Shrinking Ion-selective Sensors for Success
Conventional bulk ion-selective sensors have been extensively studied and are well understood. Now, they must be miniaturized for cutting-edge applications, allowing us to blur the line between sensing and bulk solution chemistry.
Eric Bakker, Xiaojiang Xie |
Given the increasing number of complex molecular species under scrutiny, it can be easy to disregard small inorganic ions as attractive targets for chemical and biological research. But nothing could be further from the truth; the impact of inorganic ions on environmental and biochemical systems is far from being understood. Ionophore-based ion-selective electrodes (ISEs) utilize selective polymeric membranes to provide voltage readings to directly reflect the concentration of ions in solution. Today, they are indispensible sensing tools in clinical diagnostics applications for the detection of electrolytes in whole blood. Corresponding optical sensors, making use of much the same sensing chemistry, have also emerged over the past few decades.
There has been significant interest in the miniaturization of ion-selective sensors in recent years; the ability to perform measurements in extremely small spaces, for example, inside cells, is tantalizing; however, it would be impossible using bulk sensors. Unfortunately, uncertainties and new challenges emerge with our desire to reduce size.
The response theory for conventional ISEs and optodes is now well established. But does this theory still apply at the nanoscale? For instance, to what extent does electroneutrality still hold for optodes based on extraction principles? Our recent work offers an answer, showing that even with a diameter of around 40 nm, optical nanosensors still behave on the basis of ion exchange principles and maintain electroneutrality (1). However, other unanswered questions remain: is the selectivity the same with bulk optodes? What is the detection limit going to be?
In terms of intracellular use, we feel optical sensors may have a brighter future given their compatibility with state-of-art imaging equipment, such as fluorescence microscopes. ISEs have been miniaturized for intracellular experiments, but the noise level, detection limit, lifetime and physical robustness are not satisfactory and require rigorous operator training. In our opinion, there is still a long way to go before an analytical chemist will be able to handle miniaturized ISEs with ease. Still, optical sensors also have drawbacks, for example, their tendency to photobleach – an area where ISEs still hold an advantage.
In either case, we must also consider biocompatibility of the associated sensing materials. Most ISEs and optodes use PVC-based matrix materials, although other polymers, such as polyacrylamide, polystyrene and methacrylic co-polymers, have been reported. Clearly, researchers must continue to explore new materials and evaluate their behavior in vivo.
Despite the above uncertainties and challenges, micro or nanometer sized ion sensors show great potential, so our group continues to solve problems and push forward. Historically, ion optodes have suffered from a proton cross response. To overcome this limit, we recently proposed an exhaustive sensing mode where the analyte can be completely consumed by the sensor, which allows a pH independent response (2). Suspensions of ultra-miniaturized optodes are very attractive in this respect, as the sensor response is dramatically faster compared to bulk optode films. Notably, this exhaustive sensing mode is not a ‘jack-of-all-trades’ and the nanoprobes are suitable only when the experiment of interest can tolerate total analyte consumption.
Ionophore-based ion-exchange nanosensors may also contribute to other interesting directions that blur the lines between solution chemistry and chemical sensing. For example, we are investigating ionophore-based nanoprobes as novel complexometric titration reagents. Water-soluble organic chelators, such as EDTA, have been widely applied for chelometry, but the selectivity and working pH range have not really evolved in the past 60 years. Ionophore-based nanoparticle suspensions may overcome existing drawbacks and potentially replace these reagents, especially if the materials become sufficiently inexpensive.
A second example comes from our recent work on photodynamic ion sensors (3, 4). Switching the sensor ‘on’ and ‘off’ is followed by an ion flux at the sensor/sample interface. Therefore, when a photodynamic ion sensor is miniaturized down to the nanoscale, it can also serve as a light responsive tool for ion concentration perturbations in the sample (5.) The light controlled release or uptake of ionic species could also form new platforms for uncaging reagents and drug delivery.
Finally, we anticipate that light frequency modulated concentration changes will form new and attractive tools for probing the kinetic response of complex systems to such perturbations. Exciting times – but let’s not, in our eagerness, underestimate complications associated with in vivo experiments and the aforementioned biocompatibility considerations.
Many fascinating opportunities are ahead of us, with much unknown and yet to be explored. As analytical scientists, it is our job to understand these micro- and nanoscale sensing tools – identifying and solving problems along the way – so that we can apply them in exciting new areas.
- 1. X. Xie, G. Mistlberger, and E. Bakker, “Ultrasmall Fluorescent Ion-Exchanging Nanospheres Containing Selective Ionophores”, Anal. Chem., 85 (20), 9932–9938 (2013).
- X. Xie, J. Zhai, and E. Bakker, “Oxazinoindolines as Fluorescent H+ Turn-On Chromoionophores For Optical and Electrochemical Ion Sensors”, Anal. Chem., 86 (6), 2853–2856 (2014).
- X. Xie, G. Mistlberger, and E. Bakker, “Reversible Photodynamic Chloride-Selective Sensor Based on Photochromic Spiropyran”, J. Am. Chem. Soc., 134 (41), 16929–16932 (2012).
- G. Mistlberger et al., “Photoresponsive Ion Extraction/Release Systems: Dynamic Ion Optodes for Calcium and Sodium Based on Photochromic Spiropyran”, Anal. Chem., 85 (5), 2983–2990 (2013).
- X. Xie and E. Bakker, “Light-Controlled Reversible Release and Uptake of Potassium Ions from Ion-Exchanging Nanospheres”, ACS Appl. Mater. Interfaces, 6 (4), 2666–2670 (2014).