Biophotonics for lymphatic theranostics in animals and humans

Nowadays, lymphatic theranostics as an integration of diagnosis and therapy is one of the fast-growing emerging branches of biomedical optics to provide early diagnosis and, hence, advanced well-timed therapy of human diseases (Figure 1A). Nevertheless, lymphatic research is not young (Figure 1B). Historically, the timelines of blood and lymphatic research are comparable but with dramatically less attention to lymphatics for a long time [1, 2]. First references on the lymphatic system are related to the B.C. era with no progress in its studies over the next 15 centuries. The science in Renaissance and lymphatic discoveries of Aselli (Aselli, G.: De Lactibus sive Lacteis Venis, Milan: G.B. Bidelli, 1627) provoked some interest to lymphatic research. However, the lymphatic network was considered as secondary and inessential, which again resulted in a lack of attention.

FIGURE 1.

Clinical importance of lymphatic theranostics (A) and history of lymphatic research (B)

In the middle of the 20th century, a few research groups worldwide tried to prove that the lymphatic system is a key player in human diseases but it was challenging due to the technical limitations at that time. Compared to the blood vasculature, lymph vessels are colorless, with relatively low pressure and low concentration of cells. As a result, lymph sampling yields only a few microliters at a time and requires long-term cannulation making it difficult to test lymph in routine clinical practice. Furthermore, finding the colorless lymph channel in vivo requires additional labeling (lymphography; introduced by Kinmonth in 1952) that was only utilized as a clinical method in the second part of the 20th century. Indeed, our PubMed search has demonstrated that progress in lymphographic and microscopic methods corresponded to an increase of lymphatic-related publications in 1960s to 1990s (Figure 1B). The recent Biophotonic Leap Forward associated with the development of advanced intra-vital video microscopies, single-photon emission computed tomography, computed tomography, magnetic resonance imaging, ultrasound imaging, positron emission tomography, optical coherence tomography (OCT), Doppler, speckle interferometry, photothermal techniques and photoacoustics, as well as progress in molecular, genetic and epigenetic analysis has driven the lymphatic research toward its Golden Age [1–9]. To the best of our knowledge, we were the first who demonstrated application of speckle (1996), photothermal (2004), photoacoustic (2005), Raman (2009) and optical clearing (2007) methods as well as theranostic approach (2008) in lymphatic research [3–5, 8–9, and review by Sun et al in this issue].

The advantages of modern photonic technologies, which include, but not limited to, their noninvasiveness, high image contrast, and low cost, hold promise to open new lymphatic avenues. To date, multiple experimental and clinical studies have evidenced an importance and, often, primary role of the lymphatic system in supporting the human homeostasis (eg, immunity) and in the development of a wide range of diseases from cancer to genetic abnormalities. Literally, it is difficult to find any process in the human body that does not involve the lymphatic system. However, until now, our knowledge of many aspects of lymphatic function/dysfunction is still fragmentary. In particular, lymphatic theranostics is not well developed. Lymphatic studies are still mostly focused on lymph nodes. Imaging of lymphatic vessels, measuring lymph flow and analysis of circulating lymphatic cells remain out of scientific and clinical focus.

This Special Issue of Journal of Biophotonics entitled “Photonics Meets Lymphatics” presents new trends and emerging tools for lymphatic theranostics with focus on lymphatic vasculature and lymph circulation. Specifically, the in vivo advances in monitoring of single lymphatic vessel functionality (eg, contractions, flow and valve dynamic) are presented in two original manuscripts. Blatter et al used OCT and Doppler OCT for the characterization of pumping activity of vessels and for three-dimensional and four-dimensional dynamic imaging of valve [e201700017]. Sarimollaoglu et al developed new software that provides long-term continuous tracking of fast-moving objects (eg, circulating cells) in lymph flow in vivo and on isolated vessels in vitro using high-speed optical imaging with CMOS camera [e201700126]. The clinical relevance of OCT and the simplicity of experimental optical imaging hold promise to be broadly applicable by researches and physicians to better understand lymphatic disturbances in diseases and to improve treatment options. In particular, promising experimental results were demonstrated by Gong et al to diagnose conjunctival lymphatic vessels using OCT [e201800070]. Authors expected that future in vivo studies and their clinical translation will benefit diagnosis and guiding surgery in glaucoma.

Olszewski, who has great clinical experience in diagnosis of lymphatic vessels in patients with lymphedema, cancer and other pathologies, shared with us his new clinical results using ICG-fluorescent lymphography alone in one paper (Zaleska and Olszewski) [e201700150] and in combination with iodinated oil X-ray and isotopic approaches in another paper (Zaleska and Olszewski) [e201700132]. The advantages and disadvantages of these three most commonly used imaging methods are discussed based on retrospective and recent collections of lymphangiograms from large cohorts of patients.

Our attention to the use of the lymphatic system for advanced drug delivery into the sentinel lymph nodes at cancer metastasis is directed by Fujii et al [e201700401]. Using mouse and drug models, the researchers determined the range of injection rate for optimal delivery of model drug to lymph nodes.

The capability of photodynamic therapy and near-infrared spectroscopy for the assessment of glymphatics, a network of lymphatic vessels in the central nervous system, is explored by Semyachkina-Glushkovskaya et al [e201700287] and Myllyla et al [e201700123].

The interesting perspectives of using photobiomodulation to prevent atrophy of the thymus, a lymphoid organ associated with aging, are discussed by Odinokov and Hamblin [e201700282].

Finally, two reviews by Sun et al [e201700124] and Lokmic [e201700117] summarize the achievements in the diagnosis of genetic abnormalities of lymphatic vessels including lymphatic malformation. The existing challenges in molecular and cellular markers to detect lymphatic malformation are highlighted by Lokmic. The future look on theranostics of malformed lymphatic vessels using clinically relevant photoacoustically guided photothermal therapy is presented by Sun et al. Furthermore, the authors discussed the feasibility of optical clearing approach to improve photo-acoustic imaging contrast of lymphatics.

In Golden Lymphatic Age, we hope that this Special Issue will stimulate future technical innovations and closer collaboration of engineers, biomedical researchers, and clinicians for further understanding of lymphatic biology and for conducting clinical trials to achieve advanced early theranostics of severe diseases including cancer, leukemia, inflammation, infections and lymphedema.

Biography

Valery V. Tuchin is a Professor and Head of Optics and Biophotonics at Saratov State University (National Research University of Russia) and several other universities. His research interests include tissue optics, laser medicine, tissue optical clearing, and nanobiophotonics. He is a Fellow of SPIE and OSA, has been awarded Honored Science Worker of the Russia, Honored Professor of Saratov University, SPIE Educator Award, FiDiPro (Finland), Chime Bell Prize of Hubei Province (China), and Joseph W. Goodman Book Writing Award (OSA/SPIE). He has 20192 citations and an h-index of 65 (Google Scholar, July 6, 2018).

Vladimir P. Zharov is a Professor and director of the Arkansas Nanomedicine Center at the University of Arkansas for Medical Sciences. His research interests include laser spectroscopy, biophotonics and nanomedicine. He is one of the pioneers of high resolution photoacoustic spectroscopy, photoacoustic tweezers, nanobubble-based theranostics of cancer and infections, in vivo photoacoustic flow cytometry, and biomedical application of spaser (smallest—20 nm—plasmonic nanolaser) with 54 patents and 9 papers in the Nature journals. Dr. Zharov is the State Prize Winner, the most prestigious national award in Russia, and the first recipient of the U.S. Maiman Award named after the inventor of the first laser.

Ekaterina I. Galanzha heads the Laboratory of Lymphatic Research, Diagnosis and Therapy (LDT) at the University of Arkansas for Medical Sciences, USA. She published >60 peer-reviewed manuscripts and 5 book chapters. She is a co-inventor of the in vivo lymph flow cytometry. Based on her medical background, extensive experience in the lymphatic research and interdisciplinary skills in photoacoustics, nanomedicine and biophotonics, she and her laboratory pursue the goal to use advanced technical approaches for discovering lymphatic-related mechanisms of human diseases and translating obtained knowledge into clinics.