5 levels

A simple rearrangement to five levels of wounds may help us better understand wound healing. It may also function as a sieve.

The levels are the following:

  • Level 0: wounds which will heal without any intervention
  • Level 1: wounds which will heal without any intervention but must be monitored
  • Level 2: wounds that heal by itself but may need additional care.
  • Level 3: wounds that will not heal due to perfusion issues.
  • Level 4: wounds that will not heal due to are metabolic issues.

This simple separation may help in understanding difficulties in wound healing because each level requires a different skill set.


Homing lymphocytes

In this small film you can see how lymfocytes are attracted to a wound in a zebraqfish model. Seeing the process makes it easier to understand. Question remains…how does the lymphocyte know what to do?


Level 1

Neutrophil chasing bacteria

What would you do if you were a microbe. Swim along or build a shelter?
A 16-mm movie made in the 1950s by the late David Rogers at Vanderbilt University.

Level 2

Diagnosis of wound infections


Brilliant lecture by Benjamin Lipsky on diagnosis of wound infections. It appears we have no tools (yet) to really analyse what is going on in the wound. This means we also do not understand exactly what the role of each bacterium is in wound healing.
This lecture rightfully  increases your uncertainty towards wound infections.

My concluson is that anyone who appears confident while making a comment on wound infection should be treated with care 🙂


Low reproducibility rates within life science research undermine cumulative knowledge production

To cite the article below: “Low reproducibility rates within life science research undermine cumulative knowledge production“. Wound care research provides an excellent example. Quoting the EWMA Study Recommendations for clinical investigations in leg ulcers and wound care (2014) “However, we are all aware that the quality of many studies in this field remains poor and we would be doing a disservice as the European Wound Management Association if we did not encourage our members to join in the challenge of raising the quality of studies for the benefit of our patients.” This is 2015!

Wound care research more than often (def)end inconclusive articles with the phrase : “more research is needed”. The result may be inconclusive but the expert opinion is not, research was flawed because it does not proved the result the author was expecting based upon his or her expert opinion. In this little sentence you may already feel the importance of the expert opinion. It is interesting to notice meta analyses with conclusive results are put aside to the benefit of expert opinions. The expert opinion is leading in wound care. This means the wound care specialist concludes the meta analyses are based on wrong data and prefer their own opinion (expert opinion).

The “expert opinion” leads to the following observation: either it is impossible to do wound care research or we have a massive logical error preventing us to come up with widely accepted meta analyses. Anyway, following the international guidelines meta analyses are leading, not the expert opinion. But no matter who is right, in 2015 we still are using the same paradigms as in 1943.

So the conclusion of this article is valid for wound care; yes, there has been no cumulative knowledge production in wound care. (for 70 years)

Freedman LP, Cockburn IM, Simcoe TS (2015) The Economics of Reproducibility in Preclinical Research. PLoS Biol 13(6): e1002165. doi:10.1371/journal.pbio.1002165
E L Howes. The rate and nature of epithelization in wounds with loss of substance SGO 1943 Vol 76 (738-745)

below are two random articles, feel free to do your own research…

Level 2 Level 4

Microbiome; the shepherd and the flock

Many bacteria in the wound are unknown to us. This is why they call it dark matter in the article below. We know it is there but cannot see it. The entire system in a wound bed is called the microbiome, it may be compared to a city in its diversity and complexity. We are now beginning to understand what this means to wound healing. In a healthy subject, the microbiome may well be part of the normal wound healing process whereas in a compromised wound it may have a very different role.

One reason for looking into this is pure curiosity. Another may be to discover new bacteria and new ways bacteria and human cells live together in the wound. The last and more intriguing reason is S aureus and P. aeruginosa may be just the flock while we still have to find the shepherd. Like P. gingivalis is a shepherd in gingivitis. In the article of Hajishengallis it is described that a les abundant microbe is actually controlling the mouth microbiome like a shepherd controls a flock. Metagenomic research may bring us something, if only if S.aureus and P.aeruginosa are flock or shepherd. Hopefully, it will unravel the systems in the wound which may be more important that the individual cells. (meaning the system describes roles to be fulfilled and which organism actually fulfills it is less important.) Anyway, let us hope we are abele to discern between detrimental microbes and microbes which have a more positive role in wound healing.

In the end, this type of research will allow us to decide when and how to remove the microbiome or when it makes sense to take a more probiotic approach.

  2. Hajishengallis, G. Lamont, R. J. Breaking bad: Manipulation of the host response by Porphyromonas gingivalis.  Eur. J. Immunol. 44.2.1521-4141
Level 3 Level 4

Refuelling cells

Elegant article on delivering intracellular ATP in a “level 3” animal model.  It’s like refuelling the tank.  Due to the ischaemia the cells may have been somewhat starved for energy. External energy in the form of ATP in lipid vehicles, which apparently reaches inside the cell, leads to faster wound healing. Not all cells respond similarly, granulation tissue responds with a kind of hyper granulation. Apparently it is more sensible to the ATP or just receiving more because it is at the surface of the wound bed. They have looked in depth at the energy  metabolism in the cell and thoudn bed. A refreshing approach to non-healing wounds where these days reseach focusses on inflammation and infection. What would happen if we combine this level 4 metabolic approach, to a proteomic/metobolomic shotgun analysis.  Until then, as the authors cite a 1943 study: “Howes tested the healing effects of various drugs and concluded that: 1) epithelialization begins after a latent period of 3–6 days, during which the underlying connective tissue is hardly regenerated at all; 2) a suitable granulating base is necessary for epithelialization to begin; and 3) the requirement for frequent dressing changes prolongs the latent period due to tearing away of the regenerating cells”. It appears wound care is still in the previous century.

Howard JD, Sarojini H, Wan R, Chien S. Rapid Granulation Tissue Regeneration by Intracellular ATP Delivery-A Comparison with Regranex. Yamamoto M, ed.PLoS ONE. 2014;9(3):e91787. doi:10.1371/journal.pone.0091787. /
E L Howes. The rate and nature of epithelization in wounds with loss of substance SGO 1943 Vol 76 (738-745)

Level 4

Bacteria and phagocytosis

The dynamic host-microbe interaction keeps getting better.

You just think; once a bacterium has been eaten by a macrophage it is the end!  Well it may be, but it may be not.

Apparently some bacteria benefit from being phagocytosed.  Pseudomonas aeruginosa and E.coli have some genes which allow them to metabolise lysosome fluid. Are they hitchhiking on a macrophage to get to places they normally would not come? It will be a matter of time before we describe a similar process for S. aureus, they already behave suspicious. And how does that make you feel about wound healing and the microbiome?

Bacterial itaconate degradation promotes pathogenicity.
Sasikaran J, Ziemski M, Zadora PK, Fleig A, Berg IA.
Nat Chem Biol. 2014 May;10(5):371-7. doi: 10.1038/nchembio.1482. Epub 2014 Mar 23.

Kicking Out Pathogens in Exosomes.
Sergeeva OA1, van der Goot FG2.Cell. 2 015 Jun 4;161(6):1241-2. doi: 10.1016/j.cell.2015.05.040.

Level 1 Level 2

Diabetic Foot Complications

As we read through the literature we get a view on the severity of diabetic foot ulcerations. Copy/pasting from the articles below we get the following picture.

Chronic nonhealing neuropathic foot ulcers occur in approximately 15% of patients with diabetes. In 2011, there were an estimated 366,000,000 adults with diabetes. Worldwide global projections indicate that this figure will increase to 552,000,000 by 2030. It is estimated (2003) that 24.4% of the total health care expenditure among diabetic population is related to foot complications and the total cost of treating diabetic foot complications is approaching 11 billion USD in USA and 456 million USD in UK. Wound care in general costs 2-5% of your national health expenditure. (billions) Hospital-based studies have shown that mortality rates in individuals with diabetic foot ulcers are about twice those observed in individuals with diabetes without foot ulcers.

To sum it up, diabetic foot lesions involve a lot of people, a lot of suffering, a lot of money and time and they “have legs for breakfast” and may “kill you overnight”.

So what do we do about it… not much!

Despite the effort of many dedicated clinicians who, we cannot thank them enough, take up the Sisyphean task of point out the importance of prevention, monitoring and treatment we still are stuck with an ever increasing number of diabetics suffering from ulcers. Some policy makers even cut cost on this issue with dramatic effects.  The number of diabetic foot ulcers can be reduced significantly. Therefore it is today still shocking to see how many “chronic” ulcers heal within 7 weeks in the right hands.

Just to make sure; anyone dealing with diabetic ulcers is supposed to know and apply the national and international guidelines;

Make no mistake, diabetic ulcers can be very hard to treat for many reasons and some will never heal. The problems “behind the ulcers” are daunting and need to be solved. Nevertheless, as often, the first steps to treat a foot ulcus are straightforward.

First and best is to make sure someone who has a diabetic foot wound gets basic wound care. It is not rocket science but for some reason the average medical professional is having a tough time to set up prevention and often is not able to deliver level 1 and 2 wound care.

What is level 1 and 2 wound care?

Level 1 and 2 wound care are on both sides of the wound healing equilibrium.

A healthy person can handle most wounds without much ado (Vigor), level 1 is aimed at increasing Vigor. If the wound is large or complicated the body will need help (Severity). Level 2 is aimed at reducing severity.

Ergo, the equilibrium:        Balans-EN

Level 1 is to make sure the patient has the best possible health under the circumstances: 1. take care of diabetes regulation 2. remove stress (and get some sleep) 3. eat properly and 4 mobilize as much as you can.

Level 2 is debride the wound at least twice a week (debriding = remove anything which is not living cells (debriding is not mopping a wound with a gauze)) and secondly apply enough pressure to the wound to handle oedema. That is it.

If you do not know how to debride a wound properly or are not able to; transfer the patient to someone who is better able to treat the ulcer.

If the wound does not start healing in 2 weeks, step up your effort or even better, transfer the patient to someone who is better able to treat the ulcer.

Once healed, step up prevention and monitoring to the max.  (Thank you Lian)

(Debriding is a medical intervention which only skilled medical professionals are allowed to do. A non-healing wound has to be seen by a specialised doctor or nurse.)

Level 1

Gut biofilms could spur cancer

Microbiome remains an interesting issue:

Some articles make you think about wound care and what is happening in the wound, This is one

Chemicals secreted by gut bacteria are linked to human colon cancers.
Metabolites called polyamines are made by gut bacteria to help them to form sticky aggregates called biofilms, and are used by human cells to regulate proliferation. Cynthia Sears at Johns Hopkins University in Baltimore, Maryland, Gary Siuzdak at the Scripps Research Institute in La Jolla, California, and their colleagues compared tissue samples from human colon cancers to those from healthy people, both with and without biofilms.

They found that cancer tissue with biofilms had 62 times more of the polyamine metabolite N1,N12- diacetylspermine than did healthy tissue with biofilms. Yet in samples that were biofilm-free, the cancer tissue contained only around 7 times more polyamine than the healthy sample.  Antibiotic treatment reduced levels of this metabolite, suggesting that it comes from bacteria. Therapies that target polyamine formation and biofilms could be a way to treat colon cancer, the authors note. Cell Metab. (2015)