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From Wound toScar: Scarring Explained—Pathophysiology ofWound Healing
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growth factor receptors of the broblasts are
downregulated, and some of the broblasts
undergo apoptosis (especially the broblast
cells).
Re-epithelialization
Re-epithelialization of the wound begins within a
few hours after injury. Starting from the skin
appendages (e.g., hair follicles) and the wound
margins, epidermal keratinocytes gradually cover
the wound surface with an epithelial turf, thus
closing the wound surface [41, 42].
Migration, proliferation, and differentiation of
keratinocytes are crucial steps. The otherwise
very grounded keratinocytes change their appearance and function. Cohesion among keratinocytes is lost as retraction of tonolaments occurs
and intercellular desmosomes are dissolved.
Finally, the epithelial cells also lose their adhesion to the basement membrane because the
hemidesmosomes of the basal keratinocytes are
also dissolved. The keratinocytes atten, form
foot-like projections, and actively migrate laterally toward the wound matrix [43].
A prerequisite for the migration of keratinocytes is the formation of new adhesion molecules
for attachment to the provisional matrix or wound
dermis. Fibronectin/tenascin, vitronectin, and collagen receptors ensure the necessary adhesion and
alignment to the corresponding matrix proteins
during keratinocyte locomotion. The amoeboid
locomotion of keratinocytes is enabled by intracellular contractile actinomyosin laments, which
alternately contract and redistribute accordingly
in the newly formed lamellipodia [25, 34, 43].
The keratinocytes migrate horizontally individually or in cell assemblies. They typically glide
over the newly formed epidermal cell seam.
Migration and proliferation of keratinocytes
from the wound edge are induced by the lack of
contact with (destroyed) neighboring cells (“free
edge effect”) and stimulated by local release of
growth factors (e.g., EGF, TGF-α, and -β) and
expression of growth factor receptors-β, keratinocyte growth factor (KGF). As soon as epithelial
cell fronts meet, keratocyte migration is halted
by contact inhibition. Parallel to progressive
re- epithelialization, the basement membrane—
fundamental connection and separating layer
between epidermis and dermis—is also restored.
The nal step is the xation of the basal lamina by
the anchoring brils. In the end, keratinocyte proliferation and differentiation lead to the formation
of a regular keratinizing epidermis [10, 15, 22].
Epithelialization proceeds most rapidly with
a clean wound bed, intact basal lamina, and
moist wound conditions. Necrotic tissue, debris,
or crusts slow down epithelialization. The
advancing epithelial front undermines wound
coatings and forces its way between the necrosis
zone and the granulation tissue. To enable this
penetration, keratinocytes release plasminogen
activator for brinolysis using plasmin present
in the coagulum and MMPs for lysis of collagen
[15, 30, 32].
Remodeling Phase
The remodeling phase includes the transformation from granulation tissue to scar. It begins at
the same time as the granulation phase, lasts up to
2 years, and completes wound healing. In this
phase, a slow remodeling of the connective tissue
takes place, during which the scar acquires its
nal properties such as function, strength, and
appearance. The remodeling phase is characterized by the coexistence of collagen degradation
and collagen synthesis: type 3 collagen, which
was synthesized during the rst weeks of wound
healing, is now continuously replaced by stable
type 1 collagen [40, 41].
Collagen bers are dissolved by specic
MMPs released into the extracellular space by
macrophages, granulocytes, epidermal cells,
endothelial cells, and broblasts in the wound
area. While remodeling, the activity of MMPs
steadily decreases, while the activity of inhibitors
increases. The presence of TIMPs protects
against excessive proteolysis. A balanced ratio of
MMPs and their inhibitors in the wound is thus
an absolute prerequisite for trouble-free healing.
The ongoing synthesis of stable collagen, its
consolidation with the formation of cross-links,
the interweaving into thicker bundles, and their
proper alignment contribute to the increasing
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strength of the healing wound. The orientation
of the collagen bundles is adapted to local and
functional requirements. Nevertheless, scar tissue never becomes as strong as healthy tissue.
Two weeks after an injury, the healing wound has
on average only regained 5% of its original resilience, 3weeks later about 20%, and 1month later
about 40%. Even after an optimal healing process, the tensile strength of the scar tissue always
remains below 80% of its initial state [41].
At the end of the remodeling phase, the scar
is poor in cells and vessels, with loss of skin
appendages. The density of the collagen bers
increases, and the originally complex interwoven collagen is replaced by dense parallel bundles. The connective tissue becomes cell
depleted as macrophages and broblasts are
reduced by apoptosis. Capillary growth stops
and blood vessels are reduced; the reddish
color of the friable vascular scars gives way to
the pale discoloration of the vascular-poor old
scar.
Chronic Wounds
In western industrialized nations, about 1–2% of
the population suffers from chronic wounds. The
incidence increases with age and reaches 4–5%
after the age of 80 [11]. Especially arterial,
venous, and diabetic ulcers, as well as decubital
ulcers, occur more frequently in older than in
younger people. The main causes are certainly
the numerous comorbidities of the elderly, consumptive diseases, prolonged administration of
drugs with negative inuence on healing such as
steroids, antiphlogistic, or cytostatic, limited
mobility, malnutrition, and nally cellular and
biochemical changes in the aging skin.
Although most wound specialists have
very concrete ideas of what a chronic wound
is, there is yet no binding definition of it.
Some already speak of a chronic wound at a
healing time of >4 weeks, others only at a
healing time of >12weeks. In the documents
of World Union of Wound Healing Societies,
6weeks is a critical time to define a wound as
a chronic wound. However, time limits alone
can only reflect the actual wound condition
to a limited extent. A chronic wound is characterized above all by the fact that, despite
intensive therapy, healing does not occur
within a reasonable period. According to the
guidelines of the German Society for
Phlebology, a leg ulcer is considered chronic
if it shows no healing tendency within
3months or has not healed within 12months
[14, 16, 22, 28].
Biology of Chronic Wounds
In chronic wounds, physiologic phasic healing
is disrupted, and the process is “stuck,” usually
in the inammatory or proliferative phase.
Growth factors, cytokines, proteases, cells, and
ECM are the main components of healing; alterations and disturbances of individual elements
can severely slow down wound healing. Wound
healing is also signicantly impaired by excessive inammation, tissue damage by free oxygen radicals, cell aging, disease-specic factors
such as metabolic disorders (e.g., diabetes mellitus), hypoxia of various origins, or nutritional
deciencies. Necrotic tissue, exudate, and infection also hinder healing in the long term [4, 5,
12, 23, 36, 43, 48].
In chronic venous leg ulcers, for example,
increased neutrophils and macrophages can be
detected in the tissue. These are activated and
release more reactive oxygen species and various
proteases. The inammatory phase with neutrophils and macrophages persists and severely
affects the subsequent phases of matrix deposition and re-epithelialization [40].
The main characteristics of a chronic wound
are essentially
• An increased activity of matrix metallopro-
teinases (MMPs).
• A decreased response to growth factors.
• Senescence of cells (cell aging).
In undisturbed healing of acute wounds, there
is a balance between catabolic and anabolic processes, and production and activity of tissue pro-
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teinases are under tight and effective control. In
chronic ulcers, however, the enzymatic activity
of MMPs is increased. At the same time, the
activity of MMP inhibitors in the tissue is
decreased. This leads to a sustained and excessive degradation of ECM proteins (e.g., collagen,
bronectin, and vitronectin). Since the latter are
invisible guiding structures for the proliferation,
migration and spatial orientation of broblasts,
endothelial cells, and keratinocytes, their continuous destruction results in a wound-healing arrest
[18, 23, 29].
However, it is not only the permanent degradation of matrix proteins that leads to a halt in
cell proliferation and cell migration in the chronic
wound. Cytokines and growth factors cannot
exert their healing-promoting effects in the
wound area, as they are also enzymatically
degraded and inactivated by MMPs [24]. In addi-
tion, there is evidence that MMPs in chronic
wounds can also inactivate receptor proteins for
cytokines and growth factors, further enhancing
their anti-healing effects [7, 9, 16, 21, 23]. This
“aggressive microenvironment” may explain the
widespread failure of locally applied recombinant growth factors in the therapy of chronic
wounds [40].
Chronic wounds are usually characterized by
excessive inammation. Indeed, the exudate of
chronic wounds is rich in pro-inammatory
cytokines such as TNF-α and IL-1 β. These
cytokine levels correlate closely with the clinical course and decrease with the onset of wound
healing. Approximately 100-fold higher concentrations of TNF-α and IL-1 β were measured
in wound uid from chronic wounds than in
acute wound uid after mastectomy [23]. In cell
cultures of healthy broblasts, endothelial cells,
and keratinocytes, the addition of exudate from
chronic wounds causes growth inhibition [6],
whereas exudate from acute wounds increases
proliferation.
The cellular inammatory response is also
altered; neutrophilic leukocytes from patients
with chronic venous ulcers are more active and
produce more oxygen-free radicals than from
healthy control subjects [39, 40]. In contrast,
macrophages from patients with chronic venous
ulcers are insufciently activated and the release
of healing-promoting cytokines and growth factors is unsuppressed [12].
The so-called replicative senescence (“aging”)
of broblasts is also to blame for the poor healing
tendency of chronic wounds [17]: physiologically, all cells have a limited proliferative capacity, i.e., the number of possible cell divisions is
limited. At the end of their proliferative lifespan,
broblasts change their phenotype, become resistant to apoptotic cell death, and lose their proliferative capacity [28, 37, 39, 41].
In chronic venous ulcers with poor healing
tendency, more broblasts can be detected in the
stage of senescence [17]. They divide more
slowly than broblasts from healthy tissue and
can only generate a limited number of daughter
cells [33, 40].
On the one hand, pro-inammatory cytokines,
oxidative stress, or bacterial toxins probably
cause the phenomenon of premature cell aging in
the chronic wound environment. Experimental
evidence suggests that chronic wound uid inhibits DNA synthesis and broblast growth [6, 32].
On the other hand, prolonged excessive and
uncoordinated cell divisions may deplete proliferative capacity in chronic wounds [1, 16].
Senescent broblasts produce increased
amounts of proteolytic enzymes such as collagenase, elastase, and stromelysin and decreased
TIMP-1 and TIMP-9 compared to healthy cells.
The accumulation of senescent broblasts in the
wound area thus probably contributes decisively to
the chronic course [17]. Table2 summarizes several factors inuencing wound healing (Table2).
Table 2 Extrinsic and intrinsic factors with inuence in
wound healing
Extrinsic factor Intrinsic factor
Radiation Indirect gen
defects
Mechanical stress Collagen diseases
Nutrition Ethnicity
Thermal damage Metabolic stress
Medication (e.g., cyclooxygenase
inhibitor)
Chronic
inammation
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Wound Healing in Old Age
Aging skin is more vulnerable overall and wound
healing is delayed [12]. Certain diseases (e.g.,
chronic venous insufciency, arterial perfusion
disorders), comorbidities (e.g., cardiovascular
insufciency, diabetes mellitus), medication
(e.g., anti-inammatory drugs), and the manifold
structural and functional changes in aging skin
increase the risk of developing chronic ulcers.
The skin of the elderly is thinned in all layers, has
fewer cells, and is rareed at the function-bearing
structures. There is a slower turnover of epidermis, the mitotic rate is reduced, and the reepithelization of wounds takes about twice as
long. The sawtooth prole of the dermoepidermal junctional zone is leveled, and the rete
cones atten or disappear. This leads to increased
mechanical vulnerability to shear trauma, tendency to blistering, and poorer nutritional conditions of the epidermis. Parallel to the general
weakening of immune competence, the
Langerhans cells of the epidermis decrease by
about 50% with age. Inammatory and immunemediated reactions are slower and milder.
Rarefaction of all components also occurs in the
dermis. The percentage of senescent broblasts
with low proliferation increases. In addition,
there is an altered composition and reduced quality of ECM proteins. Reduced tissue turgor and
lower tensile strength are the consequences. The
vascular system is also massively affected by the
aging process: Dilatation and wall rigidity of
postcapillary venules lead to telangiectasias and
hemorrhages after trivial trauma. The number of
capillaries dwindles and there is a loss of up to
30% of the cumulative cross-section [15].
Hyperspectral Imaging
as a Measurement Method for Skin,
Tissue Wounds, and Scars
Compared to other optical measurement methods, hyperspectral imaging (HSI) simultaneously
enables the acquisition of information about biochemical, structural, and physiological functional
properties of the measured volume. This is lim-
ited in the usual spectral range of 400–1000nm
in skin and similar perfused tissue to a depth of
approx. 5–8 mm [44, 45]. However, HSI, as a
non-contact measurement method, allows relatively large-area imaging in a relatively short
time (a few seconds), so that not only highly
localized samples can be measured, but also, for
example, the blood ow quality of larger areas
can be determined.
The measurement of biochemical properties is
essentially based on the different absorption
behavior of different components. The strongest
shape imprinting is given to the remission spectrum by the absorption of hemoglobin [39, 45, 46].
Structural features, such as the different layers
of the skin, are essentially imprinted in the remission spectrum by the scattering of the incident
light and the different penetration depths depending on the wavelength.
Physiological-functional properties, primarily
blood ow, can be recorded and evaluated via the
absorption of hemoglobin in conjunction with the
structural features [46].
The remission spectra show a complicated
nonlinear dependence on the system structure and
the system parameters due to the different volume
fractions of various components (melanin, collagen, hemoglobin, etc.) depending on the depth
(layer structure of the skin) and the paths of the
light through the layers to remission caused by
scattering. The spectra are heterogeneous depending on the wavelength, i.e., spectral components
of different wavelengths refer to different measurement volumes. This dependence prevents
almost in principle an unambiguous solution of
the inverse problem, i.e., the computation of system parameters from the spectra [46–48].
In practice, mostly simple system models are
assumed, which allow the calculation of parameters from the spectra, but which, with respect to
the real structure, represent more or less strongly
averaged and only very limited comparable
values.
Models based on Monte Carlo simulations of
the remission by more realistic structures are in
principle more appropriate, but the inverse determination of the model parameters is also here a
process that cannot be solved unambiguously,
500
1000 nm
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since an adjustment to the current actual structure
is hardly possible.
An alternative method is based on a description of the remission process by a reasonably
realistic skin model (six layers with all relevant
components) and a modeling based on a 3D
cablelike description supported by MC
simulations.
Again, the model imposes a limitation on
the determination of real physiological parameters, but the advantage is the consistency of
the transformation of the spectral information
into the model parameters, which allow a complete reproduction of the actual spectra by the
model.
This practically does not mean a physically
strictly correct solution of the inverse problem,
but a consistent transformation of the information content of the spectra into a parameter space,
which at least allows an interpretation of the
parameters much closer to physiology (example:
Perfusion proles charts).
From the modeling, so-called perfusion proles (depth proles) for the relative volume frac-
tion of hemoglobin (vHb) and oxygen saturation
(xHbO2) can be displayed to assess the perfusion
conditions corresponding to the six layers of the
skin model. The depth axis does not correspond
to an actual depth or the layer thicknesses; the
relative scaling of the vHb values against each
other is globally xed. In addition, the relative
volume fraction of water (vH2O) is also determined [46–49].
vHb as an index parameter is scaled from 0 to
2.5; xHbO2 means the percentage of oxygen
(0.0.100%) and ranges from [0.0.1] (Figs. 4, 5,
and 6).
Microcirculation
Due to its limited penetration depth, HSI measures properties of the skin’s microcirculatory
system in the 400–1000nm spectral range.
The microcirculation is the area where the
metabolism between the blood and the surrounding tissue takes place. Thus, for the supply of the
tissue, this is crucial. The macrocirculation, of
Fig. 4 Normal circulation
Fig. 5 Venous hyperten-
sion: increased deep t-vHb,
reduced xHbO
2
vHb
0.93
0.79
1.05
1.03
1.70
vHb
0.77
1.04
1.80
0.99
0.96
xHbO2
0.27
1.18
1.20
0.27
xHbO2
0.38
0.30
0.38
0.41
0.48
0.63
0.60
0.77
0.77
0.61
22
0.71
0.67
0.84
0.12
0.43
vHb
0.84 0.71 0.67 0.84 1.78 1.76 0.12 0.12 0.16 0.43 0.61 0.61
xHbO2
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Fig. 6 Arterial hypertension: reduced supercial
vHb, increased deep-vHb,
esp. supercial severe
reduced xHbO
2
0.84
1.78
1.76
0.12
0.16
T. Wild et al.
0.61
0.61
course, ensures adequate inow and outow of
blood. Essential for the assessment of tissue supply is thus the ratio of micro- to macrocirculation: how much blood/oxygen is brought in and is
available in the capillary, arteriolar and venular
systems, how much of it is consumed.
In general, it is important to detect microcirculatory disturbances even before the onset of tissue
damage, e.g., due to a reduced oxygen supply.
Averaged oxygen saturations (tissue oximetry) or pure ow values (LDI) are inadequate or
at least suboptimal for a differentiated assessment of microcirculation.
More adequate model-based evaluations (see
above) allow a more advanced structural representation of perfusion properties, e.g., perfusion
values (relative volume fraction and oxygen saturation of hemoglobin in a six-layer model of the
skin). This results in so-called perfusion (depth)
proles, which can serve as an information- rich
and specic basis for the analysis and evaluation
of skin perfusion [48, 49].
Evaluation of the Measurement
Results/Parameters
Global quantitative assessment of microcirculation at least of the skin is very difcult. Numerous
adaptation and control mechanisms lead to a high
variation of measured blood ow parameter values on the skin, both inter- and intrapersonally,
dependent on time and situation. Globally, the
range for “normal values” strongly overlaps with
that of patients with “circulatory disorders.”
Global parameters are also difcult to achieve
because penetration depths or measurement volumes vary for different skin types and locations.
Temporal singular measurements do not account
for variation in blood ow due to vasomotion
rhythms, for example, comparable and scalable
parameters can be determined by spatial or temporal relativity, by response to provocations or to
treatments [48–50].
Evaluation of heterogeneous spectra in terms
of measurement depth with the determination of
perfusion proles allows at least evaluation of the
relative ratio of depth to surface perfusion.
HSI Measurements on Chronic
Wounds
Inadequate perfusion and tissue supply is a signicant factor in the development of hard-to-heal
chronic wounds. This is often due to a systemic
or regional circulatory disorder, i.e., insufcient
supply of arterial blood to certain areas and the
resulting insufcient quality of microcirculatory
perfusion and oxygen supply to the tissue, which
favors wound development. In the wound that
then develops, the same factors ensure a signicantly impaired healing process.
In addition to the treatment and improvement
of the basic blood circulation problem, the regular control of skin blood circulation in high-risk
From Wound toScar: Scarring Explained—Pathophysiology ofWound Healing
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patients (diabetes, PAVK, nursing patients with
low mobility) can help prevent the development
of wounds, especially in the known localizations. For this purpose, HSI represents a simple
measurement method that is not burdensome for
the patient and that can reliably detect deterioration of the condition and preliminary stages of
wound formation (via the formation of local
edema and inammation) by measuring large
areas and observing the course of values over
time [44–47, 49].
The HSI evaluation generates perfusion
parameters of the upper skin layers, which are
well comparable and meaningful, at least relatively over time. Increased vH2O values (relative
volume fraction of water in the tissue) are often
also conspicuous in such patients [50].
In the treatment of already existing wounds
that are difcult to heal, ensuring sufcient blood
ow and oxygen supply, at least in the wound
area and the wound environment, is an important
factor among others. Here, too, the regular measurement of the wound area and the wound environment by means of HSI can generate decisive
information on the current and temporal development of the blood ow quality.
In addition, evaluation of the shape characteristics of the remission spectra, which correlate with
certain biochemical features, enables qualitative
and, in some cases, quantitative determination of
relevant wound components (various tissue types,
such as necrosis, brin, critical, undersupplied tissue, granulation, epithelialization). Using these
spectral features and imaging, an exact segmentation and classication of the wound area are possible, resulting in an overall comprehensive objective
description of the wound and wound progression,
which allows optimization of wound treatment and
thus wound healing via analysis of the objectied
and quantied response of the wound to various
treatments. The advantage over the imprecise, individually different visual wound assessment by the
physician is the availability of objective parameters
which cannot be determined in a similar way with
any other methods at present and which allow a
much earlier assessment and evaluation of the
wound process [45, 47, 48] (Figs. 7, 8, and 9).
Excessive scarring, consisting essentially of
collagen structures, is characterized by low
supercial perfusion values and the clear expression of collagen in the spectrum (Fig. 10). An
improvement by treatment, which leads to the
degradation or remodeling of the scar tissue with
an increase in perfusion, can be observed and
controlled by means of the perfusion proles
over time as well as the change in the individual
collagen types.
Fig. 7 Keloid after burn 15years before with several stula with infection
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Fig. 8 HIS show the pathological perfusion and oxygenation, important for planning any kind of intervention and
controlling the postinterventional effects in short time and long time follow up
500 1000 nm
xHbO2vHb
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Fig. 9 Detection of microbiological burden in the spectrum from 390 to 430nm, important for local removement
and short time and longtime follow up
Fig. 10 Strong scar tissue:
collagen input is essential in
the front part of the spectrum,
the determination of the blood
Scar: collagen
ow is only possible below the
scar tissue in the depth
1.10 1.14
0.67 0.68
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