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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

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IRIDIAN


Group Publisher Karen A. Newman

Editorial StaffManaging Editor Laura S. Marshall

Senior Editor Melinda A. RoseFeatures Editor Lynn M. Savage

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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]


7/44BioPhotonics March 2012

Photonics Medias industry-leading site features the latest industry news and events

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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


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.
http://pubs.acs.org/doi/abs/10.1021/nl203811qhttp://pubs.acs.org/doi/abs/10.1021/nl203811q


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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


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


13/44BioPhotonics March 2012 13

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
http://www.edmundoptics.com/we-make-ithttp://www.edmundoptics.com/we-make-it



b BIOSCAN

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.


15/44BioPhotonics March 2012

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


16/44

b BIOSCAN


Ashley N. [email protected]

Melinda A. Rose

[email protected]

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]


17/44

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


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

[email protected]

In that glow

is all the

information you

need about the

molecules that

are there.

Robert Alfano


18/44


19/44


20/44

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,


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.


21/44


22/44

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.


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.


23/44

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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24/44

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


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


25/44

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-


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.


26/44

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.
http://www.blueskyresearch.com/http://www.blueskyresearch.com/


27/44

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.


Photosensitizers

Lynn [email protected]
mailto:[email protected]:[email protected]://sales.hamamatsu.com/http://sales.hamamatsu.com/http://hamamatsucameras.com/flash4mailto:[email protected]


28/44

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



29/44

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.




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.

[email protected]

Clinical Cancer Imaging

UK-based Michelson Diagnostics developed andoffers a clinical OCT scanner for dermatologists.Courtesy of Michelson Diagnostics Ltd.


31/44BioPhotonics March 2012 31

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

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