Repair and Healing

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Repair and Healing

• March 6, 2009
• Eileen McKay, MD

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Objectives

• List the two types of tissue repair.
• Review the stages of the cell cycle.
• Define and list examples of labile, stable and
  permanent cells.
• Describe fibrosis.
• Describe granulation tissue.
• Discuss the two types of biological wound
  closure.
• List the systemic factors that affect wound
  healing.
• List local factors that affect wound healing.
• List potential complications of wounds.

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Repair

• REGENERATION
• Restoration of normal tissue
• Requires intact connective tissue scaffold
• Compensatory growth (liver and kidney) versus
  regeneration (epithelium and bone marrow)

• HEALING with tissue reconstitution and scar
  formation
• Occurs when extracellular matrix is also injured
• Permanent tissues can only heal not regenerate
  (myocardium)
• Involves deposition of extracellular matrix

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Cell Cycle
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Tissue Types

• Labile continually dividing cells including
  skin gastrointestinal epithelium, and uterine
  lining
• Stable quiescent cells capable of undergoing
  rapid division with proper stimulation including
  liver, kidney, pancreas, and mesenchyme
  (connective tissues)
• Permanent non-dividing cells including neurons,
  skeletal and cardiac muscle
• Stem cells asymmetric replication with new stem
  cell and differentiated cell line such as bone
  marrow

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Stem Cells

• Embryonic
• Derived from blastocysts
• Pluripotent
• Limited availability

• Adult
• Present in otherwise mature tissues
• May be lineage specific or have restricted
  differentiation options
• Increased accessability

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Growth Factors

• Polypeptides
• Transcription activators
• Coordinate resting/silent genes
• Regulate cell entry in to cell cycle
• Regulate progression through cell cycle

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Growth Factors

• EGF and TGF-a
• Bind to common receptor (EGFR) and stimulate
  proliferation/mitosis of epithelial cells.
• HGF/SF
• Stimulates mitosis. Acts as a morphogen causing
  cell migration. Required for survival in
  embryonic development.
• VEGF
• Induces angiogenesis.
• PDGF
• Stored in platelet granules but also produced in
  other cell types. Stimulates proliferation and
  migration of fibroblasts, smooth muscles cells
  and monocytes.
• FGF
• Multiple functions including angiogenesis, wound
  repair, development and hematopoiesis.
• TGF-ß
• A pleiotropic agent with multiplicity of effects
  which are in opposition. Inhibits growth of
  epithelium and leukocytes by increasing cell
  cycle inhibitors. Promotes fibrosis in chronic
  inflammatory conditions.

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Cell Signaling Patterns

• Autocrine ligand is secreted and detected by
  same cell
• Paracrine ligand is secreted and separately
  detected by neighboring cells
• Endocrine ligands (usually hormones) are
  secreted into the vasculature to affect distant
  target cells

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Cell Signaling Pathways
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Extracellular Matrix

• Sequesters water to provide turgor and minerals
  to tissues.
• Reservoir for growth factors and stable
  mesenchymal cells.
• Provides base for cell-cell interactions, cell
  migration/proliferation/adherence.

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Regeneration

• Complete restitution of tissue following injury
  as occurs in bone fracture, partial hepatectomy,
  or reepithelialization of cutaneous wounds.
• Requires an intact connective tissue scaffold.
• Tissues incapable of regeneration undergo scar
  formation (ie myocardial infarction).

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Sequential Processes in Healing

• Induction of an inflammatory process in response
  to the initial injury, with removal of damaged
  and dead tissue
• Proliferation and migration of parenchymal and
  connective tissue cells
• Formation of new blood vessels (angiogenesis) and
  granulation tissue
• Synthesis of ECM proteins and collagen deposition
  
• Tissue remodeling
• Wound contraction
• Acquisition of wound strength
• Adapted from Robbins p. 107

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Biological Wound Healing

• Primary
• Wound edges in close proximity allowing for
  reepithelialization.

• Secondary
• Wound edges are less regular and widely separated
  requiring deposition/filling-in of tissue.
• Associated with increased inflammation and
  increased amounts of granulation tissue.
• Requires subsequent contraction.

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Cutaneous Wound Healing
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Granulation Tissue

• Vascular proliferation
• Edema
• Fibroblast proliferation
• Variable inflammation

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Fibrosis

• Cutaneous scar represents localized fibrosis.
• Fibrosis, in general, refers to any fibroblast
  proliferation with deposition of excess
  extracellular matrix which is mostly collagen.
• Leads to functional loss.

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Complications of Wounds

• Deficient scar formation wound dehiscence/
  ulceration
• Excess repair keloid formation, stoma
  granulation tissue
• Excess contraction joint contractures/
  intra-abdominal adhesions

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Keloid
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Factors Affecting Repair Healing

• Local Factors
• Impaired vascular supply
• Foreign bodies
• Infection

• Systemic Factors
• Anemia
• Malnutrition
• Disease (diabetes)
• Genetic disorders (ie. defective collagen)