tissue repair and healing

Tissue repair and healing
Regeneration refers to growth of cells and tissues to replace lost structures, liver and kidney growth after, respectively, partial hepatectomy and unilateral nephrectomy
Tissues with high proliferative capacity, such as the hematopoietic system and the epithelia of the skin and gastrointestinal tract

Healing is usually a tissue response
(1) to a wound (commonly in the skin)
(2) to inflammatory processes in internal organs
(3) to cell necrosis in organs incapable of regeneration
Healing consists of variable proportions of two distinct processes 1-regeneration
2-the laying down of fibrous tissue, scar formation. . Superficial wounds, such as a cutaneous wound that only damages the epithelium, can heal by epithelial regeneration. Incisional and excisional skin wounds that damage the dermis heal through the formation of a collagen scar

. Scarring also occurs in the myocardium after infarction, as the original tissue is not reconstituted and is replaced by collagen . Inflammatory conditions of the pleura, peritoneum, and pericardium often heal through scar formation, creating adhesions between the visceral and parietal layers of these tissues. The development of a dense, fibrous scar in the pericardium can lead to a serious condition called constrictive pericarditis in cirrhosis of the liver and in some forms of coal- and silica-induced lung disease. In parenchymal organs, the replacement of inflammatory infiltrates by granulation tissue and ultimately fibrosis is called organization.

Regeneration requires an intact connective tissue scaffold. By contrast, healing with scar formation occurs if the extracellular matrix (ECM) framework is damaged causing alterations of the tissue architecture.
ECM scaffolds are essential for wound healing because they provide the framework for cell migration and maintain the correct cell polarity for the re-assembly of multilayer structure
Control of Normal Cell Proliferation and Tissue Growth
In adult tissues, the size of cell populations is determined by the rates of cell proliferation, differentiation, and death by apoptosis

terminally differentiated cells: include
A-Myocytes
B- neurons
proliferative tissues :
the bone marrow
the multilayered epithelia of the skin and gut, the they replaced by new cells arising from stem cells.
Extracellular Matrix (ECM) and Cell-Matrix Interactions
(1) fibrous structural proteins, such as the collagens and elastins
(2) a diverse group of adhesive glycoproteins.
(3) proteoglycans and hyaluronic acid.
interstitial matrix and basement membrane (BM). The interstitial matrix is present in spaces between epithelial, endothelial, and smooth muscle cells and in connective tissue. It consists of fibrillar and nonfibrillar collagen, elastin, fibronectin, proteoglycans, hyaluronate
TISSUE-PROLIFERATIVE ACTIVITY

continuously dividing tissues ( labile tissues) cells proliferate throughout life, replacing those that are destroyed. These tissues include surface epithelia, such as stratified squamous surfaces of the skin, oral cavity, vagina, and cervix; the lining mucosa of all the excretory ducts of the glands of the body
Quiescent (or stable) tissues normally have a low level of replication; however, cells from these tissues can undergo rapid division in response to stimuli and are thus capable of reconstituting the tissue of origin
Repair by Healing, Scar Formation, Fibrosis
• Induction of an inflammatory process in response to the initial injury, with removal of damaged and dead tissue
• Formation of new blood vessels (angiogenesis) and granulation tissue
Synthesis of ECM proteins and collagen deposition
• Tissue remodeling
• Wound contraction
• Acquisition of wound strength




Factors effect tissue repair
• The tissue environment and the extent of tissue damage
• The intensity and duration of the stimulus
• Conditions that inhibit repair, such as the presence of foreign bodies or inadequate blood supply
• Various diseases that inhibit repair (diabetes in particular), and treatment with steroids.




• The goal of the repair process is to restore the tissue to its original state
• Some tissues can be completely reconstituted repair is accomplished by connective tissue deposition, producing a scar. after injury
• If damage persists, inflammation becomes chronic, and tissue damage and repair may occur concurrently. Connective tissue deposition in these conditions is usually referred to as fibrosis

Repair begins early in inflammation. Sometimes as early as 24 hours after injury, if resolution has not occurred, fibroblasts and vascular endothelial cells begin proliferating to form a specialized type of tissue that is the hallmark of healing, called granulation tissue. its pink, soft, granular appearance on the surface of wounds, but it is the histologic features that are characteristic: the formation of new small blood vessels (angiogenesis) and the proliferation of fibroblasts

Angiogenesis from Pre-Existing Vessels
there is vasodilatation and increased permeability of the existing vessels, degradation of ECM, and migration of endothelial cells
• Vasodilation in response to nitric oxide and VEGF-induced increased permeability of the pre-existing vessel
• Proteolytic degradation of the BM of the parent vessel by metalloproteinases and disruption of cell-to-cell contact between endothelial cells of the vessel by plasminogen activator


• Migration of endothelial cells toward the angiogenic stimulus
• Proliferation of endothelial cells, just behind the leading front of migrating cells
• Maturation of endothelial cells, which includes inhibition of growth and remodeling into capillary tubes
• Recruitment of periendothelial cells (including pericytes for small capillaries and vascular smooth muscle cells for larger vessels) to support the endothelial tubes and form the mature vessel.



SCAR FORMATION
(1) emigration and proliferation of fibroblasts in the site of injury,
(2) deposition of ECM, and (3) tissue remodeling

Fibroblast Migration and Proliferation
Granulation tissue contains numerous newly formed blood vessels
VEGF promotes angiogenesis but is also responsible for a marked increase in vascular permeability
Migration of fibroblasts to the site of injury and their subsequent proliferation are triggered by multiple growth factors, including TGF-?, PDGF, EGF, FGF, and the cytokines IL-1 and TNF
Macrophages are important cellular constituents of granulation tissue, clearing extracellular debris, fibrin, and other foreign material at the site of repair


mast cells, eosinophils, and lymphocytes may also accumulate. Each of these cells can contribute directly or indirectly to fibroblast migration and proliferationTGF-? appears to be the most important because of the multitude of effects that favor fibrous tissue deposition. TGF-? is produced by most of the cells in granulation tissue and causes fibroblast migration and proliferation, increased synthesis of collagen and fibronectin, and decreased degradation of ECM by metalloproteinases
ECM Deposition and Scar Formation
As repair continues, the number of proliferating endothelial cells and fibroblasts decreases Fibroblasts progressively deposit increased amounts of ECM Fibrillar collagens form a major portion of the connective tissue in repair sites and are important for the development of strength in healing wounds, collagen synthesis by fibroblasts begins within 3 to 5 days after injury and continues for several weeks, depending on the size of woundcollagen synthesis isenhanced by several factors, including growth factors (PDGF, FGF, TGF-?) and cytokines (IL-1, IL-13), which are secreted by leukocytes and fibroblasts in healing wounds

. Net collagen accumulation, however, depends not only on increased collagen synthesis but also on decreased degradation. the granulation tissue scaffolding is converted into a scar composed of spindle-shaped fibroblasts, dense collagen, fragments of elastic tissue, and other ECM components. As the scar matures, vascular regression continues, eventually transforming the richly vascularized granulation tissue into a pale, avascular scar
HEALING BY FIRST INTENTION (WOUNDS WITH OPPOSED EDGES)
is the healing of a clean, uninfected surgical incision approximated by surgical sutures
Such healing is referred primary union or healing by first intention. The incision causes death of a limited number of epithelial and connective tissue cells as well as disruption of epithelial basement membrane continuity. The narrow incisional space immediately fills with clotted blood containing fibrin and blood cells; dehydration of the surface clot forms the well-known scab that covers the wound
Tissue Remodeling
The replacement of granulation tissue with a scar involves transitions in the composition of the ECM. Some of the growth factors that stimulate synthesis of collagen and other connective tissue molecules also modulate the synthesis and activation of metalloproteinases, enzymes that degrade these ECM components. The balance between ECM synthesis and degradation results in remodeling of the connective tissue framework—an important feature of both chronic inflammation and wound repair.


• Within 24 hours, neutrophils appear at the margins of the incision, moving toward the fibrin clot. In 24 to 48 hours, spurs of epithelial cells move from the wound edges (with little cell proliferation) along the cut margins of the dermis, depositing basement membrane components as they move. They fuse in the midline beneath the surface scab, producing a continuous but thin epithelial layer that closes the wound.
• By day 3, the neutrophils have been largely replaced by macrophages. Granulation tissue progressively invades the incision space


Collagen fibers are now present in the margins of the incision, but at first these are vertically oriented and do not bridge the incision. Epithelial cell proliferation thickens the epidermal layer.
• By day 5, the incisional space is filled with granulation tissue. Neovascularization is maximal. Collagen fibrils become more abundant and begin to bridge the incision
• During the second week, there is continued accumulation of collagen and proliferation of fibroblasts. The leukocytic infiltrate, edema, and increased vascularity have largely disappeared.


At this time, the long process of blanching begins, accomplished by the increased accumulation of collagenwithin the incisional scar, accompanied by regression of vascular channels • By the end of the first month, the scar is made up of a cellular connective tissue devoid of inflammatory infiltrate, covered now by intact epidermis. The dermal appendages that have been destroyed in the line of the incision are permanently lost. Tensile strength of the wound increases thereafter, but it may take months for the wounded area to obtain its maximal strength
HEALING BY SECOND INTENTION (WOUNDS WITH SEPARATED EDGES)
1- large tissue defects generate a larger fibrin clot that fills the defect and more necrotic debris and exudate that must be removed.
2-Consequently the inflammatory reaction is more intense
• Much larger amounts of granulation tissue are formed.
• Perhaps the feature that most clearly differentiates primary from secondary healing is the phenomenon of wound contraction, which occurs in large surface wounds.


. Permanent wound contraction requires the action of myofibroblasts Contraction of these cells at the wound site decreases the gap between the dermal edges of the wound
• Substantial scar formation and thinning of the epidermis

WOUND STRENGTH
usually at the end of the first week, wound strength is approximately 10% that of unwounded skin, but strength increases rapidly over the next 4 weeks. This rate of increase then slows at approximately the third month after the original incision, and reaches a plateau at about 70% to 80% of the tensile strength of unwounded skin, a condition that may persist for life.

LOCAL AND SYSTEMIC FACTORS THAT INFLUENCE WOUND HEALING
• Nutrition has profound effects on wound healing. Protein deficiency, for example, and particularly vitamin C deficiency, inhibit collagen synthesis and retard healing.
• Metabolic status can change wound healing. Diabetes mellitus, for example, is associated with delayed healing, as a consequence of the microangiopathy that is a frequent feature of this disease
• Circulatory status can modulate wound healing. Inadequate blood supply, usually caused by arteriosclerosis or venous abnormalities



Hormones, such as glucocorticoids, have well-documented anti-inflammatory effects that influence various components of inflammation. These agents also inhibit collagen synthesis.



COMPLICATIONS IN CUTANEOUS WOUND HEALING
(1)deficient scar formation, (2) excessive formation of the repair components, and (3) formation of contractures. Inadequate formation of granulation tissue or assembly of a scar can lead to two types of complications: wound dehiscence and ulceration Dehiscence or rupture of a wound is most common after abdominal surgery and is due to increased abdominal pressure. This mechanical stress on the abdominal wound can be generated by vomiting, coughing, or ileus.


Wounds can ulcerate because of inadequate vascularization during healing. For example, lower extremity wounds in individuals with atherosclerotic peripheral vascular disease typically ulcerate The accumulation of excessive amounts of collagen may give rise to a raised scar known as a hypertrophic scar; if the scar tissue grows beyond the boundaries of the original wound and does not regress, it is called a keloid . Another deviation in wound healing is the formation of excessive amounts of granulation tissue, which protrudes above the level of the surrounding skin and blocks re-epithelialization. This has been called exuberant granulation

Contraction in the size of a wound is an important part of the normal healing process. An exaggeration of this process is called a contracture and results in deformities of the wound and the surrounding tissues. Contractures are particularly prone to develop on the palms, the soles, and the anterior aspect of the thorax. Contractures are commonly seen after serious burns and can compromise the movement of joints


Nondividing (permanent) tissues contain cells that have left the cell cycle and cannot undergo mitotic division in postnatal life
Role of Stem Cells in Tissue Homeostasis
the liver contains stem cells in the canals of Hering niche can give rise to a population of precursor cells known as oval cells, which are bipotential progenitors, capable of differentiating into hepatocytes and biliary cells.

GROWTH FACTORS
Epidermal Growth Factor (EGF) and Transforming Growth Factor-? (TGF-?).
EGF is mitogenic for a variety of epithelial cells, hepatocytes, and fibroblasts. , EGF is produced by keratinocytes, macrophages, and other inflammatory cells that migrate into the area
Hepatocyte Growth Factor (HGF).:known as scatter factor It has mitogenic effects in most epithelial cells, including hepatocytes and cells of the biliary epithelium in the liver, and epithelial cells of the lungs, mammary gland, skin, and other tissues



Phases of cutaneous wound healing



Clean wound healing

The incision causes death of a limited number of epithelial and connective tissue cells and disruption of epithelial basement membrane continuity.

Re-epithelialization to close the wound occurs with formation of a relatively thin scar.

Healing by secondary union or by second intention

The repair process is more complicated when large defects on the skin surface, causing extensive loss of cells and tissue.

The healing of these wounds involves a more intense inflammatory reaction, the formation of abundant granulation tissue and extensive collagen deposition, leading to the formation of a substantial scar, which generally contracts.



The sequence of events in wound healing
Formation of Blood Clot.

Wounding causes the rapid activation of coagulation pathways, which results in the formation of a blood clot on the wound surface.
In addition to entrapped red cells, the clot contains fibrin, fibronectin, and complement components.
The clot serves to stop bleeding and also as a scaffold for migrating cells, which are attracted by growth factors, cytokines and chemokines released into the area.

In wounds causing large tissue deficits, the fibrin clot is larger, and there is more exudate and necrotic debris in the wounded area.


Formation of Granulation Tissue.
Fibroblasts and vascular endothelial cells proliferate in the first 24 to 72 hours.


Granulation tissue progressively invades the incision space; the amount of granulation tissue that is formed depends on the size of the tissue deficit created by the wound and the intensity of inflammation.

5 to 7 days, granulation tissue fills the wound area and neovascularization is maximal.