Periodontology 2000, Vol.
22, 2000, 44–50
Printed in Denmark ¡ All rights reserved
Biology of wound healing
I KRAMUDDIN A UKHIL
Periodontal tissues represent a unique system in the
human body where epithelial, soft and mineralized
connective tissues come together to form a junction.
This junction, referred to as the dentogingival junc-
tion, is a complex structure, and maintenance of the
integrity of this junction is critical for the preser-
vation of underlying bone and periodontal ligament.
Unfortunately, with chronic inflammation associated
with periodontal diseases, the structure of this junc-
tion is lost. Hence, attempts to control the destruc-
tive effects of chronic periodontal diseases and to
some extent regenerate the lost tissues would require
the re-establishment of a dentogingival junction.
Conventional periodontal therapy, be it surgical or
nonsurgical in nature, usually involves instrumen-
tation in the inflamed dentogingival complex. Such
therapies result in wounding of the already inflamed
periodontal tissues. Thus, the consequence of such
therapeutic procedures depends largely on the cellu-
lar and molecular events associated with wound
healing. Many of the cellular and molecular events
in healing of periodontal wounds are similar to those
seen in wounds elsewhere in the body except that, in
the periodontal wounds, there is a mineralized tissue
interface at the junction of epithelium and connec-
tive tissue.
Immediately following periodontal surgical pro-
cedures, the tissues represent surgically wounded
sites and a cascade of cellular and molecular events
set in to initiate wound repair. Over the past two
decades, numerous advances have been made in
understanding the biology of wound healing. At the
same time, advances in the biology of the peri-
odontal tissues have led to the development of surgi-
cal procedures that facilitate regeneration of the
periodontal tissues lost because of chronic inflam-
mation. The newly described principle of guided
tissue regeneration (2) for the surgical treatment of
periodontal lesions represents a classic example of
how basic knowledge of cell biology could be applied
to enhance the clinical outcomes of therapy. The
purpose of this chapter is to examine some of the
current basic concepts of wound healing and is
44
Copyright C Munksgaard 2000
PERIODONTOLOGY 2000
ISSN 0906-6713
based on two excellent reviews on wound healing
that the readers are referred to for more details (10,
21). Since the biological principles of wound repair
would almost be the same, no distinction will be
made between the healing in different types of peri-
odontal defects. It is hoped that this review will allow
the extrapolation of some of the basic principles of
wound healing to the various periodontal surgical
wounds.
As per the classic description of wound healing,
initially there is temporary repair characterized by
the formation of a clot in the wounded tissues. In-
flammatory cells followed by fibroblasts and endo-
thelial cells then invade the clot to form a granu-
lation tissue, while the epithelial cells migrate to
cover the denuded surfaces (or form a junction at
the tooth interface). Finally, maturation of the heal-
ing tissue matrix is seen along with contraction or
scarring. It is important to mention that these vari-
ous phases of wound healing overlap somewhat in
time. This oversimplified explanation of wound heal-
ing basically summarizes the events at large, but nu-
merous studies in the last two decades have shed
light on some of the important cellular and molecu-
lar mechanisms. It is hoped that this new knowledge
would some day allow therapeutic manipulation to
enhance wound healing.
The fibrin clot and
inflammatory cells
Injury to the blood vessels during surgery/peri-
odontal therapeutic procedure causes extravasation
of blood. A fibrin-rich clot formed by blood coagu-
lation and platelet aggregation plugs the cut blood
vessels and also serves to protect the denuded
tissues temporarily (10). The clot itself consists of
platelets within a network of cross-linked fibrin
fibers along with plasma fibronectin, vitronectin and
thrombospondin (21). Among the important func-
tions of the clot are its role as a reservoir of growth
factors and cytokines that are released by the de-

granulation of activated platelets and serving as a
provisional matrix for cell migration. The growth fac-
tors and cytokines present in the fibrin clot in fact
might be providing the start signals for wound re-
pair. At first, there is recruitment of inflammatory
cells to the wound site followed by epithelialization,
granulation tissue formation and angiogenesis.
Neutrophils and monocytes are usually recruited
initially by the signals present in the clot. The neu-
trophils cleanse the wound of foreign particles and
debris and bacteria. It is important to note that neu-
trophils remove the bacterial debris through the re-
lease of enzymes and toxic oxygen products (10).
Hence, increasing numbers of contaminating bac-
teria in the wound increase the potential for neutro-
phil-mediated tissue destruction. Neutrophils also
serve as a source of pro-inflammatory cytokines pro-
viding signals that activate adjacent fibroblasts and
keratinocytes (17). Neutrophil infiltration ceases
after a few days, and they are eventually phagocytos-
ed either by macrophages or fibroblasts (10). Peri-
pheral blood monocytes that continue to be re-
cruited into the wound site become macrophages
upon activation. Fibrin along with fibronectin in the
clot acts as a provisional matrix for the influx of
monocytes and fibroblasts (5). Macrophages con-
tinue the task of phagocytosing bacterial, cellular
and matrix debris in the wound. Growth factors and
cytokines are continually synthesized and secreted
into the wound environment by macrophages. Thus,
the wound repair signals initiated by degranulating
platelets and neutrophils are maintained by macro-
phages.
Re-epithelialization of wounds
In the normal gingival tissues, the basal layer of epi-
thelium is attached to the basal lamina. The keratino-
cytes use receptors on their surface, known as inte-
grins, to bind to laminin in the basal lamina. Integrins
are a family of cell adhesion receptors that mediate
cell surface interactions with extracellular matrix and
in some cases with other cells (19, 24, 32). There are
approximately 20 members of this family of cell sur-
face receptors, and each integrin is a heterodimer
made up of one a and one b subunit in a non-covalent
complex (33). The current list of the combinations of
various integrins and their respective biological
ligands is presented in Table 1. Changes in the combi-
nations of the various a and b subunits offer the inte-
grins specificity for the ligand. Since migration of cells
is fundamental to wound healing, it is important to
Biology of wound healing
Table 1. The integrin family of adhesion
receptors
Integrins Ligands
a, b; a2b1 Fibrillar collagen, laminin
a3b1 Fibronectin, entactin, epilgrin,
laminin, denatured collagen
a4b1 Fibronectin, VCAM-1
a5b1 Fibronectin (RGD)
a6b1; a7b1; a6b4 Laminin
a8b1 Fibronectin, vitronectin
a9b1 Tenascin
avb1; avb5 Fibronectin, vitronectin
avb3; a11bb3 Vitronectin (RGD); fibronectin,
fibrinogen, von Willenbrand factor,
thrombospondin, denatured
collagen
avb6 Fibronectin, tenascin
a4b7 Fibronectin (IIIcs)
avb8 Vitronectin
aMb2 Factor X, fibrinogen
aXb2 Fibrinogen
consider changes in the expression of integrins by
cells migrating into the wound.
In the normal tissues, keratinocytes use the inte-
grins a6b4 to bind to laminin in the basal lamina,
and these integrins have intracellular links with the
keratin cytoskeletal network (21). In preparation for
migration, the keratinocytes at the edge of the surgi-
cal wound have to dissolve the hemidesmosome
attachment and begin to express other integrins that
are more suitable for the wound environment (Fig.
1). The migrating keratinocytes will start expressing
the integrins a5b1 and aVb6 (for binding to
fibronectin and tenascin respectively), the integrins
aVb5 for binding to vitronectin and, finally, reorgan-
ize the distribution of the integrins a2b1 (collagen
receptor). This mobilization and expression of new
integrins facilitates adhesion of keratinocytes to ma-
trix molecules in the provisional matrix as well as the
adjacent wound debris. This can explain the lag time
between wounding and the initiation of epithelial
migration. It is generally believed that the basal cells
provide the majority of migrating keratinocytes, al-
though there is some evidence that some of the sup-
rabasal cells may also migrate (13). Once the mi-
gration of epithelial cells has begun, cells of the basal
layer small distance away from the wound edge un-
dergo proliferation, providing an extra source of
basal cells. The apical-basal polarity of the basal cell
layer at the wound edge is lost, and instead pseudo-
podia are seen extending from their free basolateral
sides into the wound. Not much is known about the
mechanisms that drive the epithelial cell migration,
but candidates include chemotactic factors, active
45
Aukhil
Fig. 1. Diagrammatic illustration of some of the major
events during healing of dermal wounds and periodontal
surgical wounds. a. The dermal wound. b. A healing peri-
odontal wound with infrabony defects. Zones A represent
the borders of the wound where the epithelium (basal
layer) will migrate into the wound during epithelializ-
ation. At this edge, the cells will have to dissolve the hemi-
desmosome attachment, downregulate the expression of
integrin receptors a6b4 (used to bind to laminin), and up-
regulate integrin receptors a5b1, aVb6 and aVb5 that are
suitable for adhesion to provisional matrix components.
Growth factors epidermal growth factor, transforming
growth factor-a, heparin-binding epidermal growth factor
and keratinocyte growth factor are involved in stimulating
the proliferation of the epithelial cells here. Zone B ini-
tially represents the fibrin clot consisting of platelets
within a network of cross-linked fibrin fibers along with
contact guidance, absence of neighboring cells or a
combination of the above (10). Interestingly, epi-
thelial cell migration does not appear to depend on
cell proliferation since molecules such as trans-
forming growth factor-b, despite being a potent in-
hibitor of keratinocyte proliferation, promote the
migration of epithelial cells in organ cultures (10).
Once re-epithelialization is complete, the compo-
nents of basal lamina are deposited in a sequential
manner starting from the wound margin and the
epithelial cells revert to their normal phenotype.
Several growth factors seem to be key players in
regulating the proliferation of keratinocytes in heal-
ing wounds. Among the key growth factors are the
46
plasma fibronectin, vitronectin and thrombospondin.
This fibrin clot also serves as a reservoir for many of the
growth factors listed in Table 2. This is followed by recruit-
ment of inflammatory cells in zone B, resulting in the
phagocytosing of debris and bacteria. Again zone B serves
as a reservoir of growth factors and cytokines. Zones C
represent the borders of the wounds formed by the con-
nective tissue. Here, fibroblasts and endothelial cells show
proliferation in response to specific growth signals they
receive as wound healing progresses. Matrix degradation
is seen in zones B and C in preparation for the migration
of these cells into zone B. Finally, granulation tissue forms
in zone B followed by contraction of the wound and ma-
trix remodeling. In the case of periodontal wounds, the
apical part of zone B may be populated by cells originat-
ing from bone and periodontal ligament, while the more
coronal part of zone B may get epithelialized.
epidermal growth factor, transforming growth factor-
a, heparin-binding epidermal growth factor and
keratinocyte growth factor. A list of growth factors
active in the healing wounds, their possible sources
and biological effects are presented in Table 2.
Matrix degradation and
the wound-cleaning process
Migration of epithelial cells through the fibrin clot or
along the junction between the clot and underlying
connective tissue (mucoperiosteal flap surface in the
case of periodontal surgery) requires the creation of
 Biology of wound healing

Table 2. Growth factors involved in wound healing

Growth factor
Fibroblast growth factors 1, 2 and 4
Transforming growth factor-a
Transforming growth factors b1 and b2
Epidermal growth factor
Platelet-derived growth factor
(isoforms AA, AB and BB)
Keratinocyte growth factor
Insulin-like growth factor
Vascular endothelial growth factor
Interleukin 1a and b
Tumor necrosis factor-a
Source
Macrophages, endothelial cells
Macrophages, keratinocytes
Platelets, macrophages
Platelets
Platelets, macrophages,
keratinocytes
Dermal fibroblasts
Plasma, platelets
Keratinocytes, macrophages
Neutrophils
Neutrophils
Effect
Fibroblast proliferation and angiogenesis
Re-epithelialization
Fibroblast and macrophage chemotaxis;
extracellular matrix synthesis; secretion of
protease inhibitors
Re-epithelialization
Fibroblast and macrophage chemotaxis,
fibroblast proliferation, and matrix synthesis
Keratinocyte proliferation
Endothelial and fibroblast proliferation
Angiogenesis
Activate growth factor expression in
macrophages, keratinocytes and fibroblasts
Activate growth factor expression in
macrophages, keratinocytes and fibroblasts

a migrating path. This is achieved by the dissolution
of the fibrin barrier by the enzyme plasmin that is
derived from the activation of plasminogen in the
clot. The two activators, tissue-type plasminogen ac-
tivator and urokinase-type plasminogen activator
along with its receptor, are upregulated in the mi-
grating keratinocytes (21). The importance of plas-
minogen in wound re-epithelialization is demon-
strated by the lack of re-epithelialization of wounds
in mice where the plasminogen gene has been
knocked out (21). In addition to the fibrinolytic en-
zyme plasmin that causes lysis of fibrin, several
other proteases are also expressed to clear the path
for cell migration. Matrix metalloproteinases (MMP)
are a family of enzymes with each member of the
family specifically cleaving a subset of matrix pro-
teins. MMP-1 (also known as interstitial collagenase)
is secreted by those basal cells that have gone past
the free edge of the basal lamina. MMP-1 degrades
native collagens and aids cell migration by destroy-
ing collagens I and III. Similarly, MMP-9 (also known
as gelatinase B) can cleave the collagen in basal lam-
ina (type IV) and the collagen that forms the an-
choring fibrils (type VII), thereby releasing the basal
cells from their adhesion to the basal lamina. MMP-
10 (also known as stromelysin-2) is also expressed in
wounds and is thought to have a wide spectrum of
substrate specificity (21).
Granulation tissue and
contraction of the wound
Granulation tissue formation usually can begin
around day 4 after the wounding and consists
mainly of new capillaries, macrophages, fibroblasts
and some loose connective tissue. Needless to say,
granulation tissue is a complex reservoir of cytokines
possessing chemoattractive, mitogenic and other
regulatory activities (21). Growth factors are also
present in the granulation tissue and, at this stage of
healing, are derived mostly from macrophages. De-
pending on the stage of the granulation tissue and
the predominant cytokines, numerous activities are
seen occurring such as cell proliferation, chemotaxis
and phenotypic expression of cells (27). It is, how-
ever, important to note that the activities of certain
cell types and the nature of the extracellular matrix
environment influence to a large extent the final
phenotype expression by the cells.
During the formation of granulation tissue,
macrophages, fibroblasts and new blood vessels
grow into the wound space in a coordinated manner
(Fig. 1). Their interdependence is illustrated by the
release of cytokines by macrophages that stimulate
fibroblasts to synthesize an extracellular matrix. This
extracellular matrix serves to support cell and vascu-
lar in-growth carrying nutrients to sustain the cellu-
lar functions (21). The term fibroplasia is used to re-
fer to that part of the granulation tissue made up
of predominantly fibroblasts and extracellular matrix
they make. In addition to macrophages, fibroblasts
themselves express many cytokines to which they
can also respond in an autocrine manner (27). Cyto-
kines induce proliferation of fibroblasts and regulate
the production of extracellular matrix. Similarly,
growth factors are also involved in wound fibroplas-
ia. Wounds supplemented with purified growth fac-
tors show accelerated granulation tissue formation
(20, 28).

47
Aukhil
The extracellular matrix and fibroblasts function
in a reciprocal manner during wound healing. Com-
ponents of the extracellular matrix such as fibronec-
tin and collagen facilitate the adhesion and mi-
gration of fibroblasts in the granulation tissue. Fibro-
blasts synthesize and decorate the extracellular
matrix, and in turn the extracellular matrix regulates
gene expression and the general behavior of fibro-
blasts (10). Fibroblasts adhere to fibronectin, colla-
gen and vitronectin via the integrin receptors listed
in Table 1. It is important to note that fibroblasts,
like the keratinocytes, have to rearrange their inte-
grin expression profiles in preparation for migration.
In the normal tissues, fibroblasts reside in collagen-
rich matrices. In response to wounding, the fibro-
blasts in the vicinity of the wound have to downreg-
ulate the integrin receptors for collagen and up-
regulate those needed for adhesion to components
of the provisional matrix such as fibrin, fibronectin
and vitronectin. The ability of fibroblasts to respond
to signals from the extracellular environment is re-
markable. For example, when simultaneously chal-
lenged by signals from both the provisional matrix
(fibrin or fibronectin) as well as growth factors (such
as platelet-derived growth factor), fibroblasts re-
spond by upregulating the receptors for provisional
matrix components. However, when challenged by
the same growth factor (platelet-derived growth fac-
tor) in the presence of a collagenous matrix, fibro-
blasts respond by upregulating the receptors for col-
lagen and not the provisional matrix receptors (31).
Not much is known about the effects of extracellular
matrix molecules in the wound environment on the
regulation of gene expression in fibroblasts. This is
complicated by the fact that some of the extracellu-
lar matrix molecules occur in different isoforms due
to alternative splicing of their transcripts at the pre–
messenger RNA level. For example, the well-known
molecule fibronectin occurs as different isoforms
due to the splicing in or out of the alternatively
spliced domains EIIIB and EIIIA in its gene structure.
While the fibronectin from plasma does not contain
either of the two spliced domains, the fibronectin
synthesized by fibroblasts and macrophages in
wounds includes the spliced domains EIIIB and
EIIIA. Remarkably, the EIIIB and EIIIA inclusive iso-
form of fibronectin seen in healing wounds is the
predominant form of fibronectin in embryonic
tissues where cell migration is active (11). The ad-
vantages of including the spliced domains EIIIB and
EIIIA in fibronectin during embryonic development
and wound healing are not clear. Recent studies have
suggested that inclusion of these domains in the
48
fibronectin molecule may be facilitating the mi-
gration of cells by modulating the adhesiveness of
the substrata (8, 15). Another spliced domain of
fibronectin, the CS-III domain, also may be involved
in the migration of cells in wounds. Fibroblasts use
the integrin receptor a4b1 (Table 1) to bind to the
CS-III domain of fibronectin. Interestingly, it has
been shown in cell culture studies that the express-
ion of the integrin a4b1 facilitates migration, while
the classic fibronectin receptor a5b1 that binds to
the RGD sequence can retard movement (7, 14).
Fibroblasts in healing wound have been known to
over-express the spliced domain CS-III (5, 11). Once
cell migration into wounds is completed, fibroblasts
show an increased expression of the classic a5b1
integrin (29). Fibroblasts in wounds also use vi-
tronectin and fibrin directly as substrata for ad-
hesion during migration. This is facilitated by the
availability of cell membrane receptors for these ma-
trix proteins (Table 1). Finally, the migration of
fibroblasts in wounds is also stimulated indirectly by
growth factors such as platelet-derived growth factor
and transforming growth factor-b by upregulating
some of the integrin receptors mentioned above (1,
12).
As wound healing progresses, the provisional ma-
trix is replaced by a new, collagen-rich matrix syn-
thesized by fibroblasts migrating into the wound.
The synthesis of specific extracellular matrix mol-
ecules by fibroblasts in the wound is regulated by
transforming growth factor-b1 and some other
growth factors listed in Table 2 (10, 21). Cytokines
such as interleukin-4 can also induce expression of
collagenous matrices in wounds (23). Once the re-
quired amount of collagenous matrix is synthesized,
the signals that induce down-regulation of collagen
synthesis are not clearly known. It is possible that
there may exist some kind of regulation by the colla-
gen matrix itself (9). Around 7–10 days after
wounding, some of the fibroblasts in the wound
transform into myofibroblasts and express a-smooth
muscle actin. Such transformation allows these myo-
fibroblasts to generate strong contractile forces that
is responsible for wound contraction (21). In the fi-
nal stages of fibroplasia, the number of fibroblasts
and myofibroblasts in the healing wound are de-
creased by programmed cell death. Compared with
wounds in the adult tissues, embryonic wounds heal
without much contraction and scarring. In the em-
bryos, there is no conversion of fibroblasts to myo-
fibroblasts and the angiogenic response is also of a
lesser magnitude. Compared with wounds in adult
tissues, wounds in embryos show low but transient

levels of expression of transforming growth factor-b1
(30) and since transforming growth factor-b1 has
been implicated in pathofibrotic conditions, this can
explain the tendency for adult wounds to show scar-
ring and contraction. Antibodies that neutralize the
effects of transforming growth factor-b1 in healing
wounds have been shown to reduce scarring when
delivered to wounds (26).
Angiogenesis of wounds
Angiogenesis refers to the formation of new blood
vessels and is a crucial event during the healing of
wounds. The term granulation tissue in wounds was
coined in reference to the red granular appearance
of new blood vessels that invade the healing connec-
tive tissues. As listed in Table 2, several growth fac-
tors are important in the induction of angiogenesis
in healing wounds. Fibroblast growth factor-2 is syn-
thesized by macrophages and damaged endothelial
cells, while vascular endothelial growth factor is in-
duced in wound-edge keratinocytes and macro-
phages. Experiments where fibroblast growth factor-
2 is depleted show blockage of wound angiogenesis
(3). As in the case of fibroblasts and keratinocytes,
the endothelial cells also have to upregulate specific
integrins (aVb3) on their surface in order to respond
to angiogenic signals. All the signals that induce pro-
liferation, migration and phenotype expression in
endothelial cells have not been completely under-
stood yet. It is clear that angiogenesis is a complex
process and relies on the availability of an appropri-
ate matrix in the wound. As endothelial cells migrate
into the provisional matrix, they form tubes sur-
rounded by their own provisional matrix initially fol-
lowed by a true basement membrane. As in the case
of fibroblasts, endothelial cells involved with angio-
genesis in wounds also undergo programmed cell
death during the ultimate maturation of the matrix
characterized by regression of capillaries.
Applied clinical aspects and
future approaches to enhance
wound healing
With the explosion in knowledge of growth factors,
cell adhesion molecules and cytokines in the last two
decades, understanding of the cellular and molecu-
lar biology of wound healing has improved signifi-
cantly. Some of this new knowledge is already being
Biology of wound healing
applied to manipulate the process of wound healing.
For example, application of epidermal growth factor
and transforming growth factor-a to burn wounds
in animal models has been shown to enhance re-
epithelialization (4, 25). Similarly, application of
keratinocyte growth factor to skin wounds has been
shown to have mitogenic effects on the healing epi-
thelium (22). Since cell adhesion and migration are
essential to wound healing, attempts have been
made in the past to use topical application of
fibronectin in periodontal wound healing (18). How-
ever, using recombinant molecules as exogenous
sources to supplement wound healing has to be ap-
proached with caution. For example, in the case of
fibronectin, the plasma form of fibronectin (without
spliced domains EIIIB and EIIIA) is already available
in large quantities in the provisional matrix of a heal-
ing wound. Supplementing the same has no biologi-
cal rationale and enhanced effects should not be ex-
pected. The biological functions of the spliced do-
mains EIIIB, EIIIA and the CS-III segments are not
known. Should their roles be specific in enhancing
cell migration (15), specific isoforms of cell adhesion
molecules that allow weak cell adhesion but favor
migration of cells would be useful, and studies to
this effect are currently in progress. The provisional
matrix is rich in growth factors in the normal,
healthy subjects. Systemic conditions such as dia-
betes may be accompanied by reduction in the avail-
ability of some of the growth factors; in these cases,
supplementing the appropriate growth factor may
be beneficial. Since the half-life for some of the
growth factors may be short, supplementing wounds
with the appropriate growth factors during the later
stages of healing via some sort of delayed release
mechanism could be useful in the healing of wounds
in healthy subjects as well. Preliminary data on the
use of recombinant growth factors during peri-
odontal surgery to treat osseous defects shows
promising results (16).
Future research will have to be directed towards
understanding in more detail the molecular mech-
anisms of differential gene expression in healing
wounds. Wound healing is achieved by a series of
coordinated efforts by inflammatory cells, keratino-
cytes, fibroblasts and endothelial cells responding to
a complex array of signals. Many of these events
have start and stop signals. A thorough understand-
ing of these signals and their consequences (differ-
ential gene expression) in responder cells should
make possible, hopefully in the near future, thera-
peutic manipulation of wounds that leads to real re-
generation of the damaged tissues.
49
Aukhil
Acknowledgments
This work was supported in part by a grant from the
National Institutes of Health (DE-07801). I thank
Donna Yeager for assistance in the preparation of
this manuscript.
References
1. Ahlen K, Rubin K. Platlet-derived growth factor-BB stimu-
lates synthesis of the integrin a2 subunit in human diploid
fibroblasts. Exp Cell Res 1994: 215: 347–353.
2. Aukhil I. Potential contributions of cellular and molecular
biology to periodontal tissue regeneration. Curr Opin Dent
1992: 2: 91–96.
3. Broadley KN, Aquino AM, Woodward SC, Buckley-Sturrock
A, Sato Y, Rifkin DB, Davidson JM. Monospecific antibodies
implicate basic fibroblast growth factor in normal wound
repair. Lab Invest 1989: 61: 571–575.
4. Brown GL, Curtsinger L, Brightwell JR, Ackerman DM, Tob-
in GR, Polk HC, George-Nascimento C, Valenzuela P,
Schultz GS. Enhancement of epidermal regeneration by
biosynthetic epidermal growth factor. J Exp Med 1986: 163:
1319–1324.
5. Brown LF, Dubin D, Lavigne L, Logan B, Dvorak HF, Van de
Water F. Macrophages and fibroblasts express embryonic
fibronectins during cutaneous wound healing. Am J Pathol
1993: 142: 793–801.
6. Brown LF, Lanir N, McDonagh J, Tognazi K, Dvorak AM,
Dvorak HF. Fibroblast migration in fibrin gel matrices. Am
J Pathol 1993: 142: 273–283.
7. Chan BM, Kassner PD, Schiro JA, Byers R, Kupper TS,
Hemler ME. Distinct cellular functions mediated by differ-
ent VLA integrin a subunit cytoplasmic domains. Cell 1992:
68: 1051–1060.
8. Chen W, Culp L. Adhesion mediated by fibronectin’s alter-
natively spliced EIIIB and its neighboring type III repeats.
Exp Cell Res 1996: 223: 9–19.
9. Clark RAF, Nielsen LD, Welch MP, McPherson JL. Collagen
matrices attenuate the collagen synthetic response of cul-
tured fibroblasts to TGF-b. J Cell Sci 1995: 108: 1252–1261.
10. Clark RAF. Wound repair: overview and general consider-
ations. In: The molecular and cellular biology of wound re-
pair. 2nd edn. New York: Plenum Press, 1996.
11. French-Constant C, Van de Water L, Dvorak HF, Hynes RO.
Reappearence of an embryonic pattern of fibronectin spli-
cing during wound healing in the adult rat. J Cell Biol 1989:
109: 903–914.
12. Gailit J, Bueller H, Clark RAF. Platelet-derived growth factor
and inflammatory cytokines have differential effects on the
expression of integrins a1b1 and a5b1 by human dermal
fibroblasts in vitro. J Cell Physiol 1996: 169: 281–289.
13. Garlick JA, Taichman LB. Fate of human keratinocytes dur-
ing reepithelialization in an organotypic culture model. Lab
Invest 1992: 70: 916–924.
14. Giancotti FG, Ruoslahti E. Elevated levels of the a5b1
fibronectin receptor suppress the transformed phenotype
of chinese hamster ovary cells. Cell 1990: 60: 849–859.
50
15. Hashimoto-Uoshima M, Yan YZ, Schneider G, Aukhil I. The
alternatively spliced domains EIIIB and EIIIA of human
fibronectin affect cell adhesion and spreading. J Cell Sci
1997: 110: 2271–2280.
16. Howell TW, Fiorellini JP, Paquette DW, Offenbacher S, Gian-
nobile WV, Lynch S. A phase I/II clinical trial to evaluate a
combination of recombinant human platelet derived
growth factor-BB and recombinant human insulin-like
growth factor-I in patients with periodontal disease. J Peri-
odontol 1997: 68: 1186–1193.
17. Hubner G, Branchle M, Smola H, Madlener M, Fassler R,
Werner S. Differential regulation of pro-inflammatory cyto-
kines during wound healing in normal and glucocorticoid
treated mice. Cytokine 1996: 8: 548–556.
18. Hynes RO. Wound healing, inflammation and fibrosis. In:
Fibronectins. Berlin: Springer-Verlag, 1990.
19. Hynes RO. Integrins: versatility, modulation, and signaling
in cell adhesion. Cell 1992: 69: 11–25.
20. Lynch SE, Colvin RB, Antoniades HN. Growth factors in
wound healing. Single and synergistic effects on partial
thickness porcine skin wounds. J Clin Invest 1989: 84: 640–
646.
21. Martin P. Wound healing – aiming for perfect skin regenera-
tion. Science 1997: 276: 75–81.
22. Pierce GF, Yanagihara D, Klopchin K, Danilenko DM, Hsu
E, Kenney WC, Morris CF. Stimulation of all epithelial ele-
ments during skin regeneration by keratinocyte growth fac-
tor. J Exp Med 1994: 179: 831–840.
23. Postlethwaite AE, Holness MA, Katai H, Raghow R. Human
fibroblasts synthesize elevated levels of extracellular matrix
proteins in response to interleukin-4. J Clin Invest 1992: 90:
1479–1485.
24. Ruoslahti E. Integrins. J Clin Invest 1991: 87: 1–5.
25. Schultz S, White M, Mitchell R, Brown G, Lynch J, Twardzik
DR, Todaro GJ. Epithelial wound healing enhanced by
transforming growth factor alpha and vaccinia growth fac-
tor. Science 1987: 235: 350–352.
26. Shah M, Foreman DM, Ferguson MWJ. Control of scarring
in adult wounds by neutralizing antibodies to transforming
growth factor-b. Lancet 1992: 339: 213–214.
27. Sporn M, Roberts AM. Peptide growth factors and inflam-
mation, tissue repair, and cancer. J Clin Invest 1986: 78:
329–332.
28. Sporn M, Roberts AM, Shull JH, Smith JM, Ward JM, Sodek
J. Polypeptide transforming growth factor isolated from bo-
vine sources and used for wound healing in vitro. Science
1983: 219: 1329–1331.
29. Welch MP, Odland GF, Clark RAF. Temporal relationships of
F-actin bundle formation, collagen and fibronectin matrix
assembly, and fibronectin receptor exression to wound
contraction. J Cell Biol 1990: 110: 133–145.
30. Whitby DJ, Ferguson MWJ. Immunohistochemical localiz-
ation of growth factors in fetal wound healing. Dev Biol
1991: 147: 207–215.
31. Xu J, Clark RAF. Extracellular matrix alters platelet derived
growth factor regulation of fibroblast integrins. J Cell Biol
1996: 132: 239–249.
32. Yamada KM. Adhesive recognition sequences. J Biol Chem
1991: 266: 12809–12812.
33. Yamada KM, Gailit J, Clark RAF. Integrins in wound repair.
In: Clark RAF, ed. The molecular and cellular biology of
wound repair. 2nd edn. New York: Plenum Press, 1996.