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Glioblastoma (GBM) is a highly malignant brain tumour characterised by limited treatment options and poor prognosis. The tumour microenvironment, particularly the central hypoxic region of the tumour, is known to play a pivotal role in GBM progression. Cells within this region adapt to hypoxia by stabilising transcription factor HIF1-α, which promotes cell proliferation, dedifferentiation and chemoresistance. In this study we sought to examine the effects of NNC-55-0396, a tetralol compound which overactivates the unfolded protein response inducing apoptosis, using the organ-on-chip technology. We identified an increased sensitivity of the hypoxic core of the chip to NNC, which correlates with decreasing levels of HIF1-α in vitro. Moreover, NNC blocks the macroautophagic process that is unleashed by hypoxia as revealed by increased levels of autophagosomal constituent LC3-II and autophagy chaperone p62/SQSTM1. The specific effects of NNC in the hypoxic microenvironment unveil additional anti-cancer abilities of this compound and further support investigations on its use in combined therapies against GBM.

Glioblastoma (GBM) is a highly malignant brain tumor with a poor survival prognosis of 12–15 months despite current therapeutic strategies. Diagnosing GBM is challenging, often requiring invasive techniques such as tissue biopsy and imaging methods that can provide inconclusive results. In this regard, liquid biopsy represents a promising alternative, providing tumor‐derived information from less invasive sources such as blood or cerebrospinal fluid. However, the typically low concentrations of these biomarkers pose challenges for traditional detection techniques, limiting their sensitivity and specificity. Recent advances in microfluidics offer a potential solution by enhancing the isolation and detection of tumor‐derived cells and molecules, thus improving their detectability. This review discusses the latest progress in microfluidic‐based liquid biopsy systems for glioblastoma, laying the basis for future diagnostic practices that are less invasive and more accurate. As these technologies evolve, they hold the potential to transform GBM diagnosis and monitoring, ultimately improving patient outcomes.

Immunotherapy remains more effective for hematologic tumors than for solid tumors. One of the main challenges to immunotherapy of solid tumors is the immunosuppressive microenvironment these tumors generate, which limits the cytotoxic capabilities of immune effector cells (e.g., cytotoxic T and natural killer cells). This microenvironment is characterized by hypoxia, nutrient starvation, accumulated waste products, and acidic pH. Tumor-hijacked cells, such as fibroblasts, macrophages, and T regulatory cells, also contribute to this inhospitable microenvironment for immune cells by secreting immunosuppressive cytokines that suppress the antitumor immune response and lead to immune evasion. Thus, there is a strong interest in developing new drugs and cell formulations that modulate the tumor microenvironment and reduce tumor cell immune evasion. Microphysiological systems (MPSs) are versatile tools that may accelerate the development and evaluation of these therapies, although specific examples showcasing the potential of MPSs remain rare. Advances in microtechnologies have led to the development of sophisticated microfluidic devices used to recapitulate tumor complexity. The resulting models, also known as microphysiological systems (MPSs), are versatile tools with which to decipher the molecular mechanisms driving immune cell antitumor cytotoxicity, immune cell exhaustion, and immune cell exclusion and to evaluate new targeted immunotherapies. Here, we review existing microphysiological platforms to study immuno-oncological applications and discuss challenges and opportunities in the field.

The aromatic compound p -coumaric acid (p-CA) is a secondary metabolite produced by plants. This aromatic acid and derived compounds have positive effects on human health, so there is interest in producing them in biotechnological processes with recombinant Escherichia coli strains. To determine the physiologic response of E. coli W3110 to p-CA, dynamic expression analysis of selected genes fused to a fluorescent protein reporter as well as RNA-seq and RT-qPCR were performed. The observed transcriptional profile revealed the induction of genes involved in functions related to p-CA active export, synthesis of cell wall and membrane components, synthesis of amino acids, detoxification of formaldehyde, phosphate limitation, acid stress, protein folding and degradation. Downregulation of genes encoding proteins involved in energy production, carbohydrate import and metabolism, as well as several outer and plasma membrane proteins was detected. This response is indicative of cell envelope damage causing the leakage of intracellular components including amino acids and phosphate-containing compounds. The cellular functions responding to p-CA that were identified in this study will help in defining targets for production strains improvement.

Nephrotoxicity stands as one of the most limiting effects in the development and validation of new drugs. The kidney, among the organs evaluated in toxicity assessments, has a higher susceptibility, with nephrotoxic potential frequently evading detection until late in clinical trials. Traditional cell culture, which has been widely used for decades, does not recapitulate the structure and complexity of the native tissue, which can affect cell function, and the response to cytotoxins does not resemble what occurs in the kidney. In the current study, we aimed to address these challenges by creating in vitro kidney models that faithfully biomimic the dynamics of the renal proximal tubule, using the well-established RPTEC/TERT1 cell line. For doing so, two models were developed, one recreating tubule-like structures (2.5D model) and the other using microfluidic technology (kidney-on-a-chip). The 2.5D model allowed tubular structures to be generated in the absence of hydrogels, and the kidney-on-a-chip model allowed shear stress to be applied to the cell culture, which is a physiological stimulus in the renal tissue. After characterization of both models, different nephrotoxic compounds such as cisplatin, tacrolimus, and daunorubicin were used to study cell responses after treatment. The developed models in our study could be a valuable tool for pre-clinical nephrotoxic testing of drugs and new compounds.

The clinical use of pulsed electromagnetic fields (PEMF) in osteoarticular pathology is widely extended, although the mechanisms involved are unknown. The aim of this study was to evaluate the action of a new protocol of treatment with PEMF on liquid medium cultures of fibroblast-like cells derivates of mononuclear peripheral blood cells. Fibroblast-like cells growth was obtained in liquid medium culture from mononuclear cells (MNC) of human peripheral blood. The PEMF irradiation protocol included an intensity of 2.25 mT, a frequency of 50 Hz and an application time of 15 min on days 7, 8 and 9 of cell culture. Immunophenotype was performed with specific heterologous monoclonal antibodies for each cell receptor (Vimentin, Cytokeratin, CD34, CD41, CD61 and CD68). The cytokines’ production was determined in the supernatant of the culture medium by means of the Luminex technology. The immunophenotype did not show any statistical difference on comparing treated against non-treated cell cultures on any of the days. In the treatment cell population, the proinflammatory cytokines, IL-1β and TNF-α showed a significant decrease on days 14 and 21 of the culture, whilst IL-10 increased significantly on day 21. It is concluded that PEMF irradiation does not alter the cell immunophenotype of the fibroblast-like cell population, but does provoke a decrease in the production of inflammatory-type cytokines (IL-1β, TNF-α) and an increase in cytokines of lymphocytic origin (IL-10). These facts coincide with the chronology of the clinical effect undergone by patients with osteoarticular pathology after PEMF irradiation.

Current available animal and in vitro cell-based models for studying brain-related pathologies and drug evaluation face several limitations since they are unable to reproduce the unique architecture and physiology of the human blood–brain barrier. Because of that, promising preclinical drug candidates often fail in clinical trials due to their inability to penetrate the blood–brain barrier (BBB). Therefore, novel models that allow us to successfully predict drug permeability through the BBB would accelerate the implementation of much-needed therapies for glioblastoma, Alzheimer’s disease, and further disorders. In line with this, organ-on-chip models of the BBB are an interesting alternative to traditional models. These microfluidic models provide the necessary support to recreate the architecture of the BBB and mimic the fluidic conditions of the cerebral microvasculature. Herein, the most recent advances in organ-on-chip models for the BBB are reviewed, focusing on their potential to provide robust and reliable data regarding drug candidate ability to reach the brain parenchyma. We point out recent achievements and challenges to overcome in order to advance in more biomimetic in vitro experimental models based on OOO technology. The minimum requirements that should be met to be considered biomimetic (cellular types, fluid flow, and tissular architecture), and consequently, a solid alternative to in vitro traditional models or animals.

We report the first application of a microfluidic device to observe chemotactic migration in multicellular spheroids. A microfluidic device was designed comprising a central microchamber and two lateral channels through which reagents can be introduced. Multicellular spheroids were embedded in collagen and introduced to the microchamber. A gradient of fetal bovine serum (FBS) was established across the central chamber by addition of growth media containing serum into one of the lateral channels. We observe that spheroids of oral squamous carcinoma cells OSC-19 invade collectively in the direction of the gradient of FBS. This invasion is more directional and aggressive than that observed for individual cells in the same experimental setup. In contrast to spheroids of OSC-19, U87-MG multicellular spheroids migrate as individual cells. A study of the exposure of spheroids to the chemoattractant shows that the rate of diffusion into the spheroid is slow and thus, the chemoattractant wave engulfs the spheroid before diffusing through it.

[...]selecting the optimal radiation dose to selectively destroying the tumor cells while minimizing radiation exposure to normal tissue can be challenging since local hypoxia within the tumor reduces the efficacy of radiotherapy. [...]Chan et al. developed a methodology to calculate the GT dose required to damage and destroy cancer cells depending on the oxygen concertation [12]. Next, their in vitro results showed that osteoblasts protected metastatic breast cancer cells from oxidative stress through the formation of gap junctions, potentially providing a glutathione reservoir for the cancer cells. [...]they used mathematical modelling to develop a model to predict the likelihood of developing metastatic growth based on the number of osteoblasts in the surrounding bone microenvironment. Using RT-qPCR and western blot in human specimens, they demonstrated a positive correlation between FAK/PyK2 activation in tumor cells and platelet-derived growth factor β(PDGFβ), stromal-derived factor 1α (SDF-1α), IL-6, IL-8, and epidermal growth factor (EGF) secretion in microglia.

In the pursuit of achieving a more realistic in vitro simulation of human biological tissues, microfluidics has emerged as a promising technology. Organ-on-a-chip (OoC) devices, a product of this technology, contain miniature tissues within microfluidic chips, aiming to closely mimic the in vivo environment. However, a notable drawback is the presence of inert material between compartments, hindering complete contact between biological tissues. Current membranes, often made of PDMS or plastic materials, prevent full interaction between cell types and nutrients. Furthermore, their non-physiological mechanical properties and composition may induce unexpected cell responses. Therefore, it is essential to minimize the contact area between cells and the inert materials while simultaneously maximizing the direct contact between cells and matrices in different compartments. The main objective of this work is to minimize inert materials within the microfluidic chip while preserving proper cellular distribution. Two microfluidic devices were designed, each with a specific focus on maximizing direct cell–matrix or cell–cell interactions. The first chip, designed to increase direct cell–cell interactions, incorporates a nylon mesh with regular pores of 150 microns. The second chip minimizes interference from inert materials, thereby aiming to increase direct cell–matrix contact. It features an inert membrane with optimized macropores of 1 mm of diameter for collagen hydrogel deposition. Biological validation of both devices has been conducted through the implementation of cell migration and cell-to-cell interaction assays, as well as the development of epithelia, from isolated cells or spheroids. This endeavor contributes to the advancement of microfluidic technology, aimed at enhancing the precision and biological relevance of in vitro simulations in pursuit of more biomimetic models.