wounds normally heal in a very orderly and efficient manner
characterized by four distinct but overlapping phases: hemostasis,
inflammation, proliferation and remodeling.
factors have an impact on the healing process, from the initial
inflammatory reaction to the final maturation of the fibrous scar.
Any impairment in the normal reparative process may lead to either
delayed healing or excess fibrosis (1). Skin ulcers, including
diabetic foot ulcers, venous ulcers and pressure ulcers are among the
most frequent and characteristic type of chronic non-healing wounds.
One of the major causes of delayed healing is the persistence of
inflammation or an inadequate angiogenic response (2, 3). In
contrast, overhealing, or excessive fibrosis of wounds, is observed
in fibroproliferative disorders such as keloids and hypertrophic
scars. The precise etiologic factors associated with keloid formation
are elusive, with the exception of tissue trauma; however, keloids
have been reported in the absence of trauma. Adverse wound healing
characteristics, such as infection and excessive wound tension, are
associated with keloids and hypertrophic scars.These conditions are
characterized by abnormal accumulation of collagen within the wound
site as a result of failure to eliminate granulation tissue cells
(1). The expression of vascular endothelial growth factor (VEGF) and
several enzyme systems, including nitric oxide synthase (NOS),
cyclooxygenase (COX) and Arginase, are vital for maintaining the
different phases of wound healing (2). Research in wound healing has
been concerned primarily with one of three clinical objectives. The
first involves the search for agents that could improve the end
result of the healing process. The second concerns the search for
treatments that could accelerate the early phases of the healing
process under normal conditions. The third involves the development
of protocols to close difficult or non-healing wounds.
progress in wound management is mainly in terms of physiological
support of healing. Since infections delay healing and worsen scar
formation, there is a desire to achieve closure as soon as possible.
The main goals of wound care are prevention of infection, maintenance
of a moist environment, protection of the wound, and minimum scar
is the second most abundant polysaccharide in nature (after
cellulose). At least 10 gigatons of chitin are synthesised and
degraded each year in the biosphere. Chitin mainly consists of the
aminosugar N-acetylglucosamine, which is partially deacetylated. The
mostly deacetylated form of chitin is called chitosan. Chitin is
present in nature usually complexed with other polysaccharides and
with proteins. Chitin is a renewable resource and is isolated from
crab and shrimp waste. It is used for waste water clearing, for
cosmetics and for medical and veterinary applications. Chitin has
some unusual properties which accelerate healing of wounds in humans.
Recently a novel method for the production of nanofibrillar chitin
has been developed, which is sustainable from an industrial
manufacturing standpoint and suitable for producing chitin
nanofibrils with improved properties which are free from other
crystalline components (5). Nanofibrils are extremely small objects,
each of which is composed of fewer than 20 polysaccharide chains that
recognize each other. From a biological point of view, the
crystalline nanofibrils themselves stimulate keratinocytes to grow
quickly and encourage fibroblasts to produce the right amount and
quality of collagen fibrils. Chitin is recognized easily by the
cutaneous enzymes and hydrolized in N-acetyl glucosamine (5).
main biochemical activities of chitin and chitosan-based materials
are: polymorphonuclear cell activation, fibroblast activation,
cytokine production, giant cell migration and stimulation of type IV
collagen synthesis (6, 7).
this study the effects of a new chitin nanofibrils-based gel on the
rate and quality of wound healing were investigated in a clinical
patients (20 males and 28 females, mean age 50.2 years) were treated
and controlled according to a standard protocol for 3
months and were divided in three groups. Members of the first group,
20 patients, were treated for wounds of different origin (trauma,
surgery, lasers, etc.) in different parts of the body. Those in the
second group, 19 patients, were treated for difficult wounds which
showed severe slowing of the healing process (delays in excess of one
month). Patients in the third group, 9 in number, were treated “split
manner” (after written informed consent had been obtained): one
part of the wound, or in case of two adjacent wounds only one of
these, was medicated with the new gel, the other part or the other
wound was medicated traditionally.
chitin nanofibrils-based gel used in this study was Mavimed Gel®
produced by MAVI SUD s.r.l. Aprilia (LT), Italy.
product was applied in a home-based protocol twice a day in every
case. Before every application the wound was washed with 0.9%
isotonic saline solution. No other local antiseptic was employed. The
patients in the second group – these with difficult wounds
– were also treated with other appropriate systemic therapies (i.e.
correct insulin administration in those with diabetes), removable
elastic bandages (i.e. venous ulcers), mechanical or erbium:YAG laser
debridment of the fibrin coat excess if present. In none of the
patients there were signs of acute infections. The wound surface did
not exceed 90 cm2
in any case. The assessment of the wounds progress was made for every
group at 2, 6, 10, 14 and 30 days, and at 3 months.
surgical wounds were evaluated for early phases of the healing
process and the end result of it (i.e. hypertrophic scarring or
wounds (i.e. laser surgery, traumas or ulcers) were also evaluated
with the computation of the percentage of wound healing. A
semi-transparent paper was placed on the location of the wound and
its shape drawn on the paper. The percentage of wound healing was
calculated by Walker formula (Tab. 1) after measurement of the wound
area (8). Percentage
of wound healing was computed at the beginning of the treatment and
then at 2, 6, 10, 14 and 30 days. In the second group the percentage
of wound healing was also computed the week before starting the
application, at day 1 and 7.
t-test and ANOVA were
used to test differences in the healing speed between different areas
of the same wound or different wounds in the same patient.
were considered significant when P<0.05. Results are given as
means of values.
3-month scar assessment was made with a modified Singer&Hollander
(2007) evaluation scale (9). Scars were assigned 0 or 1 point each
for the presence or absence of the following:
greater than 2 mm, elevation or depression, colour alterations,
paresthesias, and overall poor appearance. A total score was
then calculated by adding the individual scores on each of the five
categories ranging from 0 (worst) to 5 (best).
patient treated with the new chitin nanofibrils-based gel had
complete healing. The assessment at 3 months for the first group of
patients, based on scar features, registered only 3 cases (15%) of
serious hypertrophic trend (badly oriented surgical wounds).
Moreover, in two patients with keloid scar
history was observed normal healing of the treated wounds. The
average score was 3.95 (modified Singer&Hollander evaluation
the second group every patient had a resumption of healing at day 6,
and the difference between the percentage of wound healing calculated
by Walker formula (see Tab. 1) the week before starting the
application of the gel and a week after application was statistically
significant (P<0.05) (Graph 1, Fig. 1).
the third group, in 7 patients (77.7%), a statistically significant
higher percentage of wound healing of the treated area than the
non-treated one was seen, starting at day 6 (P<0.05) (Fig. 2,
Fig. 3). In this group the assessment at 3 months also showed a
better average score of the treated areas than the non-treated ones:
4.2 treated ones vs 3 non treated ones. In one patient, with
hypertrophic scarring history, different Er:YAG laser abrasions of
the shoulders were treated. The treated ones at 3
months showed normal healing, the non-treated ones hypertrophic trend
major or minor complications were associated with the use of the
repair must occur in a physiological environment conducive to tissue
repair and regeneration. Alteration in the sequence of wound healing
may result in the development of an abnormal wound, leading to either
delayed healing or excessive fibrosis (10). The most common examples
of delayed healing include diabetic foot ulcers, venous leg ulcers
and pressure ulcers. Overhealing is observed in fibroproliferative
disorders such as hypertrophic scars and keloids, which are
characterized by excessive accumulation of collagen fibers within the
wound site (11). Several clinically significant factors are known to
hinder wound healing, including hypoxia, infections, metabolic
disorders such as diabetes mellitus, the presence of debris and
necrotic tissue, certain medications, etc. The objective in wound
management is to heal the wound in the shortest time possible, with
minimal pain, discomfort, and scarring to the patient. At the site of
wound closure a flexible and fine scar with high tensile strength is
chitin nanofibrils have a microstructure typical of crustacean and
insect cuticles. From a biological point of view, when a gel
containing these structures is applied to a wound it is able to form
a protective biofilm, thin, elastic and water soluble, which promotes
tissue healing. It was demonstrated that these extremely small
objects (each of them is composed of fewer than 20 polysaccharide
chains that recognize each other) stimulate keratinocytes and
fibroblasts to proliferate faster and lead the fibroblasts to produce
the right amount and quality of collagen (5). Because of the chemical
bonds that can be established with many molecules, the chitin and
chitosan induce fast blood coagulation following adsorption of some
enzymes and blood platelets on its surface. Moreover, chitin
nanofibrils act on the cells by modulating the cytokines production;
hence they have an interesting anti-inflammatory action (5).
if the first group of this study is not considered representative of
the general population, the frequency of hypertrophic scarring
observed – 15%, 3 in 20 –
is much less than the frequency in previous reports (in skin surgery
it is about 35.3%) (12). Moreover, in the patient of the third group
with hypertrophic scars history the laser abrasions treated with the
chitin nanofibrils gel showed normal healing, while the abrasions
which were not treated showed hypertrophic trend. Finally, the two
patients with keloid scars history and a surgical wound treated with
the gel had normal wound healing.
chitin nanofibrils-based gel seems to prevent hypertrophic scarring
and keloid scarring, probably through two different mechanisms: the
first promotes prevention of infections, the maintenance of a moist
environment and the protection of the wound; the second involves
modulation of fibroblasts proliferation and collagen production, also
through its antinflammatory activity. The modulation of fibroblasts
proliferation is probably also related to the mechanical inhibition
due to the presence of the chitin network in the wound environment
results of this clinical study confirm that chitin nanofibrils-based
gel promotes rapid and physiological healing of different types of
of its protective activities the nanofibrils based gel can be used
for the treatment of superficial wounds, abrasions, sores (I–IV)
and surgical wounds, and it is useful in all cases of delayed or
difficult healing. It seems to prevent hypertrophic scarring and
keloid scarring. The natural film that it forms on the skin is well
tolerated and devoid of side effects.
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