Development of Specialized Microelectrode Arrays with Local Electroporation Functionality.

When a cell or tissue is exposed to a pulsed electric field (100-1000 V/cm), the cellular membrane permeabilizes for biomolecules that cannot pass an intact cellular membrane. During this electropermeabilization (EP), plasmid deoxyribonucleic acid sequences encoding therapeutic or regulatory genes can enter the cell, which is called gene electrotransfer (GET). GET using micro-/nano technology provides higher spatial resolution and operates with lower voltage amplitudes compared to conventional bulk EP. Microelectrode arrays (MEAs), which are usually used for the recording and stimulation of neuronal signals, can be utilized for GET as well. In this study, we developed a specialized MEA for local EP of adherent cells. Our manufacturing process provides a most flexible electrode and substrate material selection. We used electrochemical impedance spectroscopy to characterize the impedance of the MEAs and the impact of an adherent cellular layer. We verified the local EP functionality of the MEAs by loading a fluorophore dye into human embryonic kidney 293T cells. Finally, we demonstrated a GET with a subsequent green fluorescent protein expression by the cells. Our experiments prove that a high spatial resolution of GET can be obtained using MEAs.

Universal protocol for the wafer-scale manufacturing of 2D carbon-based transducer layers for versatile biosensor applications.

In this manuscript, we present a comprehensive fabrication protocol for high-performance graphene oxide (GO) sensor concepts. It is suitable for a variety of biosensing applications and contains the essential process steps, starting with vapor phase evaporation for siloxane monolayers, followed by spin-coating of GO as a nanometer-thin transducer with exceptional homogeneity and micromechanical surface methods which enable seamless transformation of GO transducers to be desired micro and nano dimensions. In addition to linking basic research and innovative sensor concepts with an outlook for commercial applications of point-of-care systems for early-stage diagnostics, the authors consider it necessary to take a closer look at the manufacturing processes to create more transparency and clarity, to manufacture such specific sensor concepts systematically. The detailed manufacturing approaches are intended to motivate practitioner to explore and improve this GO-based key technology. This process development is illustrated below using the manufacturing methods for three types of sensors, namely sensors based on i) surface plasmon resonance spectroscopy (SPR), ii) impedance spectroscopy and iii) bio-field effect transistors (ISFETs). The obtained results in this work prove successful GO sensor productions by achieving:•Uniform and stable immobilization of GO thin films,•High yield of sensor units on a wafer scale, here up to 96 %,•Promising integration potential for various biomedical sensor concepts to early-stage diagnostic.

AI-enabled epidermal electronic system to automatically monitor a prognostic parameter for hypertension with a smartphone.

We present a wearable, flexible, wireless and smartphone-enabled epidermal electronic system (EES) for the continuous monitoring of a prognostic parameter for hypertension. The thin and lightweight EES can be tightly attached to the chest of a patient and synchronously monitor first lead electrocardiograms (ECG) and seismocardiograms (SCG). To demonstrate the concept, we developed the EES using state-of-the-art cleanroom technologies. Two types of sensors were integrated: A pair of metal electrodes to contact the skin and to record ECG and a vibration sensor based on a thin piezoelectric polymer to record SCG from the same location of the chest, simultaneously. The complete EES was powered by the near field communication functionality of the smartphone. We developed a machine-learning algorithm and trained it on public ECG data and recorded SCG signals to extract characteristic features of the recordings. Binary classifiers were used to automatically annotate peaks. After training, the algorithm was transferred to the smartphone to continuously analyze the timing between particular ECG and SCG peaks and to extract the Weissler's index as a prognostic parameter for hypertension. Tests with data of healthy control persons and clinical experiments with patients diagnosed with cardio-pulmonary hypertension showed a promising prognostic performance. The presented EES technology could be utilized for pre-screening of cardio-pulmonary hypertension, which is a strong burden in our today's healthcare system.

Lock-in photothermal method for in-plane thermal diffusivity measurements using arrayed temperature sensors on suspended SiNx membranes.

A device consisting of a line- or spiral-shaped temperature sensor array on a two-dimensional (2D) silicon nitride (SiNx) membrane of thickness 50 or 150 nm is developed for use in the lock-in photothermal method to determine the in-plane thermal diffusivity of SiNx membranes in air and in vacuum. The results of 2D heat diffusion are analyzed by the quadrupole method, and the system is approximated to the one-dimensional (1D) fin standing in a surrounding media (the fin approximation). The results show that 2D thermal diffusion on the membrane is affected not only by heat exchange with the surrounding environment but also by parallel thermal diffusion caused by heat conduction in the air along the membrane surface. The measurement using photothermal heating and contact detection of the temperature response enables the phenomenon to be detected consistently at a wide frequency range of temperature waves (50-1000 Hz). The measured thermal diffusivity values of the SiNx membrane are much smaller than those of bulk material, which can be reasonably considered an effect of the confined state of the phonon in the nanoscale geometry of the membrane.

A Combined Plasmonic and Electrochemical Aptasensor Based on Gold Nanopit Arrays for the Detection of Human Serum Albumin.

Electrochemical and optical platforms are commonly employed in designing biosensors. However, one signal readout can easily lead to inaccuracies due to the effect of nonstandard test procedures, different operators, and experimental environments. We have developed a dual-signal protocol that combined two transducer principles in one aptamer-based biosensor by simultaneously performing electrochemical- and extraordinary optical transmission (EOT)-based plasmonic detection using gold nanopit arrays (AuNpA). Compared with full hole structures, we found that nanopits, that did not fully penetrate the gold film, not only exhibited a better plasmonic bandwidth and refractive index sensitivity both in the finite-difference time-domain simulation and in experiments by shielding the gold/quartz mode but also enlarged the electrochemical active surface area. Therefore, the periodic non-fully penetrating AuNpA were modified with ferrocene-labeled human serum albumin aptamer receptors. The formation of the receptor layer and human serum albumin binding complex induced a conformational change, which resulted in variation in the electron transfer between the electro-active ferrocene units and the AuNpA surface. Simultaneously, the binding event caused a surface plasmon polaritons wavelength shift corresponding to a change in the surface refractive index. Interestingly, although both transducers recorded the same binding process, they led to different limits of detection, dynamic ranges, and sensitivities. The electrochemical transducer showed a dynamic detection range from 1 nM to 600 µM, while the optical transducer covered high concentrations from 100 µM to 600 µM. This study not only provides new insights into the design of plasmonic nanostructures but also potentially opens an exciting avenue for dual-signal disease diagnosis and point-of-care testing applications.

Toward the Next Generation of Neural Iontronic Interfaces.

Neural interfaces are evolving at a rapid pace owing to advances in material science and fabrication, reduced cost of scalable complementary metal oxide semiconductor (CMOS) technologies, and highly interdisciplinary teams of researchers and engineers that span a large range from basic to applied and clinical sciences. This study outlines currently established technologies, defined as instruments and biological study systems that are routinely used in neuroscientific research. After identifying the shortcomings of current technologies, such as a lack of biocompatibility, topological optimization, low bandwidth, and lack of transparency, it maps out promising directions along which progress should be made to achieve the next generation of symbiotic and intelligent neural interfaces. Lastly, it proposes novel applications that can be achieved by these developments, ranging from the understanding and reproduction of synaptic learning to live-long multimodal measurements to monitor and treat various neuronal disorders.

Transformative Materials to Create 3D Functional Human Tissue Models In Vitro in a Reproducible Manner.

Recreating human tissues and organs in the petri dish to establish models as tools in biomedical sciences has gained momentum. These models can provide insight into mechanisms of human physiology, disease onset, and progression, and improve drug target validation, as well as the development of new medical therapeutics. Transformative materials play an important role in this evolution, as they can be programmed to direct cell behavior and fate by controlling the activity of bioactive molecules and material properties. Using nature as an inspiration, scientists are creating materials that incorporate specific biological processes observed during human organogenesis and tissue regeneration. This article presents the reader with state-of-the-art developments in the field of in vitro tissue engineering and the challenges related to the design, production, and translation of these transformative materials. Advances regarding (stem) cell sources, expansion, and differentiation, and how novel responsive materials, automated and large-scale fabrication processes, culture conditions, in situ monitoring systems, and computer simulations are required to create functional human tissue models that are relevant and efficient for drug discovery, are described. This paper illustrates how these different technologies need to converge to generate in vitro life-like human tissue models that provide a platform to answer health-based scientific questions.

A sigh-performance hydrogen gas sensor based on Ag/Pd nanoparticle-functionalized ZnO nanoplates.

As a source of clean energy, hydrogen (H2) is a promising alternative to fossil fuels in reducing the carbon footprint. However, due to the highly explosive nature of H2, developing a high-performance sensor for real-time detection of H2 gas at low concentration is essential. Here, we demonstrated the H2 gas sensing performance of Ag/Pd nanoparticle-functionalized ZnO nanoplates. Bimetallic Ag/Pd nanoparticles with an average size of 8 nm were prepared and decorated on the surface of ZnO nanoplates to enhance the H2 gas sensing performance. Compared with pristine ZnO, the sensor based on ZnO nanoplate doped with Ag/Pd (0.025 wt%) exhibited an outstanding response upon exposure to H2 gas (R a/R g = 78 for 500 ppm) with fast response time and speedy recovery. The sensor also showed excellent selectivity for the detection of H2 over the interfering gases (i.e., CO, NH3, H2S, and VOCs). The superior gas sensing of the sensor was dominated by the morphological structure of ZnO, and the synergistic effect of strong adsorption and the optimum catalytic characteristics of the bimetallic Ag/Pd enhances the hydrogen response of the sensors. Thus, bimetallic Ag/Pd-doped ZnO is a promising sensing material for the quantitative determination of H2 concentration towards industrial applications.

Direct measurement of oxygen reduction reactions at neurostimulation electrodes.

Objective. Electric stimulation delivered by implantable electrodes is a key component of neural engineering. While factors affecting long-term stability, safety, and biocompatibility are a topic of continuous investigation, a widely-accepted principle is that charge injection should be reversible, with no net electrochemical products forming. We want to evaluate oxygen reduction reactions (ORR) occurring at different electrode materials when using established materials and stimulation protocols.Approach. As stimulation electrodes, we have tested platinum, gold, tungsten, nichrome, iridium oxide, titanium, titanium nitride, and poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate). We use cyclic voltammetry and voltage-step amperometry in oxygenated versus inert conditions to establish at which potentials ORR occurs, and the magnitudes of diffusion-limited ORR currents. We also benchmark the areal capacitance of each electrode material. We use amperometric probes (Clark-type electrodes) to quantify the O2and H2O2concentrations in the vicinity of the electrode surface. O2and H2O2concentrations are measured while applying DC current, or various biphasic charge-balanced pulses of amplitude in the range 10-30µC cm-2/phase. To corroborate experimental measurements, we employ finite element modelling to recreate 3D gradients of O2and H2O2.Main results. All electrode materials support ORR and can create hypoxic conditions near the electrode surface. We find that electrode materials differ significantly in their onset potentials for ORR, and in the extent to which they produce H2O2as a by-product. A key result is that typical charge-balanced biphasic pulse protocols do lead to irreversible ORR. Some electrodes induce severely hypoxic conditions, others additionally produce an accumulation of hydrogen peroxide into the mM range.Significance. Our findings highlight faradaic ORR as a critical consideration for neural interface devices and show that the established biphasic/charge-balanced approach does not prevent irreversible changes in O2concentrations. Hypoxia and H2O2can result in different (electro)physiological consequences.

Realization of a PEDOT:PSS/Graphene Oxide On-Chip Pseudo-Reference Electrode for Integrated ISFETs.

A stable reference electrode (RE) plays a crucial role in the performance of an ion-sensitive field-effect transistor (ISFET) for bio/chemical sensing applications. There is a strong demand for the miniaturization of the RE for integrated sensor systems such as lab-on-a-chip (LoC) or point-of-care (PoC) applications. Out of several approaches presented so far to integrate an on-chip electrode, there exist critical limitations such as the effect of analyte composition on the electrode potential and drifts during the measurements. In this paper, we present a micro-scale solid-state pseudo-reference electrode (pRE) based on poly(3,4-ethylene dioxythiophene): poly(styrene sulfonic acid) (PEDOT:PSS) coated with graphene oxide (GO) to deploy with an ion-sensitive field-effect transistor (ISFET)-based sensor platform. The PEDOT:PSS was electropolymerized from its monomer on a micro size gold (Au) electrode and, subsequently, a thin GO layer was deposited on top. The stability of the electrical potential and the cross-sensitivity to the ionic strength of the electrolyte were investigated. The presented pRE exhibits a highly stable open circuit potential (OCP) for up to 10 h with a minimal drift of ~0.65 mV/h and low cross-sensitivity to the ionic strength of the electrolyte. pH measurements were performed using silicon nanowire field-effect transistors (SiNW-FETs), using the developed pRE to ensure good gating performance of electrolyte-gated FETs. The impact of ionic strength was investigated by measuring the transfer characteristic of a SiNW-FET in two electrolytes with different ionic strengths (1 mM and 100 mM) but the same pH. The performance of the PEDOT:PSS/GO electrode is similar to a commercial electrochemical Ag/AgCl reference electrode.

Delineating charge and capacitance transduction in system-integrated graphene-based BioFETs used as aptasensors for malaria detection.

Despite significant eradication efforts, malaria remains a persistent infectious disease with high mortality due to the lack of efficient point-of-care (PoC) screening solutions required to manage low-density asymptomatic parasitemia. In response, we demonstrate a quantitative electrical biosensor based on system-integrated two-dimensional field-effect transistors (2DBioFETs) of reduced graphene oxide (rGO) as transducer for high sensitivity screening of the main malaria biomarker, Plasmodium falciparum lactate dehydrogenase (PfLDH). The 2DBioFETs were biofunctionalized with pyrene-modified 2008s aptamers as specific PfLDH receptors. While we systematically optimize biosensor interface for optimal performance, aptamer-protein transduction at 2DBioFETs is elucidated based on delineation of charge and capacitance in an updated analytical model for two-dimensional rGO/biofunctional layer/electrolyte (2DiBLE) interfaces. Our 2DBioFET-aptasensors display a limit-of-detection down to 0.78 fM (0.11 pg/mL), dynamic ranges over 9 orders of magnitude (subfemto to submicromolar), high sensitivity, and selectivity in human serum validating their diagnostic potential as rapid PoC tests for malarial management.

The antioxidant Rutin counteracts the pathological impact of α-synuclein on the enteric nervous system in vitro.

Motoric disturbances in Parkinson's disease (PD) derive from the loss of dopaminergic neurons in the substantia nigra. Intestinal dysfunctions often appear long before manifestation of neuronal symptoms, suggesting a strong correlation between gut and brain in PD. Oxidative stress is a key player in neurodegeneration causing neuronal cell death. Using natural antioxidative flavonoids like Rutin, might provide intervening strategies to improve PD pathogenesis. To explore the potential effects of micro (mRutin) compared to nano Rutin (nRutin) upon the brain and the gut during PD, its neuroprotective effects were assessed using an in vitro PD model. Our results demonstrated that Rutin inhibited the neurotoxicity induced by A53T α-synuclein (Syn) administration by decreasing oxidized lipids and increasing cell viability in both, mesencephalic and enteric cells. For enteric cells, neurite outgrowth, number of synaptic vesicles, and tyrosine hydroxylase positive cells were significantly reduced when treated with Syn. This could be reversed by the addition of Rutin. nRutin revealed a more pronounced result in all experiments. In conclusion, our study shows that Rutin, especially the nanocrystals, are promising natural compounds to protect neurons from cell death and oxidative stress during PD. Early intake of Rutin may provide a realizable option to prevent or slow PD pathogenesis.

Process Variability in Top-Down Fabrication of Silicon Nanowire-Based Biosensor Arrays.

Silicon nanowire field-effect transistors (SiNW-FET) have been studied as ultra-high sensitive sensors for the detection of biomolecules, metal ions, gas molecules and as an interface for biological systems due to their remarkable electronic properties. "Bottom-up" or "top-down" approaches that are used for the fabrication of SiNW-FET sensors have their respective limitations in terms of technology development. The "bottom-up" approach allows the synthesis of silicon nanowires (SiNW) in the range from a few nm to hundreds of nm in diameter. However, it is technologically challenging to realize reproducible bottom-up devices on a large scale for clinical biosensing applications. The top-down approach involves state-of-the-art lithography and nanofabrication techniques to cast SiNW down to a few 10s of nanometers in diameter out of high-quality Silicon-on-Insulator (SOI) wafers in a controlled environment, enabling the large-scale fabrication of sensors for a myriad of applications. The possibility of their wafer-scale integration in standard semiconductor processes makes SiNW-FETs one of the most promising candidates for the next generation of biosensor platforms for applications in healthcare and medicine. Although advanced fabrication techniques are employed for fabricating SiNW, the sensor-to-sensor variation in the fabrication processes is one of the limiting factors for a large-scale production towards commercial applications. To provide a detailed overview of the technical aspects responsible for this sensor-to-sensor variation, we critically review and discuss the fundamental aspects that could lead to such a sensor-to-sensor variation, focusing on fabrication parameters and processes described in the state-of-the-art literature. Furthermore, we discuss the impact of functionalization aspects, surface modification, and system integration of the SiNW-FET biosensors on post-fabrication-induced sensor-to-sensor variations for biosensing experiments.

Dry Film Resist Laminated Microfluidic System for Electrical Impedance Measurements.

In micro-electrical-mechanical systems (MEMS), thick structures with high aspect ratios are often required. Dry film photoresist (DFR) in various thicknesses can be easily laminated and patterned using standard UV lithography. Here, we present a three-level DFR lamination process of SUEX for a microfluidic chip with embedded, vertically arranged microelectrodes for electrical impedance measurements. To trap and fix the object under test to the electrodes, an aperture is formed in the center of the ring-shaped electrodes in combination with a microfluidic suction channel underneath. In a proof-of-concept, the setup is characterized by electrical impedance measurements with polystyrene and ZrO2 spheres. The electrical impedance is most sensitive at approximately 2 kHz, and its magnitudes reveal around 200% higher values when a sphere is trapped. The magnitude values depend on the sizes of the spheres. Electrical equivalent circuits are applied to simulate the experimental results with a close match.

PEDOT:PSS-Based Bioelectronic Devices for Recording and Modulation of Electrophysiological and Biochemical Cell Signals.

To understand the physiology and pathology of electrogenic cells and the corresponding tissue in their full complexity, the quantitative investigation of the transmission of ions as well as the release of chemical signals is important. Organic (semi-) conducting materials and in particular organic electrochemical transistor are gaining in importance for the investigation of electrophysiological and recently biochemical signals due to their synthetic nature and thus chemical diversity and modifiability, their biocompatible and compliant properties, as well as their mixed electronic and ionic conductivity featuring ion-to-electron conversion. Here, the aim is to summarize recent progress on the development of bioelectronic devices utilizing polymer polyethylenedioxythiophene: poly(styrene sulfonate) (PEDOT:PSS) to interface electronics and biological matter including microelectrode arrays, neural cuff electrodes, organic electrochemical transistors, PEDOT:PSS-based biosensors, and organic electronic ion pumps. Finally, progress in the material development is summarized for the improvement of polymer conductivity, stretchability, higher transistor transconductance, or to extend their field of application such as cation sensing or metabolite recognition. This survey of recent trends in PEDOT:PSS electrophysiological sensors highlights the potential of this multifunctional material to revolve current technology and to enable long-lasting, multichannel polymer probes for simultaneous recordings of electrophysiological and biochemical signals from electrogenic cells.

PEDOT:PSS organic electrochemical transistors for electrical cell-substrate impedance sensing down to single cells.

The adhesion of cells on organic electrochemical transistors (OECT) is investigated down to a single cell resolution using an impedimetric readout method of the transistors. For this purpose a fabrication protocol for micro-sized OECTs based on Poly(3,4-ethylenedioxythiophene):poly(styrene sulfonic acid) (PEDOT:PSS) was developed. OECTs with gate dimensions of 20 µm × 20 µm with cut-off frequencies up to 10 kHz at -3 dB were fabricated. Impedance spectra of the OECTs changed drastically when HEK 293 cells were adhered to the OECT gates. To confirm the single-cell sensitivity, individual cells were removed from the device surface with patch-clamp pipettes while impedance measurements were performed. In addition, the calcium chelator EGTA was used to demonstrate the reproducible activation and deactivation of tight gap junctions in Madin Darby Canine Kidney cells adhered on the OECT gates. We applied an analytical mathematical model combined with an electrically equivalent circuit model to describe the measured impedance spectra and to calculate the cell-related parameters of the adherent cells. The novel technique of impedimetric readout of OECTs for the detection of single cell adhesion offers various future applications.

Sensitive impedimetric detection of troponin I with metal-organic framework composite electrode.

Metal-organic frameworks (MOFs) are promising materials for biosensing applications due to their large surface to volume ratio, easy assembly as thin films, and better biocompatibility than other nanomaterials. Their application in electrochemical biosensing devices can be realized by integrating them with other conducting materials, like polyaniline (PANI). In the present research, a composite of a copper-MOF (i.e., Cu3(BTC)2) with PANI has been explored to develop an impedimetric sensor for cardiac marker troponin I (cTnI). The solvothermally synthesized Cu3(BTC)2/PANI composite has been coated as a thin layer on the screen-printed carbon electrodes (SPE). This electroconductive thin film was conjugated with anti-cTnI antibodies. The above formed immunosensor has allowed the impedimetric detection of cTnI antigen over a clinically important concentration range of 1-400 ng mL-1. The whole process of antigen analysis could be completed within 5 min. The detection method was specific to cTnI even in the co-presence of other possibly interfering proteins.

Point-of-care-ready nanoscale ISFET arrays for sub-picomolar detection of cytokines in cell cultures.

Rapid and frequent screening of cytokines as immunomodulation agents is necessary for precise interventions in severe pathophysiological conditions. In addition to high-sensitivity detection of such analytes in complex biological fluids such as blood, saliva, and cell culture medium samples, it is also crucial to work out miniaturized bioanalytical platforms with potential for high-density integration enabling screening of multiple analytes. In this work, we show a compact, point-of-care-ready bioanalytical platform for screening of cytokines such as interleukin-4 (IL-4) and interleukin-2 (IL-2) based on one-dimensional ion-sensitive field-effect transistors arrays (nanoISFETs) of silicon fabricated at wafer-scale via nanoimprint lithography. The nanoISFETs biofunctionalized with receptor proteins alpha IL-4 and alpha IL-2 were deployed for screening cytokine secretion in mouse T helper cell differentiation culture media, respectively. Our nanoISFETs showed robust sensor signals for specific molecular binding and can be readily deployed for real-time screening of cytokines. Quantitative analyses of the nanoISFET-based bioanalytical platform was carried out for IL-4 concentrations ranging from 25 fg/mL (1.92 fM) to 2.5 µg/mL (192 nM), showing a limit of detection down to 3-5 fM, which was found to be in agreement with ELISA results in determining IL-4 concentrations directly in complex cell culture media. Graphical abstract.

Comprehensive Understanding of Silicon-Nanowire Field-Effect Transistor Impedimetric Readout for Biomolecular Sensing.

Impedance sensing with silicon nanowire field-effect transistors (SiNW-FETs) shows considerable potential for label-free detection of biomolecules. With this technique, it might be possible to overcome the Debye-screening limitation, a major problem of the classical potentiometric readout. We employed an electronic circuit model in Simulation Program with Integrated Circuit Emphasis (SPICE) for SiNW-FETs to perform impedimetric measurements through SPICE simulations and quantitatively evaluate influences of various device parameters to the transfer function of the devices. Furthermore, we investigated how biomolecule binding to the surface of SiNW-FETs is influencing the impedance spectra. Based on mathematical analysis and simulation results, we proposed methods that could improve the impedimetric readout of SiNW-FET biosensors and make it more explicable.

Photothermal effects induced by surface plasmon resonance at graphene/gold nanointerfaces: A multiscale modeling study.

Surface plasmon resonance (SPR) biosensors have enormous potential in biological recognitions and biomolecular interactions, especially for the real time measurement of disease diagnosis and drug screening. Extensive efforts have been invested to ameliorate the sensing performances, while the photothermal effects, which are induced by the plasmon resonance, have an obvious impact. However, due to the limitations of experimental approaches, the theoretical mechanisms and specific influences of the SPR sensors with photothermal effects are few researched. Here, a multiscale simulation method is developed to investigate the photothermal effects at graphene/gold (Au) nanointerfaces, and to calculate the quantitative contribution of the photothermal effects towards high reliability SPR sensors in order to elucidate their influence on the sensing performances by means of first-principle calculations and molecular dynamics simulations. Our results indicate that the sensitivity and detection accuracy of graphene/Au SPR sensors can be tailored from 0 K to 600 K, due to the tunable dielectric constants of Au and graphene films through temperature variation. By controlling the its material thickness, interfacial combination and lattice strain, an optimized graphene/Au SPR sensor with higher sensitivity, detection accuracy, and reliability to the temperature rising has been achieved. Such multiscale simulation method, which is capable of seeking both the role and the underlying mechanism of the interfacial phenomena, can serve as an excellent guideline for the performance optimization and commercialized application of SPR sensors in the analytical chemistry and biomedical fields.