Furthermore, each amputation procedure can cost well over $35,000 ( Gordois et al., 2003 Sen et al., 2009 Carls et al., 2011). Similarly, in the United States, the average cost of Medicare spending on pressure and arterial ulcers in 2014 was $3696 and $9015 per patient, respectively-the two most expensive of all types of wounds included in the study ( Nussbaum et al., 2018). In England, costs for pressure ulcer treatment can reach up to 6500 pounds per patient (>$8,000 U.S. In the United States, over $25 billion dollars are spent annually on chronic wound care ( Sen et al., 2009). With so many people suffering from chronic wounds, and so many failed attempts at treating them, it is not surprising that wound care costs are also enormous. Since many chronic wounds do not improve with standard care, treatment quickly becomes expensive with the introduction of advanced therapies, and sometimes amputation. In fact, two thirds of all lower-limb amputations are due to diabetic ulcers ( Sen et al., 2009). In the case of wounds in which infection and severe tissue damage cannot be controlled, the effects of which may otherwise be life-threatening, amputation is performed. Other possible treatments include hyperbaric or topical oxygen treatment in order to restore oxygen to the wound. These include negative pressure wound therapy, topically applied platelet-derived growth factor (PDGF) (Regranex), acellular extracellular matrices (Integra, Matristem, Theraskin), and bioengineered cell-containing therapies (Apligraf, Dermagraft), to name a few. Advanced therapies are available for wounds that do not improve after several weeks of standard care. Standard wound care involves patient and wound assessments, offloading, debridement of necrotic and infected tissue, treatment with antibiotics, and regular wound dressing changes ( Falanga, 2005 Frykberg and Banks, 2015). Unfortunately, the staggering number of chronic, non-healing wounds is growing much faster than the emergence of new, effective therapies.

The numbers of pressure and venous ulcers are rising at rates of 6–7% annually, and growth is even larger for diabetic ulcers (9%) due to the increased incidence of diabetes in the developed world. In recent years, there were ~4.5, 9.7, and 10 million pressure, venous, and diabetic ulcer wound patients globally ( MedMarket Diligence, 2012, 2015).

Furthermore, as surgical wounds become less of a problem due to the advances of minimally invasive surgery, chronic wounds are on the rise, as they often occur in growing populations, such as the elderly, obese, and diabetic. Whereas, a majority of surgical incisions and lacerations are categorized as acute wounds and often heal with minimal complications, ulcers are chronic wounds that resist healing and require expensive treatments. We recognize the challenges and controversies that exist in this field, such as standardization of macrophage phenotype nomenclature, definition of their distinct roles and understanding which phenotype is optimal in order to promote healing in chronic wounds.Ĭlinical and Economic Significance of Chronic Woundsįollowing surgical incisions and minor lacerations, diabetic, venous, and pressure ulcers are the most common wounds on a global scale ( MedMarket Diligence, 2012, 2015). These include endogenous M1 attenuation, exogenous M2 supplementation and endogenous macrophage modulation/M2 promotion via mesenchymal stem cells, growth factors, biomaterials, heme oxygenase-1 (HO-1) expression, and oxygen therapy.

We also discuss aberrations that occur in macrophage populations in chronic wounds, and attempts to restore macrophage function by therapeutic approaches. This review discusses the physiology of monocytes and macrophages in acute wound healing and the different phenotypes described in the literature for both in vitro and in vivo models. Thus, local macrophages retain pro-inflammatory characteristics. Non-healing chronic wounds, such as pressure, arterial, venous, and diabetic ulcers indefinitely remain in inflammation-the first stage of wound healing. As wounds heal, the local macrophage population transitions from predominantly pro-inflammatory (M1-like phenotypes) to anti-inflammatory (M2-like phenotypes). Macrophages play key roles in all phases of adult wound healing, which are inflammation, proliferation, and remodeling.

2Chemical & Biomolecular Engineering, The Ohio State University, Columbus, OH, United States.

1Biomedical Engineering, Rutgers University, The State University of New Jersey, Piscataway, NJ, United States.

Paulina Krzyszczyk 1, Rene Schloss 1, Andre Palmer 2 and François Berthiaume 1 *

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