Level 0 Level 1 Level 2 Level 3 Level 4

An open letter to the Presidents of NPUAP and EPUAP

Open letter to the Presidents of NPUAP and EPUAP

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Dear Madam Presidents,

We have been engaged and working within the ‘inbed’ * patient care sector for over 20 years; as health and social care practitioners, researchers and product developers. Today, we are deeply concerned that the NPUAP changes in ‘pressure injury’ terminology and ‘pressure ulcer’ classifications do not reflect the underlying causes of skin and tissue damage and that there has been selective use of the research from which the review was initiated.

We call on EPUAP during its review of the terminology and classifications to consider the views below and we suggest both NPUAP and its Staging Task Force to consider – in the light of the points below – whether their process really did produce the best outcome.

The pressure ulcer staging consensus is a further development of the original guidelines published in 1975. The updating processes in is described in the your first reference [1].  The procedure was divided in two parts, statements from which are backed by research and are a result of the consensus processes. However, it is not clear on what ground decisions were referred to either research or consensus. For example:

  • Do not use DTPI to describe vascular, traumatic, neuropathic, or dermatologic conditions

This is in conflict with the research findings where vascular disease is a causing factor of deep tissue injury[2–6].

  • The statement from the first reference in the document: “The staging system for pressure injury of the skin cannot be used to stage mucosal membrane pressure injury”.

In what way are mucosal membranes so different anatomically that not one of the proposed seven stages is applicable?

  • The literature selection process: “The CINAHL and MEDLINE electronic databases were searched individually; this search yielded 3652 articles. Task Force members completed title and abstract reviews, along with full text review. Two hundred forty-two articles were deemed relevant to the task at hand. In addition, references submitted by stakeholders and the public during the comment period were retrieved and reviewed for relevance to the goals of the Task Force.”

This statement Is biased due to the addition of stakeholder references for two reasons. Firstly, adding extra articles by stakeholders implies the original algorithm is sub optimal. Secondly, hand picking articles is biased by definition; especially since they added to the original 242 articles.

  • It appears the consulted professional and government or regulatory organisations are primarily nursing-based organisations rather than a balanced sample of stakeholders.

Position Statement 1: The diagnosis of a “pressure injury” does not mean that the health care provider(s) “caused” the injury.

Tissue damage associated with patients being cared for ‘inbed’ have been historically called pressure ulcers, pressure sores, bed sores/ulcers, decubitus ulcers and other names. The latest term being used is pressure injury. Since the word pressure is used to describe pressure, shear and tension depending on the direction of the forces involved, a more accurate description is ‘force-related tissue damage’ and so we will be using this term throughout this response.

The fact that an entire paragraph is dedicated to the word “injury”, indicates that the NPUAP foresees legal problems in the words used.

For example, anticipatory design of both products and practices must be used to enable tissue damage prevention when moving and stabilising a patient being cared for ‘inbed’ by:

  • creating the correct resting-surface/patient synergetic support layers
  • requiring the products/practices to work with gravity, rather than against it.
  • preventing tissue strain in static and moving situations

Position Statement 2: Some pressure injuries are unavoidable despite provision of evidence based care by the health care team.

The second position statement is on the avoid-ability of force-related tissue damage. However, NPUAP fails to provide qualitative or quantitative data on the number of an unavoidable force related injuries.

  • Whilst the references speak of unavoidable “pressure sores”, they do so in relation to the availability of high-quality care. This qualitative approach indicates a larger chance of developing an “unavoidable “ulcer yet no quantitative evidence is provided to substantiate this.
  • However well-intentioned the currently accepted and evidence-based ‘inbed’ care practices and products are, patients are still suffering. Some patients are more prone and of a higher risk to tissue damage (for example due to spinal cord injury or are of older age). However, there are those patients who don’t fit into these categories that are also prone and are at risk to tissue damage when the body’s threshold of resistance and/or ability to recover from damage, is exceeded.
  • The real issue of this statement is a cost-benefit analysis and indicates that the number of so-called unavoidable ulcers can be reduced even further with the use of advanced medical and nursing techniques. A casual glance at related medical fields like cardiology, nephrology and brain research shows there are many readily available diagnostic techniques and interventions to prevent and/or resolve forced-induced injuries. However, this raises the question whether society is able or willing to carry the cost involved with avoiding “the last ulcer”.

The second part of paragraph 2 points the eventual plaintiff towards asking if the best available care has been applied. Available care would include current available standard medical procedures which are applicable for wound care. It would be fair to say that the non-availability of these tools would and should not be accepted as a reasonable argument by a judge in 2017. This raises the question why non-availability of basic medical procedures is acceptable for a health care provider or any other medical professional.

The best available care would indicate that all the ways external forces can compromise a patient’s ‘inbed’ tissue integrity have been avoided. These would include:

  • Avoiding any unnecessary external forces that can be generated by how the patient is rested, how they are moved and how they are re-stabilised, both during and after their body mass has been re-orientated.
  • Avoiding harmful forces generated as a result of both inconsistent manual handling practices and the use of mechanical means that are working against gravity and trying to overcome the gravitational pull forces that are keeping the patient stable.
  • That these external forces are controlled in a way that any patient movement and stabilisation works with rather than against gravity. Allowing the body to move and be re-orientated safely, further compliments and supports the body’s innate homeostasis to keep the patients skin and tissues within its natural threshold of resistance and repair. Thereby, maintaining its optimum tissue integrity.

NPUAP and EPUAP needs to recognise that new research is available to show that the best available care would also include managing the one major external factor in the patient’s environment in all ‘inbed’ tissue damage occurrences: the patient interfaces with a resting/support surface.

Position Statement 3: The numerical staging system does NOT imply linear progression of pressure injuries from Stage 1 through Stage 4, nor does it imply healing from Stage 4 through Stage 1.

The fact that the third position statement actually states that there is no logical connection between the stages in the consensus document is interesting because the four-stage wound healing process is exactly describing healing from stage 4 to stage 1 (Wikipedia).

By stating this, NPUAP appears to be concluding that each stage has its own specific aetiology and that underlying pathology may be a connection between the stages. We agree and challenge NPUAP and EPUAP that force related tissue injuries should therefore be staged/classified based on the underlying pathology.

Position Statement 4: The NPUAP Staging System classifies pressure injuries based on the type of tissue loss that can be visualized or directly palpated.

The fourth position statement is identifying the exact problem. The classification is based on type of tissue loss that can be visualised or directly palpated. Not only is the classification superficial, it also denies underlying pathology, for example, why is a mucosal force related injury unstageable?

Imagine what the clinical relevance a classification based on type of tissue that can be visualised directly palpated for any type of wound would be? It is immediately clear that this classification is descriptive but bears no relation to the aetiology or possible interventions and is therefore not clinically relevant. Categorising a wound as unstageable can, under circumstances, be considered evidence of neglect due to lack of debridement.

Classical diagnostic tools such medication (STOPP/START) screening [7,8], lab values[9,10], biomarkers[11,12], tissue sampling[13,14] and imaging[15,16] are not mentioned in the guidelines. Advanced diagnostic tools such as (epi) genetic[13,17–19], proteomic[20] and metabolomic[21,22] screening are also not mentioned.

Position Statement 5: The pressure injury may be more extensive than initially apparent. The wound base and surrounding tissue should be assessed for variations in sensation, temperature, firmness, color and any expression of drainage from surrounding tissues when palpated.

Position statement five is claiming that there is more than meets the eye. However, these findings are to be noted but are neither qualified, quantified or part of the staging process. This is a very true statement. There are at least 22 internal factors that can contribute to the loss of optimum tissue integrity i.e. that can cause/contribute to both a reduction in the tissue resistance threshold and/or a reduction in tissue recovery. These include generic factors (such as stress), systematic factors, structural factors and local factors.

It would be better therefore, if statement 5 would be reframed to diagnosis of pre-clinical events leading to stress, injury and damage at a molecular, cellular, tissue organ and organism level. That would be a nice starting point for bringing wound care to this century.

Position Statement 6: Deep Tissue Pressure Injury (DTPI) may evolve into a full thickness wound despite optimal care.

Position statement six is actually the same as position statement five. In court, however, this would make a difference. Interesting statements such as NPUAP’s “Off-loading the area still offers the best chance for tissue that is ischemic or injured, but not infarcted” is in conflict with medical ethics where chance should be avoided at all times. You may consider: “diagnostic tools for assessing and grading DTI, endothelial status and reperfusion injury are being investigated”.

Position Statement 7: Any pressure injury should be treated in accordance with current evidence-based practices and monitored closely for changes that require re-evaluation of treatment strategies.

Position statement seven is correct. However, guidelines do not allow proper execution of the statement. Close monitoring for changes that require re-evaluation of treatment strategies based on the six stages is dangerous and ethically questionable. NPUAP appears to realise this because they provide examples of deep tissue injury developing into a stage IV injury. However, having to explain this implies that the current guidelines are not sufficient for prescribing and handling the events related to force related injuries.

However, we challenge NPUAP and EPUAP to promote that force-related tissue damage prediction and  prevention rather than treatment is always the preferred approach to maintaining optimum tissue integrity. Evidence-based care should be demonstrating that

  • The patient’s ‘inbed’ environment provides the optimal synergetic resting support surface layers including the bed frame, bed mattress, bed mattress cover, sheets, any incontinence slide, the patient’s clothing, the patient’s skin and tissue
  • That external forces are controlled in a way that any patient movement and stabilisation works with rather than against gravity to maintain optimum tissue integrity. i.e. allows the body to move and be re-orientated safely, by allowing the body’s innate homeostasis to keep the patients skin and tissues within its natural threshold of resistance and repair.
  • The care provided allows the body to protects and repairs its internal environment by using both physiological and biomechanical mechanisms (tensegrity) and homoeostasis to maintain optimum tissue integrity.


The NPUAP document on current staging of pressure related injuries is superficial and does not make use of current available knowledge and techniques. It does not measure up to modern standards of care.  The fact that the methodology used is entirely ignoring underlying pathology in a way that it would be criminal to use pressure injury staging methodology on, for instance, a leg ulcer.

The claim that,” The NPUAP has provided the gold standard for diagnosis and classification of pressure injuries for nearly three decades, and counting.” Is therefore not entirely correct.

The document focuses solely on treatment rather than prevention:

  • It does not address the gap of what should be and what is available for both the caregiver and the care receiver.
  • It does not promote the best-practice for designing out unsafe practice (higher-level hierarchy risk control),
  • It does not eliminate the use of unsuitable products
  • It continues to rely on monitoring compliance
  • It overlooks the designing-in prevention and a safer care trajectory

By taking this safer, combined ergonomic and biomechanical approach, NPUAP and EPUAP can make a real difference to the occurrence of force-related tissue damage and remove the risks to both carers and patients associated with ‘inbed’ care and positioning.

NPUAP and EPUAP need to promote the evaluation and use of technology to fill in the gaps for inconsistencies in patient care and should give the patient and carer what they need:

  • Patients need a safe environment (social or hospital) to enhance their care.
  • Whilst being cared for ‘inbed’, they need to avoid tissue damage.
  • They require effective infection control that prevents them contracting other infections whilst receiving their care.
  • They need to be at an optimum temperature.
  • Nurses and carers need products that are intuitive and easy to use, and are compliant with safe patient care expectations and regulation.


Phil Strong SRN RNMS Cert. Ed CT NT, Managing Director & Product Designer, Ergo-Ike Ltd, Associate Member of the CIEHF

Harm J Smit MSc, Wound Care Biologist, BioMedServ

*    By “inbed” we mean: any resting /support surface facility which enables the patient to receive care, support and movement. This can include for example: beds (domestic/clinical), theatre tables, theatre trolleys, gurneys and X-ray tables, chairs and wheelchairs. Although this list is not exhaustive.


1           Edsberg LE, Black JM, Goldberg M, et al. Revised National Pressure Ulcer Advisory Panel Pressure Injury Staging System: Revised Pressure Injury Staging System. J wound, ostomy, Cont Nurs Off Publ Wound, Ostomy Cont Nurses Soc2016;43:585–97. doi:10.1097/WON.0000000000000281

2           Farid KJ. Applying observations from forensic science to understanding the development of pressure ulcers. Ostomy Wound Manage 2007;53:26–8, 30, 32 passim.

3           Mekkes JR, Pasch MC, Meijs M, et al. Acquired arteriovenous malformation induced by pressure: a case report. Vasc Med 2003;8:201–2. doi:10.1191/1358863x03vm497cr

4           Nagel T, Loerakker S, Oomens CWJ. A theoretical model to study the effects of cellular stiffening on the damage evolution in deep tissue injury. Comput Methods Biomech Biomed Engin 2009;12:585–97. doi:10.1080/10255840902788603

5           Loerakker S, Solis LR, Bader DL, et al. How does muscle stiffness affect the internal deformations within the soft tissue layers of the buttocks under constant loading? Comput Methods Biomech Biomed Engin 2013;16:520–9. doi:10.1080/10255842.2011.627682

6           Solis LR, Liggins AB, Seres P, et al. Distribution of internal strains around bony prominences in pigs. Ann Biomed Eng 2012;40:1721–39. doi:10.1007/s10439-012-0539-y

7           Hill-Taylor B, Walsh KA, Stewart S, et al. Effectiveness of the STOPP/START (Screening Tool of Older Persons’ potentially inappropriate Prescriptions/Screening Tool to Alert doctors to the Right Treatment) criteria: Systematic review and meta-analysis of randomized controlled studies. J Clin Pharm Ther 2016;41:158–69. doi:10.1111/jcpt.12372

8           Levine JM. The Effect of Oral Medication on Wound Healing. Adv Skin Wound Care 2017;30:137–42. doi:10.1097/01.ASW.0000512112.60254.28

9           Gould LJ, Olney CM, Nichols JS, et al. Spinal Cord Injury survey to determine pressure ulcer vulnerability in the outpatient population. Med Hypotheses2014;83:552–8. doi:10.1016/j.mehy.2014.08.027

10         Callahan D, Keeley J, Alipour H, et al. Predictors of Severity in Diabetic Foot Infections. Ann Vasc Surg Published Online First: 2015. doi:10.1016/j.avsg.2016.01.003

11         Lindley LE, Stojadinovic O, Pastar I, et al. Biology and Biomarkers for Wound Healing. Plast Reconstr Surg 2016;138:18S–28S. doi:10.1097/PRS.0000000000002682

12         Tegl G, Schiffer D, Sigl E, et al. Biomarkers for infection: enzymes, microbes, and metabolites. Appl Microbiol Biotechnol 2015;99:4595–614. doi:10.1007/s00253-015-6637-7

13         Januszyk M, Gurtner GC. High-Throughput Single-Cell Analysis for Wound Healing Applications. Adv wound care 2013;2:457–69. doi:10.1089/wound.2012.0395

14         Voegeli D, Lwaleed B. Back to basics: histological, microbiological and biochemical sampling in wound care. J Wound Care 2013;22:650–2, 654. doi:10.12968/jowc.2013.22.11.650

15         Stekelenburg A, Strijkers GJ, Parusel H, et al. Role of ischemia and deformation in the onset of compression-induced deep tissue injury: MRI-based studies in a rat model. J Appl Physiol 2007;102:2002–11. doi:10.1152/japplphysiol.01115.2006

16         Linder-Ganz E, Gefen A. Stress analyses coupled with damage laws to determine biomechanical risk factors for deep tissue injury during sitting. J Biomech Eng 2009;131:11003. doi:10.1115/1.3005195

17         Anderson AE, Galko MJ. Rapid clearance of epigenetic protein reporters from wound edge cells in Drosophila larvae does not depend on the JNK or PDGFR/VEGFR signaling pathways. Regeneration 2014;1:11–25. doi:10.1002/reg2.12

18         Zhang S, Duan E. Epigenetic regulations on skin wound healing: implications from current researches. Ann Transl Med 2015;3:227. doi:10.3978/j.issn.2305-5839.2015.07.12

19         Cutroneo KR, Chiu JF. Comparison and evaluation of gene therapy and epigenetic approaches for wound healing. Wound Repair Regen 2000;8:494–502. doi:10.1046/j.1524-475X.2000.00494.x

20         Förster Y, Schmidt JR, Wissenbach DK, et al. Microdialysis sampling from wound fluids enables quantitative assessment of cytokines, proteins, and metabolites reveals bone defect-specific molecular profiles. PLoS One 2016;11:1–24. doi:10.1371/journal.pone.0159580

21         Zang T, Broszczak DA, Broadbent JA, et al. The biochemistry of blister fluid from pediatric burn injuries: proteomics and metabolomics aspects. Expert Rev Proteomics 2016;13:35–53. doi:10.1586/14789450.2016.1122528

22         Kalkhof S, Förster Y, Schmidt J, et al. Proteomics and Metabolomics for In Situ Monitoring of Wound Healing. Biomed Res Int 2014;2014:1–12. doi:10.1155/2014/934848


Level 4

Nerves and wound healing

Typically ignored is the role nerves have in  wound healing.

We always think that neuropathy has a role in the origin of wounds. That is not the whole story. It also has an influence on t5issue regeneration.

The best example of the importance of nerves on wound healing is in amphibians. Amphibians have the capacity for full regeneration. But only if the nerves are ok. No nerves, no limbs.(1)

In fetal wound care, you can observe another function of nerves. If you make a wound in an unborn lamb, the inflicted wound will be 14% smaller in a few days. But if you cut the nerve, the wound size will have increased by 60% in the same time. Somewhere this makes sense because you use muscle cells (myofibroblasts) for wound contraction. Muscle cells are guided by nerves.(2)

The myofibroblasts are not the only issues in a de-nerved wound. In these wounds you also have an increased amount of granulation tissue because both growth and death of new cells is not functioning properly. And all this tissue also leads to a larger scar.(3)


But this is not all, as most of you know, nails and fingertips regenerate perfectly, even in humans. That is depending on how much tissue is lost and the age of the patient. Mouse research discovered central in this process is the formation of a blastema. This functions like a growing nucleus of mesenchymal cells. This is a very common process in nature, both in plants and animals.(4)

The blastema only functions when innervated. Regeneration will fail if there is no proper nervature in the tissue. Both in mice and men.(5) The pure blastema seems lost in mammalian skin regeneration. It is not lost completely because mouse strains with almost full regeneration exist. This is why there is attention for mesenchymal cells in regeneration.

Nerve cells are also involved in producing all kinds of inflammatory mediators. In the diabetic neuropathic skin impaired nerves cause all kinds of regulatory problems and are one of the many causes for impaired “diabetic” healing.(6) Research took off when doctors realised that paraplegics had impaired wound healing beyond the lesion in their spine.(7)

This was a clear indication of the importance of functional nerves on wound healing.

All in all the so-called type C-nerve fibres (pain) appear to have a larger than expected influence on wound healing. They do not only directly control cells and vessels, but also play a role in the organisation of the wound healing process by means of narrow mediators.  It influences on myofibroblast proliferation(8), mitosis and apoptosis, amount of granulation tissue


Leading to larger scars (l1), increased amount of granulation tissue (l2), is reduced re-epithelialisation (l2), reduced wound contraction (l3) reduced vasodilatation (l3) and reduced proliferation (l4). The good news is that new formation of these type of nerves can be stimulated with electricity.(9)

Before I started writing this little text I was not aware how much innovation influences wound healing. This is only a simple text, by no

This is only a simple text, by no means it is supposed to be the truth. Discussion is welcomed.


Nederlandse tekst op


  1. Cannata, S. M., Bagni, C., Bernardini, S., Christen, B. & Filoni, S. Nerve-independence of limb regeneration in larval Xenopus laevis is correlated to the level of fgf-2 mRNA expression in limb tissues. Dev. Biol. 231, 436–446 (2001).
  2. Stelnicki, E. J. et al. Nerve dependency in scarless fetal wound healing. Plast. Reconstr. Surg. 105, 140–7 (2000).
  3. Smith, P. G. & Liu, M. Impaired cutaneous wound healing after sensory denervation in developing rats: Effects on cell proliferation and apoptosis. Cell Tissue Res. 307, 281–291 (2002).
  4. Neufeld, D. A. Partial blastema formation after amputation in adult mice. J. Exp. Zool. 212, 31–36 (1980).
  5. Takeo, M. et al. Wnt activation in nail epithelium couples nail growth to digit regeneration. Nature 499, 228–232 (2013).
  6. Spenny, M. L. et al. Neutral endopeptidase inhibition in diabetic wound repair. Wound Repair Regen. 10, 295–301 (2002).
  7. Basson, M. D. & Burney, R. E. Defective wound healing in patients with paraplegia and quadriplegia. Surg. Gynecol. Obstet. 155, 9–12 (1982).
  8. Ashrafi, M., Baguneid, M. & Bayat, A. The Role of Neuromediators and Innervation in Cutaneous Wound Healing. Acta Derm. Venereol. (2014). doi:10.2340/00015555-2321
  9. Kao, C. H. et al. High-frequency electrical stimulation can be a complementary therapy to promote nerve regeneration in diabetic rats. PLoS One 8, (2013).


Level 1 Level 2

3 reasons, marine sponges are interesting for wound healing.

Looking at a simpler model of something as complex as wound healing usually provides interesting insights. Sponges are animals with a very simple structure and are known for their regenerating capacity. The reason they are interesting are:

  1. obvious similarities between sponge and human response to injury.
  2. not so obvious similarities between sponge and human response to injury.
  3. clues what to look for in human response to injury.

This tells us something about the basic events in wound healing. Translating these findings to human wound healing is tempting, but should be considered with caution.

Sponges are animals with a very simple structure and are known for their regenerating capacity.

The sponge consists of layers of pinacocytes and choanocytes which resemble the epithelium of more complex animals. This layer covers a gel type body wherein the cells move freely. They do not have a nervous system but are nevertheless able to respond to be environment by means of neurotransmitters which guides movement. ( A sponge actually has two types of cells which play a role in regeneration. Cells which provide matrix (collencytes) and cells which proliferate into other cells (archeocytes).


Structurally a sponge has a primitive version of an epidermis, a dermis and a skeleton and its regeneration system runs roughly on two types of cells. The similarities are striking1,2,3,4.

The obvious similarity between sponge and human response to injury.

  • Age matters, tissue age limits regeneration. Young tissue regenerates faster.
  • Genotype matters, regeneration varies among genetically distinct sponges.
  • Wound size matters, larger wounds heal slower than small wounds.
  • Wound depth matters, as more deep tissue and skeletal elements are involved wounds heal slower.
  • Wound location matters, distal wounds heal faster than wounds on the base of a sponge. In general, if the transport of material for regeneration is easy, wounds heal faster.
  • Water temperature matters, in warmer water the metabolism runs faster, and thus regeneration is faster.
  • Food availability, if more nutrients are available, there are also more nutrients available for regeneration.
  • Sedimentation matters, if more sedimentation falls into the wound, more energy is needed to remove it and this energy is not available for regeneration.
  • Disturbance history, previously injured sponges are more likely to be damaged.


The not so obvious similarity between sponge and human response to injury.

  • Post regeneration strategies are aimed at closing the “skin” as fast as possible to prevent fouling, the marine version of a biofilm.
  • Wound perimeter matters, a circular wound heals faster than a linear wound of the same surface area.
  • Energy balance is important, regeneration draws energy from the organism. Actually, there is a competition for resources between regeneration and other functions of life.
  • Size matters, larger sponges generate better, simply because they have a larger metabolic capacity.


Clues what to look for in human response to injury.

  • The G1 checkpoint; reduced growth of cells adjacent to the wound be due to cells being halted in their progression through the cell cycle as a result of insufficient energy to progress past the G1 checkpoint in eukaryotic cell division.
  • Distance; cell proliferation is lower at 1 cm from the wound compared to cell proliferation 3 cm from the wound.


And the sponge is only one of several model organisms for wound care.

Have fun.




Refs: these articles are cited “loosely”.


  1. Henry, L. A. & Hart, M. Regeneration from injury and resource allocation in sponges and corals – A review. Int. Rev. Hydrobiol. 90, 125–158 (2005).
  2. Alexander, B. E. et al. Cell kinetics during regeneration in the sponge Halisarca caerulea : how local is the response to tissue damage? PeerJ 3, e820 (2015).
  3. Wulff, J. Regeneration of sponges in ecological context: Is regeneration an integral part of life history and morphological strategies? Integr. Comp. Biol. 50, 494–505 (2010).
  4. Hoppe, W. F. Reproductive patterns in three species of large coral reef sponges. Coral Reefs 7, 45–50 (1988).
Level 0 Level 3

Peeking at the neighbours… translating findings in other fields to wound care.

To close a wound new tissue has to be formed guided and shaped. Let’s have a look at how adjacent fields of life-sciences handle the issue. One of the problems of new tissue is you need specific cell types at the wound site. This means that cells have to be transported to the wound bed, they have to multiply and/or have to change function, proliferate.

In heart regeneration they have the same issue, how to regrow damaged tissue. But cardiologists have an extra problem, we can do without a significant portion of tissue, as long as it is not heart tissue or another vital piece of human hardware! They can not wait for nature to do its thing. Therefore, they targeted this subject by means of in vivo cardiac reprogramming. This is also called transdifferentiation, or direct reprogramming. It is a potentially compelling regenerative strategy where reprogramming factors are delivered directly to the damaged organ or tissue to induce regeneration in vivo. Wouldn’t that be nice for wound care?

Why heart regeneration? To grow new tissue the body needs to develop the “tissue-infrastructure” to support regeneration, this means neoangiogenesis. That is where the cardiologists come in. They know how to get from an endothelial cell to a capillary. So even if the subject is not similar, there are things to learn.

Another, much overlooked, piece of infrastructure is innervation. Damaged nerves have a negative impact on wound healing, so new nerves also have to be formed. Luckily even skin fibroblasts theoretically can morph into neurons. So here the same applies.

But even if you are able to produce tissue infrastructure at the wound site we still need some kind of information to get the right tissue at the right place. What phenomena guide the architecture of the new tissue? The obvious targets are of course other cells and growth factors. But we tend to overlook that a cell actually has dimensions so it cannot fit in every part of the tissue. There are also not many “open spots” in a wound, it is actually quite a crowded place. This can mean not only cells and growth factors play a role. Also extracellular matrix plays a role it also determines the available space which not only guides cells in where to go, but the cell also gets information on how to change its role in the tissue.

In adjacent fields like cardiology and neurology, we may learn how to influence the formation of new tissue beyond a generic level. Some day we may be able to steer the formation of vessels and nerves.

So a lot of exiting developments in adjacent fields of life sciences. Of course the usual warning, a heart is is not a wound. Plus, even in these fields, they have the level 0 and 1 problem. What you see in a young lab animal might be a very different thing in a real patient.

Nevertheless, keep watching; you never know what you learn.

Refs: and its original article and


Level 4

Quorum sensing

Why try to explain when you have this youtube video.

Level 4

Science of wound care

This simple overview from the website of Cell magazine, is their view on important domains in life sciences. It is actually also a nice map for wound care science. Linking wound care science to these apparent important scientific fields (if not Cell would have used a different selection) makes a nice exercise.

The good news is that wound care science can make good use of the developments in insight and technology in all of these fields. The bad news is it is rarely done.

Landmark cell reviews

Let’s walk through each domain

Aging; the future cornerstone of wound care science is aging. Even casual observers will notice that most “wound owners” are older people. However, the influence of age on wound healing is not clear. The field of inflammaging and its mathematical modelling is really promising.

Cancer; although not interesting at first sight, but if we see cancer as regeneration gone wrong the idea changes. Cancer also provides us with processes playing a role in tissue generation.

Cell biology; it reveals the way each cell and groups of cells function and behave. Even though we know the players in the wound-healing process we do not know how they behave in a more complex wound or in a stressed environment. Here we have to find the difference in wound healing in a healthy young animal and a compromised human. Bridging that gap is still a challenge.

Immunology; our immune system is evolutionary slightly younger than tissue repair yet plays an important role in keeping us healthy by removing all that is unwanted. It’s role in wound care is not simply to remove bacteria, but actually, it has a complex regulatory role. However, it is not functioning flawlessly and, therefore, is either may be a symptom or a cause of a non-healing wound.

Neuroscience; apart from the obvious in relation to pain, I have to confess I am a bit lost, suggestions? Nevertheless, I am sure the nerve system plays a role in regulating wound healing.

Noncoding RNA’s, this field is now not relevant for wound healing. Not because it does not play a role but because it will be discovered for wound care in approx 5 years from now.

Metabolism is the counterpart of anatomy and describes the processes in wound healing. Metabolic issues are at the heart of wound healing. Any problem in anatomy or physiology will, in the end, influence cell metabolism which leads to an alteration in function, proliferation and eventually apoptosis.

Transcription and epigenetics; We are already looking into the genomics of wound healing, if only by linking telomere length to wound incidence. And epigenetic-wise I am looking forward to the first articles describing how DNA methylation alters metabolic pathways in chronic wounds.

Signaling; we have not yet seen the end of the research on growth factors and other signals regulating tissue regeneration. especially the relation between a growth factor and its role in different stages of wound healing.

Stem cells; wound healing and regeneration depends on forming new tissue. These can be formed by either simple division of epidermal cells or have to be formed by proliferating one cell-type to another or by bringing in new (stem) cells to the wound bed.

Development; this field will, together with stem cel research learn us why and how each specific cell and function ends up at the right spot in the new tissue. It may also learn us where this process can derail.

Microbiology; the role of microbes in the living body is rapidly becoming more complex. They are not all bad. Lessons from the gut are to be taken to the wound. We may one day discover that the speed of wound healing depends on what is living in your wound.


When finished I cannot help but ask myself: what would the grid for wound care science look like?

The following blocks may be interesting
Anatomy and physiology; classic medical subjects too often overlooked in wound care

Systems biology; which seems to hold more promises for wound healing

Genetics; straight hereditary research may provide some insights and help us discover more genes involved in wound healing.

Mathematical modelling; in the next decade the science of life will be overtaken by mathematical models to find correlations we would not have found otherwise.

All in all a nice exercise (that is, for me) of linking wound care to science.

Let’s end with a citation:

In der lebendigen Natur geschieht nichts, was nicht in einerVerbindung mit dem Ganzen steheund wenn uns dieErfahrungen nur isoliert erscheinenwenn wir die Versuchenur als isolierte Fakta anzusehen habenso wird dadurchnicht gesagtdaß sie isoliert seien, es ist nur die Frage: wiefinden wir die Verbindung dieser PhänomenedieserBegebenheiten?

            Johann Wolfgang von Goethe

(Very free translation: all living things are connected, if you do not see the connection between isolated facts, you may have to look harder)

Level 2

Everything you always wanted to know about biofilms but …

The question: “Is there a biofilm in the wound?” reveals it is still hard to understand biofilms for wound care professionals.

To ask this simple question is uncovering a knowledge gap.

There is no such thing as A biofilm. Her are two thoughts which may enlighten you.

  1. most microbes are able to produce biofilms.
  2. If a biofilm will increase their chance of survival they will produce one, if it does not they will not.

This immediately implies that every imaginable combination of species and numbers of each species will have an influence on the biofilm.

This also implies no two biofilms are the same, stay the same or that there is only one biofilm in the wound. There will be deep tissue biofilms and superficial biofilms. The whole combination of microbes and biofilms may be more comparable to a city than a glass house. Its appearance will depend on the size of the city and the number of different inhabitants and their needs.

Luckily even biofilms will have to follow some natural or mathematical rules and therefore the number of clinical relevant biofilms may be not infinite.

Not all biofilms are bad either. As we know, every nine out of ten cells in your body are not really you. There are biofilms in the intestine which are essential for a proper functioning body. They are so important the appendix functions as a special reservoir for spare biofilms in the case something goes wrong.

In the wound it is very well imaginable that a biofilm has a ECM like function. So presumably not all biofilms are bad.

So in the end, the question is not if there is a biofilm in the wound, the question is if there is a (good or bad) clinical relevant microbiome in the wound.

For more information: Elisabeth Bik has a nice blog on biofilms and the microbiome. Here you may find this nice example of biofilm dynamics.


Level 3

PAD and the DFU

Thanks to David Armstrong for sharing


Level 4

Discovering tools for wound assessment

Evaluating the 2015 WoundsUk posters  revealed that the most used inclusion criteria to match a patient to any intervention were A. “stalled” wound healing or B “suitability” of the patient; not exactly an exact approach.

Of course we have Time, Wagner etc etc. But these are based upon “superficial” examination. Even after assessment there are patients who do not follow expectations. This is because they describe the current state of the wound but only partially. They do not describe what is causing a delay in healing. I would love to have the possibility to look under the hood and  have some more clues about what is happening in the wound healing process. It is amazing we do not have a standard set of parameters which will help us assess the gravity of the wound.

Luckily medical science is more than wound care so it makes sense to look for progress in other fields.  Here are some thoughts.

The first idea is to do an immuno assay. Recently, application of mass cytometry in patients undergoing hip arthroplasty revealed strong immune correlatesm_cover of surgical recovery in blood samples collected shortly after surgery. In the study below it is shown that the Immune correlates identified in presurgical blood samples mirrored correlates identified in postsurgical blood samples. Hence the immune status can predict the recovery. I think it is worth while to see if this also has an effect on wound healing.

And there are more factors worth investigating to assess the chronicity of a given wound. Another example may be serum albumin. Which not only reflects the nutritional status of a patient but also has a link to IL6 and TNFα. See and it already has an application in DFU and in and distal bypass surgery 

or as we see here, simply collecting basic parameters may already provide some clues.

And this is all old techniques, imagine what we may find with some of the newer analytic techniques.

All in all, discovering parameters is not rocket science but we have not done it yet so it is time to do it.


Straight Talk Tuesday; Caroline Fife

Carolyne Fife demonstrates in her columns “the horror of providing wound care”. In two blogs (below) she describes the impact the apparent low stature of wound healing has. Basically; the lack of underpinning of interventions leads to a dramatic reduction of funding. As it should. However, in the case of wound care the lack of underpinning is not a result of lack of efficacy but a lack of research outcomes. So here the reduction of funding is a result of the dysfunction of research. The cause is very simple; having a wound is generally regarded a complication and therefore not interesting. Sadly society and (have to say) most doctors are not interested, lack knowledge, do no research and are astoundingly unaware of the numbers. As a result, the science of wound healing is under-represented and under-developed in the medical profession. (Why don’t we have regeneration specialists? ) Therefore, even if Caroline would have generated data and healed patients (which should not be the same) we still lack a proper framework to translate findings in a wider context. This would be no problem if having a wound was a rare phenomenon. But it is not, wounds lead to massive human suffering and consume a relatively big part of health care spending. But the latter is a financial issue. Luckily the financial guru’s know that if you cut the budget the cost will go down, as simple as that. Doctors agree and push the patients out of their budget (back to home care) asap. The fact that budget cuts cause massive suffering (but numbers do not cry or die) and that the costs resurface somewhere else in the system in a 10-fold time or so is not interesting because that is NIMB-cost. (Not In My Budget) And since 2008 we all know who pays for the final NIMB budget.

The second blog mentioned is below. Is this what you get when one applies regulations instead of knowledge: if you only have a hammer, every problem looks like a nail? Is this the future of EU healthcare funding?