Algorithmic surveillance of ICU patients with acute respiratory distress syndrome (ASIC): protocol for a multicentre stepped-wedge cluster randomised quality improvement strategy.

INTRODUCTION: The acute respiratory distress syndrome (ARDS) is a highly relevant entity in critical care with mortality rates of 40%. Despite extensive scientific efforts, outcome-relevant therapeutic measures are still insufficiently practised at the bedside. Thus, there is a clear need to adhere to early diagnosis and sufficient therapy in ARDS, assuring lower mortality and multiple organ failure. METHODS AND ANALYSIS: In this quality improvement strategy (QIS), a decision support system as a mobile application (ASIC app), which uses available clinical real-time data, is implemented to support physicians in timely diagnosis and improvement of adherence to established guidelines in the treatment of ARDS. ASIC is conducted on 31 intensive care units (ICUs) at 8 German university hospitals. It is designed as a multicentre stepped-wedge cluster randomised QIS. ICUs are combined into 12 clusters which are randomised in 12 steps. After preparation (18 months) and a control phase of 8 months for all clusters, the first cluster enters a roll-in phase (3 months) that is followed by the actual QIS phase. The remaining clusters follow in month wise steps. The coprimary key performance indicators (KPIs) consist of the ARDS diagnostic rate and guideline adherence regarding lung-protective ventilation. Secondary KPIs include the prevalence of organ dysfunction within 28 days after diagnosis or ICU discharge, the treatment duration on ICU and the hospital mortality. Furthermore, the user acceptance and usability of new technologies in medicine are examined. To show improvements in healthcare of patients with ARDS, differences in primary and secondary KPIs between control phase and QIS will be tested. ETHICS AND DISSEMINATION: Ethical approval was obtained from the independent Ethics Committee (EC) at the RWTH Aachen Faculty of Medicine (local EC reference number: EK 102/19) and the respective data protection officer in March 2019. The results of the ASIC QIS will be presented at conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: DRKS00014330.

Micropatterning of reagent-free, high energy crosslinked gelatin hydrogels for bioapplications.

Hydrogels are crosslinked polymeric gels of great interest in the field of tissue engineering, particularly as biocompatible cell or drug carriers. Reagent-free electron irradiated gelatin is simple to manufacture, inexpensive and biocompatible. Here, the potential to micropattern gelatin hydrogel surfaces during electron irradiation crosslinking was demonstrated as a promising microfabrication technique to produce thermally stable structures on highly relevant length scales for bioapplications. In the present work, grooves of 3.75 to 170 µm width and several hundred nanometers depth were transferred onto gelatin hydrogels during electron irradiation and characterized by 3D confocal microscopy after exposure to ambient and physiological conditions. The survival and influence of these microstructures on cellular growth was further characterized using NIH 3T3 fibroblasts. Topographical modifications produced surface structures on which the cultured fibroblasts attached and responded by adapting their morphologies. This developed technique allows for simple and effective structuring of gelatin and opens up new possibilities for irradiation crosslinked hydrogels in biomedical applications in which cell attachment and contact guidance are favored. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 320-330, 2018.

Influence of high energy electron irradiation on the network structure of gelatin hydrogels as investigated by small-angle X-ray scattering (SAXS).

The impact of high energy crosslinking on the network structure of gelatin hydrogels was investigated in comparison to physically entangled gels by small-angle X-ray scattering (SAXS). Physically entangled gelatin of increasing concentration exhibited a nearly constant correlation length of several nanometers. These gels had scattering behavior close to that of polymer coils swollen in a good solvent, as evidenced by the Porod exponent of 1.8. The mass fractal dimension decreased towards 1, indicating increased formation of semiflexible gelatin triple helices and rod-like structures as a function of the gelatin concentration. In contrast, electron irradiation lead to a decrease in the correlation length at doses above 20 kGy. Covalent crosslinking induced by electron irradiation lead to increased branching and formation of globular structures, as observed by a steady increase of both the Porod exponent and mass fractal dimension. Furthermore, the network mesh size systematically decreased from approximately 45 nm to under 20 nm with both additional physical and chemical crosslinking. These mesh sizes as obtained by SAXS were used to estimate the network shear modulus using several polymer models and were compared to macroscopic rheology measurements. Finally, SEM images of freeze-dried samples revealed changes in the microstructure of the irradiated hydrogels. Overall, fundamental differences in the network structures stemming from the crosslinking method were observed across a wide range of length scales.

Magnetic response of gelatin ferrogels across the sol-gel transition: the influence of high energy crosslinking on thermal stability.

As emerging responsive materials, ferrogels have demonstrated significant potential for applications in areas of engineering to regenerative medicine. Promising techniques to study the behavior of magnetic nanoparticles (MNPs) in such matrices include magnetic particle spectroscopy (MPS) and magnetorelaxometry (MRX). This work investigated the magnetic response of gelatin-based ferrogels with increasing temperatures, before and after high energy crosslinking. The particle response was characterized by the nonlinear magnetization using MPS and quasistatic magnetization measurements as well as MRX to discriminate between Néel and Brownian relaxation mechanisms. The effective magnetic response of MNPs in gelatin was suppressed, indicating that the magnetization of the ferrogels was strongly influenced by competing dipole-dipole interactions. Significant changes in the magnetic behavior were observed across the gelatin sol-gel transition, as influenced by the matrix viscosity. These relaxation processes were modeled by Fourier transformation of the Langevin function, combined with a Debye term for the nonlinear magnetic response, for single core MNPs embedded in matrices of changing viscosities. Using high energy electron irradiation as a crosslinking method, modified ferrogels exhibited thermal stability on a range of timescales. However, MRX relaxation times revealed a slight softening around the gelatin sol-gel transition felt by the smallest particles, demonstrating a high sensitivity to observe local changes in the viscoelasticity. Overall, MPS and MRX functioned as non-contact methods to observe changes in the nanorheology around the native sol-gel transition and in crosslinked ferrogels, as well as provided an understanding of how MNPs were integrated into and influenced by the surrounding matrix.

Cellular Response to Reagent-Free Electron-Irradiated Gelatin Hydrogels.

As a biomaterial, it is well established that gelatin exhibits low cytotoxicity and can promote cellular growth. However, to circumvent the potential toxicity of chemical crosslinkers, reagent-free crosslinking methods such as electron irradiation are highly desirable. While high energy irradiation has been shown to exhibit precise control over the degree of crosslinking, these hydrogels have not been thoroughly investigated for biocompatibility and degradability. Here, NIH 3T3 murine fibroblasts are seeded onto irradiated gelatin hydrogels to examine the hydrogel's influence on cellular viability and morphology. The average projected area of cells seeded onto the hydrogels increases with irradiation dose, which correlates with an increase in the hydrogel's shear modulus up to 10 kPa. Cells on these hydrogels are highly viable and exhibits normal cell cycles, particularly when compared to those grown on glutaraldehyde crosslinked gelatin hydrogels. However, proliferation is reduced on both types of crosslinked samples. To mimic the response of the hydrogels in physiological conditions, degradability is monitored in simulated body fluid to reveal strongly dose-dependent degradation times. Overall, given the low cytotoxicity, influence on cellular morphology and variability in degradation times of the electron irradiated gelatin hydrogels, there is significant potential for application in areas ranging from regenerative medicine to mechanobiology.

Tailoring the material properties of gelatin hydrogels by high energy electron irradiation.

Natural hydrogels such as gelatin are highly desirable biomaterials for application in drug delivery, biosensors, bioactuators and extracellular matrix components due to strong biocompatibility and biodegradability. Typically, chemical crosslinkers are used to optimize material properties, often introducing toxic byproducts into the material. In this present work, electron irradiation is employed as a reagent-free crosslinking technique to precisely tailor the viscoelasticity, swelling behavior, thermal stability and structure of gelatin. With increasing electron dose, changes in swelling behavior and rheology indicate increasing amounts of random coils and dangling ends as opposed to helical content, a result confirmed through Fourier transform infrared spectroscopy. Gel fraction, rheology and swelling measurements at 37 °C were used to verify thermal stability in biological conditions. Scanning electron microscopy images of dried gelatin samples support these conclusions by revealing a loss of free volume and apparent order in the fracture patterns. The degree of crosslinking and mesh size are quantified by rubber elasticity theory and the Flory-Rehner equation. Overall, precise control of material properties is demonstrated through the interplay of concentration and irradiation dose, while providing an extensive parameter-property database suitable for optimized synthesis.