Healing

Healing can occur by regeneration or by repair. In regeneration, the tissue is restored completely to normal. In repair, restoration is incomplete, and scarring and fibrosis occur.

i) Regeneration: Regeneration occurs by proliferation of parenchymal cells. It depends on the mitotic ability of the injured cells. Based on their capacity to divide, cells are classified into three groups: labile, stable, and permanent.

Labile cells keep dividing throughout life. Stable cells have limited division potential and are usually in the resting (G0) phase of the cell cycle, but they can be stimulated to re-enter the cell cycle when needed. Permanent cells do not divide and have no potential to divide. As a result, once a permanent cell is injured, healing occurs by fibrosis.

ii) Repair: Repair occurs by angiogenesis, followed by fibrogenesis. In the first phase of repair, granulation tissue forms.

A blood clot forms at the site of injury. Inflammatory processes then bring cells into the injured tissue, including neutrophils, platelets, and macrophages. Endothelial cells proliferate from the margins of the wound, initiating neovascularization and angiogenesis. Angiogenesis is influenced by VEGF (vascular endothelial growth factor), PDGF (platelet-derived growth factor), TGF (transforming growth factor) beta, basic fibroblast growth factor (FGF), and integrins.

Newly formed blood vessels are leaky and are present in an amorphous matrix. The wound matrix is composed of collagen and glycoproteins such as tissue fibronectin, thrombospondin (from platelets), tenascin, proteoglycans, and elastic fibres. This matrix provides structural support and directs cell migration and attachment. Collagen provides tensile strength to the wound, while elastic fibres are responsible for wound recoil.

Fibroblasts proliferate and lay down collagen. Some fibroblasts differentiate into myofibroblasts, which have contractile ability. As the wound matures, collagen deposition increases while angiogenesis gradually stops.

In healing by second intention, myofibroblasts help the wound contract. Actin filaments in myofibroblasts are responsible for this contractility. The wound reaches about 80% of its original strength in 3 months.

Wound strength increases further through remodelling. Remodelling (wound maturation) is carried out by metalloproteinases, which convert weaker type III collagen to stronger type I collagen. Remodelling starts around the second week and may last up to a year, depending on the wound.

Factors that interfere with wound healing include infection, poor nutrition (zinc, vitamin C, protein deficiency), diabetes, glucocorticoid use, neutrophil defects, foreign bodies, and poor blood supply. Glucocorticoids interfere with collagen formation and reduce the tensile strength of the wound.

iii) Wound healing: Depending on the type of wound, healing occurs either by first intention (primary union) or by second intention (secondary union).

Primary union is seen in clean, uninfected wounds (such as surgical incisions), wounds without much tissue loss, and wounds where the edges can be easily approximated with sutures. The following steps occur in healing by first intention:

Day 1: A blood clot forms at the wound site and bridges the gap between the wound edges. It protects against infection. Neutrophils infiltrate the wound.

Day 2: Basal cells begin to proliferate from the wound margins and migrate to close the wound. By 48 hours, the wound is covered by a layer of epithelium. Macrophages reach the wound site.

Day 3: Fibroblasts migrate into the wound by day 3 and begin collagen formation. Granulation tissue formation starts.

Days 4-6: Granulation tissue becomes prominent, and collagen bridges the wound gap.

4 weeks: Scar tissue forms, with remodelling of the wound.

Secondary union is seen in wounds with a large defect, infected wounds, wounds left open without suturing, and wounds with extensive tissue loss. The following steps occur in healing by second intention:

1. A blood clot forms at the site of the wound and bridges the gap between the wound edges. It protects against infection.
2. Neutrophils infiltrate the wound, followed in 24-48 hours by macrophages.
3. Basal cells proliferate from the wound base and margins. Because the wound is larger, the new epithelial cells are not able to cover the surface fully at first.
4. Granulation tissue formation is more prominent in secondary union. It is composed of fragile blood vessels and fibrous tissue laid down by fibroblasts. It looks pink and granular and bleeds easily when touched. Over time, collagen increases and vascularity decreases. The wound becomes paler, indicating scar formation.
5. Wound contraction is seen only in second intention healing. Myofibroblasts in the granulation tissue contract and reduce the wound size to about ⅓ rd of its original size.

iv) Healing in specialized tissues: Tissue-specific characteristics are seen in wound healing.

1. CNS: Neurons in the brain, spinal cord and ganglia cannot be regenerated once destroyed. Healing occurs by proliferation of astrocytes, called gliosis (fibrosis of the brain). Microglia (macrophages of the brain) remove debris.
2. PNS: Peripheral nerves can regenerate with the help of Schwann cells. They undergo Wallerian degeneration followed by sprouting and connection of neurofibrils.
3. Muscle: Muscle has limited regenerative capacity. If the skeletal muscle sheath is intact, healing occurs by formation of endomysial tubes (e.g. Zenker’s degeneration in typhoid fever). If the skeletal muscle sheath is damaged, contractures form (e.g. Volkmann’s ischemic contracture). Smooth and cardiac muscle are replaced by fibrosis and scarring.
4. Liver: If injury is mild and cytoarchitecture is intact, complete regeneration and restoration to normal is possible. Severe or persistent injury leads to formation of irregular nodules without sinusoids or portal triads. Resulting fibrosis may lead to cirrhosis.
5. Lung: Type II pneumocytes are responsible for repair of lung tissue. They replace both type I and type II pneumocytes.