Abstract

Common-path differential phase-contrast interferometry measures the spatial gradient of surface dipole density on a bio-optical compact disk (BioCD) and is sensitive to small changes in dipole density following molecular binding of target molecules out of solution. The recognition molecules are antibody IgG proteins that are deposited in periodic patterns on the BioCD using soft lithography or photolithography on the silanized silica surfaces of dielectric mirrors. Spatial carrier-wave sideband demodulation extracts the slowly varying protein envelope that modulates the protein carrier frequency. The experimental interferometric profilometry has surface height sensitivity down to 20pm averaged over a lateral scale of 70μm with a corresponding scaling mass sensitivity limit of 1.5pgmm. Under the conditions of an IgG immunoassay with background changes caused during incubation, the scaling mass sensitivity is approximately 7pgmm. A saturated reverse immunoassay performed with IgG at 100ngml showed false positive and false negative rates of 0.2%.

© 2007 Optical Society of America

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References

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    [CrossRef]
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    [CrossRef]

2006

M. V. Sarunic, S. Weinberg, and J. A. Izatt, "Full-field swept-source phase microscopy," Opt. Lett. 31, 1462-1464 (2006).
[CrossRef] [PubMed]

D. D. Nolte and M. Zhao, "Scaling mass sensitivity of the BioCD at 0.25 pg/mm," Proc. SPIE 6380, 63800J (2006).
[CrossRef]

2005

L. Peng, M. Varma, H. D. Inerowicz, F. E. Regnier, and D. D. Nolte, "Adaptive optical BioCD for biosensing," Appl. Phys. Lett. 86, 183902 (2005).
[CrossRef]

P. I. Nikitin, B. G. Gorshkov, E. P. Nikitin, and T. I. Ksenevich, "Picoscope, a new label-free biosensor," Sens. Actuators B 111, 500-504 (2005).
[CrossRef]

G. Gauglitz, "Direct optical sensors: principles and selected applications," Anal. Bioanal. Chem. 381, 141-155 (2005).
[CrossRef] [PubMed]

N. Ramachandran, D. N. Larson, P. R. H. Stark, E. Hainsworth, and J. LaBaer, "Emerging tools for real-time label-free detection of interactions on functional protein microarrays," FEBS J. 272, 5412-5425 (2005).
[CrossRef] [PubMed]

2004

M. M. Varma, H. D. Inerowicz, F. E. Regnier, and D. D. Nolte, "High-speed label-free detection by spinning-disk microinterferometry," Biosens. Bioelectron. 19, 1371-1376 (2004).
[CrossRef] [PubMed]

M. M. Varma, D. D. Nolte, H. D. Inerowicz, and F. E. Regnier, "Spinning-disk self-referencing interferometry of antigen-antibody recognition," Opt. Lett. 29, 950-952 (2004).
[CrossRef] [PubMed]

G. H. Cross, A. Reeves, S. Brand, M. J. Swann, L. L. Peel, N. J. Freeman, and J. R. Lu, "The metrics of surface adsorbed small molecules on the Young's fringe dual-slab waveguide interferometer," J. Phys. D 37, 74-80 (2004).
[CrossRef]

2003

F. Prieto, B. Sepulveda, A. Calle, A. Llobera, C. Dominguez, and L. M. Lechuga, "Integrated Mach-Zehnder interferometer based on ARROW structures for biosensor applications," Sens. Actuators B 92, 151-158 (2003).
[CrossRef]

2002

B. Cunningham, P. Li, and J. Pepper, "Colorimetric resonant reflection as a direct biochemical assay technique," Sens. Actuators B 81, 316-328 (2002).
[CrossRef]

M. Varma, D. D. Nolte, H. D. Inerowicz, and F. E. Regnier, "Multianalyte array microdiffraction interferometry," Proc. SPIE 4626, 69-77 (2002).
[CrossRef]

2001

2000

M. P. DeLisa, Z. Zhang, M. Shiloach, S. Pilevar, C. C. Davis, J. S. Sirkis, and W. E. Bentley, "Evanescent wave long period fiber Bragg grating as an immobilized antibody biosensor," Anal. Chem. 72, 2895-2900 (2000).
[CrossRef] [PubMed]

1999

J. Homola, S. S. Yee, and G. Gauglitz, "Surface plasmon resonance sensors: review," Sens. Actuators B 54, 3-15 (1999).
[CrossRef]

1998

1997

C. M. Feng, Y. C. Huang, J. G. Chang, M. Chang, and C. Chou, "A true phase-sensitive optical heterodyne polarimeter on glucose concentration measurement," Opt. Commun. 141, 314-321 (1997).
[CrossRef]

V. S. Y. Lin, K. Motesharei, K. P. S. Dancil, M. J. Sailor, and M. R. Ghadiri, "A porous silicon-based optical interferometric biosensor," Science 278, 840-843 (1997).
[CrossRef] [PubMed]

1994

C. Striebel, A. Brecht, and G. Gauglitz, "Characterization of biomembranes by spectral ellipsometry, surface-plasmon resonance, and interferometry with regard to biosensor application," Biosens. Bioelectron. 9, 139-146 (1994).
[CrossRef] [PubMed]

1993

R. Cush, J. M. Cronin, W. J. Stewart, C. H. Maule, J. Molloy, and N. J. Goddard, "The resonant mirror--a novel optical biosensor for direct sensing of biomolecular interactions 1. Principle of operation and associated instrumentation," Biosens. Bioelectron. 8, 347-353 (1993).
[CrossRef]

1992

1989

A. J. Pidduck, D. J. Robbins, D. B. Gasson, C. Pickering, and J. L. Glasper, "In situ laser light scattering. II. Relationship to silicon surface topography," J. Electrochem. Soc. 136, 3088-3094 (1989).
[CrossRef]

1988

C. W. See, R. K. Appel, and M. G. Somekh, "Scanning differential optical profilometer for simultaneous measurement of amplitude and phase variation," Appl. Phys. Lett. 53, 10-12 (1988).
[CrossRef]

1985

1957

Anal. Bioanal. Chem.

G. Gauglitz, "Direct optical sensors: principles and selected applications," Anal. Bioanal. Chem. 381, 141-155 (2005).
[CrossRef] [PubMed]

Anal. Chem.

M. P. DeLisa, Z. Zhang, M. Shiloach, S. Pilevar, C. C. Davis, J. S. Sirkis, and W. E. Bentley, "Evanescent wave long period fiber Bragg grating as an immobilized antibody biosensor," Anal. Chem. 72, 2895-2900 (2000).
[CrossRef] [PubMed]

Appl. Opt.

Appl. Phys. Lett.

C. W. See, R. K. Appel, and M. G. Somekh, "Scanning differential optical profilometer for simultaneous measurement of amplitude and phase variation," Appl. Phys. Lett. 53, 10-12 (1988).
[CrossRef]

L. Peng, M. Varma, H. D. Inerowicz, F. E. Regnier, and D. D. Nolte, "Adaptive optical BioCD for biosensing," Appl. Phys. Lett. 86, 183902 (2005).
[CrossRef]

Biosens. Bioelectron.

M. M. Varma, H. D. Inerowicz, F. E. Regnier, and D. D. Nolte, "High-speed label-free detection by spinning-disk microinterferometry," Biosens. Bioelectron. 19, 1371-1376 (2004).
[CrossRef] [PubMed]

R. Cush, J. M. Cronin, W. J. Stewart, C. H. Maule, J. Molloy, and N. J. Goddard, "The resonant mirror--a novel optical biosensor for direct sensing of biomolecular interactions 1. Principle of operation and associated instrumentation," Biosens. Bioelectron. 8, 347-353 (1993).
[CrossRef]

C. Striebel, A. Brecht, and G. Gauglitz, "Characterization of biomembranes by spectral ellipsometry, surface-plasmon resonance, and interferometry with regard to biosensor application," Biosens. Bioelectron. 9, 139-146 (1994).
[CrossRef] [PubMed]

FEBS J.

N. Ramachandran, D. N. Larson, P. R. H. Stark, E. Hainsworth, and J. LaBaer, "Emerging tools for real-time label-free detection of interactions on functional protein microarrays," FEBS J. 272, 5412-5425 (2005).
[CrossRef] [PubMed]

J. Electrochem. Soc.

A. J. Pidduck, D. J. Robbins, D. B. Gasson, C. Pickering, and J. L. Glasper, "In situ laser light scattering. II. Relationship to silicon surface topography," J. Electrochem. Soc. 136, 3088-3094 (1989).
[CrossRef]

J. Opt. Soc. Am.

J. Opt. Soc. Am. B

J. Phys. D

G. H. Cross, A. Reeves, S. Brand, M. J. Swann, L. L. Peel, N. J. Freeman, and J. R. Lu, "The metrics of surface adsorbed small molecules on the Young's fringe dual-slab waveguide interferometer," J. Phys. D 37, 74-80 (2004).
[CrossRef]

Nat. Biotechnol.

R. Jenison, S. Yang, A. Haeberli, and B. Polisky, "Interference-based detection of nucleic acid targets on optically coated silicon," Nat. Biotechnol. 19, 62-65 (2001).
[CrossRef] [PubMed]

Opt. Commun.

C. M. Feng, Y. C. Huang, J. G. Chang, M. Chang, and C. Chou, "A true phase-sensitive optical heterodyne polarimeter on glucose concentration measurement," Opt. Commun. 141, 314-321 (1997).
[CrossRef]

Opt. Lett.

Proc. SPIE

D. D. Nolte and M. Zhao, "Scaling mass sensitivity of the BioCD at 0.25 pg/mm," Proc. SPIE 6380, 63800J (2006).
[CrossRef]

M. Varma, D. D. Nolte, H. D. Inerowicz, and F. E. Regnier, "Multianalyte array microdiffraction interferometry," Proc. SPIE 4626, 69-77 (2002).
[CrossRef]

Science

V. S. Y. Lin, K. Motesharei, K. P. S. Dancil, M. J. Sailor, and M. R. Ghadiri, "A porous silicon-based optical interferometric biosensor," Science 278, 840-843 (1997).
[CrossRef] [PubMed]

Sens. Actuators B

B. Cunningham, P. Li, and J. Pepper, "Colorimetric resonant reflection as a direct biochemical assay technique," Sens. Actuators B 81, 316-328 (2002).
[CrossRef]

P. I. Nikitin, B. G. Gorshkov, E. P. Nikitin, and T. I. Ksenevich, "Picoscope, a new label-free biosensor," Sens. Actuators B 111, 500-504 (2005).
[CrossRef]

F. Prieto, B. Sepulveda, A. Calle, A. Llobera, C. Dominguez, and L. M. Lechuga, "Integrated Mach-Zehnder interferometer based on ARROW structures for biosensor applications," Sens. Actuators B 92, 151-158 (2003).
[CrossRef]

J. Homola, S. S. Yee, and G. Gauglitz, "Surface plasmon resonance sensors: review," Sens. Actuators B 54, 3-15 (1999).
[CrossRef]

Other

D. D. Nolte, Photorefractive Effects and Materials (Kluwer Academic, 1995).

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Figures (14)

Fig. 1
Fig. 1

Edge diffraction showing one quadrature angle for a biolayer on a high-reflectance dielectric stack with an antinode field condition at the top surface. The focused beam is Gaussian with a radius w 0 . When the optic axis is at the edge of the biolayer, the quadrature angle is defined by a relative path difference to the far field of a quarter wavelength. There are two symmetric quadrature angles. Only one is shown.

Fig. 2
Fig. 2

Quarter-wave substrate dielectric mirror centered at a 633   nm wavelength that maximizes the biolayer phase shift by placing an electric field antinode at the stack surface.

Fig. 3
Fig. 3

Calculated far-field diffracted intensity changes from a 6   nm biolayer with n p = 1.4 on a dielectric stack for two different locations of the optic axis relative to the protein edge at x = 0 and at x = w 0 .

Fig. 4
Fig. 4

Simulated protein profile in (a) and the calculated phase-contrast response to the spinning disk in (b). The beam radius is 12 μm and the protein spoke width is 128 μ m . The curves show the effect of increasing slope widths from 1 to 50 μ m .

Fig. 5
Fig. 5

(a) Theoretical phase-contrast response to a protein ridge expressed as relative intensity modulation as a function of the protein slope width. The knee occurs when the protein width is comparable to the beam radius. (b) Theoretical phase-contrast response to a sinusoidal protein profile expressed as relative intensity modulation as a function of spatial frequency. The response has a maximum at w 0 k 0 = 1 .

Fig. 6
Fig. 6

Schematics of the patterning of protein. (a) Photolithography. Photoresist is patterned on the substrate surface, which is exposed to protein solution to immobilize protein. (b) Gel stamping. A patterned polyacrylamide gel with protein is made and pressed against a functionalized substrate.

Fig. 7
Fig. 7

(Color online) Optical configuration and layout for differential phase-contrast detection of protein patterns on the spinning disk. Far-field intensity modulation is antisymmetric. A split photodetector with relative inversion converts the asymmetry into a signal that is proportional to the protein height. Photodetector has four quadrants that can be combined as the sum, left-right difference, or up-down difference.

Fig. 8
Fig. 8

(Color online) (a) Time trace of the differential phase-contrast channel in response to four protein ridges passing through the focused laser spot. The leading edge causes a negative signal while the trailing edge causes a positive signal. (b) Integrated differential signal expressed in terms of protein height. Irregularities are not noise, but are repeatable, and hence real, structures related to the protein printing.

Fig. 9
Fig. 9

Examples of phase-contrast detection of protein patterns. Pattern in (a) is gel-printed protein spokes on a silanized surface. Pattern in (b) is part of a checkerboard disk patterned by photolithography on APTES surface. (c) An example of adding the two phase-contrast channels in quadrature to extract the modulus differential topology of protein on a disk. The A-channel is the left–right detector channel, and the B-channel is the up–down detector channel. The combined channel shows uniform edge detection around the printed protein spots.

Fig. 10
Fig. 10

(a) Comparison of the power spectra of printed protein ridges, bare functionalized disk, and system noise at 3   kHz bandwidth. Surface roughness contributes 30   dB of noise when the disk spins. Protein signal is 25   dB above the spinning-disk noise floor. High-frequency detection on the spinning disk suppresses the noise floor by 50   dB relative to 1 f noise at dc. (b) Power spectrum of 1024 avidin∕biotin spokes printed photolithographically. Disk was spinning at 80   Hz , high-pass filtered, and averaged over a disk segment covering 1∕64th of the disk surface with a 3   kHz bandwidth. The power signal-to-baseline is 400:1. The baseline height of 100 pm measures the mean-squared surface roughness of the disk.

Fig. 11
Fig. 11

Example of frequency sideband demodulation. The carrier frequency neighborhood is isolated in the frequency domain and transformed to dc and inverse transformed. Data on the top are the raw data. Data on the bottom represent the protein envelope function. The filter bandpass is approximately 70 μ m .

Fig. 12
Fig. 12

Histograms of the pixel differences (expressed in nm) between two successive scans. Curves are for four different conditions: (a) straight subtraction of the direct topology without dismounting, (b) subtraction of the data in (a) after demodulation, (c) straight subtraction with a dismount and remount of the disk, and (d) the same as (c) but with demodulation. Demodulation improves the accuracy of successive scans, while dismounting degrades it. The practical limit for an assay is curve (d) with a width of 90 pm.

Fig. 13
Fig. 13

Histogram of protein height change for two assays each performed at 10 μ g / ml analyte concentration in PBS using two immobilization techniques: gel print and photolithography. Specific assay is horse-antihorse. Negative control was mouse-antihorse.

Fig. 14
Fig. 14

Histogram of the disk height change in response to a 100 ng / ml assay compared against a negative control with PBS solution and a cross-reactivity control with horse incubated against mouse antigen.

Equations (199)

Equations on this page are rendered with MathJax. Learn more.

20 pm
70 μm
1.5 pg mm
7 pg mm
100 ng ml
π / 2
50   dB
20 pm
π / 2
λ / 8
10   kHz
π / 2
w 0
π 2
θ Q
w 0   sin   θ Q = ± λ / 4 ,
θ Q = ± sin 1 ( λ 4 w 0 ) .
Ta 2 O 5 / SiO 2
635   nm
λ / 4
77.0   nm
Ta 2 O 5
106.6   nm
SiO 2
106.6   nm
λ / 4
SiO 2
1.1   mm
100   mm
15   mm
h ( x )
I ( ρ ) = 1 2 π w 0 2 ( e ρ 2 / 2 w 0 2 ) ,
ρ 2 = x 2 + y 2
g ( ρ ) = g ( x , y ) = 1 2 π w 0 e ρ 2 / 4 w 0 2 ,
G ( k x , k y ) = 2 2 π w 0 e w 0 2 k 2 .
E ( x , y ) = g ( x , y ) exp ( i ϕ 1 h ( x v t , y ) ) g ( x , y ) [ 1 + i ϕ 1 h ( x v t , y ) ] ,
h ( x v t , y )
ϕ 1
E ( k x , k y ) = G ( k x , k y ) + i ϕ 1 F T [ g ( x , y ) h ( x v t , y ) ] = G ( k x , k y ) + i ϕ 1 H ( k , t ) ,
H ( k , t ) = F T [ g ( y , x ) h ( y , x v t ) ] .
ϕ 1 = 0
ϕ 1 = { 0 n o d a l 4 π ( n p 2 1 ) λ a n t i n o d a l ,
I ( k x , k y ; t ) = | G ( k x , k y ) + i ϕ 1 H ( k , t ) | 2 | G ( k x , k y ) | 2 + i G ( k x , k y ) [ ϕ 1 H ( k , t ) ϕ 1 * H * ( k , t ) ] = | G ( k x , k y ) | 2 + 2 G ( k x , k y ) Im ( ϕ 1 H ( k , t ) ) .
R ( k )
i d ( t ) = R ( k x , k y ) I ( k x , k y ; t ) d 2 k .
i d ( t ) = 0 I ( k x , t ) d k x 0 I ( k x , t ) d k x = 4 0 G ( k x ) Im ( ϕ 1 F ( k x , t ) ) o d d d k x ,
R ( k x )
k x = 0
Im ( ϕ 1 F ( k , t ) )
G ( k )
i d = 1 2 ϕ 1 | g ( x ) | 2 | g ( 0 ) | 2 [ d h ( x ) d x + 1 6 d 3 h ( x ) d x 3 + ] ,
h ( x )
g ( x )
i d ( t ) = 1 2 ϕ 1 [ I ( x ) I ( 0 ) d h ( x v t ) d x ] ,
n p = 1.4
h 0 = 6   nm
Δ ϕ = 4 π ( n p 2 1 ) h 0 / λ = 0.11
2 w 0 = 24 μ m
50 μ m
128 μ m
h ( x , t ) = h 0 f [ ( x ( x L v t ) ) / w ] f [ ( x ( x R v t ) ) / w ] ,
f ( x )
x L x R
n p = 1.4
6   nm
w = w 0
Δ I I = 2 π ( n p 2 1 ) 1 + ( w / w 0 ) 2 h 0 λ = d S d h h 0 1 + ( w / w 0 ) 2 .
w = w 0
n p = 1.4
d S e d g e d h = 2 π ( n p 2 1 ) λ = 0.95 % / nm
h ( x , t ) = h 0 2   sin ( k 0 ( x v t ) ) ,
h 0
E ( k ) = G ( k ) + i 1 2 ϕ 1 h 0 F T [ g ( x ) sin ( k 0 ( x v t ) ) ] .
H = F T [ g ( x ) sin ( k 0 ( x v t ) ) ] = i 2 g ( 0 ) [ exp ( i k 0 v t w 0 2 ( k + k 0 ) 2 ) exp ( i k 0 v t w 0 2 ( k k 0 ) 2 ) ] ,
E ( k ) = G ( k ) + ϕ 1 h 0 2 2 g ( 0 ) [ exp ( i k 0 v t w 0 2 ( k + k 0 ) 2 ) exp ( i k 0 v t w 0 2 ( k k 0 ) 2 ) ] ,
I ( k ) = | E ( k ) | 2 = | G ( k ) | 2 + ϕ 1 h 0 g ( 0 ) sin ( k 0 v t ) e w 0 2 ( k 2 + k 0 2 ) × sinh ( 2 w 0 2 k k 0 ) .
Δ I ( t ) I = 2 ϕ 1 h 0   sin ( k 0 v t ) 0 e w 0 2 ( k 2 + k 0 2 ) sinh ( 2 w 0 2 k k 0 ) d k
= π 2 d S d h h 0 w 0 k 0 ( 1 e r f ( w 0 k 0 1 ) ) sin ( k 0 v t ) , 
k 0
1 / w 0
k 0
w 0 k 0 = 1
Δ I / I | max = π 2 ( n p 2 1 ) / 2 λ ( h 0 )
n p = 1.4
λ = 635   nm
h 0 = 6   nm
w 0 k 0 = 1
Δ I / I = 4.5 %
d S sin d h = π 2 ( n p 2 1 ) 2 λ = 0.75 % / nm ,
20 μ m
90 ° C
10   mL
10 μ g / mL
10   mM
160   mM
10 μ g / mL
10   mM
10 μ g / mL
200 μL
10 μ g / mL
20 μ L
50 μ m
10   mM
20 μ m
80   Hz
20 μ m
120 μ m
1024 / 2 π
1   mm
1024 / 2 π
( Δ r )
20 μ m
2   nm
5   MHz
835   nm
835   nm
0.069   rad
3.6   nm
n p = 1.4
d S / d h = 2.32 % / 3.6   nm = 0.64 % / nm ,
0.95 % / nm
10 μ m
3   kHz
1 f
40   dB
25   dB
90 mm 2
2 π / 600
2 π / 400
2 π / 1024
Δ h L = Δ h meas w meas 2 A = Δ h meas w meas L ,
L = A
w meas 2
Δ m L = Δ h L ρ m A = Δ h m e a s ρ m w m e a s L .
S = Δ m L A = ρ m Δ h m e a s w m e a s ,
σ min = S A ,
Δ m A = S A ,
Δ h meas = 20   pm
r = 30   mm
80   Hz
15 m / s
15 μ m
60   kHz
80   kHz
100 μ m
80 × 100 μ m / 60 = 133 μ m
20 μ m
40 μ m
w meas 2 = 40 μ m × 133 μ m = 5.3 × 10 3 mm 2
w meas = 73 μ m
S = ( 1 pg / μ m 3 ) ( 20   pm ) ( 73 μ m ) = 1.5 pg / mm
σ m m = 1.5 pg / mm 2
( Δ h meas = 20   pm )
7 pg mm 2
200 μ m
10   mM
10 μ g / mL
10 μ g / mL
200 μ L
10 μ g / mL
10   mm
200 μ L
100 ng / mL
10 μ g / mL
10 μ g / ml
1 10 ng / ml
100 ng / ml
100 ng / ml
100 ng / ml
50   dB
1 / f
20 μ m
20 μ m
100 × 10 6
70 μ m
1.5 pg / mm
1   mm
1.5 pg / mm 2
0.25 pg / mm
w 0
633   nm
6   nm
n p = 1.4
x = 0
x = w 0
12 μm
128 μ m
50 μ m
w 0 k 0 = 1
3   kHz
30   dB
25   dB
50   dB
1 f
80   Hz
3   kHz
70 μ m
10 μ g / ml
100 ng / ml

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