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 chronic diabetic foot ulcers, many of which are already in use in specialist centers.[93][94][95][96][97][98][99][100][101] The American Diabetes Association (ADA) 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 (becaplermin [a topical formulation of recombinant 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 (bovine and 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.[24] Evidence for the use of these advanced wound therapies is growing and the ADA and the International Working Group on the Diabetic Foot (IWGDF) support considering the use of: negative-pressure wound therapy for postoperative wounds, topical oxygen therapy, placental derived products, and an autologous leucocyte, fibrin, and platelet patch (3C Patch®), as an adjunctive treatment for patients with chronic diabetic foot ulcers that have failed to heal with optimal standard care alone.[24][63] The ADA also mentions bioengineered skin substitutes and “several acellular matrices” as advanced wound therapies with randomized controlled trial evidence for their use. The use of negative-pressure wound therapy is well established in clinical practice.[9][24][63] 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.[63] See below for discussion of oxygen therapy, placental derived products, and the 3C Patch®.

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.[63][97][102][103][104] The ADA includes topical oxygen therapy as one of the randomized controlled trial-proven advanced agents that may be considered as an adjunctive treatment for patients with chronic diabetic foot ulcers that have failed to heal with optimal standard care alone.[24] The IWGDF cautiously recommends the use of topical or hyperbaric oxygen therapy as an adjunctive therapy where standard of care alone has failed, in places where the appropriate resources and equipment exist to provide them.[63] The cost effectiveness of hyperbaric oxygen therapy remains uncertain.[101]

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.[63] The ADA includes placental membranes as one of the randomized controlled trial-proven advanced agents that may be considered as an adjunctive treatment for patients with chronic diabetic foot ulcers that have failed to heal with optimal standard care alone.[24]

Autologous leukocyte/fibrin/platelet patch (3C Patch®)

The ADA and IWGDF guidelines support use of an autologous leukocyte/fibrin/platelet patch (known commercially as 3C Patch®), 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.[24][63] 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.[94]

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.[105][106]

Gene therapy

Several randomized trials have looked at various gene therapy options for peripheral artery disease.[107] 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.