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Assessment of multi-wavelength pulse photometry for non-invasive dos
circulating drugs and nanoparticles
Pratik Adhikari [a], Wakako Eklund [b], Eric Sherer [c], D. Patrick O’N
[a] Center for Biomedical Engineering and Rehabilitation Sciences (CBERS), Louisiana Tech Un[b] Pediatrix Medical Group of Tennessee, Nashville, TN.[c] Department of Chemical Engineering, Louisiana Tech University, Ruston, LA
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The Five Rights of Medication Administration: “A Destination Witho
SPIE Photon
RIGHT PATIENT
RIGHT DRUG RIGHT DOSE
RIGHT ROUTE RIGHT TIME
Volume of distribution?
point-of-care?
detection
in vivo?
pK, pD, clearance rate?
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Unmet need related to real time monitoring
SPIE Photon
• Helps make informed clinical decisions during prevention, diagnosis, treatment, an
• On the greater scheme, recent development of wearable sensors health monitorin
been instrumental in(1) enable the detection of early signs of health deterioration;
(2) notify health care providers in critical situations;
(3) find correlations between lifestyle and health;
(4) bring healthcare to remote locations and developing countries, where cell
are pervasive and in some cases the only available communications device;
•Applied in a clinical setting in a therapeutic application, real time feedback, througdata at point of care would help make informed clinical decisions, potentially impro
efficacy of the treatment.
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Pulse Oximetry: Extracting and quantifying the pulsatile/AC sign
SPIE Photon
Plethysmograph – an instrument for meas
volume (usually resulting from changes in
contained within a fixed area).
Plethysmogram (PPG) – the waveform cre
changes in volume temporally using a plet
Photoplethysmogram – a waveform obtai
sensed changes in light to track temporal f
volume.
Fig: Tamura et. al, “Wearable Photoplethysmographic Sensors—Past and Present”, 2014
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Photoplethysmography: Application in pulse oximetry
SPIE Photon
R =ΔAλ660ΔAλ940
=
log DCD C − A C
λ6
log DCD C − A C
λ9
• The ratio of pulsatile changes
using the DC and AC portions o
be equated to small changes i
referred to as ΔA.
• The ratio of ΔA’s at two wavelen
to as R, but the system is ex
wavelengths to allow
measurement of oxygen satura
target materials.
• Note: Not path-length depend
0
1000
2000
3000
4000
600 700 800 900 1000
M o l a r E x t i n c t i o n C o e f f i c i e n t ( c m - 1
)
Wavelength (nm)
HbO2
HbR
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Photoplethysmography: Other uses of pulsatile signal
SPIE Photon
V(t)
t (sec)
V(t)
t (sec)
Injection of particles
VAC
VDC
• The Δ thus obtained is the absorbance in that wavelength, caused by the introduction of the com
• The conversion of absorbance to the concentration of the compound in pulsatile blood is done em
requires blood samples.
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Effect of absorbent agent on the waveform
SPIE Photon
-6
-4
-2
0
2
4
6
0.0 0.1 0.1 0.2 0.2 0.3 0.3 0.4
A m p l i t u d e ( m V )
Time (sec)
Post injection
340 nm 660 nm 940 nm
-6
-4
-2
0
2
4
6
0 0.05 0.1 0.15 0.2 0.25 0.3 0.35 0.4 0.45 0.5
A m p l i t u d e ( m V )
Time (sec)
Pre-injection
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• Concurrent nanoparticle monitoring and oxygen saturation (SpO2)
• Extinction spectrum of nanoparticles must be known
• Real-time LabVIEW output
• Simultaneous equation solver in LabVIEW block diagram
• Three wavelength data collection to perform oximetry
• Filter signals to isolate pulses and DC levels
0
0.2
0.4
0.6
0.8
1
1.2
500 600 700 800 900
N o U n i t s
Wavelength (nm)
0
0.2
0.4
0.6
0.8
1
1.2
610 660 710 760 810 860
N o U n i t s
Wavelength (nm)
Algorithm and Rationale for selection of wavelengths
• Note: Not path-length dependent
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Multi-wavelength prototype for mice
SPIE Photon
Oscillator 3 bit
counter
3-to-8
decoder
Su
Ch
7
Ch
5
Ch
3
Ch
1
I/V
LED
Tail/Foot Clip
LEDs
Photodiode
LEDs
Photodiode
Leg and Foot/Tail Probes
• A pulse photometer, similar to pulse
oximeters, and interrogates
perfused tissue.• Real-time non-invasive optical
monitoring of intravascular NS, with
a dynamic range of ≈0.5-8
optical densities
• Designed using analog circuit
components (integrated circuits
and opto-electronics) and a
LabVIEW software interface.• LEDs :
• LZ1 UV 365 nm emitter
(Mouser)
• LED 660/940-04A (Roithner
Laser Technik)
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Example: Can a new drug be monitored using the prototype?
SPIE Photon
• Molar extinction coefficient of ABELCET® at 360 nm = 36963.6 M-1cm-1
• Molarity of 5mg/mL solution = 5.5 mM
• Dosage:
Common maintenance dosage of intravenous ABELCET® solution is 5 mg/kg/day.[1]
• The delivered dose was ≈ 5 mg/kg.
• Example dosage on a 25 gm mouse:
• Injected dosage = 25µL of ABELCET ® solution
• Molarity of resultant solution in blood (Assuming 1000 µl volume of distribution) = 0.134mM
• Predicted absorbance caused by the presence of the compound = 4.958
[1] ABELCET ® package insert, Sigma-Tau Pharmaceuticals, Inc.
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Example: Monitoring the concentration of amphotericin b
SPIE Photon
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
0 100 200 300 400 500 600 700 800
C o n c e n t r a t i o n ( O D )
Time (mins)
Injection phase
PPG
UV/Vis
Fig: Clearance curve of ABELCET ®
invasively by the PPG (blue marker
draws by UV/Vis analysis (red mark
were then fitted to a single decay e
obtain half-lives. (UV/Vis = 355 min
green markers indicate continuous
the infusion phase.
• Continuous near-real time m
• Confirmation of delivered d
• Information on pharmacolog
circulation half-life, peak co
• Possibly predict treatment e
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Comparison results from the three agents
SPIE Photon
Fig. (a) - Linear model showing agreement betwee
measured with pulse photometry and spectropho
0.0497, R2 = 0.903, n = 30). The 95% confidence (l
(small dashes) intervals are shown for the entire rdensities using the pulse photometer.
Fig. (b)- The comparison between the results of th
and the PPG readings for quinine. The graph repre
that were taken at different time points after the q
against the results from UV/ Vis analysis of the blo
(n=3 mice, 9 points from each mouse). Linear fit, 9
(dashed lines) and 95% prediction interval (dotted
are shown.
Fig. (c)- The comparison between the results of th
and the PPG readings. The graph represents the P
taken at different time points after the AmB inject
results from UV/ Vis analysis of the blood draws at
7-8 points from each mouse). Linear fit had the slo
intercept of 0.41, 95% confidence interval (dashed
interval (dotted line) for future data points are sho
Fig. (d)- Example pulsatile signals recorded by the Fig: (a) Michalak et. al 2010 JBO (15)4
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Assessing the performance of the device with three agents
SPIE Photon
Circulating
Agent
Wavelength of
interest
Linear fit with
UV/Vis
Correlation coefficient
(R2)
Precision (Bland-
Altman)
Gold nanorods 805 nm y = 0.87x+0.09 0.94 0.86 OD
Quinine 355 nm y = 0.927x+0.30 0.96 0.56 OD
Amp B 355 nm y = 0.85x+0.41 0.88 0.62 OD
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Signal Selection: Removal of Noise
SPIE Photon
A code was specifically written to extract the data points that meet all the criteria for data standards in M
• AC magnitude was in the range of 10-100 mV peak-to-peak,
• The standard deviation of R was less than 0.03,
• The heart rate measured on all three channels (660, 805 and 940 nm) were within 10% of the avera
Program description:
• Inputs:
• Raw time correlated data
• Outputs
• Graph of all collected data
• Graph of Averaged raw signal to create “discrete” time point reading
• Calculated Pharmacokinetic parameters: AUC, Elimination rate Constant, Half Life, Projected Peak
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SPIE Photon
Determine the optimum probing location
Assessed by examining the AC magnitude (SNR), signal stability, and SpO 2 at eachlocation
Foot
SpO2: 98.23% ± 0.36%
μNR: 0.0073 ± 0.0468
Tail
SpO2: 96.37% ± 0.88%
μNR: 0.0259 ± 0.0865
Leg
SpO2: 91.79% ± 0.0146%
μNR: 0.1912 ± 0.0643
Site-by-Site Analysis of Signal Quality
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Current industry use of Photoplethysmography and PDD
SPIE Photon
• Cardiac Output and Hemodynamics (blood pressure, stroke volume, blood volume, etc.)
• Estimated Continuous Cardiac Output (esCCO) – Nihon Kohden
• The principle of esCCO is an inverse correlation between stroke volume (SV) and p
(PWTT).• Systoe
• Systolic Pressure detector in digits
• Hepatic Function monitoring
• LIMON®, the technology for non-invasive measurement of liver function and splanchni
monitoring, based on elimination of ICG-PULSION
• Nicolet VasoGuard
• Four-channel PPG probes operating simultaneously. Use all four in testing upper or lowobtaining all measurements for an Ankle-Brachial index.
• PPGi systems
• Pulse Oximetry
• Blood Pressure
• Detection of respiratory events during sleep apnea
• Wearable sensors and heart rate detections
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Estimation of hemodynamic parameters using PDD: so far
SPIE Photon
Group Year Parameter Number of Subjects (n) Method 1 Method 2 Bia
Ijima et al 1998 Blood Volume 10 (healthy) Spectrometry (in vitro) PDD (nose) 2.7
PDD (finger) -0.
Haruna et al 1998 Blood Volume 27 (cardiac surgery) Spectrometry (in vitro) PDD (nose) -5.
PDD (finger) -4.
Reekers et. al. 2009 Cardiac Output 10 (healthy) High performance liquid
chromatography
PDD (nose) 30
PDD (finger) -5%
Blood Volume 10(healthy) High performance liquid
chromatography
PDD (nose) -10
PDD finger 15
Fischer et. al 2014 Cardiac Output 30 Transthoracic echocardio. esCCO
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Limitations of pulse dye densitometry in calculating cardiac out
SPIE Photon
• Errors related to signal detection by pulse spectrophotometry
• Probe motion artifact
• Poor peripheral circulation
• Presence of stray light in a clinical setting
• Presence of abnormal hemoglobin
• Errors related to distribution and determination of plasma ICG concentration
• Inadequate mixing, especially in low cardiac output states
• Errors in back-extrapolation from MTT Delayed clearance of ICG in patients with signifi
dysfunction
• Over-estimation of CBV in patients with generalised protein capillary leakage
• Errors related to derivation of CBV
• Differences in haematocrit from different sampling sites
• Correction factor not used
CBV: circulating blood volume; ICG: indocyanine green; MTT: mean
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Conclusions and Future Directions
SPIE Photon
• Technique is limited to detecting intrinsically absorptive compounds.
• While clinical devices using PDD made it into the clinic, as implemented
to translate laboratory based estimates of reliability.• Clinics report that the signal confounders included variable peripheral ci
artifacts and stray lights.
• Using PPG to measure near-real time concentration of optically absorpti
drugs is clinically feasible, given these confounders.
• Industry guidelines for signal quality, probe contact and probe pressure (
oximeters) are not standardized.• Even though PPG can be used to obtain individualized pharmacological p
as initial achieved dose, clearance rate, bioavailability) there is a lack of c
regarding the value of that information.
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Acknowledgements
SPIE Photon
NCMHD -1R41MD006167-01:
Real-Time Optical Feedback for
the Control of In Vivo
Nanoparticle Concentration
Nanospectra
Biosciences, Inc.
LEQSF (2013-16)-RD-B-03
LEQSF (2009-12) RD-B-07:
Optical Instrument for the Real-Time
Estimation of In Vivo Nanoparticle
Concentration
DMS – 1032176:
Mathematical Modeling
Biological and Biomedic
Engineering Processes
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Questions?
SPIE Photon