This article is licensed under CC-BY 4.0 www.acsami.org Research Article Integration of Metal−Organic Polyhedra onto a Nanophotonic Sensor for Real-Time Detection of Nitrogenous Organic Pollutants in Water Olalla Calvo-Lozano, Laura Hernández-López, Leyre Gomez, Arnau Carné-Sánchez,* Cornelia von Baeckmann, Laura M. Lechuga,* and Daniel Maspoch* Cite This: ACS Appl. Mater. Interfaces 2023, 15, 39523−39529 Read Online ACCESS Metrics & More Article Recommendations * sı Supporting Information ABSTRACT: The grave health and environmental consequences of water pollution demand new tools, including new sensing technologies, for the immediate detection of contaminants in situ. Herein, we report the integration of metal−organic cages or polyhedra (MOCs/MOPs) within a nanophotonic sensor for the rapid, direct, and real- time detection of small (<500 Da) pollutant molecules in water. The sensor, a bimodal waveguide silicon interferometer incorporating Rh(II)-based MOPs as specific chemical receptors, does not require sample pretreatment and enables minimal expenditure of time and reagents. We validated our sensor for the detection of two common pollutants: the industrial corrosion inhibitor 1,2,3-benzotriazole (BTA) and the systemic insecticide imidacloprid (IMD). The sensor offers a fast time-to-result response (15 min), high sensitivity, and high accuracy. The limit of detection (LOD) in tap water for BTA is 0.068 μg/mL and for IMD, 0.107 μg/mL, both of which are below the corresponding toxicity thresholds defined by the European Chemicals Agency (ECHA). By combining innovative chemical molecular receptors such as MOPs with state-of-the-art photonic sensing technologies, our research opens the path to implement competitive sensor devices for in situ environmental monitoring. KEYWORDS: metal−organic polyhedra, nanophotonic sensor, interferometer, benzotriazole, imidacloprid, environmental monitoring 1. INTRODUCTION waveguide (BiMW) sensor has demonstrated its potential for Ubiquitous pollution of natural water resources with biosensing of various analytes in diverse applications, including anthropogenic contaminants such as agriculture products, hormones, microRNAs or bacteria in clinical diagnosis,2−4 and fine chemicals, pharmaceuticals, and fuels has created a crisis algaecides or insecticides in environmental monitoring.5,6 for both human health and the environment.1 Although there Moreover, the BiMW sensor is based on silicon technology are highly accurate and sensitive analytical techniques for and microelectronic fabrication, thereby enabling its mass environmental monitoring, they present major practical production with multiplexed configuration and facilitating its limitations: for instance, most chromatography techniques integration into portable sensing devices. require expensive, specialized laboratory equipment, and The development of biosensors such as those based on EW arduous sample-preparation procedures. Accordingly, there is sensors generally requires the use of biomolecules (e.g., a pressing need for simpler tools for the rapid, accurate antibodies or DNA probes) as biorecognition elements or detection of water pollutants in situ. biological receptors.7 Due to the fragility of these receptors, A particularly promising field for environmental monitoring their production and handling can be both costly and complex: is sensing. For example, evanescent wave (EW) optical for example, as concerns the working temperature, pH, and/or sensors�especially interferometric devices�have garnered sterility.8 Another challenge for EW sensors is that the attention for accurate, highly sensitive, real-time, and label- detection of analytes smaller than 500 Da is not trivial, free detection of analytes. In these sensors, contact with the target analyte provokes an extremely subtle change in the Received: May 19, 2023 refractive index (RI) on their surface, which in turn alters the Accepted: July 28, 2023 properties of the propagated light (e.g., phase, intensity, etc.) Published: August 11, 2023 through their EW. Thus, the extent to which the light- propagation changes can be correlated with the analyte concentration. Among interferometric sensors, the bimodal © 2023 The Authors. Published by American Chemical Society https://doi.org/10.1021/acsami.3c07213 39523 ACS Appl. Mater. Interfaces 2023, 15, 39523−39529 ACS Applied Materials & Interfaces www.acsami.org Research Article Figure 1. (a) Structure of cuboctahedral Rh(II)-MOP, highlighting the 5-positions in the organic backbone (covalent anchoring sites) and the axial sites of its dirhodium paddlewheels (coordinative recognition site). (b) Schematic of the MOP-BiMW sensor, showing its main characteristics, including the covalently attached Rh(II)-MOP. especially those at low concentrations.9 Consequently, EW decorated the surface of a silicon nanowire-based field-effect sensors often demand more arduous sensing strategies, such as transistor with Cu(II)-based lantern MOPs to afford a sensor indirect competitive immunoassays that require separate steps for the detection of 2,4,6-trinitrotoluene in ethanol with a for bioconjugation, amplification, and/or preconcentration of detection limit below the nanomolar level.21 Unfortunately, the the target analyte(s).5,6 A promising solution to address both use of hydrolytically unstable Cu(II)-based MOPs as receptors, of these shortcomings is the use of porous materials as and the reversible coordinative attachment methods, precludes alternative receptors in BiMW sensors. Although the practical the use of the aforementioned sensors for real-time monitoring application of extended and crystalline porous metal−organic of aqueous samples. frameworks (MOFs) has previously been demonstrated with In this study, we explored the implementation of robust, BiMW sensors for gas sensing,10 these sensors are hindered by hydrolytically stable MOPs onto a BiMW sensor for environ- their inherent grain boundaries when the MOF is located/ mental monitoring of aqueous samples contaminated with assembled on the sensing surface. Indeed, with MOFs, the film industrial and agrochemical pollutants. We selected the robust textures (e.g. grain/crystallites sizes, grain boundaries, and Rh(II)-based cuboctahedral [Rh2(COOH-bdc)2]12 MOP mesopores), crystalline orientations, and exposed crystal facets (hereafter named COOHRhMOP, where COOH-bdc is 5- crucially induce light-scattering that suppresses the propaga- carboxy-1,3-benzenedicarboxylate)22 as a receptor, as it can tion of the EW and, consequently, directly affects the analytical efficiently capture and remove nitrogenous pollutants from performance of the optical sensor.11 This hurdle has very water,23 through the coordination reactivity of the 12 exposed recently been circumvented by miniaturizing MOF (in axial sites of the Rh(II)-paddlewheels (Figure 1a, green dots). particular, ZIF-8) particles to smaller than 30 nm and then Additionally, this Rh-MOP is water-stable in a broad pH range assembling them in dense, transparent optical films.10 (i.e., pH = 1−12)23 and is functionalized with a carboxylic acid We hypothesized that one strategy to further miniaturize the group at the 5-position of the phenyl ring of each bdc linker, molecular receptors to be incorporated in the nanophotonic such that its external surface is functionalized with a total of 24 sensors would be to use molecular metal−organic cages/ carboxylic acid groups (Figure 1, red dots). Therefore, these polyhedra (MOCs/MOPs). MOPs offer rich covalent and carboxylic groups can be used to immobilize the Rh-MOPs coordination chemistry to enable stoichiometric functionaliza- onto the previously amine-functionalized BiMW sensor tion of sensor surfaces12 to create devices that can recognize surfaces through amide couplings. Using this surface chemistry, and bind specifically target analytes. Additionally, unlike MOFs we were able to integrate COOHRhMOPs onto the BiMW or covalent organic frameworks (COFs), they can be dissolved surface, obtaining a sensor for rapid (<15 min) detection of low-weight coordinating analytes in water, without the need for and therefore easily processed. any sample pre-treatment (Figure 1b). We validated our The capability of some MOPs to trigger luminescent and optical MOP-BiMW sensor for the detection of two harmful catalytic processes in the presence of target analytes has been aqueous pollutants: the widely used industrial corrosion harnessed to develop colorimetry or fluorescence-based bulk inhibitor 1,2,3-benzotriazole (BTA, MW = 119.12 g/mol) sensors (i.e., unprocessed powders).13−19 However, given that and the systemic insecticide imidacloprid (IMD, MW = incorporating MOPs onto the surface of analytical devices is 255.661 g/mol), both of which have severe effects on animal difficult, it has only been reported twice in the literature. In the and human health. first example, Li and co-workers immobilized a Cu(II)-based lantern MOP onto the surface of a plasmonic substrate through coordinative interactions, creating a Raman sensor 2. RESULTS AND DISCUSSION that exhibited good surface-enhanced Raman scattering 2.1. Synthesis and Recognition Capabilities of the enhancement, which they exploited to detect nitro-organic MOP-Based Sensor Surface. To fabricate the MOP-BiMW compounds in dichloromethane solutions in the micro- to sensor, we began with the integration of MOPs, as the selective nanomolar range.20 Later, Smet and co-workers similarly receptor layer, onto the Si3N4 waveguide surface of the BiMW 39524 https://doi.org/10.1021/acsami.3c07213 ACS Appl. Mater. Interfaces 2023, 15, 39523−39529 ACS Applied Materials & Interfaces www.acsami.org Research Article Figure 2. (a) Left: UV−vis spectra of COONaRhMOP in water before (blue dashed line) and after the addition of either BTA (green line) or THP (pink line). Right: schematic of the resulting solution after adding BTA or THP to an aqueous solution of COONaRhMOP and the molecular structure of these pollutants. (b) From left to right: schematic of the response mechanism for the immobilized COOHRhMOP on the BiMW sensor surface in the presence of BTA and real-time sensorgram of different concentrations of BTA with the COOHRhMOP/BiMW sensor in Milli-Q water. (c) From left to right: schematic of the absence of response of the immobilized COOHRhMOP on the BiMW sensor surface in the presence of THP and real-time sensorgrams of different concentrations of THP with the COOHRhMOP/BiMW sensor in Milli-Q water. (d) Calibration curves for BTA and THP. In both calibration curves, each signal corresponds to the mean ± SD of triplicate measurements on different batches of BiMW sensor chips. (Figure 1b). To this end, the surface sensor was initially resultant MOP-BiMW sensor for the detection and quantifi- silanized with aminopropyltrimethoxysilane (APTES) to cation of organic pollutants in water. To this end, we exploited functionalize it with amino groups, which enabled subsequent the reactivity of the axial sites of the Rh(II)-paddlewheels immobilization of COOHRhMOP via carbodiimine-based units, which exhibit high affinity toward Lewis bases such as N- amide coupling. Although this procedure is employed for donor ligands. These interactions can be detected in solution silicon surface functionalization with various biomolecules,24 to by monitoring the spectroscopic changes in the bands centered the best of our knowledge, it has never previously been applied in the range from 500 to 600 nm (λmax), which corresponds to to MOPs. The solution-phase coupling was evaluated by the π* → σ* transitions of Rh-Rh bonds (Figure 2a).25 We reacting COOHRhMOP with a model aliphatic amine envisaged that this coordination chemistry could be transferred molecule, propylamine, in 2-(N-morpholino)ethanesulfonic to the BiMW sensor surface such that the coordinative acid (MES)-buffered solution (pH = 6) in the presence of pollutant-MOP interaction could be transduced into an optical the coupling agents 1-ethyl-3-(-3-dimethylaminopropyl) car- analytical signal. bodiimide (EDC, 0.2 M) and N-hydroxysuccinimide (NHS, We first evaluated our MOP-BiMW sensor for the detection 0.05 M) at room temperature for 12 h. This model reaction of BTA (Figure 2b). This began with comparing its response afforded the amide-coupled-RhMOP in a yield of 50% (i.e., 12 to that of bare or APTES functionalized BiMW sensors (i.e., of the 24 COOH groups were coupled with the model amine two lacking COOHRhMOP). Thus, a solution of BTA in molecule), thus demonstrating the viability of the coupling Milli-Q water (concentration: 1000 μg/mL) was sequentially chemistry for immobilization of COOHRhMOP onto the injected through the three sensors (Figure S8). Interestingly, APTES-modified sensor surface (Figures S2−S5). Thus, the no sensor responses (phase changes) were observed in the bare APTES-functionalized sensor was incubated in a COOH- BiMW sensor, thus ruling out any nonspecific adsorptions of RhMOP aqueous solution under the same reaction conditions the analyte onto the inert silicon nitride or amine-function- as described above. After the amide coupling, the surface of the alized sensor surface (Figure S8). Contrariwise, and sensor chip was thoroughly washed with water to remove any importantly, a significant phase variation signal was observed non-covalently attached MOP. The presence of Rh(II) on the for the MOP-BiMW sensor (Figure S8). Next, the calibration sensor chip was confirmed by in situ X-ray photoelectron and limit of detection (LOD) of the MOP-BiMW sensor were spectroscopy (XPS) and upon analysis of acid-digested calculated according to an additive-calibration curve (concen- samples by inductively coupled plasma-mass spectrometry trations: 5−1000 μg/mL; Figures 2b,d and S9), which revealed (ICP-MS) (Figure S7 and Table S1). an LOD of 0.064 μg/mL, an excellent value that is several Having successfully immobilized the COOHRhMOP onto orders of magnitude below the EC50 (i.e., the concentration the sensor surface, we next assessed the performance of the that is lethal to 50% of the population of a species) for aquatic 39525 https://doi.org/10.1021/acsami.3c07213 ACS Appl. Mater. Interfaces 2023, 15, 39523−39529 ACS Applied Materials & Interfaces www.acsami.org Research Article organisms (940 μg/mL), as established by the European Chemicals Agency (ECHA).26 Furthermore, this LOD for BTA is also well below the no observed-effect concentration (NOEC, the highest concentration proven to produce no adverse effects on aquatic organisms) of 1 μg/mL. Since we had hypothesized that the recognition mecha- nism�and consequently, the sensing process�is derived from the coordinative capabilities of the Rh(II) axial coordination sites, we next sought to confirm our hypothesis by testing the sensor against a noncoordinating analyte. To this end, thianaphthene (THP; MW = 134.20 g/mol), a molecule with similar shape, size, and polarity to BTA, was chosen as a representative non-coordinative analyte. Although Rh(II) ions also show an excellent affinity for S-donor molecules, the aromaticity of THP precludes the interaction with the Rh(II) axial sites, as the free electron pair at the S atom is delocalized within the π ring system (Figure 2a). As expected, at all tested concentrations of THP, the sensor exhibited a negligible response, thus confirming that its previously observed response toward BTA did indeed proceed by coordinative recognition (Figure 2c). By extension, these results confirmed that the selective COOHRhMOP-pollutant coordinative interactions transfer to the sensor surface. Next, we tested our MOP-BiMW sensor for the detection of IMD in water (Figure 3a). Analogously to the case of BTA, the sequential addition of increasingly concentrated solutions of IMD in Milli-Q water (range: 1−500 μg/mL) to the MOP- BiMW sensor induced a clear interferometric phase-shift, from which a calibration curve and an LOD (0.234 μg/mL) were calculated (Figures 3b,c and S10). The poorer LOD calculated for IMD relative to that for BTA was attributed to its lower coordinative affinity toward COOHRhMOP (Figure S6). Nevertheless, this LOD for IMD is still well below its EC50 for aquatic organisms, whose values range from 8.7 to 180 μg/ mL.27 Figure 3. (a) UV−vis spectra of COONaRhMOP in water before Overall, the results discussed above confirmed that the main (blue line) and after (black line) the addition of IMD. (b) Real-time interaction between the MOP-BiMW sensor and organic sensorgram of different concentrations of IMD in the presence of the pollutants in water proceeds through the coordination of the COOHRhMOP/BiMW sensor in Milli-Q water. (c) Calibration curve pollutant to the exposed Rh(II) axial sites of the sensor and molecular structure of IMD. Each signal corresponds to the mean surface-anchored COOHRhMOPs. We pondered whether the ± SD of triplicate measurements on different batches of BiMW sensor highly sensitive analytical response achieved by the MOP- chips. BiMW sensor could be achieved without structuring Rh(II) paddlewheel clusters in a caged structure. To answer this sensor chips, which we calculated as the coefficient of variation question, we functionalized the sensing area of the BiMW with (CV; expressed as %). Encouragingly, the CV that we obtained a discrete Rh(II)-based paddlewheel cluster with formula for both BTA (8%) and IMD (9%) were below the Rh2(bdc)4 (Figure S11).28 This metal−organic complex recommended maximum variability (15%) for the performance replicates a metal−organic fragment present in the MOP of commercial sensors29 (Table 1). These results confirmed structure and presents four available, un-coordinated COOH the good reproducibility and robustness of the sensing strategy groups, which makes it an ideal model compound to assess the where a very low variability may come from sensor chip impact of structuring Rh(II) sites on the analytical response of functionalization with COOHRhMOP and/or sample handling BiMW sensors. The sensitivity of the Rh2(bdc)4-BiMW sensor and preparation. toward BTA was significantly lower than that obtained for the To test the performance of our MOP-BiMW sensor in a real- MOP-BiMW sensor under otherwise identical conditions world application, we next screened it against samples of tap- (Figure S12). Specifically, the LOD obtained for the water spiked with either BTA or IMD.30,31 Figure 4 shows the Rh2(bdc)4-BiMW sensor was 0.352 μg/mL. We attributed calibration curves obtained for BTA and IMD. In both cases, the superior performance of the MOP-BiMW sensor to its the sensitivity remained in the low μg/mL range compared to higher density of analytically active Rh(II) sites (i.e., 0.15 the corresponding evaluations in Milli-Q water: 0.068 μg/mL Rh(II) sites per nm2), which translates into a higher number of for BTA and 0.107 μg/mL for IMD (Figure S13). The receptor sites on the sensor surface. sensitivity was not affected by the presence of ions or other 2.2. Reproducibility, Accuracy, and Robustness of the impurities in tap water, thus corroborating the potential of our MOP-Based Sensors. To ascertain the reproducibility of the sensor for in situ environmental control devices. Furthermore, sensor, we next measured the inter-assay variability according although receptor saturation could be assumed above 500 μg/ to the results of replicate experiments run within different mL for BTA and 250 μg/mL for IMD, the MOP-BiMW sensor 39526 https://doi.org/10.1021/acsami.3c07213 ACS Appl. Mater. Interfaces 2023, 15, 39523−39529 ACS Applied Materials & Interfaces www.acsami.org Research Article Table 1. Sensor Reproducibility Studya BTA (μg/mL) mean ± SD (Δφ) CV (%) IMD (μg/mL) mean ± SD (Δφ) CV (%) 5 1.69 ± 0.14 8 5 2.87 ± 0.25 9 10 4.99 ± 0.46 9 10 4.58 ± 0.61 13 50 13.29 ± 1.54 12 50 11.54 ± 0.71 6 100 17.58 ± 1.42 8 100 16.69 ± 1.30 8 tap water 5 5.38 ± 0.40 7 5 3.13 ± 0.16 5 10 9.09 ± 0.75 8 10 4.39 ± 0.30 7 50 18.76 ± 0.60 3 50 8.60 ± 0.25 3 100 24.88 ± 1.75 7 100 12.56 ± 1.27 10 a Interassay variability for BTA and IMD in Milli-Q and tap water. Evaluations in triplicate. responses. In both cases, a good correlation was found between the actual concentrations and those obtained with the BiMW sensor: all accuracy values were within (or close to) the accepted accuracy range of 80−120% (Table 2). These values make our MOP-based optical sensor competitive against current analytical techniques for the detection of BTA and IMD (Table S2). For the detection of BTA, our sensor is just as efficient as that of other analytical techniques and tools such as surface- enhanced Raman scattering (SERS), differential pulse voltammetry (DPV), and high-performance liquid chromatog- raphy (HPLC), yet is faster because it does not require sample pre-treatment.32−35 However, for the detection of IMD, although its sensitivity is sufficient for environmental monitoring, it is far less sensitive than solid-phase extraction (SPE), which has a reported LOD of 0.0005 μg/mL.36 Nevertheless, our sensor exhibits a sensitivity close to or even better than that of other systems.37,38 3. CONCLUSIONS Figure 4. Calibration curves for the detection of BTA (a) and IMD In summary, we have combined the molecular recognition of (b) in spiked samples of tap water by the MOP-BiMW sensor. Each discrete molecular cages with the sensing performance of signal corresponds to the mean ± SD of triplicate measurements on optical sensors to create an Rh-MOP-functionalized BiMW different batches of BiMW sensor chips. sensor for rapid, direct, and real-time detection of water pollutants. This sensor can detect the common pollutants BTA reported a wide dynamic range for pollutant concentrations and IMD in water in less than 15 min, exhibiting LODs as low from 1 to 250 or 100 μg/mL, respectively. as 0.068 μg/mL for BTA and 0.107 μg/mL for IMD. Next, we studied the reproducibility of the sensor using Importantly, we have demonstrated that the coordination spiked tap-water samples (Table 1), again observing excellent chemistry of Rh-MOPs observed in solution can be transferred sensor performance. These results further corroborated the to the sensing surface of a BiMW device, as reflected in the fact suitability of our sensor for environmental monitoring of that the sensor responded to these coordinating pollutants but coordination analytes according to the previously mentioned did not respond to a noncoordinating analyte of similar size, FDA guideline for chemical sensors (max CV < 15%). shape, and polarity (thianaphthene, THP). We assessed the Finally, we decided to assess the accuracy of the sensor for sensors for sensitivity, specificity, reproducibility, and accuracy. the quantification of low concentrations of BTA or IMD within Significantly, according to ECHA guidelines for these the dynamic range in spiked samples of tap water. As explained contaminants, our technology exceeds the required analytical in detail in the Supporting Information, the accuracy was sensitivity (low μg/mL range) for both water contaminants, calculated considering the real and interpolated concentrations whose toxicity thresholds for aquatic life range from 5 to 900 in each calibration curve after sample injections and sensor μg/mL. Furthermore, all the analytical values obtained fall Table 2. Accuracy of the MOP-BiMW Sensor for Detection of BTA or IMD in Spiked Tap-Water Samples sample # [BTA], real (μg/mL) [BTA], estimated (μg/mL) accuracy (%) sample # [IMD], real (μg/mL) [IMD], estimated (μg/mL) accuracy (%) S1 3.0 3.5 117 S6 3.0 3.5 118 S2 7.5 9.1 122 S7 7.5 9.4 125 S3 15.0 18.1 121 S8 15.0 17.2 115 S4 30.0 29.5 98 S9 30.0 33.1 110 S5 70.0 59.9 86 S10 70.0 63.7 91 39527 https://doi.org/10.1021/acsami.3c07213 ACS Appl. Mater. Interfaces 2023, 15, 39523−39529 ACS Applied Materials & Interfaces www.acsami.org Research Article within the FDA guidelines for chemical sensors. We are measurements. L.H.L., C.V.B., and A.C.-S. synthesized the confident that the integration of the specific reactivity and chemical receptors. L.G., O.C.-L., L.H.-L., and A.C.-S. recognition capabilities of molecular cages�which could designed the experiments, assisted with surface character- include coordination, electrostatic, and/or host guest-guest ization, and wrote the manuscript. A.C.-S., D.M., and L.M.L. chemistry�into BiMW sensor technology will inform the participated in scientific discussions and critical revision of the design of future sensors for rapid, selective, and sensitive in situ manuscript. All authors have given their approval on the final environmental monitoring. version of the manuscript. ■ * ASSOCIATED CONTENT sı Supporting Information Notes The authors declare no competing financial interest. The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsami.3c07213. ■ ACKNOWLEDGMENTS This work was supported by the Spanish MCIN (R&D Project Detailed experimental procedures, materials and sensor PID2019-108105RA-I00). It was also funded by the CERCA characterization, and data analysis (PDF) program/Generalitat de Catalunya. ICN2 is supported by the Severo Ochoa program from the Spanish MINECO (Grant ■ AUTHOR INFORMATION Corresponding Authors No. SEV-2017-0706). L.G. thanks BIST for the PROBIST fellowship, a Marie Sklodoswska-Curie co-fund grant agree- Arnau Carné-Sánchez − Departament de Química, Facultat ment number 754510. A.C.S. is indebted to the Ramón y Cajal de Ciències, Universitat Autònoma de Barcelona, 08193 Program (RYC2020-029749-I Fellowship) and the Europa Bellaterra, Spain; Catalan Institute of Nanoscience and Excelencia Grant (EUR2021-121997). Nanotechnology (ICN2), CSIC, and Barcelona Institute of Science and Technology, 08193 Bellaterra, Barcelona, Spain; orcid.org/0000-0002-8569-6208; Email: arnau.carne@ ■ REFERENCES (1) Landrigan, P.; Fuller, R.; Acosta, N.; Adeyi, O.; Arnold, R.; Basu, icn2.cat N.; Baldé, A.; Bertollini, R.; Bose-O’Reilly, S.; Boufford, J.; Breysse, P.; Laura M. 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