Diabetic foot ulcers (DFUs) develop through a damaging combination of neuropathy, poor blood supply, inflammation, infection, and impaired healing. When chronic limb-threatening ischemia (CLTI) is also present, patients face greater risks of tissue loss, amputation, cardiovascular events, and death. Standard wound care, glucose control, debridement, and revascularization remain essential, yet many ulcers heal slowly, recur after closure, or occur in patients who cannot undergo further vascular procedures. The global rise in diabetes, particularly in settings with limited access to specialized limb-preservation care, adds urgency to the search for scalable options. Based on these challenges, in-depth research is needed into therapies that can restore microcirculation, regulate inflammation, and support durable limb preservation.
Researchers from the University of New Mexico School of Medicine, Pasadena City College, the Keck School of Medicine of USC, Rancho Los Amigos National Rehabilitation Center, the University of California, Los Angeles, and Chongqing University Central Hospital reviewed these emerging strategies. Published (DOI: 10.1093/burnst/tkag017) on April 8, 2026, in Burns & Trauma, the article examines how neuromodulatory, humoral, and mechanotransductive interventions may produce benefits far from their application site. It compares current evidence, representative clinical findings, biological mechanisms, safety concerns, and barriers to routine use in diabetic foot disease and chronic limb-threatening ischemia.
The review organizes the field around several complementary routes. High-frequency spinal cord stimulation (SCS), delivered at 10 kilohertz (kHz), directly alters neural signaling and sympathetic activity. In a randomized trial of refractory painful diabetic neuropathy, 79% of patients receiving SCS plus conventional medical management reached the main pain-and-neurological endpoint, compared with 5% receiving medical management alone; neurological improvement was reported in 62% versus 3% at six months. Peripheral focused ultrasound (pFUS), including splenic targeting, may engage neuroimmune reflexes and reduce inflammatory cytokines, although much of the wound-healing evidence remains preclinical or early-phase. Remote ischemic conditioning (RIC) uses brief cycles of limb ischemia and reperfusion to release circulating protective mediators and improve endothelial function. Small diabetic-foot studies reported higher healing rates, including 41% complete healing versus none with placebo in one trial and 75.6% versus 36.6% by week 20 in another study. Surgical approaches such as tibial transverse transport (TTT) and lateral tibial periosteum distraction (LTPD) apply controlled mechanical tension to stimulate angiogenesis and distal perfusion. Proposed pathways include osteopontin (OPN), stromal interaction molecule 1 (STIM1), endothelial nitric oxide synthase (eNOS), and nitric oxide (NO) signaling, but clinical evidence remains geographically concentrated and methodologically uneven.
The authors said the review’s central message is that a diabetic foot ulcer should not be viewed as an isolated break in the skin, but as the visible result of disrupted neural, vascular, and immune systems. They said interventions delivered through the spinal cord, spleen, another limb, or the tibial periosteum may help recreate the biological conditions needed for healing at a distant site. However, they emphasized that encouraging early signals should not be mistaken for definitive proof, because many studies remain small, heterogeneous, short-term, or dependent on preclinical models and specialized surgical centers.
The emerging framework could eventually give clinicians more options for patients with refractory neuropathic pain, non-healing ulcers, or limited revascularization choices. Non-invasive approaches such as peripheral focused ultrasound and remote ischemic conditioning may be especially attractive where surgery or implantable devices are impractical, while spinal cord stimulation and periosteal procedures may serve carefully selected patients in specialist centers. Before broad adoption, researchers need adequately powered multicenter randomized controlled trials (RCTs) that measure amputation-free survival, ulcer recurrence, sustained perfusion, function, and quality of life over at least 12 to 24 months. Standardized dosing, patient-selection rules, safety registries, cost-effectiveness analyses, and equitable access will be essential to determine whether “action at a distance” can become dependable limb-preservation care.
###
References
DOI
10.1093/burnst/tkag017
Original Source URL
https://doi.org/10.1093/burnst/tkag017
About Burns & Trauma
Burns & Trauma is an open access, peer-reviewed journal publishing the latest developments in basic, clinical, and translational research related to burns and traumatic injuries, with a special focus on various aspects of biomaterials, tissue engineering, stem cells, critical care, immunobiology, skin transplantation, prevention, and regeneration of burns and trauma injury.