Decellularization of tumours: A new frontier in tissue engineering

Cancer is one of the leading causes of death worldwide. The tumour extracellular matrix (ECM) has unique features in terms of composition and mechanical properties, resulting in a structurally and chemically different ECM to that of native, healthy tissues. This paper reviews to date the efforts into decellularization of tumours, which in the authors’ view represents a new frontier in the ever evolving field of tumour tissue engineering. An overview of the ECM and its importance in cancer is given, ending with examples of research using decellularized tumours, which has already indicated potential therapeutic targets, unravelled malignancy mechanisms or response to chemotherapy agents. The review highlights that more research is needed in this area, which can answer important questions related to tumour formation and progression to ultimately identify new and effective therapeutic targets. Within the near-future of personalized medicine, this research can create patient-specific tumour models and therapeutic regimes

Mechano-sensing and cell migration: A 3D model approach

Cell migration is essential for tissue development in different physiological and pathological conditions. It is a complex process orchestrated by chemistry, biological factors, microstructure and surrounding mechanical properties. Focusing on the mechanical interactions, cells do not only exert forces on the matrix that surrounds them, but they also sense and react to mechanical cues in a process called mechano-sensing. Here, we hypothesize the involvement of mechano-sensing in the regulation of directional cell migration through a three-dimensional (3D) matrix. For this purpose, we develop a 3D numerical model of individual cell migration, which incorporates the mechano-sensing process of the cell as the main mechanism regulating its movement. Consistent with this hypothesis, we found that factors, such as substrate stiffness, boundary conditions and external forces, regulate specific and distinct cell movements

Biomechanical assessment and clinical analysis of different intramedullary nailing systems for oblique fractures

The aim of this study is to evaluate the fracture union or non-union for a specific patient that presented oblique fractures in tibia and fibula, using a mechanistic-based bone healing model. Normally, this kind of fractures can be treated through an intramedullary nail using two possible configurations that depends on the mechanical stabilisation: static and dynamic. Both cases are simulated under different fracture geometries in order to understand the effect of the mechanical stabilisation on the fracture healing outcome. The results of both simulations are in good agreement with previous clinical experience. From the results, it is demonstrated that the dynamization of the fracture improves healing in comparison with a static or rigid fixation of the fracture. This work shows the versatility and potential of a mechanistic-based bone healing model to predict the final outcome (union, non-union, delayed union) of realistic 3D fractures where even more than one bone is involved

Quantification of sprouting angiogenesis under the effect of different growth factors involved in the tumor microenvironmen

One of the most important problems in tumor control is the management of metastatic process. Angiogenesis or the formation of new blood vessels from preexisting ones plays a crucial role in the expansion of the tumor by providing oxygen, nutrition and conduits for cancer cells to invade and metastasize new tissues¹. Abnormalities of growth factors (GFs) released such as PDGFs (Platelet Derived Growth Factor) could be involved in malignant human diseases2,3. Inflammation and cancer present similar mechanisms of development including angiogenesis or cell proliferation4. In order to know the effect on sprouting promotion of GFs existent in the tumor environment such as VEGF (Vascular Endothelial Growth Factor), PDGF, BMP2 (Bone Morphogenetic Protein 2) or TGF-ß (Transforming Growth Factor-ß), we have developed a microfluidic-based test based on devices designed by Farahat et al. (2012)5, which allows to the user the quantification of sprouting formation under the effect of these GFs. TGF-ß pathway involved in tumor progression in multiple human cancers, instigates phenotypical changes affecting to the cell growth, differentiation and migration6. Knowing the overexpression of GFs such as VEGF or BMP2 in tumors7,8, we aimed to compare its effect on endothelial cells in angiogenesis. Analyzing the promotion of sprout in normal conditions under GFs addition would be possible to determine which of these molecules could decrease or promote the advance of the endothelial cells. The results obtained in this work indicated that VEGF is the most important factor to enhance the angiogenic process while non-specific factors such as BMP2 or TGF-ß show a low effectiveness. In the case of PDGF, the negative effect of this molecule observed in our assays could be explained by the non-optimal balance of concentration. Furthermore, we are currently working to quantify the effect of fluid flow on the sprouting promotion

A mechanistic protrusive-based model for 3D cell migration

Cell migration is essential for a variety of biological processes, such as embryogenesis, wound healing, and the immune response. After more than a century of research—mainly on flat surfaces—, there are still many unknowns about cell motility. In particular, regarding how cells migrate within 3D matrices, which more accurately replicate in vivo conditions. We present a novel in silico model of 3D mesenchymal cell migration regulated by the chemical and mechanical profile of the surrounding environment. This in silico model considers cell’s adhesive and nuclear phenotypes, the effects of the steric hindrance of the matrix, and cells ability to degradate the ECM. These factors are crucial when investigating the increasing difficulty that migrating cells find to squeeze their nuclei through dense matrices, which may act as physical barriers. Our results agree with previous in vitro observations where fibroblasts cultured in collagen-based hydrogels did not durotax toward regions with higher collagen concentrations. Instead, they exhibited an adurotactic behavior, following a more random trajectory. Overall, cell’s migratory response in 3D domains depends on its phenotype, and the properties of the surrounding environment, that is, 3D cell motion is strongly dependent on the context

Estudio de la capacidad estabilizadora del peroné en fracturas de tibia de conejo

El objetivo de este trabajo es estudiar la capacidad estabilizadora del peroné en fracturas de tibia. Si dicha capacidad es suficiente, sería posible evitar el uso de sistemas de fijación en los experimentos de laboratorio con este tipo de fracturas. Para comprobarlo se ha realizado una simulación computacional por elementos finitos de la tibia y el peroné de un conejo, con una fractura en el tercio medio superior de la diáfisis sin ningún elemento estabilizador. El conjunto ha sido sometido a las cargas más desfavorables del proceso de salto comprobándose que en este caso el peroné fracturaría en su parte inferior del mismo modo que sucede en la experimentación en laboratorio

Collagen-laponite nanoclay hydrogels for tumor spheroid growth

The extracellular matrix (ECM) plays an important regulatory role in the development and progression of tumoral tissue. Its functions and properties are crucial in determining tumor cell behavior such as invasion, migration, and malignancy development. Our study explores the role of collagen type I in cancer development and spread using engineered tumor models like multicellular spheroids grown in collagen-based hydrogels to simulate early tumor formation. We employ microfluidic techniques to test the hypothesis that (i) adding Laponite nanoclay to collagen hydrogels modifies mechanical and rheological properties and (ii) changing the stiffness of the collagen microenvironment affects tumor spheroid growth. Our findings support our theories and suggest the use of ECM components and engineered tumor models in cancer research, offering a biocompatible and biomimetic method to tailor the mechanical properties of conventional collagen hydrogels

Optical In-Situ Measurement of Relative Deformations of the LHC Main Dipole Cold Masses

The LHC cryodipoles are composed of an evacuated cryostat and a cold mass, which is cooled by superfluid helium at 1.9 K. To obey constraints imposed by beam dynamics the particle beams must be centered within the mechanical axis of the dipole with a sub-millimeter accuracy. This requires in turn that the relative displacements between the cryostat and the cold mass must be monitored with accuracy at all times. Because of the extreme environmental conditions (the displacement must be measured in vacuum and between two points at a temperature difference of about 300 degrees), no adequate existing monitoring system was found for this application. We describe here a novel optical sensor developed for our scope and we present results of measurements made during the cold test of the dipoles

Matrix architecture plays a pivotal role in 3D osteoblast migration: The effect of interstitial fluid flow

Osteoblast migration is a crucial process in bone regeneration, which is strongly regulated by interstitial fluid flow. However, the exact role that such flow exerts on osteoblast migration is still unclear. To deepen the understanding of this phenomenon, we cultured human osteoblasts on 3D microfluidic devices under different fluid flow regimes. Our results show that a slow fluid flow rate by itself is not able to alter the 3D migratory patterns of osteoblasts in collagen-based gels but that at higher fluid flow rates (increased flow velocity) may indirectly influence cell movement by altering the collagen microstructure. In fact, we observed that high fluid flow rates (1 µl/min) are able to alter the collagen matrix architecture and to indirectly modulate the migration pattern. However, when these collagen scaffolds were crosslinked with a chemical crosslinker, specifically, transglutaminase II, we did not find significant alterations in the scaffold architecture or in osteoblast movement. Therefore, our data suggest that high interstitial fluid flow rates can regulate osteoblast migration by means of modifying the orientation of collagen fibers. Together, these results highlight the crucial role of the matrix architecture in 3D osteoblast migration. In addition, we show that interstitial fluid flow in conjunction with the matrix architecture regulates the osteoblast morphology in 3D

Interstitial cells of Cajal and enteric nervous system in gastrointestinal and neurological pathology. Relation to oxidative stress

The enteric nervous system (ENS) is organized into two plexuses—submucosal and myenteric—which regulate smooth muscle contraction, secretion, and blood flow along the gastrointestinal tract under the influence of the rest of the autonomic nervous system (ANS). Interstitial cells of Cajal (ICCs) are mainly located in the submucosa between the two muscle layers and at the intramuscular level. They communicate with neurons of the enteric nerve plexuses and smooth muscle fibers and generate slow waves that contribute to the control of gastrointestinal motility. They are also involved in enteric neurotransmission and exhibit mechanoreceptor activity. A close relationship appears to exist between oxidative stress and gastrointestinal diseases, in which ICCs can play a prominent role. Thus, gastrointestinal motility disorders in patients with neurological diseases may have a common ENS and central nervous system (CNS) nexus. In fact, the deleterious effects of free radicals could affect the fine interactions between ICCs and the ENS, as well as between the ENS and the CNS. In this review, we discuss possible disturbances in enteric neurotransmission and ICC function that may cause anomalous motility in the gut