Wound healing and immunomodulation peptide

Wound Healing

Wound Healing is most commonly by primary and secondary intention. It involves hemostasis, inflammation, proliferation and remodelling.

5 Key Points on Wound Healing

• Wound Healing can be via primary, secondary or tertiary intention
• Phases of wound healing are hemostasis, inflammation, proliferation and remodelling.
• Macrophages, neutrophils and fibroblasts play integral roles in activating pathways, reducing bacterial burden, and promoting collagen formation, respectively.
• Re-epithelialisation occurs in wounds with an intact epidermal basement membrane via mobilisation, migration, mitosis and differentiation.
• Contraction occurs in wounds after 3 days and is caused by myofibroblasts.
• There are genetic conditions, acquired systemic issues and local factors that all influence wound healing.

Types of Wound Healing

There are 3 ways a wound can heal:

1. Primary closure: most common
2. Secondary intention: open wound that granulates, contracts, epithelialises
3. Tertiary Intention:delayed primary (a wound that is closed at a later date)

Here is an in-depth video tutorial.

Phases of Wound Healing

There are 4 phases to wound healing: haemostasis, inflammation, proliferation and remodelling. These stages are the same for both primary and secondary intention healing.

1. Haemostasis

This occurs acutely and is initiated once a wound has been created.

The key aspects of this include:

• Vasoconstriction from thromboxane & prostaglandins release.
• Activating platelet-activating factor, von Willebrand, & thromboxane A2.
• Platelet plug formation secondary to platelet activation
• Thrombus formation is secondary to fibrinogen converted to fibrin. This can weakly hold the wound together.

At a cellular level, macrophages release inflammatory cytokines and engage in phagocytosis, and neutrophils infiltrate the wound.

2. Inflammation

This occurs within the first 72 hours of the initial activation of the wound healing pathway.

The key aspects of this include:

• Cell proliferationis secondary to the release of platelet-derived growth factors and pro-inflammatory factors (serotonin, bradykinin, histamine).
• Vasodilation as endothelial cells swells and polymorphonuclear neutrophils travel into the tissue.
• Cellular immunity and antibody productionfrom T-lymphocytes entering the wound (influence by interleukin-1) and secreting cytokines.

At a cellular level, macrophagesbecome the dominant cell within 48 hours of the injury until fibroblast proliferation. The final cell line is lymphocytes.

3. Proliferation

This occurs after ~72 hours and is usually complete within 2-4 weeks.

The key aspects of this include:

• Matrix formationfrom fibroblasts& glycosaminoglycan production.
• Collagen & elastin productionis secondary to fibroblasts (mainly type III). This can hold the wound together quite strongly.
• Wound contraction as fibroblasts differentiates into myofibroblasts.
• Angiogenesis secondary to endothelial stem cell migration. This is assisted by macrophages stimulating nearby vascular endothelium of adjacent capillaries.

Glycosaminoglycans production includes hyaluronic acid, chondroitin-4 sulfate, dermatan sulfate and heparin sulfate.

4. Remodelling

This occurs after 2-4 weeks from injury and can last >1 year. This phase of wound healing is responsible for the tensile strength of a wound.

The key aspects of this include:

• Collagen Haemostasis:no increase in collagen production
• Collagen replacement: type III collagen is replaced by type I (stronger).
• Collagen re-organisation: becomes organised with stronger cross-links.
• Apoptosis removes the capillary network and creates a pale-looking scar.

Tensile strength increases at ~day 5 & is 80% pre-injury at ~60 days.

The type of cell involved in wound healing changes over time. The first cells are predominantly neutrophils. After 48 hours, macrophages become dominant during the inflammatory phase. Fibroblasts and myofibroblasts play an important role in proliferation and remodelling.

Re-epithelialisation in Wound Healing

This is the process of re-establishing epithelial continuity through 4 phases: mobilisation, migration, mitosis, and differentiation.

Re-epithelialisation occurs after the basement membrane of the epidermis has been breached. It occurs from the edges of the wound and epidermal appendages.

The 4 phases of re-epithelialisation are as follows:

1. Mobilisation: epithelial cells lose contact with neighbours (contact inhibition) to become flat and long and form pseudopodia.
2. Migration:epithelial cells attempt to overcome contact inhibition by moving centrally.
3. Mitosis: epithelial cells proliferate once, desmosomes and hemidesmosomes attach to the basement membrane and form a stratum germinativum.
4. Differentiation: cells differentiate to recreate normal stratified squamous epithelium.

If the basement membrane is intact then the epithelial cells are replaced by upward migration of keratinocytes.

Contraction in Wound Healing

Contraction occurs in the granulating wound when myofibroblasts contract the wound bed.

Contraction is a normal phenomenon in a granulating wound bed due to myofibroblasts. Here are some key points on myofibroblasts

• First appear ~72 hours after injury and peak at 2-3 weeks.
• Contain contractile microfilaments and distinct cellular adhesions (desmosomes and maculae adherens)
• Disappear when contraction is complete

Tip: There is less contraction when there is more dermis.

Wound Healing Factors

Wound healing is influenced by medical conditions, systemic factors and local factors.

Medical conditions

The following medical conditions negatively influence the ability of a wound to heal:

1. Pseudoxanthoma elasticum: increased collagen degradation giving a pebble-skin appearance.
2. Epidermolysis Bullosa:skin is very delicate
3. Ehler's Danlos Syndrome: abnormal collage structure
4. Cutis Laxa: mutated elastic fibres presenting in newborns as excessive laxity.
5. Werner Syndrome:mutated WRN gene presenting similarly to scleroderma.
6. Progeria: mutated LMNA gene creating an appearance of "premature ageing".

Clinical Gem: blistering after minor trauma in patients with epidermolysis bullosa is called Nikolsky Sign.

Systemic Factors

The following systemic factors play an important role in wound healing.

1. Age: as you age so too does your ability for cell re-growth and tensile strength.
2. Smoking:nicotine induces vasoconstriction, carbon monoxide decreases oxygen-carry capacity, and hydrogen cyanide impairs oxygen transport
3. Comorbidities: for example diabetes.
4. Nutrition: vitamin A (retinol) and C are required for collagen cross-linking and synthesis, respectively. Vitamin E stabilises the membrane. Low albumin is a predictor of poor wound healing.
5. Medication: steroids inhibit epithelialisation & decrease collagen production.

Local Wound Factors

Local wound issues are usually the most common reason for delayed wound healing. It can relate to:

1. Infection: reduces oxygen tension, pH, epithelialisation and angiogenesis, whilst increasing collagenase activity and inflammation
2. Radiation: occludes small vessels, and damages fibroblasts and nuclei.
3. Temperature: warm and moist increase epithelialisation and tensile strength.
4. Oxygen delivery: microvascular disease results in reduced tissue perfusion.

In a chronic wound, the wound is slow to heal due to excessive metalloproteases which promote matrix turnover.

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