Mechanical strength enhancement by grain size reduction in a soft colloidal polycrystal.

It has long been known that the mechanical strength of finely grained solid state polycrystals could be enhanced when the grain size is reduced. Indeed, the equation linking the yield stress and the inverse square root of grain size was introduced in the 1950s by Hall and Petch. Since then this relationship has been widely used to engineer structural metals and alloys. To date, no similar behavior has been reported in materials other than atomic systems where the grain size usually lies in the nanometric range. The purpose of the present work is to study the influence of grain size on the mechanical strength enhancement of a soft colloidal 'alloy' made of micellar polycrystalline grains and silica nanoparticles. The nanoparticles act as nucleation sites and their concentration promotes the variation of the polycrystalline grain size. This system bears resemblance to solid state polycrystals; however the achieved grain length scale is situated in the micrometric domain. We show that the grain size evolves non-monotonically, first decreasing then increasing, when the nanoparticle concentration increases. Our main result is that the yield stress rigorously obeys the Hall-Petch law and follows a linear variation as a function of the inverse square root of the grain diameter. We believe that our experimental approach offers new possibilities to study the poorly understood mechanical aspects of polycrystalline and nanocrystalline structures, such as their plasticity, using non-destructive techniques.

Hepatic fat fraction and visceral adipose tissue fatty acid composition in mice: Quantification with 7.0T MRI.

PURPOSE: To develop an MRI method for quantifying hepatic fat content and visceral adipose tissue fatty acid composition in mice on a 7.0T preclinical system. METHODS: MR acquisitions were performed with a multiple echo spoiled gradient echo with bipolar readout gradients. After phase correction, the number of double bounds (ndb) and the number of methylene interrupted double bounds (nmidb) were quantified with a model including eight fat components, and parametric maps of saturated, monounsaturated, and polyunsaturated fatty acids were derived. The model included a complex error map to correct for the phase errors and the amplitude modulation caused by the bipolar acquisition. Validations were performed in fat-water emulsions and vegetable oils. In vivo, the feasibility was evaluated in mice receiving a high-fat diet containing primarily saturated fatty acids and a low-fat diet containing primarily unsaturated fatty acids. RESULTS: Linear regressions showed strong agreements between ndb and nmidb quantified with MRI and the theoretical values calculated using oil compositions, as well as between the proton density and the fat fractions in the emulsions. At MRI, the mouse liver fat fraction was smaller in mice fed the low-fat diet compared with mice fed the high-fat diet. In visceral adipose tissue, saturated fatty acids were significantly higher, whereas monounsaturated and polyunsaturated fatty acids were significantly lower in mice fed the low-fat diet compared with mice fed the high-fat diet. CONCLUSION: It is feasible to simultaneously quantify hepatic fat content and visceral adipose tissue fatty acid composition with 7.0T MRI in mice. Magn Reson Med 76:510-518, 2016. © 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Enhancing digestive fistula healing by the off-label use of a thermoresponsive vessel occluder polymer associated with esophageal stent placement: A case report.

This case report relates to the first-in-man use of a vessel occluder gel medical device as a fistula occluder in a repurposing strategy. A patient with chronic colocutaneous fistula received an off-label treatment with a thermoresponsive Poloxamer 407 gel (20%) via percutaneous administration and injected under endoscopic control. Treatment consisted in the association of esophageal stent placement and gel injection. The product was administered just after the stent placement at<20°C in its liquid form, gelling at body temperature to form a fistula plug. However, the stent was removed at day 26 because of major pain and the fistula was still present. Treatment was continued a total of 14 administrations of thermoresponsive Poloxamer 407 gel during 7 weeks via the external fistula orifice. The treatment reduced fistula orifice diameter from 4.0±0.5 to 1mm and fistula daily output decreased from 425±65 to 23±4mL, when comparing the months before and after treatment. Gel administration was not associated with any toxic effects. The therapeutic outcome remained stable 1 year after treatment. The external fistula diameter and the fistula output were similar to what was observed after the last Poloxamer 407 gel administration.

Extracellular vesicles from adipose stromal cells combined with a thermoresponsive hydrogel prevent esophageal stricture after extensive endoscopic submucosal dissection in a porcine model.

In this study, we investigated the combination of extracellular (nano) vesicles (EVs) from pig adipose tissue-derived stromal cells (ADSCs) and a thermoresponsive gel, Pluronic® F-127 (PF-127), to prevent stricture formation after endoscopic resection in a porcine model. ADSC EVs were produced at a liter scale by a high-yielding turbulence approach from ADSCs 3D cultured in bioreactors and characterized in terms of size, morphology and membrane markers. The thermoresponsive property of the PF-127 gel was assessed by rheology. The pro-regenerative potency of ADSC EVs was investigated ex vivo in esophageal biopsies under starvation. In vivo tests were performed in a porcine model after extended esophageal endoscopic mucosal dissection (ESD). Pigs were randomized into 3 groups: control (n = 6), gel (n = 6) or a combination of 1.45 × 1012 EVs + gel (n = 6). Application of gel ± EVs was performed just after ESD with a follow-up finalized on day 21 post-ESD. There was a trend towards less feeding disorder in the EV + gel group in comparison with the gel and the control groups (16.67% vs. 66.7% vs. 83.33%, respectively) but without reaching a statistically significant difference. A significant decrease in the esophageal stricture rate was confirmed by endoscopic, radiological and histological examination for the EV + gel group. A decrease in the mean fibrosis area and larger regenerated muscularis mucosae were observed for the EV + gel group. In summary, the application of EVs + gel after extended esophageal endoscopic resection succeeded in preventing stricture formation with an anti-fibrotic effect. This nano-therapy may be of interest to tackle an unmet medical need considering that esophageal stricture is the most challenging delayed complication after extended superficial cancer resection by endoscopy.

Local administration of stem cell-derived extracellular vesicles in a thermoresponsive hydrogel promotes a pro-healing effect in a rat model of colo-cutaneous post-surgical fistula.

Extracellular vesicles (EVs), especially from stem/stromal cells (SCs), represent a cell-free alternative in regenerative medicine holding promises to promote tissue healing while providing safety and logistic advantages in comparison to cellular counterparts. Herein, we hypothesize that SC EVs, administered locally in a thermoresponsive gel, is a therapeutic strategy for managing post-surgical colo-cutaneous fistulas. This disease is a neglected and challenging condition associated to low remission rates and high refractoriness. Herein, EVs from a murine SC line were produced by a high-yield scalable method in bioreactors. The post-surgical intestinal fistula model was induced via a surgical cecostomy communicating the cecum and the skin in Wistar rats. Animals were treated just after cecostomy with PBS, thermoresponsive Pluronic F-127 hydrogel alone or containing SC EVs. A PET-monitored biodistribution investigation of SC EVs labelled with 89Zr was performed. Fistula external orifice and output assessment, probe-based confocal laser endomicroscopy, MRI and histology were carried out for therapy follow-up. The relevance of percutaneous EV administration embedded in the hydrogel vehicle was indicated by the PET-biodistribution study. Local administration of SC EVs in the hydrogel reduced colo-cutaneous fistula diameter, output, fibrosis and inflammation while increasing the density of neo-vessels when compared to the PBS and gel groups. This multi-modal investigation pointed-out the therapeutic potential of SC EVs administered locally and in a thermoresponsive hydrogel for the management of challenging post-surgical colon fistulas in a minimally-invasive cell-free strategy.

Structure and thermorheology of concentrated pluronic copolymer micelles in the presence of laponite particles.

Small-angle neutron scattering and thermorheology techniques are used to investigate in detail the effect of laponite particles in aqueous solutions of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide), PEO-PPO-PEO, block copolymers in the concentrated regime. At high polymer concentration or temperature, the micellar solutions exhibit a phase transition from fluid to crystal due to crowding of the micelles. The addition of laponite is found to disturb this phase transition. The adsorption of the copolymer unimers onto laponite in large amounts describes these findings. It is shown that the preferred adsorption of the copolymer chains results in a sufficient increase in free volume for the remaining micelles to yield the observed enhancement of the structural disorder.

3D Magnetic Alignment of Cardiac Cells in Hydrogels.

Tissue engineering aims to repair or replace deficient tissue by delivering constructs that mimic the native in vivo structure. One challenge in cardiac tissue engineering approaches is to achieve intrinsic cardiac organization, particularly the alignment of cardiomyocytes. Here, we propose a strategy for 3D manipulation and alignment of cardiomyocytes by combining magnetism and a hydrogel. The advantage of using magnetic forces is that they act remotely on the cells when these are endowed with magnetization via the internalization of magnetic nanoparticles. The magnetic actuation then allows obtaining, almost instantaneously and before gel transition, an aligned biomimetic cardiac tissue construct. Gel transition enables us to keep the cellular pattern once the magnetic field was removed. This cardiac tissue engineering approach was tested with both H9c2 cell line and primary cardiomyocytes, and with both a synthetic hydrogel and a natural one, Pluronic F-127 and fibrin, respectively. Key parameters of the anisotropic tissue formation were assessed. Hydrogel rheology is provided, and the impact of cell density and magnetic labeling on cell-cell alignment is assessed. Immunofluorescence confirms the presence of several cardiac markers upon chaining, demonstrating the functionality of the tissue-like cell alignment obtained via magnetic actuation.

Thermoresponsive Gel Embedded with Adipose Stem-Cell-Derived Extracellular Vesicles Promotes Esophageal Fistula Healing in a Thermo-Actuated Delivery Strategy.

Extracellular vesicles (EVs) are increasingly envisioned as the next generation of biological pro-regenerative nanotherapeutic agents, as has already been demonstrated for heart, kidney, liver, and brain tissues; lung injury repair; and skin regeneration. Herein, we explore another potential EV therapeutic application, fistula healing, together with a local minimally invasive delivery strategy. Allogenic extracellular vesicles (EVs) from adipose tissue-derived stromal cells (ASCs) are administered in a porcine fistula model through a thermoresponsive Pluronic F-127 (PF-127) gel, injected locally at 4 °C and gelling at body temperature to retain EVs in the entire fistula tract. Complete fistula healing is reported to be 100% for the gel plus EVs group, 67% for the gel group, and 0% for the control, supporting the therapeutic use of Pluronic F-127 gel alone or combined with EVs. However, only the combination of gel and EVs results in a statistically significant (i) reduction of fibrosis, (ii) decline of inflammatory response, (iii) decrease in the density of myofibroblasts, and (iv) increase of angiogenesis. Overall, we demonstrate that ASC-EV delivery into a PF-127 gel represents a successful local minimally invasive strategy to induce a therapeutic effect in a swine fistula model. Our study presents prospects for EV administration strategies and for the management of post-operative fistulas.