Figure 1. (a) Top view of the microfluidic-magnetophoretic device, (b) Schematic representation of the channel cross-sections studied in this work, and (c) the magnet position relative to the channel location (Sepy and Sepz are the magnet separation distances in y and z, respectively).

Continuous-Flow Separation of Magnetic Particles from Biofluids: How Does the Microdevice Geometry Determine the Separation Performance?

by 
Cristina González Fernández1, Jenifer Gómez Pastora2, Arantza Basauri1, Marcos Fallanza1, Eugenio Bringas1, Jeffrey J. Chalmers2 and Inmaculada Ortiz1,*
1Department of Chemical and Biomolecular Engineering, ETSIIT, University of Cantabria, Avda. Los Castros s/n, 39005 Santander, Spain
2William G. Lowrie Department of Chemical and Biomolecular Engineering, The Ohio State University, 151 W. Woodruff Ave., Columbus, OH 43210, USA
*Author to whom correspondence should be addressed.
Sensors 2020, 20(11), 3030; https://doi.org/10.3390/s20113030
Received: 16 April 2020 / Revised: 21 May 2020 / Accepted: 25 May 2020 / Published: 27 May 2020
(This article belongs to the Special Issue Lab-on-a-Chip and Microfluidic Sensors)

Abstract

The use of functionalized magnetic particles for the detection or separation of multiple chemicals and biomolecules from biofluids continues to attract significant attention. After their incubation with the targeted substances, the beads can be magnetically recovered to perform analysis or diagnostic tests. Particle recovery with permanent magnets in continuous-flow microdevices has gathered great attention in the last decade due to the multiple advantages of microfluidics. As such, great efforts have been made to determine the magnetic and fluidic conditions for achieving complete particle capture; however, less attention has been paid to the effect of the channel geometry on the system performance, although it is key for designing systems that simultaneously provide high particle recovery and flow rates. Herein, we address the optimization of Y-Y-shaped microchannels, where magnetic beads are separated from blood and collected into a buffer stream by applying an external magnetic field. The influence of several geometrical features (namely cross section shape, thickness, length, and volume) on both bead recovery and system throughput is studied. For that purpose, we employ an experimentally validated Computational Fluid Dynamics (CFD) numerical model that considers the dominant forces acting on the beads during separation. Our results indicate that rectangular, long devices display the best performance as they deliver high particle recovery and high throughput. Thus, this methodology could be applied to the rational design of lab-on-a-chip devices for any magnetically driven purification, enrichment or isolation.

Keywords: particle magnetophoresis; CFD; cross section; chip fabrication

Korea Abstract

생체 유체에서 여러 화학 물질과 생체 분자의 검출 또는 분리를위한 기능화 된 자성 입자의 사용은 계속해서 상당한 관심을 받고 있습니다. 표적 물질과 함께 배양 한 후 비드를 자기 적으로 회수하여 분석 또는 진단 테스트를 수행 할 수 있습니다. 연속 흐름 마이크로 장치에서 영구 자석을 사용한 입자 회수는 마이크로 유체의 여러 장점으로 인해 지난 10 년 동안 큰 관심을 모았습니다. 

따라서 완전한 입자 포획을 달성하기 위한 자기 및 유체 조건을 결정하기 위해 많은 노력을 기울였습니다. 그러나 높은 입자 회수율과 유속을 동시에 제공하는 시스템을 설계하는 데있어 핵심이기는 하지만 시스템 성능에 대한 채널 형상의 영향에 대해서는 덜주의를 기울였습니다. 

여기에서 우리는 자기 비드가 혈액에서 분리되고 외부 자기장을 적용하여 버퍼 스트림으로 수집되는 YY 모양의 마이크로 채널의 최적화를 다룹니다. 비드 회수 및 시스템 처리량에 대한 여러 기하학적 특징 (즉, 단면 형상, 두께, 길이 및 부피)의 영향을 연구합니다. 

이를 위해 분리 중에 비드에 작용하는 지배적인 힘을 고려하는 실험적으로 검증 된 CFD (Computational Fluid Dynamics) 수치 모델을 사용합니다. 우리의 결과는 직사각형의 긴 장치가 높은 입자 회수율과 높은 처리량을 제공하기 때문에 최고의 성능을 보여줍니다. 

따라서 이 방법론은 자기 구동 정제, 농축 또는 분리를 위한 랩온어 칩 장치의 합리적인 설계에 적용될 수 있습니다.

Figure 1. (a) Top view of the microfluidic-magnetophoretic device, (b) Schematic representation of the channel cross-sections studied in this work, and (c) the magnet position relative to the channel location (Sepy and Sepz are the magnet separation distances in y and z, respectively).
Figure 1. (a) Top view of the microfluidic-magnetophoretic device, (b) Schematic representation of the channel cross-sections studied in this work, and (c) the magnet position relative to the channel location (Sepy and Sepz are the magnet separation distances in y and z, respectively).
Figure 2. (a) Channel-magnet configuration and (b–d) magnetic force distribution in the channel midplane for 2 mm, 5 mm and 10 mm long rectangular (left) and U-shaped (right) devices.
Figure 2. (a) Channel-magnet configuration and (b–d) magnetic force distribution in the channel midplane for 2 mm, 5 mm and 10 mm long rectangular (left) and U-shaped (right) devices.
Figure 3. (a) Velocity distribution in a section perpendicular to the flow for rectangular (left) and U-shaped (right) cross section channels, and (b) particle location in these cross sections.
Figure 3. (a) Velocity distribution in a section perpendicular to the flow for rectangular (left) and U-shaped (right) cross section channels, and (b) particle location in these cross sections.
Figure 4. Influence of fluid flow rate on particle recovery when the applied magnetic force is (a) different and (b) equal in U-shaped and rectangular cross section microdevices.
Figure 4. Influence of fluid flow rate on particle recovery when the applied magnetic force is (a) different and (b) equal in U-shaped and rectangular cross section microdevices.
Figure 5. Magnetic bead capture as a function of fluid flow rate for all of the studied geometries.
Figure 5. Magnetic bead capture as a function of fluid flow rate for all of the studied geometries.
Figure 6. Influence of (a) magnetic and fluidic forces (J parameter) and (b) channel geometry (θ parameter) on particle recovery. Note that U-2mm does not accurately fit a line.
Figure 6. Influence of (a) magnetic and fluidic forces (J parameter) and (b) channel geometry (θ parameter) on particle recovery. Note that U-2mm does not accurately fit a line.
Figure 7. Dependence of bead capture on the (a) functional channel volume and (b) particle residence time (tres). Note that in the curve fitting expressions V represents the functional channel volume and that U-2mm does not accurately fit a line.
Figure 7. Dependence of bead capture on the (a) functional channel volume and (b) particle residence time (tres). Note that in the curve fitting expressions V represents the functional channel volume and that U-2mm does not accurately fit a line.

References

  1. Gómez-Pastora, J.; Xue, X.; Karampelas, I.H.; Bringas, E.; Furlani, E.P.; Ortiz, I. Analysis of separators for magnetic beads recovery: From large systems to multifunctional microdevices. Sep. Purif. Technol. 2017, 172, 16–31. [Google Scholar] [CrossRef]
  2. Wise, N.; Grob, T.; Morten, K.; Thompson, I.; Sheard, S. Magnetophoretic velocities of superparamagnetic particles, agglomerates and complexes. J. Magn. Magn. Mater. 2015, 384, 328–334. [Google Scholar] [CrossRef]
  3. Khashan, S.A.; Elnajjar, E.; Haik, Y. CFD simulation of the magnetophoretic separation in a microchannel. J. Magn. Magn. Mater. 2011, 323, 2960–2967. [Google Scholar] [CrossRef]
  4. Khashan, S.A.; Furlani, E.P. Scalability analysis of magnetic bead separation in a microchannel with an array of soft magnetic elements in a uniform magnetic field. Sep. Purif. Technol. 2014, 125, 311–318. [Google Scholar] [CrossRef]
  5. Furlani, E.P. Magnetic biotransport: Analysis and applications. Materials 2010, 3, 2412–2446. [Google Scholar] [CrossRef]
  6. Gómez-Pastora, J.; Bringas, E.; Ortiz, I. Design of novel adsorption processes for the removal of arsenic from polluted groundwater employing functionalized magnetic nanoparticles. Chem. Eng. Trans. 2016, 47, 241–246. [Google Scholar]
  7. Gómez-Pastora, J.; Bringas, E.; Lázaro-Díez, M.; Ramos-Vivas, J.; Ortiz, I. The reverse of controlled release: Controlled sequestration of species and biotoxins into nanoparticles (NPs). In Drug Delivery Systems; Stroeve, P., Mahmoudi, M., Eds.; World Scientific: Hackensack, NJ, USA, 2017; pp. 207–244. ISBN 9789813201057. [Google Scholar]
  8. Ruffert, C. Magnetic bead-magic bullet. Micromachines 2016, 7, 21. [Google Scholar] [CrossRef]
  9. Yáñez-Sedeño, P.; Campuzano, S.; Pingarrón, J.M. Magnetic particles coupled to disposable screen printed transducers for electrochemical biosensing. Sensors 2016, 16, 1585. [Google Scholar] [CrossRef]
  10. Schrittwieser, S.; Pelaz, B.; Parak, W.J.; Lentijo-Mozo, S.; Soulantica, K.; Dieckhoff, J.; Ludwig, F.; Guenther, A.; Tschöpe, A.; Schotter, J. Homogeneous biosensing based on magnetic particle labels. Sensors 2016, 16, 828. [Google Scholar] [CrossRef]
  11. He, J.; Huang, M.; Wang, D.; Zhang, Z.; Li, G. Magnetic separation techniques in sample preparation for biological analysis: A review. J. Pharm. Biomed. Anal. 2014, 101, 84–101. [Google Scholar] [CrossRef]
  12. Ha, Y.; Ko, S.; Kim, I.; Huang, Y.; Mohanty, K.; Huh, C.; Maynard, J.A. Recent advances incorporating superparamagnetic nanoparticles into immunoassays. ACS Appl. Nano Mater. 2018, 1, 512–521. [Google Scholar] [CrossRef]
  13. Gómez-Pastora, J.; González-Fernández, C.; Fallanza, M.; Bringas, E.; Ortiz, I. Flow patterns and mass transfer performance of miscible liquid-liquid flows in various microchannels: Numerical and experimental studies. Chem. Eng. J. 2018, 344, 487–497. [Google Scholar] [CrossRef]
  14. Gale, B.K.; Jafek, A.R.; Lambert, C.J.; Goenner, B.L.; Moghimifam, H.; Nze, U.C.; Kamarapu, S.K. A review of current methods in microfluidic device fabrication and future commercialization prospects. Inventions 2018, 3, 60. [Google Scholar] [CrossRef]
  15. Nanobiotechnology; Concepts, Applications and Perspectives; Niemeyer, C.M.; Mirkin, C.A. (Eds.) Wiley-VCH: Weinheim, Germany, 2004; ISBN 3527305068. [Google Scholar]
  16. Khashan, S.A.; Dagher, S.; Alazzam, A.; Mathew, B.; Hilal-Alnaqbi, A. Microdevice for continuous flow magnetic separation for bioengineering applications. J. Micromech. Microeng. 2017, 27, 055016. [Google Scholar] [CrossRef]
  17. Basauri, A.; Gomez-Pastora, J.; Fallanza, M.; Bringas, E.; Ortiz, I. Predictive model for the design of reactive micro-separations. Sep. Purif. Technol. 2019, 209, 900–907. [Google Scholar] [CrossRef]
  18. Abdollahi, P.; Karimi-Sabet, J.; Moosavian, M.A.; Amini, Y. Microfluidic solvent extraction of calcium: Modeling and optimization of the process variables. Sep. Purif. Technol. 2020, 231, 115875. [Google Scholar] [CrossRef]
  19. Khashan, S.A.; Alazzam, A.; Furlani, E. A novel design for a microfluidic magnetophoresis system: Computational study. In Proceedings of the 12th International Symposium on Fluid Control, Measurement and Visualization (FLUCOME2013), Nara, Japan, 18–23 November 2013. [Google Scholar]
  20. Pamme, N. Magnetism and microfluidics. Lab Chip 2006, 6, 24–38. [Google Scholar] [CrossRef]
  21. Gómez-Pastora, J.; Amiri Roodan, V.; Karampelas, I.H.; Alorabi, A.Q.; Tarn, M.D.; Iles, A.; Bringas, E.; Paunov, V.N.; Pamme, N.; Furlani, E.P.; et al. Two-step numerical approach to predict ferrofluid droplet generation and manipulation inside multilaminar flow chambers. J. Phys. Chem. C 2019, 123, 10065–10080. [Google Scholar] [CrossRef]
  22. Gómez-Pastora, J.; Karampelas, I.H.; Bringas, E.; Furlani, E.P.; Ortiz, I. Numerical analysis of bead magnetophoresis from flowing blood in a continuous-flow microchannel: Implications to the bead-fluid interactions. Sci. Rep. 2019, 9, 7265. [Google Scholar] [CrossRef]
  23. Tarn, M.D.; Pamme, N. On-Chip Magnetic Particle-Based Immunoassays Using Multilaminar Flow for Clinical Diagnostics. In Microchip Diagnostics Methods and Protocols; Taly, V., Viovy, J.L., Descroix, S., Eds.; Humana Press: New York, NY, USA, 2017; pp. 69–83. [Google Scholar]
  24. Phurimsak, C.; Tarn, M.D.; Peyman, S.A.; Greenman, J.; Pamme, N. On-chip determination of c-reactive protein using magnetic particles in continuous flow. Anal. Chem. 2014, 86, 10552–10559. [Google Scholar] [CrossRef]
  25. Wu, X.; Wu, H.; Hu, Y. Enhancement of separation efficiency on continuous magnetophoresis by utilizing L/T-shaped microchannels. Microfluid. Nanofluid. 2011, 11, 11–24. [Google Scholar] [CrossRef]
  26. Vojtíšek, M.; Tarn, M.D.; Hirota, N.; Pamme, N. Microfluidic devices in superconducting magnets: On-chip free-flow diamagnetophoresis of polymer particles and bubbles. Microfluid. Nanofluid. 2012, 13, 625–635. [Google Scholar] [CrossRef]
  27. Gómez-Pastora, J.; González-Fernández, C.; Real, E.; Iles, A.; Bringas, E.; Furlani, E.P.; Ortiz, I. Computational modeling and fluorescence microscopy characterization of a two-phase magnetophoretic microsystem for continuous-flow blood detoxification. Lab Chip 2018, 18, 1593–1606. [Google Scholar] [CrossRef] [PubMed]
  28. Forbes, T.P.; Forry, S.P. Microfluidic magnetophoretic separations of immunomagnetically labeled rare mammalian cells. Lab Chip 2012, 12, 1471–1479. [Google Scholar] [CrossRef]
  29. Nandy, K.; Chaudhuri, S.; Ganguly, R.; Puri, I.K. Analytical model for the magnetophoretic capture of magnetic microspheres in microfluidic devices. J. Magn. Magn. Mater. 2008, 320, 1398–1405. [Google Scholar] [CrossRef]
  30. Plouffe, B.D.; Lewis, L.H.; Murthy, S.K. Computational design optimization for microfluidic magnetophoresis. Biomicrofluidics 2011, 5, 013413. [Google Scholar] [CrossRef] [PubMed]
  31. Hale, C.; Darabi, J. Magnetophoretic-based microfluidic device for DNA isolation. Biomicrofluidics 2014, 8, 044118. [Google Scholar] [CrossRef] [PubMed]
  32. Becker, H.; Gärtner, C. Polymer microfabrication methods for microfluidic analytical applications. Electrophoresis 2000, 21, 12–26. [Google Scholar] [CrossRef]
  33. Pekas, N.; Zhang, Q.; Nannini, M.; Juncker, D. Wet-etching of structures with straight facets and adjustable taper into glass substrates. Lab Chip 2010, 10, 494–498. [Google Scholar] [CrossRef]
  34. Wang, T.; Chen, J.; Zhou, T.; Song, L. Fabricating microstructures on glass for microfluidic chips by glass molding process. Micromachines 2018, 9, 269. [Google Scholar] [CrossRef]
  35. Castaño-Álvarez, M.; Pozo Ayuso, D.F.; García Granda, M.; Fernández-Abedul, M.T.; Rodríguez García, J.; Costa-García, A. Critical points in the fabrication of microfluidic devices on glass substrates. Sens. Actuators B Chem. 2008, 130, 436–448. [Google Scholar] [CrossRef]
  36. Prakash, S.; Kumar, S. Fabrication of microchannels: A review. Proc. Inst. Mech. Eng. Part B J. Eng. Manuf. 2015, 229, 1273–1288. [Google Scholar] [CrossRef]
  37. Leester-Schädel, M.; Lorenz, T.; Jürgens, F.; Ritcher, C. Fabrication of Microfluidic Devices. In Microsystems for Pharmatechnology: Manipulation of Fluids, Particles, Droplets, and Cells; Dietzel, A., Ed.; Springer: Basel, Switzerland, 2016; pp. 23–57. ISBN 9783319269207. [Google Scholar]
  38. Bartlett, N.W.; Wood, R.J. Comparative analysis of fabrication methods for achieving rounded microchannels in PDMS. J. Micromech. Microeng. 2016, 26, 115013. [Google Scholar] [CrossRef]
  39. Ng, P.F.; Lee, K.I.; Yang, M.; Fei, B. Fabrication of 3D PDMS microchannels of adjustable cross-sections via versatile gel templates. Polymers 2019, 11, 64. [Google Scholar] [CrossRef] [PubMed]
  40. Furlani, E.P.; Sahoo, Y.; Ng, K.C.; Wortman, J.C.; Monk, T.E. A model for predicting magnetic particle capture in a microfluidic bioseparator. Biomed. Microdevices 2007, 9, 451–463. [Google Scholar] [CrossRef]
  41. Tarn, M.D.; Peyman, S.A.; Robert, D.; Iles, A.; Wilhelm, C.; Pamme, N. The importance of particle type selection and temperature control for on-chip free-flow magnetophoresis. J. Magn. Magn. Mater. 2009, 321, 4115–4122. [Google Scholar] [CrossRef]
  42. Furlani, E.P. Permanent Magnet and Electromechanical Devices; Materials, Analysis and Applications; Academic Press: Waltham, MA, USA, 2001. [Google Scholar]
  43. White, F.M. Viscous Fluid Flow; McGraw-Hill: New York, NY, USA, 1974. [Google Scholar]
  44. Mathew, B.; Alazzam, A.; El-Khasawneh, B.; Maalouf, M.; Destgeer, G.; Sung, H.J. Model for tracing the path of microparticles in continuous flow microfluidic devices for 2D focusing via standing acoustic waves. Sep. Purif. Technol. 2015, 153, 99–107. [Google Scholar] [CrossRef]
  45. Furlani, E.J.; Furlani, E.P. A model for predicting magnetic targeting of multifunctional particles in the microvasculature. J. Magn. Magn. Mater. 2007, 312, 187–193. [Google Scholar] [CrossRef]
  46. Furlani, E.P.; Ng, K.C. Analytical model of magnetic nanoparticle transport and capture in the microvasculature. Phys. Rev. E 2006, 73, 061919. [Google Scholar] [CrossRef]
  47. Eibl, R.; Eibl, D.; Pörtner, R.; Catapano, G.; Czermak, P. Cell and Tissue Reaction Engineering; Springer: Berlin/Heidelberg, Germany, 2009. [Google Scholar]
  48. Pamme, N.; Eijkel, J.C.T.; Manz, A. On-chip free-flow magnetophoresis: Separation and detection of mixtures of magnetic particles in continuous flow. J. Magn. Magn. Mater. 2006, 307, 237–244. [Google Scholar] [CrossRef]
  49. Alorabi, A.Q.; Tarn, M.D.; Gómez-Pastora, J.; Bringas, E.; Ortiz, I.; Paunov, V.N.; Pamme, N. On-chip polyelectrolyte coating onto magnetic droplets-Towards continuous flow assembly of drug delivery capsules. Lab Chip 2017, 17, 3785–3795. [Google Scholar] [CrossRef]
  50. Zhang, H.; Guo, H.; Chen, Z.; Zhang, G.; Li, Z. Application of PECVD SiC in glass micromachining. J. Micromech. Microeng. 2007, 17, 775–780. [Google Scholar] [CrossRef]
  51. Mourzina, Y.; Steffen, A.; Offenhäusser, A. The evaporated metal masks for chemical glass etching for BioMEMS. Microsyst. Technol. 2005, 11, 135–140. [Google Scholar] [CrossRef]
  52. Mata, A.; Fleischman, A.J.; Roy, S. Fabrication of multi-layer SU-8 microstructures. J. Micromech. Microeng. 2006, 16, 276–284. [Google Scholar] [CrossRef]
  53. Su, N. 8 2000 Negative Tone Photoresist Formulations 2002–2025; MicroChem Corporation: Newton, MA, USA, 2002. [Google Scholar]
  54. Su, N. 8 2000 Negative Tone Photoresist Formulations 2035–2100; MicroChem Corporation: Newton, MA, USA, 2002. [Google Scholar]
  55. Fu, C.; Hung, C.; Huang, H. A novel and simple fabrication method of embedded SU-8 micro channels by direct UV lithography. J. Phys. Conf. Ser. 2006, 34, 330–335. [Google Scholar] [CrossRef]
  56. Kazoe, Y.; Yamashiro, I.; Mawatari, K.; Kitamori, T. High-pressure acceleration of nanoliter droplets in the gas phase in a microchannel. Micromachines 2016, 7, 142. [Google Scholar] [CrossRef]
  57. Sharp, K.V.; Adrian, R.J.; Santiago, J.G.; Molho, J.I. Liquid flows in microchannels. In MEMS: Introduction and Fundamentals; Gad-el-Hak, M., Ed.; CRC Press: Boca Raton, FL, USA, 2006; pp. 10-1–10-46. ISBN 9781420036572. [Google Scholar]
  58. Oh, K.W.; Lee, K.; Ahn, B.; Furlani, E.P. Design of pressure-driven microfluidic networks using electric circuit analogy. Lab Chip 2012, 12, 515–545. [Google Scholar] [CrossRef]
  59. Bruus, H. Theoretical Microfluidics; Oxford University Press: New York, NY, USA, 2008; ISBN 9788578110796. [Google Scholar]
  60. Beebe, D.J.; Mensing, G.A.; Walker, G.M. Physics and applications of microfluidics in biology. Annu. Rev. Biomed. Eng. 2002, 4, 261–286. [Google Scholar] [CrossRef] [PubMed]
  61. Yalikun, Y.; Tanaka, Y. Large-scale integration of all-glass valves on a microfluidic device. Micromachines 2016, 7, 83. [Google Scholar] [CrossRef] [PubMed]
  62. Van Heeren, H.; Verhoeven, D.; Atkins, T.; Tzannis, A.; Becker, H.; Beusink, W.; Chen, P. Design Guideline for Microfluidic Device and Component Interfaces (Part 2), Version 3; Available online: http://www.makefluidics.com/en/design-guideline?id=7 (accessed on 9 March 2020).
  63. Scheuble, N.; Iles, A.; Wootton, R.C.R.; Windhab, E.J.; Fischer, P.; Elvira, K.S. Microfluidic technique for the simultaneous quantification of emulsion instabilities and lipid digestion kinetics. Anal. Chem. 2017, 89, 9116–9123. [Google Scholar] [CrossRef] [PubMed]
  64. Lynch, E.C. Red blood cell damage by shear stress. Biophys. J. 1972, 12, 257–273. [Google Scholar]
  65. Paul, R.; Apel, J.; Klaus, S.; Schügner, F.; Schwindke, P.; Reul, H. Shear stress related blood damage in laminar Couette flow. Artif. Organs 2003, 27, 517–529. [Google Scholar] [CrossRef] [PubMed]
  66. Gómez-Pastora, J.; Karampelas, I.H.; Xue, X.; Bringas, E.; Furlani, E.P.; Ortiz, I. Magnetic bead separation from flowing blood in a two-phase continuous-flow magnetophoretic microdevice: Theoretical analysis through computational fluid dynamics simulation. J. Phys. Chem. C 2017, 121, 7466–7477. [Google Scholar] [CrossRef]
  67. Lim, J.; Yeap, S.P.; Leow, C.H.; Toh, P.Y.; Low, S.C. Magnetophoresis of iron oxide nanoparticles at low field gradient: The role of shape anisotropy. J. Colloid Interface Sci. 2014, 421, 170–177. [Google Scholar] [CrossRef] [PubMed]
  68. Culbertson, C.T.; Sibbitts, J.; Sellens, K.; Jia, S. Fabrication of Glass Microfluidic Devices. In Microfluidic Electrophoresis: Methods and Protocols; Dutta, D., Ed.; Humana Press: New York, NY, USA, 2019; pp. 1–12. ISBN 978-1-4939-8963-8. [Google Scholar]
Full Text View
Fluid velocity magnitude including velocity vectors and blood volumetric fraction contours for scenario 3: (a,b) Magnet distance d = 0; (c,d) Magnet distance d = 1 mm.

Numerical Analysis of Bead Magnetophoresis from Flowing Blood in a Continuous-Flow Microchannel: Implications to the Bead-Fluid Interactions

Scientific Reports volume 9, Article number: 7265 (2019) Cite this article

Abstract

이 연구에서는 비드 운동과 유체 흐름에 미치는 영향에 대한 자세한 분석을 제공하기 위해 연속 흐름 마이크로 채널 내부의 비드 자기 영동에 대한 수치 흐름 중심 연구를 보고합니다.

수치 모델은 Lagrangian 접근 방식을 포함하며 영구 자석에 의해 생성 된 자기장의 적용에 의해 혈액에서 비드 분리 및 유동 버퍼로의 수집을 예측합니다.

다음 시나리오가 모델링됩니다. (i) 운동량이 유체에서 점 입자로 처리되는 비드로 전달되는 단방향 커플 링, (ii) 비드가 점 입자로 처리되고 운동량이 다음으로부터 전달되는 양방향 결합 비드를 유체로 또는 그 반대로, (iii) 유체 변위에서 비드 체적의 영향을 고려한 양방향 커플 링.

결과는 세 가지 시나리오에서 비드 궤적에 약간의 차이가 있지만 특히 높은 자기력이 비드에 적용될 때 유동장에 상당한 변화가 있음을 나타냅니다.

따라서 높은 자기력을 사용할 때 비드 운동과 유동장의 체적 효과를 고려한 정확한 전체 유동 중심 모델을 해결해야 합니다. 그럼에도 불구하고 비드가 중간 또는 낮은 자기력을 받을 때 계산적으로 저렴한 모델을 안전하게 사용하여 자기 영동을 모델링 할 수 있습니다.

Sketch of the magnetophoresis process in the continuous-flow microdevice.
Sketch of the magnetophoresis process in the continuous-flow microdevice.
Schematic view of the microdevice showing the working conditions set in the simulations.
Schematic view of the microdevice showing the working conditions set in the simulations.
Bead trajectories for different magnetic field conditions, magnet placed at different distances “d” from the channel: (a) d = 0; (b) d = 1 mm; (c) d = 1.5 mm; (d) d = 2 mm
Bead trajectories for different magnetic field conditions, magnet placed at different distances “d” from the channel: (a) d = 0; (b) d = 1 mm; (c) d = 1.5 mm; (d) d = 2 mm
Separation efficacy as a function of the magnet distance. Comparison between one-way and two-way coupling.
Separation efficacy as a function of the magnet distance. Comparison between one-way and two-way coupling.
(a) Fluid velocity magnitude including velocity vectors and (b) blood volumetric fraction contours with magnet distance d = 0 mm for scenario 1 (t = 0.25 s).
(a) Fluid velocity magnitude including velocity vectors and (b) blood volumetric fraction contours with magnet distance d = 0 mm for scenario 1 (t = 0.25 s).
luid velocity magnitude including velocity vectors and blood volumetric fraction contours for scenario 2: (a,b) Magnet distance d = 0 mm at t = 0.4 s; (c,d) Magnet distance d = 1 mm at t = 0.4 s.
luid velocity magnitude including velocity vectors and blood volumetric fraction contours for scenario 2: (a,b) Magnet distance d = 0 mm at t = 0.4 s; (c,d) Magnet distance d = 1 mm at t = 0.4 s.
Fluid velocity magnitude including velocity vectors and blood volumetric fraction contours for scenario 3: (a,b) Magnet distance d = 0; (c,d) Magnet distance d = 1 mm.
Fluid velocity magnitude including velocity vectors and blood volumetric fraction contours for scenario 3: (a,b) Magnet distance d = 0; (c,d) Magnet distance d = 1 mm.
Blood volumetric fraction contours. Scenario 1: (a) Magnet distance d = 0 and (b) Magnet distance d = 1 mm; Scenario 2: (c) Magnet distance d = 0 and (d) Magnet distance d = 1 mm; and Scenario 3: (e) Magnet distance d = 0 and (f) Magnet distance d = 1 mm.
Blood volumetric fraction contours. Scenario 1: (a) Magnet distance d = 0 and (b) Magnet distance d = 1 mm; Scenario 2: (c) Magnet distance d = 0 and (d) Magnet distance d = 1 mm; and Scenario 3: (e) Magnet distance d = 0 and (f) Magnet distance d = 1 mm.

References

  1. 1.Keshipour, S. & Khalteh, N. K. Oxidation of ethylbenzene to styrene oxide in the presence of cellulose-supported Pd magnetic nanoparticles. Appl. Organometal. Chem. 30, 653–656 (2016).CAS Article Google Scholar 
  2. 2.Neamtu, M. et al. Functionalized magnetic nanoparticles: synthesis, characterization, catalytic application and assessment of toxicity. Sci. Rep. 8(1), 6278 (2018).ADS MathSciNet Article Google Scholar 
  3. 3.Gómez-Pastora, J., Bringas, E. & Ortiz, I. Recent progress and future challenges on the use of high performance magnetic nano-adsorbents in environmental applications. Chem. Eng. J. 256, 187–204 (2014).Article Google Scholar 
  4. 4.Gómez-Pastora, J., Bringas, E. & Ortiz, I. Design of novel adsorption processes for the removal of arsenic from polluted groundwater employing functionalized magnetic nanoparticles. Chem. Eng. Trans. 47, 241–246 (2016).Google Scholar 
  5. 5.Bagbi, Y., Sarswat, A., Mohan, D., Pandey, A. & Solanki, P. R. Lead and chromium adsorption from water using L-Cysteine functionalized magnetite (Fe3O4) nanoparticles. Sci. Rep. 7(1), 7672 (2017).ADS Article Google Scholar 
  6. 6.Gómez-Pastora, J. et al. Review and perspectives on the use of magnetic nanophotocatalysts (MNPCs) in water treatment. Chem. Eng. J. 310, 407–427 (2017).Article Google Scholar 
  7. 7.Lee, H. Y. et al. A selective fluoroionophore based on BODIPY-functionalized magnetic silica nanoparticles: removal of Pb2+ from human blood. Angew. Chem. Int. Ed. 48, 1239–1243 (2009).CAS Article Google Scholar 
  8. 8.Buzea, C., Pacheco, I. I. & Robbie, K. Nanomaterials and nanoparticles: sources and toxicity. Biointerphases 2, MR17–MR71 (2007).Article Google Scholar 
  9. 9.Roux, S. et al. Multifunctional nanoparticles: from the detection of biomolecules to the therapy. Int. J. Nanotechnol. 7, 781–801 (2010).ADS CAS Article Google Scholar 
  10. 10.Gómez-Pastora, J., Bringas, E., Lázaro-Díez, M., Ramos-Vivas, J. & Ortiz, I. In Drug Delivery Systems (Stroeve, P. & Mahmoudi, M. ed) 207–244 (World Scientific, 2017).
  11. 11.Selmi, M., Gazzah, M. H. & Belmabrouk, H. Optimization of microfluidic biosensor efficiency by means of fluid flow engineering. Sci. Rep. 7(1), 5721 (2017).ADS Article Google Scholar 
  12. 12.Gómez-Pastora, J., González-Fernández, C., Fallanza, M., Bringas, E. & Ortiz, I. Flow patterns and mass transfer performance of miscible liquid-liquid flows in various microchannels: Numerical and experimental studies. Chem. Eng. J. 344, 487–497 (2018).Article Google Scholar 
  13. 13.Pamme, N. Magnetism and microfluidics. Lab Chip 6, 24–38 (2006).CAS Article Google Scholar 
  14. 14.Alorabi, A. Q. et al. On-chip polyelectrolyte coating onto magnetic droplets – towards continuous flow assembly of drug delivery capsules. Lab Chip 17, 3785–3795 (2017).CAS Article Google Scholar 
  15. 15.Gómez-Pastora, J. et al. Analysis of separators for magnetic beads recovery: from large systems to multifunctional microdevices. Sep. Purif. Technol. 172, 16–31 (2017).Article Google Scholar 
  16. 16.Tarn, M. D. & Pamme, N. On-chip magnetic particle-based immunoassays using multilaminar flow for clinical diagnosis. Methods Mol. Biol. 1547, 69–83 (2017).CAS Article Google Scholar 
  17. 17.Lv, C. et al. Integrated optofluidic-microfluidic twin channels: toward diverse application of lab-on-a-chip systems. Sci. Rep. 6, 19801 (2016).ADS CAS Article Google Scholar 
  18. 18.Gómez-Pastora, J. et al. Magnetic bead separation from flowing blood in a two-phase continuous-flow magnetophoretic microdevice: theoretical analysis through computational fluid dynamics simulation. J. Phys. Chem. C 121, 7466–7477 (2017).Article Google Scholar 
  19. 19.Furlani, E. P. Magnetic biotransport: analysis and applications. Materials 3, 2412–2446 (2010).ADS CAS Article Google Scholar 
  20. 20.Khashan, S. A. & Furlani, E. P. Effects of particle–fluid coupling on particle transport and capture in a magnetophoretic microsystem. Microfluid. Nanofluid. 12, 565–580 (2012).Article Google Scholar 
  21. 21.Modak, N., Datta, A. & Ganguly, R. Cell separation in a microfluidic channel using magnetic microspheres. Microfluid. Nanofluid. 6, 647–660 (2009).CAS Article Google Scholar 
  22. 22.Furlani, E. P., Sahoo, Y., Ng, K. C., Wortman, J. C. & Monk, T. E. A model for predicting magnetic particle capture in a microfluidic bioseparator. Biomed. Microdevices 9, 451–463 (2007).CAS Article Google Scholar 
  23. 23.Furlani, E. P. & Sahoo, Y. Analytical model for the magnetic field and force in a magnetophoretic microsystem. J. Phys. D: Appl. Phys. 39, 1724–1732 (2006).ADS CAS Article Google Scholar 
  24. 24.Tarn, M. D. et al. The importance of particle type selection and temperature control for on-chip free-flow magnetophoresis. J. Magn. Magn. Mater. 321, 4115–4122 (2009).ADS CAS Article Google Scholar 
  25. 25.Fonnum, G., Johansson, C., Molteberg, A., Morup, S. & Aksnes, E. Characterisation of Dynabeads® by magnetization measurements and Mössbauer spectroscopy. J. Magn. Magn. Mater. 293, 41–47 (2005).ADS CAS Article Google Scholar 
  26. 26.Xue, W., Moore, L. R., Nakano, N., Chalmers, J. J. & Zborowski, M. Single cell magnetometry by magnetophoresis vs. bulk cell suspension magnetometry by SQUID-MPMS – A comparison. J. Magn. Magn. Mater. 474, 152–160 (2019).ADS CAS Article Google Scholar 
  27. 27.Moore, L. R. et al. Continuous, intrinsic magnetic depletion of erythrocytes from whole blood with a quadrupole magnet and annular flow channel; pilot scale study. Biotechnol. Bioeng. 115, 1521–1530 (2018).CAS Article Google Scholar 
  28. 28.Furlani, E. P. & Xue, X. Field, force and transport analysis for magnetic particle-based gene delivery. Microfluid Nanofluid. 13, 589–602 (2012).CAS Article Google Scholar 
  29. 29.Furlani, E. P. & Xue, X. A model for predicting field-directed particle transport in the magnetofection process. Pharm. Res. 29, 1366–1379 (2012).CAS Article Google Scholar 
  30. 30.Furlani, E. P. Permanent Magnet and Electromechanical Devices; Materials, Analysis and Applications, (Academic Press, 2001).
  31. 31.Balachandar, S. & Eaton, J. K. Turbulent dispersed multiphase flow. Annu. Rev. Fluid Mech. 42, 111–133 (2010).ADS Article Google Scholar 
  32. 32.Wakaba, L. & Balachandar, S. On the added mass force at finite Reynolds and acceleration number. Theor. Comput. Fluid. Dyn. 21, 147–153 (2007).Article Google Scholar 
  33. 33.White, F. M. Viscous Fluid Flow, (McGraw-Hill, 1974).
  34. 34.Rietema, K. & Van Den Akker, H. E. A. On the momentum equations in dispersed two-phase systems. Int. J. Multiphase Flow 9, 21–36 (1983).Article Google Scholar 
  35. 35.Furlani, E. P. & Ng, K. C. Analytical model of magnetic nanoparticle transport and capture in the microvasculature. Phys. Rev. E 73, 1–10 (2006).Article Google Scholar 
  36. 36.Eibl, R., Eibl, D., Pörtner, R., Catapano, G. & Czermak, P. Cell and Tissue Reaction Engineering, (Springer, 2009).
  37. 37.Gómez-Pastora, J. et al. Computational modeling and fluorescence microscopy characterization of a two-phase magnetophoretic microsystem for continuous-flow blood detoxification. Lab Chip 18, 1593–1606 (2018).Article Google Scholar 
  38. 38.Khashan, S. A. & Furlani, E. P. Scalability analysis of magnetic bead separation in a microchannel with an array of soft magnetic elements in a uniform magnetic field. Sep. Purif. Technol. 125, 311–318 (2014).CAS Article Google Scholar 
  39. 39.Hirt, C. W. & Sicilian, J. M. A porosity technique for the definition of obstacles in rectangular cell meshes. Proc. Fourth International Conf. Ship Hydro., National Academic of Science, Washington, DC., (1985).
  40. 40.Crank, J. Free and Moving Boundary Problems, (Oxford University Press, 1984).
  41. 41.Bruus, H. Theoretical Microfluidics, (Oxford University Press, 2008).
  42. 42.Liang, L. & Xuan, X. Diamagnetic particle focusing using ferromicrofluidics with a single magnet. Microfluid. Nanofluid. 13, 637–643 (2012).

Author information

  1. Edward P. Furlani is deceased.

Affiliations

  1. Department of Chemical and Biomolecular Engineering, ETSIIT, University of Cantabria, Avda. Los Castros s/n, 39005, Santander, SpainJenifer Gómez-Pastora, Eugenio Bringas & Inmaculada Ortiz
  2. Flow Science, Inc, Santa Fe, New Mexico, 87505, USAIoannis H. Karampelas
  3. Department of Chemical and Biological Engineering, University at Buffalo (SUNY), Buffalo, New York, 14260, USAEdward P. Furlani
  4. Department of Electrical Engineering, University at Buffalo (SUNY), Buffalo, New York, 14260, USAEdward P. Furlani
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Modeling of contactless bubble–bubble interactions in microchannels with integrated inertial pumps

Modeling of contactless bubble–bubble interactions in microchannels with integrated inertial pumps

통합 관성 펌프를 사용하여 마이크로 채널에서 비접촉식 기포-기포 상호 작용 모델링

Physics of Fluids 33, 042002 (2021); https://doi.org/10.1063/5.0041924 B. Hayesa),  G. L. Whitingb), and  R. MacCurdyc)

ABSTRACT

In this study, the nonlinear effect of contactless bubble–bubble interactions in inertial micropumps is characterized via reduced parameter one-dimensional and three-dimensional computational fluid dynamics (3D CFD) modeling. A one-dimensional pump model is developed to account for contactless bubble-bubble interactions, and the accuracy of the developed one-dimensional model is assessed via the commercial volume of fluid CFD software, FLOW-3D. The FLOW-3D CFD model is validated against experimental bubble dynamics images as well as experimental pump data. Precollapse and postcollapse bubble and flow dynamics for two resistors in a channel have been successfully explained by the modified one-dimensional model. The net pumping effect design space is characterized as a function of resistor placement and firing time delay. The one-dimensional model accurately predicts cumulative flow for simultaneous resistor firing with inner-channel resistor placements (0.2L < x < 0.8L where L is the channel length) as well as delayed resistor firing with inner-channel resistor placements when the time delay is greater than the time required for the vapor bubble to fill the channel cross section. In general, one-dimensional model accuracy suffers at near-reservoir resistor placements and short time delays which we propose is a result of 3D bubble-reservoir interactions and transverse bubble growth interactions, respectively, that are not captured by the one-dimensional model. We find that the one-dimensional model accuracy improves for smaller channel heights. We envision the developed one-dimensional model as a first-order rapid design tool for inertial pump-based microfluidic systems operating in the contactless bubble–bubble interaction nonlinear regime

이 연구에서 관성 마이크로 펌프에서 비접촉 기포-기포 상호 작용의 비선형 효과는 감소 된 매개 변수 1 차원 및 3 차원 전산 유체 역학 (3D CFD) 모델링을 통해 특성화됩니다. 비접촉식 기포-버블 상호 작용을 설명하기 위해 1 차원 펌프 모델이 개발되었으며, 개발 된 1 차원 모델의 정확도는 유체 CFD 소프트웨어 인 FLOW-3D의 상용 볼륨을 통해 평가됩니다.

FLOW-3D CFD 모델은 실험적인 거품 역학 이미지와 실험적인 펌프 데이터에 대해 검증되었습니다. 채널에 있는 두 저항기의 붕괴 전 및 붕괴 후 기포 및 유동 역학은 수정 된 1 차원 모델에 의해 성공적으로 설명되었습니다. 순 펌핑 효과 설계 공간은 저항 배치 및 발사 시간 지연의 기능으로 특징 지어집니다.

1 차원 모델은 내부 채널 저항 배치 (0.2L <x <0.8L, 여기서 L은 채널 길이)로 동시 저항 발생에 대한 누적 흐름과 시간 지연시 내부 채널 저항 배치로 지연된 저항 발생을 정확하게 예측합니다. 증기 방울이 채널 단면을 채우는 데 필요한 시간보다 큽니다.

일반적으로 1 차원 모델 정확도는 저수지 근처의 저항 배치와 1 차원 모델에 의해 포착되지 않는 3D 기포-저수지 상호 작용 및 가로 기포 성장 상호 작용의 결과 인 짧은 시간 지연에서 어려움을 겪습니다. 채널 높이가 작을수록 1 차원 모델 정확도가 향상됩니다. 우리는 개발 된 1 차원 모델을 비접촉 기포-기포 상호 작용 비선형 영역에서 작동하는 관성 펌프 기반 미세 유체 시스템을 위한 1 차 빠른 설계 도구로 생각합니다.

REFERENCES

1.S. Hassan and X. Zhang, “ Design and fabrication of capillary-driven flow device for point-of-care diagnostics,” Biosensors 10, 39 (2020). https://doi.org/10.3390/bios10040039, Google ScholarCrossref
2.Q. Shizhi and H. Bau, “ Magneto-hydrodynamics based microfluidics,” Mech. Res. Commun. 36, 10 (2009). https://doi.org/10.1016/j.mechrescom.2008.06.013, Google ScholarCrossref
3.N. Mishchuk, T. Heldal, T. Volden, J. Auerswald, and H. Knapp, “ Micropump based on electroosmosis of the second kind,” Electrophoresis 30, 3499 (2009). https://doi.org/10.1002/elps.200900271, Google ScholarCrossref
4.J. Snyder, J. Getpreecharsawas, D. Fang, T. Gaborski, C. Striemer, P. Fauchet, D. Borkholder, and J. McGrath, “ High-performance, low-voltage electroosmotic pumps with molecularly thin silicon nanomembranes,” Proc. Nat. Acad. Sci. U. S. A. 110, 18425–18430 (2013). https://doi.org/10.1073/pnas.1308109110, Google ScholarCrossref
5.K. Vinayakumar, G. Nadiger, V. Shetty, S. Dinesh, M. Nayak, and K. Rajanna, “ Packaged peristaltic micropump for controlled drug delivery application,” Rev. Sci. Instrum. 88, 015102 (2017). https://doi.org/10.1063/1.4973513, Google ScholarScitation, ISI
6.D. Duffy, H. Gillis, J. Lin, N. Sheppard, and G. Kellogg, “ Microfabricated centrifugal microfluidic systems: Characterization and multiple enzymatic assays,” Anal. Chem. 71, 4669 (1999). https://doi.org/10.1021/ac990682c, Google ScholarCrossref
7.V. Gnyawali, M. Saremi, M. Kolios, and S. Tsai, “ Stable microfluidic flow focusing using hydrostatics,” Biomicrofluidics 11, 034104 (2017). https://doi.org/10.1063/1.4983147, Google ScholarScitation, ISI
8.J. Lake, K. Heyde, and W. Ruder, “ Low-cost feedback-controlled syringe pressure pumps for microfluidics applications,” PLoS One 12, e0175089 (2017). https://doi.org/10.1371/journal.pone.0175089, Google ScholarCrossref
9.M. I. Mohammed, S. Haswell, and I. Gibson, “ Lab-on-a-chip or chip-in-a-lab: Challenges of commercialization lost in translation,” Procedia Technology 20, 54–59 (2015), proceedings of The 1st International Design Technology Conference, DESTECH2015, Geelong. Google ScholarCrossref
10.E. Torniainen, A. Govyadinov, D. Markel, and P. Kornilovitch, “ Bubble-driven inertial micropump,” Phys. Fluids 24, 122003 (2012). https://doi.org/10.1063/1.4769755, Google ScholarScitation, ISI
11.H. Hoefemann, S. Wadle, N. Bakhtina, V. Kondrashov, N. Wangler, and R. Zengerle, “ Sorting and lysis of single cells by bubblejet technology,” Sens. Actuators, B 168, 442–445 (2012). https://doi.org/10.1016/j.snb.2012.04.005, Google ScholarCrossref
12.B. Hayes, A. Hayes, M. Rolleston, A. Ferreira, and J. Kirsher, “ Pulsatory mixing of laminar flow using bubble-driven micro-pumps,” in Proceedings of the ASME 2018 International Mechanical Engineering Congress and Exposition (2018), Vol. 7. Google ScholarCrossref
13.E. Ory, H. Yuan, A. Prosperetti, S. Popinet, and S. Zaleski, “ Growth and collapse of a vapor bubble in a narrow tube,” Phys. Fluids 12, 1268 (2000). https://doi.org/10.1063/1.870381, Google ScholarScitation, ISI
14.Z. Yin and A. Prosperetti, “‘ Blinking bubble’ micropump with microfabricated heaters,” J. Micromech. Microeng. 15, 1683 (2005). https://doi.org/10.1088/0960-1317/15/9/010, Google ScholarCrossref
15.M. Einat and M. Grajower, “ Microboiling measurements of thermal-inkjet heaters,” J. Microelectromech. Syst. 19, 391 (2010). https://doi.org/10.1109/JMEMS.2010.2040946, Google ScholarCrossref
16.A. Govyadinov, P. Kornilovitch, D. Markel, and E. Torniainen, “ Single-pulse dynamics and flow rates of inertial micropumps,” Microfluid. Nanofluid. 20, 73 (2016). https://doi.org/10.1007/s10404-016-1738-x, Google ScholarCrossref
17.E. Sourtiji and Y. Peles, “ A micro-synthetic jet in a microchannel using bubble growth and collapse,” Appl. Therm. Eng. 160, 114084 (2019). https://doi.org/10.1016/j.applthermaleng.2019.114084, Google ScholarCrossref
18.B. Hayes, A. Govyadinov, and P. Kornilovitch, “ Microfluidic switchboards with integrated inertial pumps,” Microfluid. Nanofluid. 22, 15 (2018). https://doi.org/10.1007/s10404-017-2032-2, Google ScholarCrossref
19.P. Kornilovitch, A. Govyadinov, D. Markel, and E. Torniainen, “ One-dimensional model of inertial pumping,” Phys. Rev. E 87, 023012 (2013). https://doi.org/10.1103/PhysRevE.87.023012, Google ScholarCrossref
20.H. Yuan and A. Prosperetti, “ The pumping effect of growing and collapsing bubbles in a tube,” J. Micromech. Microeng. 9, 402–413 (1999). https://doi.org/10.1088/0960-1317/9/4/318, Google ScholarCrossref
21.J. Zou, B. Li, and C. Ji, “ Interactions between two oscillating bubbles in a rigid tube,” Exp. Therm. Fluid Sci. 61, 105 (2015). https://doi.org/10.1016/j.expthermflusci.2014.10.021, Google ScholarCrossref
22.C. Hirt and B. Nichols, “ Volume of fluid (vof) method for the dynamics of free boundaries,” J. Comput. Phys. 39, 201–225 (1981). https://doi.org/10.1016/0021-9991(81)90145-5, Google ScholarCrossref
23.C. Borgnakke and R. E. Sonntag, Fundamentals of Thermodynamics, 8th ed. ( Wiley, 1999). Google Scholar
24.O. E. Ruiz, “ CFD model of the thermal inkjet droplet ejection process,” in Proceeding of Heat Transfer Summer Conference (2007), Vol. 3. Google ScholarCrossref
25.T. Theofanous, L. Biasi, H. Isbin, and H. Fauske, “ A theoretical study on bubble growth in constant and time-dependent pressure fields,” Chem. Eng. Sci. 24, 885–897 (1969). https://doi.org/10.1016/0009-2509(69)85008-6, Google ScholarCrossref
26.S. Timoshenko and J. Goodier, Theory of Elasticity, 3rd ed. ( McGaw-Hill, Inc., 1970). Google Scholar

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Figure 1 (A) A schematic of ovarian cancer metastases involving tumor cells or clusters (yellow) shedding from a primary site and disseminating along ascitic currents of peritoneal fluid (green arrows) in the abdominal cavity. Ovarian cancer typically disseminates in four common abdomino-pelvic sites: (1) cul-de-sac (an extension of the peritoneal cavity between the rectum and back wall of the uterus); (2) right infracolic space (the apex formed by the termination of the small intestine of the small bowel mesentery at the ileocecal junction); (3) left infracolic space (superior site of the sigmoid colon); (4) Right paracolic gutter (communication between the upper and lower abdomen defined by the ascending colon and peritoneal wall). (B) The schematic of a perfusion model used to study the impact of sustained fluid flow on treatment resistance and molecular features of 3D ovarian cancer nodules (Top left). A side view of the perfusion model and growth of ovarian cancer nodules to a stromal bed (Top right). The photograph of a perfusion model used in the experiments (Bottom left) and depth-informed confocal imaging of ovarian cancer nodules in channels with and without carboplatin treatment (Bottom right). The perfusion model is 24 × 40 mm, with three channels that are 4 × 30 mm each and a height of 254 μm. The inlet and outlet ports of channels are 2.2 mm in diameter and positioned 5 mm from the edge of the chip. (C) A schematic of a 24-well plate model used to study the treatment resistance and molecular features of 3D ovarian cancer nodules under static conditions (without flow) (Top left). A side view of the static models and growth of ovarian cancer nodules on a stromal bed (Top right). Confocal imaging of 3D ovarian cancer nodules in a 24-well plate without and with carboplatin treatment (Bottom). Scale bars: 1 mm.

Flow-induced Shear Stress Confers Resistance to Carboplatin in an Adherent Three-Dimensional Model for Ovarian Cancer: A Role for EGFR-Targeted Photoimmunotherapy Informed by Physical Stress

난소암에 대한 일관된 3차원 모델에서 카보플라틴에 대한 유동에 의한 전단응력변화에 관한 연구

Abstract

A key reason for the persistently grim statistics associated with metastatic ovarian cancer is resistance to conventional agents, including platinum-based chemotherapies. A major source of treatment failure is the high degree of genetic and molecular heterogeneity, which results from significant underlying genomic instability, as well as stromal and physical cues in the microenvironment. Ovarian cancer commonly disseminates via transcoelomic routes to distant sites, which is associated with the frequent production of malignant ascites, as well as the poorest prognosis. In addition to providing a cell and protein-rich environment for cancer growth and progression, ascitic fluid also confers physical stress on tumors. An understudied area in ovarian cancer research is the impact of fluid shear stress on treatment failure. Here, we investigate the effect of fluid shear stress on response to platinum-based chemotherapy and the modulation of molecular pathways associated with aggressive disease in a perfusion model for adherent 3D ovarian cancer nodules. Resistance to carboplatin is observed under flow with a concomitant increase in the expression and activation of the epidermal growth factor receptor (EGFR) as well as downstream signaling members mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) and extracellular signal-regulated kinase (ERK). The uptake of platinum by the 3D ovarian cancer nodules was significantly higher in flow cultures compared to static cultures. A downregulation of phospho-focal adhesion kinase (p-FAK), vinculin, and phospho-paxillin was observed following carboplatin treatment in both flow and static cultures. Interestingly, low-dose anti-EGFR photoimmunotherapy (PIT), a targeted photochemical modality, was found to be equally effective in ovarian tumors grown under flow and static conditions. These findings highlight the need to further develop PIT-based combinations that target the EGFR, and sensitize ovarian cancers to chemotherapy in the context of flow-induced shear stress.

전이성 난소 암과 관련된 지속적으로 암울한 통계의 주요 이유는 백금 기반 화학 요법을 포함한 기존 약제에 대한 내성 때문입니다. 치료 실패의 주요 원인은 높은 수준의 유전적 및 분자적 이질성이며, 이는 중요한 기본 게놈 불안정성과 미세 환경의 기질 및 물리적 단서로 인해 발생합니다.

난소 암은 흔히 transcoelomic 경로를 통해 먼 부위로 전파되며, 이는 악성 복수의 빈번한 생산과 가장 나쁜 예후와 관련이 있습니다. 암 성장 및 진행을위한 세포 및 단백질이 풍부한 환경을 제공하는 것 외에도 복수 액은 종양에 물리적 스트레스를 부여합니다. 난소 암 연구에서 잘 연구되지 않은 분야는 유체 전단 응력이 치료 실패에 미치는 영향입니다.

여기, 우리는 백금 기반 화학 요법에 대한 반응과 부착 3D 난소 암 결절에 대한 관류 모델에서 공격적인 질병과 관련된 분자 경로의 변조에 대한 유체 전단 응력의 효과를 조사합니다.

카르보플라틴에 대한 내성은 상피 성장 인자 수용체 (EGFR)의 발현 및 활성화의 수반되는 증가 뿐만 아니라 다운 스트림 신호 구성원인 미토겐 활성화 단백질 키나제/세포 외 신호 조절 키나제 (MEK) 및 세포 외 신호 조절과 함께 관찰됩니다. 키나아제 (ERK). 3D 난소 암 결절에 의한 백금 흡수는 정적 배양에 비해 유동 배양에서 상당히 높았습니다.

포스 포-포컬 접착 키나제 (p-FAK), 빈 쿨린 및 포스 포-팍 실린의 하향 조절은 유동 및 정적 배양 모두에서 카보 플 라틴 처리 후 관찰되었습니다. 흥미롭게도, 표적 광 화학적 양식 인 저용량 항 EGFR 광 면역 요법 (PIT)은 유동 및 정적 조건에서 성장한 난소 종양에서 똑같이 효과적인 것으로 밝혀졌습니다.

이러한 발견은 EGFR을 표적으로하는 PIT 기반 조합을 추가로 개발하고 흐름 유도 전단 응력의 맥락에서 화학 요법에 난소 암을 민감하게 할 필요성을 강조합니다.

Keywords: ovarian cancer, epidermal growth factor receptor (EGFR), mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK), extracellular signal-regulated kinase (ERK), chemoresistance, fluid shear stress, ascites, perfusion model, photoimmunotherapy (PIT), photodynamic therapy (PDT), carboplatin

Figure 1 (A) A schematic of ovarian cancer metastases involving tumor cells or clusters (yellow) shedding from a primary site and disseminating along ascitic currents of peritoneal fluid (green arrows) in the abdominal cavity. Ovarian cancer typically disseminates in four common abdomino-pelvic sites: (1) cul-de-sac (an extension of the peritoneal cavity between the rectum and back wall of the uterus); (2) right infracolic space (the apex formed by the termination of the small intestine of the small bowel mesentery at the ileocecal junction); (3) left infracolic space (superior site of the sigmoid colon); (4) Right paracolic gutter (communication between the upper and lower abdomen defined by the ascending colon and peritoneal wall). (B) The schematic of a perfusion model used to study the impact of sustained fluid flow on treatment resistance and molecular features of 3D ovarian cancer nodules (Top left). A side view of the perfusion model and growth of ovarian cancer nodules to a stromal bed (Top right). The photograph of a perfusion model used in the experiments (Bottom left) and depth-informed confocal imaging of ovarian cancer nodules in channels with and without carboplatin treatment (Bottom right). The perfusion model is 24 × 40 mm, with three channels that are 4 × 30 mm each and a height of 254 μm. The inlet and outlet ports of channels are 2.2 mm in diameter and positioned 5 mm from the edge of the chip. (C) A schematic of a 24-well plate model used to study the treatment resistance and molecular features of 3D ovarian cancer nodules under static conditions (without flow) (Top left). A side view of the static models and growth of ovarian cancer nodules on a stromal bed (Top right). Confocal imaging of 3D ovarian cancer nodules in a 24-well plate without and with carboplatin treatment (Bottom). Scale bars: 1 mm.
Figure 1 (A) A schematic of ovarian cancer metastases involving tumor cells or clusters (yellow) shedding from a primary site and disseminating along ascitic currents of peritoneal fluid (green arrows) in the abdominal cavity. Ovarian cancer typically disseminates in four common abdomino-pelvic sites: (1) cul-de-sac (an extension of the peritoneal cavity between the rectum and back wall of the uterus); (2) right infracolic space (the apex formed by the termination of the small intestine of the small bowel mesentery at the ileocecal junction); (3) left infracolic space (superior site of the sigmoid colon); (4) Right paracolic gutter (communication between the upper and lower abdomen defined by the ascending colon and peritoneal wall). (B) The schematic of a perfusion model used to study the impact of sustained fluid flow on treatment resistance and molecular features of 3D ovarian cancer nodules (Top left). A side view of the perfusion model and growth of ovarian cancer nodules to a stromal bed (Top right). The photograph of a perfusion model used in the experiments (Bottom left) and depth-informed confocal imaging of ovarian cancer nodules in channels with and without carboplatin treatment (Bottom right). The perfusion model is 24 × 40 mm, with three channels that are 4 × 30 mm each and a height of 254 μm. The inlet and outlet ports of channels are 2.2 mm in diameter and positioned 5 mm from the edge of the chip. (C) A schematic of a 24-well plate model used to study the treatment resistance and molecular features of 3D ovarian cancer nodules under static conditions (without flow) (Top left). A side view of the static models and growth of ovarian cancer nodules on a stromal bed (Top right). Confocal imaging of 3D ovarian cancer nodules in a 24-well plate without and with carboplatin treatment (Bottom). Scale bars: 1 mm.
Figure 2 (A) Geometry of the micronodule located at the center of the microchannel. The flow velocity is in the X-direction. The nodule is modeled as an ellipse with a semi-minor axis of 40 μm in the Z-direction. The semi-major axis varies from 40-100 μm in the X-direction. The section over which the fluid dynamics are studied is the middle part of the channel with dimensions 4 mm along the Y-axis and 250 μm along the Z-axis. The nodule is located at (0, 20 μm). The black dotted line shows the centerline of the largest nodule. (B) Shear stress distribution over the surface of the solid micro-nodule on the XZ-plane. (C) Shear stress distribution over the surface of the porous micro-nodule on the XZ-plane. (D) Flow flux distribution over the centerline of the porous micro-nodule on the XZ-plane. The flux enters the surface at the left and leaves at the right.
Figure 2 (A) Geometry of the micronodule located at the center of the microchannel. The flow velocity is in the X-direction. The nodule is modeled as an ellipse with a semi-minor axis of 40 μm in the Z-direction. The semi-major axis varies from 40-100 μm in the X-direction. The section over which the fluid dynamics are studied is the middle part of the channel with dimensions 4 mm along the Y-axis and 250 μm along the Z-axis. The nodule is located at (0, 20 μm). The black dotted line shows the centerline of the largest nodule. (B) Shear stress distribution over the surface of the solid micro-nodule on the XZ-plane. (C) Shear stress distribution over the surface of the porous micro-nodule on the XZ-plane. (D) Flow flux distribution over the centerline of the porous micro-nodule on the XZ-plane. The flux enters the surface at the left and leaves at the right.
Figure 3 Cytotoxic response in carboplatin-treated 3D OVCAR-5 cultures under static conditions. (A) Representative confocal images of 3D tumors treated with carboplatin (0-500 μM) for 96 h showing a dose-dependent reduction in viable tumor (calcein signal). (B) Image-based quantification of normalized viable tumor area in 3D OVCAR-5 cultures following treatment with increasing doses of carboplatin. A minimum nodule size cut-off of 2000 µm2 (clusters of ~15–20 cells) was applied to the fluorescence images for quantitative analysis of the normalized viable tumor area. (One-way ANOVA with Dunnett’s post hoc test; n.s., not significant; * p < 0.05; *** p < 0.001; N = 9) (C) Inductively coupled plasma mass spectrometry (ICP-MS)-based quantification of carboplatin uptake in static 3D OVCAR-5 tumors shows a dose-dependent increase in platinum levels, up to 9774 ± 3,052 ng/mg protein at an incubation concentration of 500 μM carboplatin. (One-way ANOVA with Dunn’s multiple comparisons test; n.s., not significant; * p < 0.05; ** p < 0.01; N = 3). Results are expressed as mean ± standard error of mean (SEM). Scale bars: 500 μm.
Figure 3 Cytotoxic response in carboplatin-treated 3D OVCAR-5 cultures under static conditions. (A) Representative confocal images of 3D tumors treated with carboplatin (0-500 μM) for 96 h showing a dose-dependent reduction in viable tumor (calcein signal). (B) Image-based quantification of normalized viable tumor area in 3D OVCAR-5 cultures following treatment with increasing doses of carboplatin. A minimum nodule size cut-off of 2000 µm2 (clusters of ~15–20 cells) was applied to the fluorescence images for quantitative analysis of the normalized viable tumor area. (One-way ANOVA with Dunnett’s post hoc test; n.s., not significant; * p < 0.05; *** p < 0.001; N = 9) (C) Inductively coupled plasma mass spectrometry (ICP-MS)-based quantification of carboplatin uptake in static 3D OVCAR-5 tumors shows a dose-dependent increase in platinum levels, up to 9774 ± 3,052 ng/mg protein at an incubation concentration of 500 μM carboplatin. (One-way ANOVA with Dunn’s multiple comparisons test; n.s., not significant; * p < 0.05; ** p < 0.01; N = 3). Results are expressed as mean ± standard error of mean (SEM). Scale bars: 500 μm.
Figure 4 flow-induced chemo-resistance
Figure 4 flow-induced chemo-resistance
Figure 5 The effects of flow-induced shear stress on 3D ovarian cancer biology. (A) Western blot analysis of OVCAR-5 tumors was performed 7 days after culture under static or flow conditions. A flow-induced increase in EGFR and p-ERK, compared to static cultures, was observed. Conversely, a reduction in p-FAK, p-Paxillin, and Vinculin was observed under flow, relative to static conditions. (B) Western blot analysis of 3D OVCAR-5 tumors was performed 11 days after culture under static or flow conditions, including 4 days of treatment with 500 µM carboplatin, and respective controls. In both static and flow 3D cultures, carboplatin treatment resulted in downregulation of EGFR, FAK, p-Paxillin, Paxillin, and Vinculin. Upregulation of p-ERK was observed after carboplatin treatment in both static and flow 3D cultures. (C) Baseline levels of EGFR activity and expression are maintained by a complex array of factors, including recycling and degradation of the activated receptor complex. Flow-induced shear stress has been shown to cause a posttranslational up-regulation of EGFR expression and activation, likely resulting from increased receptor recycling and decreased EGFR degradation. Activation of EGFR results in ERK phosphorylation to induce gene expression, ultimately leading to cell proliferation, survival, and chemoresistance. FAK and other tyrosine kinases are activated by the engagement of integrins with the ECM. Subsequent phosphorylation of paxillin by FAK not only influences the remodeling of the actin cytoskeleton, but also modulates vinculin activation to regulate mitogen-activated protein kinase (MAPK) cascades, thereby stimulating pro-survival gene expression.
Figure 5 The effects of flow-induced shear stress on 3D ovarian cancer biology. (A) Western blot analysis of OVCAR-5 tumors was performed 7 days after culture under static or flow conditions. A flow-induced increase in EGFR and p-ERK, compared to static cultures, was observed. Conversely, a reduction in p-FAK, p-Paxillin, and Vinculin was observed under flow, relative to static conditions. (B) Western blot analysis of 3D OVCAR-5 tumors was performed 11 days after culture under static or flow conditions, including 4 days of treatment with 500 µM carboplatin, and respective controls. In both static and flow 3D cultures, carboplatin treatment resulted in downregulation of EGFR, FAK, p-Paxillin, Paxillin, and Vinculin. Upregulation of p-ERK was observed after carboplatin treatment in both static and flow 3D cultures. (C) Baseline levels of EGFR activity and expression are maintained by a complex array of factors, including recycling and degradation of the activated receptor complex. Flow-induced shear stress has been shown to cause a posttranslational up-regulation of EGFR expression and activation, likely resulting from increased receptor recycling and decreased EGFR degradation. Activation of EGFR results in ERK phosphorylation to induce gene expression, ultimately leading to cell proliferation, survival, and chemoresistance. FAK and other tyrosine kinases are activated by the engagement of integrins with the ECM. Subsequent phosphorylation of paxillin by FAK not only influences the remodeling of the actin cytoskeleton, but also modulates vinculin activation to regulate mitogen-activated protein kinase (MAPK) cascades, thereby stimulating pro-survival gene expression.
Figure 6 PIT efficacy in 3D tumors. (A) Dose-dependent change in normalized viable tumor area in static 3D cultures treated with PIC (1 μM BPD equivalent) and increasing energy densities (10–50 J/cm2 @ 50 mW/cm2). Significant tumoricidal efficacy is observed in a light-dose-dependent manner, starting at 15 J/cm2. (One-way ANOVA with Dunnett’s post hoc test; n.s., not significant; ** p < 0.01, *** p < 0.001, N = 9) (B) Comparison of cytotoxic response in PIT-treated 3D cultures under static and flow conditions. For quantitative analysis of fluorescence images, a minimum nodule size cut-off of 2000 µm2 (clusters of ~15–20 cells) was used to establish normalized viable tumor area. PIT is equally effective in 3D tumors grown in static cultures (green) and under flow-induced shear stress (blue) (in contrast to flow-induced chemo-resistance shown in Figure 4) (Two-tailed t test; n.s., not significant; N = 9).
Figure 6 PIT efficacy in 3D tumors. (A) Dose-dependent change in normalized viable tumor area in static 3D cultures treated with PIC (1 μM BPD equivalent) and increasing energy densities (10–50 J/cm2 @ 50 mW/cm2). Significant tumoricidal efficacy is observed in a light-dose-dependent manner, starting at 15 J/cm2. (One-way ANOVA with Dunnett’s post hoc test; n.s., not significant; ** p < 0.01, *** p < 0.001, N = 9) (B) Comparison of cytotoxic response in PIT-treated 3D cultures under static and flow conditions. For quantitative analysis of fluorescence images, a minimum nodule size cut-off of 2000 µm2 (clusters of ~15–20 cells) was used to establish normalized viable tumor area. PIT is equally effective in 3D tumors grown in static cultures (green) and under flow-induced shear stress (blue) (in contrast to flow-induced chemo-resistance shown in Figure 4) (Two-tailed t test; n.s., not significant; N = 9).
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References

  1. Siegel R.L., Miller K.D., Jemal A. Cancer statistics, 2019. CA Cancer J. Clin. 2019;69:7–34. doi: 10.3322/caac.21551. [PubMed] [CrossRef] [Google Scholar]
  2. Foley O.W., Rauh-Hain J.A., Del Carmen M.G. Recurrent epithelial ovarian cancer: An update on treatment. Oncology. 2013;27:288–294, 298. [PubMed] [Google Scholar]
  3. Kipps E., Tan D.S., Kaye S.B. Meeting the challenge of ascites in ovarian cancer: New avenues for therapy and research. Nat. Rev. Cancer. 2013;13:273–282. doi: 10.1038/nrc3432. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  4. Tan D.S., Agarwal R., Kaye S.B. Mechanisms of transcoelomic metastasis in ovarian cancer. Lancet Oncol. 2006;7:925–934. doi: 10.1016/S1470-2045(06)70939-1. [PubMed] [CrossRef] [Google Scholar]
  5. Ahmed N., Stenvers K.L. Getting to know ovarian cancer ascites: Opportunities for targeted therapy-based translational research. Front. Oncol. 2013;3:256. doi: 10.3389/fonc.2013.00256. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  6. Shield K., Ackland M.L., Ahmed N., Rice G.E. Multicellular spheroids in ovarian cancer metastases: Biology and pathology. Gynecol. Oncol. 2009;113:143–148. doi: 10.1016/j.ygyno.2008.11.032. [PubMed] [CrossRef] [Google Scholar]
  7. Naora H., Montell D.J. Ovarian cancer metastasis: Integrating insights from disparate model organisms. Nat. Rev. Cancer. 2005;5:355–366. doi: 10.1038/nrc1611. [PubMed] [CrossRef] [Google Scholar]
  8. Lengyel E. Ovarian cancer development and metastasis. Am. J. Pathol. 2010;177:1053–1064. doi: 10.2353/ajpath.2010.100105. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  9. Javellana M., Hoppenot C., Lengyel E. The road to long-term survival: Surgical approach and longitudinal treatments of long-term survivors of advanced-stage serous ovarian cancer. Gynecol. Oncol. 2019;152:228–234. doi: 10.1016/j.ygyno.2018.11.007. [PubMed] [CrossRef] [Google Scholar]
  10. Al Habyan S., Kalos C., Szymborski J., McCaffrey L. Multicellular detachment generates metastatic spheroids during intra-abdominal dissemination in epithelial ovarian cancer. Oncogene. 2018;37:5127–5135. doi: 10.1038/s41388-018-0317-x. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  11. Kim S., Kim B., Song Y.S. Ascites modulates cancer cell behavior, contributing to tumor heterogeneity in ovarian cancer. Cancer Sci. 2016;107:1173–1178. doi: 10.1111/cas.12987. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  12. Bowtell D.D., Bohm S., Ahmed A.A., Aspuria P.J., Bast R.C., Beral V., Berek J.S., Birrer M.J., Blagden S., Bookman M.A., et al. Rethinking ovarian cancer II: Reducing mortality from high-grade serous ovarian cancer. Nat. Rev. Cancer. 2015;15:668–679. doi: 10.1038/nrc4019. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  13. Hoppenot C., Eckert M.A., Tienda S.M., Lengyel E. Who are the long-term survivors of high grade serous ovarian cancer? Gynecol. Oncol. 2018;148:204–212. doi: 10.1016/j.ygyno.2017.10.032. [PubMed] [CrossRef] [Google Scholar]
  14. Zhao Y., Cao J., Melamed A., Worley M., Gockley A., Jones D., Nia H.T., Zhang Y., Stylianopoulos T., Kumar A.S., et al. Losartan treatment enhances chemotherapy efficacy and reduces ascites in ovarian cancer models by normalizing the tumor stroma. Proc. Natl. Acad. Sci. USA. 2019;116:2210–2219. doi: 10.1073/pnas.1818357116. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  15. Ayantunde A.A., Parsons S.L. Pattern and prognostic factors in patients with malignant ascites: A retrospective study. Ann. Oncol. 2007;18:945–949. doi: 10.1093/annonc/mdl499. [PubMed] [CrossRef] [Google Scholar]
  16. Latifi A., Luwor R.B., Bilandzic M., Nazaretian S., Stenvers K., Pyman J., Zhu H., Thompson E.W., Quinn M.A., Findlay J.K., et al. Isolation and characterization of tumor cells from the ascites of ovarian cancer patients: Molecular phenotype of chemoresistant ovarian tumors. PLoS ONE. 2012;7:e46858. doi: 10.1371/journal.pone.0046858. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  17. Ahmed N., Greening D., Samardzija C., Escalona R.M., Chen M., Findlay J.K., Kannourakis G. Unique proteome signature of post-chemotherapy ovarian cancer ascites-derived tumor cells. Sci. Rep. 2016;6:30061. doi: 10.1038/srep30061. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  18. Gjorevski N., Boghaert E., Nelson C.M. Regulation of Epithelial-Mesenchymal Transition by Transmission of Mechanical Stress through Epithelial Tissues. Cancer Microenviron. 2012;5:29–38. doi: 10.1007/s12307-011-0076-5. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  19. Polacheck W.J., Charest J.L., Kamm R.D. Interstitial flow influences direction of tumor cell migration through competing mechanisms. Proc. Natl. Acad. Sci. USA. 2011;108:11115–11120. doi: 10.1073/pnas.1103581108. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  20. Polacheck W.J., German A.E., Mammoto A., Ingber D.E., Kamm R.D. Mechanotransduction of fluid stresses governs 3D cell migration. Proc. Natl. Acad. Sci. USA. 2014;111:2447–2452. doi: 10.1073/pnas.1316848111. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  21. Polacheck W.J., Zervantonakis I.K., Kamm R.D. Tumor cell migration in complex microenvironments. Cell Mol. Life Sci. 2013;70:1335–1356. doi: 10.1007/s00018-012-1115-1. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  22. Swartz M.A., Lund A.W. Lymphatic and interstitial flow in the tumour microenvironment: Linking mechanobiology with immunity. Nat. Rev. Cancer. 2012;12:210–219. doi: 10.1038/nrc3186. [PubMed] [CrossRef] [Google Scholar]
  23. Pisano M., Triacca V., Barbee K.A., Swartz M.A. An in vitro model of the tumor-lymphatic microenvironment with simultaneous transendothelial and luminal flows reveals mechanisms of flow enhanced invasion. Integr. Biol. 2015;7:525–533. doi: 10.1039/C5IB00085H. [PubMed] [CrossRef] [Google Scholar]
  24. Follain G., Herrmann D., Harlepp S., Hyenne V., Osmani N., Warren S.C., Timpson P., Goetz J.G. Fluids and their mechanics in tumour transit: Shaping metastasis. Nat. Rev. Cancer. 2020;20:107–124. doi: 10.1038/s41568-019-0221-x. [PubMed] [CrossRef] [Google Scholar]
  25. Rizvi I., Gurkan U.A., Tasoglu S., Alagic N., Celli J.P., Mensah L.B., Mai Z., Demirci U., Hasan T. Flow induces epithelial-mesenchymal transition, cellular heterogeneity and biomarker modulation in 3D ovarian cancer nodules. Proc. Natl. Acad. Sci. USA. 2013;110:E1974–E1983. doi: 10.1073/pnas.1216989110. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  26. Novak C., Horst E., Mehta G. Mechanotransduction in ovarian cancer: Shearing into the unknown. APL Bioeng. 2018;2 doi: 10.1063/1.5024386. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  27. Carmignani C.P., Sugarbaker T.A., Bromley C.M., Sugarbaker P.H. Intraperitoneal cancer dissemination: Mechanisms of the patterns of spread. Cancer Metastasis Rev. 2003;22:465–472. doi: 10.1023/A:1023791229361. [PubMed] [CrossRef] [Google Scholar]
  28. Sugarbaker P.H. Observations concerning cancer spread within the peritoneal cavity and concepts supporting an ordered pathophysiology. Cancer Treatment Res. 1996;82:79–100. [PubMed] [Google Scholar]
  29. Feki A., Berardi P., Bellingan G., Major A., Krause K.H., Petignat P., Zehra R., Pervaiz S., Irminger-Finger I. Dissemination of intraperitoneal ovarian cancer: Discussion of mechanisms and demonstration of lymphatic spreading in ovarian cancer model. Crit. Rev. Oncol./Hematol. 2009;72:1–9. doi: 10.1016/j.critrevonc.2008.12.003. [PubMed] [CrossRef] [Google Scholar]
  30. Holm-Nielsen P. Pathogenesis of ascites in peritoneal carcinomatosis. Acta Pathol. Microbiol. Scand. 1953;33:10–21. doi: 10.1111/j.1699-0463.1953.tb04805.x. [PubMed] [CrossRef] [Google Scholar]
  31. Ahmed N., Riley C., Oliva K., Rice G., Quinn M. Ascites induces modulation of alpha6beta1 integrin and urokinase plasminogen activator receptor expression and associated functions in ovarian carcinoma. Br. J. Cancer. 2005;92:1475–1485. doi: 10.1038/sj.bjc.6602495. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  32. Woodburn J.R. The epidermal growth factor receptor and its inhibition in cancer therapy. Pharmacol. Ther. 1999;82:241–250. doi: 10.1016/S0163-7258(98)00045-X. [PubMed] [CrossRef] [Google Scholar]
  33. Servidei T., Riccardi A., Mozzetti S., Ferlini C., Riccardi R. Chemoresistant tumor cell lines display altered epidermal growth factor receptor and HER3 signaling and enhanced sensitivity to gefitinib. Int. J. Cancer J. Int. Cancer. 2008;123:2939–2949. doi: 10.1002/ijc.23902. [PubMed] [CrossRef] [Google Scholar]
  34. Chen A.P., Zhang J., Liu H., Zhao S.P., Dai S.Z., Sun X.L. Association of EGFR expression with angiogenesis and chemoresistance in ovarian carcinoma. Zhonghua zhong liu za zhi [Chinese journal of oncology] 2009;31:48–52. [PubMed] [Google Scholar]
  35. Alper O., Bergmann-Leitner E.S., Bennett T.A., Hacker N.F., Stromberg K., Stetler-Stevenson W.G. Epidermal growth factor receptor signaling and the invasive phenotype of ovarian carcinoma cells. J. Natl. Cancer Inst. 2001;93:1375–1384. doi: 10.1093/jnci/93.18.1375. [PubMed] [CrossRef] [Google Scholar]
  36. Zeineldin R., Muller C.Y., Stack M.S., Hudson L.G. Targeting the EGF receptor for ovarian cancer therapy. J. Oncol. 2010;2010:414676. doi: 10.1155/2010/414676. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  37. Alper O., De Santis M.L., Stromberg K., Hacker N.F., Cho-Chung Y.S., Salomon D.S. Anti-sense suppression of epidermal growth factor receptor expression alters cellular proliferation, cell-adhesion and tumorigenicity in ovarian cancer cells. Int. J. Cancer. 2000;88:566–574. doi: 10.1002/1097-0215(20001115)88:4<566::AID-IJC8>3.0.CO;2-D. [PubMed] [CrossRef] [Google Scholar]
  38. Posadas E.M., Liel M.S., Kwitkowski V., Minasian L., Godwin A.K., Hussain M.M., Espina V., Wood B.J., Steinberg S.M., Kohn E.C. A phase II and pharmacodynamic study of gefitinib in patients with refractory or recurrent epithelial ovarian cancer. Cancer. 2007;109:1323–1330. doi: 10.1002/cncr.22545. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  39. Psyrri A., Kassar M., Yu Z., Bamias A., Weinberger P.M., Markakis S., Kowalski D., Camp R.L., Rimm D.L., Dimopoulos M.A. Effect of epidermal growth factor receptor expression level on survival in patients with epithelial ovarian cancer. Clin. Cancer Res. 2005;11:8637–8643. doi: 10.1158/1078-0432.CCR-05-1436. [PubMed] [CrossRef] [Google Scholar]
  40. Dimou A., Agarwal S., Anagnostou V., Viray H., Christensen S., Gould Rothberg B., Zolota V., Syrigos K., Rimm D. Standardization of epidermal growth factor receptor (EGFR) measurement by quantitative immunofluorescence and impact on antibody-based mutation detection in non-small cell lung cancer. Am. J. Pathol. 2011;179:580–589. doi: 10.1016/j.ajpath.2011.04.031. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  41. Anagnostou V.K., Welsh A.W., Giltnane J.M., Siddiqui S., Liceaga C., Gustavson M., Syrigos K.N., Reiter J.L., Rimm D.L. Analytic variability in immunohistochemistry biomarker studies. Cancer Epidemiol Biomarkers Prev. 2010;19:982–991. doi: 10.1158/1055-9965.EPI-10-0097. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  42. Del Carmen M.G., Rizvi I., Chang Y., Moor A.C., Oliva E., Sherwood M., Pogue B., Hasan T. Synergism of epidermal growth factor receptor-targeted immunotherapy with photodynamic treatment of ovarian cancer in vivo. J. Natl. Cancer Inst. 2005;97:1516–1524. doi: 10.1093/jnci/dji314. [PubMed] [CrossRef] [Google Scholar]
  43. Armstrong D.K., Bundy B., Wenzel L., Huang H.Q., Baergen R., Lele S., Copeland L.J., Walker J.L., Burger R.A., Gynecologic Oncology G. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N. Engl. J. Med. 2006;354:34–43. doi: 10.1056/NEJMoa052985. [PubMed] [CrossRef] [Google Scholar]
  44. Verwaal V.J., Van Ruth S., De Bree E., Van Sloothen G.W., Van Tinteren H., Boot H., Zoetmulder F.A. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J. Clin. Oncol. 2003;21:3737–3743. doi: 10.1200/JCO.2003.04.187. [PubMed] [CrossRef] [Google Scholar]
  45. Van Driel W.J., Koole S.N., Sikorska K., Schagen van Leeuwen J.H., Schreuder H.W.R., Hermans R.H.M., De Hingh I., Van der Velden J., Arts H.J., Massuger L., et al. Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer. N. Engl. J. Med. 2018;378:230–240. doi: 10.1056/NEJMoa1708618. [PubMed] [CrossRef] [Google Scholar]
  46. Verwaal V.J., Bruin S., Boot H., Van Slooten G., Van Tinteren H. 8-year follow-up of randomized trial: Cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy in patients with peritoneal carcinomatosis of colorectal cancer. Ann. Surg. Oncol. 2008;15:2426–2432. doi: 10.1245/s10434-008-9966-2. [PubMed] [CrossRef] [Google Scholar]
  47. DeLaney T.F., Sindelar W.F., Tochner Z., Smith P.D., Friauf W.S., Thomas G., Dachowski L., Cole J.W., Steinberg S.M., Glatstein E. Phase I study of debulking surgery and photodynamic therapy for disseminated intraperitoneal tumors. Int. J. Radiat. Oncol. Biol. Phys. 1993;25:445–457. doi: 10.1016/0360-3016(93)90066-5. [PubMed] [CrossRef] [Google Scholar]
  48. Celli J.P., Spring B.Q., Rizvi I., Evans C.L., Samkoe K.S., Verma S., Pogue B.W., Hasan T. Imaging and photodynamic therapy: Mechanisms, monitoring, and optimization. Chem. Rev. 2010;110:2795–2838. doi: 10.1021/cr900300p. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  49. Spring B.Q., Rizvi I., Xu N., Hasan T. The role of photodynamic therapy in overcoming cancer drug resistance. Photochem. Photobiol. Sci. 2015;14:1476–1491. doi: 10.1039/C4PP00495G. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  50. Liang B.J., Pigula M., Baglo Y., Najafali D., Hasan T., Huang H.C. Breaking the Selectivity-Uptake Trade-Off of Photoimmunoconjugates with Nanoliposomal Irinotecan for Synergistic Multi-Tier Cancer Targeting. J. Nanobiotechnol. 2020;18:1. doi: 10.1186/s12951-019-0560-5. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  51. Huang H.C., Rizvi I., Liu J., Anbil S., Kalra A., Lee H., Baglo Y., Paz N., Hayden D., Pereira S., et al. Photodynamic Priming Mitigates Chemotherapeutic Selection Pressures and Improves Drug Delivery. Cancer Res. 2018;78:558–571. doi: 10.1158/0008-5472.CAN-17-1700. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  52. Huang H.C., Mallidi S., Liu J., Chiang C.T., Mai Z., Goldschmidt R., Ebrahim-Zadeh N., Rizvi I., Hasan T. Photodynamic Therapy Synergizes with Irinotecan to Overcome Compensatory Mechanisms and Improve Treatment Outcomes in Pancreatic Cancer. Cancer Res. 2016;76:1066–1077. doi: 10.1158/0008-5472.CAN-15-0391. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  53. Cengel K.A., Glatstein E., Hahn S.M. Intraperitoneal photodynamic therapy. Cancer Treat. Res. 2007;134:493–514. [PubMed] [Google Scholar]
  54. Obaid G., Broekgaarden M., Bulin A.-L., Huang H.-C., Kuriakose J., Liu J., Hasan T. Photonanomedicine: A convergence of photodynamic therapy and nanotechnology. Nanoscale. 2016;8:12471–12503. doi: 10.1039/C5NR08691D. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  55. Ogata F., Nagaya T., Nakamura Y., Sato K., Okuyama S., Maruoka Y., Choyke P.L., Kobayashi H. Near-infrared photoimmunotherapy: A comparison of light dosing schedules. Oncotarget. 2017;8:35069–35075. doi: 10.18632/oncotarget.17047. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  56. Mitsunaga M., Ogawa M., Kosaka N., Rosenblum L.T., Choyke P.L., Kobayashi H. Cancer cell-selective in vivo near infrared photoimmunotherapy targeting specific membrane molecules. Nat. Med. 2011;17:1685–1691. doi: 10.1038/nm.2554. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  57. Inglut C.T., Baglo Y., Liang B.J., Cheema Y., Stabile J., Woodworth G.F., Huang H.-C. Systematic Evaluation of Light-Activatable Biohybrids for Anti-Glioma Photodynamic Therapy. J. Clin. Med. 2019;8:1269. doi: 10.3390/jcm8091269. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  58. Huang H.C., Pigula M., Fang Y., Hasan T. Immobilization of Photo-Immunoconjugates on Nanoparticles Leads to Enhanced Light-Activated Biological Effects. Small. 2018:e1800236. doi: 10.1002/smll.201800236. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  59. Spring B.Q., Abu-Yousif A.O., Palanisami A., Rizvi I., Zheng X., Mai Z., Anbil S., Sears R.B., Mensah L.B., Goldschmidt R., et al. Selective treatment and monitoring of disseminated cancer micrometastases in vivo using dual-function, activatable immunoconjugates. Proc. Natl. Acad. Sci. USA. 2014;111:E933–E942. doi: 10.1073/pnas.1319493111. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  60. Abu-Yousif A.O., Moor A.C., Zheng X., Savellano M.D., Yu W., Selbo P.K., Hasan T. Epidermal growth factor receptor-targeted photosensitizer selectively inhibits EGFR signaling and induces targeted phototoxicity in ovarian cancer cells. Cancer Lett. 2012;321:120–127. doi: 10.1016/j.canlet.2012.01.014. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  61. Rizvi I., Dinh T.A., Yu W., Chang Y., Sherwood M.E., Hasan T. Photoimmunotherapy and irradiance modulation reduce chemotherapy cycles and toxicity in a murine model for ovarian carcinomatosis: Perspective and results. Israel J. Chem. 2012;52:776–787. doi: 10.1002/ijch.201200016. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  62. Quirk B.J., Brandal G., Donlon S., Vera J.C., Mang T.S., Foy A.B., Lew S.M., Girotti A.W., Jogal S., LaViolette P.S., et al. Photodynamic therapy (PDT) for malignant brain tumors–where do we stand? Photodiagnosis Photodyn. Ther. 2015;12:530–544. doi: 10.1016/j.pdpdt.2015.04.009. [PubMed] [CrossRef] [Google Scholar]
  63. Eljamel M.S., Goodman C., Moseley H. ALA and Photofrin fluorescence-guided resection and repetitive PDT in glioblastoma multiforme: A single centre Phase III randomised controlled trial. Lasers Med. Sci. 2008;23:361–367. doi: 10.1007/s10103-007-0494-2. [PubMed] [CrossRef] [Google Scholar]
  64. Varma A.K., Muller P.J. Cranial neuropathies after intracranial Photofrin-photodynamic therapy for malignant supratentorial gliomas-a report on 3 cases. Surg. Neurol. 2008;70:190–193. doi: 10.1016/j.surneu.2007.01.060. [PubMed] [CrossRef] [Google Scholar]
  65. Akimoto J. Photodynamic Therapy for Malignant Brain Tumors. Neurol. Medico-Chirurgica. 2016;56:151–157. doi: 10.2176/nmc.ra.2015-0296. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  66. Kercher E.M., Nath S., Rizvi I., Spring B.Q. Cancer Cell-targeted and Activatable Photoimmunotherapy Spares T Cells in a 3D Coculture Model. Photochem. Photobiol. 2019 doi: 10.1111/php.13153. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  67. Savellano M.D., Hasan T. Targeting cells that overexpress the epidermal growth factor receptor with polyethylene glycolated BPD verteporfin photosensitizer immunoconjugates. Photochem. Photobiol. 2003;77:431–439. doi: 10.1562/0031-8655(2003)077<0431:TCTOTE>2.0.CO;2. [PubMed] [CrossRef] [Google Scholar]
  68. Molpus K.L., Hamblin M.R., Rizvi I., Hasan T. Intraperitoneal photoimmunotherapy of ovarian carcinoma xenografts in nude mice using charged photoimmunoconjugates. Gynecol. Oncol. 2000;76:397–404. doi: 10.1006/gyno.1999.5705. [PubMed] [CrossRef] [Google Scholar]
  69. Savellano M.D., Hasan T. Photochemical targeting of epidermal growth factor receptor: A mechanistic study. Clin. Cancer Res. 2005;11:1658–1668. doi: 10.1158/1078-0432.CCR-04-1902. [PubMed] [CrossRef] [Google Scholar]
  70. Nath S., Saad M.A., Pigula M., Swain J.W.R., Hasan T. Photoimmunotherapy of Ovarian Cancer: A Unique Niche in the Management of Advanced Disease. Cancers. 2019;11:1887. doi: 10.3390/cancers11121887. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  71. Calibasi Kocal G., Guven S., Foygel K., Goldman A., Chen P., Sengupta S., Paulmurugan R., Baskin Y., Demirci U. Dynamic Microenvironment Induces Phenotypic Plasticity of Esophageal Cancer Cells Under Flow. Sci. Rep. 2016;6:38221. doi: 10.1038/srep38221. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  72. Tasoglu S., Gurkan U.A., Wang S., Demirci U. Manipulating biological agents and cells in micro-scale volumes for applications in medicine. Chem. Soc. Rev. 2013;42:5788–5808. doi: 10.1039/c3cs60042d. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  73. Moon S., Gurkan U.A., Blander J., Fawzi W.W., Aboud S., Mugusi F., Kuritzkes D.R., Demirci U. Enumeration of CD4+ T-cells using a portable microchip count platform in Tanzanian HIV-infected patients. PLoS ONE. 2011;6:e21409. doi: 10.1371/journal.pone.0021409. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  74. White F.M. Fluid Mechanics. McGraw-Hill; Boston, MA, USA: 2011. [Google Scholar]
  75. Luo Q., Kuang D., Zhang B., Song G. Cell stiffness determined by atomic force microscopy and its correlation with cell motility. Biochim Biophys Acta. 2016;1860:1953–1960. doi: 10.1016/j.bbagen.2016.06.010. [PubMed] [CrossRef] [Google Scholar]
  76. Sarntinoranont M., Rooney F., Ferrari M. Interstitial Stress and Fluid Pressure Within a Growing Tumor. Ann. Biomed. Eng. 2003;31:327–335. doi: 10.1114/1.1554923. [PubMed] [CrossRef] [Google Scholar]
  77. Baxter L.T., Jain R.K. Transport of fluid and macromolecules in tumors. I. Role of interstitial pressure and convection. Microvasc. Res. 1989;37:77–104. doi: 10.1016/0026-2862(89)90074-5. [PubMed] [CrossRef] [Google Scholar]
  78. Malik R., Khan A.P., Asangani I.A., Cieślik M., Prensner J.R., Wang X., Iyer M.K., Jiang X., Borkin D., Escara-Wilke J., et al. Targeting the MLL complex in castration-resistant prostate cancer. Nat. Med. 2015;21:344. doi: 10.1038/nm.3830. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  79. Nath S., Christian L., Tan S.Y., Ki S., Ehrlich L.I., Poenie M. Dynein Separately Partners with NDE1 and Dynactin To Orchestrate T Cell Focused Secretion. J. Immunol. 2016;197:2090–2101. doi: 10.4049/jimmunol.1600180. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  80. Celli J.P., Rizvi I., Evans C.L., Abu-Yousif A.O., Hasan T. Quantitative imaging reveals heterogeneous growth dynamics and treatment-dependent residual tumor distributions in a three-dimensional ovarian cancer model. J. Biomed. Opt. 2010;15:051603. doi: 10.1117/1.3483903. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  81. Rizvi I., Celli J.P., Evans C.L., Abu-Yousif A.O., Muzikansky A., Pogue B.W., Finkelstein D., Hasan T. Synergistic Enhancement of Carboplatin Efficacy with Photodynamic Therapy in a Three-Dimensional Model for Micrometastatic Ovarian Cancer. Cancer Res. 2010;70:9319–9328. doi: 10.1158/0008-5472.CAN-10-1783. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  82. Glidden M.D., Celli J.P., Massodi I., Rizvi I., Pogue B.W., Hasan T. Image-Based Quantification of Benzoporphyrin Derivative Uptake, Localization, and Photobleaching in 3D Tumor Models, for Optimization of PDT Parameters. Theranostics. 2012;2:827–839. doi: 10.7150/thno.4334. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  83. Celli J.P., Rizvi I., Blanden A.R., Massodi I., Glidden M.D., Pogue B.W., Hasan T. An imaging-based platform for high-content, quantitative evaluation of therapeutic response in 3D tumour models. Sci. Rep. 2014;4:3751. doi: 10.1038/srep03751. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  84. Bulin A.L., Broekgaarden M., Hasan T. Comprehensive high-throughput image analysis for therapeutic efficacy of architecturally complex heterotypic organoids. Sci. Rep. 2017;7:16645. doi: 10.1038/s41598-017-16622-9. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  85. Rahmanzadeh R., Rai P., Celli J.P., Rizvi I., Baron-Luhr B., Gerdes J., Hasan T. Ki-67 as a molecular target for therapy in an in vitro three-dimensional model for ovarian cancer. Cancer Res. 2010;70:9234–9242. doi: 10.1158/0008-5472.CAN-10-1190. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  86. Anbil S., Rizvi I., Celli J.P., Alagic N., Pogue B.W., Hasan T. Impact of treatment response metrics on photodynamic therapy planning and outcomes in a three-dimensional model of ovarian cancer. J. Biomed. Opt. 2013;18:098004. doi: 10.1117/1.JBO.18.9.098004. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  87. Di Pasqua A.J., Goodisman J., Dabrowiak J.C. Understanding how the platinum anticancer drug carboplatin works: From the bottle to the cell. Inorg. Chim. Acta. 2012;389:29–35. doi: 10.1016/j.ica.2012.01.028. [CrossRef] [Google Scholar]
  88. Rabik C.A., Dolan M.E. Molecular mechanisms of resistance and toxicity associated with platinating agents. Cancer Treat. Rev. 2007;33:9–23. doi: 10.1016/j.ctrv.2006.09.006. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  89. Ozols R.F. Carboplatin and paclitaxel in ovarian cancer. Semin. Oncol. 1995;22:78–83. [PubMed] [Google Scholar]
  90. Neijt J.P., Lund B. Paclitaxel with carboplatin for the treatment of ovarian cancer. Semin. Oncol. 1996;23:2–4. [PubMed] [Google Scholar]
  91. Subauste C.M., Pertz O., Adamson E.D., Turner C.E., Junger S., Hahn K.M. Vinculin modulation of paxillin–FAK interactions regulates ERK to control survival and motility. J. Cell Biol. 2004;165:371–381. doi: 10.1083/jcb.200308011. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  92. Eke I., Cordes N. Focal adhesion signaling and therapy resistance in cancer. Semin. Cancer Biol. 2015;31:65–75. [PubMed] [Google Scholar]
  93. McCubrey J.A., Steelman L.S., Chappell W.H., Abrams S.L., Wong E.W., Chang F., Lehmann B., Terrian D.M., Milella M., Tafuri A., et al. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim. Biophys. Acta. 2007;1773:1263–1284. doi: 10.1016/j.bbamcr.2006.10.001. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  94. Duska L.R., Hamblin M.R., Miller J.L., Hasan T. Combination photoimmunotherapy and cisplatin: Effects on human ovarian cancer ex vivo. J. Natl. Cancer Inst. 1999;91:1557–1563. doi: 10.1093/jnci/91.18.1557. [PubMed] [CrossRef] [Google Scholar]
  95. Spring B., Mai Z., Rai P., Chang S., Hasan T. Theranostic nanocells for simultaneous imaging and photodynamic therapy of pancreatic cancer. Proc. SPIE. 2010;7551:755104. [Google Scholar]
  96. Kessel D., Oleinick N.L. Photodynamic therapy and cell death pathways. Methods Mol. Biol. 2010;635:35–46. doi: 10.1007/978-1-60761-697-9_3. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  97. Van Dongen G.A., Visser G.W., Vrouenraets M.B. Photosensitizer-antibody conjugates for detection and therapy of cancer. Adv. Drug Deliv. Rev. 2004;56:31–52. doi: 10.1016/j.addr.2003.09.003. [PubMed] [CrossRef] [Google Scholar]
  98. Ayhan A., Gultekin M., Taskiran C., Dursun P., Firat P., Bozdag G., Celik N.Y., Yuce K. Ascites and epithelial ovarian cancers: A reappraisal with respect to different aspects. Int. J. Gynecol. Cancer. 2007;17:68–75. doi: 10.1111/j.1525-1438.2006.00777.x. [PubMed] [CrossRef] [Google Scholar]
  99. Shen-Gunther J., Mannel R.S. Ascites as a predictor of ovarian malignancy. Gynecol. Oncol. 2002;87:77–83. doi: 10.1006/gyno.2002.6800. [PubMed] [CrossRef] [Google Scholar]
  100. Pourgholami M.H., Ataie-Kachoie P., Badar S., Morris D.L. Minocycline inhibits malignant ascites of ovarian cancer through targeting multiple signaling pathways. Gynecol. Oncol. 2013;129:113–119. doi: 10.1016/j.ygyno.2012.12.031. [PubMed] [CrossRef] [Google Scholar]
  101. Shender V., Arapidi G., Butenko I., Anikanov N., Ivanova O., Govorun V. Peptidome profiling dataset of ovarian cancer and non-cancer proximal fluids: Ascites and blood sera. Data Brief. 2019;22:557–562. doi: 10.1016/j.dib.2018.12.056. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  102. Parsons S.L., Watson S.A., Steele R.J.C. Malignant ascites. Br. J. Surg. 1996;83:6–14. doi: 10.1002/bjs.1800830104. [PubMed] [CrossRef] [Google Scholar]
  103. Becker G., Galandi D., Blum H.E. Malignant ascites: Systematic review and guideline for treatment. Eur. J. Cancer. 2006;42:589–597. doi: 10.1016/j.ejca.2005.11.018. [PubMed] [CrossRef] [Google Scholar]
  104. Huang H., Li Y.J., Lan C.Y., Huang Q.D., Feng Y.L., Huang Y.W., Liu J.H. Clinical significance of ascites in epithelial ovarian cancer. Neoplasma. 2013;60:546–552. doi: 10.4149/neo_2013_071. [PubMed] [CrossRef] [Google Scholar]
  105. Blagden S.P. Harnessing Pandemonium: The Clinical Implications of Tumor Heterogeneity in Ovarian Cancer. Front. Oncol. 2015;5:149. doi: 10.3389/fonc.2015.00149. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  106. Ahmed N., Latifi A., Riley C.B., Findlay J.K., Quinn M.A. Neuronal transcription factor Brn-3a(l) is over expressed in high-grade ovarian carcinomas and tumor cells from ascites of patients with advanced-stage ovarian cancer. J. Ovarian Res. 2010;3:17. doi: 10.1186/1757-2215-3-17. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  107. Mahmood N., Mihalcioiu C., Rabbani S.A. Multifaceted Role of the Urokinase-Type Plasminogen Activator (uPA) and Its Receptor (uPAR): Diagnostic, Prognostic, and Therapeutic Applications. Front. Oncol. 2018;8:24. doi: 10.3389/fonc.2018.00024. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  108. Jeffrey B., Udaykumar H.S., Schulze K.S. Flow fields generated by peristaltic reflex in isolated guinea pig ileum: Impact of contraction depth and shoulders. Am. J. Physiol. Gastrointest. Liver Physiol. 2003;285:G907–G918. doi: 10.1152/ajpgi.00062.2003. [PubMed] [CrossRef] [Google Scholar]
  109. Nagy J.A., Herzberg K.T., Dvorak J.M., Dvorak H.F. Pathogenesis of malignant ascites formation: Initiating events that lead to fluid accumulation. Cancer Res. 1993;53:2631–2643. [PubMed] [Google Scholar]
  110. Ahmed N., Abubaker K., Findlay J., Quinn M. Epithelial mesenchymal transition and cancer stem cell-like phenotypes facilitate chemoresistance in recurrent ovarian cancer. Curr. Cancer Drug Targets. 2010;10:268–278. doi: 10.2174/156800910791190175. [PubMed] [CrossRef] [Google Scholar]
  111. Latifi A., Abubaker K., Castrechini N., Ward A.C., Liongue C., Dobill F., Kumar J., Thompson E.W., Quinn M.A., Findlay J.K., et al. Cisplatin treatment of primary and metastatic epithelial ovarian carcinomas generates residual cells with mesenchymal stem cell-like profile. J. Cell Biochem. 2011;112:2850–2864. doi: 10.1002/jcb.23199. [PubMed] [CrossRef] [Google Scholar]
  112. Chan D.W., Hui W.W., Cai P.C., Liu M.X., Yung M.M., Mak C.S., Leung T.H., Chan K.K., Ngan H.Y. Targeting GRB7/ERK/FOXM1 signaling pathway impairs aggressiveness of ovarian cancer cells. PLoS ONE. 2012;7:e52578. doi: 10.1371/journal.pone.0052578. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  113. Mebratu Y., Tesfaigzi Y. How ERK1/2 activation controls cell proliferation and cell death: Is subcellular localization the answer? Cell Cycle. 2009;8:1168–1175. doi: 10.4161/cc.8.8.8147. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  114. Zebisch A., Czernilofsky A.P., Keri G., Smigelskaite J., Sill H., Troppmair J. Signaling through RAS-RAF-MEK-ERK: From basics to bedside. Curr. Med. Chem. 2007;14:601–623. doi: 10.2174/092986707780059670. [PubMed] [CrossRef] [Google Scholar]
  115. Jo H., Sipos K., Go Y.M., Law R., Rong J., McDonald J.M. Differential effect of shear stress on extracellular signal-regulated kinase and N-terminal Jun kinase in endothelial cells. Gi2- and Gbeta/gamma-dependent signaling pathways. J. Biol. Chem. 1997;272:1395–1401. doi: 10.1074/jbc.272.2.1395. [PubMed] [CrossRef] [Google Scholar]
  116. Surapisitchat J., Hoefen R.J., Pi X., Yoshizumi M., Yan C., Berk B.C. Fluid shear stress inhibits TNF-alpha activation of JNK but not ERK1/2 or p38 in human umbilical vein endothelial cells: Inhibitory crosstalk among MAPK family members. Proc. Natl. Acad. Sci. USA. 2001;98:6476–6481. doi: 10.1073/pnas.101134098. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  117. Kim C.H., Jeung E.B., Yoo Y.M. Combined Fluid Shear Stress and Melatonin Enhances the ERK/Akt/mTOR Signal in Cilia-Less MC3T3-E1 Preosteoblast Cells. Int. J. Mol. Sci. 2018;19:2929. doi: 10.3390/ijms19102929. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  118. Persons D.L., Yazlovitskaya E.M., Cui W., Pelling J.C. Cisplatin-induced activation of mitogen-activated protein kinases in ovarian carcinoma cells: Inhibition of extracellular signal-regulated kinase activity increases sensitivity to cisplatin. Clin. Cancer Res. 1999;5:1007–1014. [PubMed] [Google Scholar]
  119. Hayakawa J., Ohmichi M., Kurachi H., Ikegami H., Kimura A., Matsuoka T., Jikihara H., Mercola D., Murata Y. Inhibition of extracellular signal-regulated protein kinase or c-Jun N-terminal protein kinase cascade, differentially activated by cisplatin, sensitizes human ovarian cancer cell line. J. Biol. Chem. 1999;274:31648–31654. doi: 10.1074/jbc.274.44.31648. [PubMed] [CrossRef] [Google Scholar]
  120. Yeh P.Y., Chuang S.E., Yeh K.H., Song Y.C., Ea C.K., Cheng A.L. Increase of the resistance of human cervical carcinoma cells to cisplatin by inhibition of the MEK to ERK signaling pathway partly via enhancement of anticancer drug-induced NF kappa B activation. Biochem. Pharmacol. 2002;63:1423–1430. doi: 10.1016/S0006-2952(02)00908-5. [PubMed] [CrossRef] [Google Scholar]
  121. Wang X., Martindale J.L., Holbrook N.J. Requirement for ERK activation in cisplatin-induced apoptosis. J. Biol. Chem. 2000;275:39435–39443. doi: 10.1074/jbc.M004583200. [PubMed] [CrossRef] [Google Scholar]
  122. Qin X., Liu C., Zhou Y., Wang G. Cisplatin induces programmed death-1-ligand 1(PD-L1) over-expression in hepatoma H22 cells via Erk /MAPK signaling pathway. Cell Mol. Biol. 2010;56:OL1366-72. doi: 10.1170/156. [PubMed] [CrossRef] [Google Scholar]
  123. Basu A., Tu H. Activation of ERK during DNA damage-induced apoptosis involves protein kinase Cdelta. Biochem. Biophys. Res. Commun. 2005;334:1068–1073. doi: 10.1016/j.bbrc.2005.06.199. [PubMed] [CrossRef] [Google Scholar]
  124. Nowak G. Protein kinase C-alpha and ERK1/2 mediate mitochondrial dysfunction, decreases in active Na+ transport, and cisplatin-induced apoptosis in renal cells. J. Biol. Chem. 2002;277:43377–43388. doi: 10.1074/jbc.M206373200. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  125. Chaudhury A., Tan B.J., Das S., Chiu G.N. Increased ERK activation and cellular drug accumulation in the enhanced cytotoxicity of folate receptor-targeted liposomal carboplatin. Int. J. Oncol. 2012;40:703–710. doi: 10.3892/ijo.2011.1262. [PubMed] [CrossRef] [Google Scholar]
  126. Lok G.T., Chan D.W., Liu V.W., Hui W.W., Leung T.H., Yao K.M., Ngan H.Y. Aberrant activation of ERK/FOXM1 signaling cascade triggers the cell migration/invasion in ovarian cancer cells. PLoS ONE. 2011;6:e23790. doi: 10.1371/journal.pone.0023790. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  127. Lafky J.M., Wilken J.A., Baron A.T., Maihle N.J. Clinical implications of the ErbB/epidermal growth factor (EGF) receptor family and its ligands in ovarian cancer. Biochim. Biophys. Acta. 2008;1785:232–265. doi: 10.1016/j.bbcan.2008.01.001. [PubMed] [CrossRef] [Google Scholar]
  128. Secord A.A., Blessing J.A., Armstrong D.K., Rodgers W.H., Miner Z., Barnes M.N., Lewandowski G., Mannel R.S., Gynecologic Oncology G. Phase II trial of cetuximab and carboplatin in relapsed platinum-sensitive ovarian cancer and evaluation of epidermal growth factor receptor expression: A Gynecologic Oncology Group study. Gynecol. Oncol. 2008;108:493–499. doi: 10.1016/j.ygyno.2007.11.029. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  129. Bae G.-Y., Choi S.-J., Lee J.-S., Jo J., Lee J., Kim J., Cha H.-J. Loss of E-cadherin activates EGFR-MEK/ERK signaling, which promotes invasion via the ZEB1/MMP2 axis in non-small cell lung cancer. Oncotarget. 2013;4:2512. doi: 10.18632/oncotarget.1463. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  130. Pece S., Gutkind J.S. Signaling from E-cadherins to the MAPK pathway by the recruitment and activation of epidermal growth factor receptors upon cell-cell contact formation. J. Biol. Chem. 2000;275:41227–41233. doi: 10.1074/jbc.M006578200. [PubMed] [CrossRef] [Google Scholar]
  131. Lifschitz-Mercer B., Czernobilsky B., Feldberg E., Geiger B. Expression of the adherens junction protein vinculin in human basal and squamous cell tumors: Relationship to invasiveness and metastatic potential. Hum. Pathol. 1997;28:1230–1236. doi: 10.1016/S0046-8177(97)90195-7. [PubMed] [CrossRef] [Google Scholar]
  132. Raz A., Geiger B. Altered organization of cell-substrate contacts and membrane-associated cytoskeleton in tumor cell variants exhibiting different metastatic capabilities. Cancer Res. 1982;42:5183–5190. [PubMed] [Google Scholar]
  133. Fukada T., Sakajiri H., Kuroda M., Kioka N., Sugimoto K. Fluid shear stress applied by orbital shaking induces MG-63 osteosarcoma cells to activate ERK in two phases through distinct signaling pathways. Biochem. Biophys. Rep. 2017;9:257–265. doi: 10.1016/j.bbrep.2017.01.004. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  134. Wu D.W., Wu T.C., Wu J.Y., Cheng Y.W., Chen Y.C., Lee M.C., Chen C.Y., Lee H. Phosphorylation of paxillin confers cisplatin resistance in non-small cell lung cancer via activating ERK-mediated Bcl-2 expression. Oncogene. 2014;33:4385–4395. doi: 10.1038/onc.2013.389. [PubMed] [CrossRef] [Google Scholar]
  135. Kessel D. Apoptosis and associated phenomena as a determinants of the efficacy of photodynamic therapy. Photochem. Photobiol. Sci. 2015;14:1397–1402. doi: 10.1039/C4PP00413B. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  136. Agostinis P., Berg K., Cengel K.A., Foster T.H., Girotti A.W., Gollnick S.O., Hahn S.M., Hamblin M.R., Juzeniene A., Kessel D., et al. Photodynamic therapy of cancer: An update. CA Cancer J. Clin. 2011;61:250–281. doi: 10.3322/caac.20114. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  137. Sorrin A.J., Ruhi M.K., Ferlic N.A., Karimnia V., Polacheck W.J., Celli J.P., Huang H.C., Rizvi I. Photodynamic Therapy and the Biophysics of the Tumor Microenvironment. Photochem. Photobiol. 2020 doi: 10.1111/php.13209. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  138. Niu C.J., Fisher C., Scheffler K., Wan R., Maleki H., Liu H., Sun Y., C A.S., Birngruber R., Lilge L. Polyacrylamide gel substrates that simulate the mechanical stiffness of normal and malignant neuronal tissues increase protoporphyin IX synthesis in glioma cells. J. Biomed. Opt. 2015;20:098002. doi: 10.1117/1.JBO.20.9.098002. [PubMed] [CrossRef] [Google Scholar]
  139. Perentes J.Y., Wang Y., Wang X., Abdelnour E., Gonzalez M., Decosterd L., Wagnieres G., Van den Bergh H., Peters S., Ris H.B., et al. Low-Dose Vascular Photodynamic Therapy Decreases Tumor Interstitial Fluid Pressure, which Promotes Liposomal Doxorubicin Distribution in a Murine Sarcoma Metastasis Model. Transl. Oncol. 2014;7 doi: 10.1016/j.tranon.2014.04.010. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  140. Leunig M., Goetz A.E., Gamarra F., Zetterer G., Messmer K., Jain R.K. Photodynamic therapy-induced alterations in interstitial fluid pressure, volume and water content of an amelanotic melanoma in the hamster. Br. J. Cancer. 1994;69:101–103. doi: 10.1038/bjc.1994.15. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  141. Foster T.H., Murant R.S., Bryant R.G., Knox R.S., Gibson S.L., Hilf R. Oxygen consumption and diffusion effects in photodynamic therapy. Radiat Res. 1991;126:296–303. doi: 10.2307/3577919. [PubMed] [CrossRef] [Google Scholar]
  142. Foster T.H., Hartley D.F., Nichols M.G., Hilf R. Fluence rate effects in photodynamic therapy of multicell tumor spheroids. Cancer Res. 1993;53:1249–1254. [PubMed] [Google Scholar]
  143. Nichols M.G., Foster T.H. Oxygen diffusion and reaction kinetics in the photodynamic therapy of multicell tumour spheroids. Phys. Med. Biol. 1994;39:2161–2181. doi: 10.1088/0031-9155/39/12/003. [PubMed] [CrossRef] [Google Scholar]
  144. Cavin S., Wang X., Zellweger M., Gonzalez M., Bensimon M., Wagnieres G., Krueger T., Ris H.B., Gronchi F., Perentes J.Y. Interstitial fluid pressure: A novel biomarker to monitor photo-induced drug uptake in tumor and normal tissues. Lasers Surg. Med. 2017;49:773–780. doi: 10.1002/lsm.22687. [PubMed] [CrossRef] [Google Scholar]
  145. Garcia Calavia P., Chambrier I., Cook M.J., Haines A.H., Field R.A., Russell D.A. Targeted photodynamic therapy of breast cancer cells using lactose-phthalocyanine functionalized gold nanoparticles. J. Colloid Interface Sci. 2018;512:249–259. doi: 10.1016/j.jcis.2017.10.030. [PubMed] [CrossRef] [Google Scholar]
  146. Kato T., Jin C.S., Ujiie H., Lee D., Fujino K., Wada H., Hu H.P., Weersink R.A., Chen J., Kaji M., et al. Nanoparticle targeted folate receptor 1-enhanced photodynamic therapy for lung cancer. Lung Cancer. 2017;113:59–68. doi: 10.1016/j.lungcan.2017.09.002. [PubMed] [CrossRef] [Google Scholar]
  147. Sebak A.A., Gomaa I.E.O., ElMeshad A.N., AbdelKader M.H. Targeted photodynamic-induced singlet oxygen production by peptide-conjugated biodegradable nanoparticles for treatment of skin melanoma. Photodiagnosis Photodyn. Ther. 2018;23:181–189. doi: 10.1016/j.pdpdt.2018.05.017. [PubMed] [CrossRef] [Google Scholar]
  148. Fernandes S.R.G., Fernandes R., Sarmento B., Pereira P.M.R., Tome J.P.C. Photoimmunoconjugates: Novel synthetic strategies to target and treat cancer by photodynamic therapy. Org. Biomol. Chem. 2019;17:2579–2593. doi: 10.1039/C8OB02902D. [PubMed] [CrossRef] [Google Scholar]
  149. Hamblin M.R., Miller J.L., Hasan T. Effect of charge on the interaction of site-specific photoimmunoconjugates with human ovarian cancer cells. Cancer Res. 1996;56:5205–5210. [PubMed] [Google Scholar]
  150. Flont M., Jastrzebska E., Brzozka Z. Synergistic effect of the combination therapy on ovarian cancer cells under microfluidic conditions. Anal. Chim. Acta. 2020;1100:138–148. doi: 10.1016/j.aca.2019.11.047. [PubMed] [CrossRef] [Google Scholar]
Figure 3. (a) Velocity distribution in a section perpendicular to the flow for rectangular (left) and Ushaped (right) cross section channels, and (b) particle location in these cross sections.

Continuous-Flow Separation of Magnetic Particles from Biofluids: How Does the Microdevice Geometry Determine the Separation Performance?

Cristina González Fernández,1 Jenifer Gómez Pastora,2 Arantza Basauri,1 Marcos Fallanza,1 Eugenio Bringas,1 Jeffrey J. Chalmers,2 and Inmaculada Ortiz1,*
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생체 유체에서 자성 입자의 연속 흐름 분리 : 마이크로 장치 형상이 분리 성능을 어떻게 결정합니까?

Abstract

The use of functionalized magnetic particles for the detection or separation of multiple chemicals and biomolecules from biofluids continues to attract significant attention. After their incubation with the targeted substances, the beads can be magnetically recovered to perform analysis or diagnostic tests. Particle recovery with permanent magnets in continuous-flow microdevices has gathered great attention in the last decade due to the multiple advantages of microfluidics. As such, great efforts have been made to determine the magnetic and fluidic conditions for achieving complete particle capture; however, less attention has been paid to the effect of the channel geometry on the system performance, although it is key for designing systems that simultaneously provide high particle recovery and flow rates. Herein, we address the optimization of Y-Y-shaped microchannels, where magnetic beads are separated from blood and collected into a buffer stream by applying an external magnetic field. The influence of several geometrical features (namely cross section shape, thickness, length, and volume) on both bead recovery and system throughput is studied. For that purpose, we employ an experimentally validated Computational Fluid Dynamics (CFD) numerical model that considers the dominant forces acting on the beads during separation. Our results indicate that rectangular, long devices display the best performance as they deliver high particle recovery and high throughput. Thus, this methodology could be applied to the rational design of lab-on-a-chip devices for any magnetically driven purification, enrichment or isolation.

생체 유체에서 여러 화학 물질과 생체 분자의 검출 또는 분리를 위한 기능화된 자성 입자의 사용은 계속해서 상당한 관심을 받고 있습니다. 표적 물질과 함께 배양 한 후 비드는 자기적으로 회수되어 분석 또는 진단 테스트를 수행 할 수 있습니다.

연속 흐름 마이크로 장치에서 영구 자석을 사용한 입자 회수는 마이크로 유체의 여러 장점으로 인해 지난 10 년 동안 큰 관심을 모았습니다. 따라서 완전한 입자 포획을 달성하기 위한 자기 및 유체 조건을 결정하기 위해 많은 노력을 기울였습니다.

그러나 높은 입자 회수율과 유속을 동시에 제공하는 시스템을 설계하는데 있어 핵심이기는 하지만 시스템 성능에 대한 채널 형상의 영향에 대해서는 덜 주의를 기울였습니다.

여기에서 우리는 자기 비드가 혈액에서 분리되어 외부 자기장을 적용하여 버퍼 스트림으로 수집되는 Y-Y 모양의 마이크로 채널의 최적화를 다룹니다. 비드 회수 및 시스템 처리량에 대한 여러 기하학적 특징 (즉, 단면 형상, 두께, 길이 및 부피)의 영향을 연구합니다.

이를 위해 분리 중에 비드에 작용하는 지배적인 힘을 고려하는 실험적으로 검증된 CFD (Computational Fluid Dynamics) 수치 모델을 사용합니다.

우리의 결과는 직사각형의 긴 장치가 높은 입자 회수율과 높은 처리량을 제공하기 때문에 최고의 성능을 보여줍니다. 따라서 이 방법론은 자기 구동 정제, 농축 또는 분리를 위한 랩 온어 칩 장치의 합리적인 설계에 적용될 수 있습니다.

Keywords: particle magnetophoresis, CFD, cross section, chip fabrication

Figure 1 (a) Top view of the microfluidic-magnetophoretic device, (b) Schematic representation of the channel cross-sections studied in this work, and (c) the magnet position relative to the channel location (Sepy and Sepz are the magnet separation distances in y and z, respectively).
Figure 1 (a) Top view of the microfluidic-magnetophoretic device, (b) Schematic representation of the channel cross-sections studied in this work, and (c) the magnet position relative to the channel location (Sepy and Sepz are the magnet separation distances in y and z, respectively).
Figure 2. (a) Channel-magnet configuration and (b–d) magnetic force distribution in the channel midplane for 2 mm, 5 mm and 10 mm long rectangular (left) and U-shaped (right) devices.
Figure 2. (a) Channel-magnet configuration and (b–d) magnetic force distribution in the channel midplane for 2 mm, 5 mm and 10 mm long rectangular (left) and U-shaped (right) devices.
Figure 3. (a) Velocity distribution in a section perpendicular to the flow for rectangular (left) and Ushaped (right) cross section channels, and (b) particle location in these cross sections.
Figure 3. (a) Velocity distribution in a section perpendicular to the flow for rectangular (left) and Ushaped (right) cross section channels, and (b) particle location in these cross sections.
Figure 4. Influence of fluid flow rate on particle recovery when the applied magnetic force is (a) different and (b) equal in U-shaped and rectangular cross section microdevices.
Figure 4. Influence of fluid flow rate on particle recovery when the applied magnetic force is (a) different and (b) equal in U-shaped and rectangular cross section microdevices.
Figure 5. Magnetic bead capture as a function of fluid flow rate for all of the studied geometries.
Figure 5. Magnetic bead capture as a function of fluid flow rate for all of the studied geometries.
Figure 6. Influence of (a) magnetic and fluidic forces (J parameter) and (b) channel geometry (θ parameter) on particle recovery. Note that U-2mm does not accurately fit a line.
Figure 6. Influence of (a) magnetic and fluidic forces (J parameter) and (b) channel geometry (θ parameter) on particle recovery. Note that U-2mm does not accurately fit a line.
Figure 7. Dependence of bead capture on the (a) functional channel volume, and (b) particle residence time (tres). Note that in the curve fitting expressions V represents the functional channel volume and that U-2mm does not accurately fit a line.
Figure 7. Dependence of bead capture on the (a) functional channel volume, and (b) particle residence time (tres). Note that in the curve fitting expressions V represents the functional channel volume and that U-2mm does not accurately fit a line.
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References

  1. Gómez-Pastora J., Xue X., Karampelas I.H., Bringas E., Furlani E.P., Ortiz I. Analysis of separators for magnetic beads recovery: From large systems to multifunctional microdevices. Sep. Purif. Technol. 2017;172:16–31. doi: 10.1016/j.seppur.2016.07.050. [CrossRef] [Google Scholar]
  2. Wise N., Grob T., Morten K., Thompson I., Sheard S. Magnetophoretic velocities of superparamagnetic particles, agglomerates and complexes. J. Magn. Magn. Mater. 2015;384:328–334. doi: 10.1016/j.jmmm.2015.02.031. [CrossRef] [Google Scholar]
  3. Khashan S.A., Elnajjar E., Haik Y. CFD simulation of the magnetophoretic separation in a microchannel. J. Magn. Magn. Mater. 2011;323:2960–2967. doi: 10.1016/j.jmmm.2011.06.001. [CrossRef] [Google Scholar]
  4. Khashan S.A., Furlani E.P. Scalability analysis of magnetic bead separation in a microchannel with an array of soft magnetic elements in a uniform magnetic field. Sep. Purif. Technol. 2014;125:311–318. doi: 10.1016/j.seppur.2014.02.007. [CrossRef] [Google Scholar]
  5. Furlani E.P. Magnetic biotransport: Analysis and applications. Materials. 2010;3:2412–2446. doi: 10.3390/ma3042412. [CrossRef] [Google Scholar]
  6. Gómez-Pastora J., Bringas E., Ortiz I. Design of novel adsorption processes for the removal of arsenic from polluted groundwater employing functionalized magnetic nanoparticles. Chem. Eng. Trans. 2016;47:241–246. [Google Scholar]
  7. Gómez-Pastora J., Bringas E., Lázaro-Díez M., Ramos-Vivas J., Ortiz I. The reverse of controlled release: Controlled sequestration of species and biotoxins into nanoparticles (NPs) In: Stroeve P., Mahmoudi M., editors. Drug Delivery Systems. World Scientific; Hackensack, NJ, USA: 2017. pp. 207–244. [Google Scholar]
  8. Ruffert C. Magnetic bead-magic bullet. Micromachines. 2016;7:21. doi: 10.3390/mi7020021. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  9. Yáñez-Sedeño P., Campuzano S., Pingarrón J.M. Magnetic particles coupled to disposable screen printed transducers for electrochemical biosensing. Sensors. 2016;16:1585. doi: 10.3390/s16101585. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  10. Schrittwieser S., Pelaz B., Parak W.J., Lentijo-Mozo S., Soulantica K., Dieckhoff J., Ludwig F., Guenther A., Tschöpe A., Schotter J. Homogeneous biosensing based on magnetic particle labels. Sensors. 2016;16:828. doi: 10.3390/s16060828. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  11. He J., Huang M., Wang D., Zhang Z., Li G. Magnetic separation techniques in sample preparation for biological analysis: A review. J. Pharm. Biomed. Anal. 2014;101:84–101. doi: 10.1016/j.jpba.2014.04.017. [PubMed] [CrossRef] [Google Scholar]
  12. Ha Y., Ko S., Kim I., Huang Y., Mohanty K., Huh C., Maynard J.A. Recent advances incorporating superparamagnetic nanoparticles into immunoassays. ACS Appl. Nano Mater. 2018;1:512–521. doi: 10.1021/acsanm.7b00025. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  13. Gómez-Pastora J., González-Fernández C., Fallanza M., Bringas E., Ortiz I. Flow patterns and mass transfer performance of miscible liquid-liquid flows in various microchannels: Numerical and experimental studies. Chem. Eng. J. 2018;344:487–497. doi: 10.1016/j.cej.2018.03.110. [CrossRef] [Google Scholar]
  14. Gale B.K., Jafek A.R., Lambert C.J., Goenner B.L., Moghimifam H., Nze U.C., Kamarapu S.K. A review of current methods in microfluidic device fabrication and future commercialization prospects. Inventions. 2018;3:60. doi: 10.3390/inventions3030060. [CrossRef] [Google Scholar]
  15. Niemeyer C.M., Mirkin C.A., editors. Nanobiotechnology; Concepts, Applications and Perspectives. Wiley-VCH; Weinheim, Germany: 2004. [Google Scholar]
  16. Khashan S.A., Dagher S., Alazzam A., Mathew B., Hilal-Alnaqbi A. Microdevice for continuous flow magnetic separation for bioengineering applications. J. Micromech. Microeng. 2017;27:055016. doi: 10.1088/1361-6439/aa666d. [CrossRef] [Google Scholar]
  17. Basauri A., Gomez-Pastora J., Fallanza M., Bringas E., Ortiz I. Predictive model for the design of reactive micro-separations. Sep. Purif. Technol. 2019;209:900–907. doi: 10.1016/j.seppur.2018.09.028. [CrossRef] [Google Scholar]
  18. Abdollahi P., Karimi-Sabet J., Moosavian M.A., Amini Y. Microfluidic solvent extraction of calcium: Modeling and optimization of the process variables. Sep. Purif. Technol. 2020;231:115875. doi: 10.1016/j.seppur.2019.115875. [CrossRef] [Google Scholar]
  19. Khashan S.A., Alazzam A., Furlani E. A novel design for a microfluidic magnetophoresis system: Computational study; Proceedings of the 12th International Symposium on Fluid Control, Measurement and Visualization (FLUCOME2013); Nara, Japan. 18–23 November 2013. [Google Scholar]
  20. Pamme N. Magnetism and microfluidics. Lab Chip. 2006;6:24–38. doi: 10.1039/B513005K. [PubMed] [CrossRef] [Google Scholar]
  21. Gómez-Pastora J., Amiri Roodan V., Karampelas I.H., Alorabi A.Q., Tarn M.D., Iles A., Bringas E., Paunov V.N., Pamme N., Furlani E.P., et al. Two-step numerical approach to predict ferrofluid droplet generation and manipulation inside multilaminar flow chambers. J. Phys. Chem. C. 2019;123:10065–10080. doi: 10.1021/acs.jpcc.9b01393. [CrossRef] [Google Scholar]
  22. Gómez-Pastora J., Karampelas I.H., Bringas E., Furlani E.P., Ortiz I. Numerical analysis of bead magnetophoresis from flowing blood in a continuous-flow microchannel: Implications to the bead-fluid interactions. Sci. Rep. 2019;9:7265. doi: 10.1038/s41598-019-43827-x. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  23. Tarn M.D., Pamme N. On-Chip Magnetic Particle-Based Immunoassays Using Multilaminar Flow for Clinical Diagnostics. In: Taly V., Viovy J.L., Descroix S., editors. Microchip Diagnostics Methods and Protocols. Humana Press; New York, NY, USA: 2017. pp. 69–83. [Google Scholar]
  24. Phurimsak C., Tarn M.D., Peyman S.A., Greenman J., Pamme N. On-chip determination of c-reactive protein using magnetic particles in continuous flow. Anal. Chem. 2014;86:10552–10559. doi: 10.1021/ac5023265. [PubMed] [CrossRef] [Google Scholar]
  25. Wu X., Wu H., Hu Y. Enhancement of separation efficiency on continuous magnetophoresis by utilizing L/T-shaped microchannels. Microfluid. Nanofluid. 2011;11:11–24. doi: 10.1007/s10404-011-0768-7. [CrossRef] [Google Scholar]
  26. Vojtíšek M., Tarn M.D., Hirota N., Pamme N. Microfluidic devices in superconducting magnets: On-chip free-flow diamagnetophoresis of polymer particles and bubbles. Microfluid. Nanofluid. 2012;13:625–635. doi: 10.1007/s10404-012-0979-6. [CrossRef] [Google Scholar]
  27. Gómez-Pastora J., González-Fernández C., Real E., Iles A., Bringas E., Furlani E.P., Ortiz I. Computational modeling and fluorescence microscopy characterization of a two-phase magnetophoretic microsystem for continuous-flow blood detoxification. Lab Chip. 2018;18:1593–1606. doi: 10.1039/C8LC00396C. [PubMed] [CrossRef] [Google Scholar]
  28. Forbes T.P., Forry S.P. Microfluidic magnetophoretic separations of immunomagnetically labeled rare mammalian cells. Lab Chip. 2012;12:1471–1479. doi: 10.1039/c2lc40113d. [PubMed] [CrossRef] [Google Scholar]
  29. Nandy K., Chaudhuri S., Ganguly R., Puri I.K. Analytical model for the magnetophoretic capture of magnetic microspheres in microfluidic devices. J. Magn. Magn. Mater. 2008;320:1398–1405. doi: 10.1016/j.jmmm.2007.11.024. [CrossRef] [Google Scholar]
  30. Plouffe B.D., Lewis L.H., Murthy S.K. Computational design optimization for microfluidic magnetophoresis. Biomicrofluidics. 2011;5:013413. doi: 10.1063/1.3553239. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  31. Hale C., Darabi J. Magnetophoretic-based microfluidic device for DNA isolation. Biomicrofluidics. 2014;8:044118. doi: 10.1063/1.4893772. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  32. Becker H., Gärtner C. Polymer microfabrication methods for microfluidic analytical applications. Electrophoresis. 2000;21:12–26. doi: 10.1002/(SICI)1522-2683(20000101)21:1<12::AID-ELPS12>3.0.CO;2-7. [PubMed] [CrossRef] [Google Scholar]
  33. Pekas N., Zhang Q., Nannini M., Juncker D. Wet-etching of structures with straight facets and adjustable taper into glass substrates. Lab Chip. 2010;10:494–498. doi: 10.1039/B912770D. [PubMed] [CrossRef] [Google Scholar]
  34. Wang T., Chen J., Zhou T., Song L. Fabricating microstructures on glass for microfluidic chips by glass molding process. Micromachines. 2018;9:269. doi: 10.3390/mi9060269. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  35. Castaño-Álvarez M., Pozo Ayuso D.F., García Granda M., Fernández-Abedul M.T., Rodríguez García J., Costa-García A. Critical points in the fabrication of microfluidic devices on glass substrates. Sens. Actuators B Chem. 2008;130:436–448. doi: 10.1016/j.snb.2007.09.043. [CrossRef] [Google Scholar]
  36. Prakash S., Kumar S. Fabrication of microchannels: A review. Proc. Inst. Mech. Eng. Part B J. Eng. Manuf. 2015;229:1273–1288. doi: 10.1177/0954405414535581. [CrossRef] [Google Scholar]
  37. Leester-Schädel M., Lorenz T., Jürgens F., Ritcher C. Fabrication of Microfluidic Devices. In: Dietzel A., editor. Microsystems for Pharmatechnology: Manipulation of Fluids, Particles, Droplets, and Cells. Springer; Basel, Switzerland: 2016. pp. 23–57. [Google Scholar]
  38. Bartlett N.W., Wood R.J. Comparative analysis of fabrication methods for achieving rounded microchannels in PDMS. J. Micromech. Microeng. 2016;26:115013. doi: 10.1088/0960-1317/26/11/115013. [CrossRef] [Google Scholar]
  39. Ng P.F., Lee K.I., Yang M., Fei B. Fabrication of 3D PDMS microchannels of adjustable cross-sections via versatile gel templates. Polymers. 2019;11:64. doi: 10.3390/polym11010064. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  40. Furlani E.P., Sahoo Y., Ng K.C., Wortman J.C., Monk T.E. A model for predicting magnetic particle capture in a microfluidic bioseparator. Biomed. Microdevices. 2007;9:451–463. doi: 10.1007/s10544-007-9050-x. [PubMed] [CrossRef] [Google Scholar]
  41. Tarn M.D., Peyman S.A., Robert D., Iles A., Wilhelm C., Pamme N. The importance of particle type selection and temperature control for on-chip free-flow magnetophoresis. J. Magn. Magn. Mater. 2009;321:4115–4122. doi: 10.1016/j.jmmm.2009.08.016. [CrossRef] [Google Scholar]
  42. Furlani E.P. Permanent Magnet and Electromechanical Devices; Materials, Analysis and Applications. Academic Press; Waltham, MA, USA: 2001. [Google Scholar]
  43. White F.M. Viscous Fluid Flow. McGraw-Hill; New York, NY, USA: 1974. [Google Scholar]
  44. Mathew B., Alazzam A., El-Khasawneh B., Maalouf M., Destgeer G., Sung H.J. Model for tracing the path of microparticles in continuous flow microfluidic devices for 2D focusing via standing acoustic waves. Sep. Purif. Technol. 2015;153:99–107. doi: 10.1016/j.seppur.2015.08.026. [CrossRef] [Google Scholar]
  45. Furlani E.J., Furlani E.P. A model for predicting magnetic targeting of multifunctional particles in the microvasculature. J. Magn. Magn. Mater. 2007;312:187–193. doi: 10.1016/j.jmmm.2006.09.026. [CrossRef] [Google Scholar]
  46. Furlani E.P., Ng K.C. Analytical model of magnetic nanoparticle transport and capture in the microvasculature. Phys. Rev. E. 2006;73:061919. doi: 10.1103/PhysRevE.73.061919. [PubMed] [CrossRef] [Google Scholar]
  47. Eibl R., Eibl D., Pörtner R., Catapano G., Czermak P. Cell and Tissue Reaction Engineering. Springer; Berlin/Heidelberg, Germany: 2009. [Google Scholar]
  48. Pamme N., Eijkel J.C.T., Manz A. On-chip free-flow magnetophoresis: Separation and detection of mixtures of magnetic particles in continuous flow. J. Magn. Magn. Mater. 2006;307:237–244. doi: 10.1016/j.jmmm.2006.04.008. [CrossRef] [Google Scholar]
  49. Alorabi A.Q., Tarn M.D., Gómez-Pastora J., Bringas E., Ortiz I., Paunov V.N., Pamme N. On-chip polyelectrolyte coating onto magnetic droplets-Towards continuous flow assembly of drug delivery capsules. Lab Chip. 2017;17:3785–3795. doi: 10.1039/C7LC00918F. [PubMed] [CrossRef] [Google Scholar]
  50. Zhang H., Guo H., Chen Z., Zhang G., Li Z. Application of PECVD SiC in glass micromachining. J. Micromech. Microeng. 2007;17:775–780. doi: 10.1088/0960-1317/17/4/014. [CrossRef] [Google Scholar]
  51. Mourzina Y., Steffen A., Offenhäusser A. The evaporated metal masks for chemical glass etching for BioMEMS. Microsyst. Technol. 2005;11:135–140. doi: 10.1007/s00542-004-0430-3. [CrossRef] [Google Scholar]
  52. Mata A., Fleischman A.J., Roy S. Fabrication of multi-layer SU-8 microstructures. J. Micromech. Microeng. 2006;16:276–284. doi: 10.1088/0960-1317/16/2/012. [CrossRef] [Google Scholar]
  53. Su N. 8 2000 Negative Tone Photoresist Formulations 2002–2025. MicroChem Corporation; Newton, MA, USA: 2002. [Google Scholar]
  54. Su N. 8 2000 Negative Tone Photoresist Formulations 2035–2100. MicroChem Corporation; Newton, MA, USA: 2002. [Google Scholar]
  55. Fu C., Hung C., Huang H. A novel and simple fabrication method of embedded SU-8 micro channels by direct UV lithography. J. Phys. Conf. Ser. 2006;34:330–335. doi: 10.1088/1742-6596/34/1/054. [CrossRef] [Google Scholar]
  56. Kazoe Y., Yamashiro I., Mawatari K., Kitamori T. High-pressure acceleration of nanoliter droplets in the gas phase in a microchannel. Micromachines. 2016;7:142. doi: 10.3390/mi7080142. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  57. Sharp K.V., Adrian R.J., Santiago J.G., Molho J.I. Liquid flows in microchannels. In: Gad-el-Hak M., editor. MEMS: Introduction and Fundamentals. CRC Press; Boca Raton, FL, USA: 2006. pp. 10-1–10-46. [Google Scholar]
  58. Oh K.W., Lee K., Ahn B., Furlani E.P. Design of pressure-driven microfluidic networks using electric circuit analogy. Lab Chip. 2012;12:515–545. doi: 10.1039/C2LC20799K. [PubMed] [CrossRef] [Google Scholar]
  59. Bruus H. Theoretical Microfluidics. Oxford University Press; New York, NY, USA: 2008. [Google Scholar]
  60. Beebe D.J., Mensing G.A., Walker G.M. Physics and applications of microfluidics in biology. Annu. Rev. Biomed. Eng. 2002;4:261–286. doi: 10.1146/annurev.bioeng.4.112601.125916. [PubMed] [CrossRef] [Google Scholar]
  61. Yalikun Y., Tanaka Y. Large-scale integration of all-glass valves on a microfluidic device. Micromachines. 2016;7:83. doi: 10.3390/mi7050083. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  62. Van Heeren H., Verhoeven D., Atkins T., Tzannis A., Becker H., Beusink W., Chen P. [(accessed on 9 March 2020)];Design Guideline for Microfluidic Device and Component Interfaces (Part 2) Version 3. Available online: http://www.makefluidics.com/en/design-guideline?id=7.
  63. Scheuble N., Iles A., Wootton R.C.R., Windhab E.J., Fischer P., Elvira K.S. Microfluidic technique for the simultaneous quantification of emulsion instabilities and lipid digestion kinetics. Anal. Chem. 2017;89:9116–9123. doi: 10.1021/acs.analchem.7b01853. [PubMed] [CrossRef] [Google Scholar]
  64. Lynch E.C. Red blood cell damage by shear stress. Biophys. J. 1972;12:257–273. [PMC free article] [PubMed] [Google Scholar]
  65. Paul R., Apel J., Klaus S., Schügner F., Schwindke P., Reul H. Shear stress related blood damage in laminar Couette flow. Artif. Organs. 2003;27:517–529. doi: 10.1046/j.1525-1594.2003.07103.x. [PubMed] [CrossRef] [Google Scholar]
  66. Gómez-Pastora J., Karampelas I.H., Xue X., Bringas E., Furlani E.P., Ortiz I. Magnetic bead separation from flowing blood in a two-phase continuous-flow magnetophoretic microdevice: Theoretical analysis through computational fluid dynamics simulation. J. Phys. Chem. C. 2017;121:7466–7477. doi: 10.1021/acs.jpcc.6b12835. [CrossRef] [Google Scholar]
  67. Lim J., Yeap S.P., Leow C.H., Toh P.Y., Low S.C. Magnetophoresis of iron oxide nanoparticles at low field gradient: The role of shape anisotropy. J. Colloid Interface Sci. 2014;421:170–177. doi: 10.1016/j.jcis.2014.01.044. [PubMed] [CrossRef] [Google Scholar]
  68. Culbertson C.T., Sibbitts J., Sellens K., Jia S. Fabrication of Glass Microfluidic Devices. In: Dutta D., editor. Microfluidic Electrophoresis: Methods and Protocols. Humana Press; New York, NY, USA: 2019. pp. 1–12. [Google Scholar]
Mixing Tank with FLOW-3D

CFD Stirs Up Mixing 일반

CFD (전산 유체 역학) 전문가가 필요하고 때로는 실행하는데 몇 주가 걸리는 믹싱 시뮬레이션의 시대는 오래 전입니다. 컴퓨팅 및 관련 기술의 엄청난 도약에 힘 입어 Ansys, Comsol 및 Flow Science와 같은 회사는 엔지니어의 데스크톱에 사용하기 쉬운 믹싱 시뮬레이션을 제공하고 있습니다.

“병렬화 및 고성능 컴퓨팅의 발전과 템플릿화는 비전문 화학 엔지니어에게 정확한 CFD 시뮬레이션을 제공했습니다.”라고 펜실베이니아 주 피츠버그에있는 Ansys Inc.의 수석 제품 마케팅 관리자인 Bill Kulp는 말합니다 .

흐름 개선을위한 실용적인 지침이 필요하십니까? 다운로드 화학 처리의 eHandbook을 지금 흐름 도전 싸우는 방법!

예를 들어, 회사는 휴스턴에있는 Nalco Champion과 함께 프로젝트를 시작했습니다. 이 프로젝트는 시뮬레이션 전문가가 아닌 화학 엔지니어에게 Ansys Fluent 및 ACT (분석 제어 기술) 템플릿 기반 시뮬레이션 앱에 대한 액세스 권한을 부여합니다. 새로운 화학 물질을위한 프로세스를 빠르고 효율적으로 확장합니다.

Giving Mixing Its Due

“화학 산업은 CFD와 같은 계산 도구를 사용하여 많은 것을 얻을 수 있지만 혼합 프로세스는 단순하다고 가정하기 때문에 간과되는 경우가 있습니다. 그러나 최신 수치 기법을 사용하여 우수한 성능을 달성하는 흥미로운 방법이 많이 있습니다.”라고 Flow Science Inc. , Santa Fe, NM의 CFD 엔지니어인 Ioannis Karampelas는 말합니다 .

이러한 많은 기술이 회사의 Flow-3D Multiphysics 모델링 소프트웨어 패키지와 전용 포스트 프로세서 시각화 도구 인 FlowSight에 포함되어 있습니다.

“모든 상업용 CFD 패키지는 어떤 형태의 시각화 도구와 번들로 제공되지만 FlowSight는 매우 강력하고 사용하기 쉽고 이해하기 쉽게 설계되었습니다. 예를 들어, 프로세스를 재 설계하려는 엔지니어는 다양한 설계 변경의 효과를 평가하기 위해 매우 직관적인 시각화 도구가 필요합니다.”라고 그는 설명합니다.

이 접근 방식은 실험 측정을 얻기 어려운 공정 (예 : 쉽게 측정 할 수없는 매개 변수 및 독성 물질의 존재로 인해 본질적으로 위험한 공정)을 더 잘 이해하고 최적화하는데 특히 효과적입니다.

동일한 접근 방식은 또한 믹서 관련 장비 공급 업체가 고객 요구에 맞게 제품을보다 정확하게 개발하고 맞춤화하는 데 도움이되었습니다. “이는 불필요한 프로토 타이핑 비용이나 잠재적 인 과도한 엔지니어링을 방지합니다. 두 가지 모두 일부 공급 업체의 문제였습니다.”라고 Karampelas는 말합니다.

CFD 기술 자체는 계속해서 발전하고 있습니다. 예를 들어, 수치 알고리즘의 관점에서 볼 때 구형 입자의 상호 작용이 열 전달을 적절하게 모델링하는 데 중요한 다양한 문제에 대해 이산 요소 모델링을 쉽게 적용 할 수있는 반면, LES 난류 모델은 난류 흐름 패턴을 정확하게 시뮬레이션하는 데 이상적입니다.

컴퓨팅 리소스에 대한 비용과 수요에도 불구하고 Karampelas는 난류 모델의 전체 제품군을 제공 할 수있는 것이 중요하다고 생각합니다. 특히 LES는 이미 대부분의 학계와 일부 산업 (예 : 전력 공학)에서 선택하는 방법이기 때문입니다. .

그럼에도 불구하고 CFD의 사용이 제한적이거나 비실용적 일 수있는 경우는 확실히 있습니다. 여기에는 나노 입자에서 벌크 유체 증발을 모델링하는 것과 같이 관심의 규모가 다른 규모에 따라 달라질 수있는 문제와 중요한 물리적 현상이 아직 알려지지 않았거나 제대로 이해되지 않았거나 아마도 매우 복잡한 문제 (예 : 모델링)가 포함됩니다. 음 펨바 효과”라고 Karampelas는 경고합니다.

반면에 더욱 강력한 하드웨어와 업데이트 된 수치 알고리즘의 출현은 CFD 소프트웨어를 사용하여 과다한 설계 및 최적화 문제를 해결하기위한 최적의 접근 방식이 될 것이라고 그는 믿습니다.

“복잡한 열교환 시스템 및 새로운 혼합 기술과 같이 점점 더 복잡한 공정을 모델링 할 수있는 능력은 가까운 장래에 가능할 수있는 일을 간단히 보여줍니다. 수치적 방법 사용의 주요 이점은 설계자가 상상력에 의해서만 제한되어 소규모 믹서에서 대규모 반응기 및 증류 컬럼에 이르기까지 다양한 화학 플랜트 공정을 최적화 할 수있는 길을 열어 준다는 것입니다. 실험적 또는 경험적 접근 방식은 항상 관련성이 있지만 CFD가 미래의 엔지니어를위한 선택 도구가 될 것이라고 확신합니다.”라고 그는 결론을 내립니다.

Ottewell2
Seán Ottewell은 Chemical Processing의 편집장입니다. sottewell@putman.net으로 이메일을 보낼 수 있습니다 .

기사 원문 : https://www.chemicalprocessing.com/articles/2017/cfd-stirs-up-mixing/

Micro/Biofluidics with FLOW-3D (미세/생명 유체공학)

미세/생명유체공학에 관한 모델링

  • In-Vitro Diagnostics(IVD) : 체외 진단
  • Drug Delivery : 약물 전달
  • Point of Care Devices : 현장 진료 장비
  • Microarrays : 마이크로어레이
  • Lab-on-a-chip : 랩온어칩
  • MEMS(MicroElectroMechanical Systems) : 미세전자기계시스템

미세/생명유체공학에 관한 개념

  • 대류/확산 효과
  • 표면 장력
  • 자유 표면 역학
  • 점도 효과
  • 관성 효과
  • 다공성 매체
  • 전기 역학
  • 미립자 역학
  • 반응 속도론

Particle Model(입자모델)

Lagrangian particle model(라그랑지안 입자 모델)

라그랑지안 입자 모델(Lagrangian particle model)은 서브 그리드(Sub-grid) 모델로 계산 셀보다 작은 속성과 크기가 다른 구형(Spherical) 입자의 움직임을 추적할 수 있는 계산 모델입니다.

해석 사례

  • Aeration tank modelling(산기 탱크 모델링)
  • Bubble diffuser system(버블디퓨저 시스템)
  • Drug delivery etc.

Particle options

  • Marker particles – Massless
  • Mass particles – Solid spheres
  • Fluid particles – Droplets of fluid
  • Gas particles – Bubbles of gas

가정 및 한계(Assumptions & Limitations)

  • 입자크기(Particle size) << 격자크기(Mesh size)
  • 입자간의 상호작용을 고려하지 않습니다.
  • 입자 갯수에 제한

Marker Particles(마커 입자)

마커 입자(Marker particles)는 흐름(Flow)에 영향을 미치지 않고 주변 유체의 속도에 따라 움직이지 않는 질량이 없는 상태의 입자입니다. 그러므로, 유체 분자의 시각화로 간주될 수 있습니다.

계산영역에 마커 입자(Marker particles)를 적용함으로써, 개별 유체 분자가 따르는 경로(Paths)를 시각화할 수 있습니다.

Mass Particles(질량 입자)

질량 입자(Mass particles)는 특정 직경과 밀도를 가진 고체 구체(Spheres)로 고려됩니다. 따라서, 질량 입자(Mass particles)는 계산 영역에서 현탁된 고체(Suspended solids)의 운동을 모델링하기 위해 사용됩니다.

Fluid particles(유체 입자)

유체 입자(Fluid particles)는 유체#1의 액적(Droplets of Fluid#1)으로 생각할 수 있습니다. 유체 입자(Fluid particles)는 유체 스프레이(Fluid sprays), 적층 제조(additive manufacturing), 용접(Welding) 등과 같은 계산 셀보다 작은 모델링 유체 부피를 포함하는 수많은 시뮬레이션에 사용될 수 있습니다.

Gas particles(가스 입자)

가스 입자(Gas particles)는 가스의 구형(Spherical) 버블과 유체, 공극(Void) 및 고체 물체와의 상호 작용을 시뮬레이션하는데 사용됩니다.

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    주조분야
    • Gravity Pour 중력 주조
    • High Pressure Die Casting 고압 다이캐스팅
    • Tilt Casting 경동 주조
    • Centrifugal Casting 원심 주조
    • Investment Casting 정밀 주조
    • Vacuum Casting 진공 주조
    • Continuous Casting 연속 주조
    • Lost Foam Casting 소실 모형 주조
    • Fill and Defects Tracking 용탕 주입 및 결함 추적
    • Solidification and Shrinkage 응고 및 수축 해석
    • Thermal Stress Evolution and Deformation 열응력 및 변형 해석
    물 및 환경 응용 분야
    • Wastewater Treatment and Recovery 폐수 처리 및 복구
    • Pump Stations 펌프장
    • Dams, Weirs, Spillways 댐, 위어, 여수로
    • River Hydraulics 강 유역
    • Inundation & Flooding 침수 및 범람
    • Open Channel Flow 개수로 흐름
    • Sediment and Scour 퇴적 및 세굴(쇄굴)
    • Plumes, Hydraulic Zones of Influence 기둥, 수리 영향 구역
    • Coastal and Critical Infrastructure Wave Run-Up 연안 및 핵심 인프라 웨이브 런업

    에너지 분야
    • Fuel/cargo sloshing in oceangoing containers 해양 컨테이너 용 연료 /화물 슬로싱
    • Offshore platform wave effects 근해 플랫폼 파 영향
    • Separation devices undergoing 6 DOF motion 6 자유도 운동을하는 분리 장치
    • Wave energy converters 파동 에너지 변환기
    미세유체
    • Continuous-Flow 연속 흐름
    • Droplet, Digital 물방울, 디지털
    • Molecular Biology 분자 생물학
    • Opto-Microfluidics 광 마이크로 유체
    • Cell Behavior 세포 행동
    • Fuel Cells 연료 전지들
    용접 제조
    • Laser Welding 레이저 용접
    • Laser Metal Deposition 레이저 금속 증착
    • Additive Manufacturing 첨가제 제조
    • Multi-Layer Build 다중 레이어 빌드
    • Polymer 3D Printing 폴리머 3D 프린팅
    코팅 분야
    • Curtain Coating 커튼 코팅
    • Dip Coating 딥 코팅
    • Gravure Printing 그라비아 코팅
    • Roll Coating 롤 코팅
    • Slide Coating 슬라이드 코팅
    • Slot Coating 슬롯 코팅
    • Contact Insights 접촉면 분석
    연안 / 해양분야
    • Breakwater Structures 방파제 구조물
    • Offshore Structures 항만 연안 구조물
    • Ship Hydrodynamics 선박 유체 역학
    • Sloshing & Slamming 슬로싱 & 슬래 밍
    • Tsunamis 쓰나미 해석
    생명공학 분야
    • Active Mixing 액티브 믹싱
    • Chemical Reactions 화학 반응
    • Dissolution 용해
    • Drug Delivery 약물 전달
    • Drug Particles 마약 입자
    • Microdispensers 마이크로 디스펜서
    • Passive Mixing 패시브 믹싱
    • Piezo Driven Pumps 피에조 구동 펌프
    자동차 분야
    • Fuel Tanks 연료 탱크
    • Early Fuel Shut-Off 초기 연료 차단
    • Gear Interaction 기어 상호 작용
    • Filters 필터
    • Degas Bottles 병의 가스제거

    Fuel Tank Simulation
    Fuel Tank Simulation
    우주 항공 분야
    • Sloshing Dynamics 슬로싱 동역학
    • Electric Charge Distribution 전기 충전 배분
    • PMDs PMD

    aerospace-sloshing-simulation
    aerospace-sloshing-simulation