeibacter xylinus strains and carbon sources in static and agitated conditions, Cellulose 25 (2018) 1571–1581, https:// doi.org/10.1007/s10570-018-1699-1. [24] R. R, E. Philip, D. Thomas, et al., Bacterial nanocellulose: engineering, production, and applications, Bioengineered. 12 (2021) 11463–11483, https:// doi.org/10.1080/21655979.2021.2009753. [25] N.E.-A. El-Naggar, A.B.A. Mohammed, S.E. El-Malkey, Bacterial nanocellulose production using Cantaloupe juice, statistical optimization and characterization, Sci Rep 13 (2023), https://doi.org/10.1038/s41598-022-26642-9. [26] C. Zhong, Industrial-Scale Production and Applications of Bacterial Cellulose, Front Bioeng Biotechnol 8 (2020), https://doi.org/10.3389/fbioe.2020.605374. [27] H. El-Gendi, T.H. Taha, J.B. Ray, et al., Recent advances in bacterial cellulose: a low-cost effective production media, optimization strategies and applications, Cellulose 29 (2022) 7495–7533, https://doi.org/10.1007/s10570-022-04697-1. [28] P. Zhang, L. Chen, Q. Zhang, et al., Using in situ nanocellulose-coating technology based on dynamic bacterial cultures for upgrading conventional biomedical materials and reinforcing nanocellulose hydrogels, Biotechnol. Prog. 32 (2016) 1077–1084, https://doi.org/10.1002/btpr.2280. [29] S. Dubey, R.K. Sharma, P. Agarwal, et al., From rotten grapes to industrial exploitation: Komagataeibacter europaeus SGP37, a micro-factory for macroscale production of bacterial nanocellulose, Int. J. Biol. Macromol. 96 (2017) 52–60, https://doi.org/10.1016/j.ijbiomac.2016.12.016. [30] P. Marín, S.M. Martirani-Von Abercron, L. Urbina, et al., Bacterial nanocellulose production from naphthalene, Microb Biotechnol 12 (2019) 662–676, https:// doi.org/10.1111/1751-7915.13399. [31] S.-O. Dima, D.-M. Panaitescu, C. Orban, et al., Bacterial Nanocellulose from SideStreams of Kombucha Beverages Production: Preparation and Physical-Chemical Properties, Polymers (Basel) 9 (2017), https://doi.org/10.3390/polym9080374. [32] G. Pacheco, C.V. de Mello, B.G. Chiari-Andr´ eo, et al., Bacterial cellulose skin masks—Properties and sensory tests, J Cosmet Dermatol 17 (2017) 840–847, https://doi.org/10.1111/jocd.12441. [33] Z. Ashrafi, L. Lucia, W. Krause, Bioengineering tunable porosity in bacterial nanocellulose matrices, Soft. Matter. 15 (2019) 9359–9367, https://doi.org/ 10.1039/c9sm01895f. [34] S. Lee, A. Abraham, A.C.S. Lim, et al., Characterisation of bacterial nanocellulose and nanostructured carbon produced from crude glycerol by Komagataeibacter sucrofermentans, Bioresour. Technol. 342 (2021), https://doi.org/10.1016/j. biortech.2021.125918. [35] S. S¨ amfors, K. Karlsson, J. Sundberg, et al., Biofabrication of bacterial nanocellulose scaffolds with complex vascular structure, Biofabrication. 11 (2019), https://doi.org/10.1088/1758-5090/ab2b4f. [36] Z. Sun, X. Li, Z. Tang, et al., Antibacterial Films Made of Bacterial Cellulose, Polymers (Basel) 14 (2022), https://doi.org/10.3390/polym14163306. [37] V.S. Soeiro, L.L. Tundisi, V.A. Amaral, et al., Bacterial nanocellulose and fibroin: natural products to produce a structure membranes, Mat´ eria (Rio de Janeiro) 26 (2021), https://doi.org/10.1590/s1517-707620210004.1386. [38] M. Ferro, A. Mannu, W. Panzeri, et al., An Integrated Approach to Optimizing Cellulose Mercerization, Polymers (Basel) 12 (2020), https://doi.org/10.3390/ polym12071559. [39] S.-B. Park, E. Lih, K.-S. Park, et al., Biopolymer-based functional composites for medical applications, Prog Polym Sci 68 (2017) 77–105, https://doi.org/ 10.1016/j.progpolymsci.2016.12.003. [40] S. Torgbo, P. Sukyai, Biodegradation and thermal stability of bacterial cellulose as biomaterial: The relevance in biomedical applications, Polym. Degrad. Stab. 179 (2020), https://doi.org/10.1016/j.polymdegradstab.2020.109232. [41] G.N. Balistreri, I.R. Campbell, X. Li, et al., Bacterial cellulose nanoparticles as a sustainable drug delivery platform for protein-based therapeutics, RSC Applied Polymers 2 (2024) 172–183, https://doi.org/10.1039/d3lp00184a. [42] M. Schibeci, R. Gaglione, N. Russo, et al., Enzymatically Crafted Bacterial Cellulose Nanoparticles Functionalized With Antimicrobial Peptides: Toward Sustainable Antimicrobial Formulations, Biotechnol J 20 (2025), https://doi.org/ 10.1002/biot.202400573. [43] P. Weyell, U. Beekmann, C. Küpper, et al., Tailor-made material characteristics of bacterial cellulose for drug delivery applications in dentistry, Carbohydr Polym 207 (2019) 1–10, https://doi.org/10.1016/j.carbpol.2018.11.061. [44] P. Basu, N. Saha, R. Alexandrova, et al., Calcium Phosphate Incorporated Bacterial Cellulose-Polyvinylpyrrolidone Based Hydrogel Scaffold: Structural Property and Cell Viability Study for Bone Regeneration Application, Polymers (Basel) 11 (2019), https://doi.org/10.3390/polym11111821. [45] J.D.P. de Amorim, K.C. de Souza, C.R. Duarte, et al., Plant and bacterial nanocellulose: production, properties and applications in medicine, food, cosmetics, electronics and engineering. A review, Environ Chem Lett 18 (2020) 851–869, https://doi.org/10.1007/s10311-020-00989-9. [46] I.M. Bodea, F.I. Beteg, C.R. Pop, et al., Optimization of Moist and Oven-Dried Bacterial Cellulose Production for Functional Properties, Polymers (Basel) 13 (2021), https://doi.org/10.3390/polym13132088. [47] C.J. Zhang, L. Wang, J.C. Zhao, et al., Effect of Drying Methods on Structure and Mechanical Properties of Bacterial Cellulose Films, Adv Mat Res 239-242 (2011) 2667–2670, https://doi.org/10.4028/www.scientific.net/AMR.239-242.2667. [48] M.P. Illa, C.S. Sharma, M. Khandelwal, Tuning the physiochemical properties of bacterial cellulose: effect of drying conditions, J Mater Sci 54 (2019) 12024–12035, https://doi.org/10.1007/s10853-019-03737-9. [49] A. Stanisławska, H. Staroszczyk, M. Szkodo, The effect of dehydration/ rehydration of bacterial nanocellulose on its tensile strength and physicochemical properties, Carbohydr Polym 236 (2020), https://doi.org/10.1016/j. carbpol.2020.116023. [50] S.-Q. Chen, P. Lopez-Sanchez, D. Wang, et al., Mechanical properties of bacterial cellulose synthesised by diverse strains of the genus Komagataeibacter, Food Hydrocoll 81 (2018) 87–95, https://doi.org/10.1016/j.foodhyd.2018.02.031. [51] K. Potivara, M. Phisalaphong, Development and Characterization of Bacterial Cellulose Reinforced with Natural Rubber, Materials (Basel) 12 (2019), https:// doi.org/10.3390/ma12142323. L. Melro et al. Applied Materials Today 46 (2025) 102858 38 [52] P. Caz´ on, G. Vel´ azquez, M. V´ azquez, Characterization of bacterial cellulose films combined with chitosan and polyvinyl alcohol: Evaluation of mechanical and barrier properties, Carbohydr Polym 216 (2019) 72–85, https://doi.org/ 10.1016/j.carbpol.2019.03.093. [53] K. Liu, J.M. Catchmark, Enhanced mechanical properties of bacterial cellulose nanocomposites produced by co-culturing Gluconacetobacter hansenii and Escherichia coli under static conditions, Carbohydr Polym 219 (2019) 12–20, https://doi.org/10.1016/j.carbpol.2019.04.071. [54] M.S. Silva-L´ opez, L.E. Alc´ antara-Quintana, The Era of Biomaterials: Smart Implants? ACS. Appl. Bio Mater. 6 (2023) 2982–2994, https://doi.org/10.1021/ acsabm.3c00284. [55] A. Sharma, G.R. Kokil, Y. He, et al., Inorganic/organic combination: Inorganic particles/polymer composites for tissue engineering applications, Bioact. Mater. 24 (2023) 535–550, https://doi.org/10.1016/j.bioactmat.2023.01.003. [56] M. Zag´ orska-Dziok, M. Sobczak, Hydrogel-Based Active Substance Release Systems for Cosmetology and Dermatology Application: A Review, Pharmaceutics. 12 (2020), https://doi.org/10.3390/pharmaceutics12050396. [57] R. Portela, C.R. Leal, P.L. Almeida, et al., Bacterial cellulose: a versatile biopolymer for wound dressing applications, Microb Biotechnol 12 (2019) 586–610, https://doi.org/10.1111/1751-7915.13392. [58] J. Jankau, A. Bła˙ zy´ nska-Spychalska, K. Kubiak, et al., Bacterial Cellulose Properties Fulfilling Requirements for a Biomaterial of Choice in Reconstructive Surgery and Wound Healing, Front Bioeng Biotechnol 9 (2022), https://doi.org/ 10.3389/fbioe.2021.805053. [59] L. Zheng, S. Li, J. Luo, et al., Latest Advances on Bacterial Cellulose-Based Antibacterial Materials as Wound Dressings, Front Bioeng Biotechnol 8 (2020), https://doi.org/10.3389/fbioe.2020.593768. [60] A. Sionkowska, O. Mę˙ zykowska, J. Piątek, Bacterial nanocelullose in biomedical applications: a review, Polym Int 68 (2019) 1841–1847, https://doi.org/ 10.1002/pi.5882. [61] T. Frazier, A. Alarcon, X. Wu, et al., Clinical Translational Potential in Skin Wound Regeneration for Adipose-Derived, Blood-Derived, and Cellulose Materials: Cells, Exosomes, and Hydrogels, Biomolecules 10 (2020), https://doi. org/10.3390/biom10101373. [62] K. Maurer, M. Renkert, M. Duis, et al., Application of bacterial nanocellulosebased wound dressings in the management of thermal injuries: Experience in 92 children, Burns 48 (2022) 608–614, https://doi.org/10.1016/j. burns.2021.07.002. [63] H. Yuan, L. Chen, F.F. Hong, Homogeneous and efficient production of a bacterial nanocellulose-lactoferrin-collagen composite under an electric field as a matrix to promote wound healing, Biomater Sci 9 (2021) 930–941, https://doi.org/ 10.1039/d0bm01553a. [64] I.B. de Mattos, J.C.J. Holzer, A.-C. Tuca, et al., Uptake of PHMB in a bacterial nanocellulose-based wound dressing: A feasible clinical procedure, Burns 45 (2019) 898–904, https://doi.org/10.1016/j.burns.2018.10.023. [65] J.D.P. de Amorim, C.J.G. da Silva Junior, A.D.L.M. de Medeiros, et al., Bacterial Cellulose as a Versatile Biomaterial for Wound Dressing Application, Molecules. 27 (2022), https://doi.org/10.3390/molecules27175580. [66] N. Lin, A. Dufresne, Nanocellulose in biomedicine: Current status and future prospect, Eur Polym J 59 (2014) 302–325, https://doi.org/10.1016/j. eurpolymj.2014.07.025. [67] K.L.N. Kaminagakura, S. Sue Sato, P. Sugino, et al., Nanoskin® to treat full thickness skin wounds, Journal of Biomedical Materials Research Part B: Applied Biomaterials 107 (2018) 724–732, https://doi.org/10.1002/jbm.b.34166. [68] G. delli Santi, A. Borgognone, The use of Epiprotect®, an advanced wound dressing, to heal paediatric patients with burns: A pilot study, Burns. Open. 3 (2019) 103–107, https://doi.org/10.1016/j.burnso.2019.05.001. [69] G.F. Picheth, C.L. Pirich, M.R. Sierakowski, et al., Bacterial cellulose in biomedical applications: A review, Int. J. Biol. Macromol. 104 (2017) 97–106, https://doi.org/10.1016/j.ijbiomac.2017.05.171. [70] H. Moradpoor, H. Mohammadi, M. Safaei, et al., Recent Advances on Bacterial Cellulose-Based Wound Management: Promises and Challenges, Int J Polym Sci 2022 (2022) 1–24, https://doi.org/10.1155/2022/1214734. [71] O. Yazarlu, M. Iranshahi, H.R.K. Kashani, et al., Perspective on the application of medicinal plants and natural products in wound healing: A mechanistic review, Pharmacol. Res. 174 (2021), https://doi.org/10.1016/j.phrs.2021.105841. [72] A. Meftahi, P. Samyn, S.A. Geravand, et al., Nanocelluloses as skin biocompatible materials for skincare, cosmetics, and healthcare: Formulations, regulations, and emerging applications, Carbohydr Polym 278 (2022), https://doi.org/10.1016/j. carbpol.2021.118956. [73] M. Gao, J. Li, Z. Bao, et al., A natural in situ fabrication method of functional bacterial cellulose using a microorganism, Nat Commun 10 (2019), https://doi. org/10.1038/s41467-018-07879-3. [74] M. Shahriari-Khalaji, G. Li, L. Liu, et al., A poly-l-lysine-bonded TEMPO-oxidized bacterial nanocellulose-based antibacterial dressing for infected wound treatment, Carbohydr Polym 287 (2022), https://doi.org/10.1016/j. carbpol.2022.119266. [75] V. Tsikourkitoudi, B. Henriques-Normark, G.A. Sotiriou, Inorganic nanoparticle engineering against bacterial infections, Curr Opin Chem Eng 38 (2022), https:// doi.org/10.1016/j.coche.2022.100872. [76] A. Kushwaha, L. Goswami, B.S. Kim, Nanomaterial-Based Therapy for Wound Healing, Nanomaterials 12 (2022), https://doi.org/10.3390/nano12040618. [77] B. Ma, J.P. Chaudhary, J. Zhu, et al., Construction of silver nanoparticles anchored in carbonized bacterial cellulose with enhanced antibacterial properties, Colloids and Surfaces A: Physicochemical and Engineering Aspects 611 (2021), https://doi.org/10.1016/j.colsurfa.2020.125845. [78] A. Vasil’kov, I. Butenko, A. Naumkin, et al., Hybrid Silver-Containing Materials Based on Various Forms of Bacterial Cellulose: Synthesis, Structure, and Biological Activity, Int J Mol Sci 24 (2023), https://doi.org/10.3390/ ijms24087667. [79] H. Almasi, L. Mehryar, A. Ghadertaj, Characterization of CuO-bacterial cellulose nanohybrids fabricated by in-situ and ex-situ impregnation methods, Carbohydr Polym 222 (2019), https://doi.org/10.1016/j.carbpol.2019.114995. [80] M. Wasim, M.R. Khan, M. Mushtaq, et al., Surface Modification of Bacterial Cellulose by Copper and Zinc Oxide Sputter Coating for UV-Resistance/ Antistatic/Antibacterial Characteristics, Coatings 10 (2020), https://doi.org/ 10.3390/coatings10040364. [81] S.S. Mirtalebi, H. Almasi, Alizadeh Khaledabad, M., Physical, morphological, antimicrobial and release properties of novel MgO-bacterial cellulose nanohybrids prepared by in-situ and ex-situ methods, Int. J. Biol. Macromol. 128 (2019) 848–857, https://doi.org/10.1016/j.ijbiomac.2019.02.007. [82] B. Khodashenas, H.R. Ghorbani, Synthesis of silver nanoparticles with different shapes, Arab. J. Chem. 12 (2019) 1823–1838, https://doi.org/10.1016/j. arabjc.2014.12.014. [83] Z. Ferdous, A. Nemmar, Health Impact of Silver Nanoparticles: A Review of the Biodistribution and Toxicity Following Various Routes of Exposure, Int J Mol Sci 21 (2020), https://doi.org/10.3390/ijms21072375. [84] Y. Wan, S. Yang, J. Wang, et al., Scalable synthesis of robust and stretchable composite wound dressings by dispersing silver nanowires in continuous bacterial cellulose, Composites Part B: Engineering 199 (2020), https://doi.org/10.1016/j. compositesb.2020.108259. [85] L. Chatchawanwirote, P. Chuysinuan, T. Thanyacharoen, et al., Green synthesis of photomediated silver nanoprisms via a light-induced transformation reaction and silver nanoprism-impregnated bacteria cellulose films for use as antibacterial wound dressings, J Drug Deliv Sci Technol 54 (2019), https://doi.org/10.1016/j. jddst.2019.101305. [86] Y. Xie, L. Yue, Y. Zheng, et al., The antibacterial stability of poly(dopamine) insitu reduction and chelation nano-Ag based on bacterial cellulose network template, Appl Surf Sci 491 (2019) 383–394, https://doi.org/10.1016/j. apsusc.2019.06.096. [87] S. Jiji, S. Udhayakumar, K. Maharajan, et al., Bacterial cellulose matrix with in situ impregnation of silver nanoparticles via catecholic redox chemistry for third degree burn wound healing, Carbohydr Polym 245 (2020), https://doi.org/ 10.1016/j.carbpol.2020.116573. [88] C. Tipa, M.T. Cidade, J.P. Borges, et al., Clay-Based Nanocomposite Hydrogels for Biomedical Applications: A Review, Nanomaterials 12 (2022), https://doi.org/ 10.3390/nano12193308. [89] M. Horue, M.L. Cacicedo, M.A. Fernandez, et al., Antimicrobial activities of bacterial cellulose – Silver montmorillonite nanocomposites for wound healing, Materials Science and Engineering: C 116 (2020), https://doi.org/10.1016/j. msec.2020.111152. [90] S.R.Z. Teixeira, E.M.d. Reis, G.P. Apati, et al., Biosynthesis and Functionalization of Bacterial Cellulose Membranes with Cerium Nitrate and Silver Nanoparticles, Materials Research 22 (2019), https://doi.org/10.1590/1980-5373-mr-20190054. [91] W. He, X. Huang, Y. Zheng, et al., In situ synthesis of bacterial cellulose/copper nanoparticles composite membranes with long-term antibacterial property, Journal of Biomaterials Science, Polymer Edition 29 (2018) 2137–2153, https:// doi.org/10.1080/09205063.2018.1528518. [92] Y.-Y. Xie, X.-H. Hu, Y.-W. Zhang, et al., Development and antibacterial activities of bacterial cellulose/graphene oxide-CuO nanocomposite films, Carbohydr Polym 229 (2020), https://doi.org/10.1016/j.carbpol.2019.115456. [93] V. Dinc˘ a, A. Mocanu, G. Isopencu, et al., Biocompatible pure ZnO nanoparticles3D bacterial cellulose biointerfaces with antibacterial properties, Arab. J. Chem. 13 (2020) 3521–3533, https://doi.org/10.1016/j.arabjc.2018.12.003. [94] F. Wahid, Y.-X. Duan, X.-H. Hu, et al., A facile construction of bacterial cellulose/ ZnO nanocomposite films and their photocatalytic and antibacterial properties, Int. J. Biol. Macromol. 132 (2019) 692–700, https://doi.org/10.1016/j. ijbiomac.2019.03.240. [95] J. Jabło´ nska, M. Onyszko, M. Konopacki, et al., Fabrication of Paper Sheets Coatings Based on Chitosan/Bacterial Nanocellulose/ZnO with Enhanced Antibacterial and Mechanical Properties, Int J Mol Sci 22 (2021), https://doi.org/ 10.3390/ijms22147383. [96] N. Melnikova, A. Knyazev, V. Nikolskiy, et al., Wound Healing Composite Materials of Bacterial Cellulose and Zinc Oxide Nanoparticles with Immobilized Betulin Diphosphate, Nanomaterials 11 (2021), https://doi.org/10.3390/ nano11030713. [97] M. Khamrai, S.L. Banerjee, S. Paul, et al., A Mussel Mimetic, Bioadhesive, Antimicrobial Patch Based on Dopamine-Modified Bacterial Cellulose/rGO/Ag NPs: A Green Approach toward Wound-Healing Applications, ACS Sustain Chem Eng (2019), https://doi.org/10.1021/acssuschemeng.9b01163. [98] L. Zhang, Y. Yu, S. Zheng, et al., Preparation and properties of conductive bacterial cellulose-based graphene oxide-silver nanoparticles antibacterial dressing, Carbohydr Polym 257 (2021), https://doi.org/10.1016/j. carbpol.2021.117671. [99] X.Y. Chen, H.R. Low, X.Y. Loi, et al., Fabrication and evaluation of bacterial nanocellulose/poly(acrylic acid)/graphene oxide composite hydrogel: Characterizations and biocompatibility studies for wound dressing, Journal of Biomedical Materials Research Part B: Applied Biomaterials 107 (2019) 2140–2151, https://doi.org/10.1002/jbm.b.34309. [100] D.Z. Zmejkoski, Z.M. Markovi´ c, D.D. Miti´ c, et al., Antibacterial composite hydrogels of graphene quantum dots and bacterial cellulose accelerate wound L. Melro et al. Applied Materials Today 46 (2025) 102858 39 healing, Journal of Biomedical Materials Research Part B: Applied Biomaterials 110 (2022) 1796–1805, https://doi.org/10.1002/jbm.b.35037. [101] A. Khalid, A. Madni, B. Raza, et al., Multiwalled carbon nanotubes functionalized bacterial cellulose as an efficient healing material for diabetic wounds, Int. J. Biol. Macromol. 203 (2022) 256–267, https://doi.org/10.1016/j. ijbiomac.2022.01.146. [102] A. Salleh, M.B. Fauzi, The In Vivo, In Vitro and In Ovo Evaluation of Quantum Dots in Wound Healing: A Review, Polymers (Basel) 13 (2021), https://doi.org/ 10.3390/polym13020191. [103] S. Abolghasemzade, M. Pourmadadi, H. Rashedi, et al., PVA based nanofiber containing CQDs modified with silica NPs and silk fibroin accelerates wound healing in a rat model, Journal of Materials Chemistry B 9 (2021) 658–676, https://doi.org/10.1039/d0tb01747g. [104] L. Wang, Q. Hou, W. Zheng, et al., Fluorescent and Antibacterial Aminobenzeneboronic Acid (ABA)-Modified Gold Nanoclusters for SelfMonitoring Residual Dosage and Smart Wound Care, ACS. Nano 15 (2021) 17885–17894, https://doi.org/10.1021/acsnano.1c06139. [105] S.K. Nethi, S. Das, C.R. Patra, et al., Recent advances in inorganic nanomaterials for wound-healing applications, Biomater Sci 7 (2019) 2652–2674, https://doi. org/10.1039/c9bm00423h. [106] A.I. Ribeiro, A.M. Dias, A. Zille, Synergistic Effects Between Metal Nanoparticles and Commercial Antimicrobial Agents: A Review, ACS. Appl. Nano Mater. 5 (2022) 3030–3064, https://doi.org/10.1021/acsanm.1c03891. [107] B. Walling, P. Bharali, B. Giridharan, et al., Bacterial nanocellulose: A novel nanostructured bio-adsorbent for green remediation technology, Acta Ecologica Sinica 43 (2023) 946–967, https://doi.org/10.1016/j.chnaes.2023.02.002. [108] R. Eivazzadeh-Keihan, E. Bahojb Noruzi, K. Khanmohammadi Chenab, et al., Metal-based nanoparticles for bone tissue engineering, J Tissue Eng Regen Med 14 (2020) 1687–1714, https://doi.org/10.1002/term.3131. [109] H. Zhao, L. Zhang, S. Zheng, et al., Bacteriostatic activity and cytotoxicity of bacterial cellulose-chitosan film loaded with in-situ synthesized silver nanoparticles, Carbohydr Polym 281 (2022), https://doi.org/10.1016/j. carbpol.2021.119017. [110] S. Hamedi, S.A. Shojaosadati, Preparation of antibacterial ZnO NP-containing schizophyllan/bacterial cellulose nanocomposite for wound dressing, Cellulose 28 (2021) 9269–9282, https://doi.org/10.1007/s10570-021-04119-8. [111] R. Patwa, O. Zandraa, Z. Cap´ akov´ a, et al., Effect of Iron-Oxide Nanoparticles Impregnated Bacterial Cellulose on Overall Properties of Alginate/Casein Hydrogels: Potential Injectable Biomaterial for Wound Healing Applications, Polymers (Basel) 12 (2020), https://doi.org/10.3390/polym12112690. [112] K.U. Rahman, E.P. Ferreira-Neto, G.U. Rahman, et al., Flexible bacterial cellulosebased BC-SiO2-TiO2-Ag membranes with self-cleaning, photocatalytic, antibacterial and UV-shielding properties as a potential multifunctional material for combating infections and environmental applications, J. Environ. Chem. Eng. 9 (2021), https://doi.org/10.1016/j.jece.2020.104708. [113] A. Fadakar Sarkandi, M. Montazer, T. Harifi, et al., Innovative preparation of bacterial cellulose/silver nanocomposite hydrogels: In situ green synthesis, characterization, and antibacterial properties, J Appl Polym Sci 138 (2020), https://doi.org/10.1002/app.49824. [114] S. Song, Z. Liu, M.A. Abubaker, et al., Antibacterial polyvinyl alcohol/bacterial cellulose/nano-silver hydrogels that effectively promote wound healing, Materials Science and Engineering: C 126 (2021), https://doi.org/10.1016/j. msec.2021.112171. [115] Z. Luo, J. Liu, H. Lin, et al., In situ Fabrication of Nano ZnO/BCM Biocomposite Based on MA Modified Bacterial Cellulose Membrane for Antibacterial and Wound Healing, International Journal of Nanomedicine Volume 15 (2020) 1–15, https://doi.org/10.2147/ijn.S231556. [116] S. Zhang, Z. Yang, J. Hao, et al., Hollow nanosphere-doped bacterial cellulose and polypropylene wound dressings: Biomimetic nanocatalyst mediated antibacterial therapy, Chemical Engineering Journal 432 (2022), https://doi.org/10.1016/j. cej.2021.134309. [117] A.G. Morena, M.B. Roncero, S.V. Valenzuela, et al., Laccase/TEMPO-mediated bacterial cellulose functionalization: production of paper-silver nanoparticles composite with antimicrobial activity, Cellulose 26 (2019) 8655–8668, https:// doi.org/10.1007/s10570-019-02678-5. [118] A. Barhoum, V.K. Rastogi, B.K. Mahur, et al., Nanocelluloses as new generation materials: natural resources, structure-related properties, engineering nanostructures, and technical challenges, Mater. Today Chem. 26 (2022), https:// doi.org/10.1016/j.mtchem.2022.101247. [119] H. Ren, F. Zhao, Q. Zhang, et al., Autophagy and skin wound healing, Burns. Trauma 10 (2022), https://doi.org/10.1093/burnst/tkac003. [120] J. Hoff, B. Karl, J. Gerstmeier, et al., Controlled Release of the α -TocopherolDerived Metabolite α -13 ′ -Carboxychromanol from Bacterial Nanocellulose Wound Cover Improves Wound Healing, Nanomaterials 11 (2021), https://doi.org/ 10.3390/nano11081939. [121] K.M. Pasaribu, S. Ilyas, T. Tamrin, et al., Bioactive bacterial cellulose wound dressings for burns with collagen in-situ and chitosan ex-situ impregnation, Int. J. Biol. Macromol. 230 (2023), https://doi.org/10.1016/j.ijbiomac.2022.123118. [122] H. Yuan, L. Chen, F.F. Hong, A Biodegradable Antibacterial Nanocomposite Based on Oxidized Bacterial Nanocellulose for Rapid Hemostasis and Wound Healing, ACS Appl Mater Interfaces 12 (2019) 3382–3392, https://doi.org/10.1021/ acsami.9b17732. [123] V.V. Revin, E.V. Liyaskina, M.V. Parchaykina, et al., Bacterial Cellulose-Based Polymer Nanocomposites: A Review, Polymers (Basel) 14 (2022), https://doi. org/10.3390/polym14214670. [124] C. Alves, A. Ribeiro, E. Pinto, et al., Exploring Z-Tyr-Phe-OH-based hydrogels loaded with curcumin for the development of fressings for wound healing, J Drug Deliv Sci Technol 73 (2022), https://doi.org/10.1016/j.jddst.2022.103484. [125] W. Sajjad, F. He, M.W. Ullah, et al., Fabrication of Bacterial Cellulose-Curcumin Nanocomposite as a Novel Dressing for Partial Thickness Skin Burn, Front Bioeng Biotechnol 8 (2020), https://doi.org/10.3389/fbioe.2020.553037. [126] T. Vachanont, S. Torgbo, P. Sukyai, Release Kinetic Model and Antimicrobial Activity of Freeze-Dried Curcumin-loaded Bacterial Nanocellulose Composite, Polymer Science, Series A 62 (2020) 218–227, https://doi.org/10.1134/ s0965545x20030153. [127] A. Gupta, D.J. Keddie, V. Kannappan, et al., Production and characterisation of bacterial cellulose hydrogels loaded with curcumin encapsulated in cyclodextrins as wound dressings, Eur Polym J 118 (2019) 437–450, https://doi.org/10.1016/j. eurpolymj.2019.06.018. [128] J. Ralph, C. Lapierre, W. Boerjan, Lignin structure and its engineering, Curr. Opin. Biotechnol. 56 (2019) 240–249, https://doi.org/10.1016/j.copbio.2019.02.019. [129] D. Zmejkoski, D. Spasojevi´ c, I. Orlovska, et al., Bacterial cellulose-lignin composite hydrogel as a promising agent in chronic wound healing, Int. J. Biol. Macromol. 118 (2018) 494–503, https://doi.org/10.1016/j. ijbiomac.2018.06.067. [130] S. Tang, K. Chi, H. Xu, et al., A covalently cross-linked hyaluronic acid/bacterial cellulose composite hydrogel for potential biological applications, Carbohydr Polym 252 (2021), https://doi.org/10.1016/j.carbpol.2020.117123. [131] D. Ciecholewska-Ju´ sko, A. ˙ Zywicka, A. Junka, et al., Superabsorbent crosslinked bacterial cellulose biomaterials for chronic wound dressings, Carbohydr Polym 253 (2021), https://doi.org/10.1016/j.carbpol.2020.117247. [132] F. Gao, W. Li, J. Deng, et al., Recombinant Human Hair Keratin Nanoparticles Accelerate Dermal Wound Healing, ACS Appl Mater Interfaces 11 (2019) 18681–18690, https://doi.org/10.1021/acsami.9b01725. [133] Z. Keskin, A. Sendemir Urkmez, E.E. Hames, Novel keratin modified bacterial cellulose nanocomposite production and characterization for skin tissue engineering, Materials Science and Engineering: C 75 (2017) 1144–1153, https:// doi.org/10.1016/j.msec.2017.03.035. [134] X. Chen, D. Zhai, B. Wang, et al., Hair keratin promotes wound healing in rats with combined radiation-wound injury, Journal of Materials Science: Materials in Medicine 31 (2020), https://doi.org/10.1007/s10856-020-06365-x. [135] L. Wang, L. Mao, F. Qi, et al., Synergistic effect of highly aligned bacterial cellulose/gelatin membranes and electrical stimulation on directional cell migration for accelerated wound healing, Chemical Engineering Journal 424 (2021), https://doi.org/10.1016/j.cej.2021.130563. [136] M.L. Cacicedo, G. Pacheco, G.A. Islan, et al., Chitosan-bacterial cellulose patch of ciprofloxacin for wound dressing: Preparation and characterization studies, Int. J. Biol. Macromol. 147 (2020) 1136–1145, https://doi.org/10.1016/j. ijbiomac.2019.10.082. [137] Z. Wei, P. Pan, F.F. Hong, et al., A novel approach for efficient fabrication of chitosan nanoparticles-embedded bacterial nanocellulose conduits, Carbohydr Polym 264 (2021), https://doi.org/10.1016/j.carbpol.2021.118002. [138] N. Mohamad, E.Y.X. Loh, M.B. Fauzi, et al., In vivo evaluation of bacterial cellulose/acrylic acid wound dressing hydrogel containing keratinocytes and fibroblasts for burn wounds, Drug Deliv Transl Res 9 (2018) 444–452, https:// doi.org/10.1007/s13346-017-0475-3. [139] S. Jiji, S. Udhayakumar, C. Rose, et al., Thymol enriched bacterial cellulose hydrogel as effective material for third degree burn wound repair, Int. J. Biol. Macromol. 122 (2019) 452–460, https://doi.org/10.1016/j. ijbiomac.2018.10.192. [140] M.H. Farjah, M.R. Farahpour, Efficacy of topical platelet-rich plasma and chitosan co-administration on Candida albicans-infected partial thickness burn wound healing, Burns 46 (2020) 1889–1895, https://doi.org/10.1016/j. burns.2020.05.019. [141] C. Vilela, H. Oliveira, A. Almeida, et al., Nanocellulose-based antifungal nanocomposites against the polymorphic fungus Candida albicans, Carbohydr Polym 217 (2019) 207–216, https://doi.org/10.1016/j.carbpol.2019.04.046. [142] A. Gupta, S.M. Briffa, S. Swingler, et al., Synthesis of Silver Nanoparticles Using Curcumin-Cyclodextrins Loaded into Bacterial Cellulose-Based Hydrogels for Wound Dressing Applications, Biomacromolecules. 21 (2020) 1802–1811, https://doi.org/10.1021/acs.biomac.9b01724. [143] WHO, Journal. 2023 (2023). [144] L. Mao, L. Wang, M. Zhang, et al., Situ Synthesized Selenium NanoparticlesDecorated Bacterial Cellulose/Gelatin Hydrogel with Enhanced Antibacterial, Antioxidant, and Anti-Inflammatory Capabilities for Facilitating Skin Wound Healing, Adv Healthc Mater 10 (2021), https://doi.org/10.1002/ adhm.202100402. [145] M. Sorourian, M. Pourmadadi, F. Yazdian, et al., Engineered bacterial cellulosebased Ag nanoparticles/g-C3N4/Eucalyptus extract nanocomposites for wound dressing: In vitro evaluation, Eur. J. Med. Chem. Rep. 12 (2024), https://doi.org/ 10.1016/j.ejmcr.2024.100190. [146] FDA, Journal. 2023 (2019). [147] S. Khan, M. Ul-Islam, M.W. Ullah, et al., Fabrication strategies and biomedical applications of three-dimensional bacterial cellulose-based scaffolds: A review, Int. J. Biol. Macromol. 209 (2022) 9–30, https://doi.org/10.1016/j. ijbiomac.2022.03.191. [148] S. Mohammadi, F. Jabbari, V. Babaeipour, Bacterial cellulose-based composites as vehicles for dermal and transdermal drug delivery: A review, Int. J. Biol. Macromol. 242 (2023), https://doi.org/10.1016/j.ijbiomac.2023.124955. L. Melro et al. Applied Materials Today 46 (2025) 102858 40 [149] S.U. Islam, M. Ul-Islam, H. Ahsan, et al., Potential applications of bacterial cellulose and its composites for cancer treatment, Int. J. Biol. Macromol. 168 (2021) 301–309, https://doi.org/10.1016/j.ijbiomac.2020.12.042. [150] Z. Hussain, W. Sajjad, T. Khan, et al., Production of bacterial cellulose from industrial wastes: a review, Cellulose 26 (2019) 2895–2911, https://doi.org/ 10.1007/s10570-019-02307-1. [151] A. Subhedar, S. Bhadauria, S. Ahankari, et al., Nanocellulose in biomedical and biosensing applications: A review, Int. J. Biol. Macromol. 166 (2021) 587–600, https://doi.org/10.1016/j.ijbiomac.2020.10.217. [152] G. Surendran, A.P. Sherje, Cellulose nanofibers and composites: An insight into basics and biomedical applications, J Drug Deliv Sci Technol 75 (2022), https:// doi.org/10.1016/j.jddst.2022.103601. [153] E.Y.X. Loh, M.B. Fauzi, M.H. Ng, et al., Insight into delivery of dermal fibroblast by non-biodegradable bacterial nanocellulose composite hydrogel on wound healing, Int. J. Biol. Macromol. 159 (2020) 497–509, https://doi.org/10.1016/j. ijbiomac.2020.05.011. [154] M. Roman, A.P. Haring, T.J. Bertucio, The growing merits and dwindling limitations of bacterial cellulose-based tissue engineering scaffolds, Curr Opin Chem Eng 24 (2019) 98–106, https://doi.org/10.1016/j.coche.2019.03.006. [155] N. Petersen, P. Gatenholm, Bacterial cellulose-based materials and medical devices: current state and perspectives, Appl. Microbiol. Biotechnol. 91 (2011) 1277–1286, https://doi.org/10.1007/s00253-011-3432-y. [156] T. Aditya, J.P. Allain, C. Jaramillo, et al., Surface Modification of Bacterial Cellulose for Biomedical Applications, Int J Mol Sci 23 (2022), https://doi.org/ 10.3390/ijms23020610. [157] H.G. de Oliveira Barud, R.R. da Silva, M.A.C. Borges, et al., Bacterial Nanocellulose in Dentistry: Perspectives and Challenges, Molecules. 26 (2020), https://doi.org/10.3390/molecules26010049. [158] M. Pang, Y. Huang, F. Meng, et al., Application of bacterial cellulose in skin and bone tissue engineering, Eur Polym J 122 (2020), https://doi.org/10.1016/j. eurpolymj.2019.109365. [159] R. Guo, J. Li, C. Chen, et al., Biomimetic 3D bacterial cellulose-graphene foam hybrid scaffold regulates neural stem cell proliferation and differentiation, Colloids and Surfaces B: Biointerfaces 200 (2021), https://doi.org/10.1016/j. colsurfb.2021.111590. [160] S.L. Arias, A. Shetty, J. Devorkin, et al., Magnetic targeting of smooth muscle cells in vitro using a magnetic bacterial cellulose to improve cell retention in tissueengineering vascular grafts, Acta Biomater 77 (2018) 172–181, https://doi.org/ 10.1016/j.actbio.2018.07.013. [161] L. Zhang, F. Wei, Q. Bai, et al., Oscillating Magnetic Field Regulates Cell Adherence and Endothelialization Based on Magnetic Nanoparticle-Modified Bacterial Cellulose, ACS Appl Mater Interfaces 12 (2020) 52467–52478, https:// doi.org/10.1021/acsami.0c17213. [162] S. Campbell, N. Preciado Rivera, S. Said, et al., Injectable On-Demand Pulsatile Drug Delivery Hydrogels Using Alternating Magnetic Field-Triggered Polymer Glass Transitions, ACS Appl Mater Interfaces 15 (2023) 48892–48902, https:// doi.org/10.1021/acsami.3c09299. [163] C. Gonçalves, Y. Lalatonne, L. Melro, et al., New dextrin nanomagnetogels as contrast agents for magnetic resonance imaging, Journal of Materials Chemistry B 1 (2013), https://doi.org/10.1039/c3tb21063d. [164] A. Indoliya, R. Poddar, Hyperthermic Treatment by Superparamagnetic Iron Oxide Nanoparticles for Targeted Tumor Therapy: An In-Vivo Approach Guided by Swept-Source Optical Coherence Tomography, J Med Biol Eng 43 (2022) 32–41, https://doi.org/10.1007/s40846-022-00769-6. [165] S. Roig-Sanchez, O. Torrecilla, J. Floriach-Clark, et al., One-Step Biosynthesis of Soft Magnetic Bacterial Cellulose Spheres with Localized Nanoparticle Functionalization, ACS Appl Mater Interfaces 13 (2021) 55569–55576, https:// doi.org/10.1021/acsami.1c17752. [166] K.R. Wagner, J.T. Kaiser, S.F. DeFroda, et al., Rehabilitation, Restrictions, and Return to Sport After Cartilage Procedures, Arthrosc. Sports Med. Rehabil. 4 (2022) e115–e124, https://doi.org/10.1016/j.asmr.2021.09.029. [167] S. Gorgieva, Bacterial Cellulose as a Versatile Platform for, Research and Development of Biomedical Materials, Processes 8 (2020), https://doi.org/ 10.3390/pr8050624. [168] N.D. B˙ INgÜL, Y.E. ¨ OZ, A. S¸Endem˙ IR, et al., Microbial biopolymers in articular cartilage tissue engineering, Journal of Polymer Research 29 (2022), https://doi. org/10.1007/s10965-022-03178-0. [169] V. Horbert, J. Boettcher, P. Foehr, et al., Laser perforation and cell seeding improve bacterial nanocellulose as a potential cartilage implant in the in vitro cartilage punch model, Cellulose 26 (2019) 647–664, https://doi.org/10.1007/ s10570-019-02286-3. [170] X.-R. Ong, A.X. Chen, N. Li, et al., Nanocellulose: Recent Advances Toward Biomedical Applications, Small. Sci. 3 (2022), https://doi.org/10.1002/ smsc.202200076. [171] L. Sun, C. Chen, X. Gong, et al., Preparation and characterization of methacrylated gelatin/bacterial cellulose composite hydrogels for cartilage tissue engineering, Regen Biomater 7 (2020) 195–202, https://doi.org/10.1093/rb/ rbz050. [172] G. Li, A.G. Nandgaonkar, Y. Habibi, et al., An environmentally benign approach to achieving vectorial alignment and high microporosity in bacterial cellulose/ chitosan scaffolds, RSC Adv 7 (2017) 13678–13688, https://doi.org/10.1039/ c6ra26049g. [173] N.P. Grigull, J.I. Redeker, B. Schmitt, et al., Chondrogenic Potential of Pellet Culture Compared to High-Density Culture on a Bacterial Cellulose Hydrogel, Int J Mol Sci 21 (2020), https://doi.org/10.3390/ijms21082785. [174] P.P. Phatchayawat, A. Khamkeaw, S. Yodmuang, et al., 3D bacterial cellulosechitosan-alginate-gelatin hydrogel scaffold for cartilage tissue engineering, Biochem. Eng. J. 184 (2022), https://doi.org/10.1016/j.bej.2022.108476. [175] J. Zeng, L. Jia, D. Wang, et al., Bacterial nanocellulose-reinforced gelatin methacryloyl hydrogel enhances biomechanical property and glycosaminoglycan content of 3D-bioprinted cartilage, Int. J. Bioprint. 9 (2022), https://doi.org/ 10.18063/ijb.v9i1.631. [176] C. Dou, Z. Li, J. Gong, et al., Bio-based poly (γ-glutamic acid) hydrogels reinforced with bacterial cellulose nanofibers exhibiting superior mechanical properties and cytocompatibility, Int. J. Biol. Macromol. 170 (2021) 354–365, https://doi.org/ 10.1016/j.ijbiomac.2020.12.148. [177] K. Wang, Q. Ma, Y.-M. Zhang, et al., Preparation of bacterial cellulose/silk fibroin double-network hydrogel with high mechanical strength and biocompatibility for artificial cartilage, Cellulose 27 (2019) 1845–1852, https://doi.org/10.1007/ s10570-019-02869-0. [178] L. Bao, J. Tang, F.F. Hong, et al., Physicochemical Properties and In Vitro Biocompatibility of Three Bacterial Nanocellulose Conduits for Blood Vessel Applications, Carbohydr Polym 239 (2020), https://doi.org/10.1016/j. carbpol.2020.116246. [179] L. Bao, F.F. Hong, G. Li, et al., Implantation of air-dried bacterial nanocellulose conduits in a small-caliber vascular prosthesis rabbit model, Materials Science and Engineering: C 122 (2021), https://doi.org/10.1016/j.msec.2021.111922. [180] G. Hu, L. Bao, G. Li, et al., Vascular cells responses to controlled surface structure and properties of bacterial nanocellulose artificial blood vessel after mercerization, Carbohydr Polym 306 (2023), https://doi.org/10.1016/j. carbpol.2023.120572. [181] J. Tang, L. Bao, X. Li, et al., Potential of PVA-doped bacterial nano-cellulose tubular composites for artificial blood vessels, Journal of Materials Chemistry B 3 (2015) 8537–8547, https://doi.org/10.1039/c5tb01144b. [182] M. Wacker, J. Riedel, H. Walles, et al., Comparative Evaluation on Impacts of Fibronectin, Heparin–Chitosan, and Albumin Coating of Bacterial Nanocellulose Small-Diameter Vascular Grafts on Endothelialization In Vitro, Nanomaterials 11 (2021), https://doi.org/10.3390/nano11081952. [183] L. Bao, F.F. Hong, G. Li, et al., Improved Performance of Bacterial Nanocellulose Conduits by the Introduction of Silk Fibroin Nanoparticles and Heparin for SmallCaliber Vascular Graft Applications, Biomacromolecules. 22 (2020) 353–364, https://doi.org/10.1021/acs.biomac.0c01211. [184] L. Bao, C. Li, M. Tang, et al., Potential of a Composite Conduit with Bacterial Nanocellulose and Fish Gelatin for Application as Small-Diameter Artificial Blood Vessel, Polymers (Basel) 14 (2022), https://doi.org/10.3390/polym14204367. [185] J. Piasecka-Zelga, P. Zelga, K. Gronkowska, et al., Toxicological and Sensitization Studies of Novel Vascular Prostheses Made of Bacterial Nanocellulose Modified with Chitosan (MBC) for Application as the Tissue-Engineered Blood Vessels, Regen. Eng. Transl. Med. 7 (2021) 218–233, https://doi.org/10.1007/s40883021-00209-y. [186] L. Liu, X. Ji, L. Mao, et al., Hierarchical-structured bacterial cellulose/potato starch tubes as potential small-diameter vascular grafts, Carbohydr Polym 281 (2022), https://doi.org/10.1016/j.carbpol.2021.119034. [187] R. Tandon, R. Singh, N. Gupta, et al., Corneal transplantation in the modern era, Indian Journal of Medical Research 150 (2019), https://doi.org/10.4103/ijmr. IJMR_141_19. [188] E. Shirzaei Sani, A. Kheirkhah, D. Rana, et al., Sutureless repair of corneal injuries using naturally derived bioadhesive hydrogels, Sci Adv 5 (2019), https://doi.org/ 10.1126/sciadv.aav1281. [189] Y. Luo, G. Li, L. Chen, et al., Preparation and Evaluation of Bacterial Nanocellulose/Hyaluronic Acid Composite Artificial Cornea for Application of Corneal Transplantation, Biomacromolecules. 24 (2022) 201–212, https://doi. org/10.1021/acs.biomac.2c01052. [190] Y. Jia, W. Zhu, M. Zheng, et al., Bacterial cellulose/hyaluronic acid composite hydrogels with improved viscoelastic properties and good thermodynamic stability, Plastics, Rubber and Composites 47 (2018) 165–175, https://doi.org/ 10.1080/14658011.2018.1447340. [191] Y. Han, C. Li, Q. Cai, et al., Studies on bacterial cellulose/poly(vinyl alcohol) hydrogel composites as tissue-engineered corneal stroma, Biomedical Materials 15 (2020), https://doi.org/10.1088/1748-605X/ab56ca. [192] R. Ajdary, R. Abidnejad, J. Lehtonen, et al., Bacterial nanocellulose enables auxetic supporting implants, Carbohydr Polym 284 (2022), https://doi.org/ 10.1016/j.carbpol.2022.119198. [193] J. Piasecka-Zelga, P. Zelga, J. Szulc, et al., An in vivo biocompatibility study of surgical meshes made from bacterial cellulose modified with chitosan, Int. J. Biol. Macromol. 116 (2018) 1119–1127, https://doi.org/10.1016/j. ijbiomac.2018.05.123. [194] X. Lv, C. Feng, Y. Liu, et al., A smart bilayered scaffold supporting keratinocytes and muscle cells in micro/nano-scale for urethral reconstruction, Theranostics. 8 (2018) 3153–3163, https://doi.org/10.7150/thno.22080. [195] A. Binnetoglu, B. Demir, D. Akakin, et al., Bacterial cellulose tubes as a nerve conduit for repairing complete facial nerve transection in a rat model, European Archives of Oto-Rhino-Laryngology 277 (2019) 277–283, https://doi.org/ 10.1007/s00405-019-05637-9. [196] Z. Wu, S. Xie, Y. Kang, et al., Biocompatibility evaluation of a 3D-bioprinted alginate-GelMA-bacteria nanocellulose (BNC) scaffold laden with orientedgrowth RSC96 cells, Materials Science and Engineering: C 129 (2021), https:// doi.org/10.1016/j.msec.2021.112393. [197] Z. Wei, F.F. Hong, Z. Cao, et al., Situ Fabrication of Nerve Growth Factor Encapsulated Chitosan Nanoparticles in Oxidized Bacterial Nanocellulose for Rat L. Melro et al. Applied Materials Today 46 (2025) 102858 41