REPAIR FOR INJURYREPAIR FOR INJURY

Nantong Medical College

Chen Li

When healing is accomplished mainly by proliferation of the parenchyma elements, the process is termed regeneration and often results in complete restoration of the original tissue.

When the main contribution is made by the nonspecialized elements of connective tissue, fibrosis or scaring results, and the process is called repair.

So that repair involves two distinct process:

①regeneration, which is the replacement of injured tissue by cells of the same type

②replacement by connective tissue.

Section 1 REGENERATION

Cells of body can be divided into three groups according to their capacity to regenerate

(1)Labile cellsLabile cells (surface epithelia, hematopoietic cells, mucous membranes and cells of bone marrow and lymphnodes) continue to proliferate throughout life, replacing cells that are continuously being destroyed. With injury and loss of cells, complete regeneration is possible from remaining cells.

(2)Stabile cellsStabile cells (parenchymal cells of the liver, pancreas, kidney adrenal, thyroid and connective tissue) normally have a low level of replication but can undergo rapid division in response to physiologic and pathologic stimuli, thus reconstituting the tissue of origin. Stable cells retain the ability to proliferation throughout life.

(3)Permanent cellsPermanent cells (nerve cell, skeletal and cardiac muscle cells) essentially do not regenerate, lost their ability to proliferation around the time of birth. The most important example is the neuron of the central nervous system.

Labile cells follow the cell cycle from one mitosis to the next. Permanent cells have left the cell cycle and are destined to senesce and die. Stabile cells are at G0 but are stimulated into G1 by an appropriate stimulus. Arrest at G2 before entering mitosis results in the appearance of polyploid cells--characteristic of cells that have undergone hypertrophy but cannot undergo division.

Regeneration process of variety tissue Epithelial regeneration

There are four stages:

(1)Thrombosis and inflammation

(2)Regeneration of epithelium over the denuded surface

(3)Multiplication of the new cells

(4)Differentiation of the new epithelium.

Regeneration of stable cells

Liver has a striking regenerative capacity, successful regeneration can occur even when nearly 90% of the organ is removed.

Regeneration of permanent cells

Permanent cells occur predominantly in the central nervous system. At birth the nervous system already has its full complement of neurons, which lack a capacity for regeneration. For peripheral nerves, however, limited regeneration can occur, though it is confined to the axons.

Fibrosis (fibroplasis)

Fibrosis or fibroplasia occur on the granulation tissue framework or new vessels and loose ECM that develop early at the repair site.

The process fibrosis occur in two steps:

(1) emigration and proliferation of fibroblasts in the site of injury,

(2) deposition of ECM by these cells. The recruitment and stimulation of fibroblasts is driven by the various growth factors.

Angiogenesis Four steps under the neovascularization:

(1)   Enzymatic degradation of the basement membrane

of the parent vessel.

(2)   Migration of endothelial cells.

(3)   Proliferation of endothelial cells.

(4)   Maturation and organization into capillary tubes.

Molecular mechanisms involved in cellular regeneration

Three influences are important in cell regeneration:

growth factor

Chalon and contact inhibition

Extracellular matrix (ECM)

Growth factor

Normal growth in populations of cells is controlled by the opposing effects of growth stimulators and growth inhibitors. The most important factors in cell growth are those that recruit G0 cells into the cell cycle.

Certain growth factors also initiate cell migration, differentiation, and tissue remodeling and may be involved in various stages of wound healing.

(1) Epidermal growth factor (EGF)

(2) Platelet-derived growth factor(PDGF)

(3) Fibroblast growth factors (FGFs)

(4) Transformaing growth factor α(TGF-α)

(5) Transforming growth factor β(TGF-β)

(6) IL-l and TNF

Chalon and contact inhibition Regenerating cells cease proliferating after the injury has healed. The precise causes of this density-dependent regulation of cell growth or contact inhibition are unknown, but in the case of liver regeneration after hepatectomy, TGF-βproduced by nonparenchymal cells in the liver inhibits hepatic cell growth.

Extracellular matrix (ECM)

Interactions between cells and the extracellular matrix influence cell migration, proliferation, and differentiation. The types of collagen in the matrix, the presence of fibronectin or laminin, and the nature of the proteoglycans in the pericellular areas all seem to affect growth or inhibition processes.

Section 2 Repair by connective tissue

Granulations tissue

Scar tissue

Scar remodeling

Contraction of wounds

Granulations tissue

Definition

Its histologic appearance is characterized by proliferation of fibroblasts and numerous new thin-walled, delicate capillaries edema and a loose ECM containing occasional inflammatory cells.

gross appearance show pink, soft, granular such as that seen beneath the scab of a skin wound.

Macrophages in granulation tissue responsible for clearing extracelluar debris, fibrin, and other foreign matter at the site of injury.

Repair wound and organization ,this means the replacement ,by granulation tissue of fibrous tissue,of solid ,non-living material such as fibrin, clotter blood,intravascular thrombus and dead tissue.

Granulations tissue

Scar tissue

As healing progresses, fibroblast in granulation tissue assume a more synthetic phenotype, and increased deposition of ECM, and collagen synthesis develop strength in a healing wound site. Net collagen accumulation 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 fibroblast, dense collagen, fragments of elastic tissue, and other ECM components.

Scar remodeling

Collagen (and other ECM components) are degraded by enzymes, such as metalloproteinases and other serine proteinases, these enzymes are produced by a variety of cell types (fibroblast, macrophages, neutrophils, synovial cells, and some epithelial cells ) and their synthesis and secretion are regulated by growth factors, cytokines and phagocytic stimuli.

In site of inflammation and wound healing, collagen degradation aids in the debridement of injury sites and also in the remodeling of connective tissue necessary to repair the defect. Indeed, collagenases and their inhibitors are spatially and temporally regulated in healing wounds.

Contraction of wounds

The rapidity of the healing of wounds depends to considerable extent on the contraction that begins a few days after injury and continues for several weeks.

The phenomenon of wound contraction is also evident in parenchyma organs such as the lung and liver and “myofibroblast-like” cells have been identified in granulation tissue during the repair process. In liver the vitamin A storage cell (the Ito cell ) has been identified as a mesenchymal cell that proliferates and produces connective tissue components during fibroplasia (including desmin positivity and abundant microfilaments and attachment sites ).

WOUND HEALING Healing by first intention When surgeon sutures a clean incision, healing takes place with minimum loss of tissue and without significant bacterial infection. This is referred to as healing by first intention or primary union.

Healing by second intention means the healing of a wound where there is a more extensive of tissue that has gradually to be filled in and replaced by new connective tissue.

The major influence factors of wound healing

1. The adequacy of the blood supply

2. The nutritional status of the host, e.g. protain nutrition and vitamin C intake

3. The presence or absence of diabetes mellitus.

4. The presence or absence of infection .

5. Intercurrent glucocorticosteroid therapy , which hinders the inflammatory reparative process.

6. Adequate levels of circulating white cells.

Healing of bone fracture

A fracture is a break in the continuity of bone.

A pathological fracture happens in the area of previously abnormal bone, e.g., tumor, cyst, etc.

Stages of healing:

(1)  Heamatoma formation: The fracture severs the blood vessels in the medulla, cortex and periosteum so that a heamatoma is produced.

(2)  Organization: within 24 hours capillary coops and fibroblasts begin to grow into the heamotoma with inflammation cell infiltration—vascular granulation tissue.

(3) Provisional callus: by about the 7th day, island of cartilage and osteoid tissue appear in this granulation tissue. The osteoid tissue in the form of irregular spioules, mineralizes to form the provisional callus—completes by about 25th day.

(4) Definitive callus. The disorderly provisional callus is gradually replaced by orderly bone with Haversian system.

(5) Remodelling. Due to osteoblasts bone formation and osteoblasts resorption, the normal contour of bone is reconstituded by the process of remodeling.

Factors influencing healing of fractures

(1)   local infection, pathological fracture, poor apposition and

aliment.

(2)  general factors. Old age, poor nutrition, primary

metastatic tumor.

(3)   endocrinous disturbances e.g., hyperparathyroidisin.

(4) osteoporosis due to various factors, e.g., disused, old

age, malnutrition