Unravelling the Mysteries of the Wound Healing System

May - June 2022

Unravelling the Mysteries of the Wound Healing System

Editorial Summary

Processes in wound healing are relatively well understood, but clinical practice is complex due to confounding variables. We fundamentally lack a proper definition of the wound healing system. The wound healing system is continually monitoring tissue to detect damage. The system is geared up to detect the key preceding events that disrupt homeostasis. This article discusses the Harm scale in detail.

Introduction

So far it has been hard to produce data in wound care research. The main reason is that even though the processes in healing tissue are relatively well understood, the clinical practice is complex due to a considerable number of possible confounding variables. This makes practice rather difficult. We all know when a wound should heal, we seldom know when a wound will heal. This invited editorial is an attempt to increase our understanding of the problems; it contains ideas to encourage the exchange of thoughts, it results from many discussions and contains assumptions. It is not a scientific paper, though comments are welcome.

The confounding factors may be categorized as:

• Comorbidities

• Generic fitness issues Wound related problems

• Underlying pathology

• Genetic issues

For these the 5 level model may be useful. Keep in mind that in general practice, identifying and resolving the cause of the wound will heal at least 9 out of 10 wounds. The wound healing system is remarkably robust and will, if the source of damage is identified and removed, heal all wounds. The vast number of confounding factors give rise to some of the most obvious data issues. First of all, we have qualitative and quantitative diagnostic issues, where not only may the diagnosis be missing but also the severity of the problem is not monitored. For example, peripheral arterial disease has many

gradations and will develop in time. The second factor is failing to monitor factors which influence the outcome. Patient-related factors such as compliance and general fitness of the patient, influence the course of events in healing tissue to a large extent. The third factor is the population heterogeneity, where specific genetic factors come into play. Fundamentally, we actually lack a proper definition of the wound healing system, which I will aim to address in the next section. There are terms which require some explanation; the Harm scale, a definition of the wound healing system, expanding the current view towards structure, function and regulation and finally a model for mapping out events in damaged tissue.

Essential Wound Healing

In essence, wound healing is a response to tissue damage.

DAMAGE RESPONSE

So, we have two events occurring simultaneously, damage and response. I will call the according processes respectively β and α, where the α-processes represent the responsive processes and the β-processes represent the damage causing processes.

Mr Harm Jaap Smit

Wound Biologist, Erasmus MC Academy Rotterdam, Netherlands

“This Harm scale which consists of, respectively; homeostasis, deviation, stress, reversible damage, non-reversible damage and destruction, plays at all organisational levels as at the level of cells, tissues and organisms.”

In order to respond to damage the body has to detect it first. This implies that the wound healing system is always monitoring tissue to detect damage. In the case of damage, the sooner it is detected, the better. This means that the system is not geared towards detecting damage but more towards detecting the key preceding events that disrupt the homeostasis. This means that the α-processes, or the wound healing system, is always active, which makes sense from an evolutionary standpoint.

This suggests that the processes involved in a healing wound start after homeostasis balance is lost, much earlier than considered in the literature.

The Harm Scale

There is however a large difference between deviation of homeostasis and damage. For that reason I use the Harm Scale (the name suggestion courtesy of Carolyn Fife).

If we describe damage as a result of harm, we may consider damage levels to be related to the amount of harm inflicted. This description of damage differs from the description of the dimensions of a lesion. There is currently no good way to describe deviation from homeostasis; surrogate points can be number of cells lost or dimension of the lesion. But we can consider adopting some logical steps in the evaluation of damage.

The logical first stage of ‘damage’ would be ‘deviation’. The system has changed in a way that tissue, cells or organelles are out of homeostasis, forcing the system to adapt in order to restore homeostasis. If harm is increased and adaptation is no longer able to restore homeostasis, the system will function under stress. Further increase of harm will bring respectively reversible damage (which can be restored if the system can adapt eventually), non-reversible damage and finally, destruction.

This Harm scale, which consists of, respectively; homeostasis, deviation, stress, reversible damage, non-reversible damage and destruction, plays at all organisational levels as at the level of cells, tissues and organisms. It is important to recognise that the harmscale not only has a dimension of time, it also has a dimension of space. Destruction of an organelle can trigger anything from adaptation to destruction in a cell, similarly at the level of a cell it can cause adaption of tissue, cascading up, the destruction of a limb causes adaptation but also death for a patient. So it has a spatial and a timely dimension.

The space and time dimension of harm means it may not only worsen the condition at one point over time, it also can spread through the tissue.

The Wound Healing System

Defining the system in terms of loss of homeostasis leads to the following definition:

“The wound healing system is the system which safeguards the functional and structural integrity of the body by maintaining and restoring homeostasis. It does this by responding to deviations in homeostasis, by means of relative and proportional responses.”

This definition also allows for connecting wound care to oncology, regeneration, etc. Please keep in mind that the system usually works fine and that the wound healing speed is rarely influenced by intrinsic issues of the system. Problems occur due to limitations in removing the cause, infections and compliance.

Problems due to the wound healing system are rare. The system will keep the body within well-defined ranges of chemical, physical and biological parameters. Normally it will be able to handle minor changes within its normal function.

Unravelling the Mysteries of the Wound Healing System

“Damage can come in several forms, it can be structural, e.g., trauma, it can be functional, e.g., diabetes, or it can be regulatory, e.g., neoformation. In reality, all damage will impact all three aspects of living systems; an example may be how the increasing severity of a burn has an increasing effect on the human system.”

If however the normal function of the system is no longer able to cope with the circumstances, it will have to start other processes to respond to the new situation. And finally, if there has been damage, that has to be restored. Damage can come in several forms; it can be structural, e.g., trauma, it can be functional, e.g., diabetes, or it can be regulatory, e.g., neoformation. In reality, all damage will impact all three aspects of living systems; an example may be how the increasing severity of a burn has an increasing effect on the human system.

In all cases the system will have to firstly, monitor the system to prevent and detect damage. Secondly, if this is not sufficient, it will have to respond to damage, for instance by clearing the tissue of unwanted material, and thirdly to restore the damage. This means, in order to respond timely, proportionally (in relation to the amount of damage) and relatively (in relation to the type of damage) there have to be regulatory mechanisms in place to manage each of the three stages, probably by bifurcation. The common issue of a prolonged inflammation phase could be due to the system not being able to switch to proliferation.

The interesting issue is that the system has to manage its processes carefully to regain homeostasis without unnecessary energy consuming processes. For example, not to start proliferation in areas where there is still a blazing infection, yet being able to start it as

“Damage has effects on all dimensions of tissue, where loss of structure, function or regulation can cause further damage. If damage breaks the skin, its protective function is lost and microbes can enter the system. Large defects can cause malfunction of the entire body.“

soon as possible. The regulatory aspects of the wound healing processes are not always part of the diagnosis, while they can play a pivotal role.

Types of Damage

Damage is quantitatively categorised as singular, repetitive or continuous.

The damage causing β factors can qualitatively be grouped into two groups and four subgroups.

We can classify wounds into two groups, caused by extrinsic factors (outside the body), and wounds due to a cause from within the body (intrinsic factors).

Extrinsic Damage

1. Trauma; trauma is caused by adding energy to the body,

a. Mechanical energy, for example in cuts, tears and abrasions.

b. A special form of damage caused by mechanical energy is pressure ulcers.

c. Radiant energy, for example in the case of sunburn irradiation.

d. Thermal energy in combustion or freezing.

2. Predation; predation occurs by organisms that view the body as a food source.

a. Viruses, bacteria and fungi. b. Parasites.

Intrinsic Damage

3. Pathological events resulting from a problem in the body.

a. Diseases of the organ systems; cardiovascular abnormalities, neural abnormalities, immunological abnormalities, metabolic abnormalities, renal abnormalities, connective tissue abnormalities, etc.

b. Tissue diseases; such as connective tissue diseases.

c. Regulatory events resulting from problems in maintaining and restoring homeostasis, e.g. problems in the inflammatory processes. d. End of life events; for example, skin failure and Kennedy terminal ulcers.

4. (Epi) Genetic Factors.

a. Consequences of the natural variation between individuals, as a result of which, for example, the number of receptors on a cell can vary.

b. Consequences of unfavourable mutations, e.g. Epidermolysis bullosa, LAD syndrome, Klinefelter syndrome, sickle cell anemia, etc. c. Consequences of antagonistic pleiotropy, in which genes provide benefit at a young age while causing problems later in life; inflammation and senescence.

Damage has effects on all dimensions of tissue, where loss of structure, function or regulation can cause further damage. If damage breaks the skin, its protective function is lost and microbes can enter the system. Large defects can cause malfunction of the entire body. The interaction between factors can be very confusing, because it will not always be clear what is causing what.

The Five Level Model

The interplay between ααand β factors determines the state of the tissue involved. It should be noted that the β factors are independent of the α factors and that the ααfactors are relatively independent and stable.

As we know, the interplay is multifactorial and complex. To analyse the factors we may use the 5-level model1

The model ranges wounds in 5 levels of increasing complexity of both ααand β factors.

“Lack of physical fitness can occur in lack of condition due to reduced mobility, nutrition, condition and several forms of homeostenosis, which reduce the capacity of the healing system.”

Level 0

Level 0 wounds (0 because of 0 issues) are “accidental” wounds resulting from a singular event where the wound healing system is not compromised. These are “normal” wounds.

Level 1

Level 1 wounds are the result of a singular or repetitive event where problems arise due to a generic impairment of the healing system. This is usually in terms of physical or mental fitness. Mental fitness can occur in lack of understanding the problem or an inability to act accordingly, usually a combination of both. Diabetic patients are especially prone to this, but in venous ulceration the inconvenience of compression therapy will reduce compliance. Social economic parameters and personal traits appear to have a correlation to the outcome.

Lack of physical fitness can occur in lack of condition due to reduced mobility, nutrition, condition and several forms of homeostenosis, which reduce the capacity of the healing system.

It can also occur due to age, medication and non-directly related comorbidities.

Level 1 factors can have a dramatic impact on the events.

Level 2

Level 2 wounds are wounds of an event where the lesion itself causes reduction of healing speed. In general, this is the level where the “TIME” acronym is relevant. Usually the damaging events are edema, infection and moisture problems.

Level 3

Level 3 wounds are wounds which are the result of a repetitive or continuous event, often due

to underlying disease. These diseases are often related to problems with one or more organ systems. The most commonly occurring events are related to the cardiovascular system causing perfusion problems, followed by metabolic issues as diabetes and neurological events. Resolving the cause of the events will make way for the body to heal. In general terms, solving the disease will heal the wound. Often this will be the task of one or more medical specialists.

Level 4

Level 4 wounds are the result of regulatory problems caused by (epi) genetic events (neoformation) and in some cases antagonistic pleiotropic events like senescence and inflammaging. With the current knowledge, these problems are hard to pinpoint and can usually only be mitigated.

Some general remarks on the levels are that issues on any level can cause issues on all levels, one of the reasons wounds cascade to a more complicated stage over time. It also allows for a ‘heat map’ like analysis due to the correlations between events.

The levels are usually stacked, which means that a level 3 wound also has level 0 - 2 issues. Data also suggests that there is a Pareto type distribution of the levels with the largest numbers in level 0.

Finally, in the Netherlands we tend to assume

that level 0 requires no treatment, level 1 requires treatment at the level of the GP, level 2 at the level of a specialized nurse, level 3 by a specialist (team) and level 4 is as such not recognised and is usually treated by an appropriate specialist.

Even though the speed of healing is influenced by all levels, not all interventions are equally effective. The best intervention is to remove the cause of a level 3 wound. The rate of success in removal of the cause in level 3 often dictates the wound trajectory. Second best would be to remove an eventual level 2 infection and third is to handle the level 1 issues, like compliance.

How Should We Interpret the Data?

The speed at which a wound will heal depends on factors at all levels, but these are usually not recorded in a manner that allows proper analysis. The most obvious example are the Cochrane reviews, which are often inconclusive due to the lack of availability of good research, often due to poor recording of underlying disease. This means that, apart from resolving the cause, finding a single parameter which correlates to the wound healing trajectory is almost impossible. We may have to look at groups of parameters, in something of a network motive fashion. Another suggestion could be to see if we can categorize wound healing speeds in terms of relative size; this may help us in finding outliers.

References

1.

“Even though the speed of healing is influenced by all levels, not all interventions are equally effective.”