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Cell culture platform providing accurate environmental control and pressure to model tumour micro-environments

The xcellbio AVATAR™ System lets you fine-tune oxygen and pressure levels to cater culture conditions to your cell type of interest. Customising settings based on tumour type or native microenvironment allows cells to behave as they would in vivo

Introduction

The AVATAR™ Cell Control System lets you generate your cells of interest in the tumour microenvironment ((TME) to optimize growth rate, functional activity or phenotypic change of interest.

Using correct hypoxia conditions is now widely accepted among cell scientists (2019 Noble Prize for Medicine or Physiology, awarded to William Kaelin, Sir Peter Ratcliffe and Gregg Semenza). Today the next dimension is physiological pressure. The Avatar provides both controlled O2 and physiological pressures with absolute accuracy.

 

Key application areas for the AVATAR™ include:

Tumour Environment Modelling: Identify novel checkpoint inhibitors that work effectively under immunosuppressive tumour microenvironments

Stem Cell Differentiation: Enhance IPSC reprogramming and stem cell differentiation efficiency

Cell Therapy Optimisation: Enhance CAR-T potency, persistence and homing

Organoid Research: Generate organoids and spheroids that thrive under hypoxic culture condition

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Temperature Range – 30 – 45 degrees C @ +/- 0.1% accuracy

Oxygen Range – 0.1 – 22% @ +/- 0.1% accuracy

Carbon Dioxide Range – 0 – 20% @ +/- 0.1% accuracy

Pressure Range – 0.1 – 5 psig @+/-2.5% accuracy

Chamber Capacity – 3.7 litres (224 cubic inches)

Dimensions (W × D × H) – 34.3 × 33.3 × 30.5 cm (13.5 × 13.1 × 12 in.)

Shipping Weight – 23 kg (51 lbs.)

Comprehensive Environmental Control
Carry out hypoxia and physiological pressure studies in the same system. Study how cells respond under physiological culture conditions

Target Your Chosen Cell Population
Tune your cell’s micro-environment to control differentiation or maintain the current state, both reliably and precisely. Model the tumour microenvironment

Cell Flexibility
Work with immune cells, stem cells, tumour cells, organoids and even rare, precious cells you’ve never been able to expand before

Expand Cells Easily
Expand challenging cell types easily and reproducibly for a broad range of primary cells, reducing reagent costs

Compact and Modular Design
~30 cm cube saving valuable benchspace. Modular design allows add-on units for parallel studies

ISSCR_June2017_Application of atmospheric pressure during culture promotes neural differentiation in iPSCs

Park et al – IJMS 2020 – Pressure Stimuli Improve the Proliferation of Wharton’s Jelly-Derived Mesenchymal Stem Cells under Hypoxic Culture Conditions

Hypoxia – Cancer

  • •Carmeliet, P., & Jain, R. K. (2011). Principles and mechanisms of vessel normalization for cancer and    other angiogenic diseases. Nature Reviews Drug Discovery, 10(6), 417–427. https://doi.org/10.1038/nrd3455
    •FUKUMURA, D., DUDA, D. G., MUNN, L. L., & JAIN, R. K. (2010). Tumor Microvasculature and Microenvironment: Novel Insights Through Intravital Imaging in Pre-Clinical Models. Microcirculation, 17(3), 206–225. https://doi.org/10.1111/j.1549-8719.2010.00029.x
    •Goel, S., Duda, D. G., Xu, L., Munn, L. L., Boucher, Y., Fukumura, D., & Jain, R. K. (2011). Normalization of the Vasculature for Treatment of Cancer and Other Diseases. Physiological Reviews, 91(3), 1071–1121. https://doi.org/10.1152/physrev.00038.2010
    •Li, Y., Patel, S. P., Roszik, J., & Qin, Y. (2018). Hypoxia-Driven Immunosuppressive Metabolites in the Tumor Microenvironment: New Approaches for Combinational Immunotherapy. Frontiers in Immunology, 9(JUL). https://doi.org/10.3389/fimmu.2018.01591
    •Swartz, M. A., Iida, N., Roberts, E. W., Sangaletti, S., Wong, M. H., Yull, F. E., Coussens, L. M., & DeClerck, Y. A. (2012). Tumor microenvironment complexity: Emerging roles in cancer therapy. Cancer Research, 72(10), 2473–2480. https://doi.org/10.1158/0008-5472.CAN-12-0122
    •Keith, B., & Simon, M. C. (2007). Hypoxia-Inducible Factors, Stem Cells, and Cancer. Cell, 129(3), 465–472. https://doi.org/10.1016/j.cell.2007.04.019
    •Wilson, W. R., & Hay, M. P. (2011). Targeting hypoxia in cancer therapy. Nature Reviews Cancer, 11(6), 393–410. https://doi.org/10.1038/nrc3064
    •Semenza, G. L. (2012). Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. Trends in Pharmacological Sciences, 33(4), 207–214. https://doi.org/10.1016/j.tips.2012.01.005
    •Brown, J. M., & Wilson, W. R. (2004). Exploiting tumour hypoxia in cancer treatment. Nature Reviews Cancer, 4(6), 437–447. https://doi.org/10.1038/nrc1367
    •Kizaka-Kondoh, S., Inoue, M., Harada, H., & Hiraoka, M. (2003). Tumor hypoxia: A target for selective cancer therapy. Cancer Science, 94(12), 1021–1028. https://doi.org/10.1111/j.1349-7006.2003.tb01395.x

Hypoxia – Immunity

  • Cho, S. H., Raybuck, A. L., Blagih, J., Kemboi, E., Haase, V. H., Jones, R. G., & Boothby, M. R. (2019). Hypoxia-inducible factors in CD4 + T cells promote metabolism, switch cytokine secretion, and T cell help in humoral immunity. Proceedings of the National Academy of Sciences, 116(18), 8975–8984. https://doi.org/10.1073/pnas.1811702116
  • Gajewski, T. F., Schreiber, H., & Fu, Y.-X. (2013). Innate and adaptive immune cells in the tumor microenvironment. Nature Immunology, 14(10), 1014–1022. https://doi.org/10.1038/ni.2703
  • Nizet, V., & Johnson, R. S. (2009). Interdependence of hypoxic and innate immune responses. Nature Reviews Immunology, 9(9), 609–617. https://doi.org/10.1038/nri2607
  • Noman, M. Z., Hasmim, M., Messai, Y., Terry, S., Kieda, C., Janji, B., & Chouaib, S. (2015). Hypoxia: a key player in antitumor immune response. A Review in the Theme: Cellular Responses to Hypoxia. American Journal of Physiology-Cell Physiology, 309(9), C569–C579. https://doi.org/10.1152/ajpcell.00207.2015
  • Rama, I., Bruene, B., Torras, J., Koehl, R., Cruzado, J. M., Bestard, O., Franquesa, M., Lloberas, N., Weigert, A., Herrero-Fresneda, I., Gulias, O., & Grinyó, J. M. (2008). Hypoxia stimulus: An adaptive immune response during dendritic cell maturation. Kidney International, 73(7), 816–825. https://doi.org/10.1038/sj.ki.5002792
  • Sitkovsky, M. V. (2009). T regulatory cells: hypoxia-adenosinergic suppression and re-direction of the immune response. Trends in Immunology, 30(3), 102–108. https://doi.org/10.1016/j.it.2008.12.002
  • Sitkovsky, M. V., Lukashev, D., Apasov, S., Kojima, H., Koshiba, M., Caldwell, C., Ohta, A., & Thiel, M. (2004). Physiological control of immune response and inflammatory tissue damage by hypoxia-inducible factors and adenosine A2A receptors. Annual Review of Immunology, 22(1), 657–682. https://doi.org/10.1146/annurev.immunol.22.012703.104731

Pressure – Cancer

  • DiResta, G. R., Nathan, S. S., Manoso, M. W., Casas-Ganem, J., Wyatt, C., Kubo, T., Boland, P. J., Athanasian, E. A., Miodownik, J., Gorlick, R., & Healey, J. H. (2005). Cell Proliferation of Cultured Human Cancer Cells are Affected by the Elevated Tumor Pressures that Exist In Vivo. Annals of Biomedical Engineering, 33(9), 1270–1280. https://doi.org/10.1007/s10439-005-5732-9
  • Fernández-Sánchez, M. E., Barbier, S., Whitehead, J., Béalle, G., Michel, A., Latorre-Ossa, H., Rey, C., Fouassier, L., Claperon, A., Brullé, L., Girard, E., Servant, N., Rio-Frio, T., Marie, H., Lesieur, S., Housset, C., Gennisson, J.-L., Tanter, M., Ménager, C., … Farge, E. (2015). Mechanical induction of the tumorigenic β-catenin pathway by tumour growth pressure. Nature, 523(7558), 92–95. https://doi.org/10.1038/nature14329
  • FUKUMURA, D., DUDA, D. G., MUNN, L. L., & JAIN, R. K. (2010). Tumor Microvasculature and Microenvironment: Novel Insights Through Intravital Imaging in Pre-Clinical Models. Microcirculation, 17(3), 206–225. https://doi.org/10.1111/j.1549-8719.2010.00029.x
  • Glen F. Rall, M. J. S. B. M. D. (2018). Reengineering the Physical Microenvironment of Tumors to Improve Drug Delivery and Efficacy: From Mathematical Modeling to Bench to Bedside. Trends in Cancer, 4(4), 292–319. https://doi.org/10.1016/j.trecan.2018.02.005
  • Goel, S., Duda, D. G., Xu, L., Munn, L. L., Boucher, Y., Fukumura, D., & Jain, R. K. (2011). Normalization of the Vasculature for Treatment of Cancer and Other Diseases. Physiological Reviews, 91(3), 1071–1121. https://doi.org/10.1152/physrev.00038.2010
  • Heldin, C. H., Rubin, K., Pietras, K., & Östman, A. (2004). High interstitial fluid pressure – An obstacle in cancer therapy. Nature Reviews Cancer, 4(10), 806–813. https://doi.org/10.1038/nrc1456
  • Hofmann, M., Guschel, M., Bernd, A., Bereiter-Hahn, J., Kaufmann, R., Tandi, C., Helge, W., & Kippenberger, S. (2006). Lowering of tumor interstitial fluid pressure reduces tumor cell proliferation in a xenograft tumor model. Neoplasia, 8(2), 89–95. https://doi.org/10.1593/neo.05469
  • Nathan, S. S., DiResta, G. R., Casas-Ganem, J. E., Hoang, B. H., Sowers, R., Yang, R., Huvos, A. G., Gorlick, R., & Healey, J. H. (2005). Elevated physiologic tumor pressure promotes proliferation and chemosensitivity in human osteosarcoma. Clinical Cancer Research, 11(6), 2389–2397. https://doi.org/10.1158/1078-0432.CCR-04-2048
  • Piotrowski-Daspit, A. S., Tien, J., & Nelson, C. M. (2016). Interstitial fluid pressure regulates collective invasion in engineered human breast tumors via Snail, vimentin, and E-cadherin. Integrative Biology, 8(3), 319–331. https://doi.org/10.1039/c5ib00282f
  • Provenzano, P. P., & Hingorani, S. R. (2013). Hyaluronan, fluid pressure, and stromal resistance in pancreas cancer. British Journal of Cancer, 108(1), 1–8. https://doi.org/10.1038/bjc.2012.569
  • Rofstad, E. K., Galappathi, K., & Mathiesen, B. S. (2014). Tumor Interstitial Fluid Pressure-A Link between Tumor Hypoxia, Microvascular Density, and Lymph Node Metastasis. Neoplasia, 16(7), 586–594. https://doi.org/10.1016/j.neo.2014.07.003
  • Sarntinoranont, M., Rooney, F., & Ferrari, M. (2003). Interstitial stress and fluid pressure within a growing tumor. Annals of Biomedical Engineering, 31(3), 327–335. https://doi.org/10.1114/1.1554923
  • Sottnik, J. L., Dai, J., Zhang, H., Campbell, B., & Keller, E. T. (2015). Tumor-Induced Pressure in the Bone Microenvironment Causes Osteocytes to Promote the Growth of Prostate Cancer Bone Metastases. Cancer Research, 75(11), 2151–2158. https://doi.org/10.1158/0008-5472.CAN-14-2493
  • Wu, M., Frieboes, H. B., McDougall, S. R., Chaplain, M. A. J., Cristini, V., & Lowengrub, J. (2013). The effect of interstitial pressure on tumor growth: Coupling with the blood and lymphatic vascular systems. Journal of Theoretical Biology, 320, 131–151. https://doi.org/10.1016/j.jtbi.2012.11.031

Pressure – Immunity

  • Lider, O., Karin, N., Shinitzky, M., & Cohen, I. R. (1987). Therapeutic vaccination against adjuvant arthritis using autoimmune T cells treated with hydrostatic pressure. Proceedings of the National Academy of Sciences, 84(13), 4577–4580. https://doi.org/10.1073/pnas.84.13.4577
  • Liu, C. S. C., Raychaudhuri, D., Paul, B., Chakrabarty, Y., Ghosh, A. R., Rahaman, O., Talukdar, A., & Ganguly, D. (2018). Cutting Edge: Piezo1 Mechanosensors Optimize Human T Cell Activation. The Journal of Immunology, 200(4), 1255–1260. https://doi.org/10.4049/jimmunol.1701118
  • Solis, A. G., Bielecki, P., Steach, H. R., Sharma, L., Harman, C. C. D., Yun, S., de Zoete, M. R., Warnock, J. N., To, S. D. F., York, A. G., Mack, M., Schwartz, M. A., Dela Cruz, C. S., Palm, N. W., Jackson, R., & Flavell, R. A. (2019). Mechanosensation of cyclical force by PIEZO1 is essential for innate immunity. Nature, 573(7772), 69–74. https://doi.org/10.1038/s41586-019-1485-8
  • Swartz, M. A., & Lund, A. W. (2012). Lymphatic and interstitial flow in the tumour microenvironment: Linking mechanobiology with immunity. Nature Reviews Cancer, 12(3), 210–219. https://doi.org/10.1038/nrc3186
  • Tolar, P., & Wack, A. (2019). Monocytes work harder under pressure. In Nature Immunology (Vol. 20, Issue 11, pp. 1422–1424). Nature Publishing Group. https://doi.org/10.1038/s41590-019-0523-x
  • Walmsley, S. R. (2019). Pressure regulates immune-cell function. Nature, 573(7772), 41–42. https://doi.org/10.1038/d41586-019-02339-4
  • Wu, M., Frieboes, H. B., McDougall, S. R., Chaplain, M. A. J., Cristini, V., & Lowengrub, J. (2013). The effect of interstitial pressure on tumor growth: Coupling with the blood and lymphatic vascular systems. Journal of Theoretical Biology, 320, 131–151. https://doi.org/10.1016/j.jtbi.2012.11.031
  • Estrada, R., Giridharan, G. A., Nguyen, M. D., Roussel, T. J., Shakeri, M., Parichehreh, V., Prabhu, S. D., & Sethu, P. (2011). Endothelial cell culture model for replication of physiological profiles of pressure, flow, stretch, and shear stress in vitro. Analytical Chemistry, 83(8), 3170–3177. https://doi.org/10.1021/ac2002998
  • Hansen, U., Schünke, M., Domm, C., Ioannidis, N., Hassenpflug, J., Gehrke, T., & Kurz, B. (2001). Combination of reduced oxygen tension and intermittent hydrostatic pressure: A useful tool in articular cartilage tissue engineering. Journal of Biomechanics, 34(7), 941–949. https://doi.org/10.1016/S0021-9290(01)00050-1
  • Kaarniranta, K., Elo, M., Sironen, R., Lammi, M. J., Goldring, M. B., Eriksson, J. E., Sistonen, L., & Helminen, H. J. (1998). Hsp70 accumulation in chondrocytic cells exposed to high continuous hydrostatic pressure coincides with mRNA stabilization rather than transcriptional activation (heat shock transcription factorheat shock elementcartilagechondrocyte). In Cell Biology Communicated by Darwin J. Prockop, MCP-Hahnemann Medical School (Vol. 95). www.pnas.org.
  • Liu, S., Tao, R., Wang, M., Tian, J., Genin, G. M., Lu, T. J., & Xu, F. (2019). Regulation of Cell Behavior by Hydrostatic Pressure. Applied Mechanics Reviews, 71(4), 1–13. https://doi.org/10.1115/1.4043947
  • Ozawa, H., Imamura, K., Abe, E., Takahashi, N., Hiraide, T., Shibasaki, Y., Fukuhara, T., & Suda, T. (1990). Effect of a continuously applied compressive pressure on mouse osteoblast‐like cells (MC3T3‐E1) in vitro. Journal of Cellular Physiology, 142(1), 177–185. https://doi.org/10.1002/jcp.1041420122
  • Prystopiuk, V., Fels, B., Simon, C. S., Liashkovich, I., Pasrednik, D., Kronlage, C., Wedlich-Söldner, R., Oberleithner, H., & Fels, J. (2018). A two-phase response of endothelial cells to hydrostatic pressure. Journal of Cell Science, 131(12), jcs206920. https://doi.org/10.1242/jcs.206920
  • Schwartz, E. A., Bizios, R., Medow, M. S., & Gerritsen, M. E. (1999). Exposure of human vascular endothelial cells to sustained hydrostatic pressure stimulates proliferation: Involvement of the α(V) integrins. Circulation Research, 84(3), 315–322. https://doi.org/10.1161/01.RES.84.3.315
  • Shin, H. Y., Gerritsen, M. E., & Bizios, R. (2002). Regulation of endothelial cell proliferation and apoptosis by cyclic pressure. Annals of Biomedical Engineering, 30(3), 297–304. https://doi.org/10.1114/1.1458595
  • Sumpio, B. E., Widmann, M. D., Ricotta, J., Awolesi, M. A., & Watase, M. (1994). Increased ambient pressure stimulates proliferation and morphologic changes in cultured endothelial cells. Journal of Cellular Physiology, 158(1), 133–139. https://doi.org/10.1002/jcp.1041580117
  • Wax, M. B., Tezel, G., Kobayashi, S., & Hernandez, M. R. (2000). Responses of different cell lines from ocular tissues to elevated hydrostatic pressure. British Journal of Ophthalmology, 84(4), 423–428. https://doi.org/10.1136/bjo.84.4.423
  • Wu, J., Mak, H. K., Chan, Y. K., Lin, C., Kong, C., Leung, C. K. S., & Shum, H. C. (2019). An in vitro pressure model towards studying the response of primary retinal ganglion cells to elevated hydrostatic pressures. Scientific Reports, 9(1), 1–12. https://doi.org/10.1038/s41598-019-45510-7

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