544523

research-article2014
IJLXXX10.1177/1534734614544523The International Journal of Lower Extremity WoundsAgrawal et al

Original Review
The International Journal of Lower

Role of Polymeric Biomaterials as Wound

Extremity Wounds
2014, Vol. 13(3) 180­–190
© The Author(s) 2014
Healing Agents Reprints and permissions:
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DOI: 10.1177/1534734614544523
ijl.sagepub.com

Priyanka Agrawal, MSc1, Sandeep Soni, MSc1, Gaurav Mittal, PhD1,

and Aseem Bhatnagar, MD, PhD1

Abstract
In uncontrolled hemorrhage, the main cause of death on the battlefield and in accidents, half of the deaths are caused by
severe blood loss. Polymeric biomaterials have great potential in the control of severe hemorrhage from trauma, which
is the second leading cause of death in the civilian community following central nervous system injuries. The intent of this
article is to provide a review on currently available biopolymers used as wound dressing agents and to describe their best
use as it relates to the condition and type of the wound (acute, chronic, superficial, and full thickness) and the phases
of the wound healing process. These biopolymers are beneficial in tissue engineering as scaffolds, hydrogels, and films.
Different types of wound dressings based on biopolymers are available in the market, with various physical, chemical,
and biological properties. The use of biopolymers as a hemostatic agent depends on its biocompatibility, biodegradability,
nonimmunogenicity, and optimal mechanical property. This review summarizes different biopolymers, their physiological
characters, and their use as wound healing agents along with biomedical applications.

Keywords
wound healing, wound dressing, polymer

Wounds as scrapes, occur when the skin is rubbed away by

Any defect or damage in the skin caused by physical or
thermal factors or damage caused by an infectious disease
as a result of the presence of an underlying medical or phys-
iological condition is referred to as a wound. According to
the Wound Healing Society, a wound is the result of disrup-
tion of normal anatomical structure and function.1 Wounds
are generally classified as wounds without tissue loss (eg, in
surgery) and wounds with tissue loss (which includes burn
wounds, wounds caused by trauma, diabetic ulcers, and iat-
rogenic wounds such as skin graft donor sites and dermal
abrasions).
On the basis of the nature of the wound repair process,
wounds can be classified as follows:
1. Acute wounds: These wounds are commonly tissue
injuries that completely heal within a limited time
period—usually 8 to 12 weeks.2 These wounds are
mainly caused by mechanical injuries, which are
caused by external physical factors such as abrasions
as a result of frictional contact between the skin and
rough surfaces or gun shots and during surgery. They
also include burns and chemical injuries that occur as
a result of radiation and corrosive chemicals.
Generally, acute wounds can be classified into one of
the following 8 categories: (a) Abrasions, also known
friction against another rough surface (eg, rope burns
and skinned knees). (b) Avulsions include removal of
an entire structure or a part of it, such as the loss of a
permanent tooth or a ear lobe—eg, wounds caused by
animal bites. (c) Contusions, also known as bruises,
are the result of a trauma that causes an internal injury
without breaking the skin. Blows to the chest, abdo-
men, and head with a blunt instrument (eg, a football
or a fist) can cause contusions. (d) Crush wounds
occur when a heavy object falls onto a person, split-
ting the skin and crushing underlying internal tissues.
(e) Cuts include wounds made with a sharp instrument
such as knives. They can be small (eg, a paper cut) or
significant (eg, a surgical incision). (f) Fish hook
wound is an injury caused by a fish hook, which is
embedded in soft tissue. (g) Incised wounds involve
any sharp cut in which the tissues are not severed. (h)
Lacerations, also known as tears, are separating
1
Defence Research and Development Organization (DRDO), Delhi, India
Corresponding Author:
Aseem Bhatnagar, Department of Nuclear Medicine, Institute of Nuclear
Medicine and Allied Sciences, Defence Research and Development
Organization, Brig. SK Mazumdar Road, Delhi 110054, India.
Email: aseembhatnagar64@gmail.com
Agrawal et al 181
Table 1.  Classification of Wounds Based on Appearance.8
Wound Type Appearance
Necrotic It is black or olive green in color because of
accumulation of dead tissues
Sloughy Fluid, wet, wobbly, and gristly rehydrated
necrotic tissue that is typically yellow in
color
Granulating Involves the production of excessive
exudates with more granulation tissue;
generally red or deep pink in color
Epithelializing Involves formation of new epidermis; it is
mainly pink in color
Infected and malodorous Involves pus formation, inflammation,
infection with anaerobic bacteria, and
unpleasant odor
wounds that produce ragged edges. They are produced
by a tremendous force against the body, either from an
internal source, such as in childbirth, or from an exter-
nal source, such as a punch.
2. Chronic wounds: Chronic wounds are the tissue
injuries that heal slowly, do not have any time limi-
tation for healing, and often reoccur.3 Delayed heal-
ing in these wounds is a result of different underlying
physiological conditions, such as diabetes, constant
infections, and reduced primary treatment factors.4
Production of excessive exudates is the key feature
of chronic wounds, which causes maceration of
healthy skin tissue around the wound5 and inhibits
wound healing. Excessive exudates reduce mobility
of lymphocytes at the wound site and cause delayed
healing. It results in a disruption of the sequence of
events during the wound healing process. Chronic
wounds include pressure sores and traumatic ulcers.
On the basis of skin layers and area, wounds can be clas-
sified as follows:
1. Superficial wounds: The injury6,7 only affects the
epidermal skin surface.
2. Partial thickness wounds: The injury involves both
the epidermis and the inner dermal layers, including
the blood vessels, sweat glands, and hair follicles.
3. Full thickness wounds: They occur when the under-
lying subcutaneous tissues are damaged in addition
to the epidermis and dermal layers.
Stages of Wound Healing Affected
Wounds such as pressure sores will usually split apart
spontaneously from the healthy tissue beneath because
of autolysis; this presumably involves macrophage
activity and the action of proteolytic enzymes, which act
at the border between the necrotic and healthy tissue. A
dry environment prevents the autolytic and proteolytic
actions of macrophages and enzymes
Associated with the production of excess exudates.
Slough leads to wounds getting caught in the late
inflammatory stage of the wound healing process, leading
to delayed wound healing
Proliferative phase
Involves both migratory and proliferative phases
It involves delayed collagen synthesis, inflammation, and
infection, which prolongs the inflammatory phase,
leading to delayed wound healing
On the basis of appearance, there are 5 categories, and
these are given in Table 1.
Wound Healing Process
Wound healing is a specific biological process related to the
general phenomenon of growth and tissue regeneration.
Wound healing progresses through a series of interdepen-
dent and overlapping stages in which a variety of cellular
and matrix components act together to reestablish the integ-
rity of damaged tissue and to replace lost tissue.9,10 In normal
skin, the epidermis and dermis exist in a steady-state equilib-
rium, forming a protective barrier against the external envi-
ronment. Once the protective barrier is broken, the normal
process of wound healing is immediately set in motion.
Blood clotting is an important mechanism to help the
body to repair injured blood vessels. Blood consists of red
blood cells containing hemoglobin that carry oxygen to cells
and remove carbon dioxide (the waste product of metabo-
lism); white blood cells, which fight infection; platelets that
are part of the clotting process of the body; and blood plasma,
which contains fluid, chemicals, and proteins that are impor-
tant for body functions. Complex mechanisms exist in the
bloodstream to form clots where they are needed. If the lining
of the blood vessels becomes damaged, platelets are recruited
to the injured area to form an initial plug. These activated
platelets release chemicals that start the clotting cascade,
using a series of clotting factors produced by the body.
Ultimately, fibrin is formed, the protein that cross-links with
itself to form a mesh that makes up the final blood clot.
182 The International Journal of Lower Extremity Wounds 13(3)

Table 2.  Desirable Characteristics of an Ideal Wound Dressing.17,18

Desirable Characteristics Clinical Significance to Wound Healing

Provides cleansing of wound
Provides a moist wound environment
Removes excess wound exudates in
chronic wounds
Supports oxygen permeability or gaseous
exchange
Provides protection against microbial
infection
Maintains wound temperature
Is cost-effective, cosmetically acceptable,
biocompatible, and elastic
To increase the migration of leucocytes into the wound bed and activate them to
release enzymes to kill foreign particles
Wound healing takes place faster in moist environment. The beneficial effects of a
moist versus a dry wound environment include: prevention of tissue dehydration
and cell death, accelerated angiogenesis, increased breakdown of dead tissue and
potentiating the interaction of growth factors with their target cells
Wound exudates contains tissue-degrading enzymes that block the proliferation of
cells and degrade ECM components and growth factors responsible for wound
healing, thus causing delayed wound healing
High levels of tissue oxygen stimulate epithelialization and activation of fibroblast
cells, whereas low tissue oxygen levels stimulate angiogenesis during the healing
process
Microbial infection prolongs the inflammatory phase of wound healing and creates an
unpleasant odor
Optimum tissue temperature improves blood flow to the wound bed and increases
the migration of cells
Dressing should be made on the basis of cost-benefit ratio

Abbreviation: ECM, extracellular matric.

The classic model of wound healing has been described by
Schultz11 and involves 5 overlapping stages that involve com-
plex biochemical and cellular processes. These are described
as hemostasis, inflammation, migration, proliferation, and
maturation or remodeling phases. On injury to the skin, a set
of complex biochemical events takes place in a closely orches-
trated cascade to repair the damage. Within minutes postin-
jury, platelets (thrombocytes) aggregate at the injury site to
form a fibrin clot. This clot acts to control active bleeding
(hemostasis). Hemostasis, therefore, plays a protective role as
well as contributing to successful wound healing.12 Clots are
primarily composed of a fibrin mesh and aggregated platelets
along with embedded blood cells.13 In the inflammatory
phase, bacteria and debris are phagocytosed and removed, and
factors are released that cause the migration and division of
cells involved in the proliferative phase.
The proliferative phase is characterized by angiogenesis,
collagen deposition, granulating tissue formation, epitheli-
alization, and wound contraction. In this phase, granulating
tissue is formed by the in-growth of capillaries and lym-
phatic vessels into the wound, and collagen is synthesized
by fibroblasts, giving the skin strength and form. In angio-
genesis, new blood vessels are formed by vascular endothe-
lial cells. In fibroplasia and granulating tissue formation,
fibroblasts grow and form a new, provisional extracellular
matrix (ECM) by excreting collagen and fibronectin.
Concurrently, reepithelialization of the epidermis occurs, in
which epithelial cells proliferate and “crawl” atop the
wound bed, providing cover for the new tissue. During con-
traction, the wound is made smaller by the action of myofi-
broblasts, which establish a grip on the wound edges and
contract themselves using a mechanism similar to that in
smooth muscle cells. When the function of the cell is com-
pleted, unneeded cells undergo apoptosis. The final phase is
the remodeling or maturation phase in which the collagen is
synthesized, degraded, and reorganized.14 Collagen is ini-
tially deposited in an irregular way, after which the indi-
vidual collagen fibrils are reorganized in bundles regularly
aligned and orientated along stress lines.15
Wound Dressing
A wound dressing includes a first layer located adjacent to
the wound and comprises a material that should be bioab-
sorbable, porous, and adapted to serve as a scaffold for cell
attachment and proliferation; the second layer, which is in
contact with the first layer, comprises an absorbent and gel-
forming material adapted for serving as a barrier to cell
adhesion and penetration.16 The desirable characteristics of
an ideal wound dressing are mentioned in Table 2.
Classification of Wound Dressings
On the basis of nature of action, wound dressing products
are generally classified as follows: (a) passive products,
which include traditional dressings like gauze and tulle
dressings; (b) interactive products, which include polymeric
films and forms, which are mostly transparent, allow per-
meation of water vapor and oxygen, but prevent microbial
infection; these films are mainly used for wounds with low
exudates; (c) bioactive products, which are constructed
from material having endogenous activity; these materials
Agrawal et al 183
Table 3.  Different Types of Materials for Hemorrhage Control.25-30
Material Type/Form Examples
Biopolymers Chitosan, collagen, and fibrinogen
Synthetic materials Polyethylene Glycol (PEG)
Liquid dressing Tissue sealants
Solid dressing Thrombin, fibrinogen, chitosan, alginate,
hyaluronic acid
Solid powder QuikClot
include proteoglycans, collagen, noncollagenous proteins,
alginates, and chitosan.
Polymeric Biomaterials in Wound Healing
Biomaterials are nonviable materials used in medical
devices, which are anticipated to interact with biological
systems. They have great potential to be used in civilian as
well as in military settings19: for example, they can be used
for hemorrhage control in surgery in hospital settings20 and
for combat casualty care on the battlefield.21 Nowadays,
these materials have become very popular in health care
because of their life-saving properties.22 They have been
used to control severe hemorrhage from trauma, which is
the second leading cause of death in the civilian community
following central nervous system injuries23 and the leading
cause of death on the battlefield followed by brain inju-
ries.24 A large number of materials in different forms have
been studied to control bleeding. The criteria for biomate-
rial selection should be based on probability of success in
vivo, stability, and ease of use and manufacturing. The opti-
mal biomaterial should meet the following requirements:
biocompatibility with tissues, biodegradability at the ideal
rate corresponding to the rate of new tissue formation, non-
toxicity and nonimmunogenicity, optimal mechanical prop-
erties, and adequate porosity and morphology for
transporting of cells, gases, metabolites, nutrients, and sig-
nal molecules both within the biomaterial and between the
biomaterial and the local environment. Table 3 lists the dif-
ferent types of materials and their advantages.
Biopolymers are polymers that are biodegradable. The
word polymer means many parts (from the Greek poly,
meaning many and meros meaning parts). Polymers are
long-chain giant organic molecules assembled from many
smaller molecules called monomers, which are typically
connected by covalent chemical bonds. Biopolymers have a
long history of use as biomaterials for hemorrhage control.
An ideal polymer must have these qualities: good mechani-
cal properties, should not cause inflammatory response, and
should be metabolized and released from the body.
Biopolymers can be classified into natural and synthetic
polymers.
Advantages
Has gel- and film-forming property, biodegradable, and
biocompatible
Cheap and easy to use and has good compatibility
Universal for different wound types
High efficacy, easy to use, uniform application, and
short preparation time
Conformable and uniform application to irregular
bleeding surface with convenient storage
Natural Polymers. These are the naturally occurring poly-
mers, which are used as hemostatic agents. These polymers
include proteins (eg, fibrinogen, thrombin, collagen, gela-
tin, and albumin) and polysaccharides (chitosan, chitin,
poly (N-acetyl glucosamine), and cellulose). They have
been used in the form of solid sheets/sponges, powders, and
liquids and have received considerable attention for use in
tissue engineering because of their biocompatibility, biode-
gradability, and hydrophilicity. They are biodegradable and
bioresorbable to support the reconstruction of a new tissue
without inflammation.31 Different natural polymers, their
sources, and their applications are listed in Table 4.32-51
Synthetic Polymers. These include poly(α-hydroxy acids),
especially polylactic acid (PLA), polyglycolic acid (PGA),
polyacrylate,52-55 and their copolymers—poly(ε-caprolactone),
poly(lactic-co-glycolic acid) (PLGA), polypropylene fuma-
rate, polyorthoesters, polycarbonates, and polyanhydrides.
Particularly interesting are PLA and PGA polyesters, which
are extensively used in biodegradable implants and tissue
engineering. Hydroxyapatite used in bone repair has been
used to control bleeding in osteoporotic sternums.56,57 Syn-
thetic polymers also involve polyethylene glycol sealants,58
liquid sealants, and dispersions.59
Natural Biopolymers as Hemostatic Agents
Chitin and Chitosan.  Chitin is the principal structural com-
ponent of the exoskeleton of invertebrates, such as crusta-
ceans and insects. Chitin can be converted into soluble
derivatives, such as chitosan, caboxymethyl chitin, and gly-
cochitin. Chitin-based biopolymers are materials with great
versatility and can be processed into different forms (fibers,
sponges, membranes, beads, and hydrogels). There are 2
main polysaccharides used in hemorrhage control.60 These
are the natural polymers composed of randomly distributed
β-(1-4)-linked d-glucosamine (deacetylated unit) and
N-acetyl-d-glucosamine (acetylated unit). Chitosan is pre-
pared from deacetylation of chitin by enzymatic or alkaline
hydrolysis. It is soluble in slightly acidic media,61 in which
chitosan obtains a positive charge because of the presence
of primary amines that bind protons; This is an important
184 The International Journal of Lower Extremity Wounds 13(3)
Table 4.  Natural Polymers and Their Applications.32-51
Natural Polymer Source
Starch Plant (eg, corn, rice, potato, and
wheat)
Cellulose Plants materials such as (cotton,
wood, straw, etc), bacteria
(Acetobacter xylinum)
Arabinogalactan Plant (extracted from the
(larch gum) western larch Larix occidentalis)
Alginate Brown algae (Phaeophyceae,
mainly Laminaria), microbial
(bacteria, Pseudomonas
mendocina)
Agar Red algae: Rhodophyceae
(Gelidium and Gracilaria spp)
Chitosan Exoskeleton of crustaceans (crab, Chitosan is a bioactive product
crayfish), fungal cell walls
Dextran Microbial (bacterium Leuconostoc It is soluble in both water and
mesenteroides)
Gelatin Bacteria (Sphingomonas elodea) It melts when heated and
property of chitosan that is used in wound healing. Chitosan
dissolves when more than 50% of the amino groups are pro-
tonated,62 so the solubility of chitosan preparations
decreases as the pH of the solution increases above 6.0 to
6.5. Chitosan is mainly involved in the rapid mobilization
Properties Application
Starch has gel- and film-forming Starch-based scaffolds have
properties, so it can be used been prepared by different
as hemostatic agent. It can methods32-34 for bone TE
be easily modified either by
cross-linking or oxidized by
different oxidizing agents,
which provides it better
mechanical properties.35,36 It
is enzymatically degraded by
α-amylase37
Cellulose can be converted into Cellulose and its derivatives are
different derivatives (carboxy used to prepare scaffolds for
methyl cellulose, cellulose cardiac tissue engineering38,39
nitrate, cellulose acetate,
cellulose xanthate)40
This polymer is a highly branched It is used to prepare scaffolds for
polysaccharide that is highly tissue engineering
soluble in water41
Alginate has good gel-forming It is mainly used as a hemostatic
and film-forming properties. agent in different forms such as
The size and proportion gels, films, scaffolds, and so on.
of the monomeric units of It can also be used as a vehicle
polymer chains determines for foreign cell delivery42
the formation and strength of
gels.43 Calcium alginate is mainly
used in the formation of wound
dressings
Agarose-based gels are produced, Agarose gels and sponges have
which have the property of been used in engineered
thermal reversibility cartilage formation 44 and nerve
regeneration45,46
Chitosan is mainly used as a
soluble in slightly acidic media. hemostatic agent in different
It gradually depolymerizes forms such as gels, films,
to release N-acetyl-b-d- and scaffolds. Chitosan
glucosamine, which initiates scaffolds and tubes can be
fibroblast proliferation and produced by freeze drying and
helps in collagen deposition electrospinning for bone and
during the wound healing cartilage engineering and nerve
process. Its hemostatic regeneration48,49
properties are based on degree
of deacetylation and molecular
weight47
Scaffolds and porous hydrogels
organic solvents for TE applications50
Gelatin-based gel in tissue
solidifies when cooled again. It engineering51
is soluble in water and forms
a semicolloidal, soft, elastic,
transparent, and flexible gel
of platelet and red blood cells to the injured site during the
healing process.63 It also helps in vasoconstriction and acti-
vates blood clotting factors, which are responsible for blood
clotting. Chitosan is known to accelerate granulation during
the proliferative stage of wound healing,64 and the effect of
Agrawal et al 185
chitosan on wound healing has already been reviewed.65 In
wounds, when the vessel wall is damaged or ruptured,
platelets migrate and adhere to the site of injury to expose
subendothelial tissue, such as collagen, and this is a critical
step in hemostasis or thrombosis. The initial adhesion can
generate intracellular signals responsible for the activation
of GPIIb/IIIa, which in turn causes the release of thrombox-
ane A2, which further promotes the spread of platelets. This
reinforces the stability of adhesion of blood platelets to the
site. Chitosan significantly enhances both platelet adhesion
and aggregation, thus contributing to wound healing.66
Chitosan also possesses good film-forming properties
and is therefore used in the formulation of gels and coat-
ings. Because of its abundance, low cost, and relatively
unusual properties, chitosan and its derivatives have been
used in a diverse range of medical as well as pharmaceutical
applications. As a wound dressing material, chitosan pos-
sesses a unique set of advantages: biodegradability to harm-
less products, nontoxicity, physiological inertness,
antibacterial properties, biocompatibility, heavy metal ions
chelation, gel-forming properties, and remarkable affinity
to proteins. Chitosan is antimicrobial against a wide range
of target pathogenic organisms. Both chitosan and chitin are
used for solid wound dressings, and this is well docu-
mented.67-69 For example, chitin-chitosan dual-layer materi-
als have been prepared and used as solid wound dressing for
the treatment of mustard burns.
Chitosan provides a non–protein matrix for the 3-dimen-
sional growth of tissues, thus affecting the histoarchitec-
tural organization of tissues. It also stimulates macrophage
activity that helps in faster wound healing and scar preven-
tion. Chitosan is a hemostat, which helps in natural blood
clotting and blocks nerve endings, reducing pain. Chitosan
gradually depolymerizes to release N-acetyl-d-glucosamine,
which initiates fibroblast proliferation, helps in collagen
deposition, and stimulates increased levels of natural hyal-
uronic acid (HA) synthesis at the wound site. It allows more
oxygen permeability, which prevents oxygen deprivation in
inner tissues, and is also involved in the activation of poly-
morph nuclear neutrophil cells at the wound site.
Collagen.  Collagen is the most abundant protein present in
the human body and is the major component of skin and
other musculoskeletal tissues. It is a natural biopolymer and
plays a key role in wound dressing.70 There are at least 25
types of collagen, out of which types I and III have been
used in severe hemorrhage control. Collagen is composed
of 3 polypeptide chains with triple-helical domains. It is one
of the primary initiators of the coagulation process, and its
high thrombogenicity has led to its application as a hemo-
static agent. Collagen has been frequently used in the for-
mulation of different solid wound dressings for blood
clotting.71-78 It is found that collagen causes blood clotting
through a pathway similar to physiological hemostasis.70 It
also stimulates platelet adhesion and aggregation and acti-
vation of blood coagulation factors by interacting with an
activation factor present in blood plasma; it thus leads to
adhesion and activation of thrombocytes at the wound site
and then forms a stable thrombocyte clot. Moreover, dry
collagen materials are prepared, which physically adsorb
blood by trapping blood cells and effectively adhere them to
the wound site, providing mechanical strength. A commer-
cially available product, Colgel, has been developed from
collagen powder, and has been found to be more effective in
blood-loss reduction in the patients undergoing cardiac
operations associated with a high risk of blood loss.79 The
major source of collagen used for biomedical applications
are bovine or porcine skin or bovine or equine Achilles
tendons.
Gelatin.  It is a protein that is frequently used as a hemostatic
agent. It contains a repeating amino acid sequence of Gly-
X-Y, where X and Y are mainly proline and hydroxylpro-
line.80 It melts when heated and solidifies when cooled
again. When it is dissolved in water, it forms a semisolid
colloidal gel. Most gelatin-based solid dressings have a
spongy structure.81,82 They are considered as ideal hemo-
static materials.83,84 Gelfoam (Upjohn, Kalamazoo, MI) is a
good example of gelatin-based solid dressings. Gelatin-
based dressings are also available in powder form—for
example, SURGIFOAM powder—and can be easily spread
into the contours of the bleeding surface for hemostatic effi-
cacy.85 It is reported that gelatin stimulates macrophage
activity and does not cause antigenicity.86 Like fibrin glue,
gelatin has been widely used as a tissue adhesive for wound
closure because of its good hemostatic effect.
Hyaluronic Acid.  Hyaluronic acid or Hyaluronan is a poly-
saccharide, which is the major part of the ECM in connec-
tive tissues. It is an important ECM glycosaminoglycan,
composed of d-glucuronic acid and N-acetyl-glucosamine.
It is potentially less antigenic, and this important property
allows it to be used as a wound sealant. Through many in
vitro and in vivo studies, it is reported that HA is actively
involved in cell proliferation and differentiation during the
healing process.87 A HA-based scaffold has also been pre-
pared, which shows a very high hemostatic effect when
compared with other wound dressings. HA scaffolds were
found to be stable cell carriers and have the potential to gen-
erate volume retaining tissue. Because of the high function-
ality and charge density of HA, it can be cross-linked by a
variety of physical and chemical methods. Many deriva-
tives of HA have been prepared by modifying its functional
group, which improves its properties and is mainly respon-
sible for its medical use. HYAFFR11 (Fidia Advanced Bio-
polymers, Abano, Italy) is a derivative of HA that is
modified by esterification of the carboxylic group of gluc-
uronic acid with the benzyl group. This makes it more
186 The International Journal of Lower Extremity Wounds 13(3)
resistant to hyaluronidase activity and also increases the
hydrophobicity. Stillaert et al88 performed a pilot clinical
trial, which showed good efficacy of HA-based wound
dressings. Because HA is produced by cells during early
wound healing, this polymer has been extensively investi-
gated for wound dressing applications. HA also play a key
role during the angiogenesis phase of wound healing to
modulate wound site inflammation by acting as a free radi-
cal scavenger and is recognized by receptors on a variety of
cells associated with tissue repair. Perng and others demon-
strated that high-molecular weight HA shows adverse effect
during angiogenesis,89 but short-chain HA with 3 to 10
disaccharide units promotes angiogenesis.90,91 It is observed
that the angiogenic effect of short-chain HA is mediated by
2 receptors: a receptor for HA-mediated motility (RHAMM)
and CD44, which are related to endothelial cell prolifera-
tion and migration during the healing process.92
Alginate.  It is another widely used wound dressing biopoly-
mer.93 It is derived from seaweed and composed of either
mannuronic or guluronic acid complexes. The high func-
tionality of alginic acid makes it a favorable biopolymeric
material for use in biomedical applications. The high acid
content allows alginic acid to undergo spontaneous and
mild gelling in the presence of divalent cations, such as cal-
cium ions. Alginate has good gel-forming and film-forming
properties and, thus, can be used as a hemostatic agent.94
Many studies have been performed to evaluate the efficacy
of alginate-based wound dressing.95,96 It is observed that the
hemostatic effect of alginate is mainly based on calcium
ions because it contains mannuronic or guluronic groups
with high calcium content.97 In wound management, several
wound dressings are commercially available based on
alginic materials.98-101 The gel-forming property of alginate
helps in removing the dressing without much trauma and
reduces the pain experienced by the patient during dressing
changes.102 It provides a moist environment that leads to
rapid granulation and reepithelialization during wound
healing. Calcium alginate is widely used as a hemostatic
agent.103 In a clinical study with burn patients, calcium algi-
nate dressings were shown to yield 10 times faster healing
than normal paraffin gauze. The combined use of calcium
sodium alginate in wound dressing reduces pain and the
problem of sarcoma formation at the site of injury.104
Carboxylic-Oxidized Polysaccharides.  These are another group
of biopolymers used to prepare wound dressings. They are
fabric substrates having carboxyl moieties, which oxidize
to provide the fabrics with biodegradability and antimicro-
bial activity. Carboxylic-oxidized cellulose is mainly used
to prepare fabrics for hemorrhage control. These materials
can be oxidized either by the oxidizing agents such as dini-
trogentetroxide in a Freon medium105 or nitrogen dioxide in
a per-fluorocarbon solvent.106 By using these fabric
substrates, several wound dressings have been prepared.
These dressings show good hemostatic effect in severe
bleeding. A number of commercial products—for example,
SURGICEL and NU-KNIT—have been developed from
oxidized cellulose.107-109 A new process has been developed
to produce macroporous cellulose implants.110 In this pro-
cess, calcium carbonate powder is used as an inverse matrix
embedded into cellulose xanthate. After dissolution of the
matrix, a porous material was formed. The resulting porous
material was later oxidized for its hemostatic use.
Fibrinogen and Thrombin. These are the 2 most important
proteins involved in coagulation. Fibrinogen is a large solu-
ble glycoprotein present in blood plasma, which is com-
posed of 3 nonidentical polypeptide chains: Aa, Bb, and
g.111 Thrombin is a serine protease that catalyzes many reac-
tions during the blood coagulation process.112 In the pres-
ence of thrombin, fibrinogen converts into fibrin by the
cleavage of 4 small peptides of fibrinogen molecule into its
monomers.113 The monomers are then polymerized to form
fibrin strands.114 This fibrin is still susceptible to the fibri-
nolytic enzyme plasmin and requires the action of the
enzyme factor XIIIa to produce insoluble fibrin. This pro-
cess involves the formation of covalent bonds (cross-link-
ing) between the fibrin polymers.115 Fibrin is a biopolymer
similar to collagen that is involved in the natural blood clot-
ting process. Dry fibrin dressings have been prepared from
different combinations of fibrinogen and thrombin and have
shown good hemostatic effect in severe bleeding. One of
the first products developed from fibrin was a fibrin sealant,
which was used clinically worldwide for hemostasis and
tissue sealing in various surgical procedures. Bioseed is a
fibrin-based product obtained by mixing keratinocytes with
fibrin and is used to treat chronic wounds.
Biopolymer-Based Dressing for
Infected Wounds
Microbial contamination and persistent infection are major
causes of delayed wound healing. Most often, wounds are
contaminated by bacteria like Staphylococcus aureus,
Escherichia coli, and Pseudomonas aeruginosa. An infected
wound may be characterized by sustained pain, erythema,
pus formation, bad odor, and so on. Various local and sys-
temic complications also occur because of infected wounds,
which impair the healing process, resulting in significant
pain and discomfort for the patient. The infection can also
affect the surrounding tissues and may cause a bacterial
skin infection (cellulitis) or an acute or chronic bacterial
bone infection (osteomyelitis). If the infection spreads to
the blood vessels, the bacteria may spread and cause infec-
tion in other areas of the body.
Currently, various biopolymers are commonly used to
develop absorbent dressings for the treatment of infected
Agrawal et al 187
wounds because of their antimicrobial property. Chitosan
materials have been the object of significant attention in the
past decade because of their inherent antimicrobial activity
against a broad spectrum of bacteria.116 Wound dressings con-
taining cationic polysaccharide fibers have been shown to
promote wound healing and prevent infection while also
slowing blood loss.117,118 The interaction between the posi-
tively charged chitosan and negatively charged microbial cell
wall leads to the leakage of intracellular constituents. Chitosan
penetrates into the nuclei of the microorganisms and inhibits
gene expression. Chitosan and polyvinyl amine embedded in
cotton is used as a model system to prepare antimicrobial
wound dressings to control persistent infection in nonhealing
wounds.119 The resulting antimicrobial biopolymer-based cot-
ton dressing can be used successfully in wounds, burn, and
ulcer healing. Different biopolymers are being used to develop
polymeric antimicrobial wafers for the management of sup-
puration caused by bacterial contamination in infected
wounds. These porous, self-adhesive, nonfriable wafers are
produced with sodium alginate, guar gum, xanthan gum, and
karaya gum. Infected wounds are also cured by the use of anti-
biotics, whether applied directly to the wound (topical) or
taken orally (systemic). In the case of severe wound infection,
intravenous antibiotics may be given to combat severe blood
infection (sepsis). Biopolymers with incorporated antibiotic-
based dressings have been shown to control infection and has-
ten the healing process. Antimicrobial compounds such as
neomycin sulfate, chlorohexidine digluconate, povidone
iodine, and silver sulfadiazine are being incorporated in com-
patible biopolymers and used to develop an ideal dressing for
the treatment of infected wounds. Antimicrobial activity
depends on the sensitivity of the microorganisms to a specific
antimicrobial compound as well as its interaction with the bio-
polymer. Usually, factors such as protein content, electrolyte
content, and pH of exudate play a significant role in the effi-
cacy of absorbent dressings developed for topical application
on wounds. Additives with distinctive functions such as silver
metals or their salts can be introduced in modern wound dress-
ings, which absorb unpleasant odor from infected wounds and
provide antibacterial properties. Zinc pastes are being used to
soothe pain and relieve irritation, and sugar pastes are used as
deodorizing agents. Silver-impregnated textiles are used as
ideal dressings for wounds with severe infection.120
Antimicrobial yarns can be produced from cotton, wool, poly-
ester, nylon, and their blends incorporated with nanosilver
particles,121 For example, silver-incorporated yarns showed
effective antimicrobial activity against a broad spectrum of
bacteria, fungi, and other microbes and serve as wound care
devices for improved healing.122
Discussion
The article is an overview that deals with improvements in
wound management materials and techniques that offer
great versatility. Different biomaterial-based wound care
products are recognized, understood, and evaluated. In this
era of innovative and growing science, a paradigm shift in
the current approach for wound care will be required by both
researchers and clinicians; so that more advanced wound
healing agents can be designed and developed. There is a
paradigm shift from allopathy to natural/herbal wound care
agents. Natural products, including plant-derived extracts
and naturally derived substances, have been used for a long
time in wound care. In recent times, the interest of research-
ers has inclined toward the use of herbal remedies because
they are safer and cheaper than standard therapies.123
Many natural products possess antiseptic, astringent,
anti-inflammatory, antimicrobial, and biostimulatory prop-
erties that increase the rate of the wound healing process.
Collaborative research between allopathic medicine and
Ayurveda/naturopathy will provide a better understanding
of how the natural products can be integrated into wound
care. There are many challenges that need to be taken into
consideration in developing ideal wound care dressings.
The field is wide open for researchers to make some dreams
come true in real clinical applications.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
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