Biophotonics and beyond

Literally as a combination of biology and photonics, biophotonics is concerned with the use of light for the purpose of studying biological objects (e.g., molecules, cells, and tissue) in biology, medicine, pharmaceutical science, environmental science, and agriculture. This is, at the most fundamental level, due to the principle that light can interact with biological objects via various light-matter interaction processes (e.g., scattering, absorption, and emission). Biophotonics also embraces the development and application of optical technologies for the above purpose. The difference between “biophotonics” and “biomedical photonics” may be similar to that between “bioengineering” and “biomedical engineering” in that the former has a broader concept in which the interaction between light and biological objects is studied and exploited for both fundamental and applied studies, while the latter places more of its emphasis on medical applications of photonics. The term “biophotonics” may have been coined recently, but it dates back to the 16th century when the optical microscope was invented to visualize biological tissue. Today, with the advent of superresolution fluorescence microscopy recognized by the 2014 Nobel Prize in Chemistry, cellular architecture and function can be studied with outstanding spatial resolution down to 10 nm. Apart from basic research in biology, optical technologies are also indispensable in clinics and hospitals for both medical diagnosis and therapy. For example, endoscopy,¹ flow cytometry,² and fluorescence in situ hybridization (FISH)³ are routinely used for early detection and prognosis of cancer (e.g., breast cancer, stomach cancer, and leukemia), while optical coherence tomography (OCT)⁴ and laser-assisted in situ keratomileusis (LASIK) are powerful diagnostic and surgical tools in ophthalmology, respectively. Furthermore, high-throughput screening based on multiparameter fluorescence detection plays a critical role in drug discovery. Environmental monitoring with an array of optical sensors aided by machine learning has become an effective tool for characterizing climate change in environmental science and optimizing crop yield in agriculture. Primarily driven by the aging populations of developed countries and the advent of artificial intelligence, the field of biophotonics is expected to grow continuously and rapidly in the next decade and beyond.

Biophotonics has several prominent advantages in biology, medicine, pharmaceutical science, environmental science, and agriculture.

1. Diverse spatial scale. The spatial dimensions of biological objects that can be probed or manipulated by light range from approximately nanometer (biological molecules) to approximately centimeter (biological tissue), spanning more than several orders of magnitude in size. For example, superresolution fluorescence microscopy can image the intracellular localization of proteins and RNA in detail⁵ while endoscopy can detect cancer tumors in vivo.¹ 

2. Diverse temporal scale. The temporal dimension of biological objects that can be probed or manipulated by light ranges from approximately femtosecond (electronic transitions in biological molecules)⁶ to ∼day (time-lapse observation),⁷ covering more than ∼20 orders of magnitude in time. For example, the pump-probe technique enables femtochemistry of electronic transitions in photoreceptor proteins while long-term monitoring of cellular proliferation, secretion, metabolism, and differentiation helps us understand cellular heterogeneity, optimize metabolic engineering, and control the quality of stem cells for cell therapy and regenerative medicine.

3. Diverse invasiveness. Light interacts with biological objects but weakly. This offers the advantage of probing and manipulating biological objects in a minimally invasive manner, leaving them intact without causing significant modifications or damage to them. At the same time, powerful lasers can also be used to cut tissue in laser surgery. In other words, the degree of optical invasiveness is adjustable, depending on the optical wavelength and intensity.

4. Diverse functionality. Since light interacts with biological objects via multiple processes, numerous unique tools for observation and manipulation have been developed for biomedical applications, ranging from Raman spectroscopy to optical trapping (2018 Nobel Prize in physics).

5. High compatibility. Due to the principle that different wavelengths of light weakly interact with each other and can be detected separately, various optical sensing and manipulation tools can simultaneously be utilized without causing mutual interference or in multiple spatial and temporal domains. For example, multiple diagnostic and therapeutic techniques can concurrently be used on both the microscope and macroscopic scales. The weak interaction of light with matter also helps simultaneous use of nonoptical technologies such as atomic force microscopy (AFM), scanning electron microscopy (SEM), microfluidics, nanoparticles, and integrated electronics.

6. High practicality. In addition to their fundamental properties, optical technologies also provide practical advantages such as high usability, high compactness, and low cost. These advantages are significant in comparison with ultrasound, X-ray, computed tomography (CT), and magnetic resonance imaging (MRI) which tend to be large, bulky, and costly.

7. Big data. Due to the extremely broad spatial and temporal scales accessible by light, optical technologies can generate tremendously large amounts and many types of biomedical data. The availability of the biomedical big data has fueled the rapid advance of machine learning and its applications in biology, medicine, pharmaceutical science, environmental science, and agriculture. According to recent reports, convolutional neural networks have already surpassed pathologists in the accuracy of cancer detection.^8,9 These advantages of light do not stand independently but work hand-in-hand to lead to many degrees of freedom in the development and application of optical technologies.

As mentioned above, light interacts with biological molecules, cells, and tissue via multiple light-matter interaction processes. This principle has enabled the development of diverse optical technologies for, but not limited to, advanced applications in biology, medicine, pharmaceutical science, environmental science, and agriculture. (1) Scattering-based technologies: Raman scattering spectroscopy, dynamic light scattering, coherent anti-Stokes Raman scattering (CARS),¹⁰ stimulated Raman scattering (SRS),¹¹ surface-enhanced Raman scattering (SERS),¹² tip-enhanced Raman scattering (TERS), speckle sensing, etc. (2) Absorption-based technologies: UV-VIS spectroscopy, infrared (IR) spectroscopy, microwave spectroscopy, THz spectroscopy, Fourier-transform infrared (FTIR) spectroscopy, etc. (3) Emission-based technologies: fluorescence detection, multiphoton fluorescence detection, fluorescence resonance energy transfer (FRET), FISH, fluorescence-activated cell sorting (FACS),¹³ etc. (4) Imaging technologies: fluorescence microscopy, superresolution nanoscopy [e.g., stimulated emission depletion (STED) microscopy,¹⁴ stochastic optical reconstruction microscopy (STORM),¹⁵ photoactivated localization microscopy (PALM),¹⁶ superresolution optical fluctuation imaging (SOFI),¹⁷ structured illumination microscopy (SIM)¹⁸], volumetric imaging (e.g., confocal microscopy, multiphoton microscopy, and OCT), vibrational imaging^11,19 (e.g., Raman microscopy, CARS imaging, SRS imaging, and TERS imaging), fluorescence lifetime imaging (FLIM),²⁰ phase imaging, time-stretch imaging,²¹ etc. (5) Manipulation technologies: optical trapping, optical tweezers, photoporation, optogenetics, laser surgery, laser capture microdissection, cell sorting,²² etc. (6) Hybrid technologies: photoelectron spectroscopy, photothermal spectroscopy, plasmonic sensing, photoacoustic imaging, etc. These technologies can be used as stand-alone instruments or together for multimodal sensing, imaging, or manipulation.

Current research trends in biophotonics are mostly categorized into the following types or any combination of them. (1) More dimensions: from 1D to 2D, from 2D to 3D, and from 3D to 4D (including time). (2) Higher spatial resolution: from microscopy to nanoscopy. (3) Higher temporal resolution: from static imaging of dead cells to functional imaging of live cells. (4) Higher sensitivity: from sensing with a photodiode to single-photon counting with a photomultiplier tube (PMT) or avalanche photodetector (APD) and from spontaneous Raman spectroscopy to coherent Raman spectroscopy. (5) Higher specificity: from single-color fluorescence detection to multiplex molecular sensing. (6) Higher practicality: from laboratory testing to point-of-care testing in resource-limited settings or at home, from tissue biopsy to liquid biopsy, and from ex vivo testing to in vivo diagnosis. (7) More modalities: from diagnosis alone to multimodal diagnosis-therapy hybridization. (8) Single-cell analysis: from ensemble measurements of cellular activity to sensing the activity of numerous single cells for studying cellular heterogeneity. (9) More integration with advanced nonoptical tools: AFM, SEM, microfluidics, nanoparticles, integrated electronics, etc. (10) Closer alliance with data science and computational tools: artificial intelligence, machine learning, big data analysis, data mining, compressive sensing, etc. (11) More translational research: from basic research alone to an expedited bench-to-bedside strategy.

Since light is often used as a tool more than a research subject, there are globally few universities where the Department of Optics or Photonics exists. Paradoxically, this is an excellent attribute of biophotonics as it bridges researchers in diverse disciplines. At academic institutions, optical technologies are mainly developed by researchers in the Departments of Physics, Chemistry, Electrical Engineering, Mechanical Engineering, Bioengineering, etc., while they are mainly used in the Departments of Biology, Biochemistry, Cell Biology, Molecular Biology, Microbiology, Cancer Biology, Pharmacology, Immunology, Cardiology, Hematology, Dermatology, Urology, Ophthalmology, Regenerative Medicine, Pharmaceutical Science, Environmental Science, Agriculture, etc. Therefore, biophotonics research generally requires interdisciplinary communication, networking, and collaboration of experts in these areas for impactful outcomes since the development and application of optical technologies are not independent but built on the close alliance between technology developers and users. In other words, biophotonics essentially serves as an interdisciplinary platform.

The primary growth factor of biophotonics is the rapidly aging population in developed countries such as Japan, China, South Korea, Italy, Spain, Germany, Canada, the UK, and the USA. According to market reports, the worldwide biophotonics market is expected to witness a significant growth in the next several years, indicated by a predicted compound annual growth rate (CAGR) of 11.2% during the forecast period of 2018–2023.²³ Due to the aging population, the number of patients with chronic diseases (e.g., cancer, diabetes, Parkinson’s disease, cardiovascular diseases, and infectious diseases) has grown significantly in the last few decades. In fact, a majority of people of age 60 years or over have at least one chronic disease. Since governments in the developed countries have recognized biophotonics as one of the primary solutions to the pressing medical issue and related financial burden on both the governments and individual patients, they have launched funding programs to support biophotonics research. Fostered by this funding trend, the expansion of the biophotonics research community has followed in terms of the number of biophotonics researchers, research groups, and research institutes in both academic and industrial sectors. For example, the European Union and the US government have launched Photonics4Life (an European Network of Excellence for Biophotonics)²⁴ and the National Research Center on Biophotonics, respectively, to boost biophotonics research activity. The BRAIN initiative has also been established in the USA under the leadership of the Obama administration to strongly support neuroscience and neurology research in which optical technologies play a vital role.²⁵ For a similar purpose, China has also launched a brain-imaging factory for industrial-scale high-resolution brain mapping recently.²⁶ With the increasing need for optical technologies in biophotonics research and biomedical applications, a number of related startups have emerged while major players in the industrial sector (e.g., Hamamatsu Photonics, Olympus, Carl Zeiss, Nikon, Thermo Fisher Scientific, Becton Dickinson, Oxford Instruments) have further expanded their related R&D and product commercialization.

Biophotonics is a rapidly growing field, driven by the increasing number of patients with chronic diseases in developed countries and their strong financial support to tackle the medical and financial challenge. The recent rise of deep learning has also boosted the evolution of biophotonics. To comprehend the field of biophotonics, this editorial has covered its various aspects in an informative manner: advantages, optical technologies, current research trends, interdisciplinary nature, and growth factor. Biophotonics is a common language spoken by technology developers and research scientists in biology, medicine, pharmaceutical science, environmental science, and agriculture and, hence, fosters interdisciplinary communication, networking, and collaboration of experts in a diverse range of research fields. The strong interdisciplinarity of biophotonics serves as a gold mine of ideas, discoveries, and innovations. This is well aligned with APL Photonics—the home for significant advances in fundamental and applied multidisciplinary research anchored in photonics and the platform for next-generation innovations in the field. In fact, the journal has launched a few special topics related to the field of biophotonics such as “Coherent Raman Spectroscopy and Imaging,” “Opportunities in Neurophotonics,” and “Optoacoustics.” The future of biophotonics is bright and welcomes interested newcomers.