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Significance: Fluorescence lifetime imaging microscopy (FLIM) is a powerful technique to distinguish the unique molecular environment of fluorophores. FLIM measures the time a fluorophore remains in an excited state before emitting a photon, and detects molecular variations of fluorophores that are not apparent with spectral techniques alone. FLIM is sensitive to multiple biomedical processes including disease progression and drug efficacy. Aim: We provide an overview of FLIM principles, instrumentation, and analysis while highlighting the latest developments and biological applications. Approach: This review covers FLIM principles and theory, including advantages over intensity-based fluorescence measurements. Fundamentals of FLIM instrumentation in time- and frequency-domains are summarized, along with recent developments. Image segmentation and analysis strategies that quantify spatial and molecular features of cellular heterogeneity are reviewed. Finally, representative applications are provided including high-resolution FLIM of cell- and organelle-level molecular changes, use of exogenous and endogenous fluorophores, and imaging protein-protein interactions with Förster resonance energy transfer (FRET). Advantages and limitations of FLIM are also discussed. Conclusions: FLIM is advantageous for probing molecular environments of fluorophores to inform on fluorophore behavior that cannot be elucidated with intensity measurements alone. Development of FLIM technologies, analysis, and applications will further advance biological research and clinical assessments.

Dr. Matthew Burke is a Cognitive Neurologist in the Neuropsychiatry Program and Department of Psychiatry at Sunnybrook Health Sciences Center. He is currently the Director of Sunnybrook’s Traumatic Brain Injury Clinic and he also sees patients with functional neurological disorders, headache disorders, and other neuropsychiatric conditions. Before starting at Sunnybrook, Dr. Burke completed medical school and his neurology residency training at the University of Toronto, where he was the Chief Neurology Resident in his last year of training. He then completed a two-year Sidney R. Baer, Jr. Foundation fellowship in Cognitive Neurology and Neuropsychiatry at Beth Israel Deaconess Medical Center and Harvard Medical School.Dr. Burke’s clinical research fellowship provided specialized training in non-invasive brain stimulation and brain network mapping. His research applies these novel techniques to investigate the complex and poorly understood brain disorders at the interface between neurology and psychiatry. He also has research interests in the neurobiology of placebo effects and is an active collaborator with the Harvard Program in Placebo Studies. Finally, concurrent with his fellowship, Dr. Burke completed the Harvard Catalyst Clinical Translational Research Academy. This is a NIH-funded program that provides advanced training in methods of clinical investigation.Dr. Burke’s research to date has resulted in multiple peer-reviewed publications, media attention on platforms such as CNN and BBC, and recent recognition with the American Neuropsychiatric Association’s 2019 Young Investigator Award and the American Headache Society’s 2018 Frontiers in Headache Research Award.AbstractPlacebo effects are the beneficial therapeutic effects derived from the context surrounding the administration of a treatment rather than the treatment itself. Recent research has shifted our understanding of placebo effects from a mystical unempirical entity to a biologically-based phenomenon capable of meaningfully modulating brain regions and neurotransmitter systems. In this presentation, Dr. Burke will begin by summarizing the evidence underlying the principles and neurobiology of placebo effects. He will then discuss clinical factors that contribute to placebo effects and how placebo effects could be harnessed in the management of neuropsychiatric disorders. Finally, Dr. Burke will interrogate how our evolving understanding of placebo effects may impact the way we design, appraise and interpret research studies in neuropsychiatry and across medicine.

We report a three-orders-of-magnitude variation of carrier lifetimes in exotic crystalline phases of gold nanoclusters (NCs) in addition to the well-known face-centered cubic structure, including hexagonal close-packed (hcp) Au30 and body-centered cubic (bcc) Au38 NCs protected by the same type of capping ligand. The bcc Au38 NC had an exceptionally long carrier lifetime (4.7 microseconds) comparable to that of bulk silicon, whereas the hcp Au30 NC had a very short lifetime (1 nanosecond). Although the presence of ligands may, in general, affect carrier lifetimes, experimental and theoretical results showed that the drastically different recombination lifetimes originate in the different overlaps of wave functions between the tetrahedral Au₄ building blocks in the hierarchical structures of these NCs.

Efficient and fast scintillators are in high demand in a variety of fields, such as medical diagnostics, scientific instruments and high-energy physics. However, the trade-off between high scintillation efficiency and fast timing properties is a common challenge facing almost all scintillators. To overcome this limitation, we have developed a strategy for organic scintillators by directing all hot excitons into fast singlet emission states without involving the lowest triplet states. Our scintillator, 1,1,2,2-tetrakis(4-bromophenyl)ethylene, shows an ultrafast radiative lifetime of 1.79 ns and a light yield of ∼34,600 photons per MeV, exhibiting an excellent combination of high light yield and short decay time. Our work provides a method to design efficient and ultrafast scintillators, and paves the way towards exciting applications for ultrafast detection and imaging. Researchers overcome the typical scintillator trade-off between high efficiency and speed. In organic scintillators, researchers drove hot excitons into fast singlet emission states without involving the lowest triplet states, which led to a fast radiative lifetime and strong light yield that may be applicable to ultrafast detection and imaging.

In 2016, the estimated lifetime risk of stroke from the age of 25 years onward (as calculated from the results of the GBD Study) was 24.9%. This estimate varies according to country, region, and national level of social development. The risk increased by 8.9% from 1990 to 2016.

Significance: Fluorescence lifetime imaging microscopy (FLIM) measures the decay rate of fluorophores, thus providing insights into molecular interactions. FLIM is a powerful molecular imaging technique that is widely used in biology and medicine. Aim: This perspective highlights some of the major advances in FLIM instrumentation, analysis, and biological and clinical applications that we have found impactful over the last year. Approach: Innovations in FLIM instrumentation resulted in faster acquisition speeds, rapid imaging over large fields of view, and integration with complementary modalities such as single-molecule microscopy or light-sheet microscopy. There were significant developments in FLIM analysis with machine learning approaches to enhance processing speeds, fit-free techniques to analyze images without a priori knowledge, and open-source analysis resources. The advantages and limitations of these recent instrumentation and analysis techniques are summarized. Finally, applications of FLIM in the last year include label-free imaging in biology, ophthalmology, and intraoperative imaging, FLIM of new fluorescent probes, and lifetime-based Förster resonance energy transfer measurements. Conclusions: A large number of high-quality publications over the last year signifies the growing interest in FLIM and ensures continued technological improvements and expanding applications in biomedical research.

Fluorescence lifetime imaging (FLI) provides unique quantitative information in biomedical and molecular biology studies but relies on complex data-fitting techniques to derive the quantities of interest. Herein, we propose a fit-free approach in FLI image formation that is based on deep learning (DL) to quantify fluorescence decays simultaneously over a whole image and at fast speeds. We report on a deep neural network (DNN) architecture, named fluorescence lifetime imaging network (FLI-Net) that is designed and trained for different classes of experiments, including visible FLI and near-infrared (NIR) FLI microscopy (FLIM) and NIR gated macroscopy FLI (MFLI). FLI-Net outputs quantitatively the spatially resolved lifetime-based parameters that are typically employed in the field. We validate the utility of the FLI-Net framework by performing quantitative microscopic and preclinical lifetime-based studies across the visible and NIR spectra, as well as across the 2 main data acquisition technologies. These results demonstrate that FLI-Net is well suited to accurately quantify complex fluorescence lifetimes in cells and, in real time, in intact animals without any parameter settings. Hence, FLI-Net paves the way to reproducible and quantitative lifetime studies at unprecedented speeds, for improved dissemination and impact of FLI in many important biomedical applications ranging from fundamental discoveries in molecular and cellular biology to clinical translation.

Recombination degrades a solar cell. Shockley-Read-Hall (SRH) recombination occurs in a solar cell due to the presence of defects. Defects control the lifetime of electrons and holes, and in a good solar cell these lifetimes should be as high as possible. Thus, it is a priority to know the SRH lifetimes in a working solar cell with good precision. Only if the lifetimes are measured properly can a protocol on how to increase them by minimizing the defects be followed. Standard methods are available which extracts SRH lifetimes from solar cell test structures. In this work, we use a method which is less costly and complex and applies to solar cells directly rather than test structures. In a GaAs PIN solar cell, we study how a varying absorber thickness and electron hole lifetime asymmetry affect this method, and we suggest a way to read the SRH lifetimes from graphs of simply processed experimental data. A method to find the SRH lifetime for any absorber thickness between 1–100 μm is proposed.

Luminescence lifetimes provide insights into the local microenvironment of luminescent molecules, enabling precise measurements that can be leveraged for biomedical imaging and sensing applications. Traditional systems for measuring luminescence lifetimes rely on expensive ultrafast detectors and electronics. Here, a novel optical luminescence lifetime estimation method, modular analysis and eXtraction system for affordable lifetime imaging of fluorescence signals (MAX-alif), was developed to provide a high-speed, low-cost, and scalable solution for luminescence lifetime measurements. In MAX-alif, excitation light with sinusoidal intensity modulation is combined with synthetic path-length difference analysis and machine learning regression to compute luminescence lifetimes from intensity image features. An acousto-optical modulator within the detection path transfers the synthesized phase difference between the excitation and emission light into intensity differences that a standard camera can capture. Both simulation and experimental data were used to generate and validate models for the calibration and extraction of lifetime values from intensity datasets. MAX-alif measurements of phosphorescent and fluorescent samples achieved mean and median lifetime values within 5% of the reference lifetime values. By eliminating the need for expensive hardware and enabling accurate lifetime imaging with standard cameras, MAX-alif allows widespread, cost-effective luminescence lifetime imaging for medical diagnostics applications.

Traditional fluorescence-based tags, used for anticounterfeiting, rely on primitive pattern matching and visual identification; additional covert security features such as fluorescent lifetime or pattern masking are advantageous if fraud is to be deterred. Herein, we present an electrohydrodynamically printed unicolour multi-fluorescent-lifetime security tag system composed of lifetime-tunable lead-halide perovskite nanocrystals that can be deciphered with both existing time-correlated single-photon counting fluorescence-lifetime imaging microscopy and a novel time-of-flight prototype. We find that unicolour or matching emission wavelength materials can be prepared through cation-engineering with the partial substitution of formamidinium for ethylenediammonium to generate “hollow” formamidinium lead bromide perovskite nanocrystals; these materials can be successfully printed into fluorescence-lifetime-encoded-quick-read tags that are protected from conventional readers. Furthermore, we also demonstrate that a portable, cost-effective time-of-flight fluorescence-lifetime imaging prototype can also decipher these codes. A single comprehensive approach combining these innovations may be eventually deployed to protect both producers and consumers. Designing effective covert security features is highly regarded to deter counterfeit of goods and currency in the global markets. Here, the authors present an electrohydrodynamically printed unicolour multifluorescent-lifetime security tag system based on perovskite to provide an alternative yet affordable solution.