Over the past decade, there has been a strong growing interest in using several forms of chitosan, more
specifically nanofibers, for various biomedical applications. Chitosan has several impressive biological
characteristics including but are not limited to its great biocompatibility and biodegradability, anti-bacterial
properties, and cytocompatibility. In order to create nanofibers from this natural polymer, electrospinning has been
widely used as the most effective technique to produce a stable structure. Overtime, a number of challenges have
been overcome through the development of mechanically and structurally intact, biocompatible and multi-functional
nanofibers. The recent progress of the nanofibrous structure of chitosan and their biomedical applications in tissue
engineering, drug delivery, wound dressing, and antimicrobial are discussed.
Chitosan is an N-deacetylated product of chitin, a helical
polysaccharide macromolecule found in the exoskeleton of crustaceans
such as crabs, shrimp, insects, and other arthropods and is the second
most abundant natural biopolymer after cellulose. Both chitin and
chitosan have shown to have remarkable biological properties such as
bioresorbable degradation products, hydrophilicity, biocompatibility,
cellular binding capability, and acceleration of wound healing which
accounts for their wide variety of applications in food, cosmetic,
biomedical, and pharmaceutical industries [1]. Commercially, chitosan
is produced by exhaustive deacetylation of chitin with concentrated
solution of sodium hydroxide. Alternatively, a controlled and mild
method has been developed by using chitin deacetylase, an enzyme
that catalyzes deacetylation of N-acetyl-D-glucosamine residues of
chitin in to D-glucosamine residues of chitosan [2,3]. Once the degree
of deacetylation (DD) for chitin reaches approximately 60 to 70%,
it is referred as chitosan [1,4]. Figure 1 shows the multistep process
involved to obtain chitin from crab and shrimp shells, and comparative
chemical structures of chitin and chitosan.
Figure 1:Illustration of multistep process involved to convert crustacean’s
shells such as crabs, shrimps, lobsters etc., into chitin. Chemical structures
show enzymatic conversion of N-acetyl-D-glucosamine residues of chitin into
D-glucosamine residues of chitosan during deacetylation process.
The presence of primary aliphatic amines in the chemical structure
of chitosan makes this polymer distinct from other commonly available
polysaccharides such as cellulose, hyaluronic acid, alginate, dextran,
etc. The primary aliphatic amines of chitosan can be protonated under
acidic conditions (amine pKa is 6.3) which makes them cationic
polyelectrolyte [5]. The cationic nature of the polymer allows it to
become water-soluble after the formation of carboxylate salts, such as
formate, acetate, lactate, malate, citrate, glyoxylate, pyruvate, glycolate,
and ascorbate, etc. Important information of chitosan’s physical and
chemical properties can be found in the several review articles and
American Standard Testing Materials (ASTM) standard guides and in
the U.S. Pharmacopoeia (USP) [6,7].
Chitosan has many versatile properties which make it an excellent
excipient in controlled release formulations including non-viral
vectors for DNA-gene and drug delivery, and imaging applications
[8-11]. Chitosan has been prepared with a variety of different shapes,
geometries, and formulations that include liquid gels, powders, beads,
films, tablets, capsules, microparticles, sponges, textile fabrics, and
inorganic composites [12]. In each preparation chitosan is either physically associated or chemically cross-linked to form stable hydrogel
networks. Hydrogels are high water content materials prepared from
cross-linked polymers that are able to provide sustained, local delivery
of a variety of therapeutic agents, encapsulation of cells and proteins in
bio-friendly environment [13]. The advanced development of chitosan
hydrogels has led to new drug delivery systems that release their payloads
under varying environmental stimuli. In order to satisfy the requisite
features of a hydrogel, the chitosan polymer network must satisfy two
conditions: (1) inter-chain interactions must be strong enough to form
semi-permanent junction points in the molecular network, and (2) the
network should promote the access and residence of water molecules
inside the polymer network. Figure 2 shows the schematics of four
major physical interactions (ionic, polyelectrolyte, interpolymer
complex, and hydrophobic associations) that lead to hydrogel network
formation in chitosan [13-14]. There are many recent reviews surveying
the hundreds of papers related to chitosan processing and geometries
for various applications, but little information is available on nanofiber
processing of chitosan and their applications.
Figure 2:Schematic representation of chitosan based hydrogel networks
derived from different physical associations: (a) networks of chitosan formed
with ionic molecules, polyelectrolyte polymer and neutral polymers; (b)
thermoreversible networks of chitosan graft copolymer resulting semi solid
gel at body temperature and liquid below room temperature. (from ref [13]
with permission).
Polymeric nanofibers are of great scientific and technological
interest because of their wide-range of applications in biomedicine
and biotechnology [15-17]. Once polymer fiber materials began to be
created in the diameters of submicrons to few tens of nanometers, they
were referred to as nanofibers. In comparison to conventional large
diameter fibers, they have larger surface area to volume ratio, flexibility
in surface functionalities, and superior mechanical performance
compared with any other known form of the material used [18].
These outstanding properties make the polymer nanofibers optimal
candidates for many important applications such as tissue engineering scaffolds, wound dressing materials, therapeutic drug delivery devices,
filtration devices, etc. A number of manufacturing processes have been
explored to fabricate nanofibers which include drawing [19], self–
assembly [20], template-directed synthesis [21], and phase separation
[18,22]. Drawing is a process that is very similar to dry spinning in the
fiber industry, having the ability to produce long single nanofibers oneby-
one. Self-assembly is a process in which individual, pre-existing
components organize themselves into desired patterns and functions.
For template-directed synthesis, a nanoporous membrane is used
as a template to make nanofibers of solid (fibril) or hollow (tubule)
shape. Phase separation consists of dissolution, gelation, and extraction
using an alternate solvent, freezing, and drying resulting in nanoscale
porous foam. Unfortunately, all these techniques have substantial
disadvantages such as high time consumption, low cost effectiveness
and noncontiguous fiber formations etc.
Electrospinning: A Fascinating Technique For Nanofiber
Fabrication
Electrospinning is a fastest growing trend in the production
of fibers in laboratory to industrial scale [23-26]. Recently, these
techniques have become popular due to their ability to produce various
classes of ultrafine fibers such as polymer, ceramics, metals, composite
etc., with diameters in the range several micrometers down to tens
of nanometers. An electrostatic field is created between a syringe tip
holding electrospinning fluids (e.g. polymer solution or melts) and a
collector of good conductance so that spherical shaped droplet at the end of the syringe tip turned into a conical shape, i.e. Taylor cone. Once
the electric field goes beyond a threshold value a charged fluid jet is
ejected from the tip of the cone. If the molecular entanglements in the
fluid are sufficiently high, stream breakup does not occur (if it does,
an electrospray droplet is formed) and a charged liquid jet is formed.
As the jet dries in flight, the charge migrates to the surface of the fiber.
The jet is then elongated by a whipping process caused by electrostatic
repulsion initiated at small bends in the fiber, until it is finally deposited
on the grounded collector. The elongation and thinning of the fiber
resulting from this bending instability lead to the formation of ultrafine
fibers [27-29]. If polymer solution is used as electrospinning fluid, the
twisting and bending of the jet generates highly stretched polymeric
fiber with simultaneous rapid evaporation of the solvent. Polymer and
solution properties such as molecular weight, viscosity, conductivity,
and surface tension are very important parameters to control the fibers
size and morphology. Some other parameters which can change the
electrospinning process are applied voltage, tip-to-collector distance,
feeding rate, etc [23-26].
Two of the most fascinating characteristics of polymeric nanofibers
are the very large surface area-to-volume ratio and high porosity with
very small pore size. For these reasons, electrospun nanofibers have
shown to be promising candidates for biomedical applications such as
tissue templates, medical prostheses, artificial organ, wound dressing,
drug delivery, and pharmaceutical composition [30-35]. Electrospun
nanofibers of various biopolymers, both synthetic and natural origin
have been widely used for these applications. Among the degradable
synthetic polymers, poly (lactic acid), polycaprolactone (PCL), and
poly (D,L-lactide-co-glycolic acid) (PLGA) have been investigated
as fibrous scaffolds due to their bioresorption properties required
for tissue engineering applications and good mechanical properties.
However, synthetic polymers are typically hydrophobic and lack cellrecognition
sites for support of cell adhesion [35,36]. Natural polymers
exhibit particular advantages over synthetic polymers because of
their proven biocompatibility and their resorbable degradation
products that can be used in a wide variety of ways in biomedical
technology. Collagen, gelatin, hyaluronic acid, chitosan, and alginate
are the most commonly used natural polymers [37,38]. Chitosan, a
biodegradable, non-antigenic biopolymer, bears a proxy structure
of glycosaminoglycan (GAG), a major component of the native
extracellular matrix in human and animal tissues provides mechanical
support and regulates cellular activities [39]. The ability to generate
nanofibers from chitosan, a natural polysaccharide derived from
leftover shells after food processing, may provide virtually unlimited
resources for the development of biocompatible scaffolds to restore
damaged or dysfunctional tissues.
Progress In Eletrospinning Of Chitosan
Recently, a library of various polymer-solvent combinations
which has a crucial role in transforming chitosan into nanofibers
has been developed for many ground breaking applications in
different disciplines of biomedical technology such as such as in
tissue engineering, wound healing, drug delivery, and anti-bacterial
applications [33,34,40-47]. These studies as well as steady state growth
of number of publications of chitosan based nanofibers in each year
(Figure 3) demonstrate enormous potential of chitosan nanofibers in
the biomedical field.
Figure 3: Scientific publications on chitosan nanofibrous structures found in the
Science Direct search system with key words “chitosan” and “electrospinning”.
Challenges and successes in electrospinning of chitosan
Physical and chemical parameters of polymer solution such
as viscosity, electric conductivity, and polymer concentration can determinedly affect the formation and morphology of electrospun
fibers. These parameters are well defined for electrospinning several
synthetic polymers solutions in organic solvents. A majority of natural
polymers, including chitosan, do not dissolve in organic solvents with
an exception of highly corrosive halogenated organic acids. Although
chitosan dissolves in water at acidic pH, a major complication arises
in electrospinning due to its high viscosity in aqueous solution. At low
polymer concentrations, solutions do not contain sufficient material
to produce stable solid fibers. With increasing polymer concentration,
the number of direct inter- and intra-chain associations of chitosan
molecules in the solution increases rapidly and reaches a critical value
of forming a 3-D network structure—a highly viscous gel, rendering
the solution difficult to electrospin [48]. The associative properties of
chitosan chains arises due to the presence of strong hydrogen bonding
between -NH2 and -OH groups of chitosan molecules causing it to be
unspinnable. Nevertheless, several research groups have succeeded in
the preparation of chitosan based fibers by either blending it with other
surfactants like synthetic polymers such as polyethylene oxide (PEO)
and polyvinyl alcohol (PVA) or by mixing it with strong organic acids
[33,49,50]. The decrease in viscosity with addition of synthetic polymers
can be attributed to the change in inter and intramolecular interactions
of chitosan chains. The additive molecules bound onto chitosan
backbone disrupt the self-association of chitosan chains by forming
new hydrogen bonds between its OH groups and water molecules
[48,51]. Physically, this modulation in associative forces by surfactants
is manifested as an increase in chitosan solubility and a decrease in its
solution viscosity which a suitable condition for electrospinning.
Electrospinning of chitosan-trifluroacetic acid
The most common way to produce chitosan nanofibers is by
preparing chitosan solution in trifluoroacetic acid (TFA) and/or acetic
acid [50,51] . These solvents are best known to improve the fluidity
in chitosan solution by disrupting the 3-D networks of chitosan so
that ultrafine fibers can be produced. Ohkawa et al. [50] was able
to electrospin a chitosan-TFA solution to develop nanofiber mess
sheets. Jang et al. [52] was able to produce nanofibers by using 7%
chitosan concentration solution (chitosan Mw = 106,000 g/mol)
using 90% acetic acid. The most important solution parameter in the
electrospinning of chitosan is increasing the acetic acid concentration.
More concentrated acetic acid in the solution progressively decreases the surface tension of chitosan and concomitantly increases charged
density of the jet without significant effect on solution viscosity. The
higher the charge density carried by the jet the smoother the fiber, due
to a stronger whipping instability of the jet [52]. Unfortunately, these
solvents can cleave the backbone structure the chitosan molecules so
that the resulting nanofibers are very weak in mechanical strength and
also causing them to degrade very quickly in an aqueous environment.
Chemical crosslinking is a way to make the fibers insoluble and to retain
their structural integrity but it requires the use of toxic chemicals. At
the end, any trace amount of leftover crosslinking chemicals in the fiber
can alter its cytocompatibility. Therefore, alternative ways of making
chitosan nanofiber are warranted.
Chitin nanofibers to chitosan nanofibers
Being an ionic polymer, chitosan shows polyelectrolyte behavior in
solution which can develop enormous repulsive forces between ionic
groups within the polymer chain while it is charged under an electric
filed. This may result in the lack of continuous fiber formation during
the electrospinning process, especially during the jet stretching and
bending. Electrospinning of chitosan using different solvent systems
will have some limitation in obtaining continuous fibers. An alternative
method has been developed by using neutral nonionic form of chitin
solutions to make chitin fibers which later can be converted to chitosan
fibers through deactylation process [4,26]. Chitin powder was first
depolymerized by gamma irradiation to make it soluble. Next, it was
dispersed in 1, 1, 1, 3, 3, and 3-hexafluoro-2- propanol (HFIP) to
dissolve for three days with a concentration range of three to six percent
by weight. Electrospun fibers were deposited on a target drum. Then
the collected fibers were placed in concentrated solution of sodium
hydroxide and then washed with distilled water. Finally, the fibers were
dried under vacuum. Deacetylation reaction took place when chitin
fibers were treated with concentrated base [26]. Nam et al. [4] was also
able to generate chitosan nanofibers from chitin nanofibers by using
a heterogeneous alkaline treatment to complete the transformation of
chitosan nanofibers with different degrees of deacetylation.
Chitosan fibers form polyblends and surfactants
Arguably, the greatest challenge of producing chitosan nanofibers
is the lack of appropriate solvents to produce a solution which is
sufficient to make uniform nanofibers and at the same time, a solution
formulation that is biologically friendly. Solvents such as acetic acid,
trifluoroacetic acid (TFA) and HFIP are the most used solvents to
prepare chitosan solutions. But, due to their highly corrosive nature,
they are not compatible with biomolecules especially with cells,
proteins, peptide drugs, etc. Avoiding the corrosive/toxic organic
solvents and extra chemical processes during the nanofiber production
is always challenging. Several studies have been explored using
polyblend systems comprising of an aqueous solution of chitosan with
hydrophilic- synthetic polymers such as PVA, PEO and surfactants
such as Triton X-100 as one of the biologically friendly methods to
make chitosan nanofibers [48,50].
Bhattarai et al. [48] has developed chitosan based nanofibers from
a polyblend system of chitosan/PEO with desirable structure and
material properties, and demonstrated that the nanofibrous matrix,
when properly constructed, exhibited good structural integrity,
promoted cell attachment, and thus can potentially serve as scaffolding
material for tissue engineering. Preparation of a suitable solution for
electrospinning was crucial for their success. The PEO and chitosan
solutions were prepared separately and then mixed to create a particular
range of chitosan/PEO blend solution (Figure 4). Blend solution was further mixed with trace amount of dimethylsulphoxide (DMSO) and
Triton X-100 to achieve better structural uniformity in naonfibers
(Figure 5). PEO is a biocompatible polymer, one of the few synthetic
polymers approved for internal use in food, cosmetics, personal care
products, and pharmaceuticals. Therefore, this preparation method
was well suited for several other biomedical applications and cited in
several peer reviewed journal articles.
Figure 4: Preparation of chitosan/PEO solution for electrospinning [49].
Figure 5: SEM images of electrospun structures (chitosan/PEO ratio 90/10)
prepared from aqueous solution containing 0.5M acetic acid: (A) 0.3% Triton
X-100™, (B) and (C) 0.3% Triton X-100™ and 10% DMSO. Fibers in (B) were
collected on a stationary collector whereas fibers in (C) were collected on a
cylindrical collector with a rotating speed of 2000 rpm. Images (D) and (E)
are the high-magnification images of (B) and (C), respectively. (from ref [49]
with permission).
Another great advantage of chitosan is that it has good miscibility
properties with a number of synthetic polymers in solutions. Good
miscibility of polymer solution can create polyblend nanofibers with
increased physico-chemical properties such as mechanical strength
and biodegradation. Mechanical strength of chitosan nanofibers
are relatively weaker compared to nanofibers of synthetic polymers.
Chitosan also degrades much faster than synthetic polymers in body
fluid environments. In polyblend nanofibers, chitosan and synthetic
polymers such as poly (caprolactone) (PCL), poly (lactic acid) (PLA),
and poly (D, L-lactide-co-glycolic acid) (PLGA) have the potential to
complement each other very well. This is primarily because nanofibers
can be engineered to retain the mechanical strength and durability of
a synthetic component and the biological functionality of chitosan.
In addition to combining properties, polyblends have been used to
facilitate the electrospinning of chitosan in less rigorous processing that
does not involve corrosive acids which can cause unwanted polymer
degradation or damage [53-55]. An exhaustive list of chitosan and
chitosan–synthetic polymer blend nanofibers is provided in Table 1.
Table 1:Electrospinning of chitosan based nanofibers.
Recently, Bhattarai, et al. [35] was able to develop chitosan-PCL
polyblend nanofibers from electrospinning. Solution preparation
for their set up was very critical to obtaining stable nanofibers. The
electrospinning process was carried out immediately after mixing the
chitosan/TFA solution with the PCL/TFE solution. The PCL is subject
to the acidic hydrolysis by TFA overtime giving the resulting chitosan-
PCL solution a certain time constraint. From their detailed research,
it was found that the solution supply for electrospinning needed to be
replaced every half hour with freshly prepared chitosan-PCL solution.
For polyblend nanofibers containing a combination of natural and
synthetic polymers, blend components are usually phase separated
into the individual components and requires chemical crosslinking
to retain their structural integrity and improve mechanical strength.
This procedure requires the use of crosslinking agents which can
cause problems in biomedical applications because any trace amount of crosslinking agents found in the product can be toxic. However,
chitosan/PCL polyblend system did not require any crosslinking agents
and resulted in a successful nanofibrous product without undergoing
any phase segregation.
Cooper A et al. [75] was also able to develop an aligned chitosan-
PCL nanofibrous scaffold to investigate nerve cell organization
and function using Schwann cells and PC-12 cells. These blended
nanofibers with balanced hydrophilic nature, high structural integrity,
and free amino groups are expected to have the potential application
for nerve regeneration. Another study by the same group reported the
fabrication of a lactic acid modified chitosan nanofiber [62]. Chitosan
powder was freeze dried in a dilute lactic acid solution to prepare a
chitosan lactate salt. The chitosan salt product was dissolved in a TFA/
MC solvent for electrospinning. Once nanofibers were spun, they were
further stabilized by thermal treatment causing amidation between
chitosan and lactate salt [62].
Another form of composite polyblend nanofibers of chitosan is a
version that contains inorganic nanoparticles for specific functional
applications [67,76-78]. Over the past few years, several different
electrospun nanocomposite fibers such as PCL/CaCO3, Hap/gelatin,
silk/Hap, PLA/Hap, and triphasic Hap/collagen/PCL have been
devised and explored for potential bone regeneration applications.
One particular study done by Zhang et al. [67] was able to electrospin
composite nanofibers containing hydroxyapatite/chitosan for bone
tissue engineering to design and fabricate bioactive scaffolds that
resemble the native extracellular matrix. Preparation of these fibers
involved a two-step method, which involves firstly preparing Hap/CTS
nanocomposites by a co-precipitation synthesis approach and then
fabricating the resultant composite nanofibers with ultrahigh molecular
weight poly (ethylene oxide) (UHMWPEO) as a fiber-forming additive.
Cell culture experiments using the human fetal osteoblasts compared
the electrospun Hap/CTS to electrospun pure chitosan. The study
was able to highlight very important features of HAp/CTS composite
nanofibers in display of its great potential for bone tissue engineering
applications [68].
Biomedical Applications For Chitosan Nanofibers
Tissue engineering
Electrospun nanofibers are widely and successfully used in the
area of tissue engineering. Tissue engineering relies on the ability of
a scaffold to foster cellular in growth and rapid repopulation of new
tissue. This requires a 3-D synthetic matrix to emulate the native
extracellular matrix (ECM) found in tissues such as bone, ligament
cartilage, skin, nerve, vascular tissue, and others. Broadly, the ECM, a nanofibrous protein–polysaccharide hierarchical network provides
mechanical support for cells to create functional tissues. Physicochemical
and biological properties of ECM ultimately control cell shape,
define tissue architecture and help regulate its physiological function.
Electrospun nanofibers of various natural and synthetic polymers
mimic such hierarchical structures found in the natural ECM. In
successful tissue engineering, scaffold should induce the formation of
neo-tissue necessitating the breakdown and clearance of the originally
implanted scaffolds. Chitosan based nanofibers, being a biodegradable
polysaccharide under cell-induced proteolytic conditions, are believed
to be an excellent proxy structure of ECM and well suited candidate for
tissue engineering applications.
There have been several chitosan based nanofibrous structures
developed in different geometries such as nonwoven sheets, fiber
bundles and tubular constructs. By electrospinning polyblends of
chitosan/PCL onto rotating spindles, nanofibers can be fabricated into tubular constructs [35]. These scaffolds are well suited as nerve guides
for peripheral nerve regeneration, where severed nerve endings cannot
be repaired with sutures. Synthetic nerve guides can take the place
of autografts, to redirect nerve growth across the critical gap. Nerve
conduit materials prepared with chitosan/PCL polyblend nanofibers
have demonstrated strong mechanical properties, capable of being
sutured to the nerve ends and maintaining structural stability in vivo.
In addition, aligned chitosan-PCL nanofibers have shown to provide
a favorable environment for nerve cell proliferation. In one study, a
fiber mat with aligned nanofibers was found to enhance the neuritis
extension and directionality of attached nerve cells [62,75]. Aligned
electrospun fibers are also of major interest for development and
remodeling of native and engineered heart tissues [49].
To mimic the biochemical and structural environment, certain
tissue systems have additional demands. In the study of skeletal muscle
tissue attachment and proliferation, Cooper et al. [79] developed a chitosan/PCL based nanofibrous scaffold with unidirectional fiber
orientation. Ideally, the matrix scaffold for muscle tissue engineering
should provide a microenvironment with appropriate topographical
and chemical cues to regulate muscle cell-material interaction. Visual
confirmation of the muscle cell differentiation and corresponding gene
expression was established by confocal fluorescence and PCR analysis.
Highly aligned chitosan-PCL nanofibrous scaffolds exhibited superior
tensile strength compared to randomly oriented nanofibers, promoting
muscle cell proliferation and inducing the formation of elongated and
anisotropically oriented myotubes (Figure 6). Muscle cells on the
aligned nanofibers demonstrated up-regulation of differentiationspecific
gene expression including troponin T and MHC. The study
concluded that the aligned chitosan-PCL nanofibrous scaffolds could
potentially serve as a cost-effective tissue-engineered construct for
enhanced muscle tissue reconstruction.
Figure 6: Confocal microscopy images showing immunocytochemistry
analysis of actin (left column, green) and myosin heavy chain (MHC) (middle
column, red) expressed by muscle cells grown on chitosan-PCL randomly
oriented and aligned nanofibrous scaffolds after culture in fusion media for five
days. The merged images with nuclei stained with DAPI (blue) are shown on
the right column. SEM images showing morphology of muscle cells grown on
chitosan-PCL nanofibers after 5 days of culture. Scale bars represent 40 μm.
(from ref [80] with permission).
Chitosan based polyblend nanofibers with synthetic biopolymer
polymers such as PEO, PLGA, PLLA, PVA and Hydroxyapatite (HAP)
have been used as potential biomimetic scaffolds to engineer several
others tissues such as bone, cartilage, tendon, etc., [48,67,76,80-84].
The ability of chitosan to support cell attachment and proliferation
is attributed to its chemical properties. The polysaccharide backbone
of chitosan is structurally similar to glycosaminoglycans, the major
component of the extracellular matrix of bone and cartilage. Other
advantages of chitosan based nanofibrous scaffolds for the tissue
engineering include the formation of highly porous scaffolds with
interconnected pores, osteoconductivity and ability to enhance bone
formation both in vitro and in vivo. By modulating the fiber alignment
and orientation, three-dimensional scaffolds can be formed to match
the mechanical properties and microenvironments of varying tissue
types (e.g. aligned ligament fibers versus spiral smooth muscle
fibers). Fiber orientation of polyblends will play an increasing role
in producing topographical cues that can direct cellular activity to
regenerate functional tissues.
Wound dressing
Nanofibrous membranes are highly soft materials with high
surface‐to‐volume ratios, and therefore can serve as excellent carriers
for therapeutic agents that are antibacterial or accelerate wound
healing. For quick healing of traumatic or postsurgical wounds,
several factors should be considered while selecting a wound dressing,
which includes eliminating infection, limiting inflammation, wound
cleansing, maintaining moist environment of wound, controlling
wound exudates, promoting tissue growth, and oxygenating the wound
[85-88]. Chitosan based nanofibers along with other natural polymer
based nanofibers have recently attracted a great deal of attention to be
used as wound dressing. Chitosan is most suitable for this application
because it meets several requirements such as histocompatibility,
biodegradability, lack of antigenicity and also promotes wound healing
[89-91].
In the area of wound healing, care, and management, antibacterial
resistance of microorganisms is a major concern. Very recently, there
has been a lot of focus on the development of new antibacterial to
treat wounds infected with antibacterial resistant microorganisms.
Chitosan derivatives with quaternary ammonium groups have
been known to possess high efficacy against bacteria and fungi [93].
Several studies have documented the use of chitosan scaffolds to treat
patients with deep burn, wounds, etc. Ignatova et al. [54] was able to
use photo-cross-linked electrospun mats with quaternized chitosan
to efficiently inhibit the growth of Gram-positive bacteria and Gramnegative
bacteria. These results demonstrate that quaternized chitosan/ PVP electrospun mats are favorable materials for wound dressing
applications. A polyblend nanofibrous membrane of chitosan/collagen
was found to induce cell migration and proliferation while assisting in
wound healing. Chen et al. [93] reports that nanofibrous membrane
have beneficial effects better than gauze and commercial collagen
sponge when conducting animal studies. Nanofibers have greater
water-retention capacity because of very high-specific surface area and
are very soft, so that the dressing will not chafe the wound. A wound
dressing made up of a chitosan based nanofiber would be a promising
dressing material.
Drug release
Nanofiber scaffolds have been identified as local drug delivery
vehicles owing to their large surface area and controlled degradation.
Drugs can be loaded into the nanofiber by premixing the polymer
solution with the therapeutic before electrospinning. In addition
to blending the drug into the polymer mixture, a composite drug–
polymer can be prepared by encapsulation of drugs or biomolecules
by coaxial electrospinning, forming core-shell structures [95,96]. The
drug or any biomolecule can be simply prepared in the core solution,
protected from denaturing. The controlled release of the material can
be regulated by the degradation rate or porosity of the polymer shell.
Recently, chitosan nanofibrous structures have found their place as a
unique drug release process [1]. Composite membranes composed of
PLGA and PEG-g-chitosan prepared by electrospinning have shown
the ability to be loaded with the anti-inflammatory drug known as
ibuprofen [69]. The PEG-g-chitosan gave evidence of significantly
reducing the initial burst of ibuprofen from electrospun composite
membranes. Furthermore, ibuprofen can be joined to the side chains of
PEG-g-chitosan to sustain its release for more than two weeks (Figure
7).
Figure 7: Release profiles of ibuprofen from an electrospun (A) PLGA
membrane (5% ibuprofen), (B) a PLGA/PEG-g-chitosan membrane (5%
ibuprofen), and (C) a PLGA/PEG-g-chitosan membrane conjugated with
ibuprofen (4.4% ibuprofen). Electrospun membranes were incubated in 0.1 M
PBS (pH 7.4) at 37°C. (from ref. [70] with permission)
Recently, electrospun fibers as antitumor drug carriers have
attracted a great deal of attention because it is a promising approach
for the targeting delivery of the antitumor drugs at tumor tissue,
especially in postoperative local chemotherapy. The drug release profile
from these systems can be controlled by modulation of the nanofiber
morphology, porosity, and composition. Chitosan and its derivatives
have drawn a great attention as antitumor drug carriers such as
doxorubicin hydrochloride (DOX) [96-98]. This is due to the set of advantageous properties of these polymers, for example, nontoxicity,
biodegradability, biocompatibility, intrinsic antibacterial properties,
and immuno-stimulating effect. Chitosan has shown good antitumor
activity, which is mainly due to its polycationic nature. Ignatova et al.
[99] developed a one-step preparation of DOX-containing nanofibrous
materials by electrospinning of DOX/poly (l-lactide-co-d, l-lactide)
(coPLA) and DOX/quaternized chitosan (QCh)/coPLA solutions.
These nanofibers showed high antitumor activity which renders these
types of nanofibrous materials promising candidates for the treatment
of cervical tumor, which remains a critical public health problem.
Antimicrobial
Chitosan is known to have antimicrobial activity due to the fact
that it is a cationic polyelectrolyte polymer. A polymer solution of
chitosan/PET with TFA/HFIP as a solvent was electrospun to produce
nanofibrous matrices to inhibit the growth of S. aureus and K.
pneumoniae. Results showed that they were more effective than pure
PET matrices[67]. Spasova et al. [100] examined the effect of potassium
5-nitro-8-quinolinolate (K5N8Q) intergrated into chitosan/PEO
nanofiber matrices on antimicrobial and antimycotic activity against
gram negative and positive bacteria (E. coli and S. aureus) and fungi
(C. albicans). In comparison, only nanofibrous matrices containing
K5N8Q comprised of sterile zones. Thin chitosan films can also be
used to modify by nanofibrous matrices to further incorporate antibacterial
properties. A simple chitosan film can be deposited on the
electrospun nanofibers to increase the amount of chitosan along with
the hemostatic activity of the matrices. PLA and PLA/PEG polyblend
fibrous matrices were prepared by electrospinning and then coated
with chitosan [100]. Both chitosan coated matrices demonstrated to
have anti-bacterial activity against S. aureus.
Conclusion
This review gives an overall summary on how chitosan based
nanofibrous structure research has evolved over the years and the
biomedical applications in which they can possibly make a huge
impact. Nanofibers prepared from electrospinning of chitosan
represent a simple, efficient and scalable method that is well suited to
prepare clinically relevant materials. The future challenges of chitosan
nanofibrous structures include optimizing the fabrication process with the most effective solvents, the various combinations of electrospinning
parameters and the hybrid of natural and/or synthetic polymers,
chitosan derivatives, composites, etc. for each specific targeted
application. Whether it’s the regeneration of nerve tissue, delivery of
anti-inflammatory drugs, or keeping a wound sterilized from infection,
each form of biomedical application requires extensive research. The
amount of research being conducted is growing rapidly every year
to meet these demands. Although, thorough toxicity studies needs to
be conducted before this new class of materials can be identified as
suitable for human application.
Acknowledgements
The authors acknowledge the support from Engineering Research Center-
Revolutionizing Metallic Biomaterials (ERC-RMB) (NSF-0812348) at North
Carolina A&T State University and also from College of Engineering for its startup
funds for new faculty research.
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