Factors Affecting Wound Healing

Original Editor - Stacy Schiurring based on the course by Dana Palmer

Top Contributors - Stacy Schiurring and Jess Bell

Introduction

There are many factors to take into consideration when practicing wound care. Some of these factors are within the control of the rehabilitation professional, and some are not. By gaining an understanding of these key factors, the rehabilitation professional will be able to adjust the wound care treatment plan to obtain the best possible healing outcome. There are three types of factors which can affect wound healing: (1) intrinsic, (2) extrinsic, and (3) iatrogenic.

Understanding the influence of these factors can help shape and inform a wound care assessment, treatment plan, and prognosis. For example, it is unrealistic to expect a wound to heal in the same manner a young healthy person as in an older person with multiple comorbidities. Providing patients with realistic expectations of the healing process improves goal setting and builds trust between patient can care provider.

Intrinsic Factors

Intrinsic factors are those related to the person that cannot be changed, but may be managed.

1. Age. The epidermis becomes thinner with age and has a slower turnover. Collagen, elastin, and hyaluronic acid production also decreases as skin ages and this makes older skin more susceptible to tears and wounding. Human growth hormone plays a significant role in tissue healing and this decreases with age as well. Once older skin is wounded, it heals slower due to slower turnover of keratinocytes, reduced blood flow to the dermis, and a slowing of the complex healing cascade.
2. Genetics. Researchers found that people will tend to be susceptible to infections by certain pathogens depending on their genotype. This is in part related to the wound microbiome and therefore the host's microbiome. It is not just the presence of bacteria alone, but the variety of bacteria present. The more varied the wound microbiome, the faster a wound heals. While the microbiome is somewhat modifiable, much of the baseline is related to genotype and to the microbiome you are born with and then seeded from the birth process. Skin elasticity and ability to lay down collagen and fibrin is also genetically linked and can be seen in things like scars, formation of stretch marks, and wrinkles. Research in mice has found wound healing to be genetically controlled with a heritability rate of up to 86%. Other research in humans has found specific gene expression to be associated with the onset and progression of wound healing.
3. Sex hormones. This is a complex topic. This graphic is specifically looking at genetically determined sex hormone averages, and does not take into account those with altered sexual expression or hormonal levels outside of the average range. The research is mixed with some showing oestrogens to speed healing and others in favour of androgens, depending on what phase the wound is in. This is likely not a big concern. The main reason I mention it is in case you have a patient that is taking synthetic hormones or going through an abrupt hormonal change, such as menopause, then you may want to consider whether that may be affecting their healing potential.
4. Systemic diseases. Common medical conditions that may affect healing are (1) diabetes, (2) vascular diseases, (3) pulmonary diseases, (4) immunocompromised or autoimmune conditions, and (5) conditions that affect the autonomic nervous system. Both sympathetic and parasympathetic divisions play important roles in the wound healing phases.

1. • Diabetes. Hyperglycaemia delays healing, therefore blood glucose levels need to be kept as close to ideal range as possible.
   • Venous insufficiency. A wound will not heal when persistent oedma is present. Oedema results in fibrinogen leaking out of capillaries into the dermis, which blocks oxygen and nutrients from being delivered to the tissues. This reduces blood flow and results in tissue hypoxia. Tissue hypoxia impairs tissue repair and increases susceptibility to infection by anaerobic microbes. It also inhibits fibroblast function and suppresses epithelial cells.
   • Arterial insufficiency. Blood flow to tissue needs to be optimised to facilitate wound closure. Insufficient perfusion reduces delivery of the oxygen cells and nutrients necessary for healing.
   • Idiopathic pulmonary fibrosis. Pulmonary fibrosis reduces tissue oxygenation and negatively affects the tissue repair mechanisms via widespread epithelial injury.
   • Other chronic pulmonary diseases that affect tissue oxygenation can also impact healing.
   • Immunocompromised conditions. Such conditions prevent the necessary inflammatory response to initiate the healing cascade. This leads to an increased risk of infection, decreased phagocytosis, and decreased fibroblast activity.
   • Sensory and autonomic neuropathy. The neurotransmitters and neuropeptides produced by the cutaneous nerves are essential for all phases of repair. These substances are responsible for plasma extravasation, vasodilation, and neurogenic inflammation. Neuropathy limit the production of these substances.

Extrinsic Factors

Extrinsic factors are things external to the wound that we can directly control.

1. Medications. It is important to perform a medication review and investigate any potential effects which could delay healing.
   • Steroids will delay all phases of wound healing. However they can also contribute to elevated glucose levels with long-term use, recall how hyperglycaemia can delay healing as discussed above.
   • Anticoagulants inhibit the coagulation cascade and can result in tissue necrosis. That's especially common in fatty tissue.
   • NSAIDs delay wound healing by suppressing the inflammatory response, decreasing collagen synthesis, reducing tensile strength and increasing risk of infection. This effect is typically only seen with long-term use and short-term use of NSAIDs is not shown to be detrimental to healing, but something to keep in mind.
   • Chemotherapy drugs interfere with cell proliferation, they prolong inflammation, inhibit protein synthesis, and decrease collagen synthesis. Nausea and vomiting that's associated with chemotherapy may also impair nutrition, which further affects tissue repair.
   • Immunosuppressive or antirejection medications impair fibroblast formation, increase risk of infection and decrease wound tensile strength. Gastrointestinal side effects of these drugs can also impair nutrition.
2. nutrition, there are many key nutrients required for wound healing. A few of the most important are water, carbohydrates, protein, particularly protein building-blocks, like the amino acids arginine and glutamine, vitamin A, vitamin C, vitamin D, zinc. And a few others that are needed for optimal healing are vitamin E, magnesium, manganese, copper, and omega-3 fatty acids. Metabolic pathways for new protein synthesis are tightly regulated. So it does not take much to result in the protein malnutrition. This can be due to a true protein deficiency on intake, the amount they're eating, or due to the increased energy requirements for tissue repair. So keep in mind that requirements for tissue healing are increased beyond the levels recommended for routine tissue maintenance or the recommended daily allowance, or RDAs, you see listed for these type of nutrients. To use water as an example, when healing a wound, more water is needed to help with tissue repair. This depends on size of wound and patient's overall health. But estimates are that water requirements are increased by around 20 to 30% from the normal requirements. And that's why some dietitians or physicians will prescribe supplements at a dose that's above the recommended daily amounts for different vitamins. This is usually done for short periods of two to 12 weeks while wound healing is initiated and then reduce back to the RDA levels or weaned off completely once healing is complete and a regular diet is established.
3. Stress and elevated cortisol levels have also been shown to be detrimental to wound healing. Stress results in an increase in incidence of opportunistic infection, reduced expression of human growth hormone, and delayed healing. In one study that investigated mucosal punch biopsies, okay, of young college students, it was found that students took an average of three days longer to heal a 3.5 millimetre wound when they were under stress during exams, compared to how long it took them to heal the same wound when not under stress. So this represented a 40% longer healing time for a small standardised wound in a young and otherwise healthy population. As we have already established, those who are older with multiple comorbidities are already at risk for delayed healing and stress further compounds that. In addition, people that are stressed are more likely to engage in other habits that can delay wound healing, such as the use of alcohol, tobacco or drugs, less physical activity, less sleep, poor nutrition, a lack of medication compliance, all of these things kind of factor in when we're looking at the total picture.
4. Research has demonstrated the many health benefits of sleep and the detrimental effects of sleep deprivation. A few of that specifically relates to wound healing, such as increased cortisol production, elevated rates of illness and infection, delayed skin barrier recovery, reduced growth hormone production, and impaired healing potential. Keep in mind that sleep disturbances can also be a common side effect of many medications and underlying health conditions. Ideally adults should aim for eight to nine hours of sleep per night.
5. We all know that smoking is a clear risk factor for heart and lung disease, strokes and cancer. Smoking also causes hypoxia, tissue ischaemia, blood vessel inflammation, and interferes with every phase of wound healing. Smoking just one cigarette has been shown to reduce tissue oxygen concentrations. People that are pack-per-day smokers experience tissue hypoxia during a significant portion of each day. Even 20 minutes without smoking has been shown to improve blood flow to the hands and feet. After 12 hours without smoking, the oxygen level in the blood begins to return to near normal levels. And after 24 hours without smoking, the nerves begin to recover. Smoking cessation has been shown to restore the tissue microenvironment and cellular functions within four weeks. For heavy smokers that are unable to quit, even cutting down to less than one pack per day may show improvement in tissue healing ability compared to more than one pack per day. So gradual reduction of smoking should continue as able beyond that point. Strategies such as smoking only three-quarter, one-half, or one-quarter of each cigarette can further reduce the detrimental effects that are caused by smoking. Smokers have also been shown to have significantly lower levels of plasma vitamin C compared to non-smokers. For these people, diets that are higher in vitamin C or including vitamin C supplementation may be considered to mitigate blood vessel damage and then further promote healing.
6. Likewise, alcohol delays wound closure, and increases the risk of infection. It also reduces angiogenesis, impairs collagen production, and interferes with epithelialisation and induces tissue hypoxia. So even a few exposures to alcohol that's above the legal limit can affect wound healing.
7. Let's talk a little about infection now. So all wounds are colonised with bacteria. Some bacteria are harmless and actually necessary for wound healing. Chronic wounds will have more bacterial colonisation than acute wounds and tend to have more pathogenic bacteria. As long as this is of a level that the body can manage, there's no problem and healing will progress. The amount of bacteria present in the wound is categorised on a spectrum. So let's take a look at that. Contamination is when non-replicating bacteria are present on the wound surface, but they have no effect on healing. Colonisation is when there's presence of replicating bacteria, but then there's no harm to the host and no effect on the healing process. Critical colonisation is when replicating bacteria are present in sufficient numbers to visibly impair the healing process. So you start to see some changes there, the wound is stagnating. Infection is the next level, when the replicating bacteria have invaded all the surrounding tissue and there's a visible effect on the wound. And also the peri-wound tissue. Finally, sepsis is when replicating bacteria are in sufficient numbers to produce a whole-body inflammatory response. Local infection delays wound healing by reducing collagen production, decreasing nutrients available for healing and also killing cells that are vital for healing. Fungal infections are particularly problematic for patients who are immunocompromised and fungal infections are sometimes seen a little more often with compression therapy, especially when the dressings stay in place for seven days. So the wound drainage and the sweat create a moist environment within that compression dressing that's ideal for fungi. And this is especially true in hot and humid environments. So it's something to watch out for. These infections are best managed through topical antifungals, more frequent dressing changes and adequate absorption to then manage all that wound drainage.
8. Moving on from infection, something very close is biofilm. It's a pretty big topic that is not yet completely understood, but much research is being done. Bacteria have evolved a variety of strategies that help to ensure their survival. So one of these is the development of a polysaccharide capsule that they sort of make around themselves and it shields them from destruction by the host's immune defences. The biofilm adheres to the wound bed and is not easily removed by other bacteria, or even by mechanical force. The biofilm can be invisible or it can also resemble a thin layer of slough on the wound's surface. It might look kind of yellowy. If it's invisible, the biofilm might make the surface appear shiny or slimy. 90% of chronic wounds will have biofilms. So if you have a wound that's not healing, it's probably got some biofilm. In order for it to progress to healing, it has to be removed. Sharp debridement is the preferred method to remove biofilm and it should be performed regularly because bacteria have the ability to form a mature biofilm in just a few days. So if you take it off, they'll just make a new one. It's important to note that antimicrobial dressings will not penetrate the biofilm to be able to kill bacteria. So that's not an acceptable method to get rid of biofilm.
9. Now we have obesity. So like smoking, obesity is a known risk factor for multiple diseases. Obesity also increases risk of wound infections, haematomas, surgical complications, venous ulcers, and pressure injuries. This is thought to be due to the decreased tissue perfusion and ischaemia in adipose tissue as well as increased tissue tension on wound edges. Inadequate delivery of antibiotics can also be a factor. Adipocytes themselves have been shown to secrete factors that interfere with the normal inflammatory and immune responses. Other things that may be more common in obese patients that have the potential to affect healing are pressure, friction, maceration, limited mobility, or a sedentary lifestyle, and oedema.

Iatrogenic Factors

Iatrogenic factors are those related to how the wound is managed. This is where we can have the biggest influence. These are things that are changed throughout the healing process, depending on response. They include compression, dressings, debridement, dependency, topical antiseptic and antibiotic ointments, and local trauma.

Finally, we're gonna look at iatrogenic factors. So these are the things typically related to how the wound is being managed. They're also things we have more control over as wound care providers. The first we're going to look at is compression. As we discussed, compression is essential for venous wounds, but is indicated for oedema reduction in other wounds as well. However, care must be taken to apply compression appropriately and monitor patient response regularly. Compression applied over an arterial wound or with incorrect technique can reduce tissue perfusion or create a tourniquet effect that damages both the wound and the peri-wound tissue. Dressing removal with poor technique can result in trauma. Inappropriate dressing choice for a wound can cause tearing or maceration. Your dressing choice should maintain a moist environment, and this requires consideration of drainage type and amount as well as planned frequency of dressing changes. The wound bed should not be allowed to dry out and should not be kept too wet. This requires repeated assessment of how the wound is responding to the chosen dressing. Too many dressing changes can also delay healing. It takes up to 40 minutes for wound tissue to regain proper temperature and cellular mitosis is disrupted for up to three hours after a dressing change.

Incorrect, unnecessary, or too frequent debridement, excessive debridement is detrimental to healing because it causes a disruption of the wound bed. While maintenance debridement is certainly necessary at times, attempts should be made to limit interruption to the healing process. This does not mean that you should avoid debriding necrotic tissue because that will definitely delay healing on its own as will the presence of biofilm, which we have already discussed. But it does mean that you should attempt to be as selective as possible to remove as much as possible at each session and not to leave it there for the next dressing change. This may mean debridement by a physician or a surgeon that allows them to go deeper and remove more down to a bleeding base.

Many chronic wounds are associated with oedema, particularly venous ulcers. Dependency increases oedema, reduces return of blood and lymph flow out of the extremity and also increases pain. Elevation should be higher than the heart and combined with calf pump exercises. If not possible, at least elevation to the level of the hip. The only wounds that should be kept dependent are wounds where tissue perfusion is compromised, such as arterial ulcers. In this case, gravity can help to improve blood flow to the wound.

Let's talk about topical antiseptics and antibiotic ointments. So cytotoxic antiseptics have a wide spectrum of action on bacteria, which results in eradication of beneficial bacteria, as well as damage to the healing cells. Common antiseptics that you may have heard of include betadine or povidone-iodine, Dakin's solution or sodium hypochlorite, chlorhexidine, hydrogen peroxide, Burow's solution or aluminium acetate, and silver nitrate. Topical antibiotics have a more narrow spectrum of action and are also less cytotoxic than antiseptics. Therefore, they are typically less destructive to the healing cells, but they can still be detrimental when used inappropriately. Research in both human and animal models has demonstrated that broad-spectrum topical antibiotics slow skin healing. Common topical antibiotics you may have heard of include bacitracin, mafenide acetate, mupirocin, neomycin, Neosporin, Polysporin, and silver sulfadiazine. In addition to delayed wound healing, some of these products can be harmful to kidney and liver and should be avoided in those with pre-existing kidney or liver impairment. These products certainly have their indications, but should be chosen with careful consideration and used for the shortest amount of time necessary to achieve the desired effect and minimise detrimental effects.

Local trauma. So external pressure applied over tissues will close capillaries, resulting in reduced blood flow and tissue oxygenation. Friction and shear forces from footwear and dressings can cause tissue damage that not only creates wounds, but impairs wound healing. This includes bumping, rubbing, scratching, excessive movement, or other disruption of the wound. These things can occur through wound cleansing, dressing changes, loose compression dressings, footwear, or patient positioning.

So now that we've looked at things that can affect wound healing, let's take a look at some of the factors that can optimise wound healing. We're going to go over five key factors that can optimise wound healing in your patients. The first is to address underlying disease process. So that is things like blood pressure, blood glucose levels, tissue perfusion, oedema management, reinforce medication compliance, offloading, and pressure relief. These may not all be in your scope of practice. However, you can provide education on how these factors will affect wound healing and also reinforce treatment plans that were established by other healthcare providers that you're working with. Always refer out as necessary.

The second is to promote nutrition. So dietitian or nutritionist referral, reinforce compliance with prescribed diet, emphasise importance of hydration for tissue healing, educate on the benefits of nutrition for healing and how what is put into the body serves as building blocks for new tissue. This may seem intuitive to us, but it isn't always to our patients.

The next is exercise and physical activity. As we know, this increases circulation and tissue perfusion, it reduces oedema and improves overall health and can reduce the negative impact of systemic disease.

Next is peer support and mindfulness. Peer support groups can be helpful in increasing patient adherence to a treatment programme. Things like walking or exercise groups, nutrition groups, support for health challenges and setbacks, breathwork, and breathing exercises. We know that beliefs and attitudes can contribute to chronic health conditions and this includes chronic wounds. This may mean that the patient puts the onus on the healthcare provider, you, to heal them rather than taking responsibility for the control that they have over their healing process. Alternatively, the patient may feel powerless or feel unsure about how to go about making the recommended changes. Okay. So patients who have been dealing with wounds for a long time and/or have seen multiple healthcare providers may feel hopeless. Mindful stress-reduction techniques, relaxation, and guided imagery have been associated with improved wound healing in the research studies. This can take many forms, such as positive self-talk about the healing ability of the body, fostering belief in the potential for healing, mindfulness exercises that address tissue oxygenation, nutrition, tissue repair, body resiliency, or also turning the focus inward to body repair rather than outward to life stresses. Guided imagery, talking them through the phases of tissue healing, breathwork, directing healing breath and healing cells towards the wound, or positive affirmations. They can be in spoken, written, or audio form. And usually a combination of these methods works best for people to integrate them.

Finally, we have education. So patient education on their specific wound and underlying condition is key. And yet this is somehow often overlooked. Knowing why you're making specific recommendations can really go a long way towards adherence to a treatment plan and will improve buy-in for interventions that promote healing. This should occur from many different healthcare providers involved in their care because this reinforces the concept. So collaboration works well for you here. It helps with intrinsic versus extrinsic locus-of-control, because then the patient knows what factors are changeable, what factors they can modify, and what factors are completely within their control. This also helps the patient in goal setting and prioritising. So if they know what factors can speed or slow healing, that then allows them to modify their lifestyle accordingly based on what fits their personal priorities and what works best for them. In addition to the reasoning for treatment and individualised goal-setting, provide the patient with strategies, right? To help implement these recommendations that you're making. What are some ideas of how they can make that happen?

There is a lot to do, and we can get very busy with treatments. But remember that this education can come in many little bites here and there. And in fact, this is usually better for retention anyway, and because we have more time, we are the optimal people to provide this.

So as we have learnt today, wound healing is complex and can be affected by many different factors. I appreciate your time, and I hope you have some valuable takeaways to use in your daily practice and to improve your patient outcomes. For more information, please take a look at the resource list provided.

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