Exosome-cargoed microRNAs: Potential therapeutic molecules for diabetic wound healing

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How good is the evidence that cellular senescence causes skin ageing?

Skin is the largest organ of the body with important protective functions, which become compromised with time due to both intrinsic and extrinsic ageing processes. Cellular senescence is the primary ageing process at cell level, associated with loss of proliferative capacity, mitochondrial dysfunction and significantly altered patterns of expression and secretion of bioactive molecules. Intervention experiments have proven cell senescence as a relevant cause of ageing in many organs. In case of skin, accumulation of senescence in all major compartments with ageing is well documented and might be responsible for most, if not all, the molecular changes observed during ageing. Incorporation of senescent cells into in-vitro skin models (specifically 3D full thickness models) recapitulates changes typically associated with skin ageing. However, crucial evidence is still missing. A beneficial effect of senescent cell ablation on skin ageing has so far only been shown following rather unspecific interventions or in transgenic mouse models. We conclude that evidence for cellular senescence as a relevant cause of intrinsic skin ageing is highly suggestive but not yet completely conclusive.     

Indirect Magnetic Resonance Arthrography May Help Avoid Second Look Arthroscopy for Assessment of Healing After Bucket Handle Medial Meniscus Repairs: A Prospective Clinico-Radiological Observational Study

ObjectivesThe objectives were: (1) to analyze the MRI healing rates of bucket-handle meniscus repair; (2) to compare the accuracy of assessment of meniscus healing for conventional MRI and Indirect Magnetic Resonance Arthrography (IMRA); and (3) to identify patients who may require second-look arthroscopy after meniscus repair.MethodsThis is a prospective observational case series of thirty-seven patients with repaired bucket-handle medial meniscus tear with a minimum one year follow-up. Meniscus healing rates were assessed on direct MRI and IMRA using Henning’s criteria. At the same time, patients’ symptoms were evaluated according to Barrett’s criteria and functional outcomes were recorded using International Knee Documentation Committee (IKDC) score, Knee Osteoarthritis and Outcomes Score (KOOS) and Tegner–Lysholm scores. A further clinical review was performed 18 months after the imaging to assess the evolution of symptoms.ResultsAt a mean of 22.3 ± 7.8 months after the meniscus repair, 56.7% patients showed complete healing and 40.5% patients demonstrated incomplete repair healing on IMRA. 52% patients with complete healing and 40% patients with incomplete healing demonstrated meniscus symptoms. At the second clinical review, 19% patients with complete healing and 20% patients with incomplete healing had meniscus symptoms. There was no co-relation between symptoms, PROMs and healing on MRI.ConclusionIndirect MR arthrography offers distinct advantages over direct MRI for assessment of meniscus healing, especially in symptomatic patients. Patient-reported outcome measures and symptomatology are not co-related with the healing status of the meniscus and they resolve in the majority on longer follow-up. A more conservative approach guided by IMRA to assess meniscus healing will avoid early re-operations.     

Prognostic tools for hypertrophic scar formation based on fundamental differences in systemic immunity

Unpredictable hypertrophic scarring (HS) occurs after approximately 35% of all surgical procedures and causes significant physical and psychological complaints. Parallel to the need to understanding the mechanisms underlying HS formation, a prognostic tool is needed. The objective was to determine whether (systemic) immunological differences exist between patients who develop HS and those who develop normotrophic scars (NS) and to assess whether those differences can be used to identify patients prone to developing HS. A prospective cohort study with NS and HS groups in which (a) cytokine release by peripheral blood mononuclear cells (PBMC) and (b) the irritation threshold (IT) after an irritant (sodium lauryl sulphate) patch test was evaluated. Univariate regression analysis of PBMC cytokine secretion showed that low MCP‐1, IL‐8, IL‐18 and IL‐23 levels have a strong correlation with HS (P < .010‐0.004; AUC = 0.790‐0.883). Notably, combinations of two or three cytokines (TNF‐a, MCP‐1 and IL‐23; AUC: 0.942, Nagelkerke R²: 0.727) showed an improved AUC indicating a better correlation with HS than single cytokine analysis. These combination models produce good prognostic results over a broad probability range (sensitivity: 93.8%, specificity 86.7%, accuracy 90,25% between probability 0.3 and 0.7). Furthermore, the HS group had a lower IT than the NS group and an accuracy of 68%. In conclusion, very fundamental immunological differences exist between individuals who develop HS and those who do not, whereas the cytokine assay forms the basis of a predictive prognostic test for HS formation, the less invasive, easily performed irritant skin patch test is more accessible for daily practice.     

The impact of sensory neuropathy and inflammation on epithelial wound healing in diabetic corneas

Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes, with several underlying pathophysiological mechanisms, some of which are still uncertain. The cornea is an avascular tissue and sensitive to hyperglycemia, resulting in several diabetic corneal complications including delayed epithelial wound healing, recurrent erosions, neuropathy, loss of sensitivity, and tear film changes. The manifestation of DPN in the cornea is referred to as diabetic neurotrophic keratopathy (DNK). Recent studies have revealed that disturbed epithelial-neural-immune cell interactions are a major cause of DNK. The epithelium is supplied by a dense network of sensory nerve endings and dendritic cell processes, and it secretes growth/neurotrophic factors and cytokines to nourish these neighboring cells. In turn, sensory nerve endings release neuropeptides to suppress inflammation and promote epithelial wound healing, while resident immune cells provide neurotrophic and growth factors to support neuronal and epithelial cells, respectively. Diabetes greatly perturbs these interdependencies, resulting in suppressed epithelial proliferation, sensory neuropathy, and a decreased density of dendritic cells. Clinically, this results in a markedly delayed wound healing and impaired sensory nerve regeneration in response to insult and injury. Current treatments for DPN and DNK largely focus on managing the severe complications of the disease. Cell-based therapies hold promise for providing more effective treatment for diabetic keratopathy and corneal ulcers.