Caroline Fife suggested I should publish a simple scale for tissue damage and call it the “Harm Scale”.

Here it is.

Analysing wounds requires to have a look at it at five levels, from the molecule up to the social environment of the patient. To understand events in wounded cells and tissue, it is important to realise that cells and tissues have a range of states related to damage. The linguistic problem is that damage is considered as, well, damage but in reality, cell and tissue damage ranges from no damage to death. Therefore, perhaps, we may refer to the scale as loss of homeostasis. Here the normal state means there is no loss of homeostasis, and the dead state means there is a maximum loss of homeostasis. This also makes sense because the body considers homeostasis the optimum and any loss of homeostasis will evoke a reaction. But the easiest option is, as Caroline pointed out, to use the word harm, which can be seen as a measure of loss of homeostasis.

What is harm?

Harm stands for how much problems a cell or a tissue has in its normal function.

Logically a cell or tissue can be in six states of harm:

1. Normal,
2. Adapted,
3. Stressed,
4. Injured,
5. Damaged,
6. Dead.

 

Normal is the normal state, where the cell or a tissue is well adapted to the circumstances and it is able to fulfil its required role. Here, the cell and tissue are in a state homoeostasis.

Adapted, if there are changes in the environment, cells or tissue adapt by changing its anatomy, physiology or behaviour. Adaptation causes cells and tissues to communicate their changed state with their environment, and the body detects those signals (Pakos‐Zebrucka et al. 2016; Erguler, Pieri, and Deltas 2013)

Stressed, when the changes lead to problems in the cells or tissue’s anatomy, physiology or behaviour becomes stressed. Here it is no longer able to fulfil all its activities normally. Stressed cells and tissues start sending out distress signals like reactive oxygen species, HIF-1a and other signals (Andreeva et al. 2015; Bohovych and Khalimonchuk 2016). These signals are not only detected by the body but some signals can also be detected in laboratory analysis (Görlach et al. 2015; Pichu et al. 2018).

Injured, if the changes have led to small-scale damage, like a leaking cell membrane or tissue damage, problems can begin to arise. Leaking for instance ATP and calcium through membranes and other forms of damage (DAMPS) are interpreted as unwelcome events (Horn and Jaiswal 2018; Tang and Marshall 2017). This implies that the signals resulting from cell and/or tissue injury may already elicit an inflammatory response (Jagannathan and Tucker-Kellogg 2016; Rathinam and Chan 2018). Often injury may be repaired, allowing for full regeneration.

Damaged, if the resultant harm has led to irreversible, yet non-lethal, damage, there are inevitable consequences. For example, loss of a limb, may not kill you, but it will reduce your functionality. The body will detect damage and respond. It might do so by apoptosis, the controlled killing of damaged cells (Karch and Molkentin 2015). IApart from liver or skin tissue, full regeneration of damage is not an option. Here the negative consequence of fibrotic repair can take place (Whyte, Smith, and Helms 2012; Greaves et al. 2013; Nyström and Bruckner-Tuderman 2018).

Dead, a dead cell is, well … dead. If a dead cell or tissue is not cleaned up properly, but is destructed instead, it’s organelles and DNA function as a danger signal, the so-called DAMP’s (danger associated molecular patterns) invoking inflammation and other tissue repair or regeneration processes (Pandolfi et al. 2016; Maslanik et al. 2013).

The Harm Scale has dimensions of level, size and time. A single cell moving up the Harm Scale, does not imply that the tissue containing that cell is also adapted, injured or damaged. The tissue it is in,  might very well be in perfect homeostasis. However, if more cells in the tissue start to get damaged or die, in time the tissue itself may start moving on the Harm Scale. And similarly, if a tissue is moving up the Harm Scale does not mean your body or parts of it are damaged.

Nevertheless, an inflammatory response is always imminent, inflammation is good but at the price of remaining scars, even at the molecular level (Fulop et al. 2018). Chronic inflammation is a source for age-related disease. (Franceschi et al. 2018)

So, even if harm doesn’t necessarily lead to direct damage, even little harm may cause problems over time in the li=ong run (Ashcroft, Mills, and Ashworth 2002).

 

Why is this important?

The body detects and responds to any deviation from homeostasis and will react to regain homeostasis. If the reaction is insufficient, the tissue damage will increase in size and magnitude and cause serious problems for the patient.

If you consider most non-traumatic wounds result from an underlying condition, the Harm Scale begins to make sense. It draws attention to the pre-clinical events which impact the clinical events to follow. If the harm is not handled properly, you are setting up your topical treatment for failure.

Flatly, if you fail to recognise the obstructed vessel, your dressing is not going to do much.

Even stressed cells may already have an impaired ability to handle harm, this condition may worsen if the harm moves up the scale. If the surrounding cells or tissues are in a grave state, the situation can spiral out of control, like in the case of skin failure at the end of life (Levine 2016).

Recognising the existence of harmed tissue highlights how a patient, who does not yet have a wound, might still suffer enough from harm to develop a wound in the near future. Or even worse, a closed wound does not mean there is no tissue damage, setting the stage for recurrence.

Neglecting the level of harm in tissue, can cause to you take action which may result in an avoidable lesion. (Black et al. 2011)

The Harm Scale also points out that, not only the tissue in the wound but also the cells and tissue surrounding the wound may be harmed, impairing the ability to repair or regenerate tissue. In general, it will be safe to say that processes, like proliferation, will take place outside the wound, even perhaps outside of the inflamed zone (Park et al. 2017). This means that the quality of the surrounding tissue plays an important role in the wound healing process.

Figure 1 Schematic representation of harm in and outside the wound.

In this paper we treat the Harm Scale at level 2 of the Five Level Model for Wound Analysis and Treatment. The five level model is a system to describe factors influencing the cause and resolution of wounds at a normal (0), general (1), local (2), systemic (3) and cellular-molecular (4) level. The levels represent a connection between where problems occur and common clinical and scientific practice. (Smit 2018)

Level 2 is local, the level of the wound. However, the Harm Scale also exists at other levels, examples are:

• Level 1; inflammaging (Chen et al. 2014),
• Level 3; organ-system damage (San Miguel-Ruiz and García-Arrarás 2007) and
• Level 4; (epigenetic) DNA damage (Nanduri, Semenza, and Prabhakar 2017; Jasiulionis 2018).

Using the Harm Scale at all 5 levels opens up the possibility of making use of preventive and curative toolkits used in other types of tissue damage like renal, brain or heart damage. It also allows us to make use of the insights from inflammation research, like inflammaging (Castellani et al. 2016).

 

How the Harm Scale can help.

In today’s wound care we only casually touch on the subject of tissue damage, because the most used solution for a wound is a dressing. The Harm Scale may help us in evaluating tissue in, under and around wounds.

Having some kind of definition of harm will improve communication on the complexities of the state tissues and cells are in. Acquiring a better understanding of the level of harm in tissue allows us for assessment and modalities to maintain homeostasis.

It may be helpful to notice that, though adapted, stressed, injured and damaged cells signal their harm state to their environment, the body can under- or over-react. If the patient is compromised these early signals may be missed, masking what is really happening. On the other hand, if injured, damaged and dead cells invoke a dramatic response, this in itself, may spiral out of control in a compromised patient.

The Harm Scale is also helpful in determining where to inject growth factors, miRNA’s and other interventions. Zones in which cells are barely surviving maybe not the best place for your intervention. You have to locate the proper location in, around and under the wound for a (maximal) effect (Berlanga et al. 2013).

Perhaps, if we start diagnosing and treating issues which reduce the body’s ability to repair or regenerate tissue, we might find better ways to predict and/or prevent wounds. A Harm Scale type assessment can be a useful addition to the toolbox.

And in the process, we will learn how to achieve much better results from our current treatment modalities.

© Harm Smit (2018)

Ps. It is really weird, writing a text like this when your name is … Harm.

 

References

Andreeva, Elena R., Margarita V. Lobanova, Olga O. Udartseva, and Ludmila B. Buravkova. 2015. “Response of Adipose Tissue-Derived Stromal Cells in Tissue-Related O2 Microenvironment to Short-Term Hypoxic Stress.” Cells Tissues Organs 200 (5): 307–15. https://doi.org/10.1159/000438921.

Ashcroft, Gillian S, Stuart J Mills, and Jason J Ashworth. 2002. “Ageing and Wound Healing.” Biogerontology 3 (6): 337–45. https://doi.org/5100237 [pii].

Berlanga, Jorge, D V M Ms, José I Fernández, Ernesto López Ms, Pedro a López, Amaurys Río, Carmen Valenzuela Ms, et al. 2013. “Heberprot-P: A Novel Product for Treating Advanced Diabetic Foot Ulcer.” Medic Review 15: 11–15. https://www.ncbi.nlm.nih.gov/pubmed/23396236

Black, Joyce M, Laura E Edsberg, Mona M Baharestani, Diane Langemo, Margaret Goldberg, Laurie McNichol, Janet Cuddigan, and National Pressure Ulcer Advisory Panel. 2011. “Pressure Ulcers: Avoidable or Unavoidable? Results of the National Pressure Ulcer Advisory Panel Consensus Conference.” Ostomy/Wound Management 57 (2): 24–37. http://www.ncbi.nlm.nih.gov/pubmed/21350270.

Bohovych, Iryna, and Oleh Khalimonchuk. 2016. “Sending Out an SOS: Mitochondria as a Signaling Hub.” Frontiers in Cell and Developmental Biology 4 (October): 109. https://doi.org/10.3389/fcell.2016.00109.

Castellani, Gastone C., Giulia Menichetti, Paolo Garagnani, Maria Giulia Bacalini, Chiara Pirazzini, Claudio Franceschi, Sebastiano Collino, et al. 2016. “Systems Medicine of Inflammaging.” Briefings in Bioinformatics 17 (3): 527–40. https://doi.org/10.1093/bib/bbv062.

Chen, Pei-Yu, Lingfeng Qin, Zhen W Zhuang, George Tellides, Irit Lax, Joseph Schlessinger, and Michael Simons. 2014. “The Docking Protein FRS2α Is a Critical Regulator of VEGF Receptors Signaling.” Proceedings of the National Academy of Sciences of the United States of America 111 (15): 5514–19. https://doi.org/10.1073/pnas.1404545111.

Erguler, Kamil, Myrtani Pieri, and Constantinos Deltas. 2013. “A Mathematical Model of the Unfolded Protein Stress Response Reveals the Decision Mechanism for Recovery, Adaptation and Apoptosis.” BMC Systems Biology 7: 16. https://doi.org/10.1186/1752-0509-7-16.

Franceschi, Claudio, Paolo Garagnani, Paolo Parini, Cristina Giuliani, and Aurelia Santoro. 2018. “Inflammaging: A New Immune–metabolic Viewpoint for Age-Related Diseases.” Nature Reviews Endocrinology. https://doi.org/10.1038/s41574-018-0059-4.

Fulop, Tamas, Anis Larbi, Gilles Dupuis, Aurélie Le Page, Eric H. Frost, Alan A. Cohen, Jacek M. Witkowski, and Claudio Franceschi. 2018. “Immunosenescence and Inflamm-Aging As Two Sides of the Same Coin: Friends or Foes?” Frontiers in Immunology 8 (January). https://doi.org/10.3389/fimmu.2017.01960.

Görlach, Agnes, Katharina Bertram, Sona Hudecova, and Olga Krizanova. 2015. “Calcium and ROS: A Mutual Interplay.” Redox Biology 6: 260–71. https://doi.org/10.1016/j.redox.2015.08.010.

Greaves, Nicholas S., Kevin J. Ashcroft, Mohamed Baguneid, and Ardeshir Bayat. 2013. “Current Understanding of Molecular and Cellular Mechanisms in Fibroplasia and Angiogenesis during Acute Wound Healing.” Journal of Dermatological Science 72 (3): 206–17. https://doi.org/10.1016/j.jdermsci.2013.07.008.

Horn, Adam, and Jyoti K. Jaiswal. 2018. “Cellular Mechanisms and Signals That Coordinate Plasma Membrane Repair.” Cellular and Molecular Life Sciences, no. 0123456789. https://doi.org/10.1007/s00018-018-2888-7.

Jagannathan, N. Suhas, and Lisa Tucker-Kellogg. 2016. “Membrane Permeability during Pressure Ulcer Formation: A Computational Model of Dynamic Competition between Cytoskeletal Damage and Repair.” Journal of Biomechanics 49 (8): 1311–20. https://doi.org/10.1016/j.jbiomech.2015.12.022.

Jasiulionis, Miriam G. 2018. “Abnormal Epigenetic Regulation of Immune System during Aging.” Frontiers in Immunology 9 (FEB): 1–14. https://doi.org/10.3389/fimmu.2018.00197.

Karch, Jason, and Jeffery D. Molkentin. 2015. “Regulated Necrotic Cell Death: The Passive Aggressive Side of Bax and Bak.” Circulation Research 116 (11): 1800–1809. https://doi.org/10.1161/CIRCRESAHA.116.305421.

Levine, Jeffrey M. 2016. “Skin Failure: An Emerging Concept.” Journal of the American Medical Directors Association 17 (7): 666–69. https://doi.org/10.1016/j.jamda.2016.03.014.

Maslanik, Thomas, Lucas Mahaffey, Kate Tannura, Lida Beninson, Benjamin N. Greenwood, and Monika Fleshner. 2013. “The Inflammasome and Danger Associated Molecular Patterns (DAMPs) Are Implicated in Cytokine and Chemokine Responses Following Stressor Exposure.” Brain, Behavior, and Immunity 28: 54–62. https://doi.org/10.1016/j.bbi.2012.10.014.

Nanduri, Jayasri, Gregg L. Semenza, and Nanduri R. Prabhakar. 2017. “Epigenetic Changes by DNA Methylation in Chronic and Intermittent Hypoxia.” American Journal of Physiology-Lung Cellular and Molecular Physiology 313 (6): L1096–1100. https://doi.org/10.1152/ajplung.00325.2017.

Nyström, Alexander, and Leena Bruckner-Tuderman. 2018. “Injury- and Inflammation-Driven Skin Fibrosis: The Paradigm of Epidermolysis Bullosa.” Matrix Biology, no. 2017: 1–14. https://doi.org/10.1016/j.matbio.2018.01.016.

Pakos‐Zebrucka, Karolina, Izabela Koryga, Katarzyna Mnich, Mila Ljujic, Afshin Samali, and Adrienne M Gorman. 2016. “The Integrated Stress Response.” EMBO Reports 17 (10): 1374–95. https://doi.org/10.15252/embr.201642195.

Pandolfi, Franco, Simona Altamura, Simona Frosali, and Pio Conti. 2016. “Key Role of DAMP in Inflammation, Cancer, and Tissue Repair.” Clinical Therapeutics 38 (5): 1017–28. https://doi.org/10.1016/j.clinthera.2016.02.028.

Park, Sangbum, David G. Gonzalez, Boris Guirao, Jonathan D. Boucher, Katie Cockburn, Edward D. Marsh, Kailin R. Mesa, et al. 2017. “Tissue-Scale Coordination of Cellular Behaviour Promotes Epidermal Wound Repair in Live Mice.” Nature Cell Biology 19 (2): 155–63. https://doi.org/10.1038/ncb3472.

Pichu, Sivakamasundari, Selvaraj Vimalraj, Jayalalitha Sathiyamoorthy, and Vijay Viswanathan. 2018. “Association of Hypoxia Inducible Factor-1 Alpha Exon 12 Mutation in Diabetic Patients with and without Diabetic Foot Ulcer.” International Journal of Biological Macromolecules 119: 833–37. https://doi.org/10.1016/j.ijbiomac.2018.08.011.

Rathinam, Vijay A.K., and Francis Ka Ming Chan. 2018. “Inflammasome, Inflammation, and Tissue Homeostasis.” Trends in Molecular Medicine xx (3): 1–15. https://doi.org/10.1016/j.molmed.2018.01.004.

San Miguel-Ruiz, José E., and José E. García-Arrarás. 2007. “Common Cellular Events Occur during Wound Healing and Organ Regeneration in the Sea Cucumber Holothuria Glaberrima.” BMC Developmental Biology 7: 1–19. https://doi.org/10.1186/1471-213X-7-115.

Smit, Harm Jaap. 2018. “A Five-Level Model for Wound Analysis and Treatment.” Wounds UK 14 (4): 24–29. https://www.wounds-uk.com/journals/issue/548/article-details/five-level-model-wound-analysis-and-treatment.

Tang, Sindy K Y, and Wallace F Marshall. 2017. “Self-Repairing Cells: How Single Cells Heal Membrane Ruptures and Restore Lost Structures.” Science (New York, N.Y.) 356 (6342): 1022–25. https://doi.org/10.1126/science.aam6496.

Whyte, J. L., a. a. Smith, and J. a. Helms. 2012. “Wnt Signaling and Injury Repair.” Cold Spring Harbor Perspectives in Biology 4 (8): a008078–a008078. https://doi.org/10.1101/cshperspect.a008078.

Ps. It is really weird, writing a text like this when your name is … Harm.