Simulations and test beam studies of the iMPACT calorimeter

This contribution describes the first results obtained within the iMPACT project, which aims to build a novel proton computed tomography (pCT) scanner for protons of energy up to 230 MeV, as used in hadron therapy. We will first describe the design of the iMPACT scanner, which is composed by a tracker and a range calorimeter. Results of test-beams, focused on the characterization of the building elements of the prototype of the calorimeter, will be presented and compared with simulations

3D Cell Culture: Recent Development in Materials with Tunable Stiffness

It is widely accepted that three-dimensional cell culture systems simulate physiological conditions better than traditional 2D systems. Although extracellular matrix components strongly modulate cell behavior, several studies underlined the importance of mechanosensing in the control of different cell functions such as growth, proliferation, differentiation, and migration. Human tissues are characterized by different degrees of stiffness, and various pathologies (e.g., tumor or fibrosis) cause changes in the mechanical properties through the alteration of the extracellular matrix structure. Additionally, these modifications have an impact on disease progression and on therapy response. Hence, the development of platforms whose stiffness could be modulated may improve our knowledge of cell behavior under different mechanical stress stimuli. In this review, we have analyzed the mechanical diversity of healthy and diseased tissues, and we have summarized recently developed materials with a wide range of stiffness

Characterization of structural bone properties through portable single-sided nmr devices: State of the art and future perspectives

Nuclear Magnetic Resonance (NMR) is a well-suited methodology to study bone composition and structural properties. This is because the NMR parameters, such as the T2 relaxation time, are sensitive to the chemical and physical environment of the1H nuclei. Although magnetic resonance imaging (MRI) allows bone structure assessment in vivo, its cost limits the suitability of conventional MRI for routine bone screening. With difficulty accessing clinically suitable exams, the diagnosis of bone diseases, such as osteoporosis, and the associated fracture risk estimation is based on the assessment of bone mineral density (BMD), obtained by the dual-energy X-ray absorptiometry (DXA). However, integrating the information about the structure of the bone with the bone mineral density has been shown to improve fracture risk estimation related to osteoporosis. Portable NMR, based on low-field single-sided NMR devices, is a promising and appealing approach to assess NMR properties of biological tissues with the aim of medical applications. Since these scanners detect the signal from a sensitive volume external to the magnet, they can be used to perform NMR measurement without the need to fit a sample inside a bore of a magnet, allowing, in principle, in vivo application. Techniques based on NMR single-sided devices have the potential to provide a high impact on the clinical routine because of low purchasing and running costs and low maintenance of such scanners. In this review, the development of new methodologies to investigate structural properties of trabecular bone exploiting single-sided NMR devices is reviewed, and current limitations and future perspectives are discussed

The psoriatic shift induced by interleukin 17 is promptly reverted by a specific anti-IL-17A agent in a three-dimensional organotypic model of normal human skin culture

Interleukin 17A (IL-17A), mainly produced by the T helper subclass Th17, plays a key role in the psoriatic plaque formation and progression. The clinical effectiveness of anti-IL-17A agents is documented, but the early and specific mechanisms of their protection are not identified yet. The challenge of the present study is to investigate the possible reversal exerted by a specific anti-IL-17A agent on the psoriatic events induced by IL-17A in a three-dimensional organotypic model of normal human skin. Bioptic skin fragments obtained after aesthetic surgery of healthy women (n=5) were incubated with i) IL-17A biological inhibitor (anti-IL-17A), ii) IL-17A, iii) a combination of IL-17A and its specific IL-17A biological inhibitor (COMBO). A Control group was in parallel cultured and incubation lasted for 24 and 48 h epidermal-side-up at the air-liquid interface. All subjects were represented in all experimental groups at all considered time-points. Keratinocyte proliferation and the presence of epidermal Langerhans cells were quantitatively estimated. In parallel with transmission electron microscopy analysis, immunofluorescence studies for the epidermal distribution of keratin (K)10, K14, K16, K17, filaggrin/occludin, Toll-like Receptor 4, and Nuclear Factor kB were performed. IL-17A inhibited cell proliferation and induced K17 expression, while samples incubated with the anti-IL-17A agent were comparable to controls. In the COMBO group the IL-17A-induced effects were almost completely reverted. Our study, for the first time, elucidates the most specific psoriatic cellular events that can be partially affected or completely reverted by a specific anti-IL-17A agent during the early phases of the plaque onset and progression. On the whole, this work contributes to expand the knowledge of the psoriatic tableau

3D printable acrylate polydimethylsiloxane resins for cell culture and drug testing

Nowadays, most of the microfluidic devices for biological applications are fabricated with only few well-established materials. Among these, polydimethylsiloxane (PDMS) is the most used and known. However, it has many limitations, like the operator dependent and time-consuming manufacturing technique and the high molecule retention. TEGORad or Acrylate PDMS is an acrylate polydimethylsiloxane copolymer that can be 3D printed through Digital Light Processing (DLP), a technology that can boast reduction of waste products and the possibility of low cost and rapid manufacturing of complex components. Here, we developed 3D printed Acrylate PDMS-based devices for cell culture and drug testing. Our in vitro study shows that Acrylate PDMS can sustain cell growth of lung and skin epithelium, both of great interest for in vitro drug testing, without causing any genotoxic effect. Moreover, flow experiments with a drug-like solution (Rhodamine 6G) show that Acrylate PDMS drug retention is negligible unlike the high signal shown by PDMS. In conclusion, the study demonstrates that this acrylate resin can be an excellent alternative to PDMS to design stretchable platforms for cell culture and drug testing

Materials Testing for the Development of Biocompatible Devices through Vat-Polymerization 3D Printing

Light-based 3D printing techniques could be a valuable instrument in the development of customized and affordable biomedical devices, basically for high precision and high flexibility in terms of materials of these technologies. However, more studies related to the biocompatibility of the printed objects are required to expand the use of these techniques in the health sector. In this work, 3D printed polymeric parts are produced in lab conditions using a commercial Digital Light Processing (DLP) 3D printer and then successfully tested to fabricate components suitable for biological studies. For this purpose, different 3D printable formulations based on commercially available resins are compared. The biocompatibility of the 3D printed objects toward A549 cell line is investigated by adjusting the composition of the resins and optimizing post-printing protocols; those include washing in common solvents and UV post-curing treatments for removing unreacted and cytotoxic products. It is noteworthy that not only the selection of suitable materials but also the development of an adequate post-printing protocol is necessary for the development of biocompatible devices

A Novel Approach for an Integrated Straw tube-Microstrip Detector

We report on a novel concept of silicon microstrips and straw tubes detector, where integration is accomplished by a straw module with straws not subjected to mechanical tension in a Rohacell $^{\circledR}$ lattice and carbon fiber reinforced plastic shell. Results on mechanical and test beam performances are reported on as well.Comment: Accepted by Transactions on Nuclear Science (2005). 11 pages, 9 figures, uses lnfprep.st

Suspected breast implant rupture: our experience, recommendations on its management and a proposal for a model of informed consent

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Morphological analysis of JAK1 intracellular pathway activation after pro-inflammatory psoriatic cytokines exposure: inside-out and outside-in the epidermis

For their normal growth, cells depend on a continuous flow of signals from the environment. The Janus kinases (JAK) 1 transducers signalling pathway is a pleiotropic cascade used to transduce a multitude of signals among cells. A variety of ligands including cytokines, hormones, growth factors, and their receptors stimulate the JAK1 pathway. Cytokines, a large and very heterogeneous family of small and generally soluble glycoproteins, both control multiple biological processes as haematopoiesis, inflammation, and immunity playing a central role in cell-cell communication. Their action is mediated by the binding to specific receptors on the cell surface, thus transducing biological information to target cells [1]. Pro-inflammatory cytokines play a pivotal role in several inflammatory illnesses including psoriasis. Among them, interleukin (IL)-17, IL-22, IL-23 and tumor necrosis factor (TNF)-alpha play a central role. In the formation and progression of the psoriatic lesion a typical marker is keratin (K) 17 which is correlated with psoriasis severity. The aims of this study were to evaluate the early, direct, and specific effects of pro-inflammatory psoriatic cytokines i) on the activation of the intracellular pathway JAK1 and ii) on the correlation with the induction of K17 expression in a three-dimensional model (3D) of human skin (n=7) by immunofluorescence. Biopsies were cultured overnight epidermal side-up in a Transwell system and exposed to 50 ng/ml IL-17, or 100 ng/ml IL-22, or 50 ng/ml IL-23 or 100 ng/ml TNF-alpha. Samples were harvested 24 (T24), 48 (T48), and 72 (T72) hours after cytokine incubation. In samples not exposed to cytokines, a JAK1 slight labelling was observed throughout the epidermis, decreasing at T72 in the lower layers. At T24, IL-17 and IL-22, but not IL-23 and TNF-alpha, induced an expression of JAK1 in the spinous layer. At T72, JAK1 immunostaining decreased in all samples, similarly to controls. K17 immunopositivity was induced and progressively increased with time in the suprabasal layers of epidermis in all experimental groups, with the exception of the TNF-alpha group. These results suggest that cytokines exert parallel effects on JAK1 pathway activation and K17 induction. In conclusion, 3D this model, reproducing some features of psoriatic microenvironment, represents a useful experimental approach to dissect the specific role of each cytokine in the different steps of psoriatic lesion formation

Effect of TNF-alpha and IL-17 on TLR expression and Langerhans cells phenotype in a three-dimensional model of normal human skin: a morphological study

Toll-like receptors (TLRs) are essential for innate immunity and contribute to create the skin barrier. Their abnormal stimulation is involved in the development of several dermatological diseases, among which psoriasis. Tumor Necrosis Factor (TNF)-alpha and interleukin (IL)-17 play a pivotal role in the pathogenesis of psoriatic plaques and their proinflammatory activity can affect Langerhans cell (LC) phenotype. In a well characterized three-dimensional model of organotypic cultures of normal human skin [1-3] we evaluated the effect of TNF-alpha and IL-17 on the expression of TLR2 and 9 by immunofluorescence, on the ultrastructural morphology of keratinocytes and LCs by transmission electron microscopy (TEM). Human skin explants (n=7) were cultured at the air-liquid interface overnight in a Transwell system and exposed to 50 ng/ml IL-17 or 100 ng/ml TNF-alpha or a combination of both cytokines. Samples were harvested 24 (T24) and 48h (T48) after cytokines incubation. After incubation with IL-17 and IL-17+TNF-alpha, TLR2 immunostaining was not detectable in the basal layer, differently from controls and TNF-alpha-treated samples. Conversely, TLR9 expression was progressively induced in granular keratinocytes in all cytokine-exposed groups. By TEM, enlargements of intercellular spaces were evident especially and, after IL-17 treatment, LCs showed an activated phenotype. At T24 LCs number increased indicating that TNF-alpha and IL-17+TNF-alpha exert a chemoattractant activity, while at T48 only IL-17+TNF-alpha maintained this effect on trapping LCs in epidermis. TNF-alpha and IL-17 differently affect LCs behaviour and TLR expression, with a specific contribution to the inflammatory loop underlying the lesion formation. The simultaneous inhibition of the effect of different cytokines - all with a defined role in the pathogenesis of psoriasis - could further improve psoriasis treatment