Finding your way around the human metabole

Wound care gets very interesting if you move away from casual observations or intervention comparisons. This has become easier the last decade, especially the “omic-type” diagnostic tools allow for analysis of large and complex systems. This enables us to move away from the trial and error type of research and look in depth into the wound. In general wound care articles mention genes or proteins.  Since genes and proteins are a major part of processes regulation in the body it makes sense to unravel the way they operate in regenerating tissue.  Freely quoting Goethe: All living things are connected if you do not see the connection you have not looked good enough. So we should be able to connect the dots, amongst others by reading literature or doing research. The knowledge in literature is fragmented. Luckily there are tools available to explore the context of the information:  The site reactome shows how the processes at a basic level are organised and thus allows us to connect at least some of the dots. The plug in ferret  provides depth and backround to the articles in pubmed etc. Both are tools for our endeavour to understand the incoherence of current wound care research.

Diabetic foot guideline reveals poor state of wound care science

Everyone knows diabetic foot wound treatment is challenging and should be undertaken with the utmost care. Even something seemingly simple as callus removal can lead to dramatic complications. The recommendations of the latest guidance on wound healing “IWGDF Guidance on use of interventions to enhance the healing of chronic ulcers of the foot in diabetes” are clear. Provide basic wound care for diabetic foot ulcers, this means clean, debride and take care of callus.  In this guideline there is no text regarding offloading,  vascular, neurological, immunological assessment etc. This does not mean it is not important, it means diabetic wound management is complex and those involved have to make sure they are competent. Do not apply any intervention lightheartedly.

In summary: Never forget to apply basic wound healing principles and know the limits of your expertise, you could very well be liable.

So far the good news.

The underpinning of the first part of this recommendation is as follows: GRADE strength of recommendation: Strong; Quality of Evidence: Low. 

GRADE is used because it appears to be better suited than the normal meta-analysis which provides even more dramatic results.

This means the working group cannot find any better evidence than “LOW” for a recommendation considered cornerstone to wound healing. For some reason I think; if they cannot find it, there is a good possibility it does not exist.

So today, 2015 the only thing we know about diabetic wound care is the experts have strong feelings but lack facts. We feel we should have a clean wound and select dressings based on absorption, comfort and cost. The latest facts could be over 60 years ago when captain Bloom made some observations using cellophane.

This leads to the following conclusions:

  1. We know very little about interventions to enhance healing.
  2. There is a lack of good research leading to recommendations. (cause 1 for finding 1, above)
  3. Most “hot” treatment options lack underpinning because a. they may not work or b. research is not well set up. (See finding 2, above)
  4. Lack of relevant and underpinned findings gives way to the wildest of treatment regimens. (See finding 3, above)
  5. The flurry of “research” and “protocols” might mask relevant findings. Therefore:
  6. We need clear and well-written guidelines until we have our research in order.
  7. To get our research in order, we have to stop doing the same type of research over and over again. (as we did the last 50+ years)
  8. If I am wrong (which I hope) please explain why the guidelines are written the way they are.

Finally, it just might be a good idea to do a reproducibility test on all wound care research. Like the recently done on psychology. Findings in this guideline point towards an even higher non-reproducibility rate for wound care research compared to psychology.

Guidance on wound healing 2015


The other natural dressing

The biofilm may be, next to the scab, the other natural dressing. The difference is the biofilm has to be changed like any other dressing.

Animal life and thus humans have evolved in the presence of microbes. This means there always have been bacteria, yeasts and fungi (microbes) in wounds.

It makes no sense for a microbe in a wound to cause an infection. If you kill your host you also destroy your home. As a microbe, it makes a lot more sense to create a situation in which the wound stays open and you and your host live long and (or not) happy.

This open wound situation would be an equilibrium between the microbe on the one end and the human body on the other. If you are a healthy person this will not be a problem. There is a reason we say “time heals all wounds”. Only if you are weakened by age or illness the balance can tip in the “advantage” of the microbe.

The biofilm is part of this game. At the beginning of times the first life was only primitive bacteria, They lived in the sea. They invented the biofilm which glued them to the rock and protected them against the waves and hostile chemicals.

If you as a microbe, want the wound to stay open you have first of all to protect yourself against the host immune system. This means you need a shelter. If not, here you can see what will happen. Apart from keeping it open you also have to protect the host and the wound against trauma and also against other pathogens which might me not so interested in the well-being of the host. During the human development the biofilm has been produced by microbes for this purpose; create and protect a living environment. It is pretty strong and made of sugars, proteins and is glued to the environment using eDNA.

The biofilm is a dynamic shelter or layer which is replaced regularly, animals lick their wounds and you brush your teeth. Apparently replacing it regularly is part of the equilibrium, just like any other bandage. Nature is used to this removal and within hours after removal, the microbe has started on a new biofilm. If this process or balance is disturbed an infection may occur. (in that case nature invented the maggot as a last resource to prevent infection) So the microbe-wound balance is a dynamic process which involves removal and rebuilding the biofilm. It can be disturbed by aggressive pathogens or by weakened hosts (patients).

All in all, I think the biofilm has two functions in the game between the human and the microbe.

  • protect the microbe.
  • protect the host.

All this is nice to know but what are the implications for today’s wound care?

Giving the average condition of our patients it is advisable to deal with biofilms.

The best way to remove a biofilm is to debride the wound. That is a good idea anyway because by debridement you remove also other sources of infection and cell death. As you will understand from above, debriding means cutting, brushing, rinsing and all kinds of other forms of mechanical cleaning.

All in all the biofilm can be seen as a natural bandage. And just like any other bandage you have to change it regularly, check for signs of infection and do not leave it in the body (and certainly not on prostheses.

Treating wounds is a delicate game. Looking at it as a biologist makes a lot of fun and hopefully will help us learn how to hack the wound healing process. If you have a question, just contact me via LinkedIn.

If you think the idea is worth spreading, liking it will help.

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.

The question

There is one question wound care specialists typically do not ask. If Winter and Hinman proved the use of cling film speeds up wound healing by 40%, why are there hardly any studies repeating the phenomenon in a clinical setting and do meta-analyses invariably deliver hardly any or no effect.  It seems to me the gap between Winter (animal research, evidence level C), Hinman (evidence level B) +40% and meta-analyses  (evidence level A1) +/- 0% requires an explanation. To me it is a logical question for a logical problem: the gap is too large, we cannot find 40% and 0% outcome at the same time. So who sheds some light on the logic behind the phenomenon?

Basic steps in wound care: debridement

Debridement is considered a cornerstone in wound care. Common sense dictates only a clean wound heals. Observing animals lick their wounds adds to this.
It remains the question if and how debridement translates to the clinical practice.

IF: Wilcox checked this in 2013. In  a study of 154 644 patients with 312 744 wounds of all causes debridement were checked as a parameter.  He found the following. The more frequent the debridements, the better the healing outcome. Although limited by retrospective data, this study’s strength was the analysis of the largest wound data set to date.


The bias is in the quality of the data where you do not know if debridement was the only parameter which differs between the groups, however this is offset by “n”, the sheer number of subjects. They explain further in the article.

The best way to debride is to surgical debridement were all dead material is removed using scalpels, forceps, scissors etcetera. If sharp debridement is not possible alternative methods may be used.

It is important to also keep biofilms in mind, they may be not visible. In a non-healing wound it should be removed, in a healing wound it may be wise to leave it in situ. Common sense dictates removing is more damaging than leaving it in situ.

Frequency of Debridements and Time to Heal: A Retrospective Cohort Study of 312 744 Wounds.  James R. Wilcox, RN ; Marissa J. Carter, PhD, MA; Scott Covington, MD

HOW: debridement works seems simple but leads to other questions. It works because you remove debris and other causes of infection in the wound.You also help the body removing unwanted material.  But if you rephrase the answer to it works because you remove barriers to healing you may have to take a second look. Not only debris itself but also tissue directly adjacent to the wound may be a barrier to healing. This leads to the question: which living tissue is a barrier to healing. ..the road to debridement 2.0

Debridement 2.0
Sometimes it may make sense to debride the wound to the point where you remove some living tissue as well. For instance in burns. Presumably in the near future we discover other instances where removing living tissue. Al in all the affected area is usually larger than the wound itself. This is often overlooked in research. Subjects: burn wounds, but also scar tissue and, but we do not know that, metabolically impaired tissue. This is one of the almost uncharted areas in wound care.

nihms235813f4In some cases a closer observation will reveal which “visible” healthy tissue is compromised. This allows to identify and remove more damaged tissue. In the future, this may speed up healing.

Using Gene Transcription Patterns (Bar Coding Scans) to Guide Wound Debridement and Healing
Marjana Tomic-Canic, PhD, RN, Director, Elizabeth A. Ayello, PhD, RN, ACNS-BC, ETN, FAPWCA, FAAN, President, Olivera Stojadinovic, MD, Instructor, Michael S. Golinko, MD, MA, General Surgery Resident, and Harold Brem, MD, Chief

Surgical wound debridement sequentially characterized in a porcine burn model with multispectral imaging.
King DR, Li W, Squiers JJ, Mohan R, Sellke E, Mo W, Zhang X, Fan W, DiMaio JM, Thatcher JE.




Take away:

  1. Proper debriding makes sense.
  2. Proper means clean but also by using the right knowledge and skills.
  3. And thinking on something as simple a removing stuff from a wound may bring progress.
  4. Agree to disagree…discussion improves wound care

Here is a lecture on debridement.

Woundcare spending

How much do we spend on wound care in relative and absolute terms is a hard question to answer. Luckily we have some information thanks to the Welsh NHS system which provides some data.

The article in the total cost of managing patients with chronic wounds in Wales amounted to £328·8 million – an average cost of £1727 per patient and 5·5% of total expenditure on the health service in Wales.  With a prevalence of 6%. Not too far away from the Welsh expenses on Cancer. The figures for 2012-13 show the total spend has increased from £356.8m in 2011-12 to £360.9m in 2012-13.

So there you have it!

Wound care is expensive, it equals the cancer expenses (90%). Wound care costs were generally believed to be somewhere between 1,5-4% on any healthcare budget. This article adds the number 5.5%. If wounds were a disease it would be easily in the top five of any health care list. I am no specialist but I would bet these numbers are not that different for any EU country.  However, apparently it is not a disease because it rarely shows up on those lists.

First question to answer is: is this real? The answer is: we do not know. We have combined figures from very different sources, there may be logical errors in combining them. And wound care costs are varying from 1 to 5,5%… also not exactly strong data.  And then the question inevitably is: what costs are inside the data we compare?

But even if the data are questionable there are a few issues we should think about.: The sheer number of people literally suffering from wounds; not a few but a significant part of your population up to 6%. And even at low estimates the numbers demand attention.

So how are wounds looked at?
Insurers may see it as a cost disease (Baumol).
Most doctors see it as a complication instead of an indication.

Reality is, it is not a disease but an expensive complication where we, even though many suffer from it, know very little of. I would strongly advice to make it an indication, have a fresh look at the issue and start over. Research not progressing to the point where we have a strong underpinning is paradoxically a chance. I am happy to explain the intellectual challenges and opportunities this field has. Proper research will not magically shrink expenses or turn it into a disease, it will only justify why we spend so much on it. And hopefully bring the much needed attention.


Sources: Estimating the costs associated with the management of patients with chronic wounds using linked routine data – Phillips – 2015 – International Wound Journal – Wiley Online Library

Epic failure: Hyperbaric oxygen therapy for treating chronic wounds

The Cochrane published the review Hyperbaric oxygen therapy for treating chronic wounds (original article)

Here are the results:

  • For diabetes-related foot ulcers, we found that HBOT seemed to improve the chance of healing in the short term (up to six weeks), but not with longer term follow-up. HBOT may reduce the number of major amputations in people with diabetes who have chronic foot ulcers.
  • For chronic wounds caused by a disease to the veins of the leg, we found that HBOT may reduce the size of wounds.
  • For chronic wounds caused by lack of blood supply through the arteries or chronic pressure ulcers, we found no evidence to confirm or refute any effects of HBOT.

These results are to be expected. Not because HBOT is not working, but because researchers lack critical information, simply because it is not available. The Cochrane results are inevitable and reproducible non-conclusive but Cochrane is not to blame. Let’s explain two of the many logical errors causing the failure of wound care research.

It starts with the inclusion criteria. If your inclusion criterion is “a non-healing wound”, you are lost from the start. (the real list is below) There are many reasons wounds do not heal. They can, for example, be patient related, wound related, mechanical or metabolic. (Levels 1,2,3 and 4 which are usually independent of each other)

The first notion regarding chronic wound is that wat caused it, is not necessarily preventing it from closing. Yet we place them all on a pile, sorted by cause of the wound (logical error 1) and then investigate if intervention x is functional. So you are testing in the blind, which is very different from double-blind. That is a gross neglect of reality.

Therefore, if you are lucky,  you will discover how many non-healing wounds accidentally fit your solution (logical error 2). This is very different from finding how effective your intervention is. In today’s setup, it is therefore almost impossible to discover how effective your intervention is. Because we lack markers and/or knowledge to diagnose and characterize the cause of not healing. Therefore, we have no choice but to pile wounds together. It is a pity we do not recognize this beforehand. If you cannot select the wounds which are lacking the solution you provide, the chances of success are next to 0. (logical error 1+2)

And now the real issue: it would be very interesting to figure out which wounds respond. And why and how they respond. This will enable us to recognise this the next time before we apply an expensive treatment. Or in other words, the non-responders are more interesting than the responders. Sadly research is acting in exact the opposite way.

It starts with the inclusion criteria. If your inclusion criterion is “a non-healing wound”, you are lost from the start. (the real list is below) There are many reasons wounds do not heal. They can be patient related, wound related, mechanical or metabolic. (Levels 1,2,3 and 4 which are usually independent of each other)


And now the real issue: it would be very interesting to figure out which wounds respond. And why and how they respond. This will enable us to recognise this the next time before we apply an expensive treatment.

If you need help:


Inclusion criteria varied in these trials. Doctor 1992 included any person with diabetes with a chronic foot lesion (time not specified); Faglia 1996a included people with diabetes and Wagner grade 2, 3 or 4 lesions (Wagner 1987); Lin 2001 and Kessler 2003 people with “early diabetic feet”, Wagner grades 0, 1 or 2, while Duzgun 2008; Abidia 2003 and Londahl 2010 included people with diabetes whose lesions had been present for more than four weeks, six weeks and three months respectively. In addition, Londahl 2010
required evidence of good standard wound care in a specialist clinic setting for a minimum of two months. Exclusion criteria generally followed from the specific inclusions detailed above, but Abidia 2003 also specifically excluded participants for whom vascular surgical procedures were planned and Kessler 2003 excluded all patients with transcutaneous oxygen tensions of < 30 mmHg. Ma 2013 included patients with diagnosed diabetes, at least one fullthickness wound below the ankle (Wagner grades III or less) for > 3 month, standard care for > 2 month, TcPO2 > 30 mmHg. Khandelwal 2013 included patients with a diabetic foot ulcer of at least 8 weeks duration, patients with only stage III and IV diabetic foot ulcer and the absence of vascular insufficiency.

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.