Real-Time Optical Monitoring of Endotracheal Tube Displacement

Proper ventilation of a patient with an endotracheal tube (ETT) requires proper placement of the ETT. We present a sensitive, noninvasive, operator-free, and cost-effective optical sensor, called Opt-ETT, for the real-time assessment of ETT placement and alerting of the clinical care team should the ETT become displaced. The Opt-ETT uses a side-firing optical fiber, a near-infrared light-emitting diode, two photodetectors with an integrated amplifier, an Arduino board, and a computer loaded with a custom LabVIEW program to monitor the position of the endotracheal tube inside the windpipe. The Opt-ETT generates a visual and audible warning if the tube moves over a distance set by the operator. Displacement prediction is made using a second-order polynomial fit to the voltages measured from each detector. The system is tested on ex vivo porcine tissues, and the accuracy is determined to be better than 1.0 mm. In vivo experiments with a pig are conducted to test the performance and usability of the system.

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Biodegradable Micelles for NIR/GSH-Triggered Chemophototherapy of Cancer

Nanomaterials ◽

10.3390/nano9010091 ◽

2019 ◽

Vol 9 (1) ◽

pp. 91 ◽

Cited By ~ 8

Author(s):

Chuan Zhang ◽

Yuzhuo Wang ◽

Yue Zhao ◽

Hou Liu ◽

Yueqi Zhao ◽

...

Keyword(s):

Drug Delivery ◽

Near Infrared ◽

Mixed Micelles ◽

Infrared Light ◽

Stimuli Responsive ◽

High Concentration ◽

Chemotherapy Drugs ◽

In Vivo Experiments ◽

Low Efficiency

The chemotherapy of stimuli-responsive drug delivery systems (SDDSs) is a promising method to enhance cancer treatment effects. However, the low efficiency of chemotherapy drugs and poor degradation partly limit the application of SDDSs. Herein, we report doxorubicin (DOX)-loading mixed micelles for biotin-targeting drug delivery and enhanced photothermal/photodynamic therapy (PTT/PDT). Glutathione (GSH)-responsive mixed micelles were prepared by a dialysis method, proportionally mixing polycaprolactone-disulfide bond-biodegradable photoluminescent polymer (PCL-SS-BPLP) and biotin-polyethylene glycol-cypate (biotin-PEG-cypate). Chemically linking cypate into the mixed micelles greatly improved cypate solubility and PTT/PDT effect. The micelles also exhibited good monodispersity and stability in cell medium (~119.7 nm), low critical micelles concentration, good biodegradation, and photodecomposition. The high concentration of GSH in cancer cells and near-infrared light (NIR)-mediated cypate decomposition were able to achieve DOX centralized release. Meanwhile, the DOX-based chemotherapy combined with cypate-based NIR-triggered hyperthermia and reactive oxygen species could synergistically induce HepG2 cell death and apoptosis. The in vivo experiments confirmed that the micelles generated hyperthermia and achieved a desirable therapeutic effect. Therefore, the designed biodegradable micelles are promising safe nanovehicles for antitumor drug delivery and chemo/PTT/PDT combination therapy.

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Noninvasive in vivo monitoring of methemoglobin formation and reduction with broadband diffuse optical spectroscopy

Journal of Applied Physiology ◽

10.1152/japplphysiol.00424.2004 ◽

2006 ◽

Vol 100 (2) ◽

pp. 615-622 ◽

Cited By ~ 31

Author(s):

Jangwoen Lee ◽

Naglaa El-Abaddi ◽

Andrew Duke ◽

Albert E. Cerussi ◽

Matthew Brenner ◽

...

Keyword(s):

Real Time ◽

Optical Spectroscopy ◽

Near Infrared ◽

Ex Vivo ◽

Rabbit Model ◽

Nir Spectroscopy ◽

Blood Chemistry ◽

Diffuse Optical Spectroscopy ◽

Methemoglobin Formation

We present noninvasive, quantitative in vivo measurements of methemoglobin formation and reduction in a rabbit model using broadband diffuse optical spectroscopy (DOS). Broadband DOS combines multifrequency frequency-domain photon migration (FDPM) with time-independent near infrared (NIR) spectroscopy to quantitatively measure bulk tissue absorption and scattering spectra between 600 nm and 1,000 nm. Tissue concentrations (denoted by brackets) of methemoglobin ([MetHb]), deoxyhemoglobin ([Hb-R]), and oxyhemoglobin ([HbO2]) were determined from absorption spectra acquired in “real time” during nitrite infusions in nine pathogen-free New Zealand White rabbits. As little as 30 nM [MetHb] changes were detected for levels of [MetHb] that ranged from 0.80 to 5.72 μM, representing 2.2 to 14.9% of the total hemoglobin content (%MetHb). These values agreed well with on-site ex vivo cooximetry data ( r2 = 0.902, P < 0.0001, n = 4). The reduction of MetHb to functional hemoglobins was also carried out with intravenous injections of methylene blue (MB). As little as 10 nM changes in [MB] were detectable at levels of up to 150 nM in tissue. Our results demonstrate, for the first time, the ability of broadband DOS to noninvasively quantify real-time changes in [MetHb] and four additional chromophore concentrations ([Hb-R], [HbO2], [H2O], and [MB]) despite significant overlapping spectral features. These techniques are expected to be useful in evaluating dynamics of drug delivery and therapeutic efficacy in blood chemistry, human, and preclinical animal models.

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Microscale optoelectronic infrared-to-visible upconversion devices and their use as injectable light sources

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1802064115 ◽

2018 ◽

Vol 115 (26) ◽

pp. 6632-6637 ◽

Cited By ~ 31

Author(s):

He Ding ◽

Lihui Lu ◽

Zhao Shi ◽

Dan Wang ◽

Lizhu Li ◽

...

Keyword(s):

Near Infrared ◽

Biological Fluids ◽

Visible Spectral Range ◽

Infrared Light ◽

Light Sources ◽

Fully Integrated ◽

Broadband Absorption ◽

In Vivo Experiments

Optical upconversion that converts infrared light into visible light is of significant interest for broad applications in biomedicine, imaging, and displays. Conventional upconversion materials rely on nonlinear light-matter interactions, exhibit incidence-dependent efficiencies, and require high-power excitation. We report an infrared-to-visible upconversion strategy based on fully integrated microscale optoelectronic devices. These thin-film, ultraminiaturized devices realize near-infrared (∼810 nm) to visible [630 nm (red) or 590 nm (yellow)] upconversion that is linearly dependent on incoherent, low-power excitation, with a quantum yield of ∼1.5%. Additional features of this upconversion design include broadband absorption, wide-emission spectral tunability, and fast dynamics. Encapsulated, freestanding devices are transferred onto heterogeneous substrates and show desirable biocompatibilities within biological fluids and tissues. These microscale devices are implanted in behaving animals, with in vitro and in vivo experiments demonstrating their utility for optogenetic neuromodulation. This approach provides a versatile route to achieve upconversion throughout the entire visible spectral range at lower power and higher efficiency than has previously been possible.

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Near-infrared light and tumor microenvironment dual responsive size-switchable nanocapsules for multimodal tumor theranostics

Nature Communications ◽

10.1038/s41467-019-12142-4 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 38

Author(s):

Zhiyi Wang ◽

Yanmin Ju ◽

Zeeshan Ali ◽

Hui Yin ◽

Fugeng Sheng ◽

...

Keyword(s):

Drug Delivery ◽

Tumor Microenvironment ◽

Near Infrared ◽

Infrared Light ◽

Near Infrared Light ◽

In Vivo Experiments ◽

Dual Responsive ◽

Synthetic Strategy ◽

Scientific Challenge

Abstract Smart drug delivery systems (SDDSs) for cancer treatment are of considerable interest in the field of theranostics. However, developing SDDSs with early diagnostic capability, enhanced drug delivery and efficient biodegradability still remains a scientific challenge. Herein, we report near-infrared light and tumor microenvironment (TME), dual responsive as well as size-switchable nanocapsules. These nanocapsules are made of a PLGA-polymer matrix coated with Fe/FeO core-shell nanocrystals and co-loaded with chemotherapy drug and photothermal agent. Smartly engineered nanocapsules can not only shrink and decompose into small-sized nanodrugs upon drug release but also can regulate the TME to overproduce reactive oxygen species for enhanced synergistic therapy in tumors. In vivo experiments demonstrate that these nanocapsules can target to tumor sites through fluorescence/magnetic resonance imaging and offer remarkable therapeutic results. Our synthetic strategy provides a platform for next generation smart nanocapsules with enhanced permeability and retention effect, multimodal anticancer theranostics, and biodegradability.

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Dynamic phototuning of 3D hydrogel stiffness

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1421897112 ◽

2015 ◽

Vol 112 (7) ◽

pp. 1953-1958 ◽

Cited By ~ 149

Author(s):

Ryan S. Stowers ◽

Shane C. Allen ◽

Laura J. Suggs

Keyword(s):

Near Infrared ◽

Infrared Light ◽

External Control ◽

Cell Phenotype ◽

Biological Processes ◽

Triggered Release ◽

In Vivo Experiments ◽

Cellular Microenvironments

Hydrogels are widely used as in vitro culture models to mimic 3D cellular microenvironments. The stiffness of the extracellular matrix is known to influence cell phenotype, inspiring work toward unraveling the role of stiffness on cell behavior using hydrogels. However, in many biological processes such as embryonic development, wound healing, and tumorigenesis, the microenvironment is highly dynamic, leading to changes in matrix stiffness over a broad range of timescales. To recapitulate dynamic microenvironments, a hydrogel with temporally tunable stiffness is needed. Here, we present a system in which alginate gel stiffness can be temporally modulated by light-triggered release of calcium or a chelator from liposomes. Others have shown softening via photodegradation or stiffening via secondary cross-linking; however, our system is capable of both dynamic stiffening and softening. Dynamic modulation of stiffness can be induced at least 14 d after gelation and can be spatially controlled to produce gradients and patterns. We use this system to investigate the regulation of fibroblast morphology by stiffness in both nondegradable gels and gels with degradable elements. Interestingly, stiffening inhibits fibroblast spreading through either mesenchymal or amoeboid migration modes. We demonstrate this technology can be translated in vivo by using deeply penetrating near-infrared light for transdermal stiffness modulation, enabling external control of gel stiffness. Temporal modulation of hydrogel stiffness is a powerful tool that will enable investigation of the role that dynamic microenvironments play in biological processes both in vitro and in well-controlled in vivo experiments.

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Functionalizing NaGdF4:Yb,Er Upconverting Nanoparticles with Bone-Targeting Phosphonate Ligands: Imaging and In Vivo Biodistribution

Inorganics ◽

10.3390/inorganics7050060 ◽

2019 ◽

Vol 7 (5) ◽

pp. 60 ◽

Cited By ~ 4

Author(s):

Silvia Alonso-de Castro ◽

Emmanuel Ruggiero ◽

Aitor Lekuona Fernández ◽

Unai Cossío ◽

Zuriñe Baz ◽

...

Keyword(s):

Near Infrared ◽

Ex Vivo ◽

Mri Contrast Agents ◽

Infrared Light ◽

In Vivo Biodistribution ◽

Bone Targeting ◽

Biodistribution Studies ◽

Positron Emission ◽

Pet Probes

Lanthanide-doped upconverting nanoparticles (UCNPs) transform near infrared light (NIR) into higher-energy UV and visible light by multiphotonic processes. Owing to such unique feature, UCNPs have found application in optical imaging and have been investigated for the NIR light activation of prodrugs, including transition metal complexes of interest in photochemotherapy. Besides, UCNPs also function as magnetic resonance imaging (MRI) contrast agents and positron emission tomography (PET) probes when labelled with radionuclides such as 18F. In this contribution, we report on a new series of phosphonate-functionalized NaGdF4:Yb,Er UCNPs that show affinity for hydroxyapatite (inorganic constituent of bones), and we discuss their potential as bone targeting multimodal (MRI/PET) imaging agents. In vivo biodistribution studies of 18F-labelled NaGdF4:Yb,Er UCNPs in rats indicate that surface functionalization with phosphonates favours the accumulation of nanoparticles in bones over time. PET results reveal leakage of 18F− for phosphonate-functionalized NaGdF4:Yb,Er and control nanomaterials. However, Gd was detected in the femur for phosphonate-capped UCNPs by ex vivo analysis using ICP-MS, corresponding to 6–7% of the injected dose.

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CREATION OF CLINICALLY-DIFFERENTIAL TUMOR MIMIC MODEL USING VASELINE-BASED MATERIALS WITH BARIUM SULFATE FOR THE VALIDATION OF REAL-TIME ULTRASOUND IMAGE-GUIDED LIVER BIOPSY SYSTEM

Biomedical Engineering Applications Basis and Communications ◽

10.4015/s1016237216500034 ◽

2016 ◽

Vol 28 (01) ◽

pp. 1650003

Author(s):

Cheng Li ◽

Jin Yao Teo ◽

Jiaze Wu ◽

Apoorva Gogna ◽

Bien Soo Tan ◽

...

Keyword(s):

Liver Biopsy ◽

Real Time ◽

Barium Sulfate ◽

Ex Vivo ◽

Ultrasound Image ◽

Tumor Model ◽

Palpable Mass ◽

Image Guided ◽

In Vivo Experiments

Testing objects are important for the validation of developing biopsy systems. Unfortunately, they are very hard to obtain. Motivated by this issue, the purpose of this study is to develop a technique for the easy creation of a model to simulate tumors of different sizes inside porcine livers, which could be used for ultrasound image-guided liver biopsy amongst other applications, and evaluate its performance by comparing to the more widely-used approaches in-vivo and ex-vivo. In this study, a Vaseline-based tumor model, and a more widely-used agar-based tumor model to provide comparison with the proposed method were created and injected into porcine livers as biopsy targets. The clinician located simulated tumors using real-time 2D imaging under the guidance of a robotic arm to delivery the biopsy in ex-vivo and in-vivo experiments. The results show that the optimum tumor model was created from a mixture of Vaseline, glycerol, and barium sulfate which can be easily produced and injected. All Vaseline-based simulated tumors were of solid, palpable mass on gross examination, and ultrasound imaging revealed clearly visible lesions. The clinician successfully performed ultrasound image guided liver biopsy in all the trials (10/10) in the ex-vivo experiment, and 2 out of 3 trials (2/3) in the in-vivo experiment on this optimum tumor model. We described a novel technique of creating solid liver tumor models that can be used for ultrasound image-guided liver biopsy.

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Glycan-Based Near-infrared Fluorescent (NIRF) Imaging of Gastrointestinal Tumors: a Preclinical Proof-of-Concept In Vivo Study

Molecular Imaging and Biology ◽

10.1007/s11307-020-01522-8 ◽

2020 ◽

Vol 22 (6) ◽

pp. 1511-1522 ◽

Cited By ~ 1

Author(s):

Ruben D. Houvast ◽

Victor M. Baart ◽

Shadhvi S. Bhairosingh ◽

Robert A. Cordfunke ◽

Jia Xin Chua ◽

...

Keyword(s):

Real Time ◽

Cell Lines ◽

Cancer Cell ◽

Near Infrared ◽

Ex Vivo ◽

Gastrointestinal Tumors ◽

Proof Of Concept ◽

Nirf Imaging ◽

Ht 29

Abstract Purpose Aberrantly expressed glycans in cancer are of particular interest for tumor targeting. This proof-of-concept in vivo study aims to validate the use of aberrant Lewis glycans as target for antibody-based, real-time imaging of gastrointestinal cancers. Procedures Immunohistochemical (IHC) staining with monoclonal antibody FG88.2, targeting Lewisa/c/x, was performed on gastrointestinal tumors and their healthy counterparts. Then, FG88.2 and its chimeric human/mouse variant CH88.2 were conjugated with near-infrared fluorescent (NIRF) IRDye 800CW for real-time imaging. Specific binding was evaluated in vitro on human gastrointestinal cancer cell lines with cell-based plate assays, flow cytometry, and immune-fluorescence microscopy. Subsequently, mice bearing human colon and pancreatic subcutaneous tumors were imaged in vivo after intravenous administration of 1 nmol (150 μg) CH88.2-800CW with the clinical Artemis NIRF imaging system using the Pearl Trilogy small animal imager as reference. One week post-injection of the tracer, tumors and organs were resected and tracer uptake was analyzed ex vivo. Results IHC analysis showed strong FG88.2 staining on colonic, gastric, and pancreatic tumors, while staining on their normal tissue counterparts was limited. Next, human cancer cell lines HT-29 (colon) and BxPC-3 and PANC-1 (both pancreatic) were identified as respectively high, moderate, and low Lewisa/c/x-expressing. Using the clinical NIRF camera system for tumor-bearing mice, a mean tumor-to-background ratio (TBR) of 2.2 ± 0.3 (Pearl: 3.1 ± 0.8) was observed in the HT-29 tumors and a TBR of 1.8 ± 0.3 (Pearl: 1.9 ± 0.5) was achieved in the moderate expression BxPC-3 model. In both models, tumors could be adequately localized and delineated by NIRF for up to 1 week. Ex vivo analysis confirmed full tumor penetration of the tracer and low fluorescence signals in other organs. Conclusions Using a novel chimeric Lewisa/c/x-targeting tracer in combination with a clinical NIRF imager, we demonstrate the potential of targeting Lewis glycans for fluorescence-guided surgery of gastrointestinal tumors.

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Fluorescent proteins for in vivo imaging, where's the biliverdin?

Biochemical Society Transactions ◽

10.1042/bst20200444 ◽

2020 ◽

Vol 48 (6) ◽

pp. 2657-2667

Author(s):

Felipe Montecinos-Franjola ◽

John Y. Lin ◽

Erik A. Rodriguez

Keyword(s):

Hydrogen Peroxide ◽

In Vivo Imaging ◽

Near Infrared ◽

Fluorescent Protein ◽

Fluorescent Proteins ◽

Fluorescent Imaging ◽

Infrared Light ◽

Red Fluorescent Protein ◽

Color Palette

Noninvasive fluorescent imaging requires far-red and near-infrared fluorescent proteins for deeper imaging. Near-infrared light penetrates biological tissue with blood vessels due to low absorbance, scattering, and reflection of light and has a greater signal-to-noise due to less autofluorescence. Far-red and near-infrared fluorescent proteins absorb light >600 nm to expand the color palette for imaging multiple biosensors and noninvasive in vivo imaging. The ideal fluorescent proteins are bright, photobleach minimally, express well in the desired cells, do not oligomerize, and generate or incorporate exogenous fluorophores efficiently. Coral-derived red fluorescent proteins require oxygen for fluorophore formation and release two hydrogen peroxide molecules. New fluorescent proteins based on phytochrome and phycobiliproteins use biliverdin IXα as fluorophores, do not require oxygen for maturation to image anaerobic organisms and tumor core, and do not generate hydrogen peroxide. The small Ultra-Red Fluorescent Protein (smURFP) was evolved from a cyanobacterial phycobiliprotein to covalently attach biliverdin as an exogenous fluorophore. The small Ultra-Red Fluorescent Protein is biophysically as bright as the enhanced green fluorescent protein, is exceptionally photostable, used for biosensor development, and visible in living mice. Novel applications of smURFP include in vitro protein diagnostics with attomolar (10−18 M) sensitivity, encapsulation in viral particles, and fluorescent protein nanoparticles. However, the availability of biliverdin limits the fluorescence of biliverdin-attaching fluorescent proteins; hence, extra biliverdin is needed to enhance brightness. New methods for improved biliverdin bioavailability are necessary to develop improved bright far-red and near-infrared fluorescent proteins for noninvasive imaging in vivo.

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Real-time observation of tetrapyrrole binding to an engineered bacterial phytochrome

Communications Chemistry ◽

10.1038/s42004-020-00437-3 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Yusaku Hontani ◽

Mikhail Baloban ◽

Francisco Velazquez Escobar ◽

Swetta A. Jansen ◽

Daria M. Shcherbakova ◽

...

Keyword(s):

Real Time ◽

Rational Design ◽

Near Infrared ◽

Fluorescent Proteins ◽

Covalent Bond ◽

Binding Pocket ◽

Tissue Imaging ◽

Covalent Attachment ◽

Time Resolved

AbstractNear-infrared fluorescent proteins (NIR FPs) engineered from bacterial phytochromes are widely used for structural and functional deep-tissue imaging in vivo. To fluoresce, NIR FPs covalently bind a chromophore, such as biliverdin IXa tetrapyrrole. The efficiency of biliverdin binding directly affects the fluorescence properties, rendering understanding of its molecular mechanism of major importance. miRFP proteins constitute a family of bright monomeric NIR FPs that comprise a Per-ARNT-Sim (PAS) and cGMP-specific phosphodiesterases - Adenylyl cyclases - FhlA (GAF) domain. Here, we structurally analyze biliverdin binding to miRFPs in real time using time-resolved stimulated Raman spectroscopy and quantum mechanics/molecular mechanics (QM/MM) calculations. Biliverdin undergoes isomerization, localization to its binding pocket, and pyrrolenine nitrogen protonation in <1 min, followed by hydrogen bond rearrangement in ~2 min. The covalent attachment to a cysteine in the GAF domain was detected in 4.3 min and 19 min in miRFP670 and its C20A mutant, respectively. In miRFP670, a second C–S covalent bond formation to a cysteine in the PAS domain occurred in 14 min, providing a rigid tetrapyrrole structure with high brightness. Our findings provide insights for the rational design of NIR FPs and a novel method to assess cofactor binding to light-sensitive proteins.

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