Path 6: Healing and Repair

HEALING AND REPAIR IN PATHOLOGY

COURSE DETAILS

  • Course: Healing and Repair (LGT)

  • Year: 1

  • FFP1

  • Institution: Royal College of Surgeons in Ireland (RCSI)

  • Lecturer: Professor Muna Sabah

  • Date: 16th October 2025

  • Email: pathteachcoord@rcsi.ie

LEARNING OUTCOMES

  • List the types of cells according to their proliferative activity.

  • Define regeneration and repair.

  • Describe the phases of wound healing.

  • Define healing by primary intention.

  • Define healing by secondary intention.

  • Outline examples of healing in various tissues.

  • List the pathological aspects of good and poor wound healing.

  • List the local and systemic factors that impair wound healing.

HEALING

  • Definition: Replacement of destroyed or lost tissue by a viable tissue.

  • Source: RCSI

TISSUE RESPONSE TO INJURY

  • Initial Response:

    • The initial response of a damaged tissue is acute inflammation.

  • Processes Involved:

    • Resolution

    • Regeneration

    • Repair by fibrosis

RESOLUTION

  • Characteristics:

    • No tissue destruction occurs.

    • Damaging agent and cell debris are removed.

    • Tissue returns to its pre-injury state.

  • Example: Mild heat injury.

REGENERATION AND REPAIR

  • Regeneration:

    • Replacement of the lost tissue by a tissue of the same type.

  • Repair:

    • Replacement of the destroyed tissue by a fibrous scar.

FACTORS AFFECTING THE HEALING PROCESS

  • Key Factors:

    • The ability to remove the causative agent.

    • The ability to clear inflammatory debris.

    • The degree of architectural damage.

    • The ability of cells to proliferate.

    • The extent of extracellular matrix damage.

TISSUE PROLIFERATIVE ACTIVITY

  • Categories of Cells:

    • Labile Cells:

    • Continuously dividing cells (e.g., epidermis, mucosal epithelium, GI tract epithelium).

    • Cells derived from stem cells.

    • Injury to such tissue can easily heal by regeneration if the supporting stroma is intact.

    • Stable Cells:

    • Normally low level of replication (e.g., hepatocytes, renal tubular epithelium, pancreatic acini).

    • Cells can be stimulated to divide; healing occurs by regeneration if the supporting stroma and the regenerative stem cells are intact.

    • Permanent Cells:

    • Non-dividing cells (e.g., neurons, cardiac myocytes, skeletal muscle).

    • Cannot regenerate; replaced by connective tissue.

CELL CYCLE

  • Phases of the Cell Cycle:

    • G1 (Gap 1)

    • S (Synthesis of DNA)

    • G2 (Gap 2)

    • M (Mitosis)

    • G0 (Resting phase)

  • Source: RCSI

POLYPEPTIDE GROWTH FACTORS

  • Role:

    • Most important mediators affecting cell growth.

    • Present in serum or produced locally.

    • Exert pleiotropic effects: proliferation, cell migration, differentiation, and tissue remodeling.

  • Mechanism:

    • Regulate growth of cells by controlling the expression of genes that regulate cell proliferation.

STROMA

  • Definition:

    • The extracellular matrix, including:

    • Interstitial matrix

    • Basement membranes

    • Mesenchymal cells

    • Blood vessels

  • Source: RCSI

EXTRACELLULAR MATRIX (ECM)

  • Function:

    • Not just a scaffold for cell growth but also regulates cell growth, motility, and differentiation.

  • Composition:

    • Fibrous structural proteins (collagens, elastin)

    • Adhesive glycoproteins linking ECM components to one another and to cells

    • Proteoglycans

CELL-CELL INTERACTIONS

  • Growth Factors:

    • EGF (Epidermal Growth Factor)

    • PDGF (Platelet-Derived Growth Factor)

    • FGF (Fibroblast Growth Factor)

    • VEGF (Vascular Endothelial Growth Factor)

    • TGF-β (Transforming Growth Factor Beta)

  • Cytokines and Growth Inhibitors involved in cell communication.

  • Source: RCSI

CELL-MATRIX INTERACTIONS

  • Integrins:

    • Cell surface receptors that mediate cellular attachment to the extracellular matrix.

    • They transduce signals from the ECM to cells.

REGENERATION

  • Definition:

    • Replacement of lost cells by cells of the same type through cell division.

  • Requirements:

    • The supporting framework must be intact.

    • The tissue is returned to its pre-injury state.

  • Regulatory Factors:

    • Process is controlled by stimulatory and inhibitory factors and interactions between cells and the extracellular matrix.

REPAIR BY CONNECTIVE TISSUE

  • Definition:

    • Healing by fibrosis occurs when:

    • There is destruction to both parenchymal cells and the stromal framework.

    • Death of permanent cells occurs.

    • Organisation of inflammation takes place.

  • Involvement of Granulation Tissue:

    • Granulation tissue is composed of fibroblasts, capillary buds, and myofibroblasts.

    • Angiogenesis:

    • New vessels bud from old ones.

    • Fibrosis:

    • Involves emigration and proliferation of fibroblasts and deposition of ECM (type III collagen).

    • Scar Remodeling:

    • Type III collagen is replaced by type I collagen (collagenase requires zinc).

WOUND HEALING

  • Phases of Wound Healing:

    • Inflammatory Phase

    • Proliferative Phase:

    • Includes epidermal re-growth and dermal repair.

    • Remodelling Phase:

    • Restoration of elasticity.

  • Source: RCSI

INFLAMMATORY PHASE

  • Characteristics:

    • Induction of acute inflammatory response by an initial injury.

    • Haematoma formation occurs.

    • Infiltration by neutrophils.

    • Infiltration by macrophages.

PROLIFERATIVE PHASE

  • Activities:

    • Epithelial cell proliferation.

    • Formation of granulation tissue.

    • Formation of new blood vessels (angiogenesis).

    • Proliferation of fibroblasts: synthesis of ECM proteins.

REMODELLING PHASE

  • Processes:

    • Replacement of the granulation tissue by fibrous tissue.

    • Remodeling of parenchymal elements to restore tissue function.

    • Remodeling of connective tissue to achieve wound strength.

    • Degradation of excessive extracellular matrix occurs, facilitated by metalloproteinases.

TYPES OF WOUND HEALING

  • Primary Intention

  • Secondary Intention

  • Source: RCSI

STAGES OF WOUND HEALING BY PRIMARY INTENTION

  • Day 1:

    • Wound filled with blood clot.

    • Acute inflammation in the surrounding tissue.

    • Proliferation of epithelial cells.

  • Day 2:

    • Presence of macrophages.

    • Epithelial cells cover the surface.

  • Day 3:

    • Formation of granulation tissue.

  • Day 5:

    • Collagen deposition occurs.

  • Day 7:

    • Sutures are removed.

WOUND STRENGTH

  • Measurement of Strength:

    • After sutures are removed at one week, wound strength is only about 10% of unwounded skin (referred to as Walker’s Law).

    • By 3 to 4 months, wound strength increases to about 80% of unwounded skin (Walker’s Law).

WOUND HEALING BY SECONDARY INTENTION

  • Characteristics:

    • The process is similar to primary intention; however,

    • The edges are not approximated, and granulation tissue fills the gap.

    • The process is slower; the inflammatory reaction is more intense.

    • Involves wound contraction (mediated by myofibroblasts) and results in more scarring.

PATHOLOGIC ASPECTS OF WOUND HEALING

  • Deficient Scar Formation:

    • May lead to wound rupture.

  • Excessive Scar Formation:

    • Keloid formation associated with type III collagen; genetic predisposition may play a role.

  • Contracture Deformity:

    • May occur as a result of scar formation.

  • Malignant Transformation:

    • Extremely rare but noted as a possible outcome.

EXAMPLES OF HEALING IN VARIOUS TISSUES

  • Mucosal Surfaces:

    • Erosion heals by regeneration.

    • Ulceration can be healed by both regeneration and fibrosis.

  • Liver:

    • A single short-lived injury is healed by regeneration.

    • Chronic injury leads to cirrhosis.

  • Nervous System:

    • Central nervous system: gliosis occurs.

    • Peripheral nerves may undergo regeneration.

  • Muscle:

    • Cardiac muscle generally leads to fibrosis.

    • Skeletal muscle can heal via fibrosis.

FACTORS INFLUENCING HEALING

LOCAL FACTORS

  • Variables Impacting Local Healing:

    • Poor vascular supply

    • Infection

    • Presence of foreign material

    • Excessive movement at the site

    • Poor approximation of wound edges

    • Size, site, and type of injury

SYSTEMIC FACTORS

  • Overall Factors Impacting Systemic Healing:

    • Age of the patient

    • Nutrition, including critical components:

    • Proteins

    • Vitamin C (important for collagen formation)

    • Copper (cross-linking of collagen)

    • Zinc (conversion of type III collagen to type I collagen)

    • Metabolic status (e.g., Diabetes Mellitus)

    • Hormonal influences (steroids)

    • Conditions like malignancy

    • Effects of chemotherapy and radiotherapy