Applying two-dimensional (2D) materials in developing biosensors has transformed the biomedical field. This article covers the properties, applications, and challenges involved with the practical application of 2D materials-based biosensors.
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Introduction to 2D Materials-Based Biosensors
Biosensors are devices that detect and evaluate biochemical or biological processes using a very small probe and electrical, magnetic, or optical technology. Today's growing population has made biosensors the widely used electroanalytical devices for a range of medical applications.1
Recent advancements in biosensor technology have simplified its usage in medical diagnosis and biochemical investigations. Nowadays, 2D materials are widely used in the fabrication of biosensors.1
Two-dimensional (2D) materials such as black phosphorus, graphene, hexagonal boron nitride (h-BN), and transition metal dichalcogenides (TMDs) like molybdenum disulphide (MoS2), have nanoscale size and unique physical features that significantly improve biosensor performance.2
Properties and Characteristics of 2D Materials
2D materials are more effective at interacting with external stimuli because of their intrinsic openness and for device regulation compared to other materials. It is simpler to mechanically, electrically, magnetically and optically manipulate the material attributes in two-dimensional systems.1
These materials are also rich in active surface sites over a large surface area, which makes them ideal for biochemical sensing applications.3
Importantly, the 2D material family can exhibit a wide range of electrical characteristics, including metallic or semimetallic (e.g., graphene), semiconducting (e.g., black phosphorus), and insulating.
They also cover a wide spectrum of optical characteristics, such as plasmonic behavior and fluorescence emission or quenching. 2D materials can be engineered to respond precisely to certain analytes by altering their surface chemistry via functionalization/ defect engineering.4
This diverse set of characteristics, together with their layer-dependent band configuration and ability to create hetero-structures (by direct growth or transfer methods), make 2D materials an interesting class of materials for biosensor fabrication and healthcare applications.3
Design and Fabrication of Biosensors using 2D Materials
The design and manufacture of biosensors using 2D materials entails incorporating these materials into sensing platforms capable of detecting biological molecules of interest with exceptional specificity and sensitivity.
High-quality 2D materials for biosensor development are produced using various manufacturing techniques, including chemical vapor deposition (CVD), mechanical exfoliation, and solution-based approaches.5
CVD is often utilized to produce high-quality 2D materials. Carbon-based precursors are injected into a high-temperature furnace, where they react or decompose, depositing carbon on substrates like silicon oxide (SiO2), sapphire, or transition-metal copper (Cu) catalysts to generate single- or multi-layer 2D materials.5
Making biosensors with 2D materials generally entails selecting appropriate materials, preparing the substrate, depositing the 2D material, patterning, functionalizing the surface, incorporating a transduction mechanism, and assessing for performance.6
TMD-based biosensors, for example, take advantage of these materials' strong light-matter interaction to perform optical biosensing.7 After manufacturing, the biosensor is put through a detailed testing process to evaluate its selectivity, sensitivity, stability, and repeatability. This testing includes electrical measurements, SEM, and AFM.8
Applications of 2D Materials-Based Biosensors in the Biomedical Field
There are an increasing number of reports on the use of 2D material-based biosensors to detect metabolites (e.g. glucose, ascorbic acid), neurotransmitters (e.g. dopamine), inflammatory markers (reactive oxygen and nitrogen species, such as hydrogen peroxide), nucleic acids, proteins, heavy metals and bacterial cells.5
Skin monitoring is an essential application area for 2D materials-based biosensors. Research has shown that these sensors can be tailored and built to the exact application location on the skin, adhering tightly to the skin without affecting sensitivity over several hours.9
Electrical skin (e-skin), which aims to convert data acquired by human skin into signals, is an important component of 2D-based sensors. Researchers created a wearable continual blood pressure (BP) monitoring system with graphene electronic tattoos serving as human bio-electronic interfaces.9
This device provided a non-invasive, continuous recording of blood pressure with an accuracy of 0.2 ± 4.5 mmHg for diastolic and 0.2 ± 5.8 mmHg for systolic measurements. These graphene-based electronic tattoos can track arterial blood pressure for over 300 minutes, much longer than in earlier research.9
Detection of Cancer Markers
Optical sensors that use fluorescence enhancement or quenching, such as Förster resonance energy transfer (FRET), measure changes in fluorescence in the presence or absence of the targeted analyte in cancer diagnostics.5
Kong et al. developed a sensor for detecting prostate-specific antigen (PSA), a key sign for prostate cancer. The sensor used lithium (Li)-intercalated MoS2 nanosheets with a fluorescently modified single-stranded (ss) DNA probe affixed to the surface. Fluorescence was significantly suppressed when PSA was not present, but it was regenerated when PSA was added.10
The stated dynamic response range was from 0.5 to 300 ng/ml, with a linearity range of 0.5 to 60 ng/ml.10
They obtained a limit of detection of 0.2 ng/ml, and the approach was selective in the presence of prevalent interfering proteins such carcinoembryonic antigen (CEA). Given that PSA values above four ng/ml can suggest prostate cancer, this has important therapeutic implications.10
Neural Interfacing
Neural interfacing is a bidirectional flow of information that establishes a direct link between the brain and a readout system.3
Driscoll et al. designed a titanium carbide (Ti3C2) MXene-based sensor for neural applications. In rat experiments, these sensors outperformed gold (Au) electrodes in terms of background noise and signal quality.3,11
They also had greater signal-to-noise ratios and identified more distinct brain spikes. Cytotoxicity experiments revealed no substantial decrease in cell viability after a week, indicating biocompatibility.3
Challenges and Future Perspectives
Since 2004, there has been tremendous development in 2D material research, with an exponential growth in publication volume each year. Advancements in the synthesis, fabrication, processing, and final integration of two-dimensional devices are required before they may be widely used in healthcare applications.
A major difficulty is achieving affordable, controlled material synthesis to achieve large-scale homogeneity. Existing synthesis methods, such as CVD, provide issues for flexible substrates because of the high-temperature treatment requirements, which necessitate distinct growth and transfer stages.3
Environmental stability and biocompatibility are other key issues. In many cases, 2D materials must be exposed to complicated biological environments, which might compromise device performance over time. Therefore, understanding 2D material toxicity is critical for in vivo applications.12
2D platforms provide options for next-generation healthcare, including fitness tracking, augmented reality systems, and in-vitro diagnostics. Additional studies and collaborations are required to fully exploit the potential of 2D materials in customized medicine and biotechnology.
References and Further Reading:
1. Singh N, Dkhar DS, Chandra P, Azad UP. Nanobiosensors Design Using 2D Materials: Implementation in Infectious and Fatal Disease Diagnosis. Biosens 2023, Vol 13, Page 166. 2023;13(2):166. doi:10.3390/BIOS13020166
2. Ramezani G, Stiharu I, van de Ven TGM, Nerguizian V. Advancement in Biosensor Technologies of 2D MaterialIntegrated with Cellulose—Physical Properties. Micromachines. 2024;15(1). doi:10.3390/MI15010082
3. Bolotsky A, Butler D, Dong C, et al. Two-Dimensional Materials in Biosensing and Healthcare: From in Vitro Diagnostics to Optogenetics and beyond. ACS Nano. 2019;13(9):9781-9810. doi:10.1021/ACSNANO.9B03632/ASSET/IMAGES/LARGE/NN9B03632_0009.JPEG
4. Kalantar-Zadeh K, Ou JZ. Biosensors Based on Two-Dimensional MoS2. ACS Sensors. 2016;1(1):5-16. doi:10.1021/ACSSENSORS.5B00142/ASSET/IMAGES/MEDIUM/SE-2015-00142C_0007.GIF
5. 2D Materials Matter: A Perspective on Biosensing Applications. https://www.sigmaaldrich.com/IN/en/technical-documents/technical-article/materials-science-and-engineering/bioelectronics/2d-biosensing. Accessed March 8, 2024.
6. Sulleiro MV, Dominguez-Alfaro A, Alegret N, Silvestri A, Gómez IJ. 2D Materials towards sensing technology: From fundamentals to applications. Sens Bio-Sensing Res. 2022;38:100540. doi:10.1016/J.SBSR.2022.100540
7. Negm A, Howlader MMR, Belyakov I, et al. Materials Perspectives of Integrated Plasmonic Biosensors. Materials (Basel). 2022;15(20). doi:10.3390/MA15207289
8. Deepa C, Rajeshkumar L, Ramesh M. Preparation, synthesis, properties and characterization of graphene-based 2D nano-materials for biosensors and bioelectronics. J Mater Res Technol. 2022;19:2657-2694. doi:10.1016/J.JMRT.2022.06.023
9. Wang Y, Li T, Li Y, Yang R, Zhang G. 2D-Materials-Based Wearable Biosensor Systems. Biosens 2022, Vol 12, Page 936. 2022;12(11):936. doi:10.3390/BIOS12110936
10. Kong RM, Ding L, Wang Z, You J, Qu F. A novel aptamer-functionalized MoS2 nanosheet fluorescent biosensor for sensitive detection of prostate specific antigen. Anal Bioanal Chem. 2015;407(2):369-377. doi:10.1007/S00216-014-8267-9/METRICS
11. Driscoll N, Richardson AG, Maleski K, et al. Two-Dimensional Ti3C2 MXene for High-Resolution Neural Interfaces. ACS Nano. 2018;12(10):10419. doi:10.1021/ACSNANO.8B06014
12. Kurapati R, Kostarelos K, Prato M, Bianco A. Biomedical Uses for 2D Materials Beyond Graphene: Current Advances and Challenges Ahead. Adv Mater. 2016;28(29):6052-6074. doi:10.1002/ADMA.201506306
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