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Fact or Myth? Collagen Production is Dependent on Post Treatment Inflammation

Fact or Myth? Collagen Production is Dependent on Post Treatment Inflammation

It is commonly believed by therapists that the amount of collagen produced in the skin after a treatment like dermapen relies on the severity of the inflammation caused by, and resulting from, the treatment itself and that anything you do to minimise this inflammation will negate the results you are trying to achieve. But are the two processes really linked in this way?

Recent advances in genetic studies have shed new light on the role of inflammation in wound healing1. The traditional view that inflammation plays a key role in wound healing is being challenged by new findings, which we examine in this article.

Traditionally, wound healing has been understood to pass through three basic phases: inflammation, proliferation and maturation2.

Inflammation

The medical community agrees, almost unanimously, that the first phase of healing is inflammation, which is the body’s natural response to trauma. After the wound has been inflicted, homeostasis begins – the blood vessels constrict and seal themselves off as platelets create substances that form a clot to stop the bleeding. Once bleeding stops the blood vessels dilate again allowing nutrients, white blood cells, antibodies, enzymes and other beneficial elements into the affected area to promote good wound healing and stave off infection. This is when someone would begin to experience the effects of inflammation: swelling, pain, heat and redness.

Proliferation

In the second stage of wound healing, proliferation, the injured area starts to be rebuilt with new, healthy granulation tissue. For the granulation tissue to be formed the blood vessels must receive a sufficient supply of nutrients and oxygen. This new tissue is made up of a mixture of extracellular matrix and collagen - a tough fibre in your body that gives the skin strength and flexibility - which allows for the development of a new network of blood vessels to replace the damaged ones (a process called angiogenesis). The colour of the granulation tissue is an indicator of the health of the wound. For example, a reddish or pinkish colour generally means that it is healthy, while a darker tissue is often an indicator of infection or inadequate delivery of blood to the wound bed.

In addition to developing granulation tissues, the body transforms damaged mesenchymal cells into fibroblasts, which serve as bridges that help cells move around the affected area. If your wound is healthy, these fibroblasts begin to appear within three days of the wound and will secrete liquids and collagen. This secretion helps to strengthen the wound site. During proliferation, the wound continues to grow stronger as the fibroblasts continually reorganize aiding in the development of new tissue and accelerate the healing process.

Maturation

Maturation, also known as remodelling, is the last stage of the wound healing process. It occurs after the wound has closed and can take as long as two years to complete. During this phase, the dermal tissues are overhauled to enhance their tensile strength and non-functional fibroblasts are replaced by functional ones. Cellular activity declines with time and the number of blood vessels in the affected area start to recede and decrease.

Even after maturation these areas tend to remain up to 20 percent weaker than they initially were.

What is a scar? In simple terms, a scar is a mark left behind when an injury to the skin has healed. The collagen that your body creates in this process essentially reconnects the tissues broken apart by the injury. If the wound was deep enough to reach the mid-level dermis then the scar will be visible, either pale pink, brown, or silver depending on your skin type. Collagen secretion and maturation could also result from a more superficial injury, but in this case, it will not be visible from outside.

The deceitful nature of inflammation

The deceitful nature of inflammation in wound healing has long been recognized3, 4. While most wounds heal without difficulty, there are some instances where the body’s natural healing process is deregulated, and wounds fail to progress through the typical orderly sequence of repair in a timely fashion. Disruption of one or more of the healing stages can result in a prolonged and incomplete repair, with lack of restoration of integrity.

Non-healing wounds are a significant problem for healthcare systems all over the world. These wounds can cause significant pain and suffering, loss of independence and often interfere with a person’s quality of life. A variety of chronic wounds exist; some are associated with complications from diabetes and circulatory problems (venous and diabetic ulcers) whilst others can result from immobility, traumatic injuries like deep burns or from non-healing surgical incisions.

Often the delay in tissue repair results from a disruption in the inflammatory phase of repair mentioned above. Several factors may contribute to poor healing such as wound infection, foreign objects such as sutures, or the presence of debris and necrotic (dead) tissue. Non-healing wounds have some distinct characteristics. They frequently have a high bacterial load in combination with growth factor, plus inflammatory mediator and proteolytic enzyme imbalances that favour tissue degradation instead of repair.

Infection in the wound or the presence of foreign bodies can also result in the formation of a keloid within the scar tissue. A keloid by definition is when more scar tissue forms than is necessary to heal the wound. A keloid also stretches beyond the scars edges and is usually painful or itchy. Unfortunately, some people and certain skin types are more prone to keloids than others. Extra care must be taken to keep a wound clean and free of infection if a client has a history of keloids.

White blood cells (neutrophils) and macrophages are abundant in infected or non-healing wounds and secrete many of the bioactive substances that in high concentrations exacerbate tissue damage. Excess secretion of proteases - capable of degrading essentially all extracellular components and basement membrane proteins - can lead to substantial tissue damage.

Excess protease secretion can induce uncontrolled tissue degradation even in new granulation tissue and impact growth factors - delaying collagen deposition and impairing the repair process. These enzymes, and others in the wound, activate additional enzymes, release growth factors from the cell surface, cleave cell adhesion molecules from the plasma membrane, and convert wound cytokines - contributing to the non-healing phenotype.

The continued production of pro-inflammatory messengers further attracts and activates additional inflammatory cells, perpetuating the non-healing condition.

Necrotic tissue itself also impairs healing as it provides a rich growth environment for bacteria, increasing the chance of infection and so increasing inflammation in the wound. Endotoxins from the devitalized tissue also inhibit fibroblast and keratinocyte migration into the wound. So, for non-healing wounds the increased numbers of immune cells, their secreted bioactive substances and inflammation can inhibit repair - greatly prolonging healing time3, 4.

From this process, it is clear that inflammation is a side effect of the healing process. It has negative symptoms and signs associated with its presence (pain, redness, heat and swelling) and excessive inflammation inhibits the healing process on numerous levels. Chronic non-healing wounds all exhibit excessive inflammation, infection with biofilm formation and an abundance of necrotic material. Varying amounts of granulation tissue can be seen in a non-healing wound, unrelated to the amount of inflammation present.

Increased inflammation, therefore, does not lead to better healing.

A recent study confirmed the presence of the genes responsible for inflammation5. A significant finding in this study is that this is the same group of genes (NF-kB) that is also responsible for ageing and disease. The inflammation, disease-forming and ageing NF-kB genes are different from the genes that are activated with injury and responsible for healing1.

When an injury occurs, it is postulated that the body not only activates the healing genes, but also the NF-kB genes in the same way as it reacts to disease. This two-pronged approach is therefore aimed at healing the wound, as well as setting in motion the immune response to mobilize the HOCl-generating granulocytes to the site of injury to modulate healing and control inflammation.

Consider that it is not the inflammation that is responsible for the next steps in the healing process, but that healing can happen without inflammation being present. It stands to reason that this inflammation-free healing still leads to the formation of visible or invisible intradermal scar tissue.

HOCl inhibits inflammation and accelerates healing

In an in-vitro model, the healing genes were activated without the associated NF-kB activation. The NF-kB activation was inhibited by the addition of HOCl to the experimental model. The result being that healing happened in the same orderly fashion (only faster) and in the absence of inflammation. It was described as regenerative healing, which contrasts with reparative healing, which happens when inflammation is present.

All of this is thanks to separate genes being stimulated by the Hypochlorous Acid (HOCl) from the white blood cells during the healing response. This response is even stronger when HOCl is also applied to the wound.

In conclusion

Regenerative healing happens faster than reparative healing and without the tell-tale signs of inflammation. The formation of scar tissue due to collagen secretion was not influenced by the absence of inflammation in the model above but appeared in a more orderly fashion and at a faster rate than when in the presence of inflammation.

It is well-known that the normal healing process that is associated with inflammation can take up to 2 years to complete2. This is very much the case when skin manipulation treatments are done for aesthetic purposes. The presence of inflammation for an extended period gives a false sense of a “positive result” as the prolonged swelling that is present masks fine lines and wrinkles.

As the swelling disappears over time the lines and wrinkles will recur. Treatment with HOCl as an after-care product will therefore not only accelerate the healing process but provide for a true (swelling-free) result more rapidly.

In the presence of HOCl, healing is accelerated whilst the same amount of scar tissue is formed. The desired result (a stimulation in collagen) is still obtained, only more quickly. The amount of scar tissue is therefore dependent on the severity of the injury and not the intensity (or presence) of inflammation.

References

  1. MD Cardonaire; cDNA Microarray Study: Genes Expression Profile Analysis in a Model of In Vitro Wound Healing Research & Innovation, Padova, Italy. Jan 2009.
  2. Rajan, V et al: The duplicitous nature of inflammation in wound repair. Wound Practice and Research. Vol. 16, No. 3, August 2008.
  3. Barrick B, Campbell EJ & Owen CA. Leukocyte proteinases in wound healing: roles in physiologic and pathologic processes. Wound Repair Regen. 1999; 7(6): 410-22.
  4. Gill SE & Parks WC. Metalloproteinases and their inhibitors: regulators of wound healing. Int J Biochem Cell Biol 2008; 40(6-7): 1334-47.
  5. Research article: Leung H. et al. Topical hypochlorite ameliorates NF-kB mediated skin disease in mice. Department of Developmental Biology, Dept. of Dermatology and Radiation Oncology. Stanford University School of Medicine. Journal of Clinical Investigation. Vol. 123, No.12 Dec 2013.
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