Wound Healing and Tissue Repair

Wound Healing and Repair

• Wound healing aims to restore tissue architecture and function after injury.
• Critical for survival, it eliminates injury-causing agents and restores tissue normalcy.
• Key terminologies include repair, healing, regeneration, restoration, and restitution.
• When tissue is damaged a wound is formed

Required Elements

• Cells are essential for tissue repair.
• Cytokines and growth factors (GF) play a crucial role.
• The extracellular matrix (ECM) provides structural support.
• A balanced interplay of cells, cytokines, growth factors, and the ECM determines the adequacy of tissue repair.
• Environmental factors and stimuli are also important, forming a triangle of influence.

Cell Development and Types

• Stem cells are categorized into labile and stable cells.
• Labile cells have high turnover and good proliferative capacity, for example tissues in the skin.
• Stable cells have a slow or limited proliferation rate which is only activated when injured.
• Permanent cells are non-proliferative or minimally proliferative, terminally differentiated and not sufficient to replace lost tissue.

Growth Factors

• Growth factors are produced temporarily as stimulus.
• They mainly include polypeptide proteins secreted by lymphocytes, macrophages, platelets, endothelial cells, keratinocytes, fibroblasts, and smooth muscle cells.
• They bind to target cell receptors at the site of damage.
• Such factors encourage growth control genes that stimulate cell proliferation, survival, migration, differentiation, and angiogenesis.

Extracellular Matrix (ECM)

• ECM is a protein meshwork surrounding cells with two basic components.
• The two components are the interstitial matrix and the basement membrane.
• It provides strength and acts as a scaffold for tissue repair, supporting cell migration and adhesion.
• It serves as a reservoir of growth factors.
• Vitamin C is essential for collagen cross-linking in the ECM.
• An intact ECM is crucial for regeneration; otherwise, healing results in scarring.

Tissue Repair Mechanisms

• Tissue repair occurs through regeneration or scar formation (fibrosis).
• Regeneration is when labile cells replace damaged cells returning the tissue to normal or near normal.
• Scar formation occurs when stable or permanent cells and large defects/contaminated wounds are treated to form fibrous tissues

Types of Healing

• Primary intention involves minor, clean cuts with closely apposed edges, leading to minimal scarring.
• Secondary intention involves large defects and left open to granulate, and re-epithelialization resulting in moderate scarring. Also required packing.
• Tertiary intention involves cleaning and debriding contaminated wounds, left open for 4-7 days, before delayed primary closure.

Stages of Wound Repair

• The healing process occurs in 3 stage.
• Inflammation, starting immediately after injury.
• Cell proliferation and matrix deposition
• Matrix remodeling

Angiogenesis

• Angiogenesis occurs from day 3 onward, involving the development of new blood vessels from existing ones at the injury site.
• Growth factors like VEGF, FGF-2, PDGF, and TGF-ß are involved.
• Inflammation causes vasodilation via nitric oxide.
• ECM enzymes enable vascular tube extension, setting the stage for ECM remodeling.
• This stage is seen as granulation tissue.

Granulation Tissue

• Pink granular tissue forms at the wound base.
• Granularity results from new vessel buds.
• New thin vessels can be fragile and lead to serum leakage causing swelling
• This can cause an oedematous loose ECM

Scar Formation

• Connective tissue is laid down on the granulation tissue.
• Myofibroblasts migrate, proliferate, and deposit ECM.
• Collagen degradation is inhibited.
• Macrophages, mast cells, and granulation tissue cells are involved.
• TGF-ß, PDGF, and FGF-2 are key growth factors, along with cytokines IL-1 and IL-13.
• Balance must be met between matrix synthesis, degradation, and remodeling.
• A balance is struck between MMPs and TIMPs

Matrix Metalloproteinases (MMPs)

• MMPs are a family of proteases with enzymatic activity that degrade collagen which otherwise has excessive amounts.
• They are zinc and calcium-dependent endopeptidases.
• Secreted by fibroblasts, macrophages, polymorphs, and synovial cells
• Tissue inhibitors of MP (TIMPs) halt collagen breakdown.
• Steroids inhibit MMPs and doxycycline (an antibiotic) lowers MMP levels in chronic wounds.

Factors Influencing Wound Healing

• Tissue and wound type
• Infection with foreign body.
• Age, with infants and the elderly facing impaired healing.
• Nutrition: collagen synthesis is vital.
• Scurvy (vitamin C deficiency) can impair proline hydroxylation, weakening collagen.
• PEM (protein-energy malnutrition) and deficiencies in iron, copper, zinc, calcium, magnesium, and manganese can hinder healing.
• Insufficient tissue vascularity, denervation, excessive steroids, and co-morbidities affect healing.

Abnormal Wound Healing Examples

• Can include secondary infection.
• Another example is excessive granulation tissue (proud flesh).
• Dehiscence/gapping: occurs post suturing due to collagen synthesis. Predisposing factors are infection, inflammation, weak abdominal muscles and obesity.
• Hypertrophic scars: excess collagen within wound boundaries.
• Keloid scars: excess collagen beyond wound edges.
• Contracture: A permanent tightening of skin that may affect the muscles and tendons underneath.
• Fibrous bands causing intestinal obstruction.

Wound Healing Summary

• Wound healing depends on wound and cell/tissue type, growth factors, ECM, and nutrition.
• Balanced interplay between elements is crucial.
• The two mechanisms of wound healing are regeneration and scar formation.
• There are three types of wound healing: primary, secondary, and tertiary intention.
• Opening wound dressing and examining for complications.