scholarly journals Volumetric quantification of wound healing by machine learning and optical coherence tomography in adults with type 2 diabetes: the GC-SHEALD RCT

2021 ◽  
Author(s):  
Yinhai Wang ◽  
Ramzi Ajjan ◽  
Adrian Freeman ◽  
Paul M Stewart ◽  
Francesco Del Galdo ◽  
...  
Keyword(s):  
Machine Learning ◽  
Type 2 Diabetes ◽  
Wound Healing ◽  
Optical Coherence Tomography ◽  
Granulation Tissue ◽  
Wound Repair ◽  
Optical Coherence ◽  
Impaired Wound Healing ◽  
Volumetric Quantification

Type 2 diabetes mellitus is associated with impaired wound healing, which contributes substantially to patient morbidity and mortality. Glucocorticoid (stress hormone) excess is also known to delay wound repair. Optical coherence tomography (OCT) is an emerging tool for monitoring healing by 'virtual biopsy', but largely requires manual analysis, which is labour-intensive and restricts data volume processing. This limits the capability of OCT in clinical research. Using OCT data from the GC-SHEALD trial, we developed a novel machine learning algorithm for automated volumetric quantification of discrete morphological elements of wound healing (by 3mm punch biopsy) in patients with type 2 diabetes. This was able to differentiate between early / late granulation tissue, neo-epidermis and clot structural features and quantify their volumetric transition between day 2 and day 7 wounds. Using OCT, we were able to visualize differences in wound re-epithelialisation and re-modelling otherwise indistinguishable by gross wound morphology between these time points. Automated quantification of maximal early granulation tissue showed a strong correlation with corresponding (manual) GC-SHEALD data. Further, % re-epithelialisation was improved in patients treated with oral AZD4017, an inhibitor of systemic glucocorticoid-activating 11β-hydroxysteroid dehydrogenase type 1 enzyme action, with a similar trend in neo-epidermis volume. Through the combination of machine learning and OCT, we have developed a highly sensitive and reproducible method of automated volumetric quantification of wound healing. This novel approach could be further developed as a future clinical tool for the assessment of wound healing e.g. diabetic foot ulcers and pressure ulcers.

Abstract 199: Type 2 Diabetes Impairs Wound Healing By DNMT1-dependent Reduction of Hematopoietic Stem Cell Differentiation towards Monocytes/Macrophages and Skewing of the M1/M2 Polarization

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Jinglian Yan ◽  
Guodong Tie ◽  
Lyne Khair ◽  
Elena Filippova ◽  
Louis Messina
Keyword(s):  
Type 2 Diabetes ◽  
Wound Healing ◽  
Epigenetic Modification ◽  
Stem Cell Differentiation ◽  
M1 Macrophages ◽  
Hematopoietic Stem ◽  
Impaired Wound Healing ◽  
Inflammatory Phase ◽  
M2 Polarization

Rationale: People with Type 2 Diabetes Mellitus (T2DM) have a 25x higher risk of limb loss than non-diabetics due in large part to impaired wound healing. The mechanisms that cause impaired wound healing remain incompletely characterized. Objective: We hypothesize that T2DM impairs wound healing by epigenetic modifications in hematopoietic stem cells (HSC) that reduce their differentiation towards monocytes/macrophages and disrupts the balance in M1/M2 polarization during the three phases of wound healing. Methods and Results: Wounds were created on the back of mice. Wound healing was significantly slower in diabetic db/db than in WT mice. During the early inflammatory phase, db/db wounds exhibited a significant decrease in total macrophages and M1 macrophages. Then, total macrophages and M2 macrophages were decreased, while M1 macrophages increased in tissue formation phase. In the late tissue remodeling phase, total macrophages and M1 macrophages were persistently increased. The impaired wound healing phenotype of db/db mice was recapitulated in WT recipients which were resconstituted with db/db HSCs, demonstrating that the impaired differentiation of HSCs towards macrophages as well as their M1/M2 polarization was due to a cell autonomous mechanism. Epigenetic studies indicated that DNMT1-dependent hypermethylation of Notch1, Pu.1 and KLF4 in T2D HSCs was responsible for the impaired differentiation towards monocytes/macrophages as well as the skewed M1/M2 polarization. Knockdown of DNMT1 in HSCs from db/db mice transplanted into lethally irradiated WT mice led to improved wound healing by an increase in macrophage infiltration as well as a normalization of the M1/M2 polarization. Conclusion: This study indicates that the dynamic changes of macrophage concentration and M1/M2 polarization in wound healing are regulated at the level of HSCs. Moreover, T2DM impairs wound healing by inducing DNMT1-dependent reduction of HSCs’ differentiation towards macrophages and their M1/M2 polarization. This novel finding indicates that inflammation is regulated at the level of HSCs, which creates new opportunities to develop epigenetic modification related therapies for T2DM and potentially other conditions that result from dysinflammation.

Abstract 13373: Exercise Improves Angiogenic Function of Circulating Exosomes in Type 2 Diabetes: Role of Extracellular SOD

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Kareem Abdelsaid ◽  
Sudhahar Varadarajan ◽  
Archita Das ◽  
Yutao Liu ◽  
Xuexiu Fang ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Wound Healing ◽  
Endothelial Dysfunction ◽  
Wound Repair ◽  
Cell Communication ◽  
Tube Formation ◽  
Skin Wound ◽  
Skin Wound Healing

Background: Exosomes, key mediators of cell-cell communication, derived from type 2 diabetes mellitus (T2DM) have detrimental effects. Exercise not only improves endothelial dysfunction and angiogenesis in T2DM but also induces secretion of exosomes into circulation. Extracellular superoxide dismutase (ecSOD) is a major secretory Cu containing antioxidant enzyme that catalyzes dismutation of O 2 •- to H 2 O 2 and its full activity requires Cu transporter ATP7A. We reported that ecSOD-derived H 2 O 2 in endothelial cells (ECs) enhances angiogenesis while impaired ATP7A-ecSOD axis in diabetes induces endothelial dysfunction. Here we examined whether exercise-derived exosomes (Exe-Exo) may have pro-angiogenic effects via regulating ATP7A-ecSOD axis in T2DM. Results: Two weeks of voluntary wheel exercise of control C57Bl6 mice increased plasma exosome levels (6.2-fold) characterized by Nanosight, TEM and exosome markers (CD63, CD81, Tsg101). Treatment of HUVECs with equal number of exosomes revealed that angiogenic responses such as EC migration (1.8-fold) and tube formation (1.7-fold) were significantly enhanced by Exe-Exo compared to sedentary-derived exosomes (Sed-Exo). This was associated with increased ATP7A (2.9-fold) and ecSOD (1.4-fold) expression in Exe-Exo. Sed-Exo from high fat-induced T2DM mice significantly decreased EC migration (40%) and tube formation (10%) as well as ATP7A expression (28%) compared to Sed-Exo from control mice, which were restored by T2DM Exe-Exo, but not by T2DM/ecSOD KO Exe-Exo. Furthermore, exosomes overexpressing ecSOD (ecSOD-Exo) which mimic exercise increased angiogenesis and H2O2 levels in ECs, which were inhibited by overexpression of catalase. In vivo, skin wound healing model showed that direct application of T2DM Sed-Exo delayed while T2DM Exe-Exo enhanced wound healing of control mice. Furthermore, defective wound healing in T2DM mice or ecSOD KO mice were rescued by ecSOD-Exo application. Conclusion: Exercise training improves pro-angiogenic function of circulating exosomes in T2DM via increasing ATP7A-ecSOD axis, which may provide an effective therapy for promoting angiogenesis and wound repair in metabolic and cardiovascular diseases.

scholarly journals Prognostic irrelevance of plaque vulnerability following plaque sealing in high-risk patients with type 2 diabetes: an optical coherence tomography study

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Rosalia Dettori ◽  
Andrea Milzi ◽  
Kathrin Burgmaier ◽  
Mohammad Almalla ◽  
Martin Hellmich ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Optical Coherence Tomography ◽  
High Risk ◽  
Clinical Parameters ◽  
Optical Coherence ◽  
Plaque Vulnerability ◽  
High Risk Patients ◽  
Risk Patients

Abstract Background Type 2 diabetes mellitus (T2DM) is associated with an increased cardiovascular risk related at least in part to a more vulnerable plaque phenotype. However, patients with T2DM exhibit also an increased risk following percutaneous coronary intervention (PCI). It is unknown if plaque vulnerability of a treated lesion influences cardiovascular outcomes in patients with T2DM. In this study, we aimed to assess the association of plaque morphology as determined by optical coherence tomography (OCT) with cardiovascular outcome following PCI in high-risk patients with T2DM. Methods 81 patients with T2DM and OCT-guided PCI were recruited. Pre-interventional OCT and systematic follow-up of median 66.0 (IQR = 8.0) months were performed. Results During follow-up, 24 patients (29.6%) died. The clinical parameters age (HR 1.16 per year, 95% CI 1.07–1.26, p < 0.001), diabetic polyneuropathy (HR 3.58, 95% CI 1.44–8.93, p = 0.006) and insulin therapy (HR 3.25, 95% CI 1.21–8.70, p = 0.019) predicted mortality in T2DM patients independently. Among OCT parameters only calcium-volume-index (HR 1.71 per 1000°*mm, 95% CI 1.21–2.41, p = 0.002) and lesion length (HR 1.93 per 10 mm, 95% CI 1.02–3.67, p = 0.044) as parameters describing atherosclerosis extent were significant independent predictors of mortality. However, classical features of plaque vulnerability, such as thickness of the fibrous cap, the extent of the necrotic lipid core and the presence of macrophages had no significant predictive value (all p = ns). Conclusion Clinical parameters including those describing diabetes severity as well as OCT-parameters characterizing atherosclerotic extent but not classical features of plaque vulnerability predict mortality in T2DM patients following PCI. These data suggest that PCI may provide effective plaque sealing resulting in limited importance of local target lesion vulnerability for future cardiovascular events in high-risk patients with T2DM.

Enhanced Depth Imaging Optical Coherence Tomography in Type 2 Diabetes

2012 ◽  
Vol 53 (10) ◽  
pp. 6017 ◽  
Author(s):  
Giuseppe Querques ◽  
Rosangela Lattanzio ◽  
Lea Querques ◽  
Claudia Del Turco ◽  
Raimondo Forte ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Optical Coherence Tomography ◽  
Enhanced Depth Imaging ◽  
Optical Coherence ◽  
Depth Imaging ◽  
Imaging Optical Coherence Tomography

scholarly journals A randomised controlled pilot trial of oral 11β-HSD1 inhibitor AZD4017 for wound healing in adults with type 2 diabetes mellitus

2021 ◽  
Author(s):  
Ramzi Ajjan ◽  
Elizabeth MA Hensor ◽  
Kave Shams ◽  
Francesco Del Galdo ◽  
Afroze Abbas ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Wound Healing ◽  
Wound Repair ◽  
Chronic Wounds ◽  
Pilot Trial ◽  
Punch Biopsy ◽  
Preclinical Research ◽  
Double Blind ◽  
Randomised Controlled

Chronic wounds (e.g. diabetic foot ulcers) have a major impact on quality of life, yet treatments remain limited. Glucocorticoids impair wound healing; preclinical research suggests that blocking glucocorticoid activation by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) improves wound repair. This investigator-initiated double-blind, randomised, placebo-controlled parallel-group phase 2b pilot trial investigated efficacy, safety and feasibility of 11β-HSD1 inhibition for 35 days by oral AZD4017 (AZD) treatment in adults with type 2 diabetes (n=14) compared to placebo (PCB, n=14) in a single-centre secondary care setting. Computer-generated 1:1 randomisation was pharmacy-administered. From 300 screening invitations, 36 attended, 28 were randomised. There was no proof-of-concept that AZD inhibited 24 hour skin 11β-HSD1 activity at day 28 (primary outcome: adjusted difference AZD-PCB 90% CI (diffCI)=-3.4,5.5) but systemic 11β-HSD1 activity (median urinary [THF+alloTHF]/THE ratio) was 87% lower with AZD at day 35 (PCB 1.00, AZD 0.13, diffCI=-1.04,-0.69). Mean wound gap diameter (mm) following baseline 2mm punch biopsy was 34% smaller at day 2 (PCB 1.51, AZD 0.98, diffCI=-0.95,-0.10) and 48% smaller after repeat wounding at day 30 (PCB 1.35, AZD 0.70, diffCI=-1.15,-0.16); results also suggested greater epidermal integrity but modestly impaired barrier function with AZD. AZD was well-tolerated with minimal side effects and comparable adverse events between treatments. Staff availability restricted recruitment (2.9/month); retention (27/28) and data completeness (95.3%) were excellent. These preliminary findings suggest that AZD may improve wound healing in patients with type 2 diabetes and warrant a fully-powered trial in patients with active ulcers. [Trial Registry: www.isrctn.com/ISRCTN74621291. Funding: MRC Confidence in Concept and NIHR Senior Investigator Award.]

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