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GENERAL INTRODUCTION
GENERAL INTRODUCTION
HYPERTROPHIC SCAR FORMATION
The skin is our largest organ and serves as a protective barrier against infection and
excessive water loss, and helps our bodies to maintain the right temperature. The skin
can be divided into an epidermal and a dermal layer. The epidermis mainly contains
keratinocytes, whereas the dermal part consists of two compartments. The first is the
cellular compartment, which is typically composed of fibroblasts. The second is the
acellular compartment, which mainly contains the extracellular matrix (ECM). All these
compartments and different components have their own specific function and work
closely together.
The skin is also one of the most easily injured organs. When cutaneous integrity
is violated wound healing is crucial to restore this barrier. The healing process of the
injured site, which normally results in the formation of a scar, is an extremely complex
process involving numerous cell types, cytokines and ECM components1. Excessive
blood loss from injured blood vessels is prevented by the formation of a blood clot,
which further acts as a provisional wound matrix that attracts and guides inflammatory
cells, endothelial cells, fibroblasts, and keratinocytes. Together they form new blood
vessels, produce ECM and create a new layer that covers the surface of the wound.
Many fibroblasts transform into myofibroblasts, which initiate collagen deposition and
wound contraction1.
Except for superficial (burn) wounds that heal within a few days, most wounds
will become a visible scar. Moreover, in some individuals, and particularly in burn
victims, the wound healing processes may lead to excessive production of ECM,
resulting in a raised hypertrophic scar. They are easily identified by color mismatch,
stiffness and rough texture. Patients frequently complain about itching and pain, and
experience serious functional and cosmetic problems, which are caused by a myriad
of complications, including compression, stiffness sensation, loss of joint mobility and
anatomic deformities2,3. These complications may require several surgical corrections,
unfortunately not always with satisfying results.
Hypertrophic scars are different from keloids, which also raise above skin level, but
proliferate or originate beyond the confines of the original lesion4. Most of the available
literature on hypertrophic scars and keloids still does not precisely differentiate between
both scar types, although several pathological and biochemical differences between
hypertrophic scars and keloids suggest that different mechanisms are responsible for
their development4-6. Therefore, it is important to clearly differentiate between these
two types of scars when trying to unravel the pathogenesis of either of these. In this
thesis, we focused specifically on the identification of factors, both at a clinical and
molecular level, that are involved in human hypertrophic scar formation.
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CHAPTER 1
AIMS AND OUTLINE OF THE THESIS
Research on the molecular and cellular mechanisms of wound healing and scar
formation has led to a better understanding of mechanisms that are involved in
hypertrophic scar formation. Presently, most research on wound healing is performed
using animal models and in vitro cell systems. Animal models include the mouse,
guinea pig, rabbit and pig7. Experiments performed in vitro are performed in a
controlled environment like a test tube or tissue culture flask. It is well established that
in wound healing, all cells involved in the process strongly respond to local changes
and quickly change their environmentally imprinted behavior. Intricate interactions
in scar tissue, both via cell-cell contact and secreted products, are spatiotemporally
controlled and difficult to mimic in in vitro cell systems, thereby largely hampering
extrapolation of in vitro observations to the wound in a patient. Furthermore, wound
healing in other species presents significant differences when compared with wound
healing in humans. Moreover, hypertrophic scar formation is a condition that naturally
only occurs in humans. Therefore, studying cell (dys)function during hypertrophic
scar formation in the complex microenvironment of the human wound remains a
prerequisite. This thesis focuses on unraveling both clinical and molecular differences
between normotrophic and hypertrophic scar formation in humans specifically.
The current knowledge concerning molecular and cellular causes of hypertrophic
scar formation is reviewed in chapter 2. Despite this knowledge, hypertrophic scars
remain difficult to treat and an actual preventive treatment is still lacking. The currently
used modalities for both preventive and curative management of hypertrophic scar
formation are reviewed in chapter 3.
Over the past decades, a considerable amount of research has been performed
concerning the predisposition and risk factors for keloid formation. Little is known
about risk factors specific for hypertrophic scar formation, as hypertrophic scars and
keloids are yet not always well differentiated. In chapter 4 we describe the incidence
of hypertrophic scar formation in standardized human wound healing models and
investigated its association with several patient characteristics.
When looking at hypertrophic scars at a cellular level, these scars display epidermal
abnormalities that strongly resemble the epidermal alterations observed in the skin
disorder psoriasis8-11. Psoriasis can be effectively treated with topical application of
calcipotriol, a synthetic derivative of vitamin D. We thus hypothesized that topical
application of calcipotriol could prevent hypertrophic scar formation by altering the
biochemical properties of the epidermis. Therefore, a randomized, double-blind,
placebo-controlled trial was performed to investigate the preventive effect of topical
calcipotriol on hypertrophic scar formation, and to further analyze the biochemical
properties of the epidermis associated with hypertrophic scar formation (chapter 5).
To study the influence of the early inflammatory response on hypertrophic scar
formation we conducted a prospective cohort study using a standardized model of
presternal scars caused by cardiothoracic surgery through a median sternotomy incision
(chapter 6). Presternal scars have a high incidence of hypertrophic scar formation. It
is custom to administer dexamethasone systemically at high dose before and after
GENERAL INTRODUCTION
cardiac surgery that requires the use of cardiopulmonary bypass. Hypertrophic scar
formation in the study group was assessed and measured, and differences between
patients who did and who did not receive dexamethasone perioperatively were
analyzed.
In chapter 7, first steps are made towards identifying the macrophage phenotype
during the development of normotrophic versus hypertrophic scars. Macrophages
are considered key players in wound healing, as they serve as a source for various
cytokines and chemokines essential for orchestrating the wound healing process and
ECM production. Since the role of macrophage phenotype has been highlighted in
fibrosis in several studies, while other studies underline the importance of macrophages
in wound healing, the interest in macrophage function in wound repair is rising. The
aim of this study was to determine the macrophage phenotype associated with
normotrophic and hypertrophic scar formation in time.
Besides differences in the phenotype of inflammation, it has been previously
reported that, compared with normal skin, hypertrophic scars have an increased number
of blood vessels and a higher blood flow12,13. This implies the presence of an increased
vascular network in hypertrophic scars compared with normotrophic scars. We thus
hypothesized that new blood vessel formation is increased during hypertrophic scar
formation. In chapter 8 we provide insight in, and identify new molecular details about
the angiogenic profile during normotrophic and hypertrophic scar formation. Our study
is the first to detail on the time course of the angiogenic response during hypertrophic
scar formation in humans in comparison with normotrophic scar formation.
Finally, in chapter 9 the findings described in this thesis are summarized and
discussed in the context of the current developments in wound healing research.
Conclusions are presented and future directions for research on wound healing and
hypertrophic scar formation are proposed.
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van der Veer, W.M., et al. Potential cellular
and molecular causes of hypertrophic scar
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Bock, O., Schmid-Ott, G., Malewski, P.
& Mrowietz, U. Quality of life of patients
with keloid and hypertrophic scarring.
Arch Dermatol Res 297, 433-438 (2006).
Mazharinia, N., Aghaei, S. & Shayan, Z.
Dermatology Life Quality Index (DLQI)
scores in burn victims after revival. J Burn
Care Res 28, 312-317 (2007).
Atiyeh, B., Costagliola, M. & Hayek, S.
Keloid or hypertrophic scar: the controversy: review of the literature. Ann Plast
Surg 54, 676-680 (2005).
Niessen, F.B., Spauwen, P.H., Schalkwijk,
J. & Kon, M. On the nature of hypertrophic
scars and keloids: a review. Plast Reconstr
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Santucci, M., Borgognoni, L., Reali, U.M.
& Gabbiani, G. Keloids and hypertrophic
scars of Caucasians show distinctive
morphologic and immunophenotypic
profiles. Virchows Arch 438, 457-463
(2001).
Ramos, M.L.C., Gragnani, A. & Ferreira,
L.M. Is there an ideal animal model to
study hypertrophic scarring? J Burn Care
Res 29, 363-368 (2008).
Andriessen, M.P., Niessen, F.B., Van de
Kerkhof, P.C. & Schalkwijk, J. Hypertrophic
scarring is associated with epidermal
abnormalities: an immunohistochemical
study. J Pathol 186, 192-200 (1998).
Niessen, F.B., Schalkwijk, J., Vos, H. &
Timens, W. Hypertrophic scar formation
is associated with an increased number of
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epidermal Langerhans cells. J Pathol 202,
121-129 (2004).
10. Machesney, M., Tidman, N., Waseem,
A., Kirby, L. & Leigh, I. Activated keratinocytes in the epidermis of hypertrophic
scars. Am J Pathol 152, 1133-1141 (1998).
11. Freedberg, I.M., Tomic-Canic, M.,
Komine, M. & Blumenberg, M. Keratins
and the keratinocyte activation cycle. J
Invest Dermatol 116, 633-640 (2001).
12. Niessen, F.B., Spauwen, P.H., Robinson,
P.H., Fidler, V. & Kon, M. The use of silicone
occlusive sheeting (Sil-K) and silicone
occlusive gel (Epiderm) in the prevention of hypertrophic scar formation. Plast
Reconstr Surg 102, 1962-1972 (1998).
13. Amadeu, T., et al. Vascularization pattern
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