Definition of healingThe word healing refers to the body replaced the destroyed tissue by living tissue.
III. Processes of healing
The healing involves two distinct processes:
Regeneration, the replacement of lost tissue by tissues similar in type
Repair (healing by scaring), the replacement of lost tissue by granulation tissue which matures to form scar tissue.
Healing by fibrosis is inevitable when the surrounding specialized cells do not possess the capacity to proliferate.
Whether healing takes place by regeneration or by repair (scarring) is determined partly by the type of cells in the damaged organ & partly by the destruction or the intactness of the stromal frame work of the organ. Hence, it is important to know the types of cells in the body.
Types of cellsBased on their proliferative capacity there are three types of cells.Cell types and cell cycle phases
Constantly dividing labile cells continuously cycling from one mitosis to the next. Nondividing permanent cells have exited the cycle and are distended to die without further division. Quiescent stable cells in G0 are neither cycling nor dying and can be induced to re-enter the cycle by an appropriative stimulus.
b. Repair (Healing by connective tissue)3. In growth of granulation tissueThis is characterized by proliferation of fibroblasts and an in growth of new blood vessels into the area of injury, with a variable number of inflammatory cells.Fibroblasts actively synthesize and secrete extra-cellular matrix components, including fibronectin, proteoglycans, and collagen types I and III. The fibronectin and proteoglycans form the ‘scaffolding’ for rebuilding of the matrix. Fibronectin binds to fibrin and acts as a chemotactic factor for the recruitment of more fibroblasts and macrophages. The synthesis of collagen by fibroblasts begins within 24 hours of the injury although its deposition in the tissue is not apparent until 4 days. By day 5, collagen type III is the predominant matrix protein being produced; but by day 7 to 8, type I is prominent, and it eventually becomes the major collagen of mature scar tissue. This type I collagen is responsible for providing the tensile strength of the matrix in a scar. Coincident with fibroblast proliferation there is angiogenesis (neovascularization), a proliferation and formation of new small blood vessels. Vascular proliferation starts 48 to 72 hours after injury and lasts for several days.
Summary Following tissue injury, whether healing occurs by regeneration or scarring is determined by the degree of tissue destruction, the capacity of the parenchymal cells to proliferate, and the degree of destructon of stromal framework as illustrated in the diagram below (See Fig. 4.2).In the above discussion, regeneration, repair, and contraction have been dealt with separately. Yet they are not mutually exclusive processes. On the contrary, the three processes almost invariably participate together in wound healing.…………………………………………………………………………………………………………………………………………….Figure 4.2 Diagram showing healing process following acute inflammatory injury
IV. Molecular control of healing processAs seen above, healing involves an orderly sequence of events which includes regeneration and migration of specialized cells, angiogenesis, proliferation of fibroblasts and related cells, matrix protein synthesis and finally cessation of these processes. These processes, at least in part, are mediated by a series of low molecular weight polypeptides referred to as growth factors.
These growth factors have the capacity to stimulate cell division and proliferation. Some of the factors, known to play a role in the healing process, are briefly discussed below.
Sources of Growth Factors:Following injury, growth factors may be derived from a number of sources such as:1. Platelets, activated after endothelial damage,2. Damaged epithelial cells,3. Circulating serum growth factors,4. Macrophages, or5. Lymphocytes recruited to the area of injuryThe healing process ceases when lost tissue has been replaced. The mechanismsregulating this process are not fully understood. TGF-β acts as a growth inhibitor for both epithelial and endothelial cells and regulates their regeneration.
1. Healing by first intention (primary union)The least complicated example of wound healing is the healing of a clean surgical incision (Fig. 4-4, left). The wound edges are approximated by surgical sutures, and healing occurs with a minimal loss of tissue. Such healing is referred to, surgically, as “primary union” or “healing by first intention”. The incision causes the death of a limited number of epithelial cells as well as of dermal adnexa and connective tissue cells; the incisional space is narrow and immediately fills with clotted blood, containing fibrin and blood cells; dehydration of the surface clot forms the well-known scab that covers the wound and seals it from the environment almost at once. Within 24 hours, neutrophils appear at the margins of the incision, moving toward the fibrin clot. The epidermis at its cut edges thickens as a result of mitotic activity of basal cells and, within 24 to 48 hours, spurs of epithelial cells from the edges both migrate and grow along the cut margins of the dermis and beneath the surface scab to fuse in the midline, thus producing a continuous but thin epithelial layer. By day 3, the neutrophils have been largely replaced by macrophages. Granulation tissue progressively invades the incisional 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.
Arm, healing surgical incision. This image demonstrates healing by first intention which occur in clean, un infected wounds that have apposed edges.
2. Healing by second intention (secondary union) When there is more extensive loss of cells and tissue, such as occurs in infarction,inflammatory ulceration, abscess formation, and surface wounds that create large defects, the reparative process is more complicated. The common denominator in all these situations is a large tissue defect that must be filled. Regeneration of parenchymal cells cannot completely reconstitute the original architecture. Abundant granulation tissue grows in from the margin to complete the repair. This form of healing is referred to as “secondary union” or “healing by second intention.” Secondary healing differs from primary healing in several respects:
Wound healing by primary and secondary union1. Inevitably, large tissue defects initially have more fibrin and more necrotic debris and exudate that must be removed. Consequently, the inflammatory reaction is more intense.
2. Much larger amounts of granulation tissue are formed. When a large defect occurs in deeper tissues, such as in a viscus, granulation tissue bears the responsibility for its closure, because drainage to the surface cannot occur.
3. Perhaps the feature that most clearly differentiates primary from secondary healing is the phenomenon of wound contraction, which occurs in large surface wounds.
4. Healing by second intention takes much longer than when it occurs by first
Wound with large tissue defect healed by secondary intention. Note the red granular appearance of the granulation tissue. A whitish- greenish- yellow neutrophilic exudates represent an inflammatory response to bacterial invasion of the wound.
Hand healed by secondary intentionAs the granulation tissue matures, the myofibroblast contract to close the wound. They then become mature fibroblast, which produce collagen, forming a fibrous scar. The contraction that takes place can lead to decrease mobility.
• Type, size, and location of the woundA clean, aseptic wound produced by the surgeon’s scalpel heals faster than a woundproduced by blunt trauma, which exhibits aboundant necrosis and irregular edges. Small blunt wounds heal faster than larger ones. Injuries in richly vascularized areas (e.g., the face) heal faster than those in poorly vascularized ones (e.g., the foot). In areas where the skin adheres to bony surfaces, as in injuries over the tibia, wound contraction and adequate apposition of the edges are difficult. Hence, such wounds heal slowly. • Vascular supplyWounds with impaired blood supply heal slowly. For example, the healing of leg wounds in patients with varicose veins is prolonged. Ischemia due to pressure produces bed sores and then prevents their healing. Ischemia due to arterial obstruction, often in the lower extremities of diabetics, also prevents healing. • InfectionWounds provide a portal of entry for microorganisms. Infection delays or prevents healing, promotes the formation of excessive granulation tissue (proud flesh), and may result in large, deforming scars.
• MovementEarly motion, particularly before tensile strength has been established, subjects a wound to persistent trauma, thus preventing or retarding healing. • Ionizing radiationPrior irradiation leaves vascular lesions that interfere with blood supply and result in slow wound healing. Acutely, irradiation of a wound blocks cell proliferation, inhibits contraction, and retards the formation of granulation tissue.
Systemic Factors• Circulatory statusCardiovascular status, by determining the blood supply to the injured area, is important forwound healing. Poor healing attributed to old age is often due, largely, to impaired circulation.• Infection Systemic infections delay wound healing. • Metabolic statusPoorly controlled diabetes mellitus is associated with delayed wound healing due to increase the risk of infection. In diabetic patients, there can be impaired circulation secondary to arteriosclerosis and impaired sensation due to diabetic neuropathy. The impaired sensation renders the lower extremity blind to every day hazards. Hence, in diabetic patients, wounds heal the very slowly.
• Nutritional deficiencies Protein deficiencyIn protein depletion there is an impairment of granulation tissue and collagen formation, resulting in a great delay in wound healing. Vitamine deficiencyVitamin C is required for collagen synthesis and secretion. It is required in hydroxylation of proline and lysine in the process of collagen synthesis. Vitamin C deficiency (scurvy) results in grossly deficient wound healing, with a lack of vascular proliferation and collagen deposition. Trace element deficiencyZinc (a co-factor of several enzymes) deficiency will retard healing by preventing cellproliferation. Zinc is necessary in several DNA and RNA polymerases and transferases; hence, a deficiency state will inhibit mitosis. Proliferation of fibroblasts (fibroplasia) is, therefore, retarded. • HormonesCorticosteroids impair wound healing, an effect attributed to an inhibition of collagensynthesis. However, these hormones have many other effects, including anti-inflammatory actions and a general depression of protein synthesis. It also inhibits fibroplasia and neovascularization. Both epithelialization and contraction are impaired. It is, therefore, difficult to attribute their inhibition of wound healing to any one specific mechanism.
Thyroid hormones, androgens, estrogens and growth hormone also influence woundhealing. This effect, however, may be more due to their regulation of general metabolic status rather than to a specific modification of the healing process. • Anti-inflammatory drugsAnti-inflammatory medications do not interfere with wound healing when administered at the usual daily dosages. Asprin and indomethalin both inhibit prostaglandin synthesis and thus delay healing.
VII. Complications of Wound HealingAbnormalities in any of the three basic healing processes – contraction, repair, andregeneration – result in the complications of wound healing.
b. Ulceration: Wounds ulcerate because of an inadequate intrinsic blood supply or insufficientvascularization during healing. For example, leg wounds in persons with varicose veins or severe atherosclerosis typically ulcerate. Non healing wounds also develop in areas devoid of sensation because of persistent trauma. Such trophic or neuropathic ulcers are occasionally seen in patients with leprosy, diabetic peripheral neuropathy and in tertiary syphilis from spinal involvement (in tabes dorsalis). 3. Excessive Scar FormationAn excessive deposition of extracellular matrix at the wound site results in a hypertrophic scar or a keloid (See Figure 4-5 and 4-6). The rate of collagen synthesis, the ratio of type III to type I collagen, and the number of reducible cross-links remain high, a situation that indicates a “maturation arrest”, or block, in the healing process.
KeloidKeloid nodular masses of of hyperplastic scar tissue, occur when the wound healing process runs unchecked. They are more commonly in people of African descent. surgical excision leads to repeated keloid formation.
Implantation (or epidermoid cyst: Epithelial cells which flow into the healing wound may later sometimes persist, and proliferate to form an epidermoid cyst.
VIII. Fracture HealingThe basic processes involved in the healing of bone fractures bear many resemblances to those seen in skin wound healing. Unlike healing of a skin wound, however, the defect caused by a fracture is repaired not by a fibrous “scar” tissue, but by specialized bone forming tissue so that, under favorable circumstances, the bone is restored nearly to normal.
Stages in Fracture Healing (Bone Regeneration)Stage 4: Formation of granulation tissue. Following this phase of demolition, there is an ingrowth of capillary loops and mesenchymal cells derived from the periosteumand the endosteum of the cancellous bone. These cells have osteogenic potentialand together with the newly formed blood vessels contribute to the granulation –tissue formation. Stage 5: Woven bone and cartilage formation. The mesenchymal “osteoblasts” next differentiate to form either woven bone or cartilage. The term “callus”, derivedfrom the Latin and meaning hard, is often used to describe the material uniting thefracture ends regardless of its consistency. When this is granulation tissue, the“callus” is soft, but as bone or cartilage formation occurs, it becomes hard.
Stage 6: Formation of lamellar bone. The dead calcified cartilage or woven bone is next invaded by capillaries headed by osteoclasts. As the initial scaffolding(“provisional callus”) is removed, osteoblasts lay down osteoid, which calcifies toform bone. Its collagen bundles are now arranged in orderly lamellar fashion, forthe most part concentrically around the blood vessels, and in this way theHaversian systems are formed. Adjacent to the periosteum and endosteum thelamellae are parallel to the surface as in the normal bone. This phase of formationof definitive lamellar bone merges with the last stage. Stage 7: Remodelling. The final remodeling process involving the continued osteoclastic removal and osteoblastic laying down of bone results in the formation of a bone, which differs remarkably little from the original tissue. The external callus is slowly removed, the intermediate callus becomes converted into compact bonecontaining Haversian systems, while the internal callus is hollowed out into amarrow cavity in which only a few spicules of cancellous bone remain.