Integration and application of optical chemical sensors in microbioreactors.

The quantification of key variables such as oxygen, pH, carbon dioxide, glucose, and temperature provides essential information for biological and biotechnological applications and their development. Microfluidic devices offer an opportunity to accelerate research and development in these areas due to their small scale, and the fine control over the microenvironment, provided that these key variables can be measured. Optical sensors are well-suited for this task. They offer non-invasive and non-destructive monitoring of the mentioned variables, and the establishment of time-course profiles without the need for sampling from the microfluidic devices. They can also be implemented in larger systems, facilitating cross-scale comparison of analytical data. This tutorial review presents an overview of the optical sensors and their technology, with a view to support current and potential new users in microfluidics and biotechnology in the implementation of such sensors. It introduces the benefits and challenges of sensor integration, including, their application for microbioreactors. Sensor formats, integration methods, device bonding options, and monitoring options are explained. Luminescent sensors for oxygen, pH, carbon dioxide, glucose and temperature are showcased. Areas where further development is needed are highlighted with the intent to guide future development efforts towards analytes for which reliable, stable, or easily integrated detection methods are not yet available.

[1]  Yohei K. Sato,et al.  Two-wavelength Raman imaging for non-intrusive monitoring of transient temperature in microfluidic devices , 2014 .

[2]  Koji Suzuki,et al.  Imaging of electrochemical enzyme sensor on gold electrode using surface plasmon resonance. , 2002, Biosensors & bioelectronics.

[3]  Detlev Belder,et al.  Microfluidic free-flow electrophoresis chips with an integrated fluorescent sensor layer for real time pH imaging in isoelectric focusing. , 2013, Chemical communications.

[4]  O. Wolfbeis,et al.  Monitoring cell cultivation in microfluidic segments by optical pH sensing with a micro flow-through fluorometer using dye-doped polymer particles , 2009 .

[5]  M. Natali,et al.  An optical sensor for pH supported onto tentagel resin beads , 2008 .

[6]  Axel Duerkop,et al.  Optical methods for sensing glucose. , 2011, Chemical Society reviews.

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

[8]  S. Morrison,et al.  Metabolic regulation of stem cell function , 2014, Journal of internal medicine.

[9]  O. Geschke,et al.  Microfluidic dissolved oxygen gradient generator biochip as a useful tool in bacterial biofilm studies. , 2010, Lab on a chip.

[10]  Martin Strobl,et al.  Fast pesticide detection inside microfluidic device with integrated optical pH, oxygen sensors and algal fluorescence. , 2017, Biosensors & bioelectronics.

[11]  Enhancing performance in optical sensing with magnetic nanoparticles , 2009 .

[12]  Verena Charwat,et al.  Opto-chemical sensors based on integrated ring-shaped organic photodiodes: progress and applications , 2012, Other Conferences.

[13]  I. Klimant,et al.  Online analysis of oxygen inside silicon-glass microreactors with integrated optical sensors , 2016 .

[14]  Sytsma,et al.  Time‐gated fluorescence lifetime imaging and microvolume spectroscopy using two‐photon excitation , 1998 .

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

[16]  B. Nidetzky,et al.  Shine a light on immobilized enzymes: real-time sensing in solid supported biocatalysts. , 2013, Trends in biotechnology.

[17]  Aongus McCarthy,et al.  Optically trapped microsensors for microfluidic temperature measurement by fluorescence lifetime imaging microscopy. , 2011, Lab on a chip.

[18]  M. Halter,et al.  A noninvasive thin film sensor for monitoring oxygen tension during in vitro cell culture. , 2009, Analytical chemistry.

[19]  N. Nguyen,et al.  Fundamentals and Applications of Microfluidics , 2002 .

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

[21]  Gwo-Bin Lee,et al.  Microfluidic pH-sensing chips integrated with pneumatic fluid-control devices. , 2006, Biosensors & bioelectronics.

[22]  S. Ohla,et al.  An integrated microfluidic chip enabling control and spatially resolved monitoring of temperature in micro flow reactors , 2014, Analytical and Bioanalytical Chemistry.

[23]  I. Klimant,et al.  NIR-emitting aza-BODIPY dyes--new building blocks for broad-range optical pH sensors. , 2015, The Analyst.

[24]  Matthew I.J. Davies,et al.  Characterisation of an Adhesive-free Packaging System for Polymeric Microfluidic Biochemical Devices and Reactors , 2014 .

[25]  Stephanus Büttgenbach,et al.  Monolithically integrated biophotonic lab-on-a-chip for cell culture and simultaneous pH monitoring. , 2013, Lab on a chip.

[26]  Jan Vanfleteren,et al.  Real-time monitoring of metabolic function in liver-on-chip microdevices tracks the dynamics of mitochondrial dysfunction , 2016, Proceedings of the National Academy of Sciences.

[27]  Ingo Klimant,et al.  Integrated catheter system for continuous glucose measurement and simultaneous insulin infusion. , 2015, Biosensors & bioelectronics.

[28]  Erik Beckert,et al.  Rapid isoelectric point determination in a miniaturized preparative separation using jet-dispensed optical pH sensors and micro free-flow electrophoresis. , 2014, Analytical chemistry.

[29]  Andrew Mills,et al.  Equilibrium studies on colorimetric plastic film sensors for carbon dioxide , 1992 .

[30]  Ulrich Krühne,et al.  Hydrodynamic guiding for addressing subsets of immobilized cells and molecules in microfluidic systems , 2003, BMC biotechnology.

[31]  John M. Woodley,et al.  Carbon‐Carbon Bond Synthesis , 1996 .

[32]  Bennett L. Ibey,et al.  Measurement of pH and dissolved oxygen within cell culture media using a hydrogel microarray sensor , 2008 .

[33]  J. Alonso-Chamarro,et al.  Low cost and compact analytical microsystem for carbon dioxide determination in production processes of wine and beer. , 2016, Analytica chimica acta.

[34]  F. E. Wiria,et al.  Low Distortion Solvent Bonding of Microfluidic Chips , 2016 .

[35]  Wilhelm T S Huck,et al.  A Method for Detecting Circulating Tumor Cells Based on the Measurement of Single-Cell Metabolism in Droplet-Based Microfluidics. , 2016, Angewandte Chemie.

[36]  D. Sinton,et al.  Measurement of CO2 diffusivity for carbon sequestration: a microfluidic approach for reservoir-specific analysis. , 2013, Environmental science & technology.

[37]  Michael Bauer,et al.  A microfluidically perfused three dimensional human liver model. , 2015, Biomaterials.

[38]  Birgit Ungerböck,et al.  Imaging of oxygen in microreactors and microfluidic systems , 2015, Methods and applications in fluorescence.

[39]  Micro-patterning and characterization of PHEMA-co-PAM-based optical chemical sensors for lab-on-a-chip applications. , 2012, Sensors and actuators. B, Chemical.

[40]  Ruth Shinar,et al.  Glucose biosensors based on organic light-emitting devices structurally integrated with a luminescent sensing element , 2004 .

[41]  O. Wolfbeis,et al.  Optical methods for sensing and imaging oxygen: materials, spectroscopies and applications. , 2014, Chemical Society reviews.

[42]  Regine Eibl,et al.  Novel probes for pH and dissolved oxygen measurements in cultivations from millilitre to benchtop scale , 2016, Applied Microbiology and Biotechnology.

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

[44]  B. Valeur,et al.  Molecular Fluorescence: Principles and Applications , 2001 .

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

[46]  Jia Li,et al.  Inkjet printing for biosensor fabrication: combining chemistry and technology for advanced manufacturing. , 2015, Lab on a chip.

[47]  Michael V. Pishko,et al.  Immobilization of multi-enzyme microreactors inside microfluidic devices , 2005 .

[48]  Nicolas Szita,et al.  Oxygen Transfer Characteristics of Miniaturized Bioreactor Systems , 2013, Biotechnology and bioengineering.

[49]  R. Mathies,et al.  Integrated microfluidic systems for high-performance genetic analysis. , 2009, Trends in biotechnology.

[50]  Jonathan P. Metters,et al.  New directions in screen printed electroanalytical sensors: an overview of recent developments. , 2011, The Analyst.

[51]  J. Severinghaus,et al.  Electrodes for blood pO2 and pCO2 determination. , 1958, Journal of applied physiology.

[52]  L. Chrostowski,et al.  Fabrication and laser patterning of polystyrene optical oxygen sensor films for lab-on-a-chip applications. , 2014, The Analyst.

[53]  Rajeev J Ram,et al.  Microfluidic chemostat and turbidostat with flow rate, oxygen, and temperature control for dynamic continuous culture. , 2011, Lab on a chip.

[54]  Lewis D. Griffin,et al.  Real‐time monitoring of specific oxygen uptake rates of embryonic stem cells in a microfluidic cell culture device , 2016, Biotechnology journal.

[55]  P. Ertl,et al.  Simultaneous Determination of Oxygen and pH Inside Microfluidic Devices Using Core-Shell Nanosensors. , 2016, Analytical chemistry.

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

[57]  T. Ohsaka,et al.  Continuous and simultaneous electrochemical measurements of glucose, lactate, and ascorbate in rat brain following brain ischemia. , 2014, Analytical chemistry.

[58]  B. Nidetzky,et al.  Tailor-made resealable micro(bio)reactors providing easy integration of in situ sensors , 2017 .

[59]  Krist V Gernaey,et al.  Application of microbioreactors in fermentation process development: a review , 2009, Analytical and bioanalytical chemistry.

[60]  Min-Hsien Wu,et al.  Development of high throughput optical sensor array for on-line pH monitoring in micro-scale cell culture environment , 2009, Biomedical microdevices.

[61]  W. Wen,et al.  Facile and high spatial resolution ratio-metric luminescence thermal mapping in microfluidics by near infrared excited upconversion nanoparticles , 2016 .

[62]  B. Nidetzky,et al.  Dual-lifetime referencing (DLR): a powerful method for on-line measurement of internal pH in carrier-bound immobilized biocatalysts , 2012, BMC Biotechnology.

[63]  Frank Baganz,et al.  Real-time pH monitoring of industrially relevant enzymatic reactions in a microfluidic side-entry reactor (μSER) shows potential for pH control. , 2017, Biotechnology journal.

[64]  L. Gui,et al.  Temperature measurement in microfluidic chips using photobleaching of a fluorescent thin film , 2008 .

[65]  Keisuke Ito,et al.  Metabolic requirements for the maintenance of self-renewing stem cells , 2014, Nature Reviews Molecular Cell Biology.

[66]  N. Opitz,et al.  Opticl fluorescence sensors for continuous measurement of chemical concentrations in biological systems , 1983 .

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

[68]  L. Whitman,et al.  Reusable, compression-sealed fluid cells for surface mounting to planar substrates. , 2009, Lab on a chip.

[69]  I. Klimant,et al.  Highly Photostable Near-Infrared Fluorescent pH Indicators and Sensors Based on BF2-Chelated Tetraarylazadipyrromethene Dyes , 2012, Analytical chemistry.

[70]  T. Mayr,et al.  Quick and simple integration of optical oxygen sensors into glass-based microfluidic devices , 2015 .

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

[72]  Ali Khademhosseini,et al.  A microfluidic optical platform for real-time monitoring of pH and oxygen in microfluidic bioreactors and organ-on-chip devices. , 2016, Biomicrofluidics.

[73]  Richard M Crooks,et al.  Hydrogel-based microreactors as a functional component of microfluidic systems. , 2002, Analytical chemistry.

[74]  Gavin Sinclair,et al.  Characterisation of spatial and temporal changes in pH gradients in microfluidic channels using optically trapped fluorescent sensors. , 2006, Lab on a chip.

[75]  S. Nagl,et al.  Microfluidic platforms employing integrated fluorescent or luminescent chemical sensors: a review of methods, scope and applications , 2015, Methods and applications in fluorescence.

[76]  Alex Groisman,et al.  An easy to assemble microfluidic perfusion device with a magnetic clamp. , 2009, Lab on a chip.

[77]  Samantha M. Grist,et al.  Designing a Microfluidic Device with Integrated Ratiometric Oxygen Sensors for the Long-Term Control and Monitoring of Chronic and Cyclic Hypoxia , 2015, Sensors.

[78]  T. Mayr,et al.  Magnetic optical sensor particles: a flexible analytical tool for microfluidic devices. , 2014, The Analyst.

[79]  Elisabeth Verpoorte,et al.  Development and characterization of a microfluidic glucose sensing system based on an enzymatic microreactor and chemiluminescence detection , 2012, Science China Chemistry.

[80]  Shideh Kabiri Ameri,et al.  Microfluidic optoelectronic sensor based on a composite halochromic material for dissolved carbon dioxide detection , 2014 .

[81]  Wolfgang Göpel,et al.  Chemical and biochemical sensors , 1991 .

[82]  Elisabeth Verpoorte,et al.  Implementing oxygen control in chip-based cell and tissue culture systems. , 2016, Lab on a chip.

[83]  Weihong Zhu,et al.  A NIR luminescent copolymer based on platinum porphyrin as high permeable dissolved oxygen sensor for microbioreactors , 2013 .

[84]  S. Borisov,et al.  In-line monitoring of pH and oxygen during enzymatic reactions in off-the-shelf all-glass microreactors using integrated luminescent microsensors , 2017, Microchimica Acta.

[85]  Tomasz Glawdel,et al.  Method for microfluidic whole-chip temperature measurement using thin-film poly(dimethylsiloxane)/rhodamine B. , 2008, Analytical chemistry.

[86]  O. Wolfbeis,et al.  Fiber optical fluorosensor for determination of halothane and or oxygen , 1985 .

[87]  Hongkai Wu,et al.  Highly Fluorescent Poly(dimethylsiloxane) for On‐Chip Temperature Measurements , 2009 .

[88]  Birgit Ungerböck,et al.  Online oxygen measurements inside a microreactor with modeling of transport phenomena , 2013 .

[89]  S. Nagl,et al.  Microchamber arrays with an integrated long luminescence lifetime pH sensor , 2016, Analytical and Bioanalytical Chemistry.

[90]  Verena Charwat,et al.  Microfluidic oxygen imaging using integrated optical sensor layers and a color camera. , 2013, Lab on a chip.

[91]  P. Abbyad,et al.  Sickling of red blood cells through rapid oxygen exchange in microfluidic drops. , 2010, Lab on a chip.

[92]  J. Köhler,et al.  Oxygen sensor nanoparticles for monitoring bacterial growth and characterization of dose–response functions in microfluidic screenings , 2014, Microchimica Acta.