Chapter 39: Tissue and Wound Healing

1, 2, 3,

The structure of the skin

• largest organ in body

  • 1.2-2.2 square meters

  • 4-5 kilograms (9-11 pounds)

• Function

  • Serves as first line of defense; waterproof barrier

  • Minimizes excessive water loss

  • Maintains thermoregulation

  • Contains receptors for somatic sensations

  • participates in metabolism and activation vitamin D

• Two layers: epidermis and dermis

Epidermis

• Upper layer of skin 

  • Stratified squamous epithelial cells; keratinocytes

  • Meloncytes, dendritic (Langerhans) cells, tactile (Merkel) cells; sensory receptors for touch 

• Keratinization

  • Keratin is water-insoluble proteins, helps keep water in the body 

  • Keratinocytes filled with keratin; dead at surface 

Dermis

• Contains

  • Blood vessels 

  • Skin appendages

  • Sensory receptors for pain, touch, temperature 

  • Smooth and skeletal muscle cells

• Two layers 

  • Papillary layer (superficial): less cells, more matrix

  • Reticular layer (thicker and deeper): connective tissue 

Papillary layers 

• Loosely and irregularly organized connective tissue 

• Fibroblasts, macrophages, plasma cells, mast cellss, endothelial cells, adipose cells 

Reticular layer

Dense connective tissue

Dermal-epidermal junction (DEJ)

• Barrier against passage of substances into and out of body 

• Framework to restore architecture of the tissue 

Extracellular matrix (ECM)

• Ground substance 

• Tissue growth and wound healing 

• Fibrous structural proteins: collagen and elastin

• Adhesive glycoproteins

• Glycosaminoglycans (GAGs)

Cell-matrix and cell-cell interaction 

• Integrins 

  • Transmit information bidirectionally 

  • Bind extracellular substances 

  • Adhesion molecules

• Cytokines and growth factors: allow healing of the skin

Acute wound

• Wound occurs suddenly or over brief period 

• Restoration of structural and functional integrity in 4 to 6 weeks 

Chronic wound

• Occurs over long period 

• Does not heal in organized and timely manner

• Impairment of structural and function integrity 

Partial thickness wound

• Damage extends through epidermis; dermis intact 

• Reepitheliaization: Epithelial cells migrate to area and replicate by mitosis 

Full thickness wound

• Damage extends through epidermis and dermis

• Possibly extends into subcutaneous tissue, muscle, bone

• Scar formation

Wound healing phases

• Hemostasis

• Inflammation

• Proliferation/granulation 

• Remodeling/maturation 

Chemical mediators 

• neutrophils, macrophages, lymphocytes, platelets, keratinocytes, fibroblasts, endothelial cells

• Growth factor 

  • Stimulate growth, division, differentiation of other cells

  • Regulate intercellular communication 

• Cytokines  

  • Initiate healing process

  • Produce growth factors and cytokines

  • Stimulate expression of growth factors

  • Develop the ECM

  • Coordinate intercellular communication

• Nitric oxide 

  • Direct effect: bacterial killing 

  • Indirect effect: modulate cytokine and growth factor activity 

Types of Wound Healing

• Depends on:

  • Type of injury 

  • Extent of tissue loss

  • Infection, necrotic tissue, or secondary tissue breakdown

  • Type of cells involved

Primary intention (primary closure)

• Surgical closure of wound 

• Repair: formation of new ECM

• Regeneration: reepithelialization 

• Little granulation tissue: small scar formation 

Secondary intention (secondary or spontaneous closure)

• Full thickness wound heals without closure attempt 

• Large amount of granulation tissue 

• Longer healing time; larger scar

• Skin grafting; skin substitutes 

Tertiary intention (delayed primary closure)

• Combination of primary and secondary intention 

• Contaminated wound cleaned, left open drainage

• Scarring> primary intention and < secondary intention 

Hemostasis

• Goals 

  • Prevent additional tissue injury 

  • Prepare wound for healing and regeneration 

• Phases 

  • Platelet adhesion, platelet activation, platelet plus 

  • Fibrin clot formation 

  • Recruitment of phagocytic cells and wound debridement 

Inflammatory response

• Goals

  • To clean the wound 

  • Prevent additional tissue injury 

  • Prepare wound for healing and regeneration 

• Recruitment of phagocytic cells and wound debridement 

Proliferative Phase

• Goal: wound healing guided toward tissue repair 

• Steps 

  • Granulation tissue: foundation for collagen-based matrix that replaces fibrin-based provisional matrix 

  • Fibroblasts: produce collagen, adhesive proteins for ECM

  • Myofibroblasts 

  • Endothelial cells: angiogenesis (neovascularization)

  • Reepithelialization: regeneration of keratinocytes 

Remodeling Phase

• Restores structural and functional integrity of skin

• Dermal matrix not regenerated; mended

• Steps 

  • Wound contraction and closure 

  • Continuous turnover of collagen

  • Decreased capillary density 

  • Declining cellular content 

  • Mature scar tissue devoid of skin appendages

  • Maturation of scar tissue continues for minimum of one year

Factors that Impede Would Healing 

• Local 

  • Blood flow and hypoxia

  • Infection and contamination 

  • Movement/tension

  • Desiccation 

  • Excessive edema 

  • Denervation 

• Systemic

  • Advanced age

  • Malnutrtional status

  • Immune deficiency 

  • Smoking

  • Medications 

  • Metabolic status

Hypoxia

• Tissue is not receiving enough oxygen

• Delays or stops wound healing process

• leading cause of wound infection 

• inhibits fibroblast activity 

• collagen deposition in matrix

Infection and Contamination 

• Badly contaminated wound may overwhelm host defenses

• Surgical wound handling

• Contamination: Necrotic tissue, foreign or exogenous material, endogenous substances 

Nutritional Status 

• Major role in wound healing

• Essential macronutrients: carbohydrates and fats 

• Effect of negative nitrogen balance

  • Impaired immune and inflammatory responses

  • Delayed wound healing; increased wound infection 

  • Diminished angiogenesis 

• Vitamin and mineral deficiencies 

  • Associated with chronic, non-healing wounds in nutritionally debilitated individuals 

Medications

• Corticosteroids 

  • Promote breakdown of carbohydrates, fats, proteins

  • Anti-inflammatory action impedes inflammatory phase of wound healing 

  • Various negative effects 

• Antineoplastic drugs 

  • Potent immunosuppressants 

  • Impair reepithelialization, granulation tissue formation, angiogenesis

Metabolic Status

• Diabetes mellitus 

  • Insufficient insulin, insulin resistance, or both 

  • Hyperglycemia with untreated diabetes

    • Chronic macrovascular disease

    • Atherosclerosis; tissue ischemia and hypoxia

    • Thickening of basement membranes: diabetic lesions 

  • With impaired perfusion

    • Impaired granulocyte function and chemotaxis

    • Reduced ability to fight infection

  • Sensory neuropathy

    • Reduces pain sensation associated with wounds 

Abnormal Wound Healing: Excessive

Abnormally high connective tissue deposition resulting in altered tissue structure and function 

Fibrosis

• Replacement of normal tissue excessive with nonfunctional collagen or scar tissue

• Excess synthesis and/or delayed degradation

Keloids

Lesions of dermal scar or fibrotic tissue

Hypertrophic scars

• Excess fibrotic tissue 

• Raised above level of surrounding skin

• Grow within boundaries of original injury; regress spontaneously 

Contractures

• Abnormal exaggeration of wound contraction

• Shrinking scars severely deform wound; reduce mobility 

• Compromise mobility of involved joints 

Abnormal Wound Healing: Deficient 

Insufficient deposition of dermal connective tissue matrix weakens tissue to wound failure 

Wound dehiscence

• Extrafascial: partial or complete separation of outer layers of sutured wound; underlying fascial layer remains intact

• Fascial: evisceration; separation of fascial layers 

• Clinical manifestations of impending wound disruption

  • Signs of infection

  • Absence of healing ridge by 5th to 9th postoperative day 

  • Seroma or hematoma formation

  • Increase in serous discharge 

Chronic nonhealing wounds

• Do not proceed through healing process

• Progress through healing process but cannot maintain structural and functional integrity

• Arrest in inflammatory phase

• Harbor bacteria; imbalance between neutrophilic proteolytic enzymes and their inhibitors

• Increased levels of inflammatory mediators; chronic inflammation, necrosis, fibrosis