Most diabetic foot ulcers are expected to heal with good standard care: sharp debridement, pressure offloading, infection control, moisture-balanced dressings, and attention to perfusion. Yet a substantial minority do not. These hard-to-heal wounds account for a disproportionate share of infections, hospital admissions, and lower-extremity amputations, and they are the wounds for which clinicians consider advanced or adjunctive therapies. Which of these therapies is actually supported by evidence — and when they should be introduced — has become a central question in diabetic foot care.
Recognizing the Wound That Is Not Going to Heal on Its Own
The decision to escalate treatment depends on first identifying a stalled wound. The most widely used prognostic marker is percentage area reduction (PAR) at four weeks: wounds that fail to shrink by roughly 50% within the first month are unlikely to close by week 12 and are generally classified as recalcitrant.
A post hoc analysis by Serena and colleagues, published in the Journal of Wound Care in 2024, revisited this threshold using data from a large multicentre randomised trial. Among patients whose ulcers achieved greater than 50% area reduction at week four, 65.4% went on to complete closure by week 12. The receiver operating characteristic curve showed strong discrimination for predicting non-healing (area under the curve 0.92; negative predictive value 87.2%). A wound that has not measurably shrunk after four weeks of appropriate care therefore warrants reassessment — of perfusion, infection, and offloading adherence — and consideration of adjunctive therapy.
Bioactive Dressings: The Sucrose Octasulfate Evidence
Among topical agents, the sucrose octasulfate (TLC-NOSF) dressing has one of the more robust evidence bases. The EXPLORER trial, reported by Edmonds and colleagues in The Lancet Diabetes & Endocrinology in 2018, was an international, double-blind, randomised controlled trial across 43 specialist diabetic foot clinics in five European countries. It enrolled 240 patients with non-infected neuroischaemic ulcers, randomising them to a sucrose octasulfate dressing or an identical dressing without the active agent, with both groups receiving the same standard of care over 20 weeks.
Wound closure occurred in 48% of the sucrose octasulfate group compared with 30% of controls — an 18 percentage point difference, with an adjusted odds ratio of 2.60 (95% CI 1.43–4.73, p=0.002). Adverse events, predominantly wound infection, were no more frequent in the treatment arm.
A subsequent post hoc analysis by Lázaro-Martínez and colleagues in the Journal of Wound Care (2019) examined the influence of ulcer duration. Closure rates declined sharply as baseline wound duration increased, from 57% in ulcers present two months or less to 19% in those present more than eleven months. The treatment advantage was greatest in the newest wounds: 71% closure versus 41% in ulcers of two months’ duration or less. The clinical implication is that chronicity itself is a barrier, and that adjunctive therapy applied late is working against a steeper gradient.
Skin Substitutes and Matrix-Like Products
Cellular, acellular, and matrix-like products (CAMPs) — a category encompassing bioengineered skin, acellular dermal matrices, and amniotic and placental membranes — are used to supply a scaffold and, in some cases, growth factors and viable cells to a wound bed that has been adequately prepared.
The Cochrane review by Santema, Poyck, and Ubbink (2016) pooled 17 randomised trials involving 1,655 participants. Skin grafts and tissue replacements used alongside standard care increased healing rates compared with standard care alone (risk ratio 1.55, 95% CI 1.30–1.85), with fewer amputations in the two studies reporting that outcome (RR 0.43, 95% CI 0.23–0.81). The authors rated the evidence as low quality, however, and noted that 15 of the 17 studies involved industry funding or authorship, alongside funnel plot asymmetry suggesting publication bias.
A more recent systematic review by Banerjee and colleagues in Advances in Wound Care (2024) analysed randomised trials of CAMPs using risk ratios to reduce between-trial variability in standard-of-care outcomes. Adjunctive CAMP use was associated with superior wound closure compared with standard care alone (RR 1.72, 95% CI 1.56–1.90, p<0.00001). Notably, the review found insufficient evidence to distinguish between broad product categories — cellular versus acellular, amniotic versus non-amniotic — meaning product selection cannot yet be guided by category alone.
What Current Guidelines Conclude
The 2023 update of the International Working Group on the Diabetic Foot (IWGDF) guideline on wound healing interventions, authored by Chen and colleagues and published in Diabetes/Metabolism Research and Reviews, applied GRADE methodology to produce 29 recommendations.
The guideline offers conditional supportive recommendations for sucrose octasulfate dressings, negative pressure wound therapy for post-operative wounds, placental-derived products, the autologous leucocyte/platelet/fibrin patch, topical oxygen therapy, and hyperbaric oxygen. Two qualifications run through all of them: these interventions are for wounds that best standard of care has failed to heal on its own, and they presuppose that the resources for delivery are available. The authors are candid that despite improvement, the overall certainty of evidence in this field remains poor, and they call for better — not merely more — trials, including health economic analysis.
Clinical Summary
Advanced wound therapies are adjuncts, not substitutes. Debridement, offloading, infection management, and revascularization where indicated remain the foundation on which any additional intervention depends. The four-week percentage area reduction threshold provides a practical trigger for reassessment and escalation. Where escalation is warranted, sucrose octasulfate dressings and cellular or matrix-based products have the strongest supporting trial data, with evidence favouring earlier rather than later application. At the same time, the certainty of that evidence is moderate at best, industry involvement in the trial literature is pervasive, and comparative data between individual products remain limited.
References
- Chen P, Vilorio NC, Dhatariya K, et al. Guidelines on interventions to enhance healing of foot ulcers in people with diabetes (IWGDF 2023 update). Diabetes/Metabolism Research and Reviews. 2023;40(3):e3644. doi:10.1002/dmrr.3644
- Edmonds M, Lázaro-Martínez JL, Alfayate-García JM, et al. Sucrose octasulfate dressing versus control dressing in patients with neuroischaemic diabetic foot ulcers (Explorer): an international, multicentre, double-blind, randomised, controlled trial. The Lancet Diabetes & Endocrinology. 2018;6(3):186–196. doi:10.1016/S2213-8587(17)30438-2
- Lázaro-Martínez JL, Edmonds M, Rayman G, et al. Optimal wound closure of diabetic foot ulcers with early initiation of TLC-NOSF treatment: post-hoc analysis of Explorer. Journal of Wound Care. 2019;28(6):358–367. doi:10.12968/jowc.2019.28.6.358
- Santema TB, Poyck PPC, Ubbink DT. Skin grafting and tissue replacement for treating foot ulcers in people with diabetes. Cochrane Database of Systematic Reviews. 2016;2:CD011255. doi:10.1002/14651858.CD011255.pub2
- Banerjee J, Lasiter A, Nherera L. Systematic review of cellular, acellular, and matrix-like products and indirect treatment comparison between cellular/acellular and amniotic/nonamniotic grafts in the management of diabetic foot ulcers. Advances in Wound Care. 2024;13(12):639–651. doi:10.1089/wound.2023.0075
- Serena T, Yaakov S, Yaakov R, King E, Driver VR. Percentage area reduction at week 4 as a prognostic indicator of complete healing in patients treated with standard of care: a post hoc analysis. Journal of Wound Care. 2024;33(Sup9):S36–S42. doi:10.12968/jowc.2024.0141
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