the practice and science of wound healing history and physiology of wound healing

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Wound Care: The practice and science of wound healing: history and physiology of wound healing

2010;14(3)Professional Nursing Today

The practice and science of wound healing: history and physiology of wound healing

Naude L, BCur, MCur (UP), Certifi cate in Wound Care (UFS), Certifi cate in Wound Care (Hertfordshire)Correspondence to: Liezl Naude, e-mail: [email protected]

www.eloquent.co.za

AbstractThis is the fi rst in a series of articles focusing on wound management. In this article, I will discuss the history and physiology of wound healing, utilising a comparison of wound healing to a building site.

Introduction

Wound healing is a complex process infl uenced by various factors such as the host (the patient), the environment, and the multi-disciplinary team.1 Wound care practitioners can no longer make use of a single modality for the progressive care of a wound. They must critically select wound healing therapy according to the phase of healing of each wound.

The fi rst documentation of wound care can be found in the ancient Egyptian Edwin Smith Papyrus of 1600 BC, with a description of the removal of devitalised skin and pus following war injuries.2 The Hippocratic Collection of 400 BC provides us with some insight into the Greek practice of using drains to evacuate pus from abscesses.

Joseph Lister introduced the modern “germ theory” by demonstrating the benefi cial effects of carbolic acid in the dressings of infected wounds at the turn of the century.3 Debridement, skin cleansing and the use of antiseptics became common practice thereafter. During the same period gloves, gowns, and masks were introduced by William Halsted, and silver foil was revived as an antiseptic in dressings.3 Modern wound care really took off when, in 1908, Elie Metchnikoff identifi ed and characterised phagocytosis as it applied to infl ammation and wound debridement.4

DP Kane describes the wound environment as part of a larger human ecosystem,1 and I couldn’t agree more. No wound should be treated as an isolated phenomenon. If each wound is treated as part of a macroenvironment, this will result in sustainable wound repair. Comorbidities and other factors that can potentially affect healing should always be considered. These factors to be considered include arterial insufficiency, chronic illness, diabetes mellitus, cancer, surgery, trauma and venous insufficiency.

Looking at wound healing like a builder

The process of wound healing is explained by Kane as being similar to that of rebuilding a house after it has been damaged for some reason.1

According to this model, the major cells responsible for wound healing are like the builders who have been hired to repair the house. The initial phase is characterised by the formation of a temporary platelet plug to stop the bleeding (haemostasis), which is like the contractors capping the conduits to prevent further loss. Within the infl ammatory phase, the neutrophils responsible for phagocytosis are represented by the labourers who have to clean up the landfi ll. The proliferation phase depends on the macrophage in the same way as the rebuilding process depends on the building supervisor on site.

The macrophage is the key mediator in signalling other “subcontractors” such as the lymphocytes (specific site preparers or cleaners), angiocytes (plumbers) and neurocytes (electricians). The fibroblasts can be seen as the frame workers or builders of reinforcement structures, the basic building blocks ensuring a solid appearance. The keratinocytes are the roofers providing the waterproofing and an external barrier. Remodelling of scar tissue occurs over the next two years in the same way we would do interior decorating of our houses.

Matrix metalloproteinases (MMPs), and their effect on the extracellular matrix (ECM), are missing from this model.5 According to Gibson and Schultz, MMPs form part of the key proteins that regulate the actions of the wound cells and they are essential to remove the denatured ECM and to digest “holes” in the basement membrane surrounding capillaries to enable vascular endothelial cells to migrate and form new capillaries. The ECM can also be compared to the blueprint prepared by the structural engineer or architect, which


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provides the plan for the rebuilding project.7 The ECM is key to ensuring that the fi nal product is delivered according to the building plan.

Wound healing from a physiological perspective

For wound healing to take place, both the macro- and microvascular structures must be intact, with adequate cardiac output and fl ow to perfuse the wound environment. Adequate nutrition and a well-balanced and functioning immune system are also important. Without these, white cell debridement, bio-burden control and wound repair cannot take place, resulting in a non-healing wound.

The stages of the wound healing process

Figure 1: The stages of the wound healing process

Injury

Eary Infl ammation

Haemostasis

Late Infl ammation

Angiogenesis

Granulation

Epithelialisation

Remodelling

ProliferationPhase

MaturationPhase

Infl ammatoryPhase

InjuryTissue injury is followed by the different phases of wound healing.

HaemostasisThe predominant cells active duriadothelium stimulates platelets to release factors essential for vasoconstriction and endothelial and other platelet activation,resulting in the initiation of the coagulation cascade.1 Thrombin, followed by a temporary fibrin clot, causes the initial matrix to stop bleeding. Complement prostaglandin, vascular endothelial transforming growth factors, nitric oxide and other cytokines are released at the site of injury, resulting in the production and migration and attraction of a host of inflammatory cells at the wound site.

Figure 2: Schematic representation of haemostasis with vasoconstriction and platelet releasing growth factors. (Graphics used with permission from Dr G Schultz.) It is important to note that fi brin clot forms a provisional wound matrix that promotes coagulation and migration of fi broblasts and vascular endothelial cells, and that platelets release growth factors that initiate healing by stimulating chemotaxis, proliferation, and matrix synthesis.

Aggregated Platelets

PDGFEGF VEGF

FGF

RBC

TGFß

Fibrin net

Infl ammationAs soon as the clot stops the bleeding, neutrophils are attracted by the infl ammatory messengers within the coagulum.

The released endothelial prostaglandins, kinins, and hista-mines promote vasodilatation and neutrophil leakage into the ECM, along with infl ammatory proteins, causing oedema. These non-specifi c white cells produce MMPs and reactive oxygen species (ROS) in order to combat invading microbes and begin the phagocytic removal of debris and micro-organisms. The cell signalling attracts monocytes, which will morph into activated macrophages (“Pac-Man cells”). The macrophages synthesise nitric oxide, creating more toxic free radicals, vasodilatation and phagocytosis. The activated macrophages are essential and central to the progress towards the proliferative stage.1

Proliferation The predominant cells during this phase are lymphocytes and fi broblasts. The activated macrophages release several chemical activators and messengers to promote healing. Several released growth factors (see Table I) stimulate vessel development and angiogenesis. Connective tissue formation or fi brogenesis of the ECM is generated from some of these growth factors.

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Figure 3: The infl ammatory phase. The proteases and reactive oxygen species act like cleaners. The neutrophils and the macrophages act like debris removers

Figure 4: Schematic representation of controlled infl ammation. (Graphics used with permission from Dr G Schultz.) Infl ammatory cells kill micro-organisms by phagocytosis and with free radicals (O

2-, H2O2, HOCl), and release proteases (MMPs, elastase) that remove

denatured ECM components and permit wound healing to proceed through the infl ammatory phase.

MMPs continue to break down the debris, creating a granular foundation for the wound. Angiogenesis provides the “conduits” for further cell migration towards the centre of the wound. Peripheral keratinocytes migrate there, and then the “scaffolding” provided by the connective tissue and fi broblasts for cover and closure of the wound. Fibroblasts and endothelial cells are the primary cells in the proliferation phase, which is under T-cell control.

Table I: Growth factors involved in wound healing

Growth Factor Abbreviation Source Activity

Transforming growth factor

TGF platelets macrophages lymphocytes fi broblasts keratinocytes

angiogenesis fi broblast proliferation collagen synthesis cell division

Platelet-derived growth factor

PDGF platelets macrophages keratinocytes endothelial cells fi broblasts

macrophage, fi broblast and smooth muscle cell migration collagen synthesis

Fibroblast growth factor

FGF macrophages fi broblasts

angiogenesis fi broblast proliferation keratinocyte proliferation

Epidermal growth factor

EGF platelets macrophages keratinocytes

collagen synthesis epithelialisation

Hepatocyte growth factor

HGF macrophages fi broblasts

angiogenesis fi broblast proliferation keratinocyte proliferation

Vascular endothelial growth factor

VEGF endothelium angiogenesis

Maturation and remodelling The fi broblasts are essential for scar remodelling. The remodelling of the ECM is a very complex process, since it contains collagen, proteoglycans, fi bronectin and elastin. Fibroblasts produce proteoglycans, and fibronectin consists of protein connections necessary for wound healing.

The average wound contracts by 0.6-0.75 mm/day towards its centre, with this process beginning four to fi ve days post-injury. Myofi broblasts are responsible for wound contraction. Keratinocytes are responsible for the re-epithelialisation from the wound edges. Wound tensile strength is dramatically increased by the process of scar remodelling. This process of scar remodelling continues for 6-24 months, depending on the duration of wound healing.

Wound Care: The practice and science of wound healing: history and physiology of wound healing Wound Care: The practice and science of wound healing: history and physiology of wound healing Wound Care: The practice and science of wound healing: history and physiology of wound healing

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Figure 5: The proliferation phase

Proliferation

Maturation

Figure 6: The maturation or remodelling phase

Wound Care: The practice and science of wound healing: history and physiology of wound healing Wound Care: The practice and science of wound healing: history and physiology of wound healing Wound Care: The practice and science of wound healing: history and physiology of wound healing Wound Care: The practice and science of wound healing: history and physiology of wound healing

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Figure 7: Sequence of molecular and cellular events in skin wound healing. (Graphics used with permission from Dr G Schultz.)

Conclusion

A firm knowledge of the different phases of wound healing will enable the practitioner to understand advanced wound management. Multiple factors influence wound healing, and holistic wound management utilising a multidisciplinary team is important. Each wound and patient is unique and should be treated as such. By comparing the wound healing process to that of building or renovating a house we are able to form a much better visual understanding of the complexity of wound healing. Just like a blueprint is followed for building a house, so the body has a similar plan for which certain requirements must be met in order to facilitate wound healing. The concept of matching the right wound healing phase to the specific wound dressing will be addressed in future articles in this series.

References

1. Kane DP. Chronic wound healing and chronic wound management. In: Rodeheaver GT, Sibbald RG, Krasner DL, editors. Chronic wound care: a clinical source book for healthcare professionals. 4th ed. Wayne: Health Management Publications Inc, 2007; p. 11-24.

2. Majuno G. The healing hand: man and wound in the ancient world. Cambridge: Harvard University Press; 1975.

3. Helling T, McNabney WK. The role of amputation in the management of battlefi eld casualties: a history of two millennia. J Trauma. 2000;49:930-939.

4. Tauber AI. Metchnikoff and the phagocytosis theory. Nature Rev Mol Cell Biol. 2003;4:897-901

5. Gibson DJ, Schultz G. Chronic wound diagnostic for matrix metalloproteinase. Wound Heal Southern Afr. 2002;2(2):58-70.

6. Aronow WS. Management of peripheral arterial disease. Cardiol Rev. 2005;13(2):61-68.

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