Nano-pillar-based biosensing device

The present disclosure relates generally to medical diagnostics and relates more specifically to nano-pillar-based biosensing devices.

The detection and/or monitoring of serious health conditions often involves performing diagnostics on blood, sweat, or other fluids. For instance, once a person has been diagnosed with diabetes, he will typically need to continuously monitor his blood glucose levels in order to facilitate insulin intake. In other cases, cancer survivors may need to monitor their blood for particular biomarkers (e.g., protein molecules) including receptors or antigens that can indicate a recurrence of the disease. In addition, blood tests such as enzyme-linked immunosorbent assay (ELISA) and reverse transcriptase polymerase chain reaction (PCR) can quickly identify certain types of infectious diseases.

In one example, a device includes a trench formed in a substrate. The trench includes a first end and a second end that are non-collinear. A first plurality of semiconductor pillars is positioned near the first end of the trench and includes integrated light sources. A second plurality of semiconductor pillars is positioned near the second end of the trench and includes integrated photodetectors.

In another example, a device includes a trench formed in a substrate. The trench has an angular shape including at least one bend. A first plurality of semiconductor pillars is positioned near a first end of the trench and includes integrated light sources. A second plurality of semiconductor pillars is positioned near a second end of the trench and includes integrated photodetectors. A light blocker positioned inside the bend.

In another example, a method includes treating a fluid sample with a fluorophore that binds to particles in the fluid sample. The sample is then passed through a trench including a plurality of microfluidic channels, wherein a first end of the trench includes a first plurality of pillars having integrated light sources. Contact between the particles and at least one of the light sources causes the fluorophore to emit light. Trajectories of the particles are tracked through the plurality of microfluidic channels by detecting the light, using a photodetector integrated into one of a second plurality of pillars positioned near a second end of the trench.

The teachings of the present disclosure can be readily understood by considering the following detailed description in conjunction with the accompanying drawings, in which:

FIG. 1 illustrates a top view of an example biosensing device of the present disclosure;

FIG. 2 illustrates cross sectional views of three general examples of functionalized nano-pillars that may be used in the biosensing device of FIG. 1 ;

FIG. 3 illustrates a cross sectional view of one example of a nano-pillar that has been configured to emit light;

FIGS. 4A-4C illustrate a cross sectional views of three examples of a nano-pillar that have been configured to operate as detectors; and

FIG. 5 is a flow diagram illustrating one example of a method for processing a sample.

To facilitate understanding, identical reference numerals have been used, where possible, to designate identical elements that are common to the Figures.

In one example, a nano-pillar-based biosensing device is disclosed. As discussed above, the detection and/or monitoring of serious health conditions often involves performing diagnostics on blood, sweat, or other fluids. In many cases, the demand has grown for small, lightweight devices that can perform these diagnostics, including portable or wearable devices. For instance, continuous monitoring of blood glucose levels has been facilitated by the availability of portable glucose meters. However, the diagnoses of many other health conditions require that a sample of blood or other fluid, once obtained, be transported to a laboratory or other remote facility for analysis (e.g., with discrete optical imaging systems, microscopes, or other device). This can delay diagnoses of time-critical conditions and also compromise the integrity of the sample, leading to inaccurate results.

Examples of the present disclosure provide a portable system-on-chip (SoC) that integrates microfluidic channels with light sources, detectors, and complementary metal-oxide-semiconductor (CMOS) circuitry. By integrating light sources or photodetectors into nano-pillars that are also capable of sorting proteins (e.g., based on size), a compact device can be fabricated for performing biosensing applications. The device can be fabricated as a standalone device that performs collection, processing, and diagnostics on a fluid sample, or the device can communicate with a remote portable device (e.g., a smart phone or tablet computer) that includes software for performing diagnostics.

FIG. 1 illustrates a top view of an example biosensing device 100 of the present disclosure. As illustrated, the device 100 generally comprises a substrate 102 , a trench 104 formed in the substrate 102 , and a light blocker 106 positioned on the substrate 102 , adjacent to the trench 104 .

The substrate 102 may comprise, for example, a silicon substrate. The trench 104 comprises a recess in the substrate 102 , i.e., an area in which a portion of the substrate material is removed to form a passage. In one example, the trench 104 has an angular shape, e.g., such that the ends of the trench are not collinear. For instance, the trench 104 may form a right angle, as illustrated in FIG. 1 . However, in other examples, the angle formed by the trench may be smaller or greater than ninety degrees. In further examples still, the trench 104 may have a curved shaped. In each instance, however, the trench 104 includes at least one bend or corner 108 at which the passage formed by the trench 104 changes direction. In one example, the light blocker 106 is positioned inside of the corner 108 . The light blocker may comprise, for instance, a layer of metal.

A plurality of nano-pillars 110 is positioned inside the trench 104 . In one example, the nano-pillars 110 comprise silicon-based, nano-scale pillars that extend upward from the recessed surface of the substrate 102 . The sizing and spacing of the nano-pillars 110 creates a plurality of microfluidic channels through which a sample fluid (e.g., blood or other fluid) can flow from one end of the trench 104 to the other end. In addition, the sizing of and spacing between the nano-pillars 110 can be optimized to sort proteins in the sample fluid, e.g., such that proteins of certain sizes are forced along particular channels of the plurality of microfluidic channels.

In one example, subsets of the nano-pillars 110 are functionalized. That is, the subsets include nano-pillars that have been configured to provide functions in addition to sorting. For instance, the device 100 illustrated in FIG. 1 includes two functionalized subsets of nano-pillars 110 . A first subset 112 positioned near a first end of the trench 104 comprises nano-pillars 110 that include integrated light sources, such as integrated light emitting diodes (LEDs). The specific wavelength or wavelengths that can be emitted by a given nano-pillar 110 may be tuned in one example by adjusting the size of the pillar (e.g., diameter) and/or the material from which the pillar is fabricated to enable excitation of one or more particular fluorophores. For instance, a nano-pillar 110 integrating an indium gallium nitride-based light source may emit light in the 300-400 nanometer wavelength range; a nano-pillar 110 integrating a gallium arsenide-based or aluminum gallium arsenide-based light source may emit light in the 700-850 nanometer wavelength range; and a nano-pillar 110 integrating an indium gallium arsenic phosphide-based light source may emit light in the 1310-1550 nanometer wavelength range. Thus, the configurations of the nano-pillars 110 in the first subset 112 need not be identical, but may include nano-pillars 110 of varying sizes, materials, and configurations. In one example, each nano-pillar 110 in the first subset 112 is individually addressable (e.g., by an active matrix or passive matrix circuits) to emit light. One specific example of a nano-pillar including an integrated light source is discussed in further detail in connection with FIG. 3 .

A second subset 114 positioned near a second end of the trench 104 comprises nano-pillars 110 that include integrated photodetectors that are tuned to detect light of specific wavelengths. The specific wavelength or wavelengths that can be detected by a given nano-pillar 110 may be tuned in one example by adjusting the size of the pillar (e.g., diameter) and/or the material from which the pillar is fabricated. For instance, a nano-pillar 110 integrating an indium gallium nitride-based photodetector may detect light in the 300-400 nanometer wavelength range; a nano-pillar 110 integrating a silicon-based photodetector may detect light in the 400-850 nanometer wavelength range; a nano-pillar 110 integrating a gallium arsenide-based photodetector may detect light in the 500-850 nanometer wavelength range; and a nano-pillar 110 integrating an indium gallium arsenide-based photodetector may detect light in the 850-1550 nanometer wavelength range. Thus, the configurations of the nano-pillars 110 in the second subset 114 need not be identical, but may include nano-pillars 110 of varying sizes, materials, and configurations. Some specific examples of nano-pillars including integrated photodetector functionality are discussed in further detail in connection with FIGS. 4A-4C .

In this case, the light blocker 106 is positioned to minimize detection by the second subset 114 of light emitted by the first subset 112 . The shape of the trench 104 also helps in this respect. As discussed in further detail below, the first and second subsets 112 and 114 of nano-pillars 110 allow the device 100 to track particles in a sample fluid, which, in turn, may aid in the detection and diagnosis of certain medical conditions.

In some examples, the biosensing system 100 can be fabricated as a disposable, one-time-use chip. In this case, a separate reader device may be fabricated to analyze data collected by the biosensing system 100 .

FIG. 2 illustrates cross sectional views of three general examples of functionalized nano-pillars 200 a - 200 c that may be used in the biosensing device 100 of FIG. 1 . Thus, any of the nano-pillars 200 a - 200 c may be used as the basis for a nano-pillar with integrated light source or a nano-pillar with an integrated photodetector, e.g., as illustrated in the first subset 112 and second subset 114 of the nano-pillars 110 .

In general, each of the nano-pillars 200 a - 200 c is fabricated as a p-i-n diode on a semiconductor substrate 202 . In one example, the semiconductor substrate 202 may be n-doped.

In a first example, the nano-pillar 200 a comprises an undoped, intrinsic layer 204 a fabricated directly on the n-doped substrate 202 . A p-doped layer 206 a is then fabricated directly on the intrinsic layer 204 a.

In a second example, the nano-pillar 200 b comprises an n-doped layer 208 fabricated directly on the n-doped substrate. An undoped, intrinsic layer 204 b is fabricated directly on the n-doped layer 208 . A p-doped layer 206 b is then fabricated directly on the intrinsic layer 204 b.

In a third example, the nano-pillar 200 c comprises a pillar of p-doped material 206 c fabricated directly on the n-doped substrate 202 . The pillar of p-doped material 206 c includes an undoped, intrinsic core 204 c.

The configurations illustrated in FIG. 2 may be used to fabricate nano-pillars having integrated light sources (e.g., such as the nano-pillars 110 in the first subset 112 of FIG. 1 ) or nano-pillars having integrated photodetectors (e.g., such as the nano-pillars 110 in the second subset 114 of FIG. 1 ). Where the nano-pillars include integrated light sources, a light source such as an LED light source may be fabricated in the intrinsic layer of the p-i-n diode. Where the nano-pillars include integrated photodetectors, the p-i-n diode may form the photodiode, as described in further detail with respect to FIGS. 4A-4C .

FIG. 3 illustrates a cross sectional view of one example of a nano-pillar 300 that has been configured to emit light. Thus, the nano-pillar 300 may be used, for instance, in the first subset 112 of nano-pillars 110 illustrated in FIG. 1 .

As illustrated, the nano-pillar 300 is fabricated on a semiconductor substrate 302 such as a silicon substrate. The substrate 302 may be patterned with a series of trenches. The sidewalls of the trenches may be lined with a layer 304 of insulating material, such as silicon dixode. A layer 306 of a semiconductor material, such as germanium, may line the bottoms of the trenches. A light emitting diode 308 , such as an LED formed from one or more Group III-V materials, is grown on the layer 306 of semiconductor material.

FIGS. 4A-4C illustrate cross sectional views of three examples of nano-pillar 400 a - 400 c that have been configured to operate as photodetectors. Thus, the nano-pillar 400 a , 400 b , or 400 c may be used, for instance, in the second subset 114 of nano-pillars 110 illustrated in FIG. 1 . In each example, the nano-pillar 400 a , 400 b , or 400 c is fabricated as a p-i-n photodetector on a semiconductor substrate. However, in other examples, the photodetectors may be fabricated as p-n diodes, without an intervening intrinsic layer.

Referring to FIG. 4A , the example nano-pillar 400 a is fabricated on a semiconductor substrate 402 a , such as a gallium arsenide substrate. The substrate 402 a may have a thickness of approximately 850 nanometers. A first contact 404 a , formed, for example, from an n-type semiconductor material such as n+ gallium arsenide is fabricated on the substrate 402 a . An absorber layer 406 a , formed, for example, from undoped, intrinsic gallium arsenide, is then fabricated on the first contact 404 a . A second contact 408 a , formed, for example, from p+ gallium arsenide, is then fabricated on absorber layer 406 a . Thus, the first contact 404 a , absorber layer 406 a , and second contact 408 a collectively form a gallium arsenide p-i-n diode on a gallium arsenide substrate 402 a.

Referring to FIG. 4B , the example nano-pillar 400 b is fabricated on a semiconductor substrate 402 a , such as a silicon substrate. The substrate 402 b may have a thickness of approximately 850 nanometers. A first buffer layer 410 b , formed, for example, from germanium, is fabricated on the substrate 402 b . A second buffer layer 412 b , formed, for example, from indium gallium phosphide, is fabricated on the first buffer layer 410 b . A first contact 404 b , formed, for example, from an n-type semiconductor material such as n+ gallium arsenide is fabricated on the second buffer layer 412 b . An absorber layer 406 b , formed, for example, from undoped, intrinsic gallium arsenide, is then fabricated on the first contact 404 b . A second contact 408 b, formed, for example, from p+gallium arsenide, is then fabricated on absorber layer 406 b. Thus, the first contact 404 b , absorber layer 406 b , and second contact 408 b collectively form a gallium arsenide p-i-n diode on a silicon substrate 402 b (with a multi-layer buffer formed between the p-i-n diode and the substrate).

Referring to FIG. 4C , the example nano-pillar 400 c is fabricated on a semiconductor substrate 402 c , such as a silicon substrate. The substrate 402 c may have a thickness between approximately 1310 and 1550 nanometers. A first buffer layer 410 c, formed, for example, from germanium, is fabricated on the substrate 402 c . A second buffer layer 412 c , formed, for example, from gallium arsenide, is fabricated on the first buffer layer 410 c . A third buffer layer 414 c , formed, for example, from indium phosphide, is fabricated on the second buffer layer 412 c . A first contact 404 c , formed, for example, from an n-type semiconductor material such as n+ indium gallium arsenide is fabricated on the third buffer layer 414 c . An absorber layer 406 c , formed, for example, from undoped, intrinsic indium gallium arsenide, is then fabricated on the first contact 404 c . A second contact 408 c , formed, for example, from p+ indium gallium arsenide, is then fabricated on absorber layer 406 c . Thus, the first contact 404 c , absorber layer 406 c, and second contact 408 c collectively form an indium gallium arsenide p-i-n diode on a silicon substrate 402 c (with a multi-layer buffer formed between the p-i-n diode and the substrate).

FIG. 5 is a flow diagram illustrating one example of a method 500 for processing a sample. The method 500 may be performed, for instance, using the biosensing device 100 illustrated in FIG. 1 . As such, reference is made in the discussion of the method 500 to various elements of FIG. 1 . However, it will be appreciated that the method 500 could be performed using a device with a configuration that differs from the configuration shown in FIG. 1 .

The method 500 begins in step 502 . In step 504 , a sample is obtained. In one example, the sample is a fluid sample, such as blood or another fluid. The sample is to be analyzed for evidence of one or more medical conditions.

In step 506 , the sample is treated with one or more fluorophores (i.e., fluorescent chemical compounds that emit light upon excitation). Different fluorophores will bind to different particles that may or may not be present in the sample.

In step 508 , the first subset 112 of nano-pillars 110 is activated. For instance, the nano-pillars 110 including integrated light sources may be activated to emit light of one or more wavelengths.

In step 510 , the fluorophore-treated sample is passed through the first end of the trench 104 in the biosensing device 100 , such that the sample comes into contact with the first subset 112 of nano-pillars 110 . As the particles in the sample hit the nano-pillars 110 in the first subset 112 , the fluorophores that have bound to the particles will become excited and cause the particles to emit fluorescence. The emitted fluorescence will exhibit signatures that are unique to the fluorophores.

In step 512 , the second subset 114 of nano-pillars 110 detects the fluorescence emitted by the fluorophore-bound particles. In one example, the position of the light blocker 106 ensures that the light detected by the second subset 114 of nano-pillars 110 is the fluorescence emitted by the particles of the sample rather than the light emitted by the light sources of the first subset 112 of nano-pillars 110 .

In step 514 , the second subset 114 of nano-pillars 110 tracks the trajectories of the particles through the trench 104 , based on tracking of the emitted fluorescence. That is, because each fluorophore is selected to bind to a specific particle and emits a unique signature fluorescence when excited, the trajectory taken by the specific particle can be tracked by detecting and following the emission of the signature fluorescence.

In step 516 , a diagnosis is made based on the tracking of particle trajectories. In particular, particles of different sizes will have different trajectories (e.g., based on the sizing and spacing of the nano-pillars 110 , which will force particles of certain sizes along particular microfluidic channels). Thus, based on the trajectory, the particle size can be estimated. Then, based on the particle size, a medical diagnosis may be made (e.g., based on the presence or absence of particles of a certain size). The diagnosis may indicate that no medical conditions of concern are present, or the diagnosis may indicate the potential presence of a condition that requires medical attention.

The method 500 ends in step 518 .

Although various embodiments which incorporate the teachings of the present invention have been shown and described in detail herein, those skilled in the art can readily devise many other varied embodiments that still incorporate these teachings.