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www.Photonics.comOPTICS, LASERS, IMAGING, MICROSCOPY, SPECTROSCOPY
March 2012
Laser Turn SignalsGuide Nerve Fiber Growth
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8 BIOSCANBioPhotonics editors curate the most significant headlines
of the month for photonics in the life sciences and take
you deeper inside the news. Featured stories include:
Particle manipulation using light made accessible Optochemical genetics to turn pain off, sight on
Single step creates quantum dots in bulk
for biomedical imaging
17 BUSINESSSCANSPIE honors Robert Alfano with Britton Chance Award
NEWS
20
BioPhotonics March 2012
20 COLLABORATION SPARKS NERVE-FIBER TURN SIGNAL DISCOVERYby Laura S. Marshall, Managing Editor
A recent multidisciplinary, multi-institution, multinational project has found
a way to direct nerve-fiber growth using laser-driven spinning microparticles.
24 PDT FOR CANCER DEPENDS ON IMPROVED PHOTOSENSITIZERSby Lynn Savage, Features Editor
Compared with chemotherapy and radiation, photodynamic therapy may target
tumors more precisely, but the technique demands better photosensitizers
than are currently available.
28 MOVING NONINVASIVE CANCER IMAGING INTO THE CLINICby Gary Boas, News Editor
The challenges of applying coherence imaging technologies to cancer treatment
include developing turnkey systems, overcoming business hurdles and
building clinical partners.
31 TRANSORAL LASER MICROSURGERY FIGHTS LARYNGEAL CANCERby Lynn Savage, Features Editor
The benefits of light-based microsurgery include speed,
precision and the various options for follow-up care.
FEATURES
NEWS
www.photonics.comVolume 19 Issue 3
6 EDITORIAL
35 BREAKTHROUGHPRODUCTS
40 APPOINTMENTSUpcoming Courses and Shows
41 ADVERTISER INDEX
42 POST SCRIPTS
by Laura S. Marshall, Managing EditorThe art of science
DEPARTMENTS
PHOTONICS
The technology of generating and harnessing light and other forms of radiant energy whosequantum unit is the photon. The range of applications of photonics extends from energy generation
to detection to communications and information processing.
BIOPHOTONICS
The application of photonic products and techniques to solve problems for researchers,product developers, clinical users, physicians and others in the fields of medicine,
biology and biotechnology.
THE COVER
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www.iridian.ca
IRIDIAN
BioPhotonics March 2012
Group Publisher Karen A. Newman
Editorial StaffManaging Editor Laura S. Marshall
Senior Editor Melinda A. RoseFeatures Editor Lynn M. Savage
News Editors Gary Boas, Caren B. Les, Ashley N. Paddock
Contributing Editors Hank Hogan, Marie FreebodyCopy Editors Judith E. Storie, Patricia A. Vincent,
Margaret W. Bushee
Creative Staff
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Designer Janice R. Tynan
Director of Publishing Operations Kathleen A. Alibozek
Electronic Media Staff
Director Charley RoseMultimedia Services & Marketing
Web Development Team Leader Brian L. LeMireWeb Developers Alan W. Shepherd
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Corporate Staff
Chairman/CEO Teddi C. LaurinPresident Thomas F. LaurinController Mollie M. Armstrong
Accounting Manager Lynne LemanskiAccounts Receivable Manager Mary C. Gniadek
Business Manager Elaine M. FiliaultHuman Resources Coordinator Carol J. Atwater
Business Staff
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Subscription Policy BioPhotonics ISSN-1081-8693 (USPS 013913) is published 10 times per year by LaurinPublishing Co. Inc. TITLE reg. in US Library of Congress. The issues will be as follows: January, February,March, April, May/June, July/August, September, October, November/ December. Copyright 2012 by Lau-rin Publishing Co. Inc. All rights reserved. POSTMASTER: Periodicals postage paid at Pittsfield, MA, and at ad-ditional mailing offices. Postmaster: Send form 3579 to BioPhotonics, Berkshire Common, PO Box 4949,Pittsfield, MA 01202-4949, +1 (413) 499-0514. CIRCULATION POLICY: BioPhotonics is distributed without charge
to qualified researchers, engineers, practitioners, technicians and management personnel working with thefields of medicine or biotechnology. Eligibility requests must be returned with your business card or organi-zations letterhead. Rates for others as follows: $45 domestic and $56.25 outside US per year prepaid. Over-seas postage: $30 airmail per year. Publisher reserves the right to refuse nonqualified subscriptions. ARTICLESFOR PUBLICATION: Individuals wishing to submit an article for possible publication in BioPhotonics shouldcontact Laurin Publishing Co. Inc., Berkshire Common, PO Box 4949, Pittsfield, MA 01202-4949; phone: +1 (413)499-0514; fax: +1 (413) 442-3180; email: [email protected]. Contributed statements and opinions ex-
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Light Is Cancers Latest Foe
The race to cure a killer disease first got federal support back
in 1937, when US President Franklin D. Roosevelt signed
the National Cancer Institute (NCI) Act. On Jan. 3, 1938, the
National Advisory Cancer Council recommended approval of the
first cancer research fellowships.
Decades of research, both privately and federally funded, have
certainly broadened our understanding of this disease about the
causes, risk factors, treatments and more yet so much about
cancer is still unknown or not well understood. Meanwhile, can-
cer deaths are projected to continue rising, with an estimated 13.1
million deaths expected in 2030, according to the World Health
Organization.
In its 2012 annual plan and budget report, Cancer: Changing
the Conversation, the NCI discussed our new understanding ofthe disease and its complexity as well as the range of opportuni-
ties to confront its many incarnations.
The report also described a vital opportunity to speed up
cancer study and treatment. The emerging scientific landscape
offers the promise of significant advances for current and future
cancer patients, just as it offers scientists at the National Cancer
Institute and in the thousands of laboratories across the United
States that receive NCI support the opportunity to dramatically
increase the pace of lifesaving discoveries where progress has
long been steady but mostly incremental.
Biophotonics is part of that emerging scientific landscape. Agreat deal of effort is going into applying light to cancer research,
diagnosis and treatment throughout the photonics community,
with coherence imaging for cancer diagnosis among the topics
getting a lot of attention lately. There also is a growing under-
standing among researchers about just what it will take to
increase the pace of lifesaving discoveries.
In Moving Noninvasive Cancer Imaging into the Clinic
(page28),BioPhotonics news editor Gary Boas reveals the
challenges researchers face in getting their light-based technolo-
gies into clinical trial and use, and talks with two researchers
working to move new imaging options into clinical use. In the
article, Jon Holmes, CEO of Kent, UK-based Michelson Diag-nostics Ltd., advises physics and engineering groups should
closely partner with clinical teams and work with them on a
specific clinical need over a long period of time (decades) in a
focused manner with a clear long-term goal of developing an
exploitable device evaluated with clinical trials. Funders should
also actively support this type of collaborative work.
BioPhotonics features editor Lynn Savage contributes two
reports on the topic of cancer. PDT for Cancer Depends on
Improved Photosensitizers (page 24)explains how photody-
namic therapy could be the future of cancer treatment.
Photodynamic therapy (PDT) is proving to be a more than
viable option for cancer treatment. Compared with other treat-
ments, such as chemotherapy and radiation therapy, PDT is more
selective, causing far less damage to healthy cells near cancer-
ous targets due to the precise way in which photosensitizers
can locate and infiltrate tumor cells.
In his second article, Transoral Laser Microsurgery FightsLaryngeal Cancer (page31), Lynn says that, thanks to laser
surgery refinements, your life or your voice is a choice fewer
people in the world have to face. In the US alone, 10,000 people
are diagnosed each year with laryngeal carcinoma, according
to the American Cancer Society. This cancer affects the vocal
cords and the connective tissues surrounding them, and laser
microsurgery could help save both lives and voices.
Despite the very long strides taken over the past few decades,
there is much more work to be done to further our understanding
of this disease of many parts. Asking new questions based on
the growing body of knowledge, finely focusing and directing
research, and adequately funding those efforts will go a longway toward achieving the ultimate goal of many fewer deaths
from cancer. Light and the dedicated people in this industry who
harness it to understand this killer are bringing new direction to
the fight.
6 BioPhotonics March 2012
EDITORIAL
Karen A. [email protected]
mailto:[email protected]:[email protected] -
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Photonics Medias industry-leading site features the latest industry news and events
from around the world.
Welcome to
Biophotonics News:
A round-up of the industrys topbio-related research headlines.
Visit: Photonics.com/Biophotonics
Editors fromphotonics.com,Photonics Spectra and Bio-
Photonics magazines bringyou the top photonic researchand business news of the week.
For the photonics industrysonly weekly newscast,visit: Photonics.com/LightMatters.
Photonics.com Forum
Join the Discussion!Our photonics communityprovides a place where allmembers can discuss and askfor help on a wide variety oftechnical topics. Membershipis free, so sign up today andjoin in on the discussions!
Visit: Photonics.com/Forum
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BIOSCAN
URBANA, Ill. Dexterous optical tweez-ing and size-sorting of particles can now
be done by tuning the properties of laser
light illuminating arrays of metal nano-
antennas.
In work conducted at the University of
Illinois at Urbana-Champaign, assistant
professor of mechanical science Kimani
Toussaint Jr. and his research team have
demonstrated for the first time the use of
gold bowtie nanoantenna arrays for multi-
purpose optical trapping and manipulation
of submicrometer- to micrometer-size
objects. The findings could prove usefulfor the growing interest in lab-on-a-chip
devices.
The field enhancement and confinement
properties of bowtie nanoantenna arraysalso make them accessible for formation
of optical matter, manipulation of biologi-
cal matter with reduced specimen photo-
damage and for basic physics studies of
colloidal dynamics.
We believe that our work shows that
optical nanoantennas could serve as inte-
gral components in potential lab-on-chip
devices, Toussaint said. The basic idea
is to use nanoantennas to augment the
optical forces on objects (e.g., cells) in
aqueous environments. This will consider-
ably relax the requirements on the opticsused for such experiments.
Using empirically obtained optical
trapping phase diagrams to achieve the
desired trapping response, the researchersdemonstrated several types of particle ma-
nipulation, including single-beam optical
tweezing of single particles over the entire
nanoantenna area, single-beam optical
tweezing of two-dimensional hexagonal-
packed particles over the entire nano-
antenna area, and optical sorting of parti-
cles by size. They also showed stacking
of submicron- to micron-size particles in
three dimensions.
For a given particle size, wavelength
and desired type of manipulation, the trap-
ping phase diagrams provide informationon the input power and nanoantenna array
spacing required to achieve the desired
task. They are empirically derived and
become an easy way to harness the forces
in the nanoantenna platform that are
otherwise complex to fully model,
Toussaint said.
This is the first demonstration of a
range of particle manipulation behavior
for a given nanoantenna array, according
to Toussaint.
Perhaps the most immediate impact is
that we have helped to make general parti-
cle manipulation (using light) accessible,
he said. Single- and multiple-particle
trapping, as well as sorting, is now very
doable using a fixed nanoantenna platform
and without the use of high-power lasers,
extremely tight focusing or multiple laser
beams.
In fact, his team conducted most of its
experiments using an average power at
least 1000 times less than that of a stan-
dard laser pointer. A laser pointer was
used for some proof-of-concept experi-
ments to show that ubiquitous off-the-
shelf technology could be used easily withthe nanoantenna system because of the
structures ability to enhance optical
fields, he said.
The beam quality of a laser pointer is
often not ideal for conventional optical
trapping experiments without a fair
amount of spatial filtering, but for our
system it does not matter, he said. We
could get away with using relatively
cheap and dirty optics.
The research appeared online Dec. 30
inNano Letters (doi: 10.1021/nl203811q).
Particle manipulation using light made accessible
8 BioPhotonics March 2012
A closer look at the most significant biophotonics research and technology headlines of the month
Concept art depicting the various potential bowtie nanoantenna array trapping states. Courtesy of
Kimani C. Toussaint Jr., University of Illinois.
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BERKELEY, Calif., and MUNICH Optogenetic tools that use light to control
neurons could lead to highly targeted pain
relief and might even restore sight to the
blind, say biologists at the University of
California, Berkeley (UCB) and Ludwig
Maximilian University (LMU) of Munich.
UCBs Richard H. Kramer and Dirk
Trauner of LMU sought to develop a mol-
ecule that can block the activity of pain-
sensing neurons in a controlled and re-
versible way. Local anesthetics suppress
pain by blocking the activity of pain-
sensing neurons, but most act nonselec-tively on all nervous system cells.
The researchers synthesized the mole-
cule quaternary ammonium-azobenzene-
quaternary ammonium, or QAQ, which is
structurally similar to a lidocaine derivate
they had used in the past. While the two
molecules use the same mechanism to
selectively enter pain-sensing neurons,
QAQ features an important difference: Its
activity can be controlled by light. Specifi-
cally, ultraviolet light turns it on, and
green light turns it off.
They demonstrated the capacity of QAQ
as a light-sensitive analgesic in the retina
of living rats in a paper published online
Feb. 19 inNature Methods (doi: 10.1038/
NMETH.1897).
Unblinded by the light
Another collaborative venture between
chemists at the two universities success-
fully converted an intrinsically blind re-
ceptor molecule into a photoreceptor, a
feat that one day might allow use of such
synthetic photoreceptors to restore sight to
those with certain types of blindness, said
Trauner, a professor of chemical biologyand genetics at LMU and one of the pro-
jects leaders.
Communication between nerve cells
relies on specialized receptor molecules
on the surfaces of the neurons to relay sig-
nals back and forth. But the investigators
found that they could use molecular ge-
netic techniques to attach what amounts
to a light-controlled chemical switch to
a receptor that normally is activated by
the endogenous neurotransmitter acetyl-
choline.
These molecular machines transmit
nerve impulses by converting an incoming
chemical signal into an electrical response,
which is then propagated along the length
of the nerve fiber. Binding acetylcholineto the external surface of the receptor acts
as a switch a research method known
as optochemical genetics.
As with the light-sensitive pain relief
applied to rat eyes, the synthetic photo-
receptors can be switched on using UV
light and switched off using green light.
The project was carried out under the
auspices of the Collaborative Research
Center on Formation and Function of
Neuronal Circuits in Sensory Systems,
which is funded by the German Research
Foundation.
Trauner received a European Research
Council grant in 2010 for a project that is
also based on a photopharmacological
approach. The long-term goal of thisongoing research is to find ways of com-
pensating for the loss of dedicated photo-
receptors in the eye, the most common
cause of blindness. He is working to
develop hybrid photoreceptors.
The basic idea, which has in principle
been shown to work in animal models,
is to confer light sensitivity on surviving
neurons in the eye that do not normally
respond to light, Trauner said.
The work was published online Jan. 8 in
Nature Chemistry (doi: 10.1038/NCHEM.
1234).
BioPhotonics March 2012 9
Optical control of pain-sensing neurons. QAQ selectively enters pain-sensing neurons and silencestheir activity (top, green light). Illumination with violet light (bottom) quickly restores signal conduction.Courtesy of Alexandre Mourot.
Optochemical genetics to turn pain off, sight on
http://www.nature.com/nmeth/journal/vaop/ncurrent/full/nmeth.1897.htmlhttp://www.nature.com/nmeth/journal/vaop/ncurrent/full/nmeth.1897.htmlhttp://www.nature.com/nmeth/journal/vaop/ncurrent/full/nmeth.1897.htmlhttp://www.nature.com/nmeth/journal/vaop/ncurrent/full/nmeth.1897.htmlhttp://www.nature.com/nchem/journal/v4/n2/full/nchem.1234.htmlhttp://www.nature.com/nchem/journal/v4/n2/full/nchem.1234.htmlhttp://www.nature.com/nchem/journal/v4/n2/full/nchem.1234.htmlhttp://www.nature.com/nchem/journal/v4/n2/full/nchem.1234.htmlhttp://www.nature.com/nmeth/journal/vaop/ncurrent/full/nmeth.1897.html -
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protein analysis, cell tracking and other
biomedical applications, Gao said. Tests at
Houstons MD Anderson Cancer Center
and Baylor College of Medicine on two
human breast cancer lines showed that the
quantum dots easily found their way into
the cells cytoplasm and did not interferewith their proliferation.
The green quantum dots yielded a very
BioPhotonics March 2012 11
bBIOSCAN
good image, said co-author Rebeca
Romero Aburto, a graduate student in the
Ajayan Lab who also studies at MD An-
derson. The advantage of graphene dots
over fluorophores is that their fluores-
cence is more stable and they dont photo-
bleach. They dont lose their fluorescenceas easily. They have a depth limit, so they
may be good for in vitro and in vivo stud-
ies, but perhaps not optimal for deep tis-
sues in humans.
The quantum dots could help bioimag-
ing, she said. In the future, these graphene
quantum dots could have high impact be-
cause they can be conjugated with other
entities for sensing applications too.The results were published online Jan. 4
inNano Letters (doi: 10.1021/nl2038979).
Superlens nears reality in theoryHOUGHTON, Mich. A new theoretical
model shows that a superlens could view
objects as small as 100 nm using visible
light. If this model is realized, ultrahigh-
resolution microscopes could become as
commonplace as cell phone cameras.
Scientists have yet to create a superlens,or perfect lens, although they have tried.
Optical lenses are shackled by the diffrac-
tion limit, so even the best cannot see ob-
jects smaller than 200 nm across, or about
the size of the smallest bacterium. Scan-
ning electron microscopes can capture ob-
jects that are significantly smaller about
1 nm wide but they are heavy, expensive
and large about the size of a desk.
Metamaterial model
Scientists are beginning to fabricate
metamaterials in their quest to make real
seemingly magical phenomena like invisi-
bility cloaks, quantum levitation and
superlenses. At Michigan Technological
University, Durdu Guney has demon-
strated a theoretical model for stretching
metamaterial to refract light from the
infrared to the visible and ultraviolet
regimes.
An assistant professor of electrical and
computer engineering, Guney demon-
strated through his model that the secret
lies in plasmons charge oscillations near
the surface of thin metal films that com-
bine with special nanostructures. Whenexcited by an electromagnetic field, the
surface plasmons gather light waves from
an object and refract them in a manner
known as negative refraction. This phe-
nomenon enables the lens to overcome
the diffraction limit, and in the case of
Guneys model, could enable scientists
to see objects smaller than 1/1000th the
width of a human hair. His research
appeared in the journalPhysical Review B
(doi: 10.1103/PhysRevB.84.195465).
Producing the superlenses is inexpen-
sive, according to Guney, which is why
they could find their way into cell phones.
Lithography would be another suitable
application, since the size of a feature to
be produced depends on lens size. Even
smaller features could be created, and at
a lower cost, by replacing old lenses with
the theoretical superlenses, Guney said.
With the help of these superlenses, even
a red laser could be used to produce com-
puter chips, he explained.
The publics access to high-powered
microscopes is negligible, Guney said.
With superlenses, everybody could be
a scientist. People could put their cells on
Facebook. It might just inspire societys
scientific soul.
An illustration of Durdu Guneys theoretical negative-index metamaterial, which would be the heart of a perfectlens. The colors show magnetic fields generated by plasmons. The black arrows show the direction of electricalcurrent in metallic layers, and the numbers indicate current loops that contribute to negative refraction.Courtesy of Durdu Guney, Michigan Technological University.
http://pubs.acs.org/doi/abs/10.1021/nl2038979http://prb.aps.org/abstract/PRB/v84/i19/e195465http://prb.aps.org/abstract/PRB/v84/i19/e195465http://pubs.acs.org/doi/abs/10.1021/nl2038979 -
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b BIOSCAN
LONDON The technology used for full-
body security scanners could one day lead
to the development of a handheld scanner
similar to the tricorder made famous by
Star Trek. The device will be suitable formedical scanning thanks to a new tech-
nique for creating terahertz waves (T-
rays).
Scientists from the Institute of Materials
Research and Engineering (IMRE), a
branch of the Agency for Science, Tech-
nology and Research in Singapore, and
from Imperial College London have made
T-rays into a much stronger directional
beam than previously thought possible and
have done so in room-temperature condi-
tions. This breakthrough should allow
future T-ray systems to be smaller, moreportable, easier to operate and cheaper to
develop than current devices.
The researchers say the stronger, more
efficient continuous-wave T-rays could be
used to make better medical scanning
gadgets.
The scanner and detector could function
much like the tricorder a portable sens-
ing, computing and data communications
device because the waves can detect
biological events such as increased blood
flow around tumorous growths, the re-searchers say. Future scanners also could
perform fast wireless data communication
to transfer a high volume of information
on the measurements it makes.
T-rays, waves in the far-infrared part of
the electromagnetic spectrum, are already
in use in airport security scanners, proto-
type medical scanning devices and in
spectroscopy systems for materials analy-
sis. They can sense molecules such as
those present in cancerous tumors and liv-
ing DNA because every molecule has its
unique signature in the terahertz range.They also can be used to detect explosives
or drugs, to monitor gas pollution, or to
nondestructively test semiconductor inte-
grated circuit chips.
Current T-ray imaging devices are very
expensive and operate only at a low output
power because creating the waves con-
T-rays could lead to real-life tricorder
Research author professor Stefan Maier in thelaboratory. Courtesy of Imperial College London.
sumes large amounts of energy and must
take place at very low temperatures.
In the new technique, the researchers
demonstrated that it is possible to produce
a strong beam of T-rays by shining light
of differing wavelengths on a pair of elec-
trodes two pointed strips of metal sepa-
rated by a 100-nm gap on top of a semi-
conductor wafer. The structure of the
tip-to-tip nanosize-gap electrode greatly
enhances the terahertz field and acts as a
nanoantenna to amplify the wave gener-
ated. In this method, terahertz waves are
produced by an interaction between the
electromagnetic waves of the light pulses
and a powerful current passing between
the semiconductor electrodes. The scien-
tists can tune the wavelength of the T-rays
to create a usable beam in the scanning
technology.
The secret behind the innovation lies
in the new nanoantenna that we had devel-
oped and integrated into the semiconduc-
tor chip, said Dr. Jing Hua Ten of IMRE,
who was the lead author of the study. The
work was published inNature Photonics
(doi: 10.1038/nphoton.2011.322).
Arrays of these nanoantennas create
much stronger terahertz fields that gener-
ate a power output 100 times higher than
that of commonly used terahertz sources
that have conventional interdigitated an-
tenna structures. A stronger T-ray source
gives more power and higher resolution
to the T-ray imaging devices.
T-rays promise to revolutionize med-
http://www.nature.com/nphoton/journal/v6/n2/full/nphoton.2011.322.htmlhttp://www.prior.com/mailto:[email protected]://www.prior.com/http://www.prior.com/http://www.nature.com/nphoton/journal/v6/n2/full/nphoton.2011.322.html -
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bBIOSCAN
ical scanning to make it faster and more
convenient, potentially relieving patients
from the inconvenience of complicated
diagnostic procedures and the stress of
waiting for accurate results, said Stefan
Maier, a visiting scientist at IMRE and
professor in the department of physics atImperial College London.
With the introduction of a gap of only
0.1 micrometers into the electrodes, we
have been able to make amplified waves
at the key wavelength of 1000 microme-
ters that can be used in such real-world
applications.
Photoacoustic device
hunts melanomaCOLUMBIA, Mo. A new photoacoustic
device will aid the fight against metastatic
melanoma by detecting single melanoma
cells in blood samples at a fraction of the
cost of current cancer tests.
Melanoma, an aggressive cancer, is char-
acterized by skin growths that in and of
themselves arent seriously dangerous but
that can become a quick killer: After metas-
tasis, patients often live less than a year,
and fewer than 20 percent live five years,
which is why early detection is critical.
But finding metastatic melanoma as it
spreads through the body has proved diffi-
cult. Detection with MRI or CT imaging
equipment requires tumors that are at least
a few millimeters in diameter (similar to
a grain of rice); at that size, they already
consist of millions of cells.
With the new test, scientists can look
in the blood system for single melanoma
cells propagating through the body, said
John Viator of the Bond Life Sciences
Center at the University of Missouri.
This is much more effective, because
youre looking for a cancer sooner than
you could ever detect it with an imagingtest, he said. Thats good for the patient,
and its good for the clinician, because if
you can find cancer when its just at the
cellular level, then youre fighting a small
number of cells versus trying to fight a
tumor the size of a softball thats growing
around your kidney.
The prototype, when refined into a com-
mercial product, should be about the size
of a small copy machine. Clinicians would
put blood samples into the device, which
would then provide a readout of the sam-
ples results in about 10 minutes. Com-
pared to current techniques for testing, this
new machine has the advantages of being
inexpensive, fast, compact and easy to use,
along with offering earlier detection.
At its center is a photoacoustic technol-
ogy called laser-induced ultrasound. Viator
uses this tool in conjunction with the prop-erties of density, light, heat and color to
cause cancer cells to react in a manner that
makes them detectable and distinguishable
from surrounding cells.
A first step in the testing process is
using a centrifuge to separate a patients
blood into white and red blood cells. Mela-
noma cells are about the same density as
white blood cells but less dense than redones, so melanoma cells are naturally
thrown in with white blood cells as the
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No more finger-sticks: Chip measures glucose in salivaPROVIDENCE, R.I. A new sensor mea-
sures blood sugar levels by determining
glucose concentrations in saliva, which
could mean that diabetics no longer have
to draw their own blood.
Drawing blood through finger-sticks or
other means is invasive and at least mini-mally painful but for the 26 million
Americans with diabetes, it is the most
prevalent and effective method of check-
ing glucose levels on a daily basis.
Each plasmonic interferometer thousands of themper square millimeter consists of a slit flanked bytwo grooves etched in a silver metal film. Theschematic shows glucose molecules dancing onthe sensor surface, illuminated by light with differentcolors. Changes in light intensity transmitted throughthe slit of each plasmonic interferometer yield infor-mation about the concentration of glucose molecules
in solution. Courtesy of Domenico Pacifici.
blood separates. The resulting batch of
white blood cells (plus any cancer cells
present) is then pumped through narrow
tubing that contains a tiny glass box where
the cells are hit with a short pulse of high-
intensity laser light as they pass by. Be-
cause white objects reflect light, the white
blood cells are not affected, but any cell
with pigment will absorb the light. The
intense laser beam heats such a cell rap-
idly, causing thermoelastic expansion,
which in turn causes the expanding cell
to emit a measurable pressure wave.
Detection equipment senses this photo-
acoustic wave and thus locates the can-
cer cell.
Using this method, pigmented mela-
noma cells stand out and can be separated
from the healthy white blood cells, whichthen are individually tested using biomole-
cular assays or imaging.
Not all melanoma cells are the same,
Viator said. You can do some molecular
tests and find out [details such as] do they
have this genetic type? Or do they have
these cell surface markers? We know that
such-and-such a cell responds really well
to this type of drug, so you could person-
alize your cancer therapy, potentially, by
capturing the cells youve detected
in the blood sample and understanding
the disease better.Current treatment tools for melanoma
include surgery and a drug, interferon,
which is only about 20 percent effective,
Viator said. But two new melanoma drugs
have been approved this year, and a dozen
more are in Phase III trials.
The availability of melanoma therapies
is going to explode, Viator said. The
more therapies there are, the more valuable
this [photoacoustic technology] will be,
because it can track response to disease.
Initially, the tool will detect and monitor
only metastatic melanoma. But Viators
lab is continuing research, with the goal
of using photoacoustic methods to detect
other cancers such as breast and prostate.
Viator recently signed royalty and
licensing agreements with the university
to clear the way for his new company,
Viator Technologies Inc., to develop a
commercial prototype.
Due to the machines comparativelylow cost, he is confident that early cancer
diagnosis will become more accessible
because it could be available in places
where medical facilities cant justify
purchasing a much higher-priced MRI
machine.
Unfortunately for cancer patients, the
new device may not be available for a
few more years, as it has not passed FDA
tests for safety and effectiveness. Viator
is confident, however, that these required
tests will demonstrate that it is highly
reliable. The machine can grab and saveany suspect cell; therefore, the cells can
be examined microscopically or geneti-
cally to confirm their identity.
The machine does not need FDA clear-
ance before it is used for research. Scien-
tists in academia or industry could use the
device for cancer studies as soon as it is
produced. Thus, companies testing new
cancer drugs could use it to assess their
drugs effectiveness.
The desktop device should be available
to researchers by the end of next year;
after two or three more years, it may be
commercially available for clinical use,
Viator said.
John Viator, associate professor of biomedicalengineering and dermatology, demonstrates a newphotoacoustic method with a tabletop device thatscans a lymph node biopsy with laser pulses. Thismethod could help doctors identify the stage ofmelanoma with more accuracy. Courtesy ofUniversity of Missouri.
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bBIOSCAN
The new technique, developed at Brown University, combines
nanotechnology and surface plasmonics. The Brown engineers
etched thousands of plasmonic interferometers onto a fingernail-
size biochip and measured the concentration of glucose molecules
in water on the chip. Their results showed that the specially de-
signed biochip can detect glucose levels similar to those found in
human saliva, where it typically is about 100 times less concen-trated than in blood.
The technique also could be used to detect chemicals and sub-
stances such as anthrax in biological compounds.
The researchers created the sensor by carving a 100-nm-wide
slit and etching two 200-nm-wide grooves on either side. The
slit captures incoming photons and confines them, while the
grooves scatter the incoming photons, which interact with the
free electrons bounding around on the sensors metal surface.
The free electron-photon interactions create a surface plasmon
polariton. These surface plasmon waves move along the sen-
sors surface until they encounter the photons in the slit.
The interference between the two waves determines maxima
and minima in the light intensity transmitted through the slit.The presence of an analyte on the sensor surface generates a
change in the relative phase difference between the two surface
plasmon waves, which in turn causes a change in light intensity,
which the researchers measure in real time.
The slit is acting as a mixer for the three beams the incident
light and the surface plasmon waves, said Domenico Pacifici,
assistant professor of engineering.
The scientists discovered that they could vary the phase shift
for an interferometer by changing the distance between the
grooves and the slit, meaning that they can tune the wave-
generated interference. They tuned thousands of interferome-
ters to establish baselines, which then could be used to accur-
ately measure concentrations of glucose in water as low as
0.36 mg/dl.
It could be possible to use these bio-chips to carry out the
screening of multiple biomarkers for individual patients, all at
once and in parallel, with unprecedented sensitivity, Pacifici
said.
The research was published inNano Letters (doi: 10.1021/
nl203325s) and was funded by the National Science Foundation
and Brown (through a Richard B. Salomon Faculty Research
Award).
Microscopy revealsskin-allergen connectionGOTHENBURG, Sweden Two-photon microscopy has shown
that skin absorbs various substances differently, depending upon
what is mixed with them. These differences may determine
whether a material causes contact allergy.
We have also been able to identify specific cells and proteins
in the skin with which a contact allergen interacts, said Carl
Simonsson of the University of Gothenburg. The results increase
our understanding of the mechanisms behind contact allergy.
The skin is the largest organ in the human body and plays
many vital roles, one of which is to prevent harmful microorgan-
isms from invading the body. The principal barrier is the stratum
corneum a layer of skin cells about a few microns thick. De-
http://pubs.acs.org/doi/abs/10.1021/nl203325shttp://pubs.acs.org/doi/abs/10.1021/nl203325shttp://pubs.acs.org/doi/abs/10.1021/nl203325shttp://pubs.acs.org/doi/abs/10.1021/nl203325shttp://www.89north.com/mailto:[email protected]://www.89north.com/http://pubs.acs.org/doi/abs/10.1021/nl203325s -
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BioPhotonics March 2012
Ashley N. [email protected]
Melinda A. Rose
spite being so thin, this layer effectively
protects us from bacteria and viruses.
The skin, however, has not adapted to
deal with and prevent absorption of many
of the chemicals to which we are exposed
today. This may lead to various types of
diseases, such as contact allergy, which
affects approximately 20 percent of people
in Sweden.
With two-photon microscopy, sub-
stances can be followed as they are ab-
sorbed into the skin. The method is uniquein that it allows researchers not only to see
how well a substance is absorbed, but also
what happens to it, and to find the location
in the skin where the substance eventually
arrives.
In addition, the skin barrier and the way
in which various substances are absorbed
are highly significant for the development
of new drugs. Creams and ointments are
for many reasons an interesting alternative
to tablets, which must be taken orally. The
barrier properties of the skin may present,
in this case, an obstacle to drug absorp-
tion, making it difficult for sufficient
amounts of the drug to penetrate the skin
to produce a clinical effect.
We have used two-photon microscopy
to study a new type of ointment that it
may be possible to use to improve the
absorption, and thus the clinical effect,
of certain drugs that are used on the skin,
Simonsson said.
Skin photographed in a two-photon microscope, showing epidermal cells and the collagen presentin the dermis. Courtesy of Carl Simonsson.
Carl Simonsson, whose thesis showed the utility of two-photon microscopy in the exploration of contact
allergens in the skin. Courtesy of University of Gothenburg.
mailto:[email protected]:[email protected]://www.lumencor.com/http://www.lumencor.com/mailto:[email protected]:[email protected] -
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BUSINESSSCAN
SAN FRANCISCO To recognize his
pioneering work in biomedical optics and
ultrafast laser spectroscopy, SPIE pre-
sented Robert Alfano, distinguished pro-
fessor of physics at City College of NewYork, with the first Britton Chance Bio-
medical Optics Award during the BiOS
conference at Photonics West.
Some of Alfanos work has focused on
using light to perform noninvasive optical
biopsies that reveal molecular information
on the spot. The techniques can eliminate
the wait for test results and reduce the
physical trauma of surgery, since there
is no need to remove tissue unless cancer
is found.
This field was nonexistent before
1984. Thats when we discovered youcould use the colors of light to detect can-
cer, Alfano said. When you shine a little
light on the tissue, it glows.
He found that different combinations of
molecules on healthy and cancerous sam-
ples produced specific spectral emissions
when excited by a laser. The colors of the
emissions are different. If the molecules
are good, you get one glow; if theyre bad,
you get another.
Its like a fingerprint, he added. In
that glow is all the information you need
about the molecules that are there.
In 1991 Alfano and his colleagues ex-
tended their early work using Raman scat-
tering, which doesnt rely on fluorescence
and has higher resolution and sharper spec-
tral lines to detect differences between
cancerous, precancerous and normal tis-
sue. More recently, his lab has been refin-
ing cancer detection using Stokes shift
spectroscopy, which combines absorption
and fluorescence for a higher degree of
accuracy.
Alfano also co-discovered the supercon-
tinuum ultrafast white light source, among
other achievements recognized by theaward, which spans from the visible to the
near-infrared part of the light spectrum.
The discovery enabled research resulting
in two Nobel Prizes. The winner of the
chemistry Nobel in 1999 used the super-
continuum to monitor chemical reactions.
Winners of the 2005 Nobel Prize in phys-
ics tapped it to create the most accurate
clock in existence. Others, Japanese re-
searchers in particular, are using it in com-
munications to boost available channels
and bandwidth into the terabits-per-second
range.
He was instrumental in the founding of
the BiOS symposium and has published
more than 700 papers; he also holds 108
patents and has been cited more than
11,000 times. He has served as a member
of the editorial board of the Journal of
Biomedical Optics since the journals
founding in 1996, and he long contributed
to Photonics Medias publications as an
editorial advisory board member.
His most recent achievement was the
approval of a patent for a pill-size cancer
detection device. But theres more to come.
Someday, he said, I want to have a cell
phone to diagnose cancer.
In his acceptance speech at the Photon-
ics West event, Alfano credited Britton
Chance and others for their inspiration and
contributions to the field. Britton Chance
was the real giant, he said. Everything is
built on giants its not done alone. But
Britton was one of those guys that did it
alone.Chance pioneered the field of biomed-
ical optics and contributed to a wide range
of fields, including the identification and
functioning of enzyme-substrate com-
pounds, and made advancements in breast
cancer diagnostics, radio-frequency elec-
tronics, spectroscopy for noninvasive clin-
ical diagnosis, and other areas.
Brit Chances research, training and
leadership have helped fuel the growth
of biomedical optics and biophotonics
throughout the world, said Bruce Trom-
berg, director of the Beckman Laser Insti-
tute at the University of California, Irvine,
and a longtime colleague of Chance. His
lifelong passion for measuring and under-
standing physiology and metabolism using
light has inspired our community for
decades.
More than any other individual, Britbrought together people and ideas that
spanned across disciplines, creating a spe-
cial spirit of creativity, innovation and en-
thusiasm that has characterized the field of
biomedical optics.
SPIE honors Alfano with Britton Chance Award
BioPhotonics March 2012 17
Dr. Katarina Svanberg of Lund University in Sweden, a past president of SPIE, presents Dr. Robert Alfano withthe Britton Chance Award for Biomedical Optics during the BiOS portion of Photonics West. Courtesy of SPIE.
Laura S. Marshall
In that glow
is all the
information you
need about the
molecules that
are there.
Robert Alfano
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BY LAURA S. MARSHALL, MANAGING EDITOR
T
he human brains billions of neurons
make countless connections every
day, collaborating to help us eat,dress, read, exercise, avoid danger and
more. Its a big job, but by working to-
gether, they get it done.
The human research teams who study
them have a daunting job and, like the
neurons themselves, they have to work
together to do it.
One multidisciplinary, multi-institution,
multinational project recently found a way
to direct nerve-fiber growth by using
laser-driven spinning microparticles. The
breakthrough could someday lead to chip-
grown neuronal networks and even ad-
vanced treatments for injuries to the brain
or spinal cord.
It started with an idea that neuronscould show responses to physical cues
such as fluid flow, not just chemical cues.
As neurons grow and develop in a fetus
a process called neurogenesis the flow
of spinal fluid can guide neurons to their
destinations, said Samarendra Mohanty,
now an assistant professor of physics at
the University of Texas at Arlington.
As a postdoctoral fellow working in
Michael Berns lab at the Beckman Laser
Institute at the University of California,
Irvine, Mohanty observed that a spinning
calcite microparticle could direct neuron
growth; the particles rotation creates a mi-
crofluidic flow, causing a shearing effect,
and guiding the neuron to turn left or right.This is the first report to demonstrate
that neurons can be turned in a controlled
manner by microfluidic flow, Mohanty
said. With this method, we can direct
them to turn right or turn left, and we can
quickly insert or remove the rotating beads
as needed.
The UC Irvine researchers, in collabora-
tion with professor Halina Rubinsztein-
Dunlop of the University of Queensland
in Brisbane, Australia, switched from the
calcite to more controllable and more uni-
form 8-m-diameter vaterite particles,
20 BioPhotonics March 2012
Collaboration Sparks Nerve-Fiber
Turn Signal DiscoveryGlobal, multidisciplinary cooperation has led to a significant advance
in neuroscience a way to guide growth in neurons that ultimately
could have big implications for nerve disorders.
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Laboratory, who developed the physical
model described in the paper and who
were the group that produced and rotated
vaterite particles in optical tweezers by
transfer of spin angular momentum of
light. The study was supported by the US
Air Force Office of Scientific Research,
the Beckman Laser Institute Foundation
and the Australian Research Council.
I am very grateful that we could work
together on this problem, Rubinsztein-
Dunlop said. In fact, I am looking for-
ward to further collaboration and further
experiments that can explain more fully all
the questions that we were asking.
As Berns pointed out, These days, one
person cannot claim ownership on such
a complex study as this.
22 BioPhotonics March 2012
Nerve-Fiber Growth
The Beckman Laser Institute inIrvine, Calif. like all re-search institutions strives tobring ideas to life. Its leadersencourage collaboration as anessential part of advancing sci-entific and human interests.
One of their main goals is to
translate technology from benchto bedside, according to Dr.Bruce Tromberg, BLIs director.
Were really focused on put-ting insights we can get frommeasurements and computa-tional models of light-tissue in-teractions to work in the clinic,Tromberg said. It takes a longtime, a lot of investment and acertain culture.
And a lot of people with verydifferent backgrounds. Wehave 20 faculty-level scientists about 100 to 120 peoplehere, he said. Its an interdisciplinary group: chemistry,biology, veterinary science, medicine, math ... We have techlabs, bio labs, cell culture, histopathology, biochemistry, mo-lecular pathology.
These diverse teams pursue fundamental research andtechnology development in a wide range of fields, especiallybiology and medicine, from cancer to brain injury to woundhealing.
Any good research institution has people who are visionar-ies, said George Peavy, BLIs veterinary director. Hes a bigproponent of multidisciplinary collaboration, within a lab andaround the world. Everybody here works really well together.They know what they know and what they dont know, too.
Were not just focusing on photonics. Collaboration allowsus to do what we do.
In the BLI clinic, there is an advanced technology suite whereresearchers conduct Institutional Review Board-approved stan-dardization on patients using new techniques and instruments,from a laser breast scanner based on diffuse optical spectros-copy to multiphoton tomography, optical coherence tomogra-phy, photodynamic therapy, and laser therapies, dynamiccooling, spatial frequency domain imaging, speckle tomogra-phy and more. Its not just abstract diagnosis, Trombergsaid, but also about providing clinicians with feedback forreal decision making.
The Military Photomedicine Program is one such effort. As
part of that project, researchers including teams from BLI,Stanford University and Harvard University are working todevelop new technologies for battlefield medicine. One deviceat UCI is a laser scanner to detect hemorrhagic shock beforeits too late, Peavy said. He added that the same scannerultimately could be used for breast imaging, brain perfusionassessment (especially in anesthetized patients) and hydrationmonitoring, among other applications.
Many concepts are also undergoing commercialization,Tromberg pointed out. Companies working with BLI currentlyhave about $5 million in Small Business Innovation Researchgrants, with prototypes in studies around the world. Oneproject under way in Japan combines optics, positron emissiontomography and MRI to measure oxygenation in tumors;multimodality clinical studies such as this are too expensiveto do here.
Developing prototypes and improving instrumentation inadvance of commercialization are big opportunities for smallcompanies, Tromberg said. This is risk abatement. Big com-panies want to acquire low-risk smaller companies, but theydont like to develop the technology themselves.
On the academic side, we innovate we dont just iterateand improve. But with commercialization, we have to be ableto duplicate and standardize the technology.
Some of these ventures will succeed; others will fail. But,ultimately, its worth the risk. Its like Vegas, Peavy said. Youhear stories about big wins, but theres a lot of money left onthe table.
Collaboration in Action: Beckman Laser Institute
Collaboration allows us to dowhat we do, says George Peavy,
the Beckman Laser Institutesveterinary director. Photos by
Laura S. Marshall.
One of the clinic rooms at the Beckman Laser Institute andMedical Clinic at the University of California, Irvine.The institute exemplifies the spirit of collaboration.
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The implications of the research for
treatment of brain and spinal cord injuries
may be stimulating. It will definitely be
useful for fabrication of in vitro neuronal
circuits and [interfacing with a] silicon-
based stimulation and detection device,
Mohanty said. Such a chip might be im-planted to connect injured nerves, possibly
regenerating or restoring certain functions.
But we arent there yet. It will take
years for the nerve-growth discovery to af-
fect human lives directly, Berns cautioned.
This is a tool/method to understand, and
based on future studies, new ways to ap-
proach the treatment of brain and spinal
cord injury may be developed.
It certainly opens up a new way to
study nerve cells and, in particular, how
the growth cones the key element of the
nerve cell responsible for its growthand migration function. Understanding
the molecular signaling that causes the
growth cone to turn one way or another
is important to understanding how they
form networks and interconnections,
so there is normal nervous system func-
tion.
Until that is accomplished, the work
will spawn further studies as any break-
through research will do. Mohanty is
working on a method that allows long-
range optical guidance of neurons without
any additional external objects.
Flow can be generated by any means,Mohanty said. He noted that it would be
easier to use a microfluidic tube for work
within the human body. We are trying
microfluidic flow in channels to further
this idea. Laser trapping in vivo and rotat-
ing beads is a little unrealistic, though our
lab has developed a method to trap and ro-
tate beads fiber optically.
Only light can guide neurons without
trapping or rotating bead-generating fluid
flow. So, we can use just optical fiber
(without bead, trapping, rotation, etc.)
to do axonal guidance with almost 100percent efficiency. It amazes me how
unplanned research can lead to exciting
discoveries.
Collaboration is what science is all
about. We are all very specialized now,
so bringing people together with different
expertise to attack a problem is very pow-
erful and successful if everyone gets
along and puts egos aside, Berns said. He
and his team are working on a number of
projects with fellow researchers around
the globe and he wouldnt have it any
other way. Collaboration both within and
outside an institution is vital. Its whateach person/lab brings to the project that
is important, not necessarily whether it is
inter-institution or intra-institution.
Mohanty agrees; his lab also has several
projects at various stages of development
with several outside researchers. The bio-
medical or biological problems are no
longer confined to specific disciplines, he
said. The advantages are: First, it leads to
cross-fertilization of ideas. Second, com-
plementary expertise and, third, sharing
of resources reduces burden on one lab.
Also, funding agencies seem to like that.
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Photodynamic therapy could be
the future of cancer treatment
that is, once the photoactive
chemicals behind it start doing
their jobs better.
Photodynamic therapy (PDT) is prov-
ing to be a more than viable option
for cancer treatment. Compared with
other treatments, such as chemotherapy
and radiation therapy, PDT is more selec-
tive, causing far less damage to healthy
cells near cancerous targets due to the
precise way in which photosensitizers can
locate and infiltrate tumor cells.
The task remains to find the best combi-
nations of photosensitizers and conjugates
to propel the technique past chemotherapyand other traditional methods.
Basically, a photoreactive chemical
compound called a photosensitizer is in-
troduced into a patient, where it aggre-
gates near an active tumor site. A clinician
then shines light from a diode laser or
LED source onto the tumor region. The
light, which has a specific wavelength,
activates the photosensitizer without af-
fecting surrounding healthy tissue. Once
activated, the photosensitizer transfers
some of its energy to nearby ground-state
molecular oxygen, producing excited sin-
glet oxygen. The result is oxidation of
tumor cells in the site, destroying the can-
cer while harming as few of the adjacenthealthy cells as possible.
Bringing light to the site is an ongoing
issue. Early studies of PDT focused on
skin cancers, such as various types of
for Cancer Depends
on Improved Photosensitizers
24 BioPhotonics March 2012
Fluorescence micrographs of HeLa cells show how the photosensitizer chlorin e6 (top row) and a complex of chlorin e6 and
poly-L-lysine (bottom row) accumulate inside HeLa cells after 10 min (left), 1 h (center) and 2 h (right). Note how the photosensitizer
alone remains in the cytoplasm near the cell membrane, while the conjugated pair works its way from the inner wall to the cell
nucleus. Courtesy of Current Topics in Medicinal Chemistry.
BY LYNN SAVAGE, FEATURES EDITOR
PDTPDT
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melanoma, because it was easier to shine
near-infrared wavelengths a couple of mil-
limeters through the skins surface to the
tumor site. This drove design of the first
photosensitizers to favor compounds that
would preferentially react to light in that
range. More recently, advances in endo-scopic light-delivery systems have made
deeper tumors easier to reach and have
broadened the range of potential wave-
lengths and matching photosensitizers.
Different compounds are now used
as photosensitizers, including phthalo-
cyanine, chlorine, bacteriochlorin and
porphyrin. None, however, is a perfect
candidate.
Getting a photosensitizer to find and at-
tach itself to a tumor cell is a major battle.
The bodys immune system, for example,
seeks out and annihilates some forms ofphotosensitizers, reducing the effective-
ness of the overall treatment. Adding anti-
bodies to photosensitizers can help their
affinity for cancer cells, but some re-
searchers feel that protecting them with
shells composed of lipoproteins is a better
way to go. Lipoproteins not only help
their cargo locate and infiltrate tumors, but
also help protect them from enzymes and
macrophages that might alter or destroy
them before they even arrive at the treat-
ment site.
Gold nanoparticles and liposomes also
have been considered as adjuncts that
could help photosensitizers directly enter
cancer cells.
Gold rushResearchers at Rhodes University in
Grahamstown and in the biophotonics
department of the National Laser Center
in Pretoria, both in South Africa, are
among the groups looking at the possible
improvements to photosensitizer action
provided by gold nanoparticles.
Tebello Nyokong of Rhodes University
and her colleagues had gold nanoparticlesin mind during efficiency tests of a partic-
ular photosensitizer, as they reported in
the Feb. 6 issue of the Journal of Photo-
chemistry and Photobiology B: Biology.
Phthalocyanine compounds strongly ab-
sorb in the 600- to 800-nm range, yet tis-
sues are transparent to a useful degree to
these wavelengths. The result is an ability
to reach deeply into tissue and provide
sufficient energy to the photosensitizer to
activate it.
Several attributes must be considered
when designing a photosensitizer, said
Nyokong, director of the Nanotechnology
Innovation Center at Rhodes. One is that it
should have a high specificity for cancer,
which is achieved through inclusion and
coordination of molecules such as folic
acid and vitamin B12
. Another highly val-
ued attribute is good absorption in the red
wavelengths, which is aided by sulfur link-
ages in the photosensitizer compound. The
final product also should be water-soluble
and initiate large production of singlet oxy-
gen, which drives tumor cell death.
The groups candidate was [2,9,17,23-
tetrakis-(1,6-hexanedithiol)phthalocyani-
nato]zinc(II), a second-generation phthalo-
cyanine-based compound. Its target:
human malignant breast cancer cells
(MCF-7).
The researchers chose zinc over more
typical sulfur in their compound because itenhances the production of singlet oxygen
while being somewhat easier to assemble.
After forming the phthalocyanine com-
plexes, they introduced some to gold
nanoparticles, which self-assembled with
the compound. Others were bound to lipo-
somes as a delivery vehicle.
Using a Shimadzu spectrophotometer,
a Varian Inc. spectrofluorimeter, and a sin-
gle-photon counter and diode laser made
by PicoQuant GmbH, the investigators
measured the absorption spectra, fluores-
cence excitation and fluorescence lifetimes
of their photosensitizer in action against
MCF-7.
After determining that a light dose of
4.5 J/cm2 provided adequate intensity
without harming nearby healthy cells, the
researchers compared how well the gold
nanoparticles and the liposomes aided the
overall phototoxic effect.
They found that, after photoactivation
of the two complexes, 60.1 percent of thetumor cells treated with nanoparticle-
enhanced phthalocyanine remained viable,
whereas the liposome-enhanced com-
BioPhotonics March 2012 25
Controlled release can eliminate sideeffects but the active treatment isphototoxicity, so you still need an efficientphotosensitizer.
Bruno Therrien, University of Neuchtel
Side and top views show 3-D models of prism-shaped (left) and cubic (right)
metalla-cages designed to transport photosensitizers to tumor cells.
Courtesy of theJournal of the American Chemical Society.
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plexes fared much better with 51.9 percent
cell viability.
Nyokongs work with PDT is focused
on synthesizing bifunctional agents com-
pounds that serve two functions, generally
enhancing location and attachment to
tumor cells. In her lab, the desired resultis agents that combine the action of PDT
and other treatments, such as hyperthermia
(destroying tumors with applied heat,
which increases the uptake of oxygen,
thus accelerating cell destruction).
Nyokongs lab also is looking at combi-
nations of chemotherapy and PDT via in-
troduction of platinum to common photo-
sensitizers. Next up for her group is the
ongoing search for water-soluble phthalo-
cyanine compounds that include lipo-
somes. Better water solubility, the re-
searchers say, should improve the ability
of phthalocyanine to generate singlet oxy-gen inside cells.
Cage death matchesPhthalocyanine- and porphyrin-based
photosensitizers struggle to reach the
tumor site because they are fairly poorly
water soluble. Placing either type of com-
plex inside the hydrophobic cavity of an
otherwise water-soluble vessel designed to
wend its way breezily toward target cancer
cells is thought by several research groups
potentially to improve the situation.
The tricky part is getting the vessel to
unload its cargo upon arrival.
Another way to bring the photosensi-tizer to the cell is to wrap it inside an
organometallic cage. This helps address
the water-solubility issue while offering
control of photosensitizer release, accord-
ing to Bruno Therrien, an associate pro-
fessor at the University of Neuchtel in
Switzerland.
Therrien and his colleagues at the uni-
versity and at Centre Hospitalier Vaudois
in Lausanne, Switzerland, devised and
tested two types of carrier vessels to ferry
porphyrin to its target. One, in the form of
a prism, locks the porphyrin tightly; theother, a cubelike structure, is a more flexi-
ble jacket. Both vessels are made with
ruthenium-based compounds.
Within the metalla-prism, its a ship-
in-the-bottle system only breakage of the
cage can release the guest, Therrien said.
However, from the metalla-cube, the
Before and after images show the effect of a porphyrin-based photosensitizer that
was carried into HeLa cells by a ruthenium-based, cube-shaped cage. Courtesy of
theJournal of the American Chemical Society.
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porphyrin is free to go through one of the
apertures without [breaking] the cage.
With either vessel, the porphyrin re-
mains unreactive to light and only be-
comes photosensitive once released.
The group studied the uptake of both
vessel types and their cargo into HeLa
cells, and then used a 488-nm laser madeby Spectra-Physics at various doses to re-
lease, then activate, the porphyrin once the
metalla-cages were inside the cell mem-
branes.
Once released, porphyrin discharged
from either cage performed well at gener-
ating singlet oxygen and thus destroying
the HeLa cells. Interestingly, the porphyrin
delivered via the cubelike metalla-cages
packed more punch, requiring one-tenth
the energy (0.2 J/cm2) to reach the thresh-
old where half the cells are killed com-
pared with the metalla-prism combo(2.1 J/cm2).
Both controlled release of the photosen-
sitizer and its ultimate phototoxicity are
important, according to Therrien. Con-
trolled release can eliminate side effects,
such as skin photosensitivity after and dur-
ing treatment, but the active treatment is
phototoxicity, so you still need an efficient
photosensitizer.
The ultimate goal of Therrien and his
colleagues is to be able to irradiate at a
specific wavelength to break up the cage
where and when it is desired and, after re-
lease, apply a second dose of light to acti-
vate the photosensitizer.
Location, location, location
One of the most troubling disadvantages
of first- and second-generation photosen-
sitizers, according to researchers at the
Tokyo Institute of Technology, is that they
do not locate cancer cells as well as they
might. The more specifically diseased
cells are targeted, the more healthier
viable cells can remain.
(A) photosensitizer which shows high
tumor localization shows low phototoxic-
ity for normal tissue, said Shun-IchiroOgura of the institutes department of bio-
molecular engineering. It is quite impor-
tant for tumor therapy.
But as importantly, the short lifetime of
singlet oxygen (measured in no more than
microseconds) means that the closer they
are to the right target, the more damage
they can do. Therefore, improving local-
ization can improve PDT efficacy.
Some photosensitizers, such as por-
phyrin-based constructions, accumulate
in a target cells plasma membrane. How-
ever, the nucleus is the place to be if you
want maximum destructive impact. Ogura
and his colleagues found that one possibleway to get to the cell nucleus effectively is
to combine the popular photosensitizer
chlorin e6 with poly-L-lysine. By itself,
chlorin e6 stays in the cytoplasm of the
cell, but the conjugated pair ultimately
travels to the nucleus. After subsequent
light exposure, the complex offered high
phototoxicity.
The group presents its findings on the
localization capabilities of several photo-
sensitizer types in the February issue of
Current Topics in Medicinal Chemistry.
BioPhotonics March 2012 27
Photosensitizers
Lynn [email protected]
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Y
ou have probably heard the facts and
figures: One of the leading causes of
death worldwide, cancer accounted
for 7.6 million roughly 13 percent of alldeaths in 2008, according to the World
Health Organization. And deaths from
cancer are on the rise: By 2030, we will
likely see 13.1 million per year world-
wide.
The need for new ways of diagnosing
cancer has never been greater. Today we
are seeing a variety of new diagnostic
techniques that leverage the benefits of
noninvasive and less-invasive optical tech-
nologies and that are made possible by
the development of novel treatments. Op-portunities for these techniques have been
advanced by new therapies, said Adam
Wax, professor of biomedical engineering
at Duke University in Durham, N.C.
Weve seen this in a number of cancer
models, with radio-frequency ablation and
cryospray ablation, for example. With
therapies targeting cancers at earlier stages,
we need diagnostics that can detect those
early cancers.
Take coherence imaging, for example.
Wax was one of several researchers whospoke about coherence imaging and cancer
during the BiOS Hot Topics session at this
years Photonics West meeting in San Fran-
cisco (many of the Hot Topics talks can
be viewed on the SPIE website and on
YouTube). In his talk, Early Cancer De-
tection with Coherence Imaging, he de-
scribed a suite of spectroscopic techniques
Moving NoninvasiveCancer Imaging into the Clinic
Above: Neil Terry (left), Adam Wax (right) and their colleagues at Duke University have described a technique called angle-resolved low-coherence interferometry that
can detect dysplasia in patients with Barretts esophagus, for example, and have developed it further for clinical application. Courtesy of Adam Wax.
So you came up with this great idea for a medical device for cancer imaging, and
even found a way to make it work. Now what? Several researchers involved with
coherence imaging technologies discuss the challenges of clinical translation.
BY GARY BOAS, NEWS EDITOR
28 BioPhotonics March 2012
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designed to assess cell structure and diag-
nose disease using low-coherence interfer-ometry (LCI) to detect scattered light.
The techniques combine the advantages
of optical coherence tomography and
light-scattering approaches. Angle-re-
solved LCI, for instance, marries the
ability of LCI to isolate scattering from
subsurface tissue layers to the ability of
light-scattering spectroscopy to obtain
structural information using angular
scattering measurements.
The researchers explored the clinical
potential of angle-resolved LCI for in vivo
depth-resolved nuclear morphology mea-
surements to detect dysplasia in patients
with Barretts esophagus, who are at in-
creased risk of developing esophageal can-
cer. The results, reported in the January
issue of Gastroenterology, showed that the
technology can provide quantitative depth-
resolved measurements of nuclear mor-
phology measurements used by patholo-
gists for cancer diagnosis without having
to rely on image interpretation or use of
exogenous contrast agents.
Also during this years BiOS Hot Top-
ics session, Stephen Boppart, Bliss profes-
sor of engineering at the Beckman Insti-tute for Advanced Science and Technology
at the University of Illinois at Urbana-
Champaign, spoke about his work with
coherence imaging and cancer. In his talk,
Coherence Imaging of Cancer with Novel
Optical Sources, he described a technique
called nonlinear interferometric vibrational
imaging, or NIVI.
NIVI offers the high spectral resolution
of Raman spectroscopy with the high
acquisition rates of coherent anti-Stokes
Raman scattering microscopy. Boppart
and colleagues have shown that they could
obtain NIVI spectra with the accuracy of
Raman but at speeds 200 to 500 timesfaster, and thus demonstrated the potential
of the technique for rapid tissue imaging,
characterization and diagnosis for diag-
nosis of cancer, for example.
At the same time, they have been devel-
oping novel optical sources to use with
the technique. Weve worked out ways of
controlling the phase and generating a
supercontinuum thats completely coher-
ent, Boppart said in a phone interview
just prior to the BiOS portion of Photonics
West. The sources have been described
in a series of papers all involving
Dr. Haohua Tu, also of the University of
Illinois as well as in Bopparts recent
Hot Topics talk.
Getting into the clinicWith technologies intended for clinical
application, identifying and solving the
problem is, of course, only half the battle.
Clinical translation involves a variety of
challenges, many of which are unique to
this stage of technology development.
You labor under the illusion that youre
going to come up with a solution and
companies are just going to run to youwith bags of money, Wax said, but there
exist any number of hurdles that must be
overcome before the technology gets into
the clinic. In parallel with his academic
efforts, Wax has been seeking to commer-
cialize the technology through a company
he started, Oncoscope Inc., and has run up
against several of these.
The whole translational pathway is full
of challenges, he continued. Its not the
most glamorous work. The most glam-
orous work is really that first paper
describing the breakthrough.
Some of the hurdles have little if any-
thing to do with the technology itself. In
the past several years, for example, com-
panies developing new clinical devices
and techniques have had to contend with
the credit crisis. Other times, they are all
about the technology. For example, many
devices which in the early development
stages might occupy an entire corner of a
room, with fibers and assorted incompre-
hensible add-ons protruding from them,
Academic-ClinicalPartnerships
Jon Holmes, CEO of Kent, UK-
based Michelson DiagnosticsLtd., has a few thoughts about
developing technology for clinicalapplication. He developed andoffers the VivoSight OCT scannerfor dermatologists. The device usesmultibeam OCT to obtain higher-resolution, clearer images than canbe achieved with conventional sin-gle-beam Fourier-domain OCTsystems.
Many academic groups workingon OCT have developed from phys-
ics or engineering departments, andso they are focused primarily on de-veloping the underlying technology,he said. Put simply, their researchwill be published if it studies an ad-vance in technology, whereas pa-pers on developments in the clinicalapplicability (such as the probe er-gonomic design) are less likely to bepublished.
The upshot, he continued, is thatany technology developed by aca-demic groups for biomedical appli-cations might not be properly evalu-ated, and in many cases it maynever reach commercial exploi-tation.
My advice is that physics andengineering groups should closelypartner with clinical teams and workwith them on a specific clinical needover a long period of time (decades)in a focused manner with a clearlong-term goal of developing anexploitable device evaluated withclinical trials. Funders should alsoactively support this type of collabo-
rative work.
Researchers at the University of Illinois at Urbana-Champaign have reported a technique called nonlinearinterferometric vibrational imaging, or NIVI, and are now developing it for breast cancer detection in theclinic. Shown here is a NIVI image of a tumor, compared to histology. Courtesy of Stephen Boppart.
BioPhotonics March 2012 29
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suggesting nothing so much as an evil
scientists creation will have to be re-
designed before they can be introduced
clinically, providing a reliable, compact,
robust, turnkey system.
There have been heroic studies where
mode-locked lasers have been brought into
the clinic, Boppart said. For translation,
though, youve really got to have these
systems better designed and better engi-
neered.
For example, the angle-resolved LCI in-
strument reported by Wax and colleagues
was developed further by Oncoscope to be
sufficiently robust for broader use. The
Duke prototype was typically operated
by PhD scientists and grad students whocould tune up the instrument if needed and
were able to instantly assess if something
was not functioning correctly, Wax said.
In contrast, the Oncoscope device needs
to be stand-alone, so that a physician can
operate it without difficulty. To achieve
this, they re-engineered several of the in-
ternal components to make them less vul-
nerable to outside influences and added
automated routines to ensure calibration.
The University of Illinois researchers
also are working to translate their technol-
ogy for use in the clinic. At the time of
writing, they were waiting to receive final
word about an Academic-Industry Partner-
ship proposal they had submitted to the
NIH National Cancer Institute to develop
NIVI for intraoperative use, detecting mo-
lecular tumor margins during breast cancer
surgery (the proposal had been scored
very highly).
Boppart noted several challenges to be
addressed in developing the technology
for clinical application. These include:
(1) developing compact, portable, turnkey
fiber-based sources for nonlinear optical
imaging to replace the current mode-
locked lasers, multi-laser systems or opti-
cal parametric oscillators that keep these
techniques in the lab; (2) developing theimaging, processing and analysis algo-
rithms to make NIVI diagnostically useful;
and (3) developing the portable system
cart and handheld probe for use in clinical
settings. These are all the goals for our
Academic-Industry Partnership, but are
also what is needed to move this field
forward, he said.
For this project, the researchers are de-
veloping handheld microelectromechanical
systems-based scanners for use with NIVI
in the operating room. These, by them-
selves, are rather novel, Boppart said,
because few optical probes currently
exist for intraoperative use in the sterile
surgical field. His startup company, Diag-
nostic Photonics Inc., has developed such
a surgical probe for interferometric syn-
thetic aperture microscopy, a computed
imaging approach to OCT, and began
clinical trials in February.
The NCI proposal included both aca-
demic and industry partners, of course, but
also a clinical partner: Carle Foundation
Hospital of Urbana, Ill. Building strong
relations in the clinical arena is especially
important to translation, Boppart said.
When you have a good clinical partner,
you can step into this very different envi-
ronment and culture the clinical setting and still be accepted.
The technology still must be well de-
signed and as unobtrusive as possible,
though, if it has any chance of finding
support from the medical community.
Youll find that, where a lot of these
technologies succeed, theres minimal
disruption to the standard of care, he
said. As engineers, we tend to want
to have complicated solutions, but if it
causes clinical practice to change too dra-
matically, its just not going to happen.
Clinical Cancer Imaging
UK-based Michelson Diagnostics developed andoffers a clinical OCT scanner for dermatologists.Courtesy of Michelson Diagnostics Ltd.
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BY LYNN SAVAGE, FEATURES EDITOR
In the US alone, 10,000 people are diag-
nosed each year with laryngeal carci-
noma, according to the American Cancer
Society. This cancer affects the vocal
cords and the connective tissues surround-
ing them. Of these, nearly 4000 will die of
the disease. Smoking tobacco is the majorforce behind laryngeal cancer, also known
as glottic cancer, although alcohol con-
sumption seems to magnify the effect
smoking has.
When a patient is first diagnosed with
glottic cancer, the immediate goal is cure
of the disease. Secondarily, the physician
strives to preserve the patients voice and
ability to swallow well, which both can
be dramatically affected after chemical,
radiation or surgical treatment. Laser mi-
crosurgery is becoming an effective tool
to help doctors me