Abstract
Background
In the last decades, autologous fat grafting has been used to treat adherent dermal scars. The observed regenerative and scar-reducing properties have been mainly ascribed to the ...tissue-derived stromal vascular fraction (tSVF) in adipose tissue. Adipose tissue’s components augment local angiogenesis and mitosis in resident tissue cells. Moreover, it promotes collagen remodeling. We hypothesize that tSVF potentiates fat grafting-based treatment of adherent scars. Therefore, this study aims to investigate the effect of tSVF-enriched fat grafting on scar pliability over a 12-month period.
Methods and design
A clinical multicenter non-randomized early phase trial will be conducted in two dedicated Dutch Burn Centers (Red Cross Hospital, Beverwijk, and Martini Hospital, Groningen). After informed consent, 46 patients (≥18 years) with adherent scars caused by burns, necrotic fasciitis, or degloving injury who have an indication for fat grafting will receive a sub-cicatricic tSVF-enriched fat graft. The primary outcome is the change in scar pliability measured by the Cutometer between pre- and 12 months post-grafting. Secondary outcomes are scar pliability (after 3 months), scar erythema, and melanin measured by the DSM II Colormeter; scar quality assessed by the patient and observer scales of the Patient and Observer Scar Assessment Scale (POSAS) 2.0; and histological analysis of scar biopsies (voluntary) and tSVF quality and composition. This study has been approved by the Dutch Central Committee for Clinical Research (CCMO), NL72094.000.20.
Conclusion
This study will test the clinical efficacy of tSVF-enriched fat grafting to treat dermal scars while the underlying working mechanism will be probed into too.
Trial registration
Dutch Trial Register NL 8461. Registered on 16 March 2020
In recent decades, adipose tissue transplantation has become an essential treatment modality for tissue (volume) restoration and regeneration. The regenerative application of adipose tissue has only ...recently proven its usefulness; for example, the method is useful in reducing dermal scarring and accelerating skin-wound healing. The therapeutic effect is ascribed to the tissue stromal vascular fraction (tSVF) in adipose tissue. This consists of stromal cells, the trophic factors they secrete and the extracellular matrix (ECM), which have immune-modulating, pro-angiogenic and anti-fibrotic properties. This concise review focused on dermal regeneration using the following adipose-tissue components: adipose-tissue-derived stromal cells (ASCs), their secreted trophic factors (ASCs secretome), and the ECM. The opportunities of using a therapeutically functional scaffold, composed of a decellularized ECM hydrogel loaded with trophic factors of ASCs, to enhance wound healing are explored as well. An ECM-based hydrogel loaded with trophic factors combines all regenerative components of adipose tissue, while averting the possible disadvantages of the therapeutic use of adipose tissue, e.g., the necessity of liposuction procedures with a (small) risk of complications, the impossibility of interpatient use, and the limited storage options.
For decades, facial fat grafting has been used in clinical practice for volume restoration. The main challenge of this technique is variable volume retention. The addition of supplements to augment ...fat grafts and increase volume retention has been reported in recent years.
The aim of this systematic review was to investigate which supplements increase volume retention in facial fat grafting as assessed by volumetric outcomes and patient satisfaction.
Embase, Medline, Ovid, Web of Science Core Collection, Cochrane Central Register of Controlled Trials, and Google Scholar were searched up to November 30, 2020. Only studies assessing volume after facial fat grafting with supplementation in human subjects were included. Outcomes of interest were volume or patient satisfaction. The quality of the studies was assessed with the Effective Public Health Practice Project tool.
After duplicates were removed 3724 studies were screened by title and abstract. After reading 95 full-text articles, 27 studies were eligible and included for comparison. Supplementation comprised of platelet-rich plasma, platelet-rich fibrin, adipose tissue-derived stromal cells or bone marrow-derived stromal cells, cellular or tissue stromal vascular fraction, or nanofat. In 13 out of 22 studies the supplemented group showed improved volumetric retention and 5 out of 16 studies showed greater satisfaction. The scientific quality of the studies was rated as weak for 20 of 27 studies, moderate for 6 of 27 studies, and strong for 1 study.
It remains unclear if additives contribute to facial fat graft retention and there is a need to standardize methodology.
The brain is an extraordinarily complex system that facilitates the optimal integration of information from different regions to execute its functions. With the recent advances in technology, ...researchers can now collect enormous amounts of data from the brain using neuroimaging at different scales and from numerous modalities. With that comes the need for sophisticated tools for analysis. The field of network neuroscience has been trying to tackle these challenges, and graph theory has been one of its essential branches through the investigation of brain networks. Recently, topological data analysis has gained more attention as an alternative framework by providing a set of metrics that go beyond pairwise connections and offer improved robustness against noise. In this hands-on tutorial, our goal is to provide the computational tools to explore neuroimaging data using these frameworks and to facilitate their accessibility, data visualisation, and comprehension for newcomers to the field. We will start by giving a concise (and by no means complete) overview of the field to introduce the two frameworks and then explain how to compute both well-established and newer metrics on resting-state functional magnetic resonance imaging. We use an open-source language (Python) and provide an accompanying publicly available Jupyter Notebook that uses the 1000 Functional Connectomes Project dataset. Moreover, we would like to highlight one part of our notebook dedicated to the realistic visualisation of high order interactions in brain networks. This pipeline provides three-dimensional (3-D) plots of pairwise and higher-order interactions projected in a brain atlas, a new feature tailor-made for network neuroscience.
Repetitive transcranial magnetic stimulation (rTMS) is used to investigate normal brain function in healthy participants and as a treatment for brain disorders. Various subject factors can influence ...individual response to rTMS, including brain network properties. A previous study by our group showed that “virtually lesioning” the left dorsolateral prefrontal cortex (dlPFC; important for cognitive flexibility) using 1 Hz rTMS reduced performance on a set‐shifting task. We aimed to determine whether this behavioural response was related to topological features of pre‐TMS resting‐state and task‐based functional networks. 1 Hz (inhibitory) rTMS was applied to the left dlPFC in 16 healthy participants, and to the vertex in 17 participants as a control condition. Participants performed a set‐shifting task during fMRI at baseline and directly after a single rTMS session 1–2 weeks later. Functional network topology measures were calculated from resting‐state and task‐based fMRI scans using graph theoretical analysis. The dlPFC‐stimulated group, but not the vertex group, showed reduced setshifting performance after rTMS, associated with lower task‐based betweenness centrality (BC) of the dlPFC at baseline (p = .030) and a smaller reduction in task‐based BC after rTMS (p = .024). Reduced repeat trial accuracy after rTMS was associated with higher baseline resting state node strength of the dlPFC (p = .017). Our results suggest that behavioural response to 1 Hz rTMS to the dlPFC is dependent on baseline functional network features. Individuals with more globally integrated stimulated regions show greater resilience to rTMS effects, while individuals with more locally well‐connected regions show greater vulnerability.
Proximal tubules in the kidney play a crucial role in reabsorbing and eliminating substrates from the body into the urine, leading to high local concentrations of xenobiotics. This makes the proximal ...tubule a major target for drug toxicity that needs to be evaluated during the drug development process. Here, we describe an advanced
in vitro
model consisting of fully polarized renal proximal tubular epithelial cells cultured in a microfluidic system. Up to 40 leak-tight tubules were cultured on this platform that provides access to the basolateral as well as the apical side of the epithelial cells. Exposure to the nephrotoxicant cisplatin caused a dose-dependent disruption of the epithelial barrier, a decrease in viability, an increase in effluent LDH activity, and changes in expression of tight-junction marker zona-occludence 1, actin, and DNA-damage marker H2A.X, as detected by immunostaining. Activity and inhibition of the efflux pumps P-glycoprotein (P-gp) and multidrug resistance protein (MRP) were demonstrated using fluorescence-based transporter assays. In addition, the transepithelial transport function from the basolateral to the apical side of the proximal tubule was studied. The apparent permeability of the fluorescent P-gp substrate rhodamine 123 was decreased by 35% by co-incubation with cyclosporin A. Furthermore, the activity of the glucose transporter SGLT2 was demonstrated using the fluorescent glucose analog 6-NBDG which was sensitive to inhibition by phlorizin. Our results demonstrate that we developed a functional 3D perfused proximal tubule model with advanced renal epithelial characteristics that can be used for drug screening studies.
Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique to treat psychiatric disorders, such as obsessive-compulsive disorder (OCD). However, the rTMS response ...varies across subjects.
We hypothesize that baseline network properties of the rTMS target may help understand this variation and predict response.
Excitatory rTMS to the dorsolateral prefrontal cortex (dlPFC) was applied in 19 unmedicated OCD patients, while inhibitory dlPFC-rTMS was applied in 17 healthy controls. The vertex was used as an active control target (19 patients, 18 controls). The rTMS response was operationalized as the individual change in state distress rating during an emotion regulation task. At baseline, subjects underwent resting-state functional MRI. The brain network was constructed by calculating wavelet coherence between regional activity of regions in the Brainnetome atlas. Local and integrative static connectivity and the dynamic network role of the target were calculated. Baseline target region network features were non-parametrically correlated to rTMS response.
In the dlPFC-stimulated patients, greater local connectivity (Kendall’s Tau = −0.415, p = 0.013) and less promiscuous role of the target (Kendall’s Tau = 0.389, p = 0.025) at baseline were related to greater distress reduction after excitatory rTMS. There were no significant associations in healthy subjects nor in the active control stimulated patients.
Pre-treatment network topological indices predict rTMS-induced emotional response changes in OCD, such that greater baseline resting-state local connectivity and less temporal integration of the target region imply greater stimulation effects. These results may lead the way towards personalized neuromodulation in OCD.
•Pre-treatment network topology of the target region predicts rTMS-response.•Greater baseline local connectivity implied greater stimulation effects.•Less temporal integration also predicted greater stimulation effects.
Proximal tubule epithelial cells (PTEC) are susceptible to drug-induced kidney injury (DIKI). Cell-based, two-dimensional (2D) in vitro PTEC models are often poor predictors of DIKI, probably due to ...the lack of physiological architecture and flow. Here, we assessed a high throughput, 3D microfluidic platform (Nephroscreen) for the detection of DIKI in pharmaceutical development. This system was established with four model nephrotoxic drugs (cisplatin, tenofovir, tobramycin and cyclosporin A) and tested with eight pharmaceutical compounds. Measured parameters included cell viability, release of lactate dehydrogenase (LDH) and N-acetyl-β-d-glucosaminidase (NAG), barrier integrity, release of specific miRNAs, and gene expression of toxicity markers. Drug-transporter interactions for P-gp and MRP2/4 were also determined. The most predictive read outs for DIKI were a combination of cell viability, LDH and miRNA release. In conclusion, Nephroscreen detected DIKI in a robust manner, is compatible with automated pipetting, proved to be amenable to long-term experiments, and was easily transferred between laboratories. This proof-of-concept-study demonstrated the usability and reproducibility of Nephroscreen for the detection of DIKI and drug-transporter interactions. Nephroscreen it represents a valuable tool towards replacing animal testing and supporting the 3Rs (Reduce, Refine and Replace animal experimentation).
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