Diabetic Foot Osteomyelitis in Patients with and without Peripheral Arterial Disease: Two Different Diseases?

The aim of the current study was to evaluate the outcomes of patients with diabetic foot osteomyelitis (DFO), comparing subjects with and without peripheral arterial disease (PAD). The study is a prospective study including a population of patients affected by a DFO located in the forefoot. All patients were managed by a surgical conservative approach defined by the removal of the infected bone, in association with the antibiotic therapy. Patients were divided into two groups: those with PAD (neuro-ischaemic DFO) and those without (neuropathic DFO). After 1 year of follow-up, the following outcome were evaluated and compared between groups: healing, healing time, minor amputation, major amputation, hospitalization, need for surgical re-intervention. Overall, 166 patients were included, 87(52.4%) of them had neuro-ischaemic DFO and 79 (47.6%) neuropathic DFO. Patients with neuro-ischaemic DFO in comparison to neuropathic DFO were older (72.5 ± 9 vs 64.1 ± 15.5 years, P < .0001), had longer diabetes duration (21.8 ± 5.6 vs 16.4 ± 7.6 years, P < .0001), higher rate of dialysis (13.8 vs 1.3%, P = .001) and ischaemic heart disease (79.3 vs 12.7%, P < .0001). Outcomes for neuro-ischaemic DFO and neuropathic DFO were: healing (96.5 vs 97.5%, P = .7), healing time (7.8 ± 6.2 vs 5.7 ± 3.7 weeks, P = .01), minor amputation (16.1 vs 3.8%, P = .006), major amputation (0 vs 0%, ns), hospitalization (90.8 vs 51.9%, P < .0001), surgical re-intervention (14.9 vs 8.8%, P = .004) respectively. In addition, PAD resulted in an independent predictor of minor amputation, hospitalization, and surgical re-intervention. DFO in patients with PAD was characterized by longer healing time, more cases of minor amputation, hospitalization, and surgical re-intervention. PAD independently predicted the risk of minor amputation, hospitalization, and surgical re-intervention, while it was not associated with the healing rate.

Prevalence of Diabetes Mellitus and Clinical Differences in Patients with Severe Osteoporosis and Fragility Fractures.

Background: Diabetes mellitus (DM) and osteoporosis are two of the most widespread metabolic diseases in the world. The aim of this study is to investigate the prevalence of DM among patients affected by osteoporosis and fragility fractures, and to search for differences in clinical characteristics. Methods: This is a single-center retrospective, case-controlled study. A total of 589 patients attending CTO Bone Unit between 2 January 2010 and 31 May 2023, due to osteoporosis and fragility fractures, were divided into two groups, according to the diagnosis of DM. The clinical and bone characteristics of patients were compared. Results: Prevalence of DM was 12.7%. Compared to patients without DM, the median age at the time of first fracture was similar: 72 years ± 13.5 interquartile range (IQR) vs. 71 years ± 12 IQR; prevalence of combination of vertebral and hip fractures was higher (p = 0.008), as well as prevalence of males (p = 0.016). Bone mineral density (BMD) at all sites was higher in DM group; trabecular bone score (TBS), instead, was significantly lower (p < 0.001). Conclusions: Patients with fragility fractures and DM more frequently show combination of major fractures with higher BMD levels. In these patients, TBS could be a better indicator of bone health than BMD and, therefore, might be used as a diagnostic tool in clinical practice.

Effect of a multidisciplinary team approach in patients with diabetic foot ulcers on major adverse limb events (MALEs): systematic review and meta-analysis for the development of the Italian guidelines for the treatment of diabetic foot syndrome.

The treatment of patients with diabetic foot ulcers (DFUs) is extremely complex, requiring a comprehensive approach that involves a variety of different healthcare professionals. Several studies have shown that a multidisciplinary team (MDT) approach is useful to achieve good clinical outcomes, reducing major and minor amputation and increasing the chance of healing. Despite this, the multidisciplinary approach is not always a recognized treatment strategy. The aim of this meta-analysis was to assess the effects of an MDT approach on major adverse limb events, healing, time-to-heal, all-cause mortality, and other clinical outcomes in patients with active DFUs. The present meta-analysis was performed for the purpose of developing Italian guidelines for the treatment of diabetic foot with the support of the Italian Society of Diabetology (Società Italiana di Diabetologia, SID) and the Italian Association of Clinical Diabetologists (Associazione Medici Diabetologi, AMD). The study was performed using the Grading of Recommendations Assessment, Development, and Evaluation approach. All randomized clinical trials and observational studies, with a duration of at least 26 weeks, which compared the MDT approach with any other organizational strategy in the management of patients with DFUs were considered. Animal studies were excluded. A search of Medline and Embase databases was performed up until the May 1st, 2023. Patients managed by an MDT were reported to have better outcomes in terms of healing, minor and major amputation, and survival in comparison with those managed using other approaches. No data were found on quality of life, returning-to-walking, and emergency admission. Authors concluded that the MDT may be effective in improving outcomes in patients with DFUs.

Early Treatment of Acute Stage 0/1 Diabetic Charcot Foot Can Avoid Major Amputations at One Year.

Background: If unrecognized, Charcot neuro-osteoarthropathy (CNO) can be a devastating complication of diabetes. Methods: The aim of this retrospective study was to evaluate the outcomes in a cohort of diabetic patients diagnosed with active CNO managed in a tertiary level diabetic foot clinic (DFC). We included consecutive patients with active CNO, stage 0-1, according to the Eichenholtz-Shibata classification, who were referred from 1 January 2019 to 27 September 2022. Diagnosis of CNO was based on clinical signs and imaging (X-rays and magnetic resonance). All patients were completely offloaded by a total-contact cast (TCC) or removable knee-high device. Each patient was closely monitored monthly until CNO remission or another outcome. At 12 months of follow-up, the following outcomes were analyzed: remission, time to remission, major amputations (any above the ankle), and surgical indication. Results: Forty-three patients were included. The mean age was 57.6 ± 10.8 years; 65% were males and 88.4% had type 2 diabetes, with a mean duration of 20.6 ± 9.9 years. At baseline, 32.6% was affected by peripheral artery disease. Complete remission was recorded in 40/43 patients (93%), with a mean time to remission of 5.6 ± 1.5 months; major amputation and surgical indication occurred, respectively in 1/43 patients (2.3%) and 3/43 patients (7%). Conclusions: Early treatment of active Stage 0/1 CNO leads to high rates of remission and limb salvage.

Peripheral Blood Mononuclear Cells: A New Frontier in the Management of Patients with Diabetes and No-Option Critical Limb Ischaemia.

The current study aimed to evaluate the effectiveness of peripheral blood mononuclear cell (PB-MNC) therapy as adjuvant treatment for patients with diabetic foot ulcers (DFUs) and no-option critical limb ischaemia (NO-CLI). The study is a prospective, noncontrolled, observational study including patients with neuro-ischaemic DFUs and NO-CLI who had unsuccessful revascularization below the ankle (BTA) and persistence of foot ischaemia defined by TcPO2 values less than 30 mmHg. All patients received three cycles of PB-MNC therapy administered through a "below-the-ankle approach" in the affected foot along the wound-related artery according to the angiosome theory. The primary outcome measures were healing, major amputation, and survival after 1 year of follow-up. The secondary outcome measures were the evaluation of tissue perfusion by TcPO2 and foot pain defined by the numerical rating scale (NRS). Fifty-five patients were included. They were aged >70 years old and the majority were male and affected by type 2 diabetes with a long diabetes duration (>20 years); the majority of DFUs were infected and nearly 90% were assessed as gangrene. Overall, 69.1% of patients healed and survived, 3.6% healed and deceased, 10.9% did not heal and deceased, and 16.4% had a major amputation. At baseline and after PB-MNC therapy, the TcPO2 values were 17 ± 11 and 41 ± 12 mmHg, respectively (p < 0.0001), while the pain values (NRS) were 6.8 ± 1.7 vs. 2.8 ± 1.7, respectively (p < 0.0001). Any adverse event was recorded during the PB-MNC therapy. Adjuvant PB-MNC therapy seems to promote good outcomes in patients with NO-CLI and neuro-ischaemic DFUs.

Hospital Readmission in Patients With Diabetic Foot Ulcers: Prevalence, Causes, and Outcomes.

The aim of the current study was to evaluate the rate of readmission in patients affected by diabetes and foot ulcers (DFUs), and causes and outcomes of patients requiring a new hospitalization. The current study is a retrospective observational study including patients who have required hospitalization since January 2019 to September 2022 due to a DFU. Once patients were discharged, they were regularly followed as outpatients. Within 6 months of follow-up, the rate of hospital readmission for a diabetic foot problem was recorded. According to the readmission or not, patients were divided into 2 groups, readmitted and not readmitted patients, respectively. Hence, all patients were followed for 6 months more and outcomes of the 2 groups were analyzed and compared. Overall, 310 patients were included. The mean age was 68 ± 12 years, the majority of patients reported type 2 diabetes (>90%), and the mean diabetes duration was approximately 20 years. Sixty-eight (21.9%) patients were readmitted. The main reason for hospital readmission was the presence of critical limb ischemia (CLI) in the contralateral limb (6.1%), the recurrence of CLI in the previous treated limb (4.5%), and the onset of new infected DFU in the contralateral foot (4.5%). Readmitted patients reported lower rate of healing (51.5% vs 89.2%, P < .0001) and higher rate of major amputation (10.3% vs 4.5%, P = .2) in comparison to not readmitted patients. Critical limb ischemia resulted in the only independent predictor of hospital readmission. Hospital readmission is a frequent issue among patients with DFUs, and readmitted patients showed a lower chance of wound healing. Critical limb ischemia resulted in the main cause of new hospitalization.

Diabetic Polyneuropathy and Physical Activity in Type 1 Diabetes Mellitus: A Cross-Sectional Study.

BACKGROUND: The purpose of this study is to access whether a personal attitude to physical activity (PA) may influence the appearance of diabetic polyneuropathy (DPN) patients with well-controlled type 1 diabetes mellitus. METHODS: Ninety patients attending the diabetes technology outpatient clinic were enrolled. DPN was investigated according to the Toronto consensus diagnostic criteria. PA was assessed using the International Physical Activity Questionnaire. RESULTS: PA was low in 21.1%, moderate in 42.2% and high in 36.7% of patients. According to Toronto criteria, we defined two categories: the first one with DPN absent or possible (57 (63.3%)) and a second one with DPN certain or probable (33 (36.7%)). The χ2-test of the PA groups and the DPN categories showed a statistically significant difference (p < 0.001), with less neuropathy in patients belonging to the group of moderate/high PA. Exposure to a minimum of 600 MET minutes/week was protective factor against the onset of DPN (odd ratio 0.221, c.i. 0.068-0.720, p = 0.012). CONCLUSIONS: This study suggests that DPN is less present in type 1 diabetic patients with good metabolic control and a good personal habit of PA. Moderate-to-vigorous PA of at least 600 MET minutes/week might be a protective factor against DPN.

Risk Factors for Ulcer Recurrence in Diabetic Patients Managed by an Integrated Foot Care Protocol.

The aim of our study was to identify risk factors for the recurrence of diabetic foot ulcers (DFUs) in a selected population of patients in secondary prevention treated, according to International Guidelines, with an integrated foot care protocol by a referral diabetic foot clinic. A retrospective study was performed with the inclusion of selected outpatients with diabetes at higher risk for ulceration with a history of previous ulcer and/or amputation followed in our diabetic foot clinic between January 2015 and December 2021. According to the presence or absence of recurrence, patients were divided into 2 groups: ulcer recurrence and without ulcer recurrence. One hundred twenty-seven (127) patients were included, 47 patients (37%) developed an ulcer recurrence while 80 patients (63%) did not. The mean age was 71.7 years; 65% were male; 97% were affected by type 2 diabetes with a mean duration of 21.1 years, the mean HbA1c was 63 + 21 mmol/mol. Both groups of patients had foot deformities, such as claw and hammertoes; hallux valgus, and prominent metatarsal heads (MTHs). The presence of deformity was significantly associated with ulceration. The group with ulcer recurrence showed a higher rate of prominence MTHs in comparison to a group without ulcer recurrence. The MTHs resulted as the only independent predictor for recurrence. This study shows that the presence of the prominent MTH is a significant risk factor for ulcer recurrence in a selected population of diabetic foot patients treated in the best way with integrated foot care.

A multidisciplinary team reduces in-hospital clinical complications and mortality in patients with diabetic foot ulcers.

AIMS: The current study aims to evaluate the effectiveness of a multidisciplinary diabetic foot team (MDFT) in the management of in-patients affected by diabetic foot problems. MATERIALS AND METHODS: The study was a retrospective observational study. Consecutive patients with a diabetic foot problem requiring hospitalisation were included. All patients were managed by a MDFT led by diabetologists according to the guidance. The rate of in-hospital complications (IHCs), major amputation, and survival were recorded at the end of patient's hospitalisation. IHC was defined as any new infection different from wound infection, cardiovascular events, acute renal injury, severe anaemia requiring blood transfusion, and any other clinical problem not present at the assessment. RESULTS: Overall, 350 patients were included. The mean age was 67.9 ± 12.6 years, 254 (72.6%) were males, 323 (92, 3%) showed Type 2 diabetes with a mean duration of 20.2 ± 9.6 years; 224 (64%) had ischaemic diabetic foot ulcers (DFUs) and 299 (85.4%) had infected DFUs. IHCs were recorded in 30/350 (8.6%) patients. The main reasons for IHCs were anaemia requiring blood transfusion (2.8%), pneumonia (1.7%), acute kidney failure (1.1%). Patients with IHCs showed a higher rate of major amputation (13.3 vs. 3.1%, p = 0.02) and mortality (16.7 vs. 0.6%, p < 0.0001) in comparison to those without. Ischaemic heart disease (IHD) and wound duration at the assessment (>1 month) were independent predictors of IHC, whereas IHCs, heart failure, and dialysis were independent predictors of in-hospital mortality. CONCLUSIONS: The multidisciplinary management of diabetic foot problems leads to an IHC rate of 8%. The risk of IHCs is higher in patients with IHD and long wound duration.

Development of the Italian clinical practice guidelines for the treatment of diabetic foot syndrome: design and methodological aspects.

AIMS: Diabetic foot syndrome (DFS) and its complications are a growing public health concern. The Italian Society of Diabetology (SID) and the Italian Association of Clinical Diabetologists (AMD), in collaboration with other scientific societies, will develop the first Italian guidelines for the treatment of DFS. METHODS: The creation of SID/AMD Guidelines is based on an extended work made by 19 panelists and 12 members of the Evidence Review Team. Grading of Recommendations, Assessment, Development and Evaluations (GRADE) methodology has been used to decide aims, reference population, and target health professionals. Clinical questions have been created using PICO (Patient, Intervention, Comparison, Outcome) conceptual framework. The definition of questions has been performed using a two-step web-based Delphi methodology, a structured technique aimed at obtaining by repeated rounds of questionnaires a consensus opinion from a panel of experts in areas wherein evidence is scarce or conflicting, and opinion is important. RESULTS: The mean age of panelists (26.3% women) was 53.7 ± 10.6 years. The panel proposed 34 questions. A consensus was immediately reached for all the proposed questions, 32 were approved and 2 were rejected. CONCLUSIONS: The areas covered by clinical questions included diagnosis of ischemia and infection, treatment of ischemic, neuropathic, and infected ulcers, prevention of foot ulceration, organization and education issues, and surgical management. The PICO presented in this paper are designed to provide indications for healthcare professionals in charge of diabetic foot treatment and prevention, primarily based on clinical needs of people with diabetic foot syndrome and considering the existing organization of health care.

Microbiological and Clinical Characteristics of Infected Diabetic Foot Ulcers Managed in a Tertiary Level Diabetic Foot Service.

The study aimed to evaluate the clinical and microbiological characteristics of diabetic foot infections (DFIs) in patients referring to a specialized diabetic foot service (DFS). The study is a retrospective observational study conducted in a single center, including patients who were referred for a new DFI. All patients were managed through a limb salvage protocol according to international guidelines. The following items were recorded: type of bacteria, presence of single or polymicrobial infection, and the antibiotic resistance. Overall, 268 patients were included. The mean age was 68.9 ± 10.9 years, 75% were male, and 97.2% had type 2 diabetes with a mean diabetes duration of 16 ± 9 years. One hundred thirty-nine (51.9%) DFU were ischemic, 120 (44.7%) patients had osteomyelitis, 107 (39.9%) had gangrene, 37 (13.9%) had phlegmon/abscess/cellulitis and 4 (1.5%) had necrotizing fasciitis. Among 370 bacteria isolated, gram positive were found in 207 (55.9%) cases, and gram negative in 163 (44.1%) cases. The higher rates of isolates were Staphylococcus aureus (32.9%), Pseudomonas aeruginosa (10.8%), and Enterococcus faecalis (8.9%). Polymicrobial infection was reported in 33.6% of cases and antibiotic resistance was recorded in 16.5% of isolates. Among them, 10.3% were methicillin-resistant S. aureus (MRSA). Antibiotic resistance was detected in 40.9% of cases in association with gangrene and osteomyelitis. The current study shows as polymicrobial infections and antibiotic resistance is frequently reported in DFIs, and antibiotic resistance was more associated with gangrene and osteomyelitis. Among bacteria reporting antimicrobial resistance, the highest rate was found for MRSA.

The Neuro-Ischaemic Charcot Foot: Prevalence, Characteristics and Severity of Peripheral Arterial Disease in Acute Charcot Neuro-Arthropathy.

The study aimed to evaluate the prevalence, characteristics and outcomes of patients affected by Charcot neuro-arthropathy (CN) and peripheral arterial disease (PAD) compared to CN without PAD. Consecutive patients presenting with an acute CN were included. The sample size was calculated by the power analysis by adopting the two-tailed tests of the null hypothesis with alfa = 0.05 and a value of beta = 0.10 as the second type error and, therefore, a test power equal to 90%. Seventy-six patients were identified. Twenty-four patients (31.6%) had neuro-ischaemic CN; they were older (66 vs. 57yrs), p = 0.03, had a longer diabetes duration (19 vs. 14yrs), p < 0.001, and more cases of end-stage-renal-disease (12.5 vs. 0%), p = 0.04 and ischaemic heart disease (58.3 vs. 15.4%), p < 0.0001 than neuropathic CN. Fifty patients (65.8%) had concomitant foot ulcers, 62.5% and 67.3% (p = 0.3), respectively, in CN with and without PAD. Neuro-ischaemic CN show arterial lesions of 2.9 vessels, and PAD was located predominantly below-the-knee (75%) but not below-the-ankle (16.7%). The outcomes for neuro-ischaemic and neuropathic CN patients were, respectively: wound healing (86.7 vs. 94.3%), p = 0.08; minor amputation (25 vs. 7.7%), p = 0.003; major amputation (8.3 vs. 1.9%), p = 0.001; hospitalization (75 vs. 23%), p = 0.0001. The study showed a frequent association between CN and PAD, leading to a neuro-ischaemic Charcot foot type. Neuro-ischaemic CN leaded to an increased risk of minor and major amputation and hospitalization, compared to neuropathic CN.

Results of a prospective observational study of autologous peripheral blood mononuclear cell therapy for no-option critical limb-threatening ischemia and severe diabetic foot ulcers.

BACKGROUND: Cell therapy with autologous peripheral blood mononuclear cells (PB-MNCs) may help restore limb perfusion in patients with diabetes mellitus and critical limb-threatening ischemia (CLTI) deemed not eligible for revascularization procedures and consequently at risk for major amputation (no-option). Fundamental is to establish its clinical value and to identify candidates with a greater benefit over time. Assessing the frequency of PB circulating angiogenic cells and extracellular vesicles (EVs) may help in guiding candidate selection. METHODS: We conducted a prospective, non-controlled, observational study on no-option CLTI diabetic patients that underwent intramuscular PB-MNCs therapy, which consisted of more cell treatments repeated a maximum of three times. The primary endpoint was amputation rate at 1 year following the first treatment with PB-MNCs. We evaluated ulcer healing, walking capability, and mortality during the follow-up period. We assessed angiogenic cells and EVs at baseline and after each cell treatment, according to primary outcome and tissue perfusion at the last treatment [measured as transcutaneous oxygen pressure (TcPO2)]. RESULTS: 50 patients were consecutively enrolled and the primary endpoint was 16%. TcPO2 increased after PB-MNCs therapy (17.2 ± 11.6 vs 39.1 ± 21.8 mmHg, p < .0001), and ulcers healed with back-to-walk were observed in 60% of the study population (88% of survivors) during follow-up (median 1.5 years). Patients with a high level of TcPO2 (≥ 40 mmHg) after the last treatment showed a high frequency of small EVs at enrollment. CONCLUSIONS: In no-option CLTI diabetic patients, PB-MNCs therapy led to an improvement in tissue perfusion, a high rate of healing, and back-to-walk. Coupling circulating cellular markers of angiogenesis could help in the identification of patients with a better clinical benefit over time.

Below-the-ankle arterial disease: a new marker of coronary artery disease in patients with diabetes and foot ulcers.

AIM: The aim of the current study is to evaluate the association between below-the-ankle (BTA) arterial disease and coronary artery disease (CAD) in patients with diabetic foot ulcers (DFUs). METHODS: The study group was composed of patients with an active neuro-ischaemic DFUs managed in a tertiary care diabetic foot clinic. All patients received a pre-set limb salvage protocol including lower limb revascularization. By a retrospective analysis of individual angiograms, patients were divided in two groups: below-the-ankle (BTA) and above-the-ankle (ATA) arterial disease groups. The rate of CAD at baseline assessment and the new events of acute myocardial ischaemia (AMI) during 1-year of follow-up were evaluated and compared between the two groups. RESULTS: Two hundreds seventy-two (272) patients were included, 120 (44.1%) showed BTA arterial disease while 152 (55.9%) ATA arterial disease. The mean age was 68.9 ± 9.6 years, 198 (72.8%) were male, 246 (90.4%) had type 2 diabetes, the mean diabetes duration was 20.7 ± 11.6 years, the mean HbA1c was 7.8 ± 4.2% (62 ± 22 mmmol/mol). The whole population reported CAD in 172 cases (63.4%), and the rate in the BTA group was significantly higher than in ATA group, respectively, 90 (75.4%) vs 82 (54.1%), p < 0.0001. During the follow-up, BTA group had 5% of new cases of AMI in comparison to 1.3% in ATA group (p < 0.001). At the multivariate analysis BTA resulted an independent marker of CAD [OR 1.9 CI 9 5% (1.3-4.5) p = 0.0001]. CONCLUSION: The current study shows a significant association between BTA arterial disease and CAD. A close cardiovascular screen should be required in patients with DFUs.

Bioactive Glass in a Multi Drug Resistance Osteomyelitis in Diabetic Foot: Case Report.

Diabetic foot osteomyelitis (DFO) is a clinical problem with high risk of amputation. The treatment of DFO is still an unsolved challenge. Surgical therapy, antibiotic therapy or conservative treatment are still debated for the timing and the consequences. Long antibiotic therapies expose the selection of multidrug-resistant bacteria. Nowadays the use of new bone substitutes aims to support the load of the bone segments and to ensure the eradication of the infectious process after surgical treatment. A case report of digital osteomyelitis due to a multidrug resistant bacteria was treated with a conservative treatment and use of bioglass (Bonalive) that has the ability to inhibit bacterial growth. A long follow-up shows the resolution of infectious process, no ulcer recurrence and persistent recovery of its ability to walk. Our results agree with literature data and suggest that bioglass may be considered a useful option to manage DFO and achieve healing with a very conservative approach.

Effectiveness of Sucrose Octasulfate Dressing in the Treatment of Neuro-Ischaemic Diabetic Foot Heel Ulcers: A Retrospective Single arm Study.

The study aimed to evaluate the effectiveness of the use of sucrose octasulfate impregnated dressing (TLC-NOSF [Technology Lipido-Colloid-Nano-OligoSaccharide Factor]) in the management of persons with neuro-ischaemic heel diabetic foot ulcers (DFUs). Consecutive patients who referred for an active non-infected neuro-ischaemic heel DFU belonging to grade IC (superficial) or IIC (deep to tendons, muscle or capsule) according to Texas University Classification were included. All patients were managed by a pre-set limb salvage protocol in the respect of International guidelines and the TLC-NOSF dressing was used as primary and specific dressing. Patients were evaluated any 2 to 4 weeks until wound healing or different outcomes. Primary outcome was the rate of complete wound healing after 24 weeks of follow-up. The secondary outcomes assessed the healing time, the rate of wound regression, the re-ulceration in the case of complete healing and the safety. Thirty patients were included. The mean age was 67 ± 11 years, 17 (56.7%) were male, all of them were affected by type 2 diabetes with a mean duration of 18 ± 7 years. Twenty patients (66.7%) showed deep ulcers (grade 2 of Texas University Classification); the mean TcPO2 at the inclusion was 42 ± 7 mm Hg. Twenty-two patients (73.3%) healed by Week 24. The mean time of healing was 84 ± 32 days, 2 (6.7%) patients had ulcer relapse after healing, 28 (93.3%) had wound regression >50%, 2 (6.7%) had mild infection, 1 (3.3%) reported major amputation. No serious adverse events related to TLC-NOSF dressing or local reactions were reported. This current study showed the potential benefit of sucrose octasulfate for treating neuro-ischaemic heel DFUs in addition to the standard of care.

The Immune-Centric Revolution in the Diabetic Foot: Monocytes and Lymphocytes Role in Wound Healing and Tissue Regeneration-A Narrative Review.

Monocytes and lymphocytes play a key role in physiologic wound healing and might be involved in the impaired mechanisms observed in diabetes. Skin wound macrophages are represented by tissue resident macrophages and infiltrating peripheral blood recruited monocytes which play a leading role during the inflammatory phase of wound repair. The impaired transition of diabetic wound macrophages from pro-inflammatory M1 phenotypes to anti-inflammatory pro-regenerative M2 phenotypes might represent a key issue for impaired diabetic wound healing. This review will focus on the role of immune system cells in normal skin and diabetic wound repair. Furthermore, it will give an insight into therapy able to immuno-modulate wound healing processes toward to a regenerative anti-inflammatory fashion. Different approaches, such as cell therapy, exosome, and dermal substitute able to promote the M1 to M2 switch and able to positively influence healing processes in chronic wounds will be discussed.

Macrophage Activation and M2 Polarization in Wound Bed of Diabetic Patients Treated by Dermal/Epidermal Substitute Nevelia.

Clinical evidences have shown good results using dermal/epidermal substitutes (DESs) to treat diabetic foot ulcers. Recent studies suggest that, in addition to their scaffold action, DESs may favor wound healing by influencing wound bed inflammatory cells. This study aims to investigate whether DES may influence the inflammatory infiltrate and macrophages polarization toward a reparative phenotype. Fifteen diabetic patients with chronic foot ulcers have been randomly enrolled: 5 treated only by standard of care, served as control group (CG), and 10 treated with DES composed of type 1 bovin collagen (Nevelia, SYMATESE) considered as test group (TG). A biopsy was taken at baseline (T0) and after 30 days (T1). From bioptic paraffin specimen histological, immunohistochemical, and immunofluorescence analysis was performed. Immunohistochemistry reactions evaluated the number of M1 macrophage (CD38+) and M2 macrophage (CD163+). TG patients displayed general macrophage activation and their greater polarization toward M2 subpopulation 30 days after DES implant, compared with CG. From T0 to T1 there was a significant decrease of CD38+ (230 ± 42 and 135 ± 48 mm2, respectively; P < .001) and significant increase of CD163+ (102 ± 21 positive cells/mm2 and 366 ± 42 positive cells/mm2, respectively; P < .001). Confocal microscopy confirmed an increase of M2 cells as expressed by the reduced CD68+/CD163+ ratio. After 6 months of observation 6 patients (60%) of the TG completely healed, while only 1 patient (20%) healed in the CG (P < .01). The tested DES makes possible to treat diabetic foot ulcers inducing tissue reparative processes through macrophage activation and M2 reparative polarization.