2.7 about 32 minDeep Learning viewL2 p.47–52

Regeneration and repair

Damaged tissue is restored in one of two ways: surviving cells divide and rebuild the original (regeneration), or new vessels and fibroblasts fill the gap with collagen (repair by scar). Which one happens depends on whether the cells can divide and whether the framework survived.

Regeneration or scar: cells and scaffold

L2 p.47

Regeneration needs two things: cells that can still divide, and an intact extracellular-matrix scaffold (basement membranes and stroma) to guide them back into the original architecture.

Cells by their capacity to divideL2 p.47

  • Labile

    Behaviour
    Divide continuously from stem cells
    Examples (lecture examples in bold)
    Basal layer of the epidermis (skin cut), gut epithelium, hematopoietic cells (anemia), lining epithelia

  • Stable

    Behaviour
    Quiescent, but divide when stimulated
    Examples (lecture examples in bold)
    Hepatocytes, renal tubular cells, type II pneumocytes (lung injury), fibroblasts, endothelium, smooth muscle

  • Permanent

    Behaviour
    Cannot divide meaningfully after birth
    Examples (lecture examples in bold)
    Neurons, cardiac myocytes (scar after myocardial infarction); skeletal muscle has only limited satellite-cell repair

The scaffold decides as much as the cell. After acetaminophen injury, hepatocytes die but the reticulin framework survives, so the liver regenerates its lobules perfectly. In a liver abscess, the framework is destroyed with the cells, so the same stable hepatocytes cannot rebuild the architecture and the defect heals by scar. Repeated injury with framework loss produces cirrhosis: regenerating nodules separated by scar. The lecture's rule follows: repair by connective tissue occurs when injury is severe or persistent, or when the cells are permanent.

The wound-healing sequence

L2 p.47–50Ch. II cases p.5, 16

Healing a skin wound runs through overlapping phases. The timing below is for a clean, sutured incision; larger wounds follow the same order more slowly.

Teaching schematic

Wound-healing timeline01 d3 d5 d2 wk1 mo3 moHemostasisInflammationProliferation (granulation tissue)Remodelingtype III collagentype I collagenstrength → ~80%~10% at 1 week
Overlapping phases of wound healing, the switch from type III to type I collagen, and the slow return of tensile strength.L2 p.47–50Ref. · Robbins, cutaneous wound healing

What a biopsy would show, day by dayRef. · Robbins

  • Minutes–hours

    Phase
    Hemostasis
    What is happening
    Platelets and fibrin plug the gap; platelets release PDGF and TGF-β; the clot is a provisional matrix

  • 24 h

    Phase
    Inflammation
    What is happening
    Neutrophils at the margins; basal epidermal cells start to migrate and divide (re-epithelialization begins)

  • Days 2–3

    Phase
    Inflammation → proliferation
    What is happening
    Macrophages replace neutrophils, clear fibrin and debris, and release growth factors; granulation tissue begins

  • Day 5

    Phase
    Proliferation
    What is happening
    Granulation tissue fills the incision; neovascularization peaks; type III collagen; epidermis restored to normal thickness

  • Week 2

    Phase
    Proliferation
    What is happening
    Collagen accumulates, fibroblasts proliferate; fewer leukocytes, less edema, fewer vessels (blanching)

  • Month 1 onward

    Phase
    Remodeling
    What is happening
    Cellular scar of collagen; type III replaced by type I; cross-linking by lysyl oxidase; collagenases (MMPs) reshape it; contraction by myofibroblasts

Re-epithelialization. Epidermal cells at the wound edge (and from surviving hair follicles) lose their attachments, migrate across the provisional matrix under the scab, and proliferate under EGF, TGF-α and KGF until the layers meet; then they stratify. In a sutured wound this happens within 24–48 hours.

Strength. When skin sutures are removed at about a week, the wound has roughly 10% of normal strength. Strength rises quickly over the next two months as collagen is made and cross-linked, plateaus at about 70–80% by three months, and never fully returns.

Granulation tissue and angiogenesis

L2 p.47–49

Granulation tissue is the initial phase of repair and the precursor of scar. To the eye it is soft, pink and granular, and bleeds easily; each “granule” is a loop of new capillary. Under the microscope it has three components: new, leaky blood vessels, activated fibroblasts and myofibroblasts, and macrophages (with some other inflammatory cells), in an edematous matrix containing type III collagen.

Lecture image

Loose tissue with many small new capillaries, plump fibroblasts and scattered inflammatory cells
Granulation tissue: many small, thin-walled new capillaries, plump fibroblasts and scattered inflammatory cells in loose, edematous matrix.L2 p.49
  1. Vasodilation (nitric oxide) and increased permeability (VEGF).
  2. Pericytes separate, and matrix metalloproteinases break down the basement membrane.
  3. Endothelial cells migrate toward the wound and proliferate behind the leading tip cell.
  4. The sprouts form tubes and connect into loops.
  5. Pericytes and smooth-muscle cells are recruited and the new vessels stabilize; until then they leak, which is why granulation tissue is edematous.
L2 p.48Ref. · Robbins, angiogenesis

Case image

Leg ulcer whose base is red, moist and granular (arrow)
A diabetic leg ulcer whose base (arrow) is granulation tissue: red, moist and granular (Simulation Q15).Midterm sim. p.6

Growth factors that drive repair

L2 p.48

The lecture's five factorsL2 p.48

  • VEGF

    Main sources
    Macrophages, many cells under hypoxia (HIF-1α)
    Main actions
    Angiogenesis: endothelial migration and proliferation; vascular permeability

  • FGF (FGF-2)

    Main sources
    Macrophages, endothelium, mast cells
    Main actions
    Angiogenesis; fibroblast proliferation; epithelial migration

  • PDGF

    Main sources
    Platelets, macrophages, endothelium
    Main actions
    Migration and proliferation of fibroblasts and smooth-muscle cells; attracts monocytes

  • EGF (and TGF-α)

    Main sources
    Platelets, macrophages, saliva, keratinocytes
    Main actions
    Keratinocyte migration and proliferation (re-epithelialization); fibroblast proliferation

  • TGF-β

    Main sources
    Platelets, macrophages, many cells
    Main actions
    The main fibrogenic factor: fibroblast migration and proliferation, more collagen and fibronectin, less matrix breakdown (MMPs ↓, TIMPs ↑); also anti-inflammatory

Healing by primary, secondary and tertiary intention

L2 p.50

Teaching schematic

  1. Primary intention

    Clean incision
    Sutured
    Fine scar

  2. Secondary intention

    Gaping wound
    Granulation fills it
    Contracted, larger scar

  3. Tertiary intention

    Contaminated wound
    Cleaned first
    Closed late
The same skin, three ways to close it. The size of the gap decides how much granulation tissue, contraction and scar is needed.L2 p.50

Three ways to close a woundL2 p.50

  • Primary

    What is done
    Edges approximated by suture
    When
    Clean surgical incisions
    Result
    Little granulation tissue; thin, fine scar

  • Secondary

    What is done
    Wound left open to fill from the base and close by re-epithelialization
    When
    Large or highly contaminated wounds, ulcers, drained abscesses
    Result
    Abundant granulation tissue, marked contraction by myofibroblasts, larger scar

  • Tertiary (delayed primary)

    What is done
    Repeated débridement and antibiotics for several days, then surgical closure
    When
    Contaminated wounds that need cleaning first
    Result
    Closure once infection is controlled; scar intermediate

Core activity · One Fact Changes

One Fact Changes

Answer a case and name the decisive clue. Then exactly one fact changes. Decide whether the answer moves, and why.

1 · The original case

A 25-year-old cook cuts the back of his hand on a clean knife. The edges are sutured the same day. He returns on day 5. A tiny biopsy is taken from the wound.

What dominates the wound now?

Which fact decided it?

What slows healing

L2 p.51

Collagen is made in steps, and several nutrients and drugs act at specific steps. That is why the lecture's list of factors that impair healing reads like a map of collagen synthesis.

Teaching schematic

  1. Pro-α chains made on rough ER (Gly-X-Y repeats)Impaired by Protein malnutrition
  2. Hydroxylation of proline and lysineImpaired by Vitamin C deficiency; hypoxia
  3. Triple helix (procollagen) secretedImpaired by Glucocorticoids ↓ synthesis
  4. Ends cleaved → tropocollagen → fibrils
  5. Cross-linking by lysyl oxidaseImpaired by Copper deficiency
  6. Remodeling by collagenases (MMPs); type III → type IImpaired by Zinc deficiency
Collagen synthesis and remodeling, with the step each deficiency or drug affects.L2 p.51

Factors that impair wound healingL2 p.51

  • Persistent infection

    Mechanism
    The single most important local factor: prolongs inflammation and tissue destruction

  • Diabetes mellitus

    Mechanism
    Microangiopathy (poor perfusion), impaired neutrophil function, glycation of matrix, neuropathy and repeated trauma

  • Poor perfusion

    Mechanism
    Atherosclerosis or venous stasis: too little oxygen and nutrients for fibroblasts (oxygen is needed for prolyl and lysyl hydroxylation)

  • Vitamin C deficiency

    Mechanism
    Prolyl and lysyl hydroxylases need ascorbate; unhydroxylated procollagen cannot form a stable triple helix (scurvy)

  • Copper deficiency

    Mechanism
    Lysyl oxidase, a copper enzyme, cross-links collagen; weak cross-linking, weak scar

  • Zinc deficiency

    Mechanism
    Cofactor of collagenases (matrix metalloproteinases) that remodel matrix, and of enzymes for DNA synthesis and cell proliferation

  • Glucocorticoids

    Mechanism
    Suppress inflammation and TGF-β, reduce collagen synthesis: weaker scar, lower tensile strength

  • Others

    Mechanism
    Mechanical stress on the wound, foreign bodies, malnutrition (protein), large wound size

Hypertrophic scars, keloids and contractures

L2 p.52Ch. II cases p.17, 19

Repair can overshoot. Too much collagen gives a raised scar; too much contraction gives a contracture.

Hypertrophic scar versus keloid

Hypertrophic scar

  • Raised, red, stays within the original wound
  • Develops within weeks; often over joints or after burns
  • Collagen bundles parallel to the epidermis, nodules with myofibroblasts
  • Frequently regresses spontaneously

Keloid

  • Raised, grows beyond the borders of the wound
  • Genetic predisposition: more common with darker skin; earlobes, chest, shoulders
  • Thick, glassy, haphazard bundles of type I and III collagen
  • Persists; recurs after excision; refractory to treatment
L2 p.52

Lecture image

Raised linear scar on a forearm that stays within the line of the original wound
Hypertrophic scar: raised but confined to the line of the original wound.L2 p.52

Lecture image

Two large, smooth, dark nodules on an earlobe
Keloids of the earlobe: nodules that have grown far beyond the original piercing.L2 p.52

Both are driven by excess TGF-β signalling and fibroblast activity, and an imbalance between collagen synthesis and breakdown.

Myofibroblasts are fibroblasts that express α-smooth-muscle actin. They appear in granulation tissue and pull the wound edges together, which is helpful in secondary intention. When contraction is excessive, especially after burns over joints, palms, soles or the front of the chest, the scar shortens and fixes the joint: a contracture.

Core activity · Almost Twins

Almost Twins

Two look-alikes side by side. Decide what they share, then pick the clue that separates them and say why it works.

Look-alike A

Hypertrophic scar

Lecture image

Raised linear scar on a forearm that stays within the line of the original wound
Forearm scar (lecture image).
  • Raised, firm scar
  • Stays within the borders of the original wound
  • Often regresses over months
  • Collagen bundles parallel to the epidermis

Step 1 · What they share

What do the two scars share?

Select every feature that both show.

Granuloma versus granulation tissue

L2 p.42, 47–49

The words look alike and both appear in inflamed tissue, but they are different structures with different purposes. A granuloma is a defence: macrophages walling off something they cannot destroy. Granulation tissue is repair: vessels and fibroblasts filling a gap.

Make it unmistakableL2 p.42–44, 47–48

  • Purpose

    Granuloma
    Contain a persistent agent
    Granulation tissue
    Fill a defect and build a scar

  • Key cells

    Granuloma
    Epithelioid macrophages, giant cells, lymphocyte cuff
    Granulation tissue
    New capillaries, fibroblasts and myofibroblasts, macrophages

  • Shape

    Granuloma
    Compact, round nodule
    Granulation tissue
    Diffuse layer filling a wound bed

  • Driven by

    Granuloma
    IL-12 → Th1 → IFN-γ; TNF
    Granulation tissue
    VEGF, FGF, PDGF, TGF-β

  • Matrix

    Granuloma
    Little; fibrous rim when old
    Granulation tissue
    Edematous, type III collagen

  • Gross look

    Granuloma
    Pale, white nodule
    Granulation tissue
    Red, moist, granular, bleeds easily

  • Examples

    Granuloma
    TB, sarcoidosis, Crohn disease, foreign body
    Granulation tissue
    Healing wound or ulcer, organizing infarct, abscess wall

  • Becomes

    Granuloma
    Fibrosis and calcification, or reactivation
    Granulation tissue
    Scar (type I collagen)

Core activity · Almost Twins

Almost Twins

Two look-alikes side by side. Decide what they share, then pick the clue that separates them and say why it works.

Look-alike A

Granuloma

Lecture image

Tight nodule of pale epithelioid macrophages without central necrosis, ringed by lymphocytes
Lymph node in sarcoidosis (lecture image).
  • Contains macrophages
  • Compact nodule of epithelioid macrophages, giant cells, lymphocyte cuff
  • Driven by IL-12 → Th1 → IFN-γ; TNF holds it together
  • Purpose: contain an agent that cannot be destroyed

Step 1 · What they share

What do these two share?

Select every feature that both show.

Knowledge check · 2.7

Answer, read why, and try again whenever you like. Answers are kept in both study modes.

0 of 7 correct
  1. Q1Day 5: granulation tissueL2 p.47–48Ch. II cases p.5

    A 36-year-old man was cut on the lower leg by a machine at work 5 days ago. He cleaned and bandaged the shallow 5-cm laceration, which now shows slight redness, minimal swelling and no drainage.

    Which finding is most likely on pathologic examination of the wound?

  2. Q2Granulation tissue: angiogenesis + type III collagenL2 p.47–48Ch. II cases p.16

    A 3-year-old boy is seen 5 days after a forehead laceration. The linear wound is well approximated, clean and dry, with a small amount of pink granulation tissue.

    Microscopic examination of the wound would most likely show:

  3. Q3Granulation tissue cellsL2 p.47, 49Midterm sim. p.5–6

    A 70-year-old woman with diabetes develops an ulcer on her right leg. The ulcer bed (arrow) is covered with granulation tissue.

    Case image

    Leg ulcer whose base is red, moist and granular (arrow)

    Which are the principal cellular components in the bed of this wound?

  4. Q4Zinc and wound healingL2 p.51Ch. II cases p.10

    A 38-year-old man has two months of hair loss, a rash and a metallic taste. He has Crohn disease treated with several small-bowel resections and no regular care. There is a red rash around his mouth, excoriated erythema around the anus and buttocks, and patchy scalp alopecia.

    He is deficient in which element, which would also impair his wound healing?

  5. Q5Hypertrophic scar: TGF-βL2 p.48, 52Ch. II cases p.17

    Six months after a lower-segment cesarean section, a 26-year-old woman has a linear, red, raised suprapubic scar confined within the original wound margins. Biopsy shows dense collagen fibres arranged parallel to the epidermis.

    Increased production of which mediator is most likely responsible?

  6. Q6Contracture: myofibroblastsL2 p.47Ch. II cases p.19

    A 30-year-old man is seen a month after a chemical burn over the back of his right hand and forearm. The hand is hyperextended at the wrist; the skin over the dorsum is tense, with a thick, epithelialized scar, and wrist motion is restricted.

    The contracture is most likely due to the activity of which cells?

  7. Q7Granulation tissue vs granuloma: image recognitionL2 p.47–49

    A biopsy is taken from the base of a skin ulcer that has been healing for two weeks.

    Lecture image

    Loose tissue with many small new capillaries, plump fibroblasts and scattered inflammatory cells

    What is this tissue?

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