Perhaps wounds (like strokes) can have a penumbra– let’s call it a zone of Harm (after its author)!

via (2) The Harm Scale

Analysing wounds requires to have a look at it at five levels, from the molecule up to the social environment of the patient (Smit 2018). To understand events in wounded cells and tissue, it is important to realise that cells and tissues have a range of states related to damage. The linguistic problem is that damage is considered as, well, damage but in reality, cell and tissue damage ranges from no damage to death. Therefore, perhaps, we may refer to the scale as loss of homeostasis. Here the normal state means there is no loss of homeostasis, and the dead state means there is a maximum loss of homeostasis. This also makes sense because the body considers homeostasis the optimum and any deviation of homeostasis will evoke a reaction in the body. But the easiest option is, as Caroline pointed out, to use the word harm, which can be seen as “a measure of the level of deviation of homeostasis”.

What is harm?

Harm stands for how much problems a cell or a tissue has in maintaining its normal function.

Logically a cell or tissue can be in six states of harm:

  1. Normal,
  2. Adapted,
  3. Stressed,
  4. Injured,
  5. Damaged,
  6. Dead.

Normal is the normal state, where the cell or a tissue is well adapted to the circumstances and it is able to fulfil its required role. Here, the cell and tissue is in the state of homeostasis.

Adapted, if there are changes in the environment, cells or tissue adapt by changing its anatomy, physiology or behaviour. Adaptation causes cells and tissues to communicate their changed state with their environment, and the body detects those signals (Pakos‐Zebrucka et al. 2016; Erguler, Pieri, and Deltas 2013)

Stressed, when the changes lead to problems in the cells or tissue’s anatomy, physiology or behaviour it becomes stressed. Here it is no longer able to fulfil all its activities normally. Stressed cells and tissues start sending out distress signals like reactive oxygen species, HIF-1a and other signals (Andreeva et al. 2015; Bohovych and Khalimonchuk 2016). These signals are not only detected by the body but some signals can also be detected in laboratory analysis (Görlach et al. 2015; Pichu et al. 2018).

Injured, if the changes have led to small-scale damage, like a leaking cell membrane or tissue damage, problems can begin to arise. Leaking for instance ATP and calcium through membranes and other forms of damage (DAMPS) are interpreted as unwelcome events (Horn and Jaiswal 2018; Tang and Marshall 2017). This implies that any signal resulting from cell and/or tissue injury may already elicit an inflammatory response (Jagannathan and Tucker-Kellogg 2016; Rathinam and Chan 2018). Often injury may be repaired, allowing for full regeneration.

Damaged, if the resultant harm has led to irreversible, yet non-lethal, damage, there are inevitable consequences. For example, loss of a limb, may not kill you, but it will reduce your functionality. The body will detect damage and respond. It might do so by apoptosis, the controlled killing of damaged cells (Karch and Molkentin 2015). Apart from liver or skin tissue, full regeneration of damage is not an option. Here the negative consequences of (fibrotic) repair are taking place (Whyte, Smith, and Helms 2012; Greaves et al. 2013; Nyström and Bruckner-Tuderman 2018).

Dead, a dead cell is, well … dead. If a dead cell or tissue is not cleaned up properly, but is destructed instead, it’s organelles and DNA function as a danger signal, the so-called DAMP’s (danger associated molecular patterns) invoking inflammation and other repair or regeneration processes (Pandolfi et al. 2016; Maslanik et al. 2013).

The Harm Scale has dimensions of level, size and time. A single cell moving up the Harm Scale, does not imply that the tissue containing that cell is also adapted, injured or damaged. The tissue it is in, might very well be in perfect homeostasis. However, if more cells in the tissue start to get damaged or die, in time the tissue itself may start moving on the Harm Scale. And similarly, if a tissue is moving up the Harm Scale does not mean your body or parts of it are damaged.

Nevertheless, an inflammatory response is always imminent, inflammation is good but at the price of remaining scars, even at the molecular level (Fulop et al. 2018). Chronic inflammation is a source for age-related disease. (Franceschi et al. 2018)

So, even if harm doesn’t necessarily lead to direct damage, even little harm may cause problems over time in the long run (Ashcroft, Mills, and Ashworth 2002).

Why is this important?

The body detects and responds to any deviation from homeostasis and will react to regain homeostasis. If the reaction is insufficient, the tissue damage will increase in size and magnitude and cause serious problems for the patient.

If you consider most non-traumatic wounds result from an underlying condition, the Harm Scale begins to make sense. It draws attention to the pre-clinical events which impact the clinical events to follow. If the harm is not handled properly, you are setting up your topical treatment for failure.

Basically, if you fail to recognise the obstructed vessel, your dressing is not going to do much.

Even stressed cells may already have an impaired ability to handle harm, this condition may worsen if the harm moves up the scale. If the surrounding cells or tissues are in a grave state, the situation can spiral out of control, like in the case of skin failure at the end of life (Levine 2016).

Recognising the existence of harmed tissue highlights how a patient, who does not yet have a wound, might still suffer enough from harm to develop a wound in the near future (Black et al. 2011). Or even worse, a closed wound does not mean there is no tissue damage, setting the stage for recurrence.

Neglecting the level of harm in tissue, can cause to you take action which may result in an avoidable lesion.

The Harm Scale also points out that, not only the tissue in the wound, but also the cells and tissue surrounding the wound may be harmed, impairing their ability to repair or regenerate tissue. In general it will be safe to say that processes, like proliferation will take place outside the wound, even perhaps outside of the inflamed zone (Park et al. 2017). This means that the quality of the surrounding tissue plays an important role in the wound healing process.

Figure 1 Schematic representation of harm in and outside the wound.

In this paper we treat the Harm Scale at level 2, of the Five-Level Model for Wound Analysis and Treatment. (Smit 2018) The five level model is a system to describe factors influencing the cause and resolution of wounds at a normal (0), general (1), local (2), systemic (3) and cellular-molecular (4) level. The levels represent a connection between where problems occur and common clinical and scientific practice. (Smit 2018)

Level 2 is the level of the wound. However, the Harm Scale also exists at all the other levels, examples are:

  • Level 1; inflammaging(Chen et al. 2014),
  • Level 3; organ-system damage (San Miguel-Ruiz and García-Arrarás 2007) and
  • Level 4; (epigenetic) DNA damage (Nanduri, Semenza, and Prabhakar 2017; Jasiulionis 2018).

Using the Harm Scale at all 5 levels (0-4) opens up the possibility of making use of preventive and curative toolkits used in other types of tissue damage like renal, brain or heart damage. It also allows us to make use of the insights from inflammation research, like inflammaging (Castellani et al. 2016).

How the Harm Scale can help.

In today’s wound care we only casually touch on the subject of tissue damage, because the most used solution for a wound is a dressing. The Harm Scale may help us in evaluating tissue in, under and around wounds.

Having some kind of definition of harm will improve communication on the complexities of the state tissues and cells are in. Acquiring a better understanding of the level of harm in tissue allows us for assessment and modalities to maintain homeostasis.

It may be helpful to notice that, though adapted, stressed, injured and damaged cells signal their harm state to their environment, the body can under- or over-react. If the patient is compromised these early signals may be missed, masking what is really happening. On the other hand, if injured, damaged and dead cells invoke a dramatic response, this in itself, may spiral out of control in a compromised patient.

The Harm Scale is also helpful in determining where to inject growth factors, miRNA’s and other interventions. Zones in which cells are barely surviving maybe not the best place for your intervention. You have to locate the proper location in, around and under the wound for a (maximal) effect (Berlanga et al. 2013).

Perhaps, if we start diagnosing and treating issues which reduce the body’s ability to repair or regenerate tissue, we might find better ways to predict, prevent and treat wounds. A Harm Scale type assessment can be a useful addition to the toolbox.

During that process we will learn how to achieve better results from our current treatment modalities.

© Harm Smit (2018)

Ps. It is really weird, writing a text like this when your name is … Harm.

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