Implantable semiconductor biosensor for continuous in vivo sensing of far-red fluorescent molecules

O’Sullivan, Thomas D.; Munro, Elizabeth A.; Parashurama, Natesh; Conca, Christopher; Gambhir, Sanjiv S.; Harris, James S.; Levi, Ofer

doi:10.1364/oe.18.012513

Cited by 28 publications

(28 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Using these approaches, we achieved autofluorescence-limited sensitivity to subcutaneous fluorophore in a nude mouse. Cy5.5 concentrations as low as 5nM in vitro and 50nM in vivo were detected, with depth sensitivity estimated to be 1-2mm [6]. Furthermore, in those studies we detected kinetics of injected molecular probes, and a signal to background ratio of a molecular probe that targeted tumors was measured at approximately 2.4-3.6 to 1, similar to measurements in with a cooled CCD camera, and showing that the VCSEL biosensor functioned accurately.…”

Section: Optoelectronic Componentssupporting

confidence: 73%

“…The optoelectronic components have been previously described in detail [6,8,11]. For completeness, we summarize those results here.…”

Section: Optoelectronic Componentsmentioning

confidence: 99%

“…These optical components were separately evaluated and validated in vitro and in vivo in previous studies in a subcutaneous dye model, a phantom model, and a tumor model in which fluorescent molecular probe is injected systemically and accumulates in tumors [6,8]. Using these approaches, we achieved autofluorescence-limited sensitivity to subcutaneous fluorophore in a nude mouse.…”

Section: Optoelectronic Componentsmentioning

confidence: 99%

“…These approaches, while non-invasive and highly sensitive, limit the ability to perform long-term, continuous measurements greater than several hours because of the inherent requirement to confine the animal subject to a light-tight box. We and others have developed miniature fluorescence-sensing systems that can be directly mounted on, or implanted in, an animal model [4][5][6][7][8][9][10] for continuous molecular monitoring in freely-moving subjects. Although potentially invasive, an implant also allows monitoring of deep tissues which may not be accessible with epi-illumination techniques.…”

Section: Introductionmentioning

confidence: 99%

“…We have previously reported the fabrication and testing of a miniature, integrated semiconductor fluorescence sensor designed for the detection of Cyanine 5.5 (Cy5.5; GE Healthcare/Amersham)-based far-red / near-infrared (NIR) fluorescent probes [6,8,11]. The sensor incorporated three essential components of a fluorescence system, including a 670nm vertical-cavity surface-emitting laser (VCSEL) excitation source, a Gallium Arsenide (GaAs) p-i-n photodiode, and a fluorescence emission filter.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Real-time, continuous, fluorescence sensing in a freely-moving subject with an implanted hybrid VCSEL/CMOS biosensor

O’Sullivan¹,

Heitz²,

Parashurama³

et al. 2013

Biomed. Opt. Express

Self Cite

View full text Add to dashboard Cite

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 1cm 3 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 Optical Society of America

show abstract

Section: Optoelectronic Componentssupporting

confidence: 73%

“…The optoelectronic components have been previously described in detail [6,8,11]. For completeness, we summarize those results here.…”

Section: Optoelectronic Componentsmentioning

confidence: 99%

Section: Optoelectronic Componentsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Real-time, continuous, fluorescence sensing in a freely-moving subject with an implanted hybrid VCSEL/CMOS biosensor

O’Sullivan¹,

Heitz²,

Parashurama³

et al. 2013

Biomed. Opt. Express

Self Cite

View full text Add to dashboard Cite

show abstract

Compliant, Heterogeneously Integrated GaAs Micro‐VCSELs towards Wearable and Implantable Integrated Optoelectronics Platforms

Kang

Lee

et al. 2014

Advanced Optical Materials

View full text Add to dashboard Cite

optical communication, [ 2,3 ] data scanning and sensing, [ 4,5 ] infrared illumination, [ 6,7 ] laser printing, [ 8,9 ] and others. [ 10,11 ] More recently, VCSELs have been also rapidly emerging as a coherent excitation light source for biomedical detection and imaging. [ 12,13 ] Despite such increasingly versatile utilities, established modes of exploiting VCSELs have been intrinsically limited as they rely mainly on devices that operate on their native growth substrates, which is attributed to diffi culties in materials growth, processing, and assembly methods that are not readily compatible with programmable distribution on unusual substrates over large area, as well as heterogeneous integration with dissimilar materials and devices. [ 14,15 ] Furthermore, VCSELs, typically built on rigid and brittle semiconductor wafers, restricted their capacity to integrate effectively onto systems with a soft, non-planar interface, which can be extremely useful for many unconventional applications. [ 16,17 ] Whereas a number of different approaches such as fl ip-chip integration, [ 18,19 ] wafer bonding, [20][21][22] fl uidic assembly, [ 23,24 ] epitaxial lift-off (ELO), [ 25,26 ] and appliqué [ 14,27,28 ] have been developed for integrating VCSELs on non-native substrates with their own advantages, none of them are suitable for commercial implementation and for achieving systems that satisfy all of above-described features due to many diffi cult and persistent challenges including little or no control over areal coverage and spatial layout, compromised performance during the fabrication and assembly (e.g., etching or wafer bonding), poor cost-effectiveness and low throughput, as well as limited choices of substrate materials. Although the conventional ELO process has been successfully used for solar cells and other optoelectronic devices in the past decades, [ 16,[29][30][31][32] its application to VCSELs remained great challenges owing to signifi cant damages in active materials such as mirror layers and quantum wells during the sacrifi cial removal of AlAs, and resulting strongly deteriorated device performance. Furthermore, all of aforementioned approaches are lack of capabilities to manipulate individual or selective sets of microscale VCSELs with customizable device layouts to meet specifi c requirements of applications. Here we present an approach to overcome all of Vertical cavity surface emitting lasers (VCSELs) represent a ubiquitous light source with unique performance characteristics that excel for edge-emitting lasers or light-emitting diodes. VCSELs are available, however, mostly on growth wafers in rigid, planar formats over restricted areas, thereby frustrating their use for applications that benefi t greatly from unconventional design options including large-scale, programmable assemblies on unusual substrates, hybrid integration with dissimilar materials and devices, or mechanically compliant constructions. Here, materials design and fabrication strategies are presented to overcome these limitations of ...

show abstract

Valve controlled fluorescence detection system for remote sensing applications

James

Scullion

Ashok

et al. 2011

Microfluid Nanofluid

View full text Add to dashboard Cite

We demonstrate a microfluidics-based fluorescence detection device where the filters, source, detector, and electronically controlled valves are embedded into a Polydimethylsiloxane (PDMS)-based microfluidic chip. The device reported here has been specifically designed for chlorophyll a fluorescence sensing in autonomous systems, such as oceanic applications. In contrast to a monolithic approach, the modular approach made the fabrication of this device simpler and cheaper. For fluorescence detection, an InGaN/GaN LED is used as the excitation source to specifically excite chlorophyll a; a metal-dielectric FabryPerot filter was used to extinguish out-of-band excitation. A simple Si photodiode is used as detector and provided with a thermally evaporated CdS emission filter to block the excitation source. This filter combination provides an excellent solution to the difficult problem of combining high-rejection excitation and emission filters in an integrated thin-film format. Furthermore, the metal-dielectric filter provides a much broader angular response than a comparable multilayer Bragg mirror, which is a key advantage in the integrated format. We use a novel paraffin wax-based valve design affords low power single-use actuation, between 0.5 and 1 J per actuation and withstands 0.6 bar differential pressure, which provides better performance than its previously reported counterparts. The remote valve-controlled operation of the fluorescence detection system is demonstrated, illustrating the measurement of a chlorophyll a solution, with a detection limit of 340 lM and subsequent valve-controlled flushing of the measurement reservoir.

show abstract

Implantable semiconductor biosensor for continuous in vivo sensing of far-red fluorescent molecules

Cited by 28 publications

References 35 publications

Real-time, continuous, fluorescence sensing in a freely-moving subject with an implanted hybrid VCSEL/CMOS biosensor

Real-time, continuous, fluorescence sensing in a freely-moving subject with an implanted hybrid VCSEL/CMOS biosensor

Compliant, Heterogeneously Integrated GaAs Micro‐VCSELs towards Wearable and Implantable Integrated Optoelectronics Platforms

Valve controlled fluorescence detection system for remote sensing applications

Contact Info

Product

Resources

About