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PLENARY PAPER
From the Division of Developmental Biology, Children's
Hospital Research Foundation, Cincinnati, OH; Department of Pathology,
Vanderbilt University Medical Center; and Department of Veterans
Affairs Medical Center, Nashville, TN.
In addition to its key role in the control of blood loss following
injury, fibrin(ogen) has been proposed to play an important role in
tissue repair by providing an initial matrix that can stabilize wound
fields and support local cell proliferation and migration. To test
directly these concepts, the effect of fibrinogen deficiency on
cutaneous tissue repair in mice was investigated using incisional and
excisional wounds. The time required to overtly heal wounds was similar
in fibrinogen-deficient and control mice, but histologic evaluation
revealed distinct differences in the repair process, including an
altered pattern of epithelial cell migration and increased epithelial
hyperplasia. Furthermore, granulation tissue in fibrinogen-deficient
mice failed to adequately close the wound gap, resulting in persistent
open wounds or partially covered sinus tracts. The tensile strength of
these wounds was also reduced compared with control mice. The most
profound defect in wound tissue organization was observed in
fibrinogen-deficient mice following the subcutaneous implantation of a
porous tubing chamber. Cells migrated into the wall of the implants at
a similar rate as control mice, but cells from fibrinogen-deficient
animals were unable to efficiently organize and migrate into wound
fluid-filled dead space within the center of the implants. These
studies show that re-epithelialization, granulation tissue
formation, including the establishment of neovasculature, and the
formation of fibrotic scar tissue can proceed in the absence of
fibrin(ogen) and all of its proteolytic derivatives. However,
fibrin (ogen) is important for appropriate cellular migration and
organization within wound fields and in initially establishing wound
strength and stability.
(Blood. 2001;97:3691-3698) Cutaneous wound healing is a process involving the
formation of a new extracellular matrix, cellular infiltration and
organization of the wound field, tissue remodeling, and ultimately,
mature scar formation. Immediately after injury, wound fields fill with blood components leading to the exposure of plasma coagulation factors
to the VIIa binding protein, tissue factor. Subsequent thrombin
generation and thrombin-mediated cleavage of both soluble fibrinogen
and platelet-associated protease activated receptors (eg, PAR-1, -3, and -4) results in thrombus formation and the deposition of a
provisional fibrin-rich matrix. Several hours after injury, epithelial
migration begins to restore epithelial integrity while leukocytes
invade the fibrin clot. After several days, the provisional matrix
becomes infiltrated with new capillary endothelium and activated
fibroblasts that serve to produce a new collagen-rich matrix.
Eventually, the provisional matrix is degraded as the wound contracts,
leaving a collagen-rich scar.
The conversion of soluble fibrinogen to an insoluble fibrin polymer is
of fundamental importance in the control of blood loss following
vascular injury. However, a broader role for fibrin matrices in tissue
repair has long been suspected. In particular, fibrin is thought to be
an essential component of the provisional matrix that protects the
underlying tissue and supports the migration and proliferation of
inflammatory cells, endothelial cells, and stromal cells participating
in tissue repair. Fibrin may also provide a reservoir for cytokines and
growth factors released from platelets and inflammatory cells (reviewed
in Martin1). Notably, in addition to supporting cell
adhesion and proliferation through integrin (eg, Cutaneous wound healing can occur by primary or secondary intention.
Primary intention involves the closure of a clean, noninfected surgical
incision with sutures joining the wound edges and involves a relatively
small amount of granulation tissue formation and wound contraction.
Instead, this type of healing relies primarily upon rejoining of the
connective tissue matrix. Healing by secondary intention, however,
involves the closure of a large open defect, where wound edges are not
juxtaposed and significant granulation tissue must be produced to fill
the wound area. This process is more complicated, and resolution of the
defect relies heavily upon the production of significant amounts of
granulation tissue and substantial wound contraction.
In order to directly determine the role of provisional fibrin matrices
in tissue repair, the resolution of wounds by both primary and
secondary intention was investigated in mice with a complete lack of
circulating fibrinogen. The data reveal an abnormal pattern of tissue
repair in fibrinogen-deficient mice, including misguided and
hypertrophied epithelium, delayed wound closure, reduced wound tensile
strength, and a diminished ability to organize a dead space. However,
wound repair is ultimately completed in a time frame that is comparable
to that in control mice, and the final outcome of repair is remarkably
similar in mice with and without fibrinogen.
Creation of wounds
Tensile strength
Histologic and immunohistochemical analysis Incisional wound tissue was harvested at days 3-8, 12, and 21. Excisional wound tissue was collected at days 4, 8, 12, and 21. Wound tissues were removed by cutting a square of skin around the wound area, without disturbing the wound. Tissues were fixed in 10% neutral-buffered formalin, processed into paraffin, and 4 micron sections were prepared perpendicular to the original incision. Sections were stained with hematoxylin and eosin. Immunohistochemistry was performed on sections with the following primary antibodies: rabbit antimouse fibrinogen,8 rabbit antihuman fibronectin (Dako, Carpinteria, CA), goat antihuman procollagen 1(I) (Santa Cruz
Biotechnology, Santa Cruz, CA), goat antihuman procollagen (III) (Santa Cruz Biotechnology). Antibodies were detected with biotinylated second antibodies (Vector Laboratories, Burlingame, CA),
Vectastain ABC Elite Kit (Vector) and 3,3'-diaminobenzidine substrate
(Sigma Chemical, St Louis, MO) or Fast Red substrate (Sigma).
Hydroxyproline content To establish a defined wound field for quantitative analysis of hydroxyproline (collagen) deposition, short segments (4 mm) of open-ended (3.17 mm internal diameter) polyethylene tubing (Intramedic; Becton Dickinson, Sparks, MD) were placed subcutaneously under wounded skin. After 7 or 14 days, animals were killed and the new tissue inside the tubing was collected, weighed, and stored at -80°C. Although the area inside the tubing provided a geometrically defined wound field for tissue ingrowth measurements, its short length and open-ended configuration immediately adjacent to wound tissue did not restrict tissue invasion which would be required for an authentic dead space model of tissue repair, as did wound chambers (see below). Acid hydrolysis was performed on tissues with 6N hydrochloric acid at 110°C for 24 hours. Hydroxyproline was assessed as previously described.9Dead space implants High porosity PTFE tubing (internal diameter: 1.2 ± 0.02 mm, wall thickness: 0.63 ± 0.08 mm, pore size: 60-90 µm; International Polymer Engineering, Tempe, AZ) was cut at lengths of 6 mm to create wound chambers. The ends of the tube sections were closed by pressure from a small toothed clamp, thus all cellular infiltration required directed migration through the porous walls of the tubing. Prior to closure, tubes were filled with normal saline. Tubes were sterilized and implanted subcutaneously in the dorsum of mice. Tubes were left in place for 7, 14, and 21 days, then removed and placed in 10% neutral buffered formalin fixative. Tubes were routinely processed and embedded for cross-sectional histochemical analysis.
Healing by primary intention Longitudinal incisional wounds (1.5 cm) were generated laterally in the dorsum of 10 mice of each genotype, and the wounds were closed with interrupted sutures. All sutures remained in place overnight and were gently removed the following day to assess the competency of the union of the wound edges. In fibrinogen-expressing animals, all wounds remained closed when examined on the following day (day 2: 10 of 10 wounds closed [100%]). However, in most fibrinogen-deficient (Fib /) mice examined at the same time, contact between
the wound edges was not maintained (1 of 10 wounds closed [10%],
P < .005, chi-square test). Rather, the wounds in
Fib/ mice gaped in a manner similar to that of
unsutured wounds. When examined at day 6, wounds of control mice
appeared overtly healed (loss of eschar and re-epithelialization).
Fib/ mice re-established juxtaposed wound edges by day
6 and were resurfaced by days 10 and 11. Thus, the absence of
fibrin(ogen) greatly influenced the ability of sutured wound edges to
remain juxtaposed after removal of sutures, indicating that fibrinogen deficiency reduces initial wound stability.
Unsutured incisional wounds Longitudinal wounds (1.5 cm) were generated in the dorsum of mice, and wounds were left unsutured. Daily monitoring indicated that wounds of both control and Fib/ mice remained open initially
but gradually formed an eschar by day 2 or day 3. No gross differences
were seen between healing wounds of control mice and
Fib/ mice, with the exception of occasional wounds of
Fib/ mice that maintained persistent but minor bleeding
for up to a week. However, histologic analysis revealed that the
pattern of wound healing was markedly different in Fib/
mice as compared with control animals. Whereas epithelial proliferation and migration occurred rapidly in both genotypes, the direction of
migration was dysregulated in Fib/ mice, and epithelial
hyperplasia was common (Figure 1C-H). In Fib/ mice, the migration of keratinocytes did not
follow the typical pattern immediately below the eschar and above the
early granulation tissue. Rather, keratinocytes extending from the
original wound edge proceeded down the inner dermal edge, moving well
under the wound area and usually away from the center of the wound
field, during days 3-4 (Figure 1C). In control mice, keratinocytes
migrating away from the center of the wound occurred in only a small
fraction of control mice (3/24 wound edges [12.5%]), whereas in
Fib/ mice the vast majority of keratinocyte migration
was turned away from the center of the wound field (25/28 wound edges
[89.3%]; P < .0001, chi-square test; Figure 1B).
Despite the altered path of initial epithelial migration, wound
re-epithelialization was delayed only briefly, if at all, in
Fib/ mice relative to control animals (assessed
histologically, the median day for complete re-epithelialization was
day 5 for control mice and day 6 for Fib/ animals;
Figure 1B,F). Completion of re-epithelialization in Fib/ mice occurred by 3 distinct and aberrant pathways:
(1) lining the entire inside of the wound area (Figure 1G); (2)
unification of epithelium at the surface and abandonment of the
migrating edges leaving an internal cavity, or sinus (see section below and Figure 1D); or (3) epithelial reduplication, which resulted in a
spur which successfully rejoined with the other side (Figure 1H).
Eschars, which were more clearly discernible by microscopic analysis,
generally were lost more quickly in Fib/ mice than in
control mice (controls: median day 6; Fib/ mice: median
day 4) despite the delay in re-epithelialization. Fibrin(ogen) appears
to play a role in retention of the protective eschar, but loss of the
eschar did not retard healing, consistent with previous
reports.10,11
Formation of a cohesive provisional matrix did not occur in the wound
area of most Fib
Hydroxyproline content Analysis of wound tissue for hydroxyproline content, as a measure of collagen accumulation in the wound, indicated that collagen was more abundant in the wounds of Fib/ mice than in control
mice at both days 7 and 14 (P < .0161; Figure 3A). No increase in total hydroxyproline
was seen between days 7 and 14, consistent with other
reports.12 To directly compare the wound granulation
tissue formed in control and Fib/ mice, tissues similar
to those collected for hydroxyproline analysis were processed for
routine microscopic analysis (Figure 3B,C). The granulation tissue was
qualitatively similar in both control and Fib/ mice,
with a prominent neovascularization and similar overall cell densities,
indicating that this was unlikely to account for the differences in
collagen content of the wounds (Figure 3B,C).
Wound tensile strength The tensile strength of wounds from control and Fib/ mice was measured to quantitate the contribution
of fibrin(ogen) to the early integrity of incision wounds. The tensile
strength of early incision wounds in Fib/ mice was
visibly less than control mice, and so low that tensiometer measurements could not be made in Fib/ mice at day 5;
the extremely fragile wound edges fell apart prior to being placed in
the tensiometer. Fourteen days after incision, an advanced stage in
wound repair for both genotypes of mice, the tensile strength of wounds
in Fib/ mice remained significantly less than control
animals (Figure 4). However, in
more-mature wounds collected at day 28, the tensile strengths
were equivalent in Fib/ mice and control mice.
Thus, fibrin(ogen) contributes to wound strength in the early stages of
wound repair, but the stability of the mature scar is not dependent on
the presence of fibrin(ogen).
Healing by secondary intention To explore the role of fibrinogen in wound repair in the more challenging context of excisional wounds, a 1 cm square segment of full thickness skin was removed from the dorsum of control (n = 11) and Fib/ (n = 9) mice. Within 1 to 2 days, control mice
developed a dry eschar over the entire wound area (Figure
5). In contrast, the wound area of
Fib/ mice remained open for several days, and often
filled with blood and wound fluid. The median time required for wound
closure (stable eschar development) in control and Fib/
mice was day 2 and day 7, respectively (Figure
6). Generally, control and
Fib/ mice maintained their scabs for a similar time and
completed healing between days 12 and 17, despite delayed eschar
development. One Fib/ mouse failed to develop any
visible eschar but nevertheless granulation and contraction closed the
wound edges rapidly, completing the closure by day 11. Wound area was
measured in mice to detect whether tissue ingrowth and contraction of
the wound perimeter were occurring at similar rates in control and
Fib/ mice. There was a trend toward an increased rate
of contraction in wounds of Fib/ mice between days 5 and 14 but this did not reach significance (median change in wound area
between days 5 and 14, control mice:  0.74 ± 0.07 cm2;
Fib/ mice: 0.87 ± 0.06 cm2;
P = .06). A modest enhancement of wound contraction in
Fib/ mice may result from the diminished or absent
eschar formation in these animals.10 Thus, despite the
wound instability and inability of Fib/ mice to form an
initial blood clot in the wound area, these animals completed the
process of skin wound repair in a similar time frame as control mice
(Figure 5E,F). Histologically, excisional wounds exaggerated the
impaired healing processes observed in incisional wounds of
Fib/ mice. By day 4, keratinocyte migration in
Fib/ mice was frequently directed away from the center
of the (empty) wound field, and granulation tissue accumulated only at
the wound edges. In contrast, control mice at day 4 made significant
progress in re-epithelialization over the wound field, which was filled with early granulation tissue. Nevertheless, exuberant granulation tissue developed in the wounds of both genotypes of mice (see Figure
3B,C) by 8 days after wounding, and re-epithelialization was either
complete or near completion. Epithelial hyperplasia and sinuses were
present in some Fib/ mice at 8 days but most
wounds were healing in a manner analogous to control mice, with
the exception of some persistent sinuses (Figure 5H).
Migration into a dead space Fibrin in the provisional matrix may support the cellular reorganization of damaged tissues, but the requirement for this matrix component may be most profound in contexts where other existing extracellular matrices are not immediately available, such as in the context of a hematoma or a dead space. The sinuses that formed in the wounds of Fib/ mice may result from an impediment of
these animals to build new tissues in dead space areas. To directly
explore the role of fibrin in the organization of wound fluid-filled
dead spaces, highly porous, sealed wound chambers were implanted
subcutaneously in control and Fib/ mice. At 7, 14, and
21 days after implantation, the chambers were collected, processed into
paraffin, and sectioned for microscopic analysis of cellular
organization of the chamber cores. At day 7, cells had successfully
infiltrated the porous walls of the chambers in both control and
Fib/ mice (Figure 7A,B).
By 14 and 21 days, the lumens of the chambers implanted in control mice
contained a fibrin-rich matrix into which cells from the pores had
successfully migrated (Figure 7C,E). In contrast, the lumens of
chambers of Fib/ mice contained only amorphous
proteinaceous material that was completely devoid of cells, despite
abundant cells in the pores of the chamber wall (Figure 7D,F). At 21 days, the luminal aspects of the chambers collected from
Fib/ mice showed only occasional evidence of a layering
of cells on the walls. However, cells were not seen infiltrating deep
within the lumen even at these later time points. The presence of a
provisional fibrin matrix is apparently required for the cellular
migration into, and organization of, dead space areas. In the absence
of a provisional fibrin matrix, pervasion of the wound field with fibrotic scar tissue appears to be accomplished by gradually building layers of cells inward upon existing cellular layers, analogous to the
process seen in wounds healed by secondary intention.
Fibrinogen is a key hemostatic factor and mice lacking this
fundamental building block of fibrin clots have a life-long risk of
spontaneous bleeding events. Nevertheless, Fib Keratinocyte migration in vitro is stimulated by many extracellular
matrix components, including fibrin, fibronectin, and collagen types I
and IV, and is inhibited by contact with laminin, a component of the
intact basement membrane underlying epithelial cells.14
Consistent with the fact that several matrix proteins are supportive of
keratinocyte migration, epithelial projections from the wound edge
developed rapidly in both fibrinogen-deficient and control mice.
Furthermore, fibrin deposition is clearly not essential to the
initiation of the process of re-epithelialization. However, the pattern
of migration of epithelial sheets at the interface between the eschar
and the granulating wound bed was altered in Fib Several indirect findings support the concept that fibrin(ogen) might
be critical for the formation of granulation tissue in wound fields,
including: (1) fibrin(ogen) is a prominent component of early wound
fields; (2) endothelial cells, fibroblasts, smooth muscle cells, and
inflammatory cells can bind fibrin(ogen) through a variety of integrin
and nonintegrin receptors2,3; (3) fibrin matrices prepared
in vitro and then implanted into experimental animals support the rapid
ingrowth of neovasculature in vivo6,17; (4) specific
proteolytic derivatives of fibrin have been shown to be
angiogenic18,19; and (5) several angiogenic growth factors (FGF-2 and VEGF) interact with fibrin(ogen) with high
affinity.4,5 Nevertheless, the findings presented here
show that fibrinogen-deficient mice form copious, highly-vascularized
granulation tissue in response to injury which at the level of light
microscopy is qualitatively similar to that observed in control mice.
Comparable features include abundant fibroblasts, inflammatory cells,
neovessels, and neomatrix, indicating no apparent granulation deficit.
However, there are significant differences in the collagen content in
the granulation tissue of control and Fib Fibrin(ogen) appears to be most important in tissue repair when cells
must infiltrate and organize fluid-filled areas, such as an internal
dead space established by a porous chamber. The difficulty of cells in
Fib Based on the notion that a provisional fibrin matrix may support the
development of mature granulation tissue, the elevated levels of
collagen in early granulation tissue of Fib These studies directly establish that fibrinogen serves a broader
physiologic role than merely controlling blood loss. This hemostatic
factor contributes significantly to the reparative process following
mechanical injury to skin. Although direct analyses of repair in
Fib
We wish to acknowledge the assistance of Alicia Emley with photography and Jill M. Potter with mouse genotyping.
Supported by awards from the American Heart Association, Ohio Valley Affiliate (A.F.D.) and the Department of Veterans Affairs (J.M.D.), and grants from the National Institutes of Health (nos. AG-06528 and AR-41943 to J.M.D.; nos. HL47826 and HL63194 to J.L.D.).
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Jay L. Degen, Children's Hospital Research Foundation, Children's Hospital Medical Center, IDR-NRB Rm 2042, 3333 Burnet Ave, Cincinnati, OH 45229-3039; e-mail: degenjl{at}chmcc.org.
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Abstract
Introduction
3, 
) and
Fib
). Histologic analyses indicating similar
cell density and qualitative appearance of granulation tissue in wound
tissue collected at day 14 from control (B) and Fib
aiming for perfect skin regeneration.
Science.
1997;276:75-81