Periodontology 2000, Vol.
24, 2000, 127–152
Printed in Denmark ¡ All rights reserved
Cell biology of
gingival wound healing
L ARI H ÄKKINEN, V ELI- J UKKA U ITTO & H ANNU L ARJAVA
An overview
Wound healing is a critical process for the organism.
The attempt of this chapter is to critically summarize
the recent advancements in the wound-healing pro-
cess. Because of the excessive amount of infor-
mation (search with the key words wound healing
produced 2052 citations within the last 12 months),
we will focus on two major events in wound healing,
namely re-epithelialization and granulation tissue
formation, leaving out many other key events such
as clot formation and angiogenesis. At the end, we
will also discuss the special features of wound heal-
ing in oral cavity. It is commonly stated that oral
wounds heal better than other wounds such as der-
mal wounds. We will explore evidence supporting
this assumption.
Most of the data presented in this chapter refer to
studies with gingival and dermal full-thickness
wounds and no special attempts have been made
to focus on the healing in tooth-gingiva interphase
because only a few studies are available to report
special molecular events in humans. In addition,
several previous articles have addressed periodontal
wound healing and regeneration in great detail (114,
276). It is reasonable to assume, however, that the
basic cell biological events of wound healing will fol-
low the same principles at the tooth-gingiva inter-
phase, at least at the supracrestal locations. We will
also try to make several back-and-forth citations be-
tween in vivo and in vitro studies. This is necessary
because functional studies have been difficult to
perform with animal models of wound healing in a
manner that would allow meaningful conclusions to
be drawn. In vitro studies with cultured keratino-
cytes and fibroblasts are still the only way to explore
functions of various molecules. Recent molecular bi-
ology techniques have made it possible to eliminate
the expression of molecules of interest and investi-
gate how the function is changed consequently. In
vivo studies have dealt with immunolocalization of
Copyright C Munksgaard 2000
PERIODONTOLOGY 2000
ISSN 0906-6713
extracellular molecules and their expression using in
situ hybridization. In addition, transgenic animals
provide information how wound healing is altered in
the absence or following overexpression of a known
molecule (153). Many of these studies have provided
new critical information but others have resulted in
confusing results, such as showing no alterations
even though a molecule has been thought to be criti-
cally important for wound healing. It is believed that
in these cases there are other related proteins that
can provide similar functions and compensate for
the absence of the studied molecule. Wound healing
has become well protected during evolution because
of its critical importance. Numerous molecules ap-
pear to overlap each other’s functions. During
wound healing, several molecules that are usually
present only during embryonal development are
found in the granulation tissue. Epithelial cells start
to express extracellular matrix receptors that are not
normally present in the resting epithelium. Fibro-
blastic cells with a special phenotype are found in
the healing granulation tissue. Where they come
from is still largery unknown but possible sources
will be discussed in this chapter. Expression of vari-
ous proteins by the resident cells is also influenced
by the new environment. For example, in fibroblasts
the expression of hundreds of genes is altered by the
exposure to serum alone. Proteolytic enzymes re-
lease growth factors from the wounded basement
membrane and connective tissue matrix. Matrix
degradation produces biologically active peptides
from the matrix proteins that could have specific
functions in tissue repair. Clarification of the com-
plex interplay between new matrix, growth factors,
matrix degradation products and cells during wound
healing will be a challenging task. This review fo-
cuses on re-epithelialization and granulation tissue
formation with the special emphasis on the inte-
grins, since cell adhesion serves as a foundation for
cell migration, matrix turnover and differentiation
during wound healing.
127
Häkkinen et al.
Integrins
Integrins play key roles in re-epithelialization and
granulation tissue formation during wound healing
through their function in cell adhesion and sig-
naling. A brief overview is, therefore, presented de-
scribing the structure and function of integrins that
we hope will help the reader to better understand
how they participate in the regulation of wound
healing. Integrins are cell surface–associated dimeric
glycoproteins that function as cell-to-extracellular
matrix adhesion receptors (4, 16, 160). Through
binding to the extracellular matrix proteins integrins
mediate information transfer from the extracellular
matrix to the cell interior leading to alterations in
cell functions and ultimately in cell behaviour (100,
160). Integrins are known to play an important role
in regulating a wide range of cell functions during
growth, development, differentiation, and immune
response (4). Integrins are composed of a single a
and a single b subunit that are non-covalently linked
to each other. At least 17 different a and 8 b subunits
are currently known. These subunits can variously
combine to form more than 23 different cell surface
receptors that have distinct ligand-binding speci-
ficities. Both a and b subunits are transmembrane
glycoproteins that cooperate in integrin binding to
ligands. Ligand binding causes clustering of the re-
ceptors, which leads to cytoskeletal organization and
signaling (Fig. 1) (160). Integrin-binding sites are tar-
gets for therapeutic applications aiming at blocking
integrin function. Domain crystal structures are
Fig. 1. Integrins and cell signalling. Integrins mediate cell
adhesion to extracellular matrix proteins (ECM) leading
to organization of cytoskeleton and signaling. Integrins
also collaborate with growth factors in regulation of cell
growth. Some integrins can also directly activate growth
factors such as transforming growth factor b1 (TGFb1).
Proteolytic enzymes are also found in cell adhesion sites
allowing cells to detach and subsequently migrate.
128
being used for designing new molecules that have
high affinity to the binding site but are irrelevant to
the original peptide sequence. Commercial products
are already available for cardiovascular applications
(146). Several other compounds are in clinical trials
and many other similar products will follow and may
be used for periodontal applications in the future.
The number of proteins known to associate with
integrins is rapidly increasing (96). Integrin associ-
ated protein, transmembrane-4 superfamily, growth
factor receptors and urokinase-type plasminogen ac-
tivator receptor appear to have a regulatory function
on integrins. Growth factor receptors accumulate in
the same structures as integrins and regulate inte-
grin functions (Fig. 1) (161). In the context of wound
healing, the synergy between integrin and growth
factor receptors is probably a key process in the
regulation of cell proliferation (100). Integrins avb1
and avb6 can also bind growth factors such as trans-
forming growth factor b1 through its latency-acti-
vated peptide that contains an Arg-Gly-Asp (RGD)
peptide sequence (166, 167). It has recently been
shown that epithelial cells can bind and also activate
transforming growth factor b1 through avb6 integrin
(Fig. 1); this mechanism may play an important role
in the connective tissue bridge formation under-
neath the epithelium that has covered the wound. It
is evident that the epithelium has a much more ac-
tive role in the regulation of connective tissue forma-
tion than previously assumed.
Epithelial wound healing
Re-epithelialization
Wound healing is a complex phenomenon that in-
volves series of controlled events including the for-
mation of a provisional extracellular matrix that is
mainly composed of fibrin, fibronectin and vitronec-
tin and the migration of epithelial cells from the edg-
es of the wound (33, 108). After the epithelium has
been disrupted by tissue injury, re-epithelialization
must occur as rapidly as possible in order to re-es-
tablish tissue integrity. Keratinocytes start moving
into the defect about 24 hours after the injury (277).
Epithelial cells from residual epithelial structures
dissolve their hemidesmosomal connections and de-
tach from basement membrane and move quickly
across the wound defect. Later, as the re-epithelializ-
ation proceeds, the proliferation of keratinocytes
that feed the advancing epithelial edge becomes
more important. It is still somewhat unclear which
cells in the epithelium first move into the wound.

There is some evidence that the suprabasal keratino-
cytes are the first migratory cells sliding over the
basal keratinocytes. Epithelial cell migration on the
exposed connective tissue matrix underneath the
fibrin-fibronectin clot has been commonly de-
scribed. In small gingival wounds (Fig. 2), however,
the keratinocytes cut their way directly through the
clot and may not interact with the connective tissue
matrix at all (132). Migrating keratinocytes are highly
phagocytic, allowing them to penetrate through
tissue debris or the clot (277). Degradation of the fi-
brin clot appears to be critical for wound healing,
since wounds in animals that lack the plasminogen
gene do not re-epithelialize (199). It seems likely that
integrins play a role in the fibrin clot removal. Mi-
grating cells must be able to focalize the proteolysis
into the leading edge of epithelium (227). This could
be done by activation of proteolytic enzymes at spe-
cific sites at the cell membrane. It has been found
that urokinase type plasminogen activator receptor
is able to associate with integrins (283). This is an
example how a cell is able to focalize fibrinolysis by
plasmin and promote subsequent migration by inte-
grins. Modulation of other matrix componets may
Fig. 2. Stages of healing of full thickness gingival wounds (about 3 mm deep and 2 mm wide). FC: fibrin clot; GT:
granulation tissue.
Cell biology of gingival wound healing
also be necessary. Migrating keratinocytes express
matrix metalloprotease-9 (type IV collagenase), ma-
trix metalloprotease-1 (interstitial collagenase) and
matrix metalloprotease-10 (stromelysin), which all
may be required if the cells encounter the exposed
matrix (207, 210, 266). Blocking matrix metalloprote-
ase activity prevents keratinocyte migration into the
wounds in cell culture (147). This proteolytic modu-
lation of the matrix underneath migrating cells must
be well controlled, since overexpression of matrix
metalloproteases is a common finding in nonhealing
chronic wounds (187). In chronic inflammation, ma-
trix metalloproteases such as matrix metalloprotea-
se-9 produced by keratinocytes may bind to the cell
surface and into the extracellular matrix resulting in
a delayed clearance (147). Thus, regulation of matrix
metalloproteases and their inhibitors must be well
balanced for normal wound healing (266).
During wound healing, keratinocytes function to
rapidly cover the exposed connective tissue (236,
277). This process depends upon a variety of interac-
tions between cells and the extracellular matrix. As
the basal keratinocytes at the wound margin are ex-
posed to the new provisional matrix, the phenotype
129
Häkkinen et al.
of the cells is changed from stationary to migratory
(176). In this process, keratinocytes detach them-
selves from the basement membrane, migrate lat-
erally into the wound bed and finally regenerate the
basement membrane (124). In mucosa and in skin,
the migration seems to involve similar patterns, al-
though the source of migrating epithelial cells is dif-
ferent. In the mucosa, the basal layers of the wound
edge epithelium serves as a major source of the kera-
tinocytes migrating into the wound area. In the skin,
however, epithelial cells arise not only from the
wound edge but also from hair follicles and sweat
glands. During wound healing, most of the compo-
nents of the basement membrane zone such as type
IV and VII collagens, laminin-1 and heparan sulfate
proteoglycan are missing underneath migrating
keratinocytes (132, 178). Laminin-5, however, ap-
pears to be always deposited against the wound bed
matrix by keratinocytes during migration (Fig. 3)
(132). The role of laminin-5 appears to be critical
even for healing of the blister wounds where lamina
densa remains intact (110). It is also the first base-
ment membrane component found against the con-
nective tissue in experimental cyst formation that re-
sembles wound healing (110). Keratinocytes show
poor migration in chronic aphthous ulcers and also
fail to deposit a proper laminin-5 rich matrix (196).
Fig. 3. Keratinocyte integrins and extracellular matrix pro-
teins during re-epithelialization. A. Histological represen-
tation of a 3-day-old wound. B. Schematic view of the
same wound. Keratinocytes express a number of integrin
receptors (a2b1 to a6b4) and extracellular matrix proteins
130
Laminin-5 can be proteolytically modified (see be-
low) to produce different molecules that function
either as a nucleator of the hemidesmosomes (stop-
ping signal) or as a promoter of migration. Laminin-
5 seems to be the nucleator of a6b4 integrin and
therefore the nucleator of basement membrane or-
ganization (110). Migrating keratinocytes produce
other extracellular matrix molecules that they could
use to support their own migration. Fibronectin-EII-
IA but not EIIIB (see below) appears to be present
underneath the migrating keratinocytes in vivo (Fig.
3) (Häkkinen et al., unpublished). In addition, kera-
tinocytes in culture deposit fibronectin-EIIIA while
they migrate on substrates coated with serum
fibronectin (Koivisto et al., unpublished). Tenascin-
C large and small variants are also found underneath
the migrating keratinocytes. As we will discuss else-
where in this chapter, tenascin-C may function as a
modulator of cell adhesion to other matrix compo-
nents such as fibronectin. It appears obvious, there-
fore, that keratinocytes themselves are capable of
making extracellular matrix that they can use to sup-
port or modulate their own migration if the pro-
visional matrix is not permissive to migration. One
could question whether keratinocytes in healing
wounds migrate on the provisional matrix at all.
Some of the migration could be intraepithelial, that
(LM5: laminin-5; TN: tenascin-C; FN ED-A: fibronectin
isoform EIIIA) while they migrate through wound pro-
visional matrix. FC: fibrin clot; CT: connective tissue; E:
epithelium. πππ refers to the strong immunoreaction at
this stage of healing.

Table 1. Epithelial integrins and their ligands during wound healing
Integrin Ligand
a2b1 Collagen
Tenascin (?)
a3b1, a6b4 Laminin-5
a5b1, avb1 Serum fibronectin
Fibronectin EIII/A
a9b1 Tenascin-C
avb5 Vitronectin
avb6 Fibronectin EIIIA, fibronectin EIIIB
Transforming growth factor b1
is, suprabasal keratinocytes sliding on basal cells at
the leading edge. After reaching the provisional ma-
trix, migrating cells could stop moving and become
basal stationary keratinocytes. Two models for epi-
thelial sheet migration in wounds have been pro-
posed (236). In the sliding model the cells at the
margin are active and pull the cells behind them. In
a leap frog model, the migrating cells become non-
motile when they adhere to the provisional wound
matrix. Then the cells behind the leading edge crawl
over the newly attached keratinocytes. The exact
mechanism by which multilayered epithelium mi-
grates remains to be discovered, but it is possible
that all three mechanisms described above could
function depending on the defect and the state of
the healing. Embryonic re-epithelialization appears
to occur through a different mechanism. Epidermal
cells do not crawl by extending lamellopodia into the
wound as they do during, for example, gingival
wound healing (132). They rather use the actin
filament cables to pull wound edges together (154).
In small gingival wounds (2–3 mm distance be-
tween the wound edges), the formation of new base-
ment membrane starts when the migrating epithelial
sheets have reached each other and fused (132). The
nucleation of the basement membrane appears to
occur at multiple sites at the same time. It has been
reported that in epidermal wounds the deposition of
basement membrane starts from the wound margin
in a zipper-like fashion (35). Whether there is a real
difference in the sequence of basement membrane
organization between gingival and epidermal heal-
ing has not been shown. The reorganization of the
basement membrane is complete at 4 weeks at
which time the localization of all basement mem-
brane components such as type IV and VII collagens,
laminin-1 and heparan sulfate proteoglycan appear
normal (Häkkinen et al., unpublished). Keratinocytes
have been shown to synthesize these main compo-
Cell biology of gingival wound healing
Ligand source
Connective tissue
Keratinocytes, granulation tissue
Keratinocytes
Serum
Keratinocytes
Keratinocytes, granulation tissue
Serum, connective tissue
Keratinocytes, granulation tissue
Keratinocytes, macrophages, connective tissue cells
nents of the basement membrane zone (236). Sig-
nificant portion of the basement membrane compo-
nents are, however, synthesized by the wound
fibroblasts (65). It is obvious that the cross-talk be-
tween the wound keratinocytes and fibroblasts is
crucial during the reorganization of the basement
membrane zone.
Extracellular matrix interactions of keratinocytes
during re-epithelialization
As the epithelial cells undergo major environmental
changes during the wound healing, they have to ad-
just their cell surface receptors for the new demands.
During wound healing keratinocytes have to migrate
on the provisional matrix different from their
stationary matrix. This requires a change of express-
ion levels and distribution of old integrins and ex-
pression of some totally new integrins (Table 1, Fig.
3) (131). As discussed throughout this chapter,
fibronectin is a critical early component of the clot
and the forming granulation tissue. Initially, the
blood clot contains plasma fibronectin, which is
later replaced by cellular fibronectin produced by
keratinocytes, fibroblasts and macrophages (33).
Fibronectin can vary structurally in a tissue specific
manner by alternative splicing of three regions,
namely EIIIA, EIIIB and V(IIICS) (284). Expression of
the alternatively spliced isoforms of cellular
fibronectin containing either the EIIIA or EIIIB mod-
ules, which are omitted from the plasma fibronectin,
are upregulated specifically during embryonic devel-
opment and upon wounding (Häkkinen et al., un-
published). As discussed above, EIIIA fibronectin is
expressed by migrating keratinocytes in wounds
(Häkkinen et al., unpublished). The EIIIB fibronectin
that is expressed in embryonal tissues but not nor-
mally in adult connective tissue is strongly upregu-
lated during granulation tissue formation (Häkkinen
131
Häkkinen et al.
et al., unpublished, see below). Plasma fibronectin
and the isoforms containing the EIIIA or EIIIB mod-
ules may have different properties in cell adhesion
and migration during wound repair. Human wound
keratinocytes express two major receptors that are
able to bind to fibronectins, namely a5b1 and avb6
integrins (Table 1) (91, 132). The classical fibronectin
binding receptor is a5b1 integrin that binds to the
RGD sequence of the fibronectin molecule (1, 229).
Integrin a5b1 is considered to be a specialized recep-
tor for fibronectin and it mediates fibronectin-matrix
assembly, cell adhesion and migration on fibronec-
tin (1). Another fibronectin RGD site binding recep-
tor in epithelial cells is the avb6 integrin (17). Inte-
grin avb6 is expressed exclusively in epithelial cells,
and it functions as a receptor for the extracellular
matrix proteins fibronectin (17, 270) and tenascin
(191). Neither of the main fibronectin receptors,
a5b1 or avb6 integrin, appears to be present in kera-
tinocytes residing in the resting epithelium, but the
expression of both of these integrins can be induced
by wounding or placing epithelial cells in cell culture
(Fig. 3). These two fibronectin receptors appear in
the wound keratinocytes at different times, a5b1
during early migration and avb6 during reorganiza-
tion of the basement membrane zone suggesting
that their function may be different (91, Häkkinen
et al., unpublished). As mentioned earlier, epithelial
integrin avb6 may play a central role in the reorgan-
ization of the basement membrane zone (Fig. 4) as it
is expressed by wound keratinocytes after epithelial
sheets have joined and because it is able to activate
transforming growth factor b (167). In culture, kera-
tinocytes can switch between avb6 and a5b1 inte-
grins in fibronectin binding if one receptor is un-
functional (118).
Laminin-5 is found in the basement membrane
of skin and other epithelial tissues and serves as a
component of anchoring filaments that span
through the basement membrane (19, 203). The
extracellular domain of a6b4 integrin interacts with
laminin-5 (173, 203). This integrin is known to link
the basal keratinocytes to the underlying basement
membrane, and this link mainly relies on the inter-
action with laminin-5 in the anchoring filaments.
The functional importance of a6b4 integrin is sub-
stantiated by experiments in knockout mice that lack
either a6 or b4 integrin and cannot form hemides-
mosomes, which results in blistering of skin. Lamin-
in-5 is also recognized by a3b1 integrin (19). Trans-
genic mice lacking a3 integrin also develop localized
blistering of the skin (49). In mice and man, a3b1
integrin is occasionally found at the basal surface of
132
the basal keratinocytes, suggesting that a3b1 inte-
grin collaborates with a6b4 integrin in laminin-5
binding and they may be functionally interchange-
able in some circumstances. Integrin a6b4 is present
in migratory epithelial cells although hemidesmo-
somes are absent (132). One possible scenario could
be connected to the functions of laminin-5 during
wound healing. Intact laminin-5 appears to be a mo-
tility factor for keratinocytes, but when proteo-
lytically processed it starts to function as the nu-
cleator of hemidesmosomes and therefore promotes
the formation of basement membrane structures
(78). This is a good example demonstrating how
complex the wound-healing process is, since simple
proteolytic cleavage can totally reverse the function
of a protein important for the cell migration process.
Expression of b1 integrins is strongly upregulated
in keratinocytes during wound healing (20, 73, 97,
108, 132). Both a2b1 and a3b1 integrins seem to be
equally expressed. Integrin a3b1 is known to be able
to bind both fibronectin and laminin-5, both of
which are present in the provisional matrix (19, 132)
although its role as a fibronection receptor in kera-
tinocytes is doubtful. Integrin a2b1 is known to be
able to bind many types of collagens (Table 1), such
as type I, III, V and VI that serve as a substrate for
migrating keratinocytes. Direct interactions of kera-
tinocytes with type IV collagen are rare but may oc-
cur, for example, during healing of blister wounds,
in which case keratinocytes migrate on the compo-
nents of lamina densa. Keratinocytes are more likely
to interact with fibrillar collagens, such as types I,
III and V collagens during healing of full-thickness
wounds. In this case, interaction of keratinocytes
with collagens is mediated via a2b1 integrin. Inte-
grins are also involved in the regulation of extracellu-
lar matrix degradation. Cells in the tissue adapt to
their changing environment and sense alterations in
the matrix through integrins on the cell surface. Rec-
ognition of an altered matrix by integrins lead
changes in gene expression. For example, epithelial
and connective tissue cells attach to collagen by
a2b1 integrin which process induces the expression
of collagenase (matrix metalloproteinase-1) that can
cleave the exposed collagen matrix and facilitate the
migration of wound keratinocytes (186, 187, 278).
Vitronectin is an abundant protein present in
blood plasma, extracellular matrices and fibrin clots.
Vitronectin is known to be an active cell adhesion
mediator as well as playing a role in cell migration
and invasion (190). The avb1, avb3, avIIb3 and avb5
integrins are all vitronectin receptors binding to the
RGD cell attachment sequence of the protein (24).

Fig. 4. Hypothetical role of keratinocyte avb6 integrin in
the regulation of granulation tissue formation. A. Fibrin
staining of a 7-day-old gingival wound. Arrowheads mark
the wound area. B. Immunolocalization of avb6 integrin
in a 7-day-old wound. Basal keratinocytes of fused epi-
Migrating keratinocytes in porcine epidermis have
been reported to express the avb5 integrin (73). The
avb5 integrin is present in cultured keratinocytes
and has been shown to mediate keratinocyte mi-
gration on vitronectin (116). Vitronectin is present in
the provisional wound bed matrix and it is, therefore,
reasonable to assume that an avb5-vitronectin inter-
action can exist during wound healing (Table 1) (36).
Tenascins are a family of large extracellular matrix
proteins whose expression is tightly regulated, mak-
ing this protein particularly interesting. The express-
ion of tenascin is closely associated with morpho-
genetic events, including embryonic induction and
migration, wound healing and tumorigenesis (28,
122, 275). Tenascin-C knockout mice develop nor-
mally (208), suggesting that there are other mol-
Cell biology of gingival wound healing
thelium that cover the granulation tissue (GT) express
avb6 integrin. C. Schematic representation of the putative
role of avb6 integrin in wound healing. TGFb1: trans-
forming growth factor b1.
ecules that can replace its function and compensate
for its absence. Tenascin-C is found in developing
brain and in mesenchyme associated with epithelial-
mesenchymal interactions (28, 247). In adult tissues
tenascin-C is found in the connective tissue under-
neath epithelium (138), but its expression is strongly
upregulated during wound healing (31, 144, 275). As
mentioned above, the large and small tenascin-C
variants are found under migrating keratinocytes,
suggesting their active role in re-epithelialization.
Whether tenascins modulate keratinocyte adhesion
to other matrix components or support directly kera-
tinocyte adhesion remains to be shown. Several
keratinocyte integrins have been found to bind tena-
scin-C, namely a2b1, avb6 and a9b1 integrins (14,
191, 290, 291). Integrin a9b1 in actively migrating,
133
Häkkinen et al.
and avb6 integrin in nonmigrating wound keratino-
cytes, colocalize in the same area as tenascins (Table
1) (Häkkinen et al., unpublished). These two epi-
thelial integrins may, therefore, have a different role
in cell signaling caused by tenascin-C variants. Up-
regulation of a9b1 and tenascin-C is also observed
during corneal wound healing (239).
Transforming growth factor b and
re-epithelialization
In wounds, specific regulatory signals are required
for normal repair. Currently it is believed that trans-
forming growth factors-b have a central role in the
wound healing process. Transforming growth factors
b are a family of polypeptides that have multiple
regulatory actions in cell growth, differentiation, and
developmental processes (155, 234, 244). Three
highly homologous transforming growth factor-b
genes have been identified in mammals, represent-
ing transforming growth factor b1, transforming
growth factor b2 and transforming growth factor b3
polypeptides. Human keratinocytes of intact skin ex-
press transforming growth factor b3 (216). This
growth factor seems to play an important role in epi-
dermal maintenance. In animal studies, only small
amounts of transforming growth factor b2 and trans-
forming growth factor b3 messenger RNA have been
found in keratinocytes of intact dermis (215). All
transforming growth factor b isoforms are found in
healing wounds of animals (111, 137). However,
Schmid et al. (216) did not find any detectable levels
of transforming growth factor b2 messenger RNA in
human wound keratinocytes. Wound fibroblasts and
macrophages are known to express both trans-
forming growth factor b1 and transforming growth
factor b2 in cells adjacent to the wound (175, 267).
Transforming growth factor b1 is the major isoform
in wound keratinocytes, and induction of trans-
forming growth factor b1 in migrating keratinocytes
is crucial for the successful re-epithelialization of
skin wounds. In vitro studies have shown that trans-
forming growth factor b3 inhibits the growth of pri-
mary human keratinocytes, while transforming
growth factor b1 seems to stimulate keratinocyte
motility by switching the cells from the differentiat-
ing to regenerative phenotype (152) and by inducing
their production of fibronectin (172) and laminin-5
(110). In cultured human keratinocytes, trans-
forming growth factor b1 has also been shown to in-
crease the levels of messenger RNA for some inte-
grins, such as a5, av and b5, that may facilitate mi-
gration of wound keratinocytes (73, 292). In cultured
134
HaCaT keratinocytes, transforming growth factor b1
and 2 specifically stimulate the expression of avb6
integrin, and promote both haptotactic and epi-
thelial sheet migration (118). As we have discussed
earlier, the most important role for avb6 integrin
may be the activation of transforming growth factor
b1 that then promotes the formation of the connec-
tive tissue bridge formation under the joined wound
epithelium. The first collagen fibrils are, indeed, laid
down under the epithelium in areas where the ex-
pression of avb6 is strong and transforming growth
factor b1 is present in active form. Transforming
growth factor b1 may also stimulate the proliferation
of wound keratinocytes at the wound margins in-
directly by inducing the expression of other polypep-
tide growth factors, such as platelet-derived growth
factor (3, 22).
In addition to transforming growth factors b,
many other growth factors regulate wound healing.
This review will not try to list all possible factors in-
volved in re-epithelialization and the readers are ad-
vised to review other sources for the roles of platelet-
derived growth factor, epidermal growth factor, kera-
tinocyte growth factor, hepatocyte growth factor and
others in wound healing.
Connective tissue repair
Activation of fibroblasts
The resolution of a tissue defect after wounding re-
quires not only re-epithelialization but also prolifer-
ation and migration of fibroblasts into the wound
bed where they participate in the formation of
granulation tissue and synthesize, deposit and reor-
ganize various extracellular matrix molecules.
Wound repair involves phenotypic change of fibro-
blasts from quiescent to proliferating cells, and sub-
sequently to migratory, and then to stationary matrix
producing and contractile cells. In normal connec-
tive tissue, fibroblasts reside in a quiescent state and
have a slow proliferation rate and metabolic activity.
Upon wounding, fibroblasts become activated and
change their gene expression. This is supported by a
recent finding with quiescent fibroblasts that show a
rapid change in expression of hundreds of genes
when stimulated by serum. Interestingly, many of
the serum-activated genes are known to be involved
in the physiology of wound repair, including control
of cell cycle and proliferation, coagulation and
hemostasis, inflammation, angiogenesis, tissue re-
modeling, cytoskeletal reorganization and re-epi-
thelialization (107). This indicates that exposure of

fibroblasts to serum that is present in the blood clot
in the wound initiates not only a rapid general
stimulus for cell proliferation but also a more speci-
fic gene expression that controls function of other
cells involved in inflammation, angiogenesis and re-
epithelialization. Therefore, it is likely that fibro-
blasts play a more important role in the physiology
of wound repair than has been previously realized
(107).
In addition to serum stimulation, cell adhesion to
different matrix molecules can also alter gene ex-
pression and protein synthesis (4, 120, 121, 143). Cell
adhesion also modulates signaling initiated by
growth factors (109, 163). During tissue repair,
fibroblasts are exposed to a variety of extracellular
matrix molecules and soluble growth factors that can
exert multiple signals at the same time. Additionally,
cells experience tensional forces from the extracellu-
lar matrix during cell migration and reorganization
of the wound matrix, which can modulate signaling
inside the cell (27, 205, 228). The function of extra-
cellular matrix proteins may be further modulated
by proteolytic modification (13, 143, 227), and by
conformational changes induced by tensional forces
(295). Therefore, the regulation of fibroblast gene ex-
pression upon wounding is likely to be very complex
and dependent on the balance between different ac-
tivated signaling pathways (41).
Origin of wound fibroblasts
The multiple functions of wound fibroblasts raise
the question of whether all of the tasks are per-
formed by a single cell type or multiple different
phenotypes are involved (Table 2). If the latter case
is correct, does the heterogeneity result from mi-
gration of phenotypically different cells into wound
or does it result from differentiation of the fibro-
blasts that have populated the wound? These ques-
tions are still largely unanswered. There is evidence,
however, that connective tissue fibroblasts are het-
erogeneous in several properties, including, respon-
siveness to growth factors and in the ability to pro-
duce specific extracellular matrix proteins (93, 94,
Table 2. Origin of wound fibroblasts
Possible sources of wound fibroblasts Steps involved
Surrounding connective tissue Migration, differentiation
Pericytes Proliferation, migration
Bone marrow Systemic control, homing, differentiation
Cell biology of gingival wound healing
185, 188, 219, 225) suggesting that signals initiated
by wounding may stimulate certain subpopulations
to enter the wound space. On the other hand, there
is also evidence that some of the fibroblasts that
have migrated into wound actually change pheno-
type and differentiate into myofibroblasts (see
below).
Progenitor fibroblast populations have been iden-
tified in wounds for decades using autoradiographic
labeling techniques. Based on these studies, the
main source of wound fibroblasts seems to be the
surrounding connective tissue. Typically, 2 or 3 days
after wounding, the label-retaining cells are located
at the subepithelial connective tissue underlying the
wound edge and at the perivascular location. It
seems, however, that only a subpopulation of the lo-
cal fibroblasts proliferate in response to tissue injury
(225), suggesting that certain fibroblast subsets are
more responsive to growth stimulation than others.
Local fibroblasts are not the only source of wound
fibroblasts. After wounding, pericytes that are resi-
dents of the surroundings of the vascular endo-
thelium of capillaries and venules are also induced
to proliferate and migrate into the wound (79, 106,
158). Although fibroblasts have multiple functions in
wound repair, their hallmark characteristic is the
property to produce collagen and other structural
extracellular matrix proteins that replace the blood
clot. This property separates wound fibroblasts from
inflammatory and vascular endothelial cells that are
also involved in the formation of granulation tissue.
Accordingly, upon wounding, the pattern of gene ex-
pression in pericytes is reprogrammed from a con-
tractile to a migratory collagen-producing cell, sug-
gesting that these cells are able to function as ma-
trix-producing wound fibroblasts.
Could some of the wound fibroblasts also arise
from bone marrow stem cells? Interestingly, early
work by Cohnheim in 1867 suggested that some of
the wound fibroblasts may originate from bone mar-
row. This was further supported by recent findings
showing that genetically marked bone marrow
stromal cells serve as a source of progenitor cells for
various mesenchymal tissues. Most importantly,
135
Häkkinen et al.
these cells apparently translocate to the target tissue
where they acquire the phenotype of the resident
cells (183, 193). These ‘‘peripheral blood fibrocytes’’
accumulate in the wound already in the early acute
phase but are also present in the scar tissue (15).
Fibrocytes function as antigen presenting cells and
can prime naive T cells (25) and secrete a number of
cytokines involved in immune response, hematopo-
esis and extracellular matrix synthesis (25, 26), sug-
gesting that fibrocytes may play a role in the regula-
tion of the acute inflammatory reaction as well as in
the matrix deposition in wounds.
Taken together, the matrix-producing cells that
populate wound granulation tissue originate from
diverse tissue sources and, depending on their ori-
gin, they may serve different functions.
Integrin expression and function in fibroblasts
during wound repair
In the connective tissue, fibroblasts are surrounded
by a matrix that contains collagen and cellular
fibronectin as the major components. Consequently,
quiescent fibroblasts express collagen receptors
a1b1 and a2b1 and the major fibronectin receptor
a5b1 integrin which they use for adhesion to the ma-
trix (74, 271, 281). Fibroblasts express a3b1 (281) and
integrin heterodimers of the av subfamily (Häkkinen
et al., unpublished) that can also be used to bind
fibronectin (4). Although cultured fibroblasts are
able to express avb1, avb3 and avb5 integrins (70,
73, 92), it is not completely clear with which b sub-
units av actually combines to form integrin hetero-
dimers in quiescent fibroblasts in vivo. In cell cul-
ture, fibroblasts also express a4b1 integrin that binds
to fibronectin (72), but it is unclear whether this
integrin is actually expressed by fibroblasts in vivo.
The b1 integrins in quiescent fibroblasts are par-
tially in an inactive state and become activated after
wounding in fibroblasts that are located near the de-
fect (Häkkinen et al., unpublished). Several lines of
evidence show that integrin activation and integrin-
mediated cell adhesion to extracellular matrix is im-
portant for induction of DNA synthesis (179). Speci-
fic integrin-ligand binding is required to commence
DNA synthesis of cells. Cell adhesion to extracellular
matrix via integrins strongly influences the ability of
normal cells to respond to soluble mitogens (43, 76,
109, 221). Activated integrins can physically complex
with growth factor receptors (see above) which pro-
vides a mechanism of how different signaling mol-
ecules may be targeted to cell-matrix interaction
sites inside the cell (161, 218). It is, therefore, prob-
136
able that the decision of the fibroblast to enter the
cell cycle depends on the repertoire of integrins that
actively interact with specific extracellular matrix
proteins and on the combination of growth factors
that the cells are exposed to at the particular phase
of wound repair.
Cell migration is needed for fibroblasts to enter
the wound provisional matrix. Fibroblast migration
into the blood clot occurs only after a lag period of
3 to 5 days, the time required for cells to proliferate
(32, 157). The lag phase may also be needed for the
cells to be activated from quiescent state to be fully
active migratory cells and to be recruited from their
original location in the tissue or bone marrow to the
wound site. It is believed that, in order to detach
from a collagen-rich matrix, fibroblasts have to
downregulate their expression of collagen receptors
and upregulate integrins that bind fibronectin, fi-
brin, fibrinogen and vitronectin in the provisional
wound matrix. Accordingly, about 3 to 5 days after
injury, fibroblasts that migrate into the blood clot ex-
press the primary fibronectin receptor a5b1 integrin
and a3b1 integrin while they show downregulation
of collagen-binding a1 and a2 integrin expression at
the wound margin (74, 281). Platelet-derived growth
factor, which is abundantly expressed during early
wound repair, stimulates cell migration towards
fibronectin by increasing the synthesis of a5 and a3
integrins (74, 117). On the other hand, platelet-de-
rived growth factor downregulates a1 (74) while it
stimulates a2 integrin expression by fibroblasts in
culture. Therefore, the regulation of a2 integrin ex-
pression in vivo and in vitro is different, possibly be-
cause of the multiple signals in addition to platelet-
derived growth factor that modulate integrin ex-
pression in the tissue. One of the factors that modu-
lates integrin expression during wound repair is the
composition of the extracellular matrix. If fibroblasts
are cultured in fibrin and fibronectin-rich matrices
that resemble the early wound matrix, they show
selective upregulation of a3 and a5 integrin mRNA
as opposed to cells that are in collagen-rich matrix,
which show upregulation of a2 integrin (281). This
suggests that signals initiated by growth factors and
extracellular matrix molecules collaborate to induce
appropriate integrin expression to support cell mi-
gration on fibrin-fibronectin matrix in the early
wound repair and to allow cell adhesion on collagen
later during scar formation.
In the early wound, fibroblast migration seems to
be primarily mediated by fibronectin because
fibroblast migration from a three-dimensional colla-
gen matrix into a fibrin clot depends on the presence

of fibronectin in the matrix and can be blocked with
antibodies against a5b1 and avb3 integrins in vitro
(84). Fibroblasts can also use avb3 and avb5 inte-
grins for cell adhesion on vitronectin present in the
clot (70) and avb3 for cell adhesion and migration
on fibrin and fibrinogen, respectively (71, 84). Cell
migration is regulated by the structural organization
of the fibronectin matrix. In the normal connective
tissue, cells deposit and arrange fibronectin into a
fibrillar network between the cells and other matrix
molecules using primarily a5b1 and possibly avb3
integrins (279, 280, 287). In contrast, in the blood
clot, plasma fibronectin is cross-linked with fibrin to
form a three-dimensional scaffold (224). The vari-
ation in the architecture of the fibronectin network
can regulate multiple cell functions, suggesting that
fibronectin in the connective tissue and in the blood
clot may elicit different signals (224, 233). During
wound repair, cells are induced to deposit alterna-
tively spliced isoforms of cellular fibronectin con-
taining either the EIIIA or EIIIB modules (see above).
The EIIIA or EIIIB modules have different properties
to support cell adhesion, migration, and prolifer-
ation (95, 150, 151), suggesting that they may have
different functions in wound repair.
Wounding induces deposition of extracellular ma-
trix proteins that modulate cell adhesion. Among
these molecules, tenascin-C, thrombospondin and
secreted protein, rich in cysteine/osteonectin
(SPARC) are multifunctional molecules that can
serve as ligands for multiple cell surface receptors
(83). Typically, the expression of tenascin-C and
thrombospondin is potently stimulated early during
granulation tissue formation, while SPARC is ex-
pressed from middle to late stages of repair. Express-
ion of tenascin-C and SPARC remains elevated dur-
ing tissue reorganization while the expression of
thrombospondin is only transient (50, 144). Interest-
ingly, wounding specifically induces the expression
of the large tenascin-C splice isoform (144, Häkkinen
et al., unpublished) that is normally expressed pre-
dominantly during embryonic development (156,
192). Tenascin-C contains both adhesive and
counteradhesive domains, although mostly it is be-
lieved to reduce the adhesion of cells to fibronectin
and therefore enhance cell migration (253). The ef-
fect of tenascin-C on cell adhesion to fibronectin can
also further modulate gene expression by the cells
(253). Interestingly, the large tenascin-C splice iso-
form functions differently in regulation of cell ad-
hesion and in binding fibronectin as compared with
the more ubiquitously expressed small isoform (29,
63, 64, 113, 169, 184). Tenascin-C can serve as ligand
Cell biology of gingival wound healing
for several cell surface receptors, including avb3
integrin in fibroblasts that binds to the RGD se-
quence found in the third fibronectin type repeat of
the tenascin molecule. Ligand binding by integrins
to this repeat is modulated by other counteradhesive
domains in the molecule (40).
Thrombospondin can also, like tenascin-C, modu-
late cell adhesion, migration and proliferation (83).
It contains an RGD sequence that is recognized by
avb3 integrin expressed by fibroblasts (240, 255), but
it also contains, like tenascin-C, additional binding
sites for other cell surface receptors (240). SPARC is
also able to interfere with integrin-mediated cell ad-
hesion on extracellular matrix, and this is believed
to occur via interaction with other cell surface mol-
ecules that are able to bind SPARC and not with
steric disruption of integrin–extracellular matrix in-
teraction (168). Because of their different temporal
expression pattern during wound repair, it is poss-
ible that tenascin-C, thrompospondin and SPARC
regulate different cellular functions. Indeed, gene
knockout animal studies have indicated that throm-
bospondin plays a role in regulation of the activity
of transforming growth factor-b, collagen fiber or-
ganization and vascularization in the connective
tissue (39, 126), which are all important processes in
the physiology of wound repair.
Wound contraction
One of the tasks of fibroblasts in granulation tissue
is to bring the wound margins closer together to
allow rapid wound closure. It is not completely clear
how wound contraction actually happens in vivo.
The most widely held concepts suggest that wound
closure follows when central granulation tissue is
contracted either by myofibroblasts pulling the new
collagen matrix (69) and/or by fibroblasts changing
the organization of the wound matrix by migrating
through it (54, 67). On the other hand, experimental
removal of central granulation tissue does not seem
to prevent wound contraction, suggesting an alter-
native mechanism in which polarized coordinated
migration of a rim of densely packed fibroblasts pull
forward the wound edges (89).
Myofibroblasts are likely to play a role in wound
contraction and matrix deposition. This is supported
by findings that myofibroblasts are typically present
in tissues that are under mechanical stress but they
are only occasionally found in normal tissue (46).
Myofibroblasts become especially prominent in
pathological conditions including wound repair,
tissue fibrosis and tumor stroma (42, 46, 201). These
137
Häkkinen et al.
cells are characterized by presence of abundant
cytoplasmic microfilament bundles and a-smooth
muscle actin. They differ from normal fibroblasts
morphologically, in growth potential, expression of
proteoglycans and collagen, responsiveness to trans-
forming growth factor b, organization of focal ad-
hesions, and in their ability to organize cellular
fibronectin in culture (51, 93, 94, 212). Fibroblasts
cultured from wound granulation tissue are rich in
myofibroblasts and express a similar repertoire of
integrins as normal connective tissue fibroblasts.
They are, however, phenotypically unique in that
they show reduced cell spreading on fibronectin as
a result of altered interaction of a5b1 integrin and
fibronectin (92).
The differentiation of myofibroblasts occurs be-
tween 6 and 15 days after wounding (42, 217). After
15 days, about 70% of fibroblasts in granulation
tissue express a-smooth muscle actin. Differen-
tiation of myofibroblasts coincides with wound con-
traction, which has led to the idea that these cells
are actually involved in this process. The differen-
tiation of myofibroblasts is induced by transforming
growth factor b in vivo and in cell culture but not
with other profibrotic growth factors and cytokines
(47, 204). Importantly, myofibroblasts differentiation
is controlled by integrin mediated mechanisms and
depends on the composition of the extracellular ma-
trix and the tensional forces mediated from the ma-
trix. Recent studies have shown that the induction of
myofibroblast differentiation by transforming
growth factor-b requires deposition of cellular EIIIA
fibronectin in the pericellular matrix (226). In tissue,
differentiation of wound fibroblasts into myofibro-
blasts follows induction of EIIIA fibronectin express-
ion (226). The induction of the expression of a-
smooth muscle actin in fibroblasts by transforming
growth factor b is also regulated by the changes in
the collagen matrix around the cells and on the de-
velopment of intracellular tension (5, 171). This is in
turn regulated by interaction between a2b1 integrins
and collagen (171). The induction of a-smooth
muscle actin expression during wound repair is
thought to provide a mechanism to stop fibroblast
migration when cells reach their destination. Ter-
mination of migration and formation of prominent
focal adhesions may be needed to promote stable
(200) cell adhesion to matrix, which is required for
myofibroblasts to acquire a matrix-synthesizing and
contractile phenotype.
In ideal wound repair, scar tissue is remodeled and
reorganized to form structurally and functionally nor-
mal connective tissue. When contraction stops, the
138
myofibroblasts disappear because of apoptosis and
the scar becomes less cellular and new fibroblasts
with properties typical to normal connective tissue
fibroblasts emerge (42, 48, 217). Apoptosis of myo-
fibroblasts begins at day 12, peaks at day 20 and re-
solves by day 60 after wounding (48). Factors that in-
hibit a-smooth muscle actin expression and differen-
tiation of myofibroblasts are not well characterized. It
has been noted that interferon-g has an antifibrotic
effect, which probably results from its ability to inhibit
fibroblast differentiation into myofibroblasts (217).
Additionally, myofibroblasts are more sensitive to
basic fibroblast growth factor–induced apoptosis
than normal connective tissue fibroblasts (68), which
may provide a mechanism to reduce the amount of
myofibroblasts in the tissue when they are no longer
needed. Interestingly, myofibroblasts persist in cer-
tain pathological conditions, including hyperthroph-
ic and fibrotic lesions of many organs, suggesting that
they are involved in the accumulation of extracellular
matrix that is characteristic for these lesions (45, 217).
Therefore, for normal wound repair it is important
that the myofibroblasts undergo apoptosis and are re-
placed by normal fibroblasts when wound contrac-
tion is completed.
An interesting question is where the fibroblasts that
replace myofibroblasts and that eventually maintain
the connective tissue structure during tissue homeo-
stasis originate from. Because these cells have pheno-
typic properties characteristic to normal connective
tissue fibroblasts, it is possible that they are derived
from the connective tissue next to the wound or, alter-
natively, they differentiate from more primitive
fibroblasts that initially populate the wound. Regard-
less of their origin, it seems that replacement of the
wound fibroblasts with cells of normal connective
tissue fibroblast phenotype is necessary for the com-
plete regeneration of the tissue.
Mechanical tension
The interactions between cells and extracellular ma-
trix during granulation tissue formation can be
studied in cell culture using cell-populated three-di-
mensional fibrin or collagen gels (86, 256). In prin-
ciple, the fibrin gels correspond to the situation in
early wound repair when fibroblasts have migrated
into the fibrin containing provisional matrix while
the collagen gel model resembles later phase of
wound repair when granulation tissue fibroblasts re-
side in a newly deposited collagen-rich matrix that
undergoes remodeling. In these models, fibroblasts
attach to the proximal fibrin or collagen fibers and

in an attempt to migrate pull the fibers together to
form a dense tissue-like structure. When fibroblasts
are allowed to grow in fibrin gels they eventually re-
place the fibrin matrix with newly deposited colla-
gen (256). If the gel is not relaxed, fibroblasts trying
to pull the fibers experience high tension from the
matrix that resembles wound granulation tissue.
Contraction of three-dimensional collagen gel is me-
diated by integrins and can be stimulated by serum
and growth factors present in wound, including lyso-
phosphatidic acid, transforming growth factor b and
platelet-derived growth factor (34, 87, 90, 164, 197,
250). Currently, there is some controversy over which
specific integrin-ligand interactions actually mediate
collagen contraction. Binding between fibroblasts
and collagen fibrils is evidently the first and most
important step in the collagen gel contraction. Most
data show that in human connective tissue fibro-
blasts, collagen gel contraction is mediated by the
collagen receptor a2b1 integrin (214, 238). The rate
of contraction depends on the amount of a2b1 inte-
grins expressed by the cells (197). This is in accord-
ance with simultaneous induction of a2 integrin ex-
pression by wound fibroblasts with formation of col-
lagenous scar and beginning of wound contraction
in vivo (282).
Role of integrins in regulation of cell proliferation
and survival in granulation tissue
During the formation of granulation tissue, fibro-
blasts that emerge into the provisional wound matrix
stop migrating and undergo cell proliferation. Ac-
cordingly, about 7 to 10 days after wounding, the
granulation tissue becomes hypercellular containing
abundant fibroblasts and endothelial cells (157, 271).
After that, during tissue maturation, the cell number
in the granulation tissue gradually decreases (48,
157, 271). It appears that the organization of collagen
and mechanical tension mediated from the extracel-
lular matrix are important factors that modulate
DNA synthesis and cell survival. This is evidenced by
the finding that fibroblasts cultured under mechan-
ical tension proliferate actively, but after stress relax-
ation the DNA synthesis is rapidly downregulated
and cells start to undergo apoptosis (66, 87, 139,
162). Stress relaxation also downregulates autophos-
phorylation of growth factor receptors, which con-
tributes to the growth reduction (139, 159, 241). In a
mechanically stressed collagen gel, cells develop an
organized cell surface fibronectin network (162, 251)
that disappears after stress relaxation. Since a5b1
integrin can probably serve as a mechanoreceptor
Cell biology of gingival wound healing
and mediate signals that promote cell growth (269,
294), differences in fibronectin receptor engagement
may be a mechanism of how cell proliferation is
regulated by mechanical signals. Therefore, reduc-
tion of mechanical strain during tissue maturation
may provide a mechanism to downregulate cell
growth and induce apoptosis to normalize the cellu-
larity in the tissue. Additionally, in the later phases
of wound repair the activity of growth factors is
gradually downregulated (231, 288), which will
further reduce the number of growth stimulatory sig-
nals for fibroblasts. In the regulation of cell growth
and apoptosis in the granulation tissue, integrins
probably play an important role because they me-
diate the signals initiated by mechanical tension and
collaborate with growth factor signaling and mediate
signals that regulate cell survival (109, 205, 206, 228).
Interestingly, fibroblasts undergo apoptosis in con-
tractile collagen gels but not in fibrin gels (66), sug-
gesting that specific types of integrin–extracellular
matrix interactions are needed for initiation of
apoptosis. This may provide a mechanism to prevent
fibroblasts from undergoing apoptosis in the early
fibrin-rich provisional wound matrix and to allow
their proliferation, which is needed to populate the
granulation tissue with fibroblasts.
An additional mechanism that is likely to regulate
cell growth in the granulation tissue is the structural
organization of the extracellular matrix. During
granulation tissue formation, fibroblasts first syn-
thesize fibronectin and then type I collagen that is
gradually organized from monomeric molecules to
form a fibrillar collagen matrix (125). Monomeric
collagen through a2b1 integrin promotes cell pro-
liferation while fibrillar collagen downregulates it
(123). Additionally, studies using fibronectin de-
ficient cells have shown that assembly of fibronectin
matrix by the cells is required for fibronectin to pro-
mote cell growth on different extracellular matrix
molecules (233). Therefore, it is probable that the de-
position and organization of extracellular matrix by
fibroblasts provides a feedback mechanism to regu-
late cell growth during wound repair.
Regulation of protein synthesis and matrix
degradation in the granulation tissue
Remodeling of tissue during wound repair requires
controlled synthesis and degradation of extracellular
matrix. The most important factors that regulate
synthesis and secretion of these molecules include
growth factors and signals from the extracellular ma-
trix. There is evidence that integrin binding to its
139
Häkkinen et al.
ligand can directly induce gene expression (102, 254,
272). Most importantly, there seems to be a specific
integrin-ligand interaction that is needed for stimu-
lation of specific type of protein synthesis (254, 272).
In this process, the signals mediated by integrins are
further modulated by growth factors, the structural
architecture of the extracellular matrix as well as by
tensional forces (109, 202, 228).
During granulation tissue formation, fibroblasts
are stimulated by transforming growth factor-b to
deposit new extracellular matrix proteins. Interest-
ingly, early matrix deposition seems to occur first at
about day 7 after injury in the granulation tissue im-
mediately under the newly formed epithelium (178).
This coincides with the peak in activation of latent
transforming growth factor-b from storages in the
blood clot provisonal matrix and in the matrix of the
granulation tissue (81, 288) and with induction of
epithelial avb6 integrin which may regulate the acti-
vation of latent transforming growth factor-b (see
above, 91, Häkkinen et al., unpublished). Once acti-
vated, transforming growth factor-b can induce its
own production by fibroblasts (139), which may be a
mechanism to maintain high activity of transforming
growth factor-b in the granulation tissue.
As discussed earlier, a potent modulator of protein
synthesis is mechanical tension. Generally, when
cells are grown in collagen gels under tension they
show a relatively high protein synthesis rate, while
after stress relaxation the protein synthesis is down-
regulated (162). The signals initiated by tension in
a three-dimensional collagen matrix require specific
integrin-collagen interactions and may lead to speci-
fic gene activation. Additionally, platelet-derived
growth factor–induced upregulation of a2 integrin
expression is stimulated if fibroblasts are cultured in
collagen gel while expression of a5 and a3 integrins
is attenuated (281). Transforming growth factor-b
can also potently stimulate expression of a2 integrin
in fibroblasts that interact with collagen, and this de-
pends on the tensional forces that the cells experi-
ence (5). It seems that tension mediated from the
matrix can effectively regulate the balance between
matrix production and degradation. For example,
upon stress relaxation the expression of type I colla-
gen is downregulated while that of matrix metallo-
proteinase-1 and -13 is upregulated (30, 195, 197,
252). The regulation of collagen and matrix metallo-
proteinase genes by collagen matrix is partially regu-
lated by different collagen receptors. The downregu-
lation of collagen synthesis after stress relaxation is
mediated by a1b1 integrin and the upregulation of
matrix metalloproteinase-1 and matrix metallopro-
140
teinase-13 expression occurs by a2b1 and by both
a1b1 and a2b1 integrins, respectively (195, 197).
Integrin a1b1 seems to be able to function as a feed-
back regulator of collagen synthesis in fibroblasts
(75).
Gingival wound repair: similarities to scarless fetal
wound repair
There has been a general observation that wounds
in the oral mucosa heal faster and with less scarring
than extraoral wounds (Table 3). Scar tissue is char-
acterized by excessive accumulation of disorderly ar-
ranged collagen, mostly type I and III (219), proteo-
glycans (274, 289) and persistent myofibroblasts (42,
46, 201), which leads to aberrant function of the
tissue. Surprisingly, there are only a few reports that
have quantitatively tested this hypothesis. Neverthe-
less, based mostly on animal studies it seems that
wound healing in oral mucosa, indeed, is faster and
results in less scarring than in skin (223, 286). It is
probable that oral wound healing is enhanced partly
because of factors present in the saliva and by the
specific microflora of the oral cavity (see below). Ad-
ditionally, the properties of the cells involved in
tissue regeneration in oral mucosa are unique and
share properties of fetal cells (219). Scar formation is
developmentally regulated because, in early ges-
tation, fetal wound repair occurs without scar forma-
tion and the transition to healing with scar forma-
tion occurs late in the gestation (56, 104). Interest-
ingly, the initiation of scar formation parallels the
induction of myofibroblast differentiation during
wound repair at different stages of embryonal devel-
opment (56), suggesting that phenotypic modulation
of wound fibroblasts into myofibroblasts may be in-
volved in scar formation.
As compared with adult wounds, fetal wounds are
characterized by the absence of clot formation and
inflammatory reaction. They also show unique spa-
tial and temporal organization of extracellular matrix
and reduced expression of transforming growth fac-
tor-b (274). Several investigations have compared the
properties of adult skin and gingival fibroblasts with
fetal fibroblasts. The findings indicate that, unlike
adult skin fibroblasts, adult gingival fibroblasts
located in the papillary connective tissue share
many properties with fetal fibroblasts, including
their growth and migration properties, cell mor-
phology, production of migration stimulating factor,
and production and response to cytokines (219). Ad-
ditionally, similar to fetal fibroblasts, oral mucosal or
gingival fibroblasts are able to contract three-dimen-

Table 3. Special features of oral wound healing
Factor Mechanism
Saliva Moisture, ionic strength
Growth factors (EGF, TGFb, FGF, IGF etc.)
Unknown factors
Bacteria Stimulation of macrophage influx
Direct stimulative action on keratinocytes and fibroblasts
Phenotype of cells Fetal-like fibroblasts with unique response
Specialized epithelium and connective tissue
sional collagen matrix faster as dermal fibroblasts
(105, 237). They also populate experimental wounds
faster than their dermal counterparts in culture (2).
Gingival fibroblasts also differ from dermal fibro-
blasts in their ability to secrete proteolytic enzymes.
Matrix metalloproteinase-13, a potent collagenase
(273), is expressed in the granulation tissue during
acute wound repair at 7- and 14-day-old human gin-
gival wounds but not in dermal wounds (296). Ad-
ditionally, when gingival fibroblasts are inoculated
into three-dimensional fibrin matrix they are able to
reorganize and degrade the matrix rapidly. This is
because of high expression of tissue plasminogen ac-
tivator. Matrix reorganization and fibrinolysis is less
advanced in dermal fibroblast-inoculated matrices
(141, 142). The regulation of fibrinolysis by gingival
fibroblasts depends on the tensional forces that the
cells experience from the matrix (140). The various
findings described above suggest that several cell
functions important in tissue repair are shared by
fetal and gingival fibroblasts and differ from dermal
fibroblasts. It is possible that gingival fibroblasts are
phenotypically unique cells in adult tissue that may
contribute to the rapid healing of oral wounds with
minimal scarring in the gingiva.
Role of saliva and gingival
crevicular fluid in oral wound
healing
While it is clear that the excellent healing potential
of oral mucosa results to a large extent from the in-
trinsic tissue factors such as the presence of struc-
tural cells with potential for tissue regeneration,
dense vasculature and high turnover rate of connec-
tive tissue and epithelium, it is also apparent that
saliva provides a unique environment in the mouth
conducive for rapid tissue repair (Table 3). This be-
comes obvious from the studies showing delayed
Cell biology of gingival wound healing
healing of oral wounds in people with xerostomia
or sialadenectomized animals (12, 55, 103). Animals
instinctly lick their wounds, which appears to result
in faster healing (11). There are several physico-
chemical factors in saliva favoring gingival healing.
These include an appropriate pH, ionic strength, and
presence of ions such as calcium and magnesium
required for healing (53). Saliva also has an efficient
capacity to reduce redox activity caused by tran-
sitional metal ions and inhibit the production of free
radicals that may be beneficial for the healing pro-
cess (170). Lubrication of oral mucosa provided by
saliva is beneficial for wound healing. The advan-
tageous effects of maintaining a moist wound en-
vironment include prevention of tissue dehydration
and cell death, accelerated angiogenesis and in-
creased breakdown of fibrin and tissue debris.
Hence, the use of hydrocolloid occlusive dressing is
a useful adjunct in facilitating cutaneous wound
healing (61). The therapeutic effect of saliva on heal-
ing of skin wounds has been demonstrated exper-
imentally in calves. Compared to saline-treated
wounds, saliva-treated wounds had shorter in-
flammatory reaction and faster epithelial coverage
and connective tissue regeneration (268). It appears
that moisture and ionic strength are not the primary
factors in saliva that promote tissue repair. This po-
tential is probably due to the presence of several fac-
tors in saliva including various growth factors and
bacteria (293).
Growth factors found in saliva are synthesized by
salivary glands or derived from plasma through gin-
gival crevice. Epithelial cells and connective tissue
cells also produce their own growth factors that act
either in a paracrine or autocrine manner. Because
many of the growth factors are transported to saliva
along with gingival crevicular fluid, it is conceivable
that their concentrations in gingival tissue are higher
than elsewhere in the oral cavity. Therefore the peri-
odontium is in a favorable position with respect to
tissue healing.
141
Häkkinen et al.
As discussed above, wound healing is a complex
phenomenon involving increased proliferation, ad-
hesion and migration of cells of connective tissue
and epithelium, inflammatory reactions and re-
modeling of extracellular matrix. All these phenom-
ena are directed by growth factors (9, 10, 82). Differ-
ent growth factors have specific functions and target
cells in wound healing, and their delicate balance is
required for optimal tissue repair. The actual roles of
each growth factor in saliva are not known. The best
studied salivary growth factor, and possibly the most
important one, is epidermal growth factor. In his
pioneer studies, Cohen found that a protein compo-
nent of mouse submandibular gland induced pre-
cocious eyelid opening and incisor tooth eruption.
Later it was discovered that the factor termed epider-
mal growth factor has a multitude of effects on cell
proliferation, cell migration and extracellular matrix
metabolism (21, 37, 220). It has now become obvious
that epidermal growth factor is needed for the nor-
mal maintenance and repair of oral mucosa (174).
Interestingly, salivary epidermal growth factor also
plays a role in the maintenance of gastric and ileal
mucosal integrity (194, 213). In humans and many
other animals, salivary glands are the major epider-
mal growth factor–producing organs. In humans epi-
dermal growth factor is synthesized by both parotid
and submandibular glands. During oral wound heal-
ing, the concentration of epidermal growth factor is
increased in saliva (99, 180, 181).
Another growth factor found in saliva is the vascu-
lar endothelial growth factor (243). This protein is
important in many aspects of angiogenesis and in-
flammation such as endothelial growth, permeability
and leukocyte adherence (52). A number of other
growth factors are also present in saliva. These in-
clude nerve growth factor and members of trans-
forming growth factor b, fibroblast growth factor and
insulin-like growth factor families (230). As these
substances have specific regulatory roles in cell
growth and extracellular matrix formation, they are
important in maintaining health of the oral cavity
and in healing of oral mucosal tissues (293).
The presence of growth factors in crevicular fluid
has received limited attention. The major focus of
the studies has been pro-inflammatory cytokines,
such as interleukin-1 and tumor necrosis factor a
(177). It is important to recognize that while one ac-
tion of the crevicular fluid cytokines is promotion of
inflammation, another function is to facilitate tissue
repair. Maintenance of the normal tissue turnover
results from a delicate balance of the cytokines. An
alteration in this balance results either in persistence
142
of inflammation and tissue destruction or increased
cell growth and tissue repair.
Integrin ligands such as collagen, vitronectin,
fibronectins and laminins are involved in directing
the adhesion and migration of cells (261). It is there-
fore possible that these molecules, when present in
gingival crevicular fluid or saliva, may modulate
wound healing of gingiva. Indeed, fibronectin has
been found both in crevicular fluid and saliva (112,
129, 257). Even though not yet reported, it is reason-
able to assume that other adhesion molecules may
be present in saliva.
Extracellular matrix remodeling is an essential
part of wound repair. In this process matrix metallo-
proteinases and other neutral proteinases have an
important function. During periodontal diseases
gingival crevicular fluid and saliva are rich in col-
lagenases, gelatinases and elastases (133–136, 149,
232, 263–265). Most of these enzymes appear to de-
rive from neutrophils migrating from inflamed peri-
odontium. However, salivary gland cells and acti-
vated epithelial cells and fibroblasts of periodontium
produce their own matrix metalloproteases includ-
ing collagenase-1 (matrix metalloprotease-1), col-
lagenase-3 (matrix metalloprotease-13) and gela-
tinase A (matrix metalloprotease-2) (209, 211, 258).
In concert the matrix metalloproteases and elastases
are capable of cleaving all extracellular matrix pro-
teins and proteoglycans. As discussed earlier, proteo-
lytic enzymes are necessary for proper wound heal-
ing. These matrix metalloproteases could also re-
lease cryptic bioactive domains from matrix
molecules that may regulate cell proliferation and
migration (285). For example, fibronectin and colla-
gen fragments have been demonstrated in gingival
crevicular fluid (245) and saliva (77). Practically no
information presently exists on the possible role of
these extracellular matrix fragments in promoting
healing of oral wounds.
Role of bacteria in oral wound healing
The oral cavity harbors considerable amounts of
bacteria. More than 500 bacterial species have been
so far identified in the oral cavity (165). Recognizing
the limitation of the present detection methods, in
reality several times more species may colonize in
the mouth. It is clear that bacteria affect wound
healing in the oral cavity, and it is well established
that wounds colonized by pathogenic bacteria have
delayed healing (198, 249). Clinicians are aware of
the painful complications in extraction wound repair
that result from bacterial infection (38, 57). Much

less attention has been given to the fact that small
concentrations of bacteria may increase the rate of
wound healing.
In 1921, Carrel reported that wounds of dogs
treated with certain concentrations of Staphylococ-
cus aureus healed faster than untreated wounds.
Since then several studies have confirmed that find-
ing, also using other bacterial species. Many factors
may contribute to this effect. Inflammatory reaction
that is a prerequisite for tissue repair is accentuated
by bacterial contamination. Bacteria present in a
wound will attract macrophages into the area and
induce their cytokine secretion. As a consequence,
blood supply and granulation tissue formation are
accentuated in the wound. Proliferation of mes-
enchymal cells is increased and synthesis rate of
connective tissue components is stimulated, leading
to greater tensile strength of the contaminated
wounds in the course of healing (115, 127, 128, 136).
Bacteria contain a variety of substances, some
stimulating host cell proliferation and others
exerting toxic effects. In addition, the same sub-
stance can be either stimulatory or inhibitory, de-
pending on its concentration in tissue. Bacteria may
act directly on epithelial cells and connective tissue
cells in wounds and, depending on the type and
concentration, either accelerate or delay wound re-
generation. We found that proliferation of gingival
fibroblats in culture was increased by Prevotella in-
termedius but decreased by the same concentrations
of Porphyromonas gingivalis (133). Interestingly,
there was a great variation in this effect between
fibroblast populations obtained from different pa-
tients. These findings imply that the potential for
periodontal repair depends both on the bacterial
flora and the individual cell populations of the peri-
odontal wounds. Some bacterial factors have direct
fibroblast and epithelial cell stimulating properties.
Lipopolysaccharide of both Actinobacillus actino-
mycetemcomitans and P. gingivalis slightly increases
cell growth in vitro (98, 189). At higher concen-
trations lipopolysaccharide from different bacterial
species inhibits cell proliferation (8, 134). Lipopoly-
saccharide as well as bacterial plaque extracts in-
crease hyaluronan production in cultured gingival
fibroblasts (7, 130). Hyaluronan is a high-molecular-
weight polyanionic glycosaminoglycan that plays an
important role in wound healing through specific in-
teraction with other matrix molecules and cells (23).
S. aureus lipoteichoic acid and protein A induce
fibroblast production of hepatocyte growth factor,
which stimulates epithelial proliferation (6). There
are numerous other factors present in bacteria that
Cell biology of gingival wound healing
could modulate oral wound healing. For example, A.
actinomycetemcomitans GroEL-like heat-shock pro-
tein and phospholipase C are able to modulate epi-
thelial cell growth and cell migration (62, 80, 294).
Specific mechanisms of these effects remain to be
explored.
Conclusion
Wound healing in the oral cavity is a very complex
process. We are just starting to uncover the complex
interplay between various cell types, growth factors
and salivary components. The focus of this chapter
was to summarize the two major events of gingival
wound healing, namely re-epithelialization and the
formation of granulation tissue. Because of the
unique environment of oral cavity, we also reviewed
the special features of oral healing. The interplay be-
tween oral cells and their extracellular matrix, bac-
teria, saliva and gingival crevicular fluid involves
myriad factors dictating the nature of the tissue re-
pair process. It would be an enormous if not imposs-
ible task to sort out all these factors. Some of the
factors are already relatively well understood and
could be used for practical applications. Active
studies on certain growth factors are underway in
order to provide new tools for periodontal therapy
(101). Similar studies utilizing other factors benefi-
cial for wound healing can be expected when more
basic research has been done elucidating their speci-
fic functions. Only then we can design precision
tools to speed-up (or slow-down) re-epithelializ-
ation, granulation tissue formation and scarless
wound healing. Modulation of cell–to–extracellular
matrix adhesion will be the key target for computer
designed drugs engineered to guide optimal tissue
repair.
Acknowledgments
We thank Colin Wiebe for critical reading of the
manuscript. Wound-healing studies performed in
the laboratories of the authors are supported by the
Medical Research Council of Canada.
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