Definition of healing: complex physiological tissue repair mechanism.

Cause: skin injury.

Objective: reconstitution of the extracellular matrix (ECM) components, restoration of the structures and functional capacities of the dermis and epidermis.

Process: succession of dynamic phases, including:

  • Haemostasis and the formation of a fibrin-platelet clot,
  • Inflammatory response,
  • Formation of granulation tissue, which serves as filling tissue, with angiogenesis, mobilisation of dermal fibroblasts and neo-synthesis of a new extracellular matrix,
  • Re-epithelialisation
  • And, finally, tissue remodelling

 

The different healing stages :

The inflammatory phase

This starts immediately and lasts from a few hours to a few days: the clot formed after rupture of the blood vessels covers the wound and forms a provisional extracellular matrix composed of fibrin and fibronectin. This serves as a guide for cell migration.

The platelets secrete and trigger mediators to recruit inflammatory cells (polynuclear neutrophils and macrophages), fibroblasts and endothelial cells. At the end of the inflammatory phase, bleeding is controlled and the wound bed is clean.

 

To find out more:

Following a skin injury, the fibrin-platelet clot acts as a reservoir for cytokines and growth factors produced by coagulation processes, bruised cells and platelets in order to locally trigger the inflammatory response. Polynuclear neutrophils are very quickly attracted to the site due to the chemotactic signal emitted by the cytokines released at the site of the injury.

They penetrate the tissues by leukocyte extravasation and phagocytose bacterial intruders having penetrated the wound. The tissues bruised as a result of the injury are composed of cell fragments, along with the fibrillar and filling components making up the Extracellular Matrix (ECM): Collagen, elastin, gelatin, fibronectin, proteoglycans, etc.

It is also during the course of the inflammatory response that the body physiologically eliminates tissue fragments from the damaged matrix before reforming a new matrix during the granulation phase. Matrix Metalloproteinases (MMPs) are a family of Zinc-dependent endopeptidases capable of breaking down the extracellular matrix by enzymatic hydrolysis of its protein components [1].

It is mainly polynuclear neutrophils that synthesise MMPs, as a result of their cleaning role. These MMPs are: neutrophil collagenases (MMP1 and MMP8), gelatinases (MMP2 and MMP9), or stromelysin, also known as MMP3 (presenting a specificity for GlucoAminoGlycans or GAG) [2]. In order to protect healthy tissues from excessive proteinase activity, a physiological feedback mechanism prevents excessively prolonged release of MMPs into the matrix. This feedback mechanism works due to the synthesis of proteinase inhibitors or TIMPs (Tissue Inhibitors of Metalloproteinases).

 

The granulation phase


 This can start rapidly, with the proliferation of endothelial cells and fibroblasts to achieve the formation of new blood vessels and the synthesis of a new extracellular matrix. The fibroblasts then acquire the morphology and biochemical characteristics of smooth muscle cells, to become myofibroblasts. This essential differentiation phenomenon occurs under the effect of cytokines and growth factors released during the previous phase.

Myofibroblasts are the main cells responsible for the synthesis of the extracellular matrix and contribute to the reorganisation of this matrix, along with wound contraction. The extracellular matrix plays an important regulating role since some factors can be stored in it in latent form, these then being activated when released.

To find out more :

During the granulation phase, the initiation of tissue reconstruction involves the mobilisation and multiplication of dermal cells – fibroblasts – and the induction of marked activity to synthesise the components of a new extracellular matrix.

This phase is triggered very early on, from the platelet adhesion/aggregation phases, with the release of growth factors such as: PDGF (Platelet Derived Growth Factor), EGF (Epidermal Growth Factor) and TGF-ß (Transforming Growth Factor –ß), which are responsible for initiating fibroblastic stimulation. Subsequently, during the acute inflammation phase, immunocompetent cells – polymorphonuclears cells – take over, to in turn synthesise TGFß, EGF and bFGF (basic Fibroblast Growth Factor).

These growth factors continue to stimulate fibroblast and epithelial cell migration and their multiplication. The cellularity within the granulation tissue increases, this process being accompanied by concomitant neosynthesis of extracellular matrix proteins and neocapillaries.

 

The re-epithelialisation phase


It is this phase that closes the wound. It happens as a result of the migration of epithelial cells from the wound margins and epidermal appendages.

Differentiation of keratinocytes then leads to restoration of the epidermis’ barrier function.




To find out more:

Epithelialisation is the last stage in the healing process, leading to wound closure. Keratinocytes from the basal layer of the epidermis divide and migrate in a centripetal manner from the epidermal appendages or wound margins towards the centre of the wound. Certain factors, such as the regularity of the wound surface or the presence of fibronectin or proteins responsible for cell adhesion, play a key role in this stage of migration due to contiguity of the keratinocytes. Once the integrity of the dermis has been restored, the process continues with differentiation of keratinocytes, leading to the reformation of a stratified, functioning epidermis.

 

The last phase: Remodelling


 This phase lasts several months and leads to the scar itself. It starts early on, during the formation of granulation tissue, with the gradual reorganisation of the matrix under the influence of myofibroblasts: these cells contract the microfilament bundles linked to the extracellular matrix, inducing compaction of the collagen network and contraction of the wound.

Two new components are then secreted to increase the density of the matrix and stabilise it. The proportion of the different types of collagen is modified: the proportion of type I collagen increases, whereas that for type III collagen decreases (from 30% to 10%). The cell’s myofibroblast density decreases due to apoptosis, making way for fibroblasts, which will synthesize a better-quality extracellular matrix, more resistant to mechanical forces.

To find out more :

Once the skin defect has been completely reconstructed, with the completion of dermis and epidermis formation, the scar remodelling phase follows. This phase leads to restoration of the pre-existing cell and fibre architecture, with their specific location ensuring optimization of the functional capacities required for the tissue’s new integrity.



Healing time and consequences

The time required for the complete healing of wounds is extremely variable depending on the studies.

However, it has been observed that for certain wounds, this time is abnormally prolonged, despite well-managed, correctly followed etiological treatment. In the most critical cases, complete healing may never be achieved.

These risk factors affecting healing are not insignificant risk factors for an unfavourable course of the wound, particularly in terms of the development of infection. They also have a negative impact on the quality of life of patients and are a source of colossal healthcare spending for the community as a whole.

Factors affecting healing

A certain number of local and systemic factors have gradually been identified, making it possible to predict which wounds and which patients are predisposed to this problem.

A number of risk factors have been identified. Of course, the more risk factors, the greater the risk