Diabetes-related foot disease - Emerging treatments

Adjunctive therapies for diabetic foot ulcers

A wide range of adjunctive therapies are in development for the treatment of diabetic foot ulcers, many of which are already in use in specialist centers.[94][95][96][97][98][99][100][101][102] The American Diabetes Association refers to these collectively as "advanced wound therapy," of which there are nine broad categories: negative-pressure wound therapy (standard electrically powered and mechanically powered); oxygen therapies (hyperbaric oxygen therapy, topical oxygen therapy, oxygen-releasing sprays, and dressings); biophysical therapies (electrical stimulation, diathermy, pulsed electromagnetic fields, pulsed radiofrequency energy, low-frequency noncontact ultrasound, and extracorporeal shock wave therapy); growth factors (platelet-derived growth factor, fibroblast growth factor, and epidermal growth factor) autologous blood products (platelet-rich plasma, whole blood clot, and leukocyte, platelet, and fibrin multilayered patches); acellular matrix tissues (xenograft dermis and xenograft acellular matrices, including placental-derived amniotic tissues, amniotic fluid, and umbilical cord); bioengineered allogeneic cellular therapies (bilayered skin equivalent such as human keratinocytes and fibroblasts, and dermal replacement therapy with human fibroblasts); stem cell therapies (autogenous bone marrow-derived stem cells, and allogeneic amniotic matrix with mesenchymal stem cells); and miscellaneous active dressings including hyaluronic acid, honey dressings, and sucrose octasulfate dressing.[22] Few of these therapies have been proven to improve complete ulcer healing in high-quality trials.[53] The ADA does not provide definitive recommendations on which advanced therapies should be used, but suggests that topical growth factors, acellular matrix tissues, bioengineered cellular therapies and negative-pressure wound therapy are commonly used in wound care centers, and have an increasing amount of supporting evidence.[22] The International Working Group on the Diabetic Foot (IWGDF) conducted a comprehensive literature review on adjunctive therapies as part of its 2023 guidelines update.[62] It concluded there is evidence to support the use of negative-pressure wound therapy for postoperative wounds, as well as topical and hyperbaric oxygen therapy, placental derived products and a leucocyte, fibrin and platelet patch (the 3C Patch). See Management approach (Wound debridement) for discussion of negative-pressure wound therapy, and below for discussion of oxygen therapy, placental derived products and the 3C Patch. However, for all other adjunctive therapies, the IWGDF concluded there is currently insufficient evidence from clinical trials to support their use, and none are recommended at present.[62]

Topical and hyperbaric oxygen therapy

Hyperbaric oxygen therapy (breathing 100% oxygen at twice the atmospheric pressure of sea level) and topical oxygen therapy have both been found to improve healing of diabetic foot ulcers in some randomized controlled trials, albeit of low-quality evidence.[62][98][103][104][105] The IWGDF cautiously recommends their use as an adjunctive therapy where standard of care alone has failed, in places where the appropriate resources and equipment exist to provide them. The cost effectiveness of hyperbaric oxygen therapy remains uncertain, however.[102] The ADA does not make definitive recommendations on the use of oxygen therapies, but offers the following assessment of hyperbaric oxygen therapy: “While there may be some benefit in prevention of amputation in selected chronic neuroischemic ulcers, recent studies have shown no benefit in healing diabetic foot ulcers in the absence of ischemia and/or infection.”[22] The ADA offers a more positive assessment of topical oxygen therapy, noting that it has several high-quality randomized controlled trials and at least five systematic reviews and meta-analyses supporting its efficacy in healing chronic ulcers at 12 weeks. The fact that topical oxygen can be delivered at home, and has few reported adverse events, makes it an attractive option, according to the ADA.[22]

Placental derived products

Numerous products have been derived from human placenta to assist with healing of diabetic foot ulcers, including dehydrated amnion/chorion graft, dehydrated amniotic membrane, cryopreserved placental membrane, and dehydrated umbilical cord. Several studies have suggested these can improve and speed up healing of ulcers, and they can be considered as an adjunctive treatment where standard of care alone has failed, according to the IWGDF. However the quality of evidence is low and the cost effectiveness of these products remains unclear.[62]

3C Patch®

The 2023 IWGDF guidelines also support use of a leucocyte, fibrin, and platelet patch (the 3C Patch®, previously known as LeucoPatch®), as an adjunctive therapy for wound healing where best standard of care alone has been ineffective, and where the resources and expertise exist for the regular venepuncture required.[62] Randomized controlled trial evidence suggests that using the patch led to more ulcers healing at 20 weeks compared with standard care, and median time to ulcer healing of 72 days compared with 84 days in the standard care group.[95] The ADA does not make any recommendations about use of the 3C Patch.[22]

Local/rotational soft-tissue flaps and skin grafting

Many advanced soft-tissue and/or bone reconstruction options have been described for patients with large foot wounds; however, they are not commonly used in clinical practice. The goal of these options is to achieve an intact skin surface in a functional, weight-bearing surface on the residual foot, thereby avoiding major (above-ankle) amputation. The outcomes of these procedures can be excellent. Patients should be referred to an interdisciplinary diabetic foot clinic for evaluation for these procedures. The use of split-thickness skin grafting for defects, particularly in concert with surgery designed to reduce stress over an area, should also be strongly considered in an effort to move toward wound closure surgery.[106][107]

Gene therapy

Several randomized trials have looked at various gene therapy options for peripheral artery disease.[108] Although results are promising, gene therapy is not currently a standard component of treatment for patients with foot ulcers and/or peripheral artery disease outside of centers participating in ongoing investigation of these treatment options.