INTRODUCTION TO HEALTH AND DISEASE BLOCK. The Process of Healing in Health and Disease

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1 INTRODUCTION TO HEALTH AND DISEASE BLOCK The Process of Healing in Health and Disease MBBS 1 st Yr. Lecture Dr. U.S. Khoo December 11, :30 am Pathology Lecture Theatre Objectives: To understand the healing process in the context of repair and regeneration in various tissues To identify the factors which promote or adversely affect healing. To recognize the complications that could occur during healing, and the consequences of such. Introduction Healing means the body's replacement of damaged tissue by living tissue and involves the processes of repair and regeneration. Repair is the replacement of lost tissue by granulation tissue which matures to form scar (fibrous) tissue. This is inevitable when the tissue damage is extensive or when surrounding specialised cells do not possess the capacity to proliferate e.g. muscle and neurons. Regeneration is the process whereby lost tissue is replaced by tissue similar in type. There is a proliferation of surrounding undamaged specialised cells. Dependent on the inherent regenerative capacities, somatic cells of the human body can be divided into three types: (a) Labile cells which continue to multiply throughout life, and include epidermis, alimentary, respiratory and urinary tract epithelium and haemopoietic bone marrow. (b) Stable cells such as the liver, pancreas and other endocrine organs, which normally cease multiplication when growth ceases but retain mitotic ability during adult life so that some regeneration of damaged tissues may occur. Figure 1 - Three type of somatic cells (c) Permanent cells lose their capacity to proliferate in infancy, e.g. nerve cells and cardiac muscle. 1

2 The mechanism of wound healing Wound healing is extremely complex. It involves a number of well-orchestrated processes, including - regeneration of parenchymal cells, - migration and proliferation of parenchymal and connective tissue cells, - synthesis of extracellular matrix proteins, - remodeling of connective tissue and parenchymal components, - collagenization and aquisition of wound strength. The mechanisms underlying these events are not fully understood. However, three important processes are involved:- 1. Growth factors Many growth factors (including cytokines) are involved in chronic inflammation. They have effects on angiogenesis, chemotaxis, mitogenesis and collagen synthesis, e.g. - Fibroblast growth factor. - Vascular endothelial growth factor - Interleukin-1 - Epidermal growth factor 2. Cell-cell and cell-matrix interaction When certain normal cell lines are placed in culture, they proliferate, eventually to form a confluent monolayer of cells, after which proliferation ceases. This density dependent regulation of cell growth is important in wound healing as most cells capable of regenerating in response to injury usually cease proliferating after the defect caused by the injury has healed. 3. Extracellular matrix synthesis and collagenization The development of wound strength is related to the proliferation of fibroblasts and the laying down of collagen and other extracellular elements in healing wound. Factors influencing wound healing 1. Local factors adversely affecting healing (i) Type of wounding agent; blunt, crushing, tearing etc. (ii) Infection (iii) Foreign bodies in wound (iv) Poor blood supply (v) Excessive movement (vi) Poor apposition of margins, e.g. large haematoma formation (vii) Poor wound contraction due to tissue tethering, e.g. skin over tibia (viii) Infiltration by tumour (ix) Previous irradiation 2. General factors adversely affecting healing (i) Poor nutrition - impair collagen formation Deficiency of protein, Vitamin C and Zinc (ii) Excessive glucocorticosteroid production or administration (iii) Systemic diseases - Diabetes mellitus, renal failure, tumur cachexia, etc, 2

and exudate. (ii) Clotted blood and fibrin with dehydation forming a scab (iii) Acute inflammation during the first 24 hours.

3 Healing of skin wounds 1. Healing by primary intention - a clean wound or incision with a minimum of space between the margins Figure 2 Healing by primary intention Stages in healing by primary intention (i) Escape of blood and exudate. (ii) Clotted blood and fibrin with dehydation forming a scab (iii) Acute inflammation during the first 24 hours. (iv) Proliferation and migration of basal epithelial cells of the epidermis which undermine the superficial blood clot. This regeneration is usually complete 24 to 36 hours after injury. (v) Granulation tissue formation - Migration and proliferation of fibroblasts and endothelial cells (organisation) is seen between 48 and 72 hours. (vi) Appearance of thin branching bundles of collagen fibrils coated with ground substance (reticulin fibres) 4 to 5 days after injury. (vii) Progressive increase in mature collagen fibres during the second week forming a scar during the second week. (viii) Loss of vascularity and shrinkage of the scar. 2. Healing by secondary intention - an open or excised wound with separated edges. Secondary intention wound healing differs from primary intention in: 1. Greater tissue loss 2. More inflammatory exudate and necrotic material to remove 3. More granulation tissue therefore a bigger scar and more deformity 4. Wound contraction necessary role of myofibroblasts 5. Slower process 6. Increased liability to infection Figure 3 Healing by secondary intention 3

Complications during wound healing 1. Infection: Infection delays healing, and if severe stops it completely. Tissue destruction due to infection is common.

4 Complications during wound healing 1. Infection: Infection delays healing, and if severe stops it completely. Tissue destruction due to infection is common. Thus a simple incision, if infected, will need to heal by secondary intention. 2. Wound dehiscence: This is particularly important after laparotomy. The mortality of a burst abdomen is high. 3. Implantation: Epithelial cells which flow into the healing wound may proliferate to form an epidermoid cyst. 4. Excessive tissue formation: (a) Excessive granulation tissue formation (b) Keloid formation due to excessive formation of collagenous tissue. This results in a raised area of scar tissue. 5. Pigmentary changes: Healed chronic ulcers sometimes have a rusty colour due to deposition of haemosiderin. 6. Painful scars: A traumatic neuroma is formed when axonal sprouts of a transected peripheral nerve grow hapharzardly into scar tissue resulting in a painful swelling. 7. Weak scars: If scar tissue is subjected to continuous strain, stretching may result. An incisional hernia develops in this way. 8. Cicatrisation: This is a late reduction in the size of the scar and frequently produces great deformity, e.g. in extensive burning of the skin and in hollow viscera such as the urethra, oesophagus, and intestine leading to progressive stenosis with stricture formation. 9. Neoplasia: Very rarely squamous cell carcinoma develops in scars. Healing in Specific Tissues The main determinants of the final outcome of any wound are - the type and extent of injury, - the regenerative capacity of the constituent cells, - the extent of damage to the extracellular matrix framework. A combination of these factors dictates whether there is complete regeneration with restoration of normal function or fibrosis leading to diminished functional capacity. The general principles of wound healing apply to all tissues. Each organ, however contains specialised cells and distinctive extra-cellular matrices, and these differences impart some organ specificity to the healing response. Figure 4 - Consequences of liver injury depending on extent of tissue damage 4

5 Healing of epithelial ulceration The epithelium of internal organ (e.g. duodenum) can be ulcerated in many disease process. The mechanism of healing is similar to skin wound healing. Regeneration normally occurs. If the ulceration is extensive, there may be difficulty in restoring the normal architecture (e.g. loss of villi) and scar tissue may be formed. Healing of bone fractures Primary union of a fracture (with formation of minimal amount of callus) is exceptional, healing by the proliferation of callus being the rule. For descriptive purposes it is convenient to divide the healing process into separate stages but it must be remembered that the entire area will not all be at the same stage of healing at the same time. Stage I: Haematoma formation Stage II: Traumatic inflammation. The tissue damage excites an inflammatory response which differs in no way from those seen in other inflamed tissues. Stage III: Demolition. Any fragments of bone which have become detached from their blood supply undergo necrosis, and are removed by macrophages and osteoclasts. Stage IV: Granulation tissue formation. Ingrowth of capillary loops and mesenchymal cells derived from the periosteum of cancellous bone. The integrity of the periosteum is of great importance as the cells of its deeper layer also have osteogenic potentiality. Stage V: Callus formation. The mesenchymal osteoblasts or chondroblast next differentiate to form either new woven bone or cartilagenous tissue which unite the fracture ends. Cartilage formation occurs in fractures in which there is movement. Cartilage thus formed eventually undergoes calcification and the cartilage cells die. Stage VI: Formation of lamellar bone. The dead calcified cartilage distintegrates and is invaded by blood vessels and osteoblasts, whereas the woven bone is removed by osteoclasts. As the provisional callus is removed, osteoblasts further lay down osteoid which to form lamellar bone. Its collagen bundles are now arranged in orderly lamellar fashion and the Haversian Systems are found. Stage VII: Remodelling. This involves the continued osteoclastic removal and osteoblastic laying down of bone which differs little from the original tissue. 5

$Figure 5 Healing of a bone fracture Complications of fracture healing 1. Delayed union 2. Mal-union (i) Angulation (ii) Shortening 3.$

6 Figure 5 Healing of a bone fracture Complications of fracture healing 1. Delayed union 2. Mal-union (i) Angulation (ii) Shortening 3. Fibrous union resulting from (i) Excessive movement which may lead to the development of a false joint (pseudoarthrosis) (ii) Infection which may also give rise to osteomyelitis (iii) Ischaemia 4. Non-union if soft-tissues such as muscle or fat are interposed between the severed ends Repair of cartilage, tendon and muscle Regeneration in cartilage (such as articular cartilage) is generally poor and repair occurs by the growth of fibrous tissue. Regeneration in tendon is good, though the process is slow. Smooth muscle has limited regenerative capacity whilst cardiac muscle shows no regenerative capacity. Skeletal muscle appears to have greater regenerative capacity as shown by the formation of multinucleated sprouts from surviving ends of injured fibres. Repair of nervous tissue and nerves Repair in the central nervous system follows the same general pattern as that seen in other parts of the body. The macrophages present are derived both from microglia and blood monocytes. Instead of fibrous tissue, glial tissue is formed by astrocytes. 6

7 In contrast, peripheral nerves have considerable regenerative capacity. When a nerve is transected, there is total degeneration of the axon and secondary breakdown of the myelin sheath distal to the cut (Wallerian degeneration). If the site of injury is sufficiently distal, the nerve cell body, after having undergone transient swelling and breakdown of endoplasmic reticulum, is able to recover to support regeneration of the damaged axon. Schwann cells proliferate within the nerve sheath to form pathways along which the axons may regrow. Axonal sprouts soon emerge from the proximal ends of the interrupted axis cylinders and may grow into the distal part of the nerve. Figure 6 Response to axonal injury If the injury is proximal or involves the nerve cell body, irreversible nerve cell death may occur. If the lesion transects the nerve, many axonal sprouts may not reach the distal stump, with the formation of a traumatic neuroma. When axonal degeneration occurs due to diseases other than trauma, the term axonal neuropathy or axonopathy are used. Giant axonal swelling is seen specifically in nerve toxicity related to n-hexane, acrylamide and carbon disulphide exposure. The degenerating axons are markedly swollen, with accumulation of neurofilaments in the axoplasm. Secondary degeneration of the myelin sheath follows. These abnormalities usually start at the most distant part of the axon, extending back to the cell body, a process called retrograde degeneration or dying back neuropathy. Subsequent regeneration will thus depend on the extent of damage incurred. References: Chapter 3. Repair, Regeneration and Fibrosis. In: Pathology. Emanuel Rubin, John Farber.Philadelphia, Lippincott Company,

CHAPTER 3 HEALING. Healing 48 Wound Healing Healing Fibrosis 52 Healing Special Situations 53 60

CHAPTER 3 HEALING. Healing 48 Wound Healing Healing Fibrosis 52 Healing Special Situations 53 60 CHAPTER 3 Healing 48 Wound Healing 49 51 Healing Fibrosis 52 Healing Special Situations 53 60 Healing is the final stage of the response of tissue to injury. DAMAGE INFLAMMATION REMOVAL of DEAD TISSUE