Bacterial cellulose in biomedical applications: A review

International Journal of Biological Macromolecules 104 (2017) 97–106

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International Journal of Biological Macromolecules journal homepage: www.elsevier.com/locate/ijbiomac

Review

Bacterial cellulose in biomedical applications: A review Guilherme Fadel Picheth a , Cleverton Luiz Pirich a , Maria Rita Sierakowski a , Marco Aurélio Woehl a , Caroline Novak Sakakibara a , Clayton Fernandes de Souza b , Andressa Amado Martin a , Renata da Silva a , Rilton Alves de Freitas a,∗ a

Biopol, Chemistry Department, Federal University of Paraná, Curitiba, PR 81531-980, Brazil Chemistry Undergraduate Program, School of Education and Humanities, Pontifícia Universidade Católica do Paraná—PUCPR, Curitiba, PR 80215-901, Brazil b

a r t i c l e

i n f o

Article history: Received 12 April 2017 Received in revised form 16 May 2017 Accepted 30 May 2017 Available online 3 June 2017 Keywords: Bacterial cellulose Wound dressing Nanostructured films Nanocrystals Biomedical devices Ultra-thin films

a b s t r a c t Bacterial cellulose (BC) derived materials represents major advances to the current regenerative and diagnostic medicine. BC is a highly pure, biocompatible and versatile material that can be utilized in several applications – individually or in the combination with different components (e.g. biopolymers and nanoparticles) – to provide structural organization and flexible matrixes to distinct finalities. The wide application and importance of BC is described by its common utilization as skin repair treatments in cases of burns, wounds and ulcers. BC membranes accelerate the process of epithelialization and avoid infections. Furthermore, BC biocomposites exhibit the potential to regulate cell adhesion, an important characteristic to scaffolds and grafts; ultra-thin films of BC might be also utilized in the development of diagnostic sensors for its capability in immobilizing several antigens. Therefore, the growing interest in BC derived materials establishes it as a great promise to enhance the quality and functionalities of the current generation of biomedical materials. © 2017 Elsevier B.V. All rights reserved.

Contents 1. 2. 3.

4.

5. 6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 Production and properties of the bacterial cellulose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 BC applications in regenerative medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 3.1. BC composites in regenerative medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 3.2. Wound dressing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 Biosynthetic grafts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 4.1. Ophthalmic scaffolds and contact lenses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 4.2. Artificial blood vessels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 4.3. Skeletal and soft tissue grafts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 Bacterial cellulose-based diagnostic devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 Challenges and future perspectives for BC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104

1. Introduction Specially designed materials that regulate environmental conditions and increase cell adhesion, proliferation, migration and

∗ Corresponding author. E-mail addresses: [email protected], [email protected] (R.A. de Freitas). http://dx.doi.org/10.1016/j.ijbiomac.2017.05.171 0141-8130/© 2017 Elsevier B.V. All rights reserved.

differentiation, thereby, enhancing epithelialization rates and leading to faster wound closure processes represents the future of the regenerative medicine [1]. Such devices must possess important characteristics such as maintenance a moist wound environment, blood and exudate absorption, gas exchange, thermal insulation and low tissue adherence [2]. As a result of all such conditions, the engineering of an adequate interactive surface for cell-contact is the most critical step in the material’s development. The mediated interfacial contact plays an

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important role in the in vivo performance of biomaterials developed for wound healing [3], scaffolds [4], implants [5] and drug delivery systems [6]. The fate of all biomedical applications are determined by the specific cellular responses to the biomaterial; such interactions are mainly related to the material’s surface properties, such as wettability, topography, chemistry, surface charge and the presence of hydrophobic and hydrophilic character [7] that also contribute to the biocompatibility and mechanical properties of the biomedical device [8]. The bacterial cellulose presents important characteristics that combine several surface and macromolecular properties, which are essential for in vitro and in vivo applications (illustrated in Fig. 1). Consequently, BC is one of the most prominent materials for biomedical utilization. Thus, the aim of this review is to summarize the most recent developments of BC in biomedical applications.

Its successful in vivo utilization is mainly related to the absence of polymers or proteins during BC’s obtainment, presenting low endotoxin units (EU) levels as required by the United States food and drug administration (FDA) legislation for implants in direct contact with blood (<20 EU per device) [26]. Indeed, many BC-based materials are FDA approved to be used as tissue surgical sheets, meshes and reinforcing matrixes [27]. Those products also benefit from the lack of skin irritation and the slower coagulation rates ® ® of BC compared to other materials, such as Gore-Tex or Dacron [28]. Moreover, BC displays many advantages over cellulose obtained from different sources that might require mechanical [29], enzymatic [30], mixed [31] and expensive purifying process, some of them consisting of harsh acid, alkali and pollutant treatments [32]. Another important feature is that BC production requires simple, mild, semi-continuous static and low cost medium cultures and represents interesting alternatives for many developing industries [33].

2. Production and properties of the bacterial cellulose The BC consists of a translucent and gelatinous film, formed by an interwoven indefinite-length cellulose microfibrils, distributed in random directions. BC is produced extracellularly by the Gram-negative bacterial cultures of Gluconacetobacter, Acetobacter, Agrobacterium, Achromobacter, Aerobacter, Sarcina, Azobacter, Rhizobium, Pseudomonas, Salmonella and Alcaligenes. Among them, the most efficient BC producer belongs to the Gluconacetobacter genus [9]. During the biosynthesis, BC forms a pellicle constituted of a random microfibrilar network of cellulose chains aligned in parallel, interspersed among amorphous regions that occupies 90% of the material´ıs total volume [10] (Fig. 2). The BC chemical structure is composed by (1 → 4)-Danhydroglucopyranose chains bounded through ␤-glycosidic linkages. The material’s geometry is determined by the intra-molecular and inter-molecular hydrogen-bonding network, hydrophobic and van der Waals interactions, forming parallel chains (Cellulose Type I) [10]. Its supramolecular structure is named microfiber of cellulose [10]. The treatment of BC with 5–30 wt% of sodium hydroxide (mercerization process) forms an anti-parallel packing (Cellulose Type II), mainly stabilized by an intimate hydrogen bonding packing that generates a tridimensional arrangement of lower energy, much more stable than cellulose type I [11,12]. In particular, the mercerized BC’s spatial configuration generates a unique structure of randomly shaped nano-fibers with elevated Young modulus ® (118 GPa for a single BC filament – almost comparable to Kevlar and steel) [13]. Because of such reduced fiber diameter, BC possesses higher surface area than the cellulose obtained from vegetal sources and displays exceptional mechanical characteristics, with a stressstrain behavior that resembles those from soft tissue [9], [14]. As a result, BC is extensively utilized as reinforcement material for polymeric networks intended to anchor therapeutic agents or maintain the tensile shape-contour of scaffolds, while ensuring biocompatibility [15–17]. In fact, BC is a widely disseminate biomaterial in the academic and pharmaceutical industry, utilized as artificial skin [18], in vivo implants [19], artificial blood vessels [20], wound healing scaffolds [21], hemostatic materials [22] and electronic platforms (Table 1) [23]. All such applications are permitted for its high in vivo biocompatibility [24], elevated purity degree [3], flexibility, porosity and absence of contaminants (e.g. lignin and hemicellulose) [7]. Additionally, BC possesses exclusive properties such as high water holding capability, crystallinity, mechanical stability and hydrophilicity [25]. According to the fermentation process and conditions employed, BC might be molded to any form, size or thickness and, thus, can be precisely adapted for diverse applications [9].

3. BC applications in regenerative medicine BC membranes were introduced as an ideal wound dressing material because of its high in vivo biocompatibility [24], ability in providing an optimal three-dimensional substrate for cell attachment and a microfibrilar structure that provides flexibility, high water retention capability and gas exchange [34]. In addition, BC membranes maintain a physical barrier that reduces pain, bacterial infection and allow drug transfer into the wounded region [35,36]. Currently, the main commercial utilization of BC membranes is as wound dressing devices, commercialized under several trade® ® ® marks, such as Bionext , Membracell and Xcell that mimic the extracellular matrix to enhance epithelialization [37]. In fact, wound treatment with BC membranes exhibited a greater efficiency compared to conventional gauze or synthetic materials such ® ® as Tegaderm , Cuprophan or XeroformTM [27]. The BC membranes displays fast epithelialization and tissue regeneration rates in several wound-healing treatments, including diabetic foot wounds, chronic wounds and burns [28] (Table 1). All those materials lead to epithelialization even in second and third degree burns, without the necessity of daily exchange curative and provide the maintenance of a moist environment, exudate absorption and adaptation to the wound surface. Also, BC membranes facilitates the removal of necrotic residues [36]. They might be produced as moldable thin and transparent films to allow wound assessment along the treatment. Similar approaches employ BC sheets as a natural graft for the tympanic membrane in patients who suffered local perforation. These materials effectively occluded the wounded regions and also reduced ear pain, bleeding and hematomas compared to the current occlusion procedure with GelfoamTM [38,39] (Table 2). Nonetheless, BC has no activity against bacterial infection, a recurrent issue that normally occurs in chronic wounds and injuries of difficult healing. Moreover, attempts to adsorb drugs to treat infections or accelerate the epithelialization process often produces fast release rates, an unsuitable profile for the prolonged occlusion interval intended with the use of BC [40]. These and many others limitations inherent to the material’s structure represents important restrictions for its extensive application. 3.1. BC composites in regenerative medicine A major obstacle for an effective translation of BC to other clinical applications relies on the limited surface charge and lack of functional groups for anchoring of bioactive compounds with therapeutic or diagnostic potential.

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Fig. 1. Schematic illustration of bacterial cellulose biomedical applications.

Fig. 2. Schematic representation of bacterial cellulose organization [11].

Table 1 Commercial products, application and effects of bacterial cellulose biodevices. Brand ®

Biofill ® Gengiflex ® Bionext ® Membracell ® Xcell

Utilization

Treatment

Effects

Temporary skin substitute Dental implants, grafting material Wound-dressing Temporary skin substitute Wound-dressing

Ulcers, burns Recovery of periodontal tissues Ulcers, burns, lacerations Ulcers, burns, lacerations Venous ulcer wounds

Pain relief, reduced infection, faster healing, etc. Reduced inflammatory response and fewer surgical steps required. Pain relief, reduced infection, faster healing, etc. Fast skin regeneration Pain relief, reduced infection, faster healing, etc.

As a consequence of its supramolecular architecture, organized by the intimate hydrogen-bonding network, the material’s insolubility in water as well as in common organic solvents, hinders an efficient functionalization of active chemical groups while

preserving its biocompatibility and tridimensional structure [41]. Hence, an overall entrapment or grafting with several bioactive compounds with interest in tissue regeneration, such as drugs, polyelectrolytes or proteins, is hardly attained under mild condi-

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Table 2 Biomedical applications of bacterial cellulose composites. Application

Finding

Reference

Wound dressing Wound dressing Burn treatment Wound dressing Artificial cornea Cornea scaffold Artificial blood vessel Bone healing

BC membranes impregnated with Ag0 nanoparticles present antibacterial activity against S. aureus and E. coli. ® Chitosan-BC membranes presented faster epithelialization rates than BC or Tegaderm . BC membranes accelerated wound healing of second degree burns and lack of liver and kidney toxicity in rats. BC-Hyaluronan (0.1%) composite films presented higher regeneration rates than BC or gauze. BC/PVA composites as artificial cornea and eye bioengineering. BC-chitosan/CMC composites offer a more suitable interface for retinal pigment epithelium adhesion and proliferation Tubular BC materials were used as microvessels prosthesis BC/hydroxyapatite nanocomposites improved cellular adhesion and differentiation

[51,87] [88] [38] [54] [69] [70] [75] [89]

tions and represents a current challenge to fully adapt the potential of BC to more advanced therapeutic applications [42] (Table 2). To overcome these limitations, several cellulose functionalization techniques were developed to add interfacial charged groups, biorecognition, electrostatic potential or conductivity to, ultimately generate a more desired biomaterial for a widespread employment in the regenerative medicine. The sum of BC characteristics with the presence of specially designed chemical groups for the increase recognition of distinct targeted substrates aims the enhancement of cellular differentiation process, growth and treatment of many specific diseases [7]. To impart unusual physical-chemical and biological properties to BC, specially designed composites – comprising two or more individual materials – are constantly under investigation for the development of new biomaterials designed for tissue engineering [25]. Despite the BC’s chemical inertness towards pH variation and ionic strength, many studies succeeded to produce functional composites with applicability in a diverse range of diagnostic procedures [43] and biomedical approaches [10]. It has been shown that the BC microstructure is prone to suffer adhesion and adsorption with polysaccharides and proteins of varying polarity that enabled sequential functionalization [44] (Fig. 3). Also, several conjugation processes with chitosan [45], alginate [46], gelatin [47] and xyloglucan [44] have been reported. Such modifications are related to enhance the material’s properties, increasing molecular binding efficiency or hydration capability. For example, BC-pectin biocomposites exhibited a 20-fold increase in the compressive modulus and present higher resistance to stress and compression [48]. Also, BC containing cross-linked carboxymethyl cellulose present higher ibuprofen entrapping ability than non-modified BC, showing an interesting potential to act as drug-delivery systems [49]. Further modifications are intended to augment its porosity, in order to increase cellular communication or drug diffusion [7]. Therefore, the incorporation and generation of BC-based composites seeks the development of new materials for bioengineering that adds the advantages of BC microstructure with biologically active components. A general goal is to enhance its biomedical application in cases of bacterial infection prevention, wound healing, scaffolds and utilization as diagnostic sensors. 3.2. Wound dressing As previously described, BC is an excellent wound dressing device, eliminating exudates, avoiding infections and reducing local pain [36]. Nonetheless, BC conjugates containing distinct biomolecules can be synthesized to specific finalities, with adapted functionalities to improve tissue regeneration or enhance cellular adhesion. Such “tailored” materials display a paramount importance to the forthcoming generation of wound dressing devices and to the future regenerative medicine (Table 2). In this context, silver-containing BC (BC-Ag0 ) materials are among the most important composites already described and uti-

lized as wound-dressings for its bacteriostatic and bactericide effects. In such applications, BC acts as stabilizing agent to control particle nucleation, avoid aggregation and produce silver particles at the nanoscale [50]. Because of the surface porosity and hydrophilicity, the BC fibers play an important role in favoring the synthesis and stabilizing the nanoparticles. Although silver nanoparticles might cause cytotoxicity effects in some scenarios [51], the utilization of wound dressing materials containing silvernanoparticles presents great benefits to avoid and treat several kinds of bacterial infections, including E. coli, S. aureus, K. pneumoniae, B. subtilis and P. aeruginosa [52,53]. For all such properties, BC-Ag0 films are prominent candidates for wound dressing and burn therapeutics. The development of drug reservoirs, platforms and delivery systems might also benefit from the flexibility, macromolecular structure and the transparency of BC sheets to inspect and follow wound recovery. Many of such applications are based on in situ functionalization of the tridimensional BC nanofiber network with drugs and polyelectrolytes to control the drug diffusion kinetics. Distinct reports addressed the therapeutic efficacy of benzalkonium chloride [54], hydroxyapatite [55], Aloe vera [56] and vaccarin [57] loaded into the BC and used as wound healing. Although several studies succeeded to functionalize BC interfacial nanofibers with negatively [58] or positively charged groups [7], few provided practical utilization to such materials as biomedical devices or nanostructured drug delivery systems. Among them, in our research group Picheth et al. [59] produced oxidized BC membranes covered with chitosan and alginate layers (Fig. 4) that were able to sustain the release of epidermal growth factor in normal conditions and modulate its diffusion rate if the skin presents bacterial infection [40]. Such approach was only possible due to the negatively charged carboxyl groups introduced at the material´ıs interface that enabled a “layer-by-layer” (LbL) spray-assisted coating. This methodology is advantageous because it preserved the integrity and properties of BC nanostructure and allowed the adsorption of conformable and interfacial layers to control drug diffusibility [60,61]. Different methodologies also explored the BC’s potential to act as drug-reservoir in a wide range of clinical applications, from superficial skin infections to the treatment of cancerous tissues. Also, many drugs, such as tetracycline [62], diclofenac [63], ibuprofen [64] or doxorubicin [65] were successfully loaded into the BC structure and applied as transdermal or local delivery systems. Furthermore, an adapted sustained drug-release profile was modulated in several cases by introducing functional biomaterials (e.g. sodium alginate [65] or hydroxyethylcellulose [66], modifying drug content [62] or by irradiating BC with ␥-rays [67]. As a result, the utilization of conformable, transparent and thin BC sheets as drug reservoirs presents great potential to provide a more adequate environment to tissue repair and accelerate the process of epithelialization by combining the sustain and sensitive release of healing agents.

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Fig. 3. Schematic representation of the dry cast methodology to produce bacterial cellulose derived biocomposites with xyloglucan [45].

Fig. 4. AFM 4 × 4 ␮m topography images for oxidized bacterial cellulose membranes coated by the spray assisted layer-by-layer technique with (A) neat, (B) one, (C) two, (D) three and (E) four layers of sequentially deposited chitosan and alginate. The mean surface roughness values are indicate in the bottom [41].

4. Biosynthetic grafts 4.1. Ophthalmic scaffolds and contact lenses An interesting and innovative utilization of BC composites involves its ability to adhere and enhance the proliferation of the retinal pigment epithelium (RPE) and keratinocytes. In turn, BC grafts might potentially reduce the rejection rates of transplanted corneas and improve the treatment of eye diseases (e.g. age-related macular degeneration) by augmenting local neovascularization, diminishing side effects and surgical recovery intervals (Table 2). Hence, several BC biocomposites have been described to fully adapt the material’s properties for eye therapeutics. For example, Wang et al. [68] has increased the light transmittance and UV absorbance of BC by incorporating polyvinyl alcohol; Gonc¸alves et al. [69] demonstrated an improved RPE proliferation by increasing BC’s hydrophilicity with surface modification using chitosan and carboxymethyl cellulose. Also, distinct functionalizations are reported to produce tridimensional structures more adequate to cell growth to be employed as artificial cornea or relieve glaucoma [46], [25]. Thus, many related BC composites are able to support the growth of corneal stromal cells while preserving a full vision to the patient; these materials present a great potential to be used as eye scaffolds and replace the less biocompatible poly(methyl)methacrylate (PMMA) or hydroxyapatite systems currently utilized in the clinic [70]. BC also offers a great bioengineering potential to eye-related diseases; several methodologies of BC pressing have been developed to generate convex shapes that can be utilized in the production of

stable contact lenses for the correction of presbyopia, astigmatism, hyperopia and myopia [71,72]. Contact lenses BC based might be loaded with drugs to maintain adequate concentrations during the treatment of eye-infections and allergies; this issues was recently addressed by Cavicchioli et al. [73] that described the incorporation of ciprofloxacin/␥cyclodextrin complexes into the BC structure prior to contact lenses pressing. Therefore, contact lenses generated from BC present a great prospect to be used as wound dressing after eye surgery, replace antibiotics eye drops or ameliorate the recovery of ocular burns. 4.2. Artificial blood vessels BC can be also utilized to overcome reconstructive problems associated with trauma (e.g. tympanic membrane perforation and Dura mater replacement), degenerative process (e.g. cartilage replacement) or vascular diseases (e.g. atherosclerosis). As BC can be molded to very different shapes during its synthesis and generate an optimal substrate for cell attachment and proliferation, it has been employed in the development of several synthetic prosthesis over the last 15 years (Table 2). It has been shown by Klemm et al. [74] that BC is an excellent candidate in the replacement of atherosclerotic coronaries as artificial vessels, presenting enough moldability and similar mechanical properties to small diameter blood vessels (<5 mm). The developed ® material (BASYC ) was successfully implanted in the carotid arteries of rats and pigs, showing long-term stability while maintaining the bypass unobstructed for prolonged periods (3 months) [75].

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Fig. 5. Schematic representation of cellulose sialylation and subsequent regeneration through acid hydrolysis [95].

Fig. 6. Schematic representation of cellulose thin film carboxylation process mediated through TEMPO reaction. Once carboxylated, the BC films act as sensitive substrates to anchor polysaccharides or antibodies in a QCM-Real time follow up chamber. Adapted from Picheth et al. [60] and Pirich et al. [103].

Comparative studies have shown its advantage over commonly used materials for vascular grafting (PET and ePTFE), in which BC exhibited slower thrombin generation at the surface [76]. The replacement of atherosclerotic blood vessels with BC derived composites might became more beneficial as new mate-

rials exhibit improved properties; this is the case for blends of BC nanocrystals with PVA, which demonstrated enhanced tensile strength, low cytotoxicity and ameliorated the suture retention offered by the material, an important characteristic to maintain their long-term integrity [77].

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Other composites especially designed to improve cellular adhesion and avoid complement activation are described by grafting polyethylene glycol (PEG) chains into the BC structure. Such derived materials, published by our research group, have exhibited improved hydrophilicity as the efficient PEG coverage forms a “brush” layer that dramatically reduced the water contact angle – more than 50% – with dependency on the PEG molar mass [78]. A similar PEG functionalization demonstrated enhanced adhesion and biocompatibility towards 3T3 fibroblast cells [79]. Thus, the development of more hydrophilic BC composites present an unparalleled potential to be utilized as artificial blood vessels implants, coat cardiovascular stents to prevent bacterial adhesion or be utilize as heart valves. 4.3. Skeletal and soft tissue grafts The tridimensional structure of BC has been also explored in guided bone regeneration. Bone tissue consists of a solid matrix of inorganic calcium phosphates (e.g. hydroxyapatite and tricalcium phosphate) and collagen that engulfs osteoblasts, osteocytes and lining cells [80]. Patients that undergone trauma or suffer of bone diseases usually require biocompatible grafts to fill the defected area and also induce tissue regeneration. As autologous or allogenous bone transplantation present a great risk of rejection, pathogen transmission and exist in limited shapes or sizes, their artificial replacement with BC configures as an interesting therapeutical choice. Pure BC membranes are currently used as artificial substituent of the Dura mater membrane damaged in patients who suffered surgical procedures or trauma. Recent reports describe the BC’s membrane capability in repairing Dura mater defects in rabbits, avoid adhesion to brain tissue and generate lower inflammatory response compared to commercial Dura mater substituents ® (NormalGEN ) [81]. Furthermore, BC substituents can be easily sutured under neurosurgery conditions and potentially improve the post-operative healing period [82]. In fact, many BC composites intended for bone regeneration were described to enhance the osteogenic potential and lead to faster healing rates. Particularly, surface phosphorylated BC with increased porosity was studied by many authors for its ability in forming complexes with calcium, increasing mineralization rates during the bone regeneration processes and augment the migration of osteoprogenitor cells [83,25,84]. All such applications are based on the similarity of BC fibres with collagen; hence, its mineralization with hydroxyapatite is proposed to mimic the bone matrix in diverse fillers and bone reconstitutes [80,17]. Such BC-based bone grafts might be implanted to fill bone defects and provide long-term support to the wounded region without need of replacement. Nonetheless, more recent reports have employed different strategies to therapeutically stimulate natural bone regeneration. Among them, Hu et al. [85] describes the development of BC-calcium phosphate composites loaded with cellulosic enzymes; the biomaterial is able to locally deliver calcium phosphate and maintain a viable substrate for mouse embryo preosteoblastic cells (MC3T3-E1) growth before undergo biodegradation by the cellulose enzyme, thus acting as a temporary bone substituent [85]. 5. Bacterial cellulose-based diagnostic devices Recent approaches have displayed the potential of cellulosic fibers in replacing polymeric materials used as supports for diagnostic finalities [86]. In fact, a cellulose derivative, nitrocellulose, has long been utilized as an anchoring substrate for antibody conjugation in diagnostic assays, though its low mechanical strength,

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flammability and affinity towards all kinds of proteins (thus, causing non-specific adsorption) represents severe limitations as a platform for immunoassays [87]. Hence, due to its mechanical properties, surface area, stability and high purity degree, BC has appeared as a suitable candidate to replace the current interfaces of related biosensors. To this end, BC model surfaces with known homogeneity, morphology and thickness were assembled on top of piezoelectric sensors with nanoscale precision [59]. Such model surfaces might be prepared as ultra-thin films and deposited over several substrates [88,89], making possible the utilization of sensible surface recognition and evaluation techniques, such as quartz crystal microbalance (QCM), ellipsometry, atomic force microscopy (AFM), X-ray photoelectron spectroscopy (XPS) and surface plasmon resonance (SPR). In order to generate amorphous depositions of thin BC films without contaminants, a model of trimethylsilylated cellulose initially described by Schaub et al. [90] attracted a great interest. This process involves the dissolution of cellulosic fibers in dimethylacetamide/lithium chloride and a subsequent chemical modification with hexamethyldisilazane, to render the product soluble in organic solvents (such as chloroform and toluene). After the deposition process and solvent evaporation, the hydroxyl groups are reconstituted through a simple-step acid hydrolysis (Fig. 5), generating a cellulosic surface without contaminants [91]. Distinct methodologies of BC immobilization might also be employed, such as the direct deposition of BC nanocrystals by spin-coating; this process is usually applied to provide an active tridimensional structure with high surface area to anchor greater amounts of antibodies or other molecules of interest [92]. In summary, phenomena such as cellulose surface interactions with polyelectrolytes [93], enzymatic digestion [94] and protein immobilization [95] might be better understood and rapidly translated into the clinical practice. These materials also allow the study of interactions, morphological alterations and functionalization suffered by BC [96,97]. The utilization of BC ultra-thin films configures important and practical applications to several biomedical devices intended for cellular growth screening [98] – a tool to evaluate tissue engineering potential – adsorption of antibodies, enzymes, viruses and polyelectrolytes intended to the development of diagnostic sensors [99,59] (Fig. 6). Indeed, BC nanocrystals have demonstrated the capacity to anchor high amounts of IgG for the specific detection of dengue viruses in plasma samples; particularly, this system demonstrated a reliable detection screened by QCM with or devoid of dissipation monitoring in a costless and fast procedure compared to the common diagnostic tools currently utilized (Fig. 7). A novel application for the study of cell-signaling mechanisms, with potential diagnostic for many diseases, was recently reported [100]. The authors have produced BC films containing graphene oxide able to collect or transmit physiological signals in a cell culture medium. Hence, bacterial growth, tumor migration or other specific cell communication pathways may be in vitro rapidly detected. Such related systems also present the ability to select potential substrates for scaffold engineering and related biosensors. Another interesting approach describes the ability of chemically modified wound dressings to detect pathogens or endogenous enzymes – in particular, those that may prevent a fast healing such as esterases and lipases – once applied over the wounded area. Derikvand et al. [101] describes the development of BC sheets conjugated with 5(6)-carboxyfluorescein-tetraethylene glycol-azide (FTA) via click chemistry, which, once cleaved by esterases emit a specific fluorescence that is easily detectable by benchtop illuminators [101]. Such versatile materials may be readily extended to

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Fig. 7. (A) Immunochip assembly process on bacterial cellulose nanocrystals followed by quartz crystal microbalance (5th overtone). (B) AFM topography and phase images obtained before (top) and after (bottom) the immobilization of IgG against dengue [103].

detect wide range of specific biomarkers for direct in vivo diagnosis of inflammatory processes. As a result, the study and knowledge about BC interfacial interactions presents the potential to produce advanced materials able to act as pure, low cost, highly sensible and portable platforms for multi or specific diagnostic materials [102]. Although any application is presently commercialized, all presents great prospects. 6. Challenges and future perspectives for BC Bacterial cellulose stands out as an indispensable and versatile biomaterial to the future regenerative medicine for all the practical and innovative applications in tissue engineering and wound repair. The wide range of BC biomedical uses are supported by the easiness in production, lack of contaminants and the ability on modulating the material’s features during synthesis – such as crystallinity index, aspect ratio and morphology to perfectly fit the final application requirements. Future applications of BC are already envisioned in the pharmaceutical and cosmetic industry to act as (1) emulsion and hydrogel stabilizers with the intent in reducing the utilization of surfactants in Pickering emulsions, (2) enzyme and biomolecules immobilization for enhanced activity and higher stability in vivo, (3) as drug-delivery systems to ameliorate drug uptake by targeted cells, (4) anchoring of immunoglobulins and translation as low cost and portable devices for nano-engineered diagnostic sensors and (5) as a smart artificial skin or wound regeneration therapies. Altogether, BC offers an inestimable matrix in the development of high-tech bio-platforms to diagnose and treat a wide variety of diseases. Acknowledgments We acknowledge the Brazilian funding agencies CNPq (Conselho Nacional de Pesquisa) and Rede Nanobiotec/Capes-Brazil for financial support. References [1] C. Lucchesi, B.M.P. Ferreira, E.A.R. Duek, A.R. Santos, P.P. Joazeiro, Increased response of Vero cells to PHBV matrices treated by plasma, J. Mater. Sci.: Mater. Med. 19 (2) (2008) 635–643. [2] J.S. Boateng, K.H. Matthews, H.N.E. Stevens, G.M. Eccleston, Wound healing dressings and drug delivery systems: a review, J. Pharm. Sci. 97 (8) (2008) 2892–2923.

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