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A variety of skin substitutes that restore epidermal and dermal structures are currently available on the market. However, the main focus in research and clinical application lies on dermal and epidermal substitutes whereas the development of a subcutaneous replacement (hypodermis) is often disregarded. In this study we used fibrin sealant as hydrogel scaffold to generate a three-layered skin substitute. For the hypodermal layer adipose-derived stem cells (ASCs) and mature adipocytes were embedded in the fibrin hydrogel and were combined with another fibrin clot with fibroblasts for the construction of the dermal layer. Keratinocytes were added on top of the two-layered construct to form the epidermal layer. The three-layered construct was cultivated for up to 3 weeks. Our results show that ASCs and fibroblasts were viable, proliferated normally, and showed physiological morphology in the skin substitute. ASCs were able to differentiate into mature adipocytes during the course of four weeks and showed morphological resemblance to native adipose tissue. On the surface keratinocytes formed an epithelial-like layer. For the first time we were able to generate a three-layered skin substitute based on a fibrin hydrogel not only serving as a dermal and epidermal substitute but also including the hypodermis. [ABSTRACT FROM AUTHOR]

Fibrin biomatrices have been used for many years for hemostasis and sealing and are a well-established surgical tool. The objective of the present study was to compare two commercially available fibrin biomatrices regarding the effect of their thrombin concentration on keratinocytes and wound healing in vitro and in vivo. Keratinocytes showed significant differences in adhesion, viability, and morphology in the presence of the fibrin matrices in vitro. A high thrombin concentration (800-1,200 IU/mL) caused deteriorated cell compatibility. By using a thrombin inhibitor, those differences could be reversed. In a rat excisional wound healing model, we observed more rapid wound closure and less wound severity in wounds treated with a fibrin matrix containing a lower concentration of thrombin (4 IU/mL). Furthermore, fewer new functional vessels and a lower level of vascular endothelial growth factor were measured in wounds after 7 days treated with the matrix with higher thrombin concentration. These in vivo results may be partially explained by the in vitro biocompatibility data. Additionally, results show that low thrombin biomatrices were degraded faster than the high thrombin material. Hence, we conclude that the composition of fibrin biomatrices influences keratinocytes and therefore has an impact on wound healing. [ABSTRACT FROM AUTHOR]

An irreversible loss of subcutaneous adipose tissue in patients after tumor removal or deep dermal burns makes soft tissue engineering one of the most important challenges in biomedical research. The ideal scaffold for adipose tissue engineering has yet not been identified though biodegradable polymers gained an increasing interest during the last years. In the present study we synthesized two novel biodegradable polymers, poly(ε-caprolactone-co-urethane-co-urea) (PEUU) and poly[(L-lactide-co-ε-caprolactone)-co-(L-lysine ethyl ester diisocyanate)-block-oligo(ethylene glycol)-urethane] (PEU), containing different types of hydrolytically cleavable bondings. Solutions of the polymers at appropriate concentrations were used to fabricate fleeces by electrospinning. Ultrastructure, tensile properties, and degradation of the produced fleeces were evaluated. Adipose-derived stem cells (ASCs) were seeded on fleeces and morphology, viability, proliferation and differentiation were assessed. The biomaterials show fine micro- and nanostructures composed of fibers with diameters of about 0.5 to 1.3 µm. PEUU fleeces were more elastic, which might be favourable in soft tissue engineering, and degraded significantly slower compared to PEU. ASCs were able to adhere, proliferate and differentiate on both scaffolds. Morphology of the cells was slightly better on PEUU than on PEU showing a more physiological appearance. ASCs differentiated into the adipogenic lineage. Gene analysis of differentiated ASCs showed typical expression of adipogenetic markers such as PPARgamma and FABP4. Based on these results, PEUU and PEU meshes show a promising potential as scaffold materials in adipose tissue engineering. [ABSTRACT FROM AUTHOR]

Activating signals generated by members of the tumour necrosis factor receptor superfamily upon interaction with their cognate ligands play important roles in T-cell responses. Members of the tumour necrosis factor family namely 4-1BBL, OX40L, CD70, GITRL, LIGHT and CD30L have been described to function as costimulatory molecules by binding such receptors on T cells. Using our recently described system of T-cell stimulator cells we have performed the first study where all these molecules have been assessed and compared regarding their capacity to costimulate proliferation and cytokine production of human T cells. 4-1BBL, which we found to be the most potent molecule in this group, was able to mediate sustained activation and proliferation of human T cells. OX40L and CD70 were also strong inducers of T-cell proliferation, whereas the costimulatory capacity of human GITRL was significantly lower. Importantly CD30L and LIGHT consistently failed to act costimulatory on human T cells, and we therefore suggest that these molecules might be functionally distinct from the costimulatory members of this family. [ABSTRACT FROM AUTHOR]

Objective: Assessing diabetes therapy performance in Real World Data (RWD) is difficult as the data quantity of SMBG measurements shows strong variability. In a previous study, we proposed a new metric, Gkn/N ⇔ n out of N days :|SM BG| ≥ k, which ensures data quality so patients with skewed SMBG values or highly motivated users are not overrepresented. The classification separates users by logging habits, e.g., G1 ≅ 1 log a day. The aim of this study is to validate our metric with CGM data and determine if more logs a day increase metrics accuracy. Method: We analyzed 299 users of a data set with CGM and SMBG logs. The inclusion criteria was 70% CGM logs for 1 month with associated SMBG logs. Each user was classified into a G-group. The distribution was biased to the G4-G5 groups. Therefore, users were randomly selected and had logs randomly removed to create lower G-group users, providing an equal distribution. The percent errors of the users' mean BG, standard deviation (SD), and tests-in-range (TIR) between the SMBG and CGM logs were analyzed. With random sampling the analysis was repeated and mean results used. Results: Results had G1 users with the largest error in all metrics tested (Mean Error:BG =8%, SD =15.4%, TIR =17.5%). The error did not substantially decrease as the logs increased (correlating to a higher G-groups). Because differences were not apparent in the mean BG, SD, or TIR;t-tests were performed for each group to determine statistical differences from the other groups based on BG or SD error. The only G-group to be statistically different (p<0.05) was G1 from all higher groups. Conclusion: Results allow separating users into two groups. The error between G2 and all higher logging groups was not significant, implying metric accuracy does not increase with more logs. The validation allows the use of metrics based on mean BG or SD to a larger portion of users while limiting the bias on users' logging habits. Further analyses are necessary to compare values from each G-class with clinically reported metrics. Disclosure: R.P. Biven: None. J. Wrede: None. R.P. Bankosegger: Employee; Self; mySugr. J. Kober: Employee; Self; mySugr. B. Petersen: Employee; Self; Roche Diabetes Care. C. Ringemann: Employee; Self; Roche Diabetes Care. T. Huschto: Employee; Self; Roche Diabetes Care. [ABSTRACT FROM AUTHOR]

Objective: The mySugr App is the most widespread mobile health application in the diabetes industry, reaching 1.5M patients in 62 countries. mySugr's Integrated Diabetes Management solution, the mySugr bundle, introduces unlimited test strip delivery and Certified Diabetes Educator-led coaching. In a previous retrospective study we looked at real world changes in blood glucose (BG) in a U.S. population of mySugr Bundle users. In this follow-up study we extended the observation period of intervention to further analyse the course of effect seen before. Method: We analyzed changes in BG control (mean±SD, tests in range (TIR), estimated A1c (eA1c)) and frequency of testing. Participants monitored BG ≥3 times/day during the observation period. Data from the first 2 weeks of use (t0), 8 weeks before (t1), 8 weeks after (t2) and 8 to 16 weeks after (t3) initiation of Bundle usage were aggregated and statistically compared using two-sided t-tests. Results: Study participants were 61 users; 59% with type 1 diabetes, 32.8% with type 2 diabetes, 6.6% with LADA and 1.6% with unreported diabetes type. Baseline BG was 152.0±56.0 mg/dl, eA1c 6.9% and TIR 65%. Significant (p<0.05) improvements were observed in mean BG (-11,8 mg/dl), standard deviation (-5,48 mg/dl), TIR (+6.8%), readings above target (-7.2%) and eA1c (-0.41%) between t0 and t3. A significant improvement was also observed in monitoring frequency (+21.4%) between t1 and t3. Conclusion: Our previous study suggested use of the mySugr Bundle triggered positive changes of glucose control at 8 weeks post intervention. We were now able to show a sustainable improvement in BG control over an extended time period of 16 weeks, indicating the potential benefits of mobile interventions that combine complementary treatment strategies for therapy adherence over longer time periods. Given that improvements were observed in well-controlled patients, findings support further studies in a wider study population range. Disclosure: H. Mayer: Employee; Self; mySugr. R.P. Bankosegger: Employee; Self; mySugr. J. Kober: Employee; Self; mySugr. [ABSTRACT FROM AUTHOR]

Background: In a randomized controlled trial, the efficacy of a digital diabetes diary regarding a reduction of diabetes distress was evaluated., Methods: A randomized controlled trial with a 12-week follow-up was conducted in 41 study sites across Germany. Key eligibility criteria were a diagnosis of type 1, type 2, or gestational diabetes and regular self-monitoring of blood glucose. Participants were randomly assigned (2:1 ratio) to either use the digital diabetes logbook (mySugr PRO), or to the control group without app use. The primary outcome was the reduction in diabetes distress at the 12-week follow-up. All analyses were based on the intention-to-treat population with all randomized participants. The trial was registered at the German Register for Clinical Studies (DRKS00022923)., Results: Between February 11, 2021, and June 24, 2022, 424 participants (50% female, 50% male) were included, with 282 being randomized to the intervention group (66.5%) and 142 to the control group (33.5%). A total of 397 participants completed the trial (drop-out rate: 6.4%). The median reduction in diabetes distress was 2.41 (interquartile range [IQR]: -2.50 to 8.11) in the intervention group and 1.25 (IQR: -5.00 to 7.50) in the control group. The model-based adjusted between-group difference was significant (-2.20, IQR: -4.02 to -0.38, P = .0182) favoring the intervention group. There were 27 adverse events, 17 (6.0%) in the intervention group, and 10 (7.0%) in the control group., Conclusions: The efficacy of the digital diabetes logbook was demonstrated regarding improvements in mental health in people with type 1, type 2, and gestational diabetes., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: DE reports Advisory Board member fees from mySugr, Dexcom Germany, and Roche Diabetes Care as well as honoraria for lectures from Berlin-Chemie AG, Sanofi-Aventis, Dexcom Germany, and Roche Diabetes Care. NH reports Advisory Board member fees from Abbott Diabetes Care and Insulet as well as honoraria for lectures from Berlin-Chemie AG, Becton Dickenson, Sanofi Germany, Roche Diabetes Care, and Dexcom Germany. TR reports honoraria for lectures from Berlin-Chemie AG. JK is an employee of mySugr. VS is an employee of Roche Diabetes Care Deutschland. TH reports consulting fees from Eli Lilly, NovoNordisk, Sanofi, Boehringer Ingelheim, and Abbott Diabetes Care as well as honoraria for lectures from Abbott Diabetes Care, Sanofi, and Eli Lilly. RZ reports consulting fees from Roche Diabetes Care and mySugr as well as honoraria for lectures from Roche Diabetes Care, Dexcom, VitalAire, NovoNordisk, and Abbott Diabetes Care. He participated in data safety monitoring boards or advisory boards of Roche Diabetes Care, mySugr, Dexcom, NovoNordisk, and Eli Lilly. LH reports consulting fees from Roche Diabetes Care, Lifecare, Medtronic, Spiden, Embecta, Dexcom, Onetwenty, Perfood, Boydsense, Pharmasense, Unomedical and Sinocare. CR is an employee of Roche Diabetes Care. EB is an employee of mySugr. BK reports Advisory Board member fees from Abbott Diabetes Care, Embecta, Roche Diabetes Care, Novo Nordisk, Berlin-Chemie AG and Dexcom Germany as well as honoraria for lectures from Sanofi Germany, Novo Nordisk, Abbott Diabetes Care, Roche Diabetes Care, Berlin-Chemie AG, Embecta, Dexcom, and Feen. In addition, he reports support for travel and fees for scientific meetings from Sanofi, Roche Diabetes Care and Berlin-Chemie AG as well as unpaid obligations as workshop leader and member of working groups of the German Diabetes Association. SS is an employee of Roche Diabetes Care. The remaining authors have nothing to disclose.

A variety of skin substitutes that restore epidermal and dermal structures are currently available on the market. While the main focus in research and clinical application lies in dermal and epidermal substitutes, the development of a subcutaneous replacement, the hypodermis, is often neglected. This chapter describes the use of fibrin sealant as a hydrogel scaffold to generate a three-dimensional skin substitute. For the hypodermal layer adipose-derived stem cells (ASCs) and mature adipocytes are seeded within a fibrin hydrogel. On top, another fibrin clot with incorporated fibroblasts is placed for the construction of the dermal layer. Keratinocytes are added on top of the two-layered construct to form the epidermal layer. The three-layered construct is cultivated for up to 3 weeks with keratinocytes being exposed to air according to the air-liquid interface cultivation model.