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SERS probes in near-infrared windows for bioimaging

已有 1365 次阅读 2022-1-13 10:51 |系统分类:论文交流

Emergence of Surface-enhanced Raman Scattering (SERS) probes in near-infrared windows for biosensing and bioimaging

Hui Chena, b,【陈慧】, Ziyi Cheng a, b, 【程子译】, Xuejun Zhou a, b,【周学军】, Rui Wang a, b, *【王锐】, Fabiao Yu a, b, *【于法标】

a Key Laboratory of Hainan Trauma and Disaster Rescue, Laboratory of Neurology, The First Affiliated Hospital of Hainan Medical University, Hainan Medical University, Haikou 571199, China 

b Key Laboratory of Emergency and Trauma, Ministry of Education, Key Laboratory of Hainan Functional Materials and Molecular Imaging, College of Pharmacy, College of Emergency and Trauma, Hainan Medical University, Haikou 571199, China  

KEYWORDs: surface-enhanced Raman scattering (SERS), near-infrared windows, biosensing and bioimaging, diagnosis and therapy

Corresponding Author

*E-mail: wangrui@hainmc.edu.cn

*E-mail: yufabiao@hainmc.edu.cn

The authors declare no competing financial interest.

Author Contributions

‡These authors contributed equally. 

ABSTRACT: Since visible light (380-650 nm) incident on biological tissues is easily scattered and absorbed by surface tissues, it is not easy to penetrate deep tissues. Near-infrared (NIR, 650-1700 nm) light, known as ‘biological window/therapeutic window’, has attracted more and more attention due to its longer wavelength, less scattering and absorption to tissues, resulting in higher biological tissue penetration efficiency. The advent of NIR active surface enhanced Raman scattering (SERS) with ultrasensitive analytical capacity, manifests high specificity and sensitivity for biomedical analysis such as visualization of various intracellular biomolecules, disease diagnosis, image-guided surgical resection of the tumors and phototherapy. In this overview, we firstly summarize recent advances of different probe materials by evaluating the safety and efficacy of substrate materials and Raman reporters, then integrating different probe materials and probe functions to obtain optimized sensitivity and reproducibility for the detection of single-molecule level and subcellular imaging. Next, reviewing its application in visual detection and diagnosis in the pre-clinical and clinical biomedical field. Finally, we retrospect the SERS image-guided therapy in NIR region and discuss the related potential and challenges in the future.

The abnormal fluctuations of various biomarkers (such as intracellular nucleic acid, lipid, protein and pH, etc.) can be used as valuable diagnostic indicators for monitoring the physiological and pathological processes.1-4 Traditional detection and imaging methods often face various deficiencies and new challenges. Thus, the sensing and imaging techniques with properties of non-contact, real-time, deep tissue penetration and high spatial resolution are urgently needed, which can display intrinsic chemical components in tissues and provide useful information for biomedical applications. In the last decades, surface-enhanced Raman scattering (SERS) has received more and more attention owing to its ultrahigh sensitivity and non-invasiveness.5-7 As a powerful vibrational spectroscopic technique, SERS can provide useful information about chemical structure and surrounding environment with enhancement up to 1014-1015. Also, with very narrow peak width, usually a few tenths of the fluorescence peak width, SERS makes multiplexing target detection in single excitation light possible.8-9

Typical SERS detection can be simply divided into two types, namely direct detection without label and indirect method based on SERS labels.7, 10-12 The traditional SERS-based label-free detection can be realized through the direct interactions between the targets and the SERS-based nanostructure to obtain the vibrational spectrum information of the targets, which is limited to the complicated signal assignment, poor throughput, and limited sensitivity.7, 10 Indirect detection usually uses Raman reporter molecules to label the SERS substrates, and results in a strong SERS signal for analyte measurements, which overcomes the deficiencies encountered in the direct detection. The labeled SERS detection can obtain the intrinsic fingerprint signal of specific Raman reporter molecules, which significantly improves the stability of SERS probes and allows highly reproducible quantitative analysis of biomolecules in vitro and in vivo (Figure 1A).

The common SERS detection usually uses laser in the wavelength range of visible region (400-650 nm) as the excitation light. When applied to biological tissues, it produces a large amount of photon scattering and absorption, resulting in limited tissue penetration depth and significant interference from the tissue's autofluorescence.13-14 In order to overcome these difficulties, near-infrared (NIR) light in the two biological windows has gained much more interest for biosensing and in vivo imaging. NIR light can penetrate deep biological tissues compared to visible light owing to the less scattering and absorption at the longer wavelength light for the tissues. NIR window has been further divided into two regions, categorized as the first (650-900 nm) and the second (1000-1700 nm) NIR window.15 Accurate signal comes from efficient CCD detector. Within the spectral range of 900 nm, it is mainly defined by the silicon (Si) CCD detector, but its detection efficiency drops after 900 nm. Since the quantum efficiency of indium gallium arsenide (InGaAs) detector begins to increase dramatically after 1000 nm, the spectral boundary larger than 1000 nm is mainly defined by the InGaAs detector, both of which have low quantum efficiency in the range of 900-1000 nm (Figure 1B and 1C).16 Additionally, the selection of NIR window for SERS detection shows many advantages: (i) deep tissue penetration due to negligible absorption and low scattering in NIR; (ii) less tissue interference spontaneous fluorescence; (iii) minimal


Figure 1. (A) Schematic diagram of indirect SERS detection. In the figure (i), the biocompatible SERS nanoprobe combines reporter molecules on the substrate surface, binding targeted ligands under the protection of the peripheral coating. When the target molecule appears near the hot spot generated between two metal substrates, a significantly enhanced SERS signal can be obtained. In the figure (ii), when the reaction system environment changes, such as pH or temperature changes, SERS signal of the reporter molecule will change. (B) A schematic of the imaging setup for simultaneous detection of both NIR-I and NIR-II photons using Si and InGaAs cameras. (Reprinted from Adv. Drug Deliv. Rev., Vol. 65, Gong, H.; Peng, R.; Liu, Z. Carbon nanotubes for biomedical imaging: the recent advances, pp. 1951-1963 (ref 16). Copyright 2013, with permission from Elsevier.) (C) Sensitivity curves for typical cameras based on Si or InGaAs, which are sensitive in the first and second near-infrared windows, respectively. The excitation wavelengths at 785 nm and 1064 nm are indicated by vertical dotted lines. (D) Absorbance of oxygenated (red curve) and deoxygenated (blue curve) hemoglobin in the visible and NIR spectrum, together with water absorbance (black curve) at 1400-1500 nm. (E) Plots of the scattering attenuation coefficient as a function of wavelength for various ex vivo tissues (from top to bottom: green curve = brain tissue, yellow curve = intralipid tissue phantom, black curve = skin, brown curve = cranial bone, purple curve = mucous tissue, red curve = subcutaneous tissue, blue curve = muscle tissue). (Reprinted from Curr. Opin. Chem. Biol., Vol. 45, Lane, L. A.; Xue, R.; Nie, S. Emergence of two near-infrared windows for in vivo and intraoperative SERS, pp. 95-103 (ref 14). Copyright 2018, with permission from Elsevier.)


tissue damage (Figure 1D and 1E).16-17 These integrated advantages are suitable for biosensing and bioimaging in preclinical and clinical applications. Thus, when SERS probe was applied on active biosensor platform, it should be committed to using NIR light for excitation and low power value to prevent possible damage of living cells, and minimize the time of signal accumulation, so as to obtain accurate information of dynamic physiological and pathological process of living cells.

Although many impressive developments have been achieved on NIR SERS and its biomedical applications, Before NIR SERS is applied to practical clinical diagnosis, much efforts are needed to be devoted to improving the reliability and sensitivity of SERS detection in biological systems. The following key challenges need to be addressed, which enable SERS to address problems that other bioanalytical techniques cannot solve:

(1) Low detector efficiency in the NIR region and high cost of detector in the NIR II region;

(2) Difficulty in designing nanostructures with high SERS activity;

(3) Less Raman reporter molecules in NIR region, especially in NIR II region.

Herein, we focus on reviewing the most recent advances of NIR SERS probe in biosensing and bioimaging application. To guide the reader to better understand NIR SERS and its factors that may interfere the highly sensitive detection in biomedical applications, we first propose the key challenges to perform highly sensitive NIR SERS measurement including CCD detector and design of active NIR SERS probes. Thereafter, we introduce the fundamental design principle of NIR SERS for highly sensitive detection, covering active NIR SERS substrates, NIR Raman reporter molecules and surface encapsulation. Recently developed biosensing and bioimaging strategies in NIR biowindow, such as different molecules including nucleic acid, proteins, and small molecules, pathogens, and various biological processes, etc., are systematically reviewed. Through the innovative fabrication of NIR-active SERS probes and subsequent modification, various SERS imaging-guided therapy platforms are properly designed, demonstrating preferable in vitro and in vivo therapeutic performance. Finally, we conclude the future challenges and prospects of NIR-active SERS probes in both two near-infrared biowindows. This review aims to better understand NIR SERS biosensing and bioimaging and motivate their further clinical applications.