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Hypoxia-on-a-chip

Generating hypoxic conditions in microfluidic cell culture systems
  • Mathias Busek EMAIL logo , Stefan Grünzner , Tobias Steege , Udo Klotzbach and Frank Sonntag
Published/Copyright: September 30, 2016
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Current Directions in Biomedical Engineering
From the journal Current Directions in Biomedical Engineering Volume 2 Issue 1

Abstract

In this work a microfluidic cell cultivation device for perfused hypoxia assays as well as a suitable controlling unit are presented. The device features active components like pumps for fluid actuation and valves for fluid direction as well as an oxygenator element to ensure a sufficient oxygen transfer. It consists of several individually structured layers which can be tailored specifically to the intended purpose. Because of its clearness, its mechanical strength and chemical resistance as well as its well-known biocompatibility polycarbonate was chosen to form the fluidic layers by thermal diffusion bonding. Several oxygen sensing spots are integrated into the device and monitored with fluorescence lifetime detection. Furthermore an oxygen regulator module is implemented into the controlling unit which is able to mix different process gases to achieve a controlled oxygenation. First experiments show that oxygenation/deoxygenation of the system is completed within several minutes when pure nitrogen or air is applied to the oxygenator. Lastly the oxygen input by the pneumatically driven micro pump was quantified by measuring the oxygen content before and after the oxygenator.

Keywords: hypoxia; lab-on-a-chip; oxygenator; oxygen sensing; perfused cell culture

1 Introduction

Because of its direct and indirect participation in many metabolic processes in cells, tissues and organisms oxygen is one of the most important parameters. Especially in mammalian tissue the adequate supply of oxygen is an essential prerequisite influencing cell viability, proliferation and differentiation [1]. Oxygen shortage is called hypoxia and leads to changes in cellular behaviour. Among others it induces the release of hypoxia inducible factors (HIF) [2] and vascular endothelial growth factor (VEGF) which affect cell metabolism, wound healing [4], angiogenesis [3] and tumor metastasis [5]. Therefore a deeper understanding of cell response on oxygen limitation is of particular interest in medical basic research. For this issue lab-on-a-chip (LOC) devices have become more and more important for in-vitro cell cultivation [6]. Especially perfused LOCs are able to mimic physiological environment inducing mechanical stimulation and convective mass transfer. Currently most LOC systems are externally perfused. In contrast to that the Fraunhofer IWS developed a multilayer based LOC with on chip actuation [7]. This offers the possibility to create micro circulation systems with a high tissue to cell culture media ratio (volumes in the range of several microliters). Moreover the effect of dilution which appears in flow through LOC is negligible. The mentioned micro circulation approach is superior for the examination of metabolites and their effect on several tissue types. Due to its good optical properties established imaging technologies can be applied throughout the complete microfluidic system. The on-chip micro pump was characterized using micro-Particle-Image-Velocimetry and a mathematic model was developed [8]. In the present study an additional oxygenator element is implemented into the IWS microfluidic platform, allowing automated and reproducible hypoxia assays on the chip. In Figure 1 the principle of the perfusion controlled hypoxia is shown.

Figure 1: Hypoxia in cell culture.
Figure 1:

Hypoxia in cell culture.

Figure 2: Exploded view of the microfluidic system.
Figure 2:

Exploded view of the microfluidic system.

2 Material and methods

2.1 Microfluidic system

One of the main benefits of the presented microfluidic system is the possibility to integrate microfluidic actuators to create completely closed and perfused microfluidic circuits and microvascular systems with small volumes in the range of several μL. External pumping devices are not needed as it is mostly the case in microfluidic cell cultivation devices presented in literature [9]. The microfluidic system is produced with a layer-by-layer manufacturing technology of laser-cut polymer foils [10]. The mentioned fluidic actuators are pneumatically driven systems [11]. Therefore a flexible membrane has to be integrated into the microfluidic system, which can be easily displaced with pressure rates up to 100 kPa. A commercially available silicone foil (SILPURAN® FILM, Wacker Chemie AG) with a thickness of 200 microns and high gas permeability is perfectly suited for this application. In Figure 2 an exploded view of the microfluidic system with mounted reservoirs on top, the pneumatic part, the elastomeric membrane in the middle and the fluidic part at the bottom is shown.

The complete system is mounted in a chipholder with two connection elements which include the pneumatic fittings. In Figure 3 the developed microfluidic layout is shown. It features a micro pump for fluid actuation and an in- and outlet valve to operate the system as totally closed microfluidic circuit. In previous fluidic designs the oxygen exchange was solely performed by the gas-permeable elastomeric pump membrane. So the pump acted as a combined flow source and oxygenator [12]. This may be problematic especially when gas bubbles are produced, as reported by Goldowsky and Knapp [13]. To enhance the oxygen transport capability an additional helical oxygenator element was placed at the center of the microfluidic system utilizing the same gas-permeable membrane also used for fluid actuation whereby the gas exchange area of this oxygenator is ten times larger than that of the pump. The process gas flow at the top of the membrane can be adjusted to avoid oxygen depletion over the length of the oxygenator. Three oxygen sensing chambers (A, B, C, 3 mm diameter) are implemented to characterize both the oxygenator and the cell culture segment (oxygen consumer).

Figure 3: Microfluidic layout.
Figure 3:

Microfluidic layout.

2.2 Controlling unit

To control the oxygen content in the cell culture segment a controlling unit based on an embedded Linux device is used. Figure 4 shows a block diagram of the system.

Figure 4: Block diagram of the controlling unit.
Figure 4:

Block diagram of the controlling unit.

It switches up to 24 pneumatic outputs to actuate the pumps and valves on the chips. Furthermore it is capable to ensure stable temperature conditions and can mix three different process gases (oxygen O2, nitrogen N2 and carbon dioxide CO2) to control the oxygenator. Several digital interfaces (I2C, ETHERNET, CAN …) give the opportunity to integrate the controller in other laboratory infrastructure or laboratory information management systems.

2.3 Optical oxygen sensing

In presence of oxygen, the fluorescence lifetime of several fluorescent dyes is decreased due to quenching [14]. This decay in the fluorescence lifetime can be utilized to measure the oxygen content in the microfluidic system as shown in Figure 5 . The experimental setup was described earlier in detail [15]. Commercial available CPOx-beads (Colibri photonics, Potsdam) are immobilized with Polydimethyl-siloxane (PDMS) in each sensing chamber (A, B, C) and the fluorescence signal was measured using a compact optic block coupled to a photomultiplier. The OPAL digital lock-in amplifier (Colibri photonics, Potsdam) calculates the fluorescence decay signal and communicates to a host-PC via USB. Each measurement spot can be automatically evaluated using a 3-axis positioning system (Nanoplotter 2.1, GeSiM mbH, Großerkmannsdorf) controlled by the measurement software.

Figure 5: Optical oxygen sensing principle.
Figure 5:

Optical oxygen sensing principle.

For calibration purpose the microfluidic system was flushed with three different process gases with varying oxygen contents wO2 compared to the volume fraction of oxygen in atmosphere under standard conditions (ϕO2 = 20.9 vol.%). Those gases were: Air (wO2 = 100 %), reference gas (wO2 = 47 %) and nitrogen (wO2 = 0 %). Afterwards the microfluidic system was filled with DI water for the oxygenation and deoxygenation experiments.

3 Results

First of all the oxygenation coefficient of the oxygenator elements has to be measured:

(1)KO⁢2=cB/α⋅pO⁢2=wB/100%

Whereby KO2 is the oxygenation coefficient, cB is the oxygen concentration at the oxygenator outlet, α is the oxygen solubility in water and pO2 is the oxygen partial pressure applied to the oxygenator. This oxygenation coefficient can be determined by measuring the step response of the system when the process gas is changed. Therefore all channels were firstly flushed with DI water and afterwards pure nitrogen was applied to the oxygenator and the oxygen content at the outlet of the oxygenator was measured until it reaches a lower boundary. Afterwards the process gas was changed to air until the oxygen content of wO2 = 100 % was reached again. Figure 6 shows the up- and downstream oxygen contents (of the oxygenator) with a pumping speed of 1.2 Hz, a pumping pressure of 500 mbar and a filling vacuum of -500 mbar and compressed air as pump gas.

Figure 6: Measured oxygen content at spot A and B.
Figure 6:

Measured oxygen content at spot A and B.

As mentioned earlier the pump is gas permeable too. Therefore a parasitic oxygen input Kp can be observed which influences the transient oxygenation/deoxygenation behaviour. Both parameters can be calculated with the measured stationary up- and downstream oxygen contents (wA, wB). For the deoxygenation process and the pump operated with compressed air they are:

(2)wA=100%⋅1KO⁢2/(1KO⁢2+1Kp−1)
(3)wB=wA⁢(1−KO⁢2)

This leads to an oxygenation coefficient of KO2 = 0.4 for the oxygenator and Kp = 0.25 for the pump. Knowing those parameters gives the opportunity to develop an adapted oxygen regulator simply by varying the process gas.

4 Conclusion

A microfluidic cell cultivation device with integrated oxygenator and micro pump is presented which can be operated with different process gases to generate well-defined hypoxic conditions in one or more cell culture segments. Both, the pneumatic micro pump as well as the oxygenator is operated by a controlling unit. Due to the clearness of the used polymer foils (in the visible wavelength range) which were joined together to form the microfluidic system established imaging technologies can be applied everywhere at the microfluidic system. Therefore the impact of hypoxia can be studied online in perfused 3D cell culture models. Possible applications could be the observation of metastatic spread or wound healing processes under hypoxic conditions. Commercial available oxygen sensitive particles are immobilized at different measurement spots to characterize the oxygenation coefficients of the micro pump and the oxygenator. Firstly the oxygenator was operated with pure nitrogen as process gas resulting in a media deoxygenation. Afterwards the process gas was switched to compressed air which induces the oxygenation of the pumped fluid. Subsequent to the characterisation of the oxygenator an oxygen regulator should be implemented in the controlling unit allowing the precise adjustment and regulation of oxygen levels even for different oxygen consumers. Moreover the implementation of the previously developed substance transport model of the microfluidic system in the controller is possible, allowing a “model-in-the-loop” based regulation of the system [16].

Author’s Statement

Research funding: The authors want to express great appreciation to the Free State of Saxony and the European Union (SAB project “UNILOC”) as well as to the BMWi (ZIM project “Plasmafügen”) for the financial support. Conflict of interest: Authors state no conflict of interest. Material and Methods: Informed consent: Informed consent is not applicable. Ethical approval: The conducted research is not related to either human or animal use.

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Published Online: 2016-9-30
Published in Print: 2016-9-1

©2016 Mathias Busek et al., licensee De Gruyter.

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License.

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https://doi.org/10.1515/cdbme-2016-0019
Keywords for this article
hypoxia; lab-on-a-chip; oxygenator; oxygen sensing; perfused cell culture
Creative Commons
BY-NC-ND 4.0

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  75. Development of a skull phantom for the assessment of implant X-ray visibility
  76. Surgical navigation with QR codes
  77. Investigation of the pressure gradient of embolic protection devices
  78. Computer assistance in femoral derotation osteotomy: a bottom-up approach
  79. Automatic depth scanning system for 3D infrared thermography
  80. A service for monitoring the quality of intraoperative cone beam CT images
  81. Resectoscope with an easy to use twist mechanism for improved handling
  82. In vitro simulation of distribution processes following intramuscular injection
  83. Adjusting inkjet printhead parameters to deposit drugs into micro-sized reservoirs
  84. A flexible standalone system with integrated sensor feedback for multi-pad electrode FES of the hand
  85. Smart control for functional electrical stimulation with optimal pulse intensity
  86. Tactile display on the remaining hand for unilateral hand amputees
  87. Effects of sustained electrical stimulation on spasticity assessed by the pendulum test
  88. An improved tracking framework for ultrasound probe localization in image-guided radiosurgery
  89. Improvement of a subviral particle tracker by the use of a LAP-Kalman-algorithm
  90. Learning discriminative classification models for grading anal intraepithelial neoplasia
  91. Regularization of EIT reconstruction based on multi-scales wavelet transforms
  92. Assessing MRI susceptibility artefact through an indicator of image distortion
  93. EyeGuidance – a computer controlled system to guide eye movements
  94. A framework for feedback-based segmentation of 3D image stacks
  95. Doppler optical coherence tomography as a promising tool for detecting fluid in the human middle ear
  96. 3D Local in vivo Environment (LivE) imaging for single cell protein analysis of bone tissue
  97. Inside-Out access strategy using new trans-vascular catheter approach
  98. US/MRI fusion with new optical tracking and marker approach for interventional procedures inside the MRI suite
  99. Impact of different registration methods in MEG source analysis
  100. 3D segmentation of thyroid ultrasound images using active contours
  101. Designing a compact MRI motion phantom
  102. Cerebral cortex classification by conditional random fields applied to intraoperative thermal imaging
  103. Classification of indirect immunofluorescence images using thresholded local binary count features
  104. Analysis of muscle fatigue conditions using time-frequency images and GLCM features
  105. Numerical evaluation of image parameters of ETR-1
  106. Fabrication of a compliant phantom of the human aortic arch for use in Particle Image Velocimetry (PIV) experimentation
  107. Effect of the number of electrodes on the reconstructed lung shape in electrical impedance tomography
  108. Hardware dependencies of GPU-accelerated beamformer performances for microwave breast cancer detection
  109. Computer assisted assessment of progressing osteoradionecrosis of the jaw for clinical diagnosis and treatment
  110. Evaluation of reconstruction parameters of electrical impedance tomography on aorta detection during saline bolus injection
  111. Evaluation of open-source software for the lung segmentation
  112. Automatic determination of lung features of CF patients in CT scans
  113. Image analysis of self-organized multicellular patterns
  114. Effect of key parameters on synthesis of superparamagnetic nanoparticles (SPIONs)
  115. Radiopacity assessment of neurovascular implants
  116. Development of a desiccant based dielectric for monitoring humidity conditions in miniaturized hermetic implantable packages
  117. Development of an artifact-free aneurysm clip
  118. Enhancing the regeneration of bone defects by alkalizing the peri-implant zone – an in vitro approach
  119. Rapid prototyping of replica knee implants for in vitro testing
  120. Protecting ultra- and hyperhydrophilic implant surfaces in dry state from loss of wettability
  121. Advanced wettability analysis of implant surfaces
  122. Patient-specific hip prostheses designed by surgeons
  123. Plasma treatment on novel carbon fiber reinforced PEEK cages to enhance bioactivity
  124. Wear of a total intervertebral disc prosthesis
  125. Digital health and digital biomarkers – enabling value chains on health data
  126. Usability in the lifecycle of medical software development
  127. Influence of different test gases in a non-destructive 100% quality control system for medical devices
  128. Device development guided by user satisfaction survey on auricular vagus nerve stimulation
  129. Empirical assessment of the time course of innovation in biomedical engineering: first results of a comparative approach
  130. Effect of left atrial hypertrophy on P-wave morphology in a computational model
  131. Simulation of intracardiac electrograms around acute ablation lesions
  132. Parametrization of activation based cardiac electrophysiology models using bidomain model simulations
  133. Assessment of nasal resistance using computational fluid dynamics
  134. Resistance in a non-linear autoregressive model of pulmonary mechanics
  135. Inspiratory and expiratory elastance in a non-linear autoregressive model of pulmonary mechanics
  136. Determination of regional lung function in cystic fibrosis using electrical impedance tomography
  137. Development of parietal bone surrogates for parietal graft lift training
  138. Numerical simulation of mechanically stimulated bone remodelling
  139. Conversion of engineering stresses to Cauchy stresses in tensile and compression tests of thermoplastic polymers
  140. Numerical examinations of simplified spondylodesis models concerning energy absorption in magnetic resonance imaging
  141. Principle study on the signal connection at transabdominal fetal pulse oximetry
  142. Influence of Siluron® insertion on model drug distribution in the simulated vitreous body
  143. Evaluating different approaches to identify a three parameter gas exchange model
  144. Effects of fibrosis on the extracellular potential based on 3D reconstructions from histological sections of heart tissue
  145. From imaging to hemodynamics – how reconstruction kernels influence the blood flow predictions in intracranial aneurysms
  146. Flow optimised design of a novel point-of-care diagnostic device for the detection of disease specific biomarkers
  147. Improved FPGA controlled artificial vascular system for plethysmographic measurements
  148. Minimally spaced electrode positions for multi-functional chest sensors: ECG and respiratory signal estimation
  149. Automated detection of alveolar arches for nasoalveolar molding in cleft lip and palate treatment
  150. Control scheme selection in human-machine- interfaces by analysis of activity signals
  151. Event-based sampling for reducing communication load in realtime human motion analysis by wireless inertial sensor networks
  152. Automatic pairing of inertial sensors to lower limb segments – a plug-and-play approach
  153. Contactless respiratory monitoring system for magnetic resonance imaging applications using a laser range sensor
  154. Interactive monitoring system for visual respiratory biofeedback
  155. Development of a low-cost senor based aid for visually impaired people
  156. Patient assistive system for the shoulder joint
  157. A passive beating heart setup for interventional cardiology training
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