Advances in Biomedical and Pharmaceutical Applications of Functional Bacterial Cellulose-Based Nanocomposites
Advances in Biomedical and Pharmaceutical Applications of Functional Bacterial Cellulose-Based Nanocomposites
Advances in Biomedical and Pharmaceutical Applications of Functional Bacterial Cellulose-Based Nanocomposites
Carbohydrate Polymers
journal homepage: www.elsevier.com/locate/carbpol
Review
a r t i c l e
i n f o
Article history:
Received 22 January 2016
Received in revised form 25 April 2016
Accepted 11 May 2016
Available online 14 May 2016
Keywords:
Bacterial cellulose
Bioengineering
Biomedical application
Composites
Nanocellulose
a b s t r a c t
Bacterial cellulose (BC) synthesized by certain species of bacteria, is a fascinating biopolymer with unique
physical and mechanical properties. BCs applications range from traditional dessert, gelling, stabilizing
and thickening agent in the food industry to advanced high-tech applications, such as immobilization
of enzymes, bacteria and fungi, tissue engineering, heart valve prosthesis, articial blood vessels, bone,
cartilage, cornea and skin, and dental root treatment. Various BC-composites have been designed and
investigated in order to enhance its biological applicability. This review focuses on the application of
BC-based composites for microbial control, wound dressing, cardiovascular, ophthalmic, skeletal, and
endodontics systems. Moreover, applications in controlled drug delivery, biosensors/bioanalysis, immobilization of enzymes and cells, stem cell therapy and skin tissue repair are also highlighted. This review
will provide new insights for academia and industry to further assess the BC-based composites in terms
of practical applications and future commercialization for biomedical and pharmaceutical purposes.
2016 Elsevier Ltd. All rights reserved.
Contents
1.
2.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331
1.1.
Biosynthesis of BC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331
1.2.
Effect of bacterial strain on the properties and production of BC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331
1.3.
Properties and biocompatibility of BC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332
Applications of BC and BC-based composites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333
2.1.
Antimicrobial and antiviral lm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334
2.2.
Wound healing, articial skin and skin tissue repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
2.3.
Cardiovascular system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338
2.3.1.
Articial blood vessels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338
2.3.2.
Cardiac prosthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339
2.4.
Ophthalmic applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340
2.4.1.
Articial cornea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340
2.4.2.
Retinal pigment epithelium substrate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340
2.4.3.
Contact lenses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341
2.5.
Application in skeletal systems, cartilage and endodontics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341
2.5.1.
Bone regeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341
2.5.2.
Cartilage, intervertebral discs and articial endocranium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341
2.5.3.
Meniscus implant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343
2.5.4.
Dental root canal treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343
2.5.5.
Ligament and tendon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344
Corresponding authors.
E-mail addresses: helder.santos@helsinki. (H.A. Santos), [email protected]
(T. Khan).
http://dx.doi.org/10.1016/j.carbpol.2016.05.029
0144-8617/ 2016 Elsevier Ltd. All rights reserved.
331
2.6.
3.
1. Introduction
Cellulose is the most abundant biopolymer on earth that is frequently obtained from the plant sources (Finkenstadt, 2005; Saxena
& Brown, 2012). It is the main structural component of plant cell
wall and has an extraordinary commercial reputation in paper, textile and pulp production units (Gandini, 2008; Huber et al., 2012;
Klemm, Heublein, Fink, & Bohn, 2005). Cellulose is also biosynthesized by some oceanic animals (tunicates), and thus called as
tunicin (Zhao and Li, 2014). Other major pathways for cellulose
production are in vitro enzymatic synthesis and chemosynthesis
from glucose derivatives. The most important pathway of cellulose production is through different microbes, such as algae, fungi
(Klemm et al., 2005) and various aerobic non-pathogenic bacteria
of the genera Agrobacterium, Sarcina, Rhizobium and Glucoacetobacter (formerly Acetobacter) (Khan, Park, & Kwon, 2007; Petersen and
Gatenholm, 2011; Shezad, Khan, Khan, & Park, 2010; Shoda and
Sugano, 2005).
In 1886, Brown reported bacterial cellulose (BC) for the rst
time as a sturdy gelatinous white pellicle on a liquid medium surface during the acetic fermentations (Brown, 1886a, 1886b). The
BC membrane was produced by Bacterium xylinum with a thickness about 25 mm (Brown, 1886a, 1886b). Later on, this bacterium
was renamed as Acetobacter xylinum (A. xylinum), then as Gluconacetobacter xylinus (G. xylinus) and presently it is known as
Komagataeibacter medellinensis (Matsutani et al., 2015; Yamada
et al., 2012; Yamada, 2014).
Although BC is produced in laboratories in small scale for
research, there are some commercial outlets for BC. Besides, traditional nata de coco (Iguchi, Yamanaka, & Budhiono, 2000), a
German company, Fzmb GmbH is considered one of the largest
producers of BC for cosmetics and biomedical applications (Keshk,
2014a). In addition, Xylos Co. in USA is a producer of Prima CelTM ,
a type of BC used for wound dressing. Other brands of BC include
Gengiplex and Bioll (Keshk, 2014a) used as physical barrier for
tissue regeneration. BC is also produced and used by many food
industries in Asian countries (Budhiono, Rosidi, Taher, & Iguchi,
1999; Ng and Shyu, 2004). Sony Corporation, Japan in association
with Ajinomoto, Japan and other rms fabricated the rst BC-based
diaphragm of audio speaker. Ajinomoto, Japan also sells wet BC
(Chawla et al., 2009; Czaja, Krystynowicz, Bielecki, & Brown, 2006).
1.1. Biosynthesis of BC
G. xylinus has been employed as model microbe for basic and
applied studies on BC due to its higher production yields and its
ability to consume variety of sugars and other compounds as carbon
source (Ross, Mayer, & Benziman, 1991; Saxena and Brown, 2012).
In laboratory, glucose is usually added to the fermentation medium
and the biosynthesis of BC takes place in four enzymatic steps: (1)
phosphorylation of glucose by glucokinase to glucose-6-phosphate,
(2) isomerization of glucose-6-phosphate to glucose-1-phosphate
by phosphoglucomutase, (2) conversion of glucose-1-phosphate
332
333
Zhongm
2011), and pig meniscus
Jiang
(Bodin, Concaro, Brittberg, & Gatenholm, 2007). BC showed better desired properties than paper points for dental applications
(Yoshino et al., 2013). In biosensor applications, BC-based devices
have shown less thrombogenic effects than commercial PVC-based
electrode (Badr, Abdel-Sattar, & Keshk, 2015) and more stability than the commercial Cuprophan membrane (Eisele, Ammon,
Kindervater, Grbe, & Gpel, 1994). Such characteristics are discussed in detail in the respective sections below.
Several studies have conrmed BC and BC-based composites as
biocompatible scaffolds for cell seeding. It has been shown that
different human cells, such as smooth muscle cells (SMC) (Petersen
and Gatenholm, 2011), chondrocytes (Svensson et al., 2005), broblasts, bone forming osteoblasts (Chen et al., 2009), human umbilical
vein endothelial cells (Jeong et al., 2010), Chinese hamster ovary
cells, mouse embryo broblast 3T3 cell (Moreira et al., 2009) and
human embryonic kidney (HEK) cells (Grande, Torres, Gomez, &
2009) can grow and proliferate in the presence of BC. FurBan,
thermore, Helenius et al. (2006) demonstrated the subcutaneous
implantation of BC in rats. Under microscopy, there was no giant
cells or brotic capsule after 12 weeks of implantation, which indicated no foreign body reaction. Furthermore, no swelling, redness
or exudation was found around the implantation site. BASYC prostheses in 5 mice and 7 (out of 8) pigs have shown one year and
90 days patency, respectively, with epithelization and development
of three distinct layers, i.e., the characteristic of natural blood vessel (Schumann et al., 2009). The biocompatibility and nontoxicity
of BC-based biomaterials have been discussed in details in other
sections below.
To incorporate additional properties, such as antibacterial
activity, wound healing capability, improved cell adhesion and proliferation, more even distribution of cells, enhanced mechanical
properties, good biocompatibility and biomimetic capabilities, BCbased composites have been introduced consisting of a matrix and
reinforcement materials (Shah, Ul-Islam, Khattak, & Park, 2013;
Torres, Commeaux, & Troncoso, 2012). In this case, BC provides a
matrix for housing various materials.
Keeping in view the abovementioned exclusive properties of BC,
the objective of this review article is to provide extensive overview
on the current trends of BC-based composites for applications in
biomedical and pharmaceutical elds.
334
Fig. 2. Summary of various biomedical and pharmaceutical applications of bacterial cellulose-based nanocomposites.
335
However, this toxicity was preventable by coating Ag0 nanoparticles with a biodegradable polymer. Likewise, Koohi et al. (2011)
reported the dermal toxicity (corrosion/irritation) being more terrible with smaller sizes of Ag0 nanoparticles than with the larger
ones. Samberg et al. (2010) demonstrated the porcine dermal biocompatibility along with the dose-dependent oedema formation
and hyperplasia with Ag0 nanoparticle deposition in supercial
layers of the stratum corneum (SC). Furthermore, dose-dependent
histopathological changes in Guinea pigs bone, heart and kidney
were also reported. Moreover, in vitro size-dependent cutaneous
penetration of gold (Au0 ) nanoparticles has been reported through
the Franz diffusion cell method using rat skin model (Sonavane
et al., 2008). The smaller Au0 particles penetrated deeper while the
larger ones accumulated mostly in the supercial epidermis and
dermis (Sonavane et al., 2008). No acute toxicity was found with
Au0 nanoparticles (Connor, Mwamuka, Gole, Murphy, & Wyatt,
2005), however, the lack of toxic effects on human health associated
with long-term use of such nanoparticles has not been yet established (Korani, Rezayat, & Bidgoli, 2013). On the basis of the toxicity
concerns of these nanoparticles, the BC-based antimicrobial lms
are still far away from practical biomedical applications.
Ex situ and in situ strategies have been employed to fabricate
stable nanocomposites containing copper (Cu0 ) nanollers, i.e.,
nanospheres and nanowires in cellulose matrices (Pinto, Daina,
Sadocco, Pascoal Neto & Trindade, 2013; Pinto, Neves, Neto &
Trindade, 2012). The antimicrobial activity of these nanocomposites was tested against K. pneumonia, and S. aureus, which revealed
that the morphology and chemical stability of Cu0 has a great inuence on the antimicrobial activity. The nanowires exhibited lower
antimicrobial activity due to the smaller reactive surface for oxidation. Similarly, the antimicrobial activity of nanollers with BC
was lower than that with PC. Although both BC and PC have the
same chemical structure, the difference in antimicrobial activity
may be attributed to a lower chemical stability of Cu0 nanostructures grown on PC bres than oxidation of those present in BC
bres. Despite having good antimicrobial activity, the Cu0 nanoparticle associated toxicity on somatosensory neurons of rat (Prabhu,
Ali, Murdock, Hussain, & Srivatsan, 2010) and liver of juvenile sh
(Wang, Long, Cheng, Liu, & Yan, 2014) is still unknown. Further
studies are needed to assess the release and toxicity of metallic
nanoparticles in the BC-based nanocomposites
The combination of BC with silver sulfadiazine (SSD) formed
an antimicrobial composite (BC-SSD), which was investigated for
antimicrobial activity (Luan et al., 2012). The BC-SSD membrane
showed signicant antibacterial activity against S. aureus, E. coli
and Pseudomonas aeruginosa (P. aeruginosa) (Luan et al., 2012; Wen
et al., 2015).
Recently, BC-montmorillonite (MMT) nanocomposite lms (BCMMT) were developed with potent antimicrobial activity (Ul-Islam,
Khan, Khattak, & Park, 2013). These nanocomposites were fabricated by impregnating BC sheets with 2 and 4% suspensions of
MMT, Cu-MMT, Ca-MMT and Na-MMT. The antimicrobial activities of the composites were evaluated against S. aureus and E. coli.
BC-Cu-MMT (2%) composites showed inhibition against the tested
bacteria. The antimicrobial activity of BC-MMTs (4%) was in the
order of BC-Cu-MMT > BC-Ca-MMT > BC-Na-MMT > BC-MMT.
336
Table 1
Various applications of bacterial cellulose-based nanocomposites as antimicrobial, antiviral lm and wound dressing system.
Co-former
Method
Finding
Reference
Deacetylated chitin
Chitosan
(2004)
Ciechanska
Post-synthesis loading
Post-synthesis loading
Post-synthesis loading
PVA + SA
PVA + Ag0
Post-synthesis loading
Post-synthesis, in situ by Tollens reaction
Ag0
Li et al. (2010)
MMT
PEG
Kaolin
Col1
Post-synthesis loading
Post-synthesis loading
Post-synthesis loading
During synthesis loading
Col
RGDC and gentamicin
Vaccarin
Post-synthesis loading
Post-synthesis chemical modication with RGDC followed by
covalent attachment of gentamicin
Post-synthesis loading
Cellulases
NAcG
Post-synthesis loading
In situ by genetically modied strains
SSD
Cu0
337
BC-Ch composites have good potentiality for biomedical applications as a wound dressing material and tissue engineering scaffold
because it is biologically active, less toxic, and appropriate for cell
adhesion, epithelialization and regeneration with good mechanical
properties.
Recently, SSD particles were impregnated with BC to produce
BC-SSD composite membrane. In addition to in vitro antimicrobial activity against S. aureus, P. aeruginosa and E. coli, BC-SSD
demonstrated good wound healing activity in burnt rat models. It
also exhibited good in vitro biocompatibility for epidermal cells.
Upon histological examination, epithelialization was developed
in BC-SSD treated wound (Luan et al., 2012; Wen et al., 2015).
Likewise, Rouabhia et al. (2014) developed a BC-based wound
dressing system with enhanced surface characteristics in terms of
better physiologic interaction with human cells, and the presence
of antimicrobial agents. BC was chemically modied with RGDC
(arginine, glycine, aspartic acid, cysteine) peptide and then gentamicin was covalently attached to the surface of the BC membrane.
BC-RGDC-gentamicin membranes were bactericidal against Streptococcus mutans, but non-toxic to human dermal brobalsts.. Thus,
BC-RGDC-gentamicin may be useful for multipurpose applications,
such as wound healing along with drug delivery.
BC nanocomposite lms in combination with poly(2hydroxyethyl methacrylate) was also prepared by an in situ radical
polymerization of 2-hydroxyethyl methacrylate (HEMA), utilizing
variable amounts of poly(ethylene glycol) diacrylate (PEGDA)
as cross-linker (Figueiredo et al., 2013). The thin lms obtained
showed superior properties to both BC (improved translucency)
and poly(2-hydroxyethyl methacrylate) (PHEMA) (enhanced
mechanical performance and thermal stability). BC-PHEMA
nanocomposites demonstrated no toxicity, good biocompatibility,
and cell adhesion and proliferation for human adipose-derived
mesenchymal stem cells. Therefore, these nanocomposites were
considered promising wound dressings with stem cell-mediated
tissue regenerative capability in biomedicine.
In order to achieve biocompatible wound healing material, BCpoly(ethylene glycol) (PEG) composite (BC-PEG) were fabricated
by submersing wet BC pellicle in aqueous solution of PEG (Cai and
Kim, 2009). After freeze-drying the product acquired a foam-like
structure, in which the PEG molecules were not only layered on
the surface of BC brils but also got penetrated into the BC bre
networks. It was noted that the presence of PEG decreased the
crystallinity of BC due to a change in the preferential orientation
of the plane during the process of drying. The thermal stability was
improved from 263 to 293 C due to the strong interaction between
PEG and BC. The biocompatibility of composite was assessed by
adhesion studies using 3T3 broblast cells, which showed cell adhesion and proliferation. The above study showed that the BC-PEG
composites were more biocompatible than BC.
Similarly, a single BC-kaolin (BC-K) composite system was
developed for wound healing purposes, whereby short-term
(kaolin) and longer-term (BC) wound healing mechanisms were
combined without any adhesives to bind the BC and kaolin (Wanna,
Alam, Toivola, & Alam, 2013). Ultrane kaolin particles with a size
distribution in the range of 50800 nm were added to the BC gel in
a specic weight percentage in order to produce slurries containing 5, 15 and 30% of BC (w/w). These slurries were then pressure
ltrated into BC sheets followed by drying at 80 C. The resultant
product is a combination of short and long term biomedical wound
dressing/healing materials. However, there is still a need for further
research in order to optimize the properties of BC-K with respect to
both blood clotting potential and uid/moisture ingress for better
wound healing.
BC as wound dressing system was also established by in situ
incorporating collagen type-1 (Col1 ) into the BC pellicle. This novel
biomaterial possessed antioxidant properties and was capable to
338
Fig. 3. SEM images of the (a) BC surface, (b) BC-Col composite surface, (c) cross section of BC and (d) cross section of BC-Col.
Reproduced with permission (Zhijiang and Guang, 2011), Copyright, John Wiley and Sons.
order to create a more optimal pH microenvironment for the preferred acid cellulases. It was demonstrated that with this approach,
the activity of the cellulases was retained, with an increase in glucose release from 30% (without buffers) to 97% from degraded
materials. An improved material degradation was observed using
simulated tissue padding and body uid (SBF) that mimics real
wound environment. Moreover, the tensile strength and extensibility of the materials was similar to human skin, particularly when
hydrated with saline water (Hu and Catchmark, 2011a). Yadav et al.
(2010) also biosynthesized biodegradable BC in vivo by incorporating NAcG through genetically engineered bacterial strains. Yielding
the harmless glucose as the degradation product, these composites may be ideal for many wound dressing and tissue engineering
applications for the bioresorbable purpose.
The studies described above deal with the possible application
of BC-based composites to control bacterial, viral infections and its
potential for wound dressing system, articial skin and skin tissue
repair, which are further summarized in Table 1.
(polyester) induce thrombosis and therefore are not suitable substitutes for smaller blood vessels with diameter less than 6 mm
(Saxena and Brown, 2012).
BC and its composites are excellent candidates for articial
blood vessel formation due to its non-toxic nature, purity, greater
tensile strength, ultrane brous network, foldability and moldability (Zang et al., 2015). In this context, the development of
BASYC represents a landmark in biomedical applications of BC.
The carotid artery (small diameter blood vessel) in ve mice was
replaced with BASYC , which demonstrated one year patency
(being open). Likewise, BASYC has proved (90 days) patency in 7
out of 8 pig prostheses. The prosthesis has shown epithelialization
and developed three distinct layered structure, the characteristic of a natural blood vessel (Schumann et al., 2009). It is worthy
to mention that besides articial blood vessels, BASYC alone or
loaded with a neuroregenerative drug has also exhibited promising
resultsin terms of innervation of tissues in animal models after neurosurgery (Klemm et al., 2001, 2005). Moreover, Brown et al. (2011)
fabricated BC-brin composites treated with glutaraldehyde (GLA)
(cross-linker) that well-matched the mechanical properties with
the natural small-diameter blood vessels. The time-dependent viscoelastic behaviour of BC-brin composites was similar to that of
the natural blood vessel (bovine coronary artery). These composites also showed tensile strength, modulus, stress-strain response
and mechanical properties similar to a small-diameter blood vessel.
However, the strain at breakwas much lower than that of natural
blood vessel. Furthermore, no literature has been reported for the
assessment of cell viability, particularly cytotoxicity.
A novel approach was also used through introduction of starch
of various particle sizes and parafn wax in a culture of G. xylinus for
the preparation of scaffolds having 3D network with controllable
microporosity (Bckdahl, Esguerra, Delbro, Risberg, & Gatenholm,
2008). The BC scaffolds obtained had different morphologies and
interconnectivity. In order to achieve microporous BC scaffold,
porogens were effectively removed and no residue was detected
in physicochemical analysis. The prepared scaffolds were seeded
with SMC, which proliferated on the surface and partly into the
scaffolds. Moreover, graphene oxide (GO) was added to BC forming bacterial culture media and novel BC-GO composite material
was formulated (Zhu, Li, He, & Duan, 2015). The GO nanosheets
were entrenched in the nanobers network of BC with hydrogen
bond interaction. BC-GO composite displayed a better biocompatibility than the individual corresponding items and stimulated the
cell proliferation. Due to these properties, BC-GO has the potential
applications in articial blood vessels. In the future, these scaffolds can be investigated for the proliferation, differentiation and
migration of endothelial cells, which may lead to the preparation of semi-synthetic or articial blood vessels. Likewise, Andrade
et al. (2010) demonstrated the potential of BC modied with cellulose binding module and adhesion peptide for articial blood
vessel. The modied BC was able to enhance endothelial cell adhesion and stimulate angiogenesis. In a recent report, Leito et al.
(2016) demonstrated good tensile and suture retention strength
of BC as small-caliber blood vessel. The BC grafts were surgically
incorporated to the hind limb femoral artery of domestic limb.
All BC grafts revealed good integration into the surrounding tissue
without any signicant brosis or external evidence of inammation. Upon histological analysis, a distinct three-layered structure
was found having cellular adhesion and inltration on both the
adventitial and luminal sides of the graft, and a larger BC central region without cell adhesion. After one month of grafting,
CD31 positive cells were observed on the luminal surface and were
believed to be endothelial or progenitor endothelial cells, which
drifted from the grafted femoral artery. A one month patency was
achieved with neo-vascularization and endothelialisation. However, the graft occluded due to thrombosis after 2 months of grafting
339
340
Table 2
Applications of bacterial cellulose-based nanocomposites in articial blood vessels.
Co-former
Method
Finding
Reference
Fibrin
Post-synthesis loading
Starch and
parafn wax
GO
During synthesis
loading
During synthesis
loading
Post-synthesis
modication
Cellulose
binding
domain
Cytotoxicity assays
Cell adhesion and cell viability assay
Table 3
Applications of BC-PVA composites in cardiac prosthesis.
Method
Finding
Reference
Thermal processing
method
Post-synthesis loading
Mohammadi 2011
During synthesis
loading, cross-linked
by glyoxal
Post-synthesis loading
Post-synthesis loading
During synthesis
loadinga
a
341
non-toxic and biocompatible properties (Ramirez, 2010). Collagen, mineralized by hydroxyapatite (HAp), constitutes a major
part of bone matrix (Petersen and Gatenholm, 2011). Guided bone
regeneration (GBR) is a medical practice, which prompts in vivo
re-growth of bone tissue by the use of osteopromoting llers and
membranes. Being collagen-like material, BC bres were used as
a basis for biomimetic HAp growth with the ultimate aim of fabricating ller materials for GBR (DeMello, 2012). BC bres were
phosphorylated with phosphoric acid and preconditioned with calcium (Ca+2 ) for nucleation of HAp. SBF enhanced the growth of
HAp. Over a period of 14 days, the BC-HAp maintained a Ca-to-P
ratio as high as 1.45 0.92, covering the standard of 1.67 for HAp.
Higher Ca-to-P ratios were detected on the pellicle surface suggesting the deposition of HAp crystals. The study indicated the potential
for formation of 3D-samples and a basis for further optimization
of BC-HAp scaffold for GBR. One of the biomimetic mineralization
pathways of BC has been depicted in Fig. 4 (Na et al., 2011).
Due to its osteoconductivity, HAp was used for the fabrication of
3D network-based nanocomposites with BC via biomimetic route.
This was achieved when phosphorylated BC was soaked in SBF,
which led to the formation of uniform HAp crystals (Wan et al.,
2007) with structural similarities comparable to biological apatite.
Furthermore, Shi et al. (2009) also synthesized BC-based calcium
decient carbonate containing HAp nanocomposites (BC-CaDHAp)
using a biomimetic mineralization technique. The CaDHAp in the
nanocomposites partially contained carbonate that resembled with
apatite (Ap) of natural bone. The study demonstrated that a 3D
network of BC offered a good template for the well-organized
deposition of BC-CaDHAp spherical particles (0.5 m), which were
composed of nanosized squama-shape Ap crystals. The BC-CaDHAp
nanocomposites therefore possess a great potential for BTE.
In another study, it was shown that tubular-shaped (T-shaped)
BC was a natural nanoscale brous hydrogel scaffold for BTE. The
freeze-dried T-shaped BC and its composites demonstrated aligned
nanobrous morphological properties (Favi, 2014). Moreover,
these were cytocompatible with equine-derived bone marrow
mesenchymal stem cells (EqMSCs). Both the T-shaped BC scaffolds
and its composites supported the EqMSCs adhesion, proliferation
and osteogenic differentiation. From this study, it was concluded
that the mineralized porous and oxidized T-shaped BC scaffolds
seem to have potentiality as a scaffold for bone regeneration. Similarly, BC-HAp nanocomposites scaffold were prepared using the
biomimetic approach and investigated the differentiation and proliferation of human bone marrow derived stromal cells (hBMSC)
on these nanocomposites (Fang, Wan, Tang, Gao, & Dai, 2009). The
hBMSC seeded on the BC-HAp nanocomposites showed improved
attachment, proliferation and differentiation as compared to BC.
Real-time reverse transcription polymerase chain reaction data
showed that the expression of molecular players for bone formation and regeneration was better in the nanocomposites group than
inBC. The alkaline phosphatase (ALP) activity and the expression of
ALP, bone sialoprotein, osteocalcin and osteopontin were all higher
for up to 7 days in hBMSC cultured on the nanocomposites as compared to BC in the absence and presence of osteogenic supplements
(dexamethasone, glycerophosphate and l-ascorbic acid). BC-HAp
nanocomposites scaffold displayed in vitro biocompatibility and
had the potential to be use in BTE. Thus, all the aforementioned
studies have demonstrated that BC based biodegradable scaffolds
have an excellent potential for GBR.
2.5.2. Cartilage, intervertebral discs and articial endocranium
Regardless of the recognized usage of the total joint replacement
to treat advanced articular cartilage degeneration, the component
loosening due to osteolysis and wearing limits the durability of
these particular prostheses (Dattani, 2007). BC and its composities
have been investigated as a substitute for the cartilage due to their
342
Fig. 4. FE-SEM images of (a) BC, (b) BC-PVP, (c) 5-PVP-HAp-BC, (d) 7-PVP-HAp-BC and (e) schematic synthesis of PVP-BC-HAp by biomimetic mineralization.
Reproduced with permission (Na et al., 2011), Copyright, Elsevier.
343
Table 4
Applications of BC-based composites in bone regeneration.
Co-former
Method
Finding
Reference
HAp
Post-synthesis
phosphorylation
Loading of HAp to BC
Ca-to-P ratio
DeMello (2012)
Biomimetic approach
hBMSC
Biomimetic
mineralization
Post-synthesis loading
Crystallinity
2+
Post-synthesis
chemical reaction
In vitro EqMSCs
Favi (2014)
Ca-to-P ratio
Better mineralization
Na et al. (2011)
HAp
Biomimetic
mineralization
Post-synthesis loading
Otoliths + collagen
Post-synthesis loading
Histological examination
Post-synthesis loading
Col1
Post-synthesis
cross-linking
Post-synthesis loading
Gelatine
Post-synthesis loading
Parafn wax
Loading during
synthesis
2-chloroN,Ndimethylethylamine
hydrochloride, glycidyl
trimethyl ammonium chloride,
and monochloro acetic acid
sodium salt
HAp + PVP
was 0. All these values were closer to that for a rabbit endocranium.
Moreover, the AE was not amenable to easy tear and off-clip during
the stitching via sutures.
and mechanical performance of BC can be further improved provided that the cell migration and control on the shape is not
affected.
344
345
Fig. 5. In vitro drug release proles (a) 1% (w/v) BSA and (b) 0.5% (w/v) BSA.
Reproduced with permission (Amin et al., 2012), Copyright, Elsevier.
Table 5
Applications BC-based composites in drug delivery.
Method
Drug
Finding
Reference
Post-synthesis loading
BSA
In vitro dissolution
Post-synthesis loading
BSA
Post-synthesis loading
followed by irradiation
Post-synthesis loading
followed by irradiation
Post-synthesis loading
SA
Post-synthesis loading
Insulin
Ibuprofen and
lidocaine
hydrochloride
Diclofenac sodium
Human epidermis
Human epidermis
346
Fig. 7. Drug loaded BC membrane (a) lidocaine hydrochloride, (b) ibuprofen (SEM), and drug permeation study from (c) lidocaine hydrochloride, (d) ibuprofen.
Reproduced with permission (Trovatti et al., 2012), Copyright, Elsevier.
drug release prole and ease of application indicated the potentialities of BC membrane for transdermal administration of different
type of drugs. These studies are summarized in Table 5.
2.7. Applications in bioengineering
2.7.1. Biosensors and bioanalysis
Recently, biosensors have attained an ample attention in the
eld of nanotechnology and medicines (Hasan et al., 2014). Such
biosensors have been developed to be used in diverse elds, such
as for applications in biotechnology, tissue engineering and regenerative medicine (Malhotra, Singhal, Chaubey, Sharma, & Kumar,
2005). Receptors, antibodies and enzymes have been extensively
used in biosensors and bioanalysis as biosensing elements (Kim
et al., 2011). These devices can check real-time biological signals in
vivo, such as the release of antibodies or proteins in response damaged tissue, infections, inammatory events, cardiac infarction or
muscular dystrophy. Thus, biosensors have the capability to inform
about the health-care complications in time and thus help in earlier
detection of disease and treatment in clinical settings (Giepmans,
Adams, Ellisman, & Tsien, 2006). Synthetic BC-Ag0 nanocomposites
have been reported to be used in bioanalysis as surface enhanced
Raman scattering (SERS) substrates using 2,2-dithiodipyridine and
thiosalicylic acid as analytes (Marques, Nogueira, Pinto, Neto, &
Trindade, 2008). The detection limits for the abovementioned analytes were much lower (104 moldm3 ) than the conventional
plant derived cellulose analogues. The BC-Ag0 nanocomposites
were used in bioanalysis of amino acids (l-histidine, l-glutamine
and l-phenylalanine). Moreover, one of the most frequent biosensor in use is for blood glucose monitoring (Khatun, Nurunnabi, Cho,
& Lee, 2012). Furthermore, Wang, Gao, Zhang, and Wan (2010)
and Wang, Li et al. (2010) fabricated nanocomposite between Au0
nanoparticles and BC nanobers (BC-Au0 ) as a source for amper-
347
Fig. 8. SEM images of BC-Au0 nanocomposites prepared at pH 2.5 for 1 h (a and b) and pH 11.5 (c and d). [PEI] = 1 gL1 , [HAuCl4 ] = 1 mM. The arrows in (a) and (d) indicates
Au0 nanoparticles and naked BC nanobers, respectively. The inset in (c) shows the high magnied image of dispersed Au0 nanoparticles.
Reproduced with permission (Zhang et al., 2010), Copyright, John Wiley and Sons.
348
was approximately 100 gL1 , which was about 13% and 45% greater
than that of suspended culture (SC) and IC in Ca-alginate matrix,
respectively (Kirdponpattara and Phisalaphong, 2013). IC in BC-Al
composites gave more stable repeated-batch ethanol productions
than those using IC in Ca-alginate matrix or SC. The improved
ethanol production was attributed mainly to the properly interconnected pore structure and water uptake ability that help in
substantial mass transfer during the production process. Using the
abovementioned methods, BC can be used for ethanol production,
which is a product of pharmaceutical and medical importance.
Similarly, BC-based composites can be used for immobilization of
various types of important enzymes and cells.
It can be concluded from the abovementioned literature that BC
nanocomposites can be employed for the immobilization of numerous enzymes, and may nd potentialities for applications in the
eld of biosensors, bioelectroanalysis and bioelectrocatalysis.
Acknowledgments
Dr H. A. Santos acknowledges nancial support from the
Academy of Finland (grant nos. 252215 and 281300), the University
of Helsinki Research Funds, the Biocentrum Helsinki, and the European Research Council (FP/20072013, grant no. 310892). Hanif
Ullah is thankful to Higher Education Commission of Pakistan for
granting the scholarship under HEC Indigenous Fellowship Program and for 6 months nancial support to be a visiting researcher
at University of Helsinki, under International Research Support
Initiative Program. The manuscript was reviewed for English
language/grammar by Tamas Kriska, PhD, Department of Pharmacology and Toxicology, Medical College of Wisconsin, USA. The
authors wish to thank Tamas for his assistance.
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