Pan et al. Light: Science & Applications (2021) 10:124 Official journal of the CIOMP 2047-7538 https://doi.org/10.1038/s41377-021-00561-2 www.nature.com/lsa REVIEW ARTICLE Open Access Biophotonic probes for bio-detection and imaging Ting Pan1,DengyunLu1, Hongbao Xin 1 and Baojun Li 1 Abstract The rapid development of biophotonics and biomedical sciences makes a high demand on photonic structures to be interfaced with biological systems that are capable of manipulating light at small scales for sensitive detection of biological signals and precise imaging of cellular structures. However, conventional photonic structures based on artificial materials (either inorganic or toxic organic) inevitably show incompatibility and invasiveness when interfacing with biological systems. The design of biophotonic probes from the abundant natural materials, particularly biological entities such as virus, cells and tissues, with the capability of multifunctional light manipulation at target sites greatly increases the biocompatibility and minimizes the invasiveness to biological microenvironment. In this review, advances in biophotonic probes for bio-detection and imaging are reviewed. We emphatically and systematically describe biological entities-based photonic probes that offer appropriate optical properties, biocompatibility, and biodegradability with different optical functions from light generation, to light transportation and light modulation. Three representative biophotonic probes, i.e., biological lasers, cell-based biophotonic waveguides and bio- microlenses, are reviewed with applications for bio-detection and imaging. Finally, perspectives on future opportunities and potential improvements of biophotonic probes are also provided. 4–7 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Introduction mass or electrochemical) . With optical detection Sensitive detection of biological signals and precise techniques, real-time signals of a wide range of biological observation of pathological changes are of great impor- test samples (from molecular biomarkers to pathogens tance for the early diagnosis and treatment of infectious and cells, and even to tissues and organs) can be obtained diseases, cancer, and other health disorders. However, in a non-invasive manner with high-sensitivity and high- – owing to the low quantity of biochemical signals and resolution8 12. To date, optical detection and imaging complex microenvironment in biological systems, the have been demonstrated to be one of the most powerful detection of the targets of interest is challenging. For- technologies for detection of biological signals and for tunately, the prosperous development of optical and diagnosis of various diseases, including infectious dis- – photonic technologies in recent years provides many eases, cancer as well as other disorders13 18. choices for optical detection and imaging, holding great For a precise and flexible optical detection in a biological promises for real-time visualization of biological signals in microenvironment, photonic probes with micro/nanos- complex biological structures and processes1,2. Optical tructures are always desirable. For this purpose, the selection detection exploits optical responses, such as light of appropriate optical materials is certainly crucial, since the absorption, scattering, fluorescence, and reflectance, probing performance largely depends on their chemical and induced by biophysical/biochemical changes for bio- mechanical properties, optical functionalities as well as identification and disease diagnosis3. Due to the inher- biological performances19. To date, the most commonly ently label-free nature, optical detection is a powerful used materials for the assembly of versatile photonic com- alternative to conventional detection techniques (e.g., ponents and photonic probes are mainly based on inorganic – materials such as silica glass20 23, or organic polymers such as polymer nanowires24,25. Because of their excellent Correspondence: Hongbao Xin ([email protected])or Baojun Li ([email protected]) optical properties, such as high transparency and suitable 1Institute of Nanophotonics, Jinan University, Guangzhou 511443, China © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Pan et al. Light: Science & Applications (2021) 10:124 Page 2 of 22 mechanical strength, these materials have been applied for nanophotonic integrated devices in diversified fields of application26. For example, optical waveguides based on silica optical fibers have been widely studied and were even fi e and Mamm used for implantations in animal bodies, particularly ber- lga alian A ia c cter ells T 27,28 Ba is su optic implants in the brain for optogenetic studies . Virus es gical en However, the main disadvantage of these photonic com- olo titie Bi s L s n i B ponents based on traditional materials is low biocompat- g r o i i h o e t s t - a m ibility and biodegradability, which greatly limit their a r l m e l i c o n Biophotonic a r d o e potential in biomedical applications. High biocompatibility c i u l g probes e g g B l t n a o n l h s of a material is a fundamental requirement for in vivo io i t i e o g g o i i - s d a n L applications, which demands the absence of toxicity and low B e te im 29 ct io health threat to the living systems . Moreover, high bio- ion and b compatibility also refers to the biofunctionalities that the Lig n ht transportatio implants can perform their expected functions in vivo. Bi s oph ide Additionally, biodegradability is another essential require- otonic wavegu ment, since the materials can be degraded and metabolized bythebodywithouttheneedfor additional operations to remove the implants. With abundant natural biomaterials and biological enti- Fig. 1 Overview of biophotonic probes for bio-detection and ties, Mother Nature always inspire us to design photonic imaging. Based on biological entities, such as virus, algae & bacteria, structures and probes to manipulate light30. Indeed, living mammalian cells, and tissues. Such photonic probes include biological lasers, biophotonic waveguides, and bio-microlenses, with optical cells and microscopic organisms as well as their derivates functions from light generation, to light transportation and light such as DNA, proteins, silk and cellulose et al., show dif- modulation. Biological entities: virus88, copyright 2017, Springer ferent capabilities to interact with light, and can further Nature. Diatom154, Copyright 2014, Optical Society of America. 69 serve as different photonics devices such as waveguides, Tissues , copyright 2017, The Royal Society of Chemistry. Blood – 167 microlenses, gratings, and even lasers31 37. These natural vessel , Copyright 2019, American Chemical Society. Biological lasers: top50, Copyright 2016, Optical Society of America. Middle69, Copyright biomaterials and biological entities hold huge promise for 2017, The Royal Society of Chemistry. Bottom81, Copyright 2018, The creation of new photonic probes for bio-detection, imaging, Royal Society of Chemistry. Biophotonic waveguides: left143, Copyright and therapeutic applications19. They inherently possess 2017, WILEY‐VCH. Middle134, Copyright 2015, WILEY‐VCH. Right138, Copyright 2017, American Physical Society. Bio-microlenses: top175, excellent biological performances, including noninvasive- 154 ness, high biocompatibility, biodegradability, and resorb- Copyright 2019, American Chemical Society. Bottom , Copyright 2014, Optical Society of America ability. Moreover, another interesting feature of biological entities such as virus, cells and tissues is their ability to serve simultaneously as optical devices and diagnostic on recent progress on biophotonic probes based on specimen, which facilitate further real-time detection and biological entities, with much focus on viruses, cells and imaging in biocompatible microenvironments. Therefore, tissues, and their biomedical applications, in particular, instead of bio-derived materials and biomolecules (such as for bio-detection and imaging. We emphatically and proteins and nucleic acids), biophotonic probes introduced systematically introduce three representative biopho- in this review are mainly focused on large biological enti- tonic probes, i.e., biological lasers, cell-based biopho- ties, such as virus, bacteria, fungi, algae, mammalian cells tonic waveguides and microlenses, possessing different and tissues. By translating biological principles into man- optical functions from light generation to light trans- made designs, these biophotonic probes offer a seamless portation and light modulation (Fig. 1). Their fabrication interface between optical and biological worlds38,39. techniques, optical functionalities,