Current Trends of Raman Spectroscopy in Clinic Settings: Opportunities and Challenges

Abstract

Early clinical diagnosis, effective intraoperative guidance, and an accurate prognosis can lead to timely and effective medical treatment. The current conventional clinical methods have several limitations. Therefore, there is a need to develop faster and more reliable clinical detection, treatment, and monitoring methods to enhance their clinical applications. Raman spectroscopy is noninvasive and provides highly specific information about the molecular structure and biochemical composition of analytes in a rapid and accurate manner. It has a wide range of applications in biomedicine, materials, and clinical settings. This review primarily focuses on the application of Raman spectroscopy in clinical medicine. The advantages and limitations of Raman spectroscopy over traditional clinical methods are discussed. In addition, the advantages of combining Raman spectroscopy with machine learning, nanoparticles, and probes are demonstrated, thereby extending its applicability to different clinical phases. Examples of the clinical applications of Raman spectroscopy over the last 3 years are also integrated. Finally, various prospective approaches based on Raman spectroscopy in clinical studies are surveyed, and current challenges are discussed.

Keywords: Raman spectroscopy; biomarkers; clinic settings; clinical diagnosis; detection.

Figure 1

Application of Raman spectroscopy in clinical medicine, with respect to various common diseases.

Figure 2

Schematics of different enhancement methods for Raman signal. a) Schematic of the preparation principle of SERS with Au or Ag hybrids based on porous GaN and the utilization of the method for miRNA detection.^{[ 138 ]} Copyright 2023, Elsevier. b) Seed‐mediated growth of Ag pillar and the utilization of the method for miRNA detection.^{[ 40 ]} Copyright 2023, Elsevier. c) 3D schematic of SERS substrate preparation.^{[ 41 ]} Copyright 2023, John Wiley and Sons. d) The preparation process of SERS with alternating metal–insulator–metal layer.^{[ 42 ]} Copyright 2023, John Wiley and Sons.

Figure 3

Structure and action process of TiO2 microporous reverse opal coated with 3D Au. The interaction with the laser sample in SERS enhanced the Raman signal.^{[ 37 ]} Copyright 2020, American Chemical Society.

Figure 4

Schematic and parameter representation of the improved LENET‐5 model and results of training and testing using the model. a) Improved mode and calculation. b) Quintuple crossover and verification results of the CNN model in the improved Lenet‐5 Raman spectrum processing model.^{[ 48 ]} Copyright 2021, Wiley‐VCH.

Figure 5

Schematic of data acquisition and machine learning. a) Working flow diagram after combining Raman spectroscopy with machine learning, in which staining TMAs can be used to guide the process of Raman microscope spectral measurement. b) The orange part represents the predicted results in the test set.^{[ 50 ]} Copyright 2021, Journal of Biomedical Optics.

Figure 6

a) In vitro clinical sample testing using this method. b) The method is used to detect pig brain samples. c) Different widths of the stripe space resolution and spatial resolution. d) Objectives of the bright field images and ellipse fitting of laser spot indicator display position information, where the red line is used for imaging the ROI. e) Raman‐enhanced images were displayed by moving the probe at different speeds with five digits, representing white line contour analysis. f,h) Under a speed of 2 mm s⁻¹ and the diameter of the reconstructed molecular images combined with the actual Raman image, the white line. i) Details of the ROI. j) The blue path represents Raman‐enhanced images, the black fill represents the paracetamol's actual area, and fill in the blank with paracetamol k) indicated in black.^{[ 61 ]} Copyright 2022, Springer Nature.

Figure 7

a) Schematic of the optical core probe.^{[ 73 ]} Copyright 2018, Springer Nature. b) Inset of tumor margins, as captured by a handheld Raman scanner.^{[ 75 ]} Copyright 2023, Springer Nature. c) Peripheral Raman probe after tumor detection using a handheld Raman scanner.^{[ 76 ]} Copyright 2023, John Wiley and Sons. d) Imaging contrast diagram.^{[ 77 ]} Copyright 2019, Theranostics. e) Resection of brain tumors performed in a mouse model.^{[ 74 ]} Copyright 2019, American Chemical Society.

Figure 8

a) Schematic of optical fiber and endoscopic system imaging.^{[ 81 ]} Copyright 2015, Springer Nature. b) Schematic of Raman spectrum imaging during colonoscopy.^{[ 82 ]} Copyright 2015, Plos One. c) Schematic of the esophageal tumor model and endoscopic imaging detection in a rat model.^{[ 83 ]} Copyright 2015, Optical Society of America. d) Schematic of the spectrum and integrated endoscope system obtained by optical imaging Raman spectrum.^{[ 84 ]} Copyright 2021, Elsevier.

Figure 9

a) Schematic of different types of probes.^{[ 87} , ^{88 ]} Copyright 2020, Analyst, Copyright 2020, Springer Nature and b) FRNP formation and testing using optimized protocols in mouse models.^{[ 89 ]} Copyright 2019, Springer Nature.

Figure 10

a) Schematic of the structure of the starPART probe and the surgical treatment process using the probe.^{[ 98 ]} Copyright 2023, American Chemical Society. b) Similar to (a), the schematic of the synthesis of Au@Cu₂ XS‐FA NPs and the imaging treatment process in the mouse model.^{[ 99 ]} Copyright 2023, John Wiley and Sons. c) Schematic of the synthesis for the functional nanoprobe and the operating principle of the nanoprobe to detect oxygen levels in cancer cells.^{[ 100 ]} Copyright 2023, John Wiley and Sons.

Figure 11

Approximate size range of biological structures and the research status and hotspots of exosomes in diseases. a) Size range of different biological structures.^{[ 103 ]} Copyright 2023, Springer Nature. b) The proportion of diagnoses of different diseases in exosome‐based clinical trials registered on clinicaltrials.gov. c) Exosomes as markers of clinical diagnosis and treatment have increased from 1980 onward, and their popularity has increased in recent years.^{[ 104 ]} Copyright 2021, Elsevier.

Figure 12

Tumor markers. a) Types of tumor markers include proteins, circulating nucleic acids (NAs), exosomes, and circulating tumor cells (CTCs). b) Exosome formation, extraction, and surface‐enhanced Raman detection.^{[ 105 ]} Copyright 2023, Elsevier.

Figure 13

a) Schematic of the formation of surface‐enhanced NPs with an intermediate layer of 4‐MB.^{[ 199 ]} Copyright 2023, Journal of Materials Chemistry B. b) Formed NPs bound to aromatic amino acids. c) Action process of this NP mixture in a mouse model.^{[ 200} , ^{201 ]} Copyright 2019, American Chemical Society, Copyright 2016, Elsevier.

Figure 14

Diagnosis of breast cancer using serum albumin detection. a) Purification and extraction of serum albumin by adsorption of HAP.^{[ 201 ]} Copyright 2023, John Wiley and Sons. b) Extraction and purification of serum albumin using a cellulose acetate membrane (CA). c) Effect of HPA on serum albumin under a scanning electron microscope. d) Raman signal is strongest when Ag NPs are 417 nm. e) The TEM imaging of Ag NPs.^{[ 202 ]} Copyright 2023, Elsevier.

Figure 15

a) Schematic of the immune analysis process, sandwich immune analysis, and SERS in vitro detection of AR‐V7 protein in serum.^{[ 235 ]} Copyright 2022, American Chemical Society. b) Preparation process of the plasma sensor, schematic of PSA detection, and detected Raman spectrum.^{[ 224 ]} Copyright 2023, Elsevier. c) Schematic of the miRNA detection in urine using 3D SERS.^{[ 234 ]} Copyright 2023, Elsevier.

Figure 16

Clinical applications of Raman spectroscopic technology.