With the non-ionizing, non-invasive, high penetration, high resolution and spectral fingerprinting features of terahertz (THz) wave, THz spectroscopy has great potential for the qualitative and quantitative identification of key substances in biomedical field, such as the early diagnosis of cancer, the accurate boundary determination of pathological tissue and non-destructive detection of superficial tissue. However, biological samples usually contain various of substances (such as water, proteins, fat and fiber), resulting in the signal-to-noise ratio (SNR) for the absorption peaks of target substances are very small and then the target substances are hard to be identified. Here, we present recent works for the SNR improvement of THz signal. These works include the usage of attenuated total reflection (ATR) spectroscopy, the fabrication of sample-sensitive metamaterials, the utilization of different agents (including contrast agents, optical clearing agents and aptamers), the application of reconstruction algorithms and the optimization of THz spectroscopy system. These methods have been proven to be effective theoretically, but only few of them have been applied into actual usage. We also analyze the reasons and summarize the advantages and disadvantages of each method. At last, we present the prospective application of THz spectroscopy in biomedical field.

Chiral enantiomers have different pharmacological and pharmacokinetic characteristics. It is important to strictly detect chiral component for avoiding being harmful to the human body due to side effects. Terahertz (THz) trace fingerprint detection is essential because the molecular vibrations of various biological substances such as chiral enantiomers are located in THz range. Recent reported enhanced trace fingerprint technologies have some drawbacks. For instance, multiplexing technology suffered from narrow operation range and limitation by frequency resolution of commercial THz time domain spectroscopy; Absorption induced transparency (AIT) identification for narrowband molecular oscillations suffered from random resonance frequency drift due to fabrication error. In this paper, we proposed frequency-selective fingerprint sensor (FSFS), which can experimentally achieve enhanced trace fingerprint detection by both broadband multiplexing technology and robust AIT identification. Such FSFS is based on polarization independent reconfiguration metasurfaces array. Broadband absorption lines of trace-amount chiral carnitine were boosted with absorption enhancement factors of about 7.3 times based on frequency-selective multiplexing at 0.95–2.0 THz. Enhanced trace narrowband α-lactose fingerprint sensing can be observed at several array structures with absorption enhancement factors of about 7 times based on AIT, exhibiting good robustness. The flexibility and versatility of proposed FSFS has potential applications for boosting trace chiral enantiomer detection as well as diversity of molecular fingerprints identification by both multiplexing and AIT.

The molecular fingerprint sensing technology based on metasurface has unique attraction in the biomedical field. However, in the terahertz (THz) band, existing metasurface designs based on multi-pixel or angle multiplexing usually require more analyte amount or possess a narrower tuning bandwidth. Here, we propose a novel single-pixel graphene metasurface. Based on the synchronous voltage tuning, this metasurface enables ultra-wideband ( $$\sim$$∼ 1.5 THz) fingerprint enhancement sensing of trace analytes, including chiral optical isomers, with a limit of detection (LoD) ≤ 0.64 μg/mm². The enhancement of the fingerprint signal ( $$\sim$$∼ 17.4 dB) originates from the electromagnetically induced transparency (EIT) effect excited by the metasurface, and the ideal overlap between the light field constrained by single-layer graphene (SLG) and ultra-thin analyte. Meanwhile, due to the unique nonlinear enhancement mechanism in graphene tuning, the absorption envelope distortion is inevitable. To solve this problem, a universal fingerprint spectrum inversion model is developed for the first time, and the restoration of standard fingerprints reaches R_max² ≥ 0.99. In addition, the asynchronous voltage tuning of the metasurface provides an opportunity for realizing the dynamic reconfiguration of EIT resonance and the slow light modulation in the broadband range. This work builds a bridge for ultra-wideband THz fingerprint sensing of trace analytes, and has potential applications in active spatial light modulators, slow light devices and dynamic imaging equipments.