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 🙂
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
http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.1002165
http://ewma.org/english/publications/ewma-documents-and-articles/ewma-study-recommendations.html
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…
http://www.woundsresearch.com/article/real-world-experience-decellularized-dehydrated-human-amniotic-membrane-allograft
http://www.magonlinelibrary.com/doi/10.12968/jowc.2015.24.6.245
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.
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. / http://journals.plos.org/plosone/article?id=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)
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.
https://en.wikipedia.org/wiki/Red_Queen_hypothesis
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; http://iwgdf.org/
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: 
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.
http://www.jci.org/articles/view/32169/pdf
http://poi.sagepub.com/content/39/1/29.abstract (Thank you Lian)
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0124446
http://care.diabetesjournals.org/content/37/9/e196.extract
(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.)
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. http://doi.org/4jz (2015)
A new blog needs a new mini logo. That is why we have “W” with two arrows. It stands for: closing the gap from both sides. Which means we are trying to improve wound care both practical and theroretical.
Since 1962 we all know that wounds without a scab heal 40% faster compared to wounds with a scab. This has been tested on two pigs (Winter, Nature 1962) and seven inmates (Hinman, Nature1963). This means, since 1962, we all are convinced that a for instance diabetic wound on an 83-year-old will heal up to 40% faster, only if you apply a moist environment.
Reversibly you may also try to answer the question how much slower wounds would heal if you would use of moist gauze, which have to be changed up to 3 times a day. Almost 50 years after Winter some people have tried to answer this question (Ubbink DT et al, Arch Surg 2008). What appears was that moist wound healing was not better but actually worse than a conventional gauze treatment. But there was one remark, these findings apply only for wounds with an acute etiology (and in a hospital setting).
Ehh well yess…. what type of wounds were investigated in the Winter and Hinman papers?
But fair is fair, one study should not make a difference, scientific principles dictate a finding should be repeated several times in order to be accepted.
This is why we have organisations which examine the evidence. One of those organisation is the Cochrane foundation which has as purpose to help medical professionals in their decisions. The method they use is to ruthlessly examine all research papers against the highest standards. <http://www.cochrane.org/about-us>. And nothing is easier than to go to their website and read what they have to tell about wound care.
If I cite them randomly: negative pressure therapy, there is not enough evidence. (And it is not only Cochraine but also for instance Vig S et al, J. of Tissue Viability 2011), Alginate; there is no evidence that alginate is better than any other addressing, foams; conclusion is the same, no evidence. The only exception appears to be hydrogel were the conclusion is that hydrogel is have some evidence to be more effective compared to other dressings. Silver dressings, no evidence etc. After a quick glance I counted 105 studies with almost 10,000 patients which actually met the Cochrane criteria.
Cochrane provides one, real unnerving outcome, no one is able to prove or repeat the 40% faster promise from the original articles more than 50 years. Apparently it is not possible to design a study or do a study which is meeting current scientific criteria and show a 40% faster healing.
So we start reducing our expectations. Perhaps we are asking too much my looking for a 40% faster healing, so let’s settle for 20%, 10% or even 5%. That appears fair to me.
But even that is not possible, the most positive statement in these studies is “there is some proof”, which is quite different from 5% faster healing. Apparently it is not possible for any current wound care dressing to prove in a well-designed study it actually makes sense to use.
Now what, it appears we have a problem.
We are not able to prove how much a wound benefits from using a moist dressing. The next step would be to reverse the question, does it actually work? The answer to this question is very easy to answer, because there are plenty studies, meeting the highest scientific standards providing the answer, the Cochrane collection from above. The significant answer meeting the highest standards is: a moist environment does not lead to faster wound healing.
And this finally leads us to the heart of the problem. We have a Mexican standoff between 2 pigs, seven inmates and 285 clinical patients. I don’t believe that the Winter and Hinman articles were wrong. It doesn’t take rocket science to understand why a scab might be hindering wound healing progress. But I also don’t believe that the Cochrane findings have to be dismissed because they don’t fit our view on today’s wound care. It does mean we have a gap in our knowledge. The gap can be summarised as we are not able to explain why Cochrane and Winter are both right.
Interesting is that all stakeholders in wound care should be aware of this gap since there have been no repeating studies which proof the moist paradigm in different circumstances.
For some reason we have chosen to ignore this issue for the last 50 years which sadly also lead to 50 years of “less useful” research which papers invariably end with the conclusion “more research is needed”.
To me it appears we have some work to do.
To paraphrase: if not me, who… if not now, when.
Wether a wound heals or not is usually described as a balance, can the body handle what is going on in the wound? Logically we focus on what is going on on the “wound”-side of the balance. Nevertheless it is a balance and we may make good use of a word to summarize what is going on on the “bodily”-side of the balance. Why not use the word “vigor” ? Vigor originates from the Latin; vigere ‘be lively’. Generally it is used to describe the “force and strenght to live”. The amount of “Vigor” then has to outbalance the amount of “complexity” on the other side. Vigor is a favourable term because it is has a more holistic feel to it. Your vigor increases after a good night sleep but also with an antibiotic treatment. It also provides insight in why a wound might stall in its development (both ways).