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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

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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