Wound Healing
Wound healing is a complex process that
involves an orderly and sequential series of interactions among multiple cell
types and tissue structures. Classically, wound healing has been divided into
three phases: inflammation, new tissue formation, and matrix formation and
remodeling. Each of these phases is unique, and particular cell types play key
roles in the different phases.
Once a disruption of the skin barrier occurs, a cascade of inflammatory
mediators are released, and wound healing begins. The disruption of dermal
blood vessels allows extravasation of blood into the tissues. The ruptured
vessels undergo immediate vasoconstriction. Platelets begin the process of coagulation
and initiate the earliest phase of inflammation. The formation of the earliest
blood clot provides the foundation for future cell migration into the wound.
Many inflammatory mediators are released during this initial phase. Once
initial homeostasis is achieved, the platelets discharge the contents of their
alpha granules into the extravascular space. Alpha granules contain fibrinogen,
fibronectin, von Willebrand’s factor, factor VIII, and many other proteins. The
fibrinogen is converted into fibrin, which aids in formation of the fibrin
clot. Platelets also play a critical role in releasing growth factors and
proteases. The best known of these is platelet derived growth factor (PDGF),
which helps mediate the formation of the initial granulation tissue.
During the late portion of the inflammatory phase, leukocytes are seen
for the first time. Neutrophils make up the largest component of the initial
leukocyte response. Neutrophils are drawn into the area by various cytokines
and adhere to the activated vascular endothelium. They enter the extravascular
space by a process of diapedesis. These early-arriving neutrophils are
responsible for the recruitment of more neutrophils, and they also begin the
process of killing bacteria by use of their internal myeloperoxidase system.
Through the production of free radicals, neutrophils are efficient at killing large
numbers of bacteria. Neutrophil activity continues for a few days, unless the
wound is contaminated with bacteria. Once the neutrophil activity has cleared
the wound of bacteria and other foreign particles, monocytes are recruited into
the wound and activated into macrophages. Macro- phages are critical in
clearing the wound of neutrophils and any remaining cellular and bacterial
debris. Macrophages are capable of producing nitrous oxide, which can kill
bacteria and has also been shown to decrease viral replication. Macrophages
also release various cytokines, including PDGF, interleukin-6, and granulocyte
colony-stimulating factor (G-CSF), which in turn recruit more monocytes and
fibroblasts into the wound.
At this point, new tissue formation, the proliferative phase of wound
healing, has begun. This phase typically begins on the third day and ends about
14 days after the initial insult. It is marked by reepithelialization and
formation of granulation tissue. Reepithelialization occurs by the movement of
epithelial cells (keratinocytes) from the free edge of the wound slowly across
the wound defect. The migrating cells have the distinct phenotype of basal
keratinocytes. It is believed that a low calcium concentration in the wound
causes the keratinocytes to take on the characteristics of basal keratinocytes.
PDGF is an important stimulant for keratinocytes and is partially responsible
for this migration across the wound. The migrating keratinocytes contain the keratin pairs 5,14 and 6,16.
They secrete vascular endothelial growth factor, which promotes the production
of dermal blood vessels. At the same time the keratinocytes are migrating, the
underlying fibroblasts are synthesizing a backbone matrix, made up
predominantly of type III collagen and some proteoglycans. Some of the fibroblasts
are converted into myofibroblasts by PDGF and tumor growth factor-β1. These
myofibroblasts are important in that they cause he overlying wound to contract,
decreasing its surface.
The final phase of wound healing involves scar maturation and tissue
remodeling. This phase overlaps in time with the first two phases; it is said
to begin with the production of the first granulation tissue. This phase
extends for months and is complete when most of the collagen III and
fibronectin have been replaced by mature type I collagen. In the final mature scar,
the collagen fibers are oriented in large bundles running perpendicular to the
basement membrane zone. The resulting scar has only 80% of the tensile strength
of the uninjured skin.
