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CHAPTER FOUR
TISSUE REPAIR
REGENERATION & HEALING BY FIBROSIS
Critical to survival is the ability to repair the damage caused by injurious agents & inflammation. Repair
refers to the restoration of tissue architecture and function after an injury. This occurs by regeneration &/or
healing.
Regeneration: complete reinstitution of the damaged components of the affected tissue i.e. the tissue
essentially returns to a normal state.
Healing is a reparative process characterized by laying down of connective (fibrous) tissue that results in
scar formation. This mode occurs when
1. The injured tissues are incapable of complete regeneration, or
2. The supporting structures of the tissue are severely damaged
Although the resulting fibrous scar is not normal, it provides enough structural stability that allows the
injured tissue to function. Both regeneration and healing by fibrosis contribute in varying degrees to the
ultimate repair.
Repair involves
a. The proliferation of various cells, and
b. Close interactions between cells and the extracellular matrix (ECM).
Therefore, an understanding of the process of repair requires some knowledge of the control of cell
proliferation and the functions of the ECM.
THE CONTROL OF CELL PROLIFERATION
Several cell types proliferate during tissue repair. These include
1. The remnants of the injured tissue (which attempt to restore normal structure)
2. Vascular endothelial cells (to create new vessels that provide the nutrients for the repair process)
3. Fibroblasts (the source of the fibrous tissue that fills defects).
The proliferation of the above cell types is driven by growth factors. The production of polypeptide growth
factors, responses of cells to these factors, and the ability of these cells to divide and expand in numbers are
all important determinants of the adequacy of the repair process.
The normal size of cell populations in any given tissue is determined by a balance of cell proliferation, cell
death by apoptosis, and emergence of new differentiated cells from stem cells (Fig. 4-1).
THE CELL CYCLE
The cell cycle represents the sequence of events that control DNA replication & mitosis in the proliferation
of cells. It consists of a series of steps at which the cell checks for the accuracy of the process and instructs
itself to proceed to the next step (Fig. 4-2). The cycle consists of the presynthetic growth phase 1 (G
1
), the
DNA synthesis phase (S), the premitotic growth phase 2 (G
2
), and the mitotic phase (M). Non-dividing cells
are either in cell cycle arrest in G
1
or they exit the cycle to enter a phase called G
0
. Any stimulus that
initiates cell proliferation, such as exposure to growth factors, needs to promote the G
0
/G
1
transition and the
entry of cells into the G
1
. Further progression is determined by the ability of the cell to pass through an
intrinsic quality control mechanism for cell integrity, known as checkpoint control. Checkpoint controls
prevent DNA replication or mitosis of damaged cells and either transiently stop the cell cycle to allow for
DNA repair or eliminate irreversibly damaged cells by apoptosis. Progression through the cell cycle from G
1
is regulated by proteins called cyclins, which form complexes with enzymes called cyclin-dependent kinases
(CDKs). These complexes regulate the phosphorylation of proteins involved in cell cycle progression
leading to DNA replication and mitosis, and thus are required for cell cycle progression.
A major action of growth factors is to overcome the checkpoint controls by liberating the suppression of
CDK activity. Once cells enter the S phase, the DNA is replicated and the cell progresses through G
2
and
mitosis.
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Proliferative Capacities of Tissues
Tissue repair is critically influenced by the intrinsic proliferative capacity of the constituent cells. Based on
this criterion, the tissues of the body are divided into three groups:
1. Continuously Dividing Tissues (labile tissues): cells of these tissues are continuously being lost and
replaced by maturation from stem cells and by proliferation of mature cells. Labile cells include
hematopoietic cells in the bone marrow and the majority of surface epithelia. These tissues can readily
regenerate after injury provided the pool of stem cells is preserved.
2. Stable Tissues: cells of these tissues are quiescent (in the G
0
stage of the cell cycle) and have only
minimal replicative activity in their normal state. However, these cells are capable of proliferating in
response to injury or loss of tissue mass. Stable cells constitute the parenchyma of most solid tissues, such as
liver & kidney. They also include endothelial cells, fibroblasts, and smooth muscle cells; the proliferation of
these cells is particularly important in wound healing. With the exception of liver, stable tissues have a
limited capacity to regenerate after injury.
3. Permanent Tissues: cells of these tissues are terminally differentiated and nonproliferative in postnatal
life. The majority of neurons and cardiac muscle cells belong to this category. Accordingly, injury to brain
or heart is irreversible and results in a scar. Skeletal muscle is usually classified as a permanent tissue, but
satellite cells attached to the endomysial sheath provide some regenerative capacity for this tissue.
Stem Cells
In most continuously dividing tissues the mature cells are terminally differentiated and short-lived. As
mature cells die they are compensated for by identical differentiated cells generated from stem cells. Thus,
in these tissues there is a homeostatic equilibrium between the replication and differentiation of stem cells
and the death of the mature, fully differentiated cells. Such relationships are particularly evident in the
multilayered epithelium of the skin and the gastrointestinal tract, in which stem cell positions have been
identified near the basal layer of the epithelium. Cells differentiate progressively as they migrate to the
upper layers of the epithelium; they ultimately die and are shed from the surface of the tissue.
Stem cells are characterized by two important properties:
1. Self-renewal capacity
2. Asymmetric replication.
Asymmetric replication of stem cells means that after each cell division, some progeny enter a
differentiation pathway, while others remain undifferentiated, retaining their self-renewal capacity. Stem
cells with the capacity to generate multiple cell lineages (pluripotent stem cells) can be isolated from
embryos and are called embryonic stem (ES) cells. As mentioned above, stem cells are normally present in
proliferative tissues and generate cell lineages specific for the tissue. However, it is now recognized that
stem cells with the capacity to generate multiple lineages are present in the bone marrow and several other
tissues of adult individuals. These cells are called tissue stem cells or adult stem cells. Whether tissue stem
cells have similar differentiation capacity (differentiation plasticity) as ES cells remains the subject of active
research and much dispute. Bone marrow stem cells have the ability to generate fat, cartilage, bone,
endothelium, and muscle.
The new field of regenerative medicine has a main objective of regeneration and repopulation of damaged
organs using ES or adult stem cells. One of the most exciting prospects in this field is the type of stem cell
therapy known as therapeutic cloning. The main steps of this procedure are illustrated in (Figure 4-3)
Other potential therapeutic strategies using stem cells involve transplanting stem cells into areas of injury,
mobilization of stem cells from the bone marrow into injured tissue, and the use of stem cell culture systems
to produce large amounts of differentiated cells for transplantation into injured tissue.
GROWTH FACTORS
Cell proliferation can be triggered by
1. Growth factors
2. Hormones
3. Cytokines
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4. Signals from the ECM
The polypeptide growth factors have a major role of promoting cell survival and proliferation, which are
important in regeneration and healing. Thus, these proteins expand cell populations by stimulating cell
division as well as by promoting cell survival through protection from apoptotic death. Most growth factors
also stimulate migration, differentiation, & the synthesis of specialized proteins (such as collagen in
fibroblasts).
They induce cell proliferation by binding to specific receptors and by doing so affect the expression of genes
through
1. Relieving blocks on cell cycle progression (thus promoting replication),
2. Preventing apoptosis
3. Enhancing the synthesis of cellular proteins in preparation for mitosis
A major activity of growth factors is to stimulate the function of growth control genes, many of which are
protooncogenes (so named because mutations in them lead to unrestrained cell proliferation characteristic of
neoplasia (oncogenesis). Many of the growth factors that are involved in repair are produced by leukocytes
that are recruited & activated at the site of injury, as part of the inflammatory process. Other growth factors
are produced by the specialized tissue (parenchymal) cells or the stromal (connective tissue) cells in
response to cell injury or loss.
Signaling Mechanisms of Growth Factor Receptors
The major intracellular signaling pathways induced by growth factor receptors are similar to those of many
other cellular receptors that recognize extracellular ligands. The binding of a ligand to its receptor triggers a
series of events by which extracellular signals are transduced into the cell, leading to the stimulation or
repression of gene expression. Signaling may occur directly in the same cell (autocrine signaling e.g.
lymphocyte proliferation induced by cytokines in some immune responses), between adjacent cells
(paracrine signaling e.g. recruiting inflammatory cells to the site of infection & in wound healing), or over
greater distances (endocrine signaling e.g. a hormone, is released into the bloodstream and acts on target
cells at a distance) (Fig. 4-4).
The binding of a ligand to its cell surface receptor leads to a cascade of secondary intracellular events that
culminate in transcription factor activation or repression, leading to cellular responses. Transcription factors
bind to gene promoters and enhancers to trigger or inhibit transcription.
EXTRACELLULAR MATRIX (ECM) AND CELL-MATRIX INTERACTIONS
Tissue repair depends not only on growth factor activity but also on interactions between cells and ECM
components. The ECM is a dynamic, constantly remodeling macromolecular complex synthesized locally,
which assembles into a network that surrounds cells. It constitutes a significant proportion of any tissue. By
supplying a substrate for cell adhesion and serving as a reservoir for growth factors, ECM regulates the
proliferation, movement, and differentiation of the cells living within it. Synthesis and degradation of ECM
accompanies wound healing & chronic fibrotic processes.
ECM occurs in two basic forms:
1. Interstitial matrix, which is present in the spaces between mesenchymal (connective tissue) cells, and
between epithelium and supportive vascular and smooth muscle structures; it is synthesized by the
mesenchymal cells (e.g., fibroblasts). Its major constituents are fibrillar and nonfibrillar collagens, as well as
fibronectin, elastin, proteoglycans, hyaluronate, and other elements.
2. Basement membrane, which lies beneath the epithelium and is synthesized by overlying epithelium and
underlying mesenchymal cells; it tends to form a platelike "chicken wire" mesh. Its major constituents are
amorphous nonfibrillar type IV collagen and laminin.
Functions of the ECM
1. Mechanical support for cell anchorage and migration, and maintenance of cell polarity
2. Control of cell growth by signaling through cellular receptors of the integrin family.
3. Maintenance of cell differentiation through the type of ECM proteins, also acting largely via cell surface
integrins.
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4. Scaffolding for tissue renewal: the maintenance of normal tissue structure requires a basement membrane
or stromal scaffold. The integrity of the basement membrane or the stroma of the parenchymal cells is
critical for the organized regeneration of tissues. It is particularly noteworthy that although labile and stable
cells are capable of regeneration, injury to these tissues results in restitution of the normal structure only if
the ECM is not damaged. Disruption of these structures leads to collagen deposition and scar formation.
5. Establishment of tissue microenvironments: basement membrane acts as a boundary between epithelium
and underlying connective tissue and also forms part of the filtration apparatus in the kidney.
6. Storage and presentation of regulatory molecules. For example, growth factors like FGF is excreted and
stored in the ECM in some tissues. This allows the rapid deployment of growth factors after local injury, or
during regeneration.
Components of the Extracellular Matrix
There are three basic components of ECM:
1. Fibrous structural proteins (collagens and elastins) that confer tensile strength and recoil.
2. Water-hydrated gels (proteoglycans and hyaluronan), which permit resilience and lubrication
3. Adhesive glycoproteins that connect the matrix elements to one another and to cells.
Collagen
The collagens are fibrous structural proteins that confer tensile strength; without them human beings would
be reduced to a clump of cells connected by neurons. Collagens are composed of three separate polypeptide
chains braided into a ropelike triple helix. About 30 collagen types have been identified. Some collagen
types (e.g., types I, II, III, and V) form fibrils. The fibrillar collagens form a major proportion of the
connective tissue in healing wounds and particularly in scars. The tensile strength of the fibrillar collagens
derives from their cross-linking. This process is dependent on vitamin C; therefore, children with ascorbate
deficiency have skeletal deformities, bleed easily because of weak vascular wall basement membrane, and
heal poorly. Genetic defects in these collagens cause diseases such as osteogenesis imperfecta and Ehlers-
Danlos syndrome. Other collagens are nonfibrillar and may form basement membrane (type IV), or be a
component of intervertebral discs (type IX) or dermal-epidermal junctions (type VII).
Elastin
The ability of tissues to recoil and return to a baseline structure after physical stress is conferred by elastic
tissue. This is especially important in the walls of large vessels (which must accommodate recurrent
pulsatile flow of blood), as well as in the uterus, skin, and ligaments. Elastic fibers differ from collagen by
having fewer cross-links. The fibrillin meshwork serves as a scaffold for the deposition of elastin and
assembly of elastic fibers; defects in fibrillin synthesis lead to skeletal abnormalities and weakened aortic
walls (Marfan syndrome).
Proteoglycans and Hyaluronan
Proteoglycans form highly hydrated compressible gels conferring resilience and lubrication (such as in the
cartilage in joints). They consist of long polysaccharides called glycosaminoglycans linked to a protein
backbone. Hyaluronan, a huge molecule composed of many disaccharide repeats without a protein core, is
also an important constituent of the ECM. Because of its ability to bind water, it forms a viscous, gelatin-
like matrix. Besides providing compressibility to a tissue, proteoglycans also serve as reservoirs for growth
factors secreted into the ECM (e.g., FGF). Proteoglycans can also be integral cell membrane proteins and
have roles in cell proliferation, migration, and adhesion.
Adhesive Glycoproteins and Adhesion Receptors
Adhesive glycoproteins and adhesion receptors are structurally diverse molecules involved in cell-to-cell
adhesion, the linkage between cells and ECM, and binding between ECM components. The adhesive
glycoproteins include fibronectin (major component of the interstitial ECM) and laminin (major constituent
of basement membrane). The adhesion receptors, also known as cell adhesion molecules (CAMs), are
grouped into four families:
1. Immunoglobulins
3. Selectins
2. Cadherins
4. Integrins
Fibronectin is synthesized by a variety of cells, including fibroblasts, monocytes, and endothelium.
Fibronectins have specific domains that bind to a wide spectrum of ECM components. Tissue fibronectin
19
forms fibrillar aggregates at wound healing sites; plasma fibronectin binds to fibrin to form the provisional
blood clot of a wound, which serves as a background for ECM deposition and re-epithelialization.
Laminin is the most abundant glycoprotein in basement membrane that connects cells to underlying ECM
components such as type IV collagen and heparan sulfate. Besides mediating attachment to basement
membrane, laminin can also modulate cell proliferation, differentiation, and motility.
Integrins are a family of transmembrane glycoproteins composed of α and β chains that are the main
cellular receptors for ECM components, such as fibronectins and laminins. Some integrins are leukocyte
surface molecules that mediate firm adhesion and transmigration across endothelium at sites of
inflammation, and also play a role in platelet aggregation. Integrins are present in the plasma membrane of
most animal cells, with the exception of red blood cells. They bind to many ECM components initiating
signaling cascades that can affect cell locomotion, proliferation, and differentiation. Integrin signal
transduction utilizes the same intracellular signaling pathways used by growth factor receptors. In this
manner, extracellular mechanical forces can be coupled to intracellular synthetic and transcriptional
pathways.
CELL AND TISSUE REGENERATION
Cell renewal occurs continuously in labile tissues, such as the bone marrow, gut epithelium, and the skin.
Damage to epithelia or an increased loss of blood cells can be corrected by the proliferation and
differentiation of stem cells and, in the bone marrow, by proliferation of more differentiated progenitors.
The renewal of hematopoietic cells is driven by growth factors called colony-stimulative factors (CSFs),
which are produced in response to increased consumption or loss of blood cells.
Tissue regeneration can occur in parenchymal organs with stable cell populations, but with the exception of
the liver, this is usually a limited process. The surgical removal of a kidney elicits in the contralateral kidney
a compensatory response that consists of both hypertrophy and hyperplasia of proximal duct cells. The
regenerative response of the liver that occurs after surgical removal of hepatic tissue is striking. Up to 60%
of the liver may be removed in a procedure called living-donor transplantation, in which a portion of the
liver is resected from a normal individual and is transplanted into a recipient with end-stage liver disease
(Fig. 4-5), or after partial hepatectomies performed for tumor removal. In such cases, the tissue resection
triggers proliferation of the remaining hepatocytes (normally quiescent). Experimentally, hepatocyte
replication after partial hepatectomy is initiated by cytokines (e.g., tumor necrosis factor [TNF] and
interleukin 6 [IL-6]).
EGF (epidermal growth factor receptor, or EGFR) with intrinsic tyrosine kinase activity, is mitogenic for
hepatocytes and most epithelial cells, including keratinocytes. In cutaneous wound healing EGF is produced
by keratinocytes, macrophages, and other inflammatory cells. The main EGFR (referred to as EGFR1) is
frequently overexpressed in lung and some brain tumors and is an important therapeutic target for the
treatment of these conditions. ERB B2 (also known as HER-2/NEU) has received great attention because of
its overexpression in breast cancers, in which it is a target for effective cancer control.
It should be emphasized that extensive regeneration or compensatory hyperplasia can occur only if the
residual tissue is structurally and functionally intact, as after partial surgical resection. By contrast, if the
tissue is damaged by infection or inflammation, regeneration is incomplete and is accompanied by scarring.
REPAIR BY CONNECTIVE TISSUE
Healing or repair by connective tissue is encountered if
1. A severe or persistent (chronic) tissue injury that result in damage to parenchymal cells as well as the
stromal framework
2. Injury affects nondividing cells
Under these conditions, repair occurs by replacement of the nonregenerated cells with connective tissue, or
by a combination of regeneration of some cells and scar formation.
Repair begins within 24 hours of injury by the emigration of fibroblasts and the induction of fibroblast and
endothelial cell proliferation. By 3 to 5 days, a specialized type of tissue that is characteristic of healing,
called granulation tissue is apparent. The term granulation tissue derives from the pink, soft, granular gross
appearance, such as that seen beneath the scab of a skin wound. Its microscopic appearance is characterized
by proliferation of fibroblasts and new thin-walled, delicate capillaries (angiogenesis), in a loose ECM.
20
Granulation tissue then progressively accumulates connective tissue matrix, eventually resulting in the
formation of a scar (Fig. 4-6), which may remodel over time.
Repair by connective tissue deposition consists of four sequential processes:
Formation of new blood vessels (angiogenesis)
Migration and proliferation of fibroblasts
Deposition of ECM (scar formation)
Maturation and reorganization of the fibrous tissue (remodeling)
Angiogenesis (neovascularization)
The preexisting vessels send out capillary sprouts to produce new vessels. Angiogenesis is a critical process
in healing at sites of injury, in the development of collateral circulations at sites of ischemia, and in allowing
tumors to increase in size beyond the limits of their original blood supply. It has recently been found that
endothelial precursor cells may migrate from the bone marrow to areas of injury and participate in
angiogenesis at these sites. Much work has been done to understand the mechanisms underlying
angiogenesis, and therapies to either enhance the process (e.g., to improve blood flow to a heart ruined by
coronary atherosclerosis) or inhibit it (to interfere with tumor growth) are being developed.
New vessels formed during angiogenesis are leaky. This leakiness explains why granulation tissue is often
edematous, and accounts in part for the edema that may persist in healing wounds long after the acute
inflammatory response has resolved. Several factors induce angiogenesis, but the most important are VEGF
and basic fibroblast growth factor (FGF-2). VEGF stimulates both proliferation and motility of endothelial
cells, thus initiating the process of capillary sprouting. In angiogenesis involving endothelial cell precursors
from the bone marrow, VEGF acts through VEGFR-2 to mobilize these cells from the bone marrow and to
induce proliferation and motility of these cells at the sites of angiogenesis.
Migration of Fibroblasts and ECM Deposition (Scar Formation)
Scar formation builds on the granulation tissue framework of new vessels and loose ECM that develop early
at the repair site. It occurs in two steps:
1. Migration and proliferation of fibroblasts into the site of injury and
2. Deposition of ECM by these cells.
The recruitment and stimulation of fibroblasts is driven by many growth factors, including PDGF. One
source of this factor is the activated endothelium, but more importantly, growth factors are also elaborated
by inflammatory cells. Macrophages, in particular, are important cellular constituents of granulation tissue,
and besides clearing extracellular debris and fibrin at the site of injury, they elaborate a host of mediators
that induce fibroblast proliferation and ECM production. Mast cells and lymphocytes can contribute directly
or indirectly to fibroblast proliferation and activation.
As healing progresses, the number of proliferating fibroblasts and new vessels decreases; however, the
fibroblasts progressively become more synthetic, and hence there is increased deposition of ECM. Collagen
synthesis, in particular, is critical to the development of strength in a healing wound site. Collagen synthesis
by fibroblasts begins early in wound healing (days 3 to 5) and continues for several weeks, depending on the
size of the wound. The same growth factors that regulate fibroblast proliferation also participate in
stimulating ECM synthesis. Net collagen accumulation, however, depends not only on increased synthesis
but also on diminished collagen degradation. Ultimately, the granulation tissue scaffolding evolves into a
scar composed of largely inactive, spindle-shaped fibroblasts, dense collagen, fragments of elastic tissue,
and other ECM components. As the scar matures, there is progressive vascular regression, which eventually
transforms the highly vascularized granulation tissue into a pale, largely avascular scar. Many growth factors
are involved in the above processes, including TGF-β, PDGF, and FGF as well as cytokines (IL-1 & TNF).
ECM and Tissue Remodeling
The transition from granulation tissue to scar involves shifts in the composition of the ECM; even after its
synthesis and deposition, scar ECM continues to be modified and remodeled. The outcome of the repair
process is, in part, a balance between ECM synthesis and degradation. The degradation of collagens and
other ECM components is accomplished by a family of matrix metalloproteinases (MMPs), which are
dependent on zinc ions for their activity. MMPs include interstitial enzymes that degrade collagen,
fibronectin, proteoglycans, & laminin. MMPs are produced by a variety of cell types (fibroblasts,
macrophages, neutrophils, synovial cells), and their synthesis and secretion are regulated by growth factors,
cytokines, and other agents. Their synthesis may be suppressed pharmacologically with steroids.
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CUTANEOUS WOUND HEALING
This is a process that involves both epithelial regeneration and the formation of connective tissue scar and is
thus illustrative of the general principles that apply to wound healing in all tissues. The events are
orchestrated by interplay of growth factors and ECM.
Cutaneous wound healing has three main phases:
inflammation
formation of granulation tissue
ECM deposition and remodeling
Larger wounds also contract during the healing process. Events in wound healing overlap to a great extent
and cannot be completely separated from each other.
Based on the nature of the wound, the healing of cutaneous wounds can occur by first or second intention.
Healing by First Intention
One of the simplest examples of wound repair is the healing of a clean, uninfected surgical incision
approximated by surgical sutures. This is referred to as primary union or healing by first intention. The
incision causes only focal disruption of epithelial basement membrane continuity and death of a relatively
few epithelial and connective tissue cells. As a result, epithelial regeneration predominates over fibrosis. A
small scar is formed, but there is minimal wound contraction.
The narrow incisional space first fills with fibrin-clotted blood.
Within 24 hours, neutrophils are seen at the incision margin, migrating toward the fibrin clot.
Within 24 to 48 hours, epithelial cells from both edges have begun to migrate and proliferate along the
dermis. The cells meet in the midline beneath the surface scab, yielding a thin but continuous epithelial
layer.
By day 3, neutrophils have been largely replaced by macrophages, and granulation tissue progressively
invades the incision space. Epithelial cell proliferation continues, yielding a thickened epidermal covering
layer.
By day 5, neovascularization reaches its peak as granulation tissue fills the incisional space. The epidermis
recovers its normal thickness as differentiation of surface cells yields a mature epidermal architecture with
surface keratinization.
During the second week, there is continued collagen accumulation and fibroblast proliferation that bridge
the incision. The leukocyte infiltrate, edema, and increased vascularity are diminished.
The long process of "blanching" begins, accomplished by increasing collagen deposition within the
incisional scar and the regression of vascular channels.
By the end of the first month, the scar comprises a cellular connective tissue largely devoid of inflammatory
cells and covered by an essentially normal epidermis. The tensile strength of the wound increases with time.
However, the dermal appendages destroyed in the line of the incision are permanently lost (Fig. 4-7)
Healing by Second Intention (healing by secondary union)
When cell or tissue loss is more extensive, the repair process is more complex, the inflammatory reaction is
more intense, there is abundant development of granulation tissue, and the wound contracts by the action of
myofibroblasts. This is followed by accumulation of ECM and formation of a large scar. This mode of
healing occurs in
Large wounds
Abscesses
Ulcerations
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After infarction in parenchymal organs. (Fig. 4-7 & 4-8)
Secondary healing differs from primary healing in several respects:
A larger clot or scab rich in fibrin and fibronectin forms at the surface of the wound.
Inflammation is more intense because large tissue defects have a greater volume of necrotic debris, exudate,
and fibrin that must be removed.
Much larger amounts of granulation tissue are formed. A greater volume of granulation tissue generally
results in a greater mass of scar tissue.
Secondary healing involves wound contraction. Within 6 weeks, for example, large skin defects may be
reduced to 5% to 10% of their original size, largely by contraction. This process has been ascribed to the
presence of myofibroblasts, which are modified fibroblasts exhibiting many of the ultrastructural and
functional features of contractile smooth muscle cells.
Wound Strength
Carefully sutured wounds have approximately 70% of the strength of unwounded skin, largely because of
the placement of the sutures. When sutures are removed, usually at 1 week, wound strength is approximately
10% of that of unwounded skin, but this increases rapidly over the next 4 weeks. The recovery of tensile
strength results from collagen synthesis exceeding degradation during the first 2 months, and from structural
modifications of collagen (e.g., cross-linking and increased fiber size) when synthesis declines at later times.
Wound strength reaches approximately 70% to 80% of normal by 3 months but usually does not
substantially improve beyond that point.
PATHOLOGIC ASPECTS OF REPAIR
Wound healing may be affected by several external or internal influences that reduce the quality or adequacy
of the reparative process. Particularly important are infections and diabetes.
These adverse influences include
1. Infection is the single most important cause of delay in healing; it prolongs the inflammation phase of the
process and potentially increases the local tissue injury.
2. Nutrition has profound effects on wound healing; protein deficiency & vitamin C deficiency, inhibits
collagen synthesis and retards healing.
3. Glucocorticoids (steroids) have anti-inflammatory effects, and their administration may result in poor
wound strength due to diminished fibrosis. In some instances, however, the anti-inflammatory effects of
glucocorticoids are desirable. For example, in corneal infections, glucocorticoids are sometimes prescribed
(along with antibiotics) to reduce the likelihood of opacity that may result from collagen deposition.
4. Mechanical variables such as increased local pressure or torsion may cause wounds to pull apart, or
dehisce i.e. open out or gape.
5. Poor perfusion, due either to arteriosclerosis and diabetes or to obstructed venous drainage (e.g. in
varicose veins), also impairs healing
6. Foreign bodies such as fragments of steel, glass, or even bone impede healing.
7. The type (and volume) of tissue injured is critical. Complete restoration can occur only in tissues
composed of stable and labile cells; even then, extensive injury will probably result in incomplete tissue
regeneration and at least partial loss of function. Injury to tissues composed of permanent cells must
inevitably result in scarring with, at most, attempts at functional compensation by the remaining viable
elements. Such is the case with healing of a myocardial infarct.
8. The location of the injury and the character of the tissue in which the injury occurs are also
important. For example, inflammation arising in tissue spaces (e.g., pleural, peritoneal, synovial cavities)
develops extensive exudates. Subsequent repair may occur by digestion of the exudate, initiated by the
proteolytic enzymes of leukocytes and resorption of the liquefied exudate. This is called resolution, and in
the absence of cellular necrosis, normal tissue architecture is generally restored. However, in the setting of
larger accumulations, the exudate undergoes organization: granulation tissue grows into the exudate, and a
fibrous scar ultimately forms.
Aberrations of cell growth and ECM production
This may occur even in what begins as normal wound healing.
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1. Keloid refers to the accumulation of exuberant amounts of collagen that give rise to prominent, raised
scars. (Fig. 4-9). There appears to be a heritable predisposition to keloid formation, and the condition is
more common in blacks.
2. Exuberant granulation: healing wounds may also generate excessive granulation tissue that protrudes
above the level of the surrounding skin and hinders re-epithelialization. The restoration of epithelial
continuity requires cautery or surgical resection of the granulation tissue.
3. Disabling fibrosis associated with chronic inflammatory diseases such as rheumatoid arthritis, pulmonary
fibrosis, and cirrhosis have many similarities to those involved in normal wound healing. In these diseases,
however, persistent stimulation of fibrogenesis results from chronic immune reactions that sustain the
synthesis and secretion of growth factors, fibrogenic cytokines, and proteases. Collagen degradation by
collagenases, normally important in wound remodeling, is responsible for much of the joint destruction seen
in rheumatoid arthritis. (Fig. 4-10)