University of Massachuses Amherst
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Designing electrospun nanofiber mats to promote
wound healing – a review
Katrina A. Rieger, Nathan P. Birch and Jessica D. Schiffman
*
Current strategies to treat chronic wounds offer limited relief to the 7.75 million patients who suffer from
burns or chronic skin ulcers. Thus, as long as chronic wounds remain a global healthcare problem, the
development of alternate treatments remain desperately needed. This review explores the recent
strategies employed to tailor electrospun nanofiber mats towards accelerating the wound healing
process. Porous nanofiber mats readily produced by the electrospinning process offer a promising
solution to the management of wounds. The matrix chemistry, surface functionality, and mat
degradation rate all can be fine-tuned to govern the interactions that occur at the materials–biology
interface. In this review, first we briefly discuss the wound healing process and then highlight recent
advances in drug release, biologics encapsulation, and antibacterial activity that have been
demonstrated via electrospinning. While this versatile biomaterial has shown much progress,
commercializing nanofiber mats that fully address the needs of an individual patient remains an
ambitious challenge.
1 Introduction
Chronic wounds are a global healthcare problem. In the United
States alone, 1.25 million patients suffer from burns and an
additional 6.5 million patients endure chronic skin ulcers most
commonly caused by pressure, venous stasis, or diabetes mel-
litus. In 2011, the CDC estimated that 25.8 million people—
8.3% of the U.S. population—suffer from diabetes.
1
An esti-
mated 15% of people with diabetes mellitus will develop lower
extremity ulcers and up to one fourth of diabetic patients with
foot ulcers will eventually undergo amputation. Annually in the
U.S., approximately 100 000 lower extremity amputations are
performed on diabetic patients.
2
Though the two most common treatment options for chronic
ulcers are potentially successful, neither ensures recovery. The
rst option, negative pressure wound therapy, only effectively
treats very small chronic wounds, while the second, hyperbaric
Katrina A. Rieger is a Ph.D.
candidate in Chemical Engi-
neering at the University of
Massachusetts Amherst where
her current research focuses on
designing and electrospinning
novel bactericidal nanober
mats composed of natural
agents, such as chitosan, from
crab shells, and cinnamalde-
hyde, from cinnamon bark.
Advanced antibacterial coatings
offer an environmentally
friendly approach to preventing the spread of infectious diseases.
She was one of nine recipients nationally to receive an Eli Lilly
Travel Award and has been awarded an NSF-IGERT fellowship in
Cellular Engineering. Rieger graduated Summa Cum Laude from
Oregon State University with a B.S. in Chemical Engineering.
Nathan P. Birch is a Ph.D.
candidate in Chemical Engi-
neering at the University of
Massachusetts Amherst where
his current research focuses on
biopolymer polyelectrolyte
interactions for wound healing
and drug delivery applications.
Currently his research focuses
on chitosan–pectin interactions,
which yield nanoparticles, and
hydrogels. Birch recently
received a Ciba Travel Award in
Green Chemistry and Engineering to present at the 246
th
ACS
National Meeting and Exposition in Indianapolis, IN. Previously,
he received a B.S. in Chemical Engineering and a minor in Polymer
Science and Engineering from Michigan Technological University.
Department of Chemical Engineering, University of Massachusetts Amherst, Amherst,
MA 01003-9303, USA. E-mail: schiffman@ecs.umass.edu
Cite this: J. Mater. Chem. B, 2013, 1,
4531
Received 4th June 2013
Accepted 30th July 2013
DOI: 10.1039/c3tb20795a
www.rsc.org/MaterialsB
This journal is ª The Royal Society of Chemistry 2013 J. Mater. Chem. B, 2013, 1, 4531–4541 | 4531
Journal of
Materials Chemistry B
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oxygen therapy does not ensure success aer one year of treat-
ment.
3
Successful alternate treatments are desperately needed
and engineered drug delivery vehicles, especially electrospun
ber mats, offer a promising solution.
4
A wound dressing is a protective barrier used to assist in
many aspects of the healing process. In comparison to typical
bandages, which do not meet all the requirements of wound
care, electrospun ber mats could potentially provide an
excellent environment for healing. Thus, there has been an
increase in research focused on developing electrospun nano-
ber mats that accelerate wound healing and prevent bacterial
infections, Fig. 1.
Nanobers generated using the electrospinning process
exhibit high levels of porosity, gas permeation, and offer a high
surface-to-volume ratio. These properties promote cell respira-
tion, skin regeneration, moisture retention, removal of
exudates, and hemostasis.
5
Additionally, by electrospinning a
bioabsorbable polymer, patient comfort can be increased
because the need to change the bandage is reduced.
6
By incor-
porating therapeutic or antimicrobial agents, functionalized
electrospun mats could potentially serve as a personalized
bandage that will contour to virtually any wound surface.
7
In
this applications review, we present the ve stages of wound
healing, the electrospinning process, and strategies towards
engineering electrospun nanober mats into advanced
nanobiomaterials.
2 Wound healing process
Naturally, when the skin is damaged, the body responds via a
complex process known as wound healing.
8
Recent literature
and numerous review articles provide detailed accounts of the
wound healing process.
9–13
Therefore, in the following sections,
we aim to present only the quintessential elements of (Section
2.1) how to categorize wounds and (Section 2.2) the stages of the
wound healing process.
2.1 Categorizing wounds
Wounds—acute versus chronic—can be primarily categorized
by their healing time. A wound that heals normally is an acute
wound, while a wound that is arre sted in a phas e of healing is
known as a chroni c wound. Most oen, chronic wound s are
arrested in the inammatory phas e; high levels of matrix
metalloproteinases (MMPs) cause degradation of the extra-
cellular matrix (ECM) and of certai n growth factors. The
lengthened healing process associated with chronic wounds
can c ause a num ber of cells, particularly broblasts, present
in the wound to become less active due to senescence
(aging).
10
The type of wound—cut versus burn—also affects the natural
response of the body. Aer a cutting injury, hemostasis is ach-
ieved quickly, within the rst 15 minutes.
11
In contrast, when an
injury is caused by a burn, wounding can continue for up to
4 days aer the initial trauma. The prolonged injury period,
along with the increased extent of damage, causes a heightened
inammatory response commonly leading to extensive and
sometimes hypertrophic scarring.
12
2.2 Five stages of wound healing
During the ideal healing process, the wound progresses through
(i) wounding, (ii) hemostasis, (iii) inammation, (iv) prolifera-
tion, and nally (v) maturation (Fig. 2). These phases may
overlap in some instances, not all phases will be reached in
chronic wounds.
The wounding phase (Fig. 2A) marks the beginning of the
wound healing process. During this phase, the skin is punc-
tured leaving dead and devitalized tissue.
8
Immediately, uid
begins to leak from blood and lymphatic vessels, lling the
injured site. Bacteria start to invade the open wound.
Within 15 minutes, local hemostasis is achieved at the
wound site, (Fig. 2B).
11
Injured blood and lymphatic vessels
rapidly undergo vasoconstriction,
10
preventing blo od ow into
local tissue indicated by visibl e blanching.
11
Thrombocytes
Fig. 1 Over the past dozen years, the number of electrospinning publications
exhibit an upward trend. Plotted is the growth of publications on nanofibers
electrospun (A) for any application and (B) specifically to address the topic of this
review: wound healing or antibacterial activity. The SciFinder Scholar database
was used to determine the total number of unique results from searching (A)
“electrospinning” and (B) “electrospinning” plus “wound healing” or “antibacte-
rial”. The total counts is displayed above each bar; data analysis was conducted on
May 14, 2013. While not included in the graph, currently, there have been 1224
publications on electrospinning with 9 and 20 publications dealing with wound
healing and antibacterial applications, respectively.
Jessica D. Schiffman is an Assis-
tant Professor of Chemical Engi-
neering at the University of
Massachusetts Amherst. She
holds B.S., M. Eng., and Ph.D.
degrees in Materials Science and
Engineering from Rutgers
University, Cornell University,
and Drexel University, respec-
tively. Aerward, she was a
postdoctoral associate in the
Department of Chemical and
Environmental Engineering at
Yale University. Her research group synthesizes nano and macro-
structured materials from biopolymers in an effort to address public
health concerns in biomedical and environmental elds. Schi ff-
man's lab is interdisciplinary in nature, drawing inuences from
chemical engineering, materials science engineering, environmental
engineering, and cellular engineering.
4532 | J. M ater. Chem. B, 2013, 1, 4531–4541 This journal is ª The Royal Society of Chemistry 2013
Journal of Materials Chemistry B Application
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migrate to the wound site and bronectin is cleaved into
brin. Platelets, brin, bronectin, vitronectin, thrombo-
spondin, and various blood cells
10
join to form a clot. In later
wound healing stages, the clot serves as a pr ovisional ECM for
cell migration.
11
Fig. 2C displays the inammation phase, which follows
hemostasis and can last for up to 6 days aer the wounding
incident.
11
Vasodilation, accompanied by an increase in capil-
lary permeability, is induced by chemical signals released from
injured tissue and mast cells.
10
Polymorphonuclear cells, are
the rst inammatory cells to arrive at the wound site; these
cells are responsible for producing growth factors and removing
cellular debris, foreign particles, and bacteria.
9,11
Monocytes migrate to the wound site, where they transform
into macrophages
11
to remove necrotic tissue and foreign
particles.
9
Macrophages also stimulate broblasts to produce
collagen and inuence reepithelialization. The macrophage
population reaches a peak 4 to 5 days aer wounding and
remain at the site for multiple weeks.
11
Lymphocytes, particu-
larly CD4
+
, CD8
+
, and dendritic gd epidermal T cells (DETCs),
arrive approximately 6 days aer injury
10
to facilitate later stages
of the wound healing process.
11
The proliferation phase, Fig. 2D, is characterized by reepi-
thelialization, which occurs 24– 48 hours aer wounding. Ker-
atinocytes migrate from the surrounding tissue and nearby hair
bulges to the wound boundary. A wedge of keratinocytes,
moving in from the edges across the wound, releases enzymes
to begin the degradation of the provisional ECM.
11
The wedge
continues until it contacts another wedge, leaving a stratied
layer of keratinocytes in its wake. This migration is partially
stimulated by the contact the cell has with brin and might also
be motivated by connexins.
11
Keratinocyte migration does not
depend on the number of platelets present but is slowed by the
presence of neutrophils and macrophages, especially in dia-
betic wounds.
During the second day of healing, endothelial cells begin
migrating into the wound as part of angiogenesis—the physi-
ological process wherein new blood vessels develop from pre-
existing vessels. The migration is driven by cytokines, the
presence of an ECM, and the absence of neighboring endothe-
lial cells. MMPs stimulate the degradation of the basement
membrane and the ECM. The endothelial cells migrate through
the ECM, form tubules, and eventually form new capillaries.
Laminin production is stimulated in endothelial cells to
produce a new basement membrane.
11
Approximately 4 days into the wound healing process,
collagen-based g ranulation tissue replaces the brin-based
provis ional ECM. Granulation tissue contains broblasts,
collagen, blood vessels, and macrophages and is similar to
healthy ECM, except for the absence of elastin. In response to
bronectin, cytokines, and growth factors, the broblasts
migrate along the bronectin into the provisional ECM from
the surrounding tissue. In addition to the existing broblasts,
new broblasts are produced in r esponse to macrophage
products from n earby mesenchymal cells. All broblasts
present in the provisional ECM regulate the growth and
function of other cells withi n the matrix.
11
T cells, specically
DETCs, stimulate broblasts to produce type I collagen,
bronectin, and a5 integrin.
11
The net collagen deposition is
needed to form the granulation tissue from 3 to 21 days aer
wounding.
As new granulation tissue is being generated, the wound
undergoes contraction, 4–14 days aer wound formation.
Wound closure tends to occur at a rate of 0.6 to 0.75 mm per day
and is aided by DETCs.
9
Approximately 4 to 6 days aer
wounding, some broblasts are converted into myobroblasts,
which produce actin and decrease wound closure time.
11
In the maturation phase, tissue remodeling begins with the
replacement of granulation tissue with scar tissue approxi-
mately 3 to 6 weeks aer the wound incident and can continue
for months, Fig. 2E.
11
Over time, the proportion of type I
collagen increases, while the proportions of type III collagen,
proteoglycans, and water decreases. During remodeling,
collagen brils increase in diameter, exhibit increased inter-
bril binding, and rearrange.
11
Mast cells may be involved in the
collagen remodeling process as well.
9
In early phases of wound
healing, collagen brils are arranged haphazardly, which
results in a high level of collagen, and low relative tissue
strength. Collagen brils become signicantly more ordered
aer one year of recovery. As the scar matures, redness
decreases as the capillary density decreases. The level of scar
tissue is greatly in uenced by the presence of immune cells and
the level of inammation that the wound has undergone. For
example, the lack of immune cells has been linked to an
absence of scar formation, as well as, a lower level of brogenic
growth factor and a higher level of hyaluronic acid.
9
Scar
formation increases in the presence of neutrophils, macro-
phages, and T cells,
9,14
while a large number of mast cells causes
hypertrophic scarring.
9
Fig. 2 The schematic provides the major elements, which occur during the five
stages of wound healing. (A) During wounding, existing keratinocytes and the
healthy extracellular matrix (ECM) are damaged. (B) Hemostasis is characterized
by the formation of a clot that becomes the provisional ECM. (C) Neutrophils
infiltrate the wound during the inflammation phase. (D) In the proliferative phase,
new keratinocytes migrate into the wound as do fibroblasts, w hich produce
granulation tissue. Finally, (E) as the wound matures the underlying ECM even-
tually returns to normal. Time duration for each phase of the wound healing
process are also noted.
This journal is ª The Royal Society of Chemistry 2013 J. Mater. Chem. B, 2013, 1, 4531–4541 | 4533
Application Journal of Materials Chemistry B
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3 Commercial treatments versus
electrospun nanofiber mats
Armed with the knowledge that the wound healing process is
complex, it should come as no surprise that currently, no single
treatment modality can address all aspects of the healing
process. Hence, a plethora of options are available. As far as we
are aware, clinical “head-to-head” trials between commercial
treatments and electrospun nanober mats have not yet been
conducted. However, the unique structure-to-function rela-
tionship of nanober mats can be discussed with regard to the
properties offered by conventional treatment options. While in
Sections 4 and 5 of this review we will discuss the specics of
electrospun materials, here, we briey discuss why nanober
mats hold promise as a commercially viable alternative to the
current strategies.
Plain gauze is the most widely used material because it is
inexpensive and readily available. However, it has numerous
shortcomings, which have inspired the development of other
approaches: foams, hydrogels, lms, biologic dressings, and
hydrocolloids.
15
Conventional foams and hydrogel dressings can
adsorb only minimal exudates with moderate success
15
and lack
the additional features of more advanced dressings.
16
For
instance, the nanostructure of an electrospun ber mat allows for
an incredibly high surface area, better gas transport, and more
efficient exudate absorption than traditional lms and foams.
5
Current biologic dressings fall into one of three categories:
composite gras with epidermal and dermal components,
dermal replacements, and epidermal gras. However, they all
suffer from the major disadvantages of cost and availability.
19
On the other hand, recent advances have made electrospun
materials commercially viable for some applications.
20
Traditional antibacterial ointments have to be reapplied
oen to maintain moisture.
15
But, by properly choosing the
electrospinning technique and post-processing steps, a pro-
longed and improved release prole of antibacterial agents can
be achieved. Additionally, the frequency of dressing change
could be lowered.
5,16
To date, no commercial strategy has replicated the complex
biological functionality and biophysical properties offered by the
native ECM. However, nanotopology has been noted as key
determinant of cell proliferation and migration.
4,18
Due to the
morphology of ber mats fabricated by the electrospinning
process, they are being proposed as a better ECM analog than
current technologies.
4,5,17
Thus, unsurprisingly, electrospun
nanober mats have been demonstrated to support the adhesion,
proliferation, and differentiation of various cells. Additionally,
they have served as a delivery platform for drugs, growth factors
and other biomolecules that may further improve cell function
and tissue regeneration. In order to match the innate structural
advantages of electrospun ber mats, traditional wound dress-
ings would have to undergo extensive lithography or imprinting.
In terms of transport and materials availability, nanober mats
can be spun directly onto the open wound of a patient.
21
In sum,
the advantages that nanober mats have to offer, i.e., structural,
functional, falling cost, and ease of use, add more incentive to
fully explore their potential as wound healing scaffolds.
4 Electrospinning
Early exploration into electrodynamics laid the foundation to
our current mechanistic understanding of the electrospinning
process. Gilbert (1500s) reported that in the presence of charged
amber, spherical droplets of water could be pulled into a conical
shape.
22
Three hundred years later, the excitation of a dielectric
liquid by an electric eld was reported by Lamor.
23
Signicant
progress was documented in patents published in 1902
24,25
and
1934.
26–28
Electric elds were applied to polymer solutions using
a systems approach featuring multiple spinnerets, a moving
collection target, and a collector composed of parallel elec-
trodes. These systems pioneered the design resembling modern
laboratory and industrial electrospinning set-ups. While there
have been numerous signicant lulls in electrospinning
research over the past ve hundred years, current interest in
this inexpensive nano- and macro-ber fabrication technique
continues to be on the rise.
29
4.1 Electrospinning process
A conventional electrospinning apparatus includes a high
voltage power supply, a grounded collector, and a spinneret,
Fig. 3. Electrodes connect the collector to the spinneret, which
completes a circuit to produce an electric eld. A precursor
solution—typically a polymer, sol–gel, or melt—is loaded into
the spinneret and advanced at a low feed rate allowing for the
formation of a pendent drop held at the tip of the spinneret via
surface tension. As the voltage is increased, the repulsive elec-
trical forces pull the pendent drop into a conical shape known
as a Taylor Cone.
30,31
Once the voltage reaches a critical value,
the electrical forces overcome the surface tension forces and a
liquid jet emerges from the Taylor Cone, which reaches the
collector in 18 nanoseconds.
32
During travel, the polymeric
solution enters a bending instability where the liquid jet is
stretched and whipped forcing the solvent to evaporate before
bers are collected on the target. A polymer solution with an
insufficient viscosity will experience an additional instability
during travel known as the Rayleigh instability, which can cause
inconsistent ber morphology, i.e., beading.
Fig. 3 (A) The schematic displays an electrospinning apparatus, which is
composed of a spinneret, a high voltage supply, and a collector. Us ually, an
advancement pump is used to regulate the flow rate of the polymeric solution. (B)
The scanning electron micrograph displays the nanofiber morphology present in
an electrospun non-woven mat, a 300 nm marker is displayed.
4534 | J. M ater. Chem. B, 2013, 1, 4531–4541
This journal is ª The Royal Society of Chemistry 2013
Journal of Materials Chemistry B Application
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