Wound healing may be best understood as an organism’s global response to injury.
Wound healing represents the response of an organism to a physical disruption of a tissue/organ to re-establish homeostasis of that tissue/organ and stabilize the entire organism’s physiology.
Essentially two processes (for re-establishment of homeostasis)-
- Substitution of a different cellular matrix as a patch to immediately re-establish both a physical and physiologic continuity to the injured organ. This is the process of scar formation.
- Recapitulation of the developmental processes that initially created the injured organ. By reactivating developmental pathways, the architecture of the original organ is re-created. This is the process of
Balance between- Scarring ↔Tissue regeneration
Different tissue shows different proportion of these two process. One more than the other.
Eg. Nerve tissue – Scarring >>>Tissue regeneration
Liver and bone- Scarring <<<Tissue regeneration
Healing is different in different species- eg. Limb amputation in newts results in limb regeneration, whereas in humans, only scarring can occur.
Undesirable or dysfunctional response to injury in a tissue or organ system can occur due to any of the two processes.
It is important to establish which process is responsible for the undesirable effect and which portion of the wound is showing that effect.
Acute wound- wound that is present for less than 3-4weeks
Chronic wound- wound that persists beyond 4-6 weeks. (These wounds also called as non-healing, delayed healing, recalcitrant).
Phases of wound healing-
Three distinct but overlapping phases-
- Inflammatory phase (0-4 days)
- Proliferative phase (4-21 days)
- Remodeling phase (21days – years)
Primary purpose- to remove devitalized tissue and prevent invasive infection.
- Attainment of hemostasis
- Removal of devitalized tissues
- Prevention of colonization and invasive infection by microbial pathogens
Attainment of hemostasis-
Coagulation cascade activated- ultimately leading to formation of fibrin mesh (fibrinogen –> fibrin –> fibrin mesh). This fibrin mesh is called the provisional matrix.
Formation of platelet plug- during formation of formation of platelet plug, platelets also degranulate releasing growth factors – PDGF, TGF-β.
Other two functions are done by neutrophils and macrophages.
Inflammatory cells are attracted by-
Activation of the complement cascade
TGF-β released by degranulating platelets
Bacterial degradation products such as lipopolysaccharide.
These are the first inflammatory cells to be recruited.
Prominent type for first 2 days.
- Remove dead tissue by phagocytosis
- Prevent infection by oxygen-dependent and oxygen-independent killing mechanisms.
- Release a variety of proteases to degrade remaining ECM (to prepare the wound for healing)
Neutrophils play a role in decreasing infection but, their absence does not appear to prevent the overall progress of wound healing.
Instead, there prolonged presence has been proposed to be a primary factor in the conversion of acute wounds into non-healing chronic wounds.
- Follows after neutrophils. Appear 48 to 72 hours post-injury.
- MCP-1 attracts these monocyte/macrophage to the site of injury.
- By day 3, they are the predominant cell type.
- Macrophages phagocytize debris and bacteria.
- Produces growth factors necessary for the production of the ECM by fibroblasts and the production of new blood vessels in the healing wound.
- Unlike the neutrophil, the absence of monocyte/macrophages has severe consequences for healing wounds.
Last cell to enter the wound. [Last- Lymphocytes]
Enters between days 5 and 7 post-wounding. Its role in wound healing is not well defined.
Occur from days 4 to 21 following injury.
Re-epithelialization probably begin almost immediately following injury.
Injury –> Regression of the desmosomal connections between keratinocytes and basement membrane –> formation of actin filaments in the cytoplasm of keratinocytes –> keratinocytes actively migrate into the wound –> Keratinocytes proceed between the desiccated eschar and the provisional fibrin matrix beneath (this movement is via interactions with ECM proteins (such as fibronectin, vitronectin, and type I collagen) via specific integrin mediators)
Provisional fibrin matrix is gradually replaced by granulation tissue.
Granulation tissue is largely composed of three cell types- [EFM-G]
- Endothelial cells
Granulation tissue begins to appear by about day 4 post-injury.
Fibroblasts are the workhorses during this time –> they produce the ECM that fills the healing scar and provides a scaffold for keratinocyte migration.
Macrophages produces –> PDGF and TGF-β1 –> stimulates fibroblast –> they proliferate, migrate and produces ECM. PDGF and TGF-β1 –> Stimulates endothelial cells –> produces new blood vessels.
Provisional matrix is replaced by type 3 collagen during proliferative phase.
Type 3 collagen will then be replaced by type 1 collagen during remodeling phase.
Endothelial cells- produce new blood vessels.
Hypoxia –> induces hypoxia inducible factor-1 (HIF-1) –> ↑ Proangiogenic factors released by macrophage (VEGF, FGF-2, angiopoietin 1, and thrombospondin.) –> angioneogenesis.
Remodeling phase –
Longest phase of wound healing
Day 21 – 1 year (years)
Begins with the programmed regression of blood vessels and granulation tissue.
Two process that define remodeling phase are – Wound contraction & Collagen remodeling.
Wound contraction occurs by – myofibroblast.
Myofibroblasts are – fibroblasts with intracellular actin microfilaments capable of force generation and matrix contraction.
Myofibroblasts contract the wound through specific integrin-mediated cell-matrix interactions with the dermal environment.
Collagen remodeling – replacement of type III by type I
Collagen remodeling is a slow remodeling phase which is largely mediated by a class of enzymes known as – matrix metalloproteinases
At 3 weeks wound strength is – 20% [wound strength – 21% @ 21 DAY]
Finally, wound strength is around – 70%- 80% @ 1 year.
- Inadequate regeneration –
- CNS injury
- Bone non-union
- Corneal ulcer
- Inadequate scar formation –
- Diabetic foot ulcer
- Pressure sore
- Venous stasis ulcer
- Excessive regeneration –
- Excessive scar –
- Hypertrophic scar
Are less common – <6% of population
Have genetic component
Overgrowth of dense fibrous tissue beyond the borders of the original wound
Large thick collagen fibers composed of numerous fibrils closely packed together
Hypertrophic scars are also characterized by the formation of dense collagen fibers following injury but, in contrast to keloids, do not extend beyond the original wound margins.
Etiology and pathophysiology – unknown
Treatment Modalities –
- Steroid injections,
- Pressure therapy with silicone sheeting, and
- External beam irradiation
Recurrence rates – 75%.