For wound healing to occur, a complex, well-defined cascade of events must take place in the body’s natural host processes. When this cascade of events is disturbed, a wound can fall into a state of non-healing or chronicity.¹ In clinical practice, chronic wounds such as pressure ulcers, vascular ulcers, and neuropathic wounds behave differently and may be extremely slow to heal. A chronic wound, by definition, is a wound that has failed to progress through the “normal” healing process or is not responsive to management in a timely manner.²

Most wounds lasting longer than 30 days are considered chronic wounds; examples include pressure ulcers, traumatic wounds, and lower extremity wounds. Contributing factors include poor circulation, ongoing pressure, systemic illness, age, repeated trauma, inadequate or inappropriate treatments, increased bacterial load, excessive proteases such as matrix metalloproteinases (MPPs), elastase, and inflammatory byproducts such as cytokines that may prolong the inflammatory processes and contribute to senescent, aberrant, or quiescent cells.

The wound healing phases (hemostasis, inflammatory, proliferative, and maturation) overlap, but when the wound essentially becomes “stuck” in the inflammatory phase and this “chronic state” develops, it can last from weeks to years. Regulation of the inflammatory phase is handled by the immune system. The innate immune cells—including neutrophils, monocytes, and macrophages—become altered and persist in the wound, thereby increasing inflammation, which inhibits wound closure.³

Wound Bed Preparation and the Impact on Chronicity

The TIME (tissue, infection/inflammation, moisture, edge ) wound bed preparation model is a practical, evidence-based approach devised especially for health care practitioners to be used when conducting wound assessments, identifying barriers to healing, and developing a comprehensive plan of care. It is also a reminder to treat the whole patient, not just the hole in the patient. Getting chronic wounds back on track is the focus of the “E” of the mnemonic, which stands for keeping the wound edge healthy and the progression of epithelial cells across the surface of the wound. Examples of modalities that assist with getting chronic wounds back on track are electrical stimulation, utilization of collagen dressings, growth factor therapy, and negative pressure wound therapy (NPWT).

Specific Interventions

Electrical Stimulation

An article by Zhou et al.⁴ discussed how direct electrical current flow exists in wounds and is constant until the wound re-epithelializes completely. This electrical field guides cell migration across the wound and also stimulates nerve sprouting. When this activity is disrupted, healing stalls. The use of electrical stimulation therapy can aid in the restoration of this electrical field and stimulate vascular endothelial growth factor (VEGF) production by endothelial cells and osteoblasts. These investigators also noted that electrical stimulation can stimulate an increase in VEGF in patients with chronic ulcers and can shorten the healing time. The percentage of wound closure is significantly higher in wounds treated with electrical stimulation compared with non-treated wounds.⁵

Collagen Dressings

Using collagen dressings in the treatment of stalled wounds aids in stimulating tissue growth. This is accomplished by helping the migration of cells, including fibroblasts and keratinocytes, in the wound. Collagen is a protein and encourages all phases of wound management—including debridement, angiogenesis, and re-epithelialization—because it provides a natural scaffold or base for the growth of new tissue. These dressings also act as a diversion for and chemically bind to MMPs, which can impede wound healing, thus leaving the body’s natural collagen available for wound healing.⁶

Collagen dressings are indicated to boost the healing of partial- and full-thickness wounds including pressure injuries, foot ulcers, venous ulcers, minor burns, skin grafts and donor sites, and chronic wounds needing to be “jump-started” by reducing mediators of inflammation.⁷ The only contraindications to collagen dressing use are third-degree burns, wounds that have formed eschar, or wounds in persons with known allergies to bovine-, porcine-, or avian-derived products. Collagen is available in many forms, including sheets, pads, gels, powders, and pastes, and it can be combined with other additives such as alginates and antimicrobials.

Growth Factors

Growth factors are substances secreted by the body to stimulate the growth and proliferation of cells responsible for wound healing. Growth factors therefore increase the number of wound healing cells and facilitate faster wound healing. It takes multiple cell types and numerous growth factors and cytokines to achieve the complex process of wound healing. In recent years, the use of growth factor therapy has increased because of its efficacy in the clinical management of non-healing wounds such as pressure injuries, venous ulcers, and diabetic foot ulcers.

Currently, four growth factors and cytokines are used to aid wound healing: platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and basic fibroblast growth factor (bFGF). When wounds fall into a non-healing state, studies show that these growth factors have become deregulated, causing impaired healing. However, as a result of genetic engineering and biological technology advancements, the use of exogenous growth factors and cytokines may provide a possible solution to the problem of non-healing wounds.⁸ PDGF is important in all phases of wound healing. It is released from platelets on injury and is present in wound fluid. It helps initiate the inflammatory phase and enhances fibroblast proliferation in the proliferative phase, which produces extracellular matrix and granulation tissue formation. In chronic wounds, PDGF is decreased because of the impact of the proteolytic wound environment. This is the basis for the addition of recombinant human PDGF to chronic wounds to speed up wound closure.⁸ FGF is produced by keratinocytes, fibroblasts, endothelial cells, smooth muscle cells, chondrocytes, and mast cells.⁸ FGF is integral to wound healing because it plays a key role in granulation tissue formation, re-epithelialization, and remodeling. Its ability to aid in extracellular matrix formation increases keratinocyte mobility, thus promoting the migration of fibroblasts.

Studies showed that recombinant human bFGF topically applied to pressure injuries increased angiogenesis and produced better healing than reported in injuries treated with recombinant human GM-CSF. The key to angiogenesis is vascular endothelial growth factor, or VEGF, as a result of its early stimulation of endothelial cell migration and proliferation. This is very important to individuals with poor vascularity such as those with ischemic diabetic limbs. In addition to the topical use of VEGF in patients with diabetes and ischemic extremities, the intramuscular gene transfer of VEGF to individuals with ischemic ulcers or rest pain secondary to peripheral vascular disease demonstrated a significant decrease in rest pain.⁸

Negative Pressure Wound Therapy

The emergence of Negative Pressure Wound Therapy (NPWT) over the last few decades has essentially been a game changer in wound healing. NPWT devices are commonly used in the treatment of pressure ulcers, open abdominal wounds, sternal wounds, traumatic wounds, diabetic foot infections, second-degree burns, and skin graft recipient sites. NPWT is contraindicated in wounds containing malignant tumors, untreated fistulas, and untreated osteomyelitis.⁹

Extreme caution should be exercised when NPWT is used near vascular structures such as large blood vessels or near the heart because erosion can occur, resulting in hemorrhage. In addition, a fistula can result from use near visceral organs, also secondary to erosion. NPWT is accomplished by using an airtight wound dressing attached to a pump to create a negative pressure environment in the wound. This promotes healing and aids in managing exudate in acute, chronic, and burn wounds. Variations of the therapy are being used to control edema, treat incisional wounds, and instill irrigation fluids and antibiotics.⁹ Variations in the type of contact material may allow for variations in the intended use and a customized outcome. For instance, NPWT can be combined with other wound care products such as dermal scaffolds or allogenic or xenogenic materials and procedures to improve healing.

Conclusion

Getting back to basics and following the principles of wound care are important for obtaining high-quality outcomes. If a wound has not shown significant signs of improvement and fails to achieve sufficient healing within four weeks of treatment, reassessment of the patient and a review of underlying factors must be considered. Following wound bed preparation principles is imperative to overcoming the factors and various disorders that contribute to wound chronicity. Adopting and implementing advanced wound therapies are essential to taking a wound from a chronic state and getting it back on track to healing.

References

1. Mihai MM, Preda M, Lungu I, Gestal MC, Popa MI, Holban AM. Nanocoatings for chronic wound repair: modulation of microbial colonization and biofilm formation. Int J Mol Sci. 2018;19(4):1179–99. Available at: http://www.mdpi.com/1422-0067/19/4/1179/htm. Accessed June 9, 2018.

2. Bohn GA, Schultz GS, Liden BA, et al. Proactive and early aggressive wound management: a shift in strategy developed by a consensus panel examining the current science, prevention, and management of acute and chronic wounds. Wounds. 2017;29(11):S37–42.

3. Murray RZ, West Z.E, McGuiness W. The multi factorial formation of chronic wounds. Wound Pract Res. 2018;26(1):38–46. Available at: https://search.informit.com.au/documentSummary;dn=559466353034176;res=I…. Accessed June 9, 2018.

4. Zhou K, Ma Y, Brogan MS. Chronic and non-healing wounds: The story of vascular endothelial growth factor. Med Hypotheses. 2015;85(4):399–404 . Available at: http://dx.doi.org/10.1016/j.mehy.2015.06.017. Accessed June 9, 2018.

5. Wang Y, Zhang Z, Rouabhia M. Pulsed electrical stimulation benefits wound healing by activating skin fibroblasts through the TGFβ1/ERK/NF-kB axis. Biochim Biophys Acta. 2016;1860(7):1551–9.doi: 10.1016/j.bbagen.2016.03.023.

6. Morgan N. What You Need to Know About Collagen Wound Dressings. Wound Care Advisor. 2018. Available at: https://woundcareadvisor.com/what-you-need-to-know-about-collagen-wound…. Accessed June 9, 2018.

7. Advanced Tissue. Advantages of Using Collagen in Wound Care. 2014. Available at: from: https://www.advancedtissue.com/advantages-using-collagen-wound-care/. Accessed June 9, 2018.

8. Barrientos S, Brem H, Stojadinovic O, Tomic-Canic M. Clinical application of growth factors and cytokines in wound healing. Wound Repair Regen. 2014;22(5):569–78. doi: 10.1111/wrr.12205. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4812574/. Accessed June 9, 2018.

9. Huang C, Leavitt T., Bayer LR, Orgill, DP. Effect of negative pressure wound therapy on wound healing. Curr Probl Surg. 2014;51(7):301–31. doi: https://doi.org/10.1067/j.cpsurg.2014.04.001. Available at: https://www.currprobsurg.com/article/S0011-3840(14)00084-7/fulltext. Accessed June 9, 2018.