*6.7.2. Aspirin*

There is currently insufficient evidence for the effectiveness of aspirin in venous leg ulcers [94]. The use of acetylsalicylic acid as an adjunct for the treatment of venous ulcers has been evaluated in one pilot study and one randomized controlled trial to date. The effect of aspirin in venous ulcers is through its irreversible inhibition of cyclooxygenase, resulting in reduction in thromboxane A2 implicated in platelet aggregation [95].

### *6.7.3. Split‐thickness skin grafting*

There are no specific indications for skin grafting of the ulcers of lower extremities [4]. Surgical treatment should only be considered in patients with venous ulcers that do not heal with conservative therapies [96]. Autografts, allografts, or human skin equivalents can be used, with a resulting healing rate of 73% [97]. In venous ulcers, skin grafting can also be followed by additional treatment to accelerate healing. The outcomes of the split‐thickness skin grafting in venous ulcers vary in different studies [31]. There is still lack of evidence in the routine use of split‐skin thickness skin grafting.

### *6.7.4. Negative pressure therapy*

Negative pressure wound therapy (NPWT) is currently used widely in wound care and is promoted for use on wounds. In this system, a wound dressing is applied to the wound, to which a machine is attached. The negative pressure (or vacuum) that the machine applies sucks any wound and tissue fluid away from the treated area into a canister.

The evidence is insufficient in clinical effectiveness of NPWT in the treatment of leg ulcers. It is thought to be effective in wound healing through providing excess drainage, promoting angiogenesis, and decreasing the bacterial load of the wound [98]. There is some positive evidence that the treatment may reduce time to healing as part of a treatment, tissue granula‐ tion, area and volume reduction have also been reported. NPWT is not suggested as a primary treatment for venous leg ulcers [31, 99].

### *6.7.5. Cellular therapy*

In recent years, cellular and/or tissue‐derived products (CTPs) such as extracellular matrix (ECM; OASIS®) [100], human skin equivalent (HSE; Apligraf®) [101–103], and living skin equivalent (LSE; Dermagraft®) [104–107] have been explored as alternative therapeutic options. Studies investigating the effects of CTPs are applied to the wounds that have been stuck in the inflammatory phase. CTPs provide the healing by supplying various biological factors, reducing levels of unnecessary cytokines or enzymes (such as matrix metalloproteinases), and/ or forming a temporary ECM (which results in granulation) [108].

Recently, Apligraf, an allogeneic bilayer cellular therapy, has been approved by FDA for use in venous ulcers [31]. Before the application of cellular therapy, appropriate wound bed preparation, including the removal of debris and any necrotic tissue, should be done. The application of the graft is recommended to be done with a period of 1–3 weeks with observa‐ tions of effectiveness before reapplication is considered. And reapplication is recommended as long as the venous ulcer continues to respond to the therapy [31]. In patients with venous leg ulcers who have failed with standard therapy for 4–6 weeks, cultured allogeneic bilayer skin replacements should be used [31].

Even though cellular treatments are initially more expensive, it may be more effective and less costly in the long term in chronic venous ulcers [109].

### *6.7.6. Tissue matrices, growth factors, human tissues, or other skin substitutes*

In chronic wounds, human tissue (amniotic membrane, cryopreserved skin) or animal tissue (bladder, fetal bovine skin, others) constructs are being used. Growth factors or some other molecules, the tissues contain, may support healing process [110].

Granulocyte macrophage‐colony stimulating factor (GMCSF) is a growth factor that has stimulatory effects on keratinocyte proliferation and endothelial cell and fibroblast differen‐ tiation [111]. In some studies, both intradermal injections of GM‐CSF and topical application of GM‐CSF have been shown to be effective in healing rates of venous ulcers [98]. But, injection site and bone pain can limit the intradermal use of GM‐CSF [98].

Small intestine submucosa (SIS, Oasis®) is a biomaterial derived from porcine SIS that acts as an extracellular matrix. It is composed of Type I, III, IV, and V collagen, glycosaminogylcans, proteoglycans, proteoglycans, fibronectin, and growth factors [98, 112]. Successful results have only been reported in studies of using porcine small intestinal submucosa in venous leg ulcers [100]. It has been approved by FDA for use in wounds including venous leg ulcers. Use of porcine small intestinal submucosa tissue construct in addition to compression therapy for the treatment of venous leg ulcers is only suggested in patients who did not respond to the standard therapy for 4–6 weeks [31]. It was shown to be well tolerated and nontoxic and did not induce an adverse immunological reaction even in patients given repeated applications.

### *6.7.7. Therapeutic ultrasound*

mg three times a day. But recently, it has been proposed that the use of pentoxifylline 800 mg three times a day is more effective in venous ulcer healing. The main side effects reported were gastrointestinal disturbances such as nausea, indigestion, and diarrhea [89, 92, 93]. In studies, pentoxifylline has shown to be an effective adjuvant to compression therapy in venous leg ulcers. According to a Cochrane review, pentoxifylline plus bandaging is more effective than compression plus placebo and pentoxifylline may even be effective in the absence of com‐

There is currently insufficient evidence for the effectiveness of aspirin in venous leg ulcers [94]. The use of acetylsalicylic acid as an adjunct for the treatment of venous ulcers has been evaluated in one pilot study and one randomized controlled trial to date. The effect of aspirin in venous ulcers is through its irreversible inhibition of cyclooxygenase, resulting in reduction

There are no specific indications for skin grafting of the ulcers of lower extremities [4]. Surgical treatment should only be considered in patients with venous ulcers that do not heal with conservative therapies [96]. Autografts, allografts, or human skin equivalents can be used, with a resulting healing rate of 73% [97]. In venous ulcers, skin grafting can also be followed by additional treatment to accelerate healing. The outcomes of the split‐thickness skin grafting in venous ulcers vary in different studies [31]. There is still lack of evidence in the routine use of

Negative pressure wound therapy (NPWT) is currently used widely in wound care and is promoted for use on wounds. In this system, a wound dressing is applied to the wound, to which a machine is attached. The negative pressure (or vacuum) that the machine applies sucks

The evidence is insufficient in clinical effectiveness of NPWT in the treatment of leg ulcers. It is thought to be effective in wound healing through providing excess drainage, promoting angiogenesis, and decreasing the bacterial load of the wound [98]. There is some positive evidence that the treatment may reduce time to healing as part of a treatment, tissue granula‐ tion, area and volume reduction have also been reported. NPWT is not suggested as a primary

In recent years, cellular and/or tissue‐derived products (CTPs) such as extracellular matrix (ECM; OASIS®) [100], human skin equivalent (HSE; Apligraf®) [101–103], and living skin equivalent (LSE; Dermagraft®) [104–107] have been explored as alternative therapeutic options.

any wound and tissue fluid away from the treated area into a canister.

in thromboxane A2 implicated in platelet aggregation [95].

pression [93].

*6.7.2. Aspirin*

*6.7.3. Split‐thickness skin grafting*

296 Wound Healing - New insights into Ancient Challenges

split‐skin thickness skin grafting.

treatment for venous leg ulcers [31, 99].

*6.7.5. Cellular therapy*

*6.7.4. Negative pressure therapy*

Ultrasound has been used as a therapeutic tool for nearly 50 years [113]. Recently, ultrasound therapy has been applied for the treatment of chronic wounds in some centers [114]. Although high‐frequency ultrasound (HFU) (1–3 MHz) has been shown to promote healing of some injuries [115, 116], it has some disadvantages such as, burns or endothelial injury. However, in some studies low‐dose application of ultrasound has been reported to be more successful than high‐dose ultrasound in the treatment of skin wounds [117]. Thus, noncontact ultrasound therapy is among the newer modalities. Use of lower frequency (40 kHz) ultrasound in wound management was approved by the FDA in 2004 [118]. Low‐frequency ultrasound therapy provides wound healing via the production, vibration, and movement of micron‐sized bubbles in the coupling medium and tissue. The healing process improves by the reduced bioburden, increased angiogenesis, stimulated cellular activity, and the removal of necrotic tissues [119]. Additional studies are necessary to determine standardized protocols of therapeutic ultra‐ sound in venous ulcers treatment. Routine use of ultrasound therapy in venous ulcer man‐ agement is not suggested [31].
