Do bacterial cellulose membranes have potential in drug-delivery systems?

Review

Do bacterial cellulose membranes have potential in drug-delivery systems? 1.

Introduction

2.

BC production

3.

BC general applications

4.

BC on modified drug-delivery

Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Universitaet Zuerich on 06/03/14 For personal use only.

systems 5.

Conclusion

6.

Expert opinion

Armando JD Silvestre†, Carmen SR Freire & Carlos P Neto †

University of Aveiro, CICECO and Department of Chemistry, Aveiro, Portugal

Introduction: Bacterial cellulose (BC) is an extremely pure form of cellulose, which, due to its unique properties, such as high purity, water-holding capacity, three-dimensional nanofibrilar network, mechanical strength, biodegradability and biocompatibility, shows a high potential as nanomaterial in a wide range of high-tech domains including biomedical applications, and most notably in controlled drug-delivery systems. Areas covered: This appraisal is intended to cover the major characteristics of BC, followed by the key aspects of BC production both in static and agitated conditions, and a glance of the major applications of BC, giving some emphasis to biomedical applications. Finally, a detailed discussion of the different applications of BC in controlled drug-delivery systems will be put forward, with focus on topical and oral drug-delivery systems, using either native BC or composite materials thereof. Expert opinion: The limited number of studies carried out so far demonstrated that BC, or materials prepared from it, are interesting materials for drug-delivery systems. There is, however, a large field of systematic research ahead to develop new and more selectively responsive materials and eventually to conjugate them with other biomedical applications of BC under development. Keywords: bacterial cellulose, controlled drug delivery, dermal delivery system applications, nanocomposites, oral delivery system applications Expert Opin. Drug Deliv. [Early Online]

1.

Introduction

Cellulose is the most abundant biological macromolecule on earth; it is mostly obtained from plants, where it represents the main structural element of cell walls, and has a high economic importance in the pulp and paper industry as well as in the textile sector [1-3]. However, cellulose is also produced by a family of sea animals called tunicates, some algae species and various aerobic non-pathogenic bacteria [1]. Despite the origin, cellulose is a linear homopolymer of b-(1!4)-linked D-glucopyranose units varying mainly on purity, degree of polymerization (DP) and crystallinity index [4]. Bacterial cellulose (BC) was first reported by Adrien Brown in 1886, who noticed the formation of a very strong white gelatinous pellicle on the surface of a liquid medium, while studying acetic fermentations, which could grow up to 25 mm thick. This membrane was generated by a bacterium, named Bacterium xylinum, later renamed Acetobacter xylinum and presently known as Gluconacetobacter xylinus [5,6]. It has been suggested that BC production is a mechanism used by bacteria to maintain their position close to the culture medium surface, where there is a higher oxygen content, and it also serves as a protective coating against ultraviolet

10.1517/17425247.2014.920819 © 2014 Informa UK, Ltd. ISSN 1742-5247, e-ISSN 1744-7593 All rights reserved: reproduction in whole or in part not permitted

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A. J. D. Silvestre et al.

Article highlights. .

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Bacterial cellulose (BC) can be efficiently produced under static and agitated conditions using benign bacteria from the genera Gluconacetobacter. BC shows a panoply of promising applications in nanocomposite materials. BC is a material with high potential for transdermal delivery systems, even when compared to conventional delivery systems. BC and derived nanocomposites show promising pHresponsive properties for applications in oral drugdelivery systems. The combination of BC with other polymeric matrices responsive to external/body stimuli and other modification approaches opens new perspectives for the design of tailored drug-delivery systems based on this natural biopolymer.

This box summarizes key points contained in the article.

radiation, prevents the entrance of enemies and heavy-metal ions, whereas nutrients diffuse easily throughout the pellicle [1,7]. Other bacteria species from the genera Gluconacetobacer, Sarcina and Agrobacterium, among others, have also been reported to produce BC [4]. Gluconacetobacter xylinus is a non-pathogenic, rod-shaped, obligate aerobic Gram-negative bacterium, which can produce relatively high amounts of BC from several carbon and nitrogen sources [4,8] and remains as the reference strain for research and commercial BC production [9]. G. xylinus are ubiquitous in nature, being naturally present wherever the fermentation of sugars takes place, as, for example, on damaged fruits and unpasteurized juices, beers, wines, etc. [8]. Recently, a G. sacchari strain has also been reported to produce BC with yields comparable to those obtained with G. xylinum using different carbon sources [10,11]. BC production starts with the production of individual b-(1!4) chains between the outer and plasma membranes of the cell. A single G. xylinus cell may polymerize up to 200,000 glucose molecules per second into b-(1!4)glucan chains, followed by their release outwards through pores in the cell surface [12]. BC chains then assemble into protofibrils, with ~2 -- 4 nm of diameter, which further gather into nanofibrils of ~3 -- 15 nm thick and 70 -- 80 nm wide [1,4,13,14]. Nanofibrils, in turn, entangle into a ribbon of semi-crystalline cellulose whose interwoven produces the BC fibrous network (Figure 1) [5,15-17]. 2.

BC production

BC can be produced in two distinct conditions, namely static and agitated conditions, which affect significantly the morphology and physical and mechanical properties of the final 2

material and therefore might be chosen depending on the intended applications [18]. Static production is the most common process, yielding a highly hydrated BC membrane (or pellicle) on the air--culture media interface (Figure 2) [7,19]. As BC is biosynthesized, a membrane with increasing thickness is produced and, since oxygen is required for bacteria to grow and for cellulose production, the mature BC membrane is constantly pushed down as new cellulose is produced on the culture media--air interface [13,16]. Under static conditions it is possible to obtain uniform and smooth BC products with defined shapes, which can be employed, for instance, in the biomedical field [20] as artificial blood vessels [16] or artificial skin [21]. Moldability of BC during biosynthesis and shape retention is a feature that may enable the development of designed shape products directly in the culture media [8,22], increasing its application range. Under agitated conditions BC is produced in the form of small pellets, fibers, irregular masses or spherical particles instead of membranes [23-25]. BC produced under agitated conditions is similar in terms of chemical composition to that obtained under static conditions but its nanofibers are curved and entangled with one another, in contrast with the highly extended ones attained under static conditions, resulting in a denser structure. In addition, agitated BC has a lower DP and crystallinity index, and higher water-holding capacity than the one obtained under static conditions [19]. 3.

BC general applications

BC shows unique properties, which allow applications to which plant cellulose is not suitable. First of all, it is produced in a highly pure form, completely free of hemicelluloses, lignin and pectins [4], making its purification a simpler process as compared to plant cellulose [9]. Native BC is a highly porous material with high permeability to liquids and gases and high water-uptake capacity (water content > 90%) [16], and these properties are due to BC ultrafine network structure composed of ribbon-shaped nano- and microfibrils (Figure 1) [4], which is some 100 times thinner than those of plant cellulose fibers. BC nanofibers show low density [26], and a high degree of polymerization (~ 2000 -- 6000) [4,27]. In addition, their large aspect ratio and high surface area lead to strong interactions with surrounding components, resulting, for example, in the retention of high amounts of water, strong interactions with other polymers and biomaterials, and fixation of different types of nanoparticles [20,28-32]. Furthermore, the nanometric scale of BC fiber diameter imparts them with a feature that is not achievable by vegetable fibers, that is, transparency, which can be quite attractive, if not determining for many applications. BC shows also a high crystallinity index (60 -- 80%) [1,4,33,34], high mechanical strength, with a tensile strength of 200 -- 300 MPa [1,4], and a Young’s modulus of up to 15 GPa [1,4,16,35], as well as high thermal stability (with a

Expert Opin. Drug Deliv. (2014) 11(7)

Do bacterial cellulose membranes have potential in drug-delivery systems?

Single microfiber

Ribbon


Glucan chain aggregate HO O HO

O OH

HO O

OH

O OH n OH

Figure 1. Scanning electron microscopy (SEM) of Gluconacetobacter xylinus, BC nanofibrillar network and schematic description of the formation of bacterial cellulose. Reproduced with permission from [9].

Figure 2. Images of a laboratory static culture (with a BC membrane well noticeable in air/culture medium interface) and a purified BC wet membrane produced in static conditions. BC: Bacterial cellulose.

decomposition temperature ranging between 340 and 370 C) [36], which is a quite important parameter regarding the sterilization procedures required for several biomedical devices and products. The resistance to in vivo degradation, due to the absence of cellulases in the human body, and low solubility of BC may be advantageous for some tissue-engineering applications [37]. Finally, the biocompatibility and non-toxicity of BC have also been assessed, through in vitro and in vivo studies. Several reports indicated that BC is not cytotoxic to Chinese hamster ovary, fibroblasts and endothelial cells, in vitro. Moreover, the in vivo toxicity of BC was investigated through its subcutaneous implantation into rats and the implants evaluation with respect to any sign of inflammation, foreign body responses and cell viability [38]. The results attained revealed no macroscopic signs of inflammation around the implants and allowed concluding that BC was beneficial to cell attachment and

proliferation [38]. Another approach to these tests is through the intraperitoneal injection of various doses of BC nanofibers into mice. After several days of exposure, blood samples were collected and the results showed no effect on the biochemical profile between the control and mice exposed to BC [37]. Furthermore, in a recent skin compatibility study it was demonstrated that BC membranes produce no skin adverse reactions, and that when loaded with a small percentage of glycerol produce a beneficial moisturizing effect [39]. One of the first uses of BC was in the production of a traditional Philippines dessert called ‘nata de coco’, where BC is produced from coconut water fermentation and then cut into small pieces and immersed in a sugar syrup [1,7,28]. BC has also been investigated as potential thickening, stabilizing, gelling and suspending agent in the food industry [9]. Other applications include the BC utilization as a support for enzymes and cells immobilization [40-42], the production


3


A.


B.

BC

BC-glyc-DCF

development of nanocomposite materials based on BC that try to explore its unique properties (particularly the nanometric dimensions and nanostructured network) in novel functional materials. The exploitation of these domains is out of the scope of the present appraisal, but an excellent overview of them can be taken from some recent revisions [20,29-32], with only a brief and illustrative highlight to the nanocomposites with proteins [53-66], hydroxyapatite [67-75] and silver nanoparticles [76-96] due to their high potential for biomedical applications (the former two) and antimicrobial materials (the latter). 4.

Figure 3. A. Visual image of a BC-diclofenac membrane with a good dermal adherence. B. SEM images of pure BC (left) and BC loaded with caffeine (right). Reproduced with permission from [100]. BC: Bacterial cellulose; SEM: Scanning electron microscopy.

BC on modified drug-delivery systems

BC has been used in several systems for drug delivery as such [97-105] or after some sort of physical [106,107] or chemical modification or else in the form of nanocomposite materials with diverse polymeric matrices [108-114]. Furthermore, these systems have been mainly tested in in vitro transdermal drug delivery, oral drug delivery and tissue engineering/ regeneration. Pure BC applications Applications in transdermal drug-delivery systems

4.1

of high-quality membranes for audio headphones [4,26] and the use as an additive to produce high-strength paper [7]. The properties of BC, mentioned above, such as the high water-retention capacity, mechanical strength and biocompatibility; encouraged also the development of several products for biomedical applications, especially as wound dressing [33], temporary skin substitutes [33] and vascular implants [8,43]. Biofill, a temporary human skin substitute for second- and third-degree burns [16], and Nexfill, a BC dry bandage for burns and wounds [27], are commercial examples of BC based products. Furthermore, the extremely favorable BC mechanical properties, biocompatibility, in situ moldability and porosity (that favors cell proliferation), are ideal to explore BC also as scaffold for tissue engineering, namely artificial blood vessels [16,44], artificial cornea [45], heart valve prosthesis [46], artificial bone [47] and artificial cartilage [48,49]. In a similar vein, BC has also been described as an excellent non-allergic biomaterial for the cosmetic industry where it can be employed as facial masks for the treatment of dry skin [50], in the formulation of natural facial scrub [51] or as a structuring agent in personal cleansing compositions [52]. Native BC membranes are likewise promising nanostructured drug-release systems, as will be discussed more in detail below, because of the straightforwardness and effectiveness of preparation of the drug-loaded BC membranes and the fact that they are only composed of a single layer. Their ability to absorb exudates and to adhere to irregular skin surfaces, along with their conformability, are additional crucial issues for several clinical situations. Apart from the direct applications mentioned above, in recent years, there has been a surge of research in the 4

4.1.1

The use of BC membranes for the transdermal delivery of a series of drugs, namely lidocaine [97,98], ibuprophen [98], caffeine [99] and diclofenac [100], has been systematically studied by the group of Freire and Silvestre. In all cases, after partial removal of its water content the BC membranes were loaded by absorption of a solution of the selected drug, containing a few percent of glycerol, followed by oven drying of the solvent. The addition of glycerol played an important role specially due to its plasticizing effect, turning the membranes more flexible and suitable for dermal application and also to facilitate their rehydration/swelling. Furthermore, glycerol is also known as humectant and plasticizer of the stratum cornea, having potentially a favorable influence on epidermal penetration of the drugs. The obtained membranes are very homogeneous and either white or semitransparent as illustrated in Figure 3A for a BC sample loaded with diclofenac. Scanning electron microscopy (SEM) analysis of the pure BC and BC loaded with the various drugs demonstrated that these are uniformly distributed in the surface of the membrane (Figure 3B), as no aggregates are formed. Furthermore, SEM analysis also revealed that in the cross-section the spaces are filled due to the presence of the drugs and glycerol. The swelling of BC-loaded membranes varied between 90% for BC-lidocaine [97,98], up to 1200% for BC-diclofenac [100], passing through 284% for caffeine [99]; these differences should be related to different hydrophilic characters of each drug. The drug release was governed in all cases essentially by diffusion and the maximum release was achieved at the end



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Figure 4. Drug permeation profiles across human epidermis for A: lidocaine; B: ibuprophen; C: caffeine; D: diclofenac, compared with conventional formulations. Reproduced with permission from [97,98].

of 40, 10 and 20 min for lidocaine, caffeine and diclofenac, respectively [97,99,100]. Finally, all four drugs were tested for in vitro skin permeation [97-100] and compared with conventional formulations (Figure 4). With the exception of ibuprophen, slower permeation rates are obtained, when compared to conventional formulations, which might represent an advantage for situations where a long-term release of the drug is required. BC membranes for wound dressing have also been loaded with silver sulfadiazine, a common drug used in wound treatments [103]. It was demonstrated that after impregnation, the membranes showed antimicrobial activity against Pseudomonas aeruginosa, Escherichia coli and Staphylococcus aureus, evaluated by the disc diffusion method, demonstrating that these membranes showed good wound-dressing properties and at

the same time are suitable carriers for the delivery of specific wound treatment drugs as silver sulfadiazine. Mueller et al. [104] studied the loading and release from BC membranes of bovine serum albumin (BSA) (as a model for proteins delivery). It was demonstrated once more that protein release was controlled by diffusion. It was also demonstrated that freeze-dried BC had a lower uptake capacity for albumin than pristine BC, which was proposed to be related to changes of the fiber network during freeze drying. Furthermore, by using a biologically active protein, luciferase, the authors demonstrated that the integrity and biological activity of proteins could be retained during the loading and release processes. Very recently, Pavaloiu et al. [105] studied the release of the antibiotic amoxicillin from BC membranes in pH conditions


5


aimed at mimicking intestine release. Using experimental design tools they have demonstrated that the key factors affecting the flux of the drug were its concentration followed by the glycerol content of the dried membranes. They have also used cetyl trimethyl ammonium bromide as a common topical drug-delivery permeation enhancer, but in this case it did not show any positive impact on the flux of the drug. The pH conditions used were also considered to mimic intestinal release.


4.1.2

Applications in oral drug-delivery systems

In another drug-release application domain, Amin et al. [101] reported the use of powdered BC to coat paracetamol tablets using a spray-coating technique. Coated tablets drug release was controlled in vitro. It was demonstrated that BC formed high-quality, uniform soft, flexible and foldable films (without addition of any plasticizer) comparable to those of Aquacoat ECD (an ethyl cellulose aqueous dispersion [115]). The in vitro drug-release tests revealed that all films stayed intact for 0.5 h, showing only a moderate swelling. Drug-release rate depended on the BC loading and therefore on film thickness and was slower than for the uncoated tablets. For the latter, complete release was achieved at the end of 100 min while for BC-coated tablets (200 µm film thickness) complete release was only observed at the end of 200 min. More recently, Huang et al. [102] studied the use of BC membranes as carriers for the in vitro controlled release of berberine (an isoquinoline alkaloid). Apart from transdermal controlled-release experiments, the membranes were also tested in simulated gastric (SGF) and intestinal (SIF) fluids, as well as in acidic and alkaline solutions. The results obtained showed that the drug was released at a slower rate in low-pH fluids (as SGF), intermediate rates in alkaline conditions and the highest ratios were observed with near-neutral conditions (as SIF), with the release curves being controlled by free diffusion. The pH-dependent behavior of the release rates is associated with the swellability of BC at different pH values, as confirmed by SEM analysis of the membranes, which controls the fiber interspaces and therefore the free diffusion rate [102]. In conclusion, in most studied systems with pure BC the controlled release of the tested molecules was controlled by diffusion, and, therefore, the release rates are only systematically affected by temperature and in a more pronounced way by pH conditions as this last variable affects drastically the swelling of the nanofibers and therefore the porosity of the material. The release rates can also be tuned if the porosity of BC is controlled physically or chemically and also if the hydrophilic/phobic character of the environment is altered. For example, Stoica-Guzun et al. [106] accessed the effect of electron beam irradiation on BC for transdermal drug delivery of tetracycline, showing that upon irradiation a considerable decrease in the diffusion was observed. Similarly, Olyveira et al. [107] have also shown that g-irradiated BC membranes produced lower diffusion rates than native ones, 6

most certainly due to a high pore density, while the main thermal and mechanical properties of BC were unaffected. These two studies demonstrate that the diffusion, which, as shown above, controls the release rates, can be tailored by exposing BC to ionizing radiations, opening a way of physically controlling those rates. 4.2

BC nanocomposite material applications Applications in oral drug delivery

4.2.1

Another strategy used to modulate the controlled drug delivery is the preparation of nanocomposite materials of BC and diverse polymeric matrices. One of the nanocomposite materials that has been studied in more detail is the BCpolyacrylic acid (BC/PAA) hydrogels, in which PAA is produced by electron beam irradiation-initiated polymerization, using different radiation doses [109-111]. The authors demonstrated that the swelling degree of the hydrogels grew with increasing radiation dose and decreasing ionic strength. The hydrogels were also shown to be pH sensitive with maximum swelling at pH 7. Swelling rates also increased with temperature from 25 to 50 C. Those BC/PPA nanocomposite hydrogels were tested as pH-responsive materials for controlled in vitro drug delivery using different loadings of BSA as model compound [111]. As for pure BC, the morphology and pore size of the material are tunable by the radiation dose. The swelling behavior of these hydrogels was demonstrated to be pH dependent, with values lower than 1000% below pH 5, reaching a maximum at pH 7 (above 2000%) and then decreasing down to values between 1500 and 2000% for pH 10. The drug-release profiles were also controlled using sequentially a SGF for 2 h and then a SIF, both without enzymes. It was observed that the release in SGF was much slower and at the end of 2 h only around 15% of BSA was released. On the contrary, in SIF, the release rate was considerably higher but decreased with the increasing radiation dose. For the lowest radiation doses a complete release was achieved at the end of 8 h, whereas for the highest doses it took 13 -- 14 h. The different release rates in SGF and SIG are a clear result of the effect of pH over the swelling rate of the materials, and demonstrate the pH-responsive behavior of the material toward drug delivery, which is remarkably similar to that reported above for native BC membranes. The use of BC composites with molecularly imprinted polymeric (MIP) matrices has been studied by Bodhibukkana et al. [116] for the enantioselective transdermal delivery of racemic propranolol. MIP matrices with specific binding sites were obtained by in situ copolymerization of methacrylic acid with ethylene glycol dimethacrylate as a cross-linker, in the presence of R- or S-propranolol as the template molecules and the latter was subsequently extracted. Although selective transport of S-propranolol through the MIP composite membrane was obtained, this was mostly due to the cellulose membrane with some ancillary contributory effect from the MIP layer. Enantioselectivity in the transport of propranolol




prodrug enantiomers was found, suggesting that the shape and functional groups orientation, which are similar to that of the print molecule, were essential for enantiomeric recognition of the MIP composite membrane. The enantioselectivity of S-MIP membranes was also shown when the release of propranolol enantiomers was studied in vitro using rat skin. More recently, Stroescu et al. have reported the use of poly (vinyl alcohol)-BC mono- and multilayer films for the controlled delivery of sorbic acid [108] and vanillin [112] (as a antimicrobial ingredient), demonstrating once more that the release rate is controlled by diffusion. In a different vein, Pandey et al. [117] used solubilized and dispersed BC to prepare a superabsorbent BC/polyacrylamide cross-linked hydrogels under microwave irradiation. The obtained nanocomposite hydrogels showed a swelling behavior with maximum swelling at pH 7, and a much higher swelling rate (~2300 -- 2500%) for hydrogels prepared with dissolved BC than that reported for those prepared with BC nanofibers (~900%). Furthermore, the materials prepared using solubilized BC also showed higher porosity, drugloading efficiency and release. Applications in tissue-engineering drug-delivery systems

4.2.2

BC-based materials have also been tested as drug-delivery systems in tissue engineering and regeneration. Mori et al. [113] studied the release of antibiotics from a bone cement containing BC. It was demonstrated that incorporating cellulose into the bone cement prevented compression and fracture fragility, improved fatigue life and increased antibiotic elution. Finally, the osteogenic potential of a BC scaffold coated with bone morphogenetic protein-2 (BMP-2) has been investigated as a localized delivery system to increase the local concentration of cytokines for tissue engineering [114]. It was demonstrated that BC had a good biocompatibility and induced differentiation of mouse fibroblast-like C2C12 cells into osteoblasts in the presence of BMP-2 in vitro. In addition, in vivo subcutaneous implantation studies revealed that BC scaffolds carrying BMP-2 showed more bone formation and higher calcium concentration than the BC scaffolds alone at 2 and 4 weeks, respectively, demonstrating that BC is a good localized delivery system for BMPs and would be a potential candidate in bone tissue engineering. 5.

Conclusion

The above-made overview clearly demonstrated that BC shows several unique properties (as water-holding capacity, mechanical strength among others, arising from its threedimensional nanofibrillar network) that impart it with a high potential in a wide range of applications, among which the biomedical area and drug delivery in particular deserve special attention. This revision clearly shows that as far as drug delivery is concerned BC demonstrated to have excellent properties, both in dermal and in oral delivery system

applications, which can be further tailored by considering BC physical treatments or its use in composite materials. 6.

Expert opinion

The current appraisal demonstrated that BC is a natural material, produced by non-pathogenic bacteria with high potential for application in drug-delivery systems, both for transdermal, oral and tissue-engineering applications, apart from other biomedical applications mentioned above. However, due to the limited number of studies available in the literature (only 18 studies were reported [97-114], of which 9 dealt with pure BC [97-105], 2 with physically modified BC [106,107] and 7 with nanocomposite materials with diverse matrices [108-114]), there is still plenty of scope to proceed with the investigation in this domain in a more systematic way. The interest in developing these studies is further reinforced by the demonstrated general biocompatibility and even the traditional use as food that eliminates almost completely any risk of adverse effects, as recently demonstrated for transdermal applications [39]. In several cases, and particularly for oral delivery system applications, it will be beneficial to study in parallel the drug-delivery behavior of BC produced under static conditions (where membranes need to be cut into small fractions suitable for oral intake) and under agitated conditions (where BC can be attractively available in sphere-like forms of tunable size), since the microscopic characteristics (e.g., porosity) of BC are not exactly the same. Furthermore, this comparison of the drug-delivery behavior of BC produced under static and agitated conditions should be considered not only for pure BC applications but also when other physical/chemical modifications take place. Provided that, as demonstrated in most studies reported above, drug-delivery rates were controlled by diffusion and the tailoring of release rates will be much dependent on the search for additional physical treatments, or chemical modification/compounding approaches that would enable a higher control over the diffusion, and particularly in a responsive way against external/body stimuli. In this vein some pHresponsive materials were already mentioned above [111], but it would be extremely interesting to have materials where the drug release would for example be triggered by body temperature raise above healthy values to prevent fever effects. The production of BC-based nanocomposites for drug delivery has been tested with several polymeric matrices, namely PAA [111], polyvinyl alcohol [108,112], polyacrylamide [117] and molecularly imprinted polymers [116]; however, the realm of polymers is so vast that many others should be tested, obviously taking into considerations specific interactions with target drugs that might modulate their release. Here, polyelectrolites can be of particular interest for their interaction with charged drugs. Ultimately, the affinity of the drugs toward the material could in the case of composites be further tuned using molecular imprinted polymeric


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matrices designed on demand for each specific drug and notably for enantiomeric differentiation. Finally, the direct chemical modification of BC nanofiber surface (instead of production of nanocomposite materials) has not been attempted before. This approach would also contribute to tune the hydrophilic character and therefore the drug’s affinity toward the fiber surface and therefore the delivery behavior, by appending simple chemical groups, or even polymers following sleeving approaches (e.g., [118]). In a more sophisticated way this approach can also be used to introduce groups with enhanced selectivity for specific drugs as, for example, cyclodextrines (e.g., [119]) that will tune the absorption and the release of the drug in a much more selective way. Although to the moment most studies were centered on dermal and oral delivery systems, the application of BC should also be more studied in other areas, particularly as a complement of other BC applications, that is, to conjugate the potential of BC in wound healing and tissue repair/ Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

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Declaration of interest The authors were supported by FCT (Fundac¸a˜o para a Cieˆncia e Tecnologia) and POPH/FSE for funding the Associate Laboratory CICECO (PEst-C/CTM/LA0011/ 2013, FCOMP-01-0124-FEDER-037271) and the projects EXPL/CTM-ENE/0548/2012 (FCOMP-01-0124-FEDER027691), EXPL/CTM-POL/1802/2013 (FCOMP-01-0124FEDER-041484). C.S.R. Freire was supported by FCT/ MCTES for a research contract under the Program “Investigador FCT 2012.” The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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Affiliation

Armando JD Silvestre†1 PhD, Carmen SR Freire*2 PhD & Carlos P Neto3 PhD †,* Authors for correspondence 1 Associate Professor, University of Aveiro, CICECO and Department of Chemistry, 3810-193 Aveiro, Portugal Tel: +351 234 370 711; E-mail: [email protected] 2 Principal Researcher, University of Aveiro, CICECO and Department of Chemistry, 3810-193 Aveiro, Portugal Tel: +351 234 370 711; E-mail: [email protected] 3 Full Professor, University of Aveiro, CICECO and Department of Chemistry, 3810-193 Aveiro, Portugal

Bacterial cellulose membranes as transdermal delivery systems for diclofenac: in vitro dissolution and permeation studies.

Bacterial cellulose and hyaluronic acid hybrid membranes: Production and characterization.

Protein adsorption behaviors of carboxymethylated bacterial cellulose membranes.

bacterial cellulose gel membranes for antibacterial wound dressing: investigation in vitro and in vivo.

Bacterial cellulose membranes used as artificial substitutes for dural defection in rabbits.

Production of bacterial cellulose membranes in a modified airlift bioreactor by Gluconacetobacter xylinus.

Biogenesis of bacterial cellulose.

Flexible conductive polypyrrole nanocomposite membranes based on bacterial cellulose with amphiphobicity.

Freestanding bacterial cellulose-graphene oxide composite membranes with high mechanical strength for selective ion permeation.

Creation of macropores in three-dimensional bacterial cellulose scaffold for potential cancer cell culture.

Synthesis and characterization of bacterial cellulose and gelatin-based hydrogel composites for drug-delivery systems.

A review of bacterial cellulose-based drug delivery systems: their biochemistry, current approaches and future prospects.

Counterflow affinity isotachophoresis on cellulose acetate membranes.

What more do we have to do?

What more do we have to do?

Do rats have orgasms?

MWCNTs-like protection layer formation on bacterial cellulose bundles as a potential material for suspended resonator.

Do bacteria have sex?

Bacterial cellulose of Gluconoacetobacter hansenii as a potential bioadsorption agent for its green environment applications.

What more do we have to do?

Bacterial Cellulose Ionogels as Chemosensory Supports.

Biocompatibility of bacterial cellulose based biomaterials.

Bacterial cellulose gels with high mechanical strength.

The Efficacy of Electron Beam Irradiated Bacterial Cellulose Membranes as Compared with Collagen Membranes on Guided Bone Regeneration in Peri-Implant Bone Defects.