Scheme 1. AMACR involved pristanic acid metabolism pathway.
Limited healthcare capacity highlights the needs of integrated sensing systems for personalized health-monitoring. However, only limited sensors can be employed for point-of-care applications, emphasizing the lack of a generalizable sensing platform. Here, we report a metal organic framework (MOF) ZIF-90-ZnO-MoS2 nanohybrid-based integrated electrochemical liquid biopsy (ELB) platform capable of direct profiling cancer exosomes from blood. Using a bottom-up approach for sensor design, a series of critical sensing functions is considered and encoded into the MOF material interface by programming the material with different chemical and structural features. The MOF-based ELB platform is able to achieve one-step sensor fabrication, target isolation, nonfouling and high-sensitivity sensing, direct signal transduction, and multiplexed detection. We demonstrated the capability of the designed sensing system on differentiating cancerous groups from healthy controls by analyzing clinical samples from lung cancer patients, providing a generalizable sensing platform.
In article number 2000307, Yuan Zhang and co‐workers present a self‐organized nanohybrid consisting of metal nanopillars in a semiconducting 2H‐MoS2 matrix for accurate analysis of prostate cancer biomarker, alpha‐methylacyl‐CoA racemase (AMACR) in complex human body fluids. The explored 2H‐MoS2‐based nanohybrid is employed for the fabrication of an electrochemical microsensor and is capable of effectively differentiating prostate cancer patients with healthy controls.
Motivation Cell signaling proteins have been widely regarded as some of the most powerful biomarkers for cancer diagnosis because they are real therapy related molecules. Extracellular vesicles, exosomes, transport proteins to promote tumor growth and are stable in biofluids at room temperature.[1] Hence, detection of exosomal proteins (e.g., cluster of differentiation (CD) 9, CD 63, CD 81) would be easily deployed at the point-of-care (POC) diagnostic. A successful electrochemical biosensor is generally determined by electrodes and their modification as well as specific bio-recognition elements (BREs). Graphene like MoS2 has emerged in biosensing applications owing to their intriguing properties, such as good catalytic properties, interesting metallic-to-semiconducting transition from 1T to 2H phase, and good biocompatibility.[2] However, a particularly vexing problem for MoS2 as the sensing materials is the structural instability that the exfoliated or ultrathin two dimensional (2D) MoS2 is hard to be retained in in their freestanding state. The surface modification technologies, such as growth of building blocks could transfer the 2D to relatively stable 3D nanoarchitectures, in which each component can also exert different function. Herein, we demonstrate a nanostructure consisting of zinc oxide (ZnO) nanowires (NWs) array grown on 2D MoS2forming a new nanoarchitecture (ZnO-MoS2) providing high specific surface area and good electron transport capability. Then, zeolitic imidazolate framework 90 (ZIF-90) thin films are in-situ deposited onto ZnO NWs by using ZnO as precursor to directly react with imidazole-2-carboxyaldehyde (ICA). The integrated hybrid nanostructure, denoted as ZIF-90-ZnO-MoS2, possesses not only effective mass transport and electron transduction capabilities but also covalent bio-conjugation of BREs through the aldehyde group on the bridging ICA ligand in ZIF-90. Of particular note is the ZnO NWs array is an indispensable part of the hybrid nanostructure, since the in-situ growth of ZIF-90 and effective integration with layered MoS2 is still a challenge. Through the cooperation of three different kinds of building blocks, from signal generation, amplification to transduction could be achieved in an integrated nanoarchecture. Results and Discussion Figure 1a displays the scanning electron microscope (SEM) image of obtained ZIF-90-ZnO-MoS2 nanohybrid, from which the ordered NWs array is uniformly grown onto 2D MoS2 material. The higher magnification SEM (Figure 1b) and transmission electron microscopy (TEM) (Figure 1c) images show that the length and diameter of vertical ZnO NWs are 1.5 μm and 50 nm, respectively. Further high resolution TEM (HR-TEM) (Figure 1d) characterization demonstrates that the NWs are consisted of highly crystal ZnO core with the diameter of about 25 nm and ZIF-90 sheath with the thickness of about 12 nm. A FITC-labeled goat anti-human immunoglobulin G (IgG) is employed to verify our hypothesis. The inset of Figure 1e shows the fluorescence microscopy image of microelectrode immobilized with FITC-labeled goat anti-human IgG. It can be seen that only the region deposited with ZIF-90-ZnO-MoS2 nanohybrid visualizes green fluorescence. This result illustrates ZIF-90-ZnO-MoS2 nanohybrid possesses the capability of direct covalent bio-conjugation of antibody. And the results shown Figure 1e further confirm the developed hybrid material could effectively detect signaling protein. We next fabricated a microfluidic electrochemical microsensor chip, and the configuration is shown in Figure 1f. The microsensor chip is composed of a polydimethylsiloxane (PDMS) layer sealed with screen-printed electrodes. The microsensor is consisted of five electrodes, including counter electrode (CE), reference electrode (RE) and three different working electrodes. Among the three working electrodes, electrode 1 and 2 are locally deposited with fabricated ZIF-90-ZnO-MoS2 nanohybrid material as the test electrodes, and electrode 3 is printed with carbon conductive ink for the background signal deduction. The micro-channels on the chip are employed for the simultaneous immobilization of bio-recognition antibodies as well as dual detection of exosome markers (CD63 and CD9). From Figure 1g, our fabricated microsensor chip shows obvious response towards NCI-H 1650, and almost no signal for other cells supernatant (NCI-H 1650: human non-small cell lung cancer cells, 16 HBE: human bronchial epithelial cells, HFL-1: human fetal lung fibroblast-1 and HUVEC: human umbilical vein endothelial cells). Conclusion In summary, the ZIF-90-ZnO-MoS2 nanohybrid integrated with different kinds of building blocks realizes the cooperation of multi-function, including covalent bio-conjugation of antibodies, signal generation and transduction. To further combine with microfluidic electrochemical microsensor chip, the simultaneous immobilization of bio-recognition antibodies and dual detection of exosome markers can also be acquired. References [1] Cormac Sheridan, Nature Biotechnology 2016, 4, 359. [2] Varnika Yadav, Shounak Roy, Prem Singh, Ziyauddin Khan and Amit Jaiswal, Small 2019, 15, 1803706. Figure 1
Limited healthcare capacity highlights the needs of integrated and simple sensing systems for personalized health monitoring. However, only a limited set of sensors can be employed for point-of-care applications, emphasizing the lack of a generalizable engineering strategy for sensor construction. Here, we report a de novo rational engineering strategy for the construction of an integrated electrochemical liquid biopsy (ELB) platform capable of direct profiling cancer exosomes from blood. Using a bottom-up approach for sensor design, a series of critical sensing functions is considered and encoded into the material interface by programming the electrode material with different chemical and structure features. We present that the rationally engineered electrochemical liquid biopsy platform is able to achieve one-step sensor fabrication, target isolation, non-fouling and high-sensitivity sensing, direct signal transduction and multiplexed detection. Integrating the multiplexed sensing with principal component analysis, we demonstrate the capability of the programmed sensing system on differentiating cancerous groups from healthy controls by analyzing clinical samples from lung cancer patients.
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