Advanced cancer is still considered an incurable disease because of its metastatic spread to distal organs and progressive gain of chemoresistance. Even though considerable treatment progress and more effective therapies have been achieved over the past years, recurrence in the long-term and undesired side effects are still the main drawbacks of current clinical protocols. Moreover, a majority of chemotherapeutic drugs are highly hydrophobic and need to be diluted in organic solvents, which cause high toxicity, in order to reach effective therapeutic dose. These limitations of conventional cancer therapies prompted the use of nanomedicine, the medical application of nanotechnology, to provide more effective and safer cancer treatment. Potential of nanomedicines to overcome resistance, ameliorate solubility, improve pharmacological profile, and reduce adverse effects of chemotherapeutical drugs is thus highly regarded. Their use in the clinical setting has increased over the last decade. Among the various existing nanosystems, nanoparticles have the ability to transform conventional medicine by reducing the adverse effects and providing a controlled release of therapeutic agents. Also, their small size facilitates the intracellular uptake. Here, we provide a closer review of clinical prospects and mechanisms of action of nanomedicines to overcome drug resistance. The significance of specific targeting towards cancer cells is debated as well.
Three-dimensional printing is revolutionizing the development of scaffolds due to their rapid-prototyping characteristics. One of the most used techniques is fused filament fabrication (FFF), which is fast and compatible with a wide range of polymers, such as PolyLactic Acid (PLA). Mechanical properties of the 3D printed polymeric scaffolds are often weak for certain applications. A potential solution is the development of composite materials. In the present work, metal-PLA composites have been tested as a material for 3D printing scaffolds. Three different materials were tested: copper-filled PLA, bronze-filled PLA, and steel-filled PLA. Disk-shaped samples were printed with linear infill patterns and line spacing of 0.6, 0.7, and 0.8 mm, respectively. The porosity of the samples was measured from cross-sectional images. Biocompatibility was assessed by culturing Human Bone Marrow-Derived Mesenchymal Stromal on the surface of the printed scaffolds. The results showed that, for identical line spacing value, the highest porosity corresponded to bronze-filled material and the lowest one to steel-filled material. Steel-filled PLA polymers showed good cytocompatibility without the need to coat the material with biomolecules. Moreover, human bone marrow-derived mesenchymal stromal cells differentiated towards osteoblasts when cultured on top of the developed scaffolds. Therefore, it can be concluded that steel-filled PLA bioprinted parts are valid scaffolds for bone tissue engineering.
Decellularization procedures have been developed and optimized for the entire organ or tissue blocks, by either perfusion of decellularizing agents through the tissue’s vasculature or submerging large sections in decellularizing solutions. However, some research aims require the analysis of native as well as decellularized tissue slices side by side, but an optimal protocol has not yet been established to address this need. Thus, the main goal of this work was to develop a fast and efficient decellularization method for tissue slices—with an emphasis on lung—while attached to a glass slide. To this end, different decellularizing agents were compared for their effectiveness in cellular removal while preserving the extracellular matrix. The intensity of DNA staining was taken as an indicator of remaining cells and compared to untreated sections. The presence of collagen, elastin and laminin were quantified using immunostaining and signal quantification. Scaffolds resulting from the optimized protocol were mechanically characterized using atomic force microscopy. Lung scaffolds were recellularized with mesenchymal stromal cells to assess their biocompatibility. Some decellularization agents (CHAPS, triton, and ammonia hydroxide) did not achieve sufficient cell removal. Sodium dodecyl sulfate (SDS) was effective in cell removal (1% remaining DNA signal), but its sharp reduction of elastin signal (only 6% remained) plus lower attachment ratio (32%) singled out sodium deoxycholate (SD) as the optimal treatment for this application (6.5% remaining DNA signal), due to its higher elastin retention (34%) and higher attachment ratio (60%). Laminin and collagen were fully preserved in all treatments. The SD decellularization protocol was also successful for porcine and murine (mice and rat) lungs as well as for other tissues such as the heart, kidney, and bladder. No significant mechanical differences were found before and after sample decellularization. The resulting acellular lung scaffolds were shown to be biocompatible (98% cell survival after 72 h of culture). This novel method to decellularize tissue slices opens up new methodological possibilities to better understand the role of the extracellular matrix in the context of several diseases as well as tissue engineering research and can be easily adapted for scarce samples like clinical biopsies.
Traditional cell culture is experiencing a revolution moving toward physiomimetic approaches aiming to reproduce healthy and pathological cell environments as realistically as possible. There is increasing evidence demonstrating that biophysical and biochemical factors determine cell behavior, in some cases considerably. Alongside the explosion of these novel experimental approaches, different bioengineering techniques have been developed and improved. Increased affordability and popularization of 3D bioprinting, fabrication of custom-made lab-on-a chip, development of organoids and the availability of versatile hydrogels are factors facilitating the design of tissue-specific physiomimetic in vitro models. However, lower oxygen diffusion in 3D culture is still a critical limitation in most of these studies, requiring further efforts in the field of physiology and tissue engineering and regenerative medicine. During recent years, novel advanced 3D devices are introducing integrated biosensors capable of monitoring oxygen consumption, pH and cell metabolism. These biosensors seem to be a promising solution to better control the oxygen delivery to cells and to reproduce some disease conditions involving hypoxia. This review discusses the current advances on oxygen biosensors and control in 3D physiomimetic experimental models.
The extracellular matrix (ECM) of the lung is a filamentous network composed mainly of collagens, elastin, and proteoglycans that provides structural and physical support to its populating cells. Proliferation, migration and overall behaviour of those cells is greatly determined by micromechanical queues provided by the ECM. Lung fibrosis displays an aberrant increased deposition of ECM which likely changes filament organization and stiffens the ECM, thus upregulating the profibrotic profile of pulmonary cells. We have previously used AFM to assess changes in the Young’s Modulus (E) of the ECM in the lung. Here, we perform further ECM topographical, mechanical and viscoelastic analysis at the micro- and nano-scale throughout fibrosis development. Furthermore, we provide nanoscale correlations between topographical and elastic properties of the ECM fibres. Firstly, we identify a softening of the ECM after rats are instilled with media associated with recovery of mechanical homeostasis, which is hindered in bleomycin-instilled lungs. Moreover, we find opposite correlations between fibre stiffness and roughness in PBS- vs bleomycin-treated lung. Our findings suggest that changes in ECM nanoscale organization take place at different stages of fibrosis, with the potential to help identify pharmacological targets to hinder its progression.
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