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TIMP1*
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F. D’Andrea and F. Mosella
action in two ways: by preventing the activation
of proenzyme molecules or by blocking the activity of activated MMPs [90] The presence of
bacteria in wounds can increase protease activity.
Bacteria induce an inammatory response that
stimulates protease production. In addition, the
bacteria themselves may produce the proteases
[91].
In healthy skin, the levels of MMPs are very
low. Under physiological conditions, following
injury, there is a rapid increase in proteases that
induces degradation of the damaged ECM and
assists in neutrophil recruitment and clearance of
any foreign bodies. The peak concentration
decreases within 5days leading quickly to restitutio ad integrum. In hard-to-heal wounds, persistence of high levels of proteases responsible
for growth factor degradation and prevalence of
ECM destruction processes over deposition processes are often observed. Such conditions fur-
Fig. 23.12 Schematic
representation of MMP
activation under inammatory
and wounding conditions. (a)
Overview of the production,
activation, and inhibition of
MMPs by TIMPs. (b)
Modulation of MMPs/TIMPs
production by reactive
oxygen species, other
proteases, and by cytokines
and growth factors released
under inammatory and
wounding conditions. These
regulations are reported in the
literature and may depend on
cell types and tissue
microenvironment [92]
b
Inflammatory cells
Inflammatory cells
Reactive oxygen species
ther fuel the inammatory response and the
release of harmful reactive oxygen species
(Cullen’s circle) leading to the blockage of healing in the inammatory phase.
Pro-MMPs are the inactive forms of MMPs;
MT-MMPs are membrane-type MMPs; TIMPs,
tissue inhibitor of metalloproteinases. The thin
curved arrow indicates activation of MMPs and
inhibition of MMPs.
Increased levels of MMPs do not result in
characteristic clinical signs that would diagnose
such an alteration. Such a condition may be
hypothesized when, despite good control of the
patient’s comorbidities and appropriate local
management (debridement of LOS, control of
bacterial load, good management of examination), the lesions appear to be in a stalled phase
(Figs.23.12 and 23.13).
To date, there is still no precise denition of
dressings that act on metalloproteases.
Wounded cells
Other Proteases
Serine proteases. or
other MMPs
MT-MMP
Wounded cells
MMPs
Pro-MMPs
TIMPs
Proteases
Cytokines and growth factor
MMPs
TIMPs
IL6, IL4,
TNF, TGF
β
MMPs
TIMPs TIMP-1 and TIMP-3 TIMP2,
MMP1#MMP3
MMP7, MMP11#MMP9,
MMP14#MMP17, MMP19,
MMP25
CTGF, HGF*
MMP2#MMP3
MMP9, MMP13,
MMP14,
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Fig. 23.13 Stalled wound characteristics [93]
239
Dissemond in the 2020 review (rst MMPs
biblio) distinguished dressings active on MMPs
into:
dressings that inhibit MMPs,
dressings that modulate MMPs.
The distinction between the two classes is
that the former were specically marketed for
their action on proteases, the latter result in
their modulation by rebalancing the ulcer
microenvironment.
The dressings that inhibit the secretion of
metalloproteases are essentially two:
Oxidized regenerated cellulose (ORC)/collagen commercialized in the late 1990s.
Lipid-Collagen Technology with
NanoOligosaccharide Factor (TLC-NOSF) introduced to the market in 2000.
ORC/collagen matrix is a sterile lyophilized
pad composed of 55% collagen and 45% oxidized regenerated cellulose (ORC). It reduces the
activity of elastase, MMPs (drastically collagenase and gelatinase), and oxygen free radicals.
Interacting with the injury, it inhibits tissue
degradation and promotes granulation tissue synthesis by inducing [94]:
• the reduction of proteolytic activity and free
radical damage,
• the binding and stabilization of growth factors
(PDGF),
• the increased recruitment of macrophages and
broblasts,
• the proliferation of broblasts [95].
It is a highly conformable dressing that
degrades on contact with exudate.
In wounds with little exudate, it can be activated with a few drops of distilled water or saline.
It is indicated in cleansed wounds with mild/
moderate exudation, both acute and chronic.
The timing of dressing changes should be
evaluated according to the characteristics of the
treated wound: It should not be removed until
complete breakdown.
Formulation with silver (ionically bonded to
regenerated cellulose) may be useful in cases of
240
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F. D’Andrea and F. Mosella
critical colonization or reduced immunologic
potential of the host.
Requires secondary dressing. Can be placed
under compression bandaging.
Lipid-colloid technology dressings with
NanoOligosaccharide Factor (TLC-NOSF) are a
range of dressings composed of carboxymethylcellulose particles distributed in a vaseline network and impregnated with NOSF on a
non-occlusive, soft, non-woven polyester layer
[96]. Upon contact with the exudate, the hydrocolloid particles form a gel that interacts with the
vaseline to form a lipidocolloid lm that creates a
moist environment within the wound. This results
in a kind of microadhesiveness of the dressings
that allows control of the ulcer microenvironment
and, at the same time, a reduction in discomfort
upon removal of the dressing.
Potassium salt of sulfated oligosaccharides
[97] is able to enhance and speed up the reparative process by determining the inhibition of
MMPs, interaction with growth factors, and restoration of their biological functions. In vitro
studies on an equivalent dermal model have
shown that TLC-NOSF is able to signicantly
reduce the activity of some MMPs, such as gelatinases (MMP2 and MMP9) and collagenases
(MMP1 and MMP8) present in exudate [98, 99].
TLC-NOSF dressings can be distinguished
into.
Simple: polyester weft impregnated with a
colloidal lipid matrix rich in saccharide factors.
Interactive: composed entirely of polyacrylateabsorbent bers, detergents, and gelling agents
and a TLC-NOSF matrix. It is also marketed in
edged form with silicone adhesive margins.
With the exception of the edged dressing, they
all require secondary dressing.
The choice of type is based primarily on the
level of exudation.
They can remain in place for up to seven days.
Use is indicated in cleansed lesions, both
acute and chronic. It is noteworthy that the TLCNOSF matrix: is the only treatment recommended by Nice (UK) for the management of
patients with venous lesions of the lower extremities and diabetic foot; it has been included in the
2019 guidelines compiled by the International
Working Group on the Diabetic Foot the best
standard of care in noninfected neuropathic diabetic ulcers [100].
They require secondary dressing. They can be
placed under bandages.
There are numerous devices placed on the
market that, by regulating the characteristics of
the ulcer bed (ES pH), exert a reduction in the
levels of MMPs. These may include modulators
of the pH of the wound environment through an
ion exchange mechanism, acetate mesh media
containing potassium chloride, rubidium chloride, calcium chloride, zinc chloride, potassium
citrate, and citric acid.
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Skin Substitutes
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VitoCazzato, GraceMarchi,
MariaGiuliaSpazzapan, andGiovanniPapa
24
24.1 Introduction
The skin represents the largest external defense
system of the human body and protects the organism from the action of pathogenic agents. It is
made of three layers: the epidermis, the dermis,
and the subcutaneous tissue, and acts as physical
barrier against traumatic penetration. A vascular
system that provides the tissues with oxygen and
nutrients exists within the dermis that is made of
connective tissue, granting elasticity and mechanical resistance. The hypodermis, or subcutaneous
fat, is the deepest layer that provides both thermic
and mechanical protection.
When injured, an inammatory response with
deployment of immune cells is activated, with subsequent release of cytokines which play a key role
in re-epithelialization and cutaneous remodeling
processes. Precisely, during wound healing, broblasts’ activity is crucial for dermal repair. In primary-intention healing, they produce collagen and
extracellular matrix proteins that recreate, within
correct timing, an organized and well-cellularized
type of dermis. In the context of secondary-inten-
V. Cazzato · G. Marchi · G. Papa (*)
Plastic Surgery Unit, University of Trieste, Cattinara
Hospital, Trieste, Italy
e-mail: giovanni.papa@asugi.sanita.fvg.it
M. G. Spazzapan
Department of Molecular Biomedicine University of
Trieste, Trieste, Italy
e-mail: mariagiulia.spazzapan@phd.units.it
tion healing, broblasts’ hyperactivity forms a
brous and highly cellularized scar tissue via granulation tissue. Therefore, the newly formed scar
tissue does not allow complete functional repair,
leading to a skin with different characteristics. It is
easier that, in patients with comorbidities such as
hypovascularization, a deep wound is transformed
into chronic and re- epithelization can only take
place from the margins.
Large post-traumatic tissue loss has lead
researchers to develop new technologies to
improve wound coverage, with the aim of restoring the skin and all its functions. Injuries and
burn that reach the deep part of the dermis, or
further down beyond it, struggle to heal by secondary intention and become chronic wounds
only after a prolonged amount of time.
A reliable surgical solution has been found for
these conditions and consists of skin grafts: these
can be divided into full-thickness skin grafts
(FTSG) or split-thickness skin grafts (STSG), the
rst ones including the epidermis and the entire
dermis, the second ones including the epidermis
and only part of the dermis.
This surgical option, despite its versatility,
comes with several downsides such as donor site
pain, failed take of the graft, limited availability
of donor sites. These main reasons have encouraged researchers to consider surgical alternatives
for wound coverage, such as the use skin substitutes or bio-scaffolds to minimize donor site morbidity up to the preservation of autologous
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
M. Maruccia et al. (eds.), Pearls and Pitfalls in Skin Ulcer Management,
https://doi.org/10.1007/978-3-031-45453-0_24
245
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V. Cazzato et al.
tissues. Skin substitutes consist of biomaterials
developed to accelerate wound healing, providing extracellular matrix (ECM) substitutes [1].
Their role is to act as barrier against microorganisms, to minimize pain, encourage wound
healing, and help restore the protective function
of the skin. Moreover, their use leads to an
improvement of cutaneous regeneration (organized in consecutive phases), to a reduction of
scar contracture, and improves the quality and
the elasticity of the neodermis, along with reducing donor site morbidity.
Dermal substitutes have been largely utilized
to minimize the normal biological response
linked to myobroblast activity, such as wound
scar contracture. Nathoo etal. [2] have provided
a list of properties an “ideal cutaneous substitute”
should present:
– infection resistance
– lack of antigenicity
– sustainable costs
– wide availability
– simple application and removal
– stability and durability.
protection from liquid loss,
adaptability and exibility to the wound
bed’s characteristics [3],
restore functional and aesthetic properties
[4],
provide a stable and biodegradable scaffold
to promote development of new dermal
tissue.
allow the host cells to grow and proliferate
within the scaffold [5].
Despite constant progress in the development
of skin substitutes, to this day there is not a single
product that is considered to be the gold standard
for the treatment of wounds that require restoration of continuity and functionality.
Skin substitutes should have functional and
structural characteristics that equal those of
autologous skin. The ideal skin substitute would
be durable, entirely autologous incorporating
adnexal structures and adult stem cells. A product
with these characteristics, however, is yet to be
developed.
24.2 Characteristics
andComposition
Cellular migration within the matrix is a fundamental requirement for regenerative activity: the
latter is inuenced by the porosity of the substitute. The ideal pore diameter varies between 70
and 120nm.
Cutaneous substitutes are composed of a main
element, the scaffold, which interacts with cells
and growth factors [6, 7]. The scaffold inside the
dermal substitute represents and replicates the
extracellular matrix (ECM) and, as the latter,
consists of a tridimensional structure: its function
is to support adhesion, cellular proliferation, and
differentiation along with neo-vascularization
processes, which are essential for cellular survival. Cell-matrix interactions within the substitute are regulated by the presence of appropriate
ligands (alpha1beta1, alpha1beta2) that allow
cellular adhesion. Various polymers can be used
to create different scaffolds, and each of these
provides various diverse bio-chemical and physical properties [6, 7]. The presence of specic elements regulates the stability of the dermal
substitute in the body and its degradation time [8]
has proven that the presence of macromolecules
like chondroitin-6-sulfate stabilize the scaffold
improving its bonds with ECM cells, granting in
fact the permanence/slowness of the dermal substitute that can thus be invaded by non-cellular
components of the host organism. The lack of
macromolecules and the breakdown rapidity,
instead, allows to promote the formation of granulation tissue, preparing the wound bed for subsequent reconstructive surgery.
Three are the main types of biomaterials used
as scaffolds: natural, synthetic, and composite
(combination of natural and synthetic). Bearing
in mind that scaffolds are destined to carry similar characteristics to the ECMs of natural tissues,
for this reason natural biomaterials represent
ideal components and are therefore the most utilized for the production of scaffolds.
Biocompatible materials that are commonly used
in tissue engineering include collagen, gelatin,
elastin, hyaluronic acid (HA), brin/bronectin
[9]. Despite collagen being the main element,
24 Skin Substitutes
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247
most scaffolds gain different and specic invitro
characteristics according to which biomaterial is
added: in this way, it is also possible to predict
clinical effects of the different dermal
substitutes.
Various studies have focused on the possibility
of modifying collagen’s structure to allow the substitute to gain further characteristics: by adding
ECM proteins to type I collagen for instance, such
as tropoelastin, enhances broblasts’ proliferation
and migration rate in vitro [10]. Chitosan crosslinked collagen creates an optimal potential for the
migration of keratinocytes and re- epithelialization
of the wound [11]. The addition of broblast
growth factor 2 (FGF2) or vascular endothelial
growth factor (VEGF) to heparin reticulated collagen scaffold raises its angiogenic potential [12].
The different stability of the various biomaterials
allows substitutes to be divided into two big
groups: permanent (bio-conductor that allows dermal replacement and/or granulation tissue formation) and temporary (bio- inductors of granulation
tissue) which undergo breakdown and might need
to be renewed. This partitioning enables to easily
navigate the sea of classications and categorization currently available in this eld.
It is clear that in order to be permanent, a dermal substitute must have specic characteristics
such as no rejection reaction and/or biological
incompatibility. Particularly, analyzing histological samples of the neodermis obtained from the
dermal substitute (e.g., Integra), even after a veyear time it displays a well-dened and stable 3D
structure, with pronounced collagen and elastin
invasion and features more comparable to the
normal skin rather than to a skin graft [13]: this
gives an optimal structural support and a primary
healing. The best dermal substitute, reconstructing a well-organized neodermis, with a low
amount of cells and a proper balance between
collagene bers and ECM, supports a primary
healing, like for skin grafts or aps. On the contrary, bio-inductors are able to stimulate a rapid
inammatory response which, through a breakdown and production mechanism carried out by
macrophages and broblasts, leads to the rapid
formation of granulation tissue and a secondary
healing.
Classication of dermal substitutes divided
into dermo-conductive and dermo-inductive is
therefore supported by these principles. These
categories were originally introduced by Kim
et al. in 2007 [14]. Dermo-conductors, instead,
are products that supply a scaffold onto which
cells of the nearby tissues can migrate to reach
the wound and form the neodermis. Integra (LifeSciences, Plainsboro, NJ), GraftJackeTechnology, Arlington TN), Oasis (Smith & Nephew,
Memphis, TN), Alloderm (LifeCell, Branchburg,
NJ), and EZ Derm (Molnlycke, Gothenburg,
Sweden) are examples of these products
[15–17].
Dermo-inductors include products that provide the wound with cells that stimulate the activation of new growth factors or granulation
tissue. Example of such products available on the
market include Apligraf(Organogenesis, Canton,
MA), Dermagraft (Organogenesis, Canton, MA),
TheraSkin (Soluble Systems, LLC,
NewportNews, VA), Biobrane (Smith & Nephew,
Memphis, TN), and Epicel (Genzyme,
Cambridge, MA).
Nevertheless, these types of classications do
not consider the clinical aspect of the wound’s
healing process. Behavioral and structural properties of a permanent dermal substitute are
observed when the wound bed is suitable for
graft taking, may not be observed when placed
onto a wound bed that has not been properly prepared and shows contamination, presence of
brin, infection, or inammation.
In this case, the dermal substitute would not
adequately blend in with the host tissue.
Unsuitable host environments will lead to the
breakdown of the dermal substitute that for this
reason could only promote the formation of granulation tissue and a secondary healing.
It is clear what an important role the scaffold’s
biomaterials play in the context of dermal
substitutes.
Lets analyze in detail which scaffold biomaterials are most commonly used in tissue
engineering:
Collagen: it is considered the main source of
traction endurance of the skin [18, 19] and is the
most used biomaterial for the production of skin
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