Topologically controlled hyaluronan-based gel coatings of hydrophobic grid-like scaffolds to modulate drug delivery

[EN] Scaffolds based on poly(ethyl acrylate) having interwoven channels were coated with a hyaluronan (HA) hydrogel to be used in tissue engineering applications. Controlled typologies of coatings evolving from isolated aggregates to continuous layers, which eventually clog the channels, were obtained by using hyaluronan solutions of different concentrations. The efficiency of the HA loading was determined using gravimetric and thermogravimetric methods, and the hydrogel loss during the subsequent crosslinking process was quantified, seeming to depend on the mass fraction of hyaluronan initially incorporated to the pores. The effect of the topologically different coatings on the scaffolds, in terms of mechanical properties and swelling at equilibrium under different conditions was evaluated and correlated with the hyaluronan mass fraction. The potential of these hydrogel coatings as vehicle for controlled drug release from the scaffolds was validated using a protein model.The authors acknowledge the financing through projects FP7 NMP3-SL-2009-229239 (RECATABI) and MAT2011-28791-C03-02 and -03. This work was also supported by the Spanish Ministry of Education through M. Arnal-Pastor FPU2009-1870 and M. Perez-Garnes BES-2009-015314 grants.Arnal Pastor, MP.; Perez Garnes, M.; Monleón Pradas, M.; Vallés Lluch, A. (2016). Topologically controlled hyaluronan-based gel coatings of hydrophobic grid-like scaffolds to modulate drug delivery. Colloids and Surfaces B Biointerfaces. 140:412-420. https://doi.org/10.1016/j.colsurfb.2016.01.004S41242014

One-dimensional migration of olfactory ensheathing cells on synthetic materials: Experimental and numerical characterization

Olfactory ensheathing cells (OECs) are of great interest for regenerative purposes since they are believed to aid axonal growth. With the view set on the strategies to achieve reconnection between neuronal structures, it is of great importance to characterize the behaviour of these cells on long thread-like structures that may efficiently guide cell spread in a targeted way. Here, rat OECs were studied on polycaprolactone (PCL) long monofilaments, on long bars and on discs. PCL turns out to be an excellent substrate for OECs. The cells cover long distances along the monofilaments and colonize completely these struc- tures. With the help of a one-dimensional (1D) analytical model, a migration coefficient, a net proliferation rate constant and the fraction of all cells which undergo migration were obtained. The separate effect of the three phenomena summarized by these parameters on the colo- nization patterns of the 1D path was qualitatively dis- cussed. Other features of interest were also determined, such as the speed of the advance front of colonization and the order of the kinetics of net cell proliferation. Charac- terizing migration by means of these quantities may be useful for comparing and predicting features of the colo- nization process (such as times, patterns, advance fronts and proportion of motile cells) of different cell substrate combinations.Support of the Spanish Science & Innovation Ministery through project MAT2008-06434 is acknowledged. MMP and CMR acknowledge partial funding through the "Convenio de Colaboracion para la Investigacion Basica y Traslacional en Medicina Regenerativa" between the Instituto Nacional de Salud Carlos III, the Conselleria de Sanidad of the Generalitat Valenciana and the Foundation Centro de Investigacion Principe Felipe.Perez Garnes, M.; Martínez Ramos, C.; Barcia, JA.; Escobar Ivirico, JL.; Gomez Pinedo, UA.; Vallés Lluch, A.; Monleón Pradas, M. (2013). One-dimensional migration of olfactory ensheathing cells on synthetic materials: Experimental and numerical characterization. Cell Biochemistry and Biophysics. 65:21-36. https://doi.org/10.1007/s12013-012-9399-1S213665Stokols, S., Sakamoto, J., Breckon, C., Holt, T., Weiss, J., & Tuszynski, M. H. (2006). Templated agarose scaffolds support linear axonal regeneration. Tissue Engineering, 12(10), 2777–2787.Wei, Y. T., Tian, W. M., Yu, X., Cui, F. Z., Hou, S. P., Xu, Q. Y., et al. (2007). Hyaluronic acid hydrogels with IKVAV peptides for tissue repair and axonal regeneration in an injured rat brain. Biomedical Materials, 2(3), 142–146.Yao, L., Wang, S., Cui, W., Sherlock, R., O’Connell, C., Damodaran, G., et al. (2009). Effect of functionalized micropatterned PLGA on guided neurite growth. Acta Biomaterialia, 5(2), 580–588.Chehrehasa, F., Windus, L. C. E., Ekberg, J. A. K., Scott, S. E., Amaya, D., Mackay-Sim, A., et al. (2010). Olfactory glia enhance neonatal axon regeneration. Molecular and Cellular Neuroscience, 45(3), 277–288.Chen, B. K., Knight, A. M., de Ruiter, G. C., Spinner, R. J., Yaszemski, M. J., Currier, B. L., et al. (2009). Axon regeneration through scaffold into distal spinal cord after transection. Journal of Neurotrauma, 26(10), 1759–1771.Goto, E., Mukozawa, M., Mori, H., & Hara, M. (2010). A rolled sheet of collagen gel with cultured Schwann cells: Model of nerve conduit to enhance neurite growth. Journal of Bioscience and Bioengineering, 109(5), 512–518.Lietz, M., Dreesmann, L., Hoss, M., Oberhoffner, S., & Schlosshauer, B. (2006). Neuro tissue engineering of glial nerve guides and the impact of different cell types. Biomaterials, 27(8), 1425–1436.Radtke, C., Sasaki, M., Lankford, K. L., Vogt, P. M., & Kocsis, J. D. (2008). Potential of olfactory ensheathing cells for cell-based therapy in spinal cord injury. Journal of Rehabilitation Research and Development, 45(1), 141–151.Wei, Y., Miao, X., Xian, M., Zhang, C., Liu, X., Zhao, H., et al. (2008). Effects of transplanting olfactory ensheathing cells on recovery of olfactory epithelium after olfactory nerve transection in rats. Medical Science Monitor, 14(10), 198–204.Tennent, R., & Chuah, M. I. (1996). Ultrastructural study of ensheathing cells in early development of olfactory axons. Brain Research, Developmental Brain Research, 95(1), 135–139.Doucette, R. (1990). Glial influences on axonal growth in the primary olfactory system. Glia, 3(6), 433–449.Field, P., Li, Y., & Raisman, G. (2003). Ensheathment of the olfactory nerves in the adult rat. Journal of Neurocytology, 32(3), 317–324.Boyd, J. G., Doucette, R., & Kawaja, M. D. (2005). Defining the role of olfactory ensheathing cells in facilitating axon remyelination following damage to the spinal cord. Faseb Journal, 19(7), 694–703.Franklin, R. J., Gilson, J. M., Franceschini, I. A., & Barnett, S. C. (1996). Schwann cell-like myelination following transplantation of an olfactory bulb-ensheathing cell line into areas of demyelination in the adult CNS. Glia, 17(3), 217–224.Imaizumi, T., Lankford, K. L., Waxman, S. G., Greer, C. A., & Kocsis, J. D. (1998). Transplanted olfactory ensheathing cells remyelinate and enhance axonal conduction in the demyelinated dorsal columns of the rat spinal cord. Journal of Neuroscience, 18(16), 6176–6185.Raisman, G. (2001). Olfactory ensheathing cells - another miracle cure for spinal cord injury? Nature Reviews Neuroscience, 2(5), 369–375.Ramón-Cueto, A., Cordero, M. I., Santos-Benito, F. F., & Avila, J. (2000). Functional recovery of paraplegic rats and motor axon regeneration in their spinal cords by olfactory ensheathing glia. Neuron, 25(2), 425–435.Chuah, M. I., Choi-Lundberg, D., Weston, S., Vincent, A. J., Chung, R. S., Vickers, J. C., et al. (2004). Olfactory ensheathing cells promote collateral axonal branching in the injured adult rat spinal cord. Experimental Neurology, 185(1), 15–25.Bellamkonda, R. V. (2006). Peripheral nerve regeneration: An opinion on channels, scaffolds and anisotropy. Biomaterials, 27(19), 3515–3518.Liu, Y., Gong, Z., Liu, L., & Sun, H. (2010). Combined effect of olfactory ensheathing cell transplantation and glial cell line-derived neurotrophic factor (GDNF) intravitreal injection on optic nerve injury in rats. Molecular Vision, 16, 2903–2910.Zhu, Y., Cao, L., Su, Z., Mu, L., Yuan, Y., Gao, L., et al. (2010). Olfactory ensheathing cells: Attractant of neural progenitor migration to olfactory bulb. Glia, 58(6), 716–729.Basiri, M., & Doucette, R. (2010). Sensorimotor cortex aspiration: A model for studying Wallerian degeneration-induced glial reactivity along the entire length of a single CNS axonal pathway. Brain Research Bulletin, 81(1), 43–52.Li, Y., Carlstedt, T., Berthold, C.-H., & Raisman, G. (2004). Interaction of transplanted olfactory-ensheathing cells and host astrocytic processes provides a bridge for axons to regenerate across the dorsal root entry zone. Experimental Neurology, 188(2), 300–308.Li, Y., Yamamoto, M., Raisman, G., Choi, D., & Carlstedt, T. (2007). An experimental model of ventral root repair showing the beneficial effect of transplanting olfactory ensheathing cells. Neurosurgery, 60(4), 734–741.Ramón-Cueto, A., Plant, G. W., Avila, J., & Bunge, M. B. (1998). Long-distance axonal regeneration in the transected adult rat spinal cord is promoted by olfactory ensheathing glia transplants. The Journal of Neuroscience, 18(10), 3803–3815.Gómez-Pinedo, U., Vidueira, S., Sancho, F. J., García-Verdugo, J. M., Matías-Guiu, J., & Barcia, J. A. (2011). Olfactory ensheathing glia enhances reentry of axons into the brain from peripheral nerve grafts bridging the substantia nigra with the striatum. Neuroscience Letters, 494(2), 104–108.Graziadei, P. P., Levine, R. R., & Graziadei, G. A. (1978). Regeneration of olfactory axons and synapse formation in the forebrain after bulbectomy in neonatal mice. Proceedings of the National academy of Sciences of the United States of America, 75(10), 5230–5234.Cao, L., Liu, L., Chen, Z. Y., Wang, L. M., Ye, J. L., Qiu, H. Y., et al. (2004). Olfactory ensheathing cells genetically modified to secrete GDNF to promote spinal cord repair. Brain, 127(3), 535–549.Cao, L., Su, Z., Zhou, Q., Lv, B., Liu, X., Jiao, L., et al. (2006). Glial cell line-derived neurotrophic factor promotes olfactory ensheathing cells migration. Glia, 54(6), 536–544.Woodhall, E., West, A. K., & Chuah, M. I. (2001). Cultured olfactory ensheathing cells express nerve growth factor, brain-derived neurotrophic factor, glia cell line-derived neurotrophic factor and their receptors. Brain Research. Molecular Brain Research, 88(1–2), 203–213.Cao, L., Zhu, Y. L., Su, Z., Lv, B., Huang, Z., Mu, L., et al. (2007). Olfactory ensheathing cells promote migration of Schwann cells by secreted nerve growth factor. Glia, 55(9), 897–904.Doucette, R. (1996). Immunohistochemical localization of laminin, fibronectin and collagen type IV in the nerve fiber layer of the olfactory bulb. International Journal of Developmental Neuroscience, 14(7–8), 945–959.Franceschini, I. A., & Barnett, S. C. (1996). Low-affinity NGF-receptor and E-N-CAM expression define two types of olfactory nerve ensheathing cells that share a common lineage. Developmental Biology, 173(1), 327–343.Runyan, S. A., & Phelps, P. E. (2009). Mouse olfactory ensheathing glia enhance axon outgrowth on a myelin substrate in vitro. Experimental Neurology, 216(1), 95–104.Shen, Y., Qian, Y., Zhang, H., Zuo, B., Lu, Z., Fan, Z., et al. (2010). Guidance of olfactory ensheathing cell growth and migration on electrospun silk fibroin scaffolds. Cell Transplantation, 19(2), 147–157.Li, B.-C., Jiao, S.-S., Xu, C., You, H., & Chen, J.-M. (2010). PLGA conduit seeded with olfactory ensheathing cells for bridging sciatic nerve defect of rats. Journal of Biomedical Materials Research, Part A, 94(3), 769–780.Clements, I. P., Kim, Y. T., English, A. W., Lu, X., Chung, A., & Bellamkonda, R. V. (2009). Thin-film enhanced nerve guidance channels for peripheral nerve repair. Biomaterials, 30(23–24), 3834–3846.Martín-López, E., Nieto-Díaz, M., & Nieto-Sampedro, M. (2012). Differential adhesiveness and neurite-promoting activity for neural cells of chitosan, gelatin, and poly-l-lysine films. Journal of Biomaterials Applications, 26(7), 791–809.Cai, J., Peng, X., Nelson, K. D., Eberhart, R., & Smith, G. M. (2005). Permeable guidance channels containing microfilament scaffolds enhance axon growth and maturation. Journal of Biomedical Material Research Part A, 75(2), 374–386.Novikova, L. N., Mosahebi, A., Wiberg, M., Terenghi, G., Kellerth, J. O., & Novikov, L. N. (2006). Alginate hydrogel and matrigel as potential cell carriers for neurotransplantation. Journal of Biomedical Materials Research, Part A, 77(2), 242–252.Tang, Z. P., Liu, N., Li, Z. W., Xie, X. W., Chen, Y., Shi, Y. H., et al. (2010). In vitro evaluation of the compatibility of a novel collagen-heparan sulfate biological scaffold with olfactory ensheathing cells. Chinese Medical Journal (English), 123(10), 1299–1304.Wang, B., Zhao, Y., Lin, H., Chen, B., Zhang, J., Zhang, J., et al. (2006). Phenotypical analysis of adult rat olfactory ensheathing cells on 3-D collagen scaffolds. Neuroscience Letters, 401(1–2), 65–70.Guarnieri, D., De Capua, A., Ventre, M., Borzacchiello, A., Pedone, C., Marasco, D., et al. (2010). Covalently immobilized RGD gradient on PEG hydrogel scaffold influences cell migration parameters. Acta Biomaterialia, 6(7), 2532–2539.Ngo, T. T., Waggoner, P. J., Romero, A. A., Nelson, K. D., Eberhart, R. C., & Smith, G. M. (2003). Poly(l-lactide) microfilaments enhance peripheral nerve regeneration across extended nerve lesions. Journal of Neuroscience Research, 72(2), 227–238.Schnell, E., Klinkhammer, K., Balzer, S., Brook, G., Klee, D., Dalton, P., et al. (2007). Guidance of glial cell migration and axonal growth on electrospun nanofibers of poly-e-caprolactone and a collagen/poly-e-caprolactone blend. Biomaterials, 28(19), 3012–3025.Lim, S. H., Liu, X. Y., Song, H., Yarema, K. J., & Mao, H. Q. (2010). The effect of nanofiber-guided cell alignment on the preferential differentiation of neural stem cells. Biomaterials, 31(34), 9031–9039.Wong, D. Y., Hollister, S. J., Krebsbach, P. H., & Nosrat, C. (2007). Poly(epsilon-caprolactone) and poly (l-lactic-co-glycolic acid) degradable polymer sponges attenuate astrocyte response and lesion growth in acute traumatic brain injury. Tissue Engineering, 13(10), 2515–2523.Wong, D. Y., Krebsbach, P. H., & Hollister, S. J. (2008). Brain cortex regeneration affected by scaffold architectures. Journal of Neurosurgery, 109(4), 715–722.Wong, D. Y., Leveque, J. C., Brumblay, H., Krebsbach, P. H., Hollister, S. J., & Lamarca, F. (2008). Macro-architectures in spinal cord scaffold implants influence regeneration. Journal of Neurotrauma, 25(8), 1027–1037.Pierucci, A., de Duek, E. A., & de Oliveira, A. L. (2008). Peripheral nerve regeneration through biodegradable conduits prepared using solvent evaporation. Tissue Engineering Part A, 14(5), 595–606.Vleggeert-Lankamp, C. L., de Ruiter, G. C., Wolfs, J. F., Pego, A. P., van den Berg, R. J., Feirabend, H. K., et al. (2007). Pores in synthetic nerve conduits are beneficial to regeneration. Journal of Biomedical Material Research Part A, 80(4), 965–982.Cai, A. Q., Landman, K. A., & Hughes, B. D. (2007). Multi-scale modeling of a wound-healing cell migration assay. Journal of Theoretical Biology, 245(3), 576–594.Maini, P. K., McElwain, D. L., & Leavesley, D. I. (2004). Traveling wave model to interpret a wound-healing cell migration assay for human peritoneal mesothelial cells. Tissue Engineering, 10(3–4), 475–482.Dokukina, I. V., & Gracheva, M. E. (2010). A model of fibroblast motility on substrates with different rigidities. Biophysical Journal, 98(12), 2794–2803.Schneider, I. C., & Haugh, J. M. (2004). Spatial analysis of 3′ phosphoinositide signaling in living fibroblasts: II. Parameter estimates for individual cells from experiments. Biophysical Journal, 86(1), 599–608.Marcy, Y., Prost, J., Carlier, M.-F., & Sykes, C. C. (2004). Forces generated during actin-based propulsion: A direct measurement by micromanipulation. Proceedings of the National academy of Sciences of the United States of America, 101(16), 5992–5997.Mogilner, A., & Oster, G. (2003). Polymer motors: Pushing out the front and pulling up the back. Current Biology, 13(18), R721–R733.Cheng, G., Youssef, B. B., Markenscoff, P., & Zygourakis, K. (2006). Cell population dynamics modulate the rates of tissue growth processes. Biophysical Journal, 90(3), 713–724.Galbusera, F., Cioffi, M., Raimondi, M. T., & Pietrabissa, R. (2007). Computational modeling of combined cell population dynamics and oxygen transport in engineered tissue subject to interstitial perfusion. Computer Methods Biomechanics and Biomedical Engineering, 10(4), 279–287.Hatzikirou, H., & Deutsch, A. (2008). Cellular automata as microscopic models of cell migration in heterogeneous environments. Current Topics in Developmental Biology, 81, 401–434.Reffay, M., Petitjean, L., Coscoy, S., Grasland-Mongrain, E., Amblard, F., Buguin, A., et al. (2011). Orientation and polarity in collectively migrating cell structures: Statics and dynamics. Biophysical Journal, 100(11), 2566–2575.Chung, C. A., Yang, C. W., & Chen, C. W. (2006). Analysis of cell growth and diffusion in a scaffold for cartilage tissue engineering. Biotechnology and Bioengineering, 94(6), 1138–1146.Dunn, J. C., Chan, W. Y., Cristini, V., Kim, J. S., Lowengrub, J., Singh, S., et al. (2006). Analysis of cell growth in three-dimensional scaffolds. Tissue Engineering, 12(4), 705–716.Harms, B. D., Bassi, G. M., Horwitz, A. R., & Lauffenburger, D. A. (2005). Directional persistence of EGF-induced cell migration is associated with stabilization of lamellipodial protrusions. Biophysical Journal, 88(2), 1479–1488.Lemon, G., & King, J. (2007). Travelling-wave behaviour in a multiphase model of a population of cells in an artificial scaffold. Journal of Mathematical Biology, 55(4), 449–480.Fisher, R. (1937). The wave of advance of advantageous genes. Annals of Eugenics, 7, 355–369.Graner, F.o., & Glazier, J. A. (1992). Simulation of biological cell sorting using a two-dimensional extended Potts model. Physical Review Letters, 69(13), 2013–2016.Ouaknin, G. Y., & Bar-Yoseph, P. Z. (2009). Stochastic collective movement of cells and fingering morphology: No maverick cells. Biophysical Journal, 97(7), 1811–1821.Savill, N. J., & Hogeweg, P. (1997). Modelling morphogenesis: From single cells to crawling slugs. Journal of Theoretical Biology, 184(3), 229–235.Brockes, J. P., Fields, K. L., & Raff, M. C. (1979). Studies on cultured rat Schwann cells. I. Establishment of purified populations from cultures of peripheral nerve. Brain Research, 165, 105–118.Selinummi, J., Seppala, J., Yli-Harja, O., & Puhakka, J. A. (2005). Software for quantification of labeled bacteria from digital microscope images by automated image analysis. BioTechniques, 39(6), 859–863.Gupta, D., Venugopal, J., Prabhakaran, M. P., Dev, V. R., Low, S., Choon, A. T., et al. (2009). Aligned and random nanofibrous substrate for the in vitro culture of Schwann cells for neural tissue engineering. Acta Biomaterialia, 5(7), 2560–2569.Nisbet, D. R., Yu, L. M., Zahir, T., Forsythe, J. S., & Shoichet, M. S. (2008). Characterization of neural stem cells on electrospun poly(epsilon-caprolactone) submicron scaffolds: Evaluating their potential in neural tissue engineering. Journal of Biomaterials Science, Polymer Edition, 19(5), 623–634.Huang, Z. H., Wang, Y., Cao, L., Su, Z. D., Zhu, Y. L., Chen, Y. Z., et al. (2008). Migratory properties of cultured olfactory ensheathing cells by single-cell migration assay. Cell Research, 18, 479–490.Ekberg, J. A. K., Amaya, D., Mackay-Sim, A., & St. John, J. A. (2012). The migratory of olfactory ensheathing cells during development and regeneration. Neurosignals. doi: 10.1159/000330895 .Ruitenberg, M. J., Vukovic, J., Sarich, J., Busfield, S. J., & Plant, G..W. (2006). Olfactory ensheathing cells: characteristics, genetic engineering, and therapeutic potential. Journal of Neurotrauma, 23, 468–478.Chaikin, P. M., & Lubensky, T. C. (1995). Principles of condensed matter physics (p. 371). Cambridge, UK: Cambridge University Press.Simpson, M. J., Landman, K. A., & Hughes, B. D. (2010). Cell invasion with proliferation mechanisms motivated by time-lapse data. Physica A, 389, 3779–3790

CCL2-Expressing Astrocytes Mediate the Extravasation of T Lymphocytes in the Brain. Evidence from Patients with Glioma and Experimental Models In Vivo

CCL2 is a chemokine involved in brain inflammation, but the way in which it contributes to the entrance of lymphocytes in the parenchyma is unclear. Imaging of the cell type responsible for this task and details on how the process takes place in vivo remain elusive. Herein, we analyze the cell type that overexpresses CCL2 in multiple scenarios of T-cell infiltration in the brain and in three different species. We observe that CCL2+ astrocytes play a part in the infiltration of T-cells in the brain and our analysis shows that the contact of T-cells with perivascular astrocytes occurs, suggesting that may be an important event for lymphocyte extravasation

Incidence and mortality rates of selected infection-related cancers in Puerto Rico and in the United States

<p>Abstract</p> <p>Background</p> <p>In 2002, 17.8% of the global cancer burden was attributable to infections. This study assessed the age-standardized incidence and mortality rates of stomach, liver, and cervical cancer in Puerto Rico (PR) for the period 1992-2003 and compared them to those of Hispanics (USH), non-Hispanic Whites (NHW), and non-Hispanic Blacks (NHB) in the United States (US).</p> <p>Methods</p> <p>Age-standardized rates [ASR(World)] were calculated based on cancer incidence and mortality data from the PR Cancer Central Registry and SEER, using the direct method and the world population as the standard. Annual percent changes (APC) were calculated using the Poisson regression model from 1992-2003.</p> <p>Results</p> <p>The incidence and mortality rates from stomach, liver and cervical cancer were lower in NHW than PR; with the exception of mortality from cervical cancer which was similar in both populations. Meanwhile, the incidence rates of stomach, liver and cervical cancers were similar between NHB and PR; except for NHB women who had a lower incidence rate of liver cancer than women in PR. NHB had a lower mortality from liver cancer than persons in PR, and similar mortality from stomach cancer.</p> <p>Conclusions</p> <p>The burden of liver, stomach, and cervical cancer in PR compares to that of USH and NHB and continues to be a public health priority. Public health efforts are necessary to further decrease the burden of cancers associated to infections in these groups, the largest minority population groups in the US. Future studies need to identify factors that may prevent infections with cancer-related agents in these populations. Strategies to increase the use of preventive strategies, such as vaccination and screening, among minority populations should also be developed.</p

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

New Semi-Biodegradable Materials from Semi-Interpenetrated Networks of Poly(epsilon-caprolactone) and Poly(ethyl acrylate)

[EN] Semi-degradable materials may have many applications. Here poly(ethyl acrylate) and poly(&#1013;-caprolactone) were combined as semi-interpenetrated networks, and thoroughly characterized in terms of final composition, interactions between components, wettability, and mechanical properties. PCL modulates the mechanical properties of the PEA elastomeric network. Cultures of fibroblasts and adipose-tissue derived stem cells showed excellent biological performance of the materials. The results are relevant for applications seeking materials leaving a permanent supporting skeleton after the partial degradation, as in patches for cardiac regeneration or in abdominal wall meshes.The authors acknowledge funding through the European Commission FP7 project RECATABI (NMP3-SL-2009-229239), and from the Spanish Ministerio de Ciencia e Innovacion through projects MAT2011-28791-C03-02 and -03. Dr. J. C. Chachques (Hopital Europeen Georges Pompidou, Paris, France) and Drs. A. Bayes-Genis and C. Soler-Botija (Hospital Germans Trias i Pujol, Badalona, Spain) are thanked for kindly providing and expanding the ASCs employed in this study.Lozano Picazo, P.; Perez Garnes, M.; Martínez Ramos, C.; Vallés Lluch, A.; Monleón Pradas, M. (2015). New Semi-Biodegradable Materials from Semi-Interpenetrated Networks of Poly(epsilon-caprolactone) and Poly(ethyl acrylate). Macromolecular Bioscience. 15(2):229-240. https://doi.org/10.1002/mabi.201400331229240152Jawad, H., Ali, N. N., Lyon, A. R., Chen, Q. Z., Harding, S. E., & Boccaccini, A. R. (2007). Myocardial tissue engineering: a review. Journal of Tissue Engineering and Regenerative Medicine, 1(5), 327-342. doi:10.1002/term.46Caspi, O., Lesman, A., Basevitch, Y., Gepstein, A., Arbel, G., Habib, I. H. M., … Levenberg, S. (2007). Tissue Engineering of Vascularized Cardiac Muscle From Human Embryonic Stem Cells. Circulation Research, 100(2), 263-272. doi:10.1161/01.res.0000257776.05673.ffSteinhauser, M. L., & Lee, R. T. (2011). Regeneration of the heart. EMBO Molecular Medicine, 3(12), 701-712. doi:10.1002/emmm.201100175Atzet, S., Curtin, S., Trinh, P., Bryant, S., & Ratner, B. (2008). Degradable Poly(2-hydroxyethyl methacrylate)-co-polycaprolactone Hydrogels for Tissue Engineering Scaffolds. Biomacromolecules, 9(12), 3370-3377. doi:10.1021/bm800686hVenugopal, J. R., Prabhakaran, M. P., Mukherjee, S., Ravichandran, R., Dan, K., & Ramakrishna, S. (2011). Biomaterial strategies for alleviation of myocardial infarction. Journal of The Royal Society Interface, 9(66), 1-19. doi:10.1098/rsif.2011.0301Nair, L. S., & Laurencin, C. T. (2007). Biodegradable polymers as biomaterials. Progress in Polymer Science, 32(8-9), 762-798. doi:10.1016/j.progpolymsci.2007.05.017Shoichet, M. S. (2010). Polymer Scaffolds for Biomaterials Applications. Macromolecules, 43(2), 581-591. doi:10.1021/ma901530rCharlton, D. C., Peterson, M. G. E., Spiller, K., Lowman, A., Torzilli, P. A., & Maher, S. A. (2008). Semi-Degradable Scaffold for Articular Cartilage Replacement. Tissue Engineering Part A, 14(1), 207-213. doi:10.1089/ten.a.2006.0344Spiller, K. L., Holloway, J. L., Gribb, M. E., & Lowman, A. M. (2010). Design of semi-degradable hydrogels based on poly(vinyl alcohol) and poly(lactic-co-glycolic acid) for cartilage tissue engineering. Journal of Tissue Engineering and Regenerative Medicine, 5(8), 636-647. doi:10.1002/term.356Scholten, P. M., Ng, K. W., Joh, K., Serino, L. P., Warren, R. F., Torzilli, P. A., & Maher, S. A. (2011). A semi-degradable composite scaffold for articular cartilage defects. Journal of Biomedical Materials Research Part A, 97A(1), 8-15. doi:10.1002/jbm.a.33005Pérez Olmedilla, M., Garcia-Giralt, N., Pradas, M. M., Ruiz, P. B., Gómez Ribelles, J. L., Palou, E. C., & García, J. C. M. (2006). Response of human chondrocytes to a non-uniform distribution of hydrophilic domains on poly (ethyl acrylate-co-hydroxyethyl methacrylate) copolymers. Biomaterials, 27(7), 1003-1012. doi:10.1016/j.biomaterials.2005.07.030Rico, P., Hernández, J. C. R., Moratal, D., Altankov, G., Pradas, M. M., & Salmerón-Sánchez, M. (2009). Substrate-Induced Assembly of Fibronectin into Networks: Influence of Surface Chemistry and Effect on Osteoblast Adhesion. Tissue Engineering Part A, 15(11), 3271-3281. doi:10.1089/ten.tea.2009.0141Soria, J. M., Sancho-Tello, M., Esparza, M. A. G., Mirabet, V., Bagan, J. V., Monleón, M., & Carda, C. (2011). Biomaterials coated by dental pulp cells as substrate for neural stem cell differentiation. Journal of Biomedical Materials Research Part A, 97A(1), 85-92. doi:10.1002/jbm.a.33032Campillo-Fernandez, A. J., Pastor, S., Abad-Collado, M., Bataille, L., Gomez-Ribelles, J. L., Meseguer-Dueñas, J. M., … Ruiz-Moreno, J. M. (2007). Future Design of a New Keratoprosthesis. Physical and Biological Analysis of Polymeric Substrates for Epithelial Cell Growth. Biomacromolecules, 8(8), 2429-2436. doi:10.1021/bm0703012Campillo-Fernández, A. J., Unger, R. E., Peters, K., Halstenberg, S., Santos, M., Sánchez, M. S., … Kirkpatrick, C. J. (2009). Analysis of the Biological Response of Endothelial and Fibroblast Cells Cultured on Synthetic Scaffolds with Various Hydrophilic/Hydrophobic Ratios: Influence of Fibronectin Adsorption and Conformation. Tissue Engineering Part A, 15(6), 1331-1341. doi:10.1089/ten.tea.2008.0146Veiga, D. D., Antunes, J. C., Gómez, R. G., Mano, J. F., Ribelles, J. L. G., & Soria, J. M. (2010). Three-Dimensional Scaffolds as a Model System for Neural and Endothelial ‘In Vitro’ Culture. Journal of Biomaterials Applications, 26(3), 293-310. doi:10.1177/0885328210365005Soria, J. M., Martínez Ramos, C., Salmerón Sánchez, M., Benavent, V., Campillo Fernández, A., Gómez Ribelles, J. L., … Barcia, J. A. (2006). Survival and differentiation of embryonic neural explants on different biomaterials. Journal of Biomedical Materials Research Part A, 79A(3), 495-502. doi:10.1002/jbm.a.30803Soria, J. M., Martínez Ramos, C., Bahamonde, O., García Cruz, D. M., Salmerón Sánchez, M., García Esparza, M. A., … Barcia, J. A. (2007). Influence of the substrate’s hydrophilicity on thein vitro Schwann cells viability. Journal of Biomedical Materials Research Part A, 83A(2), 463-470. doi:10.1002/jbm.a.31297Martínez-Ramos, C., Vallés-Lluch, A., Verdugo, J. M. G., Ribelles, J. L. G., Barcia Albacar, J. A., Orts, A. B., … Pradas, M. M. (2012). Channeled scaffolds implanted in adult rat brain. Journal of Biomedical Materials Research Part A, 100A(12), 3276-3286. doi:10.1002/jbm.a.34273Woodruff, M. A., & Hutmacher, D. W. (2010). The return of a forgotten polymer—Polycaprolactone in the 21st century. Progress in Polymer Science, 35(10), 1217-1256. doi:10.1016/j.progpolymsci.2010.04.002Dash, T. K., & Konkimalla, V. B. (2012). Poly-є-caprolactone based formulations for drug delivery and tissue engineering: A review. Journal of Controlled Release, 158(1), 15-33. doi:10.1016/j.jconrel.2011.09.064Ulery, B. D., Nair, L. S., & Laurencin, C. T. (2011). Biomedical applications of biodegradable polymers. Journal of Polymer Science Part B: Polymer Physics, 49(12), 832-864. doi:10.1002/polb.22259Middleton, J. C., & Tipton, A. J. (2000). Synthetic biodegradable polymers as orthopedic devices. Biomaterials, 21(23), 2335-2346. doi:10.1016/s0142-9612(00)00101-0Sperling, L. H. (1981). Interpenetrating Polymer Networks and Related Materials. doi:10.1007/978-1-4684-3830-7Más Estellés, J., Vidaurre, A., Meseguer Dueñas, J. M., & Castilla Cortázar, I. (2007). Physical characterization of polycaprolactone scaffolds. Journal of Materials Science: Materials in Medicine, 19(1), 189-195. doi:10.1007/s10856-006-0101-2Shafy, A., Fink, T., Zachar, V., Lila, N., Carpentier, A., & Chachques, J. C. (2012). Development of cardiac support bioprostheses for ventricular restoration and myocardial regeneration. European Journal of Cardio-Thoracic Surgery, 43(6), 1211-1219. doi:10.1093/ejcts/ezs480Sarac, A. S. (1999). Redox polymerization. Progress in Polymer Science, 24(8), 1149-1204. doi:10.1016/s0079-6700(99)00026-xYagci, C., & Yildiz, U. (2005). Redox polymerization of methyl methacrylate with allyl alcohol 1,2-butoxylate-block-ethoxylate initiated by Ce(IV)/HNO3 redox system. European Polymer Journal, 41(1), 177-184. doi:10.1016/j.eurpolymj.2004.08.008Diego, R. B., Olmedilla, M. P., Aroca, A. S., Ribelles, J. L. G., Pradas, M. M., Ferrer, G. G., & Sánchez, M. S. (2005). Acrylic scaffolds with interconnected spherical pores and controlled hydrophilicity for tissue engineering. Journal of Materials Science: Materials in Medicine, 16(8), 693-698. doi:10.1007/s10856-005-2604-7García, A. J. (s. f.). Interfaces to Control Cell-Biomaterial Adhesive Interactions. Advances in Polymer Science, 171-190. doi:10.1007/12_071Dado, D., & Levenberg, S. (2009). Cell–scaffold mechanical interplay within engineered tissue. Seminars in Cell & Developmental Biology, 20(6), 656-664. doi:10.1016/j.semcdb.2009.02.001Engler, A. J., Sen, S., Sweeney, H. L., & Discher, D. E. (2006). Matrix Elasticity Directs Stem Cell Lineage Specification. Cell, 126(4), 677-689. doi:10.1016/j.cell.2006.06.04

Three-dimensional vascular microenvironment landscape in human glioblastoma

The cellular complexity of glioblastoma microenvironments is still poorly understood. In-depth, cell-resolution tissue analyses of human material are rare but highly necessary to understand the biology of this deadly tumor. Here we present a unique 3D visualization revealing the cellular composition of human GBM in detail and considering its critical association with the neo-vascular niche. Our images show a complex vascular map of human 3D biopsies with increased vascular heterogeneity and altered spatial relationship with astrocytes or glioma-cell counterparts. High-resolution analysis of the structural layers of the blood brain barrier showed a multilayered fenestration of endothelium and basement membrane. Careful examination of T cell position and migration relative to vascular walls revealed increased infiltration corresponding with tumor proliferation. In addition, the analysis of the myeloid landscape not only showed a volumetric increase in glioma-associated microglia and macrophages relative to GBM proliferation but also revealed distinct phenotypes in tumor nest and stroma. Images and data sets are available on demand as a resource for public access

Human glioma shows CCL2⁺ cells.

<p>(A) The 14 cases of glioma analyzed show CCL2 expression in the tumorigenic areas. Samples of gliomas were immunostained to detect the expression of CCL2. All 14 cases analyzed showed expression of CCL2 in the neoplasic areas. CCL2-expressing cells are localized in the brain parenchyma itself and their number and intensity increase towards the necrotic areas. CCL2-expressing cells can also be seen around BVs (16–19). In addition, counterstaining with hematoxilin is also shown at BV levels (16′–19′) to corroborate the presence of endothelial nuclei. Insert show a detail of the endothelial nuclei. Scale bar; 1–21: 400 µm, 22–24: 60 µm. (B) Tumor cells present high immunoreactivity for GFAP in tumor areas, demonstrating the typical astrocytic cell type. CCL2⁺ cells show a characteristic astrocytic morphology. Scale bar: 30 µm. (C) BVs in, or close to the putative tumorigenic areas show high immunoreactivity for CCL2 in contrast to normal tissue. Additionally, counterstaining with hematoxilin (HHS) is also shown at the same levels. The insert shows a detail of the endothelial nuclei. Scale bar: 100 µm.</p

Intracerebral blocking of CCL2 attenuates the LPS-mediated T-cell infiltration.

<p>(A) Detail of CD4⁺ and CD8⁺ T-cell immunostaining in the striatum of LPS injected mice. Scale bar: 20 µm. (B) The number of infiltrated T-cells (CD4⁺, CD8⁺ and CD3⁺ T-cells) correlates with the number of CCL2⁺ cells in the areas of LPS injection. (C) Intraparenchymal injection of anti-CCL2 antibodies attenuates the LPS-induced infiltration of lymphocytes in the mouse brain parenchyma. The diagram on the top shows the arrangement of the experiment. Graphs show the density of CD8 and CD4 T-cells in the brain parenchyma surrounding the injection site. (D) Astrocytes express CCL2 after LPS injection in mouse brain. Confocal images of the injected areas show the co-localization of GFAP⁺ astrocytes (green) and CCL2 (red) in mouse brain. DAPI (blue) was used as a nuclear counterstaing. * p<0.05 ANOVA-test.</p

T cells express CCL2 receptor.

<p>Expression of CCR2 in T-cells in human glioma (top panel) and monkey brain (bottom panel). CD3⁺ T-cells (green) express CCR2 in their surface (magenta). Nucleus is stained with DAPI (blue).</p