Why has wound training to be so hard?

Wound education is supposed to support a professional in answering the question:

What am I going to do next?

In practice, “what next” often appears straightforward.

In the Netherlands approximately 2 to 3% of the Dutch report to their GP with a wound. Obviously, the vast majority of these wounds are not problematic. They will heal regardless, even though a reassuring word from the doctor and a bandage may offer some help.

A small number of wounds close more slowly or not at all. For this, the cause of the wound must be examined, whether it is still present and what can be done about it. But here too, if you remove the cause, the wound will close relatively easily.

Problems can subsequently arise as a result of the wound itself, there may be a bacterial or fungal infection or edema that impairs wound healing. That too requires no rocket science to solve.

Finally, a small group will remain where we cannot (completely) remove the cause or where we do not understand exactly what is happening. Those will be the difficult wounds.

It will be clear that in practice most wounds are easy to heal.

“What now?” is in practice a timely diagnosis and intervention that prevents the development of problems as a result of the wound itself. Over 90% of the wounds at a GP level can be closed within a month or so.

One may almost assume that a badly healing wound cannot occur in the Netherlands. But that is not true, all in all, there are somewhere between 200,000 and 400,000 patients in the Netherlands struggling with a wound.

It is quite possible to reduce this number, but this requires knowledge, skills, and facilities.

These patients occur due to the apparent simplicity of wound treatment. Most wounds are not much of a problem. The question about the cause and thus the treatment of a wound is often easy to answer. The problem arises when the question is not easy to answer, while the practitioner is not aware of it.

False security (IKEA: is a Dutch saying for someone who believes he or she can really close every wound: Ik Kan Echt Alles) is the mother of the problem. As mentioned, most wounds will close by themselves, if there is a cause, even more wounds will close by themselves after the cause has been been removed. After these steps, you may be left with a dirty wound with thickened wound edges, but cleaning and a bottle of iodine will often be sufficient.

So, for these cases you do not really need in-depth wound training, here exudate management will with the help of a bandage and possibly an antiseptic, whether or not integrated into a bandage will be sufficient.

An education where you learn about general causes of a wound and matching dressing to the color of the wound is more than enough. As icing on the cake, you get the stages of wound healing during such training, after which you are allowed to enter the field as a “wound nurse”.

You will be successful because, even with a pack of gauze and a bottle of iodine, you can close at least nine out of ten wounds quickly. If you do not ask yourself too critical questions, you logically think you are doing fabulously. And that’s how the IKEA professional is born.

That single patient who does not heal then is the exception. Unfortunately, an exception affects thousands of Dutch people. An unnecessary problem for which you can arm yourself. But for that, you need knowledge, a lot of knowledge.

Knowledge which enables a practitioner to answer the one simple question on what to do next?

Knowledge about diagnosis and treatment options, but also other knowledge.

Knowledge far beyond the three, four or six stages of wound healing.

Knowledge about more and more in-depth (but still relatively simple because it can be written down in lists) matters such as anatomy, physiology, microbiology, comorbidities, lab values, and medication.

But wound medicine requires more knowledge. Knowledge to reason, to understand what is happening, knowledge about the rules of the game. Knowledge needed to assess your observations in a broader context; to see the analyses in their mutual relationship. Then it’s about wound_levels, math, feedback loops, organizational levels, time scales, and much more.

This will enable you to see what really is happening with your patient. In addition, you will be better able to assess the options available to you. This allows you to take the next step in a more targeted manner.

That knowledge also gives you access to many more options to intervene. Unfortunately, it also creates more impossibilities because you also learn that practice in wound medicine lags the science.

The tricky part is that this knowledge does not seem practical at all to an average practitioner. What are the benefits of growth factors, complement, feedback loops, cell types, immune system, and what not?

There is currently little you can do with that, while in practice the choice of the right bandage actually always works fine.

That is always the tricky part, training people for something they do not consider paramount, but which in the meantime makes the difference for many patients. Difficult knowledge for practitioners who want to understand what they are doing.

Practitioners who know when “What next?” is a bandage and a reassuring word, but also when “What next?” is something completely different.

What is a wound?

In order to develop a better understanding of wound medicine, we may have to rethink some of the basic concepts.

Today; the wound. The main question is to make a definition of a wound that is better suited to today’s knowledge and available interventions.

A wound; definition:

Tissue damage resulting from harm due to (usually a combination of) intrinsic and extrinsic physical, chemical, and biological phenomena, breaching the skin is what we call a wound. This leads to two notions:

  1. a wound is a form of tissue damage and
  2. if and how much damage is caused by harm depends on the individual subjected to it.

So the definition of a wound as a breach in the skin is far too simplistic to cover the events. Similarly is the term injury a result and not a cause. Injury is caused by harm. If you focus on the result you will never solve the cause.

Secondly, if you realize a wound is a form of tissue damage, why not focus on tissue damage?  This might help you to treat the wound instead of the lesion. Or better to treat the patient instead of the wound.

Do not attribute magical qualities to wound dressings.

This is a translation of the article published by the Dutch Branche organization for wound care companies.

Harm Jaap Smit is a wound biologist, CEO of BioMedServ and a member of the Wound Care Expert Group of the Netherlands Wound Platform. He also teaches at the Erasmus Medical Center and the Fontys Paramedic university of applied science.  Despite the encouraging developments in recent years, Smit sees that much has remained the same in “woundland”. According to him, the biggest gain can be achieved by making the correct diagnosis earlier.

“I always start the first lecture of the wound care course with the same case. Someone applies a bandage from knee to foot for a wound and then keeps it moist with water from a tea kettle, so I explain to the participants. What actually goes different nowadays, I ask them then. It often remains remarkably quiet, despite the body of practical experience gathered in the lecture hall. Sure, nobody uses a tea kettle anymore to achieve a moist environment. But otherwise, little has changed in the way we treat wounds. And that is telling, since this case dates from 1796. It is also easy to notice that little has changed when you open an average wound cabinet. Most of the products are still the same as they were 25 years ago. Not because no new products are being developed, on the contrary, but because it often proves difficult to incorporate new products into daily practice. ”

“Don’t get me wrong, we have pretty good wound treatment in the Netherlands. Even when you look at things like financing. If you have a problem, we will take care of you, no matter the cost. When I meet with colleagues from abroad I do realize the quality of care here. Still, at many points in the chain there is simply a lack of specialist knowledge in regard to wound care. Whether it concerns general practitioners, home care or medical specialists. No one needs to be blamed for that, it is just something like that has grown historically, but it is the situation we are in now. We all worked hard in recent years to bring about change, but at the moment there is still room for improvement. ”

Wrong conclusions

“Things go wrong in many ways. On the one hand, you have the doctor, who is not able to close a wound for months and then concludes that the dressing does not work. Then a vascular surgeon comes in, sets a proper diagnose, and both observe the wound does close. Here casual observation reinforces the faulty initial conclusion. On the other hand, you see that sometimes there is just too much faith in the products. “Wound care” which begins and ends with the selection of the proper dressing.  So we also should not attribute magical qualities to wound dressings. ”

“Of course, bandages can do a lot for a patient. I recently cut off a piece of my little finger while making a beetroot carpaccio. It is painful and takes quite a while to heal. At such a moment you think about the more serious cases you know. If the right dressing can relieve pain, remove it or make it unnecessary to redress the wound three times a day – that means something for a patient. Yet that is mainly caring, and not necessarily treatment. Keep in mind that although a wound dressing does contribute to faster healing, it is not uncommon for that effect to be masked by all other events happening in a patient with difficult wounds. If you only look at that nurturing aspect, at increasing the quality of life, you run the risk of missing something elsewhere – an infection or a tight vessel – and unintentionally cause new problems.  Conversely, this also applies if you carelessly reject the added value of bandages. “If you only have a hammer, every problem looks like a nail” is a serious challenge in wound care. ”

“In  95 out of 100 wounds; tracing and removing the cause is sufficient. If you have a wound that is difficult to heal, there is a good chance the root cause is an insufficient diagnose. And then there are the many underlying factors, ranging from behavior to (epi)genetic defects. The underlying issues are very difficult to identify. In the Dutch Journal of Wound Care, among others, I have therefore argued for the classification of wounds into five levels. At the lowest level, this is a normal wound without underlying pathology and at the highest level, for example, a wound with molecular pathology. Such a model forces treatment providers to think about the relevance of the interventions to be taken, thereby increasing the effectiveness of the treatment. ”

Costs of dressing materials negligible

“If you take a good look at the Dutch financial landscape, you will see that there is little reason to worry about the availability of dressing materials. There are around 500,000 patients in wound care each year, which together account for a cost of 3.2 billion euros. Within this, the proportion of dressing materials is 88 million euros. Relatively negligible. And the real gain in terms of costs, therefore, are to be found elsewhere

“We all know that the longer a wound exists, the harder it is to close it. If you consider that GPs hold a patient with a wound for an average of thirty weeks and/or home care often lacks specialist knowledge, you will see where the problem lies. It is therefore important that we move towards a system where expertise is more widely available and is deployed faster. Initiatives such as regional expert teams or the certification of wound professionals can play an important role in this. Such a change does not happen from today to tomorrow, but also a foot trip to China starts with the first step. “

‘WOUND’ – Multi-omics translational research for delayed-healing wounds

We applied for a NWO perspectief research grant in order to bring wound care to this century.

In the Netherlands over 400.000 patients suffer from delayed-healing wounds. This creates a personal, but also societal burden, of 3.2 billion Euros. This will grow due to increase of elderly individuals in the Netherlands, likewise in the rest of the world.

In 2013, the National Health Care Institute classified complex wounds as a separate condition (or self-contained process). However, wound care didn’t advance much last century. Current focus is on fighting symptoms, like pain and infections. The right challenge however is to elucidate the underlying pathology and find key parameters that make the wound refrain from healing and can function as (bio)markers to control the quality of selected care. They are a starting point for discovering new treatment modalities and the direct application of available, but not yet applied, treatment modalities.

This program breaks away from the conventional approach by combining leading scientific institutes, key clinical wound care professionals and the relevant users in one consortium. We will harness the latest developments from the fields of systems biology, metabolomics, proteomics, genomics, medical- and data analysis. This enables quick implementation and valorisation of the outcomes towards predictive analysis & diagnosis, personalised interventions and innovative tools for clinicians and patients. Such as point of care diagnostic tools and direct application of a novel wound treatment approach, like anti-biofilm or complement modulation therapies.

We identified three R&D lines:

1.Predictive personalized diagnosis; Multiplex omics- and data analysis strategies will reveal early determinators of patient’s wound healing and starting points for development of personalized treatment modalities.

2. Evaluation and quantification of treatment efficiency; Identify biomolecules through a.o. omics that predict treatment efficiency and disclose key factors for improved healing.

3. Identification, research and demonstrations of new interventions and treatments; Interplay between microbiome and immunomodulation will enable novel treatments such as anti-biofilm or anti-complement therapy.


Societal challenges (MU)

This program has a perfect fit with the MU ‘Health and healthcare’. It will deliver predictive tools for clinicians, to be continued in targeted personal treatments which can be either preventive, either curative or both. This enables patients to re-participate sooner, or at all, in our society. Since the consortium also consists of a large group of clinicians and users, we can guarantee a fast implementation trajectory for the tools and outcome of this program. This also makes this program an export generator; since the largest amount of e.g. diabetes patients is to be found in the Americas.


  • University of Amsterdam (UvA), Swammerdam Institute for Life Sciences – main applicant
  • ErasmusMC, Research Unit Plastic Surgery
  • University of Twente, Medical Cell Biophysics
  • Amsterdam UMC, Plastic Surgery
  • TUDelft, Chemical engineering


  • MeanderMC, Surgery
  • IsalaMC, Surgery
  • IkaziaMC, Surgery
  • AlrijneMC, Wound centre
  • Assocation of Dutch Burns Centres
  • MST, Surgery
  • Davinci clinics
  • TNO
  • Dutch Optics Centre


  • BioMedServ BV
  • ICap BV
  • VyCAP BV
  • Biocrates Life Sciences AG
  • CZ
  • Zilveren Kruis
  • Menzis
  • VGZ

Key Enabling Technologies (KET)

The KET’s this program addresses are 1) BioTechnology 2) Quantum- and Nanotechnology and 3) Photonics, both with strong links to 4) ICT. For BioTechnology, the chemistry of (complex) wound care is on large parts terra incognita. The program is an example of an integral system biological approach for health where we explicitly use the ‘Omics’ part.

Digital technologies will enable us to harvest, classify and interpret the data from analysis and for diagnosis, as well as for further development of tools and products. Enriched with quantum- and nanotechnologies, one of the proposed outcomes will be an analytic technique for rapid medical analysis of small blood, fluid and tissue samples.

For Photonics, the program will deliver techniques to perform diagnosis with non-invasive photonic hand held devices and advanced image capturing techniques for early diagnostics, such as novel light therapies for wound treatment with a digital therapy assistant.

Public meeting:  

A public meeting will be held on November 18, at the UV

A. Please contact us for more information.

Contact information:  

Drs. Harm Jaap Smit,  nlhjs@biomedserv.com,  +31 6 45444310

(Prof. dr. A.K. (Age) Smilde, A.K.Smilde@uva.nl, 0205255062)

A few fundamental issues in wound care

Recently I had a conversation with a Dutch wound care biologist, that means a conversation between two wound care biologists, that was fun, for us.

The conversation quickly went to a few of the fundamental issues in wound care. Here are some of the issues we discussed.

The first fundamental issue in wound care is that most people who are trusted to heal wounds are denied the tools to do so. I cannot help but wonder how a home care nurse is able to figure out the details about a complex patient which will allow him or her to produce a proper diagnosis. Following guidelines and using training as provided for home care nurses diagnosis technically impossible. They do not provide the knowledge and skills needed to asses a complex situation. For an example have a look at the differential diagnosis for a leg ulcer. The amount of knowledge needed for proper wound medicine is simply not always available, yet a diabetic wound can spin out of control in hours.

The second fundamental issue in wound care is that most people who are able to understand what is happening in any given wound are simply not interested and as a result lack insight. For instance, a GP often declares that he or she can close most venous leg ulcers by applying a compression bandage, literature gives a very different view on that declaration. And what do they do if their intervention is not enough to solve the problem at hand? This is one of the reasons many wounds heal “miraculously” in the hands of a wound care team after having suffered for almost a year in the hands of a GP (unpublished research). Plus there is no single medical specialist group responsible for wounds, most responsible medical specialists, usually dermatologists or some types of surgeons, are so by choice, not because wound care is an innate part of their field. (check that for pressure ulcers, or more precise force related tissue harm)

The third fundamental issue in wound care is that wound care related randomised clinical trials in a real setting, by definition are not able to produce results, simply because the relevant parameters are not controlled. Thus the results suffer badly from uncontrolled confounding factors. This is one of the ways wound care is different from other medical fields. To expect otherwise is, in the current wound care landscape, mildly put, scientifically doubtful.

The fourth fundamental issue in wound care is that the assessment of intervention outcome by means of randomised trials, which by rule of the third fundamental issue can only provide little or no results, is leading to the scientifically invalid conclusion that the intervention does not have any effect. This can be seen at the difference between “bench” and “bed” research.

The fifth fundamental issue is that the results of randomised trials and meta-analyses are used for policy. Simply looking and comparing numbers without a fundamental understanding of the underlying issues will cause problems.

The sixth fundamental issue in wound care is that we are using wound closure as an outcome, whereas any intervention usually involves only some of the processes in the wound healing cascade.

The seventh fundamental issue in wound care is that we do not undertake any activity to assess the delta and its causes. The wound healing speed should be monitored and plotted, any deviation from the expected wound healing speed has to be investigated. But it is not.

Here we ran out of time otherwise, there would have been many more fundamental issues to be listed. You may agree, which is fine. You may disagree, even better. You may add, which is best.

There are solutions to these fundamental issues, it is not that hard, but it requires some thinking. Our patients deserve that.

The Harm Scale

Caroline Fife suggested I should publish a simple scale for tissue damage and call it the “Harm Scale”.

Here it is.

Analysing wounds requires to have a look at it at five levels, from the molecule up to the social environment of the patient. 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 loss of homeostasis will evoke a reaction. But the easiest option is, as Caroline pointed out, to use the word harm, which can be seen as a measure of loss of homeostasis.

What is harm?

Harm stands for how much problems a cell or a tissue has in 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 are in a state homoeostasis.

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 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 the signals 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). IApart from liver or skin tissue, full regeneration of damage is not an option. Here the negative consequence of fibrotic repair can take 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 tissue 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 li=ong 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.

Flatly, 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. 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. (Black et al. 2011)

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 the 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. 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 local, the level of the wound. However, the Harm Scale also exists at 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 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 and/or prevent wounds. A Harm Scale type assessment can be a useful addition to the toolbox.

And in the process, we will learn how to achieve much 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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Nyström, Alexander, and Leena Bruckner-Tuderman. 2018. “Injury- and Inflammation-Driven Skin Fibrosis: The Paradigm of Epidermolysis Bullosa.” Matrix Biology, no. 2017: 1–14. https://doi.org/10.1016/j.matbio.2018.01.016.

Pakos‐Zebrucka, Karolina, Izabela Koryga, Katarzyna Mnich, Mila Ljujic, Afshin Samali, and Adrienne M Gorman. 2016. “The Integrated Stress Response.” EMBO Reports 17 (10): 1374–95. https://doi.org/10.15252/embr.201642195.

Pandolfi, Franco, Simona Altamura, Simona Frosali, and Pio Conti. 2016. “Key Role of DAMP in Inflammation, Cancer, and Tissue Repair.” Clinical Therapeutics 38 (5): 1017–28. https://doi.org/10.1016/j.clinthera.2016.02.028.

Park, Sangbum, David G. Gonzalez, Boris Guirao, Jonathan D. Boucher, Katie Cockburn, Edward D. Marsh, Kailin R. Mesa, et al. 2017. “Tissue-Scale Coordination of Cellular Behaviour Promotes Epidermal Wound Repair in Live Mice.” Nature Cell Biology 19 (2): 155–63. https://doi.org/10.1038/ncb3472.

Pichu, Sivakamasundari, Selvaraj Vimalraj, Jayalalitha Sathiyamoorthy, and Vijay Viswanathan. 2018. “Association of Hypoxia Inducible Factor-1 Alpha Exon 12 Mutation in Diabetic Patients with and without Diabetic Foot Ulcer.” International Journal of Biological Macromolecules 119: 833–37. https://doi.org/10.1016/j.ijbiomac.2018.08.011.

Rathinam, Vijay A.K., and Francis Ka Ming Chan. 2018. “Inflammasome, Inflammation, and Tissue Homeostasis.” Trends in Molecular Medicine xx (3): 1–15. https://doi.org/10.1016/j.molmed.2018.01.004.

San Miguel-Ruiz, José E., and José E. García-Arrarás. 2007. “Common Cellular Events Occur during Wound Healing and Organ Regeneration in the Sea Cucumber Holothuria Glaberrima.” BMC Developmental Biology 7: 1–19. https://doi.org/10.1186/1471-213X-7-115.

Smit, Harm Jaap. 2018. “A Five-Level Model for Wound Analysis and Treatment.” Wounds UK 14 (4): 24–29. https://www.wounds-uk.com/journals/issue/548/article-details/five-level-model-wound-analysis-and-treatment.

Tang, Sindy K Y, and Wallace F Marshall. 2017. “Self-Repairing Cells: How Single Cells Heal Membrane Ruptures and Restore Lost Structures.” Science (New York, N.Y.) 356 (6342): 1022–25. https://doi.org/10.1126/science.aam6496.

Whyte, J. L., a. a. Smith, and J. a. Helms. 2012. “Wnt Signaling and Injury Repair.” Cold Spring Harbor Perspectives in Biology 4 (8): a008078–a008078. https://doi.org/10.1101/cshperspect.a008078.

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


Five levels, how to do it.

The original 5-level article was published in WoundsUK, you can find it here.

The five levels model provide you with a holistic checklist and allow you to map what is driving the events in any given wound.

Even though it is tempting to immediately jump in, that would lead to an almost incomprehensible list of factors to check. Perhaps it is easier to do it in an iterative way, where you have a very simple first pass and then, if you do not find a proper explanation for what is happening in the wound, you do further iterative passes. Depending on the findings of the previous pass(es), you zoom in and cast a finer net.


The basic idea behind a five-level wound analysis contains three ideas:

  1. You divide your problem into two new problems and keep doing that.
  2. Use the 5 levels as a checklist to see if you have missed something.
  3. If you do not find a solution,  redo 1 and 2 asking more questions and a larger checklist.


As any professional will know; wound healing is a complex field requiring knowledge, skills and tools on a variety of issues at all levels. The amount of knowledge, skills and tools needed increases at each round of questioning or pass.  Applying the 5-level system requires experience and a profound knowledge of tissue repair and regeneration. It requires understanding and ability to execute diagnostic tests. Finally, it requires knowledge of many comorbidities, lab values and medication.

The five levels are a result of 4 questions mapping your problem.

  1. Will this wound heal normal or not?
  2. If not will it heal by itself or will it not heal?
  3. If it will heal by itself, does it require advanced wound care or can it do without?
  4. If it will not heal by itself, is it because of organ system failure (usually vascular problems or repetitive damage) or because of cellular, molecular or genetic disorders?

By definition, any complex wound will have phenomena acting simultaneously on all levels. Having a full picture will provide a better understanding of the problems and possible remedies.

First pass, analysis

  • First question: will this wound heal normally, yes or no?
    • If yes, you have a level 0 wound. Take good care of the wound. It can be as simple as putting a bandage on; any bandage.
    • Chances it is a no, is when the wound exists for a longer period, your patient is over 65 years of age and/or has diabetic, dyslipidaemic, social, mobility, cardiovascular, neurological, immunologic or renal issues.
    • If no, the wound will heal not normally, leading to the
  • Second question: will this wound heal by itself or will this wound not heal by itself?
    • If yes, it is a level 1 or 2 wound. Consider minimal intervention, intervention means disruption of the normal life which can cause issues by itself.
    • A level 1 wound does not need special care.
    • Al level 2 wound requires wound care.
    • If no, the wound will not heal by itself, it is a level 3 or 4 wound, leading to.the
  • Third question: what is preventing the wound from healing?
    • Chances it is a wound resulting from arterial problems, venous problems or tissue damage due to repetitive forces. Figure out how grave the problem is and how to handle it.
    • Level 3 wounds require specialist care to solve the cause.
    • Level 4 wounds require specialist care. Currently, most level 4 diagnostic tools and interventions are in a research stage.
    • If needed appropriate, consider referring to a specialist able to solve or reduce the problem. It can be a specialised nurse, dermatologist, vascular surgeon, internal doctor or a podiatrist. Optimally all of them combined in a specialised wound care construction (not necessarily at one location).


First pass, checklist.

  • Check all 5 levels for issues which cause the wound or which may be not a direct cause for the wound but influence its trajectory. They are listed in the article.


First pass; act.

Select and apply your interventions.  Less is more.


First pass; review.

  • If the wound improves, redo the first pass for any changes or signals the wound might not improve on the next visit.
  • If the wound does not improve it is time for the second pass.
  • The goal of the second pass is to redo the first pass:
    • double check your assumptions.
    • have a closer look at the factors influencing the wound trajectory.

Having a closer look at the factors influencing the wound is important because, for instance, an infection can have a dramatic effect on the wound healing. But there are many more factors worth investigating. Causal and correlating factors have to be considered simultaneously. Most correlating factors are found on level 1. On the other levels, both causing and correlating factors can be found.




Second pass; analysis.

  • Is the cause well defined?
    • If yes, focus in the second pass on factors related to the cause. You can use the concise checklist for generating ideas.
  • Check level 1 for any causal or correlating factors which may point to problems on level 2, 3 and 4.
    • Consider other or more precise tests.
    • Identify possible tests and issues
  • Check level 2 for any causal or correlating factors which may point to problems on level 3 and 4.
    • Consider other or more precise tests.
    • Identify possible tests and issues, debride the wound thoroughly.
  • Check level 3 for any causal or correlating factors which may point to problems on level 3 and 4.
    • Consider other or more precise tests.
    • Identify possible tests and issues
  • Check level 4 for any causal or correlating factors which may point to problems on level 1, 2, 3 and 4.
    • Consider other or more precise tests. This includes a closer look at lab values.
    • Identify possible tests and issues.


  • Consider all issues and tests, look for connections which help explain what is going on.
    • Decide which test may improve your understanding or underpin possible interventions
    • Decide which intervention(s) will have the most impact on the wound trajectory.


Second pass; act.

  • Select and apply your tests and interventions, consider referring the patient.


Second pass, review

  • See if the wound has improved as a result of your interventions
  • If the wound improves, redo the first pass for any changes or signals the wound might not improve on the next visit.
  • If the wound does not improve, do a third pass by redoing the second pass.


Third pass

  • Is the cause well defined?
  • If yes, focus in the third pass on factors related to the cause.
  • But also consider marginal interventions, not aimed at resolving the cause but at improving the body’s ability to maintain, repair or regenerate tissue.
  • Check for patterns in issues, factors can be related or even appear in an interrelated fashion.
  • Try to learn from the previous pass(es).
  • Try to improve your knowledge, skills and tools by seeking options for discussion and learning.



It will be clear that even answering question one seems simple enough, it is not, this judgement requires quite some experience. But progress in the wound after one or two weeks will tell you if the judgement was justified. After running the analysis you will have a better idea of what is happening in your patient and the wound. This will help you in finding better ways to intervene. You will also learn what the limitations are in terms of available knowledge, experience and tools. Some are unavailable to you, others do not exist.

Even though this simple way is focussing on existing wounds, the insights resulting from it can also be used to predict and prevent wounds. Especially because harm may well exist prior to the formation of a wound or lesion, it is detectable and treatable.

Harm Smit


If you have any questions, do not hesitate to ask.







Force Related Tissue Damage: A White Paper

Damage to skin and tissue is an important and expensive issue for the NHS and other organisations providing care for those who are confined to their bed or chair for any period of time. The costs are not just financial; a lot of individual suffering and loss of quality of life occur when tissue breaks down. This white paper brings together existing research into skin and tissue damage associated with patient’s being cared for in bed.
The latest term being used for this is pressure injury (NPUAP 2016). This term replaces previous terminology used such as; pressure ulcers, pressure sores, bed sores /ulcers and decubitus ulcers. However, with our extensive review of the literature into the internal and external influences, we believe a more accurate description is force related tissue damage.
This paper investigates the observations regarding unobvious causes of force related tissue damage and the events linking both biomechanical and biological processes at several organisational (pathological) levels together with external in bed events. Over 22 internal marginal influences are identified which, as countless Cochrane reviews demonstrate, wound care science struggles to diagnose and cure; mostly due to the underestimation of the complexity and processes involved regarding tissue homoeostasis, damage and regeneration.
The paper explains how there are two major causal factors connected with all in bed force related tissue damage. The patient’s resting/support surface synergy and the way the person is moving/being moved and stabilised on that surface, regardless of whether this is by manual or mechanical means. We will explore how in bed force related tissue damage can be a direct result of both manual and/or mechanical handling and the incorrect synergetic interface layers of the resting/support surface with the patient’s skin and tissues.
We strongly suggest the major causal factors involved with all in bed force related tissue damage are external and within our control. This paper proposes that a preventative trajectory is both desirable and achievable by adopting a combined ergonomic and biomechanical approach to remove the risks to both patients’ skin/tissue and the carer’s muscular-skeletal system associated with in bed care and positioning.
Harm Smit and Phil Strong 2018


Here is the link to the paper: White Paper Force related tissue damage

4 ways a cell may die

For ninety five out of hundred wounds, discovering and removing the cause is sufficient to solve the problem. If that approach fails, the wound may become a chronic wound. For adequate interventions, (in this case super-) simplified knowledge of processes at cellular level may help. At least, in presentations it is appreciated.

Understanding how cells cope with stress, injury and damage is central in understanding the development and healing of wounds. There is no abrupt transition from normal tissue to necrotic tissue, in most wounds the conditions for cells are gradually getting worse towards the lesion, This is divided into a healthy part, a part in stress, a part with repairable damage and a part with non-repairable damage. This zone classification is different for each tissue type involved which may on of the explanations of tissue undermining, this happens when the underlying tissue is more susceptible to stress and damage comparted to the tissue above.

Cell stress and damage are often caused by the action of forces on tissue (1), lack of oxygen (2) and/or lack of nutrients (3). Stress and damage may lead to cell death, however, the most common cause of cell death is apoptosis, programmed cell death(4).

The action of forces on cells leads to pressure, tensile- and shear-forces. Increased pressure may cause membrane leakage, tensile forces can lead to cell rupture and shear forces can do both. Casual observance may suggest that pressures are the main cause of problems, but that is probably not the case. Cells and tissues are often anisotropic, which means they are not equally strong in all directions. Many tissues have a special construction to handle forces in a certain direction. If force is applied from a “wrong” direction to a cell or tissue it may deform or lose its tensegrity and tear. In addition, instead of popping and rupturing, deformation may most of the time be causing damage of the cell membrane resulting in calcium ions leaking into the cell which is a direct cause for problems.[1,2].

The cell nucleus senses the properties of force applied to the cell [3], this allows her to assess the situation and respond appropriately at the cellular level. Signalling and tensegrity systems augment and translate these signals to the higher organisational levels of tissue, organs and the body.

The availability of oxygen may also cause problems; human cells depend on haemoglobin for their oxygen supply. If a human cell has no access to oxygen produced by red blood cells it will die. Oxygen related issues usually cause mitochondrial problems. Under hypoxia. Mitochondrion will adapt its processes to keep producing energy, this process also produces reactive oxygen species and nitric oxides. These reactive substances signal the cell and its surroundings about the (oxidative) stress. Too many reactive parts are damaging so if the amount of reactive oxygen surpasses a threshold the immune system will be activated to remove damaged cells. This system allows tissue to function under hypoxic circumstances[4].

Lack of nutrients will disturb the cell metabolism, which will endanger its survival. Focal in these processes is the endoplasmic reticulum, which is sensitive to intracellular circumstances. Since the endoplasmic reticulum functions as the main chemical factory of cell producing most proteins any disturbance of the necrotic reticulum will have a dramatic effect. This is called endoplasmic reticulum stress (ER-stress)[5].

Circumstances such as exerted forces, hypoxia or a lack of nutrients are noted by the cell and it will respond to counter these problems(stress responses). However, these responses influence the internal cooperation between the nucleus, mitochondrion and the endoplasmic reticulum in positive or negative manner[2]. It is important for cells to not only adapt the internal processes but also to inform its surrounding about its problems. Therefore it will start sending out signals which quite specific inform surrounding cells and tissues and the rest of the body on the nature of its problems[6,7].

Cells are part of tissue, to maintain the quality of these tissues cells which are not functioning properly have to be removed or replaced. Removing non-functional or obsolete cells by the body itself is the commonest reason for cells to die. The body prefers to remove cells in a controlled manner where cells are properly recycled. This process is called apoptosis. The opposite process necrosis were cells structural fall apart and their contents are spread in the tissue. The remains of cells in tissue are the result of an uncontrolled situation and therefore have a strong signalling function, these are the so-called damps en pamps (damage-associated molecular patterns en pathogen-associated molecular patterns)[8].

Both apoptosis and necrosis exist in several varieties[9].

Cells do not immediately fall apart or die if exposed to forces, hypoxia or lack of nutrients. For practical reasons, we may classify the level of stress in stress (no damage, fully reversible), injury (reversible damage) and damage (irreversible damage). Stress does not require regeneration, injured tissue can regenerate fully, but damaged tissue cannot be regenerated fully and the body will try to restore the main functions of the tissue. This means that the affected area is much larger than the wound itself, this implies that visually vital tissue does not have to be vital that all.

Cells and tissues can adapt to survive difficult circumstances. Continuous monitoring the circumstances and the signals cells and tissues send out allow the body to respond. This can be a short-term responses where a blood vessel is opened up or an immune response is started. Long-term responses can be by changing the composition of tissues, for example making extra blood vessels to composite for lack of perfusion or changing collagen composition in support of tissue due to forces from different angles.

Regardless of the cause of the wound, the wound bed will, due to lack of perfusion, always, always suffer from odd forces and a lack of oxygen and nutrients. Due to the damage the structures the body uses to monitor the situation in the body like sensors, vessels and nerves are also dysfunctioning. This is a perfectly normal situation and most of the disturbance is actually used to guide the wound healing process. That is in a young patient, if the wound is larger, complex and or the patient has more issues related to tissue regeneration, this perfect process is impaired.[10,11].

This impairment be qualitative, wrong signals are send or misinterpreted. It can also be qualitative, more damage leads to more signals, more signals are harder to interpret and the signal to noise ratio is also reduced. Noise and miscommunication in the body, may lead to misinterpretation of signals or the generation of wrong signals. This may seem far-fetched, in practice it is called a chronic, wound.

An out-of-control inflammation response may cause havoc in a wound bed. This may produce additional damps which only increase the (sterile) inflammation[12]. And impaired endothelial hypoxia and capillary refill a cause reperfusion injury[13,14]. Reperfusion injury is a cause of problems in other parts of the body, like the lungs[15]. A cacophony of signals in the wound bed may disable guidance for cells which may cause impaired cell movements and proliferation. These are just a few of the many causes of chronic.

Despite the difference in causes, chronic wound pathology has surprising similarities at the level (4) of the cell and the tissue. And this opens up treatment possibilities. Not only are the issues often similar, there are several possibilities to intervene and restore impaired processes. Goal will be to either guide communication or delay the stress-injury-damage cascade. Available knowledge is not always available in the wound care practice. An example is the use of pentoxifylline, which is well documented for years [16–20] yet rarely used. There are dozens of other interventions like pentoxifylline available. Not only on this level, but also on the other four levels in wound knowledge a smorgasbord of interventions is available. So the real problem is not even new knowledge but to make current knowledge available for the clinical practice.



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2         Hill S, Van Remmen H. Mitochondrial stress signaling in longevity: A new role for mitochondrial function in aging. Redox Biol 2014;2:936–44. doi:10.1016/j.redox.2014.07.005

3         Belaadi N, Aureille J, Guilluy C. Under Pressure: Mechanical Stress Management in the Nucleus. Cells 2016;5:27. doi:10.3390/cells5020027

4         Schieber M, Chandel NS. ROS function in redox signaling and oxidative stress. Curr Biol 2014;24:R453–62. doi:10.1016/j.cub.2014.03.034

5         van Vliet AR, Agostinis P. When under pressure, get closer: PERKing up membrane contact sites during ER stress. Biochem Soc Trans 2016;44:499–504. doi:10.1042/BST20150272

6         Krebs J, Agellon LB, Michalak M. Ca2+ homeostasis and endoplasmic reticulum (ER) stress: An integrated view of calcium signaling. Biochem Biophys Res Commun 2015;460:114–21. doi:10.1016/j.bbrc.2015.02.004

7         Elks PM, Renshaw S a, Meijer AH, et al. Exploring the HIFs, buts and maybes of hypoxia signalling in disease: lessons from zebrafish models. Dis Model Mech 2015;8:1349–60. doi:10.1242/dmm.021865

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9         Nikoletopoulou V, Markaki M, Palikaras K, et al. Crosstalk between apoptosis, necrosis and autophagy. Biochim Biophys Acta – Mol Cell Res 2013;1833:3448–59. doi:10.1016/j.bbamcr.2013.06.001

10       van Beek JHGM, Kirkwood TBL, Bassingthwaighte JB. Understanding the physiology of the ageing individual: computational modelling of changes in metabolism and endurance. Interface Focus 2016;6:20150079. doi:10.1098/rsfs.2015.0079

11       Yin F, Sancheti H, Liu Z, et al. Mitochondrial function in ageing: coordination with signalling and transcriptional pathways. J Physiol 2015;0:n/a-n/a. doi:10.1113/JP270541

12       Feldman N, Rotter-Maskowitz A, Okun E. DAMPs as mediators of sterile inflammation in aging-related pathologies. Ageing Res Rev 2015;24:29–39. doi:10.1016/j.arr.2015.01.003

13       Manson PN, Anthenelli RM, Im MJ, et al. The role of oxygen-free radicals in ischemic tissue injury in island skin flaps. Ann Surg 1983;198:87–90. doi:10.1097/00000658-198307000-00017

14       Lejay A, Meyer A, Schlagowski AI, et al. Mitochondria: Mitochondrial participation in ischemia-reperfusion injury in skeletal muscle. Int J Biochem Cell Biol 2014;50:101–5. doi:10.1016/j.biocel.2014.02.013

15       Mansour Z, Charles AL, Kindo M, et al. Remote effects of lower limb ischemia-reperfusion: Impaired lung, unchanged liver, and stimulated kidney oxidative capacities. Biomed Res Int 2014;2014. doi:10.1155/2014/392390

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17       Sharma R, Randhawa PK, Singh N, et al. Bradykinin in ischemic conditioning-induced tissue protection: Evidences and possible mechanisms. Eur J Pharmacol 2015;768:58–70. doi:10.1016/j.ejphar.2015.10.029

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19       Jull AB, Arroll B, Parag V, et al. Pentoxifylline for treating venous leg ulcers ( Review ). Cochrane database Syst Rev 2012;12:CD001733. doi:10.1002/14651858.CD001733.pub3

20       Falanga V, Fujitani RM, Diaz C, et al. Systemic treatment of venous leg ulcers with high doses of pentoxifylline: efficacy in a randomized, placebo-controlled trial. Wound Repair Regen 1999;7:208–13.