Ischemic Diabetic Ulcers Research Articles

Use of consecutive transcutaneous oxygen measurement when assessing the need for revascularization and association with the outcomes of ischemic diabetic ulcers.

This study compared the ankle-brachial index (ABI) with transcutaneous oxygen pressure (TcPO2 ) in assessing peripheral vascular disease (PVD) prevalence in 100 diabetic foot ulcer (DFU) patients. Patients were categorized into vascular or nonvascular reconstruction groups and underwent both ABI and TcPO2 measurements four times over 6 months. Predictive validity for PVD diagnosis was analysed using the area under the receiver-operating characteristic curve (AUC). The study found TcPO2 to be a superior predictor of PVD than ABI. Among the DFU patients, 51 with abnormal TcPO2 values underwent vascular reconstruction. Only TcPO2 values showed significant pretreatment differences between the groups and increased post-reconstruction. These values declined over a 6-month follow-up, whereas ABI values rose. For those with end-stage renal disease (ESRD), TcPO2 values saw a sharp decrease within 3 months. Pre-reconstruction TcPO2 was notably lower in amputation patients versus limb salvage surgery patients. In conclusion, TcPO2 is more effective than ABI for evaluating ischemic limb perfusion and revascularization necessity. It should be prioritized as the primary follow-up tool, especially for ESRD patients.

A novel dressing seeded with embryonic artery CD133+ cells and loaded with the Sirt1 agonist SRT1720 accelerates the healing of diabetic ischemic ulcers

Refractory ischemic ulcers that occur in patients with diabetes present a major clinical challenge. Embryonic artery cluster of differentiation 133+ cells (EACCs) may promote the healing of diabetic ulcers; however, the high glucose environment in the diabetic ulcers decreases the survival rate of transplanted EACCs and inhibit their biological function. Furthermore, microcirculation in diabetic ischemic ulcers is impaired, which inhibits the beneficial effect of EACCs. In the current study, the Sirt1 agonist SRT1720 was selected as a therapeutic drug and loaded into a dressing composed of PLGA, collagen and silk (PCSS) formed using electrospinning technology. EACCs were seeded onto the PCSS dressing and this was used to treat diabetic ulcers. The results indicated that SRT1720 promotes the proliferation of EACCs, enhances the secretion of vascular endothelial growth factor A, interluekin 8 and basic fibroblast growth factor, and inhibits the secretion of tumor necrosis factor α. Furthermore, SRT1720 promoted the paracrine function of EACCs and promoted the proliferation and migration of human umbilical vein endothelial cells. PCSS induced the steady release of SRT1720 over a 15-day period and PCSS seeded with EACCs (PCSS-EACCs) were transplanted into the diabetic ischemic ulcers of mice with diabetes. The results of these experiments indicated that angiogenesis and the healing of diabetic ischemic ulcers was significantly improved following the transplantation of PCSS-EACCs. Therefore, PCSS-EACCs may be a novel and effective treatment for diabetic ischemic ulcers.

Hyperbaric Oxygen for Ischemic Diabetic Foot Ulcers

Evidence about the effectiveness of hyperbaric oxygen therapy (HBOT) in patients with chronic ischemic leg ulcers is conflicting. In this trial from

An inflammatory memory and angiogenic self-assembling nanofiber hydrogel scaffold seeded with Akkermansia muciniphila to accelerate the healing of diabetic ischemic ulcers.

Refractory ulcers are a major challenge in the treatment of a diabetic foot, because of the immunodeficient, ischemic and high-glucose microenvironment. Inflammatory memory peptides, which were extracted from the immune mediator absent in melanoma 2 (AIM2), could effectively improve the immunodeficient microenvironment and special angiogenic peptides could effectively promote angiogenesis. Moreover, the gut flora Akkermansia muciniphila (A. muciniphila) participates in diabetic metabolism and could decrease high-glucose levels. In this research, a polypeptide skeleton (PPS) was synthesized based on 3,4-dihydroxyphenylalanine (DOPA) and peptides, forming the hydrophilic and hydrophobic parts. Inflammatory memory peptides and angiogenic peptides were synthesized and conjugated with the PPS, which then formed an anisotropic hydrogel through the self-assembling of β-sheet peptides based on hydrophobicity and DOPA oxidation. A. muciniphila was seeded into the hydrogel and transported into diabetic ischemic ulcers through subcutaneous injection, and the healing of diabetic ischemic ulcers was promoted. The inflammatory memory peptides were released based on the A. muciniphila enzyme response, and they firstly improved the immunity of the local surroundings. Then, the angiogenic peptides were also released through irradiation and they promoted angiogenesis. Additionally, the transported A. muciniphila could decrease the local glucose levels and spontaneously regress once the diabetic ischemic ulcers had healed. A. muciniphila combined with a functional polypeptide hydrogel may be a novel strategy for diabetic ischemic ulcer treatment.

Wound Healing Society 2014 update on guidelines for arterial ulcers.

Wound Healing Society 2014 update on guidelines for arterial ulcers.

Micronized cellular adipose matrix as a therapeutic injectable for diabetic ulcer.

Despite the clinical potential of adipose-derived stem/stromal cells (ASCs), there are some clinical difficulties due to the regulation of cell therapies. Micronized cellular adipose matrix (MCAM) injectable was prepared through selective extraction of connective tissue fractions in fat tissue only through mechanical minimal manipulation procedures. It retained some capillaries and ASCs, but most adipocytes were removed. The presence of viable ASCs, vascular endothelial cells was confirmed and ASCs of MCAM kept intact mesenchymal differentiation capacity. In diabetic mice, skin wounds treated with MCAM showed significantly accelerated healing compared with phosphate-buffered saline-treated ones. The proven potential of MCAM to accelerate healing in ischemic diabetic ulcers may offer a simple, safe and minimally invasive means for tissue repair and revitalization.

Effects of Electrical Stimulation on the Management of Ischemic Diabetic Foot Ulcers

BACKGROUND AND OBJECTIVE: Diabetic foot ulcer is a major complication caused by diabetes. Electrical stimulation is considered as an efficient modality of diabetic wound healing. This study aimed to investigate the effects of direct-current stimulation of cathodal on skin temperature and acceleration of ischemic diabetic foot ulcer closing. METHODS: This randomized, single-blinded, clinical trial was conducted from November 2013 to September 2014 on 20 patients with type II diabetes suffering from ischemic diabetic foot ulcers. Subjects were randomly divided into two groups of electrical stimulation and placebo. The electrical stimulation group received direct-current cathodal stimulation to the wound for one hour a day, repeating three days a week (4 weeks, 12 sessions), and the placebo group underwent the same procedure with zero-intensity electrical stimulation. Skin surface temperature was measured in the plantar and dorsal areas of the diabetic foot before and after the intervention at sessions one, six and twelve. In addition, the surface of ulcer area was measured at the same intervals (IRCT: 2014110819854 N1). FINDINGS: Comparison of the study groups indicated the mean of skin temperature changes to be significantly higher in the stimulation group compared to the placebo group at sessions one (p=0.01, 0.41±0.2 and 0.75±0.26), six (p=0.01, 0.25±0.27 and 0.6±0.21) and twelve (p=0.007, 0.25±0.27 and 0.66±0.23), respectively. In addition, reduction of the wounded area was considerably higher in the electrical stimulation group (52.68%) compared to the placebo group (38.39%) at session 12 (p=0.02). CONCLUSION: According to the results of this study, direct-current cathodal stimulation could improve skin temperature and accelerate wound closing in ischemic diabetic ulcers.

Adenosine accelerates the healing of diabetic ischemic ulcers by improving autophagy of endothelial progenitor cells grown on a biomaterial.

Endothelial progenitor cells (EPCs) seeded on biomaterials can effectively promote diabetic ischemic wound healing. However, the function of transplanted EPCs is negatively affected by a high-glucose and ischemic microenvironment. Our experiments showed that EPC autophagy was inhibited and mitochondrial membrane potential (MMP) was increased in diabetic patients, while adenosine treatment decreased the energy requirements and increased the autophagy levels of EPCs. In animal experiments, we transplanted a biomaterial seeded with EPCs onto the surface of diabetic wounds and found that adenosine-stimulated EPCs effectively promoted wound healing. Increased microvascular genesis and survival of the transplanted cells were also observed in the adenosine-stimulated groups. Interestingly, our study showed that adenosine increased the autophagy of the transplanted EPCs seeded onto the biomaterial and maintained EPC survival at 48 and 96 hours. Moreover, we observed that adenosine induced EPC differentiation through increasing the level of autophagy. In conclusion, our study indicated that adenosine-stimulated EPCs seeded onto a biomaterial significantly improved wound healing in diabetic mice; mechanistically, adenosine might maintain EPC survival and differentiation by increasing high glucose-inhibited EPC autophagy and maintaining cellular energy metabolism.

Effect of brain-derived neurotrophic factor on mesenchymal stem cell-seeded electrospinning biomaterial for treating ischemic diabetic ulcers via milieu-dependent differentiation mechanism.

Great challenges in transplantation of mesenchymal stem cells (MSCs) for treating ischemic diabetic ulcers (IDUs) are to find a suitable carrier and create a beneficial microenvironment. Brain-derived neurotrophic factor (BDNF), a member of neurotrophin family, is considered angiogenic and neuroprotective. Given that IDUs are caused by vascular disease and peripheral neuropathy, we used BDNF as a stimulant, and intended to explore the role of new biomaterials complex with MSCs in wound healing. BDNF promoted the proliferation and migration of MSCs using MTT, transwell, and cell scratch assays. The activity of human umbilical vein endothelial cells (HUVECs) was also enhanced by the MSC-conditioned medium in the presence of BDNF, via a vascular endothelial growth factor-independent pathway. Since proliferated HUVECs in the BDNF group made the microenvironment more conducive to endothelial differentiation of MSCs, by establishing co-culture systems with the two cell types, endothelial cells derived from MSCs increased significantly. A new biomaterial made of polylactic acid, silk and collagen was used as the carrier dressing. After transplantation of the BDNF-stimulated MSC/biomaterial complex, the ulcers in hindlimb ischemic mice healed prominently. More blood vessel formation was observed in the wound tissue, and more MSCs were co-stained with some endothelial-specific markers such as cluster of differentiation (CD)31 and von Willebrand Factor (vWF) in the treatment group than in the control group. These results demonstrated that BDNF could improve microenvironment in the new biomaterial, and induce MSCs to differentiate into endothelial cells indirectly, thus accelerating ischemic ulcer healing.

Is additional hyperbaric oxygen therapy cost‐effective for treating ischemic diabetic ulcers? Study protocol for the Dutch DAMOCLES multicenter randomized clinical trial 对缺血性糖尿病溃疡患者额外进行高压氧治疗的成本效益如何？荷兰DAMOCLES多中心随机临床试验的研究方案

The value of hyperbaric oxygen therapy (HBOT) in the treatment of diabetic ulcers is still under debate. Available evidence suggests that HBOT may improve the healing of diabetic ulcers, but it comes from small trials with heterogeneous populations and interventions. The DAMOCLES-trial will assess the (cost-)effectiveness of HBOT for ischemic diabetic ulcers in addition to standard of care. In a multicenter randomized clinical trial, including 30 hospitals and all 10 HBOT centers in the Netherlands, we plan to enroll 275 patients with Types 1 or 2 diabetes, a Wagner 2, 3 or 4 ulcer of the leg present for at least 4 weeks, and concomitant leg ischemia, defined as an ankle systolic blood pressure of <70 mmHg, a toe systolic blood pressure of <50 mmHg or a forefoot transcutaneous oxygen tension (TcpO2) of <40 mmHg. Eligible patients may be candidates for revascularization. Patients will be randomly assigned to standard care with or without 40 HBOT-sessions. Primary outcome measures are freedom from major amputation after 12 months and achievement of, and time to, complete wound healing. Secondary endpoints include freedom from minor amputations, ulcer recurrence, TcpO2 , quality of life, and safety. In addition, we will assess the cost-effectiveness of HBOT for this indication. The DAMOCLES trial will be the largest trial ever performed in the realm of HBOT for chronic ulcers, and it is unique for addressing patients with ischemic diabetic foot ulcers who may also receive vascular reconstructions. This matches the treatment dilemma in current clinical practice.

The effect of heme oxygenase-1 complexed with collagen on MSC performance in the treatment of diabetic ischemic ulcer

Diabetic ischemic ulcer is an intractable diabetic complication. Bone marrow mesenchymal stem cells (BMSCs) have great potential in variety of tissue repair. In fact, poor cell viability and tolerance limit their ability for tissue repair. In addition, it is difficult for stem cells to home and locate to the lesion. In this study, we explore whether over-expression of heme oxygenase-1 (HO-1) in BMSCs complexed with collagen play an important role in treatment of diabetic ischemic ulcers. In vitro, over-expression of HO-1 promoted the proliferation and paracrine activity of BMSCs and the conditioned medium of BMSCs accelerated HUVECs migration and proliferation. These processes were closely related to Akt signaling pathway and were not dependent on Erk signaling pathway. In vivo, in order to make BMSCs directly act on the wound, we choose a solid collagen as a carrier, BMSCs were planted into it, ischemic wounds of diabetic mice were covered with the complex of BMSCs and collagen. The results indicate that the complex of HO-1-overexpressing BMSCs and collagen biomaterials can significantly promote angiogenesis and wound healing. These preclinical findings open new perspectives for the treatment of diabetic foot ulcers.

Vascular Progenitor Cells in Diabetes Mellitus

See related article, pages 1095–1102 Over the centuries, diabetes mellitus–associated ischemic ulcers have driven physicians to continue to improve their skills in healing the ulcers to prevent devastating complications.1 Unfortunately, extremity amputation still remains the outcome in many cases. The recent development of vascular progenitor cell (PC) transplantation aimed at enhancing angiogenesis and wound healing may, however, provide new hope in the treatment of this old ailment.2,3 In this issue of Circulation Research , Barcelos et al show in a murine diabetes mellitus model that topical transplantation of human fetal CD133+ PCs significantly accelerates the healing of skin wounds on ischemic hind limbs.4 Their data suggest that the reparative angiogenesis is mediated by the wingless (Wnt) signaling pathway. The prominin-1 (PROM1)/CD133 gene encodes a pentaspan transmembrane glycoprotein expressed in a variety of stem cells, including hematopoietic stem cells, endothelial PCs (EPCs), and neuronal/glial stem cells.5,6 By suppressing further differentiation, PROM1 helps these cells maintain their stem cell properties. Mutations in PROM1 may result in retinitis pigmentosa,7 and its overexpression is also associated with cancer formation.8 In view of this cancer potential, overstimulation of CD133+ cells may also lead to unwanted consequences. Additionally, that human fetal CD133+ cells are not easily accessible …

Human CD133 + Progenitor Cells Promote the Healing of Diabetic Ischemic Ulcers by Paracrine Stimulation of Angiogenesis and Activation of Wnt Signaling

We evaluated the healing potential of human fetal aorta-derived CD133(+) progenitor cells and their conditioned medium (CD133(+) CCM) in a new model of ischemic diabetic ulcer. Streptozotocin-induced diabetic mice underwent bilateral limb ischemia and wounding. One wound was covered with collagen containing 2x10(4) CD133(+) or CD133(-) cells or vehicle. The contralateral wound, covered with only collagen, served as control. Fetal CD133(+) cells expressed high levels of wingless (Wnt) genes, which were downregulated following differentiation into CD133(-) cells along with upregulation of Wnt antagonists secreted frizzled-related protein (sFRP)-1, -3, and -4. CD133(+) cells accelerated wound closure as compared with CD133(-) or vehicle and promoted angiogenesis through stimulation of endothelial cell proliferation, migration, and survival by paracrine effects. CD133(+) cells secreted high levels of vascular endothelial growth factor (VEGF)-A and interleukin (IL)-8. Consistently, CD133(+) CCM accelerated wound closure and reparative angiogenesis, with this action abrogated by co-administering the Wnt antagonist sFRP-1 or neutralizing antibodies against VEGF-A or IL-8. In vitro, these effects were recapitulated following exposure of high-glucose-primed human umbilical vein endothelial cells to CD133(+) CCM, resulting in stimulation of migration, angiogenesis-like network formation and induction of Wnt expression. The promigratory and proangiogenic effect of CD133(+) CCM was blunted by sFRP-1, as well as antibodies against VEGF-A or IL-8. CD133(+) cells stimulate wound healing by paracrine mechanisms that activate Wnt signaling pathway in recipients. These preclinical findings open new perspectives for the cure of diabetic ulcers.

Human fetal aorta-derived vascular progenitor cells: identification and potential application in ischemic diseases

Vasculogenesis, the formation of blood vessels in embryonic or fetal tissue mediated by immature vascular cells (i.e., angioblasts), is poorly understood. Here we report a summary of our recent studies on the identification of a population of vascular progenitor cells (VPCs) in human fetal aorta. These undifferentiated mesenchymal cells co-express endothelial and myogenic markers (CD133+, CD34+, KDR+, desmin+) and are localized in outer layer of the aortic stroma of 11-12 weeks old human fetuses. Under stimulation with VEGF-A or PDGF-BB, VPCs give origin to a mixed population of mature endothelial and mural cells, respectively. When embedded in a three-dimensional collagen gel, VPCs organize into cohesive cellular cords that resembled mature vascular structures. The therapeutic efficacy of a small number of VPCs transplanted into ischemic limb muscle was demonstrated in immunodeficient mice. Investigation of the effect of VPCs on experimental heart ischemia and on diabetic ischemic ulcers in mice is in progress and seems to confirm their efficacy. On the whole, fetal aorta represents an important source for the investigation of phenotypic and functional features of human vascular progenitor cells.