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Some counterintuitive lessons learned from the OSA BIOMED meeting

By Kyle Quinn | Posted: 6 May 2014

With the conclusion of another BIOMED meeting, I once again left Miami impressed by the many excellent talks, clever imaging solutions, and novel biological insights.  I’ve appreciated the opportunity to share my thoughts about the conference through this blog, and in conclusion, I thought I would highlight three things that I was rather surprised to learn.

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Seeing the blood flow that helps us see

By Ken Tichauer | Posted: 30 April 2014

The quality of the posters at the the OSA biomedical optics conference this year has been exceptionally high and over the last three days I came across a number of projects that warranted highlighting in the blog. Some of these include the work of Jessica Kishimoto and Prof. Keith St. Lawrence at Western University on the application of diffuse correlation spectroscopy and ultrasound imaging to monitor blood flow changes in preterm infants with post-hemorrhagic hydrocephalus,1 and the work of William Rice and Prof. Anand Kumar at Massachusetts General Hospital on separating fluorescence from multiple similar fluorescent proteins and autofluorescence based on some elegant lifetime analysis.2 However, some of the work that stuck with me the most were some developments in the use of optical coherence microscopy to measure mean blood flow.

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Optical Tomographers Beware!

By Ken Tichauer | Posted: 30 April 2014

To all of you optical tomography researchers reading this: admit it, you’re a bit of a gadget geek. The last thing you want is to let your expensive, fancy equipment come into contact with your imaging subjects, especially animals. That’s the real reason why you keep building all of your systems in “non-contact” geometries. Well, according to Shelley Taylor from Prof. Hamid Dehghani’s lab at the University of Birmingham your OCD may finally be coming back to bite you in the a...*cough*…back.

It turns out that if you have your system in a non-contact geometry and you aren’t carrying out the appropriate free-space modeling (incorporating the orientation of the surface of the imaging subject at each detection position into your reconstruction model), you could be opening yourself up to errors in approximately 25%. Don’t take my word for it; Dr. James Guggenheim has recently published a very nice demonstration of this effect in his recent manuscript published in JOSA A.1

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The integration of optical technologies to manipulate and monitor biological samples

By Kyle Quinn | Posted: 29 April 2014

This morning at the BIOMED meeting, there were back-to-back talks in the Optical Molecular Biophysics / Neurophotonics session that highlighted the unique insights that can be obtained by integrating different optical technologies. Anna-Karin Gustavsson from Dr. Caroline Adiels group gave an interesting talk that integrated multifluidics, optical trapping, and NADH autofluorescence measurements to monitor glycolytic oscillations in individual yeast cells. Optical trapping was used to maintain and calibrate specific cell-cell distances, while a microfluidic flow chamber provided the influx of different concentrations of glucose, cyanide, and acetaldehyde to the cells. Glycolytic oscillations could then be monitored through NADH autofluorescence fluctuations measured by an EM-CCD. Using this controlled environment, fundamental studies to understand cell-cell communication and cell coupling are being explored.

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Speeding up multi-photon microscopy

By Kyle Quinn | Posted: 29 April 2014

As someone with strong research interests in multiphoton microscopy (MPM), I was excited to hear Dr. Peter So’s plenary talk on Day 3 of the BIOMED meeting. Dr. So provided an overview of the development of his multiphoton tissue cytometry equipment over the years, and its applications in neurobiology. MPM has emerged as key tool in neuroscience to non-invasively image deeper within the brain. Although multiphoton microscopy is well-positioned to provide high content information throughout the cortex of rodents and other smaller species, his work has primarily been motivated by efforts to maximize the throughput of this technology. By imaging faster and over a wider field of view, important questions regarding the functional and structural plasticity of neurons can be addressed.

Traditionally MPM involves raster scanning to produce an image one pixel at a time, but Dr. So’s work has involved the development of wide-field MPM techniques that utilize a CCD or multi-anode PMTs for the simultaneous collection of points. There are a number of technical challenges associated with the different approaches to wide-field MPM imaging, and Dr. So provided insight into the different solutions to these problems (e.g. temporal focusing, eliminating issues of dead space between PMTs, non-descanned detection) and the many iterations of his microscopes. In addition to imaging faster through these wide-field techniques, his group can take advantage of the inherent high content of microscopy techniques to acquire spectral data, such as fluorescence lifetime and phosphorescence lifetime imaging. Phosphorescence lifetime imaging is typically challenging because it requires very long image acquisition times, but his temporal-focusing wide-field MPM approaches can substantially reduce imaging times to enable relatively fast, high resolution imaging of oxygen distributions in the brain.

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The OSA BIOMED Meeting Day 1: Things are heating up in Miami

By Kyle Quinn | Posted: 28 April 2014

Greetings from Miami! BIOMED has gotten off to great start with a pair of plenary talks by Dr. Xingde Li and Dr. Adam Wax. As I mentioned in a previous post, Dr. Li has been developing and refining endomicroscopic probes to facilitate non-linear optical microscopy in hard to reach places such as the kidney, intestine, and cervix. Dr. Wax, on the other hand, has taken a different approach to delivering and detecting photons from deeper within the body through the use of low coherence interferometry (LCI).

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The Binding Finding of a Fluorescence Lifetime

By Ken Tichauer | Posted: 27 April 2014

In this afternoon’s session on Luminescence and Absorption on Cellular and Tissue Levels, Prof. Victor Chernomordik gave an overview of the extensive work he and his colleagues have been undertaking to make fluorescence molecular imaging more quantitative. Much of their work has focused specifically on how to quantify human epidermal growth factor receptor 2 (HER2) concentrations (a key receptor of interest in breast cancer) using kinetic models, and they have a number of publications in this area that I urge you to check out;1-5 however, what I was most intrigued by was there recent results demonstrating a dependence of fluorescence lifetime on the binding state of a targeted fluorescent tracer. In simpler terms, what they found was that the timing characteristics of fluorescence emission was significantly different depending on whether their fluorescent tracer was bound to the target of interest or not.6,7

This offers their group a window into separating non-specific uptake of a tracer, a major problem in conventional molecular imaging of tumors, from the more interesting bound fraction of the targeted tracer. Moreover, for reversible binding tracers (tracers that can dissociate from there targeted molecule), the ratio of the bound fraction of a tracer to the unbound fraction of tracer is directly proportional to the concentration of the targeted biomolecule.8 Therefore, as Prof. Chernomordik and his colleagues unearth the exact relationship between bound fraction and fluorescence lifetime, there is a clear pathway forward to using this approach to directly quantify HER2 concentration, something that is impossible to do with other conventional single tracer approaches in tumors.9

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The Early Photon Gets the Worm

By Ken Tichauer | Posted: 25 April 2014

One of the biggest problems with using light to analyze biological tissue is that photons in the visible and near-visible spectrum have a very high probability of scattering multiple times as they propagate through the tissue. This is a well-known problem that restricts high-resolution optical microscopy to tissue thicknesses of only a few microns. It has also led researchers to develop complicated iterative reconstruction algorithms that incorporate models of scattering light propagation as a means of achieving usable image resolution in thicker tissue samples or in small animals. Even so, the ultimate resolution of these reconstruction algorithms is on the order of millimeters, far from the impressive micron and sub-micron scale resolution achievable by microscopy.

So the question is, what if we could tell the difference between photons that took a direct route through the tissue (non-scattering photons) and photons that took a more roundabout route (scattering photons)?

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The Role of Chance in Biomedical Imaging

By Kyle Quinn | Posted: 7 April 2014

Much of my work as a postdoctoral trainee at Tufts University has focused on utilizing endogenous sources of optical contrast to assess tissue development and disease. To this end, our lab has utilized non-linear optical microscopy to non-destructively characterize tissue organization and metabolic function with an emphasis on understanding and detecting stem cell differentiation and precancerous transformations. As I think about all the researchers, past and present, that have provided fundamental contributions to my area of research, no one looms larger than Dr. Britton Chance. (Article continues below.)

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The recent evolution of biomedical optics in one graphic*

By Kyle Quinn | Posted: 27 March 2014

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Salt and Pepper (Noise): Key Ingredients for Imaging Blood Flow

By Ken Tichauer | Posted: 25 March 2014

We’ve all experienced that “salt-and-pepper”, or white noise when our favorite television show cuts out on us. Well it turns out that similar “speckle” patterns are also seen when projecting laser light onto biological tissue, owing to interference patterns of the monochromatic light source. Now you might say, “so what!” and that’s probably what most would say. However, in the early 1980’s Fercher and Brier realized that movement of blood could disturb the laser speckle pattern, and this disturbance could be used to estimate blood flow [1].

In the decades following this breakthrough, Laser Speckle Imaging has been employed to visualize blood flow in the skin [2], the retina [3], and brain [4]. To date there are over 600 published articles that have included biomedical applications of Speckle Imaging. Why so popular? There are certainly many other approaches available for monitoring blood flow such as Doppler ultrasound, laser Doppler, and a slew of dynamic contrast enhanced imaging modalities. However, none of these approaches can offer the exquisite temporal resolution (milliseconds), and spatial resolution (10s of microns) that can be attained by Laser Speckle Imaging. And nowhere have these advantages been used to greater benefit than in the study of “neurovascular coupling”, which necessitates the ability to resolve the interplay between neuronal activity and blood delivery in the brain at the millisecond and micron resolution scales only offered by Speckle Imaging.

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Reducing Drug Trial Costs with Imaging Technology

By Ken Tichauer | Posted: 4 March 2014

95% of new cancer therapeutics fail to make it past Phase II clinical trials. This means that while it should only cost about $50 million per drug for FDA approval, incorporating the cost of failures leads to an estimated cost of $1 billion per drug (1), with a recent Forbes article suggesting that this number is considerably higher (2).So why are so many drugs failing in clinical trials?

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How to fit a laser-scanning microscope into a 2mm diameter tube

By Kyle Quinn | Posted: 28 February 2014

Optical microscopy can provide high-resolution images of cellular morphology and matrix organization, which can be utilized to diagnose disease or trauma. However, achieving an adequate signal-to-noise ratio at imaging depths exceeding 1mm is very challenging.  As a result, the initial clinical applications for optical microscopy techniques have largely focused on skin pathology.  One approach to unlocking a wider spectrum of clinical applications for biomedical optics is miniaturizing the distal end of microscopes into endoscopic probes.

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Pushing the limits of imaging resolution and penetration depth

By Kyle Quinn | Posted: 28 February 2014

The development of labeling techniques capable of providing customizable molecular specificity has made optical microscopy a fundamental technique in the biomedical research, and the standard compound microscope remains a fixture in just about any clinic or biomedical lab. The popularity of optical microscopy was also driven by the ability to provide resolution at the cellular level that traditional clinical imaging modalities (e.g. ultrasound, x-ray CT, and MRI) simply cannot meet. The finer structural details of biological tissues were further elucidated through the development of transmission electron microscopy, which enabled unparalleled views at the scale of proteins and molecules. However, like all imaging technologies, there is a tradeoff between imaging resolution and penetration depth, and electron microscopy has extremely limited penetration depth.

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It takes blood, sweat, and SERS to image single cells

By Ken Tichauer | Posted: 20 February 2014

Throw out those old dusty fluorescent molecules and welcome in the next generation of optical contrast agents. SERS (Surface Enhanced Raman Scattering/Spectroscopy) nanoparticles are sophisticated new contrast agents that offer some distinct advantages over conventional fluorescent molecules for investigating molecular biology.

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Where would biomedicine be without optics?

By Kyle Quinn | Posted: 10 February 2014

Much of the emphasis in biomedical optics research has been placed on the clinical translation of our technologies -- and rightfully so!  As my fellow blogger Dr. Ken Tichauer indicates, the potential impact in the clinic is great and the future remains bright.  But as we gear up for OSA BIOMED 2014 in Miami, I will be excited to learn about some of the latest applications in basic science research where biomedical optics continues to play a key role. The field of optics has provided researchers advanced tools that are needed in a variety of other disciplines to optimize complex laboratory protocols, to elucidate the underlying mechanisms of disease, and to speed the preclinical development of novel therapies. Optogenetics






















 

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Photoimmunotherapy (PIT) busts open the doors for drug delivery

By Ken Tichauer | Posted: 6 February 2014

Over the last decade alone, it is estimated that over $200 billion has been spent just by governments to fund cancer research [1]. Despite this enormous investment, the recently released 2014 World Heath Organization (WHO) Cancer Report suggests that cancer incidence rates and deaths from cancer are on the rise, both in more developed and less developed nations.

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Beginning of a new era? Recent advances in biomedical optics light the way to long-awaited clinical translation

By Ken Tichauer | Posted: 29 January 2014

For decades biomedical optics has been touted as an ideal tool for diagnosing, monitoring and/or treating a vast array of health conditions owing to low-cost instrumentation, use of non-ionizing radiation, and incomparable sensitivity. All great characteristics; nonetheless, adoptions of optical devices in the clinic have been few and far-between. One could blame regulations, the high cost of clinical trials, and provider inertia; but these hurdles would be behind us if the optical approaches on health and healthcare costs made more more significant impact. We're not there yet.

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