Trauma and Wound Healing
Novel and Emerging Therapies
Wound Biomarkers and Diagnostics
Research into wound biomarkers that can be measured to predict outcomes and guide treatment may one day provide a more individualized approach to wound treatment. For example, high levels of compounds called matrix metalloproteases (MMPs) in wound fluid can indicate a chronic non-healing wound that may benefit from MMP-absorbent wound dressings (Lindley 2016). Systemic markers such as MMPs, cytokines, and circulating stem cells can be measured in the blood and show promise in predicting wound healing outcomes (Thom 2016).
The use of rapid DNA sequencing methods may improve the efficiency of diagnosing wound infection, identification of specific pathogens in the wound microbial community, and the selection of appropriate antimicrobials for treatment. These newer methods are more likely to identify infection-causing bacteria present in the wound but have low survival in standard bacterial culture conditions (Lindley 2016).
Antimicrobial therapy using bacteriophages, or phages (viruses that specifically infect bacteria), is not a new concept: studies from the 1920s led to their use in wound healing in Germany and the Soviet Union during the second World War (Cisek 2017). Phage therapy research was largely abandoned with the advent of antibiotics, but the growing problem of antibiotic resistance has renewed interest in bacteriophages, which do not appear to promote resistance. Naturally occurring phages are very specific in the bacteria they attack. Although they lack the broad-spectrum coverage of antibiotics, they can be supplied in "cocktails" to kill multiple strains of bacteria (Young 2015).
In one report, the cases of 6 diabetic patients with chronic, non-healing, infected toe ulcers were described. The infections in these cases were due to Staphylococcus aureus, had spread into the bone and soft tissues, and failed to respond to antibiotic therapy. Although these patients were facing likely amputation, weekly treatment with a topical solution containing a strain-specific bacteriophage resulted in healing of the ulcers in an average of seven weeks (Fish 2016). The remarkable success reported in these cases lays the groundwork for clinical trials that will prospectively assess the efficacy of phage treatment on a larger scale.
Antimicrobial peptides are immune chemicals that control microbial presence and signal cells to respond to injury. Thousands of antimicrobial peptides have been identified across various species; most are short (10‒50 amino acid), positively charged molecules that are thought to bind to and damage microbial cell membranes (Mangoni 2016). They are also thought to enhance wound healing by promoting inflammation, tissue regeneration, and blood vessel growth. Several animal studies have investigated the use of antimicrobial peptides and related biological peptides such as snake venom peptides and lantibiotics (peptide antibiotics) in animal models of skin and burn infections. Toxicity remains a concern, and further research is needed to identify lantibiotics with substantive roles in human wound healing (Otvos 2015).
Chitosan is a chemically modified preparation of chitin, the common polysaccharide found in insect and arthropod shells (Azuma 2015). Chitosan’s properties as a topical antimicrobial agent are possibly due to its positive charge, which may disrupt bacterial cell membranes. In animal models, chitosan preparations have improved healing of surgical incisions, burns, respiratory wounds, experimental wounds in the liver and kidneys, and corneal ulcers (Dai 2012). Several human studies have shown that chitosan preparations can shorten healing time at skin graft donor sites (Azad et al. 2004; Biagini 1991; Stone 2000) and reduce adhesions in surgical wounds (Valentine 2010). These preparations may also be useful in promoting healing in chronic wounds. In a randomized controlled trial of a chitosan wound dressing in 90 patients with chronic wounds (pressure ulcers, diabetic ulcers, and infected wounds), use of the chitosan dressing led to greater reductions in wound area and depth compared with a control gauze dressing (Mo 2015). In addition to its intrinsic antimicrobial properties, chitosan has been investigated as a drug delivery vehicle for local delivery of antibiotics and growth factors (Dai 2012).
Insulin – Temporary Topical Application and Local Injection
One approach to improving wound healing is to temporarily apply local growth factors that promote cellular recruitment and tissue regeneration. A limitation of this technique is that many growth factors that may work in this context are expensive. Insulin represents a low-cost growth factor that may facilitate wound healing when applied topically as part of wound dressing or via local injection (Oryan 2017).
A randomized, double-blind, placebo-controlled trial found that a topically applied insulin spray improved the wound-healing rate in 45 participants with non-infected acute or chronic wounds on their extremities. The participants applied the insulin spray twice daily to their wounds until complete wound closure. The rate of healing in the insulin group was about 46 mm2/day compared with about 32 mm2/day in the placebo group. Importantly, glucose levels did not differ before and after the topical insulin application, demonstrating a lack of a systemic effect (Rezvani 2009). Animal studies have shown that topical insulin increases immune cell activation in wound sites and helps promote the release of local inflammatory chemicals that participate in wound healing. Human trials have shown that local insulin injections can promote healing of both acute and chronic wounds. However, insulin injections have the potential for systemic side effects (eg, hypoglycemia), so careful monitoring by a qualified healthcare provider is necessary. Newer methods of local insulin delivery that may mitigate potential side effects and maximize benefits in the context of wound healing are being explored (Oryan 2017).
Hyperbaric Oxygen Therapy
Hyperbaric oxygen therapy (HBOT) involves exposure to 100% oxygen in a pressurized (1.4 atmospheres or higher) full-body chamber. The combination of high oxygen concentration and pressure may restore oxygen to tissues with poor blood supply, reduce tissue edema, increase new blood vessel formation, and provide antimicrobial activity (Klein 2014; Anderson 2016).
Although findings from clinical trials have been inconsistent, several studies point to the potential efficacy of HBOT in treatment of acute and chronic wounds. In a randomized controlled trial, HBOT was more effective than sham HBOT for treating crush wounds, resulting in more healed wounds, less need for surgical interventions, and less tissue death (Bouachour 1996). HBOT has been shown to speed the healing of burns and improve survival of skin grafts compared with usual therapies (Eskes 2011; Eskes 2013). In uncontrolled research, the use of HBOT in conjunction with usual care was associated with lower than expected rates of complications and deaths due to soft tissue infections (Escobar 2005). HBOT is a recommended treatment for chronic diabetic foot ulcers that have failed to respond to 30 days of standard wound care and show evidence of deep soft-tissue infection, infection spreading to bone, or tissue death (Anderson 2016).
Negative-Pressure Wound Therapy
In negative-pressure wound therapy, a sealed dressing is applied to the wound site and a vacuum applies negative pressure. The mechanism of action is unclear (Argenta 1997; Gould 2015; Murphy 2012; Anderson 2016). In a structured analysis of 21 studies of negative-pressure wound therapy applied preventively to surgical sites, local infections were reduced by 44‒70% (De Vries 2016). A second review of 10 studies (several of which were not included in the first review) estimated a 46% reduction in infection with the use of negative pressure in closed surgical incisions when compared with standard dressings (Hyldig 2016).
Cryopreserved Placental Membrane
Human placental membranes are a rich source of connective tissue stem cells that can differentiate into a variety of cell types, as well as collagen and growth factors (Gibbons 2015). Grafix is a product made from cryopreserved (frozen) human placenta that is reported to have over 80% cell viability after thawing. In a multicenter trial, diabetic foot ulcers treated with Grafix healed nearly four weeks faster, on average, compared with standard wound care (Lavery 2014). Case reports have also noted its benefits in treating other types of chronic wounds (Gibbons 2015).
Low-frequency ultrasound (20‒40 kHz) provides direct physical stimulation of cells and activates tissue repair (Anderson 2016). When applied to wounds, it can rapidly debride the wound surface, and may work synergistically with antibiotics to kill resistant bacteria and disrupt biofilms better than antibiotics alone (Gould 2015; Anderson 2016).
There is an electrical charge difference between the skin surface and tissues under the skin. When the skin is wounded, a natural electrical current is generated that has been shown to stimulate cells to begin healing (Anderson 2016; Torkaman 2014). Application of external low-intensity electrical current has been investigated in several animal studies of wound closure (Torkaman 2014) with mixed results. A review of 15 studies in humans determined that electrical stimulation used in conjunction with standard wound care for chronic wounds (pressure ulcers, diabetic foot ulcers, and venous leg ulcers) improved healing, with an average 27% additional reduction in the ulcer area after four weeks. For pressure ulcers alone, the effect was a nearly 43% reduction in the ulcer area (Koel 2014).