Reaching the Tumor: Mobility of Polymeric Micelles Inside an In Vitro Tumor-on-a-Chip Model with Dual ECM.

Degradable polymeric micelles are promising drug delivery systems due to their hydrophobic core and responsive design. When applying micellar nanocarriers for tumor delivery, one of the bottlenecks encountered in vivo is the tumor tissue barrier: crossing the dense mesh of cells and the extracellular matrix (ECM). Sometimes overlooked, the extracellular matrix can trap nanoformulations based on charge, size, and hydrophobicity. Here, we used a simple design of a microfluidic chip with two types of ECM and MCF7 spheroids to allow "high-throughput" screening of the interactions between biological interfaces and polymeric micelles. To demonstrate the applicability of the chip, a small library of fluorescently labeled polymeric micelles varying in their hydrophilic shell and hydrophobic core forming blocks was studied. Three widely used hydrophilic shells were tested and compared, namely, poly(ethylene glycol), poly(2-ethyl-2-oxazoline), and poly(acrylic acid), along with two enzymatically degradable dendritic hydrophobic cores (based on hexyl or nonyl end groups). Using ratiometric imaging of unimer:micelle fluorescence and FRAP inside the chip model, we obtained the local assembly state and dynamics inside the chip. Notably, we observed different micelle behaviors in the basal lamina ECM, from avoidance of the ECM structure to binding of the poly(acrylic acid) formulations. Binding to the basal lamina correlated with higher uptake into MCF7 spheroids. Overall, we proposed a simple microfluidic chip containing dual ECM and spheroids for the assessment of the interactions of polymeric nanocarriers with biological interfaces and evaluating nanoformulations' capacity to cross the tumor tissue barrier.

Lung Extracellular Matrix Hydrogels-Derived Vesicles Contribute to Epithelial Lung Repair.

The use of physiomimetic decellularized extracellular matrix-derived hydrogels is attracting interest since they can modulate the therapeutic capacity of numerous cell types, including mesenchymal stromal cells (MSCs). Remarkably, extracellular vesicles (EVs) derived from MSCs display similar functions as their parental cells, mitigating tissue damage in lung diseases. However, recent data have shown that ECM-derived hydrogels could release other resident vesicles similar to EVs. Here, we aim to better understand the contribution of EVs and ECM-vesicles released from MSCs and/or lung-derived hydrogel (L-HG) in lung repair by using an in vitro lung injury model. L-HG derived-vesicles and MSCs EVs cultured either in L-HG or conventional plates were isolated and characterized. The therapeutic capacity of vesicles obtained from each experimental condition was tested by using an alveolar epithelial wound-healing assay. The number of ECM-vesicles released from acellular L-HG was 10-fold greater than EVs from conventional MSCs cell culture revealing that L-HG is an important source of bioactive vesicles. MSCs-derived EVs and L-HG vesicles have similar therapeutic capacity in lung repair. However, when wound closure rate was normalized by total proteins, the MSCs-derived EVs shows higher therapeutic potential to those released by L-HG. The EVs released from L-HG must be considered when HG is used as substrate for cell culture and EVs isolation.

Fast cycling of intermittent hypoxia in a physiomimetic 3D environment: A novel tool for the study of the parenchymal effects of sleep apnea.

Background: Patients with obstructive sleep apnea (OSA) experience recurrent hypoxemic events with a frequency sometimes exceeding 60 events/h. These episodic events induce downstream transient hypoxia in the parenchymal tissue of all organs, thereby eliciting the pathological consequences of OSA. Whereas experimental models currently apply intermittent hypoxia to cells conventionally cultured in 2D plates, there is no well-characterized setting that will subject cells to well-controlled intermittent hypoxia in a 3D environment and enable the study of the effects of OSA on the cells of interest while preserving the underlying tissue environment. Aim: To design and characterize an experimental approach that exposes cells to high-frequency intermittent hypoxia mimicking OSA in 3D (hydrogels or tissue slices). Methods: Hydrogels made from lung extracellular matrix (L-ECM) or brain tissue slices (300-800-µm thickness) were placed on a well whose bottom consisted of a permeable silicone membrane. The chamber beneath the membrane was subjected to a square wave of hypoxic/normoxic air. The oxygen concentration at different depths within the hydrogel/tissue slice was measured with an oxygen microsensor. Results: 3D-seeded cells could be subjected to well-controlled and realistic intermittent hypoxia patterns mimicking 60 apneas/h when cultured in L-ECM hydrogels ≈500 µm-thick or ex-vivo in brain slices 300-500 µm-thick. Conclusion: This novel approach will facilitate the investigation of the effects of intermittent hypoxia simulating OSA in 3D-residing cells within the parenchyma of different tissues/organs.

Therapeutic Physical Exercise Post-Treatment in Breast Cancer: A Systematic Review of Clinical Practice Guidelines.

Advances achieved in diagnosis and improvements in treatment for breast cancer have resulted in a favourable survival rate. Therapeutic physical exercise (TPE) is presented as an intervention strategy that seeks to improve the functional capabilities of the subject. To analyse if clinical practice guidelines recommend therapeutic physical exercise to reduce the adverse effects of treatment in breast cancer survivors, and on what level of scientific evidence are these recommendations based. This systematic review was prepared by searching nine electronic databases to identify eligible studies. Thirteen met the criteria for inclusion. The Appraisal of Guidelines for Research and Evaluation (AGREE II) scale was used to analyse the quality of Clinical Practice Guideline (CPGs). The percentages obtained ranged between 30.07% and 75.70%. Specifically, the highest degree of evidence could be found in the application of TPE to offset adverse effects leading to effects such as: an increase in the quality of life, fatigue reduction, and reduction in body weight alterations. TPE is presented as an optimal intervention strategy to alleviate the negative effects that patients with breast cancer suffer as a result of the treatments received. The level of evidence that supports this claim is very strong for the majority of the side effects analysed. However, this evidence is not always included in the clinical practice guidelines.