Introduction

Biomarkers are substances or processes that can indicate both the status of a condition and a patient’s response to treatment. Wound care professionals use biomarkers for assessing wounds at each phase of healing, identifying obstacles to healing, and guiding individualized treatment through the wound healing trajectory.¹ This piece will introduce various biomarkers relevant to wound care, and how they impact the healing process. 

Overview of Important Biomarkers in Wound Care

Matrix Metalloproteinases

Matrix metalloproteinases (MMPs) comprise a group of enzymes found in both acute and chronic wounds. MMPs regulate extracellular matrix (ECM) degradation and deposition, as well as angiogenesis, all processes necessary for wound re-epithelialization. When MMP activity is excessive, however, this imbalance can lead to chronic nonhealing wounds. However, the tissue inhibitors of metalloproteinases (TIMPs) help to regulate ECM remodeling in wound healing. Successful wound healing therefore requires a complex balance of MMP activity during all wound healing phases.²

Polymorphonuclear Elastase

PMN elastase, a serine protease, has been studied as a biomarker to detect early wound infection. Chronic wounds may exhibit high PMN elastase levels. PMN elastase is also an activator of other MMPs and an inactivator of protease inhibitors. This last action can promote further protease activity in a wound and consequently can contribute to damage of host tissue.³

Growth Factors

Growth factors, which are signaling molecules, play an important part in wound healing by regulating cellular responses.⁴ Growth factor levels may be deficient in chronic wounds.⁵ When applied topically in wound care to promote healing, delivery of growth factors is available in several different formulations, including particulate systems, hydrogels, and scaffolds.⁴

Oxidative Stress and Inflammation

Research into oxidative stress and inflammation largely emphasizes diabetic wound healing. Studies emphasize characteristics of diabetic wound formation such as a persistent chronic inflammatory response, degradation of angiogenesis, and an imbalance of ECM regulation, all of which are mechanisms associated with oxidative stress. Healing of diabetic wounds is a complex process to counter inflammation and such oxidative stress and includes numerous cells, cytokines, genes, and other factors. Recent discussions cite long noncoding RNAs as critical contributors to the healing trajectory of these wounds.⁶ Another study found that hyperbaric oxygen therapy reduced oxidative stress and inflammation and increased growth factors in diabetic wounds.⁷

Angiogenesis

During wound healing, angiogenesis creates the blood-rich granulation tissue that is needed for tissue regeneration and wound healing.⁸ Capillary sprouts appear in the wound clot and form a microvascular network in the granulation tissue. Endothelial cells and angiogenic factors then interact with the ECM. When collagen accumulates in the granulation tissue to produce scar, blood vessel density in the granulation tissue begins to decrease, a sign of wound healing.⁹ 

Oxygenation

Adequate oxygenation is a prerequisite for wound healing, and, conversely, hypoxia delays healing. Efforts to improve wound oxygenation have included hyperbaric oxygen therapy, but more research is necessary.⁷ One study demonstrated improved diabetic wound closure with a sustained oxygenation system comprising oxygen-release microspheres and a reactive oxygen species–scavenging hydrogel.¹⁰ Although adequate blood flow is an important factor in providing oxygenation to wounded tissue, it is important for clinicians to understand that the blood circulation itself in larger vessels is not a guarantee of oxygen dispersal within the wound via smaller vessels. 

Nutrients

Wound healing requires adequate nutrition. However, despite the importance of nutrition in wound healing, dietary protocols often remain absent from wound care standards.¹¹ Nutritional deficiencies impair the timely movement of a wound through the stages of healing. Patients with malnutrition are at risk of infection and pressure injury in addition to wound chronicity.¹²

Epithelial Cell Migration

Groups of stem cells found in the interfollicular epidermis and hair follicle niches that form the epidermal and hair layers are responsible for maintaining the epithelium of the skin. In a wound, stem cell progenies migrate from their niche in a process known as reepithelialization. This epithelial cell migration reestablishes the skin’s barrier function and closes the wound.¹³ Conversely, barriers to epithelial cell migration pose challenges to the wound healing process. 

Granulation Tissue Induction

Granulation tissue induction occurs during the proliferation phase of wound healing.¹⁴ The prerequisites for granulation tissue induction hypothetically include fibrin matrix maturation or cell activation.¹⁵ Granulation tissue is highly vascular and contains fibroblasts, granulocytes, macrophages, capillaries, and loosely organized collagen bundles. The dominant cell is the fibroblast, which produces collagen and ECM components that provide a scaffold for cell adhesion.¹⁴

Tracking Wound Healing Through Biomarkers

Biomarkers Through the Phases of Wound Healing

Applying Biomarker Information in Wound Care Practice

Biomarker-Guided Treatment Modifications

By monitoring biomarkers during patient care, wound care providers can respond quickly to modify treatment. For example, testing for wound infection biomarkers can unmask a wound infection¹⁶ and lead to appropriate antimicrobial treatment. Excessive exudate in a wound can alert the clinician to the need for a superabsorbent dressing to manage MMPs.¹⁷ A malnourished patient may benefit from nutritional education or help from social services in accessing and affording healthy food.

Biomarkers in Wound Infection

In addition to wound cultures, C-reactive protein, presepsin, and bacterial protease are sensitive indicators of wound infection,¹⁶ which is a risk factor for wound chronicity.⁸ Procalcitonin is also a sensitive biomarker for infection, but testing is expensive and requires special training and equipment.¹⁶

Biomarker-Specific Wound Care Dressings

Because chronic wound exudates have high levels of MMPs, PMN elastase, and free radicals, which stall progress through the wound healing trajectory, management of these exudates is essential to healing. Superabsorbent polymer-containing wound dressings have a significant binding capacity for MMP-2 and MMP-9 and are therefore useful for promoting and tracking healing in chronic wounds with excessive exudate.¹⁷

Partnering With Patients

As in every aspect of wound care, engagement of the patient is ideal in tracking the progress of a healing wound. Specifically in terms of biomarkers, patients and providers may find a wound diary to be a useful tool for documenting and tracking wound exudate.¹

Conclusion

Biomarkers provide clinicians with numerous ways of looking at different aspects of wounds and wound healing. These markers offer clues to both healing and nonhealing in chronic wounds that wound care providers can use in everyday practice to optimize the care of their patients.

References

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15. McClain SA, Simon M, Jones E, et al. Mesenchymal cell activation is the rate-limiting step of granulation tissue induction. Am J Pathol. 1996;149(4):1257-1270.

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