Tag Archives: wound healing

‘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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Greaves, Nicholas S., Kevin J. Ashcroft, Mohamed Baguneid, and Ardeshir Bayat. 2013. “Current Understanding of Molecular and Cellular Mechanisms in Fibroplasia and Angiogenesis during Acute Wound Healing.” Journal of Dermatological Science 72 (3): 206–17. https://doi.org/10.1016/j.jdermsci.2013.07.008.

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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.

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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.