We describe a novel frequency-domain photon migration instrument employing direct diode laser modulation and avalanche photodiode detection, which is capable of noninvasively determinating the optical properties of biological tissues in near real time. An infinite medium diffusion model was used to extract absorption and transport scattering coefficients from 300-kHz to 800-MHz photon-density wave phase data. Optical properties measured in tissue-simulating solutions at 670 nm agreed to within 10% of those expected

Anderson, Eric R

Haskell, Richard C

Madsen, Steen J

Tromberg, Bruce J

English

Keck Graduate Institute

Claremont Colleges
Scholarship @ Claremont
All HMC Faculty Publications and Research HMC Faculty Scholarship
12-1-1994
Portable, High-Bandwidth Frequency-Domain
Photon Migration Instrument for Tissue
Spectroscopy
Steen J. Madsen
University of Nevada, Las Vegas
Eric R. Anderson
University of California - Irvine
Richard C. Haskell
Harvey Mudd College
Bruce J. Tromberg
University of California - Irvine
This Article is brought to you for free and open access by the HMC Faculty Scholarship at Scholarship @ Claremont. It has been accepted for inclusion
in All HMC Faculty Publications and Research by an authorized administrator of Scholarship @ Claremont. For more information, please contact
scholarship@cuc.claremont.edu.
Recommended Citation
Madsen, SJ, Anderson, ER, Haskell, RC, Tromberg, BJ. Portable, high-bandwidth frequency-domain photon migration instrument for
tissue spectroscopy. Opt Lett. 1994;19(23): 1934-1936.
1934 OPTICS LETTERS / Vol. 19, No. 23 / December 1, 1994
Portable, high-bandwidth frequency-domain photon
migration instrument for tissue spectroscopy
Steen J. Madsen, Eric R. Anderson, Richard C. Haskell, and Bruce J. Tromberg
Beckman Laser Institute and Medical Clinic, University of California, Irvine, Irvine, California 92715
Received July 5, 1994
We describe a novel frequency-domain photon migration instrument employing direct diode laser modulation
and avalanche photodiode detection, which is capable of noninvasively determinating the optical properties of
biological tissues in near real time. An infinite medium diffusion model was used to extract absorption and
transport scattering coefficients from 300-kHz to 800-MHz photon-density wave phase data. Optical properties
measured in tissue-simulating solutions at 670 nm agreed to within 10% of those expected.
Knowledge of the optical properties of biological tis-
sue is essential in both diagnostic and therapeutic
applications of lasers in medicine. To be useful clin-
ically, the optical properties should be determined
quickly and noninvasively, which may be possible by
use of frequency-domain photon migration (FDPM).
In FDPM the intensity of light incident upon a
material, such as biological tissue, is modulated at
a high frequency (107-109 Hz), and the diffusely
reflected or transmitted signal is measured by a
phase-sensitive detector. It has been demonstrated
that intensity-modulated light propagates through
multiple-scattering media (e.g., biological tissue) as
diffuse photon density waves with a coherent front.'-
As density wave dispersion is a function of the opti-
cal properties of the material probed, one can deter-
mine absorption qua) and transport scattering (id)
coefficients by fitting the measured frequency- and
distance-dependent behavior to analytical expres-
sions derived from diffusion theory.3
In contrast to more sensitive time-domain pho-
ton propagation techniques, such as time-correlated
single-photon counting,4 FDPM signals are continu-
ous and can generally be acquired more rapidly and
economically. Thus FDPM methods seem to be more
suitable for portable, real-time, noninvasive physio-
logical monitoring.
Several modulation-detection techniques have been
developed for FDPM. The most general consists of ex-
ternal Pockels cell modulation of the light source (arc
lamp or laser) and cross-correlation detection by use
of conventional photomultiplier tubes.5 However,
because of its limited bandwidth (200-300 MHz),
Pockels cell-photomultiplier tube instrumentation
may be insufficient for characterizing optical proper-
ties of many biological tissues. For example, FDPM
measurements on human uterine tissue indicate
that frequencies in excess of 350 MHz are required
for reliable determination of ,Iia and A' in a single
measurement.6 This bandwidth limitation can be
overcome by use of the high harmonic content of
pulsed mode-locked lasers and fast photodetectors
such as microchannel plate photomultiplier tubes.
Although such systems are ill suited to use in the
clinic because of their cost and complexity, they per-
mit recording of photon-density wave dispersion with
sufficient temporal resolution for optical properties
to be calculated in a single measurement.
In this Letter we describe a relatively simple, inex-
pensive diode-based FDPM system that operates in
near real time between 300 kHz and 1 GHz. This
FDPM system is unique because we employ, for the
first time to our knowledge, direct diode laser mod-
ulation and avalanche photodiode detection. As a
result, we can rapidly and reliably calculate optical
properties in a single multifrequency measurement.
A schematic overview of the system is illustrated
in Fig. 1. One of the unique features of the sys-
tem is the vector network analyzer (Hewlett-Packard
Model 8753C), which measures reflection and trans-
mission characteristics of devices and networks by
applying a known swept signal and measuring the
responses. Such a device has been used to measure
electrical properties of biological tissues.7 The ana-
lyzer's built-in synthesized source produces a swept
rf signal (300 kHz to 1 GHz), which is superimposed
upon the direct current of a GaAs (A = 670 nm)
laser diode (SDL, Inc., Model 7420) by means of
a bias tee (Picosecond Pulse Labs Model 5575A).
The direct current is obtained from a stabilized
current source (ILX Lightwave Model LDC-3742),
which also provides thermoelectric cooling control
for the laser diode. The laser was biased 25 mA
above lasing threshold (200 mA), and 20 dBm of rf
power was applied. Since no impedance matching
of the diode to the 50-4 source impedance was per-
formed, the actual ac optical power was much less
than 20 dBm. Although slight distortion of the si-
nusoidal output of the laser could be observed at
some modulation frequencies, we could reduce it
by changing the dc bias on the laser diode. The
laser output was coupled directly into a 600-,Am
step-index multimode fiber, which was incident upon
the material. The average optical power coupled
into the sample ranged from 30 to 40 mW. Dif-
fusely propagating photon density waves were col-
0146-9592/94/231934-03$6.00/0 © 1994 Optical Society of America
December 1, 1994 / Vol. 19, No. 23 / OPTICS LETTERS 1935
straightforward and, in terms of the phase lag (k),
is given by3
0 r[pA(Ij,. + /A!)]2( 2)
X [ 1 + (-W)) 2] - (1)
(1)
Fig. 1. Schematic of the frequency-domain instrument.
lected by an identical fiber and transmitted to a
high-gain (approximately 4 x 103) avalanche pho-
todiode (APD; New Focus, Inc., Model 1651) biased
at 15 V (New Focus, Inc., dc power supply #0901).
The dc output of the APD was monitored with
a picoammeter (Keithley Model 485). Acquisition
times of photon-density-wave phase and amplitude
over the entire 300-kHz to 1-GHz frequency spec-
trum are variable and depend primarily on inter-
mediate frequency bandwidth and signal averaging
parameters. Reasonable signals can be acquired
on the order of seconds. Shorter acquisition times
can also be realized by constraining the measure-
ment bandwidth.
The source modulation at 500 MHz is illustrated in
Fig. 2 for a 225-mA dc bias setting. There is some
distortion of the sinusoidal waveform (particularly
near threshold), which is due to the dynamic behavior
of the semiconductor laser under strong modulation.8
By adjusting the dc bias to 250 mA we were able to re-
duce this distortion at some expense to overall source
modulation depth. As a result, dc bias was main-
tained at 225 mA for all subsequent experiments.
Although the 500-MHz response is the only wave-
form shown, modulation quality generally improves
at lower frequencies and degrades with increasing
frequency. In practical terms, we were able to com-
pensate for small waveform distortions by acquiring
sample and reference data under identical conditions
(see below).
The ability of the system to determine the optical
properties of tissue-simulating solutions was tested.
The solutions consisted of 2% Intralipid (Kabivitrum,
Inc., Clayton, N.C.) and various concentrations of
nickel tetrasulfonated phthalocyanine (NiSPC; Mid-
century, Posen, Ill.). Intralipid is a highly scatter-
ing and low absorbing phospholipid emulsion with
well-characterized optical properties, and NiSPC is
a strong absorber at 670 nm. The concentrations of
Intralipid and NiSPC were chosen to correspond to
the optical properties of typical tissues. In all cases
the source and detector fibers were centered and
placed at a depth of approximately 10 cm in a 4-L
cylindrical beaker containing 3.5 L of the liquid solu-
tion. This corresponds to an infinite geometry. The
infinite geometry solution of the diffusion equation is
A nonlinear least-squares fitting routine, based on
a Marquardt-Levenberg algorithm, was used to fit
the diffusion expression [Eq. (1)] to the experimental
data. A reference measurement was taken with both
source and detector fibers inserted in the solution and
separated by 4 mm. The results are illustrated in
Fig. 3.
Figure 3 shows phase versus frequency plots as
a function of added absorber concentration at a
source-detector separation of 14 mm (effective sepa-
ration of 10 mm because the reference was recorded
at a separation of 4 mm). Each data set was ac-
quired in approximately 14 s. As expected, the
phase decreases with increased absorber, as longer-
path-length photons have a greater probability of
10
01-
Fig. 2. Si
225 mA.
160
140
W 120
lh
1W 100
1. 80
60WI 60
v 40
20
0
Time (100 ns/div.)
ource modulation at 500 MHz and dc bias of
0 200 400 600
Frequency (MHz)
800 1000
Fig. 3. Phase versus frequency response for 2% In-
tralipid as a function of NiSPC concentration. The
curves represent beat fits to the data.
1936 OPTICS LETTERS I Vol. 19, No. 23 / December 1, 1994
Table 1. Summary of Fitted and Actual Optical Properties
NiSPC Ma fit APa actual A sI fit /As' actual
(/ug/mL) (mm-1 ) (mm-') (mm'1) (mm-l)
0 (8.52 ± 0.51) x 10-4 8.52 x 10-4 2.28 ± 0.14 2.42
1.07 (1.18 ± 0.07) x 10-2 1.24 x 10-2 2.22 ± 0.14 2.42
2.0 (2.01 ± 0.12) x 10-2 2.16 x 10-2 2.22 ± 0.14 2.42
being absorbed. It is shown that, even with the addi-
tion of the absorber, reliable phase data are obtained
up to 800 MHz. The actual and fitted optical prop-
erties are summarized in Table 1. In all cases the
transport scattering coefficient agrees to within 10%
of that predicted by Mie theory (Islactual in Table 1).9
Significant variations in the absorption coefficient
of Intralipid have been reported in the literature.' 0
These differences are probably due to inconsisten-
cies in the manufacturing process. For that reason
the actual absorption coefficient for pure Intralipid
in Table 1 is taken to be that obtained from the fit.
This value is well within the range of that found by
others.' 0 In all cases the fitted absorption coefficient
is in excellent agreement with the actual value based
on the absorption of Intralipid and the absorption
of I ,Ag/mL NiSPC (1.08 X 10-2 mm-'). The uncer-
tainties quoted in Table 1 (6%) are due mainly to
uncertainties in the source-detector separation.
We examined phase precision by repeating mea-
surements at a given source-detector separation.
The results of 10 such measurements revealed a
phase precision of between 0.5% and 1%. We evalu-
ated long-term phase stability by recording the phase
at 5-min intervals over a period of 30 min under iden-
tical conditions. The phase was found to be stable
to within 2% at frequencies above 100 MHz. Be-
low 100 MHz the phase stability was rather poor
(5-10%).
In general, we were able to obtain reliable phase
information up to 800 MHz at source-detector sep-
arations up to 18 mm in the 1.07-,utg/mL tissue-
simulating solution. Rapid attenuation of the ac
signal component limited the bandwidth of our
measurements at greater distances. For example,
at a source-detector separation of 20 mm, phase
measurements were limited to frequencies below
450 MHz. In its current configuration the overall
system bandwidth is detector limited. The APD has
a 3-dB rolloff at 1 GHz; however, the response of the
detector falls by 1.5 dB at 800 MHz at the high-gain
settings used in these experiments.
Modifications to the present system should im-
prove signal-to-noise ratio characteristics and per-
mit reliable measurements up to the 1-GHz APD
limit. Such modifications ratio include (1) improv-
ing the optical coupling onto the small-area (200-
1tm-diameter) APD detector, (2) enhancing overall
detector gain by electronic amplification of the APD
signal, (3) improving source modulation character-
istics by placing a low-inductance resistor in se-
ries with the laser diode so the overall impedance
is matched to the 50-f rf output, (4) increas-
ing the source modulation depth by amplifying
the network analyzer rf output, and (5) combining
phase data with the high-quality ac and dc am-
plitude information (data not shown) to calculate
optical properties.
In summary, we describe the development of a
high-bandwidth FDPM instrument, which, for the
first time to our knowledge, employs direct diode
modulation and APD detection at multiple modu-
lation frequencies up to 1 GHz. Access to 1-GHz
multifrequency phase and amplitude information
permits rapid, noninvasive characterization of the
optical properties of most commonly encountered
tissues in a single measurement. With the incor-
poration of additional wavelength diodes the system
will be capable of monitoring various physiological
parameters, including oxygenated and deoxygenated
hemoglobin levels, drug concentration, blood volume
changes, tissue hydration status, and tissue scat-
tering properties. As the instrument is compact, it
can easily be transported to operating rooms and
bedridden patients, such as neonates in intensive
care. These features suggest that portable FPDM
devices can be constructed to provide high-bandwidth
information for a variety of applications in tissue di-
agnostics and imaging.
This research was supported by the Whitaker
Foundation (WF16493), the National Institutes of
Health (R29GM50958), and Beckman Instruments,
Inc. Address any correspondence to B. J. Tromberg.
References
1. J. Fishkin, E. Gratton, M. J. vandeVen, and W. W.
Mantulin, Proc. Soc. Photo-Opt. Instrum. Eng. 1431,
122 (1991).
2. M. A. O'Leary, D. A. Boas, B. Chance, and A. G. Yodh,
Phys. Rev. Lett. 69, 2658 (1992).
3. B. J. Tromberg, L. 0. Svaasand, T.-T. Tsay, and R. C.
Haskell, Appl. Opt. 32, 607 (1993).
4. D. V. O'Conner and D. Phillips, Time-Correlated Sin-
gle Photon Counting (Academic, New York, 1984),
Chap. 1, pp. 9-34.
5. J. R. Lakowicz, Principles of Fluorescence Spectroscopy
(Plenum, New York, 1983), Chap. 3, pp. 51-91.
6. S. J. Madsen, P. Wyss, L. 0. Svaasand, R. C. Haskell,
Y. Tadir, and B. J. Tromberg, Phys. Med. Biol. 39,
1191 (1994).
7. W. T. Joines, Y. Zhang, C. Li, and R. L. Jirtle, Med.
Phys. 21, 547 (1994).
8. W. I. Way, J. Lightwave Technol. LT-5, 305 (1987).
9. H. J. van Staveren, C. J. M. Moes, J. van Marle, S. A.
Prahl, and M. J. C. van Gemert, Appl. Opt. 30, 4507
(1991).
10. S. T. Flock, S. L. Jacques, B. C. Wilson, W. Star, and
M. J. C. van Gemert, Lasers Surg. Med. 12,510 (1992).


Portable, High-Bandwidth Frequency-Domain Photon Migration Instrument for Tissue Spectroscopy

Scholarship@Claremont

Claremont CollegesScholarship @ ClaremontAll HMC Faculty Publications and Research HMC Faculty Scholarship12-1-1994Portable, High-Bandwidth Frequency-DomainPhoton Migration Instrument for TissueSpectroscopySteen J. MadsenUniversity of Nevada, Las VegasEric R. AndersonUniversity of California - IrvineRichard C. HaskellHarvey Mudd CollegeBruce J. TrombergUniversity of California - IrvineThis Article is brought to you for free and open access by the HMC Faculty Scholarship at Scholarship @ Claremont. It has been accepted for inclusionin All HMC Faculty Publications and Research by an authorized administrator of Scholarship @ Claremont. For more information, please contactscholarship@cuc.claremont.edu.Recommended CitationMadsen, SJ, Anderson, ER, Haskell, RC, Tromberg, BJ. Portable, high-bandwidth frequency-domain photon migration instrument fortissue spectroscopy. Opt Lett. 1994;19(23): 1934-1936.1934 OPTICS LETTERS / Vol. 19, No. 23 / December 1, 1994Portable, high-bandwidth frequency-domain photonmigration instrument for tissue spectroscopySteen J. Madsen, Eric R. Anderson, Richard C. Haskell, and Bruce J. TrombergBeckman Laser Institute and Medical Clinic, University of California, Irvine, Irvine, California 92715Received July 5, 1994We describe a novel frequency-domain photon migration instrument employing direct diode laser modulationand avalanche photodiode detection, which is capable of noninvasively determinating the optical properties ofbiological tissues in near real time. An infinite medium diffusion model was used to extract absorption andtransport scattering coefficients from 300-kHz to 800-MHz photon-density wave phase data. Optical propertiesmeasured in tissue-simulating solutions at 670 nm agreed to within 10% of those expected.Knowledge of the optical properties of biological tis-sue is essential in both diagnostic and therapeuticapplications of lasers in medicine. To be useful clin-ically, the optical properties should be determinedquickly and noninvasively, which may be possible byuse of frequency-domain photon migration (FDPM).In FDPM the intensity of light incident upon amaterial, such as biological tissue, is modulated ata high frequency (107-109 Hz), and the diffuselyreflected or transmitted signal is measured by aphase-sensitive detector. It has been demonstratedthat intensity-modulated light propagates throughmultiple-scattering media (e.g., biological tissue) asdiffuse photon density waves with a coherent front.'-As density wave dispersion is a function of the opti-cal properties of the material probed, one can deter-mine absorption qua) and transport scattering (id)coefficients by fitting the measured frequency- anddistance-dependent behavior to analytical expres-sions derived from diffusion theory.3In contrast to more sensitive time-domain pho-ton propagation techniques, such as time-correlatedsingle-photon counting,4 FDPM signals are continu-ous and can generally be acquired more rapidly andeconomically. Thus FDPM methods seem to be moresuitable for portable, real-time, noninvasive physio-logical monitoring.Several modulation-detection techniques have beendeveloped for FDPM. The most general consists of ex-ternal Pockels cell modulation of the light source (arclamp or laser) and cross-correlation detection by useof conventional photomultiplier tubes.5 However,because of its limited bandwidth (200-300 MHz),Pockels cell-photomultiplier tube instrumentationmay be insufficient for characterizing optical proper-ties of many biological tissues. For example, FDPMmeasurements on human uterine tissue indicatethat frequencies in excess of 350 MHz are requiredfor reliable determination of ,Iia and A' in a singlemeasurement.6 This bandwidth limitation can beovercome by use of the high harmonic content ofpulsed mode-locked lasers and fast photodetectorssuch as microchannel plate photomultiplier tubes.Although such systems are ill suited to use in theclinic because of their cost and complexity, they per-mit recording of photon-density wave dispersion withsufficient temporal resolution for optical propertiesto be calculated in a single measurement.In this Letter we describe a relatively simple, inex-pensive diode-based FDPM system that operates innear real time between 300 kHz and 1 GHz. ThisFDPM system is unique because we employ, for thefirst time to our knowledge, direct diode laser mod-ulation and avalanche photodiode detection. As aresult, we can rapidly and reliably calculate opticalproperties in a single multifrequency measurement.A schematic overview of the system is illustratedin Fig. 1. One of the unique features of the sys-tem is the vector network analyzer (Hewlett-PackardModel 8753C), which measures reflection and trans-mission characteristics of devices and networks byapplying a known swept signal and measuring theresponses. Such a device has been used to measureelectrical properties of biological tissues.7 The ana-lyzer's built-in synthesized source produces a sweptrf signal (300 kHz to 1 GHz), which is superimposedupon the direct current of a GaAs (A = 670 nm)laser diode (SDL, Inc., Model 7420) by means ofa bias tee (Picosecond Pulse Labs Model 5575A).The direct current is obtained from a stabilizedcurrent source (ILX Lightwave Model LDC-3742),which also provides thermoelectric cooling controlfor the laser diode. The laser was biased 25 mAabove lasing threshold (200 mA), and 20 dBm of rfpower was applied. Since no impedance matchingof the diode to the 50-4 source impedance was per-formed, the actual ac optical power was much lessthan 20 dBm. Although slight distortion of the si-nusoidal output of the laser could be observed atsome modulation frequencies, we could reduce itby changing the dc bias on the laser diode. Thelaser output was coupled directly into a 600-,Amstep-index multimode fiber, which was incident uponthe material. The average optical power coupledinto the sample ranged from 30 to 40 mW. Dif-fusely propagating photon density waves were col-0146-9592/94/231934-03$6.00/0 © 1994 Optical Society of AmericaDecember 1, 1994 / Vol. 19, No. 23 / OPTICS LETTERS 1935straightforward and, in terms of the phase lag (k),is given by30 r[pA(Ij,. + /A!)]2( 2)X [ 1 + (-W)) 2] - (1)(1)Fig. 1. Schematic of the frequency-domain instrument.lected by an identical fiber and transmitted to ahigh-gain (approximately 4 x 103) avalanche pho-todiode (APD; New Focus, Inc., Model 1651) biasedat 15 V (New Focus, Inc., dc power supply #0901).The dc output of the APD was monitored witha picoammeter (Keithley Model 485). Acquisitiontimes of photon-density-wave phase and amplitudeover the entire 300-kHz to 1-GHz frequency spec-trum are variable and depend primarily on inter-mediate frequency bandwidth and signal averagingparameters. Reasonable signals can be acquiredon the order of seconds. Shorter acquisition timescan also be realized by constraining the measure-ment bandwidth.The source modulation at 500 MHz is illustrated inFig. 2 for a 225-mA dc bias setting. There is somedistortion of the sinusoidal waveform (particularlynear threshold), which is due to the dynamic behaviorof the semiconductor laser under strong modulation.8By adjusting the dc bias to 250 mA we were able to re-duce this distortion at some expense to overall sourcemodulation depth. As a result, dc bias was main-tained at 225 mA for all subsequent experiments.Although the 500-MHz response is the only wave-form shown, modulation quality generally improvesat lower frequencies and degrades with increasingfrequency. In practical terms, we were able to com-pensate for small waveform distortions by acquiringsample and reference data under identical conditions(see below).The ability of the system to determine the opticalproperties of tissue-simulating solutions was tested.The solutions consisted of 2% Intralipid (Kabivitrum,Inc., Clayton, N.C.) and various concentrations ofnickel tetrasulfonated phthalocyanine (NiSPC; Mid-century, Posen, Ill.). Intralipid is a highly scatter-ing and low absorbing phospholipid emulsion withwell-characterized optical properties, and NiSPC isa strong absorber at 670 nm. The concentrations ofIntralipid and NiSPC were chosen to correspond tothe optical properties of typical tissues. In all casesthe source and detector fibers were centered andplaced at a depth of approximately 10 cm in a 4-Lcylindrical beaker containing 3.5 L of the liquid solu-tion. This corresponds to an infinite geometry. Theinfinite geometry solution of the diffusion equation isA nonlinear least-squares fitting routine, based ona Marquardt-Levenberg algorithm, was used to fitthe diffusion expression [Eq. (1)] to the experimentaldata. A reference measurement was taken with bothsource and detector fibers inserted in the solution andseparated by 4 mm. The results are illustrated inFig. 3.Figure 3 shows phase versus frequency plots asa function of added absorber concentration at asource-detector separation of 14 mm (effective sepa-ration of 10 mm because the reference was recordedat a separation of 4 mm). Each data set was ac-quired in approximately 14 s. As expected, thephase decreases with increased absorber, as longer-path-length photons have a greater probability of1001-Fig. 2. Si225 mA.160140W 120lh1W 1001. 8060WI 60v 40200Time (100 ns/div.)ource modulation at 500 MHz and dc bias of0 200 400 600Frequency (MHz)800 1000Fig. 3. Phase versus frequency response for 2% In-tralipid as a function of NiSPC concentration. Thecurves represent beat fits to the data.1936 OPTICS LETTERS I Vol. 19, No. 23 / December 1, 1994Table 1. Summary of Fitted and Actual Optical PropertiesNiSPC Ma fit APa actual A sI fit /As' actual(/ug/mL) (mm-1 ) (mm-') (mm'1) (mm-l)0 (8.52 ± 0.51) x 10-4 8.52 x 10-4 2.28 ± 0.14 2.421.07 (1.18 ± 0.07) x 10-2 1.24 x 10-2 2.22 ± 0.14 2.422.0 (2.01 ± 0.12) x 10-2 2.16 x 10-2 2.22 ± 0.14 2.42being absorbed. It is shown that, even with the addi-tion of the absorber, reliable phase data are obtainedup to 800 MHz. The actual and fitted optical prop-erties are summarized in Table 1. In all cases thetransport scattering coefficient agrees to within 10%of that predicted by Mie theory (Islactual in Table 1).9Significant variations in the absorption coefficientof Intralipid have been reported in the literature.' 0These differences are probably due to inconsisten-cies in the manufacturing process. For that reasonthe actual absorption coefficient for pure Intralipidin Table 1 is taken to be that obtained from the fit.This value is well within the range of that found byothers.' 0 In all cases the fitted absorption coefficientis in excellent agreement with the actual value basedon the absorption of Intralipid and the absorptionof I ,Ag/mL NiSPC (1.08 X 10-2 mm-'). The uncer-tainties quoted in Table 1 (6%) are due mainly touncertainties in the source-detector separation.We examined phase precision by repeating mea-surements at a given source-detector separation.The results of 10 such measurements revealed aphase precision of between 0.5% and 1%. We evalu-ated long-term phase stability by recording the phaseat 5-min intervals over a period of 30 min under iden-tical conditions. The phase was found to be stableto within 2% at frequencies above 100 MHz. Be-low 100 MHz the phase stability was rather poor(5-10%).In general, we were able to obtain reliable phaseinformation up to 800 MHz at source-detector sep-arations up to 18 mm in the 1.07-,utg/mL tissue-simulating solution. Rapid attenuation of the acsignal component limited the bandwidth of ourmeasurements at greater distances. For example,at a source-detector separation of 20 mm, phasemeasurements were limited to frequencies below450 MHz. In its current configuration the overallsystem bandwidth is detector limited. The APD hasa 3-dB rolloff at 1 GHz; however, the response of thedetector falls by 1.5 dB at 800 MHz at the high-gainsettings used in these experiments.Modifications to the present system should im-prove signal-to-noise ratio characteristics and per-mit reliable measurements up to the 1-GHz APDlimit. Such modifications ratio include (1) improv-ing the optical coupling onto the small-area (200-1tm-diameter) APD detector, (2) enhancing overalldetector gain by electronic amplification of the APDsignal, (3) improving source modulation character-istics by placing a low-inductance resistor in se-ries with the laser diode so the overall impedanceis matched to the 50-f rf output, (4) increas-ing the source modulation depth by amplifyingthe network analyzer rf output, and (5) combiningphase data with the high-quality ac and dc am-plitude information (data not shown) to calculateoptical properties.In summary, we describe the development of ahigh-bandwidth FDPM instrument, which, for thefirst time to our knowledge, employs direct diodemodulation and APD detection at multiple modu-lation frequencies up to 1 GHz. Access to 1-GHzmultifrequency phase and amplitude informationpermits rapid, noninvasive characterization of theoptical properties of most commonly encounteredtissues in a single measurement. With the incor-poration of additional wavelength diodes the systemwill be capable of monitoring various physiologicalparameters, including oxygenated and deoxygenatedhemoglobin levels, drug concentration, blood volumechanges, tissue hydration status, and tissue scat-tering properties. As the instrument is compact, itcan easily be transported to operating rooms andbedridden patients, such as neonates in intensivecare. These features suggest that portable FPDMdevices can be constructed to provide high-bandwidthinformation for a variety of applications in tissue di-agnostics and imaging.This research was supported by the WhitakerFoundation (WF16493), the National Institutes ofHealth (R29GM50958), and Beckman Instruments,Inc. Address any correspondence to B. J. Tromberg.References1. J. Fishkin, E. Gratton, M. J. vandeVen, and W. W.Mantulin, Proc. Soc. Photo-Opt. Instrum. Eng. 1431,122 (1991).2. M. A. O'Leary, D. A. Boas, B. Chance, and A. G. Yodh,Phys. Rev. Lett. 69, 2658 (1992).3. B. J. Tromberg, L. 0. Svaasand, T.-T. Tsay, and R. C.Haskell, Appl. Opt. 32, 607 (1993).4. D. V. O'Conner and D. Phillips, Time-Correlated Sin-gle Photon Counting (Academic, New York, 1984),Chap. 1, pp. 9-34.5. J. R. Lakowicz, Principles of Fluorescence Spectroscopy(Plenum, New York, 1983), Chap. 3, pp. 51-91.6. S. J. Madsen, P. Wyss, L. 0. Svaasand, R. C. Haskell,Y. Tadir, and B. J. Tromberg, Phys. Med. Biol. 39,1191 (1994).7. W. T. Joines, Y. Zhang, C. Li, and R. L. Jirtle, Med.Phys. 21, 547 (1994).8. W. I. Way, J. Lightwave Technol. LT-5, 305 (1987).9. H. J. van Staveren, C. J. M. Moes, J. van Marle, S. A.Prahl, and M. J. C. van Gemert, Appl. Opt. 30, 4507(1991).10. S. T. Flock, S. L. Jacques, B. C. Wilson, W. Star, andM. J. C. van Gemert, Lasers Surg. Med. 12,510 (1992).

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Portable, high-bandwidth frequency-domain photon migration instrument for tissue spectroscopy.

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Portable, High-Bandwidth Frequency-Domain Photon Migration Instrument for Tissue Spectroscopy

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