Damage to skin and tissue is an important and expensive issue for the NHS and other organisations providing care for those who are confined to their bed or chair for any period of time. The costs are not just financial; a lot of individual suffering and loss of quality of life occur when tissue breaks down. This white paper brings together existing research into skin and tissue damage associated with patient’s being cared for in bed.
The latest term being used for this is pressure injury (NPUAP 2016). This term replaces previous terminology used such as; pressure ulcers, pressure sores, bed sores /ulcers and decubitus ulcers. However, with our extensive review of the literature into the internal and external influences, we believe a more accurate description is force related tissue damage.
This paper investigates the observations regarding unobvious causes of force related tissue damage and the events linking both biomechanical and biological processes at several organisational (pathological) levels together with external in bed events. Over 22 internal marginal influences are identified which, as countless Cochrane reviews demonstrate, wound care science struggles to diagnose and cure; mostly due to the underestimation of the complexity and processes involved regarding tissue homoeostasis, damage and regeneration.
The paper explains how there are two major causal factors connected with all in bed force related tissue damage. The patient’s resting/support surface synergy and the way the person is moving/being moved and stabilised on that surface, regardless of whether this is by manual or mechanical means. We will explore how in bed force related tissue damage can be a direct result of both manual and/or mechanical handling and the incorrect synergetic interface layers of the resting/support surface with the patient’s skin and tissues.
We strongly suggest the major causal factors involved with all in bed force related tissue damage are external and within our control. This paper proposes that a preventative trajectory is both desirable and achievable by adopting a combined ergonomic and biomechanical approach to remove the risks to both patients’ skin/tissue and the carer’s muscular-skeletal system associated with in bed care and positioning.
Harm Smit and Phil Strong 2018

Here is the link to the paper: White Paper Force related tissue damage

For ninety five out of hundred wounds, discovering and removing the cause is sufficient to solve the problem. If that approach fails, the wound may become a chronic wound. For adequate interventions, (in this case super-) simplified knowledge of processes at cellular level may help. At least, in presentations it is appreciated.

Understanding how cells cope with stress, injury and damage is central in understanding the development and healing of wounds. There is no abrupt transition from normal tissue to necrotic tissue, in most wounds the conditions for cells are gradually getting worse towards the lesion, This is divided into a healthy part, a part in stress, a part with repairable damage and a part with non-repairable damage. This zone classification is different for each tissue type involved which may on of the explanations of tissue undermining, this happens when the underlying tissue is more susceptible to stress and damage comparted to the tissue above.

Cell stress and damage are often caused by the action of forces on tissue (1), lack of oxygen (2) and/or lack of nutrients (3). Stress and damage may lead to cell death, however, the most common cause of cell death is apoptosis, programmed cell death(4).

The action of forces on cells leads to pressure, tensile- and shear-forces. Increased pressure may cause membrane leakage, tensile forces can lead to cell rupture and shear forces can do both. Casual observance may suggest that pressures are the main cause of problems, but that is probably not the case. Cells and tissues are often anisotropic, which means they are not equally strong in all directions. Many tissues have a special construction to handle forces in a certain direction. If force is applied from a “wrong” direction to a cell or tissue it may deform or lose its tensegrity and tear. In addition, instead of popping and rupturing, deformation may most of the time be causing damage of the cell membrane resulting in calcium ions leaking into the cell which is a direct cause for problems.[1,2].

The cell nucleus senses the properties of force applied to the cell [3], this allows her to assess the situation and respond appropriately at the cellular level. Signalling and tensegrity systems augment and translate these signals to the higher organisational levels of tissue, organs and the body.

The availability of oxygen may also cause problems; human cells depend on haemoglobin for their oxygen supply. If a human cell has no access to oxygen produced by red blood cells it will die. Oxygen related issues usually cause mitochondrial problems. Under hypoxia. Mitochondrion will adapt its processes to keep producing energy, this process also produces reactive oxygen species and nitric oxides. These reactive substances signal the cell and its surroundings about the (oxidative) stress. Too many reactive parts are damaging so if the amount of reactive oxygen surpasses a threshold the immune system will be activated to remove damaged cells. This system allows tissue to function under hypoxic circumstances[4].

Lack of nutrients will disturb the cell metabolism, which will endanger its survival. Focal in these processes is the endoplasmic reticulum, which is sensitive to intracellular circumstances. Since the endoplasmic reticulum functions as the main chemical factory of cell producing most proteins any disturbance of the necrotic reticulum will have a dramatic effect. This is called endoplasmic reticulum stress (ER-stress)[5].

Circumstances such as exerted forces, hypoxia or a lack of nutrients are noted by the cell and it will respond to counter these problems(stress responses). However, these responses influence the internal cooperation between the nucleus, mitochondrion and the endoplasmic reticulum in positive or negative manner[2]. It is important for cells to not only adapt the internal processes but also to inform its surrounding about its problems. Therefore it will start sending out signals which quite specific inform surrounding cells and tissues and the rest of the body on the nature of its problems[6,7].

Cells are part of tissue, to maintain the quality of these tissues cells which are not functioning properly have to be removed or replaced. Removing non-functional or obsolete cells by the body itself is the commonest reason for cells to die. The body prefers to remove cells in a controlled manner where cells are properly recycled. This process is called apoptosis. The opposite process necrosis were cells structural fall apart and their contents are spread in the tissue. The remains of cells in tissue are the result of an uncontrolled situation and therefore have a strong signalling function, these are the so-called damps en pamps (damage-associated molecular patterns en pathogen-associated molecular patterns)[8].

Both apoptosis and necrosis exist in several varieties[9].

Cells do not immediately fall apart or die if exposed to forces, hypoxia or lack of nutrients. For practical reasons, we may classify the level of stress in stress (no damage, fully reversible), injury (reversible damage) and damage (irreversible damage). Stress does not require regeneration, injured tissue can regenerate fully, but damaged tissue cannot be regenerated fully and the body will try to restore the main functions of the tissue. This means that the affected area is much larger than the wound itself, this implies that visually vital tissue does not have to be vital that all.

Cells and tissues can adapt to survive difficult circumstances. Continuous monitoring the circumstances and the signals cells and tissues send out allow the body to respond. This can be a short-term responses where a blood vessel is opened up or an immune response is started. Long-term responses can be by changing the composition of tissues, for example making extra blood vessels to composite for lack of perfusion or changing collagen composition in support of tissue due to forces from different angles.

Regardless of the cause of the wound, the wound bed will, due to lack of perfusion, always, always suffer from odd forces and a lack of oxygen and nutrients. Due to the damage the structures the body uses to monitor the situation in the body like sensors, vessels and nerves are also dysfunctioning. This is a perfectly normal situation and most of the disturbance is actually used to guide the wound healing process. That is in a young patient, if the wound is larger, complex and or the patient has more issues related to tissue regeneration, this perfect process is impaired.[10,11].

This impairment be qualitative, wrong signals are send or misinterpreted. It can also be qualitative, more damage leads to more signals, more signals are harder to interpret and the signal to noise ratio is also reduced. Noise and miscommunication in the body, may lead to misinterpretation of signals or the generation of wrong signals. This may seem far-fetched, in practice it is called a chronic, wound.

An out-of-control inflammation response may cause havoc in a wound bed. This may produce additional damps which only increase the (sterile) inflammation[12]. And impaired endothelial hypoxia and capillary refill a cause reperfusion injury[13,14]. Reperfusion injury is a cause of problems in other parts of the body, like the lungs[15]. A cacophony of signals in the wound bed may disable guidance for cells which may cause impaired cell movements and proliferation. These are just a few of the many causes of chronic.

Despite the difference in causes, chronic wound pathology has surprising similarities at the level (4) of the cell and the tissue. And this opens up treatment possibilities. Not only are the issues often similar, there are several possibilities to intervene and restore impaired processes. Goal will be to either guide communication or delay the stress-injury-damage cascade. Available knowledge is not always available in the wound care practice. An example is the use of pentoxifylline, which is well documented for years [16–20] yet rarely used. There are dozens of other interventions like pentoxifylline available. Not only on this level, but also on the other four levels in wound knowledge a smorgasbord of interventions is available. So the real problem is not even new knowledge but to make current knowledge available for the clinical practice.

Literatuur:

1         Carafoli E, Krebs J. Why calcium? How calcium became the best communicator. J Biol Chem 2016;291:20849–57. doi:10.1074/jbc.R116.735894

2         Hill S, Van Remmen H. Mitochondrial stress signaling in longevity: A new role for mitochondrial function in aging. Redox Biol 2014;2:936–44. doi:10.1016/j.redox.2014.07.005

3         Belaadi N, Aureille J, Guilluy C. Under Pressure: Mechanical Stress Management in the Nucleus. Cells 2016;5:27. doi:10.3390/cells5020027

4         Schieber M, Chandel NS. ROS function in redox signaling and oxidative stress. Curr Biol 2014;24:R453–62. doi:10.1016/j.cub.2014.03.034

5         van Vliet AR, Agostinis P. When under pressure, get closer: PERKing up membrane contact sites during ER stress. Biochem Soc Trans 2016;44:499–504. doi:10.1042/BST20150272

6         Krebs J, Agellon LB, Michalak M. Ca2+ homeostasis and endoplasmic reticulum (ER) stress: An integrated view of calcium signaling. Biochem Biophys Res Commun 2015;460:114–21. doi:10.1016/j.bbrc.2015.02.004

7         Elks PM, Renshaw S a, Meijer AH, et al. Exploring the HIFs, buts and maybes of hypoxia signalling in disease: lessons from zebrafish models. Dis Model Mech 2015;8:1349–60. doi:10.1242/dmm.021865

8         Herwald H, Egesten A. On PAMPs and DAMPs. J Innate Immun 2016;8:427–8. doi:10.1159/000448437

9         Nikoletopoulou V, Markaki M, Palikaras K, et al. Crosstalk between apoptosis, necrosis and autophagy. Biochim Biophys Acta – Mol Cell Res 2013;1833:3448–59. doi:10.1016/j.bbamcr.2013.06.001

10       van Beek JHGM, Kirkwood TBL, Bassingthwaighte JB. Understanding the physiology of the ageing individual: computational modelling of changes in metabolism and endurance. Interface Focus 2016;6:20150079. doi:10.1098/rsfs.2015.0079

11       Yin F, Sancheti H, Liu Z, et al. Mitochondrial function in ageing: coordination with signalling and transcriptional pathways. J Physiol 2015;0:n/a-n/a. doi:10.1113/JP270541

12       Feldman N, Rotter-Maskowitz A, Okun E. DAMPs as mediators of sterile inflammation in aging-related pathologies. Ageing Res Rev 2015;24:29–39. doi:10.1016/j.arr.2015.01.003

13       Manson PN, Anthenelli RM, Im MJ, et al. The role of oxygen-free radicals in ischemic tissue injury in island skin flaps. Ann Surg 1983;198:87–90. doi:10.1097/00000658-198307000-00017

14       Lejay A, Meyer A, Schlagowski AI, et al. Mitochondria: Mitochondrial participation in ischemia-reperfusion injury in skeletal muscle. Int J Biochem Cell Biol 2014;50:101–5. doi:10.1016/j.biocel.2014.02.013

15       Mansour Z, Charles AL, Kindo M, et al. Remote effects of lower limb ischemia-reperfusion: Impaired lung, unchanged liver, and stimulated kidney oxidative capacities. Biomed Res Int 2014;2014. doi:10.1155/2014/392390

16       Sharma K, Ishaq M, Sharma G, et al. Pentoxifylline triggers autophagy via ER stress response that interferes with Pentoxifylline induced apoptosis in human melanoma cells. Biochem Pharmacol 2016;103:17–28. doi:10.1016/j.bcp.2015.12.018

17       Sharma R, Randhawa PK, Singh N, et al. Bradykinin in ischemic conditioning-induced tissue protection: Evidences and possible mechanisms. Eur J Pharmacol 2015;768:58–70. doi:10.1016/j.ejphar.2015.10.029

18       Jull A, Waters J, Arroll B. Pentoxifylline for treatment of venous leg ulcers: a systematic review. Lancet 2002;359:1550–4. doi:10.1016/S0140-6736(02)08513-6

19       Jull AB, Arroll B, Parag V, et al. Pentoxifylline for treating venous leg ulcers ( Review ). Cochrane database Syst Rev 2012;12:CD001733. doi:10.1002/14651858.CD001733.pub3

20       Falanga V, Fujitani RM, Diaz C, et al. Systemic treatment of venous leg ulcers with high doses of pentoxifylline: efficacy in a randomized, placebo-controlled trial. Wound Repair Regen 1999;7:208–13.

Open letter to the Presidents of NPUAP and EPUAP

(https://www.linkedin.com/pulse/open-letter-presidents-npuap-epuap-phil-strong )

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.

Conclusion

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.

Signed:

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.

References

http://www.npuap.org/wp-content/uploads/2012/01/NPUAP-Position-Statement-on-Staging-Jan-2017.pdf

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.http://www.ncbi.nlm.nih.gov/pubmed/17449915

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

https://www.linkedin.com/pulse/open-letter-presidents-npuap-epuap-phil-strong

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.

#proudtobeabiologist.

Nederlandse tekst op http://woundspecialist.eu/woundspecialist.eu/?p=550

References

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).