Wound Healing

Steps of Tissue Repair

Wound healing is divided into four overlapping states: 1) homeostasis, 2) inflammatory, 3) proliferative, and 4) remodeling.

Learning Objectives

Describe the overlapping phases of tissue repair

Key Takeaways

Key Points

  • Wound healing is the process whereby the skin repairs itself after injury.
  • Wound healing can be divided into four overlapping processes; maintenance of homoeostasis, an inflammatory response, a proliferative phase, and remodeling.
  • Maintenance of homoeostasis is achieved by clotting in any damaged regions of the circulatory system.
  • The inflammatory response clears the wound site of debris and prevents infection.
  • During the proliferative phase new tissue and an extra cellular matrix to support tissue repair are laid down.
  • During the remodelling stage, the rapidly laid down tissue is altered to more closely mimic surrounding, mature tissues.
  • The wound healing process can be interrupted, leading to the formation of chronic wounds or the development of fibrosis.

Key Terms

  • fibrin: A fibrous protein involved in blood clotting.
  • fibronectin: An extra cellular matrix protein, often laid down as a component of the temporary granulation tissue seen in wound healing.
  • Granulation: The temporary connective tissue laid down during wound healing to facilitate wound closure.

Wound Healing 

Wound healing is the process by which the skin, or any injured organ, repairs itself after injury. The main aim of wound healing is to prevent or limit further damage, to clean and seal the wound against infection, to restore tissue strength, and, if possible, tissue function. 

Wounds in the skin can either be classed as epidermal (shallow, in which the dermis remains intact) or deep (in which the dermis is damaged; this is sometimes referred to as a full thickness wound).

Phases of the Wound Healing Process

The wound healing process can be characterized by four overlapping phases:

  1. An initial response to maintain homoeostasis.
  2. An inflammatory response to prevent infection.
  3. A proliferative phase to reconstitute the wound site.
  4. A remodelling phase where tissue strength and function are restored.
This is an image of a graph showing the length of time for various responses to occur during an inflammatory infection. Limits vary within faded intervals, mainly by wound size and healing conditions. The image does not include major impairments that cause chronic wounds.

Critical developments that occur during a localized inflammatory response: The phases of wound healing during an inflammatory response to infection. Limits vary within faded intervals, mainly by wound size and healing conditions. The image does not include major impairments that cause chronic wounds.

Homoeostasis

Upon wounding, the first phase of the wound response is concerned with maintaining homoeostasis within the body. Most wounds, even superficial shallow wounds, result in damage to the circulatory system. To prevent blood loss and reduce the chance of infection spreading throughout the body, circulation platelets within the blood begin to form a fibrin clot, which seals the wound site. 

Additionally, vasoconstriction initially occurs around the wound site as a means of isolating the wound site. However, this is soon followed by vasodilation so the required cells are able to be recruited to the wound site. Factors are released from damaged cells, and those around the wound site initiate the inflammatory response. This phase is very quick. 

Inflammatory

Immune cells, such as neutrophils and macrophages, are attracted by factors released from the wound site and begin to accumulate, travelling through the circulatory system. These cells are responsible for the removal of debris and killing of bacteria that easily colonize the wound site, and prepare the wound for the proliferative/remodelling phase.

Proliferative

The proliferative phase can itself be divided into four phases; in the case of shallow wounds the first two steps may not occur:

  • Re-vascularisation: New blood vessels are formed around the wound site in order to supply the cells and nutrients required to remodel the wound.
  • Granulation: Fibroblasts attracted to the wound site quickly lay down a temporary extra cellular matrix, comprised of collagen and fibronectin, upon which the epidermis can be reconstituted.
  • Re-epithelialization: The exact mechanism of re-epithelialization is poorly understood. It is thought that surviving epithelial cells around the wound edge become more motile and stretch to cover the wound site. Once a continuous epidermis is formed they lose this motility and begin to divide.
  • Contraction: Re-epithelization is thought to occur simultaneously with contraction, where myo-fibroblasts recruited around the wound site pull against each other to contract the size of the wound.

Remodeling

Following closure of the wound, remodeling can occur. The epidermis proliferates and returns to its normal character; fibroblasts and immune cells which were recruited to the site are degraded; and the temporary extra cellular matrix that was laid down is remodelled into a stronger, more permanent structure.

Issues with Wound Healing

The above mechanism describes a best-case scenario that results in the restoration of a fully functional dermis and epidermis. However, as the main aim of the wound healing process in the initial stage is to prevent further damage or infection, the intial stages can lead to a less than optimum result, as evidenced by the formation of scars. The larger and more severe the wound the more likely this is to occur.

The response to wounding is also susceptible to disruptions that can lead to the formation of chronic, non-resolving wounds such as ulcers; or the development of fibrosis if the proliferative phase does not resolve.

Epidermal Wound Healing

Epidermal wound healing describes the mechanism by which the skin repairs itself after injury.

Learning Objectives

Characterize epidermal wound healing

Key Takeaways

Key Points

  • Epidermal wounds are typically less severe than those affecting the dermis.
  • Clotting may not occur if there is no breaching of the vasculature; however, an immune response is still generated as the wound site is susceptible to infection.
  • Proliferation is not required as the dermis remains intact and is able to independently re-constitute the basement membrane required for re-epithelialization.
  • Keratinocytes surrounding the wound site, and epidermal cells found in dermal appendages (such as hair follicles ), are able to re-epithelialize the wound site.
  • Little remodeling will occur as the original, mature extracellular matrix remains intact.
  • Epidermal wounds often resolve quickly and have fewer potential issues than deeper wounds.

Epidermal wound healing refers to the repair of the epidermis in response to wounding. Epidermal only wounds are typically less severe than those affecting the dermis and so stages of the wound healing response may be missed.

As the epidermis is itself not vascularised—it is receiving blood from the dermis—a clotting and vasoconstrictive response is often not necessary. Immune cells may still be recruited to the wound site because the removal of the epidermal barrier makes the wound susceptible to infection.

Since the dermis is intact, local fibroblasts are able to contribute to the formation of a new basement membrane, upon which the epidermis sits. In very minor wounds even the basement membrane might remain intact, allowing for rapid re-epithelialization. 

Keratinocytes—epidermal epithelial cells—around the wound site migrate across the wound and close it. Additionally, epidermal cells from dermal appendages, such as hair follicles, can contribute to wound closure.

Since the dermis and underlying tissue have not been damaged very little remodelling is required. As such, small wounds only in the epidermis typically heal rapidly and are often not observable (e.g., via the formation of scar tissue) within a period of months.

Deep Wound Healing

A deep wound involves the inner, deeper layers of the skin (dermis).

Learning Objectives

Describe the process of deep wound healing

Key Takeaways

Key Points

  • Deep wounds are more difficult to heal, as the basement membrane and/or skin appendages ( hair follicles and sweat and oil glands) may be destroyed.
  • The healing of deep wounds may occur only at the edges of the wound, with scar tissue covering the center of the wound site.
  • Loss of physiological function is often associated with deep wounds as they do not heal correctly.
  • After healing, the tissue underlying a deep wound may be weaker than the surrounding mature tissue, making repeat injury more likely.

Key Terms

  • basement membrane: Controls the traffic of cells and molecules between the dermis and epidermis, and provides support to epidermal cells.
  • skin appendage: Skin-associated structures that serve a particular function, including sensation, contractility, lubrication, and heat loss.

Deep wounds that damage the dermis, or even the underlying muscle and fat, are more difficult to heal than shallow, epidermal-only wounds. The wound healing processes may be extended and scar tissue is likely to form due to improper re-epithelialization. 

Additionally, deep wounds are more susceptible to infection, and also to the development of systemic infection through the circulatory system, as well as   dysregulation that results in chronic wounds such as ulcers.

This image illustrates the inflammation response phase of wound healing over time. Time limits vary within faded intervals, mainly by wound size and healing conditions. The image does not include major impairments that cause chronic wounds.

Wound healing phases: This image illustrates the phases of wound healing. Limits vary within faded intervals, mainly by wound size and healing conditions, but the image does not include major impairments that cause chronic wounds.

The wound healing process for deep wounds is similar to that of shallow wounds. However, with the removal of the dermis and its associated skin appendages, re-epithelialization can only occur from the wound edge, with no contribution from the dermal compartment. 

Therefore, proper reconstitution of the epidermis is often only seen at the edge of the wound, with fibrous scar tissue—formed from the extracellular matrix (ECM) deposited during the proliferative phase—covering the rest of the wound site.

With the formation of a scar, the original physiological properties of the tissue are lost. For example scars are less flexible than skin, and do not feature sweat glands or hair follicles.

The ECM formed during wound healing may also be weaker in deep wounds, making the site susceptible to additional later wounding. The provisional ECM laid down during the proliferative phase is rich in fibronectin and collagen III that combine to allow quicker cell movement through the wound, which is very important during wound healing. 

However, the ECM of mature skin is rich in collagen I. In large, deep wounds the remodelling of a fibronectin and collagen III-rich ECM to a collagen-I rich ECM may not occur, leading to a weakening of the tissue.