HEALING AND REPAIR H.A .MWAKYOMA, MD

HEALING: Definition:- is the body response to injury in an attempt to restore normal structure and function. The process of healing involves 2 distinct processes:- I: REGENERATION:- is when healing takes place by proliferation of parenchymal cells and usually results in complete restoration of original tissue.

HEALING:CONT-- II: REPAIR:- is when the healing takes place by proliferation of connective tissue elements resulting in fibrosis and scarring.

I: REGENERATION: Some parenchymal cells are short-lived while others have longer life span. In order to maintain proper structure of tissues, these cells are under the constant regulatory control of their cell cycle. These factors which regulate the cell cycle include growth factors such as:- epidermal growth factor fibroblast growth factor platelet growth factor endothelial growth factor transforming growth factor β

THE CELL CYCLE Cell cycle is defined as the period between two successive cell divisions and is divided into 4 equal phases. M (Mitosis) phase: - the phase mitosis G1 (gap1) phase: - the daughter cell enters G1 phase after mitosis S (Synthesis) phase: - synthesis of nuclear DNA G2 (gap2) phase: - after completion of nuclear DNA duplication, the cell enters G2 phase. G0 (gap0) phase: - this is the quiescent or resting phase of the cell cycle after M phase.

THE CELL CYCLE

THE CELL CYCLE Not all cells of the body divide at the same pace. Some mature cells do not divide at all, while others complete the cycle every 16-24 hours. The main difference between slow-dividing and rapidly-dividing cells is the duration of G1 phase. Depending upon their capacity to divide, the cells of the body can be divided into 3 groups:-

capacity to divide of cells: Depending upon their capacity to divide, the cells of the body can be divided into 3 groups:- Labile cells Stable cells Permanent cells

Labile cells: These cells continue to multiply throughout life under normal physiologic conditions. These cells include: Surface epithelial cells of epidermis Alimentary tract Respiratory tract Urinary tract Vagina, Cervix, endometrium Haematopoietic cells of bone marrow and Cells of lymphnodes and spleen

Stable cells: Parenhymatous cell organs like; The cells decrease or lose their ability to proliferate after adolescence but retain the capacity to multiply in response to stimuli throughout adult life. These cells include:- Parenhymatous cell organs like; Liver Pancrease Kidneys Adrenals Thyroid

Stable cells: cont-- Mesenchymal cells like; Smooth muscle cells Fibroblasts Vascular endothelium Bone and cartilage cells

Permanent cells: These cells lose their ability to proliferate round the time of birth. These cells include: Neurons of CNS Skeletal muscle cells Cardiac muscle cells

RELATIONSHIP OF PARENCHYMAL CELLS WITH CELL CYCLE. If the 3 types of parenchymal cells described above are correlated with the phase of cell cycle, the following inferences can be derived:- Labile cells which are continuously dividing cells which remain in the cell cycle from one mitosis to the next Stable cells are in the resting phase (G0) but can be stimulated to enter the cycle Permanent cells are non-dividing cells which have left the cycle and die after injury.

Parenchymal cells cont-- Regeneration of any type of parenchymal cells involves the following 2 processes: Proliferation of original cells from the margins of injury with migration so as to cover the gap. Proliferation of migrated cells with subsequent differentiation and maturation so as to reconstitute the original tissue.

II: REPAIR: Definition:- repair is the replacement of injured tissue by fibrous tissue. Two processes are involved in repair:- GRANULATION TISSUE FORMATION; CONTRACTION OF WOUNDS Repair response takes place by participation of;

Participation of cells in repair Mesenchymal cells Connective tissue stem cells Fibrocytes Histiocytes Endothelial cells Macrophages Plateletes Parenchymal cells of the injured organ

GRANULATION TISSUE The following 3 phases are observed in the formation of granulation tissue. Phase of inflammation:- Following trauma, blood clots at the site of injury. There is acute inflammatory response with exudation of plasma, neutrophils and some monocytes within 24 hours.

GRANULATION TISSUE Phase of clearance:- There is a combination of; Proteolytic enzymes liberated by neutrophils, Autolytic enzymes from dead tissue cells and Phagocytic activity of macrophages clear off the necrotic tissue, debris and red blood cells.

GRANULATION TISSUE Phase of ingrowth of granulation tissue:- This phase consists of 2 main processes. Angiogenesis or Neovascularisation Formation of fibrous tissue

Angiogenesis (Neovascularisation): Formation of new blood vessels at the site of injury takes place by prolifearterioles, thin-walled venules and capillaries. ration of endothelial cells from margins of severed blood vessels The newly formed blood vessels are more leaky, accounting for the oedematous appearance of new granulation tissue Soon, these blood vessels differentiate into muscular

Angiogenesis (Neovascularisation): The process of angiogenesis takes place under the influence of the following:- Endothelial cell growth factors which act as positive stimuli and appear in granulation tissue Type IV collagen which acts as negative stimuli and appear late in the granulation tissue formation

Fibrous tissue formation: The new fibroblasts originate from fibrocytes as well as by mitotic division of fibroblasts. Some of the fibroblasts have morphologic and functional characteristic of smooth muscle cells (Myofibroblasts)

Fibrous tissue formation: cont-- Collagen fibril begin to appear by about 6th day. As maturation proceeds, more and more of collagen is formed while the active fibroblasts and new blood vessels decreases. This results in the formation of inactive looking scar known as Cicatrisation.

CONTRACTION OF WOUNDS: The wounds starts to contracting after 2-3 days and the process is completed by the 14th day. During this period, the wound is reduced by approximately 80% of its original size Contracted wounds results in rapid healing since lesser surface area of the injured tissue has be replaced.

CONTRACTION OF WOUNDS: The mechanism of wound contraction is thought to operate through the myofibroblasts which appear in active granulation tissue These cells have features intermediate between those of fibroblasts and smooth muscle cells. Their migration into the wound area and their act of contraction decreases the size of the defect.

WOUND HEALING: Healing of skin wounds provides a classical example of combination of regeneration and repair described above. This can be accomplished in one of the following two ways:- Healing by first intention (primary union; and Healing by second intention (secondary union).

Healing by first intention (primary union): This is defined as healing of a wound which has the following characteristics: clean and uninfected Surgically incised Without much loss of cells and tissue and Edges of wound are approximated by surgical sutures

The sequence of events in primary union The sequence of events in primary union are as follows:- Initial haemorrhage. immediate after injury, the space between the approximated surfaces of incised wound is filled with blood which clots and seals the wound against dehydration and infection

Acute inflammatory response. This occurs within 24 hours with appearance of polymorphs from the margins of incision By the 3rd day, polymorphs are replaced by macrophages Epithelial changes. The basal cells of the epidermis from both the cut margins start proliferating and migrating towards incisional space in the form of epithelial spurs

Epithelial changes.cont-- A well approximated wound is covered by a layer of epithelium in 48 hours. By 5th day, a multilayered new epithelium is formed. Organization. By 3rd day, fibroblasts also invade the wound area. By 5th day, new collagen fibril start forming which dominate till healing is completed.

Organization cont-- In 4 weeks the scar tissue with scanty cellular and vascular elements, a few inflammatory cells and epithelialised surface is formed.

II: Healing by second intention: This is defined as healing of wound having the following characteristics:- open with large tissue defect, at times infected having extensive loss of cells and tissues and the wound is not approximated by surgical sutures but left open.

II: Healing by second intention:cont-- The basic events in secondary union are similar to primary union but differ in having larger tissue defect which has to be bridged Healing takes place from the base upwards as well as from the margins inwards. The healing by second intention is slow and results in a large and at times ugly scar as compared to rapid healing and neat scar of primary union.

II: Healing by second intention: The sequence of events in secondary union is as follows:- Initial haemorrhage: as a result of injury, the wound space is filled with blood and fibrin clot which dries Inflammatory phase: There is initial acute inflammatory response followed by appearance of macrophages which clear the debris as in primary union.

Healing by second intention: Epithelial changes: The epidermal cells from both margins of wounds proliferate and migrate into wound in the form of epithelial spurs till they meet in the middle and reepithelialise the gap completely However, the proliferating epithelial cells do not cover the surface fully.

Healing by second intention: Granulation tissue: The main bulk of secondary healing is by granulations. Granulation tissue is formed by proliferation of fibroblasts and neovascularisation from adjoining viable elements. Wound contraction: contraction of wound is an important feature of secondary healing, not seen in primary healing. Due to action of myofibroblasts the wound contracts to one-third or to one-fourth of its original size.

Healing by second intention: Presence of infection: Bacterial contamination of an open wound delays the process of healing due to release of bacterial toxins.

COMPLICATIONS OF WOUND HEALING: Infections – due to entry of bacteria Implantation (epidermal) cyst formation due to persistence of epithelial cells in the wound after healing Deficient scar formation: - this may occur due to inadequate formation of granulation tissue Incisional hernia: - a weak scar may be the site of bursting open of a wound (wound dehiscence) or incisional hernia.

COMPLICATIONS OF WOUND HEALING: cont-- Hypertrophic scar and Keloid formation:- excessive formation of collagen in healing result in keloid Excessive contraction:- may result in formation of contractures or cicatrisation Neoplasm:- rarely scar may be the site of development of carcinoma eg. Squamous cell carcinoma

FACTORS INFLUENCING WOUND HEALING: LOCAL FACTORS: Infections: - delay the process of healing Poor blood supply:- slows healing Foreign bodies:- interfere with healing and cause intense inflammatory reaction and infection. Exposure to ionizing radiation:- delays granulation tissue

FACTORS INFLUENCING WOUND HEALING: Exposure to ultraviolet light:- facilitates healing Types, size and location of injury:- determines whether healing takes place by resolution or organization

FACTORS INFLUENCING WOUND HEALING: SYSTEMIC FACTORS: Age:- wound healing is rapid in the young and some what slow in aged and debilitated people due to poor blood supply to the injured area in the latter. Nutrition:- deficiency of constituents like protein, vitamin C (Scurvy) and Zinc delays wound healing.

FACTORS INFLUENCING WOUND HEALING: SYSTEMIC FACTORS: cont— Systemic infection:- delays wound healing Administration of glucocorticoids (drugs):- has an anti-inflammatory effect. Uncontrolled diabetics:- because are more prone to develop infections and hence delay wound healing. Haematologic abnormalities like:- defects in neutrophil function (chemotaxis and phagocytosis), Neutropenia, and Bleeding disorders – slow the process of wound healing.

Excessive Healing Excessive Healing Keloids

Hypertrophic scar

Keloids Extends beyond original bounds Raised and firm Rarely occur distal to wrist or knee Predilection for sternum, mandible and deltoid Rate of collagen synthesis increased Water content higher Increased glycosaminoglycans

Keloid

Keloid scar

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COMPLICATIONS OF WOUND HEALING: Infections – due to entry of bacteria Implantation (epidermal) cyst formation due to persistence of epithelial cells in the wound after healing Deficient scar formation: - this may occur due to inadequate formation of granulation tissue Incisional hernia: - a weak scar may be the site of bursting open of a wound (wound dehiscence) or incisional hernia.

COMPLICATIONS OF WOUND HEALING: Hypertrophic scar and Keloid formation:- excessive formation of collagen in healing result in keloid Excessive contraction:- may result in formation of contractures or cicatrisation Neoplasm:- rarely scar may be the site of development of carcinoma eg. Squamous cell carcinoma