Optical Oxygen Sensors for Applications in Microfluidic Cell Culture

The presence and concentration of oxygen in biological systems has a large impact on the behavior and viability of many types of cells, including the differentiation of stem cells or the growth of tumor cells. As a result, the integration of oxygen sensors within cell culture environments presents a powerful tool for quantifying the effects of oxygen concentrations on cell behavior, cell viability, and drug effectiveness. Because microfluidic cell culture environments are a promising alternative to traditional cell culture platforms, there is recent interest in integrating oxygen-sensing mechanisms with microfluidics for cell culture applications. Optical, luminescence-based oxygen sensors, in particular, show great promise in their ability to be integrated with microfluidics and cell culture systems. These sensors can be highly sensitive and do not consume oxygen or generate toxic byproducts in their sensing process. This paper presents a review of previously proposed optical oxygen sensor types, materials and formats most applicable to microfluidic cell culture, and analyzes their suitability for this and other in vitro applications.

[1]  Wolfgang Trettnak,et al.  Miniaturized luminescence lifetime-based oxygen sensor instrumentation utilizing a phase modulation technique , 1996 .

[2]  Jean Bennett,et al.  Imaging oxygen pressure in the rodent retina by phosphorescence lifetime. , 2006, Advances in experimental medicine and biology.

[3]  Ingo Klimant,et al.  A microoptode array for fine-scale measurement of oxygen distribution , 1997 .

[4]  Colette McDonagh,et al.  Optimization of Ormosil Films for Optical Sensor Applications , 1998 .

[5]  David A Boas,et al.  Optical monitoring of oxygen tension in cortical microvessels with confocal microscopy. , 2009, Optics express.

[6]  Todd Thorsen,et al.  Development of an integrated microfluidic platform for dynamic oxygen sensing and delivery in a flowing medium. , 2005, Lab on a chip.

[7]  I. Klimant,et al.  Luminescent nanobeads for optical sensing and imaging of dissolved oxygen , 2008 .

[8]  M. Dewhirst,et al.  Oxygen distributions within R3230Ac tumors growing in dorsal flap window chambers in rats. , 1998, Advances in Experimental Medicine and Biology.

[9]  Zoran Ivanovic,et al.  Hypoxia or in situ normoxia: The stem cell paradigm , 2009, Journal of cellular physiology.

[10]  Ingo Klimant,et al.  Fast Response Oxygen Micro-Optodes Based on Novel Soluble Ormosil Glasses , 1999 .

[11]  Raoul Kopelman,et al.  Ratiometric fiber optic sensors for the detection of inter- and intra-cellular dissolved oxygen , 2005 .

[12]  Can Ince,et al.  Monitoring of renal venous PO2 and kidney oxygen consumption in rats by a near-infrared phosphorescence lifetime technique. , 2008, American journal of physiology. Renal physiology.

[13]  P. Abgrall,et al.  Lab-on-chip technologies: making a microfluidic network and coupling it into a complete microsystem—a review , 2007 .

[14]  M. Simon,et al.  The role of oxygen availability in embryonic development and stem cell function , 2008, Nature Reviews Molecular Cell Biology.

[15]  Dmitry B. Papkovsky Luminescent porphyrins as probes for optical (bio)sensors , 1993 .

[16]  Shuichi Takayama,et al.  Quantitative measurement and control of oxygen levels in microfluidic poly(dimethylsiloxane) bioreactors during cell culture , 2007, Biomedical microdevices.

[17]  Dmitri B. Papkovsky,et al.  Study of migration of active components of phosphorescent oxygen sensors for food packaging applications , 2005 .

[18]  R. O. Poyton,et al.  Oxygen sensing and molecular adaptation to hypoxia. , 1996, Physiological reviews.

[19]  Raoul Kopelman,et al.  Poly(decyl methacrylate)-based fluorescent PEBBLE swarm nanosensors for measuring dissolved oxygen in biosamples. , 2004, The Analyst.

[20]  M Intaglietta,et al.  Microvessel PO2 measurements by phosphorescence decay method. , 1993, The American journal of physiology.

[21]  Claudia Fischbach,et al.  Microfluidic culture models of tumor angiogenesis. , 2010, Tissue engineering. Part A.

[22]  Mary-Ann Mycek,et al.  Time-resolved optical imaging provides a molecular snapshot of altered metabolic function in living human cancer cell models. , 2006, Optics express.

[23]  Gelii V. Ponomarev,et al.  Phosphorescent Complexes of Porphyrin Ketones: Optical Properties and Application to Oxygen Sensing , 1995 .

[24]  I. Bergman,et al.  Rapid-response Atmospheric Oxygen Monitor based on Fluorescence Quenching , 1968, Nature.

[25]  T. Korpela,et al.  Biosensors on the basis of luminescent oxygen sensor: the use of microporous light-scattering support materials , 1998 .

[26]  J. Aubin Autofluorescence of viable cultured mammalian cells. , 1979, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[27]  M. Kühl,et al.  Combined Imaging of Bacteria and Oxygen in Biofilms , 2007, Applied and Environmental Microbiology.

[28]  Rohit Srivastava,et al.  Encapsulation of glucose oxidase and an oxygen-quenched fluorophore in polyelectrolyte-coated calcium alginate microspheres as optical glucose sensor systems. , 2005, Biosensors & bioelectronics.

[29]  Andreas Manz,et al.  Latest developments in microfluidic cell biology and analysis systems. , 2010, Analytical chemistry.

[30]  Nancy Y. Ip,et al.  Precise temperature control of microfluidic chamber for gas and liquid phase reactions , 2000 .

[31]  S. Vinogradov,et al.  Intravascular oxygen distribution in subcutaneous 9L tumors and radiation sensitivity. , 1997, Journal of applied physiology.

[32]  Raymond H. W. Lam,et al.  Culturing Aerobic and Anaerobic Bacteria and Mammalian Cells with a Microfluidic Differential Oxygenator , 2009, Analytical chemistry.

[33]  Tomoyuki Yasukawa,et al.  Fabrication of miniature Clark oxygen sensor integrated with microstructure , 2005 .

[34]  W. Rumsey,et al.  Imaging of phosphorescence: a novel method for measuring oxygen distribution in perfused tissue. , 1988, Science.

[35]  Ingo Klimant,et al.  A MODULAR LUMINESCENCE LIFETIME IMAGING SYSTEM FOR MAPPING OXYGEN DISTRIBUTION IN BIOLOGICAL SAMPLES , 1998 .

[36]  T. Brey,et al.  Oxygen microoptodes: a new tool for oxygen measurements in aquatic animal ecology , 2002 .

[37]  Martin T. Suchorolski,et al.  A microwell array device capable of measuring single-cell oxygen consumption rates. , 2009, Sensors and actuators. B, Chemical.

[38]  Holger Becker,et al.  Polymer microfabrication technologies for microfluidic systems , 2008, Analytical and bioanalytical chemistry.

[39]  S. Vinogradov,et al.  Oxygen pressures in the interstitial space of skeletal muscle and tumors in vivo. , 2008, Advances in experimental medicine and biology.

[40]  D. Boas,et al.  Dendritic phosphorescent probes for oxygen imaging in biological systems. , 2009, ACS Applied Materials and Interfaces.

[41]  H. Ju,et al.  Preparation of ormosil and its applications in the immobilizing biomolecules , 2006 .

[42]  Benjamin W. Dugan,et al.  Measurement of tumor oxygenation using new frequency domain phosphorometers. , 2002, Comparative biochemistry and physiology. Part A, Molecular & integrative physiology.

[43]  Jay Lee,et al.  Hard top soft bottom microfluidic devices for cell culture and chemical analysis. , 2009, Analytical chemistry.

[44]  J. Vanderkooi,et al.  An optical method for measurement of dioxygen concentration based upon quenching of phosphorescence. , 1987, The Journal of biological chemistry.

[45]  Christoph Abels,et al.  In Vivo Phosphorescence Imaging of pO2 Using Planar Oxygen Sensors , 2005, Microcirculation.

[46]  Ingo Klimant,et al.  Determination of oxygen gradients in engineered tissue using a fluorescent sensor. , 2002, Biotechnology and bioengineering.

[47]  T. O’Riordan,et al.  Phosphorescent porphyrin probes in biosensors and sensitive bioassays. , 2000, Biochemical Society transactions.

[48]  S. Vinogradov,et al.  Tomographic imaging of oxygen by phosphorescence lifetime. , 2006, Applied optics.

[49]  W. Rumsey,et al.  The oxygen dependence of mitochondrial oxidative phosphorylation measured by a new optical method for measuring oxygen concentration. , 1988, The Journal of biological chemistry.

[50]  L. C. Clark,et al.  ELECTRODE SYSTEMS FOR CONTINUOUS MONITORING IN CARDIOVASCULAR SURGERY , 1962 .

[51]  J. Dobrucki,et al.  Interaction of oxygen-sensitive luminescent probes Ru(phen)(3)(2+) and Ru(bipy)(3)(2+) with animal and plant cells in vitro. Mechanism of phototoxicity and conditions for non-invasive oxygen measurements. , 2001, Journal of photochemistry and photobiology. B, Biology.

[52]  Ingo Klimant,et al.  Optical measurement of oxygen and temperature in microscale: strategies and biological applications , 1997 .

[53]  Dmitri B. Papkovsky,et al.  Emerging Applications of Phosphorescent Metalloporphyrins , 2005, Journal of Fluorescence.

[54]  Gerhard A. Holst,et al.  Luminescence lifetime imaging with transparent oxygen optodes , 2001 .

[55]  Tim David,et al.  Patterning, integration and characterisation of polymer optical oxygen sensors for microfluidic devices. , 2008, Lab on a chip.

[56]  T. Kosaka,et al.  In vivo visualization of oxygen transport in microvascular network. , 1994, The American journal of physiology.

[57]  Gwo-Bin Lee,et al.  A microfluidic system for automatic cell culture , 2007, TRANSDUCERS 2007 - 2007 International Solid-State Sensors, Actuators and Microsystems Conference.

[58]  T M Jovin,et al.  Time resolved imaging microscopy. Phosphorescence and delayed fluorescence imaging. , 1991, Biophysical journal.

[59]  James N. Demas,et al.  Determination of oxygen concentrations by luminescence quenching of a polymer-immobilized transition-metal complex , 1987 .

[60]  Ingo Klimant,et al.  Fiber‐optic oxygen microsensors, a new tool in aquatic biology , 1995 .

[61]  O Stern,et al.  The fading time of fluorescence , 1919 .

[62]  David A. Chang-Yen,et al.  Spin-assembled nanofilms for gaseous oxygen sensing , 2007 .

[63]  David F Wilson,et al.  Calibration of oxygen-dependent quenching of the phosphorescence of Pd-meso-tetra (4-carboxyphenyl) porphine: a phosphor with general application for measuring oxygen concentration in biological systems. , 1996, Analytical biochemistry.

[64]  M. Goligorsky Making sense out of oxygen sensor. , 2000, Circulation research.

[65]  Mengsu Yang,et al.  Microfluidics technology for manipulation and analysis of biological cells , 2006 .

[66]  James L Tatum,et al.  Hypoxia: Importance in tumor biology, noninvasive measurement by imaging, and value of its measurement in the management of cancer therapy , 2006, International journal of radiation biology.

[67]  O. Wolfbeis,et al.  Longwave luminescent porphyrin probes , 1996 .

[68]  G. Cerniglia,et al.  Localization of tumors and evaluation of their state of oxygenation by phosphorescence imaging. , 1992, Cancer research.

[69]  M. Bissell,et al.  Tumor engineering: the other face of tissue engineering. , 2010, Tissue engineering. Part A.

[70]  Colette McDonagh,et al.  Phase fluorometric dissolved oxygen sensor , 2001 .

[71]  Colette McDonagh,et al.  Optical chemical sensors. , 2008, Chemical reviews.

[72]  Jurek Dobrucki,et al.  Interaction of oxygen-sensitive luminescent probes Ru(phen)32+ and Ru(bipy)32+ with animal and plant cells in vitro , 2001 .

[73]  S. Vinogradov,et al.  Tissue Oxygen Measurements Using Phosphorescence Quenching , 2003 .

[74]  David M. Coleman,et al.  A Two-Dimensional Fluorescence Lifetime Imaging System Using a Gated Image Intensifier , 1991 .

[75]  Paul Hartmann,et al.  Oxygen flux fluorescence lifetime imaging , 1997 .

[76]  Sergei A Vinogradov,et al.  Oxygen distribution in murine tumors: characterization using oxygen-dependent quenching of phosphorescence. , 2005, Journal of applied physiology.

[77]  Max E. Lippitsch,et al.  Fibre-optic oxygen sensor with the fluorescence decay time as the information carrier , 1988 .

[78]  M. Csete,et al.  Oxygen in the Cultivation of Stem Cells , 2005, Annals of the New York Academy of Sciences.

[79]  Nicolas Szita,et al.  Development of a multiplexed microbioreactor system for high-throughput bioprocessing. , 2005, Lab on a chip.

[80]  H. Andersson,et al.  Microfluidic devices for cellomics: a review , 2003 .

[81]  D. Beebe,et al.  Physics and applications of microfluidics in biology. , 2002, Annual review of biomedical engineering.

[82]  David F Wilson,et al.  Measurement of Muscle Microvascular Oxygen Pressures: Compartmentalization of Phosphorescent Probe , 2004, Microcirculation.

[83]  Ronnie N. Glud,et al.  Fabrication and test of sol-gel based planar oxygen optodes for use in aquatic sediments , 2005 .

[84]  Raoul Kopelman,et al.  Real-time measurements of dissolved oxygen inside live cells by organically modified silicate fluorescent nanosensors. , 2004, Analytical chemistry.

[85]  Joseph R. Lakowicz,et al.  Lifetime‐selective fluorescence imaging using an rf phase‐sensitive camera , 1991 .

[86]  S. Lahiri,et al.  Historical perspectives of cellular oxygen sensing and responses to hypoxia. , 2000, Journal of applied physiology.

[87]  D. Lübbers,et al.  FLIM of luminescent oxygen sensors: clinical applications and results , 1998 .

[88]  T. Thorsen,et al.  A Microfluidic Oxygenator for Biological Cell Culture , 2007, TRANSDUCERS 2007 - 2007 International Solid-State Sensors, Actuators and Microsystems Conference.

[89]  C. Ince,et al.  Dual-wavelength phosphorimetry for determination of cortical and subcortical microvascular oxygenation in rat kidney. , 2006, Journal of applied physiology.

[90]  D. Meldrum,et al.  Using micro-patterned sensors and cell self-assembly for measuring the oxygen consumption rate of single cells , 2010 .

[91]  Sergei A Vinogradov,et al.  Oxyphor R2 and G2: phosphors for measuring oxygen by oxygen-dependent quenching of phosphorescence. , 2002, Analytical biochemistry.

[92]  Paul Urayama,et al.  A UV–Visible–NIR fluorescence lifetime imaging microscope for laser-based biological sensing with picosecond resolution , 2003 .

[93]  I. M. Mishra,et al.  Techniques for oxygen transfer measurement in bioreactors: a review , 2009 .

[94]  A. Folch,et al.  Biomolecular gradients in cell culture systems. , 2008, Lab on a chip.

[95]  G. Whitesides The origins and the future of microfluidics , 2006, Nature.

[96]  P. Vaupel,et al.  Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. , 2001, Journal of the National Cancer Institute.

[97]  Shuichi Takayama,et al.  Optical imaging in microfluidic bioreactors enables oxygen monitoring for continuous cell culture. , 2006, Journal of biomedical optics.

[98]  A C Fisher,et al.  Application of frequency-domain Fluorescence Lifetime Imaging Microscopy as a quantitative analytical tool for microfluidic devices. , 2006, Optics express.

[99]  Adrian L. Harris,et al.  Hypoxia — a key regulatory factor in tumour growth , 2002, Nature Reviews Cancer.

[100]  Dmitri B. Papkovsky,et al.  Application of frequency spectroscopy to fluorescence-based oxygen sensors , 2006 .

[101]  D. Erickson,et al.  Integrated microfluidic devices , 2004 .

[102]  B. MacCraith,et al.  Ruthenium-doped sol-gel derived silica films: Oxygen sensitivity of optical decay times , 1994 .

[103]  O. Wolfbeis,et al.  Luminescence Lifetime Imaging of Oxygen, pH, and Carbon Dioxide Distribution Using Optical Sensors , 2000 .

[104]  B. MacCraith,et al.  Tailoring of sol-gel films for optical sensing of oxygen in gas and aqueous phase. , 1998, Analytical chemistry.

[105]  Xiaojing Su,et al.  Automated High-Throughput Microchannel Assays for Cell Biology: Operational Optimization and Characterization , 2010, JALA.

[106]  C. Ince,et al.  NONRESUSCITATED ENDOTOXEMIA INDUCES MICROCIRCULATORY HYPOXIC AREAS IN THE RENAL CORTEX IN THE RAT , 2009, Shock.

[107]  Yordan Kostov,et al.  The Design and Fabrication of Three‐Chamber Microscale Cell Culture Analog Devices with Integrated Dissolved Oxygen Sensors , 2008, Biotechnology progress.

[108]  C E Riva,et al.  Oxygen distribution in the retinal and choroidal vessels of the cat as measured by a new phosphorescence imaging method. , 1992, Applied optics.

[109]  Colette McDonagh,et al.  The Photophysical Properties of Ruthenium Polypyridyl Complexes within a Sol-Gel Matrix , 1997 .

[110]  Lei Yao,et al.  Sensitivity-Enhanced CMOS Phase Luminometry System Using Xerogel-Based Sensors , 2009, IEEE Transactions on Biomedical Circuits and Systems.

[111]  S M Evans,et al.  Noninvasive imaging of the distribution in oxygen in tissue in vivo using near-infrared phosphors. , 1996, Biophysical journal.

[112]  Colette McDonagh,et al.  Development of an integrated optic oxygen sensor using a novel, generic platform. , 2005, The Analyst.

[113]  Y. Amao,et al.  Probes and Polymers for Optical Sensing of Oxygen , 2003 .

[114]  Raoul Kopelman,et al.  Optical nanoparticle sensors for quantitative intracellular imaging. , 2009, Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology.

[115]  D.M. Wilson,et al.  Sensor technologies for monitoring metabolic activity in single cells-part I: optical methods , 2004, IEEE Sensors Journal.

[116]  Ingo Klimant,et al.  Oxygen-Sensitive Luminescent Materials Based on Silicone-Soluble Ruthenium Diimine Complexes , 1995 .

[117]  David T Eddington,et al.  Precise control over the oxygen conditions within the Boyden chamber using a microfabricated insert. , 2010, Lab on a chip.

[118]  A. deMello,et al.  Time-resolved fluorescence imaging of solvent interactions in microfluidic devices. , 2005, Optics express.

[119]  I Klimant,et al.  Fluorescent imaging of pH with optical sensors using time domain dual lifetime referencing. , 2001, Analytical chemistry.

[120]  Paul Urayama,et al.  Imaging fluorescence lifetime modulation of a ruthenium-based dye in living cells: the potential for oxygen sensing , 2003 .

[121]  H. S. Wolff,et al.  iRun: Horizontal and Vertical Shape of a Region-Based Graph Compression , 2022, Sensors.

[122]  Bruce K Gale,et al.  An integrated optical oxygen sensor fabricated using rapid-prototyping techniques. , 2003, Lab on a chip.

[123]  Raoul Kopelman,et al.  Nanoparticle PEBBLE sensors in live cells and in vivo. , 2009, Annual review of analytical chemistry.

[124]  Alexander P. Savitsky,et al.  Phosphorescent polymer films for optical oxygen sensors , 1992 .

[125]  Sergei A Vinogradov,et al.  Oxygen pressures in the interstitial space and their relationship to those in the blood plasma in resting skeletal muscle. , 2006, Journal of applied physiology.

[126]  Andrew Mills,et al.  Optical Oxygen Sensors: Utilising the Luminescence of Platinum Metals Complexes , 1997 .

[127]  Dieter Trau,et al.  In-situ measurement of cellular microenvironments in a microfluidic device. , 2009, Lab on a chip.

[128]  R. Pirow,et al.  Crater landscape: two-dimensional oxygen gradients in the circulatory system of the microcrustacean Daphnia magna , 2004, Journal of Experimental Biology.

[129]  K. Jensen,et al.  Cells on chips , 2006, Nature.

[130]  Nicolas Szita,et al.  Membrane‐aerated microbioreactor for high‐throughput bioprocessing , 2004, Biotechnology and bioengineering.

[131]  J. Lakowicz,et al.  Electroluminescent lamp-based phase fluorometer and oxygen sensor. , 1992, Analytical biochemistry.

[132]  D. Beebe,et al.  Cell culture models in microfluidic systems. , 2008, Annual review of analytical chemistry.

[133]  Richard J. Blaikie,et al.  Micro-patterning of polymer-based optical oxygen sensors for lab-on-chip applications , 2007, SPIE Micro + Nano Materials, Devices, and Applications.

[134]  D. Panchision,et al.  The role of oxygen in regulating neural stem cells in development and disease , 2009, Journal of cellular physiology.

[135]  A. Manz,et al.  Lab-on-a-chip: microfluidics in drug discovery , 2006, Nature Reviews Drug Discovery.

[136]  B. J. Basu Optical oxygen sensing based on luminescence quenching of platinum porphyrin dyes doped in ormosil coatings , 2007 .

[137]  Sergey M Borisov,et al.  Multiplex bacterial growth monitoring in 24‐well microplates using a dual optical sensor for dissolved oxygen and pH , 2008, Biotechnology and bioengineering.

[138]  Interstitial Po2 Determination by Phosphorescence Quenching Microscopy , 2002, Microcirculation.

[139]  P. Hartmann,et al.  Effects of polymer matrices on calibration functions of luminescent oxygen sensors based on porphyrin ketone complexes. , 1996, Analytical chemistry.

[140]  Delyle Eastwood,et al.  Porphyrins: XVIII. Luminescence of (Co), (Ni), Pd, Pt complexes☆ , 1970 .

[141]  Dmitri B. Papkovsky,et al.  Phosphorescent oxygen-sensitive materials for biological applications , 2005 .

[142]  J. Wood,et al.  Exercise training prevents the inflammatory response to hypoxia in cremaster venules. , 2005, Journal of applied physiology.