Abstract

Performance improvements in instrumentation for optical imaging have contributed greatly to molecular imaging in living subjects. In order to advance molecular imaging in freely moving, untethered subjects, we designed a miniature vertical-cavity surface-emitting laser (VCSEL)-based biosensor measuring 1cm3 and weighing 0.7g that accurately detects both fluorophore and tumor-targeted molecular probes in small animals. We integrated a critical enabling component, a complementary metal-oxide semiconductor (CMOS) read-out integrated circuit, which digitized the fluorescence signal to achieve autofluorescence-limited sensitivity. After surgical implantation of the lightweight sensor for two weeks, we obtained continuous and dynamic fluorophore measurements while the subject was un-anesthetized and mobile. The technology demonstrated here represents a critical step in the path toward untethered optical sensing using an integrated optoelectronic implant.

© 2013 OSA

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    [CrossRef] [PubMed]
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    [CrossRef] [PubMed]
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    [CrossRef]
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    [CrossRef] [PubMed]
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2013 (1)

S. P. Nichols, A. Koh, W. L. Storm, J. H. Shin, and M. H. Schoenfisch, “Biocompatible materials for continuous glucose monitoring devices,” Chem. Rev.113(4), 2528–2549 (2013).
[CrossRef] [PubMed]

2012 (2)

N. Parashurama, T. D. O’Sullivan, A. De La Zerda, P. El Kalassi, S. Cho, H. Liu, R. Teed, H. Levy, J. Rosenberg, Z. Cheng, O. Levi, J. S. Harris, and S. S. Gambhir, “Continuous sensing of tumor-targeted molecular probes with a vertical cavity surface emitting laser-based biosensor,” J. Biomed. Opt.17(11), 117004 (2012).
[CrossRef] [PubMed]

M. L. James and S. S. Gambhir, “A molecular imaging primer: modalities, imaging agents, and applications,” Physiol. Rev.92(2), 897–965 (2012).
[CrossRef] [PubMed]

2011 (3)

K. K. Ghosh, L. D. Burns, E. D. Cocker, A. Nimmerjahn, Y. Ziv, A. E. Gamal, and M. J. Schnitzer, “Miniaturized integration of a fluorescence microscope,” Nat. Methods8(10), 871–878 (2011).
[CrossRef] [PubMed]

E. M. C. Hillman, C. B. Amoozegar, T. Wang, A. F. H. McCaslin, M. B. Bouchard, J. Mansfield, and R. M. Levenson, “In vivo optical imaging and dynamic contrast methods for biomedical research,” Philos Trans A Math Phys Eng Sci369(1955), 4620–4643 (2011).
[CrossRef] [PubMed]

P. Valdastri, E. Susilo, T. Förster, C. Strohhöfer, A. Menciassi, and P. Dario, “Wireless implantable electronic platform for chronic fluorescent-based biosensors,” IEEE Trans. Biomed. Eng.58(6), 1846–1854 (2011).
[CrossRef] [PubMed]

2010 (2)

2008 (3)

M. Beiderman, T. Tam, A. Fish, G. A. Jullien, and O. Yadid-Pecht, “A Low-Light CMOS Contact Imager With an Emission Filter for Biosensing Applications,” IEEE Trans. Biomed. Circuits Sys.2(3), 193–203 (2008).
[CrossRef]

B. A. Flusberg, A. Nimmerjahn, E. D. Cocker, E. A. Mukamel, R. P. Barretto, T. H. Ko, L. D. Burns, J. C. Jung, and M. J. Schnitzer, “High-speed, miniaturized fluorescence microscopy in freely moving mice,” Nat. Methods5(11), 935–938 (2008).
[CrossRef] [PubMed]

E. M. Sevick-Muraca and J. C. Rasmussen, “Molecular imaging with optics: primer and case for near-infrared fluorescence techniques in personalized medicine,” J. Biomed. Opt.13(4), 041303 (2008).
[CrossRef] [PubMed]

2003 (2)

T. F. Massoud and S. S. Gambhir, “Molecular imaging in living subjects: seeing fundamental biological processes in a new light,” Genes Dev.17(5), 545–580 (2003).
[CrossRef] [PubMed]

H. Ou and K. K. Chin, “Theory of gated multicycle integration (GMCI) for repetitive imaging of focal plane array,” IEEE Trans. Circuits Syst. II: Analog Digital Sig. Proc.50(7), 378–383 (2003).
[CrossRef]

1991 (1)

M. Patterson, B. Wilson, and D. Wyman, “The propagation of optical radiation in tissue. II: Optical properties of tissues and resulting fluence distributions,” Lasers Med. Sci.6(4), 379–390 (1991).
[CrossRef]

Amoozegar, C. B.

E. M. C. Hillman, C. B. Amoozegar, T. Wang, A. F. H. McCaslin, M. B. Bouchard, J. Mansfield, and R. M. Levenson, “In vivo optical imaging and dynamic contrast methods for biomedical research,” Philos Trans A Math Phys Eng Sci369(1955), 4620–4643 (2011).
[CrossRef] [PubMed]

Barretto, R. P.

B. A. Flusberg, A. Nimmerjahn, E. D. Cocker, E. A. Mukamel, R. P. Barretto, T. H. Ko, L. D. Burns, J. C. Jung, and M. J. Schnitzer, “High-speed, miniaturized fluorescence microscopy in freely moving mice,” Nat. Methods5(11), 935–938 (2008).
[CrossRef] [PubMed]

Beiderman, M.

M. Beiderman, T. Tam, A. Fish, G. A. Jullien, and O. Yadid-Pecht, “A Low-Light CMOS Contact Imager With an Emission Filter for Biosensing Applications,” IEEE Trans. Biomed. Circuits Sys.2(3), 193–203 (2008).
[CrossRef]

Bouchard, M. B.

E. M. C. Hillman, C. B. Amoozegar, T. Wang, A. F. H. McCaslin, M. B. Bouchard, J. Mansfield, and R. M. Levenson, “In vivo optical imaging and dynamic contrast methods for biomedical research,” Philos Trans A Math Phys Eng Sci369(1955), 4620–4643 (2011).
[CrossRef] [PubMed]

Burns, L. D.

K. K. Ghosh, L. D. Burns, E. D. Cocker, A. Nimmerjahn, Y. Ziv, A. E. Gamal, and M. J. Schnitzer, “Miniaturized integration of a fluorescence microscope,” Nat. Methods8(10), 871–878 (2011).
[CrossRef] [PubMed]

B. A. Flusberg, A. Nimmerjahn, E. D. Cocker, E. A. Mukamel, R. P. Barretto, T. H. Ko, L. D. Burns, J. C. Jung, and M. J. Schnitzer, “High-speed, miniaturized fluorescence microscopy in freely moving mice,” Nat. Methods5(11), 935–938 (2008).
[CrossRef] [PubMed]

Cheng, Z.

N. Parashurama, T. D. O’Sullivan, A. De La Zerda, P. El Kalassi, S. Cho, H. Liu, R. Teed, H. Levy, J. Rosenberg, Z. Cheng, O. Levi, J. S. Harris, and S. S. Gambhir, “Continuous sensing of tumor-targeted molecular probes with a vertical cavity surface emitting laser-based biosensor,” J. Biomed. Opt.17(11), 117004 (2012).
[CrossRef] [PubMed]

Chin, K. K.

H. Ou and K. K. Chin, “Theory of gated multicycle integration (GMCI) for repetitive imaging of focal plane array,” IEEE Trans. Circuits Syst. II: Analog Digital Sig. Proc.50(7), 378–383 (2003).
[CrossRef]

Cho, S.

N. Parashurama, T. D. O’Sullivan, A. De La Zerda, P. El Kalassi, S. Cho, H. Liu, R. Teed, H. Levy, J. Rosenberg, Z. Cheng, O. Levi, J. S. Harris, and S. S. Gambhir, “Continuous sensing of tumor-targeted molecular probes with a vertical cavity surface emitting laser-based biosensor,” J. Biomed. Opt.17(11), 117004 (2012).
[CrossRef] [PubMed]

Cocker, E. D.

K. K. Ghosh, L. D. Burns, E. D. Cocker, A. Nimmerjahn, Y. Ziv, A. E. Gamal, and M. J. Schnitzer, “Miniaturized integration of a fluorescence microscope,” Nat. Methods8(10), 871–878 (2011).
[CrossRef] [PubMed]

B. A. Flusberg, A. Nimmerjahn, E. D. Cocker, E. A. Mukamel, R. P. Barretto, T. H. Ko, L. D. Burns, J. C. Jung, and M. J. Schnitzer, “High-speed, miniaturized fluorescence microscopy in freely moving mice,” Nat. Methods5(11), 935–938 (2008).
[CrossRef] [PubMed]

Conca, C.

Dario, P.

P. Valdastri, E. Susilo, T. Förster, C. Strohhöfer, A. Menciassi, and P. Dario, “Wireless implantable electronic platform for chronic fluorescent-based biosensors,” IEEE Trans. Biomed. Eng.58(6), 1846–1854 (2011).
[CrossRef] [PubMed]

De La Zerda, A.

N. Parashurama, T. D. O’Sullivan, A. De La Zerda, P. El Kalassi, S. Cho, H. Liu, R. Teed, H. Levy, J. Rosenberg, Z. Cheng, O. Levi, J. S. Harris, and S. S. Gambhir, “Continuous sensing of tumor-targeted molecular probes with a vertical cavity surface emitting laser-based biosensor,” J. Biomed. Opt.17(11), 117004 (2012).
[CrossRef] [PubMed]

El Kalassi, P.

N. Parashurama, T. D. O’Sullivan, A. De La Zerda, P. El Kalassi, S. Cho, H. Liu, R. Teed, H. Levy, J. Rosenberg, Z. Cheng, O. Levi, J. S. Harris, and S. S. Gambhir, “Continuous sensing of tumor-targeted molecular probes with a vertical cavity surface emitting laser-based biosensor,” J. Biomed. Opt.17(11), 117004 (2012).
[CrossRef] [PubMed]

Fish, A.

M. Beiderman, T. Tam, A. Fish, G. A. Jullien, and O. Yadid-Pecht, “A Low-Light CMOS Contact Imager With an Emission Filter for Biosensing Applications,” IEEE Trans. Biomed. Circuits Sys.2(3), 193–203 (2008).
[CrossRef]

Flusberg, B. A.

B. A. Flusberg, A. Nimmerjahn, E. D. Cocker, E. A. Mukamel, R. P. Barretto, T. H. Ko, L. D. Burns, J. C. Jung, and M. J. Schnitzer, “High-speed, miniaturized fluorescence microscopy in freely moving mice,” Nat. Methods5(11), 935–938 (2008).
[CrossRef] [PubMed]

Förster, T.

P. Valdastri, E. Susilo, T. Förster, C. Strohhöfer, A. Menciassi, and P. Dario, “Wireless implantable electronic platform for chronic fluorescent-based biosensors,” IEEE Trans. Biomed. Eng.58(6), 1846–1854 (2011).
[CrossRef] [PubMed]

Gamal, A. E.

K. K. Ghosh, L. D. Burns, E. D. Cocker, A. Nimmerjahn, Y. Ziv, A. E. Gamal, and M. J. Schnitzer, “Miniaturized integration of a fluorescence microscope,” Nat. Methods8(10), 871–878 (2011).
[CrossRef] [PubMed]

Gambhir, S. S.

M. L. James and S. S. Gambhir, “A molecular imaging primer: modalities, imaging agents, and applications,” Physiol. Rev.92(2), 897–965 (2012).
[CrossRef] [PubMed]

N. Parashurama, T. D. O’Sullivan, A. De La Zerda, P. El Kalassi, S. Cho, H. Liu, R. Teed, H. Levy, J. Rosenberg, Z. Cheng, O. Levi, J. S. Harris, and S. S. Gambhir, “Continuous sensing of tumor-targeted molecular probes with a vertical cavity surface emitting laser-based biosensor,” J. Biomed. Opt.17(11), 117004 (2012).
[CrossRef] [PubMed]

M. A. Pysz, S. S. Gambhir, and J. K. Willmann, “Molecular imaging: current status and emerging strategies,” Clin. Radiol.65(7), 500–516 (2010).
[CrossRef] [PubMed]

T. O’Sullivan, E. A. Munro, N. Parashurama, C. Conca, S. S. Gambhir, J. S. Harris, and O. Levi, “Implantable semiconductor biosensor for continuous in vivo sensing of far-red fluorescent molecules,” Opt. Express18(12), 12513–12525 (2010).
[CrossRef] [PubMed]

T. F. Massoud and S. S. Gambhir, “Molecular imaging in living subjects: seeing fundamental biological processes in a new light,” Genes Dev.17(5), 545–580 (2003).
[CrossRef] [PubMed]

Ghosh, K. K.

K. K. Ghosh, L. D. Burns, E. D. Cocker, A. Nimmerjahn, Y. Ziv, A. E. Gamal, and M. J. Schnitzer, “Miniaturized integration of a fluorescence microscope,” Nat. Methods8(10), 871–878 (2011).
[CrossRef] [PubMed]

Harris, J. S.

N. Parashurama, T. D. O’Sullivan, A. De La Zerda, P. El Kalassi, S. Cho, H. Liu, R. Teed, H. Levy, J. Rosenberg, Z. Cheng, O. Levi, J. S. Harris, and S. S. Gambhir, “Continuous sensing of tumor-targeted molecular probes with a vertical cavity surface emitting laser-based biosensor,” J. Biomed. Opt.17(11), 117004 (2012).
[CrossRef] [PubMed]

T. O’Sullivan, E. A. Munro, N. Parashurama, C. Conca, S. S. Gambhir, J. S. Harris, and O. Levi, “Implantable semiconductor biosensor for continuous in vivo sensing of far-red fluorescent molecules,” Opt. Express18(12), 12513–12525 (2010).
[CrossRef] [PubMed]

Hillman, E. M. C.

E. M. C. Hillman, C. B. Amoozegar, T. Wang, A. F. H. McCaslin, M. B. Bouchard, J. Mansfield, and R. M. Levenson, “In vivo optical imaging and dynamic contrast methods for biomedical research,” Philos Trans A Math Phys Eng Sci369(1955), 4620–4643 (2011).
[CrossRef] [PubMed]

James, M. L.

M. L. James and S. S. Gambhir, “A molecular imaging primer: modalities, imaging agents, and applications,” Physiol. Rev.92(2), 897–965 (2012).
[CrossRef] [PubMed]

Jullien, G. A.

M. Beiderman, T. Tam, A. Fish, G. A. Jullien, and O. Yadid-Pecht, “A Low-Light CMOS Contact Imager With an Emission Filter for Biosensing Applications,” IEEE Trans. Biomed. Circuits Sys.2(3), 193–203 (2008).
[CrossRef]

Jung, J. C.

B. A. Flusberg, A. Nimmerjahn, E. D. Cocker, E. A. Mukamel, R. P. Barretto, T. H. Ko, L. D. Burns, J. C. Jung, and M. J. Schnitzer, “High-speed, miniaturized fluorescence microscopy in freely moving mice,” Nat. Methods5(11), 935–938 (2008).
[CrossRef] [PubMed]

Ko, T. H.

B. A. Flusberg, A. Nimmerjahn, E. D. Cocker, E. A. Mukamel, R. P. Barretto, T. H. Ko, L. D. Burns, J. C. Jung, and M. J. Schnitzer, “High-speed, miniaturized fluorescence microscopy in freely moving mice,” Nat. Methods5(11), 935–938 (2008).
[CrossRef] [PubMed]

Koh, A.

S. P. Nichols, A. Koh, W. L. Storm, J. H. Shin, and M. H. Schoenfisch, “Biocompatible materials for continuous glucose monitoring devices,” Chem. Rev.113(4), 2528–2549 (2013).
[CrossRef] [PubMed]

Levenson, R. M.

E. M. C. Hillman, C. B. Amoozegar, T. Wang, A. F. H. McCaslin, M. B. Bouchard, J. Mansfield, and R. M. Levenson, “In vivo optical imaging and dynamic contrast methods for biomedical research,” Philos Trans A Math Phys Eng Sci369(1955), 4620–4643 (2011).
[CrossRef] [PubMed]

Levi, O.

N. Parashurama, T. D. O’Sullivan, A. De La Zerda, P. El Kalassi, S. Cho, H. Liu, R. Teed, H. Levy, J. Rosenberg, Z. Cheng, O. Levi, J. S. Harris, and S. S. Gambhir, “Continuous sensing of tumor-targeted molecular probes with a vertical cavity surface emitting laser-based biosensor,” J. Biomed. Opt.17(11), 117004 (2012).
[CrossRef] [PubMed]

T. O’Sullivan, E. A. Munro, N. Parashurama, C. Conca, S. S. Gambhir, J. S. Harris, and O. Levi, “Implantable semiconductor biosensor for continuous in vivo sensing of far-red fluorescent molecules,” Opt. Express18(12), 12513–12525 (2010).
[CrossRef] [PubMed]

Levy, H.

N. Parashurama, T. D. O’Sullivan, A. De La Zerda, P. El Kalassi, S. Cho, H. Liu, R. Teed, H. Levy, J. Rosenberg, Z. Cheng, O. Levi, J. S. Harris, and S. S. Gambhir, “Continuous sensing of tumor-targeted molecular probes with a vertical cavity surface emitting laser-based biosensor,” J. Biomed. Opt.17(11), 117004 (2012).
[CrossRef] [PubMed]

Liu, H.

N. Parashurama, T. D. O’Sullivan, A. De La Zerda, P. El Kalassi, S. Cho, H. Liu, R. Teed, H. Levy, J. Rosenberg, Z. Cheng, O. Levi, J. S. Harris, and S. S. Gambhir, “Continuous sensing of tumor-targeted molecular probes with a vertical cavity surface emitting laser-based biosensor,” J. Biomed. Opt.17(11), 117004 (2012).
[CrossRef] [PubMed]

Mansfield, J.

E. M. C. Hillman, C. B. Amoozegar, T. Wang, A. F. H. McCaslin, M. B. Bouchard, J. Mansfield, and R. M. Levenson, “In vivo optical imaging and dynamic contrast methods for biomedical research,” Philos Trans A Math Phys Eng Sci369(1955), 4620–4643 (2011).
[CrossRef] [PubMed]

Massoud, T. F.

T. F. Massoud and S. S. Gambhir, “Molecular imaging in living subjects: seeing fundamental biological processes in a new light,” Genes Dev.17(5), 545–580 (2003).
[CrossRef] [PubMed]

McCaslin, A. F. H.

E. M. C. Hillman, C. B. Amoozegar, T. Wang, A. F. H. McCaslin, M. B. Bouchard, J. Mansfield, and R. M. Levenson, “In vivo optical imaging and dynamic contrast methods for biomedical research,” Philos Trans A Math Phys Eng Sci369(1955), 4620–4643 (2011).
[CrossRef] [PubMed]

Menciassi, A.

P. Valdastri, E. Susilo, T. Förster, C. Strohhöfer, A. Menciassi, and P. Dario, “Wireless implantable electronic platform for chronic fluorescent-based biosensors,” IEEE Trans. Biomed. Eng.58(6), 1846–1854 (2011).
[CrossRef] [PubMed]

Mukamel, E. A.

B. A. Flusberg, A. Nimmerjahn, E. D. Cocker, E. A. Mukamel, R. P. Barretto, T. H. Ko, L. D. Burns, J. C. Jung, and M. J. Schnitzer, “High-speed, miniaturized fluorescence microscopy in freely moving mice,” Nat. Methods5(11), 935–938 (2008).
[CrossRef] [PubMed]

Munro, E. A.

Nichols, S. P.

S. P. Nichols, A. Koh, W. L. Storm, J. H. Shin, and M. H. Schoenfisch, “Biocompatible materials for continuous glucose monitoring devices,” Chem. Rev.113(4), 2528–2549 (2013).
[CrossRef] [PubMed]

Nimmerjahn, A.

K. K. Ghosh, L. D. Burns, E. D. Cocker, A. Nimmerjahn, Y. Ziv, A. E. Gamal, and M. J. Schnitzer, “Miniaturized integration of a fluorescence microscope,” Nat. Methods8(10), 871–878 (2011).
[CrossRef] [PubMed]

B. A. Flusberg, A. Nimmerjahn, E. D. Cocker, E. A. Mukamel, R. P. Barretto, T. H. Ko, L. D. Burns, J. C. Jung, and M. J. Schnitzer, “High-speed, miniaturized fluorescence microscopy in freely moving mice,” Nat. Methods5(11), 935–938 (2008).
[CrossRef] [PubMed]

O’Sullivan, T.

O’Sullivan, T. D.

N. Parashurama, T. D. O’Sullivan, A. De La Zerda, P. El Kalassi, S. Cho, H. Liu, R. Teed, H. Levy, J. Rosenberg, Z. Cheng, O. Levi, J. S. Harris, and S. S. Gambhir, “Continuous sensing of tumor-targeted molecular probes with a vertical cavity surface emitting laser-based biosensor,” J. Biomed. Opt.17(11), 117004 (2012).
[CrossRef] [PubMed]

Ou, H.

H. Ou and K. K. Chin, “Theory of gated multicycle integration (GMCI) for repetitive imaging of focal plane array,” IEEE Trans. Circuits Syst. II: Analog Digital Sig. Proc.50(7), 378–383 (2003).
[CrossRef]

Parashurama, N.

N. Parashurama, T. D. O’Sullivan, A. De La Zerda, P. El Kalassi, S. Cho, H. Liu, R. Teed, H. Levy, J. Rosenberg, Z. Cheng, O. Levi, J. S. Harris, and S. S. Gambhir, “Continuous sensing of tumor-targeted molecular probes with a vertical cavity surface emitting laser-based biosensor,” J. Biomed. Opt.17(11), 117004 (2012).
[CrossRef] [PubMed]

T. O’Sullivan, E. A. Munro, N. Parashurama, C. Conca, S. S. Gambhir, J. S. Harris, and O. Levi, “Implantable semiconductor biosensor for continuous in vivo sensing of far-red fluorescent molecules,” Opt. Express18(12), 12513–12525 (2010).
[CrossRef] [PubMed]

Patterson, M.

M. Patterson, B. Wilson, and D. Wyman, “The propagation of optical radiation in tissue. II: Optical properties of tissues and resulting fluence distributions,” Lasers Med. Sci.6(4), 379–390 (1991).
[CrossRef]

Pysz, M. A.

M. A. Pysz, S. S. Gambhir, and J. K. Willmann, “Molecular imaging: current status and emerging strategies,” Clin. Radiol.65(7), 500–516 (2010).
[CrossRef] [PubMed]

Rasmussen, J. C.

E. M. Sevick-Muraca and J. C. Rasmussen, “Molecular imaging with optics: primer and case for near-infrared fluorescence techniques in personalized medicine,” J. Biomed. Opt.13(4), 041303 (2008).
[CrossRef] [PubMed]

Rosenberg, J.

N. Parashurama, T. D. O’Sullivan, A. De La Zerda, P. El Kalassi, S. Cho, H. Liu, R. Teed, H. Levy, J. Rosenberg, Z. Cheng, O. Levi, J. S. Harris, and S. S. Gambhir, “Continuous sensing of tumor-targeted molecular probes with a vertical cavity surface emitting laser-based biosensor,” J. Biomed. Opt.17(11), 117004 (2012).
[CrossRef] [PubMed]

Schnitzer, M. J.

K. K. Ghosh, L. D. Burns, E. D. Cocker, A. Nimmerjahn, Y. Ziv, A. E. Gamal, and M. J. Schnitzer, “Miniaturized integration of a fluorescence microscope,” Nat. Methods8(10), 871–878 (2011).
[CrossRef] [PubMed]

B. A. Flusberg, A. Nimmerjahn, E. D. Cocker, E. A. Mukamel, R. P. Barretto, T. H. Ko, L. D. Burns, J. C. Jung, and M. J. Schnitzer, “High-speed, miniaturized fluorescence microscopy in freely moving mice,” Nat. Methods5(11), 935–938 (2008).
[CrossRef] [PubMed]

Schoenfisch, M. H.

S. P. Nichols, A. Koh, W. L. Storm, J. H. Shin, and M. H. Schoenfisch, “Biocompatible materials for continuous glucose monitoring devices,” Chem. Rev.113(4), 2528–2549 (2013).
[CrossRef] [PubMed]

Sevick-Muraca, E. M.

E. M. Sevick-Muraca and J. C. Rasmussen, “Molecular imaging with optics: primer and case for near-infrared fluorescence techniques in personalized medicine,” J. Biomed. Opt.13(4), 041303 (2008).
[CrossRef] [PubMed]

Shin, J. H.

S. P. Nichols, A. Koh, W. L. Storm, J. H. Shin, and M. H. Schoenfisch, “Biocompatible materials for continuous glucose monitoring devices,” Chem. Rev.113(4), 2528–2549 (2013).
[CrossRef] [PubMed]

Storm, W. L.

S. P. Nichols, A. Koh, W. L. Storm, J. H. Shin, and M. H. Schoenfisch, “Biocompatible materials for continuous glucose monitoring devices,” Chem. Rev.113(4), 2528–2549 (2013).
[CrossRef] [PubMed]

Strohhöfer, C.

P. Valdastri, E. Susilo, T. Förster, C. Strohhöfer, A. Menciassi, and P. Dario, “Wireless implantable electronic platform for chronic fluorescent-based biosensors,” IEEE Trans. Biomed. Eng.58(6), 1846–1854 (2011).
[CrossRef] [PubMed]

Susilo, E.

P. Valdastri, E. Susilo, T. Förster, C. Strohhöfer, A. Menciassi, and P. Dario, “Wireless implantable electronic platform for chronic fluorescent-based biosensors,” IEEE Trans. Biomed. Eng.58(6), 1846–1854 (2011).
[CrossRef] [PubMed]

Tam, T.

M. Beiderman, T. Tam, A. Fish, G. A. Jullien, and O. Yadid-Pecht, “A Low-Light CMOS Contact Imager With an Emission Filter for Biosensing Applications,” IEEE Trans. Biomed. Circuits Sys.2(3), 193–203 (2008).
[CrossRef]

Teed, R.

N. Parashurama, T. D. O’Sullivan, A. De La Zerda, P. El Kalassi, S. Cho, H. Liu, R. Teed, H. Levy, J. Rosenberg, Z. Cheng, O. Levi, J. S. Harris, and S. S. Gambhir, “Continuous sensing of tumor-targeted molecular probes with a vertical cavity surface emitting laser-based biosensor,” J. Biomed. Opt.17(11), 117004 (2012).
[CrossRef] [PubMed]

Valdastri, P.

P. Valdastri, E. Susilo, T. Förster, C. Strohhöfer, A. Menciassi, and P. Dario, “Wireless implantable electronic platform for chronic fluorescent-based biosensors,” IEEE Trans. Biomed. Eng.58(6), 1846–1854 (2011).
[CrossRef] [PubMed]

Wang, T.

E. M. C. Hillman, C. B. Amoozegar, T. Wang, A. F. H. McCaslin, M. B. Bouchard, J. Mansfield, and R. M. Levenson, “In vivo optical imaging and dynamic contrast methods for biomedical research,” Philos Trans A Math Phys Eng Sci369(1955), 4620–4643 (2011).
[CrossRef] [PubMed]

Willmann, J. K.

M. A. Pysz, S. S. Gambhir, and J. K. Willmann, “Molecular imaging: current status and emerging strategies,” Clin. Radiol.65(7), 500–516 (2010).
[CrossRef] [PubMed]

Wilson, B.

M. Patterson, B. Wilson, and D. Wyman, “The propagation of optical radiation in tissue. II: Optical properties of tissues and resulting fluence distributions,” Lasers Med. Sci.6(4), 379–390 (1991).
[CrossRef]

Wyman, D.

M. Patterson, B. Wilson, and D. Wyman, “The propagation of optical radiation in tissue. II: Optical properties of tissues and resulting fluence distributions,” Lasers Med. Sci.6(4), 379–390 (1991).
[CrossRef]

Yadid-Pecht, O.

M. Beiderman, T. Tam, A. Fish, G. A. Jullien, and O. Yadid-Pecht, “A Low-Light CMOS Contact Imager With an Emission Filter for Biosensing Applications,” IEEE Trans. Biomed. Circuits Sys.2(3), 193–203 (2008).
[CrossRef]

Ziv, Y.

K. K. Ghosh, L. D. Burns, E. D. Cocker, A. Nimmerjahn, Y. Ziv, A. E. Gamal, and M. J. Schnitzer, “Miniaturized integration of a fluorescence microscope,” Nat. Methods8(10), 871–878 (2011).
[CrossRef] [PubMed]

Chem. Rev. (1)

S. P. Nichols, A. Koh, W. L. Storm, J. H. Shin, and M. H. Schoenfisch, “Biocompatible materials for continuous glucose monitoring devices,” Chem. Rev.113(4), 2528–2549 (2013).
[CrossRef] [PubMed]

Clin. Radiol. (1)

M. A. Pysz, S. S. Gambhir, and J. K. Willmann, “Molecular imaging: current status and emerging strategies,” Clin. Radiol.65(7), 500–516 (2010).
[CrossRef] [PubMed]

Genes Dev. (1)

T. F. Massoud and S. S. Gambhir, “Molecular imaging in living subjects: seeing fundamental biological processes in a new light,” Genes Dev.17(5), 545–580 (2003).
[CrossRef] [PubMed]

IEEE Trans. Biomed. Circuits Sys. (1)

M. Beiderman, T. Tam, A. Fish, G. A. Jullien, and O. Yadid-Pecht, “A Low-Light CMOS Contact Imager With an Emission Filter for Biosensing Applications,” IEEE Trans. Biomed. Circuits Sys.2(3), 193–203 (2008).
[CrossRef]

IEEE Trans. Biomed. Eng. (1)

P. Valdastri, E. Susilo, T. Förster, C. Strohhöfer, A. Menciassi, and P. Dario, “Wireless implantable electronic platform for chronic fluorescent-based biosensors,” IEEE Trans. Biomed. Eng.58(6), 1846–1854 (2011).
[CrossRef] [PubMed]

IEEE Trans. Circuits Syst. II: Analog Digital Sig. Proc. (1)

H. Ou and K. K. Chin, “Theory of gated multicycle integration (GMCI) for repetitive imaging of focal plane array,” IEEE Trans. Circuits Syst. II: Analog Digital Sig. Proc.50(7), 378–383 (2003).
[CrossRef]

J. Biomed. Opt. (2)

E. M. Sevick-Muraca and J. C. Rasmussen, “Molecular imaging with optics: primer and case for near-infrared fluorescence techniques in personalized medicine,” J. Biomed. Opt.13(4), 041303 (2008).
[CrossRef] [PubMed]

N. Parashurama, T. D. O’Sullivan, A. De La Zerda, P. El Kalassi, S. Cho, H. Liu, R. Teed, H. Levy, J. Rosenberg, Z. Cheng, O. Levi, J. S. Harris, and S. S. Gambhir, “Continuous sensing of tumor-targeted molecular probes with a vertical cavity surface emitting laser-based biosensor,” J. Biomed. Opt.17(11), 117004 (2012).
[CrossRef] [PubMed]

Lasers Med. Sci. (1)

M. Patterson, B. Wilson, and D. Wyman, “The propagation of optical radiation in tissue. II: Optical properties of tissues and resulting fluence distributions,” Lasers Med. Sci.6(4), 379–390 (1991).
[CrossRef]

Nat. Methods (2)

B. A. Flusberg, A. Nimmerjahn, E. D. Cocker, E. A. Mukamel, R. P. Barretto, T. H. Ko, L. D. Burns, J. C. Jung, and M. J. Schnitzer, “High-speed, miniaturized fluorescence microscopy in freely moving mice,” Nat. Methods5(11), 935–938 (2008).
[CrossRef] [PubMed]

K. K. Ghosh, L. D. Burns, E. D. Cocker, A. Nimmerjahn, Y. Ziv, A. E. Gamal, and M. J. Schnitzer, “Miniaturized integration of a fluorescence microscope,” Nat. Methods8(10), 871–878 (2011).
[CrossRef] [PubMed]

Opt. Express (1)

Philos Trans A Math Phys Eng Sci (1)

E. M. C. Hillman, C. B. Amoozegar, T. Wang, A. F. H. McCaslin, M. B. Bouchard, J. Mansfield, and R. M. Levenson, “In vivo optical imaging and dynamic contrast methods for biomedical research,” Philos Trans A Math Phys Eng Sci369(1955), 4620–4643 (2011).
[CrossRef] [PubMed]

Physiol. Rev. (1)

M. L. James and S. S. Gambhir, “A molecular imaging primer: modalities, imaging agents, and applications,” Physiol. Rev.92(2), 897–965 (2012).
[CrossRef] [PubMed]

Other (4)

T. D. O'Sullivan, E. Munro, A. de la Zerda, N. Parashurama, R. Teed, Z. Walls, O. Levi, S. S. Gambhir, and J. J. S. Harris, “Implantable optical biosensor for in vivo molecular imaging,” Proc. SPIE Opt. Fiber and Sensors for Medical Diagnostics and Treatment Applications IX 717309 (2009).

K. Murari, R. Etienne-Cummings, G. Cauwenberghs, and N. Thakor, “An integrated imaging microscope for untethered cortical imaging in freely-moving animals,” in Engineering in Medicine and Biology Society (EMBC),2010Annual International Conference of the IEEE, 2010), 5795–5798.
[CrossRef]

G. Vasilescu, Electronic Noise and Interfering Signals: Principles and Applications (Springer, Berlin, 2005).

R. T. Heitz, D. B. Barkin, T. D. O'Sullivan, N. Parashurama, S. S. Gambhir, and B. A. Wooley, “A low noise current readout architecture for fluorescence detection in living subjects,” in Solid-State Circuits Conference Digest of Technical Papers (ISSCC),2011IEEE International, 2011), 308–310.

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Figures (5)

Fig. 1
Fig. 1

(A) Implantable sensor custom PCB with bonded chips and (B) completed implantable sensor with cap, lens, and wire harness

Fig. 2
Fig. 2

Readout system architecture. The ΣΔ modulator interfaces directly to the CTIA output, without the need for a sample-and-hold stage. Before each integration cycle, both the CTIA and the ΣΔ modulator are reset. After the reset, the detector current accumulates on Cint, giving rise to a voltage ramp at the amplifier’s output. This ramp is sampled by the ΣΔ modulator M times during the integration period, and the output of the modulator is processed by a digital filter G(z) that implements a line-fitting operation similar to that described in [16]. Oversampling the ramp in this fashion reduces the readout noise by a factor of M/12.

Fig. 3
Fig. 3

Measurement of sensitivity using the on-package ROIC. Detected current increases linearly with Cy5.5 dye concentration until 25µM and are limited at the top by dye quenching effects.

Fig. 4
Fig. 4

Schematics (A, B) and photographs (C, D, E) of the miniature sensor implanted in a freely-moving nude mouse

Fig. 5
Fig. 5

Continuous measurement of implanted sensor signal in a mobile subject after tail vein injection of Cy5.5

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