Objective: The objective of this paper is to present the secondary safety and efficacy outcomes from two studies of focused extracorporeal shockwave therapy (ESWT) used adjunctively with standard care in the treatment of neuropathic diabetic foot ulcers (DFU) (1A or 2A on the University of Texas grading scheme), compared with sham treatment and standard care. Method: We carried out two multicentre, multinational, randomised, sham-controlled, double-blinded, phase III clinical studies using standard care with adjunctive focused ESWT compared with sham treatment and standard care in patients with a DFU. DFUs that did not reduce in volume by at least 50% over two weeks' standard treatment were included. DFUs were randomised and managed with standard care and focused ESWT (pulsed acoustic cellular expression; dermaPACE System, SANUWAVE Health, Inc.) active therapy, or with standard care and sham treatment, four times over a two-week treatment phase in study 1 and up to eight times over 12 weeks in study 2. Standard care continued in both studies throughout the 12-week treatment phase. Secondary outcomes were indicators of wound closure and progression, pain, infection, amputation and recurrence, and device reliability. Efficacy-related secondary endpoints were measured at 12, 20 and 24 weeks. The studies were analysed separately and following statistical comparison to justify the method, as a pooled data set. Results: Wound area reduction (48.6% versus 10.7%, p=0.015, intention to treat (ITT) population with last observation carried forward (LOCF)) and perimeter reduction (46.4% versus 25.0%, p=0.022, ITT population with LOCF) were significantly greater in the active therapy group compared with the sham-treated group, respectively. The difference in time to wound closure in the pooled ITT population was significantly in favour of the active therapy group (84 days versus 112 days for 25% of subjects to reach wound closure in the active and sham-treated groups, respectively; p=0.0346). The proportion of subjects who achieved wound area reduction (WAR) from baseline at week 12 of ≥90% was significantly higher in the active therapy group. The incidence and nature of infection were consistent with previously published studies, and pain was not increased in the active therapy group. Amputation was insignificantly higher in the sham-treated group and recurrence did not differ. The ESWT device was found to be reliable. Conclusion: The outcomes for the primary and secondary endpoints from these studies show that ESWT administered adjunctively with standard care is an effective advanced therapy for neuropathic DFUs (grade 1A and 2A) that do not respond to two weeks' standard care alone by reducing wound volume by at least 50%.

Background: Chronic wounds, especially in patients with diabetes, often represent clinical challenges. Recently, the use of a topically applied blood clot has garnered significant interest. This stromal matrix contains viable cells that are autologous, biocompatible, biological, and consistent with a metabolically active scaffold. It has been shown to be safe, effective, and cost-efficient. However, the mechanism of action of this modality remains elusive. We sought to identify a potential mechanism of action of an autologous blood clot. Methods: Review of clinical and scientific literature hypothesizes on how autologous blood clots may stimulate healing and facilitate the movement of critical substrates while lowering bioburden and fostering angiogenesis. Results: Blood serves as a carrier for many components: red blood cells, white blood cells, platelets, proteins, clotting factors, minerals, electrolytes, and dissolved gasses. In response to tissue injury, the hemostatic mechanism uses a host of vascular and extravascular responses initiating primary, secondary, and tertiary hemostasis. The scaffold created by the autologous blood clot tissue provides a medium in which the body can transform the wound from a nonhealing chronic condition into a healing acute condition. The autologous blood clot tissue also creates a protective setting for the body to use its own mechanisms to promote wound healing in an organized manner. This transient scaffold recruits surrounding fibroblasts and promotes cell ingrowth to foster granulation tissue remodeling. Cells in this matrix sense not only soluble factors but also their physical environments. This well-orchestrated mechanism includes signals from soluble molecules, from the substrate/matrix to which the cell is adherent, from the mechanical or physical forces acting on it, and from contact with other cells. Topically applied autologous blood clot tissue can lower bacterial bioburden while stimulating angiogenesis and fostering the movement of keratinocytes and fibroblasts. Conclusions: Topically applied autologous blood clot tissue is a formidable cellular and tissue-based therapy that has been shown to be safe and effective. Although the central component of this therapy is blood, the autologous clot tissue creates a scaffold that performs as a biological delivery system that functions to control the release of growth factors and cytokines over several days.

Chronic wound treatment currently relies heavily on visual assessment by clinicians; however, the clinical signs and symptoms of infection and inflammation are unreliable in chronic wounds. The specialty of wound care has witnessed the advent of advanced interventions, such as cellular and/or tissue based products (CTP). The success of advanced therapies relies on preparing the wound bed by reducing bacterial burden and inflammation. The lack of diagnostics in chronic wound care leads to uncertainty in the adequacy of wound bed preparation. Recent research suggests that two novel point-of-care diagnostic tests can assist in the detection of chronic inflammation known as elevated neutrophil derived protease activity (EPA) and bacterial pathogenesis known as bacterial protease activity(BPA) in chronic wounds. Despite the evidence, however, clinicians report that incorporating diagnostics into every day practice is challenging and across the globe, they have requested guidance on their use. Methods and Recommendations: A panel of wound care experts, experienced with these tests, met to develop guidelines on their use in wound care practice. The consensus panel concluded that the clinician should test for BPA first. The panel maintained that the risk of invasive infection resulting from the presence of pathogenic bacteria was the greatest threat to the patient’s health. If the BPA test is negative, the panel recommended testing for EPA. In addition, it was suggested that if the wound failed to progress after the elevated BPA was treated and subsequent testing was negative for BPA, the clinician should consider testing for EPA. Conclusions: In this manuscript, the consensus panel suggests pathways for testing, treating, and retesting for EPA and BPA. The panel expects that following the algorithm has the potential to improve healing outcomes, result in more cost-effective use of advanced therapies, and improve antimicrobial stewardship by guiding antimicrobial use.