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Hypothermically Stored Amniotic Membrane Successful for Diabetic Foot Ulcers

HSAM Increased the Frequency and Probability of Wound Closure vs. the Standard of Care

Published last fall, "A randomized controlled clinical trial of a
hypothermically stored amniotic membrane for use in diabetic foot ulcers" has good news for the practice of wound closure in podiatry. See the summary below, and click through to read the full study.

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SUMMARY

Aim: Determine the effectiveness of hypothermically stored amniotic membrane (HSAM) versus standard of care (SOC) in diabetic foot ulcers (DFUs). Methods: A randomized controlled trial was conducted on 76 DFUs analyzed digitally. Results: Cox wound closure for HSAM (38 wounds) was significantly greater (p = 0.04) at weeks 12 (60 vs 38%), and 16 (63 vs 38%). The probability of wound closure increased by 75% (Hazard Ratio = 1.75; 95% CI: 1.16–2.70). HSAM showed >60% reductions in area (82 vs 58%; p = 0.02) and depth (65 vs 39%; p = 0.04) versus SOC. Conclusion: HSAM increased frequency and probability of wound closure in DFUs versus SOC.

Over a million individuals suffer from nonhealing diabetic foot ulcers (DFUs) each year in the USA and it has been estimated that 15% of diabetics will develop a chronic ulcer at some point in their lives [1,2]. Once a patient develops a DFU and a wound care treatment is initiated, assessments of wound status at 4 weeks compared with baseline have been shown to be indicators of long-term clinical outcomes. Reductions in wound size at 4 weeks from baseline have been shown to be strong surrogates for DFU healing that may help guide clinicians' plans for DFU management. Using databases of over 40,000 DFUs, it has been demonstrated that size reductions of >50% and >60% were highly sensitive and specific surrogate end points for long-term healing [3–5]. The average ulcer can take 6 months to 1 year to heal completely and over 50% of subjects will have nonhealed ulcers that extend beyond 1 year [6–8]. It has been reported that within 5 years after achieving wound closure, between 70 and 100% of these healed ulcers will re-open and require additional ulcer management treatments [9]. DFUs substantially reduce patients' quality of life, are often painful, and adversely affect mobility and sleep [10–13]. Furthermore, ulcers are significantly correlated with time lost from work, job loss and high rates of adverse effects and serious adverse events [14,15]. It has been estimated that nonhealing ulcers of various etiologies cause the loss of over 2 million working days per year in the USA [16]. Costs to healthcare payers in the USA are estimated to exceed $20 billion per year considering only direct costs associated with medical resource utilization and treatment costs [17–19].

Contamination of the ulcer bed, colonization with bacteria and infection are associated with a localized inflammatory response in the ulcer bed with high levels of proteolytic enzymes, matrix metalloproteases and specific collagenases that degrade the extracellular matrix (ECM). These enzymes, if present in high concentrations in the initial inflammatory stages of wound closure interrupt the normal sequence of events that result in wound closure. If the ulcer is not modulated by the patient's own immune system or wound care techniques that down regulate the activity of proteolytic enzymes, it fails to proceed through the normal phases of wound closure. Chronic ulcers stall in the inflammatory stage of wound healing and thereby fail to progress through the normal phases of the wound closure cascade leading to full epithelialization. It has been reported that the incidence of developing a foot infection in patients diagnosed with diabetes is 9% and the most common complication is osteomyelitis [20,21]. The overall chance of a DFU becoming infected every 6 months was reported as 40% in a 2-year study of a representative population of patients presenting with uninfected DFUs. A high proportion of these DFUs developed an infection prior to healing, regardless of their ulcer type. DFUs that had healed in <3 months, between 3 and 12 months, and not healed by 12 months demonstrated infection rates of 32, 59 and 40% respectively [20]. Further, DFU infections have been shown to be a major cause of hospitalization and contribute to over 90% of nontraumatic lower limb amputations [22]. It has consistently been demonstrated that early detection and intervention for ulcers that exhibit delayed wound closure are essential to reduce the risk of serious, clinical outcomes [18,23].

Clinical studies have demonstrated the efficacy of cellular or tissue-based products such as placental-derived allografts in accelerating healing of chronic wounds [24–28]. The proposed mechanism of action is the delivery of growth factors and the reduction in proteases [29,30]. Novel processing technologies and hypothermic storage conditions of amniotic membranes that more completely preserve amnion and/or chorion components maintain viable differentiated cell populations, stem cells, growth factors, cytokines and ECM proteins. Preservation of these components may improve chronic wound management outcomes. To date, clinical trials have evaluated only dehydrated and cryopreserved grafts. This trial is the first to examine hypothermically stored amniotic membrane (HSAM).

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