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Diabetic foot ulcers and other chronic wounds with impaired healing can be treated with bioengineered skin or with growth factors. However, most patients do not benefit from these treatments. Here we report the development and preclinical therapeutic performance of a strain-programmed patch that rapidly and robustly adheres to diabetic wounds, and promotes wound closure and re-epithelialization. The patch consists of a dried adhesive layer of crosslinked polymer networks bound to a pre-stretched hydrophilic elastomer backing, and implements a hydration-based shape-memory mechanism to mechanically contract diabetic wounds in a programmable manner on the basis of analytical and finite-element modelling. In mouse and human skin, and in mini-pigs and humanized mice, the patch enhanced the healing of diabetic wounds by promoting faster re-epithelialization and angiogenesis, and the enrichment of fibroblast populations with a pro-regenerative phenotype. Strain-programmed patches might also be effective for the treatment of other forms of acute and chronic wounds.

Mast cells (MCs) are granulated, immune cells of the myeloid lineage that are present in connective tissues. Apart from their classical role in allergies, MCs also mediate various inflammatory responses due to the nature of their secretory products. They are involved in important physiological and pathophysiological responses related to inflammation, chronic wounds, and autoimmune diseases. There are also indications that MCs are associated with diabetes and its complications. MCs and MC-derived mediators participate in all wound healing stages and are involved in the pathogenesis of non-healing, chronic diabetic foot ulcers (DFUs). More specifically, recent work has shown increased degranulation of skin MCs in human diabetes and diabetic mice, which is associated with impaired wound healing. Furthermore, MC stabilization, either systemic or local at the skin level, improves wound healing in diabetic mice. Understanding the precise role of MCs in wound progression and healing processes can be of critical importance as it can lead to the development of new targeted therapies for diabetic foot ulceration, one of the most devastating complications of diabetes.

Diabetic foot ulceration (DFU) is a devastating complication of diabetes whose pathogenesis remains incompletely understood. Here, we profile 174,962 single cells from the foot, forearm, and peripheral blood mononuclear cells using single-cell RNA sequencing. Our analysis shows enrichment of a unique population of fibroblasts overexpressing MMP1, MMP3, MMP11, HIF1A, CHI3L1, and TNFAIP6 and increased M1 macrophage polarization in the DFU patients with healing wounds. Further, analysis of spatially separated samples from the same patient and spatial transcriptomics reveal preferential localization of these healing associated fibroblasts toward the wound bed as compared to the wound edge or unwounded skin. Spatial transcriptomics also validates our findings of higher abundance of M1 macrophages in healers and M2 macrophages in non-healers. Our analysis provides deep insights into the wound healing microenvironment, identifying cell types that could be critical in promoting DFU healing, and may inform novel therapeutic approaches for DFU treatment., Diabetic foot ulcers (DFUs) remain a complication of diabetes that are difficult to heal and lead to disability. Here the authors use single-cell RNA-sequencing and spatial transcriptomics to characterize the DFU cellular landscape and identify a population of fibroblasts that is associated with successful wound closure.

Diabetic foot ulcers (DFUs) are one of the most common and serious complications of diabetes mellitus, as wound healing is impaired in the diabetic foot. Wound healing is a dynamic and complex biological process that can be divided into four partly overlapping phases: hemostasis, inflammation, proliferative and remodeling. These phases involve a large number of cell types, extracellular components, growth factors and cytokines. Diabetes mellitus causes impaired wound healing by affecting one or more biological mechanisms of these processes. Most often, it is triggered by hyperglycemia, chronic inflammation, micro- and macro-circulatory dysfunction, hypoxia, autonomic and sensory neuropathy, and impaired neuropeptide signaling. Research focused on thoroughly understanding these mechanisms would allow for specifically targeted treatment of diabetic foot ulcers. The main principles for DFU treatment are wound debridement, pressure off-loading, revascularization and infection management. New treatment options such as bioengineered skin substitutes, extracellular matrix proteins, growth factors, and negative pressure wound therapy, have emerged as adjunctive therapies for ulcers. Future treatment strategies include stem cell-based therapies, delivery of gene encoding growth factors, application of angiotensin receptors analogs and neuropeptides like substance P, as well as inhibition of inflammatory cytokines. This review provides an outlook of the pathophysiology in diabetic wound healing and summarizes the established and adjunctive treatment strategies, as well as the future therapeutic options for the treatment of DFUs.

The role of dipeptidyl peptidase-IV (DPP4) as both a regulatory enzyme and a signalling factor has been evaluated and described in many studies. DPP4 inhibition results in increased blood concentration of the incretin hormones glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP). This causes an increase in glucose-dependent stimulation of insulin secretion, resulting in a lowering of blood glucose levels. Recent studies have shown that DPP4 inhibitors can induce a significant reduction in glycosylated haemoglobin (HbA(1c)) levels, either as monotherapy or as a combination with other antidiabetic agents. Research has also demonstrated that DPP4 inhibitors portray a very low risk of hypoglycaemia development. This review article focuses on the two leading agents of this category (sitagliptin and vildagliptin), providing an overview of their function along with the latest data regarding their clinical efficacy as antidiabetic agents.

Diabetes is an oxidative stress disorder as a result of both hyperglycemia and increased levels of free fatty acids. Oxidative stress has been implicated in the pathogenesis of diabetes-related complications, and treatment with antioxidants seemed to be a promising therapeutic option. Although animal studies and preliminary human studies were initially encouraging, subsequent human studies have failed to show a clear benefit of antioxidants, whereas some studies have even suggested that they can be potentially harmful. Therefore, treatment with antioxidants cannot be currently recommended as a therapeutic option.

Human diabetic peripheral neuropathy is believed to have, at least in part, a microvascular basis. This study was designed to examine the effects of restoration of arterial blood supply on peripheral nerve function in six non-insulin-dependent diabetic patients with peripheral occlusive vascular disease. In the revascularised legs, transcutaneous oxygen increased from a median 37.5 (28.5-45.7 interquartile range) mmHg to 55.5 (53.5-62.5) mmHg, p = 0.036, mean increase 20.2 (14.8-25.6, 95% confidence intervals(CI) mmHg. This was accompanied by a significant improvement in peroneal motor nerve conduction velocity from 31.7 (26.5-36.3) m/s to 33.5 (32.9-39.4) m/s, p = 0.04, mean increase 4.7 (1.7-7.7, 95% CI) m/s. There was no significant change in transcutaneous oxygen or peroneal nerve motor conduction velocity in the contralateral control limbs. This improvement in conduction velocity with improved tissue oxygenation suggests that studies of agents which might indirectly bring about improvements in microvascular blood flow should be urgently considered.

Foot ulceration results in substantial morbidity amongst diabetic patients. We have studied prospectively the relationship between high foot pressures and foot ulceration using an optical pedobarograph. A series of 86 diabetic patients, mean age 53.3 (range 17-77) years, mean duration of diabetes 17.1 (range 1-36) years, were followed-up for a mean period of 30 (range 15-34) months. Clinical neuropathy was present in 58 (67%) patients at baseline examination. Mean peak foot pressure was higher at the follow-up compared to baseline (13.5 kg.cm-2 +/- 7.1 SD vs 11.2 +/- 5.4, p less than 0.001) with abnormally high foot pressures (greater than 12.3) being present in 55 patients at follow-up and 43 at the baseline visit (p = NS). Plantar foot ulcers developed in 21 feet of 15 patients (17%), all of whom had abnormally high pressures at baseline; neuropathy was present in 14 patients at baseline. Non-plantar ulcers occurred in 8 (9%) patients. Thus, plantar ulceration occurred in 35% of diabetic patients with high foot pressures but in none of those with normal pressures. We have shown for the first time in a prospective study that high plantar foot pressures in diabetic patients are strongly predictive of subsequent plantar ulceration, especially in the presence of neuropathy.

The Neurometer is a variable constant current sine wave stimulator, and has recently been proposed as a simple non-invasive and quantitative measure of peripheral nerve function. The device is portable and battery operated; assessment of upper and lower extremities takes only a few min, in contrast to conventional assessment techniques. In order to assess its potential in the quantification of diabetic neuropathy, detection thresholds for constant current electric sine wave stimulation were measured at three different frequencies in different sites in 31 healthy control subjects and 90 diabetic patients with and without neuropathy. The device provides good discrimination between neuropathic and non-neuropathic groups (p less than 0.001) and is quick and easy to use. Comparisons with results of conventional tests of nerve function show that high frequency detection thresholds correlate best with tests of large fibre function (r = 0.42-0.69, p less than 0.001), and low frequency detection thresholds correlate with tests of small fibre function (r = 0.34-0.46, p less than 0.005). It is concluded that the device may be a simple and comprehensive way of assessing peripheral nerve function.