Biomarkers And Predictors Of Wound Healing Rates

Wounds are a part of daily life; it could be as minor as a paper cut or something bigger like a surgical incision. Waiting for a wound to heal can be uncomfortable, but have you ever wondered what happens beneath the surface as a scab begins to form and what factors can influence wound healing? 

What is wound healing?

When you injure your skin barrier, wound healing takes place. It is your body’s natural reaction as it attempts to regenerate the injured tissue to prevent further harm.¹ There are two kinds of wounds: acute and chronic.²

Acute wounds heal in an orderly manner usually without complications. Chronic wounds have an unpredictable and prolonged healing process which might lead to other problems including ulcers.²

What are the different phases of wound healing?

There are four stages of wound healing.

Haemostasis

This is the first stage that happens immediately after injury to stop bleeding. 

• Blood cells (platelets) circulating in the bloodstream adhere to the damaged tissue and activate. They recruit additional platelets to the area, forming a clot that serves as a plug to stop bleeding and prevent infection³
• The damaged blood vessel constricts (narrows) to restrict blood flow⁴
• The clot is then strengthened through a coagulation cascade, where the clotting effects are amplified
• Fibrin is produced by the cascade which is used to transform the clot into a fibrin clot, solidifying it³
• The wound now has a scab over it

Inflammation

This is the second stage occurring in the first 24 hours after initial injury where damaged cells and bacteria are removed from the area. Physical characteristics include swelling, pain, and redness at the site of the wound.²

• The injured blood vessels leak fluid resulting in localised swelling
• Vasodilation occurs when blood vessels expand allowing more blood to supply essential nutrients and oxygen to the wound¹
• Neutrophils (a type of white blood cell) kill local bacteria which helps break down dead tissue¹
• They also produce active antimicrobial substances and proteases (an enzyme that breaks down proteins), which initiate the removal of damaged tissue¹
• Around 3 days after injury, monocytes (another type of white blood cell) appear.
• Monocytes mature into macrophages. These are large cells that eat bacteria, dead neutrophils, and damaged tissue⁶
• They also release chemokines, cytokines, and growth factors, which are chemical messengers. They play a vital role in fighting off infection¹

Proliferation

The third phase of wound healing focuses on filling and covering the wound. This phase is characterised by the formation of granulation tissue (connective tissue), angiogenesis (blood vessel formation), wound contraction, and epithelialisation (the process of restoring damaged skin).²

This phase occurs around three to ten days after injury but can take weeks or more to complete.¹

• New tissue composed of collagen and extracellular matrix, which functions as a scaffold, is used to rebuild the wound⁶
• To ensure that the tissue receives enough oxygen and nutrients, new blood vessel networks are built.
• New tissue appears pink or red due to inflammatory agents⁷
• In a process known as angiogenesis, macrophages stimulate the body to produce new blood vessels and tissue
• The wound bed is then filled by the new tissue
• The final stage of proliferation is the wound edges contracting and moving closer together

Remodelling

The final stage is remodelling also known as maturation, in which the wound is strengthened, and the tissue reconstructed. Stretching and itching are common throughout this process. This phase begins in the proliferation stage and lasts for a long period of time.¹

• The regenerated tissue increases strength and flexibility, gradually
• Apoptosis or programmed cell death, removes cells that were required to repair the wound but are no longer needed⁸
• Collagen is reformed into a more organised structure during this phase, enhancing the tensile strength of the healing tissue⁸
• Healed wound areas only have 80% of the tensile strength of unwounded skin even with cross-linking¹

What are biomarkers?

Biomarkers are biological molecules that are present during the wound-healing process and can be found in blood and tissues. They play an important role in ensuring the wound is healed.⁹ They can be used to track the progress in wound healing and identify either impaired or regular healing.

What are some key biomarkers in wound healing?

Some of the different types of biomarkers involved in the process include: 

What are some of the clinical predictors of wound healing rates?

There are a range of factors that can affect wound healing rates including:

Patient factors

Age

People over the age of 60 are at higher risk of poor wound healing. Every stage of healing undergoes characteristic age-related changes including decreased secretion of growth factors, delayed angiogenesis and collagen deposition and turnover as well as decreased wound strength.⁶

Comorbidities

Diabetes patients experience impaired acute wound healing. They are also more likely to develop chronic non-healing diabetic foot ulcers which are estimated to affect 15% of people with diabetes. Several functions are dysregulated including abnormalities in phagocytosis and bactericidal capacity. This can delay or impair wound healing.⁶

Nutrition & lifestyle factors

Obesity is known to increase the risk of a variety of health conditions, including impaired wound healing. People who are obese frequently experience wound complications such as infections and pressure/venous ulcers. Difficulties with repositioning themselves can lead to an increased risk of pressure-related injuries in obese individuals. Moreover, skin folds can harbour microorganisms that thrive in moist areas leading to infection.⁶

Wound characteristics

Size & depth

Wound size and depth affect the healing rate, with larger wounds taking longer to heal due to their larger surface area compared to smaller-sized wounds. Surface-level wounds heal faster than one that penetrates deeper.⁷

Type of wound

Chronic wounds, such as pressure ulcers, do not heal predictably.⁷ They frequently have delayed healing due to underlying issues such as poor circulation. 

Genetics

Mutations in immune response genes, such as neutrophil function, can impair the body’s ability to fight infections, leading to delayed wound healing.²⁰

What are the clinical applications?

Personalised wound care

Treatment plans can be tailored based on your individual biomarker profiles. These can be created by knowing the person's estimated wound healing pace. For example, a patient with diabetes who heals at a slower rate may require more aggressive interventions compared to patients with normal healing rates.²¹ In addition, biomarkers can guide the use of specific and appropriate therapies such as growth factor treatments, specifically targeting delayed healing processes.²¹

Therapeutic targets

Researchers can target biomarkers that affect wound healing rates to develop therapies that improve or accelerate the healing process. This includes growth factors as well as wound dressings infused with therapeutic agents to regulate the healing environment.

Technological advances in wound healing

Biomarkers can be identified and used to measure the effects of wound healing. Some technology that can be used for this include the following.

Non-invasive monitoring tools

Wearable sensors and imaging techniques can be utilised to treat wounds. Wireless monitoring can play a key role in such instances, allowing medical professionals and others to remotely monitor the wound in real-time. Prolonged monitoring can help with faster treatment of a wound or injury.¹⁶

Smart bandages with integrated sensors can assess the wound site at various phases of healing, as well as look for possible risks of infection. These can provide wound-related information without requiring removal from the site.¹⁶ These may be useful when treating chronic wounds as frequent changing of dressings can cause distress.

AI and machine learning

Machine learning models are being developed to assess wound images and automatically identify wound types to predict wound healing outcomes based on characteristics such as size, colour, and tissue composition.¹⁸

AI techniques can also integrate imaging and molecular biomarker data to improve the accuracy of wound healing forecasts.¹⁷

Challenges

Wound healing involves several biological processes, and the interaction of these processes vary among individuals. This can complicate predictions of wound healing rates. Furthermore, there is no consensus on which biomarkers are the most reliable for assessing wound healing or how to measure them. Therefore, different techniques can lead to inconsistent data and conclusions.¹⁹

Summary

Wound healing is a complex process consisting of four key stages: haemostasis, inflammation, proliferation, and remodelling. Factors such as age, lifestyle choices, and the presence of other diseases can influence wound healing rates. Biomarkers can be key in predicting these rates, and new technologies are being developed to use these as a way of changing outcomes, especially for those suffering from chronic wounds.