Step 1 · General Pathology

Wound Healing & Fibrosis

Name: Wound Healing & Fibrosis
Creator: Veli Bakalov, MD

Labile-stable-permanent cells, the three phases, and collagen III to I

General Pathology·Repair·4 min read·9 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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Labile cells (skin, gut, marrow) always cycle; stable cells (hepatocytes, renal tubules, endothelium) re-enter the cycle from G0; permanent cells (neurons, cardiac and skeletal muscle) heal only by scar.
Healing phases: hemostasis and inflammation (neutrophils days 1–3, macrophages days 3–5), proliferation (granulation tissue, type III collagen, angiogenesis), remodeling (type III → type I).
The macrophage is the key cell of repair; TGF-β drives fibrosis, VEGF and FGF drive angiogenesis, and PDGF recruits fibroblasts and smooth muscle.
Granulation tissue (fibroblasts, new capillaries, loose type III collagen) is pink, soft and granular: a sign of healing, not infection.
A remodeled wound regains only ~70–80% of its original tensile strength.
Collagen types: I bone, skin, tendon and scar; II cartilage; III reticulin, vessels and granulation tissue (vascular Ehlers-Danlos); IV basement membrane (Alport, Goodpasture).
Vitamin C = prolyl/lysyl hydroxylation (scurvy); copper = lysyl oxidase cross-linking (Menkes); zinc = metalloproteinase remodeling.
Keloid: excess type I and III collagen extending beyond wound borders that recurs after excision (darker skin, earlobes); a hypertrophic scar stays within borders and may regress.
Secondary intention relies on myofibroblast wound contraction and leaves more scar; dehiscence classically occurs on post-op days 5–7.

Regeneration versus scar

Proliferative capacity decides the outcome. Whether a tissue regenerates or scars depends on whether its cells can divide. Labile cells cycle continuously. Stable (quiescent) cells rest in G0 but re-enter the cell cycle when stimulated. Permanent cells never divide, so lost cells are replaced by scar.

Who regenerates

Class	Cell cycle	Examples	Repair
Labile	Always cycling	Skin, gut epithelium, bone marrow	Regenerate readily
Stable	G0; re-enter the cycle on demand	Hepatocytes, renal tubules, endothelium	Regenerate if the tissue framework survives
Permanent	Never divide	Neurons, cardiac and skeletal muscle	Heal only by scar

Because neurons and cardiac myocytes are permanent, deficits after stroke or MI are irreversible. Infarcted myocardium becomes a collagen scar, while the CNS repairs by astrocytic gliosis rather than fibrous scar.

Phases of healing

Three overlapping phases. Healing proceeds through (1) hemostasis and inflammation (immediately to ~3 days), (2) proliferation (day 3 to weeks: granulation tissue, angiogenesis, re-epithelialization) and (3) remodeling or maturation (weeks to months: collagen strengthening).

HemostasisImmediate: platelets and fibrin clot
InflammatoryNeutrophils days 1–3, macrophages days 3–5
ProliferativeFrom day 3: granulation tissue, type III collagen
RemodelingWeeks to months: type III replaced by type I; ~70–80% of original strength

Inflammatory phase. Platelets and a fibrin clot seal the wound first. Neutrophils dominate days 1–3, and macrophages arrive on days 3–5 to clear debris and secrete the growth factors that orchestrate repair. The macrophage is the key cell of healing.

Proliferative phase. From about day 3, fibroblasts deposit type III collagen, myofibroblasts contract the wound, capillaries sprout (angiogenesis) and keratinocytes re-epithelialize. The result is granulation tissue: fibroblasts, new capillaries and a loose type III collagen matrix that looks pink, soft and granular. Despite its name, it is a sign of healing, NOT infection.

Remodeling. Over weeks to months, weak type III collagen is replaced by strong type I, and zinc-dependent metalloproteinases degrade excess collagen. Even so, the wound regains only ~70–80% of its original tensile strength.

Collagen and growth factors

Collagen types. The mnemonic "Be So Totally Cool, Read Books" gives type I bone, II cartilage, III reticulin and IV basement membrane. In a wound, type III appears first and type I, which is stronger, replaces it.

Collagen types

Type	Found in	Clinical link
I	Bone, skin, tendon, mature scar (~90% of body collagen)	Defective in osteogenesis imperfecta
II	Cartilage	Also vitreous humor and nucleus pulposus
III	Reticulin, blood vessels, granulation tissue	Defective in vascular Ehlers-Danlos
IV	Basement membrane	Alport syndrome; antibody target in Goodpasture

Collagen synthesis and its cofactors. Each nutrient maps to a step:

HydroxylationProlyl and lysyl hydroxylases need vitamin C; deficiency causes scurvy
Triple helixThree hydroxylated, glycosylated α chains wind into procollagen
Propeptide cleavageOutside the cell, procollagen becomes tropocollagen
Cross-linkingLysyl oxidase needs copper; Menkes disease and copper deficiency weaken collagen
RemodelingZinc-dependent metalloproteinases (collagenases) reshape the scar

Growth factors. TGF-β is the master driver of fibrosis (fibroblast proliferation and collagen synthesis) and is also anti-inflammatory. VEGF and FGF drive angiogenesis. PDGF, released by platelets and macrophages, recruits fibroblasts and smooth muscle cells. EGF stimulates epithelial growth.

Healing by intention and abnormal scars

Primary intention. A clean wound with apposed edges, such as a sutured incision, heals quickly with minimal scar.

Secondary intention. When the edges are not apposed (a large or infected wound), granulation tissue fills the defect from the base and myofibroblasts contract the wound, leaving more scar.

Hypertrophic scar vs keloid

Feature	Hypertrophic scar	Keloid
Extent	Stays WITHIN wound borders	Extends BEYOND original borders
Collagen	Excess, parallel fibers	Excess types I and III, disorganized
Course	May regress	Does not regress; recurs after excision
Predisposition	Any wound	Genetic; darker skin; earlobes, sternum

A keloid grows "Kout" past the borders and recurs; a hypertrophic scar stays inside the lines.

Impaired healing and complications

What slows repair. Deficiency of vitamin C, copper or zinc weakens collagen at the steps above. Glucocorticoids, which blunt inflammation and collagen synthesis, and diabetes also impair healing, as do infection and poor blood supply. Typical complications:

Dehiscence: the wound bursts open, classically on post-op days 5–7, before much collagen has been laid down.
Contracture: excessive myofibroblast contraction limits motion, as after burns.
Chronic ulcers: non-healing wounds from diabetes, ischemia, venous stasis or pressure.